Hurthle tumors: a class of thyroid malignancy with massive chromosome disturbance

Ganly et al. have recently provided elegant evidence that Hurthle cell carcinoma (1), an understudied thyroid cancer characterized by > 75% large cells with hyperchromatic nuclei and a granular cytoplasm extraordinarily rich in mitochondria, constitutes a unique class of thyroid cancer. Using a global approach, including mass spectrometry-based genotyping, array comparative genomic hybridization, and expression profiling, the authors demonstrated that mutational, transcriptional, and copy number profiles of this tumor are distinct from both papillary and follicular carcinoma. In particular, the authors highlighted that the striking feature was the finding of large regions of gain on chromosomes 5, 7, 12, and 17, suggesting the presence of chromosomal instability or selection for increased copies of specific chromosomes. These data are in line with our early observations in thyroid oncocytic neoplasms obtained by conjugating immunofluorescence and fluorescence in situ hybridization approaches (2). Single cell fluorescent immunophenotyping with an anti-mitochondrion antibody followed by FISH with centromeric DNA probes for different chromosomes not only supported our conventional G-banding and CGH results, indicating presence of chromosome gains in oncocytic follicular lesions, but substantiated that chromosome changes in Hurthle carcinoma (oncocytic variant of follicular tumors, according to the World Health Organization) were confined to the mitochondrion-rich cells. In addition, we reported that among mitochondrion-rich carcinomas only the Hurthle variant showed numerical chromosome gains, whereas the oncocytic papillary tumors were diploid. A different distribution of mitochondria between the Hurthle carcinoma and the papillary oncocytic carcinoma was also observed, the former exhibiting diffuse distribution, the latter exhibiting polar. Karyotypic and molecular cytogenetic data (2, 3) also indicated that trisomy 7 is the first numerical aberration to occur, and that numerical changes seem to accumulate according to an evolutionary scheme. We also observed that oncocytic lesions not defined as Hurthle tumor (because they contained fewer than 75% oncocytes) showed chromosome numerical changes. Based on these observations, we hypothesized that trisomy 7 may confer a proliferative advantage, priming the “cascade” of alterations with selection of cells prone to progressively accumulate specific chromosomes and mitochondria. This speculation is also consistent with the Ganly group's observation on the absence of any pattern of chromosomal gains/losses that could specifically differentiate Hurthle adenoma (by definition having > 75% oncocytic cells) from minimally and widely invasive tumors. According to our hypothesis, in fact, accumulation of chromosome numerical changes and mitochondria starts in lesions with a low percentage of oncocytes, and trisomy 7 would possibly be implicated in the mitochondria accumulation process. This led us to support the contention that follicular tumors composed of oncocytes should be regarded as a distinct subset. In our view, the Ganly report has meaningful value, adding new, conclusive evidence that the Hurthle neoplasm represents a unique class of thyroid malignancy. References Ganly I, Ricarte Filho J, Eng S, Ghossein R, Morris LG, Liang Y, Socci N, Kannan K, Mo Q, Fagin JA, Chan TA. Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. J Clin Endocrinol Metab 2013; 98:E962–E972 Dettori T, Frau DV, Lai ML, Mariotti S, Uccheddu A, Daniele GM, Tallini G, Faa G, Vanni R. Aneuploidy in oncocytic lesions of the thyroid gland: diffuse accumulation of mitochondria within the cell is associated with trisomy 7 and progressive numerical chromosomal alterations. Genes Chromosomes Cancer 2003;38:22–31 Belge G, Thode B, Rippe V, Bartnitzke S, Bullerdiek J. A characteristic sequence of trisomies starting with trisomy 7 in benign thyroid tumors. Hum Genet 1994; 94:198–202