ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION (ACGH)-BASED ALGORITHM FOR RENAL TUMOR SUBTYPING IN NEEDLE BIOPSIES

INTRODUCTION AND OBJECTIVES: Hereditary leiomyomatosis and renal cell cancer (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors each with unique pathologic features. These characteristic features, when recognized during pathology assessment of surgical specimens may prompt further clinical investigation. We evaluated the association between suspicious pathology (SP) and positive results from patients referred for subsequent genetic testing. METHODS: In an IRB approved study we identified patients who underwent FH testing during a clinical genetic evaluation from 2008-2013. Tested-relatives of HLRCC probands were excluded. We defined SP as specific report of HLRCC histologic features identified during pathologic assessment prospectively. FH testing for all patients was performed in a CLIA-certified laboratory. We analyzed clinicopathologic data in those withand without-SP and the association between SP and FH mutation using Mann-Whitney test and Fisher’s exact test. RESULTS: 29 patients comprised the study cohort; median age was 37 years (IQR 31, 49), 15 (52%) were female, and 18 (62%) were Caucasian. 39 associated pathologic specimens were identified. Pathologists reported SP in 23 of the 39 specimens (59%) from 21 of 29 patients (72%). SP positive specimens included: kidney tumor (11/18), leiomyoma [(9/15) uterine (8) and bladder (1)], and metastatic tumors (3/6). Patients with SP were younger (35 vs. 51, p1⁄40.010) and more often had stage pT3 RCC (100% vs 33%, p1⁄40.006) compared to those without SP. FH mutation was present in 8 (38%) with SP and 1 (13%) without SP (p1⁄40.37); 7 of these had kidney cancer (SP1⁄47), all with N1 disease, and 2 had only uterine leiomyoma (SP1⁄42) combined with diagnostic skin leiomyomas. Analyzing SP by tissue type identified only SP from renal tumors as significantly associated with positive testing for FH mutation (p1⁄40.013). Leiomyoma SP had 70% false positives; however 1 case led to diagnosis of skin leiomyomas and FH mutation. Genetic screening in FH+ patients identified 5 relatives also with germline FH mutation who are under surveillance. CONCLUSIONS: Only SP from kidney tumors undergoing routine pathologic assessment was significantly associated with FH mutation although identification from other tissues is possible and may prompt thorough investigation. This mechanism may be vital for identification of syndromic HLRCC cases and initiation of potentially lifesaving screening strategies.