Recent Advances in Renal Tumors with TSC/mTOR Pathway Abnormalities in Patients with Tuberous Sclerosis Complex and in the Sporadic Setting

Abstract

A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.

Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis

“…We also observed a tumor in the liver, which was most suggestive of a liver PEComa. In humans, PEComas generally have mutations in the TSC1/TSC2 genes, but MiT/TFE translocations have been observed when those are absent (16,17), suggesting that the pathways may converge, which is consistent with our earlier levels were higher than in ccRCC (Table 2). Overall, these results support the notion that in both human and murine tRCC, autophagy and mTORC1-dependent anabolic pathways are activated.…”

“…We also observed a tumor in the liver, which was most suggestive of a liver PEComa. In humans, PEComas generally have mutations in the TSC1 / TSC2 genes, but MiT/TFE translocations have been observed when those are absent ( 16 , 17 ), suggesting that the pathways may converge, which is consistent with our earlier pioneering studies ( 18 ). Thus, these GEMMs serve to model not only human tRCC but also ASPS and possibly PEComa.…”

“…cell tumors (PEComas) (14,15). Interestingly, these PEComas are characterized by the absence of more common mutations in the TSC1 and TSC2 genes, which also alter TFE3/TFEB regulation, upon which the pathogenesis may converge (16)(17)(18).…”

Hereditary Renal Cancer Syndromes

“…Von Hippel-Lindau disease Antiangiogenic therapy and multikinase inhibitors; "Watch-and-wait" approach (lesions < 3 cm in diameter) [82] Anti-HIF2-alpha therapy (belzutifan) [93][94][95][96] Fumarate hydratase deficiency Bevacizumab + erlotinib; multikinase inhibitors; immune therapy [97][98][99][100][101][102][103][104][105] Immediate surgical removal [106] Hereditary pheochromocytoma/ paraganglioma syndrome Immediate surgical removal [72] Hereditary papillary renal cell carcinoma MET inhibitors (crizotinib, capmatinib) [107][108][109] "Watch-and-wait" approach (lesions < 3 cm in diameter) [71,110] Birt-Hogg-Dubé Syndrome mTOR inhibitors (everolimus)? [111] "Watch-and-wait" approach (lesions < 3 cm in diameter) [106] Tuberous sclerosis mTOR inhibitors (everolimus) [112][113][114] "Watch-and-wait" approach for angiomyolipomas, insufficient evidence regarding RCC [115,116] BAP1 tumor predisposition syndrome Insufficient evidence, but immediate surgical removal is suggested [106] Cowden syndrome mTOR inhibitors (everolimus)? [117] Insufficient evidence…”

“…Renal involvement in TS patients is manifested by renal cysts and angiomyolipomas [150]. TSC2 deletions often extend to the neighboring gene, PKD1, leading to the simultaneous manifestation of polycystic kidney disease [6,115,155]. TSC1/2 mutation carriers have a several-fold increased risk of RCCs [115].…”