A mouse model of HPV-associated cervicovaginal carcinosarcoma with comparative analysis to human clinical cases

BACKGROUND: Carcinosarcomas of the gynecologic tract, previously referred to as malignant mixed müllerian/mesodermal tumor, are devastating malignancies that remain poorly studied due to their rarity and the lack of relevant model systems. Human papillomavirus (HPV)-associated carcinosarcomas are thought to arise from conventional HPV-driven squamous cell carcinomas or adenocarcinomas of the lower gynecologic tract, providing evidence to support the epithelial-to-mesenchymal transition (EMT) theory of carcinosarcoma tumorigenesis. Mouse models using HPV and oncogene plasmid cocktails to induce spontaneous squamous carcinomas have proven useful; however, they have not yet been applied to the study of carcinosarcomas or EMT. RESULTS: Here, we describe a new series of eight human clinical cases of HPV-associated carcinosarcoma of the uterine cervix and vagina. To study this rare and aggressive disease, we applied an established HPV-driven mouse model under extended observation conditions, which resulted in the development of tumors with features of carcinosarcoma. We then characterized the resulting tumors with respect to histologic morphology, immunohistochemical profiles, and HPV expression patterns, demonstrating that the mouse tumors recapitulate key architectural patterns and diverse histomorphology of both the carcinomatous and sarcomatous components observed in human tumors. In addition, the mouse tumors exhibit immunohistochemical and HPV expression profiles similar to those seen in the clinical cases. In particular, detection of oncogenic high-risk HPV in both the carcinomatous and sarcomatous components of the human and mouse tumors provides evidence supporting an EMT-driven process with a shared etiology, although definitive mechanistic conclusions warrant further investigation. CONCLUSIONS: We present an extended characterization of an established HPV-driven in vivo model that, under prolonged observation, gives rise to carcinosarcoma-like tumors, a previously unrecognized phenomenon. Through comparative analysis with a newly described cohort of human clinical cases, we show that this mouse model system reproduces key histologic, immunohistochemical and molecular features of HPV-associated carcinosarcoma. While further studies are required to define the precise mechanisms underlying tumor development, this model provides a useful experimental platform for studying the pathogenesis and therapeutic vulnerabilities of HPV-associated carcinosarcoma.