Thyroid Carcinoma, Nonmedullary, With Or Without Cell Oxyphilia

Description

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart.

One peculiar form of thyroid tumors is characterized by the presence of cell oxyphilia. Oxophil cells are found in a minority of thyroid tumors, either benign or malignant. These cells show a large volume of granular eosinophilic cytoplasm and are very rich in mitochondria. The familial occurrence of thyroid tumors with cell oxyphilia was reported by Katoh et al. (1998). Canzian et al. (1998) reported such a family with affected members in 3 generations and by linkage analysis mapped the gene to 19p13.

For general phenotypic information and a discussion of genetic heterogeneity of NMTC, see 188550.

Clinical Features

The family in which Canzian et al. (1998) demonstrated linkage to 19p13.2 had been reported by Kraimps et al. (1997) to be affected with familial papillary thyroid carcinoma (PTC). This 3-generation family originated from a nonendemic goiter area of western France and included 3 individuals with multinodular goiter plus 3 individuals with nonmedullary thyroid carcinoma. The age at operation in the affected individuals ranged from 10 to 63 years. None of the patients had a history of any other type of cancer-prone syndrome or radiation exposure. There was no history of autoimmune disease in the family. In this family both the benign and the malignant thyroid tumors exhibited some extent of cell oxyphilia. The findings suggested that relatives of patients with sporadic nonmedullary thyroid carcinoma with cell oxyphilia should be investigated carefully.

In an attempt to elucidate further the features of familial thyroid neoplasia of follicular cell origin, Harach et al. (1999) investigated the pathologic findings from the affected members of the family in which Canzian et al. (1998) had demonstrated linkage to 19p13.2. All the affected members of the family (7 males and 2 females; mean age 23 years) were clinically euthyroid and presented with nodular goiter. Tumor recurrence after thyroidectomy was observed in 4. In 4 of the 5 patients studied, the tumors were multifocal, bilateral well demarcated or encapsulated, and composed of follicles, papillae, trabeculae/solid areas (often resembling hyalinizing trabecular adenoma of the thyroid) or an admixture, formed by cells with pale to intense cytoplasmic eosinophilia. All tumors were of follicular cell origin as shown by immunocytochemistry. Less than one-third of the benign tumors and all 3 carcinomas showed a variable number of neoplastic cells diffusely immunostained for mitochondria. Harach et al. (1999) suggested that histologic findings of a 'multiple adenomatous goiter,' nonendemic 'multinodular goiter,' or multiple neoplasms of follicular cell origin with the morphology of those they described, particularly in young patients, should alert the pathologist and physician to the possibility of an inherited trait, with its implications for family screening. The tumors are usually benign and well demarcated but because of multicentricity and consequently increased risk of recurrence and/or progression to carcinoma, total thyroidectomy should be advocated.

Mapping

To evaluate the roles of MNG1 (138800), TCO1, PTCPRN (605642), PTEN (601728), TSHR (603372), and TRKA (191315) in familial nonmedullary thyroid cancer, Bevan et al. (2001) carried out a comprehensive mutation and linkage analysis of these loci in 22 families. One family was linked to chromosome 19q13.2, confirming that TCO1 underlies a subset of familial nonmedullary thyroid cancer. In contrast to the family previously linked to TCO1 by Canzian et al. (1998), the thyroid cancers in this family were papillary rather than Hurthle cell. None of the families was linked to MNG1 or PTCPRN, and there was no evidence to support the roles of PTEN, TSHR, or TRKA. The authors concluded that familial nonmedullary thyroid cancer is genetically heterogeneous and that none of these genes accounts for the majority of families.

In 10 families with nonmedullary thyroid cancer, 9 of which presented with cell oxyphilia, McKay et al. (2004) found evidence for linkage at both TCO1 and NMTC3 (606240), with lod scores of 1.56 and 2.85, respectively. Two-locus linkage analysis, using a multiplicative risk model for the development of nonmedullary thyroid cancer, achieved a maximum lod score of 3.92, with a lod score of 4.51 when assuming 70% of the families were linked, indicating that the segregation in these families is consistent with an interaction model. A large Tyrolean family alone achieved a 2-locus lod score of 3.21.

Molecular Genetics

Exclusion Studies

Maximo et al. (2005) excluded mutations in the GRIM19 gene (NDUFA13; 609435) in affected members of the family reported by Canzian et al. (1998).