Extragonadal Urinary Tract Neoplasms With Yolk Sac Differentiation: Clinical, Histologic, and Molecular Evidence of Derivation From Underlying Urothelial Carcinoma

Extragonadal yolk sac tumors are rare and can be difficult to distinguish from somatically derived, non-germ cell tumors such as carcinomas with yolk sac differentiation, and there are very limited data available on this phenomenon in the urinary tract. A cohort of 10 tumors primary to the urinary tract with pure or extensive yolk sac differentiation was assembled to clarify their relationship to germ cell tumors, and herein, we describe the clinical, histologic, and molecular features of these lesions. The predilection for older males (8:2 male:female ratio, mean age = 78 years), the epicenter of disease along the urinary tract mucosa, association with prior pelvic radiation (40%), and frequent previous or subsequent diagnosis of conventional urothelial carcinoma (40%) mirrored the typical clinical and demographic features of urothelial carcinoma. Pathologically, all tumors demonstrated typical morphologic and immunohistochemical features of glandular yolk sac tumors and were not associated with other germ cell tumor subtypes. A subset of cases harbored additional histologic elements including sarcomatoid or squamous features (20%) or conventional urothelial carcinoma (10%). Most tumors showed aggressive clinical behavior with 7/8 cases with available follow-up demonstrating recurrence, metastasis, or death from disease. Molecular analysis, including panel-based DNA sequencing (n = 8) and fluorescence in situ hybridization (n = 2) on a subset of cases, showed no evidence of isochromosome 12p but did reveal recurrent mutations in TP53 (8/8, 100%), the TERT promoter (3/8, 38%), and one of several genes involved in chromatin remodeling including KDM6A, CREBBP, and KMT2D (5/8, 63%), and recurrent deletions involving chromosome 9p, including homozygous deletion encompassing the CDKN2A/MTAP locus (3/8, 38%)—a constellation of findings strikingly similar to the established molecular landscape of urothelial carcinoma. These findings indicate that primary extragonadal tumors with yolk sac differentiation involving the urinary tract frequently represent a rare, diagnostically deceptive, and clinically aggressive form of urothelial carcinoma.