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Abbreviations
AFIP Armed Forces Institute of Pathology
AJCC The American Joint Committee on Cancer
ATC Anaplastic TC
BTD Benign thyroid disease
DNA Deoxyribonucleic acid
DTC Differentiated thyroid carcinoma
ERCC2 Excision repair cross-complementation group 2
FTC Follicular TC
HCC Hürthle cell cancer
HRAS Harvey rat sarcoma
HSCR Hirschsprung disease
MALT Mucosa-associated lymphoid tissue
MTC Medullary TC
OS Oxidative stress
PDTC Poorly differentiated thyroid carcinoma
PTC Papillary TC
RET Rearranged during transfection
RNA Ribonucleic acid
TC Thyroid cancer
TP53 Tumor protein 53
TSH Thyroid-stimulating hormone
TSHR Thyroid-stimulating hormone receptor
XPD Xeroderma pigmentosum group D
XRCC1 X-ray repair cross-complementing protein 1
XRCC3 X-ray repair cross-complementing protein 3
8.1 Introduction
Cancer is a large group of diseases that vary in their age of onset, rate of growth, state
of cellular differentiation, diagnostic detectability, invasiveness, metastatic potential,
response to treatment, and prognosis. From a molecular and cell biological point of
view, however, cancer may be a relatively small number of diseases caused by
similar molecular defects in cell function resulting from common types of alterations
to a cell’s genes. Cancers (carcinomas) are characterized by their unregulated growth
and spread of cells to other parts of the body (Yarbro et al. 2005). Cancer results
from an accumulation of genetic alterations in somatic cells. This accumulation of
mutations leads to a breakdown of cooperation between cells in a tissue, such that
single cells revert to selfish behavior reminiscent of unicellular organisms.
Cancer susceptibility genes can be subdivided into three categories (Michor et al.
2004) (1) Gatekeepers, such as oncogenes and tumor suppressor genes, control
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growth and differentiation pathways of the cell; alterations of such genes lead to
increased growth rates or decreased death rates as compared with neighboring cells;
(2) Caretakers maintain the genomic integrity of the cell; alterations of such genes
increase the rate of accumulating further mutations and cause genetic instabilities;
and (3) Landscapers regulate the cell’s interaction with the surrounding microenvi-
ronment; alterations of such genes contribute to the neoplastic transformation of
the cell.
The alteration of one gene, however, does not suffice to give rise to full blown
cancer. For progression toward malignancy and invasion, further mutational hits are
necessary (Knudson 2001). Epigenetic abnormalities are important factors in the
etiology of virtually all human cancer types (Goldberg Aaron et al. 2007). DNA
methylation is the most widely studied epigenetic abnormality in tumorigenesis.
Methylation defects include genome hypomethylation (resulting in epigenetic inac-
tivation of oncogenes and retroelements) and localized aberrant hypermethylation of
CpG islands, resulting in transcriptional silencing of many important genes (Ting
et al. 2006). Promoter methylation patterns in human cancers show strong specificity
with respect to tissue of origin and can be found early in tumorigenesis. DNA
polymorphisms are also playing a crucial part in unraveling the genetic basis of
tumor formation and progression in cancer. As is true of the human genome as a
whole in which over 3.1 million sequence variations have been mapped, which
represent 25–35% of the total estimated SNPs (Frazer et al. 2007).
Thyroid cancer (TC) is the most common malignancy of the endocrine system. It
accounts for approximately 2% of all newly diagnosed cancer cases and majority of
endocrine cancer related deaths each year (Sarlis and Benvenga 2004). TC can arise
from either follicular or non-follicular thyroid cells. Follicular cancers include
Papillary TC (PTC—80%), Follicular TC (FTC–11%), Hürthle cell cancer
(HCC—3%), and Anaplastic TC (ATC—2%) (Rebecca et al. 2011).
Non-follicular thyroid cancers include Medullary TC (MTC).
Genetic alterations in thyroid tumors can be divided into two categories: inherit-
able (germline) mutations and sporadic (somatic) mutations. Many gene mutations
have been studied in thyroid tumors, but only one inheritable genetic mutation and
few sporadic mutations are of good significance. The single known inheritable gene
mutation associated with thyroid cancer is a point mutation in the RET proto-
oncogene that causes medullary thyroid cancer. The associ ation of a genetic muta-
tion with medullary thyroid cancer (MTC) was first hypothesized in the late 1980s,
but was not specifically identified until 1993 (Mulligan et al. 1993). RAS oncogenes
(H, N, and K) were the first to be associated with sporadic thyroid cancer. About
30% of all human tumors contai n a mutation in a RAS allele, making this one of the
most widely mutated human proto-oncogene (McCormick and Wittinghofer 1996).
RET/PTC is a chromosomal rearrangement found in papillary thyroid cancer
(Santoro et al. 1992). As a result of the rearrangement, a portion of the RET gene
is fused to one of several possible partner genes. Two of the most common
rearrangement types are RET/PTC1 and RET/PTC3, in which RET is fused to either
CCDC6 (also known as H4) or NCOA4 (also known as ELE1 or RFG), respectively
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(Santoro et al. 1994). RET/PTC rearrangements are found on a verage in 10–20% of
adult sporadic papillary carcinomas.
Alterations in the TP53 tumor suppressor gene by inactivating point mutations,
usually involving exons 5–8, or by deletion result in progressive genome destabili-
zation, additional mutations, and propagation of malignant clones. Among thyroid
tumors point mutations of TP53 occur in approximately 60% of ATC and in 25% of
PDTC (Ito et al. 1993). The PAX8-PPARγ rearrangement leads to in-frame fusion of
exon 7, 8, or 9 of PAX8 on 2q13 with exon 1 of PPARγ on 3p25 (Nikiforov 2004).
The PAX8-PPARγ rearrangement is found in follicular thyroid carcinoma and in the
follicular variant of PTC, where it occurs in approximately 33% of all tumors
(Nikiforov 2004). The most recent and major development in the field of thyroid
cancer genetics has been the identification of the BRAF-activating point mutation as
the most common molecular defect in PTC (Xing 2005). The BRAF-activating point
mutation in thyroid cancer is almo st exclusively a thymine-to-adenine transversion
at position 1799 (T1799A) in exon 15. This leads to a valine-to-glutamate substitu-
tion at residue 600 (V600E) and subsequent constitutive activation of the BRAF
kinase (Kumar et al. 2003). Recent studies have reported a prevalence of BRAF
mutation in 29% to 83% of PTC, making it the most common oncogene identified in
sporadic forms of PTC (Kimura et al. 2003).
Besides the mutation hotspots apparently inherited polymorphisms in the RAS
sequence especially HRAS was described by many studies (Capon et al. 1983; Castro
et al. 2006) to be an important cause of the predisposition to several human cancers
including TC. HRAS T81C SNP can indicate an increased risk of skin (Kreimer-
Erlacher et al. 2001), oral (Sathyan et al. 2006), bladder (Johne et al. 2003), and
gastric cancer (Zhang et al. 2008). Castro et al. have first time investigated HRAS
T81C polymorphism in thyroid tumors and have associated it with aneuploidy in
follicular tumors of the thyroid. Although HRAS T81C polymorphism does not alter
the amino acid sequence of the protein, it may affect the expression of the gene
inducing overexpression (Castro et al. 2006). The Rearranged during Transfection
(RET) proto-oncogene encodes a membrane tyrosine kinase receptor and is
expressed in cells originating in the neural crest (Raymon et al. 2010). However,
the RET tyrosine kinase domain may also be expressed in thyroid follicular cells
(Giuseppe et al. 2000 ). Some sporadic and radiation-induced PTCs were found to
have somatic RET translocations. The RET rearrangements product results in
constitutive activation of the RET tyrosine kinase domain that can lead to PTC
carcinogenesis (Tallini and Asa 2001). In addition to these RET rearrangements, the
coding sequence of RET can exhibit polymorphisms in exon 2 (A45A; rs1800858),
in exon 11 (G691S; rs1799939), in exon 13 (L769L; rs1800861), in exon 14 (S836S;
rs1800862), and in exon 15 (S904S; rs1800863) (Elisabeth et al. 2009). RET
polymorphisms were associated with the etiology of sporadic Hirschsprung disease
(HSCR) and MTC (Lesueur et al. 2002). In papillary thyroid carcinoma, it has
recently been suggested that silent RET polymorphisms A45A (rs1800858) in
exon 2 and L769L (rs18 00861) in exon 13 may represent low-penetrance risk alleles
(Lesueur et al. 2002). RET Polymorphic Haplotypes and risk of Differentiated TC
were also described by some studies (Tang et al. 2005). The mechanism by which
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the silent polymorphisms may act in the development of PTC may include transcript
stability, RNA splicing, and DNA protein binding and protein folding.
8.2 Thyroid Cancer (TC)
Thyroid carcinoma is the most prevalent endocrine malignancy and accounts for 2%
of all human cancers. TC typically occurs in thyroid nodule s, and is relatively
common, occurring in 6% of adult women and 2% of adult men which can be
detected by palpation and imaging in a large proportion of adults. Approximately
90% of thyroid malignancies are well-differentiated thyroid carcinomas arising from
thyroid follicular epithelial cells, which are classified as papillary or follicular based
on histopathological criteria, whereas 3–5% of cancers originate from parafollicular
or C cells. Follicular adenoma is a benign tumor that may serve as a precursor for
some follicular carcinomas. Even though differentiated thyroid carcinomas are
usually curable by the combination of surgery, radioiodine ablation, and thyroid-
stimulating hormone suppressive therapy, recurrence occurs in 20–40% of patients
(Mazzaferri and Massoll 2002).
During tumor progression, cellular dedifferentiation occurs in up to 5% of cases
and is usually accompanied by more aggressive growth, metastatic spread, and loss
of iodide uptake ability, making the tumor resistant to the traditional therapeutic
modalities and radioiodine (Alessandro et al. 2010). Knowledge of genetic
alterations occurring in TC has rapidly expanded in the past decade. This improved
knowledge has provided new insights into TC etiology and has offered novel
diagnostic tools and prognostic markers that enable improved and personalized
management of patients with thyroid nodules (Nikiforov and Nikiforov 2011).
8.2.1 Classification of Thyroid Tumors (AFIP)
The Classification of Thyroid Tumors is given by the World Health Organization
(WHO) (Hedinger et al. 1988) and Armed Forces Institute of Pathology (AFIP)
(Rosai et al. 1992) with slight difference. According to AFIP, priority is given to the
cell of origin and incorporating, in each cell type, special tumor types and subtypes
designated as “variants.” Classification scheme adopted by the Armed Forces Insti-
tute of Pathology (AFIP) is discussed below;
8.2.1.1 Primary Tumors
Epithelial Tumors
Tumors originating from epithelial cells.
Tumors of Follicular Cells
Tumors originating from epithelial follicular cells.
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Benign
Localized tumors with no present features of malignancy.
Follicular Adenoma
Follicular adenoma is defined as a benign encapsulated tumor with follicular cell
differentiation showing a uniform pattern throughout the confine nodule. The fibrous
capsule varies in thickness, but is usually thin. On the basis of microscopic features,
several variants have been described, including oncocytic adenoma (Hürthle cell
adenoma), adenoma with clear cell change, atypical adenoma, hyalinizing trabecular
adenoma, adenoma with bizarre nuclei, and rare types such as adenoma with adipose
(adenolipoma) or cartilaginous (adenochondroma) metaplasia (Rosai et al. 1992).
Malignant
Cancers with metastasis.
Differentiated Thyroid Carcinoma (DTC)
Follicular Thyroid Carcinoma (FTC)
A malignant epithelial tumor showing evidence of follicular cell differentiation but
lacking the diagnostic features of papillary carcinoma. The frequency of follicular
carcinoma among thyroid malignancies ranges from 5–10% in non-iodine-deficient
areas to 30–40% in iodine-deficient areas (Rosai et al. 1992). Depending on the
degree of their invasiveness, follicular carcinomas have been divided into two major
categories: minimally invasive or encapsulated (the most common) and widely
invasive. The follicular carcinoma, oxyphilic cell type is largely or entirely com-
posed of eosinophilic cells. It should not be referred to as a Hürthle cell carcinoma, a
misnomer, or as an oxyphilic carcinoma, an incomplete term.
Papillary Thyroid Carcinoma (PTC)
A malignant epithelial tumor showing evidence of follicular cell different iation,
typically with papillary and follicular structures as well as characteristic nuclear
changes. Papillary carcinoma is the most common type of TC, comprising approxi-
mately 80% of all primary thyroid malignancies (Baloch and LiVolsi 2002). There
are several histologic variants of papillary carcinoma, some of which are associated
with a more guarded prognosis: Papillary microcarcinoma, encapsulated variant,
follicular variant, tall and columnar cell variant, diffuse sclerosing variant, solid
variant, clear cell variant, oncocytic variant and oxyphilic variant Cribriform-
Morular Variant.
Hürthle Cell Carcinoma (HCC)
A rare malignancy of the thyroid gland accounts for 3–7% of all malignant thyroid
tumors (Har-El et al. 1986). It is usually a solitary, well-encapsulated tumor that is
composed of greater than 75% Hürthle cells; HCC is a distinct clinical entity. For
example, only an estimated 10% of metastases from HCC take up radioiodine (Soh
and Clark 1996), compared with 75% of metastases from FTC (Maxon and Smith
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1990). HCC is more often multifocal and bilateral and more frequently involves
regional nodes than does FCC. Among well-differentiated thyroid carcinomas, HCC
is associated with the highest incidence of distant metastases (Elaine Yutan 2001).
Poorly Differentiated Thyroid Carcinoma (PDTC)
Poorly differentiated thyroid carcinoma represents a heterogeneous group of malig-
nant neoplasms, with various histologic patterns of growth and different biologic
behavior, that lie somewhere between well-differentiated and undifferentiated
carcinomas (Volante et al. 2004). Microscopically, most of these tumors show a
trabecular, solid, or insular growth pattern.
Undifferentiated (Anaplastic) Carcinoma
It account for 5–10% of all primary malignant tumors of the thyroid (Rosai et al.
1992). These tumors, usually present in elderly patients (mean age 60–65 years), are
rapidly growing, with massive local invasion and early distant metastases, most
frequently to lung, adrenals, and bone. Features of undifferentiated (Anaplastic)
carcinoma are high mitotic activity, extensive necrosis, and a marked degree of
invasiveness within the gland as well as to the extrathyroidal structures (LiVolsi
1990).
Tumors of C Cells and Their Variants
Medullary Thyroid Carcinoma (MTC)
Medullary thyroid carcinoma is a malignant tumor of the thyroid which shows
evidence of C-cell differentiation and usually contains calcitonin. It accounts for
up to 10% of all malignant thyroid tumors (Baloch and LiVolsi 2002). The variants
of medullary carcinoma are: glandular (composed in part of tubular or follicular
structures and may resemble follicular carcinoma), papillary (exhibiting true papil-
lary pattern of growth), small cell (resembling the intermediate variant of small cell
carcinoma of the lung), and giant cell (occasionally present or focal areas with giant
cell formation).
Mixed Follicular Parafollicular Carcinoma
Mixed medullary and parafollicular carcinomas are rare neoplasms which show
morphologic features of both follicular and C-cell differentiation (Holm et al.
1987). The dual differentiation has also been noted in their metastatic sites. WHO
is very strict in defining them as tumors showing both the morphologic features of
medullary carcinoma together with immunoreactivity for calcitonin and the morpho-
logic features of follicular carcinoma together with immunoreactivity for thyroglob-
ulin (Hedinger et al. 1988).
8.2.1.2 Thyroid Sarcomas
Sarcomas arising in the thyroid are extremely rare. Various microscopic types have
been reported in the form of isolated case reports, including fibrosarcoma,
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liposarcoma, leiomyosarcoma, chondrosarcoma, (Andrion et al. 1991) osteosar-
coma, and malignant schwannoma (Thompson et al. 1997).
8.2.1.3 Malignant Lymphomas
Primary non-Hodgkin lymphomas of the thyroid are now considered to be tumors of
mucosa-associated lymphoid tissue (MALT) (Baloch and LiVolsi 2002). They
constitute about 8% of all thyroid malignancies (Rosai et al. 1992). Primary thyroid
lymphomas have a B cell phenotype and are highly associated with lymphocytic or
Hashimotos thyroiditis. Thyroid malignant lymphomas are most common in adult or
elderly women, clinically presented in the form of an enlarged thyroid, leading to
symptoms of trachealor laryngeal compression when extended outside the gland
(Rosai et al. 1992).
8.2.1.4 Secondary Tumors of the Thyroid
Although any malignant tumor can metastasize to the thyroid gland, the latter is an
infrequent site of tumor metastases. Direct extension into the thyroid may occur in
carcinomas of the pharynx, larynx, trachea, and esophagus. Most of these neoplasms
are of squamous cell type. Hematogenous metastases to the thyroid, particularly of
malignant melanoma, lung, gastrointestinal, breast, and renal cell carcinomas are
commonly encountered at autopsy series (Chrisoula 2004).
8.2.2 Staging of Thyroid Carcinoma
The American Joint Committee on Cancer (AJCC) has designated staging for
cancers of the thyroid (Jatin and Pablo 2018). Separate stage groupi ngs are
recommended for papillary, follicular, medullary, and anaplastic cell types. In
addition, within papillary and follicular, separate stage groupings are recommended
based on age at diagnosis (20–54 and 55+). The SEER modified eighth edition
AJCC staging is given in Tables 8.1 and 8.2 .
8.2.3 Risk Factors of Thyroid Carcinoma
8.2.3.1 Gender and Age
TC is 2–4 times more frequent in women than men. Women generally exhibit a
better prognosis than men who are reported to have a higher malignant progression
of nodules. It is rare in patients aged <16 years, presenting an ann ual incidence of
0.02–0.3 per 100,000, and extremely uncommon below the age of 10 years (Landis
et al. 1998). Its incidence increases with aging and the average age at diagnosis is
45–50 years.
8.2.3.2 Ethnic Differences
A geographic and ethnic variability of TC incidence has been reported. In areas such
as Iceland, Hawaii, the Philippines, Japan, and Israel its incidence is higher than in
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North America, Canada, and USA. In the USA, the TC is more frequent in Cauca-
sian descent subjects than Afro-American, Hispanic, Hawaiian, Chinese, or Japanese
whose incidence is still twice as high in their countries of origin. All these findings
suggest that such differences may be attributable to both environmental (e.g., dietary
habits) and genetic factors (Parkin et al. 2003).
8.2.3.3 Previous Exposure to Ionizing Radiation
The role of a previous exposure to ionizing radiation in thyroid carcinogenesis has
been established since 1950 following the explosion of the atomic bomb in Japan.
Exposure to ionizing radiation for external irradiation of the neck increases the
incidence of thyroid nodules, either benign or malignant, and palpable nodules are
detected in 20–30% of people exposed to radiation (Hanson et al. 1983), as well it
happens in pediatric patients undergoing radiation therapy for oncological and
hematological malignancies such as lymphoma or leukemia (Pui et al. 2003). The
Table 8.1 TNM Classification for TC
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor is found
T1 Tumor size 2 cm in greatest dimension and is limited to the thyroid
T1a Tumor 1 cm, limited to the thyroid
T1b Tumor >1 cm but 2 cm in greatest dimension, limited to the thyroid
T2 Tumor size >2 cm but 4 cm, limited to the thyroid
T3 Tumor size >4 cm, limited to the thyroid or any tumor with minimal extrathyroidal
extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
T4a Moderately advanced disease; tumor of any size extending beyond the thyroid capsule to
invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b Very advanced disease; tumor invades prevertebral fascia or encases carotid artery or
mediastinal vessel
All anaplastic carcinomas are considered stage IV:
T4a Intrathyroidal anaplastic carcinoma
T4b Anaplastic carcinoma with gross extrathyroid extension
Regional lymph nodes (N)
Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph
nodes
NX Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
N1a Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph
nodes)
N1b Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or
retropharyngeal or superior mediastinal lymph nodes (level VII)
Distant metastasis (M)
M0 No distant metastasis is found
M1 Distant metastasis is present
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minimum latency period between exposure and clinical evidence of thyroid disease
has been reported to be at least 4–5 years, reaching the maximum peak 20 years from
exposure to decrease thereafter.
8.2.3.4 Age at the Time of Irradiation
It represents the main risk factor and after 15–20 years there is no longer an increased
risk. In children exposed to doses of 1Gy, the excess risk for TC is equal to 7.7 (Ron
Table 8.2 Stage grouping of TC
Stage grouping
Separate stage groupings are recommended for papillary or follicular (differentiated), medullary,
and anaplastic (undifferentiated) carcinoma
Papillary and follicular TC (age < 55 years)
Stage TN M
I Any T Any N M0
II Any T Any N M1
Papillary and follicular; differentiated (age 55 years)
Stage TN M
IT1 N0 M0
II T2 N0 M0
III T3 N0 M0
IVA T1–3 N1a M0
T4a N1b M0
IVB T4b Any N M0
IVC Any T Any N M1
Anaplastic carcinoma (all anaplastic carcinomas are considered stage IV)
Stage TN M
IVA T4a Any N M0
IVB T4b Any N M0
IVC Any T Any N M1
Medullary carcinoma (all age groups)
Stage TN M
IT1 N0 M0
II T2, T3 N0 M0
III T1–T3 N1a M0
IVA T4a N0 M0
T4a N1a M0
T1 N1b M0
T2 N1b M0
T3 N1b M0
T4a N1b M0
T4a N0, N1b M0
T1–T4a N1b M0
IVB T4b Any N M0
IVC Any T Any N M1
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et al. 1995). Several studies conducted after the Chernobyl nuclear disaster have
shown an increased incidence of TC in subjects that at that time were aged between
5 months and 10 years (Leenhardt and Aurengo 2000).
8.2.3.5 Previous History of Benign Thyroid Disease (BTD)
People who have certain non-cancerous (benign) thyroid diseases are slightly more
likely to develop TC. These include: an enlarged thyroid (goiter), thyroid nodules
(adenomas), and inflammation of the thyroid (thyroiditis). Approximately 1 in 5 TCs
(20%) occur in people who have had a benign thyroid disease in the past (Farbota
et al. 1985).
8.2.3.6 Contribution of Iodine in the Food
In areas with iodine deficiency, a higher incidence of thyroid nodules and TC has
been observed. However, after correction for the greatest number of nodules, the
percentage of TC in thyroid nodules is similar to the one found in areas with normal
intake of dietary iodine. In presence of a sufficient iodine intake, more than 80% of
cancer consist of PTC; whereas in areas with iodine deficiency follicular and
anaplastic figures are more frequently reported (approximately 2–3 times higher
than observed in areas with adequate iodine intake) (Belfiore et al. 1992).
8.2.3.7 Body Mass Index
Several case–control studies have shown an increased risk of TC in patients with
high body mass index (BMI). The risk would be increased by five-fold in obese men
and 2 times in obese women (>97 percentile), compared to the risk observed in
patients with weight < third percentile. In women (especially in postmenopausal
age) a weight gain >14% appears to positively correlate with the onset of TC
(Suzuki et al. 2008).
8.2.3.8 Hormonal Factors
The female: male incidence ratio has been reported to be different according to the
period of life in which TC occurs. In women of child bearing age, this ratio is about
4:1 and is reduced to 1.5:1 in older, prepuberal, and menopause individuals
(Franceschi et al. 1999).
Thyroid-stimulating hormone (TSH) regulates the growth and function of the
thyroid gland as “TSH excess hypothesis” holds good for TC (Ingbar and Woeber
1974). This hypothesis is supported by the observation that growth of some TCs is
dependent o n TSH secretion so that suppression of TSH release by administration of
thyroxin is often an effective treatment for thyroid carcinomas (Crue 1966). The
thyroxine-binding globulin level in normal females is 10–20% higher than in males
(Gershengorn et al. 1980) and in pregnancy, a 50% increase in the level of thyroxine-
binding globulin results in a similar magnitude increase in TSH level (Malkasian and
Mayberry 1970). It, therefore, appears likely that TSH levels of non-pregnant normal
females will be elevated above the level in males at some point in the menstrual cycle
although not necessarily throughout the cycle (Brian et al. 1982).
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