Thyroid Carcinoma, Hurthle Cell


A number sign (#) is used with this entry because Hurthle cell tumors are associated with chromosomal abnormalities or mutations in the RAS gene (190020), the PAX8/PPARG fusion gene (see 167415), or the NDUFA13 gene (609435).


Hurthle cell carcinoma of the thyroid accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms (Sanders and Silverman, 1998).

Hurthle cell tumors, also known as oxyphil cell tumors, are composed of cells with increased numbers of mitochondria, which corresponds morphologically to their voluminous, granular, eosinophilic cytoplasm (Maximo et al., 2005).


Chromosomal aberrations by comparative genomic hybridization (CGH) are common in Hurthle cell neoplasms. However, the relationship between the chromosomal aberrations by CGH and tumor behavior was obscure. Wada et al. (2002) investigated chromosomal aberrations in primary Hurthle cell neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the aberrations identified with tumor node metastasis stage, tumor differentiation, capsular invasion, and tumor recurrence. Chromosomal aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15) of adenomas. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Five of the 8 (63%) patients with aberrations developed recurrence, whereas 0 of 5 patients without aberrations developed recurrence. The authors concluded that chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q in Hurthle cell carcinomas are associated with tumor recurrence. They also concluded that such chromosomal aberrations may be predictive for recurrent disease in patients with Hurthle cell thyroid carcinoma.


Both papillary and follicular thyroid carcinomas may subsequently acquire further somatic genetic changes, which can result in tumor dedifferentiation and clinical progression. Certain chromosomal regions seem to be preferentially involved, suggesting that they may harbor tumor suppressor genes. The 17p13 region has been suggested to harbor a novel oncogene or tumor suppressor gene that plays a role in thyroid carcinoma progression. Farrand et al. (2002) studied a large cohort of clinically and histologically well characterized tumors, mainly typical follicular thyroid carcinoma and oxyphilic follicular thyroid carcinoma (Hurthle cell carcinoma), using a series of well mapped and closely spaced microsatellite markers. They confirmed a high 17p13 LOH rate in follicular thyroid carcinomas (18 of 20) and Hurthle cell carcinomas (13 of 19) and showed an association between 17p13 LOH and advanced tumor grade. In the Hurthle cell carcinomas the authors identified a narrow minimal common deleted region between D17S1308 (285 kb from pter) and D17S695 (696 kb from pter). This region was flanked centromerically by a breakpoint cluster, further suggesting nonrandom deletion. Farrand et al. (2002) concluded that these data suggest that a tumor suppressor gene, involved in Hurthle cell carcinoma pathogenesis, is contained within the D17S1308-D17S695 interval.

Molecular Genetics

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (e.g., 190020) mutations and PAX8-PPARG (see 167415) rearrangements for galectin-3 (153619) and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations. Nikiforova et al. (2003) concluded that follicular thyroid carcinomas can develop through different molecular pathways. While conventional follicular thyroid carcinomas develop through at least 2 distinct and nonoverlapping molecular pathways initiated by RAS point mutation or PAX8-PPARG rearrangement, Hurthle cell tumors have a low frequency of both of these genetic alterations and apparently require a unique set of mutations for their development.

In a man with papillary thyroid carcinoma composed predominantly of Hurthle cells, Maximo et al. (2005) identified a heterozygous germline mutation (609435.0001) in the NDUFA13 gene, which they called GRIM19. Heterozygous somatic mutations were identified in 3 of 26 additional sporadic Hurthle cell tumors. There was no associated loss of heterozygosity at the GRIM19 locus, suggesting either a dominant-negative mechanism or haploinsufficiency. The 4 tumors with GRIM19 mutations had significantly higher levels of ICAM1 (147840) expression in tumor tissue versus normal tissue compared to tumors without GRIM19 mutations. Maximo et al. (2005) postulated that loss of GRIM19 function may lead to mitochondrial defects and mitochondrial excess observed in Hurthle cell tumors or to defects in apoptosis.