Scandinavian Journal of Surgery 93: 261271, 2004

WELL DIFFERENTIATED THYROID CANCER

N. R. Caron, O. H. Clark
Department of Surgery, University of California, San Francisco
and UCSF Comprehensive Cancer Center at Mount Zion Hospital, San Francisco, California, U.S.A.
Key words: Well differentiated thyroid cancer; papillary thyroid cancer; follicular thyroid cancer; Hurthle
cell thyroid cancer

INTRODUCTION
Differentiated thyroid cancer (DTC) accounts for
98 % of thyroid cancer, with neoplasms arising from
the follicular cells (papillary, follicular and Hurthle
cell thyroid cancer) and parafollicular cells (medullary thyroid cancer). This paper will focus on the
well-differentiated thyroid cancers arising from the
follicular epithelial cells. By retaining the differentiated features of normal thyrocytes, these tumors
usually retain their ability to produce thyroglobulin
and to concentrate and organify iodine. Such features
facilitate diagnosis, surveillance and treatment of this
disease. There is ongoing debate over the management of DTC with respect to the extent of thyroid resection, indications for radioactive iodine treatment
and the extent of thyroid hormone suppression therapy. New elements in cancer screening, diagnosis
and treatment continue to evolve with the knowledge
gained from ongoing research in thyroid cancer molecular genetics, clinical trials for medical treatments
and retrospective studies on recurrence, survival and
clinical outcomes of current treatment modalities.
EPIDEMIOLOGY AND ETIOLOGY
Thyroid cancer is one of the most common endocrine
malignancies, second only to ovarian cancer (1). With
approximately 20,000 new cases diagnosed per year
in the United States, American Cancer Society statistics show that over 200,000 patients are monitored
annually for recurrence or progression of their thyroid cancer (2). Although overall prognosis is good,

Correspondence:
Orlo H. Clark, M.D.
University of California, San Francisco and
UCSF Comprehensive Cancer Center
at Mt. Zion Hospital
1600 Divisadero Street
Hellman Bldg. Room C3-47
San Francisco, California 94143-1674, U.S.A.
Email: clarko@surgery.ucsf.edu

approximately 510 % of thyroid carcinoma patients

will eventually die of their disease, representing
0.16 % and 0.24 % of all cancer deaths in men and
women respectively (3). The median age at diagnosis
is 45 to 50 years of age, with a male to female ratio
of 1:3 (3). In the pediatric population, DTC is rare,
with less than 10 % of all cases found in patients under 21 years of age (4). There is marked geographic
and ethnic variation in DTC incidence, with ranges
in the literature between 0.5 to 10 cases per 100,000
women per year (3).
Papillary thyroid cancer (PTC) has been associated
with exposure to various types of radiation: 1) therapeutic radiation for head and neck disease, 2) atomic
explosions or nuclear facility releases such as the
Chernobyl incident of 1986 and 3) ecological exposure secondary to occupational, geological or altitudinal sources (3). The risk of PTC secondary to radiation exposure is both dose and age dependent. This
association is greatest in the pediatric age group,
with those exposed over the age of twenty having
minimal to no increased risk of thyroid malignancy.
The maximal risk of malignancy is at 20 to 30 years
post exposure, but the latency period can extend
from 4 to 50 years. Most radiation associated thyroid
cancers are of similar aggressiveness as sporadic disease but some may be more aggressive. Inadvertent
radiation involves the entire thyroid gland, placing
it at risk for multicentric or metachronous malignancy. Radiation exposure accounts for less than 10 %
of all thyroid cancer.
Insufficient and excess dietary iodine have been
shown to be associated with different subtypes of
DTC although the overall incidence of thyroid cancer has not been conclusively different based on dietary iodine. Papillary thyroid cancer is relatively
more common in high iodine intake regions (such as
Iceland and Hawaii), while follicular (and anaplastic) thyroid cancer are relatively more common in iodine deficient regions (3).
Familial non-medullary thyroid cancer is an uncommon disease, inherited as an autosomal dominant trait, found in a younger age group (mean age
of 3538 years) and thought to be slightly more clinically aggressive than their sporadic counterparts.

262

N. R. Caron, O. H. Clark

TS
HR,

gs
p

"Hot"/Hyperfunctioning
follicular adenoma

Ras, pTEN

Follicular neoplasm /
Follicular adenoma

PAX-8/PPAR-

Ras, PAX-8/PPAR-

De novo

Follicular thyroid
carcinoma

p5
3,
R

ras
Normal follicular thyroid cell
Hurthle cell adenoma

Hurthle cell carcinoma

p53, Rb

P5
3,
rb

, si
s

ras

Anaplastic
cancer

Papillary thyroid
carcinoma

ret/PTC, BRAF, trk, met, ras

Fig. 1. Thyroid tumorigenesis pathway and proposed genetic alterations.

Papillary thyroid cancer is the most common familial non-medullary thyroid cancer and it comprises
approximately 3 % of all PTC (3). Conversely, familial follicular thyroid cancer is extremely rare. Familial thyroid cancer may be associated with familial
adenosis polyposis, Gardners syndrome, Cowdens
disease, Carneys syndrome or Multiple Endocrine
Neoplasia Type I (3, 5).
For reasons that are not clear, the overall incidence
of thyroid cancer is rising (2). Despite this, the incidence of follicular thyroid cancer is decreasing in the
United States. This is thought to be due to the eradication of iodine deficiency and the more accurate diagnosis of follicular variants of PTC and mixed papillary-follicular thyroid cancer as subtypes of PTC
rather than follicular thyroid cancer (6).
Genetic abnormalities have now been linked to the
pathogenesis of DTC. A model for the oncogenic
pathway that determines the progression of normal
thyroid epithelial cells into malignant tumors has
three proposed elements: signals which stimulate
growth (presence of oncogenes), signals which inhibit proliferation (loss of tumor suppressor genes) and
signals which regulate cellular immortalization and
apoptosis (7). Some key genetic mutations associated with development of DTC have been identified
to date (ras, ret/PTC, BRAF, PAX8/PPAR, trk, met)
and have been incorporated into a proposed multistage progression model of thyroid oncogenesis
(Fig. 1). Ras oncogenes are point mutations that result in constitutive activation and subsequent continuous unregulated growth signals. They are most consistently found in follicular adenoma and carcinomas
(up to 80 %), but also identified in 12 % of Hurthle

cell cancer (HCC) and variably in PTC (up to 50 % in

some studies) (3, 7). Activating ras mutations have
been associated with DTC in patients exposed to ionizing radiation or an iodine deficient diet (3). RAF
proteins are cytoplasmic protein kinases that are regulated by binding to ras proteins and play vital roles
in apoptotic and proliferative pathways (7). Mutated BRAF proteins are found in up to 70 % of PTC
and are not identified in other thyroid lesions, such
as follicular thyroid cancer or follicular variant of
PTC. Tyrosine kinase oncogenes (ret, trk, met) are
also highly specific for PTC with ret/PTC present in
up to 50 % of PTC, trk in 1020 % of PTC and met in
up to 80 % of PTC (3, 8). The ret/PTC oncogene is
associated with pediatric PTC, radiation exposure
and PTC microcarcinomas (3). The met oncogene has
been shown to be protective against angioinvasiveness (3), associated with an increased prevalence of
multicentric disease (3) and the only tyrosine kinase
oncogene occasionally detected in follicular thyroid
cancer (10 %) (8). Mutations in PAX-8/PPAR (peroxisome proliferator-activated receptor gamma)
genes are potentially the most important genetic abnormalities associated with follicular thyroid cancer
to date. With potential clinical applications in diagnosis and treatment, research will continue to elucidate the molecular oncogenic pathway of DTC.
PATHOLOGY
According to the World Health Organization, welldifferentiated thyroid cancer can be subdivided into
two main categories: papillary thyroid cancer and

Well differentiated thyroid cancer

263

TABLE 1
Morphologic variants of papillary thyroid cancer (PTC).
Morphologic variants of PTC

Clinical behavior
compared to
typical PTC

Salient features

Follicular

Similar

Follicles, ground glass empty nucleoli, +/ papillae

Micropapillary:occult/minimal

Similar

< 1.5 cm,

Encapsulated

Similar

Totally surrounded by fibrous capsule, +/ focal invasion

Solid/Trabecular

Similar

Foci of solid/trabecular growth in > 50 % of tumor (may be confused with

poorly differentiated thyroid CA)

Tall cell

More aggressive

Follicular cell height 2x the width, +++ eosinophilic cytoplasm lining

glandular and papillary structures, usually > 5 cm, patients older

Diffuse Sclerosing

More aggressive

Dense intrathyroidal lymphocytic invasion, ++ fibrosis, squamous metaplasia,

+ psammoma bodies, more frequent in children

Columnar

More aggressive

Epithelial cell height > 3x width, marked nuclear stratification within

papillary architecture

Oxyphil (Hurthle)

More aggressive

Hurthle cell carcinoma (with marked eosinophilic cytoplasm) that display

classic papillary architecture

follicular thyroid cancer (FTC). There is a growing

opinion that the Hurthle cell carcinoma subtype
should be considered a separate entity due to its constellation of molecular biological, histological, epidemiological and tumor characteristics that fail to conform closely to either PTC or FTC.
Papillary thyroid cancer accounts for approximately 7080 % of DTC in iodine sufficient regions. There
are eight recognized morphologic variants of PTC
and these are briefly described in Table 1. All are relatively uncommon compared to the typical PTC, except for the occult PTC (< 1.01.5cm) for which the
background prevalence is unknown. Autopsy studies have identified occult PTC in 536 % of adults (3).
This paper will focus on the typical PTC. Papillary
thyroid cancer is a firm non-encapsulated nodule
with an irregular border and whitish color that ranges in size depending on stage of presentation and virulence of tumor. Approximately 2030 % are multicentric, although this has been shown to be as high
as 80 % depending on the extent of the gland that
was evaluated, whether microscopic evaluation was
performed for occult disease and the thickness of histologic sections that were assessed. Histologically,
PTC is defined by the presence of papillae (fibrovascular stalks lined with neoplastic epithelial follicular
cells) and distinct nuclear features such as grooved
nuclei, intranuclear inclusions, hyperchromatic nuclei and absent nucleoli (orphan Annie bodies). All
PTC variants have some or all of these distinct nuclear features that define this malignancy. Vascular
invasion is uncommon, evident in only 214 % of
cases (9). Lymph node metastases are relatively common with a range of 1180 % lymph node involvement, depending on the series and whether a prophylactic lymph node dissection was performed to
detect clinically occult and microscopically positive
lymph nodes (9). Lymphatic metastases are identified preoperatively in approximately one third of
patients (9). Distant metastases to bone or lung are
identified in less than 15 % of patients (6).

Follicular thyroid cancer accounts for approximately 1015 % of thyroid malignancies. This encapsulated tumor has a microscopic follicular pattern
that must demonstrate either vascular or capsular
invasion in order to distinguish it from its benign
counterpart, the follicular adenoma. Although the
follicular architecture may vary with level of differentiation, FTC are distinct from PTC by the finding
of small follicles with no papillae and by the absence
of PTCs specific nuclear features (5, 6). Follicular
thyroid carcinoma is classically subdivided into lowrisk and high-risk groups based on capsular, vascular or adjacent thyroid parenchyma/muscle invasion.
Minimally invasive FTC may have capsular and/or
vascular invasion while widely invasive FTC demonstrates broad area(s) of transcapsular invasion with
thyroidal or extrathyroidal invasion (6). DAvanzo
et al recently recommended classifying FTC as
minimally invasive, moderately invasive or widely
invasive since prognosis varied according to these
pathological groupings (6). While in only about
10 % of patients FTC will have spread to the lymph
nodes, 30 % will demonstrate pulmonary or skeletal
metastases (6).
A challenging pathologic diagnosis is the follicular variant of papillary thyroid cancer (FVPTC). The
general consensus is that FVPTC tumors have at least
80 % pure follicular architecture (10, 11), with some
pathologists feeling that the entire tumor should exhibit a follicular pattern (12). These mixed tumors
must exhibit the nuclear features of PTC, although
whether all such features must be present for the
diagnosis or whether as few as two nuclear features
typical of PTC are enough to consider it a FVPTC remains controversial. Many studies have demonstrated that FVPTC and mixed papillary-follicular thyroid
cancer have a natural history and prognosis similar
to the typical PTC.
A controversial area within thyroid cancer pathology is the Hurthle cell carcinoma (HCC). HCC is
composed of oncocytes with an abundant granular

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N. R. Caron, O. H. Clark

cytoplasm due to the large number of mitochondria.

Based on criteria set by the World Health Organization, this tumor of follicular cell origin is a subtype
of both papillary and follicular thyroid cancer, but it
is much more commonly noted as a subtype of FTC.
Despite its persistent classification within the realm
of FTC, its histological, epidemiological and tumor
characteristics set it apart as a separate entity. Epidemiologic risk factors for HCC are more similar to
PTC than FTC; iodine-rich regions, exposure to therapeutic low-dose radiation and familial tendencies.
HCC is more likely to involve regional lymph nodes
than FTC but not nearly as often as PTC. Where both
FTC and PTC usually concentrate radioactive iodine
(75 %), only 7 % of HCC are found to do so (6). All
three types of differentiated thyroid cancer tend to
produce thyroglobulin. Many now propose that HCC
should be a separate category under the umbrella of
differentiated thyroid cancer (6, 13).
PROGNOSIS
There have been many classification systems proposed for well-differentiated thyroid cancer, with the
attempt to estimate prognosis and predict tumor behavior. Options in treatment elements such as extent
of thyroid resection, use of RAI and duration and
degree of thyroid stimulating hormone (TSH) suppression are assessed with respect to ones underlying prognosis. With careful consideration, each individual patients risk:benefit ratio is determined for
each treatment option.
Numerous patient, disease and treatment factors
are considered independent prognostic factors that
help classify risk in patients with DTC. Important
patient factors include gender (male prognosis slightly worse than females with same stage disease), age
(improved prognosis if older than 16 and under 45
years of age) and family history (with familial disease considered more aggressive). The disease factors that impact prognosis are similar to other malignancies and include tumor size, evidence of invasion (intra-thyroidal, vascular, extra-thyroidal), aggressive histopathology features and evidence of
lymphatic or distant metastases. The treatment factors that impact patient prognosis is completeness of
surgical resection and efficacy of RAI treatment. Different scoring systems have used variations of these
prognostic risk factors to help predict those with
more aggressive disease. AGES (age, histological
grade of tumor, extra-thyroidal invasion and distant
metastases and tumor size), AMES (age, distant metastases, extra-thyroidal invasion and tumor size) and
MACIS (metastases, age, completeness of resection,
extra-thyroidal invasion, tumor size) are prognostic
classification systems unique to thyroid cancer (1).
The TNM (tumor size, nodal status and distant metastases) staging system for DTC incorporates many
of the elements of the thyroid specific classifications,
including age as those under 45 years are restricted
to stage I or II, while those over age 45 have the more
classic stage I to IV criteria.
Kebebew and Clark found that most retrospective

studies in patients classified as low risk by various

classification systems reported 10 to 20 year mortality rates of 2 % to 5 %, while those deemed high risk
had mortality rates of 40 % to 50 % (1). Similarly, recurrence rates for low risk patients (10 %) and high
risk patients (45 %) differ significantly (1) and the
mortality from these recurrences is approximately
33 % to 50 % (1). Two subtypes of DTC that have a
particularly excellent prognosis are the occult PTC
and the minimally invasive FTC. Fortunately, most
differentiated thyroid cancer patients fall into the low
risk category and have an excellent overall prognosis.
DIAGNOSIS
Patients with DTC can present with a thyroid nodule, cervical lymphadenopathy, distant metastases or
combinations of these possibilities. Most commonly,
initial presentation is a palpable thyroid nodule. Cervical lymph node metastases are palpable in approximately one third of patients with PTC (with microscopic disease estimated in over 50 % of cases) (9)
while cervical lymphadenopathy is much less common in FTC (10 %) (1). On the contrary, lung and
bone are the most common sites for distant metastases and are more common in FTC (30 %) than in
PTC (215 %) (6, 9). Patient history, physical examination, serum thyroglobulin levels, RAI scintigraphy
and adjuvant radiological investigations facilitate diagnosis.
In patients with a thyroid nodule, a history of local or regional symptoms of invasion (voice change,
hemoptysis, stridor, dyspnea, dysphagia), rapid nodule growth, history of head or neck irradiation, and
personal or family history of previous thyroid cancer or other endocrine malignancy increases the likelihood of thyroid cancer. Physical examination can
reveal a firm, potentially fixed, irregular thyroid nodule, palpable cervical lymphadenopathy, or hoarse
voice. TSH and serum thyroglobulin (Tg) are useful
laboratory investigations but are not diagnostic. Normal or elevated TSH levels can rule out a hyperfunctioning nodule, of which only approximately 1 % are
associated with malignancy. Tg is a glycoprotein produced only by thyrocytes (normal and differentiated
malignant cells). While an elevated serum Tg level
may be indicative of metastatic disease if it is unusually high, many benign conditions give rise to
modestly elevated levels.
The diagnostic test of choice once a thyroid nodule is identified is a fine needle aspiration biopsy
(FNAB). There are four possible pathology results
from a FNAB: benign, malignant (papillary, medullary, anaplastic thyroid cancer), indeterminant (follicular neoplasm) or an insufficient/non-diagnostic
specimen. The diagnostic accuracy of FNAB is
greater than 95 % (9) with a false negative rate of 2
6 %. FNAB can definitively diagnose PTC, due to the
nuclear changes that are well visualized on cytological evaluation. FNAB cannot distinguish between
FTC and follicular adenoma. With the absence of distinct cytological features, diagnosis of FTC requires
histological evidence of capsular or vascular inva-

Well differentiated thyroid cancer

sion. If FNAB indicates a follicular neoplasm, the

standard recommendation is thyroid lobectomy and/
or isthmusectomy, to permit full histological evaluation, with approximately 20 % ultimately diagnosed
as follicular carcinoma. FNAB usually does not require ultrasound guidance to facilitate accurate biopsy but in small or deep-seated nodules it can be
helpful. An indeterminant cytology should warrant
a repeat FNAB. Clinically palpable or radiologically
suspicious lymph nodes may also be evaluated with
FNAB and histological staining for thyroglobulin facilitates difficult diagnoses. One must recall that a
benign pathology on FNAB should supplement clinical assessment not replace it. Regardless of the
FNAB results, rapidly growing nodules, recurrent
thyroid cysts and patients at increased risk of thyroid cancer due to a history of head or neck irradiation and/or a significant family history of DTC
should have a lobectomy and/or isthmusectomy to
definitely rule out malignancy.
Preoperative staging of DTC usually consists of the
above diagnostic elements of clinical evaluation,
FNAB and serum Tg with a chest radiograph to assess for gross pulmonary metastases. Cervical ultrasound (US) is recommended as it may detect lymphadenopathy not clinically evident. It may also
identify nodules in the contralateral thyroid lobe. US
is well suited for the thyroid gland as its superficial
location permits the use of high frequency transducers that emit a high resolution image. The high echogenicity of the gland enhances the US evaluation of
the thyroid, which results in a sensitive, cost effective imaging investigation. Other imaging such as
magnetic resonance imaging (MRI) or computed tomography (CT) should be used selectively for fixed
tumors or substernal goiters. Full staging is completed postoperatively with a RAI whole body scan and
histological evaluation of the surgical specimen.
TREATMENT
The most important treatment for thyroid cancer is
complete surgical excision of the tumor. Beyond this,
there are many controversies in the management of
DTC. The extent of excision (total or near-total thyroidectomy versus lobectomy/isthmusectomy), the
use of RAI ablation, and the use of thyroid hormone
supplementation to suppress TSH are all debated to
some degree, particularly for the low risk patient
who appears to have an excellent prognosis regardless of whether a total thyroidectomy is performed
or adjuvant treatments are utilized. Most clinicians
today use adjuvant RAI ablation and TSH suppression for most patients with DTC.
SURGERY

Advocates of total or near total thyroidectomy state

that this approach permits complete ablation of all
remaining thyroid tissue (including potential occult
DTC) with RAI so that diagnostic scans can detect
regional and distant metastases and radioiodine can
be utilized for treatment if necessary. Total or near-

265

total thyroidectomy with RAI ablation increases the

sensitivity of serum Tg as a tumor marker in the
long-term follow-up for disease recurrence. Total
thyroidectomy removes all sub-clinical multicentric
disease in the contralateral lobe (which has been documented in up to 85 % of PTC) and thereby prevents
recurrent disease in the contralateral lobe (1). With
less extensive resection the recurrence rate in the contralateral lobe is approximately 7 %, and 50 % of patients with recurrent DTC will eventually die from
this disease(1). Many large retrospective studies with
long term follow-up demonstrate decreased recurrence and improved survival in patients who have
total thyroidectomy (and RAI ablation) compared to
those patients who have less extensive procedures(1).
Although this benefit is more significant in those patients in the high-risk group, one must recall that
since many elements of these prognostic classification systems are only available postoperatively (age
and gender are the only elements one can confirm
preoperatively), they are limited in their ability to
direct initial surgical treatment. In addition, although
rare, even low-risk patients can suffer a recurrence
(5 %) and subsequent mortality (50 %) from their
well-differentiated thyroid cancer.
Advocates of less extensive procedures feel that
most patients with thyroid cancer are considered in
the low-risk group and have excellent prognosis
without extensive surgical resection. Total thyroidectomy places the contralateral parathyroid glands
and recurrent laryngeal nerve at risk, where lobectomy and isthmusectomy avoids this increase in the
operative complication rate. While the multicentricity of PTC may contribute to an increased local recurrence rate in the contralateral lobe, many studies
do not show a significant difference in overall survival and the clinical significance of multicentric disease has been questioned. Indeed, most studies conclude no survival benefit of total or near total thyroidectomy over lobectomy/isthmusectomy in lowrisk patients with occult PTC (< 1.0 cm) or microinvasive FTC.
At the University of California, San Francisco
(UCSF), we recommend total thyroidectomy for all
high-risk and most low-risk patients, as predictions
for recurrence or mortality from DTC are not guaranteed. In particular, patients with low risk tumors
but the presence of risk factors such as previous
head/neck irradiation or family history of thyroid
cancer are treated with total thyroidectomy because
any remaining tissue is at ongoing risk for malignant
transformation. Suggested indications for lobectomy
and isthmusectomy (in lieu of more extensive thyroid resections) in the low-risk patient are listed in
Table 2. In consideration of the morbidity associated
with permanent hypoparathyroidism or recurrent laryngeal nerve injury, total thyroidectomy should be
performed by surgeons with experience in this field.
The overall surgical complication rate should be less
than 2 %.
Synchronous cervical lymph node metastases may
be detected by clinical examination, staging cervical
ultrasound or intra-operative identification. If detected preoperatively, formal compartment-based

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N. R. Caron, O. H. Clark
TABLE 2
Potential indications for lobectomy/isthmusectomy in low-risk
thyroid cancer patients.

Papillary thyroid cancer < 1 cm (occult PTC)

Minimally invasive (capsular only) follicular thyroid cancer
Informed patient choice for lobectomy/isthmusectomy
Compliance concerns with post-operative thyroid
supplementation medications
RLN injury on side ipsilateral to malignant nodule
* RLN: recurrent laryngeal nerve

therapeutic lymph node dissections (LND) should be

performed at the time of the thyroidectomy. Unexpected lymphadenopathy found intraoperatively
may be assessed for metastatic disease by frozen section analysis. Positive histology of Delphian, central
or lateral cervical lymph nodes should be followed
by a central and ipsilateral cervical lymph node dissection. Only if a grossly positive contralateral lymph
node is confirmed by biopsy, is a contralateral LND
indicated (1). This approach is referred to as a therapeutic lymph node dissection and should be a formal, compartment-based lymphadenectomy as opposed to a berry picking procedure. The modified
radical (or functional) LND that is recommended involves excision of fibro-fatty tissue and associated
lymph nodes while preserving the sternocleidomastoid muscle, internal jugular vein, and the spinal accessory, vagus and cervical sensory nerves(1). Some
centers still consider prophylactic LND (when there
is no evidence of lymph node metastases) as part of
the surgical treatment of patients with PTC, since the
incidence of occult lymph node metastases is so high.
This has not been shown to improve patient prognosis and it is associated with a small but increased risk
of complications; it therefore is not generally recommended (1). The only scenario in which a prophylactic central LND is recommended is when HCC has
been confirmed, because most of these tumors do not
concentrate RAI (> 90 %), they have a higher recurrence rate and a significant rate of lymph node metastases (40 %) (1). Indications for LND and type of
resection is an ongoing debate, with most studies
confirming that therapeutic lymph node dissection
at the time of the initial surgery reduces locoregional recurrence but does not usually improve overall
survival. The clinical significance of occult cervical
metastases is still questioned.
RADIOACTIVE IODINE

A controversial element of DTC treatment is radioactive iodine (RAI) ablation. After a partial or subtotal thyroidectomy, RAI can be used for thyroid remnant ablation. After a total (or near total) thyroidectomy or thyroid remnant RAI ablation, RAI can be
used for diagnosis and treatment of recurrent or metastatic DTC. Thyrocytes trap and organify iodine and
well-differentiated thyroid cancer cells retain this

ability. As normal thyroid cells can trap approximately 100-fold more RAI than DTC cells, the amount of
remnant normal thyroid cells remaining post operatively directly impacts the amount of administered
RAI available to be trapped by the DTC(1). Post-operative RAI ablation of the thyroid remnant can improve the diagnostic and therapeutic utility of RAI
because it will then only be taken up by metastatic
or recurrent disease. In addition, with no normal thyroid cells remaining, a subsequent rise in serum Tg
level will be a highly sensitive and specific marker
of disease recurrence. RAI ablation has been shown
by many to reduce recurrences(14) and some believe
it may even improve survival in selected patients
(1, 15).
RAI is a powerful treatment modality specific for
thyroid disease. While gross disease is best treated
surgically, RAI is the treatment of choice in patients
who are suspected of having persistent and/or occult disease. Post-operative RAI treatment is administered to patients with a persistently elevated Tg
level post-operatively or a positive initial RAI scan
indicating metastatic disease. With no gross disease
identified for surgical resection, the diffuse and/or
microscopic foci of disease responsible for these elevations in serum Tg can be treated primarily with
RAI before they grow to become radiologically evident. This is especially evident with miliary pulmonary metastases. RAI is a vital adjuvant treatment
modality used not only to ablate the thyroid remnant,
but also to treat patients deemed to be at high risk of
recurrence after pathologic review (local invasion,
positive margins or aggressive histological subtype).
In order to be amenable to treatment with RAI,
malignant cells must demonstrate avidity for RAI.
Approximately 25 % of patients with recurrent nonresectable PTC will not be able to concentrate
RAI(16). Diagnostic RAI scintigraphy utilizes a small
dose of RAI that determines the extent and location
of metastases or remnant normal thyroid tissue, helps
plan subsequent treatment dose, and confirms that
the malignant cells concentrate RAI. In some circumstances, patients with persistent or recurrent disease
demonstrated by elevated serum thyroglobulin concentrations may have a negative diagnostic RAI scan
but convert to a positive scan when treated with the
higher therapeutic doses of RAI. The opposite phenomenon may occur during thyroid remnant ablation when an initially positive diagnostic scan loses
its uptake intensity. Some centers initially perform a
low dose (2 mCi) RAI scan to estimate the volume of
thyroid remnant and to assess for potential synchronous metastatic disease. While this may help to plan
the follow-up ablative dose, there is the risk that the
initial RAI dose will stun the thyrocytes (either benign or malignant) and lead to a suboptimal uptake
of the therapeutic dose. If small doses of RAI are utilized, this stunning effect is minimized (16).
To facilitate uptake of RAI by normal and malignant thyroid cells, high concentrations of TSH are
necessary. Until recently, this required withdrawal
of thyroid hormone supplementation to achieve a
hypothyroid state and subsequent serum TSH level
greater than 30 mU/l. Based on hormone half-life,

Well differentiated thyroid cancer

this target TSH level is achieved when thyroxine is

discontinued for 4 to 6 weeks and tri-iodothyronine
is discontinued for 2 weeks prior to the RAI administration(2). This preparation is associated with
symptomatic hypothyroidism. An alternative method of preparation is the administration of recombinant human (rh) TSH prior to RAI scintigraphy and
treatment. This has been shown to be a safe, effective method of stimulating RAI uptake for diagnosis
but has not yet been approved for therapeutic RAI
indications (2). The choice of rhTSH is of particular
interest for patients who cannot withstand the hypothyroid state due to concurrent illness (such as
those with brain metastases) or advanced age.
The initial RAI scan is performed 4 to 12 weeks
postoperatively in order to allow the patient to recover from the neck operation and to permit a hypothyroid state to stimulate TSH levels, if necessary.
Additional preparation includes avoidance of iodine
containing contrast media during radiological investigations and adherence to a low iodine diet for the
preceding two weeks in order to deplete endogenous
iodine stores. Although various protocols exist, most
patients receive an initial scanning dose (about 2
mCi) with the follow-up ablative dose (30 to 100 mCi)
determined by the percent uptake and approximation of thyroid remnant size. The surgeon should aim
for < 1 % uptake after a total thyroidectomy. If the
patient is at high risk of persistent disease, the dose
is increased accordingly (150 to 300 mCi) and is based
on tumor type, disease stage and the extent of residual disease anticipated (2). Repeat treatments may be
required to obtain a negative RAI whole body scan
(no evidence of remnant thyroid tissue or persistent
DTC). After a RAI whole body scan is negative, RAI
scintigraphy becomes part of the armamentarium of
investigations available to follow a patient for potential recurrence of DTC. This is particularly useful in
the event of a rising serum thyroglobulin.
RAI is associated with potential side effects and
complications. If thyroid hormone withdrawal is utilized, the requirement for TSH > 30 mU/l will produce profound symptoms of hypothyroidism in
many patients and may exacerbate medical or psychiatric conditions(2). Both endogenous TSH elevation and rhTSH can theoretically stimulate any remaining focus of DTC and rhabdomyolysis and renal failure have been reported. Other adverse reactions and potential complications are rare. These include radiation sialadenitis, xerostomia, hypogeusia,
nasolacrimal duct obstruction, transient leucopenia
and oligospermia (2). At higher cumulative doses,
there have been reports of secondary malignancies
including leukemia, small intestine, bladder and possibly breast cancer (2). It is estimated that 0.3 % of
patients who receive a cumulative dose of RAI over
500 mCi develop these secondary malignancies (2).
In patients who develop extensive iodine avid pulmonary metastases, the risk for radiation pneumonitis and fibrosis increases once a total of 80 rads or
greater is delivered (2). Women treated with RAI
should refrain from breast-feeding as the RAI can be
excreted in her milk and concentrated in the lactiferous ducts. These potential complications must be

267

considered on an individual basis when deciding

upon a treatment plan.
THYROID HORMONE SUPPRESSION OF TSH

Thyroid stimulating hormone (TSH) is a growth factor for normal and malignant thyrocytes that has
been shown to stimulate tumor growth, invasion and
angiogenesis (1) (15, 17). Evidence suggests that by
suppressing the endogenous level of this thyroid
growth factor by supraphysiologic levels of thyroid
hormone, there will be decreased growth of any remaining malignant thyroid tissue (1). Retrospective
studies have found that those patients with a history
of DTC on TSH suppression therapy have a lower
rate of tumor progression, recurrence and possibly
an increased overall survival (1, 2, 17). There are,
however, no prospective studies confirming the
benefit of long-term thyroid hormone suppression
therapy.
The most effective therapeutic TSH level and duration of suppression are debated. Suppression of
TSH requires iatrogenic mild hyperthyroidism, so
this must be balanced with each patients risk of
hyperthyroid symptoms, accelerated bone loss, atrial fibrillation, increased left ventricular thickness,
and potential precipitation of angina (2, 17). Thyroid
hormone suppression to TSH < 0.1 mU/l is the standard therapeutic goal for patients with low and moderate risk thyroid cancers, but should be adjusted if
the patient is at increased risk of cardiac or skeletal
complications. For high-risk thyroid cancer patients
the TSH level should be less than 0.05 mU/l. For
patients with low-risk DTC and in remission for
several years, the target TSH could be adjusted to a
low, but detectable range (0.10.5 mU/l) (2). At this
level of minimal suppression the serum thyroid
hormone levels (triiodothyronine and thyroxine) are
normal.
EXTERNAL BEAM RADIATION

External beam radiation is not commonly used in the

treatment of DTC and no prospective randomized
controlled trials have evaluated its role in this disease. There are limited indications for this treatment
modality but it should be considered for patients
who have DTC tumors that do not concentrate RAI
and who have either residual cervical disease postoperatively or non-resectable tumors (18). Without
adequate prospective studies to confirm, it has been
suggested that doses of 50 Gy or higher are required
to impact local control and there is no consensus on
overall time or fractionation (18). The clinical target
volume for locoregional disease is limited by the spinal cord. Potential complications include both acute
and late reactions. Acute reactions include mucositis, dysphagia, dermatologic reactions and edema.
Late reactions include skin fibrosis and tracheal compression. In addition, reoperation becomes much
more difficult in patients who have received external beam radiation. Further studies will help to
standardize treatment protocols, indications and accurately determine side effect profiles.

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N. R. Caron, O. H. Clark

NOVEL AND FUTURE TREATMENTS

RAI is a cornerstone of treatment for differentiated

thyroid cancer. Although beyond the scope of this
review paper, there is ongoing research in the fields
of molecular and cellular physiology to develop the
ability of non-iodophyllic and de-differentiated thyroid cancer cells to take up RAI. Tumors with a decreased ability to accumulate RAI are associated with
a worse prognosis. Approximately 25 % of DTC tumors initially have minimal or no RAI uptake and
this increases to 50 % in patients who develop recurrent disease (19). Once a tumor de-differentiates, it
loses the thyrocyte-specific ability to uptake iodine,
which is made possible by the sodium-iodide symporter (NIS) on the cells basolateral membrane (19).
Some novel therapy options may increase NIS gene
expression and subsequent RAI effectiveness (19).
Examples include histone deacetylase inhibitors
(such as Trichostatin A) (19) and retinoids that bind
the retinoic X receptor on the malignant thyrocytes
to enhance the expression of the NIS gene (2). Other
re-differentiating agents potentially include aromatic fatty acids, peroxisome proliferator-activated receptor gamma agonists (PPAR-gamma agonists), resveratrol and 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors (20). Current research focusing on therapy that will lead to re-differentiation of thyroid cancer cells and potentially
improve the dismal prognosis of this patient population is important. Aggressive tumor behavior, inability to monitor for early tumor recurrence with Tg,
and inability to treat with RAI all contribute to the
poorer prognosis of patients with de-differentiated
tumors.
SURVEILLANCE FOR DISEASE RECURRENCE
Once a patient with DTC is successfully treated with
thyroidectomy, RAI ablation and thyroid hormone
suppression, they must continue to be monitored for
evidence of disease recurrence. Regular clinical follow-up may elicit signs and symptoms of local, regional or distant disease and patients with a history
of DTC should be assessed every 3 to 6 months for 1
to 2 years and then annually if disease free. Monitoring for sub-clinical disease may utilize combinations of serum Tg levels, RAI scintigraphy and other
radiological investigations. This diligent surveillance
should be life-long, as recurrent DTC has been documented up to 50 years after initial treatment and
early detection of recurrence is associated with a
longer survival.
SERUM THYROGLOBULIN

Serum Tg levels can usually accurately determine

whether a patient is tumor free after total or near total thyroidectomy and RAI ablation. Elevations of
serum Tg in this scenario suggest disease recurrence,
as this glycoprotein is thyroid specific. While Tg
levels can be assessed on suppressive doses of levothyroxine, the TSH-stimulated Tg levels are most sen-

sitive (2). TSH stimulated serum Tg levels can be obtained by withdrawing hormone supplementation or
by administering rhTSH. Thyroid hormone withdrawal to achieve the target stimulated TSH level
(> 30 mCi/l) provides a greater elevation in Tg than
rhTSH, but the overall sensitivity for detecting residual or recurrent disease is similar (21). TSH stimulated serum Tg levels are utilized for postoperative
disease surveillance and the best time for determination is when the patient is in a hypothyroid state
in preparation for scanning or treatment with RAI.
A recent consensus conference concluded that serum
Tg levels measured during thyroid hormone suppression although helpful were not sensitive enough
to detect all patients with residual disease (21). It
suggested that in long-term follow-up, an undetectable stimulated serum Tg level (< 1 microgram/L) is
evidence of complete tumor ablation and only after
this level of cure is confirmed should annual serum
Tg tests be obtained during thyroid hormone suppression.
The thresholds at which elevations in serum Tg
indicate persistent or recurrent disease differ to some
degree between institutions. At UCSF, TSH-stimulated serum Tg levels > 5 ng/ml or non-stimulated serum Tg level > 2 ng/ml (in patients on hormone suppression) raise suspicion of disease recurrence and
is assessed with further investigations. The National
Comprehensive Cancer Network (NCCN) suggests
using > 10 ng/ml and > 5 ng/ml, respectively. A recent consensus report recommended a more stringent
threshold of 2 ng/ml for stimulated Tg and < 1 ng/
ml for those on hormone supplementation (21). The
quantitative level of Tg reflects not only probability
of recurrence, but can be indicative of the extent of
disease and its most likely location (distant metastases or locoregional recurrence) (2).
The primary limitation of this screening test is the
presence of thyroglobulin antibodies (Ab), which
make the various serum Tg assays unreliable. While
410 % of unselected women and 13 % of unselected men have these antibodies, up to 25 % of patients
with DTC will have detectable levels (2, 21). Therefore, serum Tg levels must be assessed simultaneously with the serum Tg Ab titer in order to determine
if Tg levels will be an accurate and appropriate
screening test for each patient with previous DTC.
Of interest, serum Tg Ab titers frequently decrease
after curative treatment in patients with DTC.
RADIOACTIVE IODINE SCINTIGRAPHY:
WHOLE BODY SCAN

Diagnostic RAI scans are an important component of

patient monitoring for recurrent DTC. Disease surveillance begins once complete remission is achieved,
which is defined by a negative RAI scan, a serum Tg
below the set threshold and no clinical or ultrasound
evidence of persistent disease. The role of the RAI
scanning in disease surveillance has evolved as the
sensitivity of serum Tg has increased. In the past, RAI
scintigraphy was a central component of ongoing
DTC surveillance. It was performed in conjunction
with serum Tg with the anticipation that this com-

Well differentiated thyroid cancer

bined regimen would increase the ability to detect

recurrent disease. With the functional sensitivity of
serum Tg assays now at least 1 ng/ml, many investigations have shown that a stimulated serum Tg
level in isolation is sufficient to follow low-risk patients who have no clinical evidence of disease and a
suppressed serum Tg level while on thyroid hormone suppression therapy (21). It has therefore been
suggested that once complete remission is confirmed,
RAI surveillance should be left for those low-risk
subjects with elevated serum Tg levels (21). For higher risk patients, regular RAI scans may detect additional patients with recurrent disease and could be
considered in selected cases (2).
As discussed, potential disadvantages of RAI scanning include: 1) the necessity of a biochemical hypothyroid state and the potential associated symptoms, 2) the potential for rapid tumor growth secondary to the elevated TSH level required, and 3) the
proposed stunning effect of the low diagnostic dose
of RAI that limits the efficacy of higher therapeutic
doses, should the diagnostic scan be positive (2). As
discussed previously, the biochemical hypothyroid
state can be achieved by thyroid hormone withdrawal (with TSH > 30 mU/l) or by administration of
rhTSH. Although costly, rhTSH provides exogenous
stimulation of potential thyroid cancer cells without
subjecting the patient to the effects of hypothyroidism. Studies have demonstrated similar sensitivity of RAI scans with thyroid hormone withdrawal
and rhTSH.
OTHER RADIOLOGICAL IMAGING

Cervical ultrasound (US) is considered one of the

most sensitive means of detecting neck recurrences.
It is an excellent study to employ for low-risk patients; especially those who demonstrate an elevated
serum Tg and negative RAI whole body scan. It is a
regular surveillance tool for higher-risk patients
where it is an adjunct to the traditional serum Tg and
RAI scans. Ultrasonography is more important for
patients with previous PTC or HCC than for patients
with FTC, as lymph node metastases are uncommon
in the latter. Sonographic features concerning for
metastatic disease include round or bulging lymph
nodes which have lost their hilar echoes, punctate
calcifications and demonstration of a hyperechoic
signal. As with initial diagnosis, cervical US is the
most commonly utilized radiological investigation
for local or regional disease recurrence. It can locate
lesions suspicious for lymph node or soft tissue recurrence and facilitate FNAB to confirm recurrent
disease.
Well-differentiated thyroid cancer cells retain capacities of their native cell type which includes
trapping and organification of iodine and production
of thyroglobulin. Such characteristics are capitalized
on with specific screening tests of RAI scans and
serum thyroglobulin, respectively. Radiological imaging can further define disease detected by elevated serum thyroglobulin or positive RAI scintigraphy
by identifying the lesion anatomically, by guiding
percutaneous FNAB of the suspicious lesion and by

269

providing important preoperative anatomic information. Local and regional recurrence is well delineated by cervical ultrasound, but may also be demonstrated with computed tomography (CT) or magnetic resonance imaging (MRI) of the region. Mediastinal metastases are best depicted with MRI while CT
is excellent for pulmonary metastases. In anticipation
for potential treatment with RAI, all imaging must
be performed without iodinated contrast. For patients with DTC whose serum Tg levels are low, MRI
or CT is not required for routine surveillance and
should be utilized on a case-by-case basis.
POSITRON EMISSION TOMOGRAPHY

While an elevated serum thyroglobulin in an ablated patient is highly suggestive of disease recurrence,
defining the extent and location of the disease is necessary in order to plan appropriate treatment. While
this is traditionally achieved by the RAI whole body
scan, non-iodophyllic disease foci can usually be
identified with additional routine radiological imaging. As discussed, these imaging options include ultrasound, CT or MRI. To facilitate identification of
occult disease, Positron Emission Tomography (PET)
using 18F-fluorodeoxyglucose (FDG) has been shown
to identify recurrent disease in 60 % to 94 % of patients with negative RAI scans (22). The sensitivity
of PET to identify recurrent DTC has been shown to
correlate with two thyroid specific factors: ability to
concentrate RAI and TSH level (23). Most RAI negative recurrences demonstrate 18F-FDG-PET uptake in
correspondence to its poor differentiation, rapid tumor growth and subsequent increase in metabolic
activity and glucose uptake (23). On the contrary,
most RAI positive scans (two thirds of DTC recurrences) have negative 18F-FDG-PET scans (23). The
sensitivity of PET scans is increased in patients with
elevated TSH from thyroid hormone withdrawal and
in patients administered rhTSH prior to investigation. This relationship may be explained by the stimulation of benign and malignant thyrocyte metabolism, glucose transport and glycolysis by thyroid
stimulating hormone (24). Overall, PET scans facilitate the identification of occult disease recurrence
that is marked by an elevated serum thyroglobulin
level but not definitely identified by the more standard imaging tests of RAI scan, ultrasound, CT or
MRI.
TREATMENT OF DISEASE RECURRENCE
Disease recurrence can be divided into cervical (locoregional) recurrence or distant metastatic disease.
Recurrence generally refers to disease that is detected after a patient with a history of DTC had previously been documented to have a negative clinical
examination, an undetectable serum Tg level and a
negative RAI scan for at least six months after treatment; disease detected within six months of initial
treatment is considered persistent thyroid cancer.
Subsequent development of signs or symptoms, rise
in serum Tg or positive RAI uptake mandates fur-

270

N. R. Caron, O. H. Clark

ther investigation to confirm the presence, the extent

and the anatomic location of the recurrence. Recurrent rates for DTC range between 10 to 20 %. Although 33 to 50 % of patients who have recurrent disease will ultimately die from their disease, treatment
can cure patients and prolong survival in those less
fortunate (1). Treatment of recurrence depends on the
location and extent of the disease, the possibility of
resection and whether avidity for RAI is maintained.
If there is any doubt in confirmation of malignancy,
any patient with a suspicious lesion should undergo
FNAB.
Locoregional recurrence defined by clinical examination and/or radiological imaging is best treated
by surgical resection with subsequent consideration
for adjuvant RAI. RAI treatment is not optimal for
macroscopic disease, especially lymph node metastases as these can only infrequently be ablated with
RAI. If the disease recurs in the jugular lymph nodes
and a formal lateral cervical lymph node dissection
has not already been performed, a modified radical
lymph node dissection is the recommended procedure. If the recurrence occurs on the background of
a previous formal neck dissection, a focused approach to resect the specific lesion in question is the
safest, most effective surgical treatment. This applies
to the central (level VI) cervical lymph node compartment as well. Post-operative administration of RAI
helps to treat any microscopic or gross unresectable
residual disease. If surgery is not thought to be safe
or feasible, a more experienced thyroid surgeon
should be consulted. RAI treatment in isolation could
then be considered. Alternatively, external beam radiation or chemotherapy can be considered for patients with non-iodophyllic unresectable disease.
The increased difficulty of repeat surgery must not
be underestimated. Central lymph node or thyroid
bed recurrence will be found within the scar tissue
of the total thyroidectomy, and places the ipsilateral
recurrent laryngeal nerve and parathyroid glands at
risk. There is an increased risk of hypoparathyroidism and recurrent laryngeal nerve injury in repeat surgery, even in the most experienced hands.
Preoperative direct or indirect laryngoscopy must be
performed to assess the function of the recurrent laryngeal nerves. The operating surgeon should know
of documented nerve palsy as it can potentially alter
the treatment plan and the patient must know that
bilateral recurrent laryngeal nerve injury could lead
to the need for a permanent tracheostomy. Similarly, in repeat lateral cervical lymph node dissections,
vital structures such as nerves (vagus, phrenic, spinal
accessory, cervical sensory, hypoglossal, brachial
plexus) and the thoracic duct must be identified and
preserved and this is more difficult at reoperation.
With the challenging repeat surgery and the need for
a multidisciplinary team to identify and optimize
treatment of recurrent disease, patients with recurrent DTC should be treated by experienced surgeons
in this field.
Distant metastases are most commonly detected in
the lung. With strict adherence to a surveillance protocol, recurrence is usually detected by serum Tg and
RAI scanning before it is evident on chest radiograph

or pulmonary CT. This miliary type of pulmonary

metastases is best treated with RAI, which achieves
remission in approximately 75 % of patients (1).
Gross pulmonary metastases detected by chest x-ray,
on the other hand are associated with a poor prognosis and are unlikely (48 %) to be definitively treated with RAI (1).
Treatment of recurrent DTC that is Tg-positive but
RAI-negative is a challenging issue. Further imaging
(US, CT, MRI, PET) can sometimes identify a cervical recurrence that is resectable, while miliary pulmonary metastases can remain elusive. Some centers advocate empiric treatment of occult recurrence
by administering a therapeutic dose of RAI (100 to
150 mCi), which is more sensitive in detecting the site
of tumor recurrence than the standard scanning doses (2 to 5 mCi). This increased dose of I131 may subsequently disclose the location of the recurrent disease on post treatment scanning as it converts the
negative scan to positive and/or this increased dose
may achieve the therapeutic result of a decreased or
normalization of serum Tg level in about one third
of patients (1). If serum Tg levels remain elevated,
additional RAI may be administered or surgical resection of subsequently localized disease can be considered. Small malignant foci of disease are more
amenable to RAI treatment than larger ones, supporting the role of RAI for occult recurrences. If a RAI
scan with a therapeutic dose is negative, no further
RAI is indicated.
As with treatment of the primary disease, other
treatment modalities are available for those who cannot be cured with surgery or I131 administration. Indications for external beam radiation are similar and
chemotherapy remains an uncommon treatment modality. With de-differentiated tumors, the novel and
experimental re-differentiating agents should be considered but more clinical data is required.
CONCLUSION
While differentiated thyroid cancer is renowned for
its good prognosis, there are patients who suffer from
persistent and recurrent disease both locoregional
and distant. Despite a standard repertoire of surgery,
nuclear medicine and medical treatment for DTC,
there are many controversies on the indications and
protocols that accompany these treatment options.
Ongoing research in molecular genetics continues to
elucidate the oncogenic pathway of this unique differentiated group of malignancies, and these study
findings will eventually add to new treatment options and hopefully an ultimate cure for thyroid cancer patients.
REFERENCES
01. Kebebew E, Clark OH: Differentiated thyroid cancer: complete rational approach. World J Surg 2000;24:942951
02. Ringel MD, Ladenson PW: Controversies in the follow-up and
management of well-differentiated thyroid cancer. Endocr
Relat Cancer 2004;11:97116
03. Busnardo B, De Vido D: The epidemiology and etiology of dif-

Well differentiated thyroid cancer

04.

05.

06.

07.
08.
09.
10.

11.
12.
13.
14.

15.

ferentiated thyroid carcinoma. Biomed Pharmacother 2000;54:

322326
Gow KW, Lensing S, Hill DA, Krasin MJ, McCarville MB, Rai
SN, Zacher M, Spunt SL, Strickland DK, Hudson MM: Thyroid carcinoma presenting in childhood or after treatment of
childhood malignancies: An institutional experience and review of the literature. J Pediatr Surg 2003;38:15741580
Hellman P, Goretzki P, Witte J, Roeher H: Follicular thyroid
cancer. In: Surgical Endocrinology. Eds G.M. Doherty, B. Skogseid. Philadelphia, Lippincott Williams & Wilkins, 2001, pp.
7586
DAvanzo A, Treseler P, Ituarte PH, Wong M, Streja L, Greenspan FS, Siperstein AE, Duh QY, Clark OH: Follicular thyroid
carcinoma: histology and prognosis. Cancer 2004;100:1123
1129
Segev DL, Umbricht C, Zeiger MA: Molecular pathogenesis
of thyroid cancer. Surg Oncol 2003;12:6990
Tallini G: Molecular pathobiology of thyroid neoplasms. Endocr Pathol 2002;13:271288
Kebebew E, Clark OH: Papillary thyroid cancer. In: Surgical
Endocrinology. Eds G.M. Doherty, B. Skogseid. Philadelphia,
Lippincott Williams & Wilkins, 2001, pp. 5974
Zidan J, Karen D, Stein M, Rosenblatt E, Basher W, Kuten A:
Pure versus follicular variant of papillary thyroid carcinoma:
clinical features, prognostic factors, treatment, and survival.
Cancer 2003;97:11811185
Carcangiu ML, Zampi G, Rosai J: Papillary thyroid carcinoma: a study of its many morphologic expressions and clinical
correlates. Pathol Annu 1985;20 Pt 1:144
LiVolsi VA: Pure versus follicular variant of papillary thyroid
carcinoma: clinical features, prognostic factors, treatment, and
survival. Cancer 2003;98:1997; author reply 19971998
Grossman RF, Clark OH: Hurthle cell carcinoma. Cancer
Control 1997;4:1317
Karam M, Gianoukakis A, Feustel PJ, Cheema A, Postal ES,
Cooper JA: Influence of diagnostic and therapeutic doses on
thyroid remnant ablation rates. Nucl Med Commun 2003;24:
489495
Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid
cancer. Am J Med 1994;97:418428

271

16. Angelos P: Current approaches to the treatment of well-differentiated thyroid cancer. Oncology (Huntingt) 2002;16:309
315; discussion 315, 318, 323304
17. McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis
NJ: Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med 2002;34:
554564
18. Ford D, Giridharan S, McConkey C, Hartley A, Brammer C,
Watkinson JC, Glaholm J: External beam radiotherapy in the
management of differentiated thyroid cancer. Clin Oncol (R
Coll Radiol) 2003;15:337341
19. Zarnegar R, Brunaud L, Kanauchi H, Wong M, Fung M, Ginzinger D, Duh QY, Clark OH: Increasing the effectiveness of
radioactive iodine therapy in the treatment of thyroid cancer
using Trichostatin A, a histone deacetylase inhibitor. Surgery
2002;132:984990; discussion 990
20. Park JW, Clark OH: Redifferentiation therapy for thyroid cancer. Surg Clin North Am 2004;84:921943
21. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson PW,
Pinchera A: A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1433
1441
22. Khan N, Oriuchi N, Higuchi T, Zhang H, Endo K: PET in the
follow-up of differentiated thyroid cancer. Br J Radiol 2003;76:
690695
23. Lind P, Kresnik E, Kumnig G, Gallowitsch HJ, Igerc I, Matschnig S, Gomez I: 18F-FDG-PET in the follow-up of thyroid
cancer. Acta Med Austriaca 2003;30:1721
24. Chin BB, Patel P, Cohade C, Ewertz M, Wahl R, Ladenson P:
Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab 2004;89:91
95

Received: September 8, 2004