[866] Renal Cancer in Tuberous Sclerosis: An Underdiagnosed Disease? Molecular, IHC and Pathologic Correlation

S Roy Chowdhuri, J Vicens, L Teller, WM Linehan, MJ Merino. National Cancer Institute, Bethesda, MD

Background: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by hamartomatous lesions involving various organs. Mutations in TSC1 (Hamartin) and TSC2 (Tuberin) are related to various phenotypic manifestations and risks of malignancy, such as an increased incidence of renal tumors. The most common renal tumors found in TSC are angiomyolipomas (AML). Renal cell carcinomas (RCC) account for about 5% of the kidney lesions. In this study we describe the morphological findings of renal cancer in patients with TSC along with correlation to molecular and IHC analysis.
Design: Renal tumors from eight female patients with ages between 42 and 64 years were reviewed. Five patients were known to have history of TSC. The remaining three patients were from the same family but had no known history of TSC. Morphological evaluation of the tumors and IHC analysis using antibodies against Tuberin, Hamartin, CK7, CK20, CD10, SMA and TFE3 was performed in all the cases. The tumors were also examined for loss of heterozygosity (LOH) at the TSC2 locus using chromosome 16p13 markers.
Results: All eight patients had RCCs with features of clear cell carcinoma. Three of the clear cell tumors had thick papillary structures containing muscle, lined by cells with abundant clear cytoplasm. Two patients from the same family had diffuse subcapsular and intra parenchymal nodules of smooth muscle proliferation. One patient had multiple tumors within the same kidney consisting of oncocytic lesions, chromophobe and clear cell RCC. Three patients had clear cell RCC with associated AMLs. By IHC the clear cell carcinomas of TSC patients stained positive with Tuberin in all cases and three showed diffuse loss of staining with Hamartin. The chromophobe tumor and one AML showed negative staining for Hamartin. The subcapsular smooth muscle proliferation had reduced staining with Tuberin and was negative for Hamartin. Analysis for loss of heterozygosity at the TSC2 locus demonstrated LOH in two clear cell RCCs and one chromophobe RCC. No LOH was seen in the smooth muscle lesions.
Conclusions: Although the most common TSC-associated renal carcinoma is clear cell with solid or papillary features, oncocytic neoplasms and chromophobe RCC can also occur. The presence of solid smooth muscle proliferation within the kidney should alert the pathologist of the possibility of TSC. Molecular and IHC data suggest that Tuberin and Hamartin may play specific pathogenic roles in these tumors.
Category: Genitourinary (including renal tumors)

Monday, March 9, 2009 9:30 AM

Poster Session I Stowell-Orbison/Autopsy Award # 134, Monday Morning