Familial Thyroid Carcinoma: A Diagnostic Algorithm Vânia Nosé ...
Familial Thyroid Carcinoma: A Diagnostic Algorithm
Vânia Nosé, M. D., Ph. D.
Department of Pathology
Brigham and Women's Hospital
Harvard Medical School
Boston, MA 02115
Endocrine Pathology Society Companion Meeting
Saturday, March 1st, 2008
Familial Thyroid Carcinoma: A Diagnostic Algorithm
Bullet Points Summary:
• Thyroid carcinoma derived from follicular cells is the most common
endocrine malignancy and papillary thyroid carcinoma (PTC) is the most
common type of thyroid malignancy.
• Papillary and follicular thyroid carcinomas (FTC) are usually sporadic.
Familial forms have been acknowledged in recent years. The familial non-
medullary thyroid carcinoma (NMTC) can be divided into:
1. Syndromic (familial tumor syndromes with preponderance of non-
• Familial Adenomatous Polyposis: distinct cribriform-morular thyroid
• PTEN-hamartoma Tumor Syndrome - Cowden Disease: numerous
adenomatous nodules, follicular adenomas, PTC, and FTC
2. Non-syndromic (familial tumor syndromes characterized by a
predominance of NMTC), as pure FPTC with or without oxyphilia, FPTC
with renal papillary tumor, and FPTC with multinodular goiter.
• Medullary thyroid carcinoma (MTC) is derived from thyroid C cells, is
familial in approximately 25% of cases as a component of MEN 2, or
familial MTC syndrome. C cell hyperplasia is the precursor of heritable
• The characteristic thyroid pathology findings should alert the pathologist of
a possible familial cancer syndrome, which may lead to further molecular
Thyroid carcinoma derived from follicular cells (papillary and follicular thyroid
carcinoma, poorly differentiated thyroid carcinoma and anaplastic carcinoma) is
the most common endocrine malignancy. Papillary thyroid carcinoma is the most
common type of thyroid malignancy, comprising about 80% of all thyroid cancers.
Medullary thyroid carcinoma refers to those neoplasms arising from the
calcitonin-producing C thyroid cells derived from neural crest tissue. Medullary
thyroid carcinomas are known to have a familial predisposition in about 25% of
cases, and are associated with RET gene mutation. In contrast, the case for a
familial predisposition of non-medullary thyroid carcinoma (NMTC) is only now
beginning to emerge.
Familial thyroid cancer can arise from follicular cells (familial non-medullary
thyroid carcinoma) or from the C cell (familial medullary thyroid carcinoma).
1. Follicular cell neoplasms:
Papillary and follicular thyroid carcinomas are usually sporadic. Sporadic tumors
have an incidence of approximately 1 per 25,000 individuals per year. Familial
forms have been acknowledged in recent years. Approximately 5% of
nonmedullary thyroid cancers are of familial origin.
Familial forms may be caused by an inherited genetic predisposition and can be
divided into two groups. The first group has an increased prevalence of non-
medullary thyroid carcinoma (NMTC) within a familial cancer syndrome with a
preponderance of nonthyroidal tumors (familial tumor syndromes characterized
by a preponderance of nonthyroidal tumors). In the second group the
predominant neoplasm is NMTC (familial tumor syndromes characterized by a
predominance of NMTC), although other neoplasms may occur with increased
1a. Familial tumor syndromes characterized by a preponderance of
Familial tumor syndromes characterized by a preponderance of non-thyroidal
tumors, NMTC has been found with a greater frequency than expected in familial
adenomatous polyposis, Cowden syndrome (PTEN-hamartoma familial
syndrome), Carney complex, Werner syndrome, and in multiple endocrine
neoplasia type 2A, within others. Thyroid pathology in these syndromes can be
distinct from those sporadic forms. The characteristic morphological findings
should alert the pathologist to the possibility of a familial cancer syndrome, as the
correct histological interpretation may lead to further molecular genetic evaluation
of the patient and family members.
• Familial Adenomatous Polyposis (FAP):
Familial adenomatous polyposis (FAP) is an inherited autosomal dominant
syndrome caused by germline mutations in the adenomatous polyposis coli
(APC) gene on chromosome 5q21, characterized by hundreds to thousands
of adenomatous colonic polyps that develop until early adulthood.
Extracolonic manifestations in FAP, included osteomas, epidermal cysts,
desmoid tumors, upper gastrointestinal tract polyps-hamartomas, congenital
hypertrophy of the retinal pigmented epithelium, hepatoblastomas and thyroid
tumors. Papillary thyroid carcinoma is one of the extracolonic manifestations
of FAP. Young women with FAP are at particular risk of developing thyroid
cancer, and their chance of being affected is approximately 160 times higher
than that of normal individuals, and PTC occurs with a frequency of about 10
times that expected for sporadic PTC.
Thyroid carcinomas associated with FAP is usually bilateral, multifocal, with
histological features different from sporadic tumors, with the characteristic
histopathology of cribriform pattern (figure below) with solid areas and a
spindle cell component, most often is associated with marked fibrosis. The
characteristic cellular and nuclear findings of sporadic PTC as grooved,
overlapping, and clear nuclei are absent in this subtype.
The cribriform-morular variant of papillary thyroid carcinoma (CMv-PTC) is a
very rare subtype of papillary thyroid carcinoma representing approximately
0.1-0.2% of all papillary carcinoma cases. The overall prognosis of the CMv-
PTC is similar to that of classical variant of PTC with less than 10% of cases
demonstrating an aggressive clinical behavior.
Among patients with FAP who have synchronous PTC, over 90% of these
cases have been reported to exhibit histologic features of the cribriform-
morular variant. While not all CMv-PTC are associated with FAP, a very
significant proportion of the cases are.
The distinct CMv-PTC seen in FAP-related thyroid carcinomas is very
unusual in sporadic PTC, and its identification should raise the possibility of
this familial tumor syndrome, and any patient presenting with this rare
carcinoma should be evaluated for FAP.
• PTEN-hamartoma tumor syndrome (PHTS; Cowden Syndrome):
PTEN-Hamartoma Tumor Syndrome (PHTS) is a complex disorder caused by
germline inactivating mutations of the PTEN tumor suppressor gene, which
maps to 10q23.3, and includes Cowden syndrome (CS), Bannayan-Riley-
Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like
syndrome. In CS, germline intragenic PTEN mutations have been found in up
to 81% of classically-affected patients. For the patients with a clinical
diagnosis of BRRS, intragenic mutations account for 60% of the cases. Over
90% of individuals affected with CS manifest a phenotype by the age of 20
years. By the end or during their third decade almost all patients (99%)
develop at least the pathognomonic mucocutaneous lesions.
Affected individuals with CS will develop both benign and malignant tumors in
a variety of tissues, such as breast, uterus, and thyroid. Thyroid pathologic
findings in this syndrome typically affect follicular cells. Follicular carcinoma,
with a frequency of 5-10%, is a major diagnostic criteria for the diagnosis of
Cowden syndrome; multinodular goiter and follicular adenomas are minor
criteria, with a frequency of 50-67%.
The thyroid pathology has one very characteristic finding: multiple
adenomatous nodules (MAN), as multiple firm yellow-tan well-circumscribed
nodules are diffusely involving the thyroid gland. Microscopically, they are
well-circumscribed non-encapsulated solid cellular nodules sharing features
similar to follicular adenomas (see figure below). Follicles are not dilated, and
some nodules may have a discontinuous rim of fibrous tissue simulating a
capsule. The nodules range in size from 0.1 cm up to 8 cm, and the number
of nodules per thyroid can be over 100 distinct nodules.
Follicular adenomas are very common and usually multiple in this syndrome.
Follicular carcinoma is an important feature in CS and BRRS; these tumors
are more frequently multicentric, and progress from a pre-existing follicular
adenoma. The majority of thyroid lesions occurring in PHTS are of follicular
origin; however, PTC is rarely been associated with this entity. The
occurrence of papillary microcarcinoma in CS is usually attributed as chance
occurrence as such tumors may be present in up to 30% of the adult
Medullary thyroid carcinoma is not considered part of the spectrum of PHTS,
however previous studies, one by us, have identified C-cell hyperplasia in
individuals affected with this syndrome. The presence of C-cell hyperplasia
and an abnormal distribution of C cells are seen in PHTS. This finding
suggests that PTEN-associated tumor syndromes should be considered in
the differential diagnosis of C-cell hyperplasia of the thyroid.
In summary, the multicentric thyroid pathology characterized by the presence
of numerous adenomatous nodules, follicular adenomas, FTC, and PTC is
characteristic finding in PHTS. The presence of numerous MANs in younger
patients should raise the suspicion for the diagnosis of CS. Thyroid cancer is
an important aspect of this syndrome, and all these findings should alert
pathologists to notify clinicians of the possibility of PTEN-Hamartoma Tumor
• Carney Complex:
Carney Complex is an autosomal dominant disease, characterized by skin
and mucosal pigmentation, diverse pigmented skin lesions, non-endocrine
and a variety of endocrine neoplasias (pituitary adenoma, pigmented nodular
adrenal disease, Sertoli and Leydig cell tumors, and thyroid tumors). The
thyroid is multinodular with multiple adenomatous nodules, follicular
adenomas, and both PTC and FTC are present in about 15% of patients with
• Werner Syndrome:
Werner syndrome is an autosomal recessive connective tissue disease,
characterized by premature aging, bilateral cataracts, gray hair, and skin
atrophy. Patients with this syndrome have increased risk of a variety of
neoplasias, including benign thyroid lesions and an increased incidence of
PTC (only tumor present in white patients), FTC and anaplastic thyroid
carcinomas (all variants present in Japanese patients). This latter neoplasm
occurs in this syndrome at a higher frequency as compared to the general
population. Thyroid carcinoma occurs at a younger age (mean age of 34)
with a lower female to male ratio (2:1).
• Multiple Endocrine Neoplasia 2A (MEN2A):
The frequency of microscopic PTC is approximately twice as great in thyroid
glands of MEN2A patients. These cases usually present with multiple
microscopic PTCs. These microscopic PTCs are likely to carry only modest
clinical significance since microscopic PTCs often remain clinically silent and
since affected subjects carrying germline RET mutations undergo
thyroidectomy at a young age.
Occasionally the occurrence of both tumors together, as a collision tumor, is
identified on MEN2A patients (see figure below).
1b. Familial Tumor Syndromes Characterized By A Predominance Of Non-
medullary Thyroid Carcinoma:
"Familial Non-medullary Thyroid Carcinoma Syndrome" (FNMTC) is diagnosed
when two or more family members have nonmedullary thyroid cancer in the
absence of other known associated syndromes. Statistical estimates suggest
that a grouping of 2 family members with NMTC could represent the concurrence
of sporadic tumors but thyroid tumors in 3 or more members in kindred, or the
diagnosis of PTC in men and children, is more suggestive of a familial
Familial non-medullary thyroid carcinoma is now recognized as a distinct clinical
entity and accounts for up to 10.5% of all follicular cell origin thyroid carcinomas.
Familial nonmedullary thyroid carcinoma has a high incidence of multifocality and
association with multiple benign nodules. FNMTC patients have shorter disease-
free survival than do sporadic disease patients because of frequent locoregional
The genetic inheritance of FNMTC remains unknown, but it is believed to be an
autosomal dominant mode with incomplete penetrance and variable expressivity.
Genetic analyses of large FNMTC kindreds not only support the hypothesis of an
inherited genetic predisposition to FNMTC, but also represent the first steps in
identification of the putative susceptibility genes.
Linkage analyses have identified three different chromosomal regions that may
harbor an FNMTC susceptibility gene.
• Familial Papillary Thyroid Carcinoma (FPTC) is characterized by
multicentric tumors, and multiple adenomatous nodules with or without
Familial PTC enriched in thyroid carcinoma with oxyphilia (TCO) has been
mapped to chromosomal region 19p13, and FNMTC without oxyphilia has
also been mapped to 19p13.31. Tumor-specific loss of heterozygosity is
found in sporadic FTC with and without oxyphilia at both 19p13 and
2q21.32 (see figure).
• Familial PTC associated with renal papillary neoplasia, presents with
the usual classical variant of PTC, and with no special features. The
papillary renal neoplasia syndrome (fPTC/ PRN), mapped to chromosomal
region 1q21, includes not only PTC and the expected benign thyroid
nodules, but also papillary renal neoplasia and possibly other
malignancies as well.
• The familial nonmedullary thyroid carcinoma type 1 (fNMTC1)
syndrome (chromosomal region 2q21) is characterized by PTC without
any distinguishing pathologic features and without an obvious increase in
frequency of non thyroidal neoplasms in kindred members.
• In familial multinodular goiter (FMNG) syndrome, which is mapped to
14q, some patients may develop an associated PTC.
Sporadic PTC has BRAF mutation in approximately 40% of cases; however, no
BRAF mutation was found in a group of 40 patients with FNMTC as germline
mutation or a susceptibility genetic event for FNMTC.
FNMTC has been shown the presence of multiple benign nodules, to be more
aggressive, and to have a worse prognosis than sporadic nonmedullary thyroid
cancer. Individuals with FNMTC have an increased risk of multifocal disease,
local invasion, increased local or regional recurrence and lymph node
metastases. These aggressive features appear to contribute to the higher
recurrence rate and decreased disease-free survival seen in FNMTC patients
compared to those with sporadic differentiated thyroid cancer. Compared to the
patients with sporadic disease, the FNMTC patients were more likely to have
intraglandular dissemination. FNMTC is an independent predictor of shorter
Overall, the literature is limited based on the low prevalence of FNMTC, the
difficulty in identifying familial cases, the variable study designs, and mostly due
to the limited long-term follow-up. Improved awareness and screening of
FNMTC will permit earlier detection, a timely intervention, and improved
outcomes for patients and their families.
2. C cell neoplasm: Medullary Thyroid Carcinoma (MTC):
MTC is a rare malignancy of the calcitonin-producing thyroid C-cells. It occurs in
sporadic or hereditary (25% of cases) forms, as part of Multiple Endocrine
Neoplasia type II (MEN II) syndromes or as the MTC-only syndrome. A germline
point mutation in the RET gene on chromosome 10q11.2 is responsible for the
hereditary MTC. MEN IIA is associated with pheochromocytoma and parathyroid
hyperplasia, while MEN IIB is associated with marfanoid habitus, mucosal
neuromas, ganglioneuromatosis, pheochromocytoma, and rarely with parathyroid
disease. The aggressiveness of MTC is usually related to the clinical
presentation, if presents as a hereditary or sporadic forms, and the type of RET
All patients with medullary thyroid carcinoma should then be screened for familial
disease. The hereditary tumor is usually preceded by C-cell hyperplasia (CCH),
and these tumors are usually bilateral and multicentric. The presence of C cell
hyperplasia is considered a paradigm of a genetically determined condition.
Two types of CCH that differ by their characteristics are identified: neoplastic
CCH and reactive or physiological CCH. Neoplastic CCH progresses to MTC
following a time line that depends on the RET mutation involved. CCH may
actually be a misnomer for the neoplastic condition "in situ-MTC". Reactive CCH
is considered to be caused by a stimulus that is external to the C-cell, and its
premalignant potential is not documented. Many situations such as
hypercalcemia, hyperparathyroid, chronic lymphocytic thyroiditis or follicular
tumors have been associated with reactive CCH.
The characteristic and distinct thyroid pathology findings in these syndromes
should alert the pathologist of a possible familial cancer syndrome, as the correct
histological interpretation may lead to further molecular genetic evaluation of the
patient and family members. Most of the patients with familial disease are
asymptomatic and are discovered through genetic screening in predisposing
families. The identification of hereditary cases and early diagnosis makes
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