[Clinicopathological features of TSC/mTOR mutation-associated renal cell carcinoma with leiomyomatous stroma: report of nine cases].

Objective: To study the clinicopathological features, immunophenotype, diagnosis, and prognosis of TSC/mTOR mutation-associated renal cell carcinoma with leiomyomatous stroma (M/TSC-RCC-LMS). Methods: Nine cases of molecularly confirmed M/TSC-RCC-LMS were collected at the Affiliated Hospital of Qingdao University (7 cases) and No. 971 Hospital of the People's Liberation Army, Qingdao, China (2 cases) between December 2011 and August 2024. Histological evaluation, immunohistochemical staining, and molecular analysis were performed, along with literature review. Results: Among the 9 patients, 1 was male and 8 were female, with their ages 48(35,55) years. Eight cases were detected during routine physical examinations, while 1 case presented with painless gross hematuria. All 9 cases were located within the renal parenchyma, presenting nodular masses with tumor diameters 2.0(1.4,2/7) cm. The lesions were well-circumscribed. The tumors were solid, grayish-white, grayish-yellow or grayish-red in color, and soft in consistency, while one case showed cystic-solid characteristics. All 9 cases exhibited thick fibromuscular pseudocapsules. In 8 cases, smooth muscle components within the capsule were observed extending into the tumor, dividing the neoplastic tissue into nodular and clustered patterns. The tumor cells were primarily arranged in tortuous, elongated branching tubular structures, with focal areas showing small amounts of delicate papillary structures containing fibrovascular cores. They also had abundant cytoplasm that was pale-staining or mildly eosinophilic, occasionally clear. The nuclei were round or irregular in shape, with some showing conspicuous nucleoli. All the 9 cases showed patchy to diffusely strong expression of CK7 (70%-100%). Carbonic anhydrase Ⅸ (CAⅨ, 6/9) and CD10 (membranous positivity, 8/9) demonstrated variable extent and intensity of expression. Glycoprotein nonmetastatic melanoma protein B (GPNMB) showed diffusely moderate to strong positivity in 7 of the 9 cases. The 9 cases were all negative for α-methylacyl-CoA racemase (AMACR), TFE3, TFEB, TCEB1, HMB45, and Melan A, with Ki-67 proliferative index ranging from 1% to 10%. Whole exome sequencing revealed mTOR gene mutations in 5 cases, concurrent TSC2 and mTOR mutations in 1 case, a TSC2 mutation in 1 case, and germline TSC1 mutations in 2 cases. Follow-up of the cases ranged from 6 to 159 months. All patients were alive at the end of the follow-up, with no recurrence or metastasis. Conclusions: M/TSC-RCC-LMS exhibits unique morphological and immunophenotypic characteristics. The tumor cells exhibit abundant pale or mildly eosinophilic cytoplasm, forming elongated, tortuous branching tubules accompanied by stromal smooth muscle components. These are typically morphological features of this renal cell carcinoma subtype. The contribute to the diagnosis and differential diagnosis of the tumor diffusely strong positivity of CK7 and the positivity of GPNMB. This type of renal cell carcinoma often demonstrates indolent biological behaviors with favorable prognosis and is expected to be newly classified as an independent subtype of renal cell carcinoma.