SMARCB1(INI1)-deficient renal cell carcinoma: medullary and beyond : Evolving concepts

Abstract

During the last decades, the SWI/SNF chromatin-remodeling complex has received enormous recognition as amajor player in the molecular pathogenesis of diverse neoplasms. Accordingly, SWI/SNF defects affecting different subunits of the complex became defining genetic features in the nosology of different neoplastic entities. In the kidney, loss of SMARCB1(INI1) as amajor component of the SWI/SNF complex has emerged as the defining genetic marker for renal medullary carcinoma and pediatric malignant rhabdoid tumor. Diagnosis of these two rare entities is based on aset of defined demographic, clinicopathological, immunophenotypic, and genetic (SMARCB1 loss) criteria. Moreover, the sickle cell trait is considered aprerequisite for renal medullary carcinoma. Current knowledge illustrates that SMARCB1 loss is encountered in three major tumor categories in the kidney: (1)histologically defined neoplasms that are primarily driven by de novo SMARCB1 loss (renal medullary carcinoma and malignant rhabdoid tumor); (2)SMRACB1-deficient renal cell carcinoma (RCC) with variable non-specific histology ranging from collecting duct-like, papillary high-grade (papillary type2), or medullary-like (lacking sickle cell trait), to fully undifferentiated; and (3)biphasic (dedifferentiated) RCC showing a variable SMARCB1-deficient undifferentiated component. The latter variant most frequently originates from pre-existing clear cell RCC but may rarely superimpose on papillary or chromophobe RCC. This review summarizes the major defining features of the emerging SMARCB1-deficient renal neoplasms. All SMARCB1-deficient carcinomas have apoor prognosis in common. Therefore, exact diagnosis of these tumors is aprerequisite for studies investigating new therapies.