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 Luca Giovanella
Giorgio Treglia
Roberto Valcavi Editors
Atlas of
Head and Neck
Endocrine Disorders

Special Focus on
Imaging and Imaging-
Guided Procedures

123
Atlas of Head and Neck
Endocrine Disorders
Luca Giovanella • Giorgio Treglia
Roberto Valcavi
Editors

Atlas of Head and Neck

Endocrine Disorders
Special Focus on Imaging
and Imaging-Guided Procedures
Editors
Luca Giovanella Roberto Valcavi
Department of Nuclear Medicine Endocrinologia
and Thyroid Center Centro Palmer
Oncology Institute of Southern Reggio Emilia
Switzerland Italy
Bellinzona and Lugano
Switzerland

Giorgio Treglia
Department of Nuclear Medicine
and Thyroid Center
Oncology Institute of Southern
Switzerland
Bellinzona and Lugano
Switzerland

ISBN 978-3-319-22275-2 ISBN 978-3-319-22276-9 (eBook)

DOI 10.1007/978-3-319-22276-9

Library of Congress Control Number: 2015952689

Springer Cham Heidelberg New York Dordrecht London

© Springer International Publishing Switzerland 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
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The publisher, the authors and the editors are safe to assume that the advice and information in
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Printed on acid-free paper

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To our patients and their families for giving meaning to our
work
To all our staff who supported us throughout this project
Luca Giovanella
Giorgio Treglia
Roberto Valcavi
Preface

Head and neck endocrine disorders include several diseases involving differ-
ent organs and with variable outcome and prognosis.
A crucial step for the correct management of these disorders is the early
diagnosis, the proper differential diagnosis, and, when appropriate, an accu-
rate disease staging. Beyond clinical and laboratory data, different imaging
modalities are now available to evaluate head and neck endocrine disorders.
These imaging modalities include both morphological and functional imag-
ing methods, sometimes combined by using hybrid devices.
The aim of this atlas is to provide a comprehensive overview on endocrine
disorders of the head and neck region, with particular emphasis on the role of
imaging and image-guided procedures.
We strongly believe that a multidisciplinary approach is needed for the
proper diagnosis and management of head and neck endocrine disorders in
the current clinical practice. Accordingly, several international experts in
endocrine disorders, including endocrinologists, pathologists, radiologists,
nuclear medicine physicians, and surgeons were involved as authors of chap-
ters in this atlas in order to provide a multidisciplinary approach.
The first section discusses the basic characteristics of the imaging methods
and other techniques used for evaluation and diagnosis, including ultrasonog-
raphy, nuclear medicine techniques, computed tomography, and magnetic
resonance imaging. Furthermore, a summary of pathology findings in head
and neck endocrine disorders is provided.
The remainder of this book focuses on the application of imaging methods
in thyroid, parathyroid, and other endocrine disorders of the head and neck
region. The coverage is wide ranging, encompassing Graves’ disease, toxic
multinodular goiter, toxic adenoma, thyroiditis, nontoxic goiter, benign thy-
roid nodules, and the different forms of thyroid carcinoma, as well as primary
hyperparathyroidism, paragangliomas, and other neuroendocrine tumors of
the head and neck region.
We hope that the high-quality images provided in this atlas could assist the
clinicians in their diagnostic approach to these disorders.

Bellinzona, Switzerland Prof. Dr. med. Luca Giovanella, MD, PhD

Bellinzona, Switzerland Giorgio Treglia, MD, MSc
Reggio Emilia, Italy Roberto Valcavi, MD, FACE

vii
Contents

Part I Basic Characteristics of Imaging Methods

and Other Techniques for Evaluation of Neck
Endocrine Diseases

1 Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Pierpaolo Trimboli
2 Nuclear Medicine Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Luca Ceriani, Giorgio Treglia, and Luca Giovanella
3 Computed Tomography and Magnetic
Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Mariana Raditchkova and Giorgio Treglia
4 Percutaneous Minimally Invasive Techniques. . . . . . . . . . . . . . 25
Massimiliano Andrioli and Roberto Valcavi
5 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Massimo Bongiovanni and Antoine Nobile

Part II Thyroid Diseases

6 Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Luca Giovanella
7 Thyroid Autonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Luca Giovanella
8 Thyroiditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Pierpaolo Trimboli and Luca Giovanella
9 Nontoxic Uninodular Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Massimiliano Andrioli and Roberto Valcavi
10 Nontoxic Multinodular Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Luca Giovanella
11 Differentiated Thyroid Carcinoma. . . . . . . . . . . . . . . . . . . . . . . 73
Luca Giovanella and Giorgio Treglia

ix
x Contents

12 Medullary Thyroid Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . 83

Pierpaolo Trimboli and Luca Giovanella
13 Anaplastic Carcinoma and Other Tumors . . . . . . . . . . . . . . . . 89
Luca Giovanella and Giorgio Treglia

Part III Parathyroid Diseases

14 Primary Hyperparathyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . 99
Jukka Schildt, Virpi Tunninen, Marko Seppänen,
and Camilla Schalin-Jäntti

Part IV Other Endocrine Diseases of the Neck

15 Head and Neck Paragangliomas. . . . . . . . . . . . . . . . . . . . . . . . . 109

Alexander Stephan Kroiss and Irene Johanna Virgolini
16 Other Neuroendocrine Tumors of Head
and Neck Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Giorgio Treglia and Luca Giovanella
Contributors

Massimiliano Andrioli, MD EndocrinologiaOggi, Rome, Italy

Massimo Bongiovanni, MD Department of Laboratory, Institute
of Pathology, University Hospital of Lausanne, Lausanne, Switzerland
Luca Ceriani, MD Department of Nuclear Medicine,
PET/CT and Thyroid Centre, Oncology Institute of Southern Switzerland,
Bellinzona and Lugano, Switzerland
Luca Giovanella, MD, PhD Department of Nuclear Medicine,
PET/CT and Thyroid Centre, Oncology Institute of Southern Switzerland,
Bellinzona and Lugano, Switzerland
Alexander Stephan Kroiss, MD Department of Nuclear Medicine,
Innsbruck Medical University, Innsbruck, Austria
Antoine Nobile, MD Department of Laboratory, Institute of Pathology,
University of Lausanne, Lausanne, Switzerland
Mariana Raditchkova, MD Department of Nuclear Medicine,
PET/CT and Thyroid Centre, Oncology Institute of Southern Switzerland,
Bellinzona and Lugano, Switzerland
Camilla Schalin-Jäntti, MD, PhD Division of Endocrinology,
Department of Medicine, Abdominal Center, University of Helsinki
and Helsinki University Hospital, Helsinki, Finland
Jukka Schildt, MD Department of Clinical Physiology and Nuclear
Medicine, University of Helsinki and Helsinki University Hospital,
Helsinki, Finland
Marko Seppänen, MD Department of Clinical Physiology and Nuclear
Medicine and PET Centre, University of Turku and Turku
University Hospital, Turku, Finland
Giorgio Treglia, MD, MSc Department of Nuclear Medicine,
PET/CT and Thyroid Centre, Oncology Institute of Southern Switzerland,
Bellinzona and Lugano, Switzerland

xi
xii Contributors

Pierpaolo Trimboli, MD Section of Endocrinology and Diabetology,

Ospedale Israelitico of Rome, Rome, Italy
Department of Nuclear Medicine and Thyroid Centre,
Oncology Institute of Southern Switzerland, Bellinzona and Lugano,
Switzerland
Virpi Tunninen, MD Department of Nuclear Medicine,
Satakunta Central Hospital, Pori, Finland
Roberto Valcavi, MD Endocrinologia, Centro Palmer, Reggio Emilia, Italy
Irene Johanna Virgolini, MD Department of Nuclear Medicine,
Innsbruck Medical University, Innsbruck, Austria
 Part I
Basic Characteristics of Imaging Methods
and Other Techniques for Evaluation of
Neck Endocrine Diseases
 Ultrasonography
1
Pierpaolo Trimboli

Abstract
The aim of this chapter is to discuss the general aspects of ultrasonography
(US) for the evaluation of head and neck endocrine diseases. The normal
US presentation of the thyroid gland is discussed and US evaluation of
thyroid diseases is summarized. Furthermore some paragraphs are dedi-
cated to elucidate the significance of incidental lesions detected by US, the
role of this method in the follow-up of thyroid cancer patients, and the use
of US to guide fine-needle aspiration cytology (FNAC) or core needle
biopsy (CNB). Lastly, the role of US in evaluating hyperfunctioning para-
thyroid glands is briefly described.

Keywords
Ultrasonography • Ultrasound • Thyroid nodule • Thyroid cancer •
Parathyroid • Neck

P. Trimboli, MD
Section of Endocrinology and Diabetology,
Ospedale Israelitico di Roma, Via Fulda 14, 00148
Rome, Italy
Department of Nuclear Medicine and Thyroid Centre,
Oncology Institute of Southern Switzerland,
Bellinzona, Switzerland
e-mail: [email protected]

© Springer International Publishing Switzerland 2016 3

L. Giovanella et al. (eds.), Atlas of Head and Neck Endocrine Disorders: Special Focus on Imaging
and Imaging-Guided Procedures, DOI 10.1007/978-3-319-22276-9_1
4 P. Trimboli

1.1 Thyroid Ultrasonography 1.1.2 Normal Ultrasound

Presentation of Thyroid Gland
1.1.1 General Aspects
The thyroid gland is more echo-dense than the
In the last decades ultrasonography (US) has adjacent structures and appears as homogenous.
become the most common imaging tool for the thy- As a main rule, normal cells/colloid ratio gives
roid gland. In fact, US allows to accurately evaluate homogeneous and normoechoic thyroid presenta-
thyroid size, morphology, and structure [1, 2]. tion at US, while hypoechogenicity of the thyroid
Furthermore, the main strength of thyroid US is the gland is due to higher cells/colloid ratio. The size
detection of those lesions that are not evident at of the normal thyroid can be estimated by ellip-
palpation or using other imaging instruments [1, 2]. soid volume formula applied to each lobe. The
The procedure is safe, takes about ten minutes, and normal dimension of one lobe is up to 5 cm in
is relatively cheap. The test does not require dis- longitudinal axis, 2 cm in anterior-posterior axis,
continuation of any medication or preparation of and 2 cm in transverse axis. The isthmus (gener-
the patient. Due to these reasons US has begun the ally not included in the size formula) has a depth
optimal in-office instrument for thyroidologists. of 3 mm. Normal references of adult thyroid size
The most diffuse application of thyroid US is range from 7 to 18 ml [3–8]. Normal thyroid
to detect thyroid nodules and select suspicious appearance at US correlates with normal thyroid
ones for cytology examination. Overall, based on function and negative thyroid antibodies measure-
the US risk stratification, up to 80 % of thyroid ment [9, 10]. On the contrary, hypoechoic and
cancers are correctly identified [1, 2]. However, inhomogeneous thyroid gland is highly suspi-
specificity of US in this context was reported as cious for autoimmune thyroid diseases (i.e., auto-
low. Then, the high reliability in detecting non- immune thyroiditis, Graves’ disease) [11, 12].
palpable nodules combined with poor specificity
for cancer led to a worldwide clinical and socio-
economical problem [1, 2]. 1.1.3 Ultrasound Evaluation
Main reliability of thyroid US is in the: of Thyroid Lesions

• Detection of non-palpable thyroid lesions Thyroid nodules are a very common entity (prev-
• Stratification of risk for malignancy of nod- alence up to 70 %) and US can detect a lot of
ules, regardless of their size clinically nonrelevant nodules. As a consequence,
• Diagnosis of autoimmune thyroid diseases performing US in patients with no clear risk fac-
• Detection of suspicious neck lymph nodes tors (i.e., previous neck irradiation) or clinical
• Identification of neck recurrence/persistence indications is strongly discouraged (see below).
of thyroid cancers When nodules are detected at clinical examina-
tion, and vice versa, US is very useful to stratify
Thyroid US examination is also frequently the risk of malignancy. The following nodule’s
used to: features must be evaluated to discriminate nod-
ules at risk of malignancy from lesions probably
• Verify the presence of thyroid lesions after benign [1, 2]:
suspicious palpation
• Assist nodule’s fine-needle aspiration cytol- A. Relevant features:
ogy (FNAC) or core needle biopsy (CNB) • Echogenicity: thyroid cancers are often
• Assess thyroid and neck lymph nodes before solid hypoechoic because of their high
surgery, when indicated cells/colloid ratio. Some particular cancers
• Verify thyroid remnants after total thyroidec- (i.e., medullary type) may manifest by
tomy (limited sensitivity) other fashions (such as mixed or spongi-
• Follow up patients previously treated for thy- form). Rarely, papillary cancers have cys-
roid cancer tic presentation.
1 Ultrasonography 5

• Microcalcifications: these are the most Overall, none of the above features alone is
specific features; however, microcalcifica- accurate to discriminate thyroid cancers from
tions may be detected in up to 20 % of benign nodules, while the combination of all fea-
thyroid cancers. Macrocalcifications do tures achieves relevance to identify malignant
not raise the risk for cancer. nodules. Table 1.1 illustrates the diagnostic accu-
• Perilesional hypoechoic halo: it represents racy of main US single characters in detecting
the most accurate feature to identify a thyroid cancer.
benign nodule. Rarely, papillary cancers
have a halo.
B. Ancillary features: 1.1.4 The Dilemma of Small Non-
• Shape: nodules that are taller than wide palpable Thyroid Nodules
should be viewed as at enhanced risk for Incidentally Discovered by US
malignancy. Nevertheless, new studies are
needed to confirm this information. Micronodules are often detected by thyroid
• Vascularization: regardless of the enthusi- US. Because the large majority of these subclini-
astic studies of 1990s, the intranodular cal diseases are discovered during US of other
vascular signal should not be considered neck structures (i.e., carotid, jugular veins, etc.),
as a single diagnostic factor for thyroid their actual clinical significance is questionable
cancer. A few cancers have intranodular [13]. Rarely, one micronodule is a cancer (gener-
vascularization, but this aspect is low ally papillary carcinoma), but the clinical rele-
accurate. vance of detecting these cancers at a preclinical
• Elastography: the recently introduced stage is highly debatable. In addition, US has
elastographic examination should increase lower accuracy in lesions with size <1 cm, and the
the sensitivity of thyroid cancer detection abovementioned US risk factors are difficult to
by US. However, different color scales and assess due to the small size of the nodule. Also,
elastographic methods have been reported fine-needle aspiration cytology (FNAC) is not
and future studies have to be performed simple to be performed, and cytologic sample is
before to routinely introduce thyroid often unsatisfactory due to the poor cellular
elastography. amount. Only micronodules with high clinical/
• Margins: up to 30 % of thyroid cancers echographic/laboratory risk for malignancy should
appear with irregular, spiculated, or be submitted to FNAC or, alternatively, strictly
blurred borders. However, to detect these monitored by serial US examinations [1, 2].
characteristics needs an expert US
examiner.
1.1.5 Neck Ultrasonography
in the Follow-Up of Thyroid
Table 1.1 Diagnostic accuracy of main ultrasound fea- Cancer Patients
tures of thyroid nodule in detecting cancers
More sensitive features After surgery and iodine-131 ablation, persistent
Hypoechogenicity Sensitivity 85 % or recurrent disease is diagnosed in about 20 % of
Hardness at elastography Sensitivity 85 % cases during follow-up over time. In the large
Taller shape Sensitivity 85 % majority of cases, the relapse of disease occurs in
More specific features the neck, being frequently discovered in cervical
Presence of microcalcifications Specificity 90 % lymph nodes or more rarely in the thyroid bed.
Absence of halo Specificity 85 % Distant extracervical metastases are more rare [1,
Intranodular vascularization Specificity 80 % 2]. Ultrasonography is highly reliable in detect-
Irregular or blurred margins Specificity 85 % ing thyroid cancer persistence and recurrence
6 P. Trimboli

when they are localized in the neck, with the several potential markers to diagnose thyroid nod-
exception of the central compartment more diffi- ules with indeterminate FNAC report. However,
cult to be examined by US. Thus, US has become no laboratory, US, scintigraphic, molecular, or
the most diffused and useful imaging procedure clinical feature can be used alone to exclude thy-
in patients followed up for these cancers. roid malignancy. In these cases the diagnostic sur-
In 2013 the European Thyroid Association gery remains mandatory.
(ETA) task force on US in thyroid cancer follow-up Until the 1990s FNAC was performed without
has assessed a sort of guidelines on this topic. US guidance, and the rate of inadequate samples
There, sensitivity and specificity of several US was high; also, the overall accuracy of the technique
signs are reported. Of very high utility in clinical was reported as suboptimal. In the last years
practice, the authors describe the rate of normal US-guided FNAC has been worldwide diffused. So,
(i.e., nonmetastatic) lymph nodes with specific US the accuracy of cytologic reports has been signifi-
signs; microcalcifications and cystic changes are cantly improved. Real-time US guidance improves
never recordable in normal nodes, and round shape, accuracy in positioning the needle into the nodule.
peripheral vascularization, and hyperechogenicity Moreover, complications are very rare and FNAC
are rarely present in these nodes. Thus, these have can be performed in ambulatory office [1, 2].
to be considered as major risk factors [14]. Generally, a 23–27 gauge needle attached to a
Finally, US should be useful in the operating syringe is used. Several fashions can be adopted
room during surgery. This intraoperative US for thyroid FNAC. Free-hand mode is one of
examination can improve the localization of those more diffuse. On the other hand, the use of
metastases to be excised. In this view, the preop- a device is frequently adopted. In these methods
erative US in patients with thyroid cancer has to the needle is inserted parallel to the probe or at an
be routinely performed to reduce the need of angle of that. The parallel approach is more com-
reoperation for recurrent/persistent disease. fortable for the operator because the needle may
be viewed as it traverses the nodule. A perpen-
dicular approach is largely used due to its sim-
1.1.6 Use of Ultrasound to Guide plicity for less experienced operators.
Fine-Needle Aspiration Complications are reduced by the latter.
Cytology (FNAC) or Core Regardless of fashion to perform the aspiration,
Needle Biopsy (CNB) US is highly useful to guide the procedure.
Once obtained the cytologic sample, the speci-
1.1.6.1 Fine-Needle Aspiration men is traditionally prepared on slides (in a number
Cytology (FNAC) of 4 to 6, the majority of which are fixed for
Cytologic evaluation of thyroid nodule aspirates Papanicolaou stain). Recently, the thin-layer prepa-
represents a pivotal tool to assess patients with dis- ration is diffusing; the needle is washed into a
covered thyroid lesion(s). Usually, cytologic sam- syringe of solution and the sample is prepared for
ples are satisfactory and permit to be classified as cell block. In specific conditions, such as nodules
diagnostic. In fact, false-negative and false-posi- with prior indeterminate FNAC report, ancillary
tive FNAC reports are very rare (i.e., <2 %) [1]. studies (i.e., immunocytochemistry for galectin-3)
However, a non-negligible rate (up to 15–25 %) of may be applied to cell blocks. As an extension of
thyroid cytology is inconclusive due to inadequate cytologic examination, the measurement of calcito-
material (Thy 1, Category I) or indeterminate nin in the washout fluids of the needle achieves
diagnosis (Thy 3, Category III or IV). Nodules high interest in those patients with suspicious med-
with Thy 1 or Category I need to undergo new ullary thyroid cancer; this approach significantly
FNAC, and those lesions with repeated inadequate improves the detection of this cancer [15, 16].
sample should be addressed to diagnostic surgery As mentioned above, US is an accurate
or CNB (see below) [2]. A large amount of articles method for identifying suspected recurrence of
published in the last decade focused on the use of thyroid cancer in enlarged lymph nodes; then,
1 Ultrasonography 7

neck lymph nodes suspicious for metastases from or inadequate (i.e., Thy 1/Category I) FNAC
thyroid cancers can be aspirated. The procedure, report [18]. Data from these papers are so inter-
generally, is easy. However, the cytologic sample esting that this biopsy has been included in
may not be adequate for diagnosis. The measure- AACE/AME/ETA guidelines.
ment of thyroglobulin in the washout of the nee-
dle is necessary; high levels of thyroglobulin can
detect a metastasis from differentiated thyroid 1.1.7 Thyroid Ultrasound Reports
cancer [17]. Furthermore, high calcitonin value
in a cervical lymph node identifies a metastasis The thyroid US report must answer the question
from medullary cancer [16]. that has been posed by the clinician and not be
just a routine recitation. Then it has to be per-
1.1.6.2 Core Needle Biopsy (CNB) formed by well-trained physicians and should be
Similarly to FNAC, US is highly useful also for brief and concise. The examiner should interpret
guidance of CNB. In the last decade, several the images based on the above criteria and the
papers described the use of CNB as a second-line specific question posed by the attending physi-
approach to assess those thyroid nodules with cian. Some examples of US findings are reported
prior indeterminate (i.e., Thy 3/Category III–IV) in Figs. 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, and 1.8.

Fig. 1.1 Hypoechoic and solid thyroid nodule in the left

lobe. Margins are not defined and the invasion of gland’s
capsule is evident. The histological examination after sur-
gery demonstrates papillary cancer (pT3)
8 P. Trimboli

Fig. 1.2 Hypoechoic and solid thyroid nodule. Elastographic examination shows a hard structure. Papillary cancer
(T1b) is demonstrated at histology

Fig. 1.3 Metastasis from papillary carcinoma (5 mm) at Fig. 1.4 Isoechoic nodule with hypoechoic halo.
right neck level III Cytology was benign (Thy 2)
1 Ultrasonography 9

Fig. 1.5 Small (4 mm) solid hypoechoic nodule with cal- Fig. 1.7 Multiple neck metastases from medullary can-
cification (medullary carcinoma at histology) cer in the left cervical level IV

Fig. 1.8 Normal echographic appearance of thyroid

Fig. 1.6 Neck metastasis from papillary cancer at right
level III. Lymph node appears mixed with cystic changes
and spots of vascularization
10 P. Trimboli

1.2 Ultrasonography References

of Parathyroid Glands
1. Cooper DS, Doherty GM, Haugen BR et al (2009)
Revised American Thyroid Association management
Generally, parathyroid glands are not detectable guidelines for patients with thyroid nodules and dif-
by US (similarly to the other image techniques). ferentiated thyroid cancer. Thyroid 19:1167–1214
Parathyroids may be observed only when they 2. Gharib H, Papini E, Paschke R et al (2010) American
are enlarged. They are less ultrasonographically Association of Clinical Endocrinologists, Associazione
Medici Endocrinologi, and European Thyroid
dense (hypoechoic) than thyroid tissue. For these Association medical guidelines for clinical practice
reasons a specific US examination of the parathy- for the diagnosis and management of thyroid nodules. J
roid gland should be performed only in case of Endocrinol Invest 33:1–50
true hyperparathyroidism to localize the hyper- 3. Rago T, Bencivelli W, Scutari M et al (2006) The
newly developed three-dimensional (3D) and two-
plastic lesion or adenoma producing parathyroid dimensional (2D) thyroid ultrasound are strongly cor-
hormone (PTH). related, but 2D overestimates thyroid volume in the
A parathyroid lesion producing PTH is often presence of nodules. J Endocrinol Invest 29:423–426
solid and hypoechoic, with regular margins and 4. Shapiro RS (2003) Panoramic ultrasound of the thy-
roid. Thyroid 13:177–181
with 1–3 cm in size. At echo-color-Doppler 5. Lyshchik A, Drozd V, Reiners C (2004) Accuracy of
examination, a main vascular septum is present. three-dimensional ultrasound for thyroid volume
Remarkably, specificity of US in localized measurement in children and adolescents. Thyroid
enlarged parathyroids is low, and scintigraphy is 14:113–120
6. Deveci MS, Deveci G, LiVolsi VA et al (2007)
mandatory. Then, surgeons should consider that Concordance between thyroid nodule sizes measured
US cannot exclude multiple parathyroid diseases. by ultrasound and gross pathology examination:
effect on patient management. Diagn Cytopathol
35:579–583
7. Vejbjerg P, Knudsen N, Perrild H et al (2006) The
association between hypoechogenicity or irregular
echo pattern at thyroid ultrasonography and thyroid
function in the general population. Eur J Endocrinol
155:547–552
8. Trimboli P, Ruggieri M, Fumarola A et al (2008) A
mathematical formula to estimate in vivo thyroid vol-
ume from two-dimensional ultrasonography. Thyroid
18:879–882
9. Trimboli P, Rossi F, Condorelli E et al (2010) Does
normal thyroid gland by ultrasonography match with
normal serum thyroid hormones and negative thyroid
antibodies? Exp Clin Endocrinol Diabetes
118:630–632
10. Trimboli P, Rossi F, Thorel F et al (2012) One in five
subjects with normal thyroid ultrasonography has
altered thyroid tests. Endocr J 59:137–143
11. Marcocci C, Vitti P, Cetani F et al (1991) Thyroid ultra-
sonography helps to identify patients with diffuse lym-
phocytic thyroiditis who are prone to develop
hypothyroidism. J Clin Endocrinol Metab 72:209–213
12. Rago T, Chiovato L, Grasso L et al (2001) Thyroid
ultrasonography as a tool for detecting thyroid auto-
immune diseases and predicting thyroid dysfunction
in apparently healthy subjects. J Endocrinol Invest
24:763–769
13. Tan GH, Gharib H (1997) Thyroid incidentalomas:
management approaches to nonpalpable nodules dis-
covered incidentally on thyroid imaging. Ann Intern
Med 126:226–231
1 Ultrasonography 11

14. Leenhardt L, Erdogan MF, Hegedus L et al (2013) fluids has higher sensitivity than cytology in detecting
European thyroid association guidelines for cervical medullary thyroid cancer: a retrospective multicentre
ultrasound scan and ultrasound-guided techniques in study. Clin Endocrinol 80:135–140
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Calcitonin measurement in aspiration needle washout
 Nuclear Medicine Techniques
2
Luca Ceriani, Giorgio Treglia, and Luca Giovanella

Abstract
This chapter provides an introduction to nuclear medicine technique use-
ful for evaluating head and neck endocrine diseases. Different radiotracers
can be used for thyroid imaging and they can be classified in two groups:
a) radiotracers describing the function of follicular cells and b) radiotrac-
ers mapping the proliferative activity of follicular cells. The first group
includes technetium-99m-pertechnetate (99mTcO4–) and radioiodine; the
second group includes Tc99m-methoxyisobutylisonitrile (99mTc-MIBI)
and fluorodeoxyglucose (18F-FDG).
About parathyroid nuclear imaging, 99mTc-MIBI is the most used tracer in
clinical practice, usually combined with a thyroid tracer. Planar and tomo-
graphic images can be used for detecting hyperfunctioning parathyroid
glands. The role of PET tracers seems promising.
Lastly, several tracers evaluating different metabolic pathways can be
used to detect neuroendocrine tumors of head and neck region.

Keywords
Thyroid • Parathyroid • Neuroendocrine • Scintigraphy • SPECT • PET

2.1 Introduction
L. Ceriani, MD (*) • G. Treglia, MD, MSc
Prof. Dr. med. L. Giovanella, MD, PhD Nuclear medicine techniques were first employed
Department of Nuclear Medicine and PET/CT for the diagnosis and therapy of thyroid diseases
Center, Oncology Institute of Southern Switzerland, in the 1950s. Despite the subsequent develop-
Via Ospedale 12, CH-6500 Bellinzona and Lugano,
ment of thyroid ultrasound and fine-needle aspi-
Switzerland
e-mail: [email protected]; [email protected]; ration (FNA), thyroid scintigraphy with either
[email protected] iodine or iodine-analogue isotopes remains the

© Springer International Publishing Switzerland 2016 13

L. Giovanella et al. (eds.), Atlas of Head and Neck Endocrine Disorders: Special Focus on Imaging
and Imaging-Guided Procedures, DOI 10.1007/978-3-319-22276-9_2
14 L. Ceriani et al.

only method able to characterize functionally the trapping of different radioactive thyroid tracers.
thyroid tissue and especially to demonstrate the Iodine-123 (123I) is an ideal thyroid radiopharma-
presence of autonomously functioning nodules ceutical due to low radiation burden and optimal
[1]. An increased tracer uptake within a nodule imaging quality, as opposed to the use of
excludes malignancy with high accuracy and, iodine-131 (131I), which is strongly discouraged
additionally, allows a timely and appropriate for routine diagnostic use because of its much
treatment. More recently, different tracers have higher radiation burden to the thyroid. Finally,
become available to evaluate the proliferation iodine-124 (124I) is a positron-emitting isotope
rate of the thyroid cells and, due to their very that allows high-quality imaging of the thyroid.
high negative predictive values, have proved to Currently, however, its use is restricted to clinical
be useful for reducing the number of unnecessary trials involving patients with differentiated thy-
thyroidectomies [2, 3]. Finally, novel imaging roid cancer while it is not indicated for the diag-
technologies such as single-photon emission nostic workup of patients with thyroid nodules.
computed tomography (SPECT) and positron The thyroid uptake of a different tracer, 99mTc-
emission tomography (PET) are now available pertechnetate, is also related to NIS expression.
and consistently increase the quality of nuclear Importantly, it is not a substrate for any metabolic
medicine images and allow sophisticated quanti- pathways and a complete washout from thyroid
fication procedures [3]. These technological cells occurs in about 30 min. However, although
developments associated to the introduction of the thyroid does not organify 99mTc-pertechnetate,
new tracers allowed more recently to extend the in the majority of cases the uptake and imaging
diagnostic role of nuclear medicine imaging data provide all the information needed for accu-
toward patients with parathyroid diseases and rate diagnosis [1, 5]. 99mTc-pertechnetate has a
neuroendocrine tumors of head and neck region. shorter half-life and a preferred energy for scinti-
graphic imaging compared to 123I. Additionally, it
is cheaper and readily available in nuclear medi-
2.2 Thyroid Diseases: cine departments. As a consequence, it has gen-
Radioactive Tracers erally been adopted as the primarily used thyroid
and Nuclear Medicine tracer in clinical practice [1, 5].
Methods

Thyroid radiotracers can be classified in two 2.2.2 Radiotracers Mapping Cellular

groups: (a) radiotracers describing the function Proliferative Activity
of follicular cells and (b) radiotracers mapping
the proliferative activity of follicular cells. The thyroid cells may be stimulated to proliferate
by controlled growth mechanisms leading to
benign diseases (i.e., benign goiters) or lose their
2.2.1 Radiotracers Describing differentiation following uncontrolled growth
the Function of Follicular Cells mechanisms leading to malignant diseases (i.e.,
thyroid cancer). The more the follicular cells
Normal thyroid tissue is characterized by the become undifferentiated, the more they lose NIS
unique capability of its follicular cells to trap and expression [5]. The loss of NIS expression
to process stable iodine (I) which is subsequently reduces the ability of the thyroid cells to trap and
incorporated in thyroglobulin (Tg) in order to concentrate iodine. Recently, oncotropic radio-
form thyroid hormones. The I uptake into the fol- tracers, mapping cell density and cellular metab-
licular cells is regulated by the sodium-iodide olism and viability, have been developed. The
99m
symporter (NIS), a transmembrane protein that Tc-MIBI is a lipophilic cation that crosses the
carries sodium and iodine from the blood into the cell membrane and penetrates reversibly into the
follicular cells [4, 5]. The NIS allows the thyroid cytoplasm via thermodynamic driving forces and
2 Nuclear Medicine Techniques 15

then irreversibly passes the mitochondrial mem- The characteristics of various nuclides used
brane using a different electrical gradient regu- for the visualization of the thyroid gland are
lated by a high negative inner membrane potential shown in Fig. 2.1 and Table 2.1.
[6]. The cancer cells, with their greater metabolic
turnover, are characterized by a higher electrical
gradient of mitochondrial membrane, thus deter- 2.2.3 Thyroid Diseases: Nuclear
mining an increased accumulation of 99mTc-MIBI Medicine Imaging Methods
compared to normal cells. Recent studies demon-
strate that dedifferentiating follicular thyroid Thyroid scans with either 99mTc-pertechnetate, 123I,
cells reduce the expression of the NIS while they or 99mTc-MIBI are obtained by a gamma-camera
increase glucose metabolism [7–9]. Interestingly, equipped with a parallel-hole collimator.
the glucose metabolism can be tracked by a Sometimes dedicated “pinhole” collimators are
radioactive glucose analogue, fluorodeoxyglu- employed to increase focal resolution, in particu-
cose (18F-FDG). As glucose, it is transported into lar to increase the detection rate of little nodular
the blood flow and can diffuse into the cells lesions. Nevertheless, a significant geometric dis-
through selective and specific transporters. The tortion should be taken into account. Planar
best known glucose transporter is an insulin- images, acquired in the anterior view for some
independent transmembrane protein, the glucose minutes, provide a reliable map of thyroid func-
transporter 1 (GLUT 1). Once entering the cells, tion and metabolism (Fig. 2.2). Additional views
18
F-FDG is phosphorylated to glucose-6- may be useful when searching for ectopic tissue.
phosphate and trapped in the cells [10]. A posi- Tomographic techniques, such as SPECT and
tive relationship between GLUT 1 overexpression SPECT/CT, may be very useful to better localize
and aggressive biology of thyroid tumors has in the body the pathological findings, particularly
been shown [11]. In addition, overexpression of in case of ectopic tissue or intrathoracic goiter. To
hexokinase I has also been demonstrated in thy- be noted, as the diagnostic specificity is decreased
roid cancer cells as reflected by an increased 18F- in lesions that are below the resolution threshold
FDG uptake [12]. of gamma-cameras, thyroid scans are not indi-

Fig. 2.1 Molecular basis of

nuclear imaging of follicular
thyroid cell. 18F-FDG
fluorodeoxyglucose,
18
F-FDG-6P
fluorodeoxyglucose-6-
phosphate, *I-Na radioiodine,
99m
Tc-MIBI Tc99m-
methoxyisobutylisonitrile,
99m
TcO4− Tc99m-
pertechnetate, TSH thyroid
stimulating hormone, Tg
thyroglobulin (Figure
modified from Ref. [5])
16 L. Ceriani et al.

Table 2.1 Thyroid scintigraphy: tracers and technical procedures

99m 123 99m 18
TcO4– I Tc-MIBI F-FDG
Administration i.v. o.a. i.v. i.v.
Activity (adults) 74–111 MBq 7.4–14.8 MBq 185–370 MBq 200–370 MBq
Technique Planar Planar Planar (ev. SPET or PET or PET/CT
SPET/CT)
Acquisition start 15 min p.i 4 and 24 h p.o. 30–45 min p.i. 60 min. p.i.
Acquisition time 5 min 10 min 10 min 12 min (whole body)
Effective dose (mSv/MBq) 0.013 0.20 0.009 0.02 (PET)
0.04 (PET/CT)
Adapted at Department of Nuclear Medicine and PET/CT Centre – Oncology Institute of Southern Switzerland
Abbreviations: CT computed tomography, i.v. intravenous, mSv millisievert, MBq megabecquerel, o.a. oral administra-
tion, PET positron emission tomography, p.i. post injection, p.o. post oral administration, SPET single-photon emission
computed tomography, 99mTcO4– 99mTc-pertechnetate

a b

Fig. 2.2 Normal technetium-99m pertechnetate [99mTcO4−] (a) and technetium-99m methoxyisobutylisonitrile [99mTc-
MIBI] (b) scintigraphy

cated in patients with subcentimetric nodules [5]. 2.3 Parathyroid Nuclear

For oncologic indications a planar whole body Medicine Imaging
imaging in both anterior and posterior views is the
technique of choice for the assessment of meta- The peculiarity of the parathyroid scintigraphy
static spread of the disease. The recent introduc- derives from the fact that a specific tracer able to
tion in the current practice of the SPET/CT derived characterize selectively the parathyroid tissue
hybrid imaging improved the interpretation of and to map the function of the parathyroid cells
abnormal uptakes, particularly in studies with does not exist. Consequently, it is not possible to
radioiodine, providing integrated anatomical and visualize normal parathyroid glands or use the
metabolic images suitable also to plan the further uptake of tracers to grade/measure the parathy-
therapeutic strategies [3]. Finally, the use of posi- roid function.
tron-emitting tracers, such as 18F-FDG and 124I, In routine parathyroid nuclear medicine imag-
requires dedicated PET scanners or, preferably, ing, oncotropic radiotracers mapping cell density
hybrid PET/CT scanners that provide whole body and cellular metabolism and viability are
integrated morphologic-metabolic images [13]. employed. These tracers are taken up not only by
2 Nuclear Medicine Techniques 17

the hyperfunctioning parathyroid glands but also Positron emission tomography (PET) tracers
by other tissues. The detection of the hyperfunc- have met variable success in this field. 18F-FDG is
tioning lesions is, therefore, due to the contrast considered of limited usefulness for the identifi-
between the increased metabolism of the para- cation of parathyroid adenomas. Recent studies
thyroid glands and that of the surrounding nor- seem to demonstrate that 11C-methionine PET/
mal tissues [14, 15]. CT may play a role in the localization of hyper-
99m
Tc-MIBI is the most used tracer for para- functioning parathyroid glands, especially for the
thyroid scintigraphy. The well-known high detection of the smaller lesions [19]. However,
uptake of the thyroid parenchyma makes neces- all the experiences agree to define 11C-methionine
sary, in particular to detect hyperfunctioning PET/CT a useful complementary imaging tech-
parathyroid glands localized within the thyroid nique to identify parathyroid adenoma or hyper-
parenchyma, a comparison with a second tracer, plastic glands in 99mTc-MIBI SPECT/CT-negative
which is taken up by the thyroid gland only, such patients with or without previous neck surgery
as 99mTc-pertechnetate (99mTcO4−) or 123I. The dis- [19].
tributions of the two tracers can be compared Preliminary results demonstrate that radiola-
and, afterward, the thyroid scan can be digitally beled choline PET/CT could be a promising tool
subtracted from the parathyroid scan to remove for localization of hyperfunctioning parathyroid
the thyroid activity and enhance the visualization glands, providing clearer images than 99mTc-
of parathyroid tissue. This technique of images is MIBI, equal or better accuracy, and quicker and
defined as “dual-tracer scintigraphy” [14, 15]. easier acquisition [20].
99m
Tc-MIBI usually washes out from normal
and possibly abnormal thyroid tissue more rap-
idly than from abnormal parathyroid tissue. A 2.4 Nuclear Medicine Imaging
“dual-phase” imaging with early and delayed in Head and Neck
images, generally obtained 20 min and 2 h after Neuroendocrine Tumors
99m
Tc-MIBI injection, has been proposed to max-
imize this characteristic and it is used in many The majority of the head and neck neuroendo-
centers to increase the detection rate of parathy- crine tumors are represented by paragangliomas
roid lesions [14, 15]. (PGLs) derived from the cells of the parasympa-
99m
Tc-tetrofosmin can be used alternatively to thetic paraganglia and the medullary thyroid car-
99m
Tc-MIBI using the dual-tracer subtraction proce- cinomas (MTC) derived from thyroid
dure. 99mTc-tetrofosmin localizes in both parathy- parafollicular cells, both developed from the neu-
roid tissue and functioning thyroid tissue, but in ral crest cells.
contrast to 99mTc-MIBI, there is no differential wash- For the imaging of these neuroendocrine
out between thyroid and parathyroid tissues [16]. tumors, several radiopharmaceuticals are avail-
The standard protocols with planar images able (Fig. 2.3) with variable affinity and diagnos-
have been recently replaced by tomographic tic accuracy for the different subtypes [21–23]. In
techniques. SPECT and SPECT/CT allow more such complex anatomical district, the use of a
precise anatomic localization, particularly for tomographic imaging hybrid (PET/CT or SPET/
localizing ectopic lesions [17, 18]. The combina- CT) is fundamental to enhance sensitivity and
tion of anatomic and functional imaging, that is, specificity increasing diagnostic confidence in
SPECT/CT, provides the optimal localization for image interpretation by means of the proper loca-
surgical planning and additional diagnostic infor- tion of lesions.
mation. Moreover the tomographic imaging can Based on the most recent studies, 18F-DOPA
be associated with a “dual-phase” protocol and, PET/CT has been shown to be a useful addition
today, a SPECT/ CT dual-phase 99mTc-MIBI to anatomical imaging in the preoperative local-
scintigraphy, performed on an integrated SPECT/ ization and molecular assessment of head and
CT device, can be considered the optimal techni- neck PGLs. It is estimated that the frequency of
cal approach for parathyroid imaging [18]. metabolically active head and neck PGLs on
18 L. Ceriani et al.

18
Fig. 2.3 Molecular basis of nuclear imaging of neuroendo- F-DOPA fluorodihydroxyphenylalanine, LAT-1 large
crine tumor cell. 18F-FDG fluorodeoxyglucose, 18F-FDG-6P amino acid transporter, ST receptor somatostatin receptor,
fluorodeoxyglucose-6-phosphate, 123I-MIBG metaiodoben- asterisk catecholamines and their precursors which can be
zylguanidine, hNET human norepinephrine transporter, radiolabelled (Figure modified from Ref. [22])

18
F-FDOPA PET/CT in this region is higher than References
90 %. For patients with hereditary PGL syn-
dromes, 18F-FDG PET/CT should be reserved. 1. Giovanella L (2009) Thyroid nodules: clinical man-
Imaging of somatostatin receptors using agement and differential diagnosis. Praxis 98:83–90
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2. Treglia G, Caldarella C, Saggiorato E et al (2013)
In-pentetreotide or 68Ga-labeled somatostatin Diagnostic performance of 99mTc-MIBI scan in pre-
analogues plays an important role in selecting dicting the malignancy of thyroid nodules: a meta-
patients for targeted peptide radioreceptor ther- analysis. Endocrine 44:70–78
apy [21, 22]. 3. Wonga KT, Choi FP, Lee YY et al (2008) Current role
of radionuclide imaging in differentiated thyroid can-
In detecting MTC recurrence, 18F-DOPA is the cer. Cancer Imaging 8:159–162
best radiopharmaceutical with significant diag- 4. Baker CH, Morris JC (2004) The sodium-iodide sym-
nostic performance if calcitonin values are higher porter. Curr Drug Targets Immune Endocr Metabol
than 150 pg/mL; an early image acquisition start- Disord 4:167–174
5. Giovanella L, Ceriani L, Treglia G (2014) Role of iso-
ing during the first 15 min is advised. 18F-FDG tope scan, including positron emission tomography/
PET/CT could be particularly useful if calcitonin computed tomography, in nodular goitre. Best Pract
and CEA levels are rapidly rising. Somatostatin Res Clin Endocrinol Metab 28:507–518
receptor imaging by SPECT or PET tracers could 6. Moretti JL, Hauet N, Caglar M et al (2005) To use
MIBI or not to use MIBI? That is the question when
be performed when 18F-DOPA or 18F-FDG PET/ assessing tumour cells. Eur J Nucl Med Mol Imaging
CT are inconclusive [23]. 32:836–842
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