Download Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis

clinical practice guidelines
Annals of Oncology 21 (Supplement 5): v214–v219, 2010
doi:10.1093/annonc/mdq190
Thyroid cancer: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up
F. Pacini1, M. G. Castagna1, L. Brilli1 & G. Pentheroudakis2
On behalf of the ESMO Guidelines Working Group*
1
Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, Section of Endocrinology and
Metabolism, University of Siena, Siena, Italy; 2Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece
incidence
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via
L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: [email protected]
Approved by the ESMO Guidelines Working Group: February 2008, last update
December 2009. This publication supercedes the previously published version—Ann
Oncol 2009; 20 (Suppl 4): iv143–iv146.
Conflict of interest: The authors have reported no conflicts of interest.
diagnosis
Thyroid cancer presents as a thyroid nodule detected by
palpation and more frequently by neck ultrasound. While
thyroid nodules are frequent (4%–50% depending on the
diagnostic procedures and patient’s age), thyroid cancer is rare
(5% of all thyroid nodules). Thyroid ultrasound (US) is
a widespread technique that is used as a first-line diagnostic
procedure for detecting and characterizing nodular thyroid
disease. US features associated with malignancy are
hypoechogenicity, microcalcifications, absence of peripheral
halo, irregular borders, solid aspect, intranodular blood flow
and shape (taller than wide). All these patterns taken singly are
poorly predictive. When multiple patterns suggestive of
malignancy are simultaneously present in a nodule, the
specificity of US increases but the sensitivity becomes
unacceptably low. Fine-needle aspiration cytology (FNAC) is an
important technique that is used along with US for the
diagnosis of thyroid nodules. FNAC should be performed in
any thyroid nodule >1 cm and in those <1 cm if there is any
clinical (history of head and neck irradiation, family history of
thyroid cancer, suspicious features at palpation, presence of
cervical adenopathy) or ultrasonographic suspicion of
malignancy. The results of FNAC are very sensitive for the
differential diagnosis of benign and malignant nodules
although there are limitations: inadequate samples and
follicular neoplasia. In the event of inadequate samples FNAC
should be repeated while in the case of follicular neoplasia, with
normal thyroid-stimulating hormone (TSH) and ‘cold’
appearance at thyroid scan, surgery should be considered. The
use of various immunohistochemical markers in cytological
samples to differentiate papillary thyroid carcinoma from other
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
Several recent studies have reported an increase in the incidence
of thyroid cancer during the last decades in Canada, in the
United States and in Europe. This phenomenon is mainly due
to an increase in micropapillary (<2 cm) histotype while there
is no significant change in the incidence of the less common
histological categories: follicular, medullary and anaplastic
cancers. The increase is attributable to better detection of small
papillary carcinomas as a result of improved diagnostic
accuracy (neck ultrasound and fine-needle aspiration cytology).
It is common experience in thyroid cancer referral centres that
nearly 60%–80% of thyroid carcinomas detected nowadays are
micropapillary thyroid carcinomas (<1 cm in size) carrying an
excellent long-term prognosis. However, more recently, an
increased incidence of all sizes of thyroid tumour has been
reported in the United States. In 1997–2005 the annual
percentage change (APC) for primary tumours <1.0 cm has
been 9.9 in man and 8.6 in women. A significant increase was
also observed for tumours >4 cm among men (1988–2005: APC
3.7) and women (1988–2005: APC 5.7). These data indicate
that increased diagnostic scrutiny is not the only explanation
but environmental influence should also be considered. The
only established environmental risk factor for thyroid
carcinoma is exposure to ionizing radiation, and the risk,
particularly of papillary carcinoma, is greater in subjects of
younger age at exposure. An increased incidence of thyroid
cancer in children and adolescents was observed in Ukraine,
Belarus and certain regions of Russia as early as 4 years after the
Chernobil accident. The pre-Chernobyl incidence of thyroid
cancer in Ukrainian children was very low (0.5–1.0 per
1000 000 children). Following the explosion of the Chernobyl
nuclear reactor in 1986, a dramatic increase in the incidence of
benign and malignant thyroid tumours (80 times more) was
observed in children born or conceived around the time of the
accident in a considerable area surrounding the reactor. Despite
increasing incidence, the mortality from thyroid cancer has
tended to decline over the last three decades. In the European
Union from 1992 to 2002 the mortality for thyroid cancer
declined in both men and women (–23% and –28%,
respectively). It is unclear how much of the decline in mortality
is due to better diagnosis rather than to improved treatment of
thyroid neoplasm.
clinical practice guidelines
Annals of Oncology
follicular-derived lesions of thyroid have been explored during
the last years but none of the markers appears to be specific
enough to be employed as the diagnostic marker for the
cytological diagnosis of papillary thyroid carcinoma. Two
prospective studies reported that by molecular testing of thyroid
for nodules BRAF, RAS, RET/PTC and PAX8/PPARc mutations
in cytological material, the difference of any mutation was
a strong indicator of cancer because 97% of mutation-positive
nodules had malignant diagnosis at histology. Thyroid function
test and thyroglobulin (Tg) measurement are of little help in the
diagnosis of thyroid cancer. However, measurement of serum
calcitonin is a reliable tool for the diagnosis of the few cases of
medullary thyroid cancer (5%–7% of all thyroid cancers), and
has higher sensitivity compared with FNAC. For this reason
measurement of calcitonin should be an integral part of the
diagnostic evaluation of thyroid nodules.
initial treatment
The initial treatment of differentiated thyroid carcinoma
(DTC) should always be preceded by careful exploration of the
neck by US to assess the status of lymph node chains. The
initial treatment for DTC is total or near-total thyroidectomy
whenever the diagnosis is made before surgery and the nodule
is ‡1 cm, or regardless of the size and histology (papillary or
follicular) if there is metastatic, multifocal or familial DTC. Less
extensive surgical procedures may be accepted in the case of
unifocal DTC diagnosed at final histology after surgery
performed for benign thyroid disorders, provided that the
tumour is small, intrathyroidal and of favourable histological
type (classical papillary or follicular variant of papillary or
minimally invasive follicular). The benefit of prophylactic
central node dissection in the absence of evidence of nodal
disease is controversial. There is no evidence that it improves
recurrence or mortality rate, but it permits an accurate staging
of the disease that may guide subsequent treatment and followup. However, it is not indicated in follicular thyroid cancer.
Compartment-oriented microdissection of lymph nodes should
be performed in cases of preoperatively suspected and/or
intraoperatively proven lymph node metastases. In expert
hands surgical complications such as laryngeal nerve palsy and
hypoparathyroidism, are extremely rare (<1%–2%). Surgery is
usually followed by the administration of 131I activities aimed at
ablating any remnant thyroid tissue and potential microscopic
residual tumour. This procedure decreases the risk of
locoregional recurrence and facilitates long-term surveillance
staging and risk assessment
Several staging systems have been developed by authoritative
centres. Each of these staging systems provides good risk
stratification based on data available shortly after initial
therapy. The most popular is the American Joint Committee on
Cancer/International Union Against Cancer (AJCC/IUAC)
TNM staging system based mainly on the extent of tumour and
age. Although all staging systems are able to predict high or low
risk of cancer mortality, they fail to predict the risk of
recurrence. Therefore, the addition of a postoperative
clinicopathological staging system should be use in conjunction
with the AJCC staging system to improve prediction of risk for
recurrence and to dictate the most appropriate therapy. In the
recent guidelines, estimate of risk of recurrence and risk of
disease-specific death are used to guide both initial treatment
and follow-up recommendations. In accordance with this
system, a European Consensus Report defined three categories
of risk to establish the indication for radioiodine ablation
therapy (Table 1): no indication for radioiodine ablation in
very low-risk patients [unifocal T1 (<1 cm) N0 M0, no
Table 1. Risk stratification for DTC patients according to the European Consensus Report
Very low risk
Low risk
High risk
Intrathyroidal tumour (T1 £1 cm)
No aggressive histology
No local or distant metastases
Intrathyroidal tumour (T1 >1 cm and T2)
Aggressive histology
No local or distant metastases
Complete surgery
Less than total thyroidectomy
Intrathyroidal tumour (T3)
Micro or macroscopic invasion (T3–T4)
Locoregional metastases
Distant metastases
Incomplete tumour resection
Volume 21 | Supplement 5 | May 2010
doi:10.1093/annonc/mdq190 | v215
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
differentiated thyroid cancer
based on serum Tg measurement and diagnostic radioiodine
whole body scan (WBS). In addition the high activity of 131I
allows obtaining a highly sensitive post-therapeutic WBS.
Radioiodine ablation is recommended for all patients except
those at very low risk (those with unifocal T1 tumours, <1 cm
in size, with favourable histology, no extrathyroidal extension
or lymph node metastases) (Table 1). Effective thyroid ablation
requires adequate stimulation by TSH. The method of choice
for preparation to perform radioiodine ablation is based on the
administration of recombinant human TSH (rhTSH) while the
patient is on levo-thyroxine (LT4) therapy. A recent
multicentre and prospective study has demonstrated that this
preparation is highly effective and safe and that the rate of
successful ablation is similar to that obtained with LT4
withdrawal. Based on these results the use of rhTSH was
approved in Europe in February 2005 by the European
Medicine Agency (EMEA) and in the USA in December 2007
by the FDA, as preparation for radioiodine ablation of postsurgical thyroid remnants in patients with well-differentiated
thyroid carcinoma without evidence of metastatic disease, using
a fixed dose of 3700 MBq (100 mCi) of 131I. However, a recent
randomized prospective study has showed that, in patients
prepared with rhTSH, a lower dose of 1850 MBq (50 mCi)
of 131I is equally effective as 3700 MBq (100 mCi), even in the
presence of lymph node metastases and that, further, reduces
radiation exposure to the whole body.
clinical practice guidelines
short-term follow-up
The aim of the follow-up is the early discovery and treatment of
persistent or recurrent locoregional or distant disease. The large
majority of local recurrences develops and is detected in the
first 5 years after diagnosis. However, in a minority of cases,
local or distant recurrence may develop in late follow-up, even
20 years after the initial treatment.
Two to three months after initial treatment thyroid function
tests (FT3, FT4, TSH) should be obtained to check the
adequacy of LT4 suppressive therapy. At 6–12 months the
follow-up is aimed to ascertain whether the patient is free of
disease (Table 2). This follow-up is based on physical
examination, neck US, basal and rhTSH-stimulated serum Tg
measurement with or without diagnostic WBS. At this time
most (nearly 80%) of the patients will belong to the low-risk
categories and will disclose normal neck US and undetectable
(<1.0 ng/ml) stimulated serum Tg in the absence of serum
Tg antibodies. Diagnostic WBS does not add any clinical
information in this setting and may be omitted. These patients
may be considered in complete remission and their rate of
subsequent recurrence is very low (<1.0% at 10 years).
long-term follow-up
The subsequent follow-up of patients considered free of disease
at the time of their first follow-up will consist of physical
examination, basal serum Tg measurement on LT4 therapy and
neck US once a year. No other biochemical or morphological
tests are indicated unless some new suspicion arises during
evaluation. The question of whether a second rhTSHstimulated Tg test should be performed in disease-free patients
is a matter of debate. Recent studies reported that this
procedure has little clinical utility in patients who had no
biochemical (undetectable serum Tg) or clinical (imaging)
evidence of disease at the time of their first rhTSH-Tg. In this
group, the second test confirmed complete remission in almost
all patients. Recently, new methods for serum Tg measurement
with a functional sensitivity of <0.1 ng/ml have become
available. Using these systems some authors reported a much
higher sensitivity of the assays. In their experience undetectable
basal serum Tg (<0.1 ng/ml) using ultrasensitive assays should
give the same information as a stimulated Tg value and thus the
authors recommended that rhTSH-Tg testing should be
abandoned. However, the higher sensitivity of these tests is at
the expense of lower specificity.
Patients with evidence of persistent disease, or with
detectable levels of serum Tg increasing with time, require
imaging techniques for the localization of disease and
appropriate treatment, including therapeutic doses of 131I.
Included in this category are the 5%–10% of DTC patients
presenting with local or distant metastases at diagnosis and an
additional 5%–10% that develop recurrent disease during
follow-up. During the evaluation of metastatic patients, 18FDGPET scanning is gaining more and more attention as
a diagnostic and prognostic tool. Several studies have shown
that, in differentiated thyroid carcinoma, 18FDG-PET can be
used to detect recurrence or metastases with a high degree of
sensitivity (80%–90%) and it is particularly indicated for
patients who do not take up radioiodine. FDG-PET may also
give prognostic information. 131I-WBS-negative and 18FDGPET-positive patients indicate a group of patients with
more aggressive and less differentiated disease carrying
a worse prognosis with respect to 131I-WBS-positive and
18
FDG-PET-negative patients, who have less aggressive disease
and better prognosis.
Table 2. Initial treatment and follow-up based on risk stratification
Ablative radioiodine therapy
Follow-up:
Tg on LT4
Stimulated Tg
Neck US
Diagnostic WBS
v216 | Pacini et al.
Very low risk
Low risk
High risk
No indication
Probable indication
Definitive indication
Every 6–12 months
Not useful
Every 6–12 months
At 12 months if Tg on LT4 is
undetectable
Every 6–12 months
Nor required if stimulated Tg
is undetectable
Every 6–12 months
At 12 months if Tg on LT4 is
undetectable
Every 6–12 months
May be helpful
Every 6–12 months
Not useful
Volume 21 | Supplement 5 | May 2010
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
extension beyond the thyroid capsule, favourable histology],
definite indication in high-risk (any T3 and T4 or any T, N1, or
any M1) and probable indication in low-risk [T1 (>1 cm) or T2
N0 M0 or multifocal T1 N0 M0, or unfavourable histology]
(Table 2). Recently, Tuttle et al. have proposed an ‘ongoing risk
stratification’ which takes into account the response to therapy.
On this basis, patients can be classified as having an
excellent, acceptable or incomplete response to therapy.
Patients with an excellent response (undetectable basal and
stimulated Tg, negative AbTg and negative neck US) should
have a very low risk of recurrence and their long-term followup will be based on yearly physical examination and suppressed
Tg value. Patients with an acceptable response (undetectable
basal Tg, stimulated Tg <10 ng/ml, trend of Tg in decline, AbTg
absent or declining, substantially negative neck US) require
a closer follow-up reserving additional treatment in the case of
evidence of disease progression. Patients with an incomplete
response (detectable basal and stimulated Tg, trend of Tg stable
or rising, structural disease present, persistent or recurrent RAIavid disease present) require continued intensive follow-up
with neck ultrasound, cross-sectional imaging, RAI imaging
and FDG-PET imaging. The majority of these patients will
require additional therapy such as surgical resection, RAI
therapy, external beam irradiation and systemic therapies.
Annals of Oncology
Annals of Oncology
clinical practice guidelines
levo-thyroxine therapy
Thyroid hormone suppression therapy is also an important
part of the treatment of thyroid cancer and is effective in
stopping the growth of microscopic thyroid cancer cells or
residual thyroid cancer. Several reports have shown that
hormone-suppressive treatment with LT4 benefits high-risk
thyroid cancer patients by decreasing progression and
recurrence rates, and cancer-related mortality. No significant
improvement has been obtained by suppressing TSH in
patients with low-risk thyroid cancer. The duration of
suppression therapy in cancer patients is currently being
debated. According to the current guidelines, low-risk patients
free of disease after initial treatment may be shifted from
suppressive to replacement LT4 therapy, with the goal of
maintaining serum TSH level within the normal range. A
significant proportion of patients defined as high risk at the
time of diagnosis may appear free of disease at their first followup after initial treatment. In these patients, however, the risk of
relapse in the long-term follow-up may be significant, therefore
it is advisable to maintain these patients on suppressive doses of
LT4 therapy (TSH 0.1 lUI/ml) for 3–5 further years.
medullary thyroid cancer
Medullary thyroid cancer (MTC) arises from the parafollicular
calcitonin-producing C cells of the thyroid and accounts for
between 5% and 8% of all thyroid malignancies, with 1000
new diagnoses in the United States each year. Since malignant
transformed C cells produce and secrete large amounts of
Volume 21 | Supplement 5 | May 2010
peptides, including CEA and calcitonin (CT), with few
exceptions, elevated serum CT is a marker of the presence of
MTC or metastatic MTC after surgery. Up to 75% of MTC
cases occur sporadically, while the hereditary form of MTC
shows an autosomal dominant pattern of transmission.
Familial MTC arises as part of multiple endocrine neoplasia
(MEN) syndrome type 2A or 2B or familial MTC (FMTC).
Important prognostic factors that predict adverse outcome
include CT doubling time (DT), advanced age at diagnosis,
extent of primary tumour, nodal disease and distant metastases.
initial treatment and follow-up of MTC
For MTC patients with no evidence of lymph node metastases
by physical examination and cervical US the treatment consists
in total thyroidectomy for both sporadic and hereditary MTC
associated with prophylactic central lymph node dissection
(level VI). Lateral neck dissection (levels IIA, III, IV, V) may be
best reserved for patients with positive preoperative imaging. In
presence of distant metastatic disease, less aggressive neck
surgery may be appropriate to preserve speech, swallowing and
parathyroid function while maintaining locoregional disease
control to prevent central neck morbidity. Postoperatively, the
TNM classification and other factors, such as the postoperative
CT level and the CT and CEA DTs, should be used to predict
outcome and to help plan long-term follow-up of patients with
MTC. After surgery serum CT level normalizes (undetectable)
in 60%–90% of cases in patients with no lymph node
involvement but in only 20% of those with lymph node
metastases. In patients with detectable CT level after surgery
imaging techniques are required to detect metastatic disease,
although many patients may have elevated CT levels without
evidence of disease. Distant metastases are the main cause of
MTC-related death. They occur predominantly in patients who
present initially with a large-sized tumour, extra-thyroidal
growth and lymph node involvement. Distant metastases often
affect multiple organs including lungs, bones and liver, and
more rarely the brain, skin and breast.
therapy of metastatic MTC
In advanced disease mono- or poly-chemotherapy has not
shown significant clinical benefit (<20% response rate).
Radiotherapy is often used in the presence of local invasion. In
the case of liver metastases chemo-embolization may be
effective in reducing tumour mass.
Also in MTC, new compounds (e.g. TKI) target signalling
pathways essential for tumour cell survival, proliferation and
metastases. Preliminary evidence indicates that they may have
important clinical benefits. The most promising TKIs being
tested against MTC in clinical trials include motesanib
diphosphate, vandetanib, sorafenib and sunitinib, and all
together resulted in a partial response ranging from 6% to 20%
and in stable disease from 47% to 87% with tolerable and
manageable toxicities.
anaplastic thyroid cancer
Anaplastic thyroid cancer (ATC) is the most aggressive thyroid
tumour and one of the most aggressive cancers in humans. It
arises from the follicular cells of the thyroid gland but does not
retain any of the biological features of the original cells, such as
doi:10.1093/annonc/mdq190 | v217
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
Treatment of locoregional disease is based on the combination
of surgery and radioiodine therapy. External beam radiotherapy
may be indicated when complete surgical excision is not possible
or when there is no significant radioiodine uptake in the tumour.
Distant metastases are more successfully cured if they take up
radioiodine, are of small size located in the lungs (not visible at
X-rays). Lung macro-nodules may benefit from radioiodine
therapy but the definitive cure rate is very low. Bone metastases
have the worst prognosis even when aggressively treated by
a combination of radioiodine therapy and external beam
radiotherapy. Brain metastases are relatively rare and usually
carry a poor prognosis. Surgical resection and external beam
radiotherapy represent the only therapeutic options.
Chemotherapy is no longer indicated due to lack of effective
results and should be replaced by enrollment of the patients in
experimental trials with tyrosine kinase inhibitor (TKI).
Molecules that block kinase activity at distal steps in the MAP
kinase pathway are logical candidate drugs for thyroid cancer.
TKIs being tested against differentiated thyroid cancer in clinical
trials include motesanib diphosphate, axitinib, gefitinib,
sorafenib and sunitinib. None of these is specific for one
oncogene protein but they target several TK receptors and proangiogenic growth receptors. The results of phase II–III clinical
trials conducted so far are promising with a partial response
ranging from 14% to 32% and stable disease from 50% to 67%.
All together, the preliminary results of these trials are promising
and indicate that targeted therapy might become the first-line
treatment of metastatic refractory thyroid cancer in the near
future.
clinical practice guidelines
uptake of iodine and synthesis of thyroglobulin. The peak
incidence is in the sixth to seventh decades (mean age at
diagnosis 55–65 years) and the prevalence is fortunately very
low (<2% of all thyroid tumours). ATC may arise de novo but
in most cases it develops from a pre-existing well-differentiated
thyroid tumour, which has undergone additional mutational
events, mainly p53 mutation.
treatment
Treatment of ATC has not been standardized and unfortunately
there is not yet an efficient treatment; surgery, chemotherapy,
radiotherapy alone or in combination do not improve survival.
The most common single cytotoxic agent used against
anaplastic carcinomas is doxorubicin alone or in combination
with cisplatin. The results have been disappointing. Adding
bleomycin or other agents does not enhance the efficacy of this
combination. Recently paclitaxel has been used in clinical trial
and it has shown some improvement in response but not in
survival. Novel treatment strategies are necessary; future
strategies include targeted therapy, tumour suppressor gene
therapy or induction of cell cycle arrest.
literature
1. Liu S, Semenciw R, Ugnat AM, Mao Y. Increasing thyroid cancer incidence in
Canada, 1970–1996: time trends and age-period-cohort effects. Br J Cancer
2001; 85: 1335–1339.
2. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid
cancer in the United States, 1988–2005. Cancer 2009; 115: 3801–3807.
3. Reynolds RM, Weir J, Stockton DL et al. Changing trends in incidence and
mortality of thyroid cancer in Scotland. Clin Endocrinol 2005; 62: 156–162.
4. Colonna M, Danzon A, Delafosse P et al. Cancer prevalence in France: time
trend, situation in 2002 and extrapolation to 2012. Eur J Cancer 2008; 44:
115–122.
5. Fahey TJ 3rd, Reeve TS, Delbridge L. Increasing incidence and changing
presentation of thyroid cancer over a 30-year period. Br J Surg 1995; 82:
518–520.
6. Galanti MR, Hansson L, Bergström R et al. Diet and the risk of papillary and
follicular thyroid carcinoma: a population-based case-control study in Sweden
and Norway. Cancer Causes Control 1997; 8: 205–214.
7. Leenhardt L, Bernier MO, Boin-Pineau MH et al. Advances in diagnostic practices
affect thyroid cancer incidence in France. Eur J Endocrinol 2004; 150: 133–139.
8. Nagataki S, Aashizawa KS. Cause of childhood thyroid cancer after the chernobyl
accident. Thyroid 1998; 8: 115–117.
9. Mettler FA Jr, Williamson MR, Royal HD et al. Thyroid nodules in the population
living around Chernobyl. JAMA 1992; 268: 616–619.
10. Anspaugh LR, Catlin RJ, Goldman M. The global impact of the Chernobyl reactor
accident. Science 1988; 16(242): 1513–1519.
v218 | Pacini et al.
11. Pacini F, Vorontsova T, Molinaro E et al. Thyroid consequences of the Chernobyl
nuclear accident. Acta Paediatr Suppl 1999; 88: 23–27.
12. Tronko MD, Bogdanova TI, Komissarenko IV et al. Thyroid carcinoma in children
and adolescents in Ukraine after the Chernobyl nuclear accident: statistical data
and clinicomorphologic characteristics. Cancer 1999; 86: 149–156.
13. Jacob P, Bogdanova TI, Buglova E et al. Thyroid cancer among Ukrainians and
Belarusians who were children or adolescents at the time of the Chernobyl
accident. J Radiol Prot 2006; 26: 51–67.
14. Bosetti C, Bertuccio P, Levi F et al. Cancer mortality in the European Union,
1970–2003, with a joinpoint analysis. Ann Oncol 2008; 19: 631–640.
15. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin
Endocrinol Metab 2008; 22: 901–911.
16. Rago T, Vitti P. Role of thyroid ultrasound in the diagnostic evaluation of thyroid
nodules. Best Pract Res Clin Endocrinol Metab 2008; 226: 913–928.
17. Pacini F, Schlumberger M, Dralle H et al. European Thyroid Cancer Taskforce.
European consensus for the management of patients with differentiated thyroid
carcinoma of the follicular epithelium. Eur J Endocrinol 2006; 154: 787–803.
18. Cooper DS, Doherty GM, Haugen BR et al. American Thyroid Association
Guidelines Taskforce. The American Thyroid Association Guidelines Taskforce
Management guidelines for patients with thyroid nodules and differentiated
thyroid cancer. Thyroid 2006; 16: 109–142.
19. Baloch ZW, LiVolsi VA. Fine-needle aspiration of the thyroid: today and tomorrow.
Best Pract Res Clin Endocrinol Metab 2008; 22: 929–39.
20. Nikiforov YE, Steward DL, Robinson-Smith TM et al. Molecular testing for
mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J
Clin Endocrinol Metab 2009; 94: 2092–2098.
21. Elisei R, Bottici V, Luchetti F et al. Impact of routine measurement of serum calcitonin
on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864
patients with nodular thyroid disorders. J Clin Endocrinol Metab 2004; 89: 163–168.
22. Pacini F, Ladenson PW, Schlumberger M et al. Radioiodine ablation of thyroid
remnants after preparation with recombinant human thyrotropin in differentiated
thyroid carcinoma: results of an international, randomized, controlled study.
J Clin Endocrinol 2006; 91: 926–932.
23. Pilli T, Brianzoni E, Capoccetti F et al. A comparison of 1850 (50 mCi) and 3700
MBq (100 mCi) 131-iodine administered doses for recombinant thyrotropinstimulated postoperative thyroid remnant ablation in differentiated thyroid
cancer. J Clin Endocrinol Metab 2007; 92: 3542–3546.
24. Cancer Staging Manual. 6th edition. American Joint Committee on Cancer:
AJCC, New York, USA: Springer 2002.
25. Tuttle RM. Risk-adapted management of thyroid cancer. Endocr Pract 2008; 14:
764–774.
26. Kloos RT, Mazzaferri EL. A single recombinant human thyrotropin-stimulated
serum thyroglobulin measurement predicts differentiated thyroid carcinoma
metastases three to five years later. J Clin Endocrinol Metab 2005; 90:
5047–5057.
27. Castagna MG, Brilli L, Pilli T et al. Limited value of repeat recombinant human
thyrotropin (rhTSH)-stimulated thyroglobulin testing in differentiated thyroid
carcinoma patients with previous negative rhTSH-stimulated thyroglobulin and
undetectable basal serum thyroglobulin levels. J Clin Endocrinol Metab 2008;
93: 76–81.
28. Iervasi A, Iervasi G, Ferdeghini M et al. Clinical relevance of highly sensitive Tg
assay in monitoring patients treated for differentiated thyroid cancer. Clin
Endocrinol 2007; 67: 434–441.
29. Smallridge RC, Meek SE, Morgan MA et al. Monitoring thyroglobulin in
a sensitive immunoassay has comparable sensitivity to recombinant human TSHstimulated thyroglobulin in follow-up of thyroid cancer patients. J Clin Endocrinol
Metab 2007; 92: 82–87.
30. Schlumberger M, Hitzel A, Toubert ME et al. Comparison of seven serum
thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer
patients. J Clin Endocrinol Metab 2007; 92: 2487–2495.
31. Robbins RJ, Wan Q, Grewal RK et al. Real-time prognosis for metastatic thyroid
carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission
tomography scanning. J Clin Endocrinol Metab 2006; 91: 498–505.
32. Feine U, Lietzenmayer R, Hanke JP et al. Fluorine-18-FDG and iodine-131-iodide
uptake in thyroid cancer. J Nucl Med 1996; 37: 1468–1472.
Volume 21 | Supplement 5 | May 2010
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
diagnosis
The diagnosis is usually easy based on typical clinical aspects:
large, hard mass invading the neck and causing compressive
symptoms (dyspnoea, cough, vocal cord paralysis, dysphagia
and hoarseness). Almost 50% of the patients present with
distant metastasis, mostly in the lungs but also in bones, liver
and brain. Due to its aggressive behaviour the latest AJCC
Staging Manual classifies all ATCs as T4 and stage IV tumours,
regardless of their size and overall tumour burden. The mean
overall survival is often <6 months, whatever treatment is
performed.
Annals of Oncology
Annals of Oncology
clinical practice guidelines
33. Wang W, Macapinlac H, Larson SM et al. [18F]-2-fluoro-2-deoxy- D-glucose
positron emission tomography localizes residual thyroid cancer in patients with
negative diagnostic (131)I whole body scans and elevated serum thyroglobulin
levels. J Clin Endocrinol Metab 2000; 85: 2082–2083.
34. Dietlein M, Scheidhauer K, Voth E et al. Fluorine-18 fluorodeoxyglucose positron
emission tomography and iodine-131 whole-body scintigraphy in the follow-up
of differentiated thyroid cancer. Eur J Nucl Med 1997; 24: 1342–1348.
35. Durante C, Haddy N, Baudin E et al. Long-term outcome of 444 patients with
distant metastases from papillary and follicular thyroid carcinoma: benefits and
limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91: 2892–2899.
36. Sherman SI, Wirth LJ, Droz JP et al. for the Motesanib Thyroid Cancer Study
Group. Motesanib diphosphate in progressive differentiated thyroid cancer.
N Engl J Med 2008; 359: 31–42.
37. Ezra EW Cohen, Lee S et al. Axitinib is an active treatment for all histologic
subtypes of advanced thyroid cancer: results from a phase II study J Clin Onc
2008; 28: 4708–4713.
38. Pennell NA, Daniels GH, Haddad RI et al. A phase II study of gefitinib in patients
with advanced thyroid cancer. Thyroid 2008; 18: 317–323.
39. Gupta-Abramson V, Troxel AB, Nellore A et al. Phase II trial of sorafenib in
advanced thyroid cancer. J Clin Oncol 2008; 26: 4714–4719.
40. Biondi B, Filetti S, Schlumberger M. Thyroid-hormone therapy and thyroid
cancer: a reassessment. Nat Clin Pract Endocrinol Metab 2005; 1: 32–40.
41. Jemal A, Murray T, Ward E et al. Cancer statistics. CA Cancer J Clin 2005; 55:
10–30.
42. Schlumberger MJ, Elisei R, Bastholt L et al. Phase II study of safety and efficacy
of motesanib in patients with progressive or symptomatic, advanced or
metastatic medullary thyroid cancer. J Clin Oncol 2009; Jun 29.
43. Kober F, Hermann M, Handler A, Krotla G. Effect of sorafenib in symptomatic
metastatic medullary thyroid cancer. J Clin Oncol 2007; 25: 14065.
44. Kebebew E, Greenspan FS, Clark OH et al. Anaplastic thyroid carcinoma:
treatment outcome and prognostic factors. Cancer 2005; 1(103):
1330–1335.
45. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular
pathogenesis and emerging therapies. Endocr Relat Cancer 2009; 16:
17–44.
46. Cantare S, Capezzone M, Marchisotta S, Capuano S, Busanero G, Toti P,
Di Santo A, Caruso G, Carli AF, Brilli L, Montanaro A, Pacini F. Impact of protooncogene mutation detection in cytological specimens from thyroid nodules
improves the diagnostic accuracy of cytology. J Endocrinal Metab 2010; 95(3):
1365–1369.
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 14, 2013
Volume 21 | Supplement 5 | May 2010
doi:10.1093/annonc/mdq190 | v219