Pathological complete response following neoadjuvant chemoimmunotherapy in cancer of unknown primary: a case report

Background: Cancers of unknown primary (CUP) are a heterogeneous group of metastatic malignancies in which a primary tumor cannot be identified despite comprehensive diagnostic evaluation. Most CUP patients have a poor prognosis, and only 15–20% can be classified into favorable subgroups. Although molecularly guided therapy (MGT) has shown survival benefits in global phase II studies, the overall outcomes remain unsatisfactory. In particular, intrathoracic lymph node metastasis of unknown origin represents a clinical dilemma, with limited evidence guiding treatment decisions. Case Description: We describe a 61-year-old male with a history of smoking and alcohol consumption who presented with elevated carcinoembryonic antigen (CEA) and mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) revealed multiple hypermetabolic mediastinal and right hilar lymph nodes without a detectable primary tumor. Bronchoscopic biopsy confirmed malignancy, but immunohistochemistry was inconclusive. Next-generation sequencing identified Tumor Protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) mutations, suggesting an epithelial origin, most likely lung. Based on multidisciplinary team (MDT) consensus, the patient underwent three cycles of neoadjuvant nivolumab plus albumin-bound paclitaxel and carboplatin. Tumor markers normalized and metabolic activity of involved lymph nodes decreased. Despite new transient lymphadenopathy at the hepatic hilum and retroperitoneum, interpreted as immune-related changes, the disease was assessed as stable under Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection were subsequently performed. Postoperative pathology revealed a pathological complete response (pCR) without viable tumor. Serial circulating tumor DNA (ctDNA) minimal residual disease (MRD) monitoring remained negative before and after surgery. At 25.1 months of follow-up, the patient exhibited no disease recurrence and maintained a good quality of life. Conclusions: Neoadjuvant chemoimmunotherapy may provide clinical benefit in CUP with intrathoracic nodal metastasis, even without a confirmed primary tumor. Integration of MDT decision-making and MRD monitoring may provide valuable information to inform perioperative strategies and optimize patient prognosis.