RET rearrangements in archival oxyphilic thyroid tumors: new insights in tumorigenesis and classification of Hürthle cell carcinomas?

Abstract

Oncocytic carcinomas (Hürthle cell carcinomas [HCCs]) are commonly considered a subgroup of follicular thyroid carcinomas (FTCs). Recent characterization of a subgroup of "Hürthle cell" papillary thyroid carcinomas (PTCs) was based on the identification of PTC-specific RET hybrid oncogenes in HCCs. We examined 27 HCCs, 4 oxyphilic FTCs, 5 oxyphilic PTCs, 2 poorly differentiated carcinomas arising from HCCs (HCC-UTCs), and 16 oxyphilic adenomas. Total RNA was extracted from paraffin-embedded thyroid neoplasms by a novel macrodissection technique that uses a cylindric punch. After reverse transcription-polymerase chain reaction-based screening for RET rearrangements, the samples were tested for all known RET/PTC 1 to 11 hybrids with the use of artificially constructed chimeric sequences as controls. The elimination of C cells by punching dissection significantly reduced RET wild-type expression. RET hybrid oncogenes (7x RET/PTC1, 1x RET/PTC1L, 2x RET/PTC3, 5 uncharacterized RET/PTCx) were demonstrated in 7 of 27 HCCs, in 0 of 4 oxyphilic FTCs, in 4 of 5 oxyphilic PTCs, in 1 of 2 HCC-UTCs, and in 3 of 16 oxyphilic adenomas. Our results suggest that the expression of rearranged RET hybrid oncogenes (1) is present in a similar percentage of HCCs when compared with the literature on nonoxyphilic PTCs, (2) defines PTC-like HCCs better than histomorphologic characterization, (3) excludes HCCs as a subgroup of FTCs, and (4) may play a role in the early tumorigenesis of oncocytic tumors.