Morphology spectrum and molecular landscape in eosinophilic solid and cystic renal cell carcinoma

Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a novel renal tumor entity incorporated in the 2022 WHO classification with a female predilection. To further investigate its morphological and molecular features, we analyzed 17 ESC RCC cases with comprehensive morphological, clinicopathological and next-generation sequencing data, and reviewed 63 previously reported cases with confirmed TSC gene mutations. Clinically, our cohort had a male-to-female ratio of 1.4:1. Fifteen patients with a median follow-up of 55 months (range, 5-144 months) remained disease-free. Morphologically, 10/17 tumors showed classic solid-cystic growth and 7/17 showed predominant solid growth. Two distinctive morphological features were identified: a novel phenotype of condensed eosinophilic cytoplasm forming inclusion-like appearance (5 cases) and the recently described xanthomatous giant cell feature (4 cases). Immunohistochemically, CK20 was positive in 15/17 cases, and all cases showed strong positivity for mTOR downstream markers (GPNMB, p-S6, p-4EBP1). Molecularly, TSC1 mutations were detected in 8/17 cases, and TSC2 mutations in 9/17. All 5 cases with condensed eosinophilic cytoplasm uniformly harbored TSC1 mutations. Analysis of our 17 cases and 63 reported cases showed TSC2 mutations in 50/80 (62.5%), TSC1 mutations in 31/80 (38.8%), and concurrent TSC1/2 mutations in 1/80 (1.3%). Totally 110 distinct mutation sites were found with only 7.3% being repeatedly reported in no more than 3 patients. Truncating variants (frameshift, nonsense, splice site) were the predominant type (90.9%), while missense mutations only account for 9.1%. Collectively, our research expanded the morphological spectrum of ESC RCC, depicted a wide molecular mutation landscape and confirmed its indolent behavior without gender predilection in Chinese patients.