Tuberous Sclerosis-Associated Renal Cell Carcinoma: Morphologic Spectrum and Molecular Characterization
Ying-Bei Chen, Anuradha Gopalan, Hikmat Al-Ahmadie, Samson W Fine, Helen Won, AR Brannon, Michael F Berger, Victor E Reuter, Satish K Tickoo. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Renal cell carcinoma (RCC) is a rare presentation of tuberous sclerosis complex (TSC), seen in only 2-4% patients. The reported histology of TSC-related renal epithelial tumors has been quite heterogeneous, including clear cell, chromophobe, unclassified RCC and oncocytoma etc. It remains unclear if these tumors are histologically and molecularly similar to their sporadic counterparts.
Design: We identified 34 renal epithelial tumors resected from 6 TSC patients. H&E slides of all cases were reviewed. DNA samples from 3 tumors and matched normal controls were analyzed by a targeted next-generation exome sequencing platform.
Results: The 6 TSC patients were 4 men and 2 women. Mean age at first nephrectomy was 24.2 yr (12-43). The number of tumors resected from each individual ranged from 1 to 15. Two patients had bilateral nephrectomies. Multiple angiomyolipomas, often microscopic, were found in the adjacent kidney of all cases. The feature common to all 34 epithelial tumors was intricate, branching fibrovascular septations similar to that seen in clear cell RCC. However, many other features were distinctive. Cytology ranged from exclusively clear cells with voluminous cytoplasm traversed by cobweb-like strands to purely eosinophilic cytoplasm with variably-sized pink granules. 15 of 34 (44%) showed admixed clear and eosinophilic cells, 15 (44%) had predominantly pink cells with focal, minimal cytoplasmic clearing, 3 tumors were entirely clear and 1 entirely eosinophilic. Architecturally they had often admixed nests, tubules, solid sheets, and variable papillary areas (16; 47%). Nuclei were high grade in all tumors (Fuhrman grade 3). Psammomatous calcifications were seen in 10 (29%). Scattered stromal histiocytes and lymphocytes were found in some tumors. Many tumors, or areas within the same tumor, bore superficial resemblance to clear cell, papillary or chromophobe RCC. Molecular study of 3 tumors with different cytology (clear, mixed, and eosinophilic) showed that complete loss of TSC1/2 by germline and somatic mutations was the main molecular event detected in all. No classic molecular alterations of sporadic clear cell, papillary or chromophobe RCC were identified. All 3 tumors had diffuse and strong immunoreactivity to pS6 and p4EBP1, suggesting mTOR pathway activation.
Conclusions: TSC-associated renal epithelial neoplasms, although morphologically diverse, show unique histologic features that can distinguish them from common sporadic renal tumors. Molecular features of these tumors are quite dissimilar from sporadic RCCs, supporting their distinction from the sporadic RCCs.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 84, Tuesday Morning