How does lymphovascular space involvement (LVSI) impact treatment decisions in endometrial cancer?

LVSI presence impacts endometrial cancer treatment by indicating a higher risk of nodal metastasis, which may necessitate more aggressive treatment options. Patients with LVSI may require adjuvant therapy post-surgery to reduce recurrence risks and improve survival outcomes. The decision regarding lymphadenectomy or increased surveillance is influenced by this factor .

What roles do HPV vaccination play in reducing the burden of cervical cancer?

HPV vaccination significantly reduces the burden of cervical cancer by preventing infections with HPV types 16 and 18, which are responsible for approximately 70% of cervical cancer cases. Quadrivalent vaccines also protect against HPV types 6 and 11, reducing the incidence of genital warts and recurrent respiratory papillomatosis. High efficacy rates are maintained over several years, reducing persistent infection and cytological abnormalities linked to the primary cancer-causing HPV strains .

What are the considered benefits and disadvantages of HPV vaccines?

The benefits of HPV vaccines include high immunogenicity, significant reduction in cervical cancer incidence, and cross-protection against additional HPV strains. They are safe and well tolerated. However, disadvantages include high cost, requirement for proper storage, and the need for multiple injections. The protection is limited to only specific HPV oncogenic types, and the cross-protection effect's longevity is uncertain .

Discuss the implications of HER2 overexpression in ovarian cancer management.

HER2 overexpression in ovarian cancer implies a more aggressive disease course and may guide therapeutic decisions. Targeted therapy with agents like trastuzumab (Herceptin) can be effective in managing HER2-positive tumors by inhibiting cancer cell growth. Identification of HER2 status assists in personalizing treatment, allowing for optimized therapeutic strategies .

How does the efficacy of the OVA1 test compare with other ovarian cancer risk assessment tools?

The OVA1 test has a high sensitivity for detecting malignancy (92% when combined with radiological tests) but suffers from a high false positive rate (64%) compared to other tools like the Risk of Malignancy Index (RMI) and the Risk of Ovarian Malignancy Algorithm (ROMA). ROMA, for instance, has a sensitivity of 94% and specificity of 75% when used in clinical evaluation .

How effective is cervical cancer screening in preventing cancer-related mortality?

Cervical cancer screening is effective in preventing cancer-related mortality by detecting precancerous lesions early, allowing for timely intervention. Screening methods such as Pap smears and HPV testing significantly reduce incidence and mortality rates through early detection and removal of abnormal tissues . This effectiveness hinges on regular screening and follow-ups.

What is the impact of CA125 levels on the prognosis of epithelial ovarian cancer?

CA125 levels are a significant prognostic factor in epithelial ovarian cancer. Elevated CA125 levels are often associated with a worse prognosis as they can indicate advanced disease or tumor burden . Monitoring CA125 levels can help in assessing treatment response and disease progression .

Compare the use of oral etoposide and taxanes in the treatment of platinum-resistant ovarian cancer.

Oral etoposide is used in platinum-resistant ovarian cancer due to its oral administration and demonstrated activity in prolonging progression-free survival. Taxanes (like paclitaxel and docetaxel) are also used, often in combination with other agents, due to their efficacy in inhibiting tumor mitosis. Both drug classes are options, but choice depends on patient tolerance and specific clinical scenarios .

Explain the significance of BRCA mutations in the context of ovarian cancer risk.

BRCA mutations significantly increase ovarian cancer risk, especially among BRCA1 carriers who have a lifetime risk of about 40-50%, compared to about 1.6% in the general population. These mutations can inform risk-reduction strategies, such as prophylactic oophorectomy, and influence treatment decisions by identifying patients who might benefit from PARP inhibitors due to their role in DNA repair mechanisms .

What are the significant prognostic factors for endometrial cancer recurrence after initial treatment?

Significant prognostic factors for endometrial cancer recurrence include the depth of myometrial invasion, FIGO grade, and presence of lymphovascular space invasion. A deep myometrial invasion (>50%) and high FIGO grades (such as grade 3) are associated with higher recurrence risk. The presence of lymphovascular invasion significantly increases the likelihood of lymph node metastasis and recurrence .

Open navigation menu

Upload

100% found this document useful (1 vote)

785 views826 pages

Noor PDF

Uploaded by

Anonymous d1CGjMTi

We take content rights seriously. If you suspect this is your content, claim it here.

Available Formats

Download as PDF, TXT or read online on Scribd

100% found this document useful (1 vote)

785 views826 pages

Noor PDF

Uploaded by

Anonymous d1CGjMTi

We take content rights seriously. If you suspect this is your content, claim it here.

Available Formats

Download as PDF, TXT or read online on Scribd

This page intentionally left blank

Gynaecologic
Cancer
A Handbook for Students and
Practitioners

Rushdan Noor
Eng Hseon Tay
Jeffrey Low
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2014 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Version Date: 20140530

International Standard Book Number-13: 978-981-4463-07-2 (eBook - PDF)

This book contains information obtained from authentic and highly regarded sources. Reason-
able efforts have been made to publish reliable data and information, but the author and publisher
cannot assume responsibility for the validity of all materials or the consequences of their use. The
authors and publishers have attempted to trace the copyright holders of all material reproduced in
this publication and apologize to copyright holders if permission to publish in this form has not
been obtained. If any copyright material has not been acknowledged please write and let us know so
we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced,
transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or
hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.
[Link] ([Link] or contact the Copyright Clearance Center, Inc.
(CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organiza-
tion that provides licenses and registration for a variety of users. For organizations that have been
granted a photocopy license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and
are used only for identification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
[Link]
and the CRC Press Web site at
[Link]
Contents

Preface xxxv

1. World Cancer Statistics and Burden of Gynaecological

Cancer 1
Introduction 2
World Cancer Burden and Contributing Factors 4
Breast Cancer 7
Cervical Cancer 7
Uterine Cancer 8
Ovarian Cancer 9
Other Gynaecological Cancers 9
Glossary of Terms 9

2. Genes and Carcinogenesis 13

Basic Structure of DNA 13
Gene 13
Genes and Carcinogenesis 15
Phases of Carcinogenesis 16
Initiation Phase 16
Promotion Phase 16
Progression Phase 17
Stem Cell and Cancer 17
Chronic Inlammation and Cancer 17
Infection and Cancer 18
Genetic Alterations in Cancer 18
Human Genome and Cancer 18
Types of Genetic Alteration in Cancer 19
Germ Line Mutations 19
Somatic Mutations 19
vi Contents

Genetic Alterations in Cancer 19

Pathways of Carcinogenesis in Familial and Sporadic
Gynaecologic Cancers 20
Speciic Genetic Alterations Responsible in
Carcinogenesis 20
Genes and Malignant Transformation 21
Proto-Oncogenes 21
Tumour Suppressor Genes 21
Oncogenes 22
Other Genes Responsible in Carcinogenesis 23
Additional Facts about Oncogenes and Tumour Suppressor
Genes 24
Proposed Mechanism How Oncogenes Can Transform
Normal Cells to Malignant Cells 25
Cancer Spread (Invasion and Metastases) 26
Apoptosis 26
Telomerase and Cancer 27
Genetic Studies in Gynaecologic Malignancies 27
Ovarian Cancer 27
Cervical Cancer 28
Vulvar Cancer 29
Endometrial Cancer 29
Clinical Implications of Molecular Genetics in
Gynaecological Cancer 30
Proteomics and Cancer 31

3. Cancer of Vulva 35
Introduction to Anatomy of Vulva 36
Vulva 36
Blood Supply and Innervation of the Vulva 38
Lymphatic Supply of the Vulva 39
Premalignant Vulvar Lesions 41
Lichen Sclerosus 41
Treatment for Lichen Sclerosus 42
Extramammary Paget’s Disease of Vulva 42
Contents vii

Treatment for Non-mammary Paget’s Disease 44

Vulva Intraepithelial Neoplasm 44
Usual Vulvar Intraepithelial Neoplasia 44
Treatment of Vulva Intraepithelial Neoplasm 45
Surgical Treatment for Vulva Intraepithelial
Neoplasm 46
Medical Treatment for Vulva Intraepithelial
Neoplasm 46
Photodynamic Therapy for Cervical Intraepithelial
Neoplasia 46
Differentiated Vulva Intraepithelial Neoplasm 47
Vulvar Cancer 48
Presentations and Diagnosis 49
Patterns of Spread in Vulvar Cancer 49
Staging of Vulvar Cancer 50
Prognostic Factors in Squamous Cell Carcinoma of Vulvar 52
Management of Squamous Cell Carcinoma of Vulva 53
Surgical Treatment 53
Surgery for Early Stage 54
Surgical Tips during Vulvectomy and Inguino-Femoral
Lymphadenectomy 55
Lymphatic Mapping and Sentinel Node Biopsy 56
Lymphatic Mapping and Sentinel Node Biopsy in
Vulva Cancer 56
Method of Sentinel Node Detection 58
Radiotherapy in Early-Stage Vulvar Cancer 59
Objectives of Radiotherapy in Vulvar Cancer 60
Treatment for Advanced-Stage Carcinoma of Vulva 62
Treatment for Locally Advanced Disease 62
Treatment for Metastatic and Recurrent Disease 63
Post-Operative Care for Vulvectomy 65
General measures 65
Urinary catheter 65
Drain 65
Perineal care 65
viii Contents

Bowel 66
Mobilization 66
Complications of Surgery in Vulva Cancer 66
Follow-Up of Patients with Vulvar Cancer 67
Prognosis 67
Other Carcinoma of Vulvar Carcinoma 67
Verrucous carcinoma 67
Basal cell carcinoma 68
Merkel-cell tumours 68
Transitional cell carcinoma 69
Carcinoma of Batholin’s gland 69
Other Malignant Tumour of Vulva 69
Malignant melanoma of the vulva 69
Vulvar sarcoma 71
Other vulvar malignancies 72
Appendix 72

4. Carcinoma of Vagina 81
Basic Anatomy of the Vagina 82
Carcinoma of Vagina 83
Aetiology of Vaginal Cancer 84
Histological Types of Primary Vaginal Cancer 84
Adenocarcinoma of the Vagina 84
Clear Cell Adenocarcinoma of the Vagina 85
Vaginal Intraepithelial Neoplasia 86
Treatment of Vaginal Intraepithelial Neoplasm 87
Clinical Presentation of Vaginal Carcinoma 89
Staging of Vaginal Carcinoma 89
Management of Vaginal Cancer 90
Surgery in Stage 1 Disease 90
Treatment of Stage 2–4 Vaginal Cancer 90
Radiation Therapy in Vaginal Cancer (Stage by Stage) 91
Radiation Therapy for Stage 1 91
Radiation Therapy for Stage 2A 92
Radiation Therapy for Stage 2B, Stage 3 and Stage 4A 92
Contents ix

Survival 92
Vaginal Melanoma 92
Small Cell Carcinoma of Vagina 93
Clear Cell Adenocarcinoma of Vagina 93
Vaginal Recurrences 94
Other Vaginal Cancers 94

5. Screening for Cervical Cancer 97

Basics in Cancer Screening 98
How to Calculate Sensitivity and Speciicity 98
Cervical Cancer Prevention 99
Screening of Cervical Cancer 99
Screening Population 101
Cytologic Screening for Cervical Cancer and Its
Precursors 102
Liquid-Based Cytology 104
Technologies Related to Liquid-Based Cytology 105
ThinPrep Pap Test 105
AutoCyte PREP 106
PapNet 106
AutoPap 106
ThinPrep Imaging System 106
Bethesda System of Reporting Pap Smear Results 107
Terminology of Cytologic Reports 107
Bethesda 2001 Reporting System 107
Non-Cytologic Method of Screening 108
Visual Inspection 109
Steps to Perform VIA/VILI 110
HPV Testing 111
Role of HPV Testing 111
Triage of Women with Equivocal Cytology 112
Follow-Up of Patient after Treatment for CIN 2–3 113
HPV Testing in Screening and Treat Approach 113
HPV Testing as Primary Screening Test for
Cervical Cancer 114
x Contents

Optoelectronic Device for Cervical Cancer Screening 120

New Technologies in Cervical Cancer Screening 121

6. Human Papillomavirus and HPV Vaccination 129

HPV Infection in Lower Genital Tracts 130
Human Papillomavirus 130
Transmission of HPV 134
Burden of HPV Infections 135
Pathogenesis of HPV Infections 138
HPV Infection in Man 140
Methods of HPV Detection 142
HPV Vaccine 143
HPV Vaccine Trial 149
Quadrivalent Vaccine Trials 149
Bivalent HPV Vaccine Trials 153
Safety of Quadrivalent HPV Vaccine 156
Safety of Bivalent Vaccine 157
WHO Global Advisory Commitee (GAC) Statement
on the Update of HPV Vaccine Safety by 2013 158
HPV Vaccination in Males 159
HPV Vaccine: Policy and Administration Guidelines 160
Future Direction 163

7. Management of Preinvasive Disease of the Cervix 171

Introduction 172
Management of Abnormal PAP Smear 173
Colposcopy 173
Indications for Colposcopy 176
Objectives of Colposcopy 176
HPV Testing and Colposcopic Referral 178
Management of Cervical Intraepithelial Neoplasm 179
Loop Electrosurgical Excision Procedure 183
Counselling after LEEP/LLETZ 184
Cryotherapy 186
Post-Cryotherapy Care 187
Contents xi

Side Effects of Cryotherapy (Very Rare) 188

Laser Treatment for Preinvasive Lesions of Cervix 188
Types of Transformation Zone 189
Management of Abnormal PAP Smear, CIN and
Colposcopy during Pregnancy 190
Cervical Adenocarcinoma in situ 191
HPV Testing and Other Markers in the Follow-Up
after Treatment for CIN 192

8. Cancer of Cervix 197

Anatomy 198
Cancer of Cervix 200
Epidemiology 200
Aetiology of Cervical Cancer 200
HPV and Cervical Carcinogenesis 202
Types of HPV in Cervical Cancer 204
Risk Factors for Cervical Cancer 204
Histopathological Subtypes of Cervical Cancer 206
Natural History and Pattern of Spread 207
Presentations 208
Diagnosis 209
Staging Carcinoma of Cervix 209
Prognostic Factors 212
Management of Cervical Cancer 214
Treatment for Early-Stage Cervical Cancer 215
Surgical Treatment for Stage 1A1 215
Surgical Treatment for Stage 1A2 216
Surgical Treatment for Stage 1B1 and Stage 2A1 Cervical
Cancer 217
Treatment for Stage 1B2 and 2A2 218
Treatment for Stage 2B-4 220
Role of Adjuvant Radiotherapy or Chemoradiation after
Surgery 220
Radical Hysterectomy for Cervical Cancer 222
Nerve-Preserving Radical Hysterectomy 226
xii Contents

Complications of Radical Hysterectomy 227

Fertility-Preserving Surgery in Cervical Cancer 228
Radical Trachelectomy 228
Neoadjuvant Chemotherapy Followed by
Fertility-Preserving Surgery 230
Cone Biopsy or Simple Trachelectomy 230
Radiotherapy in Cervical Cancer 230
Concurrent Chemoradiation in Cervical Cancer 234
Chemotherapy in Cervical Cancer 238
Chemotherapy for Metastatic and Recurrent Cervical
Cancer 239
Neoadjuvant Chemotherapy in Cervical Cancer 242
Treatment for Non-Squamous Cell Carcinoma of Cervix 245
Recurrent Carcinoma of Cervix 247
Recurrence after Deinitive Irradiation 248
Recurrence after Previous Surgery 250
Appendix 250

9. Carcinoma of Endometrium 263

Anatomy of the Uterus 264
Epithelial Uterine Cancer 266
Epidemiology 266
Type of Endometrial Cancer 267
Risk Factors for Endometrial Cancer 270
Pre-Malignant Lesions of Endometrium and
Pathogenesis of Endometrial Cancer 272
Prevention of Endometrial Cancer 277
Presentation and Diagnosis 278
Investigations and Staging 280
FIGO Staging of Endometrial Cancer 282
Treatment for Pre-Malignant Lesions of Endometrium 283
Treatment for Endometrial Carcinoma 287
Surgery 287
Radiotherapy 292
Combination of Radiotherapy and Chemotherapy 297
Contents xiii

Systemic Treatment for Endometrial Cancer 298

Uterine Papillary Serous Carcinoma 300
Epithelial Endometrial Cancer: Prognosis and Recurrent
Disease 302
Targeted Therapy in Endometrial Cancer 304

10. Uterine Sarcoma 315

Introduction 316
Presentation and Pre-Operative Diagnosis of
Uterine Sarcoma 317
Staging for Uterine Sarcoma 318
Leiomyosarcoma 319
Treatment for Uterine Leiomyosarcoma 321
Endometrial Stromal Sarcoma 324
Treatment for Endometrial Stromal Sarcoma 326
Poorly Differentiated and Undifferentiated Uterine
Sarcoma 327
Adenosarcoma 327
Uterine Carcinosarcoma 328
Treatment of Uterine Carcinosarcoma 330

11. Cancer of Fallopian Tube 339

Introduction 340
Anatomy 340
Clinical Presentation 341
Diagnostic Work-Up 341
Pathology 342
Four Criteria for Pathologic Diagnosis of Primary Fallopian
Tube Carcinoma 344
Pre-Invasive Carcinoma of Fallopian Tube 344
General Management 344
Surgery 344
Chemotherapy in Fallopian Tube Carcinoma 345
Adjuvant Radiation Therapy 346
xiv Contents

12. Cancer of Ovary (Epithelial Ovarian Cancer) 349

Introduction 350
Anatomy of Ovary 350
Epidemiology 351
Incidence and Mortality 351
Aetiology 352
Reproductive Factors 352
Genetic Factors 353
Environmental Factors 354
Hereditary Ovarian Cancer Syndromes 354
Site-Speciic Ovarian Cancer 355
Hereditary Breast-Ovarian Cancer 355
Hereditary Non-Polyposis Colorectal Syndrome 355
Other Hereditary Syndromes Predisposing to
Ovarian Cancer 356
Somatic Mutation in Sporadic Ovarian Cancer 356
Mechanisms of Ovarian Carcinogenesis 356
Prevention of Ovarian Cancer 357
Hereditary Ovarian Cancer and Genetic Testing 359
Screening for Ovarian Cancer 361
Pelvic Examination 361
Ultrasound Scans 361
Tumour Markers 362
CA125 362
Additional Markers 362
Multi-Modal Screening Tests 363
Histologic Classiication of Ovarian Neoplasm (General) 365
Serous Tumour of the Ovary 365
Mucinous Tumour of the Ovary 368
Endometrioid Tumours 368
Clear Cell Tumours 369
Transitional Cell Tumour (Brenner Tumour) 369
Undifferentiated Carcinoma of Ovary 370
Hypercalcaemic Type 370
Contents xv

Pulmonary Type 371

Natural History and Patterns of Spread in Epithelial
Ovarian Cancer 371
Diagnosis and Clinical Evaluation 372
Biomarkers and Risk Assessment 373
Risk of Malignancy Index 373
OVA1 Test 374
Risk of Ovarian Malignancy Algorithm 375
New Tumour Markers in Ovarian Cancer 375
Staging Carcinoma of Ovary 376
Prognostic Factors for Epithelial Ovarian Cancer 378
CA125 as Prognostic Factor in Epithelial Ovarian
Cancer 379
Other Prognostic Factors for Ovarian Cancer 379
Ploidy Analysis 379
Image Cytometry 379
Genetic and Biologic Factors 380
Borderline Tumour (Tumour of Low Malignant Potential) 380
Management of Tumours with Low Malignant Potential 382
Early-Stage Disease 382
Stage 3 and 4 Borderline Tumour 382
Treatment for Invasive Epithelial Ovarian Cancer 382
Treatment for Early Stage of Epithelial Ovarian
Cancer 382
Chemotherapy in Early Stage (Stages 1 and 2) 383
Management of Patients with Advanced Epithelial
Ovarian Cancer 384
Cytoreductive Surgery 384
Post-Operative Chemotherapy (First Line) in Ovarian
Cancer 388
Chemotherapeutic Drugs as First Line Regimen in Ovarian
Cancer (Post-Operative Adjuvant Treatment) 388
Platinum Compounds 388
Doxorubicin and Platinum Combination 389
Taxanes 390
xvi Contents

Dose of Platinum and Paclitaxel 391

Addition of Targeted Agents and Novel Agents to
Platinum/Taxanes Regimen (Triplets) 393
Trials on Alternative Regimen as First Line
Chemotherapy in Ovarian Cancer 394
Intraperitoneal Chemotherapy 396
Hyperthermia Intraperitoneal Chemotherapy 398
Open Abdominal Technique 398
Close Abdominal Technique 398
Maintenance Therapy 399
Neoadjuvant Chemotherapy 399
Recurrent Ovarian Cancer 402
Treatment of Platinum-Sensitive Patients 403
Secondary Cytoreduction for Platinum-Sensitive
Patients 404
Chemotherapy for Platinum-Sensitive Patients 405
Options of chemotherapy for platinum-sensitive
tumour 405
Treatment for Platinum-Resistant and Refractory
Epithelial Ovarian Cancer 407
Chemotherapy for Platinum-Resistant and Refractory
Ovarian Cancer 408
Topotecan 408
Gemcitibine 408
Pegylated Lyposomal Doxorubicin 408
Oral Etoposide 409
Paclitaxel and Docetaxel 409
Second Look Laparotomy/Laparoscopy 410
Techniques of Second Look Laparotomy 410
Novel Anticancer Agents for Platinum-Resistant/
Refractory Epithelial Ovarian Cancer 411
Novel Cytotoxic Agents 412
Epothilones 412
Canfosfamide (Telcyta TLK286) 412
Yondelis (ET-743) 413
Phenoxodiol 413
Contents xvii

Targeted Agents 414

Monoclonal Antibody (Large Molecule Inhibitors) 414
Bevacizumab (Avastin) 415
Cetuximab (Erbitux) 415
Trastuzumab (Herceptin) 416
Small-Molecule Inhibitors 416
Imatinib Mesylate (Gleevec) 416
Geitinib (Iressa) 416
Erlotinib (Tarceva, OS1774) 417
Sorafenib (Nexavar, BAY 43-0006) 417
Sunitinib (Sutent) 417
Pazopanib (Votrient) 417
Cediranib 418
Other Targeted Therapies 418
Special Consideration in Ovarian Cancer Management 419
Radiation Therapy in Ovarian Cancer 419
Radiation Therapy after Chemotherapy in
Advanced Disease 421
Radiation as Palliative Treatment for Ovarian
Cancer 421
Palliative Surgery for Ovarian Cancer 422
Hormonal Therapy and Receptors in Ovarian
Carcinoma 422
Biologic Therapy for Ovarian Cancer 423
Reversal of Drug Resistance 424
Gene Therapy 425

13. Ovarian Germ Cell Tumours 437

Introduction 438
Epidemiology 438
Clinical Features 438
Classiication of Ovarian Germ Cell Tumours 439
Tumour Markers in Malignant Ovarian Germ Cell
Tumours 440
Dysgerminoma 441
Yolk Sac Tumour (Endodermal Sinus Tumour) 443
xviii Contents

Mature Teratoma 444

Immature Teratomas 446
Growing Teratoma Syndrome 448
Embryonal Carcinoma and Choriocarcinoma 449
Mixed Germ Cell Tumour 449
Management 450
Surgery and Adjuvant Chemotherapy in Malignant
Germ Cell Tumours 450
Primary Surgery 451
Cytoreductive Surgery 452
Chemotherapy in Advanced Disease 452
Chemotherapy for Recurrent Disease 453
Late Effect of Therapy 454

14. Ovarian Sex Cord-Stromal Tumours 457

Introduction 458
Classiication of Sex Cord-Stromal Tumours 458
Granulosa-Stromal Cells Tumour 459
Granulosa Cell Tumours 459
Adult-Type Granulosa Cell Tumour 461
Juvenile-Type Granulosa Cell Tumour 462
Tumour in the Thecoma-Fibroma Group 463
Thecoma (Theca Cell Tumour) 463
Fibroma 464
Sclerosing Stromal Tumour 465
Signet-Ring Stromal Tumour 465
Sertoli-Stromal Cell Tumours 466
Sertoli Cell Tumour 466
Sertoli–Leydig Cell Tumours 466
Sertoli–Leydig Cell Tumour with Heterologous
Elements 467
Retiform Variants 467
Sex Cord-Stromal Tumours of Mixed or Unclassiied Cell
Types 468
Contents xix

Sex Cord Tumour with Annular Tubules 468

Gynandroblastoma 468
Steroid Cell Tumours 469
Stromal Luteoma 469
Leydig Cell Tumours 470
Steroid Cell Tumours, Not Otherwise Speciied 470
Treatment of Ovarian Sex Cord-Stromal Tumours 471
Operative Management 471
Post-Operative Management 472

15. Gestational Trophoblastic Diseases 475

Introduction 476
Epidemiology 476
Risk Factors for Gestational Trophoblastic Disease 476
Classiication of Gestational Trophoblastic Disease 477
Pathogenesis of Gestational Trophoblastic Disease 478
Hydatidiform Mole 478
Presentations of Hydatidiform Mole 480
Presentations of Complete Hydatidiform Mole 481
Presentations of Partial Mole 482
Diagnosis of Hydatidiform Mole 482
Human Chorionic Gonadotropin in Gestational
Trophoblastic Disease 483
Management of Hydatidiform Mole 484
Natural History of Molar Pregnancy and Prognostic
Factors 486
Gestational Trophoblastic Neoplasm 486
Metastatic Gestational Trophoblastic Neoplasm 489
Staging and Prognostic Scoring in Gestational
Trophoblastic Neoplasm 490
Treatment of Low-Risk Gestational Trophoblastic
Neoplasm 492
Treatment for High-Risk and Metastatic Gestational
Trophoblastic Neoplasm 494
Treatment of Placental Site Trophoblastic Tumour 495
xx Contents

Post Chemotherapy Follow-Up 496

Chemotherapy Regimen for Gestational Trophoblastic
Neoplasm 497

16. Breast Cancer for Gynaecologic Oncologist 503

Basic Anatomy of the Breast 504
Introduction to Breast Cancer 505
Aetiology of Breast Cancer 506
Breast Cancer Risks 506
Reproductive Factors/Endogenous Hormones 506
Pregnancy and Lactation 507
Family History and Other Gynaecological Cancer 507
Oral Contraceptive Pills 508
Hormone Replacement Therapy 508
Personal History 509
Risk Assessment of Breast Cancer 509
Breast Cancer and Genetic Factors 510
Screening for Breast Cancer 512
Breast Self-Examination and Clinical Breast
Examination 512
Mammography 512
Reporting of Mammogram 514
Magnetic Resonance Imaging 514
Evaluation of Patients with Breast Cyst and Solid Breast
Lump 515
Breast Cyst 515
Solid Breast Lump 516
Evaluation of Non-Palpable Mammographic
Abnormalities 516
Ductal Carcinoma in situ 517
Lobular Carcinoma in situ 518
Mammary Paget Disease 518
Invasive Carcinoma of Breast 518
Prognostic Factors of Invasive Carcinoma of Breast 519
Presentation 520
Contents xxi

Evaluation of Patients with Breast Cancer 521

Staging of Breast Cancer 522
Treatment for Breast Cancer 523
Surgical Treatment 523
Types of Surgical Treatment for Breast Cancer 524
Radiotherapy 525
Systemic Therapy 526
Chemotherapy for Breast Cancer 527
Hormonal Therapy for Breast Cancer 527
Targeted Therapy for Breast Cancer 528
Human Epidermal Growth Factor Receptor (HER 2)
Inhibitor 528
Lapatinib 530
Anti-Angiogenesis 530
Locally Advanced Breast Cancer 530
Prevention of Breast Cancer 531
Current Recommendations of Chemoprevention 532

17. Gynaecologic Cancer during Pregnancy 539

Introduction 540
Radiation Exposure during Pregnancy 540
Radiotherapy during Pregnancy 543
Chemotherapy and Targeted Therapy during Pregnancy 543
Management of Gynaecological Cancer during Pregnancy 545
Breast Cancer 546
Cervical Cancer 546
Ovarian Cancer 549
Vulvar Cancer 551
Carcinoma of Endometrium 551
Choriocarcinoma 551

18. Tumour Markers in Gynaecologic Cancers 555

Introduction 556
Tumour Markers in Ovarian and Fallopian Tube Cancer 557
Cancer Antigen 125 557
xxii Contents

Serum Biomarkers in Screening of Epithelial Ovarian

Cancer 559
Serum Biomarkers in the Evaluation of Women with
Pelvic Masses 560
Biomarkers for Monitoring the Disease Status in
Epithelial Ovarian Cancer 562
Carcinoembryonic Antigen 562
Alpha-Fetoprotein 562
Human Chorionic Gonadotrophin 563
Lysophosphatidic Acid 563
Inhibin and Activins 563
New Tumour Markers in Ovarian Cancer 563
Tumour Markers in Cervical Cancer 565
Squamous Cell Carcinoma Antigen 565
CA125 in Cervical Cancer 566
CYFRA 211-1 566
Other Markers in Cervical Cancer 567
Tumour Markers in Endometrial Cancer 567

19. Diagnostic Imaging in Gynaecologic Oncology 571

Introduction 572
Imaging Study: Technique, Description and Normal
Anatomy 572
Ultrasound 572
Ultrasound Features of Normal Uterus and Ovary 573
Computed Tomography 573
Magnetic Resonance Imaging 574
Advantages of Magnetic Resonance Imaging 575
Disadvantages of MRI 576
Imaging in Cervical Carcinoma 576
CT Scan and Cervical Cancer 576
Magnetic Resonance Imaging in Cervical Cancer 577
Imaging in Endometrial Carcinoma 578
Ultrasound Scan in Endometrial Carcinoma 578
Contents xxiii

CT Scan in Endometrial Carcinoma 578

Magnetic Resonance in Endometrial Carcinoma 579
Imaging in Gestational Trophoblastic Disease 580
Ultrasound in Gestational Trophoblastic Disease 580
CT Scan in Gestational Trophoblastic Disease 580
Magnetic Resonance Imaging in GTD 581
Imaging in Carcinoma of Ovary 581
Ultrasound Scan and Doppler in Ovarian Carcinoma 581
CT Scan in Ovarian Carcinoma 581
MRI in Ovarian Carcinoma 583
Imaging in Vulvar Cancer 583
Ultrasound Scan in Vulvar Cancer 583
CT Scan in Vulvar Cancer 584
MRI in Vulvar Cancer 584
Lymphoscintigraphy and Sentinel Node Detection
in Vulvar Cancer 584
Positron Emission Tomography in Gynaecologic
Malignancies 585
F-FDG Pet Scan in Cervical Cancer 586
F-FDG Pet Scan in Endometrial Cancer 586
F-FDG PET Scan in Ovarian Cancer 587

20. Peri-Operative Care for Gynaecologic Cancer Patients 589

Introduction 590
Peri-Operative Morbidity and Mortality Risk Prediction 590
Peri-Operative Care to Optimize High-Risk Surgical
Patients Undergoing Gynaecological Cancer Surgery 592
Informed Consent and Counselling 592
Peri-Operative Care in Gynaecological Cancer Patients
History and Physical Examination 593
Pre-Operative Investigations 593
Optimization of Co-Morbid Illnesses 593
Endocrine-Related Conditions 593
Cardiac Disease 594
xxiv Contents

Respiratory Disease 595

Renal Disease 595
Haematological Disorders 596
Peri-Operative Thromboprophylaxis 596
Peri-Operative Nutritional Support for Cancer Patients 599
Peri-Operative Fluid and Electrolyte Management 601
Bowel Preparation 603
Pain Management 605

21. Basic Anatomy and Principles of Surgery in

Gynaecologic Oncology 609
Basic Anatomy of the Pelvis 610
Pelvic Ligaments 611
Pelvic Spaces 611
Internal Iliac Artery 613
Ureter 613
Pelvic Lymph Nodes 615
Pelvic Nerve 617
Introduction to Anatomy of Vulva 618
Vulva 618
Blood Supply and Innervation of the Vulva 621
Lymphatic Supply of the Vulva 621
Peritoneal Cavity 623
Omentum 624
Blood Supply to the Bowel 625
Bowel Injury and Basic Bowel Surgery 625
Small and Large Bowel Resection and Anastomosis 627
Urinary Tract Injuries and Repair 628
Basic Surgical Techniques in Gynaecological Surgery 629
Fasting and Bowel Preparation 629
Skin Preparation 630
Skin Incision 630
Surgical Drain 632
Basic Principles in Gynaecologic Oncology
Surgery 633
Contents xxv

22. Basic Principles of Radiotherapy 637

Introduction 638
Biologic Effects of Radiation 640
Radiocurability and Radiosensitivity 640
Effects of Irradiation on Foetus 642
General Concepts of Clinical Radiation Therapy 642
Effects of Irradiation on Abdominal and Pelvic Normal
Tissues 645
Potential Sites and Nature of Radiation Injuries in
Gynaecologic Cancer Patients 646
Combination of Irradiation with Other Therapeutic
Modalities 647
Processes of Radiation Therapy 648
Current Developments in Radiotherapy 650
Intensiied Modulated Radiation Therapy 650
Image-Guided Radiation Therapy 651
Stereotactic Radiosurgery 651
Other Types and Methods of Radiotherapy 652
Electron Radiation Therapy 652
Proton Beams 652
Neutron Beam Therapy 652
Intra-Operative Radiation Therapy 652
Hyperthermia and Radiotherapy 653
Basic Equipment for Radiotherapy in Gynaecology
Oncology 653
Shielding for EBRT 656

23. Basic Principles of Chemotherapy 659

Introduction 660
Basic Cell Cycles 660
Stages of Cell Cycle 660
Interphase 661
Mitosis 661
Gompertzian Growth Concepts 662
Generation and Doubling Time 662
xxvi Contents

Types of Anti-Neoplastic Agents Related to Cell Cycle 663

Drug Resistance 665
Possible Mechanisms Associated with Resistance to
Some Commonly Used Anti-Cancer Drugs 667
Categories of Chemotherapeutic Drugs Used in the
Treatment of Gynaecological Cancer 667
Alkylating Agents 667
Platinum 668
Anti-Tumour Antibiotics and Anthracylines 668
Anti-Metabolites 669
Vinca Alkaloids 670
Topoisomerase Inhibitors 670
Taxanes 671
Chemotherapy and Toxicity 672
Haematologic Toxicity 672
Gastrointestinal Toxicity 672
Skin Reactions 672
Cardiac Toxicity 673
Genitourinary Toxicity 673
Neurologic Toxicity 673
Gonadal Dysfunction 673
Carcinogenicity 673
Basic Practical Chemotherapy 674
Evaluation of New Agents 674
Important Considerations before Using
Chemotherapeutic Drugs 674
Performance Status 675
Types of Chemotherapy 676
Deinitions of Response (WHO Guidelines) 676
Response Evaluation Criteria in Solid Tumours 677
Calculation of Dosage 678
Important Tips in Chemotherapy 679
Management of Recurrent Disease 679
Principle of combination chemotherapy 679
Contents xxvii

Supportive and Preventive Care for Chemotherapy-Induced

Myelosuppression 679
GM-CSF and G-CSF 680
Erythropoietin 681
Overcoming Nausea and Vomiting during Chemotherapy 681
General Principles 683
Type of Chemotherapy-Induced Nausea and
Vomiting 683
Dose Modiication Guidelines 684
General Principle of Dose Modiication 685

24. Modulating Agents, Biologic Response Modifiers and

Targeted Therapy in Gynaecological Cancer 687
Modulating Agents in Cancer 688
Modulating Agents 688
Folinic Acid 688
Dexrazoxane (Zinecard) 689
Thiol-Based Chemoprotectors 689
Glutathione 689
Amifostine (Ethyol) 690
Sodium Thiosulphate 690
Mesna 691
Glutamine 691
Fibroblast Growth Factors 692
Recombinant Human Erythropoetin 692
Granulocyte-Colony Stimulating Factor and Granulocyte
Macrophage-Colony Stimulating Factor 693
Biologic Response Modiiers 694
Inlammation and Tumour 694
Cytokines and Tumour Growth 695
Chemokines and Tumour Growth 695
Cyclooxygenase and Tumour 696
Biologic Response Modiiers in Current Clinical Practices 697
Interferons 697
xxviii Contents

Interleukins (IL-1, 2, 3, 4) 697

Tumour Necrosis Factor 698
Retinoids 698
Modulators of Resistance to Chemotherapy 698
Modulators of P-Glycoprotein 699

25. Immunotherapy and Hormonal Therapy in

Gynaecological Cancer 703
Tumour Immunology and Immunotherapy 704
Principles of Immunotherapy 707
Immunotherapeutic Approaches 708
Active Immunotherapy 708
Passive Immunotherapy 708
Potential Approaches for Cancer Vaccination Strategy 709
Anti-Idiotypic Antibody-Based Vaccine (Using
Monoclonal Antibody Technology) 709
Dendritic Cell-Based Vaccines 709
DNA and RNA Vaccines 709
Viral Vector-Based Vaccines 709
Particle-Based Vaccines 710
Hormonal Interactions and Hormonal Therapy in Cancer 710
Hormones 710
Types of Hormones 710
Receptors 710
Hormonal Interactions in Breast Cancer 711
Endogenous Sex Steroid and Breast Cancer 711
Exogenous Sex Steroid and Breast Cancer 711
Oestrogen and Anti-Oestrogen in Breast Cancer 712
Progestogen and Breast Cancer 713
Hormonal Therapy in Endometrial Adenocarcinoma 713
General 713
Progestogen Therapy in Endometrial Neoplasia 714
Endometrial Hyperplasia 714
Endometrial Carcinomas 714
Contents xxix

Other Potential Hormonal Treatment for

Endometrial Carcinoma 714
Steroid Receptors and Predictive Tests for
Endometrial Cancer 715
Endometrial Stromal Sarcoma 715
Hormonal Therapy and Receptors in Ovarian Carcinoma 716
HRT in Patients Treated for Gynae Malignancy 716
OCP and Prevention of Ovarian and Endometrial Cancer 717

26. Management of Long-Term Side Effects of

Gynaecologic Cancer Treatment 721
Introduction 722
Side Effects of Chemotherapy 722
Mucositis 722
Alopecia 722
Myelodysplastic Syndrome and Acute
Non-Lymphocytic Leukaemia 722
Cardiac Toxicity 723
Pulmonary Toxicity 723
Neurotoxicity 724
Renal Insuficiency 724
Infertility and Mutagenic Potential 725
Neutropenic Sepsis 725
Central Nervous System Adverse Effects Induced by
Chemotherapy 726
Side Effects of Radiation Therapy 727
Predisposing Factors to Radiation-Related Complications 728
Host Factors 728
Disease-Related Predisposing Factors 728
Treatment-Related Predisposing Factors 728
Gastrointestinal Radiation Toxicity 728
Pathogenesis of Acute and Late Radiation Toxicity 730
Urinary Tract Radiation Injury 730
Ureteric Radiation Injury 730
xxx Contents

Bladder Radiation Injuries 731

Sexual Function 731
Secondary Malignancies 731
Surgical Complications in Gynaeoncologic Surgery 732
Urinary Tract Injuries 732
Intestinal Injuries 733
Intra-operative Injuries 733
Post-operative Injuries 733
Appendix 734
Common Toxicity Criteria (Simpliied CTC Ver. 3.0) 734
Non-Haematological Toxicities 737

27. Nutritional Support for Gynaecologic cancer Patients 741

Nutritional Assessment 743
Methods of Nutritional Assessment 743
Anthropometric and Biochemical Markers 743
Subjective Global Assessment 744
Aetiology of Malnutrition 744
Decreased Food Intake 744
Malabsorption 744
Metabolic Derangement 745
Nutritional Therapies 745
Goals of Nutritional Therapy 745
Enteral Nutrition 746
Types of Administration of Enteral Feeding 747
Bolus Feeding 747
Continuous Infusion 747
Eficacy of Enteral Feeding 747
Indications for Enteral Nutrition in Cancer Patients 748
Complications of Enteral Nutrition 748
Home Enteral Nutrition 748
Oral Dietary Therapy 749
Pharmacologic Agents 750
Appetite Stimulants 750
Contents xxxi

Cytokine Inhibitors 750

Other Agents and Modality to Increase Weight 750
Total Parenteral Nutrition 751
Indications of Total Parenteral Nutrition 751
Roles of Total Parenteral Nutrition in Cancer
Patients 752
Indications for TPN in Hospitalized Patients with
Gynaecologic Cancers 752
Ethical Consideration of Nutritional Support in
Terminally Ill Patients 753

28. Basic Surgical Procedures in Gynaecologic Oncology 757

Urethral Catheterization 758
Pleurocentesis 758
Characteristics of Normal Pleural Fluid 759
Causes of Pleural Effusion 759
Symptoms 759
Purpose of Pleurocentesis 759
Contraindications 760
Techniques of Pleurocentesis 760
Potential Complications of Pleurocentesis 761
Chest Tube Insertion 761
Indications 761
Contraindications 761
Equipment 762
Techniques of Chest Tube Insertion 762
Complications of Chest Tube Insertion 763
Pleurodesis 764
Potential Risks of Pleurodesis 765
Abdominal Paracentesis for Ascites 765
Causes of Ascites 765
Contraindications of Paracentesis 766
Techniques of Abdominal Paracentesis 766
Additional Facts 767
xxxii Contents

Potential Complications of Paracentesis 768

Bladder Retraining and Care of Suprapubic Urinary
Catheter 768
Bladder Retraining (Instruction to Patient) 769
Care of Suprapubic Catheter (Instruction to Patient) 769
Chemoport 771
Indications for Use of Chemoport 772
Contraindications 772
Possible Complications 772
Implantation Instructions 772
Accessing Implanted Port 774

29. Laparoscopic and Robotic Surgery in Gynaecologic

Oncology 775
Introduction 776
Endometrial Cancer 776
Ovarian Cancer 777
Role of Laparoscopy in the Evaluation of
Adnexal Mass 777
Role of Laparoscopy in the Staging and Re-Staging 778
Role of Laparoscopy in Advanced Ovarian Cancer 778
Cervical Cancer 779
Primary Surgical Treatment for Early-Stage Disease 779
Locally Advanced Cervical Cancer 779
Radical Trachelectomy with Laparoscopic
Lymphadenectomy 780
Other Roles of Laparoscopy in Cervical Cancer 780
Robotic Surgery 780
Complications of Laparoscopy 782
Key Factors Related to Complications Laparoscopy 782
Vascular Injuries 783
Gastrointestinal Injuries 783
Urinary Injuries 784
Incisional Hernias 784
Contents xxxiii

Port-Site Metastases 784

Gas Embolism 785

Index 789
This page intentionally left blank
Preface

Gynaecologic oncology is a very challenging ield and an important

component of gynaecology and oncology. It is one of the most
important subjects in gynaecology. The management of patients
with gynaecological cancers is complex, as the impact of the outcome
of such cancers can be critical. Gynaecologic oncology is always
perceived as the most dificult subject in obstetrics and gynaecology.
However, this handbook will prove it otherwise. This handbook of
gynaecologic oncology is a new addition to the current academic
tomes and covers the essential breadth of knowledge ranging from
the basics of carcinogenesis to the latest advances in the prevention
and management of all gynaecological cancers, including breast
cancer. It aims to provide readers with the information and data
in a systematic and easy-to-understand format with numerous
illustrations and images. It is designed to be handy and compact
but with the content equivalent to that of a standard textbook.
The book also introduces the readers to the new FIGO staging
system, including FIGO staging 2014 for ovarian and fallopian
tube carcinoma. It will serve as a useful reference for everyone in
the medical ield, including researchers, clinicians, house oficers,
pharmacists, doctors, specialists, postgraduate students, fellows
and sub-specialty trainees in gynaecologic, radiation and medical
oncology and lecturers in universities.

Rushdan Noor
Eng Hseon Tay
Jeffrey Low
This page intentionally left blank
Chapter 1

World Cancer Statistics and Burden of

Gynaecological Cancer

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
2 World Cancer Statistics and Burden of Gynaecological Cancer

Introduction
Cancer is a group of diseases characterized by uncontrolled growth
and spread of abnormal cells that can iniltrate to other parts of
the body through the blood and lymphatic systems. Unlike normal
cells, cancer cells do not undergo programmatic death known as
apoptosis and instead continue to grow and divide. There are
more than 100 diﬀerent types of cancer. The aetiology of cancer
is multifactorial and involves a very complex process known as
carcinogenesis. Cancer carcinogenesis is discussed in Chapter 2.
Cancer kills more people than AIDS, tuberculosis and malaria
combined and will soon become the world’s single leading cause
of death. According to a report by GLOBOCAN 2012, higher
proportion of the cancer burden occurs in less developed regions
both in terms of cancer incidence (57% new cancers in 2012 occur
within less developed regions) and cancer mortality (65% of cancer
deaths) (IARC Globocan, 2012).
Smoking, alcohol intake and low fruit and vegetable intake
were the leading risk factors for death from cancer worldwide
in low- and middle-income countries while in high-income
countries, smoking, alcohol use and overweight and obesity were
the most important causes of cancer. Smoking alone is estimated
to have caused 21% of deaths from cancer worldwide. Low- and
middle-income countries accounted for about 50% of all cancers
worldwide in 1975; this proportion increased to 56% in 2008 and is
projected to reach 61% by 2050 (Bray and Moller, 2006; GLOBOCAN,
2008). A summary of overall cancer statistics in 2008 is shown in
Tables 1.1, 1.2 and 1.3 (Globocan, 2008; Ferlay et al., 2010).

Table 1.1 Summary of world cancer statistics 2012

Statistics Male Female Both

Population (million) 3557.717 3496.728 7054.446
Number of new cancer cases (million) 7.4271 6.6630 14.0901
Age-standardized rate* 205.4 165.3 182.3
Risk getting cancer before age 75(%) 21.0 16.4 18.5
Number of cancer death (million) 4.6531 3.5479 8.2010
Risk of dying from cancer before age 75(%) 12.7 8.4 10.4

*per-100,000 population
Source: Globocan, 2012; Ferlay et al., 2010.
Introduction 3

Table 1.2 Summary of world cancer statistics in more developed regions

in 2012 (GLOBOCAN 2012)

More developed regions*

Statistics Male Female Both
Population (million) 605.963 639.750 1245.713
Number of new cancer cases 3.2435 mil 2.8324 mil 6.0759 mil
Age-standardized rate 308.7 240.6 268.3
Risk getting cancer before age 30.9 23.3 26.8
75 (%)
Number of cancer death 1.5912 mil 1.2867 mil 2.8779 mil
Risk of dying from cancer 14.3 9.0 11.4
before age 75 (%)
Five most frequent cancers Prostate, Lung, Breast, Breast,
Colorectum, Colorectum, Prostate, Lung
Bladder, Lung, Corpus Colorectum,
Stomach uteri, Ovary Stomach
Source: Globocan, 2012; Ferlay et al., 2010.
*The rates for the more developed regions have been calculated as the population-
weighted average of Northern America, Japan, Eastern Europe, Northern Europe,
Southern Europe, Western Europe, Australia/New Zealand.

Table 1.3 Summary of world cancer statistics in less developed regions

in 2012
Less developed regions*
Statistics Male Female Both
Population (million) 2951.754 2856.978 5808.732
Number of new cancer cases 4.1836 mil 3.8306 mil 8.0143 mil
Age-standardized rate# 163.0 135.8 147.7
Risk getting cancer before 16.6 13.4 14.9
age 75 (%)
Number of cancer death 3.0619 mil 2.2612 mil 5.3231 mil
Risk of dying from cancer 12.0 8.1 9.9
before age 75 (%)
Five most frequent cancers Lung, Liver, Breast, Cervix Lung, Breast,
Stomach, Prostate, uteri, Lung, Stomach,
Colorectum Colorectum, Liver,
Stomach Colorectum
Source: Globocan, 2012; Ferlay et al., 2010.
*The less developed regions: Eastern, Middle, Northern, Southern, Western Africa,
Caribbean, Central America, South America, Eastern Asia, South Eastern Asia, Western
Asia, Melanesia, Micronesia, Polynesia.
#Age standardized rate: A rate is number of new cases or deaths per 100,000 persons

per-year
4 World Cancer Statistics and Burden of Gynaecological Cancer

World Cancer Burden and Contributing Factors

The International Agency for Research on Cancer (IARC) has
predicted that by 2030, 27 million new cancer cases and 17 million
cancer deaths will occur each year worldwide. This compares to
14.1 million new cancers and 8.2 million cancer death reported by
GLOBOCAN 2012. Based on current trends, the rate at which new
cancers are diagnosed is expected to grow by 1% annually. China,
Russia and India are projected to have the biggest increases in
cancers and cancer deaths (Danaei et al., 2005; Globocan, 2008;
Ferlay et al., 2010).
The three most important factors that contribute to these
trends are
(a) growth and increase in life expectancy of population;
(b) cigarette smoking;
( c ) diet, obesity and physical inactivity.
Tobacco use is the single largest preventable cause of cancer
and premature death worldwide. Estimated 1.3 billion people in
the world currently smoke tobacco. If current trends in smoking
and population growth continue, the number of current smokers
is expected to be 2 billion worldwide by 2030. Overweight and
obesity are also important contributing factors to cancer risk;
The WHO estimates that the number of overweight adults in 2005
was approximately 1.6 billion and 300 million were obese
(BMI > 30). The number of overweight is expected to increase to
2.3 billion by 2015. The main reasons for this trend are overeating,
increased availability of high-calorie food and physical inactivity.
Obesity is known to be a risk factor for breast, endometrial, ovarian,
colorectal, oesophagus and kidney cancers (Danaei et al., 2005;
Globocan, 2008; Ferlay et al., 2010; Sankaranarayanan and Ferlay,
2006).
Chronic infections are known to be primary aetiology for many
cancers such as stomach cancer (Helicobacter pylori), cervical
cancer (human papillomavirus), liver cancer (Hepatitis B and C
infections), Kaposi’s sarcoma (human herpes virus 8), bladder
cancer (Schistosoma haematobium), etc. Persistent infections with
these various organisms contribute for approximately 18% of
cancer worldwide and developing countries have three times the
World Cancer Burden and Contributing Factors 5

higher percentage of infection-related cancers than developed

countries.
Increasing number of elderly population is known contributing
factors to increasing rate of cancer incidence worldwide. The life
expectancy of the world is 67.2 years: 65 years for males and 69.5
years for female for 2005–2010 according to United Nations World
Population Prospects 2006 Revision. Among countries with the
highest life expectancy are Japan (82.6), Hong Kong (82.2), Iceland
(81.8), Switzerland (81.7) and Australia (81.2) (Ferlay et al., 2010;
Globocan, 2008).
According to GLOBOCAN 2012, the total of 14.1 million new
cancer cases and 8.2 million cancer deaths have been reported in
2012. Lung cancer remains the most common cancer in the world,
both in term of cases (1.8 million cases, 13.0% of total) and deaths
(1.6 million deaths, 19.4% of total) (Table 1.4). Breast cancer is the
second most common cancer overall with 1.7 million new cases
reported in 2012 or 11.9% of total new cancer cases worldwide.
While, colorectal cancer is the third most common cancer with
1.4 million new cases reported and 693,881 deaths reported in
2012.

Table 1.4 World’s 10 most frequent cancers in men and women in 2012
(GLOBOCAN 2012)

ASR (per
Type of cancer Number (%) 100,000) Mortality (%)
Lung 1,824,701 13.0 23.1 19.4
Breast 1,676,633 11.9 43.3 6.4
Colorectum 1,360,602 9.7 17.2 8.5
Prostate 1,111,689 7.9 31.1 3.7
Stomach 952,594 7.9 12.1 8.8
Liver 782,451 5.6 10.1 9.1
Cervix uteri 527,624 3.7 14.0 3.2
Oesophagus 455,784 3.2 5.9 4.9
Bladder 429,793 3.1 5.3 2.0
Non-Hodgkin lymphoma 385,741 2.5 5.1 2.4
6 World Cancer Statistics and Burden of Gynaecological Cancer

The most common causes of cancer death are lung (1.59 million,
19.4% of total), liver cancers (0.75 million, 9.1%) and stomach
(0.72 million, 8.8%). Despite being the second most common cancer,
breast cancer ranks ifth as cause of deaths. This is probably due to
early detection and more eﬀective treatment; furthermore, breast
cancer is more prevalence in developed countries with adequate
facilities, inance and human resources for screening and treatment.
The world 10 most frequent cancers in men and women are
shown in Table 1.5 and 1.6 respectively.

Table 1.5 World’s 10 most common cancers in men (GLOBOCAN 2012)

Type of cancer Number (%) ASR (per 100,000) Mortality (%)

Lung 1,241,601 16.7 34.2 23.6
Prostate 1,111,689 15.0 31.1 6.6
Colorectum 746,298 10.0 20.6 8.0
Stomach 631,293 8.5 17.4 10.1
Liver 554,369 7.5 15.3 11.2
Bladder 330,380 4.4 9.0 2.6
Oesophagus 323,008 4.3 9.0 6.0
Non-Hodgkin lymphoma 217,643 2.5 6.0 2.5
Kidney 213,924 2.9 6.0 2.0
Leukaemia 200,676 2.7 5.6 3.3

Table 1.6 World’s 10 most common cancer in women (GLOBOCAN

2012)

Type of cancer Number (%) ASR (per 100,000) Mortality (%)

Breast 1,676,633 25.2 43.3 14.7
Colorectum 614,304 9.2 14.3 9.0
Lung 583,100 8.8 13.6 13.8
Cervix 527,624 7.9 14.0 7.5
Stomach 320,301 4.8 7.5 7.2
Corpus uteri 319,605 4.8 8.3 2.1
Ovary 238,719 3.6 6.1 4.3
Thyroid 229,923 3.5 6.1 0.8
Liver 228,082 3.4 5.3 6.3
Non-Hodgkin 168,098 2.5 4.1 2.4
lymphoma
Cervical Cancer 7

The regions with the highest cancer incidence rate in females

are North America (ASR 274.4 per 100, 000), Australia/New Zealand
(ASR 276.4), Northern and Western Europe (ASRs 249.4 and 250.9
respectively) mainly due to the high breast cancer incidence in
these regions. The lowest cancer incidence in women is in Middle
Africa and Northern Africa (ASR < 100 per 100, 000) (Danaei et al.,
2005; Ferlay et al., 2010; Globocan, 2008).

Breast Cancer
Breast cancer is the most common cancer in women and the second
most common cancer in both men and women. It was estimated 1.68
million cases or 25.2% of all new women’s cancer cases reported
in 2012. The incidence rates are highest in developed countries
(except Japan). According to GLOBOCAN 2012 reports, breast
cancer incidence has increased by more than 20% in 2012
compared to 2008. The mortality rate has also increased by 14%.
Incidence rates remains highest in more developed regions,
but mortality rate is relatively much higher in less developed
countries due to a lack of early detection and access to treatment
facilities. The incidence rate in Western Europe is 90 per 100,000
women while in Eastern Africa is 30 per 100,000 women. Breast
cancer contributes 12.7% of cancer death in both developing
and developed regions (Ferlay et al., 2010; Globocan, 2008;
Sankaranarayanan and Ferlay, 2006, GLOBOCAN 2012).

Cervical Cancer
Cervical cancer is the fourth most common cancer in women
and the seventh most common overall cancer in 2012. In 2012,
cervical cancer is the fourth most common cancers in women
worldwide, after breast, colorectal and lung cancers. GLOBOCAN
(2012) estimated 527,624 new cases of cervical cancer have
been reported in 2012, and this constitutes 7.9% of all female
cancer. Regions with high-risk cervical cancer are Eastern Africa
(ASR 42.7 per 100,000), Melanesia (ASR 33.3), Southern Africa
(ASR 31.5), South Central Asia (ASR 24.6), Middle Africa (ASR
8 World Cancer Statistics and Burden of Gynaecological Cancer

30.6) and South America (ASR 23.9). While, the risk of cervical
cancer is lowest in Western Asia (ASR 4.4), Northern America
(ASR 5.7), Australia (ASR 5.0) and New Zealand (ASR 5.0). Age-
standardized incidence of cervical cancer in South East Asia is
15.8 per 100,000 population. Cervical cancer is responsible for a
total of 265,653 deaths in 2012 (mortality:incidence ratio of 0.52),
accounting 7.5% of all female cancer deaths. Approximately 88%
of cervical cancer death occurs in developing countries; 159,800
deaths (58%) were reported from Asia (Ferlay et al., 2010; Globocan,
2008; Globocan 2012, Sankaranarayanan and Ferlay, 2006).
According to GLOBOCAN 2012, cervical cancer is also the fourth
most common cause of cancer death in women worldwide (266,000
deaths in 2012) and almost 70% of the global burden falls in areas
with lower levels of development. Mortality varies 18-fold between
the diﬀerent regions of the world, with rates ranging from less than
2 per 100,000 in Western Asia, Western Europe and Australia/New
Zealand, to more than 20 per 100,000 in Melanesia (20.6), Middle
(22.2) and Eastern Africa (27.6) (GLOBOCAN 2012).

Uterine Cancer
According to GLOBOCAN 2012, uterine cancer is the sixth most
common women cancer worldwide and a total of 319,605 new
cases had been reported with ASR of 8.3 per 100,000 population
constituting 4.8% from total women cancers. The highest incidences
are observed in United State with ASR of 19.48 per 100,000 women.
More than 90% of patients with uterine cancer are more than 50
years old (Ferlay et al., 2010; Globocan, 2008; Sankaranarayanan
and Ferlay, 2006, GLOBOCAN 2012).
The incidence of uterine cancer is more common in developed
regions (50% of total cases were reported from more developed
regions) ranking fourth the most common cancer in women after
breast, colorectal and lung. Cancer of the uterine body is also the
most common gynaecological cancer in developed regions. A total
of 76,155 deaths had been reported in 2012 due to uterine cancer
(Globocan 2012). Cancer of the uterus has much more favourable
prognosis than ovarian and cervical cancer with 5-year survival
rates around 80–90% in developed countries and 70% in the
developing countries.
Other Gynaecological Cancers 9

Ovarian Cancer
The cancer of the ovary is one of the most lethal gynaecological
malignancies due to late presentation, poor response to treatment
and high recurrence rate. Ovarian cancer has a similar geographic
distribution to uterine cancer and it is the seventh most common
cancer in women and the third most common gynaecological cancer
worldwide after cervical and uterine cancer. There was a total of
238,719 new cases of ovarian cancer reported in 2012, which is
3.6% of all women cancer and 151,905 deaths have been reported
on the same year (4.3% of all cancer deaths in women). The
cumulative risk of developing ovarian cancer is 0.7 (0.7 per 100
lifetime risk). The incidence rates are higher in developed regions
(overall ASR of 8–11 per 100,000 compared to 3–5 per 100,000 in
less developed regions) and 100,254 new cases (45% from total
cases worldwide) of ovarian cancer were reported in more developed
regions in 2008 (Ferlay et al., 2010; Globocan, 2008; Globocan 2012,
Sankaranarayanan and Ferlay, 2006).

Other Gynaecological Cancers

Vulvar cancer is rare, accounting for 3% of all gynaecological
cancers. Approximately, 27,000 cases have been reported annually
and 58% of cases are from developed countries. The incidence of
vulvar cancer is highest in North America, South America and
Europe. The incidence rates are between 1–1.5 per 100,000. Vulvar
cancer is rare in developing countries, including Asia.
Vaginal cancer is also rare gynaecological cancer: It is estimated
that 13,000–14,000 new cases have been reported annually but the
majorities are from developing countries. The incidence rates do
not exceed 0.8 per 100,000 women. More than 75% of cases occur
in women older than 60 years old.

Glossary of Terms
• Incidence: Incidence is the number of new cases that arise in
a given period in a speciied population. It can be expressed
as an absolute number of cases per year or as a rate per
100,000 persons per year. The rate provides an approximation
of an average risk of developing cancer.
10 World Cancer Statistics and Burden of Gynaecological Cancer

• Prevalence: Prevalence is deined as the total number of cases

of the disease in the population at a given time, or the total
number of cases in the population, divided by the number
of individuals in the population. It is used as an estimate of
how common a condition is within a population over a certain
period of time.
• Mortality: Mortality is the number of deaths that occur in
a given period in a speciied population. It can be expressed
as an absolute number of deaths per year or as a rate per
100,000 persons per year.
• Crude rate: Data on incidence or mortality are often
presented as rates. For a speciic tumour and population,
a crude rate is calculated simply by dividing the number of
new cancers or cancer deaths observed during a given time
period by the corresponding number of person years in the
population at risk. For cancer, the result is usually expressed
as an annual rate per 100,000 persons at risk.
• Age-standardized rate (ASR): ASR is a summary measure
of the rate that a population would have if it had a standard
age structure. Standardization is necessary when comparing
several populations that diﬀer with respect to age because
age has a powerful inluence on the risk of cancer. The most
frequently used standard population is the world standard
population. The calculated incidence or mortality rate is then
called age-standardized incidence or mortality rate (world). It
is also expressed per 100,000.
• Cumulative risk: Cumulative incidence/mortality is the
probability or risk of individuals getting/dying from the
disease during a speciied period. For cancer, it is expressed
as the number of new born children (out of 100, or 1000) who
would be expected to develop or die from a particular cancer
before the age of 75 if they had the rates of cancer observed
in the period in the absence of competing causes.
Source: [Link]

References

Bray F, Moller B. Predicting the future burden of cancer. Nat Rev Cancer
2006; 6(1): 63–74.
References 11

Danaei G, Hoorn SV, Lopez AD, et al. Causes of cancer in the world:
comparative risk assessment of nine behavioural and environmental
risk factors. Lancet 2005; 366: 1784–1793.
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer
in 2008: GLOBOCAN 2008. Int. J. Cancer 2010, DOI: 10.1002/
ijc.25516.
IARC GLOBOCAN 2008 website: [Link]
IARC GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and
Prevalence Worldwide in 2012. website: [Link]
Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer:
the size of the problem. Best Pract Res Clin Obstet Gynaecol 2006;
20(2): 207–225.
Thun MJ, DeLancey JO, Center MM, et al. The global burden of cancer:
priorities for prevention. Carcinogenesis 2010; 31(1): 100–110.
This page intentionally left blank
Chapter 2

Genes and Carcinogenesis

Basic Structure of DNA

Deoxyribonucleic acid, or DNA, is a polymer with the basic unit
known as nucleotide, which consists of three parts: (1) standard
unit of ive carbon deoxyribose (sugar) with phosphate and (2)
variable unit known as bases known as purine and pyrimidine.
Purine comprises adenine (A) and guanine (G), while Pyrimidine
comprises cytosine (C) and thiamine (T). Nucleotides are connected
to each other through their phosphate group. The bases are free to
interact with each other, i.e. Adenine is interacted with Thiamine
(A–T), Guanine is interacted with Cytosine (G–C). The DNA molecules
are associated with speciic proteins to form a chromatics in the
nucleus (Figs. 2.1 and 2.2).

Gene
The gene is a fundamental unit of inheritance, and in a normal
human cell, DNA contains 30,000 to 100,000 genes. The genes
exert their eﬀect through two steps: (1) transcription (DNA to
mRNA) and (2) translation of mRNA into protein. Every gene has
two main functional units, namely (1) promoter region and (2)
coding region. The promoter region determines when and what

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
14 Genes and Carcinogenesis

tissue will be expressed, while the coding region determines the

structures of protein produced. Interestingly, gene can be dissected
from the DNA using an enzymatic process known as restriction
endonucleases. The dissected gene can be captured and replicated
by inserting it into a bacterial plasmid or virus. The plasmid is able
to replicate independently, and at the same time, the genes that
have been inserted to it will also replicate. This process is called
cloning and the cloned gene is also known as a probe. Using based
pairing on the probes, the cloned gene (DNA sequences) will be
identiied and this process is called nucleic acid hybridization.
Hybridization is the basic concept of many DNA analyses such
as Southern blot, microarray analysis and polymerase chain
reaction.

Figure 2.1 Nucleotide is a basic unit of nucleic acids. Each nucleotide has
three components: (a) bases belonging to the class of purine
or pyrimidine, (b) a ive carbon or pentose sugar and (c) a
phosphate group.

The DNA will undergo transcription (genetic materials will be

copied) to mRNA by mRNA polymerase II enzyme. Subsequently,
mRNA will be transported to a cytoplasm. The cytoplasmic mRNA
can be detected by northern blotting, nucleus protection assay and
modiied polymerase chain reaction. It is known that the process
of translation to protein is more complex than transcription. After
translation, protein has to undergo modiication to make it fully
functional. The translation from mRNA to protein can be induced
in vitro using the cellular extract from animal reticulocytes and
wheat germ.
Genes and Carcinogenesis 15

The end result of translation is a functional protein and its

acid amino sequences that can be analyzed by various techniques
such as electrophoresis, immunoblotting, immunosorbent assay,
immune precipitation, mass spectrometry and others. Full process
from DNA transcription to RNA and subsequently translation of
RNA into protein can be repeated in vivo using the expression
system also known as a vector (example of vectors: yeast cell, insect
cells and plant cells).

Figure 2.2 DNA molecule. The shape of the DNA is called double helix.
The sides of the ladder are a linked chain of alternating sugar
and phosphate molecules. Both strands are connected with
each other through bases. There are four bases: (a) A: Adenine,
(b) T: Thymine, (c) C: Cytosine, and (d) G: Guanine. Adenine is
linked to thymine, while cytosine linked to guanine.

Genes and Carcinogenesis

All multicellular organisms have the potential to develop cancer,
and the process of cancer development is called carcinogenesis.
Carcinogenesis is a highly controversial subject, and it involves
many steps and functional processes. Carcinogenesis is built on the
foundation of non-lethal genetic changes and these changes may
be attributed to acquired factors such as environmental factors
16 Genes and Carcinogenesis

(chemical, toxin, radiation, infection, etc.,) and may be inherited

from the parent, e.g. defects in repair genes or genes responsible for
cell growth and apoptosis.

Phases of Carcinogenesis
Carcinogenesis can be divided into three phases:
(1) initiation phase (irreversible)
(2) promotion phase (reversible)
(3) progression phase

Initiation Phase
The initiation phase follows exposure to carcinogens/mutagens,
which are also known as initiators. This phase is an irreversible
step cause by DNA damage leading to somatic mutation and
mutation to tumour suppressor genes is said to be the irst step
of carcinogenesis (Fearon–Vogelstein model). During the initiation
phase, there will be little or no observable changes in cellular or
tissue morphology (Saracin, 2003; Vincent and Gatenby, 2008).

Promotion Phase
The promotion phase consists of changes in tumour suppressor
genes and oncogenes, which reduce the tumour cell response to
normal tissue proliferation constraints. This phase is a result of
prolonged exposure to carcinogens and increased susceptibility
of cells to promoters. Promoters are the factors that trigger the
promotion phase by promoting the proliferation of mutated cells.
The cells have to be irst initiated before it can take the eﬀect
and enter the promotion phase of carcinogenesis. Therefore,
the promoter has no eﬀect on uninitiated cells. In contrast to
initiation phase, promotion phase may be reversible. There are
two types of promoters: (1) speciic promoters, which act on
the speciic receptors, and (2) non-speciic promoters, which
alter gene expression without interaction with receptors. Wound
and inlammation are two examples of promoters that promote
tumour growth through an increase in local blood low. In the
Chronic Inflammation and Cancer 17

promotion phase, changes in the cellular or tissue morphology (self-

limited tumour growth) may be observed, but it is still reversible
(Saracin, 2003; Vincent and Gatenby, 2008).

Progression Phase
The third phase in carcinogenesis is the progression phase. During
this phase, the cells that have been promoted are transformed to
the malignant cells. One of the most important changes that take
place during the progression phase is karyotypic changes leading to
aneuploidy. Subsequently, these karyotypic changes will be coupled
with an increased growth rate, invasiveness, metastasis and an
alteration in biochemistry and morphology.

Stem Cell and Cancer

A stem cell is a special cell type that has both the ability to
reproduce exact copies of itself (also called self-renewal)
and the ability to change (differentiate) into one of the many
specialized cell types in the body. An alternative theory of cancer
development is the cancer stem cell theory. This theory explained
why in some tumours, more than one type of differentiated
cell co-exist within a single tumour. The stem cells can also be
predisposed to mutagen or carcinogen and undergo mutation.
It was also hypothesized that mutated differentiated cells can
“reverse backward” and acquire stem cell abilities (Carbone and
Pass, 2004; Laconi, 2008).
Cancer stem cells have the ability to produce cells of many
different types creating the mixture of cells found in a tumour.
Stem cells theory also explained why in many cancers, treatment
is dificult, drug resistance is common and recurrence rate is high.
Stem cells are more dificult to be killed than normal cell because of
their anti-apoptotic properties.

Chronic Inflammation and Cancer

Inlammation has long been associated with the development of
cancer. Chronic inlammation due to infection or to conditions
such as chronic inlammatory bowel disease is associated with
18 Genes and Carcinogenesis

up to 25% of all cancers. Chronic inlammation is an important

factor in tumour development due to three main factors (1) It
can alter the behaviour of cells, (2) Stimulation of the growth of
new blood vessels (angiogenesis) and (3) Tissue remodelling. A
recent study done by researchers at Ohio State University found
that inlammation stimulates a rise in levels of a molecule called
microRNA-155 (miR-155). This, in turn, causes a drop in levels
of proteins involved in DNA repair, resulting in a higher rate of
spontaneous gene mutations, which can lead to cancer (Laconi
et al., 2008).

Infection and Cancer

Infection is an established cause of many cancers in the human
being. The Lancer Oncology review, which looked at incidence rates
for 27 cancers in 184 countries, found four main infections that
contribute to cancer development are human papillomaviruses,
Helicobacter pylori and hepatitis B and C, account for 1.9 million
cases of cervical, gut and liver cancers. Some viruses and bacteria
have been linked with the initiation and promotion of tumour
growth. Viruses such as HPV and hepatitis B can cause cancer from
a direct eﬀect on cell division and mutation of gene. Microorganisms
such as Schistosoma, H. Pylori and Leishmania induce malignant
transformation through chronic inlammation.

Genetic Alterations in Cancer

Human Genome and Cancer
A complete constituent of the DNA, all genes and spaces in between
them are called genome. A Human Genome Project has identiied
every chemical base and discovered approximately 25,000
genes in the human genome (Liang et al., 2000; Roest et al., 2000;
Sachidanandan et al., 2001). These genes actually contribute to
only 3% of total components of genome. Genomics is the study of
genes and their functions, while cancer genomics refers to study
of human cancer genome. Cancer genomics enable scientists to
identify genetic alterations in cancer because all cancer cells have
some degree of alteration in gene expression. Formerly, most of
Genetic Alterations in Cancer 19

the information on genetic alterations in cancer was obtained

from the study done in leukaemia and lymphoma because in
these cancers, a single malignant cell is easier to be obtained, i.e.
peripheral blood or bone marrow.

Types of Genetic Alteration in Cancer

There are two types of genetic alterations in cancer: (a) germ line
mutations and (b) somatic mutations. In most cancers,mutation
of p53 occurs as a somatic mutation/event but germ line p53
mutations have been identiied in some families with rare
Li–Fraumeni syndrome. Individuals inheriting the germ line
abnormalities are at higher risk of developing malignancy as the
penetrance of most of these genes is of the order of 80%. Low
penetrance means a relatively small proportion of individuals
with the genetic abnormality develop cancer (Elmasry and Gayther,
2006). Malignant transformation is also attributed to epimutation.
Epimutation encompasses mechanisms that modify the inal outcome
of the genetic code without altering the underlying DNA sequence.
Three most important epigenetics processes that involved in the
normal control of genetic activities are DNA mehylations, histone
modiication and RNA-mediated silencing. Epimutation is when
these processes become deregulated such as hypermethylation or
hypomethylation of the DNA.

Germ Line Mutations

The mutations that occur in germ cells are also known as germ line
mutations. They may occur de novo (for the irst time) or may be
inherited from parents. Germ line mutations may involve all cells,
including tumour and normal cells, and they can also be passed to
descendant and cause cancer family syndromes such as familial
adenomatous polyposis and multiple endocrine neoplasia 2B. The
occurrences of germ line mutations can be identiied in the DNA
obtained from normal cells, e.g. peripheral blood sample.

Somatic Mutations
When the mutations occur in non-germ cells line, they are called
somatic mutations. Somatic mutations are usually located on
the autosomes, and in contrast to germ line mutations, somatic
20 Genes and Carcinogenesis

mutations are only found in the tumour cells but not in normal
cells. Therefore, they cannot be passed on to the descendants of
the patient.

Pathways of Carcinogenesis in Familial and Sporadic

Gynaecologic Cancers
Ovarian and endometrial cancer can develop as one of the
components of two familiar cancer syndromes, i.e. familial breast/
ovarian cancer and Lynch II syndromes.
Persistent infection by high-risk human papillomavirus
can initiate genetic alteration involving oncogenes and tumour
suppressor genes and subsequently malignant transformation of
epithelial cells leading to invasive cancer.
In sporadic ovarian cancer, environmental factors with
carcinogenesis operated indirectly by increasing the opportunity
of spontaneous mutation.

Specific Genetic Alterations Responsible in Carcinogenesis

In carcinogenesis, the malignant transformation is initiated by
various alterations in the genetic make-up of the cells.
Following are speciic genetic alterations responsible in
carcinogenesis:
(1) Translocations and inversions: An example is ovarian
adenocarcinoma (t(6;14)(q21;q24)).
(2) Chromosomal deletions are most common genetic altera-
tions in solid tumour. Deletion causes loss of function that
regulates cell proliferation and diﬀerentiation. The p53 tu-
mour suppressor gene-containing region of chromosome 17p
is deleted or mutated in a wide variety of human cancers.
(3) Frameshift mutations occur as a result of addition or loss of
a nucleotide(s).
(4) Splice-site mutation occurs within the non-coding regions
(introns) resulting in the production of non-functioning
proteins.
(5) Point mutations involved single base changes in DNA
sequences and the most common type of alteration in DNA.
(6) Gene’s ampliications are manifested as an increase in
the number of genes or number of chromosomes. Example:
Tumour Suppressor Genes 21

Ampliication of gene her-2/neu in advanced breast and

ovarian cancer.
(7) Aneuploidy: Gross changes in the number of chromosome
occur as tumour progress in the malignant process. In general,
tumours that remain localized without metastases have a
much lower incidence of aneuploidy.

Genes and Malignant Transformation

The genetic alterations can be acquired either from exposure to
exogenous carcinogens or inherited from parents. Three important
genes responsible in initiation and progression of cancer are mutated
proto-oncogenes, tumour suppressor genes and oncogenes. Proto-
oncogenes and tumour suppressor genes exist in normal cells and
involved in normal cellular functions. However, genetic alterations
to these genes can lead to cellular malfunctions and abnormal
proliferation of cells.

Proto-Oncogenes (e.g. c-src, c-abl and c-myc)

The proto-oncogene is a unit of genetic information that encodes a
speciic protein with speciic functions, including cells regulation
and diﬀerentiation. Actually, proto-oncogene is a normal genetic
constituent and it involves in normal cellular functions and growth
factors. These genes (growth promoting genes) are responsible in
carrying code for proteins that encourage and stimulate cellular
replication and control of cell division. Proto-oncogene expression
patterns altered (ampliication) in malignant tissue as compared
to normal tissue; for example, ampliication of c-myc was found in
small cell carcinoma cell lines.

Tumour Suppressor Genes (e.g. p53, PTEN,

BRCA1, BRCA2, APC, RB1)
Tumour suppressor genes are also a normal genes that slow down
cell division, repair DNA mistakes and tell cells when to die
(apoptosis). Their inactivation and deletion will promote tumour
growth. Most of the mutations of tumour suppressor genes are
22 Genes and Carcinogenesis

acquired, e.g. mutation of p53 has been found in more than 50%
of human cancers. Mutations of tumour suppressor genes can
also be inherited, e.g. mutation of APC gene leads to the familial
adenomatous polyposis. In some cancers, tumour suppressor
genes are normal structurally but not functionally. For example,
p53 in cervical cancer is blocked by E6 protein (from HPV).
There are two main categories of tumour suppressor genes: (1)
“Gatekeeper genes”; these genes are responsible to stop cell cycle
progression when DNA damage is detected. Example of “Gatekeeper
genes” is p53, (2) “Caretaker genes”, responsible in repairing the
damaged DNA during the cell cycle arrest. Example of “Caretaker
genes” is BRCA and Mismatch repair genes (MMR genes).

Oncogenes
Oncogenes are mutated proto-oncogenes. In other words, oncogene
is a carcinogenic form of proto-oncogene. In contrast to proto-
oncogene and tumour suppressor gene, oncogene does not exist
in normal cells. Most of the mutations involving oncogenes are
acquired, not inherited (e.g. chromosome rearrangement leads to a
formation of oncogenes called BCR-ABL that leads to chronic myeloid
leukaemia). Some mutations can also be inherited, e.g. inherited
mutation of genes called KIT causing hereditary gastrointestinal
stromal tumours (GIST). The comparisons between proto-oncogenes
and tumour suppressor genes are shown in Table 2.1.

Table 2.1 Comparison between proto-oncogenes and tumour suppressor

genes

Tumour suppressor
Properties Proto-oncogenes gene
Number of mutational One (one alleles Two (both alleles have
event required to mutated is suficient) to be defective) Recessive
initiate cancer Dominant
Germ line inheritance No Frequent

Action of mutated Gain in function Loss of function

gene
Somatic mutations Yes Yes
contribute to cancer
Other Genes Responsible in Carcinogenesis 23

Genetic alteration Point mutation, Point mutation, deletion

ampliications, gene
rearrangements.
Eﬀect on growth Active cell Negatively regulate
control proliferation growth-promoting gene

Tissue speciicity of Not speciic to certain Commonly tissue-speciic

mutation tissue (one oncogene
may be active in more
tissue type)

There are six categories of proto-oncogenes: (1) Transcription

factors; proteins that bind to DNA regulatory domains to cause
transcription of genes, (2) Growth factors; a soluble factors that
inluence the growth of neighboring cells or the releasing cell itself,
(3) Growth factor receptors; a transmembrane proteins that signal
intracellular molecules to carry out cell proliferation, (4) Chromatin
remodelers; proteins that alter chromatic structure to promote
or repress gene transcription, (5) Signal transducer; proteins that
carry out receptor signals to initiate gene transcription and (6)
Apoptosis regulators; apoptosis contro the net cell production.
Mutated proto-oncogenes will become oncogenes and this mutation
could be inherited or acquired from exposure to carcinogen.
There are many types of mutation involving proto-oncogenes
such as point mutation, deletions, insertion and chromosomal
translocation.

Other Genes Responsible in Carcinogenesis

Carcinogenesis involves very complex processes and poorly
understood. Studies have shown that there are actually more genes
involved in this process and alterations of one or more of these
genes can potentially lead to malignant transformation. Following
is the list of genes that have been linked with carcinogenesis:
(1) DNA repair genes
(2) carcinogen-activating genes
(3) carcinogen-deactivating genes
(4) cell cycle genes
24 Genes and Carcinogenesis

(5) cell cycle checkpoint genes

(6) cell death genes
(7) cell signalling genes
(8) cellular diﬀerentiation genes
(9) cellular senescence genes
(10) metastasis/invasion genes

Additional Facts about Oncogenes and Tumour

Suppressor Genes
• Studies have shown that the genes implicated in malignant
diseases were often altered forms of human genes (not
a virus genes) that were picked up by viruses during their
travels. Or in other occasions, this virus activated the “rest”
gene. This is so in “virus-induced” cancer.
• Majority of cancer is not virus-related and the only explanation
for this is a spontaneous mutation of proto-oncogene into
carcinogenic forms called oncogenes.
• Some viruses carry a speciic gene that is capable of
transforming the infected cell to become a malignant cell. This
type of transforming gene is termed as the viral oncogene.
Viral oncogene can cause alteration to proto-oncogene and
transforming it to become oncogene.
• Mutation of proto-oncogene can also be due to certain
chemical or physical elements.
• Knowledge about tumour suppressor genes and oncogenes
can assist researchers and clinicians in preventing and
treating cancers. Knowing about these genes can also
assist in predicting the risk of cancer recurrence and
prognosis.
• Detection of inherited form of mutated tumour suppressor
genes and oncogenes can also be useful information for
calculating the risk of developing a certain type of cancer.
• Genetic testing can be done to identify such mutation.
• Studies have shown that oncogene activation, resulting in
increased gene expression (ampliication) or the synthesis of
an altered gene product (mutation), plays an important role in
the process of malignant transformation.
Proposed Mechanism How Oncogenes Can Transform Normal Cells to Malignant Cells 25

• Women whose tumours contained ampliication or

overexpression of certain genes were more likely to develop
recurrence and had shortened overall survival. (1) Women
with breast cancer who produce too much of HER2/neu
proteins had the worse prognosis. Drugs such as trastuzumab
are designed to attack cells with too much HER2/neu.
(2) HER-2/neu oncogene has also been studied in ovarian
carcinoma. More aggressive lesions were more likely to
have Her-2/neu ampliication. Therefore, some oncogene
alteration can be used as a prognostic factor. (3) Expression
of c-myc proto-oncogene correlates with the proliferative
capacity of a number of malignant and non-malignant cell
types.
• Following are the examples how laboratory testing can
demonstrate the eﬀect on tumour suppressor gene:
(a) Injection of anti p53 monoclonal antibody to the mouse
cell line with wild type p53 will result in cell growth
being arrested.
(b) Rat embryonic ibroblast injected with p53 cDNA will
cause cell immortalization while if the same cell injected
with p53cDNA and activated Ha-ras will lead to the
transformation of the cell.

Proposed Mechanism How Oncogenes Can

Transform Normal Cells to Malignant Cells
The growth and division of normal cell within the normal tissue
is controlled largely by its surrounding. The normal cells listen
to and obey messages that originate from its neighbours in the
tissue. These messages may carry growth-stimulatory or growth-
inhibitory information/signal, which is conveyed largely by growth
factors that are released by some cells. This growth factor will
attach to the receptor in the surface of recipient cell. Each recipient
cell possesses complex machinery that enables it to receive these
signals, process and launch a growth program.
Proto-oncogene encodes many of the proteins in this process
that enables a normal cell to respond to exogenous growth factors.
However, when proto-oncogene becomes an oncogene, it required
26 Genes and Carcinogenesis

no external stimuli to activate this process. The oncogene forces

a cell to grow; even its surroundings contain none of the clues
normally required to provoke growth. However, in many occasions,
the oncogene cannot act alone. It needs other factors to be present
before it can be eﬀective. The other factor that equally important is
tumour suppressor genes.

Cancer Spread (Invasion and Metastases)

Malignant cells are deined by their ability to invade adjacent normal
structures and be disseminated or metastasize. Metastasis is a
process whereby there is spread of malignant cells from a primary
origin to a distant site. It can occur through a direct mechanism
or transfers of malignant cells via the blood streams or the
lymphatics. For metastases to take place, sequential process must
take place, which includes proliferation, angiogenesis, invasion,
embolisation, circulation and transport, adherence to vessel walls
and organs of distant site and extravasation of malignant cells at
the new site.
At the molecular level, interactions between the malignant cells
and host cells are an integral part of cancer growth created by more
stimulatory signals being produced as opposed to the inhibitory
signals. An example of stimulatory signals is vascular endothelial
growth factor A (VEGF-A), which induces angiogenesis by increasing
vascular permeability, stimulates endothelial cells proliferation
and migration thus enhancing cancer cells survival. Metastasis is
induced by activation of EGFR and through complex chain of events
eventually it produce enzyme metalloproteinases (MMP). MMP
degrade the collagen to allow cancer cell migrate towards vessels.
MMP also causes enzymatic action of the basement membranes
of the vessel to allow cancer cell enter into the blood stream or
lymphatic channels.

Apoptosis
Apoptosis or programmed cell death is one of mechanism by
which organism limits the growth and replication of the cellls.
Apoptosis occur in normal cell allows to removed the damaged cells
and maintain the balance between cell death and cell proliferation.
In average human adult, there are 50–70 billion cells undergo
Genetic Studies in Gynaecologic Malignancies 27

apoptosis everyday. Apoptosis is activated by two pathways: (1)

Death receptor or extrinsic pathway, by activation of tumour
necrosis factor receptor and (2) Mitochondrial or Intrinsic pathway
triggered by DNA damage. Both of these pathways ultimately
stimulated the set of enzymes called Caspases enzymes which
interact with inhibitor of apoptosis protein i.e., IAP and Bcl-2 family
proteins. Overexpressed of these anti-apoptotic proteins and loss
of function of pro-apoptotic proteins contributed to malignant
transformation.

Telomerase and Cancer

Telomere is a region of repetitive nucleotide sequences at each end
of a chromatid which protects the end of the chromosome from
deteriorating or fusion with neighboring chromosome. Telomere
control the number of DNA replication and cell division or it act
as “division counter”. The telomeres are consumed during cell
division and when it become shortened, this will blocks cell division,
therefore it acts as protective mechanism against uncontrolled
cell division. It has also been linked to the mechanism of human
cellular ageing. With this mechanism, cell is said to have their
own biological clock and it will programmed to die after 50–60
reproductions. Natural loss of telomere can be replenish by an
enzyme known as telomerase. Activation of telomerase enzyme
allows addition of new repeats at the end of chromosomes or
telomere. Therefore, telomerase prevents shortening of the DNA
during each cell reproduction. Telomerase is almost undetectable
in most normal somatic cells and increase telomerase expression
produces vulnerability of uncontrolled cell division and malignant
transformation. In contrast, inhibition of telomerase may limits
the growth of human cancer celis. Research on anti-telomerase or
telomerase inhibitor as one of the anti-cancer therapy is ongoing.

Genetic Studies in Gynaecologic Malignancies

Ovarian Cancer
In ovarian cancer, there are two types of genetic alterations
either inheritance (familial) or somatic mutation (sporadic) and
approximately, 90% of ovarian cancers are sporadic.
28 Genes and Carcinogenesis

Inherited genetic alterations are related to BRCA1 and BRCA2

genes. Altered BRCA1 (BRCA: breast cancer) may be passed from
one generation to another. BRCA1 mutant is associated with
breast and/or ovarian cancer.
Studies on families with breast–ovarian cancer syndrome
indicate that 52% are due to BRCA1, 32% due to BRCA2 and 16%
due to neither. Studies have suggested a lifetime risk of ovarian
cancer in BRCA1 carriers is 39% compared with 11% in BRCA2
carriers.
In sporadic ovarian cancer, BRCA1 mutation is detected in 7%
of cases. Some ovarian cancer is also associated with over–
expression of oncogene erb B-2 (her-2neu). Ampliication of erb
B-2 oncogene is observed in approximately 26% of primary
ovarian malignancies, and it correlates with a poor clinical outcome
(Elmasry and Gayther, 2006; Hogdall et al., 2003).
Beside BRCA 1 and BRCA 2 mutation, the other genetic
alterations discovered in ovarian cancer are ampliication of C-myc
(oncogene) observed in 30–50% of ovarian carcinoma and p53
mutations, found in 36–50% of cases. Overexpression of p53 is
noted in 50% of advanced ovarian cancer.
The other genetic mutations found are Ki-ras mutation occurs
in 48% of borderline tumour and 57% mucinous cystadeno–
carcinoma. PTEN (tumour suppressor gene) mutation has been
identiied in about 20% of endometrioid ovarian cancers but rare
in other histotype (Elmasry and Gayther, 2006).

Cervical Cancer
In cervical cancer, genetic alterations not associated with HPV
are possible such as loss of function of PTEN tumour suppressor
gene (mainly in adenocarcinoma and HPV negative tumour) and
reduced expression of p14 and p16. Human papillomavirus DNA
sequences have been found integrated near cellular oncogene
c-myc and n-myc in at least a few cervical cancer cell lines.
The molecular basis for diﬀerences in the oncogenic potential
between various strains of HPV remains unclear. Overexpressions
of proteins E6 and E7 are observed in cervical cancer cell lines.
Overexpression of proteins E6 and E7 is due to the deletion of E2 and
E4, which control the function of former oncogenes/oncoproteins.
E6 and E7 proteins will bind to p53 and Rb protein leading to
Genetic Studies in Gynaecologic Malignancies 29

inactivation and subsequently cell transformation. Despite powerful

association between HPV infection and cervical cancer, the genetics
of cervical cancer remains poorly understood. For details on
carcinogenesis in cervical cancer, see Chapter 6.

Vulvar Cancer
Human papillomavirus types 16 and 18 have been identiied in
vulvar intraepithelial neoplasm and invasive squamous carcinoma
of the vulvar (mainly in younger and baseloid subtype). P53
inactivation (with or without HPV) is observed in 50–80% of cases
of squamous cell carcinoma of the vulva. Loss of functions on PTEN
and CDKN2A genes are also identiied in 60% and 68% of vulvar
carcinoma respectively.

Endometrial Cancer
Approximately, 10% of endometrial cancers have a hereditary
basis as part of Hereditary Non-polyposis Coli Syndrome (HNPCC)
or Lynch II syndrome. Endometrial cancer has it pre-invasive
stage (hyperplasia); however, compared with other gynaecological
cancers, particularly cervical and ovarian cancer, the knowledge
related to carcinogenesis and genetic alterations in endometrial
cancer is still limited. Small proportion of endometrial cancers
occurred as part of the Lynch II syndrome (HNPCC). Defective MMR
genes were identiied in 85% of HNPCC-associated endometrial
carcinoma. Individual with germ line MSH6 mutations are more
likely to develop endometrial cancer than patients with MLH1
mutations.
Majority of endometrial cancers are sporadic, i.e. due
to somatic mutations. Somatic mutations demonstrated in
sporadic endometrial cancer include microsatellite instability in
17–32%, mutations of tumour suppressor genes such as PTEN
(37–61%) and p53 and mutations of proto-oncogene KRAS. PTEN
mutation/deletion is more common in endometrioid type. Loss of
expression of oestrogen and progesterone receptors correlates
with poor prognosis (Elmasry and Gayther, 2006).
The other genetic alterations noted in endometrial cancer
is mutations of P53 tumour suppressor gene demonstrated in
10–20% of endometrial cancers, mainly in advanced stage and in
30 Genes and Carcinogenesis

Type 2 endometrial cancers such as clear cell and serous carcinoma.

Mutations of Ki-ras genes are detected in 19% of endometrial
cancers and overexpression and ampliication of ErbB2 oncogenes
were reported in 10–30% of cases mainly in serous papillary
tumour.

Clinical Implications of Molecular Genetics in

Gynaecological Cancer
The knowledge about molecular genetics and genetic alterations
in cancers, including gynaecological cancers will beneit patients
in many ways. Genetic analysis will allow accurate assessment of
familial cancer risk. Molecular genetic can provides a basis for design
cancer preventative techniques such as (a) genetic analysis may
help to identify pre-malignant conditions amenable to conventional
therapy, tb) in familial cancer syndromes, it may be possible to
transfer normal copies of the abnormal gene (e.g. p53, BRCA 1) to the
tissue at risk using tissue speciic viral vectors, (c) development of
Vaccine, e.g. HPV vaccine and (d) possible to generate an immune
response to viral transforming proteins, i.e. E6, E7 using either
a protein vaccine or presentation of these antigens in a viral or
bacterial vector.
The knowledge can also assist in the detection of cancer at an
early stage, example (a) screening of ovarian cancer based upon
genetic markers via identiication of gene products in peripheral
blood, (b) protein products of abnormal genes involved in
carcinogenesis can be detected in the serum, e.g. protein product
of M-CSF gene increase in ovarian cancer and (c) endometrial
sampling can be used for genetic analysis to detect mutation of
gene associated with endometrial cancer.
The genetic markers can also be valuable as prognostic
indicators. The behaviour of a malignancy is a consequence of
the complex interaction of all of the genetic alterations, which
have accumulated during the process of carcinogenesis, e.g.
erbB2 ampliication is associated with reduce survival in ovarian
cancer. Genetic study has also found that p53 mutation does not
correlate with prognosis. Studies have shown that loss of
heterozygosity (LOH) on chromosome 3 or 11 results in high-
grade malignancy, while LOH on chromosome 6 is consistent with
Proteomics and Cancer 31

a well-diﬀerentiated phenotype (ovarian cancer). Interestingly,

pattern of LOH is an independent prognostic indicator for ovarian
cancer.
Molecular genetics are also important in the research of
gene therapy. There are two types of gene therapy namely ex
vivo approaches of gene therapy and in situ approaches of
gene therapy. In ex vivo approaches, the cells from an individual
are removed and manipulated in vitro, the altered cells are then
re-injected into the body to trigger an immune response. Example
of this approach is removing tumour cells from patients with
cancer and inserting genes encoding cytokines or MHC clonal Ag
in vitro to enhance their immunogenicity then re-injecting it into
cancer patients to stimulate an immune response. Immune system
will then acts against respective tumour antigens and destroy
cancer cells. In situ approaches of gene therapy involves replacing
a normal copy of tumour suppressor gene, e.g. p53 or suppression
expression of the product of an oncogene, e.g. K-ras. This is based
on evidence inserting a wild type p53 and anti sense K-ras into
the tumour cells with abnormalities of these genes, which had
shown to suppress a tumourigenicity.

Proteomics and Cancer

There are four causes of genetic message alterations in cancer:
(1) DNA mutation
(2) chromosomal aberrations
(3) epigenetic modiication
(4) protein–protein interaction
Generally, 2% of diseases are monogenic (caused by mutation
of single gene) and 98% of major diseases involve multiple
genes (polygenic). The proteins are the end product of genes
and proteomics is the analysis of the protein complement of the
genome. Proteomics encompasses knowledge of the structure,
function and expression of all proteins as a function of time, age,
state and external factors (Baak, 2003; Li et al., 2002).
There are approximately 100,000–10 millions proteins,
but only a small percentage of it had been studied. The study of
these proteins is a step forward and will provide new molecular-
biological insights, tumour markers and drugs.
32 Genes and Carcinogenesis

There are various methods of proteomics techniques (method

to analyze protein) such as 2D poly-acrylamide gel electrophoresis
(2D-PAGE), high-performance liquid chromatography (HPLC),
capillary array (CA), yeast two-hybrid system (Y2HS), protein
microarrays, luorescence resonance energy transfer (FRET) and
others (Baak et al., 2003; Li et al., 2002).
Potential role of proteomics in cancer are for detection,
diagnosing, monitoring (including identiication of new
biomarkers) and treatment. An example of the application of
proteomic in detection of cancer is the study by Li and colleagues
in which they used a proteomic and bioinformatic approach to
identify biomarkers for breast cancer with SELDI-TOF-MS; they
discovered three discriminatory biomarkers with sensitivity of
93% and speciicity of 91%.
Researchers hope that proteomics research will help ind new
ways to diagnose cancer early, identify the best screening and
treatment method for speciic type of cancer and determine the
best way to monitor patients during and after treatment.

References
Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed.
New York: Garland Press, 2002.
Baak JPA, Path FRC, Hermsen MAJA, Meijer G, Schmidt J, Janssen EAM.
Review genomics and proteomics in cancer. Eur J Cancer 2003;
39: 1199–1215.
Bookman MA, Darcy KM, Clarke-Pearson D, et al. Evaluation of monoclonal
humanized anti-HER2 antibody, trastuzumab, in patients with
recurrent or refractory ovarian or primary peritoneal carcinoma
with overexpression of HER2: a phase II trial of the Gynecologic
Oncology group. J Clin Oncol 2003; 21: 283–290.
Carbone M, Pass HI. Multistep and multifactorial carcinogenesis: when
does contributing factor become a carcinogen? Semin Cancer Biol
2004; 14: 399–405.
Elmasry K, Gayther SA. Genetic mutations in gynaecological cancers. Rev
Gynaecol Perinat Pract 2006; 6: 115–125.
Hogdall EV, Christensen L, Kjaer SK, et al. Distribution of HER-2
overexpression in ovarian carcinoma tissue and its prognostic
value in patients with ovarian carcinoma: from the Danish MALOVA
Ovarian Cancer Study. Cancer 2003; 98: 66–73.
References 33

Laconi E, Doratiotto S, Vineis P. The microenvironments of multistage

carcinogenesis. Semin Cancer Biol 2008; 18: 322–329.
Li J, Zhang Z, Rosenzweig J, Wang YY, Chan DW. Proteomics and
bioinformatics approaches for identiication of serum biomarkers
to detect breast cancer. Clin Chem 2002; 48: 1296–1304.
Liang F, Holt I, Pertea G, et al. Gene index analysis of the human genome
estimates approximately 120,000 genes. Nat Genet 2000; 25:
239–240.
Roest CH, Jaillon O, Bernot A, et al. Estimate of human gene number
provided by genome-wide analysis using Tetraodon nigroviridis
DNA sequence. Nat Genet 2000; 25: 235–238.
Sachidanandan R, Weissman D, Schmidt SC, et al. A map of human genome
sequence variation containing 1.42 million single nucleotide
polymorphisms. Nature 2001; 409: 928–933.
Saracin A. An overview of mechanisms of mutagenesis and carcinogenesis.
Mutat Res 2003; 544: 99–106.
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a
monoclonal antibody against HER2 for metastatic breast cancer
that overexpresses HER2. N Engl J Med 2001; 344: 783–792.
Sonnenschein C, Soto AM. Review: Theories of carcinogenesis: an emerging
perspective. Semin Cancer Biol 2008; 18: 372–377.
Tili E, Michaille J-J, Wernicke D, Alder H, Costinean S, Volinia S, Croce
CM. Mutator activity induced by microRNA-155 (miR-155) links
inlammation and cancer. Proc Natl Acad Sci 2011; 108 (12): 4908
DOI: 10.1073/pnas.1101795108.
Vincent TL, Gatenby RA. An Evolutionary model for initiation, promotion
and progression in Carcinogenesis. International. J Oncol 2008;
32: 729–737.
This page intentionally left blank
Chapter 3

Cancer of Vulva

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
36 Cancer of Vulva

Introduction to Anatomy of Vulva

Vulva
The vulva includes mon pubis, labia minora, labia majora, clitoris,
vestibule, glands (Bartholin’s glands, skene glands and minor
vestibular glands) and perineal body. The other term for vulva is
pudendum. Vulva is bounded by anterior abdominal wall and mon
pubis superioly, labia-crural fold at a medial thigh laterally and anus
posteriorly (Fig. 3.1).

Figure 3.1 The female external genitalia. A: mons pubis, B: prepuce of

clitoris, C: glans of clitoris, D: urethral meatus, E: vestibule, F:
hymen, G: vagina opening, H: fourchet, I: perineum, J: anus, K:
labia-crural fold, L: labia majora, M: labia minora.

The mons pubis is the superior border of the vulva described

as directly anterosuperior to the pubic symphysis. This area is
covered by skin where sexual hair development occurs at the time
of puberty.
The labia majora form the lateral boundaries of the vulva.
They are composed of folds of adipose and ibrous tissue. The labia
majora correspond to the scrotum in male. Labia majora fuse
anteriorly into the mons pubis and posteriorly they terminate
3–4 cm in front of the anus where they are united by the posterior
commissure or fourchette. The labia majora is covered by skin
contains of stratiied squamous epithelium.
Introduction to Anatomy of Vulva 37

The labia minora or nymphae consists of two folds of connective

tissue which has little or no adipose tissue. Labia minora is situated
between the labia majora and extending from the clitoris to the
fourchette. Labia minora is divided into two parts anteriorly, one
part passes over the clitoris to form the prepuce, while the other
part joins beneath the clitoris to form a frenulum. Posteriorly, labia
minora blend with the medial surfaces of the labia majora. The
skin and mucosa covering the labia minora are rich in sebaceous
glands.
The clitoris is situated at the middle and upper part of the
labia minora. The clitoris is an erective structure, homologous
with the penis. The clitoris is made up of two crura, which attach
to the periosteum of the ischiopubic rami. It has two small muscles
called ischiocarvernosa, which are inserted into the crura of the
clitoris. The average length of the clitoris is 1.5–2.0 cm and about
1 cm width in adult female. Clitoris is innervated by the terminal
branch of the pudendal nerve known as dorsal nerve of the clitoris.
The vestibule is the area (triangular shape) between the
labia minora and behind the gland of clitoris and extends to the
fourchette posteriorly. The vestibule is where the urethral meatus
and vaginal oriices are found. It also gives rise to the opening of
the glands, i.e. Skene glands and Bartholin’s glands bilaterally. It
is lined by non-keratinized squamous epithelium. The squamous
cells in the epithelium are well glycogenated and resemble the
vaginal or cervical squamous cells. The structures found in the
vestibule include the Bartholin’s glands (Major vestibular glands),
the minor vestibular glands, Skene’s glands (periurethral gland),
the opening of the urethra and vaginal oriice. The external urethral
oriice is a sagittal cleft situated about 2.5 cm behind the clitoris.
The total length of female urethra is from 3.5 to 5.0 cm.
The hymen is a thin mucous membrane partially covered the
vaginal oriice. In other words, the opening of the vaginal oriice is
actually a cleft between the hymen. The hymen has many shapes
and when stretched, the posterior part is the broadest. It can be
absent or form a complete septum across the vaginal opening and
this condition is known as imperforate hymen. When the hymen is
ruptured, the remaining part will form rounded elevations known
as carunculae hymenales. The shallow depression between the
hymen and the frenulum of the labia is called navicular fossa.
38 Cancer of Vulva

The other structure found in the vulva is the vestibular bulbs

or bulbus vestibuli. The vestibular bulbs are two masses of erectile
tissue that lie deep to the bulbocavernosus muscles bilaterally, on
each side of the vagina oriice. Each mass measures approximately
2.5 cm in length and united to each other anteriorly by a median
band known as pars intermedia. Their posterior end is in contact
with the Bartholin’s gland. The deeper surface of vestibular bulb is in
contact with fascia of pelvic diaphragm, while supericially they are
covered by the bulbocavernosus.
Skene’s glands or periurethral glands are glands that secrete
the mucous for lubrication at the opening of the urethra. The duct of
this gland is about 0.5 to 1.5 cm long and located in the loor of the
terminal end of the urethra and open just within or external to the
meatus.
Batholin glands (or greater vestibular glands) are two small
mucus secreting glands situated within a subcutaneous tissue of the
posterior labia majora, have ducts that open onto the posterolateral
portion of the vestibule. Batholin glands are homologous of
bulbo-urethral glands in male. There are two Bartholin’s glands,
one on each side of the vaginal oriice in contact with the posterior
end of each lateral mass of the bulb of the vestibule. It has a 2 cm
duct opening immediately lateral to the hymen and medial to the
posterior part of labia minora. It secretes mucus for lubrication of
the vagina.
The minor vestibular glands are small glands corresponding to
the penile glands of Littre in male. These glands are located within
the vestibule and lined by a single layer of columnar cells secreting
a mucin.
The other glands located in the vulva are apocrine glands,
sebaceous glands and sweat glands. Sweat glands are primarily
involved in heat regulation.

Blood Supply and Innervation of the Vulva

The main blood supply to a vulva is from the internal pudendal
artery (terminal branch of anterior division of internal iliac artery)
and external pudendal artery from a femoral artery. Internal
pudendal artery supply ischiocavernosus, bulbocavercosus muscle,
perineal body, urethra and clitoris. External pudendal artery supplies
labia majora and their deep structures.
Introduction to Anatomy of Vulva 39

Figure 3.2 Anatomy of the right hemipelvis and groin. A: common iliac
vein, B: common iliac artery, C: genito-femoral nerve, D:
internal iliac vein, E: internal iliac artery, F: external iliac vein,
G: external iliac artery, H: inguinal ligament, I: round ligament,
J: right inguina-femoral lymph nodes K: pectineus muscle, K:
femoral artery, L: adductor longus muscle, M: sartorius muscle,
N: femoral vein, O: femoral artery, P: femoral nerve, Q: right
lateral cutaneous nerve of thigh, R: iliacus muscle, S: psoas
major muscle.

The mons pubis and upper labia majora are supplied by

ilioinguinal nerve (L1) and genitofemoral nerve (L1-2), while
lower vagina, labia, clitoris, perineal body and their supporting
structures are supplied by pudendal nerve (S2-3).

Lymphatic Supply of the Vulva

Lymphatic drainage of the vulva is mainly to supericial inguinal
lymph nodes (10 nodes in a triangle below, along the saphenous
vein). Some part of clitoris and middle structures drain to the pelvic
lymph nodes (obturator and iliac nodes). Generally, the lymphatic
drainage of one side of the vulva does not cross the midline. The
midline is deined as 1 cm within an imaginary line from the clitoris
to the anus.
40 Cancer of Vulva

There are two groups of inguinal lymph nodes: (a) supericial

inguinal lymph nodes (subcutaneous lymph nodes situated between
Camper’s fascia and cribriform fascia) and they are further sub-
divided into oblique and vertical groups; (b) deep inguinal lymph
nodes (within the cribriform fascia and medial to the femoral vein
and runs towards the femoral canal).
Supericial inguinal lymph nodes drain into the deep inguinal
lymph nodes and subsequently into the external iliac lymph nodes.
Direct spread of the cancer to the deep inguinal nodes without
metastasis to the supericial group has been documented, although
it is uncommon, representing in less than 5% of cases. Furthermore,
10–20% of lymphatic low from the supericial inguinal group
travels directly to the pelvis without passage through the deep
inguinal group.
The lymphatic vessels draining the midline structures of the
vulva decussate and drain to the bilateral groin nodes. The lymphatic
vessels of the anterior vulva also drain directly into the deep
nodes—accounting for the direct metastasis of cancer to the deep
nodes without involving the supericial nodes in less than 5% of
patients.
Some part of clitoris and middle structures drain to pelvic
lymph node (obturator, iliac nodes). Approximately 10–20% of
lymphatic low from the supericial inguinal group travels directly
to the pelvis without passing through the deep inguinal group.

Figure 3.3 Lymphatic drainage of the each side of vulva.

Lichen Sclerosus 41

Premalignant Vulvar Lesions

Squamous cell carcinoma is the most common vulvar carcinoma.
There are two types of squamous cell carcinoma of the vulva:
(a) HPV-related squamous cell carcinoma and (b) non-HPV-related
squamous cell carcinoma (Lyengar and Acheson, 2008; Zeaps et al.,
1990).
In some textbooks, pre-malignant squamous cell carcinoma
of vulva is also classiied into HPV related and non-HPV related.
Pre-malignant condition of the vulva is also known as vulva intra–
epithelial neoplasm (VIN). The non-HPV related VIN is more common
and often aﬀects older women with histology of diﬀerentiated
keratinizing squamous cell carcinoma. HPV-related VIN is a pre-
malignant condition of HPV-related squamous cell carcinoma
of the vulva. This type of lesions is caused by high-risk HPV,
predominantly HPV 16 and 18 and often it is also seen adjacent
to approximately 30% of squamous cell carcinoma of the vulva
(Lyengar and Acheson, 2008; Zeaps et al., 1990). Twenty-two
percent of patients with HPV-related VIN have concurrent cervical
intraepithelial neoplasia (CIN). HPV-related squamous cell
carcinoma of vulvar occurs in the younger age group of less than
50 years old. The diagnosis of VIN must be made by biopsy
preferably using keyhole biopsy or punch biopsy from the edge of
the lesion, including a small piece of normal tissue.

Lichen Sclerosus
Lichen sclerosus (LS) is a non-HPV-related premalignant condition
of the vulva. The majority of women with this condition are aged
50–70 years old; however, lichen sclerosis can occur at all ages.
Studies have shown that 7–13% of women with chronic vulvar
symptoms were found to have lichen sclerosis (Carli et al., 1995).
The exact aetiology of lichen sclerosis is unknown. Hormonal
factors have been suggested as a possible aetiology of lichen
sclerosis because the highest incidence of this condition was
observed in patients with a low oestrogen level (prepubertal girls
and postmenopausal women) (Carli, et al., 1995). There was also
a strong association between lichen sclerosis and autoimmune
disorders, e.g. vitiligo, alopecia areata, pernicious anaemia and
42 Cancer of Vulva

others. One third of women with LC are asymptomatic while others

may be presented with chronic itchiness, pain, burning sensation,
dyspareunia, bleeding and blistering (Carli et al., 1995). The lesions
are white plaques and papules with areas of erythema, ecchymosis,
hyperkeratosis, pallor, excoriation and ulceration. In extreme
lesions, the skin became scarring, labia minora disappeared and
vaginal introitus became narrower. The classical histological
features of LS are thinned epidermis, loss of a normal rete pegs,
oedema of the dermis, basal layer vacuolor changes and paucity of
melanocytes. Long term followed up of women with lichen sclerosis
revealed 2–6% risk of malignant change to squamous cell carcinoma
of the vulva. Some postulated that LS would progress to VIN and
subsequently squamous cell carcinoma of the vulva.

Treatment for Lichen Sclerosus

Generally, there is no cure for lichen sclerosus. In some cases,
spontaneous resolution is possible. Medical treatment is the irst
line treatment and the most eﬀective medical treatment is topical
superpotent corticosteroid ointment (Carli et al., 1995). The
other medical treatments are topical testosterone (controversial),
retinoids (may be indicated in refractory LS even with steroid
treatment), tacrolimus, pimecrolimus, calcipotriol, oxitomide and
others. Surgical treatment can be oﬀered to patients with lichen
sclerosis. Local excision, laser ablation, cryotherapy and even
vulvectomy are acceptable in selected patients. It is also important
to provide supportive care by treating problems related to LS such
as bacterial infection (antibiotic), fungal infection (anti-fungal),
vulvodynia (topical xylocaine), vulvar atropy (local oetrogen cream)
and itchiness (anti-histamine).

Extramammary Paget’s Disease of Vulva

Paget’s disease is a rare neoplasm of apocrine-bearing skin. Paget’s
disease of the nipple was irst described by James Paget in 1874 and
15 years later extramammary Paget’s disease aﬀecting the scrotum
and penis was reported by H. Radchliﬀe Crocker (Crocker, 1889;
Paget, 1874). First case of extramammary Paget’s disease involving
the vulva was reported by Dubreuith in 1901 (Chanda, 1985; Chang
Extramammary Paget’s Disease of Vulva 43

et al., 1996). The most common site of extramammary Paget’s disease

is a vulva, scrotum and perianal [Link] Paget’s
disease has also been described in other apocrine gland-bearing
areas such as axilla, groin, thigh, eyelid, external ear and nose. Some
described this condition as an epidermal adenocarcinoma extending
into the contiguous epithelium of the hair follicles and eccrine sweat
ducts. It may also be described as an adenocarcinoma in situ of the
vulvar skin.
Paget’s disease involving nipple always associated with
underlying malignancy of the breast. Extramammary Paget’s
disease in contrast may or may not be associated with underlying
malignancy.

Table 3.1 Comparison between Paget’s disease, Melanoma and VIN III
based on immunostaining.

Staining Paget’s disease Melanoma VIN III

PAS with diastase + – –
Mucicarmine + – –
CAM 5.2 + – –
Pankeratin + – +
S-100 – + -
Vimentin – + –

Extramammary Paget’s disease of the vulva is a rare condition,

affecting mainly white women aged 50–80 years with the peak
incidence of 65 years (Chanda, 1985; Chang et al., 1996; Levy et al.,
2010). Most common symptoms are pruritus, burning, irritation,
pain and swelling. Clinically, the lesion appeared well-demarcated
erythematous or leukoplakic plaques. Typical appearance is “cake-
icing” effect (whitish top and hyperaemic below). There may be
crusting, scaling and ulceration. Histologically, Paget’s cells are large
intraepithelial cells with abundant cytoplasm and large vesicular
nuclei. There may also present with hyperkeratosis, parakeratosis
and acanthosis. Histochemistry study can differentiate Paget’s
disease from malignant melanoma, VIN III and Bowen’s disease
(Table 3.1). Paget’s cells stain positively with periodic acid Schiff
reaction and mucicarmine. If this failed, immunohistochemical
staining for CAM 5.2, EMA, Cytokeratin 7 and GCDFP-15 are all
44 Cancer of Vulva

positive in Paget cells (Black et al., 2007; Goldblum and Hart, 1998).
Ten to ifteen percent of women with Paget’s disease of the vulva
have underlying primary adenocarcinoma and 30% of patients
will later have adenocarcinoma at other site such as breast, colon,
rectum and upper female genital tract (Black et al., 2007; Chanda,
1985).

Treatment for Non-mammary Paget’s Disease

The most acceptable mode of treatment is surgery. Excision of
the lesions must be complete and with adequate margin, during
surgery, the margin must be sent for frozen section to ensure free
from disease because recurrence rate is high. Recurrence rate after
surgical treatment is up to 32–38% despite negative surgical margin.
Patients with positive margin will have higher risk of recurrence
(up to 70% in the study done by Black, et al.). Radiotherapy is
reserved for selected patients who are unit for surgery, with
persistent disease despite surgery and those who refuse surgical
intervention (Luk et al., 2003). Topical 5-Fluorouracil may be
useful for symptomatic relief or as a cytoreductive measure prior
to surgery. Topical 5-FU is not curative because it cannot penetrate
deep enough.

Vulva Intraepithelial Neoplasm

Vulva intraepithelial neoplasm or VIN is characterized histologically
by an abnormal proliferation of cells with an increased nuclear:
cytoplasmic ratio, nuclear hyperchromasia, pleomorphism and
mitosis involving the epithelium of the vulva. The incidence of VIN
is increasing and 20% of aﬀected women are younger than 50 years
old.
The International Society for Study of Vulval Disease (ISSVD)
2004 has classiied VIN into two groups namely (a) Usual type (HPV-
related) VIN, which is subdivided into warty type, basaloid type
and mixed type and (b) Diﬀerentiated type VIN (Non-HPV related).

Usual Vulvar Intraepithelial Neoplasia

Usual type vulvar intraepithelial neoplasia or HPV-related VIN was
formerly known as Bowen’s disease. This lesion is closely related
Treatment of Vulva Intraepithelial Neoplasm 45

to human papillomavirus infection. Formerly, ISSVD classiied VIN

into VIN 1, VIN 2 and VIN 3 similar to classiication of preinvasive
lesions of the cervix (CIN) (Sideri et al., 2005). In 2003, ISSVD
decided to abolish the three grades system (VIN 1, 2, 3) because
the behaviour of VIN is not similar to CIN. Vulva intraepithelial
neoplasm 1 is not considered as premalignant lesions. Vulva
intraepithelial neoplasm 2 and VIN 3 are grouped under usual
VIN, which is further subdivided into warty VIN, Basaloid VIN and
Mixed VIN. According to ISSVD 2004 classiication, the lesion
previously known as VIN simplex is now classiied as differentiated
VIN (Sideri et al., 2005).
The incidence of usual VIN is approximately 5 per 100,000
women per-year and increasing worldwide due to Human
Papillomavirus Infection. Usual VIN relatively more common in the
younger age group as compared to differentiated VIN (Jones et al.,
2005; Joura, 2002; Lara, 2004). Almost 100% of usual VIN is due
to HPV infection, mainly HPV 16 and 18. The most common sites of
usual VIN are labia majora, labia minora and posterior fourchette.
Pruritus is the most common presenting complaint (60%). Other
symptoms are pain, ulceration and dysuria. Approximately, 20%
of patients do not have any speciic symptoms.
Clinically, the lesions are either whitish, erythematous
plaques or pigmented. Coexisting preinvasive lesions of vagina,
cervix and anus are seen in 25–66% of cases. Histologically the
epidermis is thickened and accompanied by a hyperkeratosis
and/or parakeratosis. The epithelial cells appeared enlarged, high
nuclear:cytoplasmic ratio, nuclear hyperchromasia and numerous
mitotic igures. There is also koilocytes, which represent HPV-
infected epithelial cells. Warty type of usual VIN presented with
warty lesions or condylomatous appearance while basaloid type
presented with lat and non-papillamatous lesions (Jones et al.,
2005; Joura, 2002). The malignant potential for usual VIN is lower
than differentiated VIN. Metanalysis by (van Seters et al., 2005)
and study by Jones et al. have found that the risk of progression to
invasive cancer was 3.3% and 4.2%, respectively.

Treatment of Vulva Intraepithelial Neoplasm

The treatment of VIN is not always easy. The diagnosis of VIN must
be performing with biopsy preferably using keyhole punch biopsy,
46 Cancer of Vulva

with correct procedure the diagnosis of VIN can be made accurately

and invasive lesions can be ruled out. The aims of treating the
VIN are (a) to obtain a full tissue biopsy and exclude co-existing
invasive disease, (b) to relief the symptoms, (c) to restore of
normal epithelial architecture, (d) to reduce the risk of malignant
progression and (e) to cure the disease. Treatment of VIN can be
divided into surgical and medical treatment.

Surgical Treatment for Vulva Intraepithelial Neoplasm

Wide local excision is the treatment of choice; in extensive disease,
vulvectomy may be indicated. Excision can also be done using
laser or loop electrosurgical excision procedure (LEEP). Laser
vaporization is a local destructive technique indicated in a patient
with extensive or multifocal lesions not amenable to excisional
treatment. Laser vaporization, however, will not provide tissue for
histological diagnosis. Prior to laser vaporization, invasive disease of
vulvar must irst be excluded by thorough colposcopic examination
and biopsy of suspicious areas (Joura, 2002).

Medical Treatment for Vulva Intraepithelial Neoplasm

Topical 5-luorouracil is eﬀective only in small proportion of
patients. The response rate is low (30%) and high failure rate (58%).
Imuiquimod act indirectly to inhibit HPV replication through up-
regulation of cell mediated immunity (Mathiesen et al., 2007). Data
on imuiquimod is limited, complete response rate was reported in
47–80% of patients. Interferon therapy has been tried in patients
with VIN but due to limited evidence and high cost, its use is not
widely accepted. The side-eﬀects of imuiquimod include burning,
irritation and erythema. Antiviral drug such as Cidofovir may be
potentially useful in the treatment of VIN but the data is still very
limited (Joura, 2002).

Photodynamic Therapy for Cervical Intraepithelial

Neoplasia
Photodynamic therapy is a treatment that uses a drug, called pho-
tosensitizer or photosensitizing agent and a particular type of light
(Martin, 2002). When photosensitizers are exposed to a speciic
Differentiated Vulva Intraepithelial Neoplasm 47

wavelength or light (3–4 hours after application of photosensitiz-

ing agent), they produce a form of oxygen that kills nearby cells.
In VIN, topical 5-aminolaevulinic acid was used as photosensitizer
agent. Studies involving 100 patients have shown a response rate
of 40%, best in small unifocal lesions. The type of lesions and the
optimum dose of light will determine the success of treatment. PDT
did not induce ulcers or scar formation; however, pain over the
treatment site is a known problem (Joura, 2002; Martin, 2002).

Differentiated Vulva Intraepithelial Neoplasm

Differentiated vulval intraepithelial neoplasm (Differentiated
VIN) was formerly known as intraepithelial carcinoma of simplex
type. Differentiated VIN is not related to HPV infection and occurs
mainly in postmenopausal women with mean age of 67 years (Jones
et al., 2005; Sideri et al., 2005). It may be associated with lichen
sclerosis and has close relation with squamous cell hyperplasia.
Differentiated VIN is more commonly seen adjacent to lichen
sclerosis or invasive vulvar carcinoma and it rarely exists alone.
On histology, cellular abnormalities seen in differentiated VIN are
less prominent as compared to usual VIN, and it can be mistaken

Figure 3.4 Vulva intraepithelial neoplasm 3. VIN can be presented as

hyperpigmented skin lesion as shown in A.
48 Cancer of Vulva

easily with a benign dermatosis or epithelial hyperplasia (Sideri

et al., 2005). Clinically, it can be presented as an area of red lesions
(ulcerative or erythematous) or white-grey discoloration of the
skin. Differentiated VIN is characterized by an increased amount
of eosinophilic cytoplasm in dysplastic cells immediately above the
basal cell layer and is said to be more likely to progress to invasive
cancer as compared to lichen sclerosis and usual VIN (Sideri et al.,
2005). Treatment for differentiated VIN is mainly by radical excision
and medical treatment is generally ineffective (Jones et al., 2005;
Sideri et al., 2005).

Vulvar Cancer
Vulvar cancer accounts for about 3–5% of all female genital cancers
and 1% of all malignancies in women. In Western countries, the
average annual age-adjusted incidence is 1.2 cases per 100,000
women-years (Ghurani and Penalver, 2001; Mutch, 2009).
Approximately, 75% of women with vulvar cancer are older than
60 years old. The incidence is increasing due to increase in life
expectancy and increase in prevalence of HPV infection. Since
vulvar cancer is rare and is not monitored by the World Health
Organization, the global incidence of this disease in not precisely
known. The American Cancer Society has reported a total of 3460
cases of vulvar cancer in 2008 (Mutch, 2009).
Squamous cell carcinoma of vulvar is the most common type
accounting 90% of all vulvar cancer. There are ive variants of
squamous cell carcinoma of the vulva:
(1) adenoid squamous cell carcinoma
(2) squamous cell carcinoma of giant cells
(3) sebaceous cell carcinoma
(4) spindle-cell squamous cell carcinoma
(5) squamous cell carcinoma with sarcoma like stroma
Second most common vulvar cancer is malignant melanoma.
Other histological type of vulvar cancer is adenocarcinoma of
Bartholin’s gland, adenocarcinoma related to Paget’s disease and
sarcoma. Squamous cell carcinoma of vulvar can be divided into two
groups, i.e. HPV-related and non-HPV-related vulvar cancer. Younger
Patterns of Spread in Vulvar Cancer 49

age women tend to be diagnosed as HPV-related vulvar cancer. In

older women with non-HPV-related vulvar cancer, the aetiology of
this carcinoma is attributed to chronic irritation; immunological
problems or other poorly understood co-factors.
Following are the factors associated with risks of developing
squamous cell carcinoma of vulvar:
(a) smoking; increases the risk four- to ivefold
(b) HPV infection, recent or past infection
(c) women with genital warts; relative risk of 14.5 for vulvar
cancer
(d) women with multiple sexual partners
(e) immunosuppression, HPT, DM and obesity
Approximately, 40% of patients with vulvar cancer were
diagnosed at advanced stage (3, 4) and 70% of vulvar cancers occur
in labia while, 15–20% involved clitoris and perineal body.

Presentations and Diagnosis

The most common presentation is lump or mass on the vulva and
the lesion is frequently itchy and may bleed. Other presenting
symptoms include pain, ulceration, dysuria and vaginal discharge.
The diagnosis must be made by biopsy. Punch biopsy is taken via
keyhole biopsy or Keyes dermal punch size 4–6 mm, under local
anaesthesia. Evaluation of entire vulvar, vagina and cervix should
also be done to rule out any co-existing preinvasive and invasive
lesions of other genital tracts.

Patterns of Spread in Vulvar Cancer

Direct extension is common, spread to adjacent organs, e.g.
urethra, anus, vagina and even deep to the pelvic bone. Lymphatic
spread occurs when the tumour invasion is more than 1 mm depth.
Lymphatic spread is the most common method of spread and may
occur with apparently small lesions, initially to the supericial
inguino-femoral nodes, then up to femoral nodes and into the pelvis.
Direct spread to the deep inguinal nodes without metastasis to the
supericial group has been documented although it is uncommon
50 Cancer of Vulva

representing in <5% of cases. Approximately, 20% of patients

with positive groin nodes will have involvement of pelvic nodes.
Lateralized lesions more than 1 cm from the midline will spread
to ipsilateral lymph nodes while centralized lesions may spread
to both sides of lymph nodes. The risk of contralateral lymph
node metastasis in lateralized lesion is 0.9% if the lesion is <2 cm
(Ghurani and Penalver, 2001; Hampl et al., 2008; Robison et al.,
2006). Haematogenous spread is usually a late manifestation
of vulvar cancer. Cancer can spread to solid organs, e.g. liver, lung,
bone, brain, and others.

Figure 3.5 Squamous cell carcinoma of the vulva.

Staging of Vulvar Cancer

Radiological assessment is one of the most important investigations.
Radiological examination is performed after the diagnosis of
vulvar carcinoma is conirmed and it includes chest x-ray, CT scan
or MRI of the pelvis. If suspected bone metastasis, bone scan may
be helpful. Prior to 1988, the staging for vulvar cancers was clinical
but now the staging of vulvar cancer is by surgico-pathological.
Any spread beyond inguinal lymph nodes is considered as distant
metastasis. See Tables 3.2 and 3.3 for old and new FIGO staging for
vulvar cancer (Mutch, 2009).
Staging of Vulvar Cancer 51

Table 3.2 Staging system for vulvar cancer by the International

Federation of Gynecology and Obstetrics (FIGO) Montreal
1994

Stage Descriptions
Stage 1 Lesions 2 cm or less in size conined to the vulva or perineum;
no nodal metastasis
Stage 1A Lesions 2 cm or less in size conined to the vulva or perineum
and with stromal invasion no greater than 1.0 mm*; no nodal
metastasis
Stage 1B Lesions 2 cm or less in size conined to the vulva or perineum
and with stromal invasion greater than 1.0 mm; no nodal
metastasis
Stage 2 Tumour conined to the vulva and/or perineum of more than
2 cm in the greatest dimension; no nodal metastasis
Stage 3 Tumour of any size with (1) adjacent spread of the lower
urethra and/or the vagina or anus and/or (2) unilateral
regional lymph node metastasis
Stage 4A Tumour invades any of the following: upper urethra, bladder
mucosa, rectal mucosa, pelvic bone and/or bilateral regional
node metastasis
Stage 4B Any distant metastasis including pelvic lymph nodes
*The depth of invasion is deined as the measurement of the tumour from the
epithelial-stromal junction of the adjacent most supericial dermal papilla to the
deepest point of invasion.

Table 3.3 New FIGO staging of vulva cancer (2009)

Stage Descriptions
Stage 1 Tumour conined to the vulva; no nodal metastasis
Stage 1A Lesions 2 cm or less in size conined to the vulva or perineum
and with stromal invasion no greater than 1.0 mm*; no nodal
metastasis
Stage 1B Lesions >2 cm in size or with stromal invasion >1.0 mm,
conined to the vulva or perineum; no nodal metastasis
Stage 2 Tumour of any size with extension to adjacent perineal
structures (1/3 lower urethra, 1/3 lower vagina, anus); no
nodal metastasis
(Comtinued)
52 Cancer of Vulva

Table 3.3 (Comtinued)

Stage Descriptions
Stage 3 Tumour of any size with or without extension to adjacent
perineal structures (1/3 lower urethra, 1/3 lower vagina,
anus) with positive inguino-femoral lymph nodes
Stage 3A (a) With 1 lymph node metastasis (≥5 mm), or
(b) 1–2 lymph nodes metastasis (es) (<5 mm)
Stage 3B (a) with two or more lymph node metastases (≥5 mm), or
(b) three or more lymph node metastases (<5 mm).
Stage 3C Positive nodes with extracapsular spread
Stage 4 Tumour invades other regional (2/3 upper urethra, 2/3
upper vagina), or distant structures.
Stage 4A (a) Tumour invades any of the following: upper urethra
and/or vaginal mucosa, bladder mucosa, rectal mucosa
or ixed to pelvic bone, or
(b) Fixed or ulcerated inguino-femoral lymph nodes
Stage 4B Any distant metastasis including pelvic lymph nodes
*The depth of invasion is deined as the measurement of the tumour from the
epithelial-stromal junction of the adjacent most supericial dermal papilla to the
deepest point of invasion.
Reference: (Mutch DG, 2009).

Prognostic Factors in Squamous Cell Carcinoma

of Vulvar
Nodal status is the most signiicant independent prognostic factor
for survival (Hazard ratio 3.47 (CI 95% 1.85, 7.85). The risk of nodal
metastasis is correlating with few other important factors such
as (a) Size of tumour (23% if tumour size less than 2 cm, 37%
when the diameter 2–4 cm) and (b) Depth of invasion (5% risk of
nodal metastasis if depth of invasion ≤3 mm) (Ghurani and
Penalver, 2001; Leibowitch et al., 1990; Origoni et al., 1992;
Paladini et al., 1994).
The other factors that determine the prognosis of vulvar cancer
are listed below:
(a) Presence of lymphvascular space invasion (HR 2.06, CI95%
1.57–12.07)
Management of Squamous Cell Carcinoma of Vulva 53

(b) Stage of the disease

( c ) Presence of extracapsular spread in the lymph node correlates
with survival. Patients with an intracapsular spread have
10-year survivals of 71% as compared to 30% in patients with
the extracapsular spread (Raspagliesi et al., 2006). Another
study done by Paladini et al. based on multivariate analysis
had concluded that extracapsular spread was the most
important independent prognostic factor, 5-year survivals
dropped from 51% in patients with intracapsular metastasis
to 15% if one node showed extracapsular involvement
(Paladini et al., 1994).
(d) Number of lymph nodes was found to correlate with survival
in some study but others suggested that the prognostic
value of the number of positive nodes is dependent upon the
other lymph node variables.
(e) Size of involved lymph node. Paladini et al. reported when
only one lymph node involved, the most important prognostic
factor was the greatest dimension of metastasis within the
lymph node (5-year survivals were 86% in patients with nodal
metastasis <5 mm and 40% if larger than 5 mm) (Paladini
et al., 1994).
The diameter of involved lymph node was also found to
correlate with survival. Origoni et al. reported that survival rate
varied from 90.9% for diameter of less than 5 mm and 20%
when the diameter is more than 15 mm) (Origoni et al., 1992).

Management of Squamous Cell Carcinoma

of Vulva
Surgical Treatment
Surgery is the most important primary treatment for a patient
with squamous cell carcinoma of the vulva. Traditionally, surgery
for vulvar cancer was very radical (radical vulvectomy with “en bloc”
bilateral inguino-femoral and pelvic lymphadenectomy), although
the cure rate was good but morbidity associated with this surgery
was very signiicant. The inguino-femoral lymphadenectomy or
groin node dissection is often performed together with excision
of the primary tumour. However, pelvic lymphadenectomy is not
54 Cancer of Vulva

recommended even in a patient with positive groin lymph node.

Routine pelvic lymphadenectomy was found to be inferior to
adjuvant pelvic irradiation in patients with groin node metastasis.
Routine pelvic lymphadenectomy may lead to unnecessary
procedures, as the risk of pelvic lymph node metastasis is low if
groin nodes are negative. Recently, the surgery for patients with
squamous cell carcinoma of the vulva has become more conservative
and individualized with the intention to reduce morbidity without
compromising the prognosis.

Surgery for Early Stage

Patients with tumour size less than 2 cm and stromal invasion
<1 mm (stage 1A) can be managed by wide local excision alone
(with margin of at least 10 mm). Lymphadenectomy can be omitted
because the risk of groin lymph node metastases is <1%. The
tumour free margins are the most important predictive factor for
local recurrences. Study had shown that the rate of local recurrence
is 50% if the histopathological margin is less than 8 mm (Heaps,
et al.) and in another study by de Hullu et al., no patients with
tumour free margins of >8 mm developed local recurrence. Free
surgical margin of 1 cm is safe but 2 cm margin is better if feasible
(Ve Hullu et al., 2002; Zeaps et al., 1990).
Patients with early-stage disease but with invasion more than
1 mm and/or tumour size more than 2 cm required groin node
assessment. If sentinel node mapping is not available, inguino-
femoral lymphadenectomy is indicated either unilaterally or
bilaterally depending on the location of the primary tumour. The
surgery is done via a separate incision. Separate incision technique
is deined as when inguino-femoral lymphadenectomy and
excision of primary tumour are done via separate incision. The
rationale of this technique (as compared to traditional en bloc
butterly shape incision) is based on the fact that the dissemination
of cancer to inguino-femoral lymph nodes is by embolization
and does not have continuity with the primary lesions. The risks
of wound breakdown and lymphoedema are lower in separate
incision technique. Large prospective randomized trial is not yet
available to address this concept; however, Cochrane’s review has
reported that the risk of skin bridge recurrence was only 1% and
Management of Squamous Cell Carcinoma of Vulva 55

therefore, separate skin incision is considered as a safe technique

(Van Doorn et al., 2006).
Patients with lateralized lesions and the tumour size less than
2 cm have only 0.9% risk of contralateral groin node metastasis
and therefore, unilateral inguino-femoral lymphadenectomy is
suficient. However, controversy remains whether contralateral
groin requires treatment (irradiation or inguino-femoral lympha-
denectomy) when ipsilateral lymph node metastases have been
identiied. While, patients with centralized lesions, invasion
>1 mm and/or tumour size >2 cm required bilateral inguino-femoral
lymphadenectomy.

Surgical Tips during Vulvectomy and Inguino-Femoral

Lymphadenectomy
Following are some important tips for surgeons who perform
vulvectomy and inguino-femoral lymphadenectomy:
(1) In wide local excision, surgical margin should be 1–2 cm and
depth of incision is down to the fascia lata. Primary closure is
preferable.
(2) A position of neurovascular bundles in the femoral triangle
from lateral to medial is femoral nerve, femoral artery and
femoral vein.
(3) In inguino-femoral lymphadenectomy, the skin incision can
either be parallel and 2 cm above the inguinal ligament or
vertical incision. The saphenous vein is preferably preserved
although it has not been proven to reduce morbidity mainly
lymphoedema. Femoral lymph nodes are only 1–3 in number
and always situated medial to the femoral vein within the
opening of the fossa ovalis.
(4) The perforated membrane contiguous with fascia lata is called
the cribriform fascia.
(5) In supericial inguinal lymphadenectomy, the cribriform
fascia is left intact and none of the nodes below this landmark
is removed.
(6) There is no need to remove the fascia lata lateral to the femoral
vessels.
(7) Supericial inguinal lymphadenectomy with medial femoral
lymphadenectomy are probably the most commonly perfor-
med procedure.
56 Cancer of Vulva

Lymphatic Mapping and Sentinel Node Biopsy

Lymphatic is one of the most important modes of spread in
carcinoma of the vulva and lymph node metastasis is the most
important prognostic factor for survival in squamous cell carcinoma
of the vulva. Information regarding the status of inguino-femoral
lymph nodes is also vital in the planning of treatment and adjuvant
therapy. It is known that clinical palpation of groin nodes is
unreliable with the sensitivity and speciicity of 57% and 62%,
respectively. While, ine needle aspiration cytology (FNAC) can
be used to assess enlarged lymph nodes but there is a high false-
negative rate, mainly due to sampling error. Imaging techniques
such as ultrasound, CT scan, MRI and positron emission tomography
has yet to show any promise in the detection of groin node
metastases in vulvar cancer. Lack of sensitivity is the main
problem with these imaging techniques. New technique such as
MR lymphography using ultra-small-iron-oxide-particles (USIOP)
is still investigational but promising in diﬀerentiating benign and
metastatic lymph nodes.

Lymphatic Mapping and Sentinel Node Biopsy

in Vulva Cancer
Sentinel lymph node technology has become the standard of care
in penile cancer, melanoma and breast cancer. Sentinel node is
deined as the irst lymph node in the lymphatic chain to receive
lymphatic low from the malignant lesion. If the sentinel lymph
node is free from metastatic disease, the rest of the nodes in the
lymphatic chain should theoretically be free of tumour as well
(Hampl et al., 2008; Moore et al., 2003, 2008; Robison et al., 2006).
Identiication of a sentinel node is done by injection of a tracer
around the primary tumour and to follow the course of the tracer to
the irst lymph node in the region. The tracer can be a radioactive
tracer (injection pre-operatively, 99mTc-labelled nanocolloid) or
blue dye (injection done during operation under anaesthesia).
Using hand-held gamma probe and gamma camera, accumulation
of radioactive tracer in the sentinel node will be identiied. Sentinel
node biopsy will subsequently perform and sent for histological
examination to determine the presence of metastasis. Combined
Management of Squamous Cell Carcinoma of Vulva 57

technique (radioactive tracer and blue dye) was found to be more

eﬀective in detection of a sentinel node with the detection rate of
99.5% and negative predictive value of >95% (Moore et al., 2008;
Moore et al., 2003). In patients with clinically normal nodes,
complete lymphadenectomy should be omitted if the sentinel node
biopsy (frozen section) did not show metastasis.
Not all patients with operable vulvar cancer are suitable for
sentinel node mapping. Following are the selection criteria for
lymphatic mapping in vulvar cancer:
(a) squamous cell carcinoma with depth of invasion >1 mm
(b) patient who is a candidate for primary surgical treatment
(c) technically possible to inject around the tumour
(d) no ixed lymph nodes in the groins
(e) no enlarged lymph nodes on preoperative CT scan
(f) tumour located in or close to the midline seem to be less
suitable for sentinel lymph node mapping due to higher false
negative rate (Hampl et al., 2008)
Despite the advantages and potential role in the management
of vulvar cancer, there are a number of concern arises from the
practice of lymph node mapping and sentinel node biopsy in
vulvar cancer. Some of the concerns are (a) the procedures
require training, quality control and radioactive handling, (b) the
possibility of failure to detect sentinel node, (c) false negative rate,
(d) sensitivity and speciicity of frozen section, (e) presence of skip
lesions because in small proportion of patients, femoral lymph
nodes metastases were detected despite negative inguinal lymph
nodes and (f) failure to detect micrometastases.
Moore, et al. had shown that when sentinel nodes are found to
be negative for metastatic disease the negative predictive value is
near 100% for predicting the status of the remaining inguinal nodes
(Moore et al., 2003, 2008). Robison K, et al. had also discovered
that when a sentinel node harbour only micrometastasis (<2 mm
focus of metastatic cells), remaining inguinal nodes in the same
basin will be negative to metastatic disease (Robison et al., 2006). A
multicenter prospective study on safety of the sentinel node
mapping in vulvar cancer known as Groningen International Study
on Sentinel nodes in vulvar cancer (GROINSS-V I) had completed
and following are the outcome of this trial (Van der Zee et al.,
2008); (a) the study involves 15 hospitals from year 2000 until
58 Cancer of Vulva

2006, (b) total number of patients recruited were 403 patients with
early carcinoma of vulva stage T1–T2 (<4 cm), (c) sentinel node
mapping (combined technique) and biopsy were done in all patients,
(d) approximately, 33% has positive sentinel nodes and had full
inguinal-femoral lymphadenectomy, (e) patients with negative
sentinel node did not undergo any further lymphadenectomy,
(f) women with negative sentinel node had signiicantly fewer
short and long-term complications. The 3-year disease-speciic
survival rate was 97%. Their rate of recurrence was 3%, which
was comparable to patients with early stage treated with excision
and full inguino-femoral lymphadenectomy and (g) the authors
concluded that sentinel node mapping is safe and should be part of
the standard treatment in patients with early-stage vulvar cancer
(Van Der Zee et al., 2008).

Method of Sentinel Node Detection

Two intradermal peritumoral injections on both the medial
and lateral edge of the tumour with a total of 2 mCi of uniltered
technetium-99m sulphur colloid (Tc-99m) in a volume of 1 cm3 90
to 180 minutes prior to surgery. Lymphoscintigraphy was obtained
to illustrate the presence of a sentinel node. Intraoperatively,
5–10 min prior to the groin dissection, 3 cm3 of methylene blue was
injected at the peritumoral edge in a manner and location similar
to the Tc-99m above (Moore, et al., 2003, 2008).
Prior to groin node dissection, a hand held collimated gamma
counter is used to identify the location of the sentinel node, and
this area is marked with ink on the skin. Inguinal sentinel node
dissection is performed through 2–3 cm groin incision prior to
excision of the vulvar tumour. The inguinal nodal beds are gently
dissected to identify blue lymphatic tracts leading to sentinel node
or blue stained sentinel nodes. An intraoperative hand held gamma
counter is also used to identify any lymph nodes labelled with
Tc-99m sulphur colloid. Each sentinel node that had taken up blue
dyes only is labelled as cold sentinel nodes. Sentinel nodes that
had taken up Tc-99m sulphur colloid alone were labelled as hot
sentinel nodes, while sentinel nodes that had taken up both were
labelled as hot and blue sentinel nodes. A 10s gamma count was
taken for each hot sentinel node and recorded. Radiolabelled
lymph nodes with a 10 s gamma count of at least 10% of the
hottest sentinel node are considered as hot sentinel nodes.
Management of Squamous Cell Carcinoma of Vulva 59

Upon completion of the sentinel node dissection, the lymphatic

beds were re-examined with the gamma probe to ensure that all
sentinel nodes had been removed and that the background count
of the lymphatic basin is less than 10% of the gamma count of
the hottest sentinel node. The groin incisions are closed with a
subcuticular suture or staples.
A sentinel node ultra-staging protocol was used to evaluate
each sentinel node as described in publication by Moore RG,
et al. Each sentinel node is cut at 2 mm intervals parallel to the
long axis of the node. These 2 mm-thick sections are submitted for
histologic evaluation in one or more blocks. From each block, ive
levels were cut at 100 micrometer interval with a 5 micrometer
section cut at each level and stained with hematoxylin and eosin.
Wide local excision or radical vulvectomy is performed for
the primary tumour and patients with sentinel node metastasis
will subsequently undergo a complete groin node dissection.
Patients with negative sentinel nodes for metastatic disease do not
undergo a complete groin node dissection and are followed up in
the postoperative period. If the sentinel nodes are undetected,
complete groin node dissection will be performed (unilateral groin
node dissection for lateralized lesions and bilateral dissection for
centralized lesions).

Radiotherapy in Early-Stage Vulvar Cancer

Patients with early-stage vulvar cancer can be treated with primary
radiotherapy if they are not it for surgical treatment. The main role
of radiotherapy in early vulvar cancer is an adjuvant treatment
given to patients with high-risk of recurrence (Faul, 1997; Moore,
2009; Van Doorn et al., 2006). Patients with early vulvar cancer
who undergo wide excision and inguino-femoral lymphadenectomy
do not require adjuvant treatment if the microscopic margin is
free (at least 10 mm) and no lymph node involvement. In some
institution, radiotherapy was not given if only one lymph node
involved (micrometastasis).
The indications for postoperative adjuvant radiotherapy in an
early-stage vulvar cancer are (a) positive surgical margin, (b) narrow
microscopic surgical margin of less than 10 mm and not amenable
to repeat surgical resection, (c) extracapsular spread of any lymph
node and (d) more than one lymph node with micrometastasis.
60 Cancer of Vulva

Radiotherapy has at least three major roles in vulvar cancer

(Faul, 1997; Moore, 2009): (a) postoperative adjuvant pelvic
radiotherapy (to pelvis and groin), indicated in a patient with
lymph node metastasis, (b) in a patient with narrow resection
margin, repeat excision can be performed but if, for some reason,
repeat excision is not feasible or patient refuses, radiotherapy
(brachytherapy) to the primary site is acceptable and (c) as a
primary radiotherapy to groins and pelvis, indicated in a patient
who is not it for surgical treatment or the tumour is located closed
to vital structures such as clitoris and urethra. Primary radiotherapy
consists of external beam radiotherapy followed by interstitial
brachytherapy. Complete response rates are ranging from 53%
to 89%.

Objectives of Radiotherapy in Vulvar Cancer

Generally there are four possible main objectives of radiotherapy
in the treatment of patients with vulvar carcinoma: (1) to decrease
the incidence of locoregional failures after wide local excision in
patients with early-stage disease, (2) to reduce the incidence of
post-surgical failure in patients with locally advanced disease,
(3) to serve as an alternative to inguinal or pelvic lymph node
dissection in patients with clinically negative nodes and (4) to treat
patients before surgery for locally advanced tumours that may be
considered inoperable initially. Type and indications of radiotherapy
in vulvar cancer is shown in Table 3.4.

Table 3.4 Type and indications of radiotherapy in vulvar cancer

Type of radiotherapy Indication

Local vulvar RT Resection margin involved; surgical
margin less than 1 cm; perineural
tumour involvement
Groin and Pelvic Radiotherapy Macroscopically involved lymph
(Standard vulvar EBRT* and inguinal node; more than one lymph node
nodal radiotherapy) involved; extracapsular spread of
tumour in lymph node
*Superior margin: Mid sacro-iliac join, Inferior: 1 cm beyond the vulva, Lateral:
Anterior superior iliac crest (encompass both inguinal regions).
Management of Squamous Cell Carcinoma of Vulva 61

ͳ
εͳ

ʹ

͓
Ǧ
ǣȗǡ
ǡǤ

Ǥ

ǡǡ
ǡǡ
Ǥ

ȗ ǣ ǡ

Ȁ
ǡ

ȋ
ȌǤ
͓

Ǥ

Figure 3.6 Summary of treatment for early vulvar cancer (lateralized

lesions, >1 cm away from the midline).

εͳ

ʹ

Ǧ
͓ ȋȌ

ǡǤǤǡ
ǡǡ
ȗǡǡǤ

Ǧ

Ȁ

ȗ ȋδͳͲȌǡǤ
͓
Ǥ

Figure 3.7 Summary of treatment for early vulvar cancer (centralized

lesion).
62 Cancer of Vulva

Treatment for Advanced-Stage Carcinoma of Vulva

Advanced-stage carcinoma of the vulva can be classiied into
locally advanced disease and metastatic disease. Locally advanced
disease is when the primary tumour is large involving important
local structures and tumour with obvious groin node involvement.
Approximately, one third of patients with vulvar cancer present with
locally advanced disease. Surgery in patients with locally advanced
disease will carry high morbidity not only because of the radicality
of the surgery but also related to patient’s age, physical status and
co-morbidity.

Treatment for Locally Advanced Disease

Surgery in locally advanced disease involves ultraradical surgery
consists of radical excision or radical vulvectomy followed by plastic
reconstruction. In some cases, exenterative procedure has been
undertaken. Postoperative mortality rate in patients with locally
advanced disease is ranging from 0 to 20% with a mean of 4% and
5-year survivals are <50%. The other alternative to primary surgery
is neoadjuvant radiotherapy/chemotherapy to shrink the tumour
and subsequently followed with less radical surgery (Van Doorn
et al., 2006). Radiotherapy followed by surgical excision carries a
higher rate of surgical complications due to radiation eﬀect to
the tissue and poor vascularization (Moore, 2009). Neoadjuvant
chemoradiation followed by surgery was associated with signiicant
more morbidity than either treatment given on its own (Moore,
2009). An acceptable regime for neoadjuvant chemotherapy prior
to surgical treatment for vulvar carcinoma is platinum-based
such as platinum-5-Fluorouracil or platinum-taxane given in 2–4
cycles (Moore, 2009; Thomas et al., 1989). Patients with enlarged
groin node do not require complete groin node dissection. Nodal
debulking is suficient because full groin node dissection followed
by radiotherapy carry higher risk of severe lymphoedema.
Chemoradiation (cisplatin-5-FU or Mitomycin C-5FU) in locally
advanced squamous cell carcinoma of the vulva either as primary
treatment or in neoadjuvant setting was found to be a promising
approach with mean complete response rate of 60%. Large phase
II prospective trial conducted by GOG (Protocol 101) was conducted
Management of Squamous Cell Carcinoma of Vulva 63

to evaluate the role of chemoradiation in patients with unresectable

locally advanced vulvar cancer. Two cycles of 5-FU and cisplatin
were given to shrink the tumour size prior to surgery, complete
response rate was 48%. Only 3% had an unresectable disease
following neoadjuvant chemoradiation. Despite lower dose of
radiation therapy, the result of this GOG trial was encouraging.
Subsequently, GOG conducted the trial using a higher dose of
radiation (GOG 205). The main concern about neoadjuvant chemo-
radiation is toxicity and surgical morbidity. Therefore, van Doorn,
et al. in their critical review had concluded that (1) Patients with
an inoperable primary tumour or lymph nodes beneit from
chemoradiation if an operation of lesser scope can ultimately be
performed (2) Neoadjuvant therapy is not justiied in patients with
tumours that can be adequately treated with radical vulvectomy
and bilateral groin node dissection (Van Doorn et al., 2006).

Ȁ
ǡ Ȁ
ȋǡ
Ȍ

Ǧ

ȋȌǣ
ȋ
Ȍ ȋ Ǥ
Ǥ

ȀȌ Ǥ

ǡ
Ȁ

Figure 3.8 Summary of treatment for locally advanced vulvar carcinoma.

Treatment for Metastatic and Recurrent Disease

The intention of treatment in metastatic vulvar cancer is palliative.
Metastatic squamous cell carcinoma can be treated with palliative
64 Cancer of Vulva

chemotherapy. In general, one third of patients with vulvar cancer

will develop recurrent disease and approximately 80% of re-
currences occur within irst 2 years of treatment. The treatment
for patients with recurrent vulvar cancer depends on the several
factors such as (a) the extend of recurrence disease, (b) the extend
and the nature of primary surgery, (c) previous use of radiotherapy/
chemoradiation, (d) previous regimen of chemotherapy, (e) current
medical status and performance status of patients and (f) patient’s
wishes.
Approximately, 50% of patients with recurrent vulvar
cancer have isolated local recurrence and 14% have multiple site
recurrence including distance metastases. A ive-year survival rate
for patients with recurrent vulvar cancer is 25–35%. Patients with
negative groin nodes are more likely to developed local recurrence
as compared to patients with positive groin nodes at initial
presentation. The risk of recurrence in patients with positive groin
nodes is 52% as compared to 31% in patients with negative nodes.
Treatment for isolated local recurrence is radical excision with good
surgical margin. Wider free surgical margin of 2 cm and more is
recommended and this surgery may require lap reconstruction.
Five-year survivals are ranging from 50–70%. Inguino-femoral
lymphadenectomy can also be performed if it was not done before.
The type and extend of lymphadenectomy follows the same
principles, e.g. bilateral lymphadenectomy in centralized lesions.
In radiation naïve patients, post-operative radiation therapy is
indicated if the surgical margin is involved or groin node metastasis
is presence.
In some patients with operable localized but extensive
recurrence, they may be recommended for exenterative procedure
if surgery is the only option for a cure and at the same time,
radiotherapy is not suitable for some reasons such as patients with
prior radiotherapy.
Nodal recurrence carries poorer prognosis as compared to local
recurrence. There is no standard treatment for nodal recurrence.
Nodal debulking followed by chemoradiation may be indicated in
some cases; however, if the involved lymph nodes are unresectable,
prior chemotherapy/chemoradation followed by nodal resection
may be the only option available.
Management of Squamous Cell Carcinoma of Vulva 65

Patients with distance solid organ metastasis or with multiple

paraaortic lymph node metastases, palliative chemotherapy may
be useful for symptom control. The most common chemotherapy
regimen used in squamous cell carcinoma of the vulva is platinum
(mainly cisplatin) and 5-Fluorouracil (5-FU). Combination of
5-FU and Mitomycin C was also found to be useful (Moore, 2009).

Post-Operative Care for Vulvectomy

Vulvectomy and groin node dissection potentially carries high

morbidity because the patient tends to be an elderly and has co-
morbidities. Furthermore, the surgery involves genitalia and groins,
which are easily contaminated, and prevents early ambulation. The
priorities in post-op management are analgesia, antibiotics, perineal
care, prevention of deep vein thrombosis and lymphoedema, as
well as speciic measures if reconstruction has been performed.

General measures

Provision of adequate analgesia to avoid chest complications.

Administering DVT prophylaxis according to protocol including TED
stocking and calf compressors especially for the irst 3 days.

Urinary catheter
Left for free drainage for about 5–7 days until the patient is
ambulating well and there is no signiicant periurethral oedema.
Drain
Radivac drains are usually placed in the inguinal lympha-
denectomy sites for about 10–14 days to prevent early formation of
lymphocysts.
Perineal care
An ice pack may be left at the vulvar area immediately post-
operatively to reduce the pain and swelling and this can be removed
when it is no longer cold. Nurse patient in the circumcision
frame. Perineal washing can commence on day 3 POD with the
shower or cotton swabs with normal saline three times/day. This
66 Cancer of Vulva

must be followed by drying of the area with a hair dryer on low

setting. Sitz baths are NOT recommended as this may promote
tissue maceration and wound breakdown. Ring cushions are also
not recommended as they can increase oedema to the central area.

Bowel
If involve anal canal sphincter, bower function will have to be delayed
with low residue diet and antispasmodic.

Mobilization
Important to prevent atelectasis and DVT but should be delayed
depending on the extent of vulvar reconstruction performed.
Excessive movement may disrupt healing of any graft.

Complications of Surgery in Vulva Cancer

Groin lymph node dissection is associated with the risk of lymphocyst
(7–19%) and chronic lymphoedema (10–20%) (Ghurani and
Penalver, 2001; Simcock, 2008). Lymphocyst usually presented
with asymptomatic mass at the groin. Treatment for lymphocyst is
conservative, including aspiration, pressure bandage and antibiotic
treatment. The other complications of groin node dissections are
infection (cellulitis, lymphangitis), wound breakdown, seroma, and
venous thromboembolism. The incidence of wound breakdown and
infection is approximately 15% (Simcock, 2008). Rare complications
include femoral nerve injury, femoral hernia, vaginal istula and
osteitis pubis. Chronic lymphoedema is an important complication
and more commonly experienced by patients who were treated
with a combination of surgery and radiotherapy. The other
important complications related to vulvectomy or radical excisions
of vulvar cancer are micturition problems, coital dificulties and
psychosexual problems.
Following measures can minimize the risk of complications;
(a) adequate preoperative preparation, including thromboprophy-
laxis and administration of prophylactic antibiotic, (b) good
surgical techniques, e.g. good haemostasis, tension-free wound
closure, avoiding dead space, and others, (c) adequate wound
drainage, (d) preservation of saphenous vein can reduce the risk of
Management of Squamous Cell Carcinoma of Vulva 67

lymphoedema and (e) risk of lymphoedema is higher if groin nodes

are involved and complete inguino-femoral lymphadenectomy is
performed (instead of nodal debulking).

Follow-Up of Patients with Vulvar Cancer

Close monitoring and regular follow up is very important, especially
within 2 years after treatment as 80% of recurrence occurs during
this period. The common follow up schedules are three monthly
follow up for the irst year, four monthly on the second year, six
monthly from third to ifth year and yearly from sixth year onwards.
During each visit, history and thorough physical examination must
be performed to detect any sign of early recurrence.

Prognosis
The most important prognostic factors for survival are staging and
nodal status (Homesley et al., 1991; Origoni et al., 1992). Patients
with groin node negative have 5-year survivals of 90% but may fall
to 50% if they have nodal metastases (Ghurani and Penalver, 2001).
The other important prognostic factors are the number of lymph
node involved, size of involved lymph nodes and presence
extracapsular spread of tumour (Origoni et al., 1992). Patients with
pelvic node involvement have 5-year survivals of only 10–15%
(Homesley et al., 1991). Based on FIGO staging 1994, corrected
5-year survivals rate were 90% for stage 1, 77% (stage 2), 51%
(stage 3) and 18% (stage 4).

Other Carcinoma of Vulvar Carcinoma

Verrucous carcinoma
Verrucous carcinoma is the variant of squamous cell carcinoma. It
appears as an exophytic and locally destructive tumour. This tumour
carries an excellent prognosis, rarely metastasize and majority of
cases occur in postmenopausal women. Cytogenetic study showed
diploid cells instead of eneuploid in other variants of squamous
cell carcinoma. Usually the lesions are large caulilower-like,
condylomatous lesion. It is important that diagnosis of this tumour
68 Cancer of Vulva

needs multiple biopsies to establish a correct diagnosis. Human

papilloma virus has been implicated as a causative factor and
may be detected in verrucous carcinoma in approximately 25% of
cases. Radiotherapy can transform it into anaplastic and therefore,
radiotherapy is contraindicated in verrucous carcinoma. Surgery is
the mainstay of treatment for verrucous carcinoma of the vulva.

Figure 3.9 Verrucous carcinoma of the vulva.

Basal cell carcinoma

Basal cell carcinoma of the vulvar is rare, accounts for 2–4% of
vulvar cancer and occurs more commonly in post-menopausal
women. This cancer is most commonly arises from the labia majora
and usually a locally invasive disease. The treatment is surgery and
if the margin is free (1 cm margin is adequate), most patients will
achieve a cure and no further treatment required.

Merkel-cell tumours
Merkel-cell tumour is a neuroendocrine tumour of skin and 95%
occurs in the head and neck. Merkel-cell carcinoma has similar
histological features with poorly diﬀerentiated neuroendocrine
carcinoma of the lung (oat-call carcinoma). Merkel-cell carcinoma
involving the vulva is extremely rare and it resembles small cell
carcinoma and an aggressive tumour carries poor prognosis. It can
be classiied into three types: (a) Carcinoid type, (b) Intermediate
type and (c) Oat cell (small cell) type. Treatment for this cancer is
surgery for an early disease and adjuvant treatment similar to small-
cell carcinoma of the lungs.
Management of Squamous Cell Carcinoma of Vulva 69

Transitional cell carcinoma

Transitional cell carcinoma of the vulvar is also very rare tumour
and it can be divided into primary or secondary. Secondary tumour
is more common and primary transitional cell carcinoma is arising
from Batholin’s gland.

Carcinoma of Batholin’s gland

Most of primary adenocarcinoma of the vulva is arising from
Batholin’s gland. Majority of the women is more than 50 years of
age. Therefore, it is advisable to excise an enlarged Batholin’s
gland in women above 50 years ago. The presenting symptoms are
painless lump in the posterior half of the vulva, abnormal bleeding,
pruritus and rarely vulvar pain. Carcinoembryonic antigen (CEA)
may be elevated. The diagnostic criteria for Batholin’s gland
carcinoma are shown in Table 3.5 (Copeland et al., 1986; Finan and
Barre, 2003).

Table 3.5 Diagnostic criteria of Batholin’s gland carcinoma (Copeland,

1986)

(1) Anatomical position consistent with Batholin’s gland

(2) Intact overlying skin
(3) Tumour located deep in the labia majora
(4) Normal glandular elements present on histology
(5) Areas of transition from normal to cancerous epithelium
(6) Histology tumour type consistent with a Batholin’s gland origin
(7) No evidence of a coexisting primary tumour elsewhere

Approximately, 20% of women with Batholin’s gland carcinoma

already have lymph node metastasis at irst presentation. Other
variants of carcinoma of Batholin’s gland are adenosquamous,
adenoid cystic carcinoma and squamous cell carcinoma (Copeland
et al., 1986; Finan and Barre, 2003). The treatment is similar to
squamous cell carcinoma of the vulva.

Other Malignant Tumour of Vulva

Malignant melanoma of the vulva
Malignant melanoma of the vulva accounts in 5–10% of all vulvar
cancer and second most common vulvar cancers. The median age
70 Cancer of Vulva

is approximately 67 years old (range from 18–92) (Irvin Jr et al.,

2001; Gungor et al., 2009). It can be subclassiied into three groups;
(a) Supericial spreading malignant melanoma (most frequent),
(b) Nodular melanoma (poorer prognosis) and (c) Mucosal
lentiginous melanoma. Malignant melanoma carries poor prognosis,
spread predominantly via lymphatic and metastasize early. One
of the most important diﬀerences between vulvar and cutaneous
melanomas is the recurrence rate. Vulva melanoma carries a
higher risk of recurrence and reported lower 5-year survivals rate
(27–60% versus 88%) as compared to cutaneous melanomas
(Irvin Jr, 2001; Gungor et al., 2009). Malignant melanoma of the
vulva most commonly arises in labia minora and clitoris with a
tendency for supericial spread toward urethra and vagina. Lymph
node status is the most important independent prognostic factor
in melanoma of the vulva. For node negative patients, 5-year
survivals were 65% while for node positive patients, the survival
dropped to <37% (Raspagliesi et al., 2000).
There are two staging systems in malignant melanoma, i.e.
(1) Clark’s staging system and (2) Breslow staging system (see
Table 3.6). Breslow staging system is more widely used than Clark’s
system. The comparison between Clark’s staging system and
Breslow system is shown in Table 3.6.

Table 3.6 Staging of melanoma

Clark’s staging (level) Breslow system (thickness)

Level 1 In situ melanoma: all Thickness < 0.76 mm
demonstrable tumour is above
the basement membrane in the
epidermis
Level 2 Melanoma extends through the Thickness 0.76–1.5 mm
basement membrane into the
papillary dermis
Level 3 The tumour ills the papillary Thickness 1.51–2.25 mm
dermis and extends to the reticu-
lar dermis but does not invade it.
Level 4 The tumour extend into the re- Thickness 2.26–3 mm
ticular dermis
Level 5 The tumour extends into the sub- Thickness >3 mm
cutaneous fat
Management of Squamous Cell Carcinoma of Vulva 71

The Clark system is applicable to vulvar melanoma where there

are skin appendages (cutaneous melanoma) and hence, it cannot
be used where the melanoma involves or arises in the mucosal
membrane of the vulva. Chung’s staging system is the combination
of Clark and Breslow systems. In the melanoma of the vulva, poor
prognosis is correlated to Clark’s level 5, thickness of more than
2 mm, nodal metastasis and mitotic count of more than 10/mm2.
Radical vulvectomy and bilateral inguino-femoral lympha-
denectomy is a treatment of choice, especially when the invasion is
more than 2 mm. If Breslow’s thickness is less than 0.76 mm, nodal
metastasis is very rare and a radical local excision is an adequate
treatment. Early stage could be treated with wide local excision and
sentinel node biopsy is useful to avoid unnecessary routine groin
node dissection. The actual role and appropriate type of adjuvant
therapy in malignant melanoma of the vulva are still unknown.
Dacarbazine is probably the most active chemotherapeutic
agent, which can produce response rate of 15–25% (Irvin Jr
et al., 2001). The other systemic therapy for vulva melanoma is
interferon alpha-2b (20 MIU/m2/day, 3–5 days a week for 12
weeks) (Gungor et al., 2009). Apart from dacarbazine and interferon
alpha, FDA also approves interleukin 2 for the treatment of
melanoma. There was also a report of successful treatment with
the combination of chemotherapy and biological therapy (cisplatin,
vinblastin, dacarbazine, interferon alfa or interleukin 2) (Harting
and Kim, 2004).
Radiotherapy might be oﬀered in patients who are not it or
refuse surgery and in patients with inoperable tumour to facilitate
surgical treatment. Radiotherapy is ineﬀective to treat gross disease.
Radiotherapy was also used as adjuvant treatment for nodal
metastases.

Vulvar sarcoma

Sarcoma of the vulvar is rare and there is no large prospective

series’ reporting experience with management of vulvar sarcoma.
Leiomyosarcoma is the most common primary vulvar sarcoma and
often presented with painful tender mass, which may arise in the
arrector pili muscle of the skin, vascular smooth muscle or the origin
of the round ligament. Other types of sarcomas are (a) malignant
ibrous histiocytoma, (b) epithelioid sarcoma, (c) malignant
72 Cancer of Vulva

rhabdoid tumour, (d) rhabdomyosarcoma (sarcoma botryoides

is its variant), (e) others such as angiosarcoma, Kaposi’s sarcoma,
haemangiopericytoma and liposarcoma.

Other vulvar malignancies

Vulvar lymphoma is extremely rare and chemotherapy and/or

radiation therapy regimens similar to those used for cutaneous
lymphoma. Malignant schwannoma is often associated with
neuroibromatosis. Yolk-Sac Tumour is primarily arising from the
labia and clitoris, young age. Metastatic disease to the vulva had
been reported from the primary site in endometrium, ovary, cervix,
breast, kidney, urethra and lymphoma.

Appendix
Tips on Surgical Techniques in Vulvar Cancer Surgery
(1) Traditional Radical vulvectomy and Bilateral Inguino-
femoral lymphadenectomy.
(a) Butterly incision

͘

(b) Longhorn incision

Ǧ
͹ͲΨͷǦ
ͻͲΨͳǤ
ʹΨ
͵ͲǦ
͹ͲΨǤ͹ͲΨ
Ǥ

(2) Radical Wide Excision and skin lap

(a) Margin should be 1–2 cm, 1 cm may be adequate
Appendix 73

(b) May have to do rhomboid lap repair if dificult to close

the incision.

ͳȂͳǤͷǡͶέͶ

(c) Myocutaneous laps for large vulvar and groin defect, can
use gracilis, gluteus muscle and rectus abdominis.
(3) Triple incision technique
(a) Alternative to butterly or longhorn incision is triple
incision. Triple incision technique can still preserve the
radicality of vulvar resection while retaining skin over the
groin.
(b) Incidence of wound breakdown reduced to 15–20%.

ǡ

ȋ
Ȍ

Ǥ

Contraindications for separated groin incision (triple

incision) are (a) clinically positive groin node (b) clitorial
lesion and (c) lesion in the mons pubis. Surgical margin
of resection is the best predictor of local recurrence (it
should be clear of tumour by 1 cm in all direction).
(4) Inguinal lymphadenectomy
(a) Fine needle aspiration cytology (FNAC) can be done to
assess the status of lymph node
(b) Excised enlarged lymph node because bulky lymph nodes
do not respond well to radiation.
74 Cancer of Vulva

(c) Supericial lymphadenectomy should involved removing

8–10 supericial inguinal lymph nodes along the saphenous
vein and branches.
(d) Deep inguinal (femoral) lymphadenectomy
• Nodes within the cribriform fascia (3–5 nodes)
• Medial to femoral vein
• Most supericial deep nodes known as Cloquet’s node
(5) Surgical resection of recurrence
• Radical wide resection for resectable local recurrence can
be curative. Resection is done with 2 cm margin.
• Pelvic exenteration
(a) In a selected patient
(b) Distant metastasis should be ruled out
(c) Similar like in cervical cancer
• Resection of groin recurrence
(a) In selected patient
(b) Combined with radiation in a patient with no previous
radiation
(c) The aim is to reduce the tumour bulk to achieve better
local control by subsequent radiation.

Anatomical Landmarks for Inguinal Lymphadenectomy

The above illustration shows the anatomy of the femoral

triangle after complete inguinal lymphadenectomy. Femoral nerve
lies beneath the fascia covering iliopsoas muscle. Iliopsoas muscle
lies beneath the Sartorius muscle.
References 75

Modified Radical Vulvectomy

References

Abdel-Hady ES, Martin-Hirsch P, Duggan-Keen M, et al. Immunological and

viral factors associated with the response of vulval intraepithelial
neoplasia to photodynamic therapy. Cancer Res 2001; 61: 192–196.
Black D, Tornos C, Soslow RA, et al. The outcomes of patients with positive
margins after excision for intraepithelial Paget’s disease of the vulva.
Gynecol Oncol 2007; 104: 547–550.
Booth S, Poole D, Moghissi K. Initial experience of the use of photodynamic
therapy (PDT) in recurrent malignant and pre-malignant lesions of the
vulva. Photodiagn Photodyn Ther 2006; 3: 156–161.
Carli P, Cattaneo A, De MA, Biggeri A, Taddei G, Giannotti B. Squamous cell
carcinoma arising in vulval lichen sclerosus: a longitudinal cohort
study. Eur J Cancer Prev 1995; 4(6): 491–495.
Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to
internal malignancy. J Am Acad Dermatol 1985; 13: 1009–1014.
Chang YT, Liu HN, Wong CK. Extramammary Paget’s disease: a report of
22 cases in Chinese males. J Dermatol 1996; 23: 320–324.
Chung AF, Woodruﬀ JM, Lewis Jr. JL. Malignant melanoma of the vulva:
a report of 44 cases. Obstet Gynecol 1975; 45: 638–646.
Copeland LJ, Sneige N, Gershenson DM, et al. Adenoid cystic carcinoma of
Batholin’s gland. Obstet Gynecol 1986; 67: 115–120.
Crocker HR. Paget’s disease aﬀecting the scrotum and the penis. Trans
Pathol Soc (London) 1888–1889; 40: 187–191.
76 Cancer of Vulva

Crosbie EJ, Slade RJ, Ahmed AS. Anti-Tumour Treatmen. The management
of vulval cancer. Cancer Treat Rev 2009; 35: 533–539.
Darier J, Couillaud P. Sur un cas de maladie de Paget de la region
perinea-annale et scrotale. Ann Dermatol Syphiligr 1893; 4: 25–31.
Faul CM, Mirmow D, Huang Q, Gerszten K, Day R, Jones MW. Adjuvant
radiation for vulvar carcinoma: improved local control. Int J Radiat
Oncol Biol Phys 1997; 38(2): 381–389.
Fehr MK, Hornung R, Degen A, et al. Photodynamic therapy of vulvar and
vaginal condyloma and intraepithelial neoplasia using topically
applied 5-aminolevulinic acid. Lasers Surg Med 2002; 30(4):
273–279.
Finan MA, Barre G. Bartholin’s gland carcinoma, malignant melanoma and
other rare tumours of the vulva. Best Pract Res Clin Obstet Gynaecol
2003; 17(4): 609–633.
Fischer GO. The commonest causes of symptomatic vulvar disease: a
dermatologist’s perspective. Australas J Dermatol 1996; 37(1):
12–18.
Fischer GO, Spurrett B, Fischer A. The chronically symptomatic vulva:
aetiology and management. Br J Obstet Gynaecol 1995; 102(10):
773–779.
Ghurani GB, Penalver MA. An update on vulvar cancer. Am J Obstet Gynecol
2001; 185(2): 294–299.
Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic and
immunohistochemical study of 11 cases with and without associated
rectal adenocarcinoma. Am J Surg Pathol 1998; 22: 170–179.
Gungor T, Altinkaya SO, Ozat M, et al. Primary malignant melanoma of the
female genital tract. Taiwan J Obstet Gynecol 2009; 48(2): 169–175.
Hampl M, Hantschmann P, Michels W, Hillemanns P. Validation of the
accuracy of the sentinel node procedure in patients with vulvar cancer:
Results of a multicenter study in Germany. Gynecol Oncol 2008; 111:
282–288.
Hart WR. Vulvar intraepithelial neoplasia: historical aspects and current
status. Int J Gynecol Pathol 2001; 20: 16–30.
Harting MS, Kim KB. Biochemotherapy in patients with advanced
vulvovaginal mucosal melanoma. Melanoma Res 2004; 14: 517–5120.
Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International
Federation of Gynecology and Obstetrics staging of vulvar carcinoma
relative to prognostic factors for survival (a Gynecologic Oncology
Group Study). Am J Obstet Gynecol 1991; 164(4): 997–1003.
References 77

Irvin WP Jr, Legallo RL, Stoler MH, et al. Vulvar melanoma: a retrospective
analysis and literature review. Gynecol Oncol 2001; 83: 457–465.
Jabbar AS. Perianal extramammary Paget’s disease. Eur J Surg Oncol 2000;
26: 612–614.
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects
of the natural history and outcome in 405 women. Obstet Gynecol
2005; 106: 1319–1326.
Joura EA. Epidemiology, diagnosis and treatment of vulvar intraepithelial
neoplasia. Curr Opin Obstet Gynecol 2002; 14: 39–43.
Lara-Torre E, Perlman SE. Vulvar intraepithelial neoplasia in adolescents
with abnormal pap smear results: a series report. J Pediatr Adolesc
Gynecol 2004; 17: 45–48.
Leibowitch M, Neill S, Pelisse M, Moyal-Baracco M. The epithelial changes
associated with squamous cell carcinoma of the vulva: a review of
the clinical, histological and viral indings in 78 women. Br J Obstet
Gynaecol 1990; 97(12): 1135–1139.
Levy RS, Bean SM, Vollmer RT, et al. Paget disease of the vulva: a study of
56 cases. Eur J Obstet Gynecol Reprod Biol 2010; 149: 86–91.
Luk NM, Yu KH, Yeung WK, Choi CL, Teo ML. Extramammary Paget’s disease:
outcome of radiotherapy with curative intent. Clin Exp Dermatol
2003; 28: 360–363.
Lyengar S, Acheson N. Review: Premalignant vulvar conditions. Obstet,
Gynaecol Reprod Med 2008; 60–63.
Martin-Hirsch P, Kitchener HC, Hampson IN. Photodynamic therapy of
lower genital tract neoplasia. Gynecol Oncol 2002; 84:187–189
Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar
intraepithelial neoplasia: a randomized, double-blinded study. Gynecol
Oncol 2007; 107: 219–222.
Medeiros F, Nascimento AF, Crum CP. Early vulvar squamous neoplasia:
advances in classiication, diagnosis, and diﬀerential diagnosis.
Adv Anat Pathol 2005; 12: 20–26.
Minsky B, Hoﬀman J, Kelsedeir D. Cancer of the anal region. In DeVita
V Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice
of Oncology. 6th ed. Philadelphia, Pa: JB Lippincott Co; Chapter 33,
2001: 1319–1342.
Monk BJ, Burger RA, Lin F, Parham G, Vasilev SA, Wilczynski SP. Prognostic
signiicance of human papillomavirus DNA in vulvar carcinoma. Obstet
Gynecol 1995; 85: 709–15.
78 Cancer of Vulva

Moore DH. Review: Chemotherapy and radiation therapy in the treatment

of squamous cell carcinoma of the vulva: Are two therapies better
than one? Gynecol Oncol 2009; 113: 379–383.
Moore DH, Thomas GM, Montana GS, Saxer A, Gallup DG. Preoperative
chemoradiation for advanced vulvar cancer: a phase II study of the
Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 1998; 42:
79–85.
Moore RG, Robison K, Brown AK, et al. Isolated sentinel lymph node
dissection with conservative management in patients with squamous
cell carcinoma of the vulva: a prospective trial. Gynecol Oncol
2008; 109: 65–70.
Moore RG, DePasquale S, Steinhoﬀ MM, Gajewski W, Steller MA,
Falkenberry S. Sentinel node identiication and the ability to detect
metastatic tumour to inguinal lymph nodes in vulvar malignancies.
Gynecol Oncol 2003; 89(3): 475–479.
Moore RG, Granai CO, Gajewski W, Steinhoﬀ MM. Pathologic evaluation of
inguinal sentinel nodes in vulvar cancer patients: a comparison of
immunohistochemical staining versus ultra-staging with hematoxylin
and eosin staining. Gynecol Oncol 2003; 88(2): 190.
Mutch DG. Meeting Report: the new FIGO staging system for cancers of
the vulva, cervix, endometrium and sarcomas. Gynecol Oncol 2009;
115: 325–328.
Origoni M, Sideri M, Garsia S, Carinelli SG, Ferrari AG. Prognostic value
of pathological patterns of lymph node positivity in squamous cell
carcinoma of the vulva stage III and IVA FIGO. Gynecol Oncol 1992; 45:
313–316.
Paget J. On disease of the mammary areola preceding cancer of the
mammary gland. St. Bartholomew Hosp Res (London) 1874; 10:
87–89.
Paladini D, Cross P, Lopes A, Monaghan JM. Prognostic signiicance of
lymph node variables in squamous cell carcinoma of the vulva.
Cancer 1994; 74: 2491–2496.
Piura B, Rabinovich A, Cohen Y, Friger M, Glezerman M. Squamous cell
carcinoma of the vulva in the south of Israel: a study of 50 cases.
J Surg Oncol 1998; 67(3): 174–181.
Piura B. Management of primary melanoma of the female urogenital tract.
Lancet Oncol 2008; 9: 973–981.
Preti M, van Seters M, Sideri M, van Beurden M. Squamous culvar
intraepithelial neoplasia. Clin Obstet Gynecol 2005; 48: 845–861.
References 79

Raspagliesi F, Hanozet F, Ditto A, et al. Clinical and pathological prognostic

factors in squamous cell carcinoma of the vulva. Gynecol Oncol 2006;
102: 333–337.
Raspagliesi F, Ditto A, Paladini D, et al. Prognostic indicators in melanoma
of the vulva. Ann Surg Oncol 2000; 7(10): 738–742.
Robison K, Steinhoﬀ MM, Granai CO, et al. Inguinal sentinel node dissection
versus standard inguinal node dissection in patients with vulvar
cancer: a comparison of the size of metastasis detected in inguinal
lymph nodes. Gynecol Oncol 2006; 101(1): 24–27.
Shutze WP, Gleysteen JJ. Perianal Paget’s disease: classiication and review
of management. Report of two cases. Dis Colon Rectum 1990; 33:
502–507.
Sideri M, Jones RW, Wilkinson EJ, et al. Squamous vulvar intraepithelial
neoplasia: 2004 modiied terminology, ISSVD Vulvar Oncology
Subcommittee. J Reprod Med 2005; 50(11): 807–810.
Sillman FH, Sedlis B, Boyce JG. A review of lower genital intraepithelial
neoplasia and the use of topical 5-luorouracil. Obstet Gynecol Surv
1985; 40: 190–220.
Simcock B. Review: Invasive vulval cancer. Obstet, Gynaecol Reprod Med
2008; 18(3): 64–68.
Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging
using lymphotropic nanoparticle enhanced magnetic resonance
imaging with ferumotran-10 in patients with penile cancer. J Urol
2005; 174(3): 923–927.
Thirlby RC, Hammer CJ, Galagan KA, et al. Perianal Paget’s disease:
successful treatment with combined chemoradiotherapy. Report of a
case. Dis Colon Rectum 1990; 33: 150–152.
Thomas G, Dembo A, DePetrillo A, et al. Concurrent radiation and
chemotherapy in vulvar carcinoma. Gynecol Oncol 1989; 34(3):
263–267.
Van de Nieuwenhof HP, van der Avoort IAM, de Hullu JA. Review of squamous
premalignant vulvar lesions. Crit Rev Oncol/Hematol 2008; 68:
131–156.
van der Avoort I, Shirango H, Hoevenaars BM, et al. Vulvar squamous cell
carcinoma is a multifoctorial disease following two separate and
independent pathways. Int J Gynecol Pathol 2006; 25(1): 22–29.
Van der Zee AG, Oonk MH, De Hullu JA, et al. Sentinel node dissection is
safe in the treatment of early-stage vulvar cancer. J Clin Oncol 2008;
26: 884–889.
80 Cancer of Vulva

Van Doorn HC, Ansink A, Verhaar-Langereis M, Stalpers I. Neoadjuvant

chemoradiation for advanced primary vulvar cancer. Cochrane
Database Syst Rev 2006; 3: CD003752.
van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history
of vulvar intraepithelial neoplasia III based on enough evidence?
A systematic review of 3322 published patients. Gynecol Oncol 2005;
97: 645–651.
Ve Hullu JA, Hollema H, Lolkema S, et al. Vulvar carcinoma, the price of less
radical surgery. Cancer 2002; 95: 2331.
Zeaps JM, Fu YS, Montz FZ, et al. Surgical-pathologic variables predictive
of local recurrence in squamous cell carcinoma of the vulva. Gynecol
Oncol 1990; 38: 309.
Chapter 4

Carcinoma of Vagina

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
82 Carcinoma of Vagina

Basic Anatomy of the Vagina

Vagina is a muscular tube extends from the cervix to hymenal
ring. Inner mucosal layer of the vagina is formed by a thick, non-
keratinizing, stratiied, squamous epithelium overlying a basement
membrane containing many papillae. Levator ani muscle and
urogenital diaphragm support the vagina. Vagina is attached to
the rectum posteriorly via rectal pillar and anteriorly attached to
the bladder via bladder pillar. The upper vagina receives its blood
supply from uterine and internal pudendal arteries. The lower
part of the vagina receives its blood supply from inferior rectal
artery and other branches from internal pudendal artery. Vaginal
venous plexus mainly drains into the pelvic wall through a
parametrial vein, and lesser degree to vesical and rectal plexuses.
Lymphatic drainage from the vagina is as follows: (a) lower third
to inguinal femoral then to external iliac lymph nodes, (b) middle
third to mainly internal iliac and external iliac lymph nodes and
(c) upper third to common iliac, internal iliac and pre-sacral lymph
nodes. Basic anatomy of the vagina is shown in Fig. 4.1.

Figure 4.1 Anatomy of the vagina. A: cervix, B: vagina fornix, C: vaginal

branch of uterine artery, D: vagina cavity/canal, E: vagina
mucosa, F: muscular layers of vaginal wall, G: adventitia, H:
levator ani muscle, I: hymen.
Carcinoma of Vagina 83

Carcinoma of Vagina
Carcinoma of the vagina is very rare, with primary vaginal carcinoma
representing only 2–3% of all gynaecological malignancies. The
incidence of vagina carcinoma is about 0.7 per 100,000 women
(Grigsby, 2002; Kirkbride et al., 1995). The most common site is
the upper third of the posterior vaginal wall because it is believed
that the upper posterior wall of the vagina is more predisposed to
irritating substances such as vaginal secretions and semen, which
pool in the posterior fornix.
The diagnosis of primary carcinoma of vagina is not always easy
to make; it cannot be considered a primary vaginal cancer if the
portio and external os of the cervix or vulva are also involved in the
tumour at presentation. About 80–90% of carcinomas of the vagina
are metastatic and 60% of patients with vaginal cancer have had a
prior hysterectomy. The mean age at presentation is approximately
67 years, and 20% of vaginal cancers are diagnosed in women
younger than 50 years. More than 90% are epithelial cancers, mainly
squamous cell carcinoma (about 80%), while adenocarcinoma of the
vagina accounts for about 10% of cases (Frank et al., 2007; Grigsby,
2002). Figure 4.2 showed primary vaginal carcinoma diagnosed
several years following hysterectomy for benign gynaecological
condition.

Figure 4.2 Primary vaginal cancer. Patient had hysterectomy for benign
uterine pathology. Later she presented with postmenopausal
bleeding, speculum examination showed raised, friable lesions
with contact bleeding at the posterior vaginal wall.
84 Carcinoma of Vagina

Aetiology of Vaginal Cancer

The actual aetiology of primary vaginal cancer has not been iden-
tiied. A single aetiologic factor is unlikely. The strongest aetiologic
factor for vaginal cancer is the human papilloma virus, especially
types 16 and 18. In utero exposure to DES accounts for 10% of pa-
tients with vaginal cancer (Frank et al., 2007; Herbst et al., 1971).
The number of cases is declining. Up to 30% of patients with pri-
mary vaginal cancer have a previous history of in situ or invasive
carcinoma of the cervix treated at least 5 years before the diagnosis.
Prior pelvic irradiation or chronic irritation from vaginal ring pessa-
ries may also be possible causes. There is also some association with
HIV infection, smoking and alcohol consumption.

Histological Types of Primary Vaginal Cancer

The most common histotype for primary vaginal cancer is squamous
cell carcinoma accounting 80–90% of cases and the peak age is
60 years old. Adenocarcinoma is the second most common
accounting 10% of cases; however, it occurs in a younger age
group between 7 and 34 years old (Frank et al., 2007). The other
rare variant of primary vaginal cancer are verrucous carcinoma
(rare) with peak age of 60 years old, vaginal melanoma (0.5–2%),
peak age 60 years and carries poor prognosis and leiomyosarcoma
(<2%) which can occur secondary to pelvic irradiation. Sarcoma
botryoides or embryonal rhabdomyosarcom of vagina is also a
rare cancer with a peak age of 3 years. Sarcoma botryoides is the
most common vaginal cancer in children. The other type of vaginal
cancer is endodermal sinus tumour (yolk sac tumour) which is rare
and occurs in the young age group with peak age of, this tumour
is very aggressive and is associated with raised alpha fetoprotein
(Grigsby, 2002; Kirkbride et al., 1995).

Adenocarcinoma of the Vagina

Adenocarcinoma of vagina accounts for 14% of cases and occurs
exclusively in young women under 20 years of age (Herbst et al.,
Adenocarcinoma of the Vagina 85

1971; Frank et al., 2007). There are four types of adenocarcinoma

of vagina: (a) clear cell carcinoma, (b) papillary adenocarcinoma, (c)
mucinous adenocarcinoma and (d) adenosquamous carcinoma.

Clear Cell Adenocarcinoma of the Vagina

The association of in utero exposure to diethylstilbestrol is well

known. The incidence of clear cell adenocarcinoma (CCA) of the
vagina in relation to diethylstilbestrol exposure is 1 in 1,000
exposures. Diethylstilbestrol (DES) is a synthetic oestrogen and it
was used in the irst trimester (from 1941 to 1971) to prevent
pregnancy loss; however, the FDA withdrew DES in 1971.
Approximately, 75% of patients with CCA of vagina had a history
of DES exposure, and unfortunately DES-related adenocarcinoma
of the vagina carries poorer prognosis (Frank et al., 2007; Hellman
et al., 2004).
Almost 50% of women who had in utero exposure to DES have
vaginal adenosis. Vaginal adenosis is a glandular epithelial similar
with endocervical gland in the vagina it appears red, velvety and
grapelike clusters lesions. Not all vaginal adenoses are DES-related;
congenital adenosis has been reported in patients as young as
6 years of age. Vaginal adenosis may also develop after destruction
or denudation of the overlying vagina squamous epithelium,
examples following treatment with 5-luorouracil and carbon
dioxide laser. Vaginal adenosis is usually asymptomatic; however,
some presented with vaginal bleeding and vaginal discharge. Rare
complications of vaginal adenosis are atypical adenosis and vaginal
CCA.
In the reproductive tract, clear cell carcinoma of the vagina is
more common than clear cell carcinoma of cervix with a ratio of
60%:40%. The age group of patients with this cancer is between
7 and 34 years old 70% diagnosed at stage 1 disease. The cancer
occurs mainly in the upper third of anterior vaginal wall. The risk
of clear cell carcinoma of vagina is higher if the exposure occurs
before 16-week gestation. About 60% of patients with this cancer
had an exposure during the irst trimester (Frank et al., 2007;
Herbst et al., 1971; Robboy et al., 1981).
86 Carcinoma of Vagina

Vaginal Intraepithelial Neoplasia

The preinvasive lesion of the vagina is known as vaginal
intraepithelial neoplasm (VAIN). Graham and Meigs did the irst
report of VAIN in 1952. Unlike cervical intraepithelial neoplasm,
VAIN is uncommon and does arise from a transformation zone.
The actual aetiology has not been identiied and single
aetiologic factor is unlikely. Similar to invasive carcinoma of the
vagina, the strongest aetiologic factor for VAIN is a human papilloma
virus infection, especially types 16 and 18. Vaginal intraepithelial
neoplasm is extremely rare condition, accounting for approximately
0.4% of lower genital tract intraepithelial neoplasm. The incidence
of VAIN in United State is found to be 0.2–0.4 per 100,000 women.
VAIN can be divided into VAIN 1, VAIN 2 and VAIN 3 (Kirkbride
et al., 1995). In contrast to CIN, there is very limited knowledge
about the rate of progression from VAIN to invasive cancer. VAIN 1
is characterized by slight nuclear and cellular atypia with
preservation of stratiication. While VAIN 3 demonstrated by gross
nuclear atypia involving and complete loss of stratiication. In VAIN,
only VAIN 3 is considered as high-grade lesion while VAIN 1 and 2
are low-grade lesions.
VAIN is more common among 50–60-year-old patients. A
history of tobacco use is frequent among women diagnosed with
VAIN. The other risk factors for VAIN are pelvic radiotherapy and
patient with chronic immunocompromised state such as AIDs.

Figure 4.3 Colposcopic view of VAIN lesion on the vaginal vault. Observe
the raised, irregular lesions; on further magniication, atypical
vessels were seen, representing the high-grade lesions.
Treatment of Vaginal Intraepithelial Neoplasm 87

Most of patients with VAIN are asymptomatic. Some of them

may present with vaginal discharge or abnormal vaginal bleeding.
VAIN is also often diagnosed incidentally, following assessment of
patient who had been treated for CIN or cervical carcinoma in the
past. The diagnosis of VAIN is made through colposcopic examination
and vaginal wall biopsy. Colposopic features of VAIN are lat warty
lesions with multicentric foci of dense and white epithelium after
application of acetic acid (Figs. 4.3 and 4.4). The colposcopic directed
biopsy is important for the diagnosis of VAIN and to exclude the pre-
existing invasive cancer.

Figure 4.4 Same lesions as seen in Fig. 4.2 but following the application of
Lugol’s iodine. The abnormal lesion lacks of iodine uptake.

Treatment of Vaginal Intraepithelial Neoplasm

Before treating VAIN, patient must be thoroughly evaluated to rule
out the pre-existing pre-invasive disease of the vulva and the cervix.
It is also important to rule out the invasive carcinoma of the vagina. If
the lesion is unifocal and small, local excision is the treatment of choice
and the depth of treatment must be at least 1 mm (Fig. 4.5). Local
ablative therapy is indicated in large and multifocal lesions.
Local ablative therapy can be performed by electrocoagulation,
cryotherapy or laser vaporization in superpulse or ultrapulse mode
88 Carcinoma of Vagina

(to the depth of 2–3 mm). The other option for local treatment
is application of topical 5-Fluorouracil 20% 1.5 gm weekly for
10 weeks or 1 gm nightly for one week with the response rate of
75–90%. The other option is application of 5% imiquimoid cream
especially for extensive and multifocal lesions. In some patients
who failed to respond to local ablative treatment, radical surgical
excision such as partial or total vaginectomy may be indicated with
reconstructive surgery of the vagina in sexually active women.
Radiation therapy is the last choice and not recommended in
majority of patient due to high recurrence rate and the risk of
complications such as vaginal stenosis and other radiation toxicities.
Radiotherapy in form of low dose intracavitary radiotherapy
65–80 Gy for in situ lesion and the whole vagina need to be irradiated
using 50–60 Gy to the entire vagina for multifocal lesions. Radio-
therapy and vaginectomy should be avoided in young patients as
this treatment may compromise their sexual function.
Patients with VAIN must be followed up once in three to six
months for few years because these women are at increased risk of
recurrence. Cervical and vaginal wall smear should be done during
each follow-up visit and if necessary, and repeated colposcopic
evaluation must be performed if recurrent disease is suspected.

Figure 4.5 Upper vaginectomy specimen in patient with VAIN 3.

Staging of Vaginal Carcinoma 89

Clinical Presentation of Vaginal Carcinoma

Approximately, 10–27% of patients with vaginal carcinoma are
asymptomatic. Painless vaginal bleeding is the most presenting
symptom accounting for 65–80% of the symptomatic patients. Thirty
percent of patients presented with vaginal discharge and 20% with
urinary symptoms such as bladder pain, dysuria and haematuria
(Hellman et al., 2004; Kirkbride et al., 1995). The other presenting
symptoms are postmenopausal bleeding, postcoital bleeding
and intermenstrual bleeding. Pelvic pain, tenesmus and vaginal
ulceration with utero-vaginal prolapse are rare presentation.

Staging of Vaginal Carcinoma

The staging of vaginal cancer is clinical, similar to cervical cancer.
The latest FIGO staging 2009 is shown in Table 4.1. There are no
changes in this latest staging as compared to the earlier FIGO
staging.

Table 4.1 FIGO staging (cancer of vagina)

Stage Descriptions
Stage 1 The carcinoma is limited to the vaginal wall
Stage 2 The carcinoma has involved the subvaginal tissue but has not
extended to the pelvic wall
Stage 3 The carcinoma has extended to the pelvic wall
Stage 4 The carcinoma has extended beyond the true pelvis or has
involved the mucosa of the bladder or rectum; bullous oedema as
such does not permit a case to be allotted to stage IV
Stage 4A Tumour invades bladder and/or rectal mucosa and/or direct
extension beyond the true pelvis
Stage 4B Spread to distant organs

During staging procedures, multiple cervical biopsies are

strongly recommended; if the cervical biopsy is positive, vagina
cancer is considered secondary from cervical carcinoma. In vaginal
cancer, risk of nodal metastasis is dificult to determine because
of the rarity of this disease and patients were mostly treated
with radiotherapy. The risk of pelvic recurrence depends on the
stage (stage I, 10–20%; stage II, 35%; stage III, 25–37%; stage V,
58%).
90 Carcinoma of Vagina

Management of Vaginal Cancer

Radiation therapy is a preferred modality of treatment because it
provides an excellent tumour control and good functional results
(Chyle et al., 1996; Samant et al., 2005; Lian et al., 2008). Surgery is
indicated in the following patients: (a) small localized stage 1 lesions,
(b) stage 1 CCA in young women, (c) in young women who want
to preserve fertility and ovarian function, (d) in selected stage 4A
disease, particularly in the presence of rectovaginal or vesicovaginal
istula, (e) failed radiation therapy, (f) recurrence after irradiation
(usually requiring exenteration), (g) verrucous carcinoma (radiation
therapy is contraindicated) and (h) non-epithelial tumours (Cutillo
et al., 2006).

Surgery in Stage 1 Disease

The type of surgical treatment depends on the site of the tumour.
If the tumour is located in the middle and upper third of the vagina,
radical hystero-vaginectomy and pelvic lymph nodes dissection
is the treatment of choice. For localized lesion, partial colpectomy
may be performed instead of total vaginectomy. Tumour in the lower
third of the vagina is best treated with radical vulvovaginectomy
(or hemivulvectomy and lower vaginectomy) and bilateral groin
lymph node dissection. Radical vaginectomy usually requires a
combined abdominal-perineal approach. An omental graft can be
used to cover the upper vagina, while the lower vagina requires
a split-thickness skin graft or a myocutaneous lap. In selected
young patients who wanted to preserve their fertility, a radical
wide local excision with surgical margin of at least 1 cm (radical
tumorectomy) and pelvic lymphadenectomy (laparotomy or
laparoscopically) can be considered (Cutillo et al., 2006).

Treatment of Stage 2–4 Vaginal Cancer

The treatment of choice for stage 2 and 3 vaginal cancer is radiation
therapy. In premenopausal patients, pre-treatment ovarian transpo-
sition and resection of enlarged nodes can be performed. Ovarian
transposition will minimize the risk of radiation-induced premature
menopause. Stage 4A can be treated with either radiotherapy or
Radiation Therapy in Vaginal Cancer (Stage by Stage) 91

pelvic exenteration, whereas patients with stage 4B disease are

treated with palliative intent.

Radiation Therapy in Vaginal Cancer

(Stage by Stage)
There are two types of radiation therapy: (a) external beam radio-
therapy and (b) brachytherapy (intracavitary/interstitial therapy).

Radiation Therapy for Stage 1

The majority of cases of stage 1 vaginal cancer require brachytherapy
alone. For supericial tumours, intracavitary cylinder covering the
entire vagina (60 to 70 Gy mucosal dose) and additional 20–30 Gy
mucosal dose to the tumour area are given. In larger and deeper
lesions (>1 cm, some deined as >5 mm), the above treatment is
given plus single plane interstitial implants to increase the depth
dose. Some have suggested using interstitial implants for lesions
involving the lateral and anterior wall of the lower two-thirds of
the vagina, while intracavitary BRT is favoured for posterior wall
lesions and lesions in the upper 1/3 of the vagina. More invasive,
aggressive and poorly diﬀerentiated tumours require an additional
dose to the parametrium and whole pelvis (Chyle et al., 1996; Samant
et al., 2005; Lian et al., 2008).

Figure 4.6 Example of radiation therapy technique for vaginal cancer

(diﬀerent institutions may have a diﬀerent technique).
92 Carcinoma of Vagina

Radiation Therapy for Stage 2A

Stage 2A vaginal cancer is treated with interstitial (double-plane
or volume plane) and intracavitary irradiation with greater
external irradiation to the whole pelvis with 20 Gys and additional
parametrial dose (total 45–50 Gys).

Radiation Therapy for Stage 2B, Stage 3 and Stage 4A

In more advanced stage 2B, 3 and 4A, higher dose of radiation
(40 Gy whole pelvis, 55–60 Gys additional parametrial dose) using
a similar method are given. Para-aortic irradiation may be indicated
if bulky pelvic or para-aortic nodes are present.
There is lack of good prospective data to substantiate the use
of concurrent chemotherapy with radiation in locally advanced
vaginal cancer. However, with the frequent local failure in these
high-risk patients, the use of concurrent 5-luorouracil and/or
cisplatin appears appropriate (Dalrymple et al., 2004). Lesions
involving lower part of the vagina may require additional inguinal
nodes irradiation (if node positive), i.e. a further 15–20 Gy in 7–10
fractions given in 10–14 days.

Survival
Five-year overall survival rate for vaginal cancer is 55.6%. Overall
survival is inluenced by (a) the stage (stage I and II are early
disease and have a better prognosis), (b) dose of radiotherapy
(poorer prognosis if the total dose < 70 Gy and BRT < 20 Gy) and
(c) size of tumour (>4–5 cm tumour has signiicantly lower overall
survival) (Chyle et al., 1996; Lian et al., 2008; Tabata et al., 2002).
Some study showed tumour located at the upper third of the vagina
has a better prognosis. The most important prognostic factor is the
stage. The 5-year survival rates are 70–90% for stage 1, 45%
for stage 2, 30% for stage 3 and 15% for stage 4 (Anderson et al.,
2003; Emberger et al., 2006).

Vaginal Melanoma
Primary vaginal melanoma is extremely poor prognosis and the
5-year survival rates are only 9.1%. It has a high incidence of
Clear Cell Adenocarcinoma of Vagina 93

distant metastases and the best treatment for vaginal melanoma

remains controversial. Radical surgery has been the main
treatment modality. The treatment options for vaginal melanoma
are (a) local excision/partial vaginectomy, (b) radical surgery,
(c) radiotherapy using high dose fraction and (d) surgery plus
irradiation. Small lesions in the upper vagina are treated by radical
hysterectomy, upper vaginectomy and pelvic lymphadenectomy.
Lesions in the lower vagina are treated by partial vaginectomy, total
or partial vulvectomy and bilateral inguinal lymphadenectomy.
The recurrence rate of vaginal melanoma is high: local recurrence
rate of 40.7%, regional failures in 20% and distant metastases
in 35%.

Small Cell Carcinoma of Vagina

As in small cell carcinoma of the lung, these tumours have a great
propensity for distant dissemination and can be rapidly fatal.
The usual chemotherapeutic agents used in small cell carcinoma
arecyclophosphamide, doxorubicin (Adriamycin), and vincristine
sulfate (CAV), with administration of 8–12 cycles, some before
initiation of irradiation. Cisplatin and etoposide (VP-16) are also
frequently used.
In some patients, radiotherapy is the only option and the dose
of irradiation is similar to those administered for squamous cell
carcinoma.

Clear Cell Adenocarcinoma of Vagina

Most young women with CCA of the vagina have a history of
prenatal exposure to diethylstilbestrol; however, some develop
vaginal CCA without this history. Surgery for stage I CCA may
have the advantage of ovarian preservation and better vaginal
function after skin graft; however, surgery for vaginal CCA requires
removal of most of the vagina and reconstructive procedures. A
radical hysterectomy and lymph node dissection are necessary to
encompass the area from the parametria and paracolpium to the
sidewalls of the pelvis. The periaortic nodes should be sampled
before the procedure to determine if there is a lymphatic disease
beyond the pelvis.
94 Carcinoma of Vagina

Fletcher and Wharton (1980) advocate intracavitary or

transvaginal irradiation for treatment of small tumours because
it may yield excellent tumour control with a functional vagina
and preservation of ovarian function. For more extensive lesions,
external radiation therapy is essential. Techniques are similar to
those described earlier.

Vaginal Recurrences
Post-irradiation local failures can sometimes be eﬀectively treated
with surgery. Surgical procedures range from wide local excision
or partial vaginectomy to exenterative procedures. Meticulous and
regular follow-up examinations are important to detect recurrences
early.

Other Vaginal Cancers

• Leiomyosarcoma: For low-grade tumour, local excision may
be suficient, but for high-grade lesion, the patient should
receive radiotherapy.
• Rhabdomyosarcoma of the vagina generally is treated with
a combination of surgical resection, irradiation, and sys-
temic chemotherapy. Sarcoma botryoides is treated with a
combination of chemotherapy, surgery and radiotherapy. In
small-localized lesion, local excision followed by either chem-
otherapy or radiotherapy is eﬀective. In large tumour, preop-
erative chemotherapy or radiotherapy can be administered to
facilitate surgical resection. Chemo-therapy regimen is VAC
(vincristine, actinomycin D and cyclophosphamide) regimen.
• Lymphomas: Radical surgery occasionally has been used for
treatment of localized malignant of the vagina. Satisfactory
results with a combination of external irradiation and intra-
vaginal brachytherapy combined with chemotherapy have
been reported. Six cycles of chemotherapy usually are given;
most frequently, chemotherapy consists of cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP), or CHOP
plus bleomycin sulfate (BACOP).
References 95

• Endodermal sinus tumour of the vagina is preferentially

are treated with surgery and chemotherapy (VAC regimen),
because this lesion often occurs in young women and
preservation of the ovarian function is desired. Brachytherapy
may occasionally be used.

References
Anderson ES, Hanselaar AG, Paavonen J, et al. Tumors of the vagina. In:
Tavassoli FA, Devilee P, eds. Tumors of the Breast and Female Genital
Organs. Lyon: IARC Press, 2003: 292–311.
Chyle V, Zagar GK, Wheeler JA, Wharton JT, Delsclos L. Deinitive radio-
therapy for carcinoma of vagina: outcome and prognostic factors.
Int J Radiat Oncol Biol Phys 1996; 35: 891–905.
Cutillo G, Cignini P, Pizzi G et al. Conservative treatment of reproductive
and sexual function in young woman with squamous carcinoma of
vagina. Gynecol Oncol 2006; 103: 234–237.
Dalrymple JL, Russell AH, Lee SW, et al. Chemoradiation for primary
invasive squamous carcinoma of the vagina. Int J Gynecol Cancer 2004;
14: 110–117.
Davies M, Mount S. Premalignant and malignant lesions of the vagina.
Diagn Histopathol 2010; 16(11): 508–516.
Emberger M, Lanschuetzer CM, Laimer M, Hawranek, Staudach A.
Vaginal adenosis induced by Stevens–Johnson syndrome. J Eur Acad
Dermatol Venereol 2006; 20: 896–898.
Fletcher GH, Wharton JT. Tumour of the vagina and female urethra. In:
Fletcher GH, ed. Textbook of Radiotherapy, 3rd ed. Philadelphia:
Lea & Febiger, 1980: 821–824.
Frank SJ, Deavers MT, Jhingran A, Bodurka DC, Eifel PJ. Primary
adenocarcinoma of vagina not associated with DES exposure.
Gynecol Oncol 2007; 105: 470–474.
Grigsby PW. Vaginal cancer. Curr Treat Options Oncol 2002; 3: 125–130.
Hellman K, Lundell M, Silfversward C, Nilsson B, Hellstrom AC, Frankendal
B. Clinical and histopathologic factors related to prognosis in
primary squamous cell carcinoma of the vagina. Int J Gynecol Cancer
2006; 16(3): 1201–1211.
Hellman K, Silfversward C, Nilsson B, Hellstrom AC, Frankendal B,
Pettersson F. Primary carcinoma of the vagina: factors inluencing the
96 Carcinoma of Vagina

age at diagnosis. The Radiumhemmet series 1956–96. Int J Gynecol

Cancer 2004; 14: 491–501.
Herbst A, Ulfelder H, Poskanzer D. Adenocarcinoma of the vagina: an
association of maternal stilbestrol therapy with tumor appearance in
young women. N Engl J Med 1971; 284: 878–881.
Kirkbride P, Fyles A, Rawlings GA, Manchul L, Levin W, Murphy KJ,
Simm J. Carcinoma of vagina: experience at the Princess Margaret
Hospital (1974–1989). Gynecol Oncol 1995; 56(3): 435–443.
Lian J, Dundas G, Carlone M, Ghosh S, Pearcey R. Twenty-year review
of radiotherapy for vaginal cancer: an institutional experience.
Gynecol Oncol 2008; 111: 298–306.
Martino MA, Nevadunsky NS, Magliaro TJ, Golberg MI. The DES year: bridging
the past to the future. Prim Care Update Ob/Gyns 2002; 9: 7–12.
Robboy S, Szyfelbein W, Goellner J, et al. Dysplasia and cytologic indings
in 4,589 young women enrolled in Diethystilbestrol-Adenosis
(DESAD) Project. Am J Obstet Gynecol 1981; 140: 579–586.
Samant R, Tam T, Dahrouge S. Radiotherapy for treatment of primary
vaginal cancer. Radiother Oncol 2005; 77: 133–136.
Tabata T, Taheshima N, Nishida H, et al. Treatment failure in vaginal cancer.
Gynecol Oncol 2002; 84: 309–314.
Chapter 5

Screening for Cervical Cancer

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
98 Screening for Cervical Cancer

Basics in Cancer Screening

The purpose of cancer screening is to identify asymptomatic
individuals who have a signiicant risk of acquiring cancer, which
warrants further diagnostic procedures.
Following are the criteria for an eﬀective cancer-screening
program:
• The cancer is a major health problem.
• The cancer is treatable at an early stage.
• The screening test is acceptable.
• The screening test is inexpensive.
• The screening test has high sensitivity (the bulk of subjects
with the cancer should test positive).
• The screening test has a high speciicity (the vast majority of
subjects without the cancer should test negative).
• Screening has been shown to reduce mortality in randomized
controlled trials.
• Screening has been shown to be a cost-eﬀective means of
controlling this cancer.

How to Calculate Sensitivity and Specificity

In any cancer-screening test, sensitivity and speciicity of the test
are the most important statistical measures to evaluate the efica-
cy of the test. The deinition of and how to calculate the sensitivity
and speciicity are shown in Table 5.1.
The ideal screening test must have high sensitivity and
speciicity. There are four main criteria for a good screening test:
(a) high sensitivity so the tests do not miss the cases with the
disease, (b) high speciicity to reduce the number of people with
false-positive results who require diagnostic evaluation, (c) high
positive predictive value and (d) simplicity and low cost.
Screening for any health problems is not without risk. The
possible adverse eﬀects from screening are
(a) discomfort from the test
(b) anxiety
(c) potential side eﬀects related to test, e.g. radiation exposure in
mammography
Screening of Cervical Cancer 99

(d) false positive test

(e) risk of overdiagnosis (pseudodisease) (screening can lead
to the detection of the early stage of cancer and this will
accompanied by a temporary increase in the cancer incidence;
in slow-growing tumour with excellent prognosis, screening
might lead to “overdiagnosis”; some of these tumours may
even regress spontaneously, e.g. neuroblastoma).

Table 5.1 Sensitivity and speciicity

Screen result
Cancer present Negative Positive
No A B
Yes C D

A: Number of persons who do not have cancer and screen negative

B: Number of persons who do not have cancer but screen positive
C: Number of persons who do have cancer but screen negative
D: Number of persons who have cancer and screen positive
Sensitivity = D ÷ (C + D): The proportion of disease that test positive
Speciicity = A ÷ (A + B): The proportion without disease and test negative
Positive Predictive Value = D ÷ (B + D): The proportion testing positive who will
have disease.

Cervical Cancer Prevention

Cervical cancer is preventable disease because it has the most
eﬀective screening test. There are three modalities of cervical
cancer prevention:
(a) Primary prevention: prevention of HPV infection through
sexual abstinence, healthy lifestyle and HPV vaccination;
(b) Secondary prevention: detection and treatment of
precancerous state through screening;
(c) Tertiary prevention: detection and treatment of an early
stage of cancer.

Screening of Cervical Cancer

Screening of precancerous lesions and invasive cervical cancer
is considered secondary prevention. Secondary prevention stops
100 Screening for Cervical Cancer

the progression of disease once it has already started. There has

been lack of the number of randomized trials to evaluate the impact
of screening on cervical cancer incidence and mortality. Majority
of data on the effectiveness of screening were from cohort and
case-control studies.
A comprehensive analysis of data by International Agency for
Research on Cancer (IARC) showed the following:
(a) Well-organized screening programs were effective in reducing
cervical cancer incidence and mortality.
(b) In Nordic countries, the greatest fall in a cumulative mortality
rates was in Iceland (84% from 1965 to 1982).
(c) The greatest reduction in the cervical cancer incidence was in
women aged between 30 and 49 years, for whom the focus of
screening was the most intense.
(d) Target age range of a screening program was a more important
determinant of risk reduction than frequency of screening
within the deined age range.
(e) Screening interval every 2–3 years have been found to be as
effective as annual screening (Table 5.2).
(f) The protective effect of 5 years’ screening interval in the
organized screening program was still high, i.e. more than 80%.
(g) Screening every 2 years is approximately 50% more expensive
than screening every 3 years.
(h) Risk of developing invasive cervical cancer is 3–10 times
greater in women who have not been screened. Risk also
increases with long duration following the last normal
screening test.

Table 5.2 Eﬀectiveness (reduction in cervical cancer incidence) of the

cervical cancer screening program based on the target age
group and screening interval (Sasieni et al., 2003)

20–39 years 40–54 years 55–69 years

3 yearly screening 41% 69% 73%
5 yearly screening 30% 63% 73%

There are four main modalities of screening tests for cervical

cancer: (a) cytology, (b) visual inspection, (c) HPV testing and (d)
combination.
Screening Population 101

Screening Population
One of the most important factors to determine the success of
any cancer-screening program is the target population and age
groups. In cervical cancer screening program worldwide, there are
slight variations in the target age group and interval of screening
between countries and institutions. In United Kingdom under
NHS (UK), 2004 guideline, the age group for screening is all
women between ages of 25–64, Interval: 3 yearly (age 25–49),
5 yearly (age 50–64), and for women age above 64 years old, only
screen those who have not been screened since age 50 or have
had recent abnormal tests. In United States, according to revised
ACOG guidelines, the target age group is 21–65 years old, begins at
the age of 21 years, regardless of sexual history, end at 65–70 years
old. The recommended interval of screening is 2 yearly (age 21–29)
and for women age more than 30 years old; the recommended
testing is cytology and HPV testing. If both tests are normal,
re-screening should be performed no sooner than 3 years later.
The screening is stopped at the age of 65–70 if three consecutive
smears are normal or no abnormal smears in last 10 years.
Cervical Screen program of Singapore (CSS) recommended
screening at the age of 25–64 year old (who had sexual exposure)
with the interval of 3 years; women age 35–64 years old will
receive a letter of invitation.
Based on the guidelines from US Preventive Services Task Force
(USPSTF), the target group for screening is women aged 21–65
years old, begins the screening within 3 years of onset of sexual
activity or age 21 (whichever comes irst) with the interval of at
least 3 yearly. Finally, in Australia; National Cervical Screening
Program (NCSP Australia) recommended screening at the age of
18–70 year old (sexually active women begin to screen at the age
of 18–20 or 1–2 years after irst sexual exposure, whichever is
later). National Cervical Screening Program suggested stopping
screening after age of 70 when two consecutive smears are normal
within last 5 years. The interval of screening is 2 years.
Women with high risk factors such as smokers, multiple sexual
partners, sex workers, history of in utero exposure to DES, history
of CIN and immunosuppresion (HIV, renal transplant, chronic
steroid treatment, etc.) should have yearly screening.
102 Screening for Cervical Cancer

Cytologic Screening for Cervical Cancer and Its

Precursors
Dr. George Papanicolaou irst proposed the cytologic evaluation of
cells taken from the cervix and vagina in the 1940s, and in 1947
Ayre’s introduced wooden spatula. Pap smear screening program
signiicantly reduced the incidence and mortality of cervical cancer
(see screening of cervical cancer above). In the United Kingdom,
since the introduction of the organized Pap smear screening
program in 1988, the incidence and mortality rate of cervical cancer
have fallen by more than 50%.
Studies have shown that pap smear is highly speciic in
detecting invasive cervical cancer and high-grade squamous
intraepithelial lesions, although it is less speciic in low-grade lesion.
Unfortunately, Pap smear is not very sensitive. Meta-analyses
suggested that the sensitivity of single conventional Pap test for
CIN 2/3 or higher is 50–60% (Wright, 2007; Nanda et al., 2000).
In other cross-sectional studies evaluating the accuracy of cytologic
testing from developing countries, the sensitivity of this testing
was between 44–78% (Sankaranarayanan et al., 2009).

Figure 5.1 The samplers and Pap smear.

Cytologic Screening for Cervical Cancer and Its Precursors 103

In general, cytologic testing has a wider range of sensitivity but

high speciicity ranging from 60–96% (Sankaranarayanan et al.,
2004; Denny et al., 2006; Nanda et al., 2000) and low sensitivity of
Pap smear was attributed to poor sample collection, incorrect slide
preparation and laboratory interpretation errors. False negative
rate of Pap smear is ranging from 8–50%. In order to reduce the false
negative rate, sample from the endocervix has to be taken. Many
have recommended using cytobrush to sample the cervix because
it can obtain more cells than Ayre’s spatula and cotton tipped
applicator (Figs. 5.1 and 5.2).

samples are
smeared on the cervical cells
slide seen under
micorscope

Figure 5.2 Pap smear, how the sampling is performed.

Timing and methods of taking Pap smear are very important

and there are several tips on how to obtain optimum Pap smear:
(a) Before smear, there should be no douching and vaginal
washing, and the last sexual intercourse must have happened
more than 24 hours earlier.
104 Screening for Cervical Cancer

(b) Pap smear should not be done during menses and within 1
week after discontinuation of antimicrobs.
(c) Smear is taken before a bimanual examination and no
lubricant.
(d) No acetic acid should be used before Pap smear.
(e) Ayre’s spatula rotated 360° twice or by cytobrush rotated
180° and place in same slide: Spread smear on slide and roll
brush over the same slide.
(f) Immediate ixation in alcohol: Either use spray ixative, at
a right angle to, and a distance of 20 cm from the slide or
immerse the slide in a container of 95% alcohol (ethanol) for
at least 5 minutes.
Currently, there are two types of cytologic testing: (1)
conventional cytology and (2) liquid-based cytology.

Liquid-Based Cytology
Liquid-based cytology (LBC) was introduced in the mid-1990s
to increase the sensitivity and speciicity of cervical screening.
In conventional Pap test, 80% of patient’s cell sample containing
important diagnostic information is discarded with the sample
devices. In LBC, sampling technique is similar with a conventional
method. The samples are washed in a medium (ethanol-based) and
a monolayer of cervical cells is spread on a slide. Because the cells
are not “smeared”, they do not clump together and all the samples
are preserved. The remaining samples can also be used for HPV
DNA testing.
Numerous studies have compared the accuracy of LBC and
conventional cytology; however, results have been inconsistent.
Cluster randomized controlled trial involving 89,784 women
aged 30 to 60 years indicates that LBC does not perform better
than conventional Pap tests in terms of relative sensitivity and
PPV for detection of cervical cancer precursors (Siebers et al.,
2009). A randomized controlled trial by Ronco, involving 45,000
participants, has shown that (a) liquid-based cytology showed no
statistically signiicant diﬀerence in sensitivity to conventional
cytology for detection of cervical intraepithelial neoplasia of grade
2 or more, (b) there were more positive results with LBC and
Technologies Related to Liquid-Based Cytology 105

(c) there was large reduction in unsatisfactory smear in the LBC

group (from 4.1% to 2.6%). The per test cost of LBC is higher
than the conventional Pap smear but this is compensated for by
reduction in inadequate samples, repeat tests and screening time
together with the ability to perform additional tests from the same
cervical specimen. The principle of pap smear test is shown in
Fig. 5.3.

Figure 5.3 During Pap smear, the cells exfoliated on the surface of the cer-
vical epithelium are obtained. These cells are the representa-
tives of the underlying cervical pathology.

Technologies Related to Liquid-Based Cytology

ThinPrep Pap Test
ThinPrep Pap Test is approved by the FDA in 1996. This technique
uses the ilter method and the detection rate is better than
conventional method. It separates cells from the background
material, results in uniform layers of cells and improves the detection
rate. The method is 65% more eﬀective than conventional Pap
test in detecting pre-cancerous lesions. However, some argue that
106 Screening for Cervical Cancer

this test is no better than the conventional one and that it would
result in too many false warnings, unnecessary alarming the patient.
The end result is a circular layer cells of 20 mm size and same
sample can be used to test for HPV using Digene Hybrid Capture HPV
DNA assay.

AutoCyte PREP
The other sample preparation system is AutoCyte PREP, approved
by the FDA in 1999. In this method, brush pad used to collect
cells is “disconnected” and dropped into the vial (contain ethanol-
based preservation). The end result is a circular layer cell of size
13 mm.

PapNet
PapNet is based on computerized re-screening, utilizing LBC tech-
nology. PAPNET is an automated interactive system for the analysis
of Pap smears, which has been shown to detect abnormalities that
were repeatedly missed on manual screening.

AutoPap
AutoPap system scanned slides of Pap smears and ranked specimens
according to their degree of abnormality. The system will identify
25% of slides that have the lowest risk and excluding it from
rescreening, thus reducing the screener’s workload by 25%. The FDA
has approved AutoPap in May 1998. AutoPap rescreening identiied
3–5 times more false-negative cases than traditional quality control
measures.

ThinPrep Imaging System

The ThinPrep imaging system (TIS) consists of three components:
an image processor, a PC-based computer that runs on Windows
NT and a review microscope. The TIS uses algorithms to select
22 ields of view (FOV), which include the cells most likely to be
dysplastic according to computer imaging characteristics. The TIS
has been shown to provide increased sensitivity and speciicity
Bethesda 2001 Reporting System 107

over manually reviewed ThinPrep Pap Test slides. In one study,

the TIS was found to have a 50% reduction in a false negative
fraction when compared to manually reviewed ThinPrep Pap Test
slides.

Bethesda System of Reporting Pap Smear Results

Terminology of Cytologic Reports
Cervical cytology became the standard screening test for cervical
cancer and premalignant cervical lesions with the introduction of
the Papanicolaou smear in 1941. The terminology and reporting
system was irst introduced by Papanicolaou, who devised the Class
1–5 systems. In 1973, the WHO proposed mild, moderate and severe
dysplasia, CIS, invasive Ca and adenocarcinoma. Since then, the
terminology and reporting system had gone through various stages
and changes to suit with the current technology and understanding
of preinvasive disease of the cervix. In 1988, National Institutes
of Health consensus panel formed a new terminology known as
Bethesda System. Bethesda system has been revised in 1991 and
currently been widely used worldwide. The major features of
Bethesda Systems are: (a) estimation of the adequacy of a specimen,
(b) general categorization into normal and benign cellular changes
due to inlammation and epithelial abnormality and (c) descriptive
diagnosis in details. The latest Bethesda system is Bethesda
System 2001, shown in Table 5.3.

Bethesda 2001 Reporting System

Table 5.3 Bethesda System 2001

Category Reporting
Specimen (a) Satisfactory for evaluation (note presence/absence
adequacy of endocervical/transformation zone component)
(b) Unsatisfactory for evaluation . . . (specify reason)
(c) Specimen rejected/not processed (specify reason)
(d) Specimen processed and examined, butunsatisfactory
for evaluation of epithelial abnormality because of
(specify reason)
(Continued)
108 Screening for Cervical Cancer

Table 5.3 (Continued)

General (a) Negative for intraepithelial lesion or malignancy
categorization (b) Epithelial cell abnormality
(optional) (c) Others
Interpretation/results
Negative for (a) Organisms (Trichomonas vaginalis, fungal organisms
Intraepithelial morphologically consistent with Candida species,
lesion or shift in lora suggestive of bacterial vaginosis, bacteria
malignancy morphologically consistent with Actinomyces species,
cellular changes consistent with herpes simplex
virus)
(b) Other non-neoplastic indings (optional to report;
list not comprehensive): Reactive cellular changes
associated with inlammation (includes typical
repair), radiation, intrauterine contraceptive device,
glandular cells status post-hysterectomy, atrophy
Epithelial cell (a) Squamous cell (atypical squamous cells (ASC),
abnormalities atypical squamous cell of undetermined signiicance
(ASC-US), atypical squamous cell cannot exclude
HSIL (ASC-H), low-grade squamous intraepithelial
lesion (LSIL) encompassing HPV/mild dysplasia/CIN
1, high-grade squamous intraepithelial lesion (HSIL)
encompassing moderate and severe dysplasia, CIS,
CIN2 and CIN3, squamous cell carcinoma)
(b) Glandular cell (atypical glandular cells (AGC): specify
endocervical, endometrial, or not otherwise speciied,
atypical glandular cells, favour neoplastic: specify
endocervical or not otherwise speciied, Endocervical
adenocarcinoma in situ (AIS), adenocarcinoma)
(c) Others (list not comprehensive): Endometrial cells
in a woman ≥40 years old

Non-Cytologic Method of Screening

Cytologic screening test is the most widely used primary screening
tool for cervical cancer worldwide. Besides cytology, there are
two non-cytologic methods that have been recommended for the
screening of cervical cancer: (a) visual inspection and (b) HPV
testing.
Visual Inspection 109

Visual Inspection
Visual inspection is the direct visualization of the cervix after
application of a solution of either acetic acid 3–5% (VIA) or Lugol’s
iodine (VILI). A result is obtained immediately and treatment can
be performed at the same setting (see and treat approach). Visual
inspection is a potential screening method in countries with low-
resource setting. In visual inspection with acetic acid (VIA), CIN
lesions will turn white for a few minutes after application of acetic
acid. The eﬀect of acetic acid is thought to depend on the amount
of nuclear proteins, and cytokeratins present in the cervical
epithelium, which increases in CIN.
The alternative to VIA is VILI or visual inspection with Lugol’s
iodine. Instead of acetic acid, VILI uses Lugol’s iodine, which is
taken up by the normal columnar cells, glycogen containing cervical
cells, while an abnormal epithelium remains unstained or iodine
negative. The large cross-sectional studies evaluating VIA and
VILI (detection of HSIL) involving more than 56,000 women have
reported the following results (Sankaranarayanan et al., 2003,
2004): (a) VIA (pooled data), sensitivity: 76.8% (95% Cl:
74.2–79.4%), speciicity: 85.5% (95% Cl: 85.2–85.8%), positive
predictive value: 9.4% (95% Cl: 8.8–10.8%) and negative predictive
values: 99.5% (95% Cl: 99.4–99.6%), (b) range sensitivity for VIA:
56.1–93.9%, range of speciicity: 74.2–93.8%, (c) VILI (pooled
data), Sensitivity: 91.7% (95% Cl: 89.7–93.4%), speciicity: 85.4%
(95% Cl: 85.1–85.7%), positive predictive value: 10.9% (95%
Cl: 10.2–11.6%), negative predictive values: 99.8% (95% Cl:
99.7–99.9%) and (d) range sensitivity for VILI: 56.1–93.9%, range
speciicity: 74.2–93.8%.
Compared with Pap smear, a meta-analysis shows that
screening with VIA or VILI allows detection of cervical cancer and its
precursors with an accuracy as good or even better than the
standard Pap smear test, although VIA and VILI is less speciic in
comparison to the Pap smear test; however, they are more sensitive
in detecting pre-invasive lesions (Arbyn et al., 2008; Qureshi et al.,
2010). There is evidence that VILI is at least as speciic as but more
sensitive than VIA. Similar to cytology, VIA and VILI may be less
eﬀective for older women in their 50s or 60s because of the tendency
110 Screening for Cervical Cancer

of the transformation zone together with any lesions within it to

recede into the endocervical canal.
Visual inspection was also evaluated in screening and treat
approach (single visit “see and treats” approach). Patients with a
positive screening test were offered an immediate treatment at the
same setting. The treatment was a cryotherapy. The evidence from
published studies indicates that cryotherapy is an effective, safe and
acceptable treatment with cure rates exceeds 86% if performed
by trained staff. Sankaranayanan and colleagues had evaluated
the effectiveness, safety and acceptability of “see and treat” with
VIA and cryotherapy by nurses in a cervical screening study in
India (N = 2513). The nurses were trained in performing VIA,
colposcopy and cryotherapy. Women with a colposcopic impression
of low- or high-grade lesions were advised immediate cryotherapy
after a directed biopsy (see Table 5.4). The acceptability rate was
approximately 75%. The cure rate for CIN 1 and CIN 2–3 was
81.4% and 70.6%, respectively. In this study, “see and treat” with
cryotherapy resulted in 40% of the women being unnecessarily
treated.

Steps to Perform VIA/VILI

(a) counselling
(b) visual technique not recommended in postmenopausal
women
(c) speculum examination
(d) adjusting the light source to get the best view of the cervix
(e) use of a cotton swab to remove any discharge, blood or
mucus
(f) identiication of the squamo-columnar junction and area
around it
(g) application of acetic acid 3–5% or Lugol’s iodine solution to
the cervix and then waiting for 1–2 minutes (VIA is positive if
the epithelium change to white, while VILI is positive if there
is no iodine uptake; iodine uptake is manifested as dark brown
epithelium)
(h) documentation
(i) use of fresh swab to remove any remaining acetic acid or
iodine solution from the cervix and vagina
Role of HPV Testing 111

Table 5.4 Criteria for immediate cryotherapy in see and treat approach

Criteria for immediate cryotherapy

(1) The lesion involved less than three quadrants of the

transformation zone.
(2) No extension of the lesion into the endocervical canal
(3) No extension of the lesion onto the vaginal walls
(4) Entire lesion could be covered by the cryoprobe
(5) Squamo-columnar junction was visible in its entirety
(6) No clinical or colposcopic suspicion of invasive cancer
Source: Sankaranarayanan et al., 2007, Br J Cancer; 96: 738–743.

HPV Testing
Human papillomavirus DNA is identiied in almost all (99.7%)
veriied cases of cervical cancer worldwide (Walboomers et al.,
1999). The FDA approved HPV testing using Hybrid Capture 2 in
April 2003 as a primary screening test for women age more than 30,
and currently it has been incorporated into the National Screening
Program in the United States. The speciicity of HPV testing was
found to be higher in women older than 30 years.
The recognition that cervical cancer is caused by HR-HPV led to
the development of several NTCC prevention measures:
(a) HPV DNA testing
(b) HPV RNA testing
(c) molecular markers related to HPV infection
(d) HPV vaccine

Role of HPV Testing

There are at least four potential roles of HPV testing in the prevention
of cervical cancer:
(1) triage of women with equivocal cytology
(2) follow-up of the patient after treatment of CIN
(3) HPV testing by the “see and treat” approach
(4) HPV testing as primary screening test
112 Screening for Cervical Cancer

Triage of Women with Equivocal Cytology (ASCUS)

The HPV testing can be used to triage women with equivocal
cytology result. ALTS or ASCUS-LSIL Triage Study is a randomized
multicenter trial (3488 women recruited) to determine the best way
to manage women with ASCUS and LSIL. The trial was organized
by the US National Cancer Institute, and recruitment began in
1996. Women with ASCUS and low-grade squamous intraepithelial
lesions (LSIL) on Pap smear were assigned into three study arms:
immediate colposcopy, conservative management or HPV testing
(Hybrid capture 2). Following were the results:
(a) HPV testing had high sensitivity (96%) in the detection of
CIN in women with ASCUS (9–10% had CIN2; 4–5% had
CIN 3).
(b) HPV testing is not useful for LSIL because 82.9% have a
positive test.
(c) HPV triage was found to be at least as sensitive as immediate
colposcopy for detecting CIN3 but accomplished this with
referring only about 50% as many women to colposcopy.
(d) Single enrolment HPV test identiied 92.4% of the women
diagnosed with CIN3+ over 2 years. In this study, the term
“ASCUS” was based on earlier Bethesda system. In Bethesda
2001, ASCUS is divided into two groups, i.e. ASC-US (Atypical
squamous cell of undetermined signiicance) and ASC-H
(Atypical squamous cell, cannot rule out high grade).
Arbyn and colleagues conducted meta-analyses of all valid
studies reported on the comparative accuracy of repeat cervical
cytology and HPV testing to detect CIN2+ in women with ASC-US
or LSIL. HPV testing using Hybrid Capture 2 (HC2) was found to be
more sensitive and equally speciic in comparison to cytology for the
triage of patients with ASC-US Pap results. The meta-analysis also
conirmed the high rate of HPV positivity in LSIL and therefore, HPV
testing for LSIL is not cost eﬀective.
The Italian Multicentric Study (Mistro et al., 2010) evaluated
the role of HPV testing in the triage of ASC-US. Patients with ASC-US
were randomized into immediate colposcopy, conventional Pap test
and HPV testing using Hybrid Capture 2. The results were
(a) Total samples: 749 (age 25–64).
(b) Abnormal colposcopy was reported in 34.2%.
Role of HPV Testing 113

(c) Positive high-risk HPV in 24.2%, (43.4% in women age less

than 35, 17.2% in age more than 35).
(d) HPV testing gave the highest sensitivity and speciicity in
detecting CIN2+, especially in women older than 35 years
(sensitivity 100%, speciicity 84.8% and PPV 13.7%).

Follow-Up of Patient after Treatment for CIN 2–3

Studies and meta-analyses have shown that women who test HPV
negative 6–18 months after their treatment can be safely returned
to routine screening, while those who test positive should be
followed up more closely. Meta-analysis by Arbyn and colleagues
(2005) also reported that HPV testing performed better than
follow-up cytology to predict success or failure of treatment (higher
sensitivity). In the follow-up analysis of ALTS trial, 610 women
were treated with LEEP for CIN and follow-up either with PCR
HPV testing or cytology. During follow-up, 40% of patients were
found positive to HPV. The sensitivity and speciicity of PCR HPV
testing in detecting CIN2+ was 96.9% and 69.1%, respectively,
better than cytology (HPV testing is more sensitive (96.9% versus
78.1%) but with same speciicity). Meanwhile, Hybrid Capture 2
was found to have sensitivity of 90.6% and speciicity of 63.8% as
compared to PCR HPV testing. Therefore, women treated for CIN2+
could be followed up with either cytology or combination of cytology
and colposcopy 4–6 months until three normal cytologic tests are
obtained. With HPV testing, initial follow-up can be done at longer
interval, e.g. 6 months. If three consecutive cytologies are normal or
negative to HPV DNA testing, they can continue routine screening
at a yearly interval.

HPV Testing in Screening and Treat Approach

The role of a screen/see-and-treat approach has been evaluated in
various studies using a cytologic test or visual technique, and the
results were encouraging. The treatment (either LEEP/LLETZ or
cryotherapy) is oﬀered during the same setting following a thorough
colposcopic evaluation. In low-resource setting, VIA followed by
cryotherapy was evaluated and was found to be safe, feasible and
acceptable. Trained nurses can perform the procedure, and no
114 Screening for Cervical Cancer

anaesthesia was required. High cure rate of up to 89% was reported

with this approach (Sankaranarayanan et al., 2007; Blumenthal
et al.). The concern about this approach is overtreatment (up
to 40%) due to false positive test or spontaneous regression,
especially, in low-grade lesions.
HPV testing may play an important role either as a single
test or in combinations with others in identifying a patient who
required treatment. With combination test, false positive rate
can be reduced and therefore, reducing the overtreatment rate.
Further, large randomized control trial is needed to evaluate this
approach.

HPV Testing as Primary Screening Test for Cervical Cancer

The role of HPV testing as a potential primary screening for
cervical cancer has been evaluated in various studies. Sherman and
colleagues evaluating almost 21,000 women, followed up for
10 years from 1992, they had found that the risk of developing
CIN3+ from initial Pap smear > ASCUS or positive HPV testing or
both were nearly 7% as compared to 0.79% for women with negative
test (Sherman et al., 2003). Therefore, the combination of both
negative cytology and negative HPV test provides strong
reassurance that the women will free from the disease for many
years.
In HART (HPV in Addition to Routine Testing) study, 11,085
women age 30–60 were recruited. Women with borderline cytology
and positive to high-risk HPV (using Hybrid Capture 2) were
selected and randomized to immediate colposcopy or to
surveillance by repeat HPV testing with cytology at 12 months.
HPV testing was found to be more sensitive (97.1% versus 76.6%)
in detecting CIN2+ than Pap smear without increasing colposcopy
referral rate.
The randomized study known as Canadian Cervical Cancer
Screening Trial (CCCaST) had recruited more than 10,000 women
aged 30–69 years old to compare conventional Pap smear with
Hybrid Capture 2 HPV DNA testing in screening of cervical cancer.
All trial participants were randomized to receive either cytologic
test or HPV test irst and followed by second test with the primary
end-point of CIN2+. The sensitivity and speciicity of HPV test
Role of HPV Testing 115

alone was 97.4% and 94.3%, respectively. The sensitivity of HPV

test alone was more superior to Pap smear alone (56.4%), Pap
with relex HPV (53.8%) and HPV with relex Pap (53.8%). HPV
test with relex Pap smear was found to have highest speciicity
of 99.1%. The approach that has the highest sensitivity (100%)
was HPV test plus Pap smear although the speciicity was lower
(92.5%) with higher rate of colposcopy referral (7.9%) (Mayrand
et al., 2006, 2007). See Table 5.4 for full results.
New Technologies for Cervical Cancer (NTCC) study (Italian
multicentre RCT) was designed to compare the eﬀectiveness,
acceptability and cost of HPV testing (HC2) compared with the
Pap smear or LBC as a primary screening test. Cytologic test was
compared to HPV testing using HC2. Women with ASCUS+ or HPV
positive were referred for colposcopy. The study showed that HPV
testing and/or liquid-based cytology had higher sensitivity than
conventional Pap smear. Conventional Pap smear, however, had
higher positive predictive value. By using the 2pg/ml threshold for
positive test, HPV testing alone was found to have similar relative
sensitivity but higher relative positive predictive value. Therefore,
2 pg/ml threshold may be appropriate for HPV testing as a
primary screening for cervical cancer (Ronco et al., 2006).
A study known as ARTISTIC (Randomized Trial in Screening
to Improve Cytology) was conducted to evaluate the eﬀectiveness
of HPV testing (HC2) as compared to LBC for primary cervical
screening, involving more than 24,000 women. Results: (i) 87%
of women < 30 years old with mild dyskaryosis have positive
HR-HPV, the proportion decreased with age (ii) 96% of severe
dyskaryosis have positive HR-HPV (iii) Prevalence of HR-HPV in
women above 30 was ranging from 6–18.5%, (iv) Prevalence of
moderate dyskaryosis was found to be 20–30-times higher and
severe dyskaryosis was over 100 times higher in HPV-positive
women compared with those who were HPV-negative (v) HPV
testing is more practical in women age above 30.
Systematic Review and Meta-analysis of Non-Randomized
Studies by Koliopoulos et al., 2007 involving 25 studies found
that pooled sensitivity of Hybrid Capture 2 (HC2) was higher than
cytology (ASCUS or worse), i.e. 90% versus 72.7%. However, cytology
was found to be more speciic than HC2 (91.9% versus 86.5%).
116 Screening for Cervical Cancer

Nauclear and colleagues (Swedescreen trial) evaluated the role

of HPV test (HC2) in the cervical screening strategy and reported
that the most eﬀective screening combinations were screening
irst with a HPV test and if positive, followed by Pap test (HPV test
with relex Pap smear). This approach increased the number of
screening tests by 12% but improved the sensitivity by 30%.

Table 5.5 Results from randomized trial comparing diﬀerent screening

tests either alone or in combinations

Randomized Canadian Cervical Cancer Screening Triala

(inal endpoint: CIN2+)
Sensitivity Speciicity PPP NPV Colposcopy
Test (%) (%) (%) (%) rate (%)
HPV alone 97.4 94.3 7.0 100 6.1
Pap alone 56.4 97.3 8.5 99.8 2.9
Pap with 53.8 98.7 14.9 99.8 1.6
relex HPV
HPV with 53.8 99.1 21.4 99.8 1.6
relex Pap
HPV plus 100 92.5 5.5 100 7.9
Pap
aMayrand et al. N Engl J Med 2007; 357: 1579–1588.

In 2005, the IARC/WHO recommended that HPV-DNA testing

can be used for primary screening. The irst FDA approved method
of HPV DNA testing is a Digene Hybrid Capture 2 assay, which
is tested for 13 oncogenic HPV types. This test was, however,
expensive and needs high-quality laboratory support and
maintenances and therefore may not be suitable in low-resource
setting.
Cuzick et al. (2006) have reported that negative HPV test (HC2)
oﬀered about twice the protection of a negative Pap for at least
5 years. They found that a positive HPV test was far more predictive
of increased risk in the follow-up period than a positive Pap smear.
Women with positive HPV test but negative cytology were found
to have 10% risk of cumulative incidence of CIN3+ by 6 years
while the risk in women with negative HPV test was only 0.27%.
(Dillner et al., 2009).
Role of HPV Testing 117

In general, the sensitivity of HC2 for CIN2+ in primary screening

was 33% higher than cytology at an ASC-US threshold for referral
to colposcopy; however, the speciicity was slightly lower (Cuzick
et al., 2008). Combining HPV testing and Pap smear increased
sensitivity marginally but compromise the speciicity by 5%.
Castle et al. (2009) reported that only 4% of more than 800,000
women age 30 and above have cytology negative but HPV positive
results (highest among women age 30–34 (6.76%) and lowest for
women age 60–64 (2.56%). These igures are important for cost-
analysis purposes if co-testing of Pap smear and HPV test is to be
implemented as a screening test.
A cluster-randomized trial by Sankaranarayanan, et al. in
52 clusters of villages in rural India involving more than 131,000
healthy women were conducted to evaluate the eficacy of three
cervical screening methods, i.e. HPV testing (HC2 assay), VIA and
cytologic testing. The screened group was compared to unscreened
population. The primary outcomes measured were the incidence
of cervical cancer and associated rates of death. The results were
as follows: (a) Total recruitment was 131,806 women. (b) The
positivity rate for HPV test, cytology and VIA was 10%, 7%, and
13.9%, respectively. (c) Positive predictive value for HPV test,
cytology and VIA was 11.3%, 19.3% and 7.4%, respectively (with
endpoint of detecting CIN2+). (d) After 8-year follow-up, the
age-standardized incidence of cervical cancer in women with
negative HPV test, cytology and VIA was 3.7, 15.5 and 16.0 per
100,000 person-years, respectively. There was no reduction in the
rate of cervical cancer in VIA group. (e) HPV testing was associated
with signiicant reduction in the number of advanced cervical
cancers and death from cervical cancer. No signiicant reduction in
number of advanced cancer or deaths was observed in the cytology
and VIA groups. (f) HPV testing was found to be most objective
and reproducible of all cervical screening tests and was less
demanding in term of training and quality assurance. (g) The
drawback of HPV testing with HC2 was that it is more expensive and
time consuming and requires a sophisticated laboratory infrastructure.
Two new methods of HPV testing, Digene FastHPV and Arbo
Vita E6 Strip test, were subsequently introduced specially design for
the country with low-resource setting. Digene FastHPV (careHPV)
118 Screening for Cervical Cancer

was being tested in the demonstration project in China and India,

careHPV was developed by Digene Corporation (now known
as QIAGEN). This method is more rapid, simpler, portable and
affordable. The test needs no mains electricity or running water,
and can be done by technical support staff in roughly 2.5 hours.
CareHPV uses a signal ampliication assay that detects a target
HPV-DNA from 14 different oncogenic HPV types. A cross-sectional
study of the accuracy of careHPV as rapid primary screening test
was done in rural China (comparison between care HPV, Hybrid
Capture 2, VIA and liquid-based cytology). The sensitivity and
speciicity of this new rapid test were 90.0% and 84.2%, respectively.
The sensitivity and speciicity of Hybrid Capture 2 were 97.1% and
85.6%, respectively. Liquid-based cytology and VIA had higher
speciicity (97.0%, 94.5%, respectively) but lower sensitivity
(85.3% for LBC and 41.4% for VIA) (Qiao et al., 2008).
Arbo Vita E6 Strip test is also a rapid HPV testing developed
by Arbo Vita Corporation (AVC) in 2008; the result can be obtained
in less than 20 minutes, and the test is against E6 oncoprotein of
HPV. Arbo Vita E6 strip test is expected to be cheaper.
Testing against HPV 16 and 18 (type-speciic HPV test)
was evaluated as an alternative test to HC2 (testing against 13
types). Narrowing the testing to 16 and 18 was found to improve
the predictive value of detecting CIN2+ as both of these HPV
are responsible in at least 70% of cervical cancer. Women with
positive HPV 16 have 17.2% cumulative incidence rate of ≥ CIN3
in 10 years while if they were positive to HPV 18, the incidence
was 13.6%. Detection of these oncogenic viruses may reduce the
unnecessary intervention in women with other high risks HPV
because it is known that HPV 16 and 18 carry a higher risk of
CIN3+ (Khan et al., 2005). With this new HPV test, it will now
be possible to separate Pap negative/HPV positive women into
higher risk of CIN3+ from those at lesser risk. In March 2009, FDA
announced approval two new HPV DNA diagnostic test (HPV DNA
genotyping test) that is CervistaTM HPV HR Test (testing 14 types
high-risk HPV similar to HC2 plus type 66 in three probes, i.e.
A5/6, A7, A9) and type speciic HPV 16/18 test (CervistaTM
HPV 16/18). Study comparing CervistaTM HPV 16/18 versus
HC2 demonstrated better speciicity and PPV of the former test
(Ginocchio et al., 2008). ASCCP has included this test into their
Role of HPV Testing 119

guidelines and the indications of CervistaTM HPV HR are similar to

Hybrid Capture 2 HPV DNA Assay.
In the era of HPV vaccination, it is expected that the number
of cervical lesions will decrease and so the colposcopic referral
perhaps by 40–60%. The positive predictive value of these tests/
procedures will gradually reduce especially Pap smear and
colposcopy because these tests are more subjective as compared to
HPV testing. Being more objective, HPV testing will perhaps become
a better screening test. A cost-eﬀective analysis of the cervical
screening program during HPV vaccination era have indicated
that for both vaccinated and unvaccinated women, the following
recommendation may be logical: (a) HPV testing as a triage test for
equivocal results in younger women, (b) HPV testing as a primary
screening test in older women. Figure 5.4 is a proposed algorithm
of screening test incorporating type speciic HPV test. This is only
a recommendation and may not be applicable certain countries.
The other alternative to the screening test shown in Fig. 5.4 is
primary HPV testing with relex Pap smear for women with positive
HR HPV. The second Pap smear test is to reduce the false positive
HPV testing and therefore reduce the rate of unnecessary colposcopy
(Fig. 5.5).

Cytology negative

HPV negative HPV positive

Repeat cytology and HPV 16 or 18 HPV 16 or 18

HPV in 3 years positive negative

Colposcopy Repeat cytology

and HPV in 1
year

Figure 5.4 Proposed algorithm of screening test incorporating type-

speciic HPV test (Khan et al., 2005).
120 Screening for Cervical Cancer

HPV DNA Positive

Cytology Negative Cytology Positive

Repeat HPV testing HPV High Grade Lesions Low Grade and
or cytology in 3–5 years or High Risk* Low Risk*

Repeat cytology
Colposcopy and HPV in 1
year

Figure 5.5 The alternative pathway for cervical cancer screening with
HPV DNA testing (*risk factors are smoking, multiple sexual
partners, immunosuppression, and poor compliance).

Optoelectronic Device for Cervical Cancer

Screening
Optical and electrical assessment of the cervix can be used to detect
any abnormal epithelium. To date, there are at least three devices
have been developed, i.e. TruScreen, Polaprobe and TruScan;
TruScreen was developed by Polartechnics, Sydney, Australia. The
device consists of a probe and a console, which are connected to
each other by a cable. The electrical and optical assessment of the
cervix detected by the probe is sent to a microcomputer in the
console and compared with the data of 14 tissues types studied
previously. The type of cervical tissue is diagnosed and the results
are expressed as “normal” or “abnormal” on the printed paper. This
procedure is done immediately after cytologic testing. It is used as
an adjunctive test to improve the accuracy of cytologic testing.
Women with abnormal test will be subjected for colposcopic
examination without need to wait for cytology reports. In
multicentre evaluation by Singer A et al. (2003), the sensitivities for
histologically conirmed CIN 2/3 lesions by TruScreen, Pap and
TruScreen/Pap combined were 70%, 69% and 93%, respectively.
New Technologies in Cervical Cancer Screening 121

New Technologies in Cervical Cancer

Screening
With the introduction of the HPV vaccination program, cervical
cancer prevention will become increasingly costly. Positive
predictive value of current screening strategies will be diminished
in a vaccinated population. New screening technologies should
have higher positive predictive value, able to reduce overtreatment
of low-grade lesions and have higher speciicity. Therefore, most
likely solution to the goals of improving existing screening program
is to incorporate molecular approaches into existing screening
program. Following are some of the promising new technologies
for cervical cancer screening: (a) HPV genotyping. (b) HPV mRNA.
Problem with HPV genotyping is that in a signiicant proportion
of women without disease, HR-HPV DNA can also be detected.
Detection and quantitation of mRNA from E6 and E7 genes of high-
risk genotypes could be a more speciic marker of the presence of
high-grade lesion and cancer. (c) HPV viral load. High viral load
had been associated with CIN2+ and with progression of disease.
Viral load can be quantitated using both conventional and real-
time PCR. (d) HPV integration. HPV-16 integration is commonly
detected in high-grade CIN and invasive cervical cancer. However,
the limitation of this technology is that, in many women, both HPV
DNA integration and episomal DNA often co-exist and therefore
can lead to misinterpretation and misclassiication. (e) p16
enzyme linked immunosorbent assay. p16(INK4a) is a cell
cycle regulation protein which accumulates in abnormal epithelial
cells infected with HR-HPVs. p16(INK4a) can be a potential
immunohistochemical biomarker in both histopathology and LBC
specimens. Recently, detection of p16 by immunostaining of high-
risk HPV-positive women was strongly associated with CIN2+,
suggesting that p16 may serve as a triage to high-risk HPV positive
results to increase speciicity. (f) Methylation markers. DNA
methylation is absent in disease-free women. Study in Senegal
have conirmed a high speciicity for detection of CIN3/cancer
(95–97%) using a panel of 1–3 methylated gene targets (DAPK1,
RARB and TWIST1).
122 Screening for Cervical Cancer

References

Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsh P, Dillner

J. Virologic versus cytologic triage of women with equivocal Pap
smears: a meta-analysis of the accuracy to detect high-grade
intraepithelial neoplasia. J Natl Cancer Inst 2004; 96: 280–293.
Arbyn M, Paraskevaidis E, Martin-Hirsch P, Prendiville W, Dillner J. Clinical
utility of HPV-DNA detection: triage of minor cervical lesions,
follow-up of women treated for high-grade CIN: an update of pooled
evidence. Gynecol Oncol 2005; 99(3 Suppl 1): S7–S11.
Arbyn M, Sankaranarayanan R, Muwonge R, et al. Pooled analysis of the
accuracy of ive cervical cancer screening tests assessed in eleven
studies in Africa and India. Int J Cancer 2008; 123: 153–160.
Bray F, Carstensen B, Moller H, et al. Incidence trends of adenocarcinoma of
the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev
2005; 14: 2191–2199.
Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Kinney W. Five-year
experience of human papillomavirus DNA and Papanicolaou test
cotesting. Obstet Gynecol 2009; 113: 595–600.
Colposcopy and Programme Management. Guidelines for the NHS Cervical
Screening Programme. NHSCSP Publication No 20, April 2004.
Coppleson M, Reid BL, Skladnev VN, et al. An electronic approach to the
detection of pre-cancer and cancer of the uterine cervix: a preliminary
evaluation of Polarprobe. Int J Gynecol Cancer 1994; 4: 79–83.
Cox JT. Review: history of the use of HPV testing in cervical screening and
in the management of abnormal cervical screening results. J Clin Virol
2009; 45: S3–S12.
Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North
American studies on HPV testing in primary cervical cancer screening.
Int J Cancer 2006; 119(5): 1095–1101.
Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive
for high-risk types of human papillomavirus: the HART study. Lancet
2003; 362(9399): 1871–1876.
Cuzick J, Szarewski A, Mesher D, Cadman L, Austin J, Perryman K, et al. Long-
term follow-up of cervical abnormalities among women screened by
HPV testing and cytology Results from the Hammersmith study. Int J
Cancer 2008; 122: 2294–300.
Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al.
Overview of human papillomavirus-based and other novel options
References 123

for cervical cancer screening in developed and developing countries.

Vaccine 2008; 26(Suppl 10): K29–K41.
Denny L, Sankaranarayanan R. Secondary prevention of cervical cancer. Int J
Gynecol Obstet 2006; 94: 565–570.
Dillner J, Rebolj M, Birembaut P, Petry K, Szarewski A, Munk C, et al. Long
term predictive values of cytology and human papillomavirus testing
in cervical cancer screening: joint European cohort study. BMJ 2009.
Dray M, Russel P, Dairymple C, et al. P16(INK4a) as a complementary marker
of hgh-grade intraepithelial lesions of the uterine cervix: experience
with squamous lesions in 189 consecutive cervical biopsies. Pathology
2005; 37(2): 112–124.
Gravitt PE, Coutlee F, Iftner T, et al. ICO Monograph series on HPV and
Cervical Cancer: General Overview. New technologies in cervical
cancer screening. Vaccine 2008; 26S: K42–K52.
Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader
human papillomavirus (HPV) assay and the Digene HPV Hybrid
Capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol
2008; 46: 1641–1646.
Goldhaber-Fiebert JD, Stout NK, Salomon JA, Kuntz KM, Goldie SJ.
Costeﬀectiveness of cervical cancer screening with human
papillomavirus DNA testing and HPV-16, 18 vaccination. J Natl Cancer
Inst 2008; 100: 308–320.
Hakama M, Miller AB, Day Ne, eds. Screening for Cancer of the Uterine
Cervix. Lyon, France: IARC Press; 1986. iaRC Scientiic Publication
No. 76.
IARC Working Group on Evaluation of Cervical Cancer Screening
Programmes. Screening for squamous cervical cancer: the duration of
low risk after negative result of cervical cytology and its implication
for screening policies. Br Med J 1986; 293: 659–664.
IARC, WHO. IARC Handbooks of Cancer Prevention: Cervical Cancer
Screening. Vol. 10. IARC Press; 2005.
Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The
elevated 10-year risk of cervical precancer and cancer in women with
human papillomavirus (HPV) type 16 or 18 and the possible utility
of type-speciic HPV testing in clinical practice. J Natl Cancer Inst
2005; 97: 1072–1079.
Kitchener HC, Almonte M, Wheeler P, et al. HPV testing in routine cervical
screening: cross sectional data from the ARTISTIC trial. Br J Cancer
2006; 95(1): 56–61.
124 Screening for Cervical Cancer

Koliopoulos G, Arbyn M, Hirsch PM, et al. Diagnostic accuracy of human

papillomavirus testing in primary cervical screening: A systematic
review and meta-analysis of non-randomized studies. Gynecol Oncol
2007; 104: 232–246.
Kreimer AR, Guido RS, Solomon D, Schiﬀman M, Wacholder S, Jeronimo J,
et al. Human papillomavirus testing following loop electrosurgical
excision procedure identiies women at risk for posttreatment cervical
intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol
Biomarkers Prev 2006; 15: 908–914.
Kyrgiou M, Koliopoulos G, Martin Hirsch P, et al. Management of minor
cervical cytological abnormalities: a systematic review and a meta-
analysis of the literature. Cancer Treat Rev 2007; 33(6): 514–520.
Lee SJ, Bae JH, Kim JH, et al. A real-time optoelectronic device in screening of
cervical intraepithelial neoplasia. J Women’s Med 2009; 1(2): 23–28.
Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus
DNA versus Papanicolaou screening tests for cervical cancer. N Engl
J Med 2007; 357: 1579–1588.
Mayrand MH, Duarte-Franco E, Coutlée F, et al. Randomized controlled trial
of human papillomavirus testing versus Pap cytology in the primary
screening for cervical cancer precursors: design, methods and
preliminary accrual results of the Canadian cervical cancer screening
trial (CCCaST). Int J Cancer 2006; 119(3): 615–623.
Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus
DNA versus Papanicolaou screening tests for cervical cancer. N Engl J
Med 2007; 357(16): 1579–1588.
Miller FS, Nagel LE, Kenny-Moynihan MB. Implementation of the ThinPrep
imaging system in a high volume metropolitan laboratory. Diag
Cytopath 2007; 35: 213–217.
Mistro AD, Salamanca HF, Trevisan R, et al. Triage of women with atypical
squamous cells of undetermined signiicance (ASC-US): Results of an
Italian multicentric study. Gynecol Oncol 2010; 117: 77–81.
Myers E, Huh WK, Wright JD, Smith JS. The current and future role of
screening in the era of HPV vaccination. Gynecol Oncol 2008; 109:
S31–S39.
Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test
in screening for and follow-up of cervical cytologic abnormalities:
a systematic review. Ann Int Med 2000; 132(10): 810–819.
Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Eficacy
of HPV DNA testing with cytology triage and/or repeat HPV DNA
References 125

testing in primary cervical cancer screening. J Natl Cancer Inst 2009;

101: 88–99.
Nobbenhuis MA, Meijer CJ, van den Brule AJ, et al. Addition of high-risk
HPV testing improves the current guidelines on follow-up after
treatment for cervical intraepithelial neoplasia. Br J Cancer 2001;
84(6): 796–801.
Peto J, Gilman C, Deacon J, et al. Cervical HPV infection and neoplasia in a
large population-based prospective study: the Manchester cohort.
Br J Cancer 2004; 91: 942–953.
Qiao YL, Sellors JW, Eder PS, et al. A new HPV-DNA test for cervical-cancer
screening in developing regions: a cross-sectional study of clinical
accuracy in rural China. Lancet oncol 2008; 9: 929–936.
Qureshi S, Das V, Zahra F. Evaluation of visual inspection with acetic acid
and Lugol’s iodine as cervical cancer screening tools in a low-resource
setting. Trop Doct 2010; 40: 9–12.
Ronco G, Cuzick J, Pierotti P, et al. Accuracy of liquid based versus
conventional cytology: overall results of new technologies for cervical
cancer screening: randomised controlled trial. BMJ 2007; 335: 28 (7
July).
Ronco G, Segnan N, Giorgi-Rossi P, et al. Human papillomavirus testing
and liquid-based cytology: results at recruitment from the new
technologies for cervical cancer randomized controlled trial. J Natl
Cancer Inst 2006; 98(11): 765–774.
Ronco G, Giorgi-Rossi P, Carozzi F, et al. Results at recruitment from a
randomized controlled trial comparing human papillomavirus testing
alone with conventional cytology as the primary cervical cancer
screening test. J Natl Cancer Inst 2008; 100(7): 492–501.
Sankaranarayanan R, Gafikin L, Jacob M, Sellors J, Robles S. A critical
assessment of screening methods for cervical neoplasia. Int J Gynaecol
Obstet 2005; 89 (Suppl 2): S4–S12.
Sankaranarayanan R, Rajkumar R, Esmy PO, et al. Eﬀectiveness, safety
and acceptability of “see and treat” with cryotherapy by nurses in a
cervical screening study in India. Br J Cancer 2007; 96: 738–743.
Sankaranarayanan R, Basu P, Wesley RS, et al. Accuracy of visual screening
for cervical neoplasia: results from an IARC multicentre study in
India and Africa. Intl J Cancer 2004; 110: 907–913.
Sankaranarayanan R, Wesley R, Thara S, Dhakad N, Chandralekha B,
Sebastian P, et al. Test characteristics of visual inspection with
126 Screening for Cervical Cancer

4% acetic acid (VIA) and Lugol’s iodine (VILI) in cervical cancer

screening in Kerala, India. Int J Cancer 2003; 105(3): 404–408.
Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical
cancer in rural India. New Eng J Med 2009; 360(14): 1385–1394.
Sasieni P, Adam J, Cuzick J. Beneits of cervical screening at different
ages: evidence from the UK audit of screening histories. Br J Cancer
2003; 89(1): 88–93.
Schiffman M, Soloman D. Findings to date from the ASCUS-LSIL Triage
Study (ALTS). Arch Pathol Lab Med 2003; 127(8): 946–949.
Sherman ME, Lorinzc AT, Scott DR, Wacholder S, Castle PR, Glass AG, et
al. Baseline cytology, human papillomavirus testing, and risk for
cervical neoplasia: a ten year cohort analysis. J Natl Cancer Inst 2003;
95: 46–52.
Siebers AG, Klinkhamer PJJM, Grefte JMM, et al. Comparison of liquid-
based cytology with conventional cytology for detection of cervical
cancer precursors. a randomized controlled trial. JAMA 2009;
302(16): 1757–1764.
Singer A, Coppleson M, Canfell K, et al. A real time optoelectronic device
as an adjunct to the Pap smear for cervical screening: a multicenter
evaluation. Int J Gynecol Cancer 2003; 13: 804–811.
Solomon D, et al. The 2001 Bethesda System: terminology for reporting
results of cervical cytology, J Am Med Assoc 2002; 287(16):
2114–2119.
Stoler MH Schiffman M. Interobserver reproducibility of cervical cytologic
and histologic interpretations: realistic estimates. From the ASCUS-
LSIL Triage Study, J Am Med Assoc 2001; 285(11): 1500–1505.
The ASCUS LSIL Triage Study (ALTS) Group. Results of a randomized trial
on the management of cytology interpretations of atypical squamous
cells of undetermined signiicance. Am J Obstet Gynecol 2003;
188: 1383–1392.
Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is
a necessary cause of invasive cervical cancer worldwide. J Pathol
1999; 189(1): 12–19.
Wright TC. Cervical Cervical cancer screening in the 21th century: is it time
to retire the PAP smear? Clin Obstet Gynecol 2007; 50(2): 313–323.
Wright Jr TC, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ. Solomon
D. 2006 consensus guidelines for the management of women with
References 127

abnormal cervical cancer screening tests. Am J Obstet Gynecol

2007; 197: 346–355.
Yeoh KG, Chew L, Wang SC. Cancer screening in Singapore, with particular
reference to breast, cervical and colorectal cancer screening. J Med
Screen 2006; 13 (Suppl 1): S14–S19.
This page intentionally left blank
Chapter 6

Human Papillomavirus and HPV

Vaccination

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
130 Human Papillomavirus and HPV Vaccination

HPV Infection in Lower Genital Tracts

Human Papillomavirus
The link between human papillomavirus (HPV) and cervical cancer
was irst proposed by Harald zur Hausen, Professor Emeritus at the
German Cancer Research Centre. He suggested the link between
HPV and cervical cancer since 1976 but only in 1980s, his opinion
was proven by laboratory evidence. He was awarded the 2008 Nobel
Prize in Medicine.

Figure 6.1 Human papillomavirus. The DNA is circular in shape within

the shell of the virus. The shell is formed by capsid proteins.
L2 capsid proteins are located at the central point of each
capsomer.

Human papillomavirus is a member of family Papovaviridae,

double stranded DNA virus with the diameter from 52–55 nm
(Fig. 6.1). The HPV genome comprises 8000 base-pair long
circular DNA molecules and encodes a maximum of eight proteins,
six of which are known as early proteins (E1, E2, E4, E5, E6, and E7)
and two late proteins known as L1 and L2 (Fig. 6.2). The DNA
molecules are wrapped into a protein shell (capsid) that is composed
HPV Infection in Lower Genital Tracts 131

of two molecules L1 (major capsid protein) and L2 (minor capsid

protein). L1, the major capsid protein constitutes 80% of the virion
while L2 minor capsid protein makes up the remaining 20%. The
other region in HPV genome is known as a long control region (LCR),
which has no coding potential. Early proteins are necessary for
the replication of the viral DNA and for the assembly of newly
produced virus particles within the infected cells. E6 and E7 are
oncoproteins.

Figure 6.2 Genome of Human Papillomavirus. The HPV genome comprises

8000 base-pair long circular DNA molecules and encodes a
maximum of eight proteins, six of which are known as early
proteins (E1, E2, E4, E5, E6 and E7) and two late proteins
known as L1 and L2. LCR: long control region; E: early region;
L: late region.

HPV is epitheliotropic, it infect the skin and mucous membranes

and produce local epithelial proliferation or warts. Papillomaviruses
are absolutely species-speciic; thus HPVs only infect humans, rabbit
papillomaviruses only infect rabbits, and so forth.
In contrast to other viral infections, human papillomavirus can
evade from the body immune system; antibody levels following
natural infection are low and not reliably protective. Following
are the sophisticated immune evasion mechanisms by HPV:
132 Human Papillomavirus and HPV Vaccination

(a) Infection is exclusively intraepithelial.

(b) There is no viraemia following infection.
( c)Local immunosuppression.
(d) HPV uses the natural life cycle of epithelial cells to release new
viruses and does not cause cell death.
(e) HPV infection does not induce inlammation and therefore, no
attraction of immune cells. No pro-inlammatory signals mean
no activation of dendritic cells.
(f) Production of high immunogenic capsid protein is limited to
the well-differentiated outer layers that are well away from
the basal cell and subepithelial region.
(g) Factors (a)–(f) lead to poor exposure to antigen presenting
cells.
There is a suggestive of natural protection, mainly by cell-
mediated immunity, however, antibody levels after natural infections
are low and have not been shown to be consistently protective
against re-infection with the same type.
In human, there are more than 150 genotypes of HPV
identiied by sequence of genes encoding major capsid protein
L1 and early proteins E6 and E7. The incidence of HPV positive
in women with normal smear is very variable from 4% to
43% and different subtype has different site of epithelial and
different type of lesions produced. More than 40 types of HPVs
were recognized to infect anogenital tract of human. In women
15–25 years of age, almost 80% of HPV infections are transient.
HPV-related diseases can be divided into three categories:
(1) skin lesions, (2) genital lesions and (3) non-genital lesions
(see Table 6.1). Human papillomavirus has a predilection for
either cutaneous or mucosal surfaces. Within the groups of skin
or mucosal viruses, they can be separated into high-risk HPV (HR
HPV) and low risk HPV (LR HPV) depending upon their oncogenic
potential. Most important high-risk HPVs associated with cervical
cancer are HPV 16 and 18. The WHO has recognized HPV 16 and
HPV 18 as carcinogenic agents for humans. Persistent infection is
a prerequisite for malignant transformation of cervical epithelial
cells. Evidence shows HR HPV infections tend to persist longer
than LR HPV infections. Among HR HPV, HPV 16 and 18 infections
are more likely to persist than other types.
HPV Infection in Lower Genital Tracts 133

Table 6.1 Clinical manifestations and type of HPV

Clinical manifestations Type of HPV
Skin lesions
Plantar warts 1, 2, 4
Common warts 2, 4, 26, 27, 29, 57
Butcher’s warts 7
Epidermodysplasia verruciformis 2, 3, 5, 8, 9, 10, 12, 14, 15, 17, 19,
20–25, 36, 37, 46, 47, 50
Genital lesions
Condyloma acuminata 6, 11, 16, 30, 40, 41, 42, 44, 45, 54, 55,
61
SIL, VIN, VAIN, PAIN, PIN 6, 11, 16, 18, 30, 31, 33, 35, 39, 40, 42,
45, 51, 52, 55, 59, 61, 62, 64, 66–70
Cervical cancer 16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 55,
56, 58, 59, 66, 68
Non-cervical anogenital cancers 6, 11, 16, 18, 30, 31, 33
Non-genital mucosal lesions
Mouth (local epith. Hyperplasia) 13, 32
Recurrent resp. papillovatosis 6, 11, 30
Carcinoma (head/neck/lung) 2, 6, 11, 16, 18, 30
Source: Modiied from Koutsky LA, Kiviat NB. Genital HPV. In Holmes KK, Mardh
PA, Sparling PF, et al., eds. STD (3rd ed.). New York McGraw-Hill, 1999; 347–359.

Almost 100% of cervical cancers contain HPV DNA sequences

from a high-risk HPV and the most important HPV related to cervical
cancer is HPV 16 responsible in 50–70% of cases and HPV 18, found
in 7–20% of cases. Molecular and epidemiological data suggest that
each HPV type has variants or subtypes; variants of the same type
are biologically distinct and may confer diﬀerential pathogenic risk
(e.g. HPV 16 has ive distinct phylogenetic branches, i.e. European
(E), Asian (As), Asian American (AA) and two African (Af-1, Af-2).
A clinical and epidemiological study done in Mexico had indicated
that HPV 16 variants in Asian American (AA) might be more
oncogenic than European (E) variants. Existence of HPV subtypes
or intratype distributions suggest that these viruses evolved with
134 Human Papillomavirus and HPV Vaccination

humans over a period of time (Berumen, 2001). Based on the

accumulation of molecular and epidemiologic evidence supporting a
causal association, the International Agency for Research on Cancer
(IARC) has concluded that there is suficient evidence to classify
HPV infection as a Group I carcinogen for cancers of the anus, cervix,
oropharynx, penis, vagina, and vulva.

Transmission of HPV
HPV infection is the most common sexually transmitted disease.
Based on 78 studies worldwide, the world prevalence of age-adjusted
HPV infection is 10%, highest in Africa (23%) and lowest in Asia and
Europe (8%) (Burchell, et al. 2006).
Following are the mechanisms of HPV transmissions and
acquisitions:
(1) Sexual contact
(a) Sexual intercourse
(b) Genital-genital, manual-genital, oral-genital contacts
(c) Genital HPV infection in virgin is rare, but may result from
non-penetrative sexual contact
(d) Condom use may reduce the risk of transmission but not
fully protective. Regular and consistent use of condom
can provides 60% protection against HPV infection; HPV
can still be transmitted through contact with areas of
unprotected genital skin such as the vulva or scrotal sacs.
(2) Non-sexual routes
(a) Vertical transmission from mother to newborn resulting in
respiratory papillomatosis
(b) Possibly through fomites such as undergarments, surgical
glove, and biopsy forceps, would be very rare.
At least 85% of transmission is through sexual contact
while remaining 15% is through non-sexual routes. Up to 75% of
sexually active women acquired HPV infection at least once in their
lifetime. However, 80% of infections are cleared after 12 months.
The prevalence of HPV infection in women without cervical
abnormalities varies from one continental to others; estimated
prevalence of high-risk HPV infection in Asian women without
Burden of HPV Infections 135

cervical abnormalities was 5.4%. Following are the risk factors for
HPV infection in women: (a) young age (peak age at 20–24 years old),
(b) lifetime and recent number of sex partners, (c) male partner’s
sexual behaviour, (d) uncircumcised male partners, (e) smoking,
(f) oral contraceptive use and (g) early age of irst sexual intercourse.
In men, three important risk factors for HPV infections are (a) young
age (peak age from 25–29 years old), (b) lifetime number of sex
partners and (c) being uncircumcised.

Burden of HPV Infections

The burdens of HPV infections are tremendous; it can be divided
into two categories (applicable to males and females):
(a) HPV-related precancerous and cancerous lesions
(b) HPV-related benign lesions
Human papillomavirus is attributable in 5% of human cancers,
10% of cancers in women and 15% of female cancers in developing
countries. Human papillomavirus is responsible in more than
500,000 new cases of cervical cancer worldwide in 2008. If current
incidence trends continue, incidence of cervical cancer will rise
to estimate 1 million cases per year by 2050. In 2005, more than
260,000 cervical cancer deaths occurred, resulting in 2.7 million
years of life lost. If current trends persist, cervical cancer deaths are
expected to rise by nearly 25% in the next 10 years. About 80% of
cervical cancer deaths occur in developing countries. The incidence
rates are highest in parts of Latin America and the Caribbean,
sub-Saharan Africa, Melanesia and parts of south Asia.
The burden of non-cervical cancers among men and women
are more than 95,000 cases annually worldwide, including
approximately 50,000 cancers among men (anal cancer (26%),
oropharyngeal cancer (52%) and penile cancers (22%)) and 46,000
cancers among women (anal cancers (32%), oropharyngeal cancers
(13%), vulvar/vaginal cancers (55%)) (Chaturvedi, 2010).
The worldwide burden of cervical compared to non-cervical
HPV-related cancers has demonstrated that the cervix is uniquely
most susceptible to HPV-induced carcinogenesis when compared
to other anatomic sites. In fact, when the causal relationship
between HPV infection and cervical cancer was compared to other
136 Human Papillomavirus and HPV Vaccination

non-HPV–related cancers; the relative risk of cervical cancer from

HPV infection was found to be the highest (see Table 6.3).

Table 6.2 HPV types in anogenital malignancies (both males and

females)

Lesion HPV types involved % cases HPV

Cervical carcinoma 16, 18, 31, 33, 35, 39, 45, 51, 52, >95%
66, 58, 59, 66 (26, 68, 73, 82a)
Vulval carcinoma
Basaloid 16, 18 >50%
Warty 16, 18 >50%
Keratinizing 16 <10%
Vaginal carcinoma 16, 18 >50%
Penile carcinoma
Basaloid 16, 18 >50%
Warty 16, 18 >50%

Keratinizing 16 <10%
Carcinoma of the anus 16, 18 >70%
aRare type of HPV.
Reference: Stanley M. HPV vaccines. Best Pract Res Clin Obstet Gynaecol 2006; 20(2):
279–293.

Table 6.3 The causal relationship between causative agent and cancer

Cancer and causative agent Relative risk

Cervical cancer from HPV 300–500

Liver cancer from Hepatitis B virus (Taiwan) 100

Liver cancer from Hepatitis C virus (Italy) 20

Lung cancer and smoking 10

Currently, organized cytologic screening is still implemented

in many developed countries to prevent cervical cancer; today, it
is estimated that 50 million pap tests are performed annually in
the United States alone. Although, screening program reduces the
incidence and mortality rate, the cost of implementing organized
screening program is very huge. Out of 50 million pap tests, 2–3
million women were diagnosed with atypical squamous cells (ASC),
Burden of HPV Infections 137

1.25 million with low-grade squamous intraepithelial lesions (LSIL),

300,000 with high-grade squamous intraepithelial lesions (HSIL)
and more than 10,000 with cervical cancer; many of these cases
required repeat testing, treatment and follow-up. Therefore, the
economic and psychological burden associated with screening
program is substantial. Furthermore, despite an organized screening
program, there are still many women die of cervical cancer annually.
Apart from HPV-related cancer, HPV infection is also attributed
to pre-cancerous lesions and benign genital warts. Worldwide,
approximately 10 million cases of high-grade cervical lesions
and 30 million cases of low-grade cervical lesions were reported;
all were associated to HPV infections. Low risk HPV has also
contributed to tremendous numbers of genital wart lesions with
the estimation of 30 million cases annually. Anogenital warts or
condylomata acuminata are the most commonly diagnosed viral
sexually transmitted disease (STD) in the United States and United
Kingdom. More than 90% of anogenital warts are due to HPV type
6 and 11. Majority of anogenital warts are not clinically visible. It
is estimated that 1% of US adult population has visible anogenital
warts and estimated lifetime risk of developing genital warts
is approximately 10%. Treatment modalities are often painful,
costly, required follow-up and repeat treatment. Furthermore,
the recurrence rate is high up to 75% after 6 months, despite
treatment.
Human papillomavirus can also be transmitted from mother to
a newborn through vertical transmission during delivery. Infection
to newborn may lead to recurrent respiratory papillomatosis (RRP).
More than 90% of RRP is associated with infection by HPV type
6 and 11. RRP is a rare disease characterized by the formation of
wart-like lesions on the respiratory tract, most frequently at the
larynx. The incidence of RRP is estimated to be 4.3 per 100,000
in children and 1.8 per 100,000 in adults. Both males and females
have a similar incidence. RRP is the most common benign neoplasm
of the larynx among children and the second most common cause
of chronic hoarseness. The disease is more aggressive in children,
and it can cause hoarseness of voice, stridor and airway obstruction
requiring multiple surgeries. In US, 1500 new cases have been
reported every year; 15,000 surgical procedures were involved to
treat this condition costing approximately US$ 100 million/year.
138 Human Papillomavirus and HPV Vaccination

Pathogenesis of HPV Infections

Human papillomavirus has a very unique process of infection. The
earlier understanding of HPV infection was based on in vitro studies
mostly involving either non-infectious virus-like particles, virions
generated in organotypic raft culture or infectious pseudoviruses.
Currently, in order to obtain better and more accurate understanding,
the study of pathogenesis of HPV infection has shifted to in vivo
investigations. The irst step in HPV infection is called attachment.
Major capsid protein L1 contains the major determinant for initial
attachment. The most critical attachment factors on the epithelial
cell are called heparan sulfate proteoglycans (HSPGs). The viruses
enter the epithelium through microabrasion straight to the cells in
the basement membrane. Several hours after initial binding on the
basement membrane, the capsids were detected on the surfaces of
epithelial cells. After attachment, the viral genome makes its way to
the nucleus through ways not yet completely deined. After some
time, the virus then uses the host cell DNA replication machinery
to begin its own replication process, and increasing the number
of viral to around 50–100 copies per-cell. The infected cells are
then moved toward the surface of epithelium, and now the number
of viral copies increase to 1000 per-cell. The time taken for infected
cells at basal layers to move upward until to the supericial layers
are said to be from 2–3 weeks.
Most of the infections are subclinical and transient (80–90%);
infection or any low-grade lesions developed from the infectious
processes will resolve as a consequence of the development of the
host cell- mediated immunity (CMI). In minority of women, perhaps
10–15% of them fail to eradicate the infection, and the infection
persists. These groups of women are those at risk of developing
high-grade lesions and invasive carcinoma.
The incubation period is the time from initial infection until to
the appearance of clinical lesions; the duration of the incubation
period is from 3 weeks to 8 months or even more (Fig. 6.3). Majority
of the clinical lesions are seen after 2–3 months of infection,
however, up to 30% of the infection will regress within 3 months
by CMI. The time of clearance is longer for HR HPV (12–18 months)
as compared to LR HPV (4–9 months). Persistent infection by HR
HPV; with the presence of co-factors eventually transform the
epithelial cells into neoplastic cells either as high-grade lesions such
Pathogenesis of HPV Infections 139

as CIN 2/3 or as invasive cervical cancer. During this event, viral

DNA may be integrated into the host genome, and subsequently E6/
E7 oncoproteins are overexpressed throughout the epithelium. E6
oncoprotein can inactivate p53 (tumour suppressor/DNA repair)
while E7 protein binds to pRb protein (gene transcription inhibitor).
Normally, Rb protein is responsible in preventing the cell to enter
S-phase (acting like a “brake”). When the Rb proteins are degraded
by E7 proteins, the “brake” mechanism will be eliminated and the
cell enters S-phase and continue to replicate. Protein E6 is also said
to eliminate proteins involved in regulating the shape and polarity
of the epithelial cells, therefore preventing apoptosis (anti-apoptotic
aﬀect). The epithelial cells become genetically unstable; acquiring
further mutation and have the capability of progression from CIN 2,
CIN 3 and subsequently invasive cancer. The time taken from HRHPV
infection to the development of CIN 3 is 3–5 years; progression to
invasive cancer takes much longer, i.e. 10–20 years.

Figure 6.3 Natural history of genital HPV infection. Adapted from Stanley.
Gynecol Oncol 2010; 117: S5–S10.

In general, there are two important growth characters of

malignant cells: (a) Immortalization, the cancer cells replicate
indeinitely and (b) Anchorage-independent growth; cancer cells
are able to grow when suspended in luid or semisolid agar gel and
this is a transformation character. When oncogenic HPV such as HPV
16 and 18 are introduced into already immortalized cell lines, the
cells become transformed and developed capacity of anchorage-
independent growth. These transformed cells are tumorigenic.
Immortalization is a prerequisite for cell transformation, i.e.
140 Human Papillomavirus and HPV Vaccination

tumorigenic by HPV 16 and 18. Non-immortalize cervical cells

when exposed to oncogenic viruses will be immortalized but will
not be transformed and therefore non-tumorigenic. The HPV
DNA has two separate eﬀects on cell growth that is (a) able to
immortalize (without transforming) human cells and (b) able to
transform immortalized human cells. Both eﬀects are determined
by speciic gene in HPV genome, i.e. E6/E7 oncogenes. These genes
encode speciic proteins. E7 protein is the major transforming
and immortalizing protein of HPV. These genes, through a
very complex processes act with oncogenes (activate) and tumour
suppressor gene (inhibit, e.g., p53). HPV E6 enhanced the activity
of HPV E7 oncoprotein. The binding capacity E7 and E6 protein to
oncoprotein (Rb) and tumour supressor protein (p53) respectively,
determine the level of oncogenic potential of speciic type of HPV,
e.g. HPV 16 has higher oncogenic potential than HPV 6 because E6/
E7 oncoprotein from HPV 16 has higher binding capacity than that
in HPV 6.
Majority of HPVs cause benign lesions. In benign HPV-related
lesions, majorities are asymptomatic and few clinical lesions are
manifested. In clinically visible HPV-infected lesions or condylomata
acuminata, there are four typical histologic features suggestive of
HPV infection: (a) thickening of the supericial cell layers (keratosis),
(b) presence of koilocytosis (layer of cells with enlarged nuclei,
irregular chromatin, perinuclear clearing (halo) and thickening or
thinning of the cytoplasmic border), (c) proliferation of the prickle
cell layer (acanthosis) and (d) localized hyperplasia of basal cells
(basal cell hyperplasia). Majority of HPV infections are cleared
spontaneously without treatment and study had shown that the
clearance of HPV infections likely involve both innate immunity
(non-speciic, the irst-line defence against infection, e.g. anatomic
barrier, physiologic barrier, phagocytic barrier endocytosis,
etc.) and adaptive immunity (speciic, it reacts against a speciic
microorganism; adaptive immunity has two components, i.e.,
humoral and cell-mediated immunity).

HPV Infection in Man

The prevalence of genital warts is highest among men aged 25–29
years; and similar to women, the prevalence decreases with age.
In general, the prevalence of HPV infection in males is almost
HPV Infection in Man 141

similar or even higher than female. In some report, HPV DNA of

both oncogenic and non-oncogenic type was noted in 50.5% of men
(Giuliano and Palefsky and Giuliano 2008). Approximately, 4% of
sexually active male ages between 18 and 59 years old have been
diagnosed as genital warts at least once. The most common sites of
infection (>95% of cases) are penile shaft, coronal sulcus, glan penis
and scrotum. HPV infections may be less likely to persist in men than
in women (6% versus 20%) (Van Doornum, 1994). Approximately,
75% of infections clearing within 12 months and reduced risk of
persistent infection has been observed among circumcised men
(Lu et al., 2009). Many studies have reported that prevalence of
HPV infection and HPV detection rate were lower in circumcised
men (Dunne et al., 2006; Giuliano et al., 2010; Nielson et al., 2009).
More than 90% of genital warts are due to HPV type 6 and 11. One
third of genital warts are due to multiple infections, including with
co-existing oncogenic HPV infections. Similar to women, apart
from genital warts, man can also develop recurrent respiratory
papillomatosis. The incidence of RRP in man is similar to women.
Approximately, 85% of anal canal cancer cases worldwide are
attributable to HPV and the incidence of anal cancer in men in the
United States was 1.3 per 100,000. The American Cancer Society
has estimated that 2000 new cases of anal cancer will be reported
in 2010. The DNA of HPV was found in 47% of penile squamous
cell carcinoma; HPV 16 and 18 were found in 60% and 13%
respectively. The prevalence of HPV DNA in penile tumours varies
with histological subtype—most common in basaloid and warty
subtypes.
Subsets of head and neck squamous cell carcinoma (HNSCC)
originating in the oropharynx, tonsil, base of the tongue, soft palate
and pharyngeal wall are found to be increasingly associated with
human papillomavirus infection. The prevalence of HPV infection
in oropharygeal carcinoma varies widely between studies from
18–82%. HNSCC is more common in males; American Cancer
Society has estimated that in 2010, there will be a total of 25,420
cases of oral cavity and pharyngeal cancer in males as compared
to 11,120 cases in females (US data). Most cases (90–95%) of
HPV positive oropharyngeal carcinoma is associated with HPV
type 16. Case control studies have demonstrated an association
between HPV positive oropharyngeal carcinoma and certain
sexual behaviours, including a high lifetime number of oral sex or
142 Human Papillomavirus and HPV Vaccination

vaginal sex partners, early age of irst intercourse and infrequent

use of condoms. Patients with HPV-positive head and neck
squamous carcinoma (HNSCC) has a better prognosis with 50–80%
reduction in the risk of cancer-related death as compared to
HPV-negative HNSCC (Evan and Powell 2010).

Methods of HPV Detection

There are various methods of HPV detection and each of this method
has their advantage and disadvantages (Table 6.4). Newest methods
of HPV detection are generally more sensitive but require higher
maintenance cost. In general, HPV detection can be classiied into
three broad categories:
(1) Culture methods: This method is currently not widely
available, very cumbersome and restricted to only few types
of HPV. The examples of culture methods are (a) nude-mouse
transplantation system (human epithelial tissues are exposed
to the HPV-infected tissues and transplant beneath the renal
capsule of mice; a speciic cytopathic eﬀect will be observed
after several months) and (b) Collagen-raft culture system
(culturing the human HPV-infected keratinocytes in collagen-
raft culture and treated with substances that can increase the
expression of keratinocyte diﬀerentiation accompanied with
production of HPV virion).
(2) Immunologic methods: The limitation of immunologic
methods is that HPV lack of appropriate antigen targets for
immunologic assays. HPV 16 E7 protein expressed by bacteria
has been used to produce an antibody against HPV. Only
50% patient with cervical cancer (HPV 16 related) will have
an antibody to HPV 16 E7. None of patients with HGSIL has
antibody to E7. Antibody to E7 therefore, only useful in the
advanced stage. Antibody to HPV capsid proteins is currently
being studied. This protein is also a candidate for future HPV
vaccines.
(3) Molecular detection methods: There are various molecular
detection methods to detect HPV DNA: (a) ilter hybridization
method (Southern blot Dot blot), (b) polymerase chain reaction
(PCR), (c) ligase chain reaction and (c) solution hybridization
method. Southern blots are the gold standard for detection of
HPV Vaccine 143

speciic type of HPV. PCR is more sensitive than Southern blots

for detecting speciics DNA sequence. Both PCR and Southern
blots are labour intensive and dificult. Hybrid Capture HPV
DNA assay (solution hybridization methods) is the most
widely used HPV DNA assay for clinical used, approved by
FDA. This method is using chemiluminescence principle. The
detection rate is higher when the specimen is obtained from
cervico-vaginal lavage rather than swab or spatula.

HPV Vaccine
The fact that human papillomavirus is the primary aetiology of
cervical cancer is undeniable. Persistent infection by oncogenic
HPV and presence of co-factors are prerequisites for malignant
transformation of cervical epithelial cells. Persistent cervical
infection causes cellular changes in the epithelium that can be
detected through cytologic screening. This is the basis of Pap
smear, which is currently the most common method of secondary
prevention for cervical cancer. HPV detection and genotyping are
also increasingly used as screening method either together with
cytologic screening or as a primary screening modality. Oncogenic
types of HPV are estimated to cause almost 100% of cervical cancer,
90% of anal cancers, 40% of cancers of the vulva, vagina and penis,
and at least 12% of head and neck cancers. HPV 16 is the most
common cause of cervical cancer, causing 52–58% of cases in all
regions and HPV 16 is also the most common cause of non-cervical
anogenital cancers. Overall, the top ranked HPV types responsible in
cervical cancer are 16, 18, 31, 58 and 52. Apart from precancerous
and cancerous lesions, HPVs are also responsible in large number
of benign lesions involving mucosal and non-mucosal surfaces. HPV
type 6 and 11 are non-oncogenic HPV (low-risk HPV), however, are
responsible in 90–100% cases of external anogenital warts and
recurrent respiratory papillomatosis.
Secondary prevention via cytologic testing is successful in
preventing cervical cancer in developed countries where organized
screening program and high coverage of screening population are
feasible. However, secondary prevention in developing countries
and underdeveloped countries is less successful due to poor
coverage, lack in infrastructures, inadequate facilities for treatment
144 Human Papillomavirus and HPV Vaccination

and inadequate number of human resources. Cytologic screening

is more eﬀective in detecting precancers and cancers of squamous
cell type than adenocarcinoma in situ and adenocarcinoma
because of sampling dificulties. Therefore, screening with cytology
has a limitation in prevention of endocervical lesions.

Table 6.4 Comparison of various methods of HPV detection

Method Sensitivity Speciicity Comments

Cytology Low Low Easy, relatively
inexpensive, but
subjective, insensitive
and non-speciic
Dot blot Moderate Moderate Radioactive,
commercially available,
labour intensive
Filter in situ Moderate Detect HPV in parafin-
hybridization embedded tissue
Southern blot High High Not feasible for large
hybridization scale clinical use
Hybrid capture High High Approved by FDA and
for commercial use, non-
radioactive, easier to use
and less expensive than
dot blot
PCR Very high High Uses ampliication
and so is prone to
contamination errors

Following are the limitations of secondary prevention (cytologic

test, HPV testing and visual inspection):
(a) Secondary prevention does not prevent HPV infection or pre-
invasive lesions of the cervix,
(b) Lesion that has rapid progression rate may not be detected in
time,
(c) There is a higher chance of missing the lesions in the cervical
canal,
(d) It has limited sensitivity and speciicity,
(e) It involves high cost and is labour intensive,
HPV Vaccine 145

(f) Early stages of adenocarcinoma can be dificult to detect due

to lesion within endocervical canal,
(g) Many lesions will regress and are thus “overtreated” and
(h) Adverse pregnancy outcomes are associated with treatment
of precancerous lesions.
Due to the limitations of secondary prevention, there has been
a shift in paradigm to primary prevention. Primary prevention of
cervical cancer can be achieved through prevention and control
of genital HPV infection. Primary prevention includes health
promotion strategies geared at a change in sexual behaviour, i.e.
promoting healthy sexual life, avoiding or minimizing exposure to
co-factors such as stop smoking, promoting healthy lifestyles and
perhaps the most promising eﬀort is through HPV vaccination.
Historically, vaccination has proven to be an eﬀective means to
reduce infectious disease and mortality related to it, for example,
prophylactic Hepatitis B vaccine had reduced the incidence of
infection by 72%. Study in Taiwan shows that vaccination of
newborns with hepatitis B immunoglobulin at birth (if the mother
is infected with Hepatitis B) was associated with a reduction in the
average annual incidence of hepatocellular cancer from 0.70 per
100,000 children in 1981 to 0.36 per 100,000 in year 1990–1994
(Chang et al., 1997).
The HPV vaccine was discovered by Professor Ian Frazer and
his co-researcher Dr. Jian Zhou. Ian Frazer was born in Glasgow in
1953. He met Jan Zhou in 1989 while he was working in the
Department of Immunology, University of Queensland, Australia.
They decided to work together and began to use molecular
biology to synthesize particles in vitro that could mimic the virus.
They discovered that the L1 capsid protein could be expressed in
eukaryotic cells and could self-assemble into virus-liked particles
(VLPs). VLPs contain reassembled capsid proteins without viral
genome; therefore, VLP is non-infectious (see Figs. 6.4 and 6.5).
When injected, they generate high levels of systemic anti-HPV
L1 IgG antibodies and provide type-speciic protection. Studies
have found that, they also confer some degree of protection against
phylogenetically-related HPV types.
146 Human Papillomavirus and HPV Vaccination

VLP L1 plus adjuvant to

form a HPV vaccine

Capsid proteins
reassembled to
L1 gene in HPV DNA is from VLP-L1
inserted into genome of
expression system Capsid protein

L1 gene
Expression system
Figure 6.4 Illustration of how HPV vaccine is manufactured using
recombinant technology. Expression system in quadrivalent
vaccine is the yeast cell while in Bivalent vaccine, using
Baculovirus. VLP L1: Viral-liked particle L1.

Direct exudation
of serum
Transudation antibodies at the
of the IgG into sites of trauma
the cervical that expose basal
secretion

Blood
vessels
Site of
Cervical
microabrasion
secretion

CERVIX

Figure 6.5 Theoretical mechanism of local protection by IgG after HPV

vaccination. Adapted from Schiller and Davies. Nat Rev
Microbiol 2004; 2: 343–347.

There are two potential beneits of HPV vaccination: (a)

Prevention of HPV-related precancerous and cancerous lesions
and (b) Prevention of HPV-related benign lesions. At present,
HPV Vaccine 147

there are two types of prophylactic HPV vaccines available in

the market: quadrivalent HPV vaccine against HPV 16, 18, 6, 11
and bivalent HPV vaccine against HPV 16 and 18. The diﬀerences
between quadrivalent and bivalent vaccine are shown in Table 6.5.
Both Quadrivalent and Bivalent vaccines were found to be highly
immunogenic in clinical trials, resulting in essentially 100%
seroconversion. The antibody titres reach peak at month 7, decline
over the next year and then remained relatively stable for at least
5–6 years. Both vaccines were also shown to induce production
of memory B cells. Human studies have shown that high titres of
speciic antibodies are also present in cervical secretions of women
receiving HPV 16 VLP L1. The most likely mechanism of these
indings is transudation from the cervical secretion and exudation
from the blood stream at the site of microtrauma or microabrasion.
These antibodies are said to provide local protection against HPV
infection (see Fig. 6.5). Natural HPV infection induces type-speciic
immunity to HPV infections. Individuals who are infected with
one HPV type may seroconvert and show some level of protection
against future infection with that HPV type but will remain
immunologically naïve to other HPV types.

Table 6.5 Characteristics of quadrivalent and bivalent HPV vaccine

Quadrivalent vaccine Bivalent vaccine

Manufacturer Merck, Gardasil®, Silgard® GlaxoSmithKline,
and trade name Cervarix®
HPV Genotypes 16, 18, 6, 11 16, 18
Manufacturing Yeast cells (Saccharomyces Trichoplusia ni insect
and Expression cerevisiae) with recombinant cell line infected with L1
system plasmid encoding recombinant
baculovirus
Amorphous aluminium Aluminium hydroxide and
Adjuvant hydroxyphosphate sulphate monophosphoryl lipid A
(AAHS), dose: 225 ug (ASO4); dose: 500 ug +
50 ug

Table 6.5 (Continued)

Quadrivalent vaccine Bivalent vaccine

Dose (0.5 mL per 20 ug anti HPV 6, 18 and 40 ug 20 ug anti HPV 16
injection) anti HPV 11, 16 and 18

Administration Intramuscular Intramuscular

Schedule 0, 2, 6 months 0, 1, 6 months

(3 intramuscular
inj. within 6
months)
Initial study age 16–26 years old 15–25 years old
group
Approval FDA, European Medicines FDA, European
(age group) Agency Medicine Agency (EMA)
(FDA: females 9–26 years old, (FDA: females 10–25
male aged 9–26 years old. years old, EMA: females
EMA: females 9 years or older, 10 years or older,
males 9–15 years old, M’sian Malaysia DCA: females
DCA: females 9–26) 10–45 years old)
Indications Prevention of HPV Prevention of HPV 16,
6/11/16/18–related cervical 18–related cervical
cancer, adenocarcinoma in cancer, denocarcinoma in
situ, CIN1-3, VAIN 2/3, VIN2/3, situ, CIN1-3 (approved by
vulvar cancer, vaginal cancer FDA for use in female age
and genital warts. 9–25)
Prevention of genital warts in
males (approved by FDA for
use in females age 9–26 and
males age 9–21. ACIP has given
a permissive recommendation
for male age 22–26 years
old and routine catch-up
vaccination for MSM (men
who has sex with men) and
HIV positive male in same age
group.)
Require for Yes Yes
storage and
cold-chain system
Preservative None None
Temperature Store refrigerated at 36°–46°F Store refrigerated at
storage (2°–8°); do not freeze 36°–46°F (2°–8°C). Do not
freeze
Quadrivalent Vaccine Trials 149

Table 6.6 Conditions associated with HPV type 16, 18, 6 and 11 and
potential beneits of HPV vaccination

Type of HPV Lesions Estimated attributable

HPV 16 and 18 Cervical cancer 70%
High-grade cervical 50%
abnormalities
Low-grade cervical 30%
abnormalities
Anal cancer 70%
Vulva/Vagina/Penile 40–50%
Head and neck cancers 3–12%
HPV 6 and 11 Low-grade cervical 10%
abnormalities
Genital warts 90%
Recurrent respiratory 90%
papillomatosis

HPV Vaccine Trial

The process of the development of any vaccine involves four phases
or stages of trials:
(a) proof of principles (animal model)
(b) toxicity studies (phase I)
(c) induction of immunity; immunogenicity study (phase II)
(d) prevention of mucosal infection (phase III)
In HPV vaccine development, the irst proof-of-principle study
to test the safety and immunogenicity of VLP L1 was done, and it
was found to be safe and inducing a signiicant immune response.
Subsequently, both Quadrivalent and Bivalent HPV vaccines have
been evaluated in large double blind randomized control trial.

Quadrivalent Vaccine Trials

The results of irst double blind eficacy trial using HPV VLPs were
published in November 2002 (Koutsky et al., 2002). In this irst
150 Human Papillomavirus and HPV Vaccination

proof-of-principle trial, HPV 16 VLP (plus adjuvant) was given to

women age 16–23 years old in three doses (0, 2 and 6 months); the
vaccine was found to be 100% eficacious in preventing persistent
HPV infection and 99.7% of women received the vaccine was
seroconverted and the level of the immune response was >50-fold
higher than natural infection.
The results of irst double blind randomized placebo control
trial (phase II) evaluating the eficacy of quadrivalent HPV vaccine
(involving 552 women age 16–23 years old) was published in 2005
and the primary endpoints were persistent HPV infection and
vaccine-type HPV-related diseases (Protocol 007). The vaccine was
found to be very eficacious in preventing persistent infection and
clinical diseases related to HPV 6, 11, 16 and 18. Quadrivalent HPV
vaccine was also found to be well tolerated and safe (Villa et al.,
2005). The extended follow-up for 5 years was done and the high
eficacy of this vaccine was found to be sustained. At 5 years, the
quadrivalent vaccine prevented 96% and 100% of HPV 6, 11, 16, 18
infections and cervical and genital diseases, respectively (Villa et
al., 2006). All women receiving the quadrivalent vaccine developed
neutralizing antibodies to HPV 6, 11, 16 and 18 at completion of the
vaccine regimen at month 7; the geometric mean titers decline after
month 7 until month 24 when the level was plateauing. Immune
memory was also observed among vaccinees who received an
antigen challenge after 5 years (anamnestic response) (Olsson et al.,
2007).
Quadrivalent vaccine was initially licensed and approved by
FDA for use in females aged 9–26 years old in October 2006.
The Advisory Committee on Immunization Practices (ACIP)
recommended routine quadrivalent vaccination of females
aged 11 or 12 years, and catch-up vaccination for females aged
13 through 26 years. Phase II trials were not only important
in evaluating the eficacy and safety of the vaccine but also in
guiding the appropriate dose of vaccine for subsequent phase III
trial. Phase III trial for quadrivalent HPV vaccine is also known
as FUTURE trial (Female United to Unilaterally Reduce Endo/
ectocervical disease). The aim of FUTURE trial is to further deine
the eficacy and safety of quadrivalent vaccine against HPV-6, 11,
18, 18–related infections and diseases including external genital
lesions. There are two FUTURE trials, i.e. FUTURE I and FUTURE
Quadrivalent Vaccine Trials 151

II. The study designs of FUTURE I and FUTURE II trials are shown
in Table 6.7. Combined analysis of phase II trial (Protocol 007) and
phase III trials (FUTURE I and FUTURE II trials) showed that the
quadrivalent vaccine prevented 100% of HPV 16, 18–related
high-grade cervical lesions. Vaccine also showed 100% eficacy in
preventing HPV 16, 18–related VAIN 2/3 and VIN 2/3; more than
95% eficacy in preventing HPV6, 11, 16, 18–related CIN 1/2/3,
AIS, genital warts, vulvar and vaginal neoplasias. In summary,
Quadrivalent vaccine was very eﬀective in reducing the incidence of
HPV 6/11/16/18–related disease in HPV naïve women (seronegative
and HPV DNA negative by PCR). Interestingly, vaccine also beneicial
to women who had been previously exposed to at least one
vaccine HPV type at enrolment, but had no ongoing HPV infection
(seropositive but HPV DNA negative by PCR) (Joura et al., 2007; Ault,
2007). Quadrivalent vaccine also demonstrated vaccine eficacy
against CIN2+ associated with 10 other oncogenic types, which
were 32.5% (Brown et al., 2009). The other completed and ongoing
studies related to quadrivalent HPV vaccine are phase III adolescent
immunogenicity study for males and females aged 9–15, eficacy
study in mid-adult women (age 24–45), men safety and eficacy
study (male age 16–26) and safety and immunogenicity in HIV-
infected children (protocol 021).
The results of randomized double blind trial on the safety,
immunogenicity and eficacy of quadrivalent HPV vaccine in
women aged 24–45 years old have been published in Lancet
2009. The eficacy against the HPV 6, 11, 16 and 18–related
disease or infection in per-protocol population was 90.5% while
the eficacy against second coprimary endpoint that is disease or
infection related to HPV 16 and 18 alone was 83.1%. The eficacy
of quadrivalent HPV vaccine in intention-to-treat population
(including women who had been infected) was approximately
22–30%. The authors concluded that quadrivalent HPV vaccine is
eficacious in women aged 24–45 years not infected with the
relevant type at enrolment (Munoz et al., 2009).
Men safety and eficacy study (protocol 020) is a randomized
double blind placebo control trial involving more than 4000 male
subjects (age 16–26 males including heterosexual and gays).
Preliminary analysis (after 30 months) of this study reported the
eficacy in per-protocol population of 100% for prevention of PIN
152 Human Papillomavirus and HPV Vaccination

1/2/3, 89% for prevention of condyloma and 90% for external

genital lesions (EGLs). Based on immunogenicity bridging study
among boys age 9–15 (protocol 016 and 018), FDA has agreed
that immune responses to quadrivalent vaccine in 9–15 years old
boys and girls are non-inferior to those in 16–26 years old and it
is also well tolerated. On October 2009, ACIP provided guidance
that quadrivalent HPV vaccine may be given to males age 9 through
26 years to reduce their risk of acquiring genital warts.

Table 6.7 Characteristics of trials evaluating eficacy and safety of

quadrivalent HPV vaccine

Protocol 007a FUTURE Ib FUTURE IIc

Study design (phase II trial) (phase III trial) (phase III trial)
Sample size 550 5455 12, 167
Study sites International, International, International,
multicenter, multicenter, multicenter,
double blind double blind double blind
Study vaccine Quadrivalent Quadrivalent Quadrivalent
Schedule 0, 2, 6 months 0, 2, 6 months 0, 2, 6 months
Age 16–23 16–24 15–26
Previous history Not allowed Not allowed Not allowed
of HPV-related
disease
Sexual exposure Allowed Allowed Allowed
Requirement for All abnormal All abnormal All abnormal
biopsy areas areas areas
HPV detection PCR assay on PCR assay on PCR assay on
frozen specimens frozen specimens frozen
specimens

Note: More than 20,000 women involved in the trials from Europe, North America,
Latin America and Asia Paciic region.
aVilla LL, et al. Lancet Oncol 2005; 6: 271–278.
bGarland et al. N Engl J Med 2007; 356: 1928–1943.
cFUTURE II study group. N Engl J Med 2007; 356: 1915–1927.

For quadrivalent HPV vaccine, titres of anti-HPV remained

substantially higher than those obtained after natural infection
for type 16 and 6, while as for type 18 and 11, the titres were
Bivalent HPV Vaccine Trials 153

approaching close to that of natural infection after 5-year follow-up.

Despite this observation, no breakthrough disease occurred in all
subjects, including HPV 16 and 6–related conditions.

Bivalent HPV Vaccine Trials

The bivalent HPV vaccine was irst evaluated in double blind
randomized placebo control trial (phase II) involving more than
1000 women age 15–25 years old and was published in 2004. This
study is also known as HPV-001 trial. Bivalent HPV vaccine was
found to be very eficacious, well tolerated and safe (Harper et al.,
2004). Extended follow-up study from HPV-001 trial is known as
HPV-007 trial. Both HPV-001 and HPV-007 trials are phase II trials
to evaluate the eficacy and safety of bivalent HPV vaccine. The
eficacy endpoints for HPV-007 trial were HPV 16, 18–related
incident of infection, persistent infection, abnormal cytology and
CIN lesions. Final analysis of HPV-007 (after 6.4 years) indicates that
bivalent HPV vaccine remains eficacious (97–100%) in prevention
of persistent infection (for 12 months) and HPV 16/18–related
abnormal cytology and CIN. The combined HPV-001 and 007
analyses have also shown evidence of cross protection against HPV
45 and 31. HPV-001 and HPV-007 trials have justiied the currently
used dose of bivalent HPV vaccine for clinical use and phase III
trial (PATRICIA). Long term followed up study from HPV-001/007
trial is continued in Brazil and is expected to be completed at
9.5 years; this trial is known as HPV-023 trial. De Carvalho N
and colleagues have reported the analysis of HPV-023 trial up to
7.3 years, and they have reported that vaccine eficacy up to
7.3 years was 94.5% for incident of infection, 100% for 12 months
persistent infection and 100% for CIN2+. Antibody titres for total
IgG and neutralizing antibodies remained several folds above
natural infection levels and more than 96% of women were
seropositive. Almost similar indings were elicited at 8.4 years of
HPV023 trial. The vaccine also remains safe.
Phase III double blind randomized control trial evaluating the
eficacy and safety of bivalent HPV vaccine is known as PATRICIA
trial or HPV-008 trial. PATRICIA or Papilloma Trial against
Cancer In young Adults is multinational randomized control trial,
assessing the eficacy and safety of bivalent HPV vaccine against
154 Human Papillomavirus and HPV Vaccination

persistent infection, CIN2+, CIN3+ associated with HPV 16/18 and

infection as well as lesions caused by the non-vaccine oncogenic
HPV types. Participants in this trial were healthy women age 15–25
years at the time of irst vaccination; participants were recruited
from 135 centres in 14 countries in Asia Paciic, Europe, Latin
America and North America (from May 2004). Women who had
sexual exposure were also included. Women were enrolled
irrespective of their HPV DNA status, HPV serostatus or cytology
at baseline. The results of PATRICIA were published in July 2009.
Vaccine eficacy against CIN2+ associated with HPV 16/18 was
98.4% in HPV naïve women. Vaccine eficacy against CIN2+
irrespective of HPV DNA in lesions was 30.4% in a total vaccinated
cohort (included all women receiving at least one dose, regardless
of their baseline HPV status; representing general population).
In HPV naïve women, the eficacy of bivalent HPV vaccine against
HPV 16/18–related CIN3+ was 100%. The vaccine also showed
signiicant eficacy (54%) against CIN2+ not associated with HPV
16 and 18 indicating cross protection, especially with HPV 31, 33
and 45 (Paavonen et al., 2009). This additional eficacy could
translate into approximately 11–16% extra protection against
cervical cancer over and above the protection aﬀorded by eficacy
against HPV 16 and 18 alone.
Bivalent HPV vaccine was irst licensed and approved by
FDA for use in females aged 10–25 years old in October 2009.
Vaccination with bivalent HPV vaccine induced a strong immune
response with the average level of antibodies for both HPV 16
and 18 remains 11 times greater than antibody levels associated
with natural HPV infection over a period of up to at least 8.3
years. Einstein HM and colleagues compared the immunogenicity
between bivalent and quadrivalent HPV vaccine given to
healthy women age 18–45; bivalent HPV vaccine induced higher
neutralizing antibody level for both HPV 16 and 18. Although the
bivalent vaccine induces higher antibody titres, it is unclear if this
will translate into a more durable response. Currently bivalent
HPV vaccine has been selected for national cervical cancer
immunization programs in many countries such as United Kingdom,
Netherlands, Sweden, Latvia, Gibraltar, Italy, Spain, Mexico and
Bivalent HPV Vaccine Trials 155

Malaysia. Safety and immunogenicity of bivalent HPV vaccine in

adolescent girls were evaluated in randomized controlled trial
involving over 2000 girls with the means age of 12. This study
shows that Bivalent HPV vaccine has a favourable safety proile
and stimulates high anti HPV 16 and 18 antibody levels ; higher
than in young women (Medina et al., 2010).

Table 6.8 Characteristics of clinical trials for Bivalent HPV vaccine

(Cervarix)

Study design HPV-001/007/023a PATRICIAb NCI/COSTA RICAc

Sample size 1113 (for HPV 18,644 7466
001/007)
Study sites USA, Canada, Brazil North Costa Rica
(HPV-023 trial is an America, Latin
extended trial but America,
participants are only Europe, Asia
from Brazil) Paciic and
Australia
Phase of study Phase II Phase III Phase III
Control arm 500 ug Aluminium Hepatitis Hepatitis A Vaccine
hydroxide A Vaccine
Age 15–25 15–25 18–25
Frequency of 6 months 12 months 12 months
monitoring
Primary end Incidence of type HPV 16, 18– HPV 16, 18–related
point 16/18 infections related CIN2+ persistent infection
and CIN2+
Secondary Persistent infection, Persistent Adverse effects
endpoints CIN1+; adverse infection or
effects CIN1+ by any
type of HPV;
adverse effects
aHarper et al., Lancet 2004; 364: 1757–1765; Carvalho et al., Vaccine 2010; 28:
6247–6255; HPV-023 is still ongoing.
bPaavonen et al., Lancet 2007; 369: 2161–2170, Paavonen et al., Lancet 2009;

374: 301–314.
cCosta Rica Vaccine trial sponsored by NCI (Herrero et al., Vaccine 2008; 26:

4795–808).
156 Human Papillomavirus and HPV Vaccination

Table 6.9 Eficacy of bivalent and quadrivalent HPV vaccine in female

Vaccine/endpoint/HPV type Vaccine eficacy (%, 95% CI)

Bivalent HPV vaccine
1. CIN 2/3 or adenocarcinoma in situ
HPV 16 and/or 18 92.9% (79.9–98.3)
HPV 16 95.7% (82.8–99.6)
HPV 18 86.7 % (39.7–98.7)
Quadrivalent HPV vaccine
1. CIN 2/3 or adenocarcinoma in situ
HPV 6, 11, 16 and/or 18 98.2% (93.3–99.8)
HPV 16 97.6% (91.1–99.7)w
HPV 18 100% (86.6–100.0)
2. VIN2/3 or VAIN 2/3
HPV 6, 11, 16 and/or 18 100% (82.6–100.0)
HPV 16 100% (76.5–100.0)
HPV 18 100% (<0–100.0)
3. Genital warts
HPV 6 and/or 11 99% (96.2–99.9)
Source: Adapted from Centers for Disease Control and Prevention, Morbidity and
Mortality weekly reports, Volume 59, No 20, May 2010.
CIN: Cervical intraepithelial neoplasm.
VIN: Vulvar intraepithelial neoplasm.
VAIN: Vaginal intraepithelial neoplasm.

Safety of Quadrivalent HPV Vaccine

Pain, erythema and swelling at the injection sites were the most
common side eﬀects but same problems were also found in the
placebo arm (87% versus 77%). Serious vaccine-related adverse
events were very rare, less than 2%. There was no adverse pregnancy
outcome to women who had accidentally vaccinated while pregnant
(66% of vaccine recipients and 63% in placebo recipients who
became pregnant had a live birth). HPV vaccination did not increase
the risk of the miscarriage and abnormal foetus. Among women
who received the quadrivalent vaccine while lactating, the few
adverse events among infants were judged not to be related to
vaccine.
Safety of Bivalent Vaccine 157

The 3-year post-licensure surveillance has reported that as of

June 2009, more than 25 million doses of quadrivalent HPV vaccine
had been distributed in the United States with more than 50 million
doses globally. The rate of treatment-related serious adverse
effect was 0.05% in the vaccine group as compared to 0.02% in
the placebo group. A total of 18 deaths were reported but all were
considered unrelated to study treatment. There was no difference
in the rate of new autoimmune phenomena. The vaccine adverse
events reporting system has received approximately 14,000 reports
for the quadrivalent vaccine since licensure, with only 7% being
serious adverse events, about half the average reported for licensed
vaccines in general. The authors concluded that based on review
of post-licensure safety information, the beneits of vaccination
to prevent the majority of genital tract precancers and cancers
continue to far outweigh its risks (Block et al., 2010). Based on the
oficial statements of national and international agencies and expert
immunization groups (WHO, CDC, FDA, PHAC, ATAGI, EMEA, STIKO,
PEI, etc.) to date, as well as the review of the reports presented
herein, HPV vaccine seems to be safe and effective vaccines.
However, it is vital that continued and careful monitoring is
undertaken.

Safety of Bivalent Vaccine

Pooled analysis on the safety of bivalent HPV vaccine showed
almost similar indings with quadrivalent HPV vaccine. Rate of
adverse events, including serious adverse eﬀects were generally
similar between the bivalent vaccine and control groups and there
was no increased in the risk of the autoimmune condition. Similar
to quadrivalent vaccine, injection site symptoms such as pain,
swelling and redness were reported more frequently; however,
these were transient, easily managed and did not aﬀect compliance.
The pooled safety analysis included >29,000 females aged 10
through 25 years; approximately, 16,000 females received at least
one dose of bivalent vaccine. In the bivalent vaccine group, 92%
reported injection-site pain, 48% redness, and 44% swelling
compared with 64–87%, 24–28% and 17–21% in the control
group. Fatigue, headache and myalgia were the most common
general symptoms (Descamps et al., 2009; Verstraeten el al., 2008).
158 Human Papillomavirus and HPV Vaccination

Proportions of persons reporting a serious adverse event were

similar in vaccine and control group (5.3% and 5.9% respectively).
Medically signiicant adverse events occurred in 8.1% of women
in the vaccine group and 6.2% of women in the placebo group,
no women experienced new onset chronic disease and new onset
autoimmune disease (Carvalho et al., 2010).
The outcome of pregnant women receiving bivalent HPV
vaccine was similar to placebo; there was no increase in the rate
of premature delivery, elective termination and spontaneous
miscarriage. Bivalent HPV vaccine has been classiied as
category B on the basis of animal studies that revealed no
evidence of impaired fertility or harm to the foetus. No data
are available on use of bivalent HPV vaccine in lactating women.
Overall, both bivalent and quadrivalent vaccines are well
tolerated, safe and so far there was no report on death directly
related to the content of the vaccines. In June 2013, the WHO Global
Advisory Committee on vaccine safety concluded that both HPV
vaccines are generally safe and well tolerated.

WHO Global Advisory Commitee (GAC) Statement on the

Update of HPV Vaccine Safety by 2013
At its meeting on 13 June 2013, WHO GAC reviewed updated
information about safety of HPV vaccines. There was a approximately
175 million doses of HPV vaccines have been distributed worldwide.
Although there were reported of new side-eﬀects such as syncope,
venous thromboembolism, stroke, Guillain-Barre syndrome and
complex regional pain syndrome, their occurrence were very low
and none have been found to have direct causal relationship to
HPV vaccine. Surveillance of pregnancy outcomes among women
inadvertently vaccinated during pregnancy through spontaneous
reports and registries have not detected any adverse outcomes above
expected rates. Therefore the Committee continues to reassure that
both vaccines are generally safe and well tolerated. This statements
is also endorsed by FIGO (International Federation of Gynecology
and Obstetrics) and their Gynaecologic Oncology Committee as well
as FIGO subcommittee for Cervical Cancer Prevention supports
the continued administration of the HPV vaccines in appropriate
population.
HPV Vaccination in Males 159

HPV Vaccination in Males

HPV vaccination is not only effective in females but recently,
evidence has shown that HPV vaccine is also safe and eficacious
against HPV infection and external genital lesions in young
men (Palefsky, 2010; Giuliano et al., 2008). US Food and Drug
Administration (FDA) had approved the use of Quadrivalent HPV
vaccine in males (age 9–26 years old) in October 2009 for the
prevention of genital warts. The new indication for Quadrivalent
HPV vaccine is based on two trials. The irst included 4055 males
ages 16 through 26 that measured the vaccine’s effectiveness in
preventing genital warts. Overall, the study found a 90% reduction
in genital warts and pre-cancerous lesions (PIN) caused by HPV
(Giuliano et al., 2009; Palefsky 2008). The second trial studied
immune response in boys ages 9 to 15, and the study suggested that
the vaccine should have similar effectiveness in younger boys as
the irst study found for older males (Reisinger et al., 2007).
In 2011 the US Advisory Committee on Immunisation Practices
approved and recommended routine use of Quadrivalent HPV
vaccine for boys aged 11–21 years, with approval for administration
up to age 26 years, in order to prevent genital warts and anal cancer
(Palefsky et al., 2011). HPV vaccine has been approved for use in
males by local health authority in Australia, Mexico and several other
countries, including in some Asian countries such as Malaysia.
At present, HPV vaccination to males is still not a priority and
we are still awaiting a conclusive data regarding the role of HPV
vaccination in prevention of HPV-related cancers in males and HPV
transmission to female. Following are the arguments of why HPV
vaccination in males should be considered (Zimet and Rosenthal
Rosenthal SL, 2010):
(a) The fastest way to achieve the greatest protection for females
from cervical cancer and its precursors is to vaccinate males
as well (through herd immunity).
(b) HPV vaccination to males will protect men who have sex with
men from HPV and HPV-related diseases.
(c) Vaccination of males may be more acceptable to some cultural
groups than vaccinating females.
160 Human Papillomavirus and HPV Vaccination

(d) Implementations of risk-based (or gender-based) vaccination

policies have been less effective and more confusing to the
public.
(e) HPV vaccination in males will also reduce the burden of HPV-
related precancerous, cancerous lesions as well as benign
lesions accounted by male.
The main argument against the HPV vaccination to males is
cost-effectiveness. Several studies have shown that vaccinating
both males and females is less cost-effective than vaccinating
females alone especially in young males and in countries with
limited inancial support (Kim, 2009). This cost-effective analysis
study is still inconclusive as the study had assumed that 75% of
eligible women would be vaccinated (lower than current coverage
in US). If the coverage of female HPV vaccination is low, adding
male vaccination may have clear health beneits for both genders.
Furthermore, cost-effective analysis should also include prevention
of HPV-associated diseases in men.

HPV Vaccine: Policy and Administration

Guidelines
(1) HPV vaccine is most eﬀective when given before exposure to
HPV infection.
(2) Both HPV vaccines are given intramuscularly in three doses.
(3) Second dose is administered 1–2 months after the irst dose
and the minimum interval between the irst and second dose
is 4 weeks while the minimum interval between the second
and third dose is 12 weeks.
(4) If the dose is given at the shorter minimum interval should
be readministered.
(5) Coadministration of a diﬀerent vaccine (either inactivated or
live vaccine) is permitted because HPV vaccine is not a live
vaccine.
(6) HPV vaccine can be administered to persons with immuno-
compromised state; however, the immune response may be
less in the immunocompromised patient compared with a
healthy individual.
HPV Vaccine 161

(7) Person with mild acute illness (e.g. diarrhoea, mild upper
respiratory tract infection) can receive the HPV vaccine.
Vaccination of people with moderate or severe acute illnesses
should be deferred until after the illness improves.
(8) Patient who received HPV vaccine is recommended to be
observed for about 15 minutes after vaccination as syncopal
attach is common.
(9) Whenever feasible, the same HPV vaccine should be used for
the entire vaccination series, however, if the previous vaccine
is not available, either vaccine can be used to complete the
series to provide protection against HPV 16 and 18.
(10) Testing for HPV is currently not recommended before
vaccination.
(11) HPV vaccines are not recommended for use in pregnant
women; if women are found to be pregnant after initiating
the vaccination series, the remainder of the three-dose series
should be delayed until completion of pregnancy. If the vaccine
dose has been administered during pregnancy, no intervention
is needed.
(12) It is not known whether the vaccine antigens or antibodies
are excreted in human milk. Lactating women can receive the
HPV vaccine such as this, because it is an inactivated vaccine
without live viral DNA.
(13) Women with previous abnormal cervical cytology or genital
warts can receive the HPV vaccine but it may be less eﬀective
in women who have been infected with HPV before vaccination
than in women who have not.
(14) Women with previous HPV infection will beneit from
protection against infection of HPV genotypes with which
they have not been infected.
(15) HPV vaccine can be given to patients with previous cervical
intraepithelial neoplasia, but the beneits may be limited to
protection against infection of HPV genotypes with which
they have not been infected.
(16) HPV vaccines are contraindicated for persons with a history
of immediate hypersensitivity to any vaccine component.
A person who is allergic to yeast is contraindicated from
quadrivalent HPV vaccine. While a person who is allergic
162 Human Papillomavirus and HPV Vaccination

to latex should not be given vaccine which has latex in the

rubber stopper of their preilled syringes (in bivalent HPV
vaccine).
(17) HPV vaccines should be introduced as part of a coordinated
cervical cancer and other HPV-related diseases prevention
strategy, including education on risk reducing behaviours,
diagnosis and treatment of precancerous lesions and cancer.
(18) HPV vaccine introduction should not undermine or divert
funding from eﬀective cervical cancer screening programmes
and it should not replace cervical cancer screening.

Table 6.10 Advantages and disadvantages of current prophylactic HPV

vaccines

Advantages Disadvantages
Highly immunogenic Expensive (for low-income countries, the per
dose cost would need to be less than US$ 5
for vaccination to be affordable.
High eficacy Protection only against 2 oncogenic types
and 6, 11 for quadrivalent vaccine. Cross
protection only provided extra 11–16%
reduction in cervical cancer incidence
(prediction). Furthermore, the duration of
cross protection is still unknown.
Induce memory B cells Unsure duration of protection, decay of
antibody response
Cross protection Unsure the need for booster
Beneited in older age Cost-effective analysis still unclear, perhaps
group up to 45 years old cost-effective if the cost per-dose is much
cheaper and when use in children &
adolescents
Safe and well tolerated Safety concerns and public perception
Potential effective in Require 3 injections, proper storage and cold
reducing the incidence chain
and mortality of HPV 16,
18–related precancerous
and cancerous lesions
Potential reduction in A result on inal endpoint (incidence and
the burden of HPV 6, mortality rate of cervical cancer) can only be
11–related lesions with obtained after many years of vaccination.
quadrivalent vaccine
Future Direction 163

Future Direction
Current HPV vaccine is very costly; the price will drop with time.
However, using basic structural units of the HPV capsid known as
L1 capsomer instead of whole VLPs was found to be much cheaper;
besides L1 capsomer is more thermostable. L1 capsomers can be
produced in Escherichia coli and expression of L1 in recombinant
Salmonella enteric serovars. Inventing needle free administration
route such as oral drop or nasal spray can also lower the cost
of vaccine. The spectrum of coverage by HPV vaccine can be
broadening by manufacturing multivalent HPV vaccine comprising
more oncogenic HPV types. Merck also known as MSD outside the
United State and Canada had conducted phase III clinical trials on
nine-valent vaccine, V503. In this phase III trial (Protocol 001),
V503 was compared to Quadrivalent vaccine (Gardasil) in term of
eficacy, safety and immunogenicity. V503 consists of vaccine against
9 HPV types i.e 6, 11, 16, 18, 31, 33, 45, 52, 58 and was given to 7,099
females age between 16–26 years old. The results were:
(a) 96.7% reduction in the combined incidence of high grade
lesions of cervical,vulvar and vagina, caused by HPV types 31,
33, 45, 52, 58,
(b) 97.1% reduction in the combined incidence of any grade of
CIN/VIN/VaIN,
(c) 96.0% eficacy against 6-months persistent HPV infection
with HPV types 31, 33, 45, 52 and 58,
(d) Similar immunogenicity against HPV 6, 11, 16 and 18 in V503
compared to Gardasil,
(e) similar safety proiles and frequencies of adverse event
between V503 and Gardasil.
In Protocol 002 trial, immonogenicity “bridging data” of V503
administered to younger male and female age 9–15 years old
were evaluated. Results from this study showed non-inferior
immunogenicity of V503 in adolescent males and females compared
with females 16–26 years old for all nine vaccine HPV type. The
safety and tolerability were also comparable. Both of these trials
were presented at the European Research Organisation on Genital
Infection and Neoplasia (EUROGIN) Congress in November 2013.
An eﬀort must be made to manufacture a cheaper Multivalent HPV
vaccine, which is more suitable for low-income countries. This can
164 Human Papillomavirus and HPV Vaccination

be achieved by reducing the cost of production, producing longer

shelf life vaccine, vaccine that does not require cold chain and
producing the vaccine that is eﬀective even with a single dose. The
other promising method to broaden the protection of HPV vaccine
is by using L2 minor capsid protein instead of L1 major capsid
protein. Study has shown that L2 minor capsid protein has broader
cross protection across HPV genotypes. However, L2 protein is
less immunogenic than L1 protein. Upon successfully inding an
appropriate adjuvant, this approach may be explored in clinical
trials. There is an urgent need for therapeutic HPV vaccine. The
current HPV vaccines are prophylactic, and it would take many
years through a well-organized vaccination program before it
can reduce the incidence of cervical cancer. With therapeutic
HPV vaccine, cell-mediated immunity will be employed (instead
of humoral immunity in prophylactic vaccine) to immediately
destroy the HPV-infected cells and therefore the outcome of
this vaccine will be observed in the shorter period of time. Long
overlapping peptides have stirred enthusiasm for therapeutic
HPV E6/E7 peptide-based vaccines because they could limit
the obstacle of major histocompatibility complex restriction by
broadening the range of antigenic epitopes. Long overlapping
peptides that represent E6 and E7 of HPV 16 was evaluated in
phase II trial by Kenter GG in patients with vulvar intraepithelial
neoplasia; the outcome from this trial was promising. The potency
of therapeutic vaccine can be enhanced by using DNA vaccine,
which has undergone microencapsulation to avoid degradation
by enzyme nucleases. The example of this type of vaccine is
Amolimogene bepiplasmid (ZYC101A); this vaccine comprised
plasmid DNA that encodes E6/E7 proteins of HPV16/18 and
encapsulated in biopolymer has been evaluated in the phase II/III
trial for patients with CIN2/3.
The latest morbidity and mortality weekly report from the
Centers for Disease Control and Prevention on vaccination coverage
indicates that in 2012, only 53.8% of girls between 13 and 17 years
old initiated HPV vaccination, and only 33.4% of them received all
three doses. NCI-funded phase III trial had evaluated the eficacy
of less than 3 doses of HPV vaccine (Bivalent) received by a group
of women from Costa Rica. In this study, 78, 192 and 120 women
received one, two and three doses of the vaccine respectively. The
immune response was evaluated in all of these women and compared
References 165

to 113 women who did not received the vaccine but had antibodies
against the viruses because they were infected with HPV in the
past. All vaccinated groups were found to have signiicant levels
of antibody for at least 4 years, although the lesser dose was
associated with lower antibody levels. The antibody levels in women
received one and two doses were 5–24 times higher than the levels
of antibodies in women who did not receive vaccination. Results
from this study raise the possibility that even a single dose of HPV
VLPs will induce long-term protection (Safaeian et al., 2013).

References

Agorastos T, Chatzigeorgiou K, Brotherton JML, Garland SM. Safety of

human papillomavirus (HPV) vaccines: A review of the international
experience so far. Vaccine 2009; 27: 7270–7281.
Ault KA. Eﬀect of prophylactic human papillomavirus L1 virus-like-particle
vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3,
and adenocarcinoma in situ: a combined analysis of four randomised
clinical trials. Lancet 2007; 369: 1861–1868.
Berumen J, Ordonez RM, Lazcano E, et al. Asian-American variants of human
papillomavirus 16 and risk for cervical cancer. J Natl Can Inst 2001;
93: 1325–1330.
Bonanni P, Boccalini S, Bechini A. Eficacy, duration of immunity and cross
protection after HPV vaccination: A review of the evidence. Vaccine
2009; 27: A46–A53.
Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure
safety proile of a prophylactic human papillomavirus (type 6, 11, 16
and 18) L1 virus-like particle vaccine. Pediatr Infect Dis J 2010; 29:
95–101.
Brown et al. The impact of quadrivalent human papillomavirus (HPV;
type 6, 11, 16 and 18) L1 virus-liked particle vaccine on infection and
disease due to oncogenic nonvaccine HPV types in generally HPV-naïve
women aged 16–26 years. J Infect Dis 2009; 199: 926–35.
Carvalho ND, Teixeira J, Roteli-Martin CM, et al. Sustained eficacy and
immunogenicity of the HPV 16/18 ASO4 adjvanted vaccine up to 7.3
years in young women. Vaccine 2010; 28: 6247–6255.
Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human
papillomavurus infection, and cervical cancer in female partners.
N Engl J Med 2002; 346: 1105–1112.
166 Human Papillomavirus and HPV Vaccination

Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in
Taiwan and the incidence of hepatocellular carcinoma in children.
Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997; 336(26):
1855–1859.
Chaturvedi AK. Beyond cervical cancer: burden of other HPV-related cancers
among men and women. J Adolesc Health 2010; 46: S20–S26.
Chaturvedi AK. Beyond Cervical Cancer: burden of other HPV related cancers
among men and women. J Adolesc Health 2010; 46: S20–S26.
Descamps D, Hardt K, Spiessens B, et al. Safety of human papillomavirus
(HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention:
a pooled analysis of 11 clinical trials. Hum Vaccin 2009; 5: 332–340.
Division of STD Prevention. Prevention of genital HPV infection and sequelae:
Report of an External Consultants Meeting, December 1999. Atlanta,
GA: department of Health and Human Services, Centers for Disease
Control and Prevention: 1999.
Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence
of HPV infection among men: a systematic review of the literature. J
Infect Dis 2006; 194: 1044–1057.
Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity
and safety of Cervarix and Gardasil human papillomavirus (HPV)
cervical cancer vaccine in healthy women aged 18–45 years. Hum
Vaccin 2009; 5(10): 1–15.
Evans M, Powell NG. The changing aetiology of Head and Neck Cancer: the
role of human papillomavirus. Clin Oncol 2010; 22: 538–546.
Food and Drug Administration. Product approval-prescribing information
[package insert]. Cervarix [human papillomavirus bivalent (types 16
and 18) vaccine, recombinant], Glaxo Smith Kline Biologicals: Food
and Drug Administration 2009. Available at [Link]
biologicsbloodvaccines/vaccines/approvedproducts/ucm186957.
htm. Accessed May 25, 2010.
Frazer IH, Cox JT, Mayeaux EJ, et al. Advances in prevention of cervical cancer
and other human papillomavirus-related diseases. Pediat Infect Dis J
2006; 25(2): S65–S81.
Future II Study Group. Quadrivalent vaccine against human papillomavirus
to prevent high-grade cervical lesions. N Engl J Med 2007; 356:
1915–1927.
Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter
S, et al. Quadrivalent vaccine against human papillomavirus to prevent
anogenital diseases. N Engl J Med 2007; 356: 1928–1943.
References 167

Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the
potential prevention of noncervical cancers in both men and women.
Cancer 2008; 113(S10): 3036–3046.
Gissmann L. Review Artcle: HPV vaccine: Preclinical Development. Arch Med
Res 2009; 40: 466–470.
Giuliano AR, Anic G, Nyitray AG. Epidemiology and pathology of HPV disease
in males. Gynecol Oncol 2010; 117: S15–S19.
Giuliano AR, Lazcano Ponce E, Villa LL, et al. The human papillomavirus
infection in men study: human papillomavirus prevalence and type
distribution among men residing in Brazil, Mexico, and the United
States. Cancer Epidemiol Biomarker Prev 2008; 17: 2036–2043.
Giuliano AR, Lazcano E, Villa LL, Flores R, et al. Circumcision and sexual
behavior: factors independently associated with human papillomavirus
detection among men in the HIM study. Int J Cancer 2009; 124:
1251–1257.
Giuliano AR, Palefsky J. The eficacy of quadrivalent HPV (type
6/11/16/18) vaccine in reducing the incidence of HPV-related
genital disease in young men. EUROGIN 2008; France: Abstract
SS 19-7a.
Giuliano AR, Palefsky J. The eficacy of quadrivalent HPV (type 6/11/16/18)
vaccine in reducing the incidence of HPV-related genital disease in
young men. Presented in 25th International Papillomavirus Congress,
May 8–14, 2009, Malmo, Sweden. Presentation O-01.07.
Harper DM, Franco EL, Wheeler C, et al. Eficacy of a bivalent L1 virus-
like particle vaccine in prevention of infection with human
papillomavirus type 16 and 18 in young women: a randomized
controlled trial. Lancet 2004; 364: 1757–1765.
Herrero R, Hildesheim A, Bratti C, et al. Population-based study of human
papillomavirus infection and cervical neoplasia in rural Costa Rica. J
Natl Cancer Inst 2000; 92: 464–74.
Herrero R, Hildesheim A, Rodriguez AC, Wacholder S, Bratti C, Solomon D,
et al. Rationale and design of a community-based double-blind
randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste,
Costa Rica. Vaccine 2008; 26: 4795–808.
IARC. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans.
Human Papillomaviruses, vol. 90. Lyon, France: IARC Press, 2007.
Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky
LA, et al. Eficacy of a quadrivalent prophylactic human papillomavirus
(types 6, 11, 16, and 18) L1 virus-likeparticle vaccine against high-grade
168 Human Papillomavirus and HPV Vaccination

vulval and vaginal lesions: a combined analysis of three randomised

clinical trials. Lancet 2007; 369: 1693–1702.
Kenter GG, Welters MJ, Valentijin AR, et al. Vaccination against HPV 16
oncoproteins for vulvar intraepithelial neoplasia. N Eng J Med 2009;
361: 1838–1847.
Kim JJ, Brisson M, Edmunds WJ, Goldie SJ. Modeling cervical cancer
prevention in developed countries. Vaccine 2008; 26 (Suppl 10):
K76–K86.
Kim JJ, Goldie SJ. Cost eﬀectiveness analysis of including boys in a
human papillomavirus vaccination program in the United State.
BMJ 2009; b3884: 339 doi: [Link]
Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human
papillomavirus type 16 vaccine. N Engl J Med 2002; 347: 1645–1651.
Koutsky L. The epidemiology behind the HPV vaccine discovery. Ann
Epidemiol 2009; 19: 239–244.
Lizano M, Berumen J, Garcia-Carranca A. Review Article: HPV-related
carcinogenesis: Basic concepts, viral types and variants. Arch Med
Res 2009; 40: 428–434.
Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and
clearance of human papillomavirus infection in a cohort of US men: a
prospective study. J Infect Dis 2009; 199: 362–371.
Marina VM, Poveda KT, Toledo GL, Caranca AG. Advantages and
disadvantages of current prophylactic vaccines against HPV. Arch
Med Res 2009; 40: 471–477.
Medina DMR, Valencia A, de Velsquez A, et al. Safety and immunogenicity of
the HPV 16/18 adjuvanted vaccine: A randomized, controlled trial in
adolescent girls. J Adolesc Health 2010; 46: 414–421.
McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia
and risk of invasive cancer in women with cervical intraepithelial
neoplasia 3: a retrospective cohort study. Lancer Oncol 2008; 9:
425–434.
Moscicki AB. Review article. HPV vaccines: today and in the future.
J Adolesc Health 2008; 43: S26–S40.
Munoz N, Castellsaque X, de Gonzalez AB, Gissmann L. Chapter 1: HPV in the
etiology of human cancer. Vaccine 2006; 24 (Suppl 3) S3/1–10.
Munoz N, Manalastas Jr R, Pitisuttithum P, et al. Safety, immunogenicity
and eficacy of quadrivalent human papillomavirus (type 6, 11, 16,
18) recombinant vaccine in women aged 24–45 years: a randomized,
double blind trial. Lancet 2009; 373: 1949–1957.
References 169

Nielson CM, Schiafino MK, Dunne EF, Salemi JL, Giuliano AR. Associations
between male anogenital human papillomavirus infection and circum-
cision by anatomic site sampled and lifetime number of female sex
partners. J Infect Dis 2009; 199: 7–13.
Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, et al. Induction
of immune memory following administration of a prophylactic
quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1
virus-like particle (VLP) vaccine. Vaccine 2007; 25(26): 4931–4939.
Paavonen J, Naud P, Salmeron J, et al. Eficacy of human papillomavirus
(HPV)16/18 ASO4-adjuvanted vaccine against cervical infection and
precancer caused by oncogenic HPV types (PATRICIA): inal analysis
of a double-blind, randomized study in young women. Lancet 2009;
374: 301–314.
Palefsky JM. Human Papillomavirus-related disease in men: not just
a women’s issue. J Adolesc Health 2010; 46: S12–S19.
Palefsky J, Giuliano A. Eficacy of the quadrivalent HPV vaccine against
HPV 6/11/16/18-related genital infection in young men. Presented
at the 2008 conference of the European research organization on
genital infection and neoplasia (EUROGIN); 2008 November 12–15;
Nice, France. Abstract PS 1–3a.
Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV
infection and anal intraepithelial neoplasia. N Eng J Med 2011; 365:
1576–1585.
Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immu-
nogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18
L1 virus-like particle vaccine in preadolescents and adolescents: a ran-
domized controlled trial. Pediatr Infect Dis J 2007; 26(3): 201–209.
Safaeian M, Porras C, Pan Y, et al. Durable Antibody Responses Following
One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle
Vaccine in the Costa Rica Vaccine Trial. Cancer Prev Res, November
2013; 6(11): 1242–50. doi:10.1158/[Link]-13-0203.
Schiﬀman M, Castle PE, Jeronimo J, et al. Human papillomavirus
and cervical cancer. Lancet 2007; 370: 890–907.
Stanley M. Pathology and epidemiology of HPV infection in female. Gynecol
Oncol 2010; 117: S5–S10.
The Future II Study Group. Prophylactic eficacy of a quadrivalent
HPV vaccine in women with virologic evidence of HPV infection.
J Infect Dis (in press) 2007; 196(10): 1438–1446.
170 Human Papillomavirus and HPV Vaccination

The GlaxoSmithKline Vaccine HPV 007 study. Sustained eficacy and

immunogenicity of the HPV 16/18 ASO4 adjuvanted vaccine: analysis
of a randomized placebo-controlled trial up to 6.4 years. Lancet
2009; 374: 1975–1985.
Van Doornum GJ, Prins M, Juﬀermans LH, et al. Regional distribution and
incidence of human papillomavirus infection among heterosexual
men and women with multiple sexual partners: a prospective study.
Genitourin Med 1994; 70: 240–246.
Verstraeten T, Descamps D, David MP, et al. Analysis of adverse events
of potential autoimmune aetiology in a large integrated safety
database of AS04 adjuvanted vaccines. Vaccine 2008; 26: 6630–6638.
Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, et al.
Prophylactic quadrivalent human papillomavirus (types 6, 11, 16,
and 18) L1 virus-like particle vaccine in young women: a randomised
double-blind placebo-controlled multicentre phase II eficacy trial.
Lancet Oncol 2005; 6: 271–278.
Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE,
et al. High sustained eficacy of a prophylactic quadrivalent human
papillomavirus types 6/11/16/18 L1 virus-like particle vaccine
through 5 years of follow-up. Br J Cancer 2006; 95: 1459–1466.
Villa LL. Overview of the clinical development and results of a
quadrivalent HPV (type 6, 11, 16, 18) vaccine. International J Infect
Dis 2007; 11(Suppl 2): S17–S25.
Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital
human papillomavirus infection in young women. N Engl J Med
2006; 354: 2645–2654.
Zimet GD, Rosenthal SL. HPV vaccine and males: issues and challenges.
Gynecol Oncol 2010; 117: S26–S31.
Chapter 7

Management of Preinvasive Disease of

the Cervix

Gynaecologic Cancer: A Handbook for Students and Practitioners

Rushdan Noor, Eng Hseon Tay, and Jeffrey Low
Copyright © 2014 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4463-06-5 (Hardcover), 978-981-4463-07-2 (eBook)
[Link]
172 Management of Preinvasive Disease of the Cervix

Introduction
Cytology, visual inspection and HPV testing are screening tests for
preinvasive and invasive cervical cancer. They are not diagnostic
and, therefore, their results must not be used as an indication
for treatment. Patients with a positive screening test must be
referred for diagnostic test/procedure. Colposcopy and biopsy
are diagnostic procedures for preinvasive disease of the cervix.
Diagnosis of preinvasive disease of the cervix must be made based
on histology reports from cervical biopsy. Treatment of preinvasive
disease reduces the incidence of invasive carcinoma of the cervix.
In selected patients and with the presence of well-trained
colposcopist, “screen and treat” approach may be acceptable. This
is, however, a relatively new approach and the long-term impact on
the cancer incidence has yet to be evaluated.
Descriptive histologic term for preinvasive lesion of the cervix
is called cervical intraepithelial neoplasm (CIN). CIN is subdivided
into CIN 1 (mild), CIN 2 (moderate) and CIN 3 (severe dysplasia).
The CIN subdivision is based on the degree of penetration of cellular
abnormalities from the basal membrane to the surface of the
cervical epithelium. The CIN 1 is referred to when one third of
the epithelium is involved in the dysplastic changes, two-third
involvement in CIN 2 and full-thickness involvement in CIN 3.
Many CIN lesions regress spontaneously over time even without
treatment. CIN can also progress from mild to moderate and then
to severe lesions. Progression rate is depending on the grade of
lesions and age of patients. Low-grade and younger age group
(<30 years old) are more likely to regress. Rate of progression in
biopsy-proven CIN is shown in Table 7.1.

Table 7.1 Rate of progression for biopsy-proven CIN (Ostor, 1993)

Regression Persistent Progression

CIN 1 57% 32% 11%
CIN 2 43% 35% 22%
CIN 3 32% 56% 12%

Some studies have shown that the spontaneous regression

rate for CIN 1 was actually much higher in younger women, i.e.
Colposcopy 173

>90% within 24–36 months’ follow-up (Schlecht et al., 2003;

Nobbenhuis et al., 2001; Moscicki et al., 2004).

Management of Abnormal PAP Smear

If the Pap smear is reported as unsatisfactory, identify the cause,
treat and repeat the smear in 3 months; treat the infection if it exist,
and give a course of local oestrogen therapy if the cytology reported
as atrophic changes. Refer for colposcopy if a same inding in three
consecutive smears. If the Pap smear is reported as inlammatory,
identify the cause and source of infections, treat inlammatory smears
with antifungal, antibiotic or antiviral according to the organisms
involved. Refer for colposcopy if three consecutive inlammatory
changes persist on smear.
Management of atypical squamous cells is as follows: (a) ASCUS-
H (Atypical squamous cell of unknown signiicant, cannot exclude
high-grade lesion: Refer for colposcopy, (b) ASCUS: Repeat smear in
6 months, refer for colposcopy if ASCUS persist and (c) ASCUS and
positive to high-risk HPV: Refer for colposcopy.
Patients with low-grade squamous intraepithelial lesions
(LSIL) should be referred for colposcopy if they have the following
criteria: (a) age > 30 years old, (b) poor compliance, (c) immuno-
compromised patient, (d) positive to high-risk HPV and (e) had CIN
in the past. Other low-risk patients should be managed expectantly;
repeat Pap smear in 6 months and refer for colposcopy if persistent
LSIL for more than 12 months.
Patients with following Pap smear abnormalities require
urgent colposcopy referral: (a) high-grade squamous intraepithelial
lesion (HSIL), (b) atypical glandular cells (AGUS), (c) adenocarcinoma
in situ, (d) squamous cell carcinoma and (e) adenocarcinoma.

Colposcopy
Colposcopy was irst introduced by Hinselman in 1925. A colposcope
is a low-power, stereoscopic, binocular ield microscope with a
powerful light source (Fig. 7.1). Colposcopy is the direct inspection
of magniied areas of vulva, vagina and cervix using the colposcope.
During colposcopy, biopsy will be performed from abnormal area.
Colposcopy is also done to guide the colposcopist in the treatment
174 Management of Preinvasive Disease of the Cervix

for preinvasive disease of vulva, vagina and cervix. See Table 7.2 for
the preparation and step-by-step colposcopic procedures.

Figure 7.1 Colposcopy.

Table 7.2 Preparation, equipment and step-by-step colposcopy

(1) Colposcope machine, monitor, printer ± workstation (computer,

printer, etc.)
(2) Colposcope couch
(3) Speculum, cotton swabs, sponge holding forceps, 20 cm dissecting
forceps
(4) Vaginal side wall retractor
(5) Endocervical speculum
(6) Endocervical curette
(7) Biopsy forcep (e.g. Tischler-Morgan, Townsend, etc.)
(8) Single-toothed tenaculum
(9) Acetic acid 3–5%, Lugol’s iodine solution
Colposcopy 175

Step-by-step colposcopic procedures

Counselling and explaining regarding the procedure
Obtained an informed consent
Modiied lithotomy position
Instrument tray with essential instruments for colposcopy is placed
beside the couch
Inspect the vulva
Insertion of speculum
If the vaginal wall is too lax, used vaginal wall retractor or applied a
latex condom (from the glove) on the speculum blades with opening at
the tip.
While inserting the speculum, inspect the vaginal wall
Identify the cervix and remove any excess mucous
Repeat Pap smear may be necessary if it was not done earlier or the
colposcopist interested to know the repeat test
Swab for culture is taken if indicated
Inspect the cervix quadrant by quadrant on a normal light source and
then switch to green ilter to look for abnormal vessels
Return to normal light
Identify squamo-columnar junction and transformation zone
Spray or soaked the cervix with acetic acid 3–5% for 1–2 minutes
Inspect the cervix for any abnormal epithelium characterized by white
epithelium with well-demarcated margin, looks also for abnormal
vessels such as punctation, mosaicism, etc.; please note that apart from
the abnormal epithelium, light white epithelium can also be observed
in the epithelium undergoing metaplasia
Lugol’s iodine application is an option, especially if colposcopist is
decided to perform treatment at the same setting; normal squamous
epithelium contains stores of glycogen will give a mahogany brown or
nearly black stain; abnormal epithelium and columnar epithelium do
not contain glycogen and therefore, does not take up the iodine
Biopsy is taken from the abnormal epithelium
Haemostasis is secured by applying Monsel’s solution
Endocervical biopsy or curettage is performed if necessary:
(a) Normal colposcopy but abnormal cells were seen on cytology
(b) If cytology reported the presence of abnormal glandular cells
(c) If colposcopic examination is unsatisfactory
Colposcopy is considered as unsatisfactory when the upper limit of
transformation zone or squamo-columnar junction is not seen
Endometrial biopsy/sampling is indicated if abnormal endometrial
cells were detected on cytology or presence of endometrial cells in
postmenopausal women
(Continued)
176 Management of Preinvasive Disease of the Cervix

Table 7.2 (Continued)

Withdrawn the speculum and perform a bimanual pelvic examina-
tion
Explain the indings to the patient
Document the indings
Diagnostic accuracy of colposcopy is assessed based on the
correlation between colposcopic indings and inal histological
reports; in a large retrospective analysis by (Benedet GL, 2004),
involving more than 84,000 women, the accuracy of colposcopy was
found to improve by the severity of the lesion (85% accuracy in high-
grade lesion).

Indications for Colposcopy

Following are the indications for colposcopic examination:
• recurrent unexplained postcoital bleeding
• suspicious looking cervix
• invasive carcinoma on cytology
• persistent LSIL on cytology of more than 12 months
• persistent unsatisfactory smears (3 consecutively)
• three consecutive smears showing borderline nuclear
changes
• high-grade lesion (HSIL/CIN 2, 3) on cytology
• CIN 1 or LSIL on cytology in a poorly compliant patients
• evidence of infection by oncogenic type of HPV
• VIA positive
• VILI positive
• Truscreen/Truscan/Polarprobe positive
• positive results in other screening tests

Objectives of Colposcopy
(1) to further assess abnormalities detected on cytology
(2) to conirm the diagnosis by directed biopsy
(3) to exclude invasive disease
(4) to aid in outpatient management of preinvasive disease
(5) follow-up after treatment
Objectives of Colposcopy 177

Figure 7.2 Cervical biopsy to conirm the CIN.

Figure 7.3 Normal cervix. A: cervical mucus from the endocervical canal,
B: squamo-columnar junction, C: endocervical epithelium,
D: ectocervical epithelium.
178 Management of Preinvasive Disease of the Cervix

Figure 7.4 Viral wart or condylomata acuminata. Watch a raised lesion,

white and well-deined margin without acetic acid application.
The lesion is located just outside the transformation zone.

HPV Testing and Colposcopic Referral

It is widely accepted that women with high-grade abnormalities
on cytology should be referred for colposcopy. Management of
women with borderline or minor cytological abnormalities, e.g.
ASCUS, AGUS and LSIL, is controversial although they constitute
up to 10% of total cytological reports from screened population.
Current evidence suggests that 5–47% of those borderline
abnormalities, will, in fact reveal occult high-grade lesions in
inal histological reports. Studies have shown that women with
borderline or minor cytological abnormalities on cytology and at the
same time positive to high-risk HPV is at the higher possibility of
having co-existing high-grade lesions on histology.
One of the most important trials that address the role of HPV
testing in patients with borderline smear is ASCUS-LSIL Triage
Study or ALTS. ASCUS-LSIL Triage Study (ALTS) initiated by National
Cancer Institute is a randomized controlled trial to compare
Management of Cervical Intraepithelial Neoplasm 179

between immediate colposcopy versus HPV testing followed

by colposcopy if positive to oncogenic HPV versus conservative
management (N = 5060); the subjects were women with ASCUS
and LSIL. The following are the results of ALTS study: (a) HPV
triage is not suitable for LSIL because 83% of patients were positive
(b) The most cost-eﬀective approach to ASCUS is to perform
relex HPV testing (63% positive and require colposcopy), (c) HPV
testing reduced the need for referral for colposcopy by 44% among
women with ASCUS.
Meta-analysis by Arbyn et al. to compare an approach between
repeat cytology versus HPV testing (Hybrid capture-2) as a triage
method for women with ASCUS/AGUS on initial cytology have
shown that HPV testing had a signiicantly higher sensitivity
(95% versus 82%) in predicting high-grade lesions histologically.
However, speciicity of both approaches was comparable. In LSIL
and above, HPV testing did not improve the sensitivity; in fact it
had lower speciicity.
The Trial of Management of Borderline and Other Low Grade
Abnormal Smear (TOMBOLA) is a multicentre randomized con-
trolled trial conducted in Scotland and England, compared the
eﬀectiveness and eficiency of cytological surveillance and imme-
diate colposcopy in dealing of patients with low-grade abnormal-
ity of cervical smear. The results from this study have shown that
(a) immediate colposcopy leads to overtreatment and more wom-
en experienced pain, bleeding, etc., (b) 30% of women with mild
dyskaryosis were found to have CIN 2 and worse after colposco-
py and biopsy, (c) approximately, 40% of patients with low-grade
cervical abnormalities have evidence of high-risk HPV infection,
(d) cytology surveillance might result in some cases of high-grade
disease being missed because of non-attendance or limited sensi-
tivity and (e) there is still uncertainty regarding the best form of
follow-up either colposcopy or continued cytological surveillance.

Management of Cervical Intraepithelial

Neoplasm
Cervical intraepithelial neoplasm must be diagnosed based on
histological examination either from cervical punch biopsy or
excisional biopsy. There are three types of CIN, i.e. CIN 1, CIN 2 and CIN
180 Management of Preinvasive Disease of the Cervix

3. CIN (Fig. 7.5) 1 is considered low-grade lesion, while CIN 2 and CIN
3 are high-grade lesions and are true precancerous state of cervical
cancer (Fig. 7.6). Majority of CIN 1 disappears spontaneously and
needs no treatment; however, treatment is recommended if patients
meet the following criteria: (a) poor compliance, (b) persistent CIN
1 for more than 12 months, (c) women older than 30 years and (c)
positive to oncogenic HPV or high-risk of cervical cancer.

Figure 7.5 Abnormal cervix after application of acetic acid. A: punctation,

B: acetowhite epithelium, C: ine mosaicism. Cervical biopsy-
proven CIN 1.

All women with CIN 2 and CIN 3 must be treated. There are
two main modality of treatment for preinvasive disease of cervix:
(1) local ablative treatment and (2) excisional treatment.
Following are the types of local ablative treatment:
(a) cryotherapy (see below)
(b) electrodiathermy
(c) cold coagulation
(d) carbon dioxide laser
Management of Cervical Intraepithelial Neoplasm 181

Figure 7.6 Abnormal cervix, high-grade lesion. Watch the signiicant

acetowhite, punctuation and mosaicism seen in the box.

Local ablative treatment is indicated in persistent low-grade

lesions (CIN 1). This treatment is not suitable if squamo-columnar
junction and the limits of the lesions are not seen on colposcopy.
Local ablative treatment is also not recommended if invasive disease
cannot be ruled out. The disadvantage of local ablative treatment
is there is no tissue specimen for histological examination.
In selected patients, local ablative treatment may be acceptable
for high-grade lesions (CIN 2 and CIN 3) provide, they have fulilled
the following criteria:
(1) The treatment is performed by trained colposcopist.
(2) The entire lesions are seen.
(3) The lesions are small.
(4) There is no suspicion of microinvasive, invasive and glandular
lesions.
(5) The patient is in good compliance.
182 Management of Preinvasive Disease of the Cervix

Following are the types of excisional treatment:

(a) loop electrosurgical excision procedure (LEEP) or large loop
excision of transformation zone (LLETZ)
(b) laser conization/laser excision of transformation zone
( c ) cold-knife cone biopsy
(d) trachelectomy
(e) hysterectomy
Excisional treatment is the treatment of choice for high-grade
lesions (CIN 2, 3) and also for cervical adenocarcinoma in situ. With
excisional treatment, tissue samples are obtained for histological
examination. LEEP/LLETZ is the most commonly performed
excisional treatment for preinvasive lesions of the cervix. Laser
conization has an advantage for being more precise, less lateral
thermal injuries and better haemostasis. However, laser treatment
requires special training, expensive equipment and stringent safety
precautions. The other excisional method is cold-knife cone biopsy.
Cold-knife cone biopsy is an excision of a cone-shaped area from
the cervix, using scalpel. Cold-knife conization has to be done in
the operating theatre under regional or general anaesthesia. It is
indicated if the lesions are unable to be excised completely by LEEP/
LLETZ. Some Gynaecologists prefer to do cold-knife conization in
a patient with suspicious of endocervical lesions and endocervical
adenocarcinoma in situ. Cold-knife conization carries slightly
higher rate of complications as compared to LEEP/LLETZ and laser
conization.
Risk of bleeding is small; Nuovo et al., had reported that the
risk of bleeding is 4.6% in cold-knife conization, laser ablation
(1.75%), LEEP (1.35%) and cryotherapy (0%). Systematic review
and meta-analysis by (Kyrgiou M, Koliopoulus I, Vrekoussis T, et al.
2006) have shown that all three types of excisional treatment
for preinvasive disease of cervix (LEEP, cold-knife conization
and laser conization) was associated with a small but real
increase risk of pregnancy-related morbidity such as preterm
delivery, premature rupture of membranes, low birth weight
and caesarean section. However, there was no signiicant risk to
neonatal morbidity.
Study by Klaritsch on the obstetrics outcome after cold-knife
conization of the cervix had found that, this surgery was associated
Loop Electrosurgical Excision Procedure 183

with an increased risk of delivery before 37 weeks (22.4% versus

6.6%) and preterm premature of membranes (17.1% versus 2.6%).
There was no diﬀerence in terms of mode of delivery, duration of
labour and perinatal outcome (Klaritsch P, et al. 2006).
Trachelectomy is excision of the cervix. Partial or total
trachelectomy has been successfully performed in selected patients
with recurrent high-grade lesions following conization and fertility
preserving procedure.
The patients who have completed their family and are presented
with recurrent high-grade lesions following conservative surgery
may be oﬀered hysterectomy if repeat conization is not feasible
or inappropriate. Hysterectomy is also recommended in patients
with endocervical adenocarcinoma in situ when the fertility is not
anymore an issue.

Loop Electrosurgical Excision Procedure

Loop electrosurgical excision procedure is also known as large loop
excision of the transformation zone (LLETZ) in UK and Europe. It is
the removal of abnormal areas from the cervix using a thin heated
wire by constant low voltage current from the electrosurgical unit
(Fig. 7.7). The wire is in the form of loops that is very ine stainless
steel or tungsten wire and come with diﬀerent shapes and sizes.
The loop cuts and coagulates at the same time. For the purpose of
haemostasis, ball diathermy is also available. LEEP can be done as an
outpatient procedure under local anaesthesia. Please refer to Table
7.3 for step-by-step LEEP or LLETZ.

Figure 7.7 Basic principle of LEEP.

184 Management of Preinvasive Disease of the Cervix

Table 7.3 Step-by-step LEEP/LLETZ

• Counselling and consent

• Provide oral analgesic, e.g. paracetamol/NSAIDs; to be taken 1 hour
prior to the procedure
• Prophylactics antibiotic is optional and may be warranted in patients
with higher risk of infection (e.g. immunosuppressive) or who had a
history of vaginitis/cervicitis
• Ensure the equipment is available and is in good condition
• The patient is placed in the lithotomy position
• Insert the speculum and connected it with tubing to smoke evacuator
• Clean the vagina and cervix from mucous and discharge
• Re-examine the cervix and apply Lugol’s iodine to determine the
location and borders of the lesions
• Iniltrate local anaesthetic agents, i.e. xylocaine 1% with 1:80,000
dilution of adrenaline diluted in normal saline (using 5 mL syringe and
25–27G needle). Iniltrate 1 mL in each quadrant, total maximum of
5 mL. Wait for 1–2 minutes
• Choose appropriate loop based on the size of lesions and type of
transformation zone. Loop must be wider than the lesions and the
transformation zone to be removed
• Used cutting current 35–60 W
• The loop is introduced into the tissue 5 mm outside the margin of a
lesion. The loop is directed gradually into the cervix until the horizontal
bar nearly comes to the contact of the epithelial surface. Then swipe
across from left to right preferably in a single pass
• Any bleeding from the raw area can be tackled by ball diathermy using
spray mode 50–60 W. Monsel’s solution can be applied to further secure
the haemostasis
• If a lesion involves the endocervical canal and is not likely to have
been removed with single pass, endocervical tissue can be excised via
second pass using smaller loop either smaller oval loop or square loop
(top-hat technique)
• The specimen must be orientated and marked at 12 o’clock position to
guide the pathologist
• Observe the patient for 15–30 minutes after the procedure and allow
home with oral analgesic
• Follow up the patient after 1–2 weeks

Counselling after LEEP/LLETZ

Following are most important informations that should be given to
patient following the LEEP:
• mild cramping pain for a few hours
Counselling after LEEP/LLETZ 185

• dark brownish vaginal discharge for a week

• mild vaginal spotting for 1–2 weeks
• avoid vaginal douching and tampon
• to return back if having heavy bleeding, severe pain, foul
smelling vaginal discharge and fever
• avoid sexual intercourse for 3–4 weeks

Figure 7.8 Complete healing after LEEP.

Figure 7.9 Cold cone knife conization.

186 Management of Preinvasive Disease of the Cervix

Cryotherapy
Cervical cryotherapy is a procedure which involves freezing an area
of abnormal tissue on the cervix. Cryotherapy is done by placing a
small freeze-probe known as a cryoprobe against the cervix that
cools the cervix to at least –20°C. The cells destroyed by freezing
(cryonecrosis). The advantage of cryotherapy is cheap and can be
done without anaesthesia. Cryotherapy relies on a steady supply
of compressed refrigerant gases (N2O or CO2) in transportable
cylinders. However, cryotherapy is not recommended to treat
lesions in endocervix. The reported success rate is from 88–94%.
The preparation and step-by-step cryotherapy procedures are
shown on Table 7.4.
Cryotherapy unit consists of three components: (1) cryoprobe
and cryogun, (2) gas conveying tube and (3) gas cylinder.

Table 7.4 The preparation and step-by-step cryotherapy procedures

Material and equipment for cryotherapy

(1) Speculum
(2) Glove
(3) Cotton swab
(4) Normal saline solution
(5) Acetic acid solution
(6) ± Colposcope
(7) Cryotherapy Unit
Step-by-step cryotherapy procedures
• Counsel the patient
• Inserting the speculum
• Wipe the cervix with saline to wash the discharge and mucus
• Apply acetic acid to outline the abnormalities
• Explain to women that they may feel discomfort
• Wipe the cryoprobe surface with saline
• Apply the cryoprobe tip to the cervix with a tip in the internal os
• Set timer and release the gas trigger to cool the probe
• Observe the freezing, when a frozen area extends 4–5 mm beyond the
edge of the cryoprobe, freezing is adequate
• Allow two cycles of freezing and thawing: 3 minutes’ freezing,
followed by 5-minute thawing, followed by a further 3-minute freezing
• Once the second freezing is complete, allow time for thawing before
attempting to remove the probe from the cervix. Removing it early
will pull tissue oﬀ the cervix
Cryotherapy 187

• Frozen area will appear white

• Observe for any bleeding
• Do not pack the cervix
• Remove the speculum
• Clean and sterilized the cryoprobe with alcohol 60–90%, followed by
boiling with water and disinfect with 2% glutaraldehyde

Figure 7.10 Ice-ball formation immediately after cryotherapy, the lesions

and transformation zone undergoing cryonecrosis.

Post-Cryotherapy Care
Cryotherapy is a safe procedure; studies have shown that the
complication’s rate of this procedure is low. To ensure that any
complications are kept at the minimal rate and detected at an
early stage, post-cryotherapy care is important. Following are the
counselling and recommendation of post-cryotherapy care:
Explain to a patient regarding watery and blood stained
discharge for up to 4 weeks
No sexual intercourse for 4 weeks
Advice not to use vaginal douches and tampons
Cryotherapy may increase the transmissibility of HIV infection
and using condoms is an eﬀective means of after treatment
To return if one has vaginal bleeding, severe pain, fever and
foul smelling discharge
Healing will take place 6 weeks after cryotherapy
188 Management of Preinvasive Disease of the Cervix

Follow-up in 6 weeks and then 3–6 months

Repeat cytology or VIA during follow-up

Side Effects of Cryotherapy (Very Rare)

(1) profuse vaginal discharge
(2) cramping pain
(3) vaso-vagal attack during the procedure
(4) infection
(5) bleeding
(6) incomplete treatment (5–10%)
(7) cervical stenosis <1%
(8) reduced mucus discharge in 5–10% of women
(9) no adverse eﬀect on subsequent pregnancy

Laser Treatment for Preinvasive Lesions of Cervix

Albert Einstein irst discovered the key mechanism of action
of laser in the 1990s. The word LASER is an acronym for Light
Ampliication of Stimulated of Radiation. Dr. Teodore Maiman irst
created laser with a synthetic ruby crystal in 1960. Laser radiation
is an electromagnetic wave, which is not mutagenic, and it can be
generated by many media but in gynaecology, CO2 laser is most
commonly used. The use of laser technology is limited in some areas
because of the cost of laser treatment; it requires trained personnel
and stringent safety precaution. When CO2 laser is applied to the
tissue, it will selectively absorb by extracellular and intracellular
water leading to steam formation and vaporization of cellular and
nuclear substances.
There are three diﬀerent forms of laser therapy: (a) vaporization
(b) excisional biopsy and (c) combination. Laser vaporization is
indicated for patients with CIN lesions with no suspicion of invasive
disease. The area of vaporization includes the entire transformation
zone, including surrounding tissue up to 3 mm. The depth of
tissue vaporization is set to 7 mm because more than 90% of CIN
lesions do not extend into cervical glandular crypts for more than
4 mm. Laser excisional biopsy (laser conization) is performed under
local anaesthesia. It involves the use of a high power density laser
beam to excise a piece of cylindrical or conical tissue around the
cervical os.
Types of Transformation Zone 189

Laser has an advantage over electro-diathermy for being more

precise in the depth of tissue destruction, better haemostasis
and lesser collateral thermal injuries. Laser treatment is also a
preferred method in treatment of extensive and multifocal
preinvasive lesion of cervix, vulva and vagina. It can also be used for
treatment of condylomata acuminata.
The desired power-density range for adequate ablation of
excision with minimal thermal damage to an adjacent area is
750–2000 W/cm2 (generally, 20–30 W at a continuous setting),
with an eﬀective beam diameter of 1.5–2 mm to maximize ablation
and haemostasis while minimizing lateral thermal damage.
Complications of laser therapy are similar to LEEP and cold-
knife conization, such as bleeding, pain, infection, cervical stenosis,
anaesthetic and long-term obstetrics complications. The rate of
bleeding after laser therapy had been reported to be similar to
LEEP but less than cold-knife conization. A randomized trial to
cryotherapy, carbon dioxide laser vaporization and LEEP for CIN
reveals relatively equal rates of disease persistence and recurrence.
Risk factors for recurrent CIN are large lesions, positive margin,
presence of high-risk HPV infection and older women (age > 30
years old). A large retrospective cohort analysis done by Kalliala,
involving 7466 women treated for CIN using cold-knife conization,
LEEP/LLETZ, cryotherapy and Laser conization have shown that
there was no diﬀerence between LEEP, cryotherapy and laser in
reducing the risk of future CIN 3 and invasive cervical cancer.

Types of Transformation Zone

Treatment of CIN requires skill in assessing the extent of the
lesion and ensures complete destruction or excision of the lesions
together with transformation zone. The depth and width of
excision/destruction must be adequate to prevent residual disease
and recurrent CIN. Appropriate size of the loop is important to
ensure complete excision with good surgical margin preferably
with single pass.
In order to achieve above objectives and to standardize the
description, the International Federation of Cervical Pathology
and Colposcopy (IFCPC) has adopted a classiication of the
transformation zone (TZ) into three types:
190 Management of Preinvasive Disease of the Cervix

(1) Type 1: TZ is completely ectocervical, fully visible, can be

small or large.
(2) Type 2: TZ has an endocervical components, fully visible, may
have ectocervical component which may be small or large.
(3) Type 3: TZ has an endocervical components, not fully visible,
may have ectocervical component which may be small or
large. Type of treatment and size of instrument can be based
on the type of TZ. Low-grade lesion with type 1 TZ can be
treated safely with local ablative therapy, whereas it is entirely
inappropriate to choose this treatment for any type 3 TZ.

Management of Abnormal PAP Smear, CIN and

Colposcopy during Pregnancy
Pap smear can be done during pregnancy, although the cervical
cancer-screening program during pregnancy is still controversy. Pap
smear taken during pregnancy is more likely to be unsatisfactory and
can detect cytologically normal variants, which can cause unnecessary
intervention and anxiety. Abnormal Pap smear detected during
pregnancy should be managed similarly, colposcopic examination is
indicated in high-grade lesion or if there is evidence of infection with
oncogenic HPV. The indications for colposcopy in pregnancy are
similar with non-pregnant women. Colposcopy during pregnancy
is not easy and should be performed by experience colposcopist.
Physiological changes during pregnancy can alter the colposcopic
appearance of the cervix, i.e. increase vascularity, hypertrophy of the
cervical stroma leading to eversion of the endocervical epithelium,
transformation zone displaced more laterally, increased mucus
production by endocervical glands and decidualization of the
cervix (in 20% of cases) making the epithelium looks suspicious.
For pregnant women, the primary objective of the colposcopic
examination is to rule out invasive cancer. A technique of colposcopy
in pregnant women is also similar to non-pregnant women and
biopsy is taken from the most suspicious area. If colposcopy is
normal, repeat examination should be done at 8 weeks postpartum.
If CIN is diagnosed, repeat colposcopy must be performed once
in every trimester and 8 weeks postpartum.
Cervical conization is indicated if microinvasive or invasive
cancer is suspected. The other indication for conization is in
Cervical Adenocarcinoma in situ 191

unsatisfactory colposcopy with high suspicious of high-grade

lesions. Ablative treatment is not recommended during pregnancy.
Treatment for pregnant women with all grades of CIN can be delayed
until 6–8 weeks postpartum provided there is no suspicious of
invasive cancer. If the patient is breast-feeding, local application of
oestrogen may facilitate colposcopic re-evaluation. The management
of labour is not inluenced in any way by the presence of CIN,
irrespective of severity.

Cervical Adenocarcinoma in situ

According to Bethesda 2001, endocervical glandular cell
abnormalities (on cytology) are classiied into four categories:
(a) atypical glandular cells (AGC) not otherwise speciied (NOS),
(b) AGC favour neoplastic (FN), (c) adenocarcinoma in situ and (d)
invasive adenocarcinoma. In patients with cytology AGC favour
neoplastic, 29–68% of them were found to have high-grade lesions
on histology. Women with AGC-FN must be referred for immediate
colposcopy and endocervical evaluation.
Cervical adenocarcinoma in situ and invasive adenocarcinoma
must be diagnosed by biopsy and histological examination. Cervical
adenocarcinoma in situ (AIS) had been established as a precursor
of invasive endocervical adenocarcinoma. However, the rate of
progression to invasive adenocarcinoma is unknown. HPV16 and
HPV 18 were found in an average of 89.8% cases of AIS. The
diagnosis of AIS is based on the presence of cellular stratiication,
nuclear atypia, mitosis and apoptosis in two most active glands.
Approximately, 50% of patients with AIS have co-existing squamous
dysplasia/carcinoma. Patients with cervical AIS diagnosed by
histology must be referred for cervical conization. Cervical
conization preferably cold-knife cone biopsy is done to exclude
invasive adenocarcinoma.
Margin involvement after conization is common in AIS averaging
25% of cases. Even with negative margin, the probability of residual
AIS can be as high as 15–43% (hysterectomy and repeat cone
specimens) and co-existing invasive adenocarcinoma in 1.6%. In a
patient with positive resection margin on cone specimens, the risk
of residual AIS is very high ranging from 12.5%–100% with the
average of 55%. In same patient, the risk of co-existing invasive
adenocarcinoma is 6%. Therefore, currently the gold standard for
192 Management of Preinvasive Disease of the Cervix

treatment of AIS is hysterectomy (following cervical conization

regardless the status of resection margin). However, if the patient
is keen to preserve her fertility, she must be counselled regarding
the risk of recurrent disease, co-existing invasive adenocarcinoma
and the important of close monitoring. Repeat colposcopy and
endocervical evaluation (including endocervical curettage) must be
done regularly. In this patient, repeat conization can be recommended
if the surgical margin is positive.

HPV Testing and Other Markers in the Follow-Up

after Treatment for CIN
Approximately, 10% of women may develop recurrent CIN within
4 years after excisional treatment. Early detection and treatment
of recurrent CIN is important. Repeat cytology ± colposcopy was a
common practice in following up the patient following treatment
(e.g. UK NHS Clinical Guidelines recommended cervical cytology at
6 and 12 months followed by annual cytology for next 5 years, in
some country (France), irst follow-up after treatment is 3 months
(colposcopy and cytology) then 3-monthly cytology for a year and
annually thereafter).
Arbyn and colleagues found that HPV testing was more
sensitive than cytology in detecting recurrent CIN although the
speciicity was comparable. Women with negative high-risk HPV
was found to have higher chances of cure and lesser chances of
recurrence as compared to women with positive high-risk HPV.
The other potential markers to identify women at higher risk
of recurrence are HPV viral load, L1 protein expression, E6/E7
RNA, human telomerase (hTERT), topoisomerase IIα, Cdc6 (DNA
replication licensing protein), etc.

References

ALTS Group. Comparison of three management strategies for patients with

atypical squamous cells of undetermined signiicance: baseline results
from a randomized trial. J Nat Cancer Inst 2001; 93(4): 293–299.
Arbyn M, Paraskevaidis E, Martin-Hirsch P, Prendiville W, Dillner J. Clinical
utility of HPV-DNA detection: triage of minor cervical lesions, follow up
References 193

of women treated for high grade lesions: an update of pooled evidence.

Gynecol Oncol 2005; 99(3 Suppl 1): S7–S11.
Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch J, Dillner J.
Virologic versus cytologic triage of women with equivocal Pap smears:
a meta-analysis of the accuracy to detect high-grade intraepithelial
neoplasia. J Natl Cancer Inst 2004; 96: 280–293.
Arbyn M, Sasieni P, Meijer CJ, et al. Clinical applications of HPV testing: a
summary of meta-analyses. Vaccine 2006; 24(Suppl 3): S78–S89.
ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on
the management of cytology interpretations of atypical squamous
cells of undetermined signiicance. Am J Obstet Gynecol 2003; 188(6):
1383–1392.
Bacon JL. Carbon dioxide laser surgery in cervical dysplasia. E-Med Obstet
Gynaecol Dec 5, 2007.
Baggish MS. Basic and Advanced Laser Surgery in Gynecology. 2nd ed.
Norwalk, Conn: Appleton & Lange; 1985: 207–216.
Benedet JL, Miller DM, Nickerson KG. The results of cryosurgical treatment
of cervical intraepithelial neoplasia at one, ive, and ten years. Am J
Obstet Gynecol Aug 1987; 157(2): 268–273.
Benedet JL, Matisic JP, Bertrand MA. An analysis of 84244 patients from the
British Columbia cytology-colposcopy program. Gynecol Oncol. 2004;
92: 127–134.
Bull-Phelps S, Garner EIO, Walsh CS, et al. Fertility-sparing surgery in 101
women with adenocarcinoma in situ of the cervix. Gynecol Oncol 2007;
107: 316–319.
Colposcopy and programme management: guidelines for the NHS cervical
screening programme. NHSCSP publication no. 20; 2004.
Flannelly G. The management of women with abnormal cervical cytology in
pregnancy. Best Pract Res Clin Obstet Gynaecol 2010; 24: 51–60.
Gordon HK, Duncan ID. Eﬀective destruction of cervical intraepithelial
neoplasia (CIN) 3 at 100 degrees Celcius using the Semm cold
coagulator: 14 years experience. Br J Obstet Gynaecol Jan 1991; 98(1):
14–20.
Hernadi Z, Szoke K, Sapy T, et al. Role of human papillomavirus testing in the
follow-up of patients after treatment for cervical precancerous lesions.
Eur J Obstet Gynecol Reprod Biol 2005; 118(2): 229–234.
International Agency for Research on Cancer (WHO), IARC screening group
website ([Link]
194 Management of Preinvasive Disease of the Cervix

Jeng CJ, Shen J, Huang SH. Partial trachelectomy: a new treatment choice for
persistent or recurrent high grade cervical intraepithelial neoplasia.
Gynecol Oncol Feb 2006; 100(2): 231–232.
Kalliala I, Nieminen P, Dyba T, Pukkala E, Anttila A. Cancer free survival
after CIN treatment: comparisons of treatment methods and histology.
Gynecol Oncol 2007; 105: 228–233.
Klaritsch P, Reich O, Giuliani A, Tamussino K, Haas J, Winter R. Delivery
outcome after cold-knife conisation of the uterine cervix. Gynecol
Oncol 2006; 103: 604–607.
Kyrgiou M, Tsoumpou I, Vrekoussis T, et al. The up-to-date evidence on
colposcopy practice and treatment of cervical intraepithelial neoplasia:
the Cochrane colposcopy and cervical cytopathology collaborative
group (C5 group) approach. Cancer Treat Rev 2006; 32: 516–523.
Kyrgiou M, Koliopoulos G, Hirsch PM, Arbyn M, Prendiville W, Paraskevaidis
E. Obstetrics outcomes after conservative treatment for intraepithelial
or early invasive cervical lesions: systematic review and meta-analysis.
Lancet 2006; 367: 489–498.
Keyserling HV, Kaufmann AM, Shneider A. Conference Report: HPV testing in
the follow-up after treatment of women with CIN. Gynecol Oncol 2007;
107: S5–S7.
Kim JH, Park JY, Kim DY, et al. The role of loop electrosurgical excisional
procedure in the management of adenocarcinoma in situ of the uterine
cervix. Eur J O&G Reprod Biol 2009; 145: 100–103.
Loﬀe OB. Review: recent advances in the diagnosis and classiication of
endocervical glandular lesions. Curr Diagn Pathol 2004; 10: 404–412.
Mathevet P, Dargent D, Roy M, Beau G. A randomized prospective study
comparing three techniques of conization: cold knife, laser, and LEEP.
Gynecol Oncol Aug 1994; 54(2): 175–179.
Mitchell MF, Tortolero-Luna G, Cook E, et al. A randomized clinical trial of
cryotherapy, laser vaporization, and loop electrosurgical excision
for treatment of squamous intraepithelial lesions of the cervix.
Obstet Gynecol Nov 1998; 92(5): 737–744.
Moscicki AB, Shiboski S, Hills NK, Powell KJ, Jay N, Hanson EN. Regression of
low-grade squamous intra-epithelial lesions in young women. Lancet
Nov 6–12 2004; 364(9446): 1678–1683.
Nobbenhuis MA, Helmerhorst TJ, van den Brule AJ, Rozendaal L, Voorhorst
FJ, Bezemer PD. Cytological regression and clearance of high-risk
human papillomavirus in women with an abnormal cervical smear.
Lancet Nov 24 2001; 358(9295): 1782–1783.
References 195

Nuovo J, et al. Treatment outcomes for squamous intraepithelial lesions. Intl

J Gynecol Obstet. 2000; 68(1): 25–33.
Prendiville W. Recent innovations in colposcopy practise. Best Pract Res Clin
Obstet Gynaecol 2005; 19(5): 779–792.
Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical
review. Int J Gynecol Pathol Apr 1993; 12(2): 186–192.
Quint KD, de Koning NC, Geraets DT, Quint WGV, Pirog EC. Comprehensive
analysis of Human Papillomavirus and Chlamydia trachomatis in in
situ and invasive cervical adenocarcinoma. Gynecol Oncol 2009; 114:
390–394.
Schlecht NF, Platt RW, Duarte-Franco E, Costa MC, Sobrinho JP, Prado
JC. Human papillomavirus infection and time to progression and
regression of cervical intraepithelial neoplasia. J Natl Cancer Inst Sep 3
2003; 95(17): 1336–1343.
TOMBOLA group (Cruickshank M, Murray G, Parkin D, et al.). Cytological
surveillance compared with immediate referral for colposcopy in
management of women with low grade cervical abnormalities:
multicentre randomised controlled trial. BMJ 2009; 339: b2546 doi:
[Link]
Westin MC, Derchain AF, Rabelo-Santos SH, et al. Atypical glandular cells and
adenocarcinoma in situ according to the Bethesda 2001 classiication:
cytohistoligical correlation and clinical implication. European J O&G
Reprod Biol 2008; 139: 79–85.
WHO Integrated Health Care for Sexual and Reproductive Health and Chronic
Diseases. Comprehensive Cervical Cancer Control. Guide Essent Pract
2006.
This page intentionally left blank
Chapter 8

Cancer of Cervix

Gynaecologic Cancer: A Handbook for Students and Practitioners

Anatomy
The cervix is the lower constricted segment of the uterus. Cervix
is divided into two portions, a supravaginal and vaginal portion
(portio vaginalis). Portio vaginalis is the portion of the cervix that
projecting into the vagina. The average size of portio vaginalis is 3
cm long and 2.5 cm wide. Supravaginal portio is separated in front
from the bladder by ibrous tissue known as parametrium that
extends from the sides between the broad ligaments. Posteriorly
supravaginal cervix is covered by peritoneum. The portion of the
cervix exterior to the external os is called ectocervix while the
passage between external os and endometrial cavity is referred
to the endocervical canal. Upper limit of the endocervical canal is
internal os (Fig. 8.1).

Figure 8.1 The cervix.

The main support structures of the cervix are the uterosacral

and cardinal ligaments. Uterosacral ligaments are pair of support
consisting of ibrous tissue with smooth muscle extending from the
uterus to the sacrum and run along the recto-uterine-peritoneal
fold. Cardinal ligament (transcervical/Mackenrodt’s ligament)
is a thickened connective tissue arising at upper lateral margins
Anatomy 199

of the cervix and inserting into the fascia covering of the pelvic
diaphragm.
Blood supply of the cervix is from the cervical and vaginal
branches of uterine arteries. Uterine arteries are derived from
the internal iliac arteries. Cervical branch of the uterine artery
generally descends on the lateral aspects of the cervix at 3 and
9 o’clock positions. When the internal artery is ligated, many
collateral blood supplies maintain the vascularization of the
uterus. Following internal iliac ligations, blood supply to the uterus
is maintained by collateral circulation via a middle sacral (lateral
sacral), inferior mesenteric (middle haemorrhoidal) and lumbar
(iliolumbar) artery (Bold arteries are from the aorta). The venous
drainage of the cervix is parallel to arterial supply, eventually
emptying into the hypogastric venous plexus.
Main nerve supply to the cervix is derived from the hypogastric
plexus. Sensory, sympathetic and parasympathetic ibres are
present in the cervix. The ectocervix has less sensory innervations
as compared to endocervix and therefore, ectocervix can withstand
a minor surgical procedure such as cryotherapy and biopsy
without anaesthesia. Dilatation of the endocervical canal may result
in vasovagal reaction with relex bradycardia.
The lymphatic drainage of the cervix is complex and variable as
shown in Fig. 8.2.

Paracervical/parametrial
Uterus (body and cervix) lymph nodes

Uterine fundus
Internal iliac External iliac
lymph nodes lymph nodes

Common iliac
lymph nodes

Ovarian vessels PERIOARTIC

LYMPH NODES

Figure 8.2 The lymphatic drainage of the cervix.

200 Cancer of Cervix

Cancer of Cervix
Epidemiology
More than 12 million new cases and 7.6 million cancer deaths
estimated to have occurred in 2008. Approximately, 529,100 new
cases of cervical cancer were reported leading to 275,000 deaths
worldwide in 2008 (GLOBOCAN, 2008). Unfortunately, more than
80% of annual cervical cancer deaths occur in developing countries
(50–60% occur in Asia and India alone, contributing 27% of the
total number of cases). American Cancer Society most recently
estimated that in 2009, there were approximately 11,000 new
cases of cervical cancer and 4000 women will die in America. They
also estimated that the death rate declines by nearly 4% each year
mainly in developed countries due to their eﬀective cervical cancer
prevention program and better treatment of cervical cancer.
Unfortunately, the death rate in under-developed and developing
countries are still high. Globally, cervical cancer incidence and
mortality rates have been declining since the 1960s in many
developed countries due to their successful implementation of
the organized screening program. However, the rate is still high in
many parts of the Central and South America, Africa and Asia.
Regions with high-risk cervical cancer are Eastern Africa
(ASR 34.5 per 100,000), Western Africa (ASR 33.7), Southern
Africa (ASR 26.8), South Central Asia (ASR 24.6), Middle Africa
(ASR 23.0) and South America (ASR 23.9), whereas the risk of
cervical cancer is lowest in Western Asia (ASR 4.5), Northern
America (ASR 5.7), Australia (ASR 5.0) and New Zealand (ASR 5.0).
Age-standardized incidence of cervical cancer in South East Asia is
15.8 per 100,000 population. The peak age of developing cervical
cancer is 45–60 years, declines in the incidence for older age
groups but peaks again in the early 80 years of age.

Aetiology of Cervical Cancer

The scientiic evidence obtained from virological, molecular,
clinical and epidemiological data had demonstrated conclusively
that cervical cancer is due to persistent infection of high-risk
human papillomavirus (Bosch et al., 1995). Largest series by IARC
(International Agency Research in Cancer) using standard protocol,
Cancer of Cervix 201

recruiting approximately 1000 women with conirmed cancer of

the cervix have detected HPV-DNA in 99.7% of the tumour (Bosch
et al., 1995, 2002; Walboomers et al., 1999). The associations
observed between the infection by HPV and cervical cancer is
among the highest ever identiied in research of human cancer.
The human papillomavirus (HPV) is a double-stranded DNA
virus that belongs to the Papillomaviridae family. They are very
small viruses with the diameter of 40–60 nm. The outer layer of
this virus is covered by shell or capsid comprising 70 capsomers,
and each capsomer consists of ive molecules. The inner portion of
this virus consists of 8000 base-pair long circular DNA molecules.
There are three regions in the HPV DNA: early protein regions
(E1–E7), late protein regions (L1, L2) and long control regions.
Long control regions do not have coding potential. Early protein
regions are genes responsible in virus replication and for the
assembly of newly produced viruses within the infected cells. Late
protein regions encode viral particle L1 proteins (VP L1) and viral
particle L2 proteins (VP L2) which form the capsomer. Capsomer
is the building block of the viral capsid. VP L1 is known as major
capsid protein while VP L2 is known as minor capsid protein. VPL1
is the main epitope of HPV virus.
Within the early protein regions, there are E6 and E7 genes,
which are the oncogenes. Both genes are controlled by E2 gene.
Based on the diﬀerences of DNA sequence in E6, E7 and L1 coding
regions, there are more than 100 diﬀerent types of human papil-
lomavirus identiied. The HPV virus is divided into two groups:
(a) Low-risk HPV (LRHPV) and (b) high-risk HPV (HRHPV).
Low-risk HPVs are associated with benign viral warts. Among
LRHPVs are HPV 6, 11, 40, 42, 43, 44, 54, 61, 72 and 81. More than
90% of anogenital warts were due to HPV 6 and HPV 11. High-risk
HPVs are oncogenic viruses closely linked to pre-cancerous and
cancer of male and female genital organs. Some of these viruses were
also linked with head and neck cancers. According to International
Agency for Research on Cancer, there was suficient evidence
that HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66 are
carcinogenic (high risk) while HPV 26, 68, 73 and 82 are probably
carcinogenic. More than 35 types of HPV have been isolated in
neoplastic lesions of the anogenital tract and the WHO has recognized
HPV 16 and HPV 18 as carcinogenic agents for human. Both HPV 16
and 18 are responsible for 70–80% of invasive cervical cancer.
202 Cancer of Cervix

Transmission of HPV is almost exclusively through a sexual con-

tact. Low-risk HPV can also be transmitted through vertical trans-
mission from mother to baby leading to respiratory papillomatosis.
HPV infections are very common, especially in young women; how-
ever, 70% of new infections resolve within 1 year and almost 90%
resolve within 2 years.

HPV and Cervical Carcinogenesis

Viruses reach the basal cells of the epithelium through micro-
abrasion or small breaks in the epithelium. Virus enters the cell
via an endocytic pathway and localized in the endosome, the
virus uncoats within the endosome and the genome is released.
Viral genome may remain in the basal cells for 2–5 years without
any cellular or tissue reactions (Fig. 8.3). This period is called the
latent period. Following the latent period, HPV viruses start to
replicate and viral protein E1 and E2 are essential for this process.
Infected basal cells are then push to the suprabasal compartment,
and the viruses are then released into the environment. During
these processes, infected epithelial cells become enlarged
with perinuclear halo appearance. These cells are also known as
koilocytes. Other features of koilocyte are nuclear enlargement
and nuclear hyperchromasia.

Figure 8.3 HPV infections and cervical pathology. Adapted from Goodman
A, Wilbur DC. N Engl J Med 2003; 349: 1555–1564.
HPV and Cervical Carcinogenesis 203

Figure 8.4 Pathogenesis of HPV infection and malignant transformation

of the cervical epithelial cell. (1) Virus enter the host cell, (2)
release of HPV DNA, (3) HPV DNA enters the nucleus towards
the host DNA, (4) HPV DNA integrated with host DNA, (5)
integration leads to partial deletion of E2 and E4 genes, (6)
deletion of E2 and E4 leads to overexpression of E6 and E7
genes, (7) overexpressed E6 and E7 bind to tumour suppressor
protein p53 and Rb (retinoblastoma), (8) degradation of P53
and Rb proteins, (9) disruption of normal cell cycle and release
of transcription factors, (10) transcription factors bind to the
host DNA, (11) stimulation of cell synthesis, (12) unregulated
and uncontrolled cell proliferation (neoplasm).

In some cells, viral genome is integrated into host DNA,

leading to partial deletion of E2 and E4 genes, which are essential
in controlling the E6 and E7 oncogenes. Factors that trigger these
phenomena are believed to be related to host immune system,
smoking habit, persistent infection by high-risk HPV, etc. Partial
deletion of E2 and E4 will lead to overexpression of E6 and E7
oncogenes. Subsequently, E7 oncoproteins bind to protein pRB
(tumour suppressor protein) leading to activation of the E2F
transcription factors which triggers the expression of proteins
necessary for DNA replication. Normally, this unscheduled replication
will not proceed. Instead the cells will undergo apoptosis by the
204 Cancer of Cervix

action of tumour suppressor proteins known as p53. However, in

this situation, p53 proteins have already undergone degradation
following the binding with E6 oncoproteins. The binding of E7
to protein pRB and degradation of p53 by E6 oncoproteins lead
to an increase in genomic instability, accumulation of oncogene
mutations, loss of cell-growth control and ultimately malignant
transformation (Fig. 8.4).

Types of HPV in Cervical Cancer

Based on the PCR test to identify HPV DNA, at least 70% of
invasive cervical cancers are due to HPV 16 and HPV 18. HPV
16 is the most common HPV-related cervical cancer accounting
for 54.6% of all cases (Smith et al., 2007). Combined HPV 16/18
prevalence among invasive cervical cancer cases was slightly
higher in Europe, North America and Australia (74–77%) than
Africa, Asia and South/Central America (65–70%) (Smith et al.,
2007). The next six most important types of HPV related to invasive
cervical cancer are HPV 31, 33, 35, 45, 52 and 58. In their meta-
analysis involving more than 9000 cases of squamous cell carcinoma
(SCC) of the cervix and almost 2000 cases of adenocarcinoma
of the cervix, Smith et al. found that HPV 16 and HPV 18 were
responsible in 68% of SCC (HPV 16: 55%, HPV 18: 13%) and 70%
in Adenocarcinoma of the cervix (HPV 16: 33%, HPV 18: 37%).
HPV 16 was more common in SCC cervix while HPV 18 was more
common in adenocarcinoma of the cervix.

Risk Factors for Cervical Cancer

Invasive carcinoma of the cervix can be considered as sexually
transmitted disease. Early age of sexual activity predisposed to
invasive cervical cancer because the transformation zone in early
reproductive age is believed to be more susceptible to a carcinogen.
The relative risk of having cervical cancer is 2.5 if the age of irst
sexual exposure was <18 years old. Women with history of HPV
infection are also at higher risk, the causal relationship between
high-risk HPV infection and cervical cancer are the highest of all
Risk Factors for Cervical Cancer 205

other cancers. Women with multiple sexual partners have a relative

risk of 2.8 if the number of partners ≥5. Multiparous women
are at higher risk of cervical cancer as compared to low parity or
nulliparous women. Women in lower socioeconomic class are at
higher risk of cervical cancer as compared to women from upper
socioeconomic class. Women who married to a man with multiple
sexual partners are also at higher risk of cervical cancer.
Cigarette smoking has been identiied as a signiicant risk
factor for cervical cancer by 2–5 folds. Oral contraceptive pills
(OCPs) use increased the risk of cervical cancer (relative risk
of 1.6) probably indirectly through increased sexual activity.
Following are the compounding factors that create a bias regarding
the relation between OCPs and cervical cancer risk:
(a) OCP usage has been linked with behaviour, low-risk women
less practicing OCP.
(b) Patients can protect themselves from cancer by barrier
contraception.
(c) Cancer can be detected earlier in OCP usage because women
are under more frequent and regular follow-up.
Patients with immunodeiciency are at higher risk of developing
cancer, including cervical cancer. This association is probably due to
increase susceptibility to persistent HPV infection.
In utero exposure to DES increases the risk of clear cell
adenocarcinoma of the cervix (Risk 0.14–1.4/1000 exposure).
Women with an uncircumcised sexual partner may be at higher
risk of invasive cervical cancer. Based on seven case-control studies
involving 3790 women, circumcised men had lower prevalence of
HPV infection (5.5% vs. 19.6%) and female partners of circumcised
men had a moderate but non-signiicant decrease in risk of cervical
cancer (OR 0.72, 95% CI 0.49–1.04). However, when the circumcised
sexual partner has low-risk sexual behaviour, circumcision does
not have an impact on cervical cancer risk on their female partner
(Castellsague et al., 2002). In other meta-analysis by Van Howe RS
to determine the relationship of circumcision and risk of genital
infection with HPV, he found that there is no strong evidence that
circumcision reduces the risk for genital HPV infection. The relation
of circumcision and risk of cervical cancer remain controversial.
206 Cancer of Cervix

Histopathological Subtypes of Cervical Cancer

The most common histologic variant of invasive cervical cancers
is squamous cell carcinoma (Table 8.1). The second most common
histological type is adenocarcinoma. The prevalence of adenocarci-
noma of the cervix appears to increase (15–25%) probably a relative
increase due to declined in the incidence of squamous cell carcino-
ma, especially in developed countries with a more eﬀective cervi-
cal cancer prevention program. The increase may also be absolute,
partly due to increase in detection rate. Most of our knowledge
on the management of cervical cancer comes from the studies
where the majority of the patients had squamous cell carcinoma.
Pathological subtypes of cervical cancer are shown in the Table 8.1.

Table 8.1 Histopathological subtypes of cervical cancer

Squamous cell carcinomas

Squamous cell carcinoma
Verrucous
Papillary squamous
Lymphoepithelioma-like carcinoma
Adenocarcinomas (WHO classiication)
Mucinous adenocarcinoma (most common)
Endocervical type
Intestinal type
Clear cell adenocarcinoma
Endometrioid adenocarcinoma
Serous adenocarcinoma
Mesonephric adenocarcinoma
Other carcinomas of cervix
Adenosquamous
Glassy-cell carcinoma
Adenoid cystic carcinoma
Adenoid basal carcinoma
Neuroendocrine tumour of cervix
Carcinoid tumour
Small cell carcinoma
Large cell neuroendocrine carcinoma
Undiﬀerentiated carcinoma
Other malignant tumours of cervix
Leiomyosarcoma, rhabdomyosarcoma, stromal
sarcoma, lymphoma
Natural History and Pattern of Spread 207

Natural History and Pattern of Spread

Cervical carcinoma originates in the transformation zone,
frequently preceded by cervical intraepithelial neoplasm, 10–20
years before. Thirty percent of carcinoma in situ progresses to
invasive cancer after 10 years, at 30 years, and 80% develop
invasive carcinoma. Local spread is common in cervical cancer. The
tumour may invade laterally into the parametrium, inferiorly into the
vagina, anteriorly into the bladder and rectum, posteriorly. Invasion
of tumour laterally may obstruct the ureter and leads to hydroureter
and subsequently hydronephrosis (Fig. 8.5). Bilateral ureteric
obstruction can lead to obstructive nephropathy. Renal failure
secondary to obstructive nephropathy is one of the most important
causes of morbidity and mortality in a patient with cervical cancer.
Ten to thirty percent of invasive cervical carcinoma has spread to
lower uterine segment or uterine cavity at presentation.

Figure 8.5 Direct invasion of the cervical cancer to the ureter leads to
hydroureter and hydronephrosis. Obstructive nephropathy is
one of the most common causes of morbidity and mortality in
cervical cancer.

Lymphatic spread is important as the lymph node metastasis

is one of the independent prognostic factors for survival. The risk
208 Cancer of Cervix

of nodal metastasis is related to staging of the disease, depth of

invasion, size of tumour, grade and presence of lymphovascular
space invasion. The risk of pelvic lymph node metastasis is 0–0.6%
in stage 1A1. However, in stage 1A2, the risk of nodal metastasis
increases to be 4.8–11% (average 7% but higher if present of
lymphovascular space invasion). Involvement of para-aortic lymph
node without pelvic lymph nodes is unusual. Parametrial lymph
nodes are the most commonly aﬀected lymph nodes. Approximately,
80% of patients with positive parametrial lymph node also have
positive pelvic lymph node. Generally, the risk of parametrial lymph
node metastasis is approximately 10% in stage 1B and 20% in stage
2B. The risk of pelvic lymph node metastasis increases from 16%
in stage 1B to 25–31% in stage 2 disease. The cancer can also spread
through a blood stream to distant organs such as liver, spleen,
kidney, lung, brain, bone, and others.

Presentations
In an early stage, many patients do not have any symptoms
(asymptomatic). The most common presenting symptom is
postcoital bleeding. Patients can also present with irregular vaginal
bleeding, passing out blood stained mucus per vagina, pelvic pain
and constitutional symptoms. Pelvic pain, urinary problems and
constitutional symptoms are the strong indications of advanced
stage disease. If the disease has obstructed the uterine outlow
tract, menstrual blood will be accumulated in the uterine cavity
(haematometra) and subsequently secondary bacterial infection
leading to the formation of pus in the cavity (pyometra). Patients
with pyometra often presented with pelvic pain, purulent vaginal
discharge and fever. Invasion of the tumour posteriorly may cause
tenesmus and per-rectal bleeding. In late-stage disease, patients
may be presented with shortness of breath, bone pain, severe
headache, neurological problems, loss of appetite and loss of
weight. Lymphatic obstruction may result in lower limb
lymphoedema. Venous outlow obstruction can lead to deep vein
thrombosis, and patients will present with unilateral leg swelling.
Both of these presentations are strong indications of advanced
cervical cancer. In developed countries, 70–80% of patients
presented at an early stage (stages 1 and 2); however, in under-
Staging Carcinoma of Cervix 209

developed regions only 30–40% of patients presented at an early

stage.

Diagnosis
Patients who presented with symptoms suggestive of cervical
cancer must undergo complete physical and pelvic examinations.
If the lesion is not well-visualized, colposcopic examination must
be performed to identify the abnormalities. Conirmation of the
diagnosis is made via histological examination of the cervical
biopsy. Cervical biopsy can be in the form of directed punch biopsy
or cervical cone biopsy. The optimal site to take the biopsy is from
the edge of the tumour, where the transition from invasive to non-
invasive can be clearly seen. Avoid taking biopsy from the middle of
the lesions because this will only reveal necrotic cells/tissues.

Staging Carcinoma of Cervix

Cervical cancer is staged clinically using radiographic examination
and clinical examination under anaesthesia. Surgical staging may
be more accurate. However, since 80% of cancers are diagnosed in
developing countries, clinical staging is more aﬀordable and remains
practical until today. During an examination under anaesthesia,
cystoscopy and thorough clinical assessment of the tumour
are performed. According to the latest FIGO recommendation,
cystoscopy and procto-sigmoidoscopy are not mandatory, especially
in an early stage, these procedures are indicated if the patient is
suspected to have bladder and rectal iniltration (Fig. 8.6). Suspected
lesions in the bladder and rectum should be biopsied. Bullous
oedema of the bladder and swelling of the rectal mucosa are not
accepted as deinitive criteria for staging. Chest radiography is a
routine investigation in the staging processes.
Computed tomography scans (CT scan) with contrast may
replace intravenous urogram to assess the urinary tract. CT scans is
also useful in assessing the nature of primary tumour and extends
of the disease. The other imaging techniques are MRI and PET scan.
See Chapter 19 to learn more about imaging techniques in
gynaecological malignancies.
210 Cancer of Cervix

Figure 8.6 Clinical staging for cervical cancer. Examination under

anaesthesia and cystoscopy.

Baseline investigations such as full blood count, renal function

test, liver function test, tumour markers and urinalysis are
important.
Abnormal or suspicious lymph nodes on CT scan or MRI
should be conirmed with CT-guided FNAC (ine needle aspiration
cytology), if feasible. In some centres, lymph node assessment
is done through laparoscopic examination and biopsy. Retro-
peritoneal lymph node dissection is a preferred approach to avoid
intra-abdominal adhesions and subsequent risk of radiation
injuries to the bowels. Risk of major radiation injuries following
intraperitoneal and retroperitoneal lymphadenecomy were 11%
and 4%, respectively. Sentinel node biopsy is very promising but at
present still investigational. Tables 8.2 and 8.3 show the old FIGO
staging and new FIGO staging 2009 for comparisons.

Table 8.2 FIGO staging of cervical cancer 1994

Stage Description
Stage 1 The carcinoma is strictly conined to the cervix
(extension to the corpus should be disregarded)
Stage 1A Invasive Ca diagnosed only by microscopy. All visible
lesion is stage 1B. Stroma invasion with a maximum
depth of 5 mm measured from the base of the
epithelium and horizontal spread of 7 mm or less.
Vascular space involvement, venous or lymphatic,
does aﬀect classiication.
Staging Carcinoma of Cervix 211

Stage 1A1 Stroma invasion ≤3 mm and ≤7 mm horizontal

spread
Stage 1A2 Stroma invasion >3 mm and ≤5 mm and ≤7 mm
horizontal spread
Stage 1B Clearly visible lesion conined to cervix or
microscopic lesion greater than in stage 1A2
Stage 1B1 Lesion ≤4 cm in greatest diameter
Stage 1B2 Lesion >4 cm in greatest diameter
Stage 2 Cervical carcinoma invades the uterus, but not to
the pelvic wall or to the lower third of the vagina
Stage 2A No parametrium invasion
Stage 2B Parametrium invasion
Stage 3 Carcinoma extends to the pelvic wall and/or involves
lower third of vagina or causes hydronephrosis/
non-functioning kidney
Stage 3A Tumour involves lower third of vagina, no extension
to pelvic wall
Stage 3B Tumour extends to pelvic wall or causes hydrone-
phrosis or non-Functioning kidney
Stage 4A Tumour invades bladder mucosa or rectum and/or
extends beyond true pelvis
Stage 4B Distant metastases
Note: The above old FIGO staging 1994 is purposely highlighted to guide the readers
to compare with the latest FIGO staging 2009 in the next page.

Table 8.3 Latest FIGO staging 2009

Stage Descriptions
Stage 1 The carcinoma is strictly conined to the cervix (extension to the corpus
should be disregarded)
Stage 1A Invasive cancer diagnosed only by microscopy. All visible lesion is stage
1B. Stroma invasion with a maximum depth of 5 mm measured from the
base of the epithelium and horizontal spread of 7 mm or less.
Stage 1A1 Stroma invasion ≤3 mm and ≤7 mm horizontal spread
Stage 1A2 Stroma invasion >3 mm and ≤5 mm and ≤7 mm horizontal spread
Stage 1B Clearly visible lesion conined to cervix or microscopic lesion (preclinical
cancer) greater than in stage 1Aa
(Continued)
212 Cancer of Cervix

Table 8.3 (Continued)

Stage Descriptions
Stage 1B1 Clinically visible lesions ≤4 cm in greatest diameter
Stage 1B2 Clinically visible lesion >4 cm in greatest diameter
Stage 2 Cervical carcinoma involving the upper 2/3 of vagina or parametrium
but not to the pelvic side wall
Stage 2A Involvement of upper 2/3 of vagina with no obvious parametrial
involvement
Stage 2A1 Clinically visible lesions ≤4 cm in greatest diameter
Stage 2A2 Clinically visible lesion >4 cm in greatest diameter
Stage 2B Parametrium invasion bilateral or unilateral without extension to the
pelvic sidewall
Stage 3 Carcinoma extends to the pelvic wall and/or involves lower third of
vagina or causes hydronephrosis/non-functioning kidneyb
Stage 3A Tumour involves lower third of vagina, no extension to pelvic wall
Stage 3B Tumour extends to pelvic wall or causes hydronephrosis or non-
Functioning kidney
Stage 4A Tumour invades bladder mucosa or rectum and/or extends beyond
true pelvis.
Stage 4B Distant metastases
aAllmacroscopically visible lesions—even with supericial invasion—are allotted to
Stage IB. Invasion is limited to a measured stromal invasion with a maximal depth
of invasion 5.0 mm and a horizontal extension of 7 mm. Depth of invasion should be
taken from the base of the epithelium of the original tissue—supericial or glandular.
The involvement of vascular spaces—venous or lymphatic—does not change the
stage. These rules now apply to adenoma carcinomas.
bOn rectal exam there is no cancer-free space between the tumour and the pelvic side

wall. All cases with hydronephrosis or a non-functioning kidney should be included,

unless they are known to be due to other causes.

Prognostic Factors
Clinical stage is the most important prognostic factor. Overall
5-year survival rates are 95–100% in stage 1A disease and from
75% to 90% in stage 1B. Patients with stage 4 cervical cancer have
only 5% chances to survive after 5 years. See Tables 8.4 and 8.5
for reported survival rate by Fletcher et al. and Pettersson. Depth
of tumour invasion, lymphovascular space invasion and tumour
volume or diameter are three important independent prognostic
Management of Cervical Cancer 213

factors for recurrence. Lymphovascular space invasion correlates

with the risk of lymph node metastasis. In stage 1A2 cervical cancer,
presence of lymphovascular space invasion increased the rate of
nodal metastases from 3.2% to 16.1%. Largest tumour diameter is
also an important prognostic factor. Lesion of 4 cm or less, with two
nodes positive carry 10-year survival rate of 56–70% as compared
to 13% in patients with a tumour diameter of more than 4 cm
and two positive nodes. Endometrial extension associated with
decreased survival, greater incidence of peritoneal carcinomatosis
and distant metastases.
Lymph node involvement is known to correlate with survival.
Patients with early-stage cervical cancer treated with surgical
treatment have 5-year survival of 90% if their lymph nodes were
negative. Survival decreased to 50–60% if the tumour has spread
to pelvic lymph nodes. The 5-year survival rate is further decreased
to 20–45% if the tumour has spread to para-aortic nodes. Five-year
survival rates were also inluenced by the number of lymph nodes
involved (single lymph node positive, 62% survival, two lymph
nodes positive, 36% survival rate). Survival rate of cervical cancer is
shown in Table 8.4 and 8.5.

Table 8.4 Five-year survival rate in cervical cancer (Fletcher)

Five-year survival rate of 2000 patients after treated with

radiotherapy (Fletcher)
Stage 1 91.5%
Stage 2A 83.5%
Stage 2B 66.5%
Stage 3A 45%
Stage 3B 36%
Stage 4 14%

Patients with aggressive histology type such as adenosquamous,

small cell neuroendocrine, sarcoma and poorly diﬀerentiated
tumour are known to have poorer prognosis. Other prognostic
factors are age, general conditions, including co-morbidity and
nutritional status.
214 Cancer of Cervix

Table 8.5 Survival by stage in patients with cancer of cervix (From

larger study* involving more than 32,000 patients, Pettersson,
1991)

Survival rate
Stage Three-year (%) Five-year (%)
1 86.9 81.6
2 69.5 61.3
3 44.6 36.7
4 16.6 12.1
*Pettersson F: Annual Report on the Results of Treatment in Gynecologic Cancer,
vol. 21. Statements on the results obtained in patients 1982–1986, inclusive 3- and
5-year survival up to 1990. Int J Gynecol Obstet 1991; (supp): 27–127.

Management of Cervical Cancer

Patients with cervical cancer should ideally be managed in a
centre with complete expertise and facilities for treatment of
gynaecological cancer. Final decision on the best treatment for a
patient is made based on the information regarding the pathology
and extends of the disease, taking a consideration of the patient’s
factors such as age, fertility wishes, co-morbidity, performance
status and patient’s personal choices.
Following are the principal steps for the management of cervical
cancer:
(1) Conirm the diagnosis and thorough evaluation of
histopathological features of the tumour.
(2) Determine the extent of the disease through investigations
and staging.
(3) Determine the intention of treatment either for curative or for
palliative.
(4) Review all treatment modalities and decide the best for
patients based on above indings taking into consideration
patient-speciic factors, fertility wishes, performance status,
co-morbidity, surgical and medical history, patient’s personal
choices and psychosocial background.
(5) Counsel the patient and her partner.
Surgical Treatment for Stage 1A1 215

(6) Oﬀer the patient the most appropriate treatment.

(7) Monitor.
Following are the treatment options for a patient with cervical
cancer:
(1) surgery
(2) radiotherapy or chemoradiation
(3) chemotherapy
(4) combination therapy

Treatment for Early-Stage Cervical Cancer

Early-stage disease refers to stages 1 to stage 2A. Both surgery
and radiotherapy are equally eﬀective in the treatment of a patient
in early stage. Although both surgery and radiotherapy are equally
eﬀective in early disease, controversies exist about the optimal
primary treatment for patients with bulky tumours (tumour
diameter larger than 4 cm) and positive regional lymph nodes.
Positive lymph node does not change the staging.
In other groups with early disease, surgery is obviously more
advantageous because the majority of women with cervical cancer
are relatively young and sexually active. Following are the advantages
of surgical treatment in early disease: (a) Ability to conserve the
ovarian function in premenopausal women; (b) fertility preservation
in selected patients; (c) avoidance of radiation toxicities such as
vaginal stenosis, bladder and rectal radiation injuries; vaginal
stenosis may lead to sexual dysfunction or even apareunia and
(d) availability of tumour and tissue samples for assessment and
determination of the risk of recurrence and rate of survival.

Surgical Treatment for Stage 1A1

The prognosis for stage 1A1 is excellent with 5-year survival of
more than 95% and the risk of lymph node metastasis is only 0.5%,
if no lymphovascular space invasion. Local excision (cone biopsy)
or simple hysterectomy is suficient but hysterectomy is considered
as the standard of care. Local excision is best performed by cone
biopsy, knife cone biopsy has advantages over the LEEP or laser
216 Cancer of Cervix

cone because it causes less thermal damage, and therefore, the

specimen is intact for better for pathological evaluation.
Simple hysterectomy with or without bilateral salpingo-
oophorectomy is the preferred treatment for the following patients:
(a) postmenopausal women
(b) patients with other gynaecological diseases requiring
treatment such as symptomatic leiomyoma, endometriosis,
etc.
(c) poor compliance
(d) patients in whom local excision is not feasible or there is high
possibility of incomplete resection
(e) patients with evidence of co-existing adenocarcinoma in situ
(ACIS) and who have completed their family
In a patient with evidence of lymphovascular space invasion,
the risk of nodal metastasis increases to 4%; therefore, pelvic
lymphadenectomy may be justiiable. Hysterectomy can be performed
either by open surgery (abdominal and vaginal hysterectomy) or
laparoscopically.

Surgical Treatment for Stage 1A2

The risk of nodal metastasis in stage 1A2 is approximately 7%
and the risk increases to 10% in a small subset of patients with
lymphovascular space invasion. Pelvic lymphadenectomy is indicated
in all patients with stage 1A2 cervical cancer. Surgery for primary
tumour is individualized ranging from radical trachelectomy,
modiied radical hysterectomy to radical hysterectomy. In a
patient whom the diagnosis of stage 1A2 is made following simple
hysterectomy, they do not require parametrectomy instead pelvic
lymphadenectomy alone is suficient. Glandular lesions and poor
histology type such as adenosquamous and small cell neuroendocrine
tumour should be dealt with a more radical approach. In patients
who keen to preserve her fertility, radical trachelectomy and
pelvic lymphadenectomy can be oﬀered. Trachelectomy can be
accomplished via laparotomy, vaginally or laparoscopically. Surgical
techniques will be discussed in the last section of this chapter. The
role of sentinel node biopsy in stage 1A2 is under investigation and
appears promising.
Surgical Treatment for Stage 1B1 and Stage 2A1 Cervical Cancer 217

Surgical Treatment for Stage 1B1 and Stage 2A1

Cervical Cancer
The risk of lymph node metastasis in stage 1B and 2A is 16–25%.
Under new FIGO staging, stage 2A is further subdivided into stage
2A1 and 2A2. Stage 2A1 is when the tumour’s largest diameter
is 4 cm and less, while stage 2A2, if the diameter is more than 4
cm. Radical hysterectomy and pelvic lymphadenectomy are the
standard of treatment in patients with stage 1B1 and stage 2A1,
although they can also be treated with primary radiotherapy/
chemoradiotherapy. In a prospective randomized study to
compare surgery and radiotherapy in patients with stage 1B–2A,
both treatments were equally eﬀective and had a comparable
outcome (Landoni et al., 1997). Five-year survival rates were
75–100% in patients with stage 1 to 2A treated by either surgery or
radiotherapy.
The primary aim of radical hysterectomy is to remove the
tumour with adequate margin, including parametrium and
upper part of the vagina. Microscopic margin must be at least 5 mm
and pelvic node dissection should include obturator, internal iliac,
external iliac and common iliac nodes. Para-aortic lymphadenectomy
is not mandatory. Landoni and colleagues have published a
prospective randomized study to compare radical hysterectomy
class II (modiied radical hysterectomy) versus class III involving
243 patients with small-volume stage 1B and 2A cervical cancer.
They have concluded that class II and class III radical hysterectomy
are equally eﬀective as surgical treatment for early-stage cervical
cancer (comparable 5-year survival rate). Patients who underwent
class II radical hysterectomy had fewer late complications
mainly urologic morbidity (13% vs. 28%) as compared to class III
radical hysterectomy.
Kim and colleagues evaluated 140 cases of early cervical
cancer with depth of invasion ≤5 mm in relation of lymph nodes
metastases and parametrial involvement. They found that depth
of invasion was a more important determinant of nodal metastasis
and parametrial involvement than the width of invasion. None
of the patients with depth of invasion ≤5 mm had parametrial
involvement despite horizontal spread of more than 7 mm (stage
1B1). Patients with invasion of >5 mm were found to have 15.3%
risk of parametrial involvement. The rate of nodal metastasis in
218 Cancer of Cervix

patients with depth of invasion ≤5 mm was 3.5% as compared

to 23% if the invasion was more than 5 mm. They suggested that
patients with stage 1B1 cervical cancer with depth of invasion
≤5 mm may be subjected to less radical surgery. If further
prospective clinical trials conirm that parametrectomy can be safely
omitted in low-risk patients, less radical surgery, such as simple
hysterectomy with pelvic lymphadenectomy, could be a reasonable
therapeutic option for supericially invasive stage IB1 cervical
cancer.

Treatment for Stage 1B2 and 2A2

Patients with bulky (diameter larger than 4 cm) stage 1B and 2A
are categorized as stage 1B2 and stage 2A2 disease, respectively.
The later is based on the new FIGO staging. Patients presenting
with bulky stage 1B and 2A cervical cancers represent a greater
therapeutic challenge. Several authors categorized bulky stage 1B
(1B2) and 2A (2A2) under locally advanced stage cervical cancer
(Allen and Narayan, 2005).
Measurement of tumour size is best performed by MRI and
perhaps most important diameter is the craniocaudal diameter of
the tumour. Hayashi and Kato, using a 4 cm cut-oﬀ value for
craniocaudal diameter reported a 5-year disease-free survival of
70% in tumours with a diameter of less than 4 cm and 37% in
tumours more than 4 cm in diameter. Interestingly, there was no
diﬀerence in a survival rate if the transverse diameter was taken.
Numerous studies have demonstrated that volume and size of
tumour are independent prognostic factors for tumour recurrence
and survival. Patients with bulky tumour tend to have higher
risk of nodal metastasis and surgical margin involvement. In
view of higher rate of postoperative adjuvant radiotherapy, some
Oncologist preferred to treat these patients with primary radiother-
apy/chemoradiotherapy. Although many oncologists prefer to treat
patients with bulky disease with primary radiotherapy/chemora-
diation, there is so far no concrete evidence that this approach is
superior to primary surgery in terms of overall survival. Landoni
et al. randomized 343 patients with stage 1B–2A into two groups
(1) treated with primary surgery and (2) primary radiotherapy.
Overall survival was comparable in both groups. However, on
further evaluation of stage 1B2 disease, they found that 84% of
Treatment for Stage 1B2 and 2A2 219

these patients required adjuvant radiotherapy (as compared to 54%

in stage 1B1). Although there was no diﬀerence in overall survival,
patients who underwent surgery and adjuvant radiotherapy had
higher morbidity rate.
The ive-year survival rates for stage 1B2 are 60% compared to
85% in stage 1B1. Rutledge TL and colleagues compared stage 1B1
and 1B2 cervical cancers treated with radical hysterectomy, there
found that stage 1B2 was associated with signiicantly higher rate
of nodal metastasis (28% vs. 12.8%), para-aortic node involvement
(8.1% vs. 1.8%), parametrial involvement and adjuvant radiotherapy
(52% vs. 37%).
The main concern about primary surgery in bulky disease is
treatment-related morbidity. However, with the advancement and
improvement in the surgical techniques, e.g. nerve-sparing surgery,
minimally invasive surgery and less radical surgery, treatment
morbidity related to this approach may be minimized in near
future.
Surgical treatment for stages 1B and 2A is Type III radical
hysterectomy and bilateral pelvic lymphadenectomy. In bulky
stage 1B and 2A disease, the risk of para-aortic lymph node
metastasis is expected to be higher (Stage 2A, risk 11%), perhaps
in these subgroups of patients, surgical assessment of para-aortic
lymph nodes is justiiable. Following surgical treatment, patients
with high risk of recurrence are subjected to adjuvant radiotherapy.
Besides primary surgery and primary radiotherapy, patients
with bulky disease have also been subjected to extensive studies
to evaluate the other therapeutic options. Following are the
other options of treatment for patients with stage 1B2 and 2A2
cervical cancer (please refer to the sections sections “Radiotherapy
in Cervical Cancer” and “Neoadjuvant Chemotherapy in Cervical
Cancer” of this chapter to learn more about each option and some of
these options required further evaluation):
(a) concomitant radiotherapy and chemotherapy (chemoradia-
tion)
(b) radiation therapy/chemoradiation followed by extrafascial
hysterectomy (controversial, some believe that an addition
of extrafascial hysterectomy did not improve the survival,
although it reduces the recurrence rate) or radical hysterec-
tomy
(c) neoadjuvant chemotherapy followed by radical hysterectomy.
220 Cancer of Cervix

Treatment for Stage 2B-4

Advanced stage cervical cancer can be further divided into
(1) locally advanced cervical cancer and (2) metastatic disease.
Stages 2B–4A are locally advanced stage disease, while stage 4B is
a metastatic disease. Intention of treatment in metastatic disease
is palliation. A patient with locally advanced disease is treated
with primary chemoradiation. Pelvic exenteration can be considered
in a selected patient with stage 4A cervical cancer. Pelvic failure
rate after irradiation ranges from 18–39% in stage 2B, 40–50% in
stage 3B. There is suficient evidence to conclude that concurrent
chemoradiation therapy is more superior to radiotherapy
alone. An updated RTOG trial (RTOG 90-01) on locally advanced
cervical cancer had concluded that the addition of chemotherapy
(cisplatin, 5-FU) to irradiation improved 5-year survivals from
55% to 79% and disease-free survival from 46% to 74% for
stage 1B/2A. These were achieved by reducing the rates of both
local recurrence and distant metastases. For stage 3/4A disease,
chemoradiation improved 5-year survivals from 45% to 59% and
disease-free survival from 37% to 54% (Eifel et al., 2004).

Role of Adjuvant Radiotherapy or

Chemoradiation after Surgery
Surgery is the treatment of choice for stage 1–2A1 cervical cancer.
Many of the patients with stage 1 disease do not require further
treatment if they do not have adverse prognostic factors. However,
in signiicant proportion of these patients, adjuvant treatment is
necessary, as their risk of recurrence is higher.
Following are the indications for postoperative adjuvant
radiotherapy/chemoradiation:
(a) lymph nodes metastases
(b) narrow surgical margin (<5 mm)
(c) involvement of surgical margin
(d) involvement of lower uterine segment
(e) parametrium iniltration
Role of Adjuvant Radiotherapy or Chemoradiation after Surgery 221

(f) high GOG score (score > 120) in patients with negative lymph
nodes and clear surgical margin (Refer appendix on how to
calculate GOG score)
(g) poor histology type such as adenosquamous, small cell
neuroendocrine, etc.
GOG score of higher than 120 was correlated with 41%
recurrence rate, and Sedlis et al. used a modiication of the GOG
scoring system and reported a 44% reduction of the risk of
recurrences after adjuvant radiotherapy when a combination of
three risk factors was present compared to without postoperative
irradiation. In another study using a modiication from original
GOG score, patients with at least two of the three risk factors
(pathologic tumour size >4 cm, depth of invasion >15 mm and
presence of LVSI) received total pelvic radiotherapy has a lower
rate of recurrence (12% vs. 41%) compared to without adjuvant
radiotherapy. Adjuvant radiotherapy also leads to signiicantly
longer 5-year cancer speciic survival (86% vs. 57%) and 5-year
disease-free survival (85% vs. 43%) (Pieterse et al., 2006).
The Cochrane Collaboration had reviewed the role of adjuvant
radiotherapy and chemoradiation after surgery for cervical cancer,
and it was published in 2009 (Rogers et al., 2009). The objective
of review was to evaluate the eﬀectiveness and safety of adjuvant
therapies (radiotherapy, chemotherapy followed by radiotherapy,
chemoradiation) after radical hysterectomy for early-stage cervical
cancer (FIGO stage 1B1, 1B2 and 2A). In GOG 92, phase III trial, patients
with negative lymph node but who have any of the combinations of
deep stromal invasion, large volume and lymphovascular invasion
were evaluated. The authors found that adjuvant radiotherapy
signiicantly reduces the risk of death, especially in patients with
deep stromal invasion and tumour size of more than 4 cm. Women
who received radiotherapy had a signiicantly lower risk of disease
progression within 5 years than women who received no further
treatment (HR = 0.5, 95% CI 0.4–0.9). Interestingly, only 9% of
patients with adenocarcinoma and adenosquamous tumours in
the radiotherapy arm had disease recurrence as compared to 44%
in the control arm. The impact of adjuvant radiotherapy on overall
survival is unknown. One of the main concerns about adjuvant
radiotherapy is the higher rate of toxicity.
222 Cancer of Cervix

Radical Hysterectomy for Cervical Cancer

Radical hysterectomy is indicated as primary surgical treatment in
early-stage cervical cancer. Radical hysterectomy must be combined
with pelvic lymphadenectomy; besides cervical carcinoma, it is
also indicated in endometrial cancer with cervical involvement.
Clark published the irst radical hysterectomy in 1895.
Wertheim subsequently reported the outcome of abdominal
radical hysterectomy in 1912, but during that time, the mortality
rate was 19%. Mortality rate was reduced with vaginal radical
hysterectomy introduced by Schauta. However, due to overall
high operative morbidity and mortality, surgery was replaced
by radiotherapy until it was re-introduced by Meigs in 1951. In
original Wertheim’s hysterectomy, lymphadenectomy was not
a routine procedure; however, in Meigs radical hysterectomy,
lymphadenectomy was performed routinely. Therefore, the current
radical hysterectomy and pelvic lymphadenectomy are actually
a combination of Wertheim’s and Meigs’ methods or Wertheim–
Meigs radical hysterectomy.
The primary aim of radical hysterectomy is to remove the
primary tumour with adequate surrounding tissues, including
parametrium, paracolpus and vaginal cuﬀ in order to reduce the
recurrence rate (Fig. 8.7). Piver and Rutledge irst published their
ive classiications of hysterectomy for cervical cancer in 1974, as
shown in Table 8.6.
The type 1 Piver–Rutledge–Smith (extrafascial hysterectomy)
is not a radical hysterectomy; it is almost similar to simple
hysterectomy except in extrafascial hysterectomy, ureter has to be
lateralized to enable clamping of the paracervical tissue avoiding
cervical stroma and the cervix is removed in total. Extrafascial
hysterectomy is recommended in stage 1A1 cervical cancer or in
cancer of the endometrium. At present, there are no standard
and universally accepted techniques and descriptions of radical
hysterectomy. Various methods of radical hysterectomy have been
described in the literature and demonstrated by gynaecological
oncologists around the world such as Wertheim’s radical
hysterectomy, Meigs radical hysterectomy, Okabayashi radical
hysterectomy, Nerve-sparing radical hysterectomy, total laparaos-
copic radical hysterectomy, and others.
Radical Hysterectomy for Cervical Cancer 223

Figure 8.7 Radical hysterectomy and lymphadenectomy (pelvic and

para-aortic) for cervical cancer.

Table 8.6 Classiication of hysterectomy for cervical cancer (Piver–

Rutledge–Smith classiication)

Type Description
1 Extrafascial hysterectomy; removal of all cervical tissue
2 Modiied radical hysterectomy; removal of medial half of the
cardinal and uterosacral ligaments; the uterine vessels are divided
medially to the ureter
3 Equivalent to the classical Wertheim–Meigs operation; wide radical
resection of the parametrium and paravaginal tissues with ligation
of uterine vessels lateral to ureter; ureter dissected completely to
bladder entry; uterosacral ligaments divided at origin; cardinals
divided at pelvic side-wall
4 Ureter divided from pubovesical ligament; superior vesical artery
ligated and upper two third of the vagina excised
5 Extended radical hysterectomy with possible bowel, bladder or
ureteric dissection

The Piver–Rutledge–Smith classiication of radical hyste-

rectomy is the most commonly used classiication until today.
However, this classiication has its own limitations:
224 Cancer of Cervix

(a) The classiication does not refer to clear anatomical landmarks

or international anatomical deinitions.
(b) Vaginal resection is excessive from a third to two-thirds of
the vagina.
(c) Type 1 is not radical hysterectomy.
(d) The rationale and anatomy to diﬀerentiate between types 3
and 4 are unclear.
(e) The classiication does not take into account the idea of
nerve preservation.
(f) It does not include other types of ultra-radical surgery and
fertility sparing surgery.
(g) It applies only to open surgery and does not take into account
the development of laparoscopic techniques and the revival
of vaginal surgery.
New classiication of radical hysterectomy was proposed during
International Conference on Radical hysterectomy in Kyoto, Japan
in 2007 (“Kyoto declaration”). This new classiication is based on
only the lateral extent of resection. Table 8.7 shows the proposal of
new classiication of radical hysterectomy.

Table 8.7 Newly proposed classiication of radical hysterectomy

Type Description
Type A Minimum resection of paracervix
• This is an extrafascial hysterectomy. The paracervix is
transected medial to the ureter but lateral to the cervix. The
uterosacral and vesicouterine ligaments are not transected at
a distance from the uterus. Vaginal resection is generally at a
minimum, routinely less than 10 mm, without removal of the
vaginal part of the paracervix (paracolpos)
Type B Transection of the paracervix at the ureter
• Partial resection of the ureterosacral and vesicouterine
ligaments, ureter is unroofed and rolled laterally, permitting
transaction of the paracervix at the level of the ureteric tunnel.
At least 10 mm of the vagina from the cervix or tumour is
resected
• Type B has two subtypes: Type B1: without removal of lateral
paracervical lymph nodes and Type B2: additional removal of
the lateral paracervical lymph nodesc
Radical Hysterectomy for Cervical Cancer 225

Type Description
Type C Transection of paracervix at junction with internal iliac vasculature
system
• Transection of the uterosacral ligament at the rectum and
vesicouterine ligament at the bladder. The ureter is mobilized
completely. 15–20 mm of vagina from the tumour or cervix
and the corresponding paracolpos is resected routinely,
depending on vaginal andparacervical extent
• Type C has two subcategories: Type C1: with nerve preserva-
tionb and Type C2: without preservation of autonomic nerve
Type D Laterally extended resection
• Rare operations features additional ultraradical procedures.
The most radical corresponds to the laterally extended en-
dopelvic resection (LEER) procedure
Lymph node dissection
Level 1 External and internal iliac up to bifurcation of common iliac
Level 2 Common iliac (including presacral) up to bifurcation of aorta
Level 3 Aortic infra-mesenteric (bifurcation of aorta up to inferior
mesenteric artery
Level 4 Aortic infrarenal (inferior mesenteric artery to infrarenal
vessels)
aThis classiication can be applied to fertility-sparing surgery and can be adapted to
open, vaginal, laparoscopic and robotic surgery.
bNerve preservation surgery involved transaction of uterosacral ligament after

separation of hypogastric nerve. The nerve is identiied systematically and preserved

by transaction of only the uterine branches of the pelvic plexus. The bladder branches
of the pelvic plexus are preserved in the lateral ligament of the bladder (i.e. lateral
part of bladder pillar).
cTissues that are medial and caudal to obturator nerve are classiied as paracervix,

tissues that are cranial and lateral to obturator nerves are classiied as iliac.

The decision to remove both ovaries during radical hyster-

ectomy is individualized similar to surgery for benign gynaeco-
logical conditions. Generally, bilateral salpingoophorectomy is
recommended in perimenopausal and postmenopausal women.
Bilateral salpingoophorectomy is not mandatory in young patients
with early-stage adenocarcinoma of the cervix. A review of almost
1000 women with stage 1B cervical cancer found that the risk of
ovarian metastasis was 0.5% in squamous cell carcinoma and
1.7% in adenocarcinoma (Sutton et al., 1992).
226 Cancer of Cervix

Radical hysterectomy carries the higher risk of bladder

dysfunction, anorectal dysfunction and sexual dysfunction believed
to be due to surgical trauma to sympathetic and parasympathetic
innervations of the pelvic organs. Autonomic pelvic nerve
injuries can be encountered at superior hypogastric plexus (para-
aortic node dissection), hypogastric nerve (resection of uterosacral
ligament), pelvic splanchnic nerve (during the transaction of
cardinal ligament) and bladder branch of inferior hypogastric plexus
(during resection of paracolpus and vesicovaginal ligament.
The pelvic nerve damage can be minimized by two main
approaches: (a) less radical surgery and (b) nerve-preserving
surgery.

Nerve-Preserving Radical Hysterectomy

Nerve sparing radical hysterectomy was pioneered by Japanese.
Some believe that it was irst inspired by Okabayashi since 1961
and subsequently popularized by Fujiwara in 1983, Yabuki et al.
in the 1990s and later Fujii et al. Hockel et al. from Germany
described the irst non-Japanese method of nerve-sparing radical
hysterectomy in 1998.
There are various methods of nerve-preserving surgery
published either from Eastern or from Western countries.
The main steps of nerve sparing radical hysterectomy described
by Prof Shingo Fujii from University of Kyota are as follows:
(1) isolation and separation of the deep uterine vein from the
pelvic splanchnic nerve
(2) isolation and separation of the hypogastric nerve
(3) separation of the cut end of the deep uterine vein from the
pelvic splanchnic nerve
(4) separation of blood vessels in the posterior leaf of the
vesicouterine ligament
(5) isolation and division of the inferior vesical vein
(6) separation/division of the uterine branch from the inferior
hypogastric plexus
(7) separation and division of the paracolpium
Pelvic lymphadenectomy was often performed irst prior to
nerve sparing radical hysterectomy. Raspagliesi et al. evaluated
the role of nerve sparing radical hysterectomy by comparing type
Complications of Radical Hysterectomy 227

2 RH, nerve-sparing type 3 RH and classical type 3 RH. They

conclude that type 3 nerve-sparing RH seems to be comparable
to type 2 RH and more superior than type 3 RH in terms of early
bladder dysfunction.
Nerve sparing radical hysterectomy appears to be a feasible
alternative to the classic technique of radical hysterectomy.
However, at present the technique still needs further evaluation
and revision before it can be accepted as a standard procedure.
Furthermore, there are several concerns related to this relatively
new surgical technique, such as the following:
(a) The procedure may lead to unintentionally incomplete or
inadequate tumour resection.
(b) Only experienced and trained surgeon can perform this
complex surgery.
( c ) The complexity of this technique together with the requirement
of special instruments and equipment may pose a hindrance
for this technique to be performed in under-developed and
developing countries due to cost factor.
(d) Lack of uniformity in the understanding of the anatomy and
technique.
(e) Prolonged operating time.

Complications of Radical Hysterectomy

Complications related to radical hysterectomy and pelvic lym-
phadenectomy can be divided into early complications and late com-
plications. See Table 8.8 for the lists of early and late complications.

Table 8.8 Complications of radical hysterectomy and pelvic lym-

phadenectomy

Early complications Late complications

1. Intraoperative complications such as anaestheticre- 1. Chronic bladder
lated complications, blood loss, injuries to the ureter dysfunction
(0.6–1.7%), bladder, rectum, pelvic vessels and nerve 2. Rectal sphincter
(genitor-femoral, obturator nerve). dysfunction
2. Postoperative complications such as early deep vein 3. Ureteric stricture
thrombosis (0.3%), urinary tract infections (10–16%), 4. Late istula
voiding problem and wound infection (4–6%) and 5. Lymphoedema
vesicovaginal or ureterovesical istula. 6. Sexual dysfunction
3. Lymphocoele
228 Cancer of Cervix

Fertility-Preserving Surgery in Cervical Cancer

Approximately, 45% of patients with operable early-stage cervical
cancer were diagnosed in women under the age of 40. Many of these
women wish to preserve their fertility.
Following are the options for fertility-preserved surgery in
cervical cancer:
(a) radical trachelectomy and pelvic lymphadenectomy
(b) cone biopsy or simple trachelectomy
(c) neoadjuvant chemotherapy followed by fertility-preserving
surgery

Radical Trachelectomy
Radical trachelectomy is total excision of the cervix with
surrounding tissues, including paracervical, paracolpus and vaginal
cuﬀ while retaining the uterine body and adnexae. Radical Vaginal
trachelectomy was irst described by Daniel Dargent in 1994.
Radical Vaginal trachelectomy and laparoscopic lymphadenectomy
is perhaps the most common fertility-preserved procedure for early
cervical cancer reported in the literatures. Until 2008, there were
more than 700 cases of RVT, and over 250 pregnancies had been
reported.
Apart from the vaginal approach, trachelectomy can also be
accomplished through diﬀerent techniques such as
(a) radical abdominal trachelectomy
(b) total laparoscopic radical trachelectomy
(c) robotic radical trachelectomy
Not all patients with operable cervical cancer are suitable for
radical trachelectomy. Patient selection is extremely important and
the criteria for RVT are as follows (Ramirez et al., 2008):
(1) a desire for future fertility
(2) proven diagnosis of invasive cervical cancer
(3) squamous cell carcinoma and adenocarcinoma; unfavourable
histology such as small cell neuroendocrine tumour and
adenosquamous are excluded.
(4) stage 1A1 with lymphovascular space invasion, stage 1A2 or
stage 1B1
Radical Trachelectomy 229

(5) tumour size ≤2 cm and limited to the cervix (preferably by

pre-operative MRI)
(6) no evidence of pelvic node metastasis
(7) no previous documentation of infertility
When the tumour size is dificult to assess, magnetic resonance
imaging (MRI) is the best imaging technique to determine the size
and volume of tumour. MRI is also useful to assess the degree of
paracervical and parametrium involvement.
Laparoscopic lymphadenectomy is performed either prior to
or after radical trachelectomy, preferably through retroperitoneal
approach. If sentinel node mapping and biopsy are performed,
frozen section of the sentinel node will determine the direction
of subsequent management. If pelvic nodes are positive,
trachelectomy should be abandoned.
Following radical trachelectomy, frozen section is done on
the cervical specimen to assess the superior margin. The aim is to
achieve at least 5 mm free margin. A cerclage is placed either with
Mersilene, Prolene or Ethibond suture. The placement of cerclage
at the time of radical trachelectomy is debatable, there has been
increasing concern that cerclage at the same setting may lead to
cervical stenosis, bladder irritation, erosion and chronic discharge.
Radical vaginal trachelectomy needs training and not many
gynaecological oncologists are competent to perform this surgery.
Perhaps many surgeons are more familiar with radical abdominal
trachelectomy (RAT) because the surgery is almost similar to
radical hysterectomy. Indications for RAT are similar to RVT, but
RAT is a preferred approach in the following cases: (a) patients
with distorted vaginal anatomy, (b) cervical cancer in paediatric,
young and unmarried patients and (c) cancer of a cervical stump
after subtotal hysterectomy.
The number of surgeons performing robotic radical trach-
electomy is increasing; several case reports have demonstrated
that robotic radical trachelectomy is a safe and feasible procedure
if performed by the trained surgeon.
Results from several published papers (Ramirez et al., 2008;
Olawaiye et al., 2009; Gien and Covens, 2010) reviewing the role of
radical trachelectomy have concluded that radical trachelectomy is
safe and feasible and pregnancy outcomes are favourable. Pregnancy
230 Cancer of Cervix

rates of 41–79% were achieved, and 40% of them resulted in term

delivery (Beiner and Covens, 2007; Plante, 2008).
Reported complications of radical trachelectomy are dysmenor-
rhea, irregular vaginal bleeding, problems related to cerclage suture,
premature delivery in more than 40% of cases, excessive vaginal dis-
charge, isthmic stenosis (10%), dyspareunia and amenorrhea.

Neoadjuvant Chemotherapy Followed by

Fertility-Preserving Surgery
Neoadjuvant chemotherapy in cervical cancer is still controversial,
and this topic will be discussed in the later section of this chapter.
Neoadjuvant chemotherapy may reduce the tumour size and facili-
tates subsequent fertility-preserving surgery. Maneo and colleagues
have reported 21 patients with stage 1B1 cervical cancer treated
with neoadjuvant chemotherapy (platinum-based regimen) followed
by cold-knife conization and pelvic lymphadenectomy. Twenty-one
patients underwent conization and pelvic lymphadenectomy; after
a median follow-up of 5 years 9 months, no relapses were observed.

Cone Biopsy or Simple Trachelectomy

The role of cone biopsy in stage 1A1 cervical cancer was discussed
in earlier section. The use of cone biopsy and simple trachelectomy
plus pelvic lymphadenectomy in selected patients with stage 1A2
and 1B1 is very controversial and warrant further investigation.

Radiotherapy in Cervical Cancer

There are two types of radiation therapy in cervical cancer:
(a) External photon beam (delivered by linear accelerator) and
(b) Brachytherapy.
External beam radiotherapy (EBRT) is irradiation delivered to
the whole pelvis, parametrium, pelvic and para-aortic lymph nodes
(extended beam). Brachytherapy is in the form of intracavitary radi-
otherapy targeting the cervix, vagina and medial parametrium. The
most commonly used applicator is the Fletcher–Suit intrauterine
tandem and vaginal ovoid. External pelvic irradiation is given prior
Radiotherapy in Cervical Cancer 231

to intracavitary insertion in: (a) bulky cervical lesions, (b) exophytic,

easily bleeding tumour, (c) tumour with necrosis or infection and
(d) parametrial involvement. The entire processes of radiotherapy
are demonstrated in Figs. 8.8, 8.9 and 8.10.

Figure 8.8 Linear accelerator delivers the high-voltage x-ray, as an external

beam radiotherapy.

Figure 8.9 Brachytherapy technique using Manchester applicators.

232 Cancer of Cervix

Figure 8.10 Brachytherapy delivered from the nucleatron microselectron

(the radiation source is from iridium).

Stage 1A1 can be treated with intracavitary therapy alone

with 60 Gy single insertions to point A. External pelvic irradiation
is given to a patient with stage 1A2 and more (as an alternative
to surgical treatment or as postoperative adjuvant therapy).
Inoperable stage IB1 cervical cancer patients should be treated
with both EBRT and brachytherapy. Concurrent chemotherapy
may be considered at the Oncologist’s discretion and based on the
presence of high-risk features.
Clinical stage 1B2-4A cervical cancer should be treated with
concurrent chemoradiation followed by brachytherapy.
Stage 4B cervical cancer may be palliatively treated with
brachytherapy with or without EBRT to decrease the risk of
haemorrhage or other life-threatening symptoms.
External pelvic irradiation is given in 20–25 fractions within 5
weeks and brachytherapy is inserted two to three insertion within
one week at the end of EBRT treatment. The GOG has deined three
standard pelvic points where dose designation can be planned and
correlated with clinical eﬀect (see Fig. 8.9):
(a) Point A: 2 cm from the midline of the cervical canal and 2 cm
superior to lateral vaginal fornix/cervical os. The dose at the
point A represents of the dose to paracervical triangle that
correlates well with the incidence of sequelae and 5 years’
Radiotherapy in Cervical Cancer 233

control rate. This point is an also approximate point at which

the ureter and uterine artery cross.
(b) Point B: 3 cm lateral to point A or 5 cm lateral to the centre
of the pelvis at the same level as point A. This point is of
signiicance in considering the dose to the node bearing tissue,
especially obturator nodes or lateral parametrium.
(c) Point P: located along the bony pelvic sidewall at its most
lateral point and represents the minimal dose to the external
iliac lymph nodes.
Various techniques have been developed to improve the
eﬀectiveness of radiotherapy and minimized radiation toxicity to
adjacent organs such as CT simulation, conformal blocking and
intensity-modulated radiation therapy (IMRT). External pelvic
irradiation is often given prior to brachytherapy. There are two
types of brachytherapy, i.e. (1) low dose rate brachytherapy (LDR)
and (2) high dose rate brachytherapy (HDR). In LDR brachytherapy,
intracavitary insertion delivered 50–70 cGy/hour to point A in
stage 1B and 70–75 cGy/hour in stage 2A, 2B and 3. Patients have
to stay 2–3 days in the hospital. One or two treatment sessions
are required. HDR brachytherapy has become more popular and
increasingly used in many Oncology centres. Dose rate is typically
200 to 300 cGy/minute given within <30 minutes. HDR is
administered as outpatient procedures. Studies have shown that
HDR and LDR were equally eﬀective in terms of a relapse-free
survival and overall survival rates. Two to ten insertions are
required.
If para-aortic nodes metastases are suspected, 45–50 Gys is
given to para-aortic areas (extended external beam) plus 5 Gys boost
to any enlarged nodes. The RTOG trial had found that para-aortic
EBRT conferred a survival beneit in patients with bulky stage 1
disease (>4 cm) and stage 2 cervical cancer as compared to standard
pelvic irradiation alone. There is no strong evidence regarding
the role of hyperbaric oxygen, hypoxic sensitizer (Metronidazole,
Misonidazole) and hyperthermia (microwave) in potentiating
radiation therapy.
The radiotherapy is curative for cervical cancer up to stage
4A disease. However, in metastatic disease, radiotherapy provides
symptomatic relief or palliative radiotherapy. Palliative radiotherapy
may be indicated in (a) stage 4B and recurrent carcinoma presented
234 Cancer of Cervix

with pelvic pain and bleeding and (b) single intracavitary insertion
of tandem and colpostats delivering 55 Gy to point A may control
the vaginal bleeding.

Concurrent Chemoradiation in Cervical Cancer

The combination of concomitant chemotherapy and radiation
therapy is currently recognized as standard of care in many cancer
treatments, including for locally advanced cervical cancer.
The rationales of chemoradiation are
(a) to sensitized the tumour cells to radiation (radiopotentiator)
(b) attack the diﬀerent phases of the cell cycles and give synergistic
eﬀect.
(c) decrease tumour re-population
(d) increase tumour cell oxygenation
(e) shortened treatment time
(f) inhibition of repair of sublethal radiation damage
(g) to eradicate microscopic systemic disease and micrometastasis
The introduction of chemoradiotherapy into routine clinical
practice for locally advanced cervical cancer is one of the
signiicant medical discoveries in history of cancer treatment. In
US, National Cancer Institute had irst issued the support of using
chemoradiation in cervical cancer in 1999.
The current recommendation of chemoradiation as the
standard treatment for cervical cancer is based on the results of ive
landmark phase III randomized controlled trials listed below (see
Table 8.9 for the summaries):
(1) Gynae Oncology Group (GOG) Protocol 85
(2) Gynae Oncology Group Protocol 120
(3) Gynae Oncology Group Protocol 123
(4) Southwest Oncology Group (SWOG): 1 study with GOG and
RTOG (SWOG Protocol 8797)
(5) Radiation Therapy Oncology Group (RTOG): RTOG 90-01
An updated of RTOG Protocol 90-01 trial (refer to the original
trial in Table 8.9) had reported that an addition of chemotherapy
to radiation therapy improved disease-free survival from 46% to
74% and ive-year survivals from 55% to 79% for stage 1B-2A.
Concurrent Chemoradiation in Cervical Cancer 235

Chemoradiation also improved disease-free survival from 37%

to 54% and 5-year survival rates from 45% to 59% in stage 3/4A
disease. After median follow time of 6.6 years, the overall survival
rate for patients treated with chemoradiation was signiicantly
greater than radiotherapy alone (67% vs. 41%, p < 0.0001). The
overall reduction in the risk of recurrence was 51%. Disease-free
survival (DFS) and overall survival (OS) in patients with stage
1B–2B treated with chemoradiation was signiicantly longer.
In stages 3 and 4A, chemoradiation improves PFS but not OS
(p = 0.07). The rate of serious late complications was similar
(Eifel et al., 2004).

Table 8.9 Summary of ive phase III randomized controlled trials on

chemoradiation versus radiotherapy for cervical cancer

Trial Summary
GOG 85 Subjects: Stage 2B-4A (n = 368), all para-aortic
(Whitney CW, et al. nodes negative
GOG study. J Clin Study: Irradiation + cisplatin (50 mg/m2)/5-FU
Oncol 1999; 17: (1g/m2/d vs. Hydoxyurea (80 mg/kg twice weekly)
1339) + irradiation.
Results: Cisplatin/5FU more superior in
progression free interval and survival (p < 0.05)
GOG 120 Subjects: Stage 2B, 3 and 4A (n = 526), all para-
(Rose PG, Bundy BN, aortic nodes -ve.
et al. N Engl J Med Study: Irradiation + weekly cisplatin (40 mg/m2
1999; 340: 1144) weekly for 6 weeks (during ext radiation) vs.
irradiation + hydroxyurea vs. irradiation + cisplatin/
5FU/hydroxyurea vs. irradiation + hydroxyurea.
Results: Cisplatinum-based regimen more superior
in survival and progression free survival with single
agent cisplatin has almost similar result with com-
bined regimes (45% vs. 43% reduction in risk of
progression). Because of an improved therapeutic
ratio, weekly cisplatin is the favoured regimen.
GOG 123 Subjects: Stage 1B to 2A (n = 369), all had surgical
(Keys HM, Bundy BN, assessment of para-aortic nodes
et al. N Engl J Med Study: Irradiation + extrafascial hysterectomy
1999; 340: 1154) vs. cisplatin single agent weekly + irradiation +
extrafascial hysterectomy. (GOG 71 study showed
no beneit of added hysterectomy)
(Continued)
236 Cancer of Cervix

Table 8.9 (Continued)

Trial Summary
Results: Concurrent chemoradiation shows more
superior in reduction of progression (49%) and
survival (46% reduction of death, and 3-year sur-
vival 83% vs. 74%). Chemoradiation is treatment of
choice in stage 1B and 2A.
RTOG Protocol Subjects: Stage 1B to 4A (n = 389)
90-01 (Morris M, Study: Irradiation + cisplatin/5-FU vs. RT alone. Not
et al. N Engl J Med all had surgical staging for para-aortic nodes.
1999; 340: 1137)
Results: Chemoradiation is more superior in reduc-
tion of disease progression, survival, locoregional
and distant relapses. (52% reduction in risk of pro-
gression, 41% reduction in risk of death and 5-year
survival rate from 73% (stage 1B-2A), all statisti-
cally signiicant)
SWOG Protocol Subject: Stage 1A2, 1B and 2A (n = 243), subjects
8797 (SWOG + GOG had pelvic/para-aortic LN +, positive parametrial
+ RTOG) (Peter WA, involvement, positive surgical margin after radical
Liu PY, et al. Gynecol hysterectomy. Negative common iliac and/or para-
Oncol 1999; 72: 443) aortic nodes were also included.
Study: Irradiation + cisplatin (70 mg/m2)/5-FU vs.
irradiation alone. Results: Chemoradiation is more
superior in progression free survival and survival
(51% reduction in risk of death), 3-year survival
rate was 87% vs. 77%.

The Royal College of Radiologists (RCR) in the United Kingdom

had recently published retrospective audit of cervical cancer
patients during chemoradiation era involving 1075 patients
from 42 centres in the United Kingdom. The audit showed that
chemoradiation increases overall 5-year survival rates by 11%
(44% vs. 55%) as compared to radiation alone (Vale, 2008).
The Gynecologic Oncology Group 165 trial (randomized trial)
by Lanciano et al. comparing single agent cisplatin versus single
agent 5-FU infusion in combination with radiation for advanced
cervical cancer had shown that single agent cisplatin was a better
combination. Rose PG et al. also obtained a similar result in extended
follow-up GOG 120 trial comparing single agent cisplatin, cisplatin-
Concurrent Chemoradiation in Cervical Cancer 237

5-hydroxyurea and radiotherapy in advanced cervical cancer.

Nugent et al. did an analysis of the cisplatin dosing in a
chemoradiation regimen and they found that patients who received
less than six cycles of cisplatin had a worse progression free
survival and overall survival.
The most popular and acceptable chemotherapy regimen in
chemoradiation protocol is a cisplatin-based regimen. Single agent
weekly cisplatin is the most commonly practiced followed by a
combination of cisplatin with 5-FU. However, Kim and colleagues
have found that combination cisplatin-5-FU was associated with
higher rate of grades 3 and 4 haematologic toxicity (26% vs. 43%)
with no survival advantage as compared to single agent cisplatin.
The role of other agents in combination with cisplatin was also
being evaluated such as topotecan (Long et al., 2005) and
gemcitabine (Gonzalez et al., 2005); the results were encouraging.
There are more than 20 randomized control trials on concurrent
chemoradiation versus radiation alone for cervical cancer involving
nearly 5000 patients, the trials have shown that chemoradiation
improve progression-free survival, reduction in local recurrence
and overall survival (Green et al., 2005; Vale, 2008).
Despite encouraging results from chemoradiation trials, there
are at least three main concerns related to this treatment: (a) toxicity
(60% risk of premature ovarian failure, higher haematological
and gastrointestinal toxicity); (b) approximately, 20% of patients
still develop pelvic failure and recurrence despite therapy; and
(c) chemotherapy in chemoradiation protocol may not be suficient
to tackle distance diseases.
The long-term analysis of the clinical outcome of surgery
following primary chemoradiation (cisplatin-5FU given every 4
weeks in three cycles during EBRT) was analyzed by Ferrandina et al.
Out of 174 patients who underwent radical hysterectomy following
chemoradiation for locally advanced cervical cancer, 71.3% showed
a complete pathological response. After a median follow-up of 68
months, 5-year disease-free survival (DFS) was 75.5% and 5-year
overall survival (OS) was 77.4%. Patients with no residual disease
showed a signiicant longer DFS than a patient with microscopic and
macroscopic residual tumour after treatment. Residual tumour and
stage of disease were the most relevant prognostic factors for DFS
and OS. The potential advantages of surgery after chemoradiation
238 Cancer of Cervix

are removal of potential chemo and radioresistant clone and

obtaining important prognostic information via histopathogical
examination. However, the potential disadvantages of this approach
are the side eﬀects (13–20% risk of grade 3/4 complications),
operative dificulties and impairment quality of life. Colombo PE et
al. Compared total laparoscopic radical hysterectomy (TLRH) with
abdominal radical hysterectomy (ARH) following chemoradiation
for patients with bulky stage 1B, 2A and 2B; TLRH was associated
with shorter hospital stay, less blood loss and lower morbidity
rate (including urinary complications) without compromising the
oncological outcome (PFS and OS were similar). The role of surgery
following chemoradiation warrant further evaluation by phase III
randomized control trial.

Chemotherapy in Cervical Cancer

Chemotherapy has becoming more important in the treatment of
cervical cancer especially in the chemoradiation setting. Before
1983, cervical cancer was thought to be a chemoresistant tumour.
There are ive areas where chemotherapy play an important role in
the management of cervical cancer: (a) management of recurrent
and metastatic disease not amenable to be controlled with surgical
or radiation therapy, (b) concurrent use of chemotherapy with
radiation therapy (refer to an earlier section), (c) neoadjuvant
chemotherapy for locally advanced cervical cancer (mainly in bulky
stage 1B and 2A disease), (d) other forms of combination therapy
with surgery, radiotherapy and targeted therapy (mainly in locally
advanced disease) and (e) palliative chemotherapy.
Despite the above roles in cervical cancer, chemotherapy still
has a considerable limitations because of the following reasons:
(a) good response to surgical and radiation therapy, (b) the
patient with recurrence disease had been irradiated and delivery
of chemotherapeutic drug to the tumour will be impaired due
to radiation-induced ibrosis and poor vascularization, (c) prior
irradiation also causes a tumour resistant to chemo drug, (d)
prior irradiation also causes limited bone marrow reserve and
(e) recurrent or advanced tumour often causes obstructive
nephropathy.
Chemotherapy for Metastatic and Recurrent Cervical Cancer 239

Chemotherapy for Metastatic and Recurrent

Cervical Cancer
Chemotherapy is one of the options for patients with metastatic
cervical cancer and perhaps most common treatment oﬀered to this
patient. The intention of treatment in metastatic cervical cancer
is palliation. Patients with metastatic disease may not require any
form of treatment if they are asymptomatic or if their general
health is so poor to withstand any form of therapy. In the later
group of patients, supportive treatment is the only option available
for them. Generally, platinum-based chemotherapy is the standard
regimen for patients with metastatic disease.
At least three GOG phase III randomized controlled trials (see
Table 8.10) evaluated the most eﬀective chemotherapy regimens
in metastatic and recurrent cervical cancer. The control arm was
single agent cisplatin 50 mg/m2. As shown in Table 8.10, the study
arms were cisplatin-based combined regimens (doublet). The
second cytotoxic agent included in the doublet was ifosfamide,
paclitaxel or topotecan.

Table 8.10 Phase III trials on chemotherapy in recurrent and metastatic

cervical cancer

GOG trials GOG 110a GOG 169b GOG 179c

Chemotherapy Cisplatin vs. Cisplatin vs. Cisplatin vs.
cisplatin + cisplatin + cisplatin +
ifosfamide paclitaxel topotecan
Response Rate (%) 19% vs. 31% 19% vs. 36% 13% vs. 27%d
PFS (months) 3.2% vs. 4.6% 2.8% vs. 4.8% 2.9% vs. 4.6%d
OS (months) 8 vs. 8.3 8.8 vs. 9.7 6.5 vs. 9.4d
Note: Cisplatin regimen in all trials was 50 mg/m2 every 3 weeks.
GOG, Gynaecology Oncology Group; PFS, progression-free survival, OS, overall survival.
aOmura GA, et al. J Clin Oncol 1997; 15: 165–171.
bMoore DH, et al. J Clin Oncol 2004; 22: 3113–3119.
cLong III HJ, Bundy N, Grendys Jr EC, et al. J Clin Oncol 2005; 23: 4626–4633.
dStatistically signiicant diﬀerence.

All GOG trials listed in Table 8.10 showed that cisplatin doublet
produced higher rates of response and progression-free survival
than cisplatin monotherapy but all except topotecan did not
240 Cancer of Cervix

reach statistical signiicant. Please note that in GOG 179, overall

survival in cisplatin monotherapy was lower than in other GOG
trials. The lower rate of OS in the control arm in the GOG 179 trial
led to a statistically signiicant survival beneit in the study arm.
Furthermore, in GOG 179, there were more patients received prior
chemoradiation as their primary treatment as compared to other
GOG trials (two-fold increase, nearly 60% received prior cisplatin-
based chemoradiation). Although FDA has given an approval for
the use of topotecan following the outcome of this study, the
superiority of topotecan is still questionable and GOG had initiated
the subsequent trial known as GOG 204, which had been completed
and presented (see Table 8.11). Toxicity was more in a doublet
regimen as compared to cisplatin monotherapy. However, despite
increased toxicity, combination of cisplatin/paclitaxel and cisplatin/
topotecan arms did not signiicantly reduce the patient-reported
quality of life (Monk et al., 2005; McQuellon et al., 2006). Although
a higher dose of cisplatin (75 mg/m2 and 100 mg/m2) was
associated with slightly better objective response rate compared
to lower dose of 50 mg/m2, there was no associated improvement
in the complete response rate, progression-free survival and
overall survival. Higher dose cisplatin was associated with greater
nephrotoxicity and myelosupresssion (Bonomi et al., 1985).

Table 8.11 GOG protocol 204 trial (GOG 204: A randomized phase III
trial of four cisplatin containing doublet combination in stage
4B, recurrent, or persistent cervical carcinoma: A GOG studya)

Arm 1 Paclitaxel (135 mg/m2 over 24 hours on day 1 + cisplatin 50 mg/m2

on day 2) every 3 weeks
Arm 2 Vinorelbine (30 mg/m2 on days 1 and 8) + cisplatin 50 mg/m2 on
day 2) every 3 weeks
Arm 3 Gemcitabine (1000 mg/m2 on days 1 and 8) + cisplatin 50 mg/m2
on day 2) every 3 weeks
Arm 4 Topotecan (0.75 mg/m2 on day 1, 2 and 3) + cisplatin 50 mg/m2 on
day 2) every 3 weeks
Note: Eligibility criteria included ECOG performance status of 0 or 1, acceptable end
organ function and measurable disease.
GOG, Gynecologic Oncology Group.
aWenzel LB, Huang H, Cella D, et al. J Clin Oncol 2008; 26 (May 20 suppl: abstr

LBA5504).
Chemotherapy for Metastatic and Recurrent Cervical Cancer 241

At present, there is no strong evidence to show that carboplatin

is equally effective as cisplatin. Cisplatin remains the drug of choice
for advanced squamous cell carcinoma of the cervix.
The other interesting cytotoxic agents evaluated in advanced
cervical cancer are vinorelbine and gemcitabine. Both of these drugs
have been evaluated in phase II trial, and their response rate was
encouraging ranging from 30–95%. As a follow-up of the above
studies (Table 8.10), GOG has initiated a phase III randomized control
trial (GOG protocol 204) since 2003 evaluating four cisplatin-based
doublets, i.e. cisplatin/paclitaxel, cisplatin/topotecan, cisplatin/
vinorelbine and cisplatin/gemcitabine in stage 4B, recurrent or
persistent carcinoma of the cervix. Summary of the regimens is
shown in Table 8.11.
The results of GOG 204 trial were presented in annual American
Society of Clinical Oncology (ASCO) meeting 2008. There were 513
patients recruited and following are the results:
(a) No difference in tumour response rate across all four arms
(response rate between 23.4–29.1%)
(b) No signiicant difference in progression-free survival
and overall survival across the four arms, although non-
statistically signiicant beneit to cisplatin/paclitaxel arm on
median survival (12.9 months vs. 10–10.3 months in others)
and hazard ratios for death.
(c) Quality of life (QOL) assessment shows no signiicant
difference in QOL observed between all four arms, although
QOL demonstrated a non-statistically signiicant trend towards
improvement of the outcome with cisplatin/paclitaxel as
compared to others.
(d) Toxicities did not vary signiicantly across the four arms.
(e) The authors concluded that cisplatin/paclitaxel should
remain the doublet of choice in the treatment of advanced or
recurrent cervical cancer.
Overall, treatment for advanced and recurrent cervical cancer
remains unsatisfactory with median progression-free survival less
than 6 months and median overall survival ranging from 10–12
months. Given these circumstances, all systemic chemotherapy
options for treatment of advanced or recurrent cervical cancer
should be viewed as palliative.
242 Cancer of Cervix

To role of targeted therapy or biologic agent such as bevacizu-

mab in combination with chemotherapy has been evaluated. Among
targeted therapies that have been evaluated are Geitinib (phase II
trial by Goncalves et al.), Cetuximab (ongoing study, combination
of cisplatin-cetuximab in persistent and recurrent carcinoma of the
cervix), erlotinib, trastuzumab, sunitinib and bevacizumab (com-
bination of bevacizumab with 5-FU or capecitabine, response rate
34% (Wright et al., 2006).

Neoadjuvant Chemotherapy in Cervical Cancer

Neoadjuvant chemotherapy is chemotherapy given prior to
primary surgical treatment with the intention to reduce the bulk of
tumour, facilitate surgical resection and improving the oncological
outcomes (disease-free survival and overall survival). With a
smaller tumour, surgery can also be less radical and result in lower
rate of treatment-related morbidity. The concept of neoadjuvant
chemotherapy in cervical cancer was irst published in Journal
of Gynecologic Oncology in 1983 by Friedlander et al. In cervical
cancer, neoadjuvant chemotherapy can also be administered
prior to radiotherapy. Neoadjuvant chemotherapy given before
radiotherapy may reduce the tumour size and controls micro-
metastases. This approach may also reduce radiation toxicity
(compared to concurrent chemoradiation), improve the eﬀectiveness
of radiotherapy by reducing distortion and decreasing hypoxic cells
fraction.
The rationales of giving chemotherapy prior to primary surgery
are as follows:
(a) to reduce the bulk and downstaging the tumour
(b) to increase operability (surgery may also remove the
radioresistant cell clone)
(c) smaller tumour and downstaging may also reduce surgical
radicality
(d) less radical surgery may reduce operative morbidity
(e) less radical surgery is also referred to fertility-preserving
surgery
(f) theoretically, chemotherapy given prior to surgery may
decrease intra-operative dissemination of tumour cells
Neoadjuvant Chemotherapy in Cervical Cancer 243

(g) eradication of subclinical metastases

(h) reduction in adjuvant radiotherapy rate
In evaluating the role of neoadjuvant chemotherapy in cervical
cancer, there are at least four areas of interest:
(1) neoadjuvant chemotherapy followed by radiotherapy versus
radical radiotherapy
(2) neoadjuvant chemotherapy followed by radical surgery versus
radical radiotherapy
(3) neoadjuvant chemotherapy followed by radical surgery versus
radical surgery
(4) neoadjuvant chemotherapy followed by radical surgery versus
concurrent chemoradiation.
The role of neoadjuvant chemotherapy prior to radiotherapy
was evaluated in systematic review and meta-analysis by Tierney
et al. involving 21 trials mostly stage 2–3 disease. After correcting
the signiicant heterogeneity in this analysis, the authors have
discovered that 5-year survival rates were aﬀected by the frequency
and dose intensity of cisplatin. Patients with longer chemotherapy
interval of more than 14 days and cisplatin dose intensity of less
than 25 mg/m2 had lower 5-year survival by 8% and 11%,
respectively. There were some survival beneits if the chemotherapy
interval was ≤14 days and cisplatin dose ≥25 mg/m2.
The Italian multicentre randomized study compared
neoadjuvant chemotherapy followed by radical surgery versus
primary radiotherapy in patients with stage 1B2-3 cervical cancer.
Fourteen centres were involved with almost 300 participants.
Chemotherapy was cisplatin-based with second agent bleomycin
(majority), vinristine or ifosfamide. Nine percent received cisplatin
monotherapy. This study had shown that the operability rate
following neoadjuvant chemotherapy was 85.5% for stage 1B2–2B
and 55% for stage 3 disease. There was no diﬀerence in toxicity
while the survival beneits were only observed in patients with
stage 1B2–2B receiving neoadjuvant chemotherapy; not in more
advanced stage (Benedetti-Panici et al., 2002).
Chen and colleagues had evaluated the role of neoadjuvant
chemotherapy followed by radical surgery versus radical surgery
in locally advanced cervical cancer stage 1B2–2B. In this randomized
trial, they found that patients in the neoadjuvant chemotherapy
group had lower lymph node metastases (14.4% vs. 45.5%) and
244 Cancer of Cervix

parametrial iniltration rate than in the primary surgery group. A

similar result was obtained in a study done by Cai et al. neoadjuvant
chemotherapy was given to stage 1B cervical cancer; fewer lymph
nodes metastases were noted in the neoadjuvant group. In addition,
there was also an improvement in survival and disease-free
survival in patients treated with neoadjuvant chemotherapy.
Sardi and colleagues did a long-term follow-up (7 years) of
the irst randomized trial on neoadjuvant chemotherapy in stage
1B squamous cell carcinoma of the cervix. They have found that
neoadjuvant chemotherapy can reduce a pelvic failure rate and
improve survival in bulky stage 1B (>4 cm) disease. Several other
studies, however, did not show same survival advantages in the
neoadjuvant chemotherapy arm (Napolitano et al., 2003; Eddy
et al., 2007) instead neoadjuvant chemotherapy may be detrimental
in some patients (Katsumata et al., 2006).
Several studies have shown that squamous cell carcinoma
responds better to chemotherapy than adenocarcinoma. Namkoong
et al. reported that response to neoadjuvant chemotherapy was
more favourable in squamous cell carcinoma (87%) than in
adenocarcinomas (38%). These indings were similar to study
done by Chen et al. (76.7% vs. 33.3%, p value 0.005).
Patients with large volume of tumour (>5 cm diameter) have
poorer response rate to neoadjuvant chemotherapy. Patients with
large residual tumours after neoadjuvant chemotherapy often
respond poorly to subsequent treatment and had poorer survival.
Studies comparing neoadjuvant chemotherapy followed by
surgery versus primary chemoradiation by EORTC (European
Organization for Research and Treatment of Cancer) and Tata
Memorial Hospital are still under way. Both studies are comparing
neoadjuvant chemotherapy versus chemoradiation in stage 1B2,
2A2 and 2B cervical cancer (EORTC 55994). In this study (EORTC
55994), the main eligibility criteria are (a) squamous cell carcinoma,
adenosquamous or adenocarcinoma, (b) FIGO stage 1B2, 2A2 or
2B, (c) WHO performance status 0–2, (d) Age 18–75 and (e) No
prior irradiation or chemotherapy. The neoadjuvant arm received
cisplatin-based chemotherapy with minimum cumulative cisplatin
dose of 225 mg/m2 and 25 mg/m2 per week. The chemoradiation
arm receives cisplatin 40 mg/m2, maximum 80 mg and six
administrations concurrently with EBRT (45–50 Gy) in fractions
Treatment for Non-Squamous Cell Carcinoma of Cervix 245

of 1.8 Gy to 2 Gy plus external boost or brachytherapy. The

primary endpoint is overall survival and secondary endpoints are
progression free survival, toxicity and quality of life.
The problems and dificulties in incorporating neoadjuvant
chemotherapy into the treatment protocol still exist and require
further evaluation. Among the dificulties and dilemmas related
to this practice are the following:
(1) choice of the best chemotherapeutic agents and regimen
(2) time factors, i.e. (a) duration and interval of treatment (b)
potential delaying primary treatment
(3) toxicity
(4) problem with tissue plane and dissection during radical
hysterectomy due to chemotherapy-induced ibrosis and
calciication
(5) treatment dilemma in a patient with chemoresistance
(6) chemotherapy agents could have cross-resistance with
radiotherapy, including the development of radio-resistant
cellular clones
(7) alteration of pathologic parameters by chemotherapy
(smaller node making the metastatic deposits hard to detect
by pathologist, which is called “concealing effect”)
(8) “concealing effect” may also lead to the underestimation of
the risk of recurrence and undertreatment
(9) cost-effectiveness and psycho-social problems
Neoadjuvant chemotherapy in cervical cancer is still considered
as investigational because (a) the number of studies and samples are
still inadequate, (b) heterogeneity in the study design, chemothera-
py regimens, tumour stage, and others, (c) chemotherapy regimen
used in many trials are considered outdated and (d) radiotherapy
in many published studies was radiotherapy alone and not chemo-
radiation. Chemoradiation is currently the standard treatment for
cervical cancer and should be considered in a control arm.

Treatment for Non-Squamous Cell Carcinoma of

Cervix
Almost 80% of cervical carcinoma is squamous cell carcinoma (SCC).
Approximately, 10–20% of patients with advanced and recurrent
246 Cancer of Cervix

cervical cancer are a non-SCC type. There are limited phase III trials
of chemotherapy in non-SCC cervical cancer.
In recurrent adenocarcinoma of the cervix, various chemotherapy
regimens have been evaluated in phase II trial either as a single
agent or combination therapy. Single agent paclitaxel administered
over 24-hour infusion was associated with 31% overall response
rate (Curtin et al., 2001). In platinum-naïve patients, combination
of cisplatin and taxanes are probably the most reasonable option
for patients with recurrent adenocarcinoma of the cervix.
Neuroendocrine tumours of the cervix are uncommon and
account for only 1–2% of all cervical cancers. They can be classiied
as typical carcinoid, atypical carcinoid, small-cell carcinoma and
large-cell neuroendocrine carcinoma. Most of the reported cases
are small-cell carcinomas. Small cell carcinoma, which exhibits no
squamous diﬀerentiation, should not be confused with small cell
non-keratinizing squamous cell carcinomas. The later belong to
squamous cell carcinoma histotypes.
The diagnosis of small cell neuroendocrine tumour is based
on histology and immunostaining. Up to 80% of haematoxylin
and eosin-positive small cell neuroendocrine carcinomas are also
staining positive to neuroendocrine markers such as synaptophysin,
chromogranin and CD56. Neuroendocrine markers can be negative in
20–70% of cases. Patients with small cell neuroendocrine carcinoma
of the cervix often do badly and have a very poor prognosis. It is
characterized by frequent and early nodal and distant metastases.
About 50% of the patients died of the disease, typically within 2–3
years of diagnosis. In a case series by Viswanathan et al., overall
survival rates were 43% and 29% at 2 and 5 years, respectively, and
none of the women who had the disease more extensive than stage
1B1 survived more than 30 months. Five -year survival rates for
patients with stage 1 disease are 33%. Factors that correlate with
a poorer outcome are stage, size of tumour, presence of lymph node
metastases and chromogranin positive. The primary treatment for
stage 1 and 2A disease is radical hysterectomy, and most patients
will require adjuvant treatment such as concurrent chemoradiation,
radiation therapy or chemotherapy. There is no standard adjuvant
treatment for small cell neuroendocrine tumour of the cervix.
Chemotherapy regimen for these patients is cisplatin and etoposide
with or without doxorubicin. The other chemotherapy regimen
found to be eﬀective against small cell neuroendocrine tumours is
vincristine/doxorubicin/cyclophosphamide.
Recurrent Carcinoma of Cervix 247

Patients with advanced or recurrent glassy-cell carcinoma

of the cervix can be treated with a paclitaxel and carboplatin
combination; however, data are very limited.

Recurrent Carcinoma of Cervix

The prognosis for early-stage cervical cancer is very good but
in advanced stage disease, most of the patients will experience
recurrence. Patients with recurrent cervical cancer often have
poor survival rate and 80% of recurrence is detected within 2
years of primary treatment. The 5-year survival for patients with
recurrent cervical cancer is less than 5%. Clinical diagnosis of pelvic
recurrence can nearly always be made by triad: (a) sciatic pain,
(b) leg oedema and (c) hydronephrosis. The patterns of failure in
carcinoma of cervix according to stages are shown in Table 8.12.

Table 8.12 Pattern of failure in carcinoma of cervix according to stages

Stage of cervical cancer at presentation

(FIGO 1994)
Type of recurrence 1A 1B 2A 2B 3 4A
Pelvic failure rate (%) 10 17 23 42 74
Incidence of distance 3 16 31 26 40 75
metastases (%)

In order to detect recurrence at an early stage, close monitoring

after treatment is extremely important. Diﬀerent oncology centres
have diﬀerent follow-up routines. Following is one of the examples
of follow-up schedules for patients who have completed their
treatment:
3 monthly for irst year
4 monthly for second year
6 monthly from third to ifth year
yearly from sixth year onward
Although routine follow-up is important in detection of
recurrent cancer, many studies have shown that detection at follow-
up did not provide any survival beneit, this may relate to the
limited therapeutic options available (Duyn et al., 2002; Gerdin
et al., 1994). However, in a subset of patients where the option is
248 Cancer of Cervix

available, early detection, and treatment may improve their survival.

Common sites of metastasis according to frequency are lungs,
para-aortic lymph node, abdominal cavity, supraclavicular lymph
node.
Following are the principal steps for the management of
recurrent cervical cancer :
(1) Conirm the diagnosis: recurrence should be conirmed by
histology.
(2) Assess the extent of the disease (imaging technique such as
chest x-ray, CT scan, MRI or PET scan).
(3) Determine the intention of treatment either for a cure or for
palliation.
(4) Assess a patient’s main symptom/s.
(5) Review the previous treatment.
(6) List the treatment options and decide the best one for a
patient.
(7) Start the treatment and monitor the patient.
Patients with recurrent cervical cancer can be divided into two
groups: (1) recurrence after deinitive irradiation and (2) recurrence
after surgical treatment.

Recurrence after Definitive Irradiation

Approximately, 70% of patients with cervical cancer receive
radiation therapy at some point in the past. Up to 40% of them
will develop a recurrent or persistent disease. Generally, the
patient exhibiting complete tumour regression within 30 days
after completion of radiation had a signiicantly lower incidence of
pelvic recurrences and fewer distant metastases. Local recurrence
responds poorly to chemotherapy due to postradiation eﬀects of
the pelvic tissues. Re-irradiation may be possible in highly selected
patients after a long interval of disease-free; however, radiation
toxicity is higher. Generally, re-irradiation is not advisable in patients
who had been irradiated before.
Surgery is the most reasonable option for patients with
local recurrence developed following primary treatment with
radiotherapy. Surgery may involve a highly specialized surgery or
ultra-radical procedure known as pelvic exenteration. Five-year
survival rates after successful pelvic exenteration are more than
Recurrence after Definitive Irradiation 249

30%. Operative morbidity and mortality are the main concerns in

pelvic exenteration.
Pelvic exenteration can be classiied into three main categories
according to Magrina’s classiication system:
(a) supralevator (type I)
(b) infralevator (type II)
(c) infralevator with vulvectomy (type III)
With the improvement of selection criteria (with better detection
method such as PET scan), surgical techniques, better teamwork,
better equipment and postoperative care, operative mortality of
pelvic exenteration has been reduced to 5%. In order to achieve
high cure rate after pelvic exenteration, surgery must achieve
complete microscopic resection. The eligibility criteria for pelvic
exenteration are (a) local recurrence, (b) no extrapelvic metastases,
(c) tumour not iniltrating the pelvic wall and (d) the patient is
it for surgery. Para-aortic lymph node metastasis is an absolute
contraindication for pelvic exenteration.
Recently, in some institutions, lateral pelvic wall iniltration
is no longer an absolute contraindication for pelvic exenteration.
They have implemented the so-called laterally extended endopel-
vic resection procedure (LEER). LEER permitted an excision of
the tumour iniltrating to the muscle of the pelvic wall and obtain-
ing free margin. Hoeckel has recently reported the success rate of
LEER, 5-year disease-speciic survivals were 55% and 97% of pa-
tients who underwent LEER had a clear margin. Recent review by
Jurago and colleagues on resectability rate in patients with pel-
vic side wall recurrence concluded that around one third of the
patients with clinically deined pelvic wall involvement can still
undergo a complete macroscopic resection with negative margins.
They also have reasonable chance of a long-term disease-speciic
survival rate of 33.3% at 10 years.
In pelvic exenteration, the patient may have to undergo urinary
diversion procedure (anterior or total exenteration) or colostomy
(posterior or total exenteration). An alternative to anorectal
resection and permanent colostomy, colorectal re-anastomosis and
temporary ileostomy is acceptable in selected patients. To improve
pelvic vascularization and reduce the risk of istula formation, the
omental lap can be used to ill the pelvic cavity. If omentum is
inadequate, rectus abdominis muscle or even a prosthetic material
is a good alternative. High dose intraoperative radiotherapy
250 Cancer of Cervix

(brachytherapy/implants) has been attempted in some centre to

eradicate a residual disease during pelvic exenteration. The roles
of this technique remain inconclusive and morbidity rate is high.

Recurrence after Previous Surgery

Local recurrence after surgery is increasingly less common due to
early presentation and more eﬀective treatment, including the use
of adjuvant chemoradiation therapy in high-risk patients. Patients
with bulky disease (more than 4 cm), deep tumour invasion, poor
histology type and most important with nodal metastases are at
higher risk of recurrence.
Local pelvic recurrence is best managed by radiotherapy
(External irradiation + Intracavitary insertion/interstitial implants
depend on tumour volume). Reported complete response rate was
88% for loco-regional recurrence and overall survival rate was
33–39%.
Surgical treatment (exenteration) is indicated in a selected
patient if the tumour is resectable and the patient is it for surgery.

Appendix
GOG Score for Patients with Negative Lymph Node and
Clear Surgical Margin Following Radical Hysterectomy and
Pelvic Lymphadenectomy

Relative Risk of Recurrence after Radical Hysterectomy for Stage I

Cervical Cancer
Variable Relative Risk
Depth of tumour penetration (mm)
Supericial
3a 1.0
4 3.0
5 7.2
6 14
7 21
8 26
10 21
Appendix 251

Relative Risk of Recurrence after Radical Hysterectomy for Stage I

Cervical Cancer
Variable Relative Risk
Middle
5 20
6 22
7 23
8 25
10 28
12 32
14 36
Deep
7 28
8 30
10 34
12 37
14 41
16 45
18 49
20 54
Clinical tumour size
Occult tumour 1.0
1 1.6
2 1.9
3 2.4
4 2.9
6 4.4
8 6.6
Capillary/Lymphatic spaceinvolvement
No 1.0
Yes 1.7

Source: Delgado et al., Gynaecol Oncol, 1992; 38: 352.

Note: “GOG Score” is calculated by multiplying the relative risk for the depth ×
tumour size × capillary space involvement.
Example: 8 mm supericial tumour, measuring 2 cm with VSI would be 26 × 1.9
× 1.7 = 84.
GOG Score < 40: Low risk (no need of adjuvant RT).
GOG Score 40–120: Intermediate Risk (Individualized treatment).
GOG Score >120: High risk (require standard ield RT).
aArbitrary reference for depth invasion.
252 Cancer of Cervix

References

Allen D, Narayan K. Managing advanced stage cervical cancer. Best Pract

Res Clin Obstet Gynaecol 2005; 19(4): 591–609.
American Cancer Society. (2007) Global Cancer Facts & Figures 2007.
American Cancer Society, Atlanta, GA.
Behtash N, Nazari Z, Ayatollahi H, et al. Neoadjuvant chemotherapy and
radical surgery compared to radical surgery alone in bulky stage
1B-2A cervical cancer. EJSO 2006; 32: 1226–1230.
Beiner ME, Covens A. Surgery insight: radical vaginal trachelectomy as
a method of fertility preservation for cervical cancer. Nat Clin Pract
Oncol 2007; 4: 353–361.
Benedetti-Panici P, Greggi S, Colombo A, et al. Neoadjuvant chemotherapy
and radical surgery versus exclusive radiotherapy in locally
advanced squamous cell cervical cancer: results from the Italian
multicenter randomised study. J Clin Oncol 2002; 20(1): 179–188.
Bonomi P, Blessing JA, Stehman F, et al. Randomized trial of three
cisplatin dose schedules in squamous cell carcinoma of the cervix: a
Gynecologic Oncology Group study. J Clin Oncol 1985; 3: 1079–1085.
Bosch FZ, Lorinez A, Munoz N, Meijer CJLM, Shah KV. The causal relation
between human papillomavirus and cervical cancer. J Clin Pathol
2002; 55: 244–265.
Bosch FX, Manos MM, Munoz N, et al. The IBSCC study group. Prevalence
of human papillomavirus in cervical cancer: a worldwide perspective.
J Natl Cancer Inst 1995; 87: 796–802.
Burnett AF, Roman LD, Garcia AA, et al. A phase II study of gemcitabine
and cisplatin in patients with advanced, persistent, or recurrent
squamous cell carcinoma of cervix. Gynecol Oncol 2000; 76: 63–66.
Cadron I, Gorp TV, Amant F, et al. Chemotherapy for recurrent cervical
cancer. Gynecol Oncol 2007; 107: S113–S118.
Cai HB, Chen HZ, Yin HH. Randomized study of preoperative chemotherapy
versus primary surgery for stage 1B cervical cancer. J Obstet Gynaecol
Res 2006; 32(3): 315–323.
Castellsague X. Natural history and epidemiology of HPV infection and
cervical cancer. Gynecol Oncol 2008; 110: S4–S7.
Castellsague X, Bosch X, Munoz N, et al. Male circumcision, penile human
papillomavirus infection, and cervical cancer in female partners.
N Engl J Med 2002; 346: 1105–1112.
References 253

Chemotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC).

Reducing uncertainties about the eﬀects of chemoradiotherapy for
cervical cancer: individual patient data meta-analysis. Cochrane
Database Syst Rev 2010(1): CD008285.
Chen H, Liang C, Zhang I, et al. Clinical eficacy of modiied preoperative
neoadjuvant chemotherapy in the treatment of locally advanced
(stage 1B2 to 2B) cervical cancer: a randomized study. Gynecol Oncol
2008, submitted on March 2008.
Chiva LM, Lapuente F, Cortijo LG, et al. Surgical treatment of recurrent
cervical cancer: State of the art and new achievements. Gynecol Oncol
2008; 110: S60–S66.
Cibula D, Velechovska P, Slama J, et al. Late morbidity following nerve-
sparing radical hysterectomy. Gynecol Oncol 2010; 116: 506–511.
Clark JG. A more radical method of performing hysterectomy for cancer of
the uterus. Johns Hopkins Med Bull 1895; 6: 120–124.
Colombo PE, Bertrand MM, Gutowski M, et al. Total laparoscopic radical
hysterectomy for locally advanced cervical carcinoma (stage IIB,
IIA and bulky stages IB) after concurrent chemoradiation therapy:
Surgical morbidity and oncological results. Gynecol Oncol 2009;
114: 404–409.
Covens A, Rosen B, Murphy J, et al. Changes in the demographics and
perioperative care of stage 1a2/1b1 cervical cancer over the past 16
years. Gynecol Oncol 2001; 81: 133–137.
Curtin JP, Blessing JA, Webster KD, et al. Paclitaxel, an active agent in non
squamous carcinoma of the uterine cervix: a Gynecol Oncology
Group study. J Clin Oncol 2001; 19: 1275–1278.
deSouza NM, Soutter WP, Rustin G, et al. Use of neoadjuvant chemotherapy
prior to radical hysterectomy in cervical cancer: monitoring
tumour shrinkage and molecular proile on magnetic resonance and
assessment of 3 years outcome. Br J Cancer 2004; 90: 2326–2331.
Dreyer G, Snyman LC, Mouton A, Lindeque BG. Management of recurrent
cervical cancer. Best Pract Res Clin Obstet Gynaecol 2005; 19(4):
631–644.
Duenas GA, Lopez GC, Gonzalez A, et al. A phase II study of gemcitabine
and cisplatin combination as induction chemotherapy of untreated
locally advanced cervical carcinoma. Ann Oncol 2001; 12: 541–547.
Dursun P, Ayhan A, Kuscu E. Nerve-sparing radical hysterectomy for
cervical carcinoma. Critical Rev Oncol/Hematol 2009; 70: 195–205.
254 Cancer of Cervix

Duyn A, Van Eijkeren M, Kenter G, Zwinderman K, Ansink A. Recurrent

cervical cancer: detection and prognosis. Acta Obstet Gynecol Scan
2002; 81: 351–355.
Eddy GL, Bundy BN, Creasman, et al. Treatment of (bulky) stage 1B cervical
cancer with or without neoadjuvant vincristine and cisplatin prior
to radical hysterectomy and pelvic/paraaortic lymphedenectomy: a
phase III trial of the Gynecologic Oncology Group. Gynecol Oncol 2007;
106(2): 362–369.
Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent
chemotherapy versus pelvic and para-aortic irradiation for high-risk
cervical cancer: An update of Radiation Therapy Oncology Group Trial
(RTOG) 90-01. J Clin Oncol 2004; 22: 872–880.
Ferrandina G, Margariti PA, Smaniotto, et al. Long-term analysis of clinical
outcome and complications in locally advanced cervical cancer pa-
tients administered concomitant chemoradiation followed by radical
surgery. Gynecol Oncol 2010; doi: 10.1016/[Link].2010.08.004.
Fujii S. Original ilm of the Okabayashi’s radical hysterectomy by
Okabayashi himself in 1932, and two ilms of the precise anatomy
necessary for nerve-sparing Okabayashi’s radical hysterectomy
clariied by Shingo Fujii. Int J Gynecol Cancer 2008; 18(2): 383–385.
Gerdin E, Cnattingus S, Jognson P, Pertterson B. Prognostic factors and
relapse factors in early stage cervical cancer after brachytherapy and
radical hysterectomy. Gynecol Oncol 1994; 53: 314–319.
Gien LT, Covens A. Fertility sparing options for early stage cervical cancer.
Gynecol Oncol 2010; 117: 350–357.
Gien LT, Beauchemin MC, Thomas G. Adenocarcinoma: a unique cervical
cancer. Gynecol Oncol 2010; 116: 140–146.
Goncalves A, Fabbro M, Lhomme C, et al. A phase II trial to evaluate
geitinib as second or third line treatment in patients with recurring
locoregionally advanced or metastatic cervical cancer. Gynecol Oncol
2008; 108: 42–46.
Gonzalez AD, Perez LC, Graniel CL, et al. Pathologic response and toxicity
assessment of chemoradiotherapy with cisplatin versus cisplatin
plus gemcitabine in cervical cancer: A randomied Phase II study.
Intl J Radiat Oncol Biol Phys 2005; 61(3): 817–823.
Green J, Kirwan J, Tierney J, Vale C et al. Chemoradiation in cervical cancer.
Cochrane Database Syst Rev 2005 July 20; 3: CD002225.
Hayashi T, Kato T. Usefulness of tumour size on MR imaging in assessing
the prognosis of uterine cervical cancer treated with radiation.
Nippon Igaku Hoshasen Gakkai Zasshi 1999; 59: 250–255.
References 255

Hicks ML, Piver MS, Mas E, et al. Intraoperative orthovoltage radiation

therapy in the treatment of recurrent gynaecologic malignancies.
Am J Clin Oncol 1993; 16: 497–500.
Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of
cervico-vaginal papillomavirus infection in young women. N Engl J
Med 1998; 338(7): 423–428.
Hockel M, Konerding MA, Heussel CP. Liposuction-assisted nerve sparing
extended radical hysterectomy: oncologic rationale, surgical anatomy,
and feasibility study. Am J Obstet Gynecol 1998; 178: 971–976.
Hoeckel M. Laterally extended endopelvic resection. Novel surgical
treatment of locally recurrent cervical carcinoma involving the pelvic
side wall. Gynecol Oncol 2003; 91: 369–377.
Holland CM, Shai MI. Radical hysterectomy. Best Pract Res Clin O&G
2005; 19(3): 387–401.
IARC Monograph on the evaluation of carcinogenic risks to humans.
Human Papillomaviruses, Vol. 90. Lyon: International Agency for
Research on Cancer. In press.
Ijaz T, Eifel PJ, Burke T, Oswald MJ. Radiation therapy of pelvic recurrence
after radical hysterectomy for cervical carcinoma. Gynecol Oncol
1998; 70: 241–246.
Jemal A, et al. Cancer Statistic 2006. CA Cancer J Clin 2006; 56: 1006–1030.
Jurado M, Alcazar JL, Monge RM. Resectability rates of previously irradiated
recurrent cervical cancer treated with pelvic exenteration: Is still
the clinical involvement of the pelvic wall a real contraindication?
A twenty years experience. Gynecol Oncol 2010; 116: 38–43.
Katsumata N, Yoshikawa H, Hirakawa T, et al. Phase III randomized trial of
neoadjuvant chemotherapy followed by radical hysterectomy versus
radical hysterectomy for bulky stage 1–2 cervical cancer (JCOG 0102).
Proc Am Soc Clin Oncol 2006; 24(abstract 5013).
Keys H, Bundy B, Stehman F, et al. A comparison of weekly cisplatin during
radiation therapy versus irradiation alone each followed by adjuvant
hysterectomy in bulky stage IB cervical cancer: a randomized
trial of the Gynecologic Oncology Group. N Engl J Med 1999; 340:
1154–1161.
Kim K, Kim MJ, Chung HH, et al. Inadvertent potential risk of neoadjuvant
chemotherapy in cervical cancer. Med Hypotheses 2009; 73: 1005–1007.
Kim MK, Kim JW, Kim MA, et al. Feasibility of less radical surgery for
supericially invasive carcinoma of cervix. Gynecol Oncol 2010, doi:
10.1016/[Link].2010.06.027.
256 Cancer of Cervix

Kim YS, Shin SS, Nam JH. Prospective randomized comparison of monthly
luorouracil and cisplatin versus weekly cisplatin concurrent with
pelvic radiotherapy and high-dose rate brachytherapy for locally
advanced cervical cancer. Gynecol Oncol 2008; 108: 195–200.
Kyrgiou M, Shai MI. Invasive cancer of the cervix. Obstet, Gynaecol Rep
Med 2010; 20(5): 147–154.
Landoni F, Maneo A, Cormio G, et al. Class II versus Class III Radical
Hysterectomy in Stage 1B-IIA Cervical Cancer: A Prospective
Randomized Study. Gynecologic Oncol 2001; 80(1): 3–12.
Landoni F, Maneo A, Colombo A, et al. Randomized study of radical surgery
versus radiotherapy for stage 1B–2A cervical cancer. Lancet 1997;
350: 535–540.
Lanciano R, Calkins A, Bundy BN, et al. Randomized comparison of weekly
cisplatin or protracted venous infusion of luorouracil in combination
with pelvic radiation in advanced cervix cancer: A Gynecologic
Oncology Group Study. J Clin Oncol 2005; 23: 8289–8294.
Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin
with or without topotecan in carcinoma of the uterine cervix: A
Gynecologic Oncology Group Study. J Clin Oncol 2005; 23: 4626–4633.
Magierlo JS, Narog M, Kruczek A, et al. Radical hysterectomy during the
transition period from traditional to nerve-sparing technique.
Gynecol Oncol 2010; 116: 502–505.
Magrina JF. Types of pelvic exenterations: a reappraisal. Gynecol Oncol
1990; 37: 363–366.
Maneo A, Chiara S, Bonazzi C, Mangioni C. Neoadjuvant chemotherapy and
conservative surgery for stage 1b1 cervical cancer. Gynecol Oncol
2008; 111: 438–443.
Martinez Monge R, Jurado M, Aristu JJ, et al. Intraoperative electron
beam radiotherapy during radical surgery for locally advanced and
recurrent cervical cancer. Gynecol Oncol 2001; 82: 538–543.
Martinez Monge R, Jurado M, Cambeiro M, et al. Perioperative high dose
rate brachytherapy in locally advanced and recurrent gynaecologic
cancer: initial results of a phase II trial. Brachytherapy 2006; 5:
203–210.
McGuire WP, Arseneau JC, Blessing JA, et al. A randomized comparative trial
of carboplatin and iproplatin in advanced squamous carcinoma of
the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol
1989; 7: 1462–1468.
References 257

McQuellon RP, Thaler HT, Cella D, Moore DH. Quality of life (QOL) outcomes
from a randomized trial of cisplatin versus cisplatin plus paclitaxel
in advanced cervical cancer: A Gynecologic Oncology Group study.
Gynecol Oncol 2006; 101: 296–304.
Moore DH. Chemotherapy for recurrent cervical cancer. Curr Opin Oncol
2006; 18: 516–519.
Monk BJ, Huang HQ, Cella D, Long HJ. Quality of life outcomes from a
randomized phase III trial of cisplatin with or without topotecan in
advanced carcinoma of the cervix: a Gynecologic Oncology Group
Study. J Clin Oncol 2005; 23: 4617–4625.
Morris M, Blessing JA, Monk BJ, et al. Phase II study of cisplatin and
vinorelbine in squamous cell carcinoma of the cervix: a Gynecologic
Oncology Group study. J Clin Oncol 2004; 22: 3340–3344.
Meigs JV. Radical hysterectomy with bilateral pelvic lymph node dissections;
a report of 100 patients operated on ive or more years ago.
Am J Obstet Gynecol 1951; 62: 854–870.
Moore DH. Treatment of stage 1B2 (bulky) cervical carcinoma. Cancer
Treat Rev 2003; 29: 401–406.
Moore DH, Blessing JA, McQuellon MP, et al. Phase III study of cisplatin
with or without paclitaxel in stage IVB, recurrent, or persistent
squamous cell carcinoma of the cervix: a gynecologic oncology group
study. J Clin Oncol 2004; 22: 3113–3119.
Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy
versus pelvic and para-aortic radiation for high-risk cervical cancer:
a randomized Radiation Therapy Oncology Group Clinical Trial.
N Engl J Med 1999; 340: 1137–1143.
Munoz N, Castellsague X, De Gonzalez AB, Gissmann L. HPV in the etiology
of human cancer. Vaccine 2006; 24S3: S3/1–S3/10.
Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus
types shall we vaccinate and screen? The international perspective.
Int J Cancer 2004; 111(2): 278–285.
Mutch DG. Meeting Report. The new FIGO staging system for cancers of
the vulva, cervix, endometrium and sarcomas. Gynecol Oncol 2009;
115: 325–328.
National Cancer Institute. Chemotherapy plus radiation improves survival
(press release). Bethesda, MD: National Cancer Institute; 1999.
Namkoong SE, Park JS, Kim JW, et al. Comparative study of patients with
locally advanced stage 1b and 2 cervical cancer treatment by radical
258 Cancer of Cervix

surgery with and withut preoperative adjuvant chemotherapy.

Gynecol Oncol 1995; 59: 136–142.
Napolitano U, Imperato F, Mossa B, et al. The role of neoadjuvant
chemotherapy for squamous cell cervical cancer (1b–3b): a long term
randomized trial. Eur J Gynaecol Oncol 2003; 24(1): 51–59.
Nugent EK, Case AS, Hoﬀ JT, et al. Chemoradiation in locally advanced
cervical carcinoma: An analysis of cisplatin dosing and other clinical
prognostic factors. Gynecol Oncol 2010; 116(3): 438–441.
Okabayashi H. Radical abdominal hysterectomy for cancer of the cervix
uteri. Surg Gynecol Obstet 1921; 33: 335–341.
Olawaiye A, Carmen MD, Tambouret R, et al. Abdominal radical trachelectomy:
success and pitfalls in a general gynaecologic oncology practice.
Gynecol Oncol 2009; 112: 506–510.
Omura GA, Blessing JA, Vacarello L, et al. Randomized trial of cisplatin
versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in
advanced squamous carcinoma of the cervix: a Gynecologic Oncology
Group study. J Clin Oncol 1997; 15: 165–171.
Peters WA, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic
radiation therapy compared with pelvic radiation therapy alone as
adjuvant therapy after radical surgery in high-risk early-stage cancer
of the cervix. J Clin Oncol 2000; 18: 1606–1613.
Pettersson F: Annual Report on the Results of Treatment in Gynecologic
Cancer, Vol 21. Statements on the results obtained in patients
1982–1986, inclusive 3 and 5 year survival up to 1990. Int J Gynecol
Obstet 1991; (Supp): 27–127.
Pieterse QD, Trimbos JBMZ, Dijkman A, et al. Postoperative radiation
therapy improves prognosis in patients with adverse risk factors in
localized, early stage cervical cancer: a retrospective comparative
study. Intl J Gynecol Cancer 2006; 16(3): 1112–1118.
Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy
for women with cervical cancer. Obstet Gynecol 1974; 44: 265–272.
Plante M. Vagina radical trachelectomy: an update. Gynecol Oncol 2008;
111: S105–S110.
Possover M, Queakernack J, Chiantera V. The LANN technique to reduce
postoperative functional morbidity in laparoscopic radical pelvic
surgery. J Am Coll Surg 2005; 201: 913–917.
Querleu D, Narducci F, Poulard V, et al. Modiied radical vaginal
hysterectomy with or without laparoscopic nerve-sparing dissection:
a comparative study. Gynecol Oncol 2002; 85: 154–158.
References 259

Querleu D, Morrow CP. Classiication of radical hysterectomy. Lancet

Oncol 2008; 9: 297–303.
Ramirez PT, Schmeler KM, Malpica A, Soliman PT. Safety and feasibility of
robotic radical trachelectomy in patients with early stage cervical
cancer. Gynecol Oncol 2010; 116: 512–515.
Ramirez PT, Schmeler KM, Soliman PT, Frumovitz M. Fertility preservation
in patients with early cervical cancer: Radical trachelectomy.
Gynecol Oncol 2008; 110: S25–S28.
Raspagliesi F, Ditto A, Fontanelli R, et al. Type II versus type III nerve-sparing
radical hysterectomy: Comparison of lower urinary tract dysfunction.
Gycecol Oncol 2006; 102: 256–262.
Raspagliesi F, Ditto A, Hanozet F, et al. Nerve-sparing radical hysterectomy
in cervical cancer: Evolution of concepts. Gynecol Oncol 2007;
107: S119–S121.
Rogers L, Siu SSN, Luesley D, Bryant A, Dickinson HO. Adjuvant radiotherapy
and chemoradiation after surgery for cervical cancer (Review).
The Cochrane Collaboration and published in The Cochrane Library
2009; 7(4): CD007583. doi: 10.1002/14651858.CD007583.pub2.
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based
chemoradiation improves progression free and overall survival
in advanced cervical cancer: results of a randomized Gynecologic
Oncology Group study. N Engl J Med 1999; 340: 1144–1153.
Rose PG, Ali S, Watkins E, et al. Long-term follow up of a randomized
trial comparing concurrent single agent cisplatin, cisplatin-based
combination chemotherapy, or hydroxyurea during pelvic irradiation
for locally advanced cervical cancer. A Gynecologic Oncology Group
Study. J Clin Oncol 2007; 25: 2804–2810.
Rotman M, Sedlis A, Piedmonte MR, et al. A phase III randomized trial
of postoperative pelvic irradiation in stage 1B cervical carcinoma
with poor prognostic features: follow up of a gynaecologic oncology
group study. Intl J Radiat Oncol Biol Phys 2006; 65(1): 169–176.
Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early
stage cervical cancer. Am J Obstet Gynecol 1998; 179: 1491–1496.
Sardi JE, Giaroli A, Sananes C, et al. Long-term follow-up of the irst
randomized trial using neoadjuvant chemotherapy in stage 1b
squamous cell carcinoma of the cervix: the inal results. Gynecol Oncol
1997; 67(1): 61–69.
Schiller JT, Day PM, Kines RC. Current understanding of the mechanism
of HPV infection. Gynecol Oncol 2010; 118: S12–S17.
260 Cancer of Cervix

Sedlis A, Bundy BN, Rotman MZ, et al. Randomized trial of pelvic radiation
therapy versus no further therapy in selected patients with stage
1B carcinoma of the cervix after radical hysterectomy and pelvic
lymphadenectomy: a gynaecologic oncology group study. Gynecol
Oncol 1999; 73: 177–183.
Simcock B, Shai M. Invasive cancer of the cervix. Obstet, Gynaecol Reprod
Med 2007; 17(6): 181–187.
Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution
in invasive cervical cancer and high-grade cervical lesions: a meta-
analysis update. Int J Cancer 2007; 121(3): 621–632.
Steben M, Franco ED. Human papillomavirus infection: Epidemiology and
pathophysiology. Gynecol Oncol 2007; 107: S2–S5.
Sutton GP, Bundy BN, Delgado G, et al. Ovarian metastases in stage 1B
carcinoma of the cervix: a Gynecologic Oncology Group Study. Am J
Obstet Gynecol 1992; 166: 50–53.
Tao X, Hu W, Ramirez T, Kavanagh JJ. Chemotherapy for recurrent and
metastatic cervical cancer. Gynecol Oncol 2008; 110: S67–S71.
Tierney J. Meta-analysis Group (Neoadjuvant Chemotherapy for Cervical
Cancer Meta-analysis (NACCCMA) Collaboration. Neoadjuvant chemo-
therapy for locally advanced cervical cancer: a systematic review and
meta-analysis of individual patient data from 21 randomised trials.
Eur J Cancer 2003; 39: 2470–2486.
Tierney JF, Vale C, Symonds P. Concomitant and neoadjuvant chemotherapy
for cervical cancer. Clin Oncol 2008; 20: 401–416.
Vale CI, Tierney JF, Davidson SE, Drinkwater KJ, Symonds P. Substantial
improvement in UK cervical cancer survival with chemoradiotherapy:
results of a Royal College of Radiologists audit. Clin Oncol (R Coll
Radiol) 2010: 22.
Vale C. Meta-analysis Group: Reducing uncertainties about the eﬀects of
chemoradiationtherapy for cervical cancer: A systematic review and
meta-analysis of individual patient data from 18 randomized trials.
J Clin Oncol 2008; 26: 5802–5812.
Van Howe RS. Human papillomavirus and circumcision: A meta-analysis.
J Infect 2007; 54: 490–496.
Viswanathan AN, Deavers MT, Jhingran A, et al. Small cell neuroendocrine
carcinoma of the cervix: outcome and patterns of recurrence. Gynecol
Oncol 2004; 93: 27–33.
References 261

Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a

necessary cause of invasive cervical cancer worldwide. J Pathol 1999;
189: 12–19.
Wertheim E. The extended abdominal operation for carcinoma uteri. Am J
Obstet 1912; 66: 169–232.
Whitney CW, Sause W, Bundy BN, et al. A randomized comparison of
luorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation
therapy in stages IIB-IVA carcinoma of the cervix with negative para-
aortic lymph nodes. A Gynecologic Oncology Group and Southwest
Oncology Group Study. J Clin Oncol 1999; 17: 1339–1348.
Willet CG, Czito BG, Tyler DS. Intraoperative radiation therapy. J Clin Oncol
2007; 25: 971–977.
Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy
in heavily pretreated, recurrent cervical cancer. Gynecol Oncol 2006;
103: 489–493.
Yabuki Y, Asamoto A, Hoshiba T, Nishimoto H, Satou N. A new proposal for
radical hysterectomy. Gynecol Oncol 1996; 62: 370–378.
Yabuki Y, Asamoto A, Hoshiba T, et al. Radical hysterectomy: an anatomic
evaluation of parametrial dissection. Gynecol Oncol 2000; 77:
155–163.
This page intentionally left blank
Chapter 9

Carcinoma of Endometrium

Gynaecologic Cancer: A Handbook for Students and Practitioners

Anatomy of the Uterus

The uterus is a hollow, thick-walled and muscular organ situated
between the bladder anteriorly and rectum posteriorly. Uterus
is the largest female reproductive organ in the pelvis weighing
about 30–40 grams, 8 cm long, 5 cm wide and 2.5 cm thick. It
serves as a site for the reception, retention and nutrition of the
conceptus. The portion above the isthmus is termed as the body
and that below, the cervix (Fig. 9.1). The cavity of the uterus is
triangular in shape in a coronal section and mere slit, lattened
antero-posteriorly. The total length of uterine cavity from external
os to the fundus is approximately 6.25 cm.

Uterine
body

Isthmus

Cervix

Figure 9.1 Uterine anatomy.

The uterus is composed of three layers: the endometrium,

myometrium and perimetrium. The myometrium is composed
of three layers of smooth muscle ibres. The most outer muscle
layer placed beneath the peritoneum, it consists of ibres which
pass transversely across the fundus, and converging at each
lateral angle of the uterus, continued on to the uterine tube, round
ligament and ovarian ligament. The middle layer of ibres presents
no regularity in its arrangement, being disposed longitudinally,
obliquely and transversely. The middle layer contains more blood
Anatomy of the Uterus 265

vessels than other layers. The inner layer of myometrium consists

of circular ibres arranged in the form of two hollow cones, the
apices of which surround the oriices of the fallopian tubes, their
bases intermingling with one another on the middle of the body
of the uterus. Endometrium has two layers, the stratum basalis, a
supporting layer, and the stratum functionalis, which proliferates
then degenerates during the menstrual cycle, varying from
1–6 mm in thickness. Stratum functionalis is made up of stratum
compactum and stratum spongiosum. Endometrium is the most
active layer and responds to cyclic ovarian hormone changes and
therefore is highly specialized and is essential to menstrual and
reproductive function. Both the endometrium and myometrium
exhibit substantial changes during pregnancy.
The uterus is usually bent anteriorly (antelexed) between
the cervix and body while the entire uterus is normally inclined
anteriorly (anteverted). There are many structures that lie between
the leaf of broad ligaments, i.e. fallopian tubes, round ligaments,
ovaries, epoohoron and paroophoron, connective tissue, blood
vessels and nerves.
The round ligament is ibromuscular bands represents the
lower end of the gubernaculums extends from the superolateral
angle of the uterus, through the inguinal canal to the labia
majora. Round ligament helps to keep the uterus anteverted and
antelexed. There are three condensation of the pelvic fascia
which formed three important ligaments supporting the uterus:
(a) transcervical ligament (other name: cardinal, Mackenroth’s
ligament) extending from cervix and upper part of vagina to
lateral pelvic wall, (b) uterosacral ligaments and (c) pubocervical
ligaments.
The main blood supply to the uterus is from uterine artery
a branch from internal iliac artery. The uterus is also supplied
partly by ovarian artery, which forms an anastomotic trunk with
the branches of uterine artery at the lateral wall of the uterus.
The uterine artery gives oﬀ 6 to 10 arcuate arteries, which anastomose
with one another in the myometrium. Branches from arcuate
arteries or also known as radial arteries enter the basal layer of
the endometrium, giving oﬀ straight arteries known as basal
arteries, which supply this region, and continuing upward into
the functional layer as the highly-coiled spiral arteries. Therefore,
arcuate and radial arteries supply myometrium, while basal and
266 Carcinoma of Endometrium

spiral arteries supply the endometrium. The basal arteries are

not responsive to hormones; they support the basal endometrial
layer, which provides the proliferative cells for endometrial
growth. Spiral arteries supply the functionalis layer and are
hormonal sensitive blood vessels. In pregnancy, these spiral
arteries lead to numerous arterioles, which anastomose to supply
a rich capillary bed that includes thin-walled dilated spaces called
lacunae. The lacunae or intervillous spaces provide the site for
exchange of nutrients, wastes, hormones, and gases between the
foetal and materal circulation. If the pregnancy does not occur,
spiral arteries will constrict causing endometrial breakdown with
desquamation of the glands and stroma. The venous supply of the
uterus drains through uterine, ovarian and vaginal veins into the
internal iliac vein.
Both sympathetic (T12, L1) and parasympathetic (S2, 3, 4)
nerves supply the uterus. The lymphatic of the myometrium drains
into the subserosal network. The lymphatic drainage of the uterus
follows three main routes:
(a) Fundus: it mostly follows ovarian vessels to aortic lymph
nodes, some to external iliac lymph nodes or runs along the
round ligaments to supericial inguinal lymph nodes;
(b) Body of a uterus: mainly to external iliac lymph node;
(c) Cervix: internal iliac and sacral lymph nodes.

Epithelial Uterine Cancer

Epidemiology
The incidence of endometrial cancer is increasing and each
year approximately 142,000 women have been diagnosed, and
an estimated 42,000 woman die from this cancer every year.
Endometrial cancer is fourth most common women cancer (after
breast, bowel and lung) and the most common gynaecological
cancer in America. More than 42,000 cases reported and 7780
deaths estimated in 2009. Endometrial cancer is more common in
developed countries and mortality rate was higher in black than
in white. The incidence is rising due to increase in life expectancy
and rate of obesity as well as lack in physical activity. The highest
incidence is in white North Americans have a rate seven times
Epithelial Uterine Cancer 267

higher than Chinese. Asian women who migrate to the USA develop
an incidence rate similar to the USA population. Most of the
patients with endometrial cancer were aged 50–59 years old; 20–
25% of cases were diagnosed before menopause. Approximately,
5% of women are diagnosed below 40 years of age. For all stages
taken together, the overall 5-year survival rates is around 80%
and 75% of patients presented at an early stage. Lifetime risk of
developing Ca endometrium is a woman less than 75 year old is
1–3% (1% overall risk, GLOBOCAN 2008).

Type of Endometrial Cancer

Endometrial cancers are broadly classiied into two main categories
(irst described by Bokhman in 1980s):
(a) Type I endometrial cancer: It is related to exposure to
unopposed endogenous or exogenous oestrogen. The cancers
frequently arise on a background of atypical hyperplasia
and have an association with obesity, nulliparity, insulin
resistance and hyperoestrogenism. Type I is usually well
diﬀerentiated and has a better prognosis.
(b) Type II endometrial cancer: Type II has no association with
predisposing factors as in Type I. Uterine papillary serous
and clear cell carcinoma is the example of Type II endometrial
cancer. Unlike type I, patients with type II endometrial cancer
tend to be elderly and thin and have a poorer prognosis.
Approximately 80% of endometrial cancers are type I and the
most common histologic subtype is endometrioid adenocarcinoma
accounting for 75–80% of endometrial cancer. The diﬀerences
between Type I and Type II endometrial cancer are shown in
Table 9.1.
Uterine serous carcinoma of the endometrium is the most
common type II endometrial cancer. Serous carcinoma accounts for
less than 10% of endometrial malignancies with poor prognosis.
Median age for patients with serous carcinoma is 5 years older
than those with endometrioid endometrial carcinoma. They often
spread intra-abdominally similar with ovarian cancer. Overall
5- year survival rates for patients with serous carcinoma of the
endometrium were 52.6% as compared to 83.2% in endometrioid
adenocarcinoma (Creasman et al., 2006). Clear cell carcinoma is
268 Carcinoma of Endometrium

the second most common type II endometrial cancer accounts for

about 5% of all endometrial cancers. Clear cell carcinomas are
aggressive and have a tendency to spread beyond the pelvis (40%
of patients with clinically conined to the uterus) and has high
relapse rate.

Table 9.1 Characteristic of type I and type II endometrial cancer

Characteristic Type I Type II

Unopposed oestrogen Present Absent
Menopausal status Pre- and perimenopausal Majority
postmenopausal
Obesity Yes No
Parity Low parity or Multiparous
nulliparous
Grade Low High
Myometrial invasion Minimal Deep
Histology of adjacent Hyperplastic Atrophic/cystic polyp
endometrium
Histology Endometrioid, Papillary serous
adenoacanthoma (UPSC), Clear cell
Precursor lesion Atypical hyperplasia Endometrial
(WHO) or EIN intraepithelial
(EIN nomenclature) carcinoma (EIC)
Progesterone receptor Higher positivity Negative or mildly
+/Oestrogen in grade 1 (>90%) positive (0–30%)
receptor +
PTEN (deletion or 50–80% 10–11%
mutation)
P53 overexpression 5–10% 80–90%
EGFR expression 46% 34%
P16 inactivation 10% 40%
Ploidy 67% diploid 40% diploid
Behaviour Less aggressive, better Aggressive
prognosis
Source: Adapted from (a) Kuman RJ, Zaimo R, Norris HJ. Endometrial carcinoma in
Kuman RJ (ed.): Blaustein’s Pathology of the Genital Tract, pp. 439–486. 1994, NY,
Springer-Verlag; (b) Zagouri et al., 2010.
Epithelial Uterine Cancer 269

Approximately, 10% of endometrial carcinoma shows a mixed

histology, i.e. presence of more than one component, each must be
at least 10% of the tumour. Presence of serous component in even
10% of the tumour is enough to inluence the overall prognosis.
The other variants of mixed histology type of endometrial
carcinoma are adenocarcinoma with squamous cell diﬀerentiation
or adenoacanthoma (squamous cell components are benign) and
adenosquamous carcinoma (squamous component resembles a
squamous cell carcinoma). Adenoacanthoma has the same prognosis
as endometrioid adenocarcinoma. Histological classiication of
endometrial cancer is shown in Table 9.2.

Table 9.2 Histological classiication of endometrial carcinoma by WHO

(Silverberg, et al.)

Histology type Subtype

Endometriod (a) With squamous diﬀerentiation
adenocarcinoma (b) Villoglandular
(c) Secretory
(d) With ciliated cells
Other adenocarcinomas (a) Mucinous carcinoma
(b) Serous carcinoma
(c) Clear cell carcinoma
(d) Mixed adenocarcinoma (includes
adenosquamous)
Other carcinomas (a) Squamous cell carcinoma
(b) Transitional cell carcinoma
(c) Small cell carcinoma
(d) Undiﬀerentiated carcinoma

Synchronous endometrium and ovarian carcinoma is rare

phenomena and occur in 15–20% of endometrioid adenocarcinoma
of the ovary. Differential diagnosis of synchronous tumour is
ovarian metastasis; however, metastasis to the ovary is unlikely
from the endometrium if the following features exist: (a) Ovarian
tumour is bilateral, (b) Myoinvasion is less than middle third
of endometrium, (c) There is no vascular space invasion and
(d) Endometrial carcinoma is of well-differentiated type (grade 1).
In endometrial cancer, differentiation of tumour is expressed in
grade. FIGO, the WHO and International Society of Gynaecological
270 Carcinoma of Endometrium

Pathologist are using two methods of grading. The grading of

endometrial cancer can be done preoperatively by histologic
examination of endometrial tissues taken from the endometrial
sampling procedure.
Two methods of grading are:
1. By architectural growth pattern (adenocarcinoma compo-
nent)
• Grade 1: ≤ 5% of tumour is in solid sheets
• Grade 2: 6–50% of tumour is in solid sheets
• Grade 3: >50% of tumour are in solid masses
Notable nuclear atypia (grade 3, nuclear features) will raises 1 grade.
2. By nuclear features (for non serous carcinoma)
• Grade 1: Round to oval nuclei with even distribution of
chromatin and inconspicuous nucleoli.
• Grade 2: Irregular, oval nuclei with chromatin clumping
and moderate size nucleoli
• Grade 3: Large pleomorphic nuclei with coarse chromatin
and large, irregular nucleoli.
Higher grade of tumour is associated with increased risk of
myometrial invasion and lymph node metastases.

Risk Factors for Endometrial Cancer

Generally, type I endometrial cancer is due to prolonged exposure
to oestrogen either exogenous or endogenous in origin. High level
of endogenous oestrogen is often seen in obese women. Patients
with polycystic ovarian syndrome and oestrogen-producing tumour
are also known to have a high level of unopposed oestrogen and
therefore, at higher risk of endometrial cancer. The summary of
risk factors for type I endometrial cancer is shown in Table 9.3.
About 50% of patients with endometrial cancer were found to
have a body mass index of >25 kg/m2. In premenopausal women,
obesity causes insulin resistance, ovarian androgen excess,
anovulation and chronic unopposed oestrogen. The rate of obesity
is increasing especially in developed countries due to eating
habits and sedentary lifestyle. Obesity in known to increase the
endogenous oestrogen because peripheral fat is responsible
in converting the androstenedione to oestrogen compounds.
Postmenopausal women with high BMI have a higher oestrogen
Epithelial Uterine Cancer 271

level (mainly oestrone) due to excessive peripheral conversion from

androstenedione by adipose tissues. Obese women with normal
circulating oestrogen remain at higher risk because of an alteration
in insulin-like growth factor. Diabetes and hypertension have
been recognized as risk factors independent of their association
with obesity.

Table 9.3 Risk factors for type I endometrial cancer

Risk factors Increased risk

Obesity
>30 lb ideal BW 3×
>50 lb ideal BW 10×
Nulliparous 2–3×
Late menopause (age>52) 2.5×
Heavy perimenopausal bleeding 4×
Diabetes Mellitus 2.8×
Hypertension 1.5×
Unopposed exogenous oestrogen 9.5×
Untreated Complex atypical hyperplasia 29% will developed
adenocarcinoma
Tamoxifen given for breast cancer increased the
risk of endometrial cancer
• Greatest risk after 5-year use and the risk Relative risk
remains even after stopping the tamoxifen 6.4–7.5-fold
• 36% occur within 2 years (40 mg/d)
• Excess risk of more aggressive histotype was
noted in patient taking tamoxifen, including type
II endometrial cancer and carcinosarcoma
• Risk of endometrial cancer has to weigh with the
beneit of reducing recurrent breast cancer (from
227/1000 to 123/1000 breast cancer) and pre-
venting cancer in contralateral breast (40 reduced
to 23 per 1000). The beneit outweighs the risk.
Endometrial hyperplasia Progressing to Cancer
Simple hyperplasia (no atypia) 1%
Complex (adenomatous, no atypia) 3%
Atypical
Simple (cystic with atypia) 8%
Complex (adenomatous + Atypia) 29%
272 Carcinoma of Endometrium

The use of combination oral contraceptive pills for 1 year

decreased the risk of endometrial cancers by more than 40%.
Women on combined hormone replacement therapy have also been
found to have lower risk of endometrial cancer as long as their
progestogen content is more than 10–12 days per cycle.
Approximately, 5% of endometrial cancer is hereditary
associated with a hereditary non-polyposis colon cancer syndrome
(HNPCC). The lifetime risk of having endometrial cancer is 40–60%
in patients with HNPCC. HNPCC is an autosomal dominant inherited
disorder caused by germ-line mutation in DNA mismatch repair
genes. Defective MMR genes are identiied in 85% of HNPCC-
associated endometrial carcinoma.
Smoking is said to reduce the risk of endometrial cancer due
to its eﬀect on oestrogen level. Pregnancy has a natural protective
eﬀect against endometrial cancer because of high production of
progesterone by placenta.

Pre-Malignant Lesions of Endometrium and

Pathogenesis of Endometrial Cancer
Majority of patients with Type I endometrial cancers have co-
existing endometrial hyperplasia. Endometrial hyperplasia can
be divided into simple endometrial hyperplasia without atypia,
complex endometrial hyperplasia without atypia and hyperplasia
with atypia (WHO classiication). Hyperplasia is thought to
result from excessive or unopposed oestrogen stimulation of the
endometrial glands. In some individual, hyperplasia can also be
due to an abnormal endometrial response to normal hormonal
stimulation. Cytogenetic analysis has found that the most common
genetic alterations in endometrial hyperplasia are: (a) Micro-
satellite instability (MSI) and (b) Mutation of tumour suppressor
gene PTEN (phosphatase and tensin homolog) seen in 20–30% of
atypical hyperplasia and 40% of endometrioid adenocarcinoma.
MSI and PTEN mutation can coexist in some cases.
Endometrial hyperplasia without atypia responds better
to progestogen therapy because of higher level of progesterone
receptors as compared to endometrial hyperplasia with atypia.
In simple hyperplasia, endometrium is thick with dilated,
outpouchings, invaginating and crowded glands. While in atypical
Pre-Malignant Lesions of Endometrium and Pathogenesis of Endometrial Cancer 273

hyperplasia, the abnormalities are more prominent with the

present of cytologic atypia of the glandular cell such as nuclear
hyperchromatism, nuclear enlargement and increased nuclear-
cytoplasmic ratio. Presence of cytologic atypia is a single most
important predictor of malignant potential and resistance to
medical therapy. Co-existing endometrial carcinoma was found
in 40% of hysterectomy specimens taken from patients with a
preoperative diagnosis of atypical endometrial hyperplasia.
Patients on tamoxifen therapy are also at higher risk of
endometrial pathology. Tamoxifen is an oestrogen receptor-
modulating hormone and has antioestrogen properties to breast.
Despite antioestrogen properties on breast tissue, it also has
paradoxical mild oestrogenic eﬀects on the endometrium especially
in postmenopausal women. Therefore, women taken tamoxifen
are at higher risk of endometrial hyperplasia, endometrial polyps,
endometrial cancer and even uterine sarcoma (carcinosarcoma).
The study showed that the use of tamoxifen for 2 years was
associated with an approximately twofold increased risk of
endometrial cancer, while the use for 5 or more years produces
a 4–8-fold excess risk. The overall risk of endometrial cancer
in a patient with simple hyperplasia, complex hyperplasia and
atypical hyperplasia is 1%, 2.4% and 46.2%, respectively (Baak
et al., 1992; Horn et al., 2004; Kurman et al., 1985). See Table 9.4
for details.

Table 9.4 Risk of endometrial cancer in diﬀerent types of endometrial

hyperplasia

Simple Complex Atypical

hyperplasia hyperplasia hyperplasia
Kurman et al. 1/93 (1.1%) 1/29 (3.4%) 10/35 (28.6%)
(1985)
Baak et al. 0/8 (0%) 1/6 (16.7%) 5/11 (45.4%)
(1992)
Horn et al. — 8/390 (2.0%) 58/112 (51.8%)
(2004)
Overall risk 1/101 (1%) 10/425 (2.4%) 73/158 (46.2%)

The diagnosis of atypical endometrial hyperplasia and grade

1 endometrial adenocarcinoma are known to have a poor
274 Carcinoma of Endometrium

reproducibility event among experienced Pathologists. As an

alternative to former classiication of endometrial hyperplasia,
recently a new classiication of pre-malignant lesions of the
endometrium has been proposed and currently is widely used in
United State. The new terminology for pre-malignant lesion of the
endometrium is known as endometrial intraepithelial neoplasia
(EIN) (Table 9.5).

Table 9.5 Classiication of endometrial pathology and premalignant

lesions of endometrium

EIN nomenclature Functional category Management

Benign proliferative Oestrogen eﬀect Hormonal therapy
endometrium (benign
endometrial hyperplasia)
Endometrial Pre-cancerous Hormonal or surgery
intraepithelial
neoplasia (EIN)
Adenocarcinoma Cancer Based on stage

Based on a new concept of premalignant lesions of endometrium,

endometrial pathology is now classiied into three categories:
(a) Benign endometrial hyperplasia (Disordered Proliferative
Endometrium)
(b) Endometrial intraepithelial neoplasia (EIN)
(c) Endometrial adenocarcinoma
The diagnosis of EIN is based on ive diagnostic criteria (see
Table 9.6). EIN classiication was found to be more reproducible
and has a better correlation with prognosis. EIN lesions are non-
invasive genetically altered neoplasms, which arise focally, and
may transform to malignant phenotype upon acquisition of
additional genetic damage. Patients with EIN have 45-fold
increased risk of endometrioid endometrial carcinoma and the
median interval from diagnosis of EIN to carcinoma is 4 years.
Approximately, 40% of patients with EIN were found to have
concurrent endometrial carcinoma within 1 year. A study by
Hecht et al. to evaluate the correlation between EIN classiication
and WHO classiications of pre-malignant lesions of endometrium
found that 78% of patients with atypical endometrial hyperplasia
Pre-Malignant Lesions of Endometrium and Pathogenesis of Endometrial Cancer 275

(WHO classiication) have enough criteria to diagnose EIN. Full

correlation is shown in the Fig. 9.2.

Figure 9.2 Correlation between WHO classiication and EIN Nomenclature.

Example: 78% of patients with atypical hyperplasia fulilled
the criteria for the diagnosis of EIN, while 64% of EIN was
diagnosed as atypical hyperplasia (Hecht et al., 2005).

Table 9.6 EIN diagnostic criteria (Silverberg et al., 2003)

EIN Criteria Comments

Architecture Area of glands greater than stroma
Cytology Cytology diﬀers between architecturally crowded focus
and background, or clearly abnormal.
Size > 1 mm Maximum linear dimension exceeds 1 mm.
Exclude Benign conditions with overlapping criteria: basalis,
mimics secretory, polyps, repair, etc.
Exclude cancer Carcinoma if mazelike glands, solid areas, polygonal “mo-
saic-like” glands, myoinvasion, or signiicant cribriform-
ing
276 Carcinoma of Endometrium

The EIN or endometrial intraepithelial neoplasia is the

precursor for type I endometrial cancer. The precursor lesion for
type II endometrial cancer is known as endometrial intraepithelial
carcinoma (EIC). The EIC represents a non-invasive glandular lesion
characterized by epithelial cells with marked nuclear abnormalities,
resembling nuclei similar to those seen in serous carcinoma of the
endometrium. In most cases, EIC is seen in the underlying atrophic
endometrium of older postmenopausal women and not uncommon
to detect this lesion within a polyp. The cells of EIC show negative
reaction against oestrogen and progesterone receptor analysis
but often positive to p53 and Ki-67. The Hypothetic model of the
pathogenesis of type II endometrial cancer is shown in Fig. 9.4.

Ǧ

ȀȀ

Ǧ

ͳȀʹ

!"#Ǧ$%
' ' *+

͵

Figure 9.3 Hypothetic model of the pathogenesis of type I endometrial

cancer (Horn et al., 2007).

ͷ͵
ȋȌ
ͷ͵

ͳ͸
ǦʹȀ
Ȁ

Figure 9.4 Hypothetic model of the pathogenesis of type II endometrial

cancer (Horn et al., 2007).
Prevention of Endometrial Cancer 277

Prevention of Endometrial Cancer

Treating the precursor lesions either by hormonal or surgical
treatment can prevent endometrial cancer. Adding a progestogen
for at least 10–12 days per cycle in hormone replacement therapy
can reduce the risk of endometrial cancer, particularly if the
hormone is taken continuously and in obese women. In contrast,
if the oestrogen alone is given continuously for 2 years without
progestogen, the risk of developing endometrial hyperplasia will
be many folds higher according to dose. Women taking oestrogen
1.25 mg daily dose for 2 years has 32-fold increase risk of
endometrial hyperplasia than 0.3 mg daily dose. Women with
amenorrhea or oligomenorrhea (including women with PCOS)
should be treated with cyclical progestogen to avoid prolonged
exposure of the endometrium to a high level of oestrogen. Withdrawal
bleeding of 3-monthly is suficient to prevent endometrial pathology.
There have been suggestions of a protective effect of high phyto-
oestrogen consumption on risk of endometrial cancer among
postmenopausal women (Goodman et al., 1997; Horn-Ross, 2003;
Xu et al., 2004).
The use of intrauterine devices and tubal ligation has also
been associated with a lower risk of endometrial cancer (Hubacher
and Grimes 2002; Kjaer et al., 2004). Weight reduction and physical
activities to achieve ideal body weight can reverse the effect of
prolonged exposure to a high level of oestrogen. Pregnancy is a
physiological protection against endometrial pathology due to a
high level of hormone progesterone produced by placenta. The use
of combination oral contraceptive pills for 1 year decreased the
risk of endometrial cancers by more than 40%. Combined OCP is
also known to reduce the incidence of ovarian cancer.
There is no effective screening method for endometrial cancer.
Endometrial sampling, transvaginal ultrasound, endometrial
brush sponge, endometrial aspiration, Pap smear and progestogen
challenge test have been evaluated as a screening test but their
accuracy in asymptomatic population is limited. For asymptomatic
low-risk women, novel-screening approaches from epigenetics,
proteomics and genomics are being explored. Small studies on
the role of gene methylation patterns and telomerase assays have
shown some promising results (Fiegl et al., 2004; Maida et al.,
2002). Screening for high-risk women such as patients on tamoxifen
278 Carcinoma of Endometrium

therapy and long-term oestrogen replacement therapy using

yearly transvaginal ultrasound have reported low sensitivity,
speciicity and positive predictive value in detecting endometrial
cancer (Fung et al., 2003). American Cancer Society has suggested
annual screening with endometrial biopsy for women above 35
years old with HNPCC and having lifetime risks of endometrial
cancer between 40–60% (Smith et al., 2007). In women presented
with postmenopausal bleeding, transvaginal ultrasound showing
ET of ≤5 mm and negative endometrial sampling have nearly 100%
negative predictive value.

Presentation and Diagnosis

Majority of patients with endometrial cancer are postmenopausal
women. Most common presenting symptom is postmenopausal
bleeding. Other presenting symptoms are (a) abnormal vaginal
discharge, (b) abnormal vaginal bleeding in 80% (including
postmenopausal bleeding and irregular menses in premenopausal
women), (c) symptoms due to uterine enlargement including
pressure symptoms and (d) symptoms indicative of extra-uterine
spread.
Full evaluation of the endometrium (ultrasound and
endometrial biopsy) must be performed in women presented
with postmenopausal bleeding. Women with postmenopausal
bleeding have 10–15% probability of endometrial cancer. The initial
diagnosis of endometrial cancer is often made by transvaginal
ultrasound and ofice endometrial sampling. In postmenopausal
women, normal endometrial thickness is ≤5 mm (myometrium
to myometrium). Transvaginal ultrasound is non-invasive with
sensitivity and speciicity of 91% and 96%, respectively (using cut-
oﬀ point endometrial thickness of 5 mm). Endometrial carcinoma
is seen in varieties of sonographic features, including a prominent
thickened endometrium, polypoidal lesion and mixed echogenicity.
Endometrial hyperplasia and grade 1 endometrial cancer usually
showed hyperechoic features while grade 2–3 endometrial cancers
tends to be hypoechoic on transvaginal ultrasound. Hysteroscopy
and hysterosonography are not recommended in patients with
highly suspicious of endometrial cancer because of potential risk
of tumour spread from uterine cavity into the peritoneal cavity.
Presentation and Diagnosis 279

A meta-analysis on the value of pipelle endometrial sampling

for the diagnosis of atypical hyperplasia or endometrial cancer has
reported the sensitivity of 81–99% and speciicity of 98%. There
are many more endometrial samplers available in the market such
as Kauman cannula, Tis-U-trap, Vabra aspirator and z-sampler.
Pipelle endometrial sampler is perhaps the most commonly used
method to assess the endometrium (Fig. 9.5). Ofice endometrial
sampling using pipelle sampler was found to be valuable in
terms of cost, high patient’s acceptability and high percentage
of diagnostic agreement (96%). However, result from ofice
endometrial sampling technique has a poor correlation in tumour
grading with inal histological diagnosis (from a hysterectomy
specimen). Study by Leitao Jr et al. (evaluating 490 patients with
a preoperative diagnosis of grade 1 endometrial adenocarcinoma)
have found that 15% of patients with preoperative grade 1 lesions
were actually had a higher grade lesions (mostly grade 2 and
some grade 3) on hysterectomy specimen. Combined analysis
on same correlation was done by other authors, and they found
that the rate of upgrading was even higher, up to 30% (Larson et
al., 1995; Obermair et al., 1999; Frumovitz et al., 2004; Eltabbakh
et al., 2005). Eltabbakh et al. also reported that 12.6% of patients
diagnosed as grade 1 endometrial cancer preoperatively (total 182
patients) were found to have advanced stage disease. In most of the
patients, pipelle endometrial sampling or other ofice endometrial
sampling is as good as endometrial curettage (DD&C) in detecting
endometrial cancer (Stovall, Dijkhuizen et al., 2000). However,
in some patients, due to atrophic changes of the cervix and
endometrium, endometrium is better evaluated by fractional
DD&C (curetting the endocervix should be done prior to the
endometrium). Diagnosis, dilatation and curettage was found to
be more accurate in predicting grade of tumour as compared to
ofice endometrial biopsy. The FIGO grade in the hysterectomy
specimen was upgraded in only 15% of the cases after D&C as
compared to 27% after ofice endometrial biopsy (Leito Jr et al.,
2008; Larson et al., 1995; Frumovitz et al., 2004; Daniel and
Peters, 1988). Hysteroscopy is indicated if a patient has persistent
symptoms despite normal endometrial biopsy. Hysteroscopy can
diagnose endometrial polyp or small focus of endometrial lesions
in which hysteroscopic-directed biopsy can be performed (Fig. 9.6).
280 Carcinoma of Endometrium

Hysteroscopy is also useful in patients taking tamoxifen when

transvaginal ultrasound showed evidence of endometrial lesions
suggestive of polyps and if the endometrial sample is insuficient.

Figure 9.5 Ofice endometrial sampling.

Figure 9.6 Hysteroscopy for the diagnosis of endometrial pathology.

Investigations and Staging

Once the diagnosis of endometrial cancer has been made, blood
count, renal proiles and liver function tests are performed. There
are no established tumour markers for endometrial cancer; CA125
Investigations and Staging 281

level is elevated mainly in advanced stage disease (65–80%). In

stage 1 and stage 2 endometrial cancers, CA125 is elevated only in
15% and 33%, respectively. CA125 is perhaps more useful in type
II endometrial cancer. Raised Ca125 in an apparent early stage may
indicate the presence of micrometastases. CA125 level is useful
only in follow-up setting; almost 60% of patients with recurrent
endometrial cancer showed elevated CA125.
Chest x-ray and CT scan are useful to evaluate the extent of the
disease preoperatively. MRI is increasingly used in endometrial
cancer, especially to evaluate the myometrial invasion, while CT
scan is more superior in assessing retroperitoneal lymph nodes.
The inal staging of endometrial cancer is determined after
thorough histopathological assessment of the surgical specimens
(surgico-pathological staging). Preoperative assessment of the
tumour in terms of tumour grading and the degree of myoinvasion
are important to determine the extent of surgical treatment.
The surgical staging surgery for endometrial cancer includes
exploratory laparotomy, peritoneal wash for cytology, extrafascial
hysterectomy and bilateral salpingoophorectomy, excision of
suspicious nodule or lymph nodes and omentectomy in advanced
stage or in type II endometrial cancer. The role of routine systematic
lymphadenectomy will be discussed later in this chapter.
Intraoperative assessment of myometrial invasion was found
to be dificult and often inaccurate. Frumovitz and colleagues have
evaluated 122 patients with endometrial cancer and reported
that a frozen section diagnosis of no myometrial invasion is not
accurate in 72% of cases. Furthermore, 26% of cases with a frozen
section reported >50% myometrial invasion was actually had
deeper invasion, cervical involvement, and/or extra-uterine disease.
In another study by Mao and colleagues evaluating the accuracy of
gross examination of the uterus intraoperatively, they found that
intra-operative gross examination correctly identiied the depth
of microscopic myometrial invasion in 90.3% of patients. The
sensitivity in detecting myometrial invasion was 80.6% and the
speciicity was 92.4%. With regard to cervical involvement, gross
examination had an overall accuracy of 84.3%. The sensitivity in
detecting cervical involvement was 32.6% and the speciicity was
99.0%. However, in this study, specimen was examined by four
members of experts comprising of two gynaecologic pathologists
and two experienced gynaecologic oncologists.
282 Carcinoma of Endometrium

FIGO Staging of Endometrial Cancer

FIGO has recently revised the new staging to replace FIGO staging
1988. FIGO with the collaboration of several other International
bodies such as IGCS, Gynecologic intergroup, Society of Gynecologic
Oncologists, the International Society of Gynecologic Oncologist,
International Society of Gynecologic Pathologist and AJCC have
come out with new FIGO staging for endometrial cancer (Mutch,
2009). For the purpose of comparison, both old and new FIGO
staging are shown in the Tables 9.7 and 9.8, respectively.

Table 9.7 Corpus cancer staging, FIGO 1988 (old staging)

Staging Descriptions
Stage 1 Tumour conined to corpus uteri
Stage 1A G123 Tumour limited to endometrium
Stage 1B G123 Invasion ≤ 50% of myometrium
Stage 1C G123 Invasion > 50% of myometrium
Stage 2 Tumour invades cervix but not outside uterus
Stage 2A G123 Endocervical gland involvement only
Stage 2B G123 Cervical stroma invasion
Stage 3 Local and/regional spread
Stage 3A G123 Tumour invades serosa and/or adnexae or positive
peritoneal luid cytology.
Stage 3B G123 Vaginal involvement (direct or metastases)
Stage 3C G123 Metastasis to pelvic and/or para-aortic nodes
Stage 4 Tumour invades bladder and/or bowel mucosa,
and/or distant metastases
Stage 4A G123 Tumour invades bladder mucosa and/or bowel
mucosa.
Stage 4B Distant metastasis including intra-abdominal LNs (other
than para-aortic) and/or inguinal lymph nodes.

Table 9.8 Corpus cancer staging, FIGO 2009

Staging Descriptions
Stage 1 Tumour conined to corpus uteri
Stage 1A G123 No or less than half myometrial invasion
Stage 1B G123 Invasion ≥ 50% of myometrium
Treatment for Pre-Malignant Lesions of Endometrium 283

Stage 2 Tumour invades cervical stroma but not outside

uterusa
Stage 3 Local and/or regional spread of tumour
Stage 3A G123 Tumour invades serosa and/or adnexaeb
Stage 3B G123 Vaginal and/or parametrial involvementb
Stage 3C G123 Metastasis to pelvic and/or para-aortic nodesb
Stage 3C1 G123 Positive pelvic nodes
Stage 3C2 G123 Positive para-aortic lymph nodes with or without
positive pelvic lymph nodes
Stage 4 Tumour invades bladder and/or bowel mucosa,
and/or distant metastases
Stage 4A G123 Tumour invades bladder mucosa and/or bowel
mucosa
Stage 4B Distant metastasis including intra-abdominal meta-
stases and/or inguinal lymph nodes
aEndocervical glandular involvement only should be considered as stage 1 and no
longer as stage 2.
bPositive cytology has to be reported separately without changing the stage

G123: grade 1, grade 2 or grade 3.

The changes in new FIGO staging are based on the following

issues:
(a) There was little survival diﬀerence between no myometrial
invasion and less than 50% invasion; therefore these are
combined.
(b) Parametrial involvement is now included.
(c) Peritoneal luid for cytology was found to be highly variable
based on sampling of washing hence it has been eliminated as
a staging criteria.
(d) Pelvic and para-aortic lymph nodes metastases carry diﬀerent
survival and have to be separated in the staging.

Treatment for Pre-Malignant Lesions of

Endometrium
Patients with premalignant lesions of the endometrium should be
treated by either hormonal or surgical treatment. Spontaneous
regression is possible in simple hyperplasia without atypia (72%
284 Carcinoma of Endometrium

regression rate). Endometrial hyperplasia with atypia is less likely

to regress spontaneously. The most important criteria to determine
the choice of treatment is presence of nuclear atypia. The modality
of treatment in premalignant condition of endometrium is
depending on age, need for future fertility, co-morbidities and
surgical risk.
Patients with simple or complex hyperplasia without atypia
often respond well to hormonal treatment. In general, more
than 90% of the endometrial hyperplasia without atypia showed
complete regression following hormonal treatment. The risk of
recurrence is approximately 10%.
Endometrial hyperplasia with atypia has lower response rate
ranging from 50% to 80% and the lesions tend to persist in 50%
of cases. There were also cases of progression to cancer despite the
hormonal treatment. The choices of progestogens include megestrol
acetate, medroxyprogesterone acetate, levenorgestrel-releasing
devices and vaginal micronized progesterone. Patients with
endometrial hyperplasia and atypia are often treated with high-
dose progestogen for 3–6 months followed by maintenance low
dose for another few months’ once complete regression has been
conirmed histologically. These patients should be followed up with
transvaginal ultrasound scan and endometrial sampling.
Patients diagnosed as premalignant lesions of the endometrium
using EIN classiication should be treated similar to atypical
endometrial hyperplasia (WHO classiication). Concurrent
endometrial carcinoma with atypical hyperplasia or EIN has been
reported in many studies and in some patients, invasive cancer
was discovered later during the follow-up. The study found that
40% of patients with EIN have concurrent carcinoma diagnosed
within 1 year. The GOG study reported the rate of concurrent
carcinoma with atypical endometrial hyperplasia to be 42.6%
and Giede et al. reported an incidence of 35.7%. The high rate of
concurrent carcinoma discovered in these studies was probably
due to high incidence of endometrial cancer in the studied
population (Western countries including America). Similar study
done in Korea by Hahn et al., however, reported lower rate of
concurrent carcinoma in patients with complex atypical endometrial
hyperplasia, i.e. 12.7% (simple atypical hyperplasia was excluded).
One of the explanations by the authors regarding this inding
was probably related to the accuracy of preoperative diagnosis of
Treatment for Pre-Malignant Lesions of Endometrium 285

endometrial hyperplasia in their study. In the majority of cases,

the diagnosis was done via DD&C (78%) as compared to previous
studies that mostly via ofice-based endometrial biopsy.
The eﬀectiveness of oral progestogen therapy has been
evaluated in few studies and generally the regression rate for
non-atypical hyperplasia was more than 90% while in atypical
hyperplasia in approximately 50%. Varma et al. evaluated the role
of the levonorgestrel-releasing intrauterine system (LNG-IUS)
in the treatment of endometrial hyperplasia and they found that
treatment with LNG-IUS achieved endometrial regression in 90%
of cases within 2 years. The regression rate was higher in patients
with non-atypical hyperplasia as compared to atypical hyperplasia
(92% versus 67%). In this study, follow-up pipelle endometrial
biopsy was done 3-monthly for 6 months and subsequently
6-monthly.

Figure 9.7 Endometrial hyperplasia associated with polycystic ovarian

syndrome.

Patients with atypical endometrial hyperplasia presented

after menopause, and those who had failed to respond to
conservative treatment are best treated with simple hysterectomy.
In premenopausal women, the treatment choice is individualized.
In patients who are not medically it for major surgical treatment,
endometrial resection or endometrial ablation has been advocated.
286 Carcinoma of Endometrium

They can also be treated with hormonal treatment either in oral

form or with LNG-IUS. The German Working Group of Gynaecology
Oncology has proposed a treatment guideline for patients with
endometrial hyperplasia; please refer to Fig. 9.8.

Endometrialhyperplasia

Simple Complex hyperplasia Atypical hyperplasia

hyperplasia

Pre- Post- Pre- Post-

menopause menopause menopause menopause

Expectant or Simple
Progestogen Rx,
Progestogen Rx Hysterectomy
Ultrasound and
Repeat curettage
Progestogen Rx, or hysterectomy
Ultrasound and
Progestogen Rx,
Repeat currettage
Ultrasound and
Repeat curettage or
hysterectomy

Figure 9.8 Treatment guideline for endometrial hyperplasia by German

Working Group of Gynecologic Oncology (Horn et al., 2007).

Figure 9.9 Endometrial carcinoma.

Treatment for Endometrial Carcinoma 287

Treatment for Endometrial Carcinoma

Surgery
Surgery is the most important mode of treatment in endometrial
cancer. Following are the principles of surgery for endometrial
cancer:
(a) Maylard’s incision (for early stage) and midline incision for
advanced stage when upper abdominal surgery is likely to be
performed.
(b) Thorough intraperitoneal exploration
(c) Peritoneal washing for cytology
(d) Extrafascial hysterectomy and bilateral salpingoophorectomy
(e) Pelvic ± Para-aortic lymphadenectomy
(f) Omentectomy in selected cases (in advanced type I
endometrial cancer in which the omentum is involved or in
type II endometrial cancer, i.e. serous carcinoma and clear cell
carcinoma)
Comprehensive surgical staging for endometrial cancer as
mentioned above will deine disease biology and facilitate triage of
tailored adjuvant therapy. The obturator lymph nodes (above the
obturator nerve) and iliac lymph nodes are the most common sites
for lymph node metastasis. Exploration and lymphadenectomy of
the lymph nodes over this area will allow identiication of 90% of
node-positive patients. The role of routine lymphadenectomy will
be discussed later in this chapter. Patients with positive pelvic
nodes have a higher incidence of para-aortic lymph node metastasis
and therefore require para-aortic lymphadenectomy. Para-aortic
nodes were positive in 47% of patients who had disease documented
in their pelvic nodes. Patients with deep myometrial invasion and
grade 3 tumour have at least 5% (some reported up to 18%) risk of
pelvic lymph node metastasis. Patients with pelvic node metastases
are categorized as stage 3 disease and 5-year survival rate is 60%
as compared to 97% in patients with stage 1 disease.
Patients with supericial myometrial invasion, grade 1 or 2 and
tumour’s greatest dimension of <2 cm have lower risk of pelvic
lymph nodes metastases. Lymphadenectomy may be omitted in
this group of patients if the diagnosis can be made accurately (via
preoperative and intraoperative evaluation).
288 Carcinoma of Endometrium

The routine systematic pelvic lymphadenecomy in apparent

stage 1 endometrial cancer remains controversial. The purpose
of this procedure is to establish the staging and to eradicate the
metastatic lymph nodes, which may carry a therapeutic beneit. The
irst large randomized control trial evaluating the role of routine
pelvic lymphadenectomy in apparent stage 1 endometrial cancer
was performed by Panici et al. The study accrued 524 patients
at 31 centres over 10 year’s period. In study arm, systematic
pelvic lymphadenectomy was performed while in control arm;
lymphadenectomy was not performed; however, removal of bulky
nodes (>1 cm) was allowed in the control arm. After almost 6 years,
there was no difference in the adjusted hazard ratio for relapse
and death between study and control arm. However, the results
From this trial were scrutinized with the following arguments:
(a) The trial did not meet the requirement to detect a difference
due to insuficient samples.
(b) There was no standardization of postoperative adjuvant
therapy and the Cox regression was not adjusted for
postoperative therapy.
(c) More patients received adjuvant treatment in the control
group (25.2% versus 16.7%, p = 0.033).
(d) Lymph node dissection was performed in some proportion of
patients in control arm (16% had >6 lymph nodes removes
and 11% had 10 lymph nodes removed).
(e) There was no standard deinition of “adequate” lymphadenec-
tomy.
The second randomized trial funded by Medical Research
Council and National Cancer Research Network known as MRC
ASTEC trial (eficacy of systematic pelvic lymphadenectomy in
endometrial cancer) was published. The main objective of this
trial was to determine if lymphadenectomy increase survival
independent of adjuvant radiation. The trial accrued over
1400 women (from 85 centres in four different countries) with
endometrial cancer suspected to be conined to the uterus. There
were two arms in this trial: (1) Control arm underwent standard
surgery (hysterectomy, bilateral salpingoophorectomy, para-
aortic lymph node palpation, with suspicious node removal at the
surgeon’s discretion) and (2) Study arm underwent above
procedures plus iliac and obturator nodes dissection. The primary
Treatment for Endometrial Carcinoma 289

outcome was overall survival. Patients who were unit to undergo

lymphadenectomy or whom the centre did not oﬀer the procedure
subsequently underwent standard surgery. If postoperatively they
were found to be in an intermediate risk or high-risk early stage
(stage 1A, 1B, grade 3, papillary serous or clear cell histology
or stage 1C or 2A), they were randomized either receiving
external beam radiotherapy ± brachytherapy or observation ±
brachytherapy. MRC ASTEC trial also concludes that there was no
evidence of beneit in terms of overall or recurrent-free survival
of pelvic lymphadenectomy in women with early endometrial
cancer. Similar to Panici trial, MRC ASTEC trial was also criticized
because of the following limitations: (a) Lymphadenectomy arm
had signiicantly more patients with disease spread beyond the
uterus (21% versus 19%). (b) Lymphadenectomy arm had clearer
cell or serous subtype and more stage 1C disease compared to
control arm. (c) The median number of lymph nodes removed was
12 in the lymphadenectomy arm and 12% had <5 nodes removed.
Only 65% of patients in this arm had an “adequate” lymph node
dissection (more than 10 nodes). (d) The rate of complications was
inconclusive because the results were not adjusted for adjuvant
therapy (radiotherapy). (e) Most women were low risk (49% in
control and 42% in lymphadenectomy arm) and would not have
beneited from lymphadenectomy or radiation. (f) The rate of
node positivity was low, i.e. 3.1% in a lymphadenectomy arm, low
node positivity will lead to the dificulty to detect any survival
diﬀerence.
Seam