Metastatic neuroendocrine neoplasms of unknown primary site

Abstract

Virtually all neuroendocrine neoplasms (NENs) have metastatic potential, and up to 20% of cases present as metastasis from an occult primary. The identification of the primary site is an important step toward the correct management of the patient, particularly when dealing with a well-differentiated neuroendocrine tumor (NET), as therapeutic approach may vary depending on the site and cell type. Thorough morphological and immunohistochemical analyses can provide important clues to the recognition of the site of origin of a metastatic NET. The liver represents the most frequent location of metastatic NENs; lymph nodes, peritoneum, bone, and lung represent other common secondary sites. However, virtually any body organ including those that can give rise to primary NENs may host metastatic NENs, including breast, ovary, thyroid, pancreas, and pituitary. Thus, it becomes evident that the diagnosis of a metastatic NEN gives rise to two orders of problems: (i) the identification of the occult primary site and (ii) the distinction from a putative primary NEN of the organ in which the lesion is present. Both challenges are of crucial importance in the management of the patients, and the pathologist should be aware of the diagnostic tools to approach them and of the entities which enter in the differential diagnosis. Careful interpretation of clinical, morphologic, and immunohistochemical findings using a panel approach combining cytokeratins along with anatomic site-related transcription factors, hormones, and other biomarkers can assist identifying the origin of a metastatic NEN and distinguishing metastatic from primary and multifocal tumors. The power of this approach is limited in the setting of poorly differentiated NECs.