ELOC-mutated Renal Cell Carcinoma: Clinicopathologic, Immunohistochemical, and Molecular Genetic Analysis of 35 Cases.

Abstract

ELOC-mutated renal cell carcinoma (RCC) is a recently recognized, molecularly defined entity incorporated into the 2022 World Health Organization classification of genitourinary tumors. Approximately 50 cases of ELOC-mutated RCC have been reported, and the clinicopathologic and molecular features of this rare tumor require further clarification. Herein, we reported the pathologic and molecular characteristics of 35 cases of ELOC-mutated RCC, representing the largest series from a single medical center to date. This cohort demonstrated an overwhelming male predominance (34/35), with a median age of 48.8 years, and low stage (predominantly T1aN0M0). Macroscopically, the tumors were well-circumscribed, measuring 1.0 to 5.0 cm in diameter (median, 2.5 cm), and were either solid (20/35, 57.1%) or mixed solid and cystic (15/35, 42.9%). Microscopically, the tumors showed acinar, branching tubular, papillary, or solid growth patterns and were composed of tumor cells with voluminous, clear cytoplasm and variable fibromuscular stroma. Uncommon patterns included markedly dilated cysts with small papillary tufts, myxoid areas, lymphocyte-rich stroma, and a thyroid follicle-like architecture. The nuclear grade was low. A minority of cases (5/35, 14.3%) exhibited focal areas with nuclei arranged linearly away from the basal aspect. Immunohistochemically, all tumors showed diffuse strong carbonic anhydrase IX positivity and moderate or weak cytokeratin 7 positivity. Variable CD10 expression (32/34, 94.1%), weak reactivity for alpha-methylacyl-CoA racemase (18/24, 63.2%), and negativity for glycoprotein nonmetastatic melanoma protein B (28/28, 100%) were also observed. ELOC mutations were identified in all 35 patients by Sanger sequencing and/or next-generation sequencing. The mutated amino acid sites included Y79C (30/35, 85.7%), Y79S (2/35, 5.7%), I95N (1/35, 2.8%), E92K (1/35, 2.8%), and C112fs (1/35, 2.8%). All next-generation sequencing-analyzed cases harbored ELOC mutations (28/28). Other recurrent mutations included CDH23 (6/28), ELP1 (4/28), POLE (4/28), and KMT2C (4/28). Among the 26 specimens evaluated for copy number analysis, all showed deletion of chromosome 8q, and 12/26 (46.2%) exhibited loss of 8p, consistent with biallelic ELOC inactivation. None showed 3p loss using fluorescence in situ hybridization. All patients with follow-up data were alive without evidence of disease progression. Our findings expanded the clinical, histologic, immunohistochemical, and molecular spectrum of ELOC-mutated RCC and further support its classification as a distinct renal neoplasm.