Large-cell neuroendocrine carcinomas (LCNECs) are relatively rare and aggressive neoplasms of the lung with very poor prognosis. Even though they are included in the classification of nonsmall cell carcinomas, they have a biological behaviour and physiological response to treatment more like small cell carcinomas of lung. We report an atypical case presentation of LCNEC in a 51-year-old gentleman who presented with diffuse metastases to the thoracic and lumbar spine, brain, and liver, posing a diagnostic challenge. The primary small central lung tumor was in close proximity to major vessels, rendering a biopsy of the primary cancer challenging and nearly impossible. The final diagnosis was established through immunohistochemistry staining and examination of liver biopsy from a metastatic lesion. We also included a review of the current literature pertinent to LCNEC, as well as the important role of tumor markers plus immunohistochemistry profiles in determining the origin of unknown primary tumors in such difficult patient presentations.