Renal medullary carcinoma (RMC) is an exceptionally rare and highly aggressive malignant renal tumor, exhibiting an almost absolute association with sickle cell disease or sickle cell trait. The presence of a hemoglobinopathy is now considered a fundamental diagnostic criterion [1], [2]. This tumor predominantly affects young individuals, with an average age of around 20 years and a slight male predominance [2], [3]. Its most diagnostically significant feature is the inactivation of the SMARCB1 (INI1) tumor suppressor gene, leading to loss of INI1 protein expression on immunohistochemistry (IHC) [4]. However, a distinct category of cases has been reported in the literature-those exhibiting morphological and phenotypic characteristics identical to RMC but lacking any evidence of hemoglobinopathy. According to the 2016 WHO classification of tumors of the urinary system and male genital organs, high-grade renal cell carcinomas demonstrating histomorphology, immunophenotype, or molecular features identical to medullary carcinoma, but without evidence of sickle cell trait or disease, were recommended to be diagnosed as “unclassified renal cell carcinoma with medullary phenotype” (RCCU-MP) [5]. In the 2022 WHO classification, this tumor is categorized as a subtype of renal medullary carcinoma and has been renamed “SMARCB1/INI1-deficient medullary-like renal cell carcinoma” [2].

The SMARCB1/INI1 protein is a core component of the chromatin remodeling complex. Its loss leads to widespread dysregulation of gene expression. This molecular defect translates into highly characteristic pathological morphology under the microscope: tumor cells often appear undifferentiated, rhabdoid, or basaloid, infiltrating within a loose, myxoid stroma accompanied by a prominent inflammatory reaction. The core pathogenesis of SMARCB1/INI1-deficient RMC involves biallelic inactivation of the SMARCB1 gene, resulting in loss of protein function. The protein encoded by this gene is a core subunit of the BAF chromatin remodeling complex; its loss causes widespread epigenetic dysregulation, leading to aberrant activation of oncogenes and silencing of tumor suppressor genes, thereby driving tumorigenesis [4]. For classical RMC, the unique aspect is the interaction between SMARCB1 deficiency and the renal medullary microenvironment in the context of sickle cell disease. The inherent hyperosmolar, hypoxic, and low-pH environment of the medulla predisposes to microvascular occlusion by sickled red blood cells, causing chronic hypoxia, repeated tissue injury, and regeneration [6]. This persistent proliferative stress significantly increases the risk of a second-hit mutation in SMARCB1 in renal tubular epithelial cells and provides a selective growth advantage for cells with SMARCB1 loss [7].

In the World Health Organization (WHO) 2022 edition, SMARCB1-deficient renal medullary carcinoma includes four types: Medullary carcinoma, NOS; SMARCB1-deficient medullary-like renal cell carcinoma; SMARCB1-deficient undifferentiated renal cell carcinoma, NOS; and SMARCB1-deficient dedifferentiated renal cell carcinomas of other specific subtypes. The most significant distinction between SMARCB1-deficient medullary-like renal cell carcinoma (MLRCC) and the other three types of renal medullary carcinoma is that MLRCC patients do not exhibit sickle cell trait, sickle cell disease, or related hemoglobinopathies. Before the introduction of this concept, such tumors might have been simply diagnosed as “poorly differentiated carcinoma” or “unclassified renal cell carcinoma,” failing to reflect their unique morphology and underlying clinical behavior. The pathogenesis of MLRCC remains incompletely understood. To date, our systematic literature review has identified only 15 reported cases of MLRCC globally [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. This study reports three additional cases of MLRCC and provides an in-depth analysis of their clinical features, pathological morphology, and immunohistochemical findings.