Dear Editor,

Renal cell carcinoma with fibromyomatous stroma (RCC-FMS) is a morphological terminology in an attempt to describe a number of renal neoplasms exhibiting a distinctive biphasic architecture, comprising clear cells arranged in branching tubules and papillary structures within a stroma of smooth muscle-like spindle cells that often express desmin (1-3). Several renal neoplasms including clear cell renal cell carcinoma (CCRCC), clear cell (tubulo) papillary renal cell tumor (CCPRCT), transcription factor binding to IGHM enhancer 3 (TFE3)/transcription factor EB (TFEB) altered RCC, elongin C (ELOC) mutated RCC, tuberous sclerosis complex (TSC)/mechanistic target of rapamycin (mTOR) pathway mutated RCC (either sporadic or TSC-related), and renal hemangioblastoma (1-3). These entities may be subject to significant diagnostic challenge and are critical to accurately diagnose due to the fact that a) neoplasms in the category of RCC-FMS have different expected clinical outcomes, for instance CCPRCT is considered benign, whereas CCRCC is malignant (1-3), b) RCC-FMS related to TSC/mTOR pathway mutations may be associated with germline mutations, i.e. with TSC (1, 2, 4), and c) neoplasms in this category have positive expression of carbonic anhydrase 9 (CA9), a key immunohistochemical (IHC) assay for CCRCC, frequently requiring additional IHC, cytogenetics and molecular work-up (1-4).

Cytogenetics and molecular assays in the diagnosis of renal neoplasms are often inaccessible for surgical pathologists (1). A tiered diagnostic approach (Figure 1) is recommended, beginning with morphological features as well as CA9 and keratin 7 (KRT7) staining. A CA9-positive (box-like) and KRT7-negative immunophenotype supports a diagnosis of CCRCC (Figure 2 a-d). If both CA9 and KRT7 are negative, TFE3/TFEB altered RCC should be considered in the differential diagnosis.

Co-expression of CA9/KRT7 necessitates further evaluation with an extended panel. A second-tier IHC panel—comprising GATA binding protein 3 (GATA3), glycoprotein non-metastatic melanoma protein B (GPNMB), cluster of differentiation 10 (CD10), and alpha-methylacyl-CoA racemase (AMACR)—can offer valuable diagnostic resolution (1, 4, 5). GPNMB—a transmembrane glycoprotein associated with melanocytic and histiocytic differentiation—has emerged as a marker for TSC/mTOR pathway–altered renal neoplasms (4). Isolated GATA3 positivity, in the absence of CD10, AMACR, and GPNMB expression, strongly favors a diagnosis of CCPRCT (Figure 2 e-h). In contrast, diffuse GPNMB expression, with or without weak GATA3 staining and variable CD10 or AMACR expression, supports a diagnosis within the spectrum of TSC/mTOR pathway-related renal neoplasms, including TSC/mTOR-related RCC and renal hemangioblastoma (4). A profile demonstrating GPNMB and inhibin co-positivity alongside absent GATA3 is suggestive of renal hemangioblastoma, while CD10 positivity in the absence of both GATA3 and GPNMB raises suspicion for ELOC-mutated RCC (1, 4). Our understanding in RCC-FMS continues to evolve and requires stepwise algorithmic approach with emerging immunophenotypic markers, along with more utilized and conventional markers, such as GPNMB and GATA3.