Metachronous Mediastinal Cancers of Unknown Primary: A Case of Sequential Squamous Cell Carcinoma and Adenocarcinoma in Thoracic Lymph Nodes

Cancer of unknown primary (CUP) rarely originates in the mediastinum and is even less common as a second malignancy following a prior CUP resection. A 61-year-old man with no prior malignancy was diagnosed with an anterior mediastinal tumor, resected and identified as metastatic squamous cell carcinoma of unknown primary originating in a lymph node. Eighteen months later, during pneumonia treatment, a computed tomography (CT) scan revealed enlarged lower paratracheal lymph nodes. Initial biopsy showed no malignancy, and the lymph nodes remained stable for 20 months. Over the next year, these nodes progressively enlarged, extending to the subcarinal and left hilar lymph nodes. A transbronchial biopsy confirmed the subcarinal lesion as a poorly differentiated adenocarcinoma, distinct from the initial cancer. A comprehensive systemic workup failed to identify a primary site, leading to a second CUP diagnosis. Due to chronic respiratory failure from underlying lung disease, the patient was ineligible for cancer treatment. One year after the second CUP diagnosis, a CT scan detected a mass in the right lower lobe, which grew over the following year, as confirmed by a follow-up CT scan, suggesting a hidden lung cancer that emerged later. The patient passed away 75 months after the first cancer surgery and 24 months after the second CUP diagnosis, two weeks after the final scan, without an autopsy. This case highlights the rare occurrence of sequential, histologically distinct CUPs - likely represents the first reported instance - and the diagnostic challenges in identifying primary cancer sites, compounded by the patient's comorbidities precluding treatment.