Familial Thyroid Carcinoma: A Diagnostic Algorithm Vânia Nosé ...


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Familial Thyroid Carcinoma: A Diagnostic Algorithm Vânia Nosé ...

  1. 1. 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 Denver, Colorado Saturday, March 1st, 2008 1
  2. 2. 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- thyroidal tumors): • Familial Adenomatous Polyposis: distinct cribriform-morular thyroid carcinoma (CMv-PTC) • PTEN-hamartoma Tumor Syndrome - Cowden Disease: numerous adenomatous nodules, follicular adenomas, PTC, and FTC • Others 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 MTC. • The characteristic thyroid pathology findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetic evaluation. 2
  3. 3. Introduction: 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 frequency. 1a. Familial tumor syndromes characterized by a preponderance of nonthyroidal tumors: 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 3
  4. 4. 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. 4
  5. 5. 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. 5
  6. 6. 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 population. 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 Syndrome. • 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 Carney Complex. • 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 6
  7. 7. 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 predisposition. 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 recurrence. 7
  8. 8. 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 oxyphilia. 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. 8
  9. 9. 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 disease-free survival. 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 mutation present. 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. 9
  10. 10. 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. Summary: 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 preventative surgery and adequate treatment possible. 10
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