Neuroendocrine carcinoma of unknown primary site

Neuroendocrine carcinomas of unknown primary site are uncommon, diverse tumors with variable clinical behavior, predicted by tumor grade or differentiation. Most of these carcinomas probably arise from an occult/clinically undetectable primary site in one of several locations (bronchus, pancreas, stomach, colon, rectum and several other sites). Patients with these tumors are a subset of unknown primary carcinoma with relatively favorable prognoses. Low-grade or well-differentiated tumors are frequently indolent and cases should be managed similar to advanced carcinoid tumors. Targeted therapies may have a role in the treatment of low-grade tumors. The high-grade or poorly differentiated carcinomas, including small cell and large cell neuroendocrine tumors, are rapidly growing and aggressive but responsive to platinum-based combination chemotherapy. Poorly differentiated large cell neuroendocrine tumors, first reported in 1988, are usually not recognized by routine hematoxylin and eosin light microscopy but require immunohistochemical stains or electron microscopy for their diagnosis. A review of cytotoxic chemotherapy for patients with high-grade neuroendocrine carcinomas, including a series of 99 patients, revealed an overall response rate of 70%, with a 20% complete response rate. The median survival was 15 months, and a minority of patients (13%) had long-term survival. Tumor grade/differentiation currently is an important determinant of the management of these patients, and therapy in the future will be based on a more precise knowledge of the unique biology of these tumors.