REVIEW
Pathology of Endocrine Tumors Update: World Health
Organization New Classification 2017—Other
Thyroid Tumors
Alfred King-yin Lam, MD, PhD, MBBS, FRCPA
Abstract: The data on nonmedullary thyroid tumors in the fourth edition
of the World Health Organization classification of endocrine tumors contain significant revisions. The tumors could be remembered as follicularderived neoplasms, other epithelial tumors, nonepithelial tumors, and secondary tumors. The major modifications are seen in the follicular-derived
neoplasms. Some of these changes are based on the data from The Cancer
Genome Atlas. A “borderline” tumor group—follicular tumor of uncertain malignant potential, well-differentiated tumor of uncertain malignant
potential, and noninvasive follicular thyroid neoplasm with papillary
nuclear features—is introduced in the current classification. Papillary carcinoma comprises 15 variants, which include a new histologic
variant—hobnail variant. A few variants of papillary carcinoma have their
definitions and data updated. Follicular carcinomas are subdivided into
3 groups: minimally invasive (capsule invasion only), encapsulated
angioinvasive, and widely invasive. The clinical, pathological, and molecular profiles of Hürthle cell tumors (Hürthle cell adenoma/carcinoma) are
different from follicular adenoma/carcinomas, which justify them as
separate entities. The classification also adopted the Turin criteria for the
histologic diagnosis of poorly differentiated carcinoma. Anaplastic carcinoma and squamous cell carcinoma are the 2 most clinically aggressive
entities of the group, and they may be developmentally linked. The other
thyroid tumors are uncommon, but cautions are needed to be aware of their
presence in some instances. Overall, the new classification incorporated
the new knowledge on pathology, clinical behavior, and genetics of the
thyroid tumors, which are important for management of patients with
these tumors.
Key Words: carcinoma, thyroid, tumor, WHO
(AJSP: Reviews & Reports 2017;22: 209–216)
T
he data on thyroid tumors in the fourth edition of the World
Health Organization (WHO) classification of endocrine
tumors published in 2017 contain significant revisions.1 These
revisions of the 2004 WHO classification were based on new
knowledge about pathology, clinical behavior, and most importantly the genetics of the thyroid tumors.2 In the 2017 classification, nonmedullary thyroid tumors could broadly be
remembered as follicular-derived neoplasms, other epithelial tumors, nonepithelial tumors, and secondary tumors. The following sections highlight the updates and changes noted in new
WHO classification in thyroid tumors. Table 1 is a modified list
From the Cancer Molecular Pathology, School of Medicine and Menzies Health
Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.
Reprints: Alfred King Lam, Griffith Medical School, Gold Coast Campus, Gold
Coast, Queensland 4222, Australia. E‐mail: a.lam@griffith.edu.au.
The author has no funding or conflicts to declare.
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ISSN: 2381-5949
DOI: 10.1097/PCR.0000000000000183
AJSP: Reviews & Reports • Volume 22, Number 4, July/August 2017
of all the entities of nonmedullary thyroid tumors in the 2017
classification.
FOLLICULAR DERIVED NEOPLASM
The follicular-derived neoplasm is the most common type of
thyroid neoplasm. In the new edition, they could be identified as
benign follicular tumors (follicular adenoma, hyalinizing trabecular tumor), borderline follicular tumors (follicular tumor of
uncertain malignant potential [FT-UMP], well-differentiated
tumor of uncertain malignant potential [WDT-UMP], and noninvasive follicular thyroid neoplasm with papillary nuclear features
[NIFTP]), papillary carcinoma, follicular carcinoma, Hürthle cell
tumors (Hürthle cell adenoma, Hürthle cell carcinoma), poorly
differentiated carcinoma, anaplastic carcinoma, and squamous cell
carcinoma (Table 1).
Follicular Adenoma
Follicular adenoma is a benign, encapsulated, noninvasive
neoplasm showing evidence of thyroid follicular cell differentiation and without nuclear features of papillary thyroid carcinoma.
The main differential diagnosis is from hyperplastic nodule in
nodular hyperplasia. Both lesions are benign. The differential diagnosis between the 2 lesions is not always possible or necessary
in the absence of molecular analysis.
Follicular adenoma could have a variety of architecture
growth patterns: normofollicular, macrofollicular, microfollicular,
solid, and trabecular. Other than classic follicular adenoma, there
are 8 variants of follicular adenoma. They are hyperfunctioning
adenoma, follicular adenoma with hyperplasia, lipoadenoma, follicular adenoma with bizarre nuclei, signet-ring cell follicular adenoma, clear cell follicular adenoma, spindle cell variant of
follicular adenoma, and “black” follicular adenoma.1 The latter
is a newly included variant in the classification. Black follicular
adenoma is seen in patients treated with minocycline and resulting
in black discoloration of follicular adenoma.3 Oncocytic variant of
follicular adenoma noted in the 2004 WHO classification is not
included as it becomes a separate entity. Also, the fetal adenoma
and mucinous follicular adenoma in the previous classification
are not listed separately because they could be placed as architectural pattern in classic follicular adenoma.
Hyalinizing Trabecular Tumor
Hyalinizing trabecular tumor is a follicular-derived neoplasm
composed of large trabeculae of elongated or polygonal cells
admixed with variable amounts of intratrabecular and intertrabecular hyaline material. In the largest series reported to date,
the tumor is slightly more common in the right lobe of the thyroid.4 The cytological features (nuclear grooves, pseudoinclusions,
and irregular borders) in fine-needle aspirates may suggest papillary thyroid carcinoma. The relationship with papillary thyroid
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TABLE 1. Modified Version of WHO Classification of
Nonmedullary Thyroid Tumors
I. Epithelial Tumors
Follicular cell neoplasms
Benign follicular tumors
Follicular adenoma
Hyalinizing trabecular tumor
Hürthle cell adenoma
Borderline follicular tumors/encapsulated or well-circumscribed
follicular-patterned tumors with well-developed or equivocal
nuclear features of papillary thyroid carcinoma
FT-UMP
WDT-UMP
NIFTP
Carcinoma
Papillary carcinoma
Follicular carcinoma
Hürthle carcinoma
Poorly differentiated carcinoma
Anaplastic (undifferentiated) carcinoma
Squamous cell carcinoma.
Other epithelial tumors
Salivary gland–type carcinomas
Mucoepidermoid carcinoma
Sclerosing mucoepidermoid carcinoma with eosinophilia
Mucinous carcinoma
Thymic tumors
Ectopic thymoma
Intrathyroid epithelial thymoma/CASTLE
Spindle epithelial tumor with thymus-like differentiation
II. Nonepithelial Tumors
Paraganglioma
Peripheral nerve sheath tumors
Schwannoma
Malignant peripheral nerve sheath tumor
Vascular tumors
Hemangioma, lymphangioma
Angiosarcoma
Smooth muscle tumors
Leiomyoma
Leiomyosarcoma
Solitary fibrous tumor
Histiocytic tumors
Langerhans cell histiocytosis
Rosai-Dorfman disease
Follicular dendritic cell sarcoma
Lymphoma
Teratoma
III. Secondary Tumors
carcinoma was suggested by the detection of RET/PTC1 rearrangements. However, neither RAS nor BRAF mutations have
been detected.4 Also, micro-RNA profiling did not support the
link between the 2 entities.5 In support of this, the prognosis of patients with hyalinizing trabecular tumor is extremely cases. Nearly
all cases reported had a benign clinical course.
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Encapsulated or Well-circumscribed
Follicular-Patterned Tumors With Well-developed
or Equivocal Nuclear Features of Papillary
Thyroid Carcinoma
This group of follicular-derived neoplasms comprised lesions with borderline histologic features for a diagnosis of carcinoma of follicular differentiation. It is the most important and
controversial concept introduced in the new classification of
thyroid tumors.1 The rationale behind this categorization is the
pragmatic approach adopted for these difficult cases in clinical
management. This group of tumors comprises 3 entities, namely,
FT-UMP, WDT-UMP, and NIFTP. The important histologic criterion for the first 2 entities is the “questionable capsular or vascular invasion.” If the invasion is definite and not questionable,
FT-UMP will be labeled as follicular carcinoma, whereas WDTUMP will be a papillary thyroid carcinoma.
Follicular Tumor of Uncertain Malignant Potential
Follicular tumor of uncertain malignant potential is an encapsulated or well-circumscribed tumor composed of well-differentiated
follicular cells with no papillary thyroid carcinoma–type nuclear
changes and showing questionable capsular or vascular invasion.1 This is a tumor indeterminate between follicular adenoma
and follicular carcinoma.
Well-differentiated Tumor of Uncertain
Malignant Potential
Well-differentiated tumor of uncertain malignant potential is
an encapsulated or well-circumscribed tumor composed of welldifferentiated follicular cells with well- or partially developed
papillary thyroid carcinoma–type nuclear changes and showing
questionable capsular or vascular invasion.
Noninvasive Follicular Thyroid Neoplasm With
Papillary-like Nuclear Features
Noninvasive follicular thyroid neoplasm with papillary-like
nuclear features is defined as a noninvasive neoplasm of thyroid
follicular cells with a follicular pattern and nuclear features of
papillary carcinoma. The neoplasm is formally classified as
noninvasive-type (encapsulated) follicular variant of papillary
thyroid carcinoma.
The new terminology for this group of thyroid lesions is
based on the consensus and evaluation of cases by an international
group of thyroid gland specialists and first announced in “The Endocrine Pathology Society Conference for Re-examination of the
Encapsulated Follicular Variant of Papillary Thyroid Cancer” that
was convened on March 20 and 21, 2015, in Boston, Mass. Then,
the new entity—NIFTP—first appeared in the literature in 2016.6
The rationale for the separation of this group of tumor is the extremely indolent behavior when compared with other types of
papillary thyroid carcinomas. The separation of this subgroup
was also supported by the strong association RAS mutation signatures in NIFTP rather than BRAF mutation signatures that are
characteristics of many papillary thyroid carcinomas. The authors
proposed that NIFTP is the precursor of invasive form of follicular
variant of papillary thyroid carcinoma. The clinical implication of
NIFTP by labeling the tumor as a noninvasive cancer will result in
less aggressive treatment approach, reduction in psychological
stress, and lowering the social economic cost involved in the management of this tumor. For instance, no radioactive iodine treatment is needed after lobectomy for the patients with NIFTP.
The histologic criteria for diagnosis of NIFTP include
(1) presence of complete capsule with clear demarcation of the
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AJSP: Reviews & Reports • Volume 22, Number 4, July/August 2017
tumor from adjacent thyroid, (2) no invasion of the capsule, (3) exclusively or predominately follicular growth pattern, and (4) nuclear features of papillary thyroid carcinoma. The other supportive
features of NIFTP involve the absence of psammoma bodies, less
than 30% solid/trabecular/insular growth pattern, nuclear score
of 2 or 3, no vascular or capsular invasion, no tumor necrosis,
and no high mitotic activity.
The diagnosis of nuclear features for papillary carcinoma
with follicular pattern is a very controversial area that involves
subjective interpretation and great interobserver differences as
originally documented by Lloyd and colleagues.7 The proposal
of nuclear score and other histologic features may improve the
concordance of pathologists in the diagnosis of papillary-like nuclear feature. Nevertheless, the management of this group of lesion will be conservative, no matter whether the lesion is an
NIFTP or follicular adenoma. It is more important to make sure
that the complete capsule is examined to exclude invasion (meaning the presence of invasive follicular variant of papillary carcinoma) before arriving at a diagnosis of NIFTP
Papillary Carcinoma
Papillary carcinoma of the thyroid is the most common endocrine malignancy and comprises different variants with distinctive
biological behavior (Table 2).8 Thus, it is worth to have more
details in the classification on papillary thyroid carcinoma as compared with other thyroid tumors. Over the past decade, the WHO
working group has recognized a new entity (hobnail variant),
recharacterized a few variants, and updated the follow-up and
pathologic data for many previously recognized entities. In addition, the findings of TCGA (The Cancer Genome Atlas) were incorporated to enrich the understanding of the pathogenesis of
different variants of the papillary thyroid carcinoma.9
Table 2 listed the variants of papillary thyroid carcinoma
in the new WHO classification. Although there are 15 variants
recognized in this classification, only the top 6 listed variants—
conventional, papillary microcarcinoma, encapsulated, follicular,
diffuse sclerosing, and tall cell—are more relatively common than
other variants. Thus, the prognostic data of patients with these
more commonly encountered variants of papillary thyroid carcinomas are well documented.
WHO Classification: Other Thyroid Tumors
New Pathological Variant
Over the past decade, only 1 new variant in papillary thyroid
carcinoma, hobnail variant of papillary thyroid carcinoma, has
emerged and been documented in the fourth edition of WHO classification of endocrine tumors. Hobnail papillary thyroid carcinoma is a variant of papillary thyroid carcinoma characterized
by micropapillae lacking true fibrovascular cores. The carcinoma
cells have an eosinophilic cytoplasm and apically placed nucleus
with a decreased nucleus/cytoplasm ratio and loss of cellular
cohesion resulting a “hobnail” appearance. These cells must comprise more than 30% of cancer cells. The entity was first described
in 2010 by Asioli and colleagues.10 In 2013, the group has further
deducted the characteristics of this variant of papillary thyroid carcinoma by analyzing 24 cases in 2013 and reported the cytological
features of 5 cases in 2014.11,12 In the recent years, there were
a few smaller series on the entity.13 Nearly all have confirmed
that this variant of papillary thyroid carcinoma is very rare but
with aggressive histologic features such as necrosis, mitosis,
angiolymphatic invasion, extrathyroidal extension, and so on.
Also, cancer recurrence and local and distant metastases are frequent. In many series, high mortality rates are noted in patients
with hobnail variant of papillary thyroid carcinoma.
Reclassification of Previously Recognized Variants
In this version, the WHO group recognized the encapsulated
variant of papillary thyroid carcinoma as a distinctive variant of
papillary thyroid carcinoma. Encapsulated variant is a papillary
thyroid carcinoma defined by a conventional papillary thyroid carcinoma totally surrounded by a fibrous capsule that may be intact
or only focally infiltrated by the carcinoma. This feature is well
known in some papillary thyroid carcinomas. However, in the last
edition of WHO, it was not recognized as an individual variant.
Studies have shown that this histologic feature comprises approximately 10% of all cases of papillary thyroid carcinoma.14,15 Patients with encapsulated papillary thyroid carcinoma have an
excellent prognosis, with almost 100% survival rates.
Follicular variant of papillary thyroid carcinoma is given to
papillary thyroid carcinoma with an exclusively or almost exclusively follicular pattern of growth. This type of papillary thyroid
carcinoma could be infiltrative or encapsulated with invasion.
TABLE 2. Variants of Papillary Thyroid Carcinoma
Variant
Biological Aggressiveness/Prognosis*
—
Low/more favorable
Low/more favorable
Same/similar
High/similar
High/less favorable
Variable/variable
No definite information available
High/less favorable
No definite information available
High/variable
No definite information available
No definite information available
No definite information available
Same/similar
1. Conventional/classic
2. Papillary microcarcinoma
3. Encapsulated
4. Follicular
5. Diffuse sclerosing
6. Tall cell
7. Columnar cell
8. Cribriform-morular
9. Hobnail
10. Papillary thyroid carcinoma with fibromatosis/fascitiis-like stroma
11. Solid/trabecular variant
12. Oncocytic
13. Spindle cell
14. Clear cell variant
15. Warthin like variant
*When compared with conventional/classic papillary thyroid carcinoma.
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The group also incorporates rare macrofollicular and multinodular
(diffuse) variants. However, the completely encapsulated type of
follicular variant of papillary thyroid carcinoma is removed and
reclassified as NIFTP.
Warthin-like variant of papillary thyroid carcinoma shares
histologic features with Warthin tumor of salivary gland origin.
The prognosis of this tumor type is similar to conventional papillary thyroid carcinoma, although aggressive clinical behavior
may occur.16,17 Previously, it came as a subtype of oncocytic variant. It is recognized that the oncocytic variant in pure form is extremely rare.1
Variants With Updated Information
Diffuse sclerosing variant of papillary thyroid carcinoma is
confirmed to have aggressive biological features such as higher
incidence of extrathyroidal extension, cervical lymph node metastases, distant metastases, and shorter periods of disease-free
survival when compared with conventional papillary thyroid carcinoma.18 In contrast to the aggressive biological features, mortality rates of patients with this variant are similar to those with
conventional papillary thyroid carcinoma.18 The carcinoma is also
characterized by low incidence of BRAF mutation and frequently
noted RET/PTC rearrangement.18
Tall cell variant of papillary thyroid carcinoma is defined by
cancer cells that are 2 to 3 times taller than wide in the current
classification.1 Also, at least 30% of all tumor cells that fulfill
the criteria are reasonably required for the diagnosis of this variant.19 The frequent presence of BRAF mutation and telomerase reverse transcriptase (TERT) promotor mutation is noted in tall cell
variant of papillary thyroid carcinoma.20
Cribriform-morular variant is noted to be seen almost exclusively in females. The optically clear nuclei resulting from biotin
and the nuclear β-catenin were highlighted as characteristic features of this variant.21
Genetic Profiles
The work of TCGA research network has contributed to the
classification and predication of prognosis for papillary thyroid
carcinoma. BRAF V600E mutation is a key player in human cancer and is of high prevalence in papillary thyroid carcinoma.22,23
Studies have confirmed that it is the most common driver mutation
in classic and tall cell variant papillary thyroid carcinoma.24,25
BRAFV600E-like signature carcinomas have a high prevalence
of BRAF V600E (or rearrangements such as RET/PTC and
NTRK1/3), high levels of MAPK pathway signaling, a low thyroid
differentiation score, and a relatively heterogeneous molecular
profile.25 Adverse molecular prognostic factors reported in papillary thyroid carcinoma include BRAFV600E mutation, TERT promoter mutations, and multiple concurrent mutations.26–29 The
miRNA expression pattern of papillary carcinoma is distinctive
and may contribute to aggressive nature of some tumors.30
RAS-like tumors have follicular growth pattern and are encapsulated in greater than 80% of cases, a high prevalence of
RAS mutations (or EIF1AX mutations and BRAF mutations different from BRAFV600E), low levels of MAPK pathway signaling, a
high thyroid differentiation score, and a relatively homogeneous
molecular profile.31 These tumors are now mostly reclassified as
NIFTP or WDT-UMP.
Follicular Carcinoma
The diagnosis of follicular carcinoma requires the demonstration of definite capsular and/or vascular invasion and in the absence of nuclear features of papillary thyroid carcinoma. In the
current classification, follicular carcinoma is further subdivided
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based on the extent of invasion. Follicular carcinoma is classified
into 3 groups: (1) minimally invasive (capsule invasion only) follicular carcinoma, (2) encapsulated angioinvasive follicular carcinoma, and (3) widely invasive follicular carcinoma.
Widely invasive follicular carcinoma is the most aggressive
form and with the worst prognosis.32 For the 2 less invasive subtypes of follicular carcinoma, the classification highlighted the
importance of the angioinvasion. Encapsulated angioinvasion follicular carcinoma is biologically more aggressive than minimally
invasive follicular carcinoma with capsule invasion only. Also, the
extent of vascular invasion has impact on the prognosis. Follicular
carcinomas with less than 4 vessels in the capsule involved carry
a better prognosis than those with extensive vascular invasion.33,34
Clear cell variant of follicular carcinoma, as defined as more
than 50% clear cells comprising the tumor, is one of the variants
defined in the current classification.35 In addition, other rare variants such as signet-ring-cell type, follicular carcinoma with
glomeruloid pattern, and spindle cell follicular carcinoma are
mentioned.1 It is worth noting that the oncocytic variant has been
removed and became a separate entity.
Follicular carcinomas have a significantly higher rate of numerical chromosomal abnormalities and loses and gains of specific chromosomal regions than papillary carcinomas. The most
common somatic mutations in follicular carcinomas are RAS point
mutations and PPARG gene fusions.36 Mutations involving the
PI3K/PTEN/AKT pathway genes and activating TSHR mutations
are also noted in follicular carcinoma.37,38 Similar to papillary thyroid carcinoma, TERT promoter mutations have been associated
with more aggressive clinical behavior, tumor recurrence, and
tumor-related mortality in follicular carcinoma.39,40
Hürthle Cell Tumors
Hürthle cell tumors are neoplasms composed of oncocytic
cells, with granular cytoplasm and large centrally placed nuclei
and often with prominent nucleoli. The term “Hürthle” is more
commonly used than “oncocytic.” Thus, the current classification adopted back the use of “Hürthle” to label this group of
thyroid tumors.
Hürthle cell tumors are usually encapsulated. The tumor cells
have large mitochondria and accumulate a higher frequency of mitochondrial DNA mutations than non–Hürthle cell tumors.41,42
Also, these tumors have a genetic profile different from that of
the other common types of thyroid cancer, with transcriptome
signatures consistent with activation of Wnt/β-catenin and PI3KAkT-mTOR pathways.43 They have a lower RAS mutation and
PAX8/PPARG rearrangement prevalence compared with follicular
tumors.44 In addition, aneuploidy is common in Hürthle cell tumors.45 The clinical, pathological, and molecular profiles of Hürthle
cell tumors (adenoma/carcinoma) are different from follicular
adenoma/carcinomas, which justify them as separate entities.
Hürthle Cell Adenoma
Hürthle cell adenoma is a Hürthle cell tumor without capsular and/or vascular invasion. It is a benign tumor.
Hürthle Cell Carcinoma
Hürthle cell carcinoma is a Hürthle cell tumor with capsular
and/or vascular invasion. The carcinoma is more common in men
and tends to affect older patients than those with papillary or follicular carcinomas. Also, the tumors are larger and presented at
higher pathological stages, as well as having lower patients’ survival rates than patients with follicular carcinomas.46 In addition,
the carcinoma is relatively radioiodine resistant.47
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Different from follicular carcinomas, Hürthle cell carcinoma
can spread to cervical lymph node.48 The prognosis of the carcinoma is believed to be correlated with the extent of vascular invasion. Like other follicular cell neoplasms, the carcinoma may
undergo transformation to anaplastic carcinoma.
Poorly Differentiated Carcinoma
Poorly differentiated carcinoma is a follicular-cell neoplasm
that occupies both morphologically and behaviorally an intermediate position between differentiated (follicular and papillary carcinomas) and anaplastic carcinoma. The intermediate position
of this tumor in patients’ survival is well documented in large
series.49,50 Response to radioiodine treatment is generally poor.51
For the morphological criteria, the 2017 classification adopted
the Turin proposal. The proposal was based on a consensus conference held in Turin of Northern Italy in 2006 and first published
in 2007.52
The histologic criteria for poorly differentiated carcinoma
are (1) a diagnosis of carcinoma of follicular cell derivation (by
conventional criteria); (2) solid, insular, or trabecular growth;
(3) absence of conventional nuclear features of papillary thyroid
carcinoma; and (4) at least 1 of 3 features: convoluted nuclei (ie,
“dedifferentiated” nuclear features of papillary carcinoma), mitotic activity 3 or more per 10 high-power fields, or tumor necrosis. An algorithmic approach was devised for practical use to
diagnose this carcinoma.
Poorly differentiated thyroid carcinoma is sometimes labeled
as insular carcinoma because it consists of well-defined solid nests
or “insulae” that may contain microfollicles. Extensive necrosis of
the carcinoma may result in a “peritheliomatous” appearance.49,53
There are multiple mutations noted in poorly differentiated
thyroid carcinoma including those that occur in well-differentiated
thyroid carcinomas. Genomic studies also revealed that poorly differentiated thyroid carcinomas have a mutation load intermediate
between that of well-differentiated papillary carcinomas and anaplastic carcinoma.54 Also, the microRNA profile of the tumor is different from that of well-differentiated and anaplastic carcinoma.55,56
WHO Classification: Other Thyroid Tumors
The positivity for PAX-8 is important to differentiate the carcinoma from secondary squamous cell carcinoma and in particular
from adjacent organs such as larynx.
It is worth noting that anaplastic carcinoma and papillary
carcinoma may show areas of squamous differentiation. Thus,
there is a suggested developmental relationship between squamous cell carcinoma and anaplastic carcinoma. Squamous cell
carcinoma may be a variant of anaplastic carcinoma on the biological standpoint. Also, squamous cell carcinoma is positive
for BRAF mutation.63 However, squamous cell carcinoma is rare,
with less than 100 cases reported.64 There is lack of studies to
prove the genetic relationship between squamous cell carcinoma
and anaplastic carcinoma.
OTHER EPITHELIAL TUMORS
The other epithelial tumors in the classification comprised
salivary gland–type tumors (mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia), mucinous carcinoma, spindle epithelial tumor with thymus-like differentiation,
and thymic tumors. The latter consists of ectopic thymoma and
intrathyroid epithelial thymoma/carcinoma showing thymus-like
differentiation (CASTLE).
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma is a low-grade malignant tumor with an indolent biological behavior. It is positive for
PAX-8 and TTF-1. Also, the epidermoid cells and ductal basal
cells are p63 positive. The translocation t (11;19) associated with
the CRTC1/MAML2 fusion transcript identified in salivary and
bronchial gland mucoepidermoid carcinoma has been detected
in 1 of 3 thyroid mucoepidermoid carcinomas tested.65 The carcinoma could coexist with papillary thyroid carcinoma and
may transform to anaplastic carcinoma or poorly differentiated
thyroid carcinoma.66
Sclerosing Mucoepidermoid Carcinoma
With Eosinophilia
Anaplastic Carcinoma
Anaplastic carcinoma of the thyroid is composed of undifferentiated follicular thyroid cells. It is one of the most aggressive
human cancers, and most patients with anaplastic thyroid carcinoma die within a year of diagnosis.49,57 The carcinoma presents
at advanced T stage having extensive local invasion, as well as
metastatic spread to regional lymph nodes and distant sites. The
carcinoma may arise de novo or transform from differentiated carcinoma; especially the papillary phenotype is a well-recognized
precursor setting.
Anaplastic carcinoma of the thyroid is broadly categorized
into 3 patterns: sarcomatoid, giant cell, and epithelial.1 The carcinoma
is positive for cytokeratin. TTF-1 is usually negative, but PAX-8 is
noted in approximately of 50% of the carcinomas.58,59 Thus,
PAX-8 is useful to confirm the thyroid origin of the carcinoma.
The genetic profile of anaplastic thyroid carcinoma is complex with multiple genetic alterations. The most frequently mutated
gene is p53.49 The features are consistent with dedifferentiation in
preexisting carcinoma.49,60
Squamous Cell Carcinoma
Squamous cell carcinoma is similar to anaplastic carcinoma
in clinical presentation, as well as prognosis of the patients. By
definition, squamous cell carcinoma of the thyroid should be composed predominantly or entirely of tumor cells with squamous differentiation. The carcinoma is positive for PAX-8 and p53.61,62
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Sclerosing mucoepidermoid carcinoma with eosinophilia is a
malignant epithelial neoplasm showing epidermoid and glandular
differentiation and displaying a sclerotic stroma with eosinophilic
and lymphocytic infiltration.66 It was initially considered a lowgrade tumor.67 However, recent studies have highlighted its potentially aggressive behavior with extrathyroidal extension and distant
metastases.68
Mucinous Carcinoma
Mucinous carcinoma is extremely rare. It is a malignant epithelial neoplasm characterized by clusters of neoplastic cells
surrounded by extensive extracellular mucin deposition.69 It is
positive for TTF-1 and PAX-8. The main differential diagnoses
are metastatic carcinoma and other thyroid primaries that can produce mucins. The prognosis is very poor.
Thymic-Related Tumors
Ectopic thymoma is benign, and CASTLE is the malignant
counterpart of ectopic thymoma.70,71 CD5 is an important maker
in the identification of these lesions. Carcinoma showing
thymus-like differentiation is indolent carcinoma with excellent
outcomes after curative resection. The lesion is more common in
the Asian population. The most common histologic type is a squamous cell carcinoma with lymphocyte-rich stroma.
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Spindle Epithelial Tumor With Thymus-like
Differentiation
Spindle epithelial tumor with thymus-like differentiation is
characterized by a lobulated architecture and biphasic cellular
composition featuring spindly epithelial cells that merge into glandular structures. The tumor cells are positive for high-molecularweight cytokeratin and cytokeratin 7. It is negative for TTF-1
and CD5. The carcinoma must be differentiated from synovial sarcoma, metastatic spindle cell carcinoma, and ectopic thymoma. It
is a slow-growing tumor with good prognosis.72
NONEPITHELIAL TUMORS
These tumors include paraganglioma, peripheral nerve sheath
tumors (schwannoma, malignant peripheral nerve sheath tumor),
vascular tumors (hemangioma, lymphangioma, and angiosarcoma),
smooth muscle tumors (leiomyoma and leiomyosarcoma), solitary
fibrous tumor, histiocytic tumors (Langerhans cell histiocytosis,
Rosai-Dorfman disease, and follicular dendritic cell sarcoma), lymphoma, and teratoma.1 All these tumors are rare.
Paragangliomas in the thyroid probably arise from inferior laryngeal paraganglia. With advances in understanding
paraganglioma in recent years, mutations such as succinate dehydrogenase genes (SDHx) were detected in thyroid paraganglioma
as in paragangliomas in the head and neck region.73
Angiosarcoma is relatively commonly reported in this group
of tumor.8 Current information now confirms that the tumor can
occur both in mountainous and nonmountainous areas.74,75 The
prognosis of patients with angiosarcoma of the thyroid is as worse
as anaplastic carcinoma of the thyroid.
Solitary fibrous tumor is the most frequent spindle cell mesenchymal tumor of the thyroid gland.76 The documentation of
solitary fibrous tumor as a translocation-associated neoplasm involving STAT6 gene is important as immunohistochemical detection of STAT6 could be used to confirm the diagnosis.77
Thyroid lymphoma is the most common nonepithelial tumor
of the thyroid.8,78 A high index of suspicion of the disease with
confirmation by immunohistochemistry is needed to differentiate
it from other more common epithelial neoplasms in thyroid.
Among the primary lymphomas involving the thyroid, diffuse
large B-cell lymphoma is most common, followed by extranodal
marginal zone lymphoma of mucosa-associated lymphoid tissue
(EMZL) and follicular lymphoma.79 Specific genetic mutation
of thyroid lymphoma is recognized. Translocation t(3;14)(p14;
q32) with FOXP1-IGH fusion is found in approximately onehalf of cases of thyroid EMZL, whereas other chromosomal translocations characteristic of EMZL are rarely found.80,81 Overall,
the prognosis of localized thyroid lymphoma has a favorable
prognosis.
Peripheral nerve sheath tumors (schwannoma, malignant
peripheral nerve sheath tumor), benign vascular tumors (hemangioma, lymphangioma), smooth muscle tumors (leiomyoma and
leiomyosarcoma), histiocytic tumors (Langerhans cell histiocytosis,
Rosai-Dorfman disease, and follicular dendritic cell sarcoma),
and teratoma are extremely rare. They have features similar to
the counterparts in other organs.
SECONDARY TUMORS
The thyroid gland is vascular and may harbor metastases at a
higher frequency than many organs. Secondary tumors are tumors
that arise in the thyroid by direct extension from adjacent structures or by vascular spread from nonthyroidal sites.82 Metastatic
cancer to thyroid could be associated with destructive thyroiditis.83 Squamous cell carcinoma of the larynx is the most common
214
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secondary tumor to thyroid by direct extension.84 Blood-born metastases from carcinoma of the kidney, lung, breast, or colon are
commonly found.82,85 In addition, melanoma and lymphoma
may also be noted. In recent years, fine-needle aspiration biopsy
in conjunction with the use of more specific antibodies (such as
Napsin A for lung cancer, PAX-8 for thyroid cancer) is helpful
for differentiation between primary and secondary tumors of the
thyroid.84 Also, fine-needle aspiration biopsy in secondary tumors
in the thyroid provided tissue to assess the molecular parameters
useful for planning adjuvant therapy for the primary tumor.
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