Pilomatrix-like high-grade carcinoma involving the urinary bladder: identification of APC mutation and potential for TROP-2 targeted therapy

This case report describes a 60-year-old female patient who presented with gross hematuria and a deeply invasive bladder mass. The carcinoma was characterized by basaloid nests, geographic necrosis, and shadow cells. The tumor cells were diffusely positive for CDX2 and beta-catenin (nuclear and cytoplasmic staining), focally positive for CK7, CK20, and CD56, and negative for GATA-3, synaptophysin, mammaglobin, TTF-1, and NUT. The overall morphological features and immunohistochemical findings were most consistent with pilomatrix-like high-grade carcinoma (PiMLC). Evaluation of the gynecological tract at the time of cystectomy, including accompanying hysterectomy and bilateral salpingo-oophorectomy specimen, did not reveal any carcinoma within these organs. Genomic profiling of the tumor revealed loss-of-function mutations in APC , ASXL1 , RB1 , and TP53. Although CTNNB1 was not altered, the APC mutation suggests deregulation of the Wnt signaling pathway through a process distinct from most pilomatrix-like high-grade carcinomas of the gynecological tract. Over the course of her therapy at an outside institution, the patient progressed to widely disseminated metastatic disease, including to the lungs and brain, that was unresponsive to multiple rounds of chemotherapy and immunotherapy. RNA profiling of her tumor revealed expression of TROP-2, confirmed by immunohistochemistry, and therapy with an antibody drug conjugate targeting TROP-2 resulted in a significant reduction in tumor burden. This case describes PiMLC involving the urinary bladder and highlights both an alternative activation of the Wnt signaling pathway in this tumor type, as well as a potential new treatment avenue for this frequently therapeutically unresponsive cancer type.