CHAPTER

Yuri E. Nikiforov

Thyroid Tumors: Classification, Staging,

and General Considerations
CLASSIFICATION
A histologic classification of thyroid tumors is shown in Table
7.1. It incorporates main principles of the current World Health
Organization (WHO) classification of thyroid tumors.1 Thyroid
tumors can be broadly subdivided into primary and secondary
or metastatic tumors. Metastatic thyroid tumors are rare. Most
primary thyroid tumors are epithelial tumors that originate from
thyroid follicular cells. This group encompasses the most common
types of thyroid neoplasms, that is, benign follicular adenoma and
malignant well-differentiated papillary and follicular carcinomas.
Poorly differentiated and anaplastic carcinomas also originate
from follicular cells, and many of them are believed to develop
as a result of dedifferentiation of a well-differentiated papillary
or follicular carcinoma (Fig. 7.1). It is likely that some follicular
carcinomas arise as a result of malignant transformation of preexisting follicular adenomas, whereas others may bypass this
premalignant stage. Medullary carcinomas originate from thyroid
parafollicular or C cells.
Current thyroid tumor classifications encounter several controversial issues. One is related to the placement of thyroid oncocytic (Hrthle cell) adenomas and carcinomas. These tumors
display several basic histologic features that are similar to those
of conventional follicular tumors (i.e., follicular growth pattern,
encapsulation) but are different in other microscopic features, in
certain clinical characteristics, and possibly in some molecular
alterations. Oncocytic adenomas and carcinomas are considered
by some as separate types of thyroid tumors and by others as a
variant of follicular adenoma and follicular carcinoma. The current WHO classification designates them as a variant of follicular
tumors.1 This may change in the future as new molecular studies
characterizing these tumors emerge.
Poorly differentiated thyroid carcinoma is a distinct type of thyroid cancer. However, the diagnostic criteria for this tumor have
not been universally accepted. On the basis of the characteristic
growth pattern, many of these tumors are being designated as
insular carcinomas. This term, however, places emphasis on the
growth pattern rather than the cytologic features of tumor cells,
and its use should be discouraged. The consensus diagnostic
criteria for poorly differentiated carcinoma have been proposed
based on the results of an international conference held in Turin,
Italy in 2006.2 When diagnosed based on these criteria, this tumor
falls into a distinctly intermediate prognostic category between
indolent well-differentiated papillary and follicular carcinomas
and almost always lethal anaplastic carcinoma.
The placement of hyalinizing trabecular tumor represents
another problematic issue for the classification of thyroid tumors.
This rare tumor had been originally described as hyalinizing
trabecular adenoma and typically has a benign course, despite
sharing several histologic features with papillary carcinoma.3
More recent studies suggest that this tumor may harbor molecular alterations characteristic of papillary carcinomas.4,5 Although,
currently, there is no sufficient evidence to reclassify this tumor

108

as a variant of papillary carcinoma, it deserves placement into a

separate classification group.
Owing to the difficulty in diagnosing the encapsulated follicular
variant of papillary carcinoma and the uncertainty in the malignant behavior of tumors with only partially developed nuclear
features of papillary carcinoma, attempts have been made to
introduce a different terminology for these tumors, such as welldifferentiated tumor of uncertain malignant potential.6 This terminology, however, is not widely accepted, in part because of the
lack of information on the implication of this diagnosis for clinical
management of these patients.

INCIDENCE AND EPIDEMIOLOGY

Thyroid cancer is the most common type of endocrine malignancy. It constitutes 3% of all newly diagnosed cancer cases
in the United States7 and 1.7% of all newly diagnosed cancer
cases worldwide.8 The incidence of thyroid cancer is about
three times higher among females than males in the United
States and most of other countries.7,8 For example, in the United
States, the age-adjusted incidence of thyroid cancer in 2008
was 6.47 per 100,000 men and 19.39 per 100,000 women
based on the Surveillance, Epidemiology, and End Results
(SEER) national cancer data registry.9 Worldwide, the incidence
varies in different geographic regions and is overall higher in
more economically developed countries. The highest rates are
observed in South Korea, Northern America, Australia, and the
several countries of Europe and Middle East (Fig. 7.2).8 The
incidence varies between different ethnic groups. In the United
States, thyroid cancer is about twice more common in whites
than in blacks.10,11
Thyroid cancer is rare in children, but its incidence begins to
rise sharply in the second decade of life and peaks during the fifth
and sixth decades of life (Fig. 7.3A). This age distribution reflects
the incidence of the three most common types of thyroid cancer,
namely, papillary carcinoma that constitutes ~80% of all thyroid
cancer cases, follicular carcinoma (15%), and medullary carcinoma (3%).10,12 Anaplastic carcinoma, which accounts for <2%
of thyroid tumors, typically occurs in the older age group and its
incidence continues to rise with age.
The incidence of thyroid cancer has been steadily rising over
the past three decades, and particularly since the mid-1990s, in
many countries around the world.1315 On the basis of the SEER
data, the incidence in the United States practically tripled since
1973, growing at a rate of 2.4% per year in 1980 to 1997 and
6.5% per year since 1997 (Fig. 7.3B).9 In fact, thyroid cancer is
currently the fastest-increasing cancer in the United States in
both men and women and has become the fifth most common
type of cancer in women.7 Mortality from thyroid cancer remains
low (Fig. 7.3B), although it has been rising since 1992 at a rate
of 0.6% per year.7
The increase in incidence is almost entirely attributed to papillary carcinoma, whereas the rates of follicular, medullary, and

Chapter 7

Thyroid Tumors: Classification, Staging, and General Considerations

109

Table 7.1
Histologic Classification of Thyroid Tumors
I. Primary
1. Epithelial

II. Secondary (Metastatic)

2. Nonepithelial

A. Follicular cell origin

A.1. Benign
- Follicular adenoma
a. Conventional type
b. Oncocytic type
A.2. Uncertain malignant potential
- Hyalinizing trabecular tumor
A.3. Malignant

- Primary lymphoma and plasmacytoma

- Angiosarcoma
- Teratoma
- Smooth muscle tumors
- Peripheral nerve sheath tumors
- Paraganglioma
- Solitary fibrous tumor
- Follicular dendritic cell tumor

- Papillary carcinoma

- Langerhans cell histiocytosis

- Follicular carcinoma

- RosaiDorfman disease

a. Conventional type

- Granular cell tumor

b. Oncocytic type
- Poorly differentiated carcinoma
- Anaplastic (undifferentiated) carcinoma
B. C-cell origin
- Medullary carcinoma
C. Mixed follicular and C-cell origin
- Mixed medullary and follicular carcinoma
- Mixed medullary and papillary carcinoma
D. Epithelial tumors of different or uncertain cell origin
- Mucoepidermoid carcinoma
- Sclerosing mucoepidermoid carcinoma with eosinophilia
- Squamous cell carcinoma
- Mucinous carcinoma
- Spindle cell tumor with thymus-like differentiation (SETTLE)
- Carcinoma showing thymus-like differentiation (CASTLE)
- Ectopic thymoma

anaplastic cancer did not change significantly (Fig. 7.4).14,16,17

The increase affects both classic papillary carcinoma and the
follicular variant of papillary carcinoma and is more pronounced
for tumors of 1 cm or less in size.18 However, the incidence of tumors >1 cm and even >4 to 5 cm in size is also on the rise.17,19,20
Although exact reasons for the rising incidence of thyroid cancer
are not entirely clear, several factors are likely to play a role.
First, it may be in part because of improved cancer detection by
ultrasonography and thyroid fine needle aspiration (FNA).21,22
Thyroid ultrasound has been used increasingly since the 1980s
and can detect thyroid nodules as small as 0.2 cm in size. Under
ultrasound guidance, even very small nodules can be biopsied
using FNA technique and examined cytologically. These advances
in health care are likely to have resulted in the increased detection of small asymptomatic cancer nodules, which are highly
prevalent in the general population and rarely progress to a

clinically relevant disease.23 Second, the increase may reflect a

better recognition of the follicular variant of papillary carcinoma.
In the past, many of the tumors currently diagnosed as the follicular variant of papillary carcinoma were interpreted as follicular carcinomas. In addition, owing to a progressive decrease
in the stringency of microscopic criteria for the diagnosis of the
follicular variant of papillary carcinoma during the 1990s, tumors
with partially developed nuclear features of papillary carcinoma,
which had been diagnosed as benign lesions in the past, are
now more likely to be interpreted as malignant.24 However, it is
unlikely that these factors are responsible for the entire increase
in thyroid cancer incidence. In fact, recent studies suggest that
the proportion of papillary carcinoma carrying a BRAF mutation,
which is a marker of more aggressive cancer, has been constant
or even increasing during the last decades.25,26 The growing incidence of BRAF-positive tumors and tumors >1 cm argues against

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Diagnostic Pathology and Molecular Genetics of the Thyroid

Papillary
carcinoma

Poorly
differentiated
carcinoma

Thyroid
follicular cell

Follicular
adenoma

Follicular
carcinoma

Oncocytic
adenoma

Oncocytic
carcinoma

Benign
tumor

Welldifferentiated
cancer

Poorly
differentiated
cancer

Anaplastic
carcinoma

Undifferentiated
cancer

FIGURE 7.1. Scheme of putative progression and dedifferentiation of follicular cell-derived thyroid tumors.

the possibility that thyroid cancer increase is solely because

of better medical surveillance and detection of small, clinically
irrelevant, nonprogressive thyroid cancers.

GENETIC SUSCEPTIBILITY
AND OTHER RISK FACTORS
The development of thyroid tumors is likely to involve the interaction between the genetic predisposition, the endogenous
hormonal factors, and the environmental risk factors (Table
7.2). The role of genetic predisposition is best established for
medullary carcinoma. Approximately 25% of these tumors occur as part of one of the multiple endocrine neoplasia (MEN)
syndromes, MEN type 2A, MEN type 2B, and familial medullary
thyroid carcinoma (FMTC). The disease is caused by a germline
mutation in the RET gene and has an autosomal dominant
inheritance with almost complete penetrance but variable
expressivity.
Approximately 5% of thyroid cancers of follicular cell origin
show familial occurrence. Those are either associated with welldefined hereditary cancer syndromes or inherited through yet
unidentified genetic mechanisms.27 Overall, the risk of thyroid
cancer in the first-degree relatives of patients with follicular cellderived thyroid cancer is 4- to 10-folds higher than that in the
general population.28,29 One of the known genetic syndromes is familial adenomatous polyposis (FAP), which is caused by a germline mutation of the adenomatous polyposis coli (APC) gene on
5q21. Thyroid tumors in these patients typically manifest during
the third decade of life and affect predominantly females.30 Most

of the FAP-associated thyroid tumors are papillary carcinomas,

and they exhibit distinct histologic features.31 Thyroid tumors are
found in patients affected by PTEN-hamartoma tumor syndrome,
which encompass Cowden syndrome and other rare syndromes
caused by a germline mutation of the PTEN gene on 10q23.31.
Most of these tumors are follicular carcinomas, although papillary carcinomas may also be seen in these patients.32 Thyroid
neoplasms may also present as a rare manifestation of the Carney
complex, Werner syndrome, PeutzJeghers syndrome, and MEN
syndromes. Most familial follicular cell-derived thyroid cancers,
however, are not part of the known inherited syndromes. These
tumors are also known as familial nonmedullary thyroid cancer.
Most of these tumors (~90%) are papillary carcinomas, and they
are presumed to have an autosomal dominant inheritance with
reduced penetrance.33,34 The inherited nature of these tumors
is established with certainty when three or more first-degree
relatives are diagnosed with thyroid cancer.35,36 Genetic linkage
studies have mapped susceptibility loci to chromosomes 19p13.2,
1q21, and 2q21, although no specific susceptibility genes have
been identified in these regions yet.33
Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. Both external radiation
(X-ray and g -radiation) and internal exposure to radioiodine
131
I result in the increased risk, although the risk from exposure
to radioiodine 131I is clearly established only after accidental
exposure during childhood. The risk has strong inverse correlation with age at exposure and is linear for thyroid doses
in the range of 0.1 to 2 Gy received by children <15 years
old.37,38 The minimal latent period for thyroid cancer development is 4 years after exposure, and the risk remains elevated
for >40 years.3941 Most radiation-induced cancers are papillary

Chapter 7

Thyroid Tumors: Classification, Staging, and General Considerations

6.1
14.6

7.2

15.1

2.1

4.4

1.8

4.8
10.6
5.1

<1.4

<2.5

<4.4

<6.6

<59.5

GLOBOCAN 2008, IARC

2.4
1.7

4.2
4.6

0.8

1.7

0.7

0.8
3.0
1.2

<0.4

<0.8

<1.2

<1.9

<10.9

GLOBOCAN 2008, IARC

FIGURE 7.2. Age-standardized incidence of thyroid cancer per 100,000 in females (A) and in males (B). The shown agestandardized rates are per 100,000 population per year. (From Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in
2008: GLOBOCAN 2008. Int J Cancer. 2010;127:28932917.)

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