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.

Keywords: APC; Carney complex; Cowden syndrome; Cribriform-morular thyroid carcinoma; DICER1; DICER1 syndrome; FAP; Familial non-medullary thyroid carcinoma; PRKAR1A; PTEN; PTEN-hamartoma tumor syndrome; RASAL1; SDHB; Thyroid cancer; WRN; Wermer syndrome.

Fig. 1

Non-syndromic familial non-medullary thyroid carcinoma case. Macroscopic appearance is not usually different from multinodular goiter (a). Histologically there is a combination of benign lesions (hyperplastic nodules as well as follicular adenomas) (b, c, e) with malignant follicular tumors. In this particular case, two papillary carcinomas can also be seen (d, f)

Fig. 2

Cribriform-morular variant of thyroid carcinoma. This tumor is usually encapsulated or well-defined, partially divided by fibrous septa. Histologically, there is a mixture of cribriform (a), papillary (c), follicular, trabecular (b) or morular (squamoid) (a–c) patterns. Papillary or pseudopapillary structures are lined by cuboidal or columnar cells (c). Follicular and cribriform areas are usually devoid of colloid (a, c, d). Tumor cells are usually negative for thyroglobulin; focal positivity may represent trapped nontumorous tissue (d). Tumor cells are always positive for TTF1 (f). Nuclear and cytoplasmic positivity for β-catenin is the hallmark of the cribriform-morular variant of thyroid carcinoma (e)

Fig. 3

PTEN-hamartoma tumor syndrome (PHTS). In this case, thyroid involvement is typically multinodular and bilateral (a). Microscopically, the presence of multiple bilateral adenomatous nodules (“microadenomas”) (c) and adenomas (b), including adenolipomas (d), is characteristic. Adipocytic infiltration and lymphocytic thyroiditis can also be seen (f). The loss of PTEN protein expression in thyroid nodules, whether in all nodules or in a subset of nodules with expression in endothelial cells (internal positive control), is both sensitive and specific for PHTS (e)

Fig. 4

DICER1-related thyroid disease. DICER1-related thyroidectomy specimens are grossly indistinguishable from sporadic manifestations of multinodular goiter (a; Lt refers to left; Rt refers to right; Sup refers to superior; Inf refers to inferior). Careful assessment of thyroid nodules and the non-lesional thyroid parenchyma provides additional clues to the possibility of DICER1-related thyroid disease. This composite photomicrograph illustrates features of thyroid pathology identified in a young adult patient with pathogenic germline DICER1 mutation. The thyroid gland shows multifocal follicular adenomas with intrafollicular centripetal papillary projections, which are also known as papillary adenomas (b–c). Although papillary adenomas tend to manifest with clinical or subclinical hyperthyroidism; DICER1-related papillary adenomas are seen in association with euthyroid states. In addition, follicular-patterned thyroid neoplasms including follicular adenomas and follicular variant papillary thyroid carcinomas are identified (c, f). The nontumorous thyroid gland shows variable involutional changes characterized by dilated macro-follicles (e). Papillary thyroid carcinomas account for the vast majority of malignant thyroid nodules in DICER1-related thyroid disease. Encapsulated follicular variant papillary microcarcinoma with tumor capsular invasion is illustrated (f) along with HBME1 immunoreactivity (g) and reduced membranous CD56 expression (h)

Fig. 5

Thyroblastoma. In this area, the tumor is composed of a small cell undifferentiated/immature epithelial component, and a stromal chondroid component (image courtesy of Dr. Catarina Eloy, Porto, Portugal)