FLCN-mutated eosinophilic renal tumors: clinicopathologic and molecular analysis of five cases highlighting...

Eosinophilic/oncocytic renal cell neoplasms represent a diagnostically challenging group of tumors with overlapping morphologic and immunophenotypic features. Recent advances in molecular genetics have expanded the spectrum of FLCN-mutated renal tumors, including both Birt-Hogg-Dubé (BHD) syndrome-associated and sporadic cases. This study aimed to characterize the clinicopathologic and molecular features of five FLCN-mutated eosinophilic renal tumors, emphasizing their diagnostic pitfalls and heterogeneity. The cohort included three male and two female patients (median age: 61 years) with solitary renal masses (median size: 3 cm), all incidentally detected and managed surgically (partial/radical nephrectomy). All patients lacked clinical stigmata of BHD syndrome (cutaneous fibrofolliculomas, pulmonary cysts) or relevant family history. Histologically, tumors exhibited diverse patterns (solid-nested, tubuloacinar, trabecular) with uniform eosinophilic cytoplasm, low-grade nuclei, hemorrhagic and edematous stroma, and prominent branching dilated vasculature, along with distinctive features such as intraluminal foamy histiocytes, psammomatous calcification, and thyroid follicle-like secretions (all classified as non-conventional FLCN-mutated tumors). None of the cases showed renal oncocytosis in the surrounding renal parenchyma. Immunohistochemically, all cases showed diffuse GPNMB expression, while TFE3 was weakly expressed in one case. Molecular profiling identified pathogenic/likely pathogenic FLCN mutations (truncating mutations in four cases, missense variant in one) without concurrent alterations in TSC1/2, MTOR, FH, SDHx, or MiT family genes. Over a median follow-up of 38 months, no recurrence or metastasis occurred, suggesting an indolent behavior. These findings highlight the morphologic mimicry of FLCN-mutated tumors with a spectrum of renal neoplasms characterized by low-grade eosinophilic features, particularly TSC/MTOR-altered or MiT family renal neoplasms, underscoring the necessity of integrated immunohistochemical (GPNMB) and molecular testing for accurate diagnosis. Despite their heterogeneity, FLCN-mutated tumors typically follow a benign clinical course, though rare aggressive variants warrant vigilance.