Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup

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.

Neuroendocrine tumour of the lesser omentum

“…However, in differentiated tumours, systemic therapy varies according to the primary location. Hence, it is vital to find the primary location of these metastatictumours 9…”

“…The basic morphology of cells and the patterns will aid in identifying the location of the primary. For example, stromal ossification may suggest a lung primary 9. Immunohistochemical staining can be informative but is not typically definitive in terms of the primary site 2.…”

Diagnostic Approaches for Neuroendocrine Neoplasms of Unknown Primary (NEN-UPs) and Their Prognostic Relevance—A Retrospective, Long-Term Single-Center Experience

“…In patients who did not receive a dedicated IHC analysis to further identify the primary organ, three possible reasons were identified: (I) not enough tumor material; (II) lack of clinical evidence for a NEN-UP; (III) conservation of the material for molecular pathology. Nonetheless, these markers show limited sensitivity and specificity in general, and in particular, in poorly differentiated NEC, they can be expressed divergently, which has to be considered in clinical decision-making [28,42,43]. Based on this and the fact that 43 out of 113 patients are diagnosed with NEC in our cohort, it is possible that individual markers are not sufficient for the identification of a primary tumor site here and performance rates of the respective markers have to be considered in the context of the histological subtypes.…”

Top 10 Histological Mimics of Neuroendocrine Carcinoma You Should Not Miss in the Head and Neck

“…NENs of unknown primary (NEN-UPs) are metastatic lesions without a known primary tumor location, a finding reported in 12-22% of NEN patients [34]. The importance of identifying the primary site cannot be underestimated given that the various clinical and prognostic features of NENs depend on the tumor origin site.…”

“…The importance of identifying the primary site cannot be underestimated given that the various clinical and prognostic features of NENs depend on the tumor origin site. There are several morphological clues that can be used to properly identity a NEN-UP, including amyloid deposits in MTC, psammoma bodies in somatostatinoma, a hyalinized stroma in insulinoma, as well as the hyaline globules and basophilic cytoplasm of pheochromocytoma [34]. Even so, it is not unusual for a metastatic NEN-UP to be characterized by nested cells with little or no morphological findings unique to the primary tumor site (Fig.…”