TFEB Rearranged Renal Cell Carcinoma: Pathological and Molecular Characterization of 10 Cases, with Novel Clinical Implications: A Single Center 10-Year Experience

To report our experience with the cases of TFEB rearranged RCC, with particular attention to the clinicopathological, immunohistochemical and molecular features of these tumors and to their predictive markers of response to therapy. We have retrieved the archives of 9749 renal cell carcinomas in the Institute of Urology, Peking University and found 96 rearranged RCCs between 2013 and 2022. Among these renal tumors, ten cases meet the morphologic, immunohistochemical and FISH characterization for TFEB rearranged RCC. The 10 patients' mean and median age is 34.9 and 34 years, respectively (range 23-55 years old), and the male to female ratio is 1:1.5. Macroscopically, these tumors generally have a round shape and clear boundary. They present with variegated, grayish yellow and grayish brown cut surface. The average maximum diameter of the tumor is 8.5 cm and the median 7.7 (ranged from 3.4 to 16) cm. Microscopically, the tumor is surrounded by a thick local discontinuous pseudocapsule. All tumors exhibit two types of cells: voluminous, clear and eosinophilic cytoplasm cells arranged in solid sheet, tubular growth pattern with local cystic changes, and papillary, pseudopapillary and compact nested structures are also seen in a few cases. Non-neoplastic renal tubules are entrapped in the tumor. A biphasic "rosette-like" pattern, psammomatous calcifications, cytoplasmic vacuolization, multinucleated giant cells and rhabdomyoid phenotype can be observed in some tumors. A few tumors may be accompanied by significant pigmentation or hemorrhage and necrosis. The nucleoli are equivalent to the WHO/ISUP grades 2-4. All tumors are moderately to strongly positive for Melan-A, TFEB, Vimentin and SDHB, and negative for CK7, CAIX, CD117, EMA, SMA, Desmin and Actin. CK20 and CK8/18 are weakly positive. In addition, AE1/AE3, P504s, HMB45 and CD10 are weakly moderately positive. TFE3 is moderately expressed in half of the cases. PAX8 can be negative, weakly positive or moderately-strongly positive. The therapy predictive marker for PD-L1 (SP263) is moderately to strongly positive membranous staining in all cases. All ten tumors demonstrate a medium frequency of split TFEB fluorescent signals ranging from 30 to 50% (mean 38%). In two tumors, the coincidence of the TFEB gene copy number gains are observed (3-5 fluorescent signals per neoplastic nuclei). Follow-up is available for all patients, ranging from 4 to 108 months (mean 44.8 and median 43.4 months). All patients are al