QuickScan Reviews in Pathology, July 30 2009

Background: The RET (rearranged during transfection) proto-oncogene codes for a tyrosine kinase receptor that plays an important role in the developmental regulation of the kidney and nervous systems. Sporadic mutations in RET have been well documented in cases of papillary thyroid carcinoma (PTC), the most common being RET/PTC 1 and RET/PTC 3. Although originally thought to be a specific tumor marker for PTC, RET/PTC rearrangements have also been observed in other thyroid tumors and non-neoplastic conditions, such as Hashimoto's thyroiditis and nodular hyperplasia. Objective: To determine whether RET/PTC rearrangements are present in nonthyroid papillary tumors. Methods: 57 nonthyroid tumors with a papillary growth pattern were retrieved from the pathology archives over a 16-year period at 2 hospitals in Ireland. Tumors included 15 primary peritoneal carcinomas, 10 papillary renal cell carcinomas, 10 ovarian serous carcinomas, 10 urothelial cell carcinomas, 5 endometrial serous carcinomas, 2 uterine endometrioid carcinomas, 1 uterine adenoacanthoma, and 4 mixed-phenotype carcinomas. Interphase fluorescence in situ hybridization (FISH) for RET/PTC rearrangement, interphase FISH for ploidy analysis, RT-PCR for RET/PTC 1 expression, immunohistochemistry (IHC) for RET oncoprotein expression, and BRAF mutation analysis were performed for each case. For FISH, the percentage of split RET signals was recorded. For reverse transcriptase polymerase chain reaction (RT-PCR), a score of negative (0) or positive (1) was assigned. For IHC, the intensity of immunoreactivity was classified as absent (0), weak (1), moderate (2), or strong (3). At least 10% of tumor cells had to show at least some degree of positivity for a case to be considered truly positive. Associations between RET/PTC rearrangement and various clinical and pathologic features were examined using Fisher's exact test, while FISH score comparisons were examined using a Mann-Whitney test (2-tailed; significance <0.05). Results: Using FISH, approximately 9% of tumors had split RET signals above the cut-off level. These included 27% of primary peritoneal carcinomas and 10% of papillary renal cell carcinomas. Using RT-PCR, approximately 5% of tumors had detectable RET/PTC mRNA. All 3 cases were from the primary peritoneal carcinoma group. Using IHC, approximately 21% of tumors had detectable protein. These included 40% of primary peritoneal carcinomas, 20% of urothelial carcinomas, 18% of combined serous tumors, and 10% of papillary renal cell carcinomas. The BRAF T1799A mutation was not detected in any of the 57 tumors. Statistical analysis showed that the presence of an RET/PTC rearrangement was significantly associated with the primary peritoneal carcinoma tumor type. Conclusions: RET/PTC rearrangements occur in a small subset of nonthyroid papillary carcinomas. Reviewer's Comments: The authors advance the plausible suggestion that, based on the small percentage of positive cases, RET/PTC rearrangements in these nonthyroid papillary tumors may represent so-called secondary "passenger" type mutations, rather than mutational drivers directly influencing tumor growth.