Background: Cancers of Unknown Primary (CUPs) are undifferentiated neoplasms for which standardized diagnostic work-up fails to identify the primary tumor responsible for metastatic seeding. They can be categorized into favorable and unfavorable subsets. Unfavorable subsets include poorly differentiated neuroendocrine carcinomas and poorly differentiated peritoneal serous carcinomas. Favorable subsets include metastatic squamous cell carcinoma (SCC) and adenocarcinoma confined to isolated nodes or a single metastatic site. SCC originating in the retroperitoneal cavity is exceedingly rare. Some of the cases were reported as SCC of unknown primary. Little is known about its pathogenesis and clinical features; therefore, the optimal treatment is unclear. Here, we report a case diagnosed as SCC caused by human papillomavirus (HPV) infection and possibly arising in the retroperitoneal cavity. Next-generation sequencing (NGS) determined the treatment in this rare case.

Case presentation: A 61-year-old female presented to our clinic with incidental right retroperitoneal paraaortic lymphadenopathy found on a CT scan following hospitalization for urosepsis. She underwent a biopsy at the hospital, which revealed a SCC associated with HPV. SCC was positive for HPV, a known risk factor for gynecological and head and neck cancers. Extensive ENT workup with pan endoscopy and full gynecologic workup was done, followed by colonoscopy, GI endoscopy, and mammography. No primary source was detected. NGS was performed, and it revealed ER and PIK3CA mutations, which are primarily positive in primary breast cancer. It was also positive for PD-L1 mutation, commonly found in many solid tumors. The patient was started on a 12-week chemotherapy with Paclitaxel and Carboplatin. Post-chemotherapy PET scan showed a decrease in size and intensity of lymph nodes with no hypermetabolic activity, suggestive of radiological remission. Based on the sequencing results, the patient was started on Anastrozole as she was ER-positive. Serial CT scan surveillance showed lymph nodes decreasing in size, signifying the patient was still in remission.

Discussion: The management of CUPs is highly challenging. However, with the advent of genomic sequencing, we could identify targetable mutations. In our case, three targetable mutations were detected: ER, PIK3CA, and PDL-1. These mutations give us specific targets against which very effective therapeutic options are available, highlighting the importance of genomics for the future treatment of CUP. NGS helps personalize cancer care and tailor the management of these poorly understood diseases. Further research and case studies are needed to understand better the etiology, optimal treatment strategies, and prognostic factors of this uncommon condition.