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 World Health Organization Classification of Tumours

WHO OMS

International Agency for Research on Cancer (IARC)

4th Edition

WHO Classification of
Tumours of the Urinary System
and Male Genital Organs

Edited by

Holger Moch

Peter A. Humphrey

Thomas M. Ulbright

Victor E. Reuter

International Agency for Research on Cancer

Lyon, 2016

-
 World Health Organization Classification of Tumours

Series Editors Fred T. Bosman, MD PhD

Elaine S. Jaffe, MD
Sunil R. Lakhani, MD FRCPath
Hiroko Ohgaki, PhD

WHO Classification of Tumours of the Urinary ,System and

Male Genital Organs

Editors Holger Moch, MD

Peter A. Humphrey, MD PhD
Thomas M. Ulbright, MD
Victor E. Reuter, MD

Project Assistant Asiedua Asante

Technical Editor Jessica Cox

Database Alberto Machado

Delphine Nicolas

Layout Stefanie Brottrager

Printed by Maestro
38330 Saint-lsmier, France

Publisher International Agency for

Research on Cancer (IARC)
69372 Lyon Cedex 08, France
 This volume was produced in collaboration with the University and the

University Hospital Zorich, Switzerland

The WHO Classification of Tumours of the Urinary System and Male Genital Organs
presented in this book reflects the views of a Working Group that convened for a
Consensus and Editorial Meeting at the University Hospital Zorich,
ZOrich, 11-13 March 2015.

Members of the Working Group are indicated

in the list of contributors on pages 287-293.

-
 Published by the I nternational Agency for Research on Cancer ( IARC),
1 50 Cours Albert Thomas, 69372 Lyon Cedex 08, France

© I nternational Agency for Research on Cancer, 20 1 6

Distributed by
WHO Press, World Health Organization, 20 Avenue Appia, 1 21 1 Geneva 27, Switzerland
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The authors alone are responsible for the views expressed in this publication.

The copyright of figures and charts remains with the authors.

(See Sources of figures and tables, pages 295-299.)

First print run ( 1 0 000 copies)

Format for bibliographic citations:

Holger Moch, Peter A. Humphrey, Thomas M . U l bright, Victor E. Reuter ( Eds):
WHO Classification of Tumours of the Urinary System and Male Gen ital Organs (4th edition)
IARC: Lyon 20 1 6.

IARC Library Cataloguing in Publication Data

WHO classification of tumours of the uri nary system and male genital organs I ed ited by Holger Moc h , Peter A. Humphrey,
Thomas M . U l bright, Victor E . Reuter. - 4th edition.

(World Health Organization classification of tumours)

1 . Kid ney neoplasms - genetics 2. Kidney neoplasms - pathology 3. U rolog ic neoplasms - genetics
4. Urolog ic neoplasms - pathology 5. Prostatic neoplasms - genetics 6. Prostatic neoplasms - pathology
7. Genital neoplasms, male - genetics 8. Gen ital neoplasms, male - pathology

I. Moch, Holger I I . Series

ISBN 978-92-832-2437-2 (NLM Classification: WJ 1 60)

ii
Contents
Tum ours of the kidney 11 Mix ed epi thelial and stro
70
. ma 1 tumour
WHO and TNM classifications 12 Neuroendocrine tumours
72
Rena l cell tumo urs 14 Paraganglioma
72
I ntrod uctio n 14 Renal haematopoietic neoplas
ms 73
Clear cell renal cell carcinoma 18 Germ cell tumours
75
Multil ocular cystic renal neoplasm of low Metastatic tumours
76
malignant potential 22
Papillary renal cell carcinoma 23 2 Tumours of the urinary tract
77
Hereditary leiomyomatosis and renal cell WHO and TNM classific ations 78
carcinoma-associated renal cell carcinoma 25 I nfiltrating urothelial carcinoma 81
Chromophobe renal cell carcinoma 27 Non-invasive urothelial lesi ons 99
Collecting duct carcinoma 29 I ntroduction 99
Renal medullary carcinoma 31 Urothelial carcinoma i n situ 99
MiT family translocation renal cell carcinomas 33 Non-invasiv e pap illary urotheli 1 00
al car cino ma
Succinate dehydrogenase-deficient renal cell carcinoma 35 Papillary urothelial neoplasm of
Mucinous tubular and spindle cell carcinoma 37 low malignant potential 1 03
Tubulocystic renal cell carcinoma 38 Urothelial papillom a
1 04
Acquired cystic disease-associated I nverted urothelial p apilloma 1 04
renal cell carcinoma 39 Urot helial prol iferari on of uncerta·
1n ma 1.1gnan t paten t'1a 1 1 05
Clear cell papillary renal cell carcinoma 40 Urothelial dysplasia 1 06
Unclassified renal cell carcinoma 41 Squamous cell neopla sms 1 08
Papillary adenoma 42 Pure squamous cell carcinoma 1 08
Oncocytoma 43 Verrucous carcinoma 1 10
Metanephric tumours 45 Squamous cell papilloma 1 10
Metanephric adenoma 45 Glandular neoplasms 111
Metanephric adenofibroma 46 Adenocarcinoma 111
Metanephric stromal tumour 46 Villous adenoma 1 12
Nephroblastic and cystic tumours occurring Urachal carcinoma 1 13
mainly in children 48 Tumours of MOllerian type 115
Nephrogenic rests 48 Neuroendocrine tum our s 117
Nephroblastoma 49 Sm all cell neu roendo crine carc 1 17
inoma
Cystic partially differentiated nephroblastoma 53 Lar ge cel l neu roendocri ne c arc 1 18
inoma
Paediatric cystic nephroma 53 Well- diff erent iate d neuroendoc 118
rine tum our
Mesenchymal tumours 54 Paraganglioma 1 19
Mesenchymal tumours occurring mainly in children 54 Melanocytic tumours 1 20
Clear cell sarcoma 54 Malignant melano ma 1 20
Rhabdoid tumour 55 Naevus 1 20
Congenital mesoblastic nephroma 56 Melanosis 1 20
Ossifying renal tumour of infancy 58 Mesenchymal tumours 1 22
Mesenchymal tumours occurring mainly in adults 59 Rhabdomyosarcoma 1 22
Leiomyosarcoma Leiomyosarcoma 1 23
(including renal vein leiomyosarcoma) 59 Angiosarcoma 1 23
Angiosarcoma 59 I nfla m matory myofib roblasti c tum 1 24
our
Rhabdomyosarcoma 60 Peri vasc ular epithel i oid cell tumo 1 25
ur
Osteosarcoma 60 Solitary fibrous tumour 125
Synovial sarcoma 61 Leiomyoma 126
Ewing sarcoma 61 Haemangioma 1 26
Angiom yolipom a 62 Granular cell tumour 1 27
Epithelioid angiomyo lipoma 65 Neurofibroma 1 27
��m�ma 00 Other mesenchymal tumours 127
Haeman gioma 66 Haemato poietic and lymphoid tumours 1 28
Lymphangiom a 67 Lymphoma 1 28
Haemang ioblastoma 67 Plasmacytoma 1 28
Juxtaglomerular cell tumour 68 Carcinoma of Skene, Cowper, and L ittre glands 129
Renomedullary interstitial cell tumour 68 Metastatic tumour s 130
Schwannoma 69 Epithe l ial tumours of the upper uri nary tract 1 31
Solitary fibrous tumour 69 Epith e lial tumours ari s i ng in a bladder diverticulu m 1 32
Mixed epithelial and stromal tumour family 70 Urothel ial tumou rs of the urethra 133
Adult cystic nephroma 70
3 Tumours of the prostate 135 Germ cell tumours unrelated to germ cell
WHO and TNM classifications 1 36 neoplasia in situ 218
Acinar adenocarcinoma 1 38 Spermatocytic tumour 218
High-grade prostatic intraepithelial neoplasia 1 62 Teratoma. prepubertal-type 221
lntraductal carcinoma 1 64 Mixed teratoma and yolk sac tumou r,
Ductal adenocarcinoma 1 66 prepubertal-type 223
Urothelial carcinoma 1 68 Yolk sac tumour, prepubertal-type 225
Squamous neoplasms 1 70 Sex cord-stromal tumours 227
Adenosquamous carcinoma 1 70 I ntroduction 227
Squamous cell carcinoma 1 70 Pure tumours 227
Basal cell carcinoma 171 Leydig cell tumour 227
Neuroendocrine tumours 1 72 Sertoli cell tumour, NOS 228
Neuroendocrine cells in usual prostate adenocarcinoma 1 72 Large cell calcifying Sertoli cell tumour 230
Adenocarcinoma with Paneth cell-like l ntratubular large cell hyalinizing
neuroendocrine differentiation 1 72 Sertoli cell neoplasia 231
Well-differentiated neuroendocrine tumours 1 72 Granulosa cell tumour 232
Small cell neuroendocrine carcinoma 1 72 Adult granulosa cell tumour 232
Large cell neuroendocrine carcinoma 1 74 Juvenile granulosa cell tumour 233
Mesenchymal tumours 1 75 Tumours in the fibroma-thecoma group 233
Stromal tumour of uncertain malignant potential and Mixed and unclassified sex cord-stromal tumours 234
stromal sarcoma 1 75 Emerging entity 235
Leiomyosarcoma 1 76 Tumour containing both germ cell and
Rhabdomyosarcoma 1 76 sex cord-stromal elements 236
Leiomyoma 1 77 Gonadoblastoma 236
Other mesenchymal tumours 1 77 Miscellaneous tumours of the testis and
Haematolymphoid tumours 1 78 paratesticular tissue 238
Lymphoma 1 78 Ovarian epithelial-type tumours 238
Leukaemia 1 78 Juvenile xanthogranuloma 239
Miscellaneous tumours 1 79 Haemangioma 239
Metastatic tumours 1 80 Haematolymphoid tumours 240
Seminal vesicle tumours 181 Introduction 240
Adenocarcinoma 181 Diffuse large B-cell lymphoma 240
Squamous cell carcinoma 181 Follicular lymphoma, NOS 242
Mixed epithelial and stromal tumours 1 82 Extranodal N K(T-cell lymphoma, nasal-type 242
Cystadenoma 1 82 Plasmacytoma 243
Mesenchymal tumours 1 82 Myeloid sarcoma 243
Miscellaneous seminal vesicle tumours 1 83 Rosai-Dorfman disease 243
Metastatic tumours 1 83 Tumours of collecting duct and rete testis 244
Adenoma 244
4 Tumours of the testis and paratesticular tissue 185 Adenocarcinoma 244
WHO and TNM classifications 1 86 Tumours of paratesticular structures 246
Germ cell tumours 1 89 Adenomatoid tumour 246
Germ cell tumours derived from Mesothelioma 247
germ cell neoplasia in situ 1 89 Epididymal tumours 248
Germ cell neoplasia in situ 1 99 Cystadenoma 248
Tumours of a single histological type (pure forms) 203 Papillary cystadenoma 249
Seminoma 203 Adenocarcinoma 250
Non-seminomatous germ cell tumours 205 Squamous cell carcinoma 250
Embryonal carcinoma 205 Melanotic neuroectodermal tumour 251
Yolk sac tumour, postpubertal-type 207 Nephroblastoma 252
Trophoblastic tumours 209 Paraganglioma 252
Choriocarcinoma 209 Mesenchymal tumours of the spermatic cord and
Non-choriocarcinomatous testicular adnexa 253
trophoblastic tumours 210 Adipocytic tumours 253
Teratoma, postpubertal-type 21 1 Smooth muscle tumours 254
Teratoma with somatic-type malignancy 21 3 Skeletal muscle tumours 254
Non-seminomatous germ cell tumours of more than Fibroblastic/myofibroblastic tumours 255
one histological type 215 Nerve sheath tumours 256
Mixed germ cell tumours 215 Other mesenchymal tumours o f the spermatic cord
Germ cell tumours of unknown type 21 7 and testicular adnexa 256
Regressed germ cell tumours 217 Metastatic tumours 257
5 Tumours of the penis 259
WHO and TNM classifications 260
Malignant epithelial tumours 262
Squamous cell carcinoma 262
Non-HPV-related squamous cell carcinomas 265
Squamous cell carcinoma, usual type 265
Pseudohyperplastic carcinoma 266
Pseudoglandular carcinoma 267
Verrucous carcinoma 268
Carcinoma cuniculatum 269
Papillary carcinoma, NOS 269
Adenosquamous carcinoma 270
Sarcomatoid squamous cell carcinoma 270
Mixed squamous cell carcinoma 271
HPV-related squamous cell carcinomas 272
Basaloid squamous cell carcinoma 272
Papillary-basaloid carcinoma 272
Warty carcinoma 273
Warty-basaloid carcinoma 274
Clear cell carcinoma 275
Lymphoepithelioma-like carcinoma 275
Other rare carcinomas 276
Precursor lesions 277
Penile intraepithelial neoplasia 277
Extramammary Paget disease 279
Melanocytic lesions 280
Mesenchymal tumours 280
Penile lymphomas 284
Metastatic tumours 285

Contributors 287
IARC/WHO Committee for ICD-0 294
Sources of figures and tables 295
References 300
Subject index 349
List of abbreviations 356
 CHAPTER 1

Tumours of the kidney

Clear cell renal cell carcinoma

Multilocular cystic renal neoplasm of low malignant potential

Papillary renal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma-associated

renal cell carcinoma

Chromophobe renal cell carcinoma

Collecting duct carcinoma

Renal medullary carcinoma

MiT family translocation renal cell carcinomas

Succinate dehydrogenase-deficient renal cell carcinoma

Mucinous tubular and spindle cell carcinoma

Tubulocystic renal cell carcinoma

Acquired cystic disease-associated renal cell carcinoma

Clear cell papillary renal cell carcinoma

Unclassified renal cell carcinoma

Papillary adenoma

Oncocytoma

Metanephric tumours

Nephroblastic and cystic tumours occurring mainly in children

Mesenchymal tumours

Mixed epithelial and stromal tumour family

Neuroendocrine tumours

Renal haematopoietic neoplasms

Metastatic tumours
 W H O c l assifi cati o n of t u m o u rs of the ki d n ey

Renal cell tumours Mesenchymal tumours occurring mainly in adults

Clear cell renal cell carcinoma 831 0/3 Leiomyosarcoma 8890/3
Multilocular cystic renal neoplasm of low Angiosarcoma 91 20/3
malignant potential 831 6/1 * Rhabdomyosarcoma 8900/3
Pap i l lary renal cell carcinoma 8260/3 Osteosarcoma 9 1 80/3
Hereditary leiomyomatosis and renal cell Synovial sarcoma 9040/3
carcinoma-associated renal cell carcinoma 8311 /3* Ewing sarcoma 9364/3
Chromophobe renal cell carci noma 831 7/3 Angiomyolipoma 8860/0
Collecting d uct carc i noma 831 9/3 Epithelioid angiomyolipoma 8860/ 1 *
Renal medu llary carcinoma 851 0/3* Leiomyoma 8890/0
MiT family translocation renal cell carcinomas 831 1 /3* Haemangioma 9 1 20/0
Succinate dehyd rogenase-deficient Lymphangioma 91 70/0
renal cell carcinoma Haemangioblastoma 91 6 1 / 1
Mucinous tubular and spindle cell carci noma 8480/3* J uxtaglomerular cell tumour 8361 /0
Tubulocystic renal cell carcinoma 831 6/3* Renomedullary interstitial cell tumour 8966/0
Acq uired cystic d isease-associated renal Schwannoma 9560/0
cell carcinoma 831 6/3 Solitary fibrous tumour 881 5/1
C lear cell papillary renal cell carcinoma 8323/1
Renal cell carcinoma, unclassified 831 2/3 M ixed epithelial and stromal tumour family
Papillary adenoma 8260/0 Adult cystic nephroma 8959/0
Oncocytoma 8290/0 Mixed epithelial and stromal tumour 8959/0

Metanephric tumours Neuroendocrine tumours

Metanephric adenoma 8325/0 Wel l-differentiated neuroendocrine tumour 8240/3
Metanephric adenofibroma 901 3/0 Large cell neuroendocrine carcinoma 80 1 3/3
Metanephric stromal tumour 8935/1 Small cell neuroendocrine carcinoma 8041/3
Paragangl ioma 8700/0
Nephroblastic and cystic tumours occurring
mainly in children Miscellaneous tumours
Nephrogenic rests Renal haematopoietic neoplasms
Nephroblastoma 8960/3 Germ cell tumours
Cystic partially differentiated nephroblastoma 8959/1
Paediatric cystic nephroma 8959/0 Metastatic tumours

Mesenchymal tumours
The morphology codes are from the International Classification of Diseases
Mesenchymal tumours occurring mainly in children for Oncology (ICD-0) l91 7AI Behaviour is coded /0 for benign tumours;
Clear cel l sarcoma 8964/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Rhabdoid tumour 8963/3 situ and grade Ill intraepithelial neoplasia; and /3 for malignant tumours.
Congenital mesoblastic nephroma 8960/1 The classification is modified from the previous WHO classification l756AL
Ossifying renal tumour of i nfancy 8967/0 taking into account changes in our understanding of these lesions
'New code approved by the IARC/WHO Committee for ICD-0.

12
1.
TNM c l ass ifi cati o n of re n a l cell carci noma

TNM classification•·b N - Regional lymph nodes

NX R eg io na l l y m ph nodes canno t be asses
sed
T - Primary tumour NO No regio nal lymp h node meta stasi
s
TX Primary tumour cannot be assessed N1 Regio nal lymph node metastasi s
TO No evidence of primary tumour
T1 Tumou r � 7 cm in g reatest d imension, limited to the kidney M - Distant metastasis
T1a Tumou r � 4 cm MO No distant metastasis
T1b Tumour> 4 cm but� 7 cm M1 Distant metastasis
T2 Tumour> 7 cm in g reatest dimension, limited to
the kidney Stage grouping
T2a Tumour> 7 cm but � 10 cm Stage I T1 NO MO
T2b Tumour> 10 cm Stage II T2 NO MO
T3 Tumour extends into major veins or perinephric tissues Stage I l l T1-2 N1 MO
but not into the ipsi lateral adrenal gland and not beyond T3 Any N MO
the Gerota fascia Stage IV T4 Any N MO
T3a Tumour g rossly extends into the renal vein or its Any T Any N M1
segmental (muscle-containing) branches, or tumour
invades perirenal and/or renal sinus fat but not
beyond Gerota fascia •Adapted from Edge et al 1759) - used with permission of the American
T3b Tumour grossly extends into the vena cava below Joint Committee on Cancer (AJCC), Chicago, Illinois; the original and prima­
the diaphragm ry source for this information is the AJCC Cancer Staging Manual, Seventh
T3c Tumour g rossly extends into the vena cava above the Edition (2010) published by Springer Science+Business Media - and Sobin
diaphragm or invades the wall of the vena cava et al. (2558A}.
T4 Tumour invades beyond the Gerota fascia (including "A help desk for specific questions about TNM classification is available at
contiguous extension into the ipsilateral adrenal gland) [Link]
 Moch H. Martig noni G.
Renal cell tumou rs Amin M B. Medeiros L.J
Argani P. Srig ley J . R .
Introd u ct i o n Cheville J . Tan P . H .
Delahunt B . Tickoo S.K.

Epidemiology USA and up to 40% in European coun­ and progesterone, insulin resistance,
tries [ 2295A,2295B ) . The mechanisms and i ncreased levels of growth factors
I ncidence and mortality rates have by which obesity influences renal car­ such as I G F 1 , may contribute to renal
been increas ing in many countries, ci nogenesis are unclear. Sex steroid hor­ carci nogenesis.
across d ifferent levels of socioeconomic mones may affect renal cell proliferation Prospective studies from North America
developm ent. by direct endocrine receptor-mediated and Europe found no association be­
effects. Obesity with the combined en­ tween i ntakes of red meat, processed
Incidence docrine d isorders, such as decreased meat, poultry, or seafood and renal cell
Kidney cancer was the ninth most com­ levels of sex hormone-binding globulin carci noma risk { 1 6 1 1 A, 1 6 1 1 B} .
mon cancer in men ( 2 1 4 000 cases) and
the 1 4th most common in women ( 1 24 000
cases) worldwide in 201 2 . Approximately
70% of the new cases occu rred in coun­
tries with high and very high levels of so­
cioeconomic development, with 34% of
the estimated new cases in Eu rope and
1 9% in North America. Renal cell carci­
noma is more common i n men than in
women (approximately 2: 1 ) and is rare i n
childre n . The highest incidence rates are
found in the Czech Republ ic. Elevated
rates are also found in northern and east­
ern Europe, North America, and Australia.
Low rates are estimated in much of Africa
and eastern Asia.

Morta/tty
There were an estimated 1 43 000 deaths
from kid ney cancer in 20 1 2 (91 000 in ASR (world) incidence men
men, 52 000 in women); kid ney cancer 0 5 10 15 20 25
is the 1 6th most common cause of death
from cancer worldwide. The case fatality
rate is lower in hig hly developed coun­
tries (overall mortality-to-i nc idence ratio:
0.4) than in countries with low or medium
levels of socioeconomic development
· (0.5). Only 3 . 1 % of the cases were d iag­
nosed in Africa, but 5.7% of the deaths
occurred in this reg ion.

Etiology

Obesity
There is convi ncing evidence that body
fatness is a cause of kid ney cancer. Be­
ing overweight, especially being obese,
is a risk factor for renal cancer i n both
women and men { 1 68 1 A} . The propor­ ASR (world) incidence women
tion of all cases of renal cancer attrib­
utable to overweight and obesity has Fig. 1 .01 Global distribution of estimated �ge-standardfzed (world) i �cidence rate� (ASRs) per �00 000 pop��tion, tor
been estimated to be about 40% i n the kidney cancer in men and women, 2012. From Cancer Incidence in Five Continents {848}.

14 Tumours of the kid ney

Smoking d isease (3-7%) 16911 R e n a l cancer oc­ Genetic susceptibility
Meta-analyses i ndicate that ever-smoking curri n g i n end-stage renal disease has
increases the risk of renal cancer com­ specific characteristics different from Alll1ough most renal carc ino m as are
pared with never-smoking (508A, 1 258AI. those of classic renal cancer. Papill ary sporncl ic. 2 !J% have a fam i l ial cause
There is also a dose-dependent increase renal cell carci noma was bel ieved to be Several �.JOI 1etic cJisecises me associated
wil11 r�111al ce:u1cer [756/\I Tl1c risk of renal
in risk related to the number of cigarettes the most common su btype in end-stage
cancer for a first d e gre e relative of a pa­
smoked per day. Risk decreases in the renal disease. Currently, renal cancer
-

5-year period after smoki ng cessation. associated with acq uired cystic kid ney tlenl with renal can cer is approximately
double. Ea ch ol the cornmor1 histologi cal
Epidemiological data on kidney cancer d isease is regarded as its own histologi­
causation by smoking are often biased cal subtype, but all other subtypes (clear su btypes of renal cancer has a corre­
since cancer registries do not typically cel l , papil lary, and chromophobe renal sponding familial cancer synd rome.
d ifferentiate between renal cell carci­ cell cancer) also occur i n cystic and non­
nomas and urothelial carcinomas of the cystic end-stage kidneys
renal pelvi s. For the latter, smoki ng is a Basis of nomenclature for
sign ificant risk factor. Occupational exposure
the histological classification
Trichloroethylene is a solvent that has
Hypertension been widely used as a metal degreaser I n the United States Armed Forces I n sti­
Hypertension or its treatment has been and chemical additive 1 1 41 OA) . A meta­ tute of Pathology (AFIP) Atlas of Tumour
associated with risk of renal cancer analysis of the association between ex­ Pathology, Second Series fascicle 011
( 2939A ) . Use of hypertensive med ica­ posure to trichloroethylene and clear cell tumours of the kidney, renal pelvis. and
tion , including diuretics, has been as­ renal cancer reported significant relative ureter, publ ished in 1 97 5 , the histological
soc iated with an elevated risk. The asso­ risks of kid ney cancer: 1.3 overall and 1 . 6 diversity of renal cell carcinoma (RCC)
ciations between risk of renal cancer and for hig h-exposure groups (2458A) . The In­ was acknowledged merely with the state­
hypertension are independent of obesity. ternational Agency for Research on Can­ ment "renal adenocarcinoma has many
cer ( IARC) has classified trichloroethylene faces", and accompanying microscopic
Acquired cystic kidney disease as Group 1 (carcinogenic to humans) on descriptions classified the tumours i nto
This cond ition usually develops in pa­ the basis of causing kid ney cancer two major categories: clear cell carci­
tients on long-term haemodialysis due to noma and granular cell carci noma. In the
end-stage renal disease. The incidence It is unl ikely that coffee has a su bstantial ef­ four decades s i nce that fascicle was pub­
of renal cancer is reported to be mark­ fect, or that alcohol ic drinks have an adverse lished, there has been unprecedented
edly increased i n patients with end-stage effect, on the risk of this cancer l2982AJ . i nterest in the morpholog ical su btypes of

Table 1.01 Features of hereditary renal cell tumours

Extrarenal manifestations
Syndrome Chromosome(s) Gene Protein Tumour type
In the dermis In other organs
-

Haemangioblastoma of the retina

Von and central nervous system;
Multiple, bilateral clear cell
Von Hippel-Lindau Hippel­ phaeochromocytoma; pancreatic and renal
3p25 VHL renal cell carcinoma; renal
syndrome Lindau cysts; neuroendocrine tumours; epididymal
cysts
protein and parametrial cysts; tumours of the inner
ear
Hereditary papillary renal Multiple, bilateral papillary
7p31 MET MET
cell carcinoma renal cell carcinoma (type 1 )
Hereditary leiomyomatosis Fumarate Papillary renal cell
1 q42 FH Leiomyoma Uterine leiomyoma/leiomyosarcoma
and renal cell carcinoma hydratase carcinoma (non-type 1 )
Familial papillary thyroid Papillary renal cell
1q21 Unknown Unknown Papillary thyroid carcinoma
carcinoma carcinoma. oncocytomas
Mixed epithelial and stromal
Hyperparathyroidism­ Para- Parathyroid tumours; fibro·osseous jaw
1 q25 HRPT2 tumours, papillary renal cell
jaw tumour syndrome fibromin tumours
carcinoma
Multiple chromophobe
Birt-Hogg-Dube renal cell carcinoma, hybrid Facial Pulmonary cysts; spontaneous
1 7p11 FCLN Foll icu l in
syndrome chromophobe oncocytoma, fibrofolliculoma pneumothorax
papillary renal cell carcinoma
Multiple, bilateral Cardiac rhabdomyoma; adenomatous small
Tuberous sclerosis
9q34 TSC1 Hamartin angiomyolipomas; Angiofibroma, intestine polyps; pulmonary and renal cysts;
1 6p13 TSC2 Tuberin lymphangioleiomyomatosis; subungual fibroma cortical tuber; subependymal giant cell
rare renal cell carcinomas astrocytomas
Constitutional chroma· Multiple, bilateral clear cell
3p1 3-1 4 Unknown Unknown
some 3 translocations renal cell carcinoma

1 11[:" 1c111r iin1, 15

Table 1 .02 Features of emerging/provisional renal cell carcinomas
Clinical Morphological Molecular Outcome -

• Increased incidence of renal cell

carcinoma among neuroblastoma
survivors
·Solid, cystic, and papillary
Oncocytic renal cell carcinoma • Heterogeneous group, with some MiT • • Limited follow-up
• Oncocytic cells with vacuoles and calcification No molecular marker
occurring after neuroblastoma family translocation renal cell
• No distinctive immunohistochemistry
carcinomas
• One distinct oncocytic group with or
without exposure to chemotherapy
•Tan-brown gross appearance
• Most are indolent
• Resembles thyroid parenchyma, with
•Limited studies and •There are rare
Thyroid-like follicular renal cell • Broad age range follicles and colloid
no distinctive molecular examples of
carcinoma • Slight female predominance • No distinctive immunohistochemistry, but
marker lymph node and
thyroid transcription factor 1 and
lung metastasis
thyroglobulin are negative
For paediatric cases:
• Rare (< 10 cases reported) • Medullary location
ALKrearrangement-associated
•3 distinct cases with ALK-vinculin fusion • Large polygonal/spindle cells • VCL-ALKgene fusion •Limited follow-up
renal cell carcinoma
in children with sickle cell trait • Eosinophilic cytoplasm with
intracytoplasmic lumina
•Adults
• Male predominance • Branching tubules I papillary tufts
• Historically categorized as a clear cell or •Clear cells • No 3p deletion
Renal cell carcinoma with clear cell papillary renal cell carcinoma • Prominent vascular and smooth muscle • No trisomy 7 or 1 7 • Indolent, but
(angio)leiomyomatous stroma • Has also been called renal stroma • TCEB1 gene mutation limited follow-up
angiomyoadenomatous tumour • Positive for CK?, 34�E12, and CD10; recently described
• Occurs sporadically or is associated negative for racemase
with tuberous sclerosis

adult renal epithelial neoplasia. Over the (e.g. metanephric adenoma), the ana­ appeared to be disti nct, these rare tu­
years, unique morpholog ical su btypes tomical location of the tumours ( e . g . col­ mours were not yet fully characterized by
have been descri bed , each with charac­ lecti ng duct and renal medul lary carci no­ morphology, immunohistochemi stry , and
teristic h istological features and unique mas), and a correlation with background molecular studies, and further reports
immunoprofiles, and i n many cases with renal di sease (e.g. acq u i red cystic d is­ were needed to refine their diagnostic
distinctive molecular alterations. As more ease-associated RCC) . Names referring criteria and establish clin ical outcomes.
data were reported from large institu­ to molecular alterations that are pathog­ Succinate dehydrogenase-deficient re­
tional series, it became clear that the his­ nomonic for RCC su btypes have also nal carcinoma was included in the cat­
tological subtyping of renal tumours has been used ( e . g . MiT family translocation egory of emerging entities in the Vancou­
prognostic significance, As experience carci nomas and succinate dehydroge­ ver classification but is now considered
with , and understanding of, the molecu­ nase-deficient renal carcinoma). Familial to be an establ ished entity on the basis of
lar underpi nnings of kidney cancer have predisposition has also been denoted recent publ ications {982,296 1 } .
i ncreased further, it has also become evi­ (e.g hered itary leiomyomatosis and Renal cell carc i noma ( RCC) in neuro­
dent that many of the subtypes of RCC RCC-associated RCC). The 20 1 6 WHO blastoma survivors was included in the
. have predictive sig nificance for uniq ue classification of tumours of the kid ney is 2004 WHO classification , but it is now
'
therapeutic approaches. summarized in the table at the beg i n n i n g recog n ized that the tumours d iscussed i n
As the histological classification of RCC o f t h i s chapter, a n d the d i sti nguishing that publ ication are i n fact quite diverse
has developed, the termi nology used for features of the various hered itary renal j 884, 1 858, 2967} . There is an i ncreased
desig nating its su btypes has referred to cell tumours are summarized i n Table incidence of RCC among survivors of
various descri ptive or characteristic fea­ 1 .01 , child hood neuroblastoma. Some report­
tures. Subtypes have been named on the ed cases have proven to be M iT family
basis of predom inant cytoplasmic fea­ translocation RC Cs {67, 1 1 48 j and oth­
tures and stai ning characteristics ( e . g . Emerging/provisional ers are d ifficult to classify based on the
clear c e l l and chromophobe RCCs), ar­ renal cell carcinomas publ ished patholog ical details and im­
chitectural features (e.g. pap i l lary RCC), ages. Nevertheless, there appears to be
cell type (e.g. renal oncocytoma), and The 20 1 3 I nternational Society of Uro­ a distinct oncocytic variant, which for the
combinations of these features (e.g. clear logical Pathology ( I SUP) Vancouver pu rpose of this publication is considered
cell papil lary RCC). Other approaches to Classification of [adult] Renal Neoplasia an emerg ing/provisional entity, g iven the
naming renal tumours have been based identified a category of emerg ing or pro­ lack of d i stinctive immunoh istochemical
on their resemblance to em bryological visional new e ntities ( 2590} . The classifi­ or molecular markers ( 1 858}.
structures - such as the metanephros cation noted that although these entities

16 111111rn1r�; or ii1r-; ;1liw:: y

 sl 10L1lcl I Jc: LJ'.;c;<I 111:;le;1<i lfi77 ,679,684 I
Table 1.03 WHO I International Society of Urological 2495A ,2960AI. Autl1ors llav 11sed tile
Pathology (ISUP) grading system for clear cell renal cell ter m "renal anglomyoadenomatous
tu­
mour" ( 18901. Som e of these tumours a
carcinoma and papillary renal cell carcinoma (677} For \-)r<Jcle 1 :3 tumours ti iis system cJe­
re fi11cs IL11llOL1r Cjrnclr: 011 tlw hcisi:; of nu­
Grade Description variants of clear cel l RCC o r c lea r cell
c l eol ar prorni1w11cc-; G1 aclc '1 is definccl
Nucleoli are absent or inconspicuous and papillary RCC, but there also appears to hy ti1P rnsrn1cc; of pro11rn111cc;cl 1JL1clc:nr
Grade 1 be a distinct subgroup with character istic
basophilic at x4QO magnification. plen1no1pliis1n, turnrnrr CJtimt cells, ;111cl/
Nucleoli are conspicuous and eosinophilic
morphological features. These tu mours or rl1alJ<'lo1d and/or sarcorn
aloicl clilfcr­
Grade 2 al x4QO magnification and visible but not occur sporadically and some have been e nt i ation (Table 1 03) Grode s t·1o u ld be
prominent at x1QO magnification. associated with tu berous sclerosis 1 1 086, assigr1ed on th b::isls or thes • criteria
Nucleoli are conspicuous and eosinophilic 1 874A f . The neoplasms have branch­ within lhe sin le hrgh�pow
r 11 Id sl\OW·
Grade 3
of n11clear plpo..
at x1QO magriification. ing tubules and papillae lined by clear rng lhe grea\est cl·· ree
and gran ular cells surrounded by abun­ mo!p h i s m . l t11s grncil11g sysl
m 1 ms been
There is extreme nuclear pleomorphism,
multinucleate giant cells, and/or rhabdoid dant vascular and smooth muscle stro­ valrdat d as an inci i .ator of
proc nosrs for
Grade 4
and/or sarcomatoid differentiation. ma ! 2960A f . The epithelial component c l ear cell renal ce l l cai clnornA
�1nrl papil­
ugl 1 ii 11as
stains positively for CK? and C D 1 0 and l ar y renal cel l car c inoma l\ltho
negatively for racemase, The tumours nol yet b en val Ida l ed as CJ proc, 1osu
Fewer than 20 thyroid-like fol l icular RCCs do not show 3p deletions or trisomy 7 or marke r for other 1norpl1otyp s of renal
have been descri bed . Although these 1 7 I 2960Al . A recent report associated cel l neop tasia (due p1lm. rily lo 11 · sm
1 11
tumours are histologically d istinctive, re­ TCEB 1 gene mutations with this d istinc­ n u m bers or reported cases), the syst m
semb l i ng thyroid parenchyma, they have tive RCC morphotype ( 1 099A}. can be t,JSed to descrlbA the morpl 1otogl­
no characteristic immu nohistochemical I n summary, oncocytic RCC occu rring cal fealures or these t u m ou rs .
or molecular markers 18 1 A, 5 1 6Al. Impor­ after neuroblastoma, thyroid-like follicu­
tantly, the thyroid markers thyroid tran­ lar RCC, ALK rearrangement-associated
scription factor 1 and thyrog lobu l i n are RCC , and renal carcinoma with (angio) Staging
negative . Most of these tumours have ex­ leiomyomatous stroma are cu rrently i n­
hibited i ndolent behaviour, although rare cl uded in the emerg ing entities category The 20 1 0 TNM stag ing system has two
examples with lymph node and lung me­ (Table 1 02). categories for renal-limited tumours
tastases have been descri bed ! 5 1 6Al . ( pT1 a/b and pT2a/b) , differentiated by
Fewer than 1 0 RCCs associated with tumour size. Regional spread ( pT3) in­
ALI< gene rearrangements have been Grading cludes spread to peripheral perinephric
reported in the l iterature ( 2551 Al . Three fat and central sinus fat i nvasion ( pT3a);
disti nct examples showing fusion of ALK A variety of grad ing systems have been venous invasion, including renal sinus
and the cytoskeletal protein vinculin have proposed for renal cell neoplasia; how­ and renal vein invasion ( pT3a); extension
i nvolved chil dren with sickle cell trait ever, these have not been val idated for i nto the inferior vena cava below the d ia­
1667A , 1 787 B , 255 1 A} . These med u l lary­ many of the morphotypes of renal cell phragm ( pT3b); and extension i nto the
based tumours consist of large polygo­ carcinoma that have been recently de­ i nferior vena cava above the diaphragm
nal and spindle cells with eosinophilic scri bed . Of the n u merous grad ing clas­ ( pT3c ) . Distant spread ( pT4) includes di­
cytoplasm and i ntracytoplasmic l umina. sifications that have been proposed , that rect extension i nto the adrenal g land and
Unl ike i n renal medullary carc i noma, of Fuhrman et al. j929A} is most widely i nvasion of the Gerota fascia Surgical
the Ki-67 prol iferation i ndex is relatively used . However, there are problems specimens shou ld be carefully examined
low, and SMARC B 1 (also called I N1 1 ) with the interpretation, validation, and for renal sinus invasion (i e i nfiltration of
protein expression is i ntact l 5 1 6A } . reprod ucibi lity of the Fuhrman system, renal sinus fat or loose connective tis­
In recent years, reports o f R C C associat­ and for these reasons, the four-tiered sue) and endothelial-lined l arge vascular
ed with prominent (angio)leiomyomatous WHO I I nternational Society of Urologi­ spaces within the renal sinus ! 27451.
stroma have been publ ished I 1 532A, cal Pathology ( I SUP) grad ing system

1111 odu 11n11 17

Clear cel l re n a l ce l l carc i n o m a Moch H
Bonsib S. M .
Linehan W,M .
Reuter V.E.
Delahunt B . Srigley J . R .
Eble J. Sulser T .
Egevad L. Tan P . H .
G rignon D.J.

Definition leading to the development of pulmonary

Clear cell renal cel l carci noma (ccRCC) metastases {302,303, 1 21 1 ,201 1 ) . Exten­
is a morpholog ically heterogeneous sion into the lumbar veins from the renal
group of malignant neoplasms com­ veins facil itates spread to the low-pressure
posed of cells with clear or eosinop h i l ic paravertebral venous plexus (which con­
cytopl asm . These neoplasms have typi­ nects to the dural venous sinuses) supe­
cal vessel formation and a characteristic riorly and the pelvic veins inferiorly, facili­
molecular backgrou nd, with inactivation tating central nervous system, head and Liver40%- -

-/N��:ij--
of VHL and upregulation of hypoxia-in­ neck, and central and peripheral osseous Digestive system 9,'llrft___,_
Adrenal 22%
ducible factor. metastasis { 2 1 48) . Lymphatic metastases
can involve hilar, aortic, and caval lymph Peritoneum 10%
ICD-0 code 83 1 0/3 nodes, and can enter the thoracic duct or Bone40%
involve thoracic nodes directly. These d i­ Soft tissue 34%
Synonyms verse metastatic pathways enable ccRCC
Obsolete: renal clear cell adenocarcino­ to metastasize to u nusual sites (2943,
ma; G rawitz tumour; hypernephroma 2991 ) . Fig. 1 .03 Frequency of organ involvement by
haematogenous metastasis in patients with metastatic
=
renal cell carcinoma (n 636) at autopsy (2991).
Epidemiology Localization
ccRCC accounts for 65-70% of all renal ccRCCs are typically sol itary cortical tu­ typically golden yellow, due to the high
cancers. mours that occur equally commonly in lipid content of their cells. Cysts, necro­
both kid neys . Mu ltifocality and/or bilat­ sis, and haemorrhage are common . Cal­
Etiology erality occur in less than 5% of cases. cification and ossification may occur.
ccRCCs occur sporadical ly, and some Multifocality, bilaterality, and early age
studies have shown associations with of onset are typical of hereditary cancer Histopathology
causative agents (see the Introduction syndromes such as van Hippel-Li ndau ccRCC is architectural ly d iverse, with
section at the beginning of this chapter, syndrome { 2026) . solid alveolar and acinar patterns being
p. 1 4) . Rarely, these tumours may also most common. The carcinomas typically
occur in various fam i lial setti ngs. Macroscopy contain a regular network of smal l , thin­
These carcinomas are typically g lobular walled blood vessels, a diagnostically
Clinical features tumours protruding from the renal cor­ helpful characteristic of this tumour. No
About 60-80% of kidney cancers are tex. The border with the kidney is usually lumina are apparent i n the alveolar pat­
found incidentally on u ltrasound, CT, or sharp, with a pseudocapsule. Diffuse in­ tern, whereas a central rounded luminal
M R I . The most common symptoms of kid­ filtration of the kidney is uncommon. The space filled with acidophilic serous fluid
ney cancer (in symptomatic cases) are carcinomas may be very large, but the or erythrocytes is present in the acinar
haematuria and flank pai n . Weight loss detection of small lesions is increasi ng in pattern. The alveolar and acinar struc­
and fever occur in late stages. cou ntries where rad iological procedures tures may d ilate, prod ucing microcystic
Metastasis. ccRCCs most commonly me­ are widely used . Renal sinus and renal and macrocystic patterns. Uncommonly,
tastasize haematogenously via renal si­ vein involvement may be seen, particu­ ccRCC has a distinct tubular pattern, and
nus veins, renal veins, and venae cavae, larly with large tumours. ccRCCs are (rarely) pseudopapillary arch itecture is
focally present.
The cytopla sm is commo nly filled with li­
pids and g lycoge n, which are dissolv ed
by routi ne histological prooessln , cre­
g
aling a clear cytoplasm surrounded by
distinc t cell m e m b r anes, Many ccRCCs
contain cel ls wlth eosin ophi iic cytoplasm.
This is· par t ic u l arly com mon in high-grade
tumours and adjacent to a re as of necro­
sis or haemm rhage .
In wel l-preserved preparations, the nu­
Fig. 1.02 A Left-sided clear cell renal cell carcinoma. Arterial-phase contrast-enhanced MRI. B Bilateral clear cell renal clei lend to be round wil11 evenly d is­
cell carcinoma. Arterial-phase contrast-enhanced MRI. tributed chromat i n . Depend ing on the

18 Tumours of the kidney

A
Fig. 1 .04 A Small cortical clear cell renal cell carcinoma (ccRCC) at the upper pole of the kidney with penetration of the capsule but without infiltration of neighbouring organs. Stage
pT1 . B Large ccRCC, well demarcated with yellowish areas reflecting high lipid content. C Typical cross-section of yellowish, spherical neoplasm in the upper pole of the kidney.
Note the tumour in the dilated thrombosed renal vein (arrow). In addition, there is a benign renal angiomyolipoma in the lower pole with a characteristic yellow cut surface due to fat
cells (asterisk) .
grade, nucleoli may be i nconspicuous lmmunophenotype IX staining pattern of ccRCC d iffers from
and small or large and prom i nent. Bi­ PAX8, a 48 kDa transcription factor, is the basolateral positivity observed in
zarre nuclei or very large nuclei lacking expressed i n a n uclear d istribution in clear cell papil lary renal cell carc i noma
nucleoli may occasionally be present. A virtual ly all ccRCCs, as well as i n other ( RCC) {2675) . ccRCC expresses epi­
host of u nusual histolog ical find ings have renal epithelial neoplasms {24 1 1 , 24 1 3) . thelial markers such as cytokeratin A E 1 /
been described in ccRCC. Sarcomatoid PAX2 is present in a similar distribution A E 3 , CAM5 .2, and epithelial membrane
and rhabdoid changes each occu r in as PAX8, but PAX8 is a more sensitive antigen. CK? expression is rare and lim­
about 5% of tumours and are associated marker { 1 743 , 2 1 07 ,25041 . Carbonic an­ ited to isolated cells or clusters of cells
with worse prognosis {656 ) . Some tu­ hydrase IX has a role i n carbon d ioxide in hig h-grade tumours {230 1 , 2509,2675)
mours have central areas of fibromyxoid transport and i n pH regulation. It is char­ and tumours with cystic com ponents.
stroma, areas of calcification , or areas acteristically overexpressed i n a diffuse CK? is often used to disti nguish ccRCC
of ossification. Most ccRCCs are asso­ membranous distribution in 75-1 00% of from chromophobe RCC, which dem­
ciated with little inflammatory response ; ccRCCs, although high-grade tumours onstrates d iffuse CK? positivity {2675) .
uncommonly, an i ntensely lymphocytic or may exhibit red uced expression {36,959, C D 1 0 , a proximal tubule marker, is posi­
neutrophilic i nfiltrate is present. 1 089,230 1 , 2620 ) . The complete cyto­ tive in ccRCC, i n a membranous d is­
plasmic membrane carbon ic anhyd rase tribution (326). However, at least focal

. '
A ·... •j • � •
# • • t
• \I t '

�
·
� � �
Fig. 1 .05 A Clear cell renal carcinoma in patient with on Hi el Lin d au syndrome. Note clear cells and cysts. B Clear cell renal cell carcinoma (WHO I International Society of
-

Urological Pathology [ISUP] grade 3).

C l c,,:11 c o l l rn 1 10I c d l c rn c i 1 1orna 19

 Fig. 1.07 PAXB immunohistochemistry in a renal cell
carcinoma.

immunoreactivity may be seen in other cancer syndrome ( 1 593 ) . VHL was also Hippel-Li ndau protei n (2289) . It appears
tumours. Vimentin is positive in ccRCC, shown to be biallelically genetically al­ that the loss of von Hippel-Li ndau pro­
more i ntensely i n hig h-grade areas tered in the majority of sporadi c ccRCCs tein function contri butes to tumour initia­
( 1 920). RCC marker is a monoclonal an­ ( 1 00 1 }. The VHL gene is epigenetically tion, progression, and metastasis [ 2596 ) .
tibody directed against a 200 kDa glyco­ silenced by promoter reg ion methylation Recent large-scale genomic sequencing
protein in the brush border of the proxi­ in as many as 20% of cases (390, 1 1 76 ) . studies have demonstrated that the 3p
mal renal tubules. It exhi bits cytoplasmic The protein encoded b y t h e VHL gene, locus harbours at least four additional
and membranous immunoreactivity i n von Hi ppel-Li ndau protei n , acts as an ccRCC tumour suppressor genes: the
72-84% of ccRCCs, b u t immunoreactiv­ adaptor protein to recruit various effector histone 3 lysine demethylase genes KD­
ity can also be seen in other renal tumour proteins to target proteins. These target M6A (also called UTX) and KDM5C (also
types and non-renal neoplasms [ 1 77, proteins include H I Fa, which is a tran­ called JARID 1 C), the histone 3 lysine
1 279, 1 839] . scri ption factor for oxygen-dependent methyltransferase gene SETD2, and the
ubiquiti n-med iated proteolytic deg rada­ SWl/SNF ch romatin remodelling complex
Genetic profile tion { 1 354). gene PBRM 1 . ccRCCs also harbour loss­
The VHL tumour suppressor gene was in­ A large n umber of d ifferent somatic VHL of-function mutations in the BAP 1 gene,
itially identified (by positional cloning) as mutations have been identified in sporad­ which plays a role in chromatin remodel­
the 3p25-26 gene that is altered in fami­ ic and hereditary ccRCC, with a variety of ling. BAP1-mutant tumours are typically
l ies with the von Hippel-Lindau famil ial effects on the various activities of the von

a Normoxla Hypoxia b Mutant

VHL protein

VHL VHL

HIF1-et

HIF-a VEGF GLUT 1 PDGF

degradation

VEGF
GLUT1
PDGF

Fig. 1 .08 Clear cell renal cell carcinoma. The product of the VHL gene, van Hippel-Lindau protein (VHL), forms a complex with elongin B, elongin C, cull i n 2 (CUL2), and RING-box
protein 1 ( RBX 1 ) to target HIF1a and HIF2a for ubiquitin-mediated degradation; this is a n oxygen-sensitive process. A In hormoxla, prolyl hydroxylase (PHO ) , In the presence of
2-oxogluturate (2-0G), puts two hydroxyl groups on HIFa, which enables the VHL complex lo recognize and target HIFo for degradation: in hypoxia, H IFo is not hydroxylated, the
VHL complex cannot target HIFa for degradation, and HIFa accumulates; HI Fa is a transcription factor that drives the l1<;1nscrlption of a number of hypoxia-associated genes, such
as the those that code vascular endothelial growth factor (VEGF}, platelet-derived growth factor (PDGF), and GLUT1. B When the VHL gene is mutated In clear cell kidney cancer,
the VHL complex cannot target and degrade H I Fo , so H I F 1 a and HIF2a accumulate; H I F2o is th ought lo be the critical pathway for VHL-deficlent clear cell renal cell carcinoma
,
tumorigenesis; several therapies targeting the VHL pathway, including sunitinib and pazopanlb have been approved for lreatment of advanced renal cell carcinoma. Adapted from
Li nehan et al. {1 669A}.

20 Tumours of t h e kidney
high-grade and are associated with poor Clea r Cell RCC - ISUP Grad e
outcome (390, 627 , 2 1 78,2432 1 .
I n addition t o tumou r-i n itiati ng pathways 100
involving the loss of ch romosome 3p,
Gl
other genetic characteristics that have
been associated with poor prog nosis in
ccRCC include allelic losses on ch ro­
1
80
\,
"· ····-.. .
G2

\
......
...

mosome 1 4q , loss of 4p, and loss of 9p

-.-· ....... . . ..... . _,_
·s
=
Ul
( 1 362, 1 453, 2450) . HIF1A is a l i kely tar­ 60 _
..
' ,
\ ....
- · --......
get of the 1 4q deletions. Copy number ...
'\
:e .,
gains of chromosome 5q are harboured
\
...
Qj
� .... _
40
by as many as 70% of ccRCCs {246).
""'·
The relevant target on chromosome 5q
.:.
Qj
c
- ..
... ... ... .... _ ...-
.....-

a
has recently been identified as SQSTM 1 20 ·
- ...
....- -- --- ..... ....
... - -- -
- ·--- -·
- - - -- - - •
- - -- - - - -
· --- ·
( 1 639 ) . G4

A major obstacle to the development of

effective oncolog ical therapies against 0
renal cancers may be that individual 0 10
tumours are often genetically heteroge­
Years
neous. Examples of i ntratumoural muta­
tional heterogeneity have been reported Fig. 1.09 Clear cell renal cell carcinoma (RCC). Cancer-specific survival with cases graded according to the WHO I
for mu lti ple genes. These genes had International Society of Urological Pathology (ISUP) grading system. Reprinted from Delahunt et al. {6 82).
apparently undergone multiple i nde­
pendent inactivating mutations i n d isti nct parameters are tumour g rade, presence used [677,679,684) . For g rade 1 -3 tu­
clonal populations within a single tumour of tumour necrosis, and sarcomatoid and mours, this system defines tumour grade
and its corresponding metastases {965). rhabdoid d ifferentiation {677) . lmmuno­ on the basis of nucleolar promi nence.
histochemical and molecular biomark­ Grade 4 is defined by the presence of
Genetic susceptibility ers have been widely i nvestigated as pronounced nuclear p leomorphism, tu­
ccRCC is the typical (nearly universal) potential prognostic factors for ccRCC, mour g iant cells, and/or rhabdoid and/or
manifestation of von H i ppel-Li ndau syn­ but they are not i n routine use i n clinical sarcomatoid d ifferentiation (Table 1 .03 ,
drome ; however, ccRCC can also occur practice {2675) . p. 1 7). Grade should be assigned on the
i n association with other fam i l ial renal Both sarcomatoid and rhabdoid d iffer­ basis of these criteria within the single
cancer synd romes, such as Cowden entiation in ccRCC are associated with high-power field showi ng the greatest
syndrome, Birt-Hogg-Dube synd rome poor prog nosis; the 5-year survival rate degree of nuclear pleomorphism.
1 2 1 69 1 , tuberous sclerosis 1588), and for tumours with sarcomatoid change is The presence of tumour necrosis is of
succinate dehydrogenase-deficient re­ 1 5-22% and the med i an survival for tu­ independent prognostic sig n ificance
nal cell carci noma {231 6 ) . mours with rhabdoid morphology is 8-31 {677, 1 9 1 9) . I n general , tumour necrosis
months {677 ) . accounting for > 1 0% of the total tumour
Prognosis and predictive factors A variety of g rading systems have been volume is associated with a less favour­
Prog nosis for patients with ccRCC is proposed ; however, the four-tiered able outcome. For TNM stage 1 and 2
most accurately predicted by patholog i­ WHO I I nternational Society of U rologi­ tumours, the cut-off point associ ated with
cal stage (676, 2745 ) . Among tumours cal Pathology ( I S U P) grading system has outcome is 20% of total tumour volume
of the same stage , further prog nostic been val idated for ccRCC and should be {2297) .

M� .....
Fig. 1.10 A Clear cell renal cell carcinoma with VHL deletion FISH expression. There are two signals in red (chromoso me 3) and one signal in green ( VHL gene). B Clear cell
�
renal cell carcinoma with clear cell papillary-like features in a alien! with von Hippel-Lindau syndrome. C One of multiple microtumours in the renal cortex of a patient with von
Hippel-Lindau syndrome.
M u lti l oc u l a r cysti c re nal neoplasm of Montironi R.
Cheng L.
l ow m a l i g n a nt pote nt i a l Lopez-Beltran A.
Michal M .
Moch H .

Definition Macroscopy PAX8 and carbonic anhydrase I X , a s is

Multilocu lar cystic renal neoplasm of The tumour consists exclusively of vari­ the case in typical ccRCC (2963} . The
low malignant potential is a tumour ably sized cysts separated by thin septa main d ifferential d iag noses are renal cell
composed entirely of numerous cysts, and fil led with clear, serous, or gelati­ carcinoma with cystic necrosis, tubulo­
the septa of which contain individual or nous fluid, or (much less commonly) with cystic carcinoma of the kidney, cystic
groups of clear cells without expansile haemorrhagic debris. Sol id, g rossly d is­ nephroma, clear cell papillary renal cel l
growth. This neoplasm is morphological­ cernible tumour mural nodules are in­ carcinoma with predominant cystic con­
ly indistinguishable from low-grade clear compati ble with the diagnosis {2650) . figuration, and benign multilocular renal
cell renal cell carcinoma (ccRCC) but cortical cysts { 1 828, 2964) .
recurrance or metastasis have not been Histopathology
reported {677 ) . The cysts are l ined by a single layer of Genetic profile
tumour cells with abundant clear cyto­ VHL mutations have been identified in
ICD-0 code 831 6/1 plasm and small nuclei without nucleoli 25% of these tumours {2881 ). Chromo­
(WHO I I nternational Society of Urologi­ some 3p deletion has been identified i n
Synonym cal Pathology [ISUP] g rade 1 or 2). In 89% o f ccRCC cases a n d 7 4 % o f m u l ­
Multi locular cystic renal cell carcinoma rare cases, the l i n ing of the cysts may tilocular cystic renal neoplasms o f low
(obsolete) incl ude features such as mu lti layering, malignant potential, with no significant
cells with g ranular cytoplasm , and small difference in the status of chromosome
Localization i ntracystic papillations. The septa consist 3p deletion between ccRCC and this tu­
This tumour usually presents as a unilat­ of fi brous tissue with calcification or ossi­ mour. These findings are consistent with
eral solitary lesion. fication . An important diagnostic feature the concept of mu ltilocular cystic renal
is the presence within the fibrous septa of neoplasm of low malignant potential be­
Clinical features clusters of tumour cells (without expan­ ing genetically related to ccRCC { 1 1 00 ) .
This tumour accounts for less than 1 % of sile growth) that are simi lar to those lining
all renal tumours. It affects middle-aged the cysts { 1 940) . Necrosis, vascular in­ Prognosis and predictive factors
adults, with a male-to-female ratio of vasion, and sarcomatous transformation Prog nosis is excellent. Multiple publica­
1 . 2: 1 to 2. 1 : 1 . As many as 90% of cases are incompati ble with this diagnosis. Re­ tions based on more than 200 patients,
are discovered incidentally on rad iologi­ gressing ccRCC with cystic degenera­ with follow-up times of more than 5 years,
cal evaluation for other purposes. No tu­ tion , extensive hyalinization, and haemo­ report that there was no recurrence or
mour with typical features has ever been siderin deposits should not be mistaken metastasis in patients whose tumours
reported to recur or metastasize { 1 94 1 } . for multilocular cystic renal neoplasm of were defined accordi n g to these mor­
low mal ig nant potential. The neoplas­ phological criteria 1 2590) .
tic cells are strongly immunoreactive to

Fig. 1 . 1 1 Multilocular cystic renal neoplasm of low malignant potential. A Gross appearance. B Whole-mount section showing thin septa without solid nodules. C Thin septa lined
by clear cells indistinguishable from WHO / International Society of Urological Pathology (ISUP) grade 1 clear cell renal cell carcinoma.

22 Tumours of the kidney

Pap i l l a ry ren a l cel l carc i n o m a Delahunt B. Martignoni G
Moch H .
Algaba F.
Eble J . Srigley J . R .
Chevi lle J . Tan P . H .
Amin M . B . Tickoo S . K .
Argani P.

Defin ition Localization and this i s observed more commonly

Pap i l lary renal cell carcinoma (PRCC) is PRCC occurs in the renal cortex and may than in ccRCC.
a malig nant tumour derived from renal tu­ be mu ltifocal . Multiple PRCCs may oc­ Stag ing of PRCC should be u n dertaken
bular epithel ium. It has papillary or tubu­ cur in association with renal scarring. I n using the current edition of the TNM stag­
lopapillary architecture and is often well i nstances of multiple and/or bilateral tu­ ing system.
circ ums cri bed . mours, hereditary PRCC-associated syn­
d romes should be considered. Macroscopy
ICD-0 code 8260/3 I n surgical specimens, PRCC is often
Clinical features well circumscri bed with a pronounced
Synonyms The cli nical features of PRCC are simi lar pseudocapsule. The tumour varies in
Not recommended: tubulopapillary renal to those of other forms of RCC , although colour from grey to yellow, tan , or dark
cell carcinoma; renal papil lary adenocar­ the typical c l i n ical triad of abdom inal brown , depending on the deg ree of i ntra­
ci noma; chromophil renal cell carcinoma mass , flank pain, and haematuria is tumoural haemorrhage. The tumour usu­
present in only 5-1 0% of cases . PRCC ally has a friable consistency, and larger
Epidemiology is more likely than ccRCC to undergo tumours may contain fibrosis and foci
PRCC is the second most commonly en­ ischaemic necrosis and spontaneous of necrosis and/or cystic degeneration.
countered morphotype of renal cell car­ haemorrhage , with spontaneous haemor­ Tumours associated with renal scarring
cinoma (RCC). In reported large series of rhage seen in approximately 8% of cases or PRCC-related hered itary tumour syn­
RCCs, the proportion of PRCCs is as high ( 1 227) . In contemporary series, in which d romes often show mu ltifocality.
as 1 8.5% { 78}. Patients range i n age from many tumours were d iscovered during
the paediatric age g roup to extreme old imag ing as incidental findings, as many Histopathology
age. Among adults, the mean age distri­ as 50% of PRCCs were asymptomatic PRCCs are often circumscribed carci­
bution (59-63 years) is simi lar to that of { 78, 1 065}. nomas with a prominent pseudocap­
clear cell RCC (ccRCC ) . Among paedi­ On imaging, PRCC contain s foci of calci­ sule, composed of papillae formed by
atric patients, the proportion of PRCCs fication i n approximately 30% of cases. delicate fibrovascular cores that often
present in series of renal parenchymal Radiologically, the tumours may appear contain foamy macrophages and psam­
tumours is higher than that observed hypovascular secondary to spontaneous moma bodies. Occasionally, the cores
among adults { 78,397,866 , 1 065 , 2448). tumour necrosis ! 1 88} . On multiphase are expanded by oedema fluid or hyalin­
CT, PRCC shows lower mean attenua­ ized connective tissue (674,678}. Some
Etiology tion values on the corticomedullary and tumours show a predominantly tubular
There are no specific etiological features, nephrograph ic phases compared with morphology, or the papi llae may be tight­
although PRCC occurs more commonly ccRCC {201 ]. As seen in ccRCC, tu­ ly packed, imparti ng a sol id appearance
in end-stage renal disease with scarring mour spread is predominantly vascular, (2298} . Sarcomatoid change is present
or acq u i red cystic d isease { 1 048,27 1 7) . via the renal sinus, renal vei n , and in­ in approximately 5% of PRCCs {678 ) .
Rarely, PRCC occurs in association with ferior and su perior venae cavae, to the Tumours that have papillary architecture
genetic syndromes, and the hered itary lung. Tumour may i nfiltrate the perirenal but show features of recognized morpho­
PRCC syndrome has a particularly high fat, resu lting in retroperitoneal spread. types of RCC (i.e. MiT family transloca­
degree of penetrance in affected families Lymphatic spread with extension to the tion RCC, hereditary leiomyomatosis and
(3059). nodes of the renal hilum may also occur, RCC-associated RCC, collecting duct

Fig. 1.12 Large right-sided papillary renal cell carcinoma. Fig. 1.13 Papillary renal cell carcinoma. The tumour has a Fig. 1.14 Type 1 papillary renal cell carcinom a. With
Arterial-phase conlrClst-enhanced MRI. friable consistency, with central necrosis and haemorrhage. dilated papillae.
 ·������. .
Fig. 1.15 A Type 1 papillary renal cell carcinoma. B Type 2 papillary renal cell carcinoma.

carcinoma, and muci nous tubular and this category. PRCCs with voluminous, CK7 expression is more common in
spindle cell carcinoma) should not be di­ finely granular, evenly distributed eosino­ type 1 PRCCs than in the type 2 tumours
agnosed as PRCC . philic cytoplasm and oncocytoma-l i ke { 285 ,68 1 , 1 439, 1 584, 1 631 , 2 1 88 } .
PRCC has traditionally been su bdivided nuclei (usually with low nucleolar g rade)
i nto two types {678 ,681 }. Type 1 carci­ have been called oncocytic PRCCs Genetic profile
nomas have papillae covered by cells { 1 1 9 1 , 2589 ,2992) . Their nuclei are typi­ Trisomy and tetrasomy of chromosome 7 ,
with nuclei arranged in a single layer cally single-layered and li nearly aligned. trisomy o f chromosome 1 7 , a n d loss of
on the papillary cores, often with scanty Tumours with this morphology are not yet the Y chromosome are characteristically
pale cytoplasm. Type 2 carcinomas are fully characterized. Necrosis and haem­ associated with PRCC. A wide variety of
characterized by the presence of nuclear orrhage are common, and haemosiderin other aberrations have also been report­
pseudostratification. They are often of granules may be present i n tumour cell ed for these tumours, including trisomy 8,
higher nucleolar grade, with cells con­ cytoplasm, particularly i n type 1 tumours 1 2, 1 6 , and 20, and loss of 1 p, 4q, 6q ,
tai ning abundant eosinophilic cytoplasm . { 1 775). 7, 9p, 1 3q , Xp, and Xq { 1 3 1 8 , 1 402, 1 507,
A su bset of tumours have mixed histol­ PRCCs often show positive immunohis­ 2449). Separate studies have also dem­
ogy. I ncreasing experience and molecu­ tochemical reactions for cytokeratin A E 1 / onstrated amplification of 8q and over­
lar studies suggest that type 2 tumours AE3, CAM5. 2 , high-molecular weight cy­ expression of MYC {929) . Approximately
may not in fact constitute a single well­ tokeratins, epithelial membrane antigen, 1 3% of sporad ic PRCCs demonstrate
defined entity, but the type 2 designation AMACR, RCC antigen, vimenti n , and MET mutations ( 2656A} . I n kidneys with
remains a useful morphological descrip­ co r n 1 1 58,678 ,68 1 , 1 857,2094 , 2742 ) . multiple PRCCs, i nd ivid ual tumours show
tor. Ongoing studies will help further re­ loss of at least one of the chromosomes
fine the characterization of tumours i n 3p 1 4, 7q3 1 , 9p2 1 , 1 6q23, 1 7q 2 1 , and
1 7p 1 3 ; however, the lack of a consistent
pattern i n dicates that multiple tumours
Papillary RCC - ISUP Grade
arise i ndependently [ 1 340) . Loss of het­
erozygosity of VHL and FHIT have been
-
100 -r= -
· - .·r
----------------
.
-------� Gl
reported in PRCC { 1 249 , 1 950, 2852).
G2
Type 1 and type 2 PRCCs have been
I, _ · · - - ·

I
shown to have d ifferent genetic profiles.
I - - - - - '
80 ·
' - --
- - - -- - • - · • • • G3 Type 1 tumours typically show gains of
l
-1
'!
,
I
7p and 1 7p, whereas LOH of chromo­
'---
somes 1 p, 3p, Sq, 6, 8, 9p, 1 0, 1 1 , 1 5 ,
al ,
60
I
" '--- 1 1 8, and 22 has been reported in type 2
"
!E tumours { 1 09, 1 3 1 8, 1 452, 2409,3047) . I n
_____ ,
GI
40 I one series, LOH i n chromosomes 7, 1 2 ,
� L----- - -- � - - - - - - - - - � - - - - - - - - - - - - - - - - - - - - - - - - --- G4 1 6 , 1 7 , and 20 was seen in both type 1
"
GI
I:
and type 2 tumours and in papillary ad­
a 20 enoma, and type 2 tumours add itionally
exhibited alterations in chromosomes 5,
6, 8, 1 0 , 1 1 , 1 5 , 1 8, and 22 { 1 09). The
0
0 5 10
results of a recent molecular characteri­
zation confirmed that type 1 and type 2
Years papil lary renal-cell carcinomas are differ­
Fig. 1 .16 Papillary renal cell carcinoma (RCC). Cancer-specific survival with cases graded according to the WHO / ent types of renal cancer, characterized
International Society of Urological Pathology (ISUP) grading system. Reprinted from Sukov et al. {2637). by specific genetic alterations, with type 2

24 Tumours of the kid ney

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