Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

Abstract

Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be “sporadic” is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.

Sex Bias in Differentiated Thyroid Cancer

“…Interestingly, thyroid cancer in this case is a peculiar variant, namely the cribriform-morular variant. The women to men ratio is higher than 60/1 [ 38 ]. Depending on the studies, the number of cases and the way the results are expressed, thyroid carcinoma also have a higher frequency in women affected by PTEN (phosphatase and TENsin homologue) Hamartoma tumor syndrome, encompassing the Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome [ 39 ].…”

“…Some tumor predisposing syndromes offer nice illustrations of the impact of estrogens on thyroid tumorigenesis and or tumor growth. The thyroid cancer associated with familial adenomatous polyposis (FAP) syndrome is frequently a variant form, namely the cribriform morula carcinoma, and affects almost exclusively women [ 38 , 98 ]. The tumors have a strong expression of estrogen receptors and a lighter one of androgen receptors [ 98 ].…”

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys

“…In fact, it has been calculated that when the FNMTC definition is based on the presence of two affected members, the probability of a family origin is 47%, while when it is based on a minimum of 3 firstdegree relatives, the probability of being related rises to more than 95% (6)(7)(8). Clinical studies show that NS-FNMTC shows more extrathyroidal extension, multifocality, combination with both benign thyroid nodules and Hashimoto disease, and a younger age at onset (3,4,9). In contrast, in most articles describing susceptibility genes for NS-FNMTC, however, the histopathological characteristics of TC are usually not very precise (Figure 1).…”

“…While RET gene mutations play a fundamental role in the development of C cell-derived thyroid carcinomas including the familial forms of medullary thyroid carcinoma ( 2 ), the genetic-molecular profile of follicular cell-derived TC is more heterogeneous. Hereditary follicular cell TC is commonly referred to as familial non-medullary TC (FNMTC) and its genetic basis remains to be established ( 3 , 4 ).…”

“…Most authors agree that the clinical diagnosis of FNMTC is based on the evidence of papillary thyroid carcinoma (PTC) in two or more first-degree relatives, or on the finding of multinodular goiter (MNG) in at least three first- or second-degree relatives of a PTC patient, always in the absence of a history of ionizing radiation exposure ( 3 , 4 ). FNMTC is generally classified into two large groups: syndromic familial non-medullary thyroid cancer (S-FNMTC) when the TC is associated with syndromes that have extrathyroid manifestations, and non-syndromic familial non-medullary TC (NS-FNMTC) ( 3 , 4 ). S-FNMTC is generally secondary to germline mutations in the APC , PTEN , DICER1 , PRKAR1A , or WRN genes ( 3 , 4 ).…”