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Neuroendocrine neoplasms of unknown primary site

John D Hainsworth, MD
F Anthony Greco, MD
Jonathan R Strosberg, MD
Section Editors
James R Jett, MD
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD


Cancer of unknown primary site (CUP) is a relatively common clinical entity, accounting for 4 to 5 percent of all invasive cancers [1]. Within this category, tumors from many primary sites with varying biology are represented. Neuroendocrine neoplasms constitute less than 5 percent of all CUPs [2]. (See "Overview of the classification and management of cancers of unknown primary site".)

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that differ in biologic behavior, histologic appearance, and response to treatment (table 1). Several types of these neoplasms (eg, well-differentiated NET of the tubular gastrointestinal tract [carcinoid tumors] and pancreas [pancreatic NETs or PNET], medullary thyroid cancers, pheochromocytomas) are characterized by slow growth and frequent secretion of hormones or vasoactive substances [3-5]. In most cases, these tumors also have typical histologic appearance and are accurately diagnosed with standard pathologic methods (light microscopy and immunohistochemical staining). Others, as typified by small cell carcinoma of the lung, are highly aggressive neoplasms, classified as neuroendocrine carcinomas, and are usually advanced when diagnosed. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system".)

This review will cover the evaluation and treatment of patients with biopsy-proven metastatic NETs of unknown primary. The diagnostic workup of rare patients who present with symptoms suggestive of an underlying neuroendocrine hormonal syndrome (eg flushing, diarrhea, hypoglycemia, hyperglycemia) is discussed elsewhere. (See "Diagnosis of the carcinoid syndrome and tumor localization" and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors)", section on 'Functionality and nomenclature'.)


Neuroendocrine tumors (NETs) of unknown primary site are relatively uncommon, accounting for 10 to 14 percent of all NETs:

In a review of over 35,000 patients diagnosed with NETs over a 31-year period (most had well-differentiated tumors arising from the gastrointestinal tract), a primary site could not be found or classified in only 13 percent [6].

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Literature review current through: Nov 2017. | This topic last updated: Dec 22, 2016.
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