Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which renal manifestations are prominent. There are three major renal lesions in TSC: angiomyolipomas, cysts, and renal cell carcinoma (RCC). Major recent advances have revolutionized our understanding of TSC-associated RCC, including two series that together include more than 100 TSC-RCC cases, demonstrating a mean age at onset of about 36 years, tumors in children as young as 7, and a striking 2:1 female predominance. These series also provide the first detailed understanding of the pathologic features of these distinctive tumors, which include chromophobe-like features and eosinophilia, with some of the tumors unclassified. This pathologic heterogeneity is distinctive and reminiscent of the pathologic heterogeneity in Birt–Hogg–Dube-associated RCC, which also includes chromophobe-like tumors. Additional advances include the identification of sporadic counterpart tumors that carry somatic TSC1/TSC2/mTOR mutations. These include unclassified eosinophilic tumors, eosinophilic solid cystic RCC (ESC-RCC), and RCC with leiomyomatous stroma (RCCLMS). A variety of epithelial renal neoplasms have been identified both in patients with tuberous sclerosis complex (TSC) and in the nonsyndromic setting associated with somatic mutations in the TSC1 and TSC2 genes. Interestingly, whether tumors are related to a germline or somatic TSC1/2 mutation, these tumors often display similar morphologic and immunophenotypic features. Finally, recent work has identified molecular links between TSC and BHD-associated tumors, involving the TFEB/TFE3 transcription factors.
Highlights
Since all of in these two series were HMBHMB-45-negative. These series confirm the finding of the original smaller series that Tuberous sclerosis complex (TSC)-renal cell carcinoma (RCC)
The TSC1 and TSC2 genes behave as classical tumor suppressor genes, with germline loss-of-function mutations accompanied by somatic loss-of-function of the remaining wildtype allele in tumors including angiomyolipomas [10,21]
Recent work has clarified the histologic features of TSC-associated RCC, based on more than 100 tumors in two large series
Summary
TSC is caused by germline loss-of-function mutations of either the TSC1 or TSC2 gene. TSC affects multiple organs, including the brain (subependymal giant cell astrocytomas (SEGAs), cerebral cortical tubers), heart (rhabdomyomas), kidney (angiomyolipomas (AMLs), cysts, renal cell carcinomas), lung (lymphangioleiomyomatosis (LAM)), and skin (angiofibromas). Tumors in TSC, including angiomyolipomas and renal cell carcinomas, develop after somatic “second hit” inactivation of the remaining wild-type allele of TSC1 or TSC2. Pivotal clinical trials have demonstrated that the mTORC1 inhibitors sirolimus (rapamycin) and everolimus (Afinitor) partially decrease the size of AML and SEGA [1,2] and prevent loss of lung function in LAM [3,4]. When mTORC1 inhibitory therapy is stopped, the AML and SEGA tend to regrow and lung function decline resumes. Continuous (and perhaps lifelong) therapy is required to suppress disease
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