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94. Alvarez-Nunez F, Bussaglia E, Mauricio D, et al. PTEN
promoter methylation in sporadic thyroid carcinomas.
Thyroid 2006;16:17–23.
95. Nakamura N, Carney JA, Jin L, et al. RASSF1A and
NORE1A methylation and BRAFV600E mutations in
thyroid tumors. Lab Invest 2005;85:1065–75.
96. Xing M, Cohen Y, Mambo E, et al. Early occurrence of
RASSF1A hypermethylation and its mutual exclusion
with BRAF mutation in thyroid tumorigenesis. Cancer
Res. 2004;64:1664–8.
97. Knudson AG. Two genetic hits (more orless) tocancer.
Nat Rev Cancer. 2001;1:157–62.
98. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4:143–53.
99. Galusca B, Dumollard JM, Lassandre S, et al. Global
DNA methylation evaluation: potential complementary
marker in differential diagnosis of thyroid neoplasia.
Virchows Arch. 2005;447:18–23.
100. Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C,
Dammann R. CpG island methylation of tumor-related
promoters occurs preferentially in undifferentiated
carcinoma. Thyroid. 2006;16:633–42.
101. Cras A, Darsin-Bettinger D, Balitrand N, et al. Epigenetic patterns of the retinoic acid receptor beta2 promoter in retinoic acid-resistant thyroid cancer cells.
Oncogene. 2007;26:4018–24.
102. Furuya F, Shimura H, Suzuki H, et al. Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid
cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology. 2004;145:2865–75.
8
Well-Differentiated Thyroid Cancer: An Overview and the Chernobyl Effect
Shamly V. Dhiman Amara, Robert McConnell,
and William B. Inabnet
Introduction
Thyroid cancer is the most common endocrine
malignancy and its incidence is increasing
[1, 2]. Differentiated thyroid cancer consists
of papillary, follicular, and Hurthle cell histological types. Although it typically has a good
prognosis due to its long, indolent, and welltolerated natural history, lifelong follow-up is
recommended as late recurrences may occur
after surgery. Advances in diagnostic modalities and pathologic analysis continue to
evolve. High-resolution ultrasound plays an
increasingly important role in the management of thyroid cancer, including diagnosis
of malignancy, preoperative lymphatic mapping and postoperative surveillance. Surgery
remains the mainstay of therapy; however,
thyroid suppression and radioactive iodine
ablation also contribute to the treatment. The
first section of this chapter contains an overview of the clinical characteristics of welldifferentiated thyroid cancer including risk
factors, symptoms, diagnosis, histologic
types, management and follow-up strategies.
The second part will provide a more detailed
evaluation of the effects of the Chernobyl
nuclear accident on the subsequent development of well-differentiated thyroid cancer.
Risk Factors
The incidence of thyroid cancer continues to
increase at a rate greater than that of any other
cancer; approximately 7% a year [3]. Although
the reason for this increase is still unknown and
under investigation, several theories have been
proposed, such as environmental influences
and an increase in the detection of papillary
thyroid cancer (PTC) less than 2 cm in diameter
[4]. More frequent use of medical imaging has
led to an increased detection rate of small, subclinical tumors, which in turn may explain the
perceived higher incidence of differentiated
thyroid carcinoma [5]. Certain risk factors
may increase suspicions for thyroid malignancy. These include but are not limited to
age, gender, history of childhood head and
neck irradiation, familial syndromes, cytology
on fine needle aspiration (FNA), presence of
symptoms that indicate invasion of surrounding structures and nodule size of greater than
4 cm. Patient age is the single most important
prognostic factor of well-differentiated thyroid
cancer, with patients younger than age 45 years
having the best prognosis. In fact, patients less
than 45 years of age who have widespread metastatic disease are still classified as having stage II
disease (Table 8.1). Although this disease is
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_8, Ó Springer-Verlag London Limited 2009
111
112
ENDOCRINE SURGERY
Table 8.1. Staging of well-differentiated thyroid cancer
[25]
STAGE Age <45 years AGE > 45 years
I Any T, Any N, M0 T1, N0, M0
II Any T, Any N, M1 T2, N0, M0
III Any T, N1, M0 T3, N0, M0
IV Any T, Any N, M1 T4, N0, M0
TX: Primary tumor cannot be assessed.
T0: No evidence of primary tumor.
T1: The tumor is 2 cm (slightly less than an inch) across or smaller.
T2: Tumor is between 2 cm and 4 cm (slightly less than 2 inches)
across.
T3: Tumor is larger than 4 cm or has begun to grow into nearby
tissues outside the thyroid.
T4a: Tumor of any size and has grown extensively beyond the
thyroid gland into nearby tissues of the neck T4b: Tumor has
grown either back toward the spine or into nearby large blood
vessels.
N1a: Cervical LN.
N1b: Lateral Cervical, Contralateral, Bilateral, Upper Mediastinal.
Source: Used with the permission of the American Joint Committee
on Cancer (AJCC), Chicago, Illinois. The original source for this
material is the AJCC Cancer Staging Manual, Sixth Edition (2002)
published by Springer Science and Business Media LLC,
www.springerlink.com
more prevalent in females and therefore the
overall risk is higher for females, males have
an increased risk of thyroid carcinoma over a
lifetime [6]. The lifetime risk of being diagnosed
with thyroid cancer, both males and females, is
about 1% [7].
The likelihood of cancer increases sevenfold if a palpable thyroid nodule has any of
the following features:firmorfixedtoadjacent structures; regional lymphadenopathy;
vocal cord paralysis; rapid growth; or invasion
into neck structures [8]. An important risk
factor for PTC is previous history of radiation
exposure, especially to the head and neck
region during childhood [6]. Following the
Chernobyl incident of April 1986, radiation
exposure, especially among children, resulted
in a tremendous increase in the number of
thyroid cancers, the details of which are discussed in the second portion of this chapter.
Another risk factor for follicular thyroid cancer is iodine deficiency [9]. However, in the
USA, a recent data analysis has indicated that
the nonpregnant adult population is iodine
sufficient [10].
Symptoms
Although thyroid cancer most often presents as a
solitary nodule, the majority of thyroid nodules
are benign. Many patients have an incidental
finding of a thyroid nodule by an unrelated radiologic study or more commonly when found on
routine examination by their primary care physician. The index of suspicion for cancer is highest in patients with one or more risk factors,
including radiation exposure, family history of
thyroid malignancy and a personal history of
thyroid cancer that was treated by less than
total thyroidectomy. A workup ensues appropriately with a cervical ultrasound and FNA.
Although most patients are asymptomatic,
advanced or large thyroid cancers can present
with noticeable symptoms that suggest invasion
of surrounding structures. These symptoms can
often include but are not limited to the ‘‘3 D’s:
dysphasia, dysphonia and dyspnea.’’ Other signs
of cancer include nodules with a hard consistency,
presence of palpable nodal disease, and/or rapid
growth of a nodule or mass. Other physical or
radiological findings include vocal cord paralysis,
fixation of the thyroid nodule, and tracheal deviation or invasion of surrounding structures [6]
(Fig. 8.1). More aggressive histological subtypes
may present with distant metastatic disease.
Fig. 8.1. A large papillary thyroid cancer with left sided
esophageal invasion.
113
WELL-DIFFERENTIATED THYROID CANCER
Diagnosis
With the increasing use of ultrasound, thyroid
nodules are detected on a more regular basis.
Features suggestive for thyroid malignancy can
also be detected on ultrasound such as hypoechoic echotexture (86%), microcalcifications
(42%) or no calcifications (47%), well-defined
margins (47%), and intrinsic hypervascularity
(69%) [11, 12]. Less common features include
hyperechoic or mixed echo texture, cystic elements, irregular margins, hypovascularity, and
coarse or peripheral calcifications [11]. Preoperative lymphatic mapping using ultrasound is
a relevant development in the evaluation of
patients with involved lymphadenectomy.
The diagnosis of thyroid cancers relies on
FNA of thyroid nodules. A recent study suggests
that an increase in the number of thyroid
nodules undergoing FNA leads to an increase
in the rate of surgical excision [13]. Although
FNA is an accurate diagnostic test for papillary
carcinomas, it cannot reliably discriminate
between follicular thyroid cancers and benign
follicular adenomas. For follicular tumors the
diagnosis cannot rely upon FNA findings since
certain histologic features such as blood vessel
or tumor capsule invasion are required for a
diagnosis of cancer. Although some surgeons
use intraoperative frozen section to guide
operative management, frozen section is not
useful for follicular or Hurthle cell cancers, as
the tissue processing distorts the architecture of
the nodule and does not permit accurate assessment of capsular or vascular invasion [14].
Other diagnostic modalities for accurate localization and anatomic definition of disease are
Computed Tomography (CT) or magnetic resonance imaging (MRI) scans of the neck and
positron emission tomography (PET) scanning.
Since patients commonly undergo CT scans
and PET scanning for unrelated conditions, incidental thyroid findings are frequently encountered. However, there is no indication for routine
use of CT scans or PET scans to determine presence or histology of thyroid nodules. If, however, certain pathologic clinical findings are
noted or metastatic disease is encountered then
further investigational studies such as CT and
PET scans are employed. A retrospective review
from the Mayo Clinic reported focally high
uptake of 18F-FDG in the thyroid as anincidental
finding in 1.1% of patients and malignancy was
confirmed or suspected in 17/48 (35%) of those
patients that had adequate follow-up [15]. CT
scanning of the neck is most helpful when localregional invasion is suspected based on presentation and physical examination. If malignancyis
strongly suspected, it is important not to use
intravenous contrast during CT scanning, as the
associated iodine load will delay radioactive
iodine ablation by 3–4 months.
Papillary Carcinoma
of Thyroid
PTC is the most common thyroid cancer,
accounting for more than 80% of cancers found
in iodine-rich areas. Although PTC has a favorable prognosis, it is multicentric in 35–85% of
cases and lymph node metastases are found in
approximately 40% of adults, and more often in
children. Also the presence of psammoma bodies
is evident about 40% of the time. Autopsy studies
in the early 1960s and 1970s demonstrated that
80% of clinically relevant PTCs will have microscopic contralateral lobe involvement, and up to
80% will have microscopic foci in ipsilateral
lymph nodes [16, 17].
Local recurrence can be frequent; and recent
literature has advocated a more aggressive surgical approach so that mortality rates related to
locoregional recurrence are reduced [18]. However, external radiotherapy improves local failure free survival in patients with pathologically
confirmed positive resection margins and
reduced local failures in patients with T4 disease
[18]. Consensus guidelines recommend total
thyroidectomy rather than thyroid lobectomy
to treat potentially multicentric disease, to
insure maximal uptake of adjuvant radioactive
iodine, and to facilitate posttreatment follow-up
by monitoring serum thyroglobulin (Tg) levels
[19]. The follicular variant of PTC (FVPTC) has
characteristics similar to those of the classical
variety. Similar tumor characteristics between
classical and follicular variant of PTC exist in
terms of tumor size, presence of multifocality,
capsular invasion, lymphovascular permeation,
and perineural infiltration. However, FVPTC
patients have significantly fewer histologically
confirmed cervical lymph node metastases and
extrathyroidal involvement [20].
114
ENDOCRINE SURGERY
Another type of PTC is the tall cell variant
(TCV) of papillary cancer, representing 1–5%
of all thyroid cancers. The TCV of PTC is typically more aggressive than classic PTC and often
presents with involved local lymph nodes
(Fig. 8.2A, B). Other clinical characteristics
include older age at presentation, larger tumor
size, and high frequency of extrathyroid tumor
extension [21]. General consensus for treatment
of TCV is total thyroidectomy. Another subtype
of PTC is the aggressive insular type. This type
of tumor is defined as well differentiated yet
contains islands of poorly differentiated cells
and requires total thyroidectomy.
a
b
Further debate exists regarding extent of
lymph node dissection for PTC. Options for
treatment of palpable and involved lymph
nodes depend on the location and extent of
involvement: central versus modified lymph
node dissection and routine versus selective
dissection. During a central lymph node dissection, level VI nodes are resected en bloc. The
borders for a level VI dissection include the
hyoid bone superiorly, the sternal notch inferiorly, and the carotid artery laterally and should
also include the paratracheal or ‘Delphian’
lymph node. Adenopathy may also be located
lateral to the sternocleidomastoid muscle. In
these instances it is standard of care to complete
a modified radical neck dissection in which
levels II [(upper jugular chain), III (middle
jugular chain), IV (lower jugular chain) and V
lymph nodes are removed, sparing the sternocleidomastoid muscle, internal jugular vein, and
spinal accessory nerve (cranial nerve XII)]. Two
schools of thought exist concerning routine central node dissection versus selective dissection
of only involved nodes. One recent study advocated a formal central compartment dissection
for PTC not based on patient gender or age but
on large tumor size and multifocal disease [22].
Recently, measurement of Tg in the wash out of
the needle (FNAB-Tg) has been proposed for
early detection of neck lymph node metastasis
in patients with differentiated thyroid cancer
[23]. Other types of node dissection used
include selective neck dissection, modified radical neck dissection, and routine cervical lymph
node sampling with modified radical neck dissection in patients with metastatic carcinoma
evident on frozen section, and aggressive ‘‘compartment micro-dissection.’’[24]
Figure 8.2. (A, B) CT Neck demonstrating tall cell variant of
papillary thyroid cancer with extensive adenopathy.
Follicular Carcinoma
and Hurthle Cell Carcinoma
FNA is far less able to discriminate follicular
and Hurthle cell carcinomas from benign adenomas, because the diagnostic criterion for
these malignancies requires histological
demonstration of vascular or capsular invasion
[25]. Surgical biopsy is advisable, because
approximately 20% of all such lesions are follicular carcinomas [25]. The World Health Organization classification considers Hurthle cell
115
WELL-DIFFERENTIATED THYROID CANCER
Table 8.2. Features of papillary and follicular thyroid cancer
Papillary CA Follicular CA
Percent of total 80% 10–20%
Predominant Age 3–5th decades 5–6th decades
Clinical pathology Nonencapsulated, sharp circumscribed Larger, Encapsulated, Noncystic
Microscopic pathology Papillary fronds of epithelium, 50% calcified
deposits (Psammoma bodies)
Spread Lymphatic Hematogenous
Main risk factor Previous radiation exposure, family history Iodine deficiency
Cervical Lymph Node
Metastases
10-Year Survival 80–95% 70–95%
More common 10% at initial presentation Distant Mets:
Capsular and Vascular invasion
33% Lung and Bone
carcinoma as a variant of follicular carcinoma
[26]. This variant is rare, has a worse prognosis,
and has a more frequent tendency for cervical
lymph node metastases. Although most management options are the same for follicular
and Hurthle cell carcinomas, metastatic Hurthle
cell is less likely toconcentrate
documented that both follicular and Hurthle
cell carcinomas have an increased chance
(10%) of local–regional invasion. It is important
to note normal cellular biology of the thyroid
gland so the cytologic examination will not skew
the diagnosis; for example, the finding of
Hurthle cells on FNA is not diagnostic for
malignancy and may also be found in Hashimoto’s thyroiditis or Graves’ disease. Multicentricity is not restricted to papillary cancers
because follicular tumors are multicentric in
up to 23% of cases [27]. Differences between
papillary and follicular carcinoma are delineated in Table 8.2.
131
I [25]. It is well
Operative Management
Today’s consensus is that patients with highrisk thyroid cancer, such as those whose histology is poorly differentiated, with vascular,
neural, or capsular invasion should undergo
total thyroidectomy at initial operation. Except
for minimally invasive follicular thyroid carcinoma (minimal capsular invasion with or without vascular invasion) and occult papillary
microcarcinomas, debates regarding lobectomy
versus total thyroidectomy for differentiated
thyroid cancer in low-risk patients seem to be
waning, as total thyroidectomy has been shown
to improve disease-free survival and reduce
recurrence rates [28–30]. The American Association of Clinical Endocrinologists and the
American Association of Endocrine Surgeons
have recommended near-total or total thyroidectomy as the initial procedure of choice for
well-differentiated thyroid cancer [31, 32]. Total
thyroidectomy greatly facilitates the use of
radioactive iodine ablation and Tg during follow-up [31]. The extent of surgery may also be
influenced by surgeon experience. High-volume
surgeons (>100 thyroid procedures/year) are
more likely to operate on patients with cancer
and have the shortest length of stay and lowest
complication rate [33]. High-volume surgeons
have two-thirds fewer complications when
treating thyroid cancer [33]. Surgical treatments
are summarized in Table 8.3.
Overall Prognosis
Classification for staging both papillary and follicular thyroid cancer is shown in Table 8.3.In
the USA, the 10-year overall relative survival
rates for patients with papillary, follicular, and
Hurthle cell carcinoma was 93, 85, and 76%,
respectively [34]. Avoiding delays in diagnosis
as well as an accurate and precise follow-up is
crucial to assure optimal patient care.
Differentiated Thyroid
Cancer: The Chernobyl Effect
The Chernobyl Nuclear Power plant accident in
April 1986 exposed the residents of southern
Belarus, northern Ukraine, and the southwestern
116
ENDOCRINE SURGERY
Table 8.3. Surgical strategy for well-differentiated thyroid
cancer
Current accepted surgical treatments
Papillary CA Total thyroidectomy
Tall Cell Total thyroidectomy
Insular Total thyroidectomy
Columnar Total thyroidectomy
Follicular Lobectomy if benign adenoma or
minimally invasive cancer Total
thyroidectomy if angioinvasive or
widely invasive follicular carcinoma on
frozen section or final pathology
Hurthle Cell Total thyroidectomy
Russian Federation to massive amounts of radioactive isotopes of iodine, mainly
131
Ithatwas
ingested as contaminated milk. The most important public health consequence has been an enormous increase in thyroid cancers, primarily of
the papillary subtype, among those who were
exposed as children [35, 36]. Although it was an
enormous social and environmental disaster
[37], Chernobyl provides a unique opportunity
to quantify the risk of thyroid cancer following
exposure to radioactive iodine [38], which is
widely used in thyroid diagnosis and therapy.
Although three early, case–control studies
suggested a relationship between estimated
radiation dose after Chernobyl and thyroid cancer [39–41], it was only recently that a large
Ukrainian cohort study found a strong, positive,
approximately linear increased risk with radiation doses that were obtained shortly after the
accident [42]. This study also found that the
oncogenic effects of childhood exposure to
radioactive iodine were not appreciably different than those of external irradiation, a widely
recognized risk factor for thyroid cancer [43].
Because their thyroid gland was small and
they consumed more milk, children were estimated to have received doses that were many
times higher than adults [44]. Since the child’s
thyroid was also very sensitive to radiation [45,
46], there was considerable concern about thyroid cancer as a consequence of the catastrophe.
Beginning in 1990, only four years after the accident and an extremely short latency, a dramatic
increase in the number of thyroid cancers, largely of the papillary subtype, was observed
among younger children from the most heavily
contaminated regions (Table 8.4) [43, 44, 47].
Although there was legitimate concern that the
increasing incidence might be a consequence of
intensive screening, about 75% of the excess risk
was estimated to be radiation exposure [48–50].
By 1994 almost 300 cases had accumulated in the
three most heavily contaminated areas. In the
Gomel region of Belarus, located immediately
adjacent to the plant, there was an almost 200fold increase in the number of childhood thyroid
cancers during the decade spanning the accident.
There were a number of notable differences
between these post-Chernobyl cancers and
sporadic pediatric cancers in the USA and Europe [51–54]. One was the large number of
younger children in the former Soviet states
(Table 8.5). In Ukraine, a total of 426 cases in
children less than 15 years of age had accumulated in the first decade after the accident. In the
other countries, a comparable number of cases
were collected over a verymuch longer period of
time, and from a much larger population. For
example, the 154 cases from the UK occurred
over three decades. About one half of the
exposed children were less than 10 years of
age, while in the other countries only one quarter to one third were of this age group, suggesting a shift to younger ages in the radiationexposed group.
Table 8.4. Pediatric thyroid cancer in territories contaminated by the Chernobyl accident (April 1986) during three different
time periods before and after the accident
1981–1985 1986–1990 1991–1994
No. of cases Rate
Gomel, Belarus 1 0.5 2.1 10.5 143 96.4
Northern Ukraine 1 0.1 2.1 2.0 97 11.5
Russian Federation 0 0 3 1.2 20 10.0
*
Number of pediatric thyroid cancers per million population.
*
No. of cases Rate
*
No. of cases Rate
*
117
WELL-DIFFERENTIATED THYROID CANCER
Table 8.5. Age of onset of pediatric thyroid cancer in five
different countries
Ukraine
Age (yr)
<40% 0%7%2%
4–9 47 23 22 38
10–14 53 69 71 69
Number 125 71 154 134
[51]
USA
[52]UK[53]
Italy and
France [54]
Another difference between exposed and
unexposed children was the gender ratio. In
adults, differentiated thyroid cancer is far more
commoninwomenthaninmen,andinunexposed pediatric populations, younger children
have a lower ratio than do older children [55]. In
contrast, in both Belarus and Ukraine the gender
ratio varied between 1 and 2 regardless of age,
roughly that expected in a prepubertal unexposed
population [51, 54].Therefore, radiation exposure
appeared to blunt the rise in the gender ratio that
normally happens with advancing age.
The early surgical experience suggested that
the cancers found among exposed children
demonstrated high rates of extrathyroidal extension, locoregional and pulmonary metastases, and
postoperative recurrence [47, 54, 56]. Compared
to pediatric cancers in Europe, they were more
often PTCs, occurred in younger children, had a
lower gender ratio, and were generally more
aggressive (Table 8.6). In addition, the postChernobyl carcinomas were more often associated with autoimmune findings, such as elevated
serum thyroid autoantibodies and lymphocytic
infiltration of the thyroid gland [54]. As experience was gained with multifocal and widespread
disease, the completeness of initial surgery
evolved from an early reliance upon lobectomy
or subtotal thyroid gland resections to total thyroidectomy with unilateral and bilateral neck
resection, completion thyroidectomy, and postoperative radioactive iodine ablation [56–58].
The histology of the papillary cancers also differed from those seen in western countries. The
majority was notable for an unusual solid or solidfollicular growth pattern, characterized by solid
sheets of thyroid follicular cells separated by
bands of fibrous tissue [51, 56, 59, 60]. Although
solid variants also occur among unexposed children, they do so at younger ages and at lower
frequencies [53]. Recent pathomorphologic studies have linked the solid subtype among the
radiation-exposed group to shorter latency regardless of age at exposure, whereas longer latency is
characterized by a more typical papillary architecture [60, 61]. This observation suggests that the
pathology of the Chernobyl cancers may be changing with increasing time since the accident [61].
Research into the molecular biology underlying the post-Chernobyl papillary thyroid carcinoma epidemic has largely focused upon activation of the RET (rearranged during transfection)
gene through radiation-induced chromosomal
reordering to form the RET/PTC protooncogene
[62–66]. Under normal circumstances, RET
codes for a cell-surface tyrosine kinase receptor
that regulates growth, development, and survival
of neural crest cells, but is not expressed in thyroid follicular cells. However, double-strand DNA
breaks generated by radiation exposure can produce chromosomal rearrangements that fuse the
tyrosine kinase domain of RET to portions of
various other genes, creating the chimeric RET/
PTC oncogenes, resulting in gene products that
are constitutively active, ligand-independent
Table 8.6. Post-Chernobyl pediatric thyroid cancers compared to spontaneous
cancers in Italy and France
Belarus [54] Ukraine [56] Italy and France [54]
% <14 yrs 78.8 87.0 42.6
F/M ratio 1.6/1 1.3/1 2.5/1
% PTC 93.9 93.1 82.1
Extrathyroid, % 49.1 54.8 24.9
Lymph nodes, % 64.6 57.3 53.9
Distant metastases, % 7.8
*
Distant metastases diagnosed by chest X-ray.
y
Distant metastases diagnosed by chest X-ray and
*
y
14.5
131
I whole-body scan.
17.3
y
118
ENDOCRINE SURGERY
receptor tyrosine kinases [67–69]. Although at
least 11 RET/PTC rearrangements have been
reported, the most common rearrangements,
also found in the majority of post-Chernobyl
papillary carcinomas, are RET/PTC 1 and RET/
PTC 3, the latter linked to the aggressive solidfollicular subtype [66, 69]. RET/PTC is found in
between 20 and 40% of unexposed adult papillary cancers, but in up to 80% of post-Chernobyl
disease [62–65, 70]. However, recent experience
suggests that the frequency of RET/PTC may be
falling with longer latency [71].
Because of its known effect upon thyroid physiology, iodine has been considered as a possible
modifier of radiation-related risk, either by affecting the dose delivered at exposure or by modulating the response to the dose received. There is a
long history of iodine deficiency in the territories
affected by Chernobyl.[72] Although the introduction of iodized salt during the 1950s leads to
a significant decline in the goiter rate, less importance was being placed on salt iodization at the
time of the accident [73]. However, coincident
with the rise in the number of thyroid cancers
during the 1990s, renewed attention was given to
iodine nutrition [73]. Studies in children suggested a mild to moderate deficiency throughout
the country, although the Gomel region may have
been less severely affected than other areas of the
country [74]. Mandatory salt iodization programs
in Belarus and Ukraine during 2000–2001 have
partially addressed this problem, and there is reliable evidence that iodine nutrition is now improving [75].
An ecological study carried out in the Brynask region of southwestern Russia found an
inverse relationship between regional iodine
excretion and the risk of thyroid cancer, a finding subsequently confirmed by research in
Belarus that estimated soil iodine at the time of
the accident [41, 76]. However, work from
Ukraine found no association with iodine excretion at the time of screening [42].
References
1. Hodgson NC, ButtonJ, SolorzanoCC. Thyroidcancer: is
the incidence still increasing? Ann Surg Oncol 2004;
11(12):1093–7.
2. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005.
CA Cancer J Clin. 2005; 55(1):10–30.
3. Heller KS. Do all cancers need to be treated? The role of
thyroglobulin in the management of thyroid cancer: the
2006 Hayes Martin lecture. Arch OtolaryngolHead Neck
Surg. 2007; 133(7):639–43.
4. Davies L, Welch HG. Increasing incidence of thyroid
cancer in the United States, 1973–2002. JAMA. 2006;
295(18):2164–7.
5. Kent WD, Hall SF, Isotalo PA, et al. Increased incidence
of differentiated thyroid carcinoma and detection of
subclinical disease. CMAJ. 2007; 177(11):1357–61.
6. Feig BW, Berger David H., Fuhrman George M. The M.
D. Anderson surgical oncology handbook. 3rd ed. Lippincott,. Williams, and Wilkins, Philadelphia; 2003.
7. Ries LAG, Eisner M, Kosary CL, et al. SEER cancer statistics review. Bethesda, MD: National Cancer Institute; 2004.
8. Sosa JA, Udelsman R. Total thyroidectomy for differentiated thyroid cancer. J Surg Oncol. 2006; 94(8):701–7.
9. Kotwal A, Priya R, Qadeer I. Goiter and other iodine
deficiency disorders: a systematic review of epidemiological studies to deconstruct the complex web. Arch
Med Res. 2007; 38(1):1–14.
10. Haddow JE, McClain MR, Palomaki GE, Hollowell JG.
Urine iodine measurements, creatinine adjustment, and
thyroid deficiency in an adult United States population.
J Clin Endocrinol Metab. 2007; 92(3):1019–22.
11. Chan BK, Desser TS, McDougall IR, et al. Common and
uncommon sonographic features of papillary thyroid
carcinoma. J Ultrasound Med. 2003; 22(10):1083–90.
12. Belfiore A, La Rosa GL, La Porta GA,et al. Cancer risk in
patients with cold thyroid nodules: relevance of iodine
intake, sex, age, and multinodularity. Am J Med. 1992;
93(4):363–9.
13. Deveci MS, Deveci G, LiVolsi VA, et al. Concordance
between thyroid nodule sizes measured by ultrasound
and gross pathology examination: effect on patientmanagement. Diagn Cytopathol. 2007; 35(9):579–83.
14. Callcut RA, Selvaggi SM, Mack E, et al. The utility of
frozen section evaluation for follicular thyroid lesions.
Ann Surg Oncol. 2004; 11(1):94–8.
15. Bogsrud TV, Karantanis D, Nathan MA, et al. The value
of quantifying 18F-FDG uptake in thyroid nodules
found incidentally on whole-body PET-CT. Nucl Med
Commun. 2007; 28(5):373–81.
16. Russell WO, Ibanez ML, Clark RL, White EC. Thyroid
carcinoma. classification, intraglandular dissemination,
and clinicopathological study based upon whole organ
sections of 80 glands. Cancer 1963; 16:1425–60.
17. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of thethyroid. I.Developing patternof metastasis.
Cancer 1970; 26(5):1053–60.
18. Chow SM, Yau S, Kwan CK, et al. Local and regional
control in patients with papillary thyroid carcinoma:
specific indications of external radiotherapy and radioactive iodine according to T and N categories in AJCC
6th edition. Endocr Relat Cancer 2006; 13(4):1159–72.
19. Elaraj DM, ClarkOH. Changingmanagement inpatients
with papillarythyroid cancer.Curr Treat OptionsOncol.
2007; 8:305–13.
20. Lang BH, Lo CY, Chan WF, et al. Classical and follicular
variant of papillary thyroid carcinoma: a comparative
study on clinicopathologic features and long-term outcome. World J Surg. 2006; 30(5):752–8.
21. Ghossein RA, Leboeuf R, Patel KN, et al. Tall cell variant
of papillary thyroid carcinoma without extrathyroid
extension: biologic behavior and clinical implications.
Thyroid. 2007; 17(7):655–61.
119
WELL-DIFFERENTIATED THYROID CANCER
22. Fu JY, Wu Y, Wang ZY, et al. Clinical and pathological
analysis of central compartment dissection in patients
with papillary thyroid cancer with negative clinical
lymph node metastasis. Zhonghua Wai Ke Za Zhi.
2007; 45(7):470–2.
23. Uruno T, Miyauchi A, Shimizu K, et al. Usefulness of
thyroglobulin measurement in fine-needle aspiration
biopsy specimens for diagnosing cervical lymph node
metastasis in patients with papillary thyroid cancer.
World J Surg. 2005; 29(4):483–5.
24. Moley JF, Wells SA. Compartment-mediated dissection
for papillary thyroid cancer. Langenbecks Arch Surg.
1999; 384(1):9–15.
25. National Comprehensive Cancer Network: Practice
Guidelines in oncology for thyroid carcinoma. 2007.
26. Hedinger CE. Problems in the classification of thyroid
tumors. Their significance for prognosis and therapy.
Schweiz Med Wochenschr. 1993; 123(36):1673–81.
27. Hay ID, McConahey WM, Goellner JR. Managing
patients with papillary thyroid carcinoma: insights
gained from the Mayo Clinic’s experience of treating
2,512 consecutive patients during 1940 through 2000.
Trans Am Clin Climatol Assoc. 2002; 113:241–60.
28. Mazzaferri EL, Young RL. Papillary thyroid carcinoma:
a 10 year follow-up report of the impact of therapy in
576 patients. Am J Med. 1981; 70(3):511–8.
29. Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting
outcome in papillary thyroid carcinoma: development
of a reliable prognostic scoring system in a cohort of
1779 patients surgically treated at one institution during
1940 through 1989. Surgery. 1993; 114(6):1050–7; discussion 1057–8.
30. DeGroot LJ, Kaplan EL, Straus FH, Shukla MS. Does the
method of management of papillary thyroid carcinoma
make a difference in outcome? World J Surg. 1994;
18(1):123–30.
31. Udelsman R, Shaha AR. Is total thyroidectomy the best
possible surgical management for well-differentiated
thyroid cancer? Lancet Oncol. 2005; 6(7):529–31.
32. AACE/AAES medical/surgical guidelines for clinical
practice: management of thyroid carcinoma. American
Association of Clinical Endocrinologists. American
College of Endocrinology. Endocr Pract. 2001; 7(3):
202–20.
33. Sosa JA, Bowman HM, Tielsch JM, et al. The importance
of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg. 1998; 228(3):
320–30.
34. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A
National Cancer Data Base report on 53,856 cases of
thyroid carcinoma treated in the U.S., 1985–1995 [see
comments]. Cancer. 1998; 83(12):2638–48.
35. Bard D, Verger P, Hubert P. Chernobyl, 10 years after:
health consequences. Epidemiol Rev. 1997; 19(2):
187–204.
36. Williams D. Health consequences of the Chornobyl accident. Science. 2001; 292(5524):2010–1.
37. Robbins J. Lessons from Chernobyl: the event, the aftermath fallout: radioactive, political,social. Thyroid.1997;
7(2):189–92.
38. Stezhko VA, Buglova EE, Danilova LI, et al. A cohort
study of thyroid cancer and other thyroid diseases after
the Chornobyl accident: objectives,design andmethods.
Radiat Res. 2004; 161(4):481–92.
39. Astakhova LN, Anspaugh LR, Beebe GW, et al. Chernobyl-related thyroid cancer in children of Belarus: a casecontrol study. Radiat Res. 1998; 150(3):349–56.
40. Davis S, Stepanenko V, Rivkind N, et al. Risk of thyroid
cancer in the Bryansk Oblast of the Russian Federation
after the Chernobyl Power Station accident. Radiat Res.
2004; 162(3):241–8.
41. Cardis E, Kesminiene A, Ivanov V, et al. Risk of thyroid
cancer after exposure to 131I in childhood. J Natl Cancer
Inst. 2005; 97(10):724–32.
42. Tronko MD, Brenner AV, Olijnyk VA, et al. Autoimmune thyroiditis and exposure to iodine 131 in the
Ukrainian cohort study of thyroid cancer and other
thyroid diseases after the Chornobyl accident: results
from the first screening cycle (1998–2000). J Clin Endocrinol Metab. 2006; 91(11):4344–51.
43. Ron E, Lubin JH, Shore RE, et al. Thyroid cancer after
exposure to external radiation: a pooled analysis of
seven studies. Radiat Res. 1995; 141(3):259–77.
44. Likhtarev IA, Sobolev BG,Kairo IA, et al. Thyroidcancer
in the Ukraine. Nature. 1995; 375(6530):365.
45. Shore RE. Issues and epidemiological evidence regarding radiation-induced thyroid cancer. Radiat Res. 1992;
131(1):98–111.
46. Robbins J, Schneider AB. Thyroid cancer following
exposure to radioactive iodine. Rev Endocr Metab Disord. 2000; 1(3):197–203.
47. Kazakov VS, Demidchik EP, Astakhova LN. Thyroid
cancer after Chernobyl. Nature. 1992; 359(6390):21.
48. Shigematsu I, Thiessen JW. Childhood thyroidcancer in
Belarus. Nature. 1992; 359(6397):681.
49. Beral V, Reeves G. Childhood thyroid cancer in Belarus.
Nature. 1992; 359(6397):680–1.
50. Tronko MD, Howe GR, Bogdanova TI, et al. A cohort
study of thyroid cancer and other thyroid diseases after
the chornobyl accident: thyroid cancer in Ukraine
detected during first screening. J Natl Cancer Inst.
2006; 98(13):897–903.
51. 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(1):149–56.
52. Zimmerman D, Hay ID, Gough IR, et al. Papillary thyroid carcinoma in children and adults: long-term followup of 1039 patients conservatively treated at one institution during three decades. Surgery. 1988; 104(6):
1157–66.
53. Harach HR, Williams ED. Childhood thyroid cancer in
England and Wales. Br J Cancer. 1995; 72(3):777–83.
54. Pacini F, Vorontsova T, Demidchik EP, et al. Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid
carcinoma in Italy and France. J Clin Endocrinol Metab.
1997; 82(11):3563–9.
55. Sherman SI. Thyroid carcinoma. Lancet. 2003;
361(9356):501–11.
56. Rybakov SJ, Komissarenko IV, Tronko ND, et al. Thyroid cancer in children of Ukraine after the Chernobyl
accident. World J Surg. 2000; 24(11):1446–9.
57. Miccoli P, Antonelli A, Spinelli C, et al. Completion total
thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident. Arch Surg. 1998; 133(1):
89–93.