Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup

SIMPLE SUMMARY: While most neuroendocrine neoplasms are indolent and slow-growing tumors, subsets of cases will spread beyond the tissue of origin. Given the rather slow progress, some lesions are incidentally discovered as metastatic deposits rather than primary masses. In these cases, a biopsy is often taken to allow the pathologist to identify the tumor type and possibly the primary tumor site via microscopic examination. In this review, the authors present a simplified guide on how to approach metastatic neuroendocrine tumors from a pathologist’s perspective. ABSTRACT: Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor is not easily identified using conventional imaging techniques because of small primary tumor sizes. In this setting (which is referred to as a “NEN of unknown primary”; NEN-UP), a tissue biopsy is often procured to allow the surgical pathologist to diagnose the metastatic lesion. If indeed a metastatic NEN-UP is found, several clues can be obtained from morphological assessment and immunohistochemical staining patterns that individually or in concert may help identify the primary tumor site. Herein, histological and auxiliary analyses of value in this context are discussed in order to aid the pathologist when encountering these lesions in clinical practice.