Algorithmic approach to neuroendocrine tumors in targeted biopsies: Practical applications of immunohistochemical markers

Abstract

Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms with distinct biological behaviors, depending on the site of origin and the degree of tumor proliferation. Although advances in biochemical and radiological modalities have enhanced the ability to detect NETs, tissue diagnosis remains the gold standard to assess tumor characteristics for treatment decision making. In an era with growing demands for precision diagnostics based on smaller tissue samples, immunohistochemistry has become an indispensable tool in the pathologist's repertoire. In conjunction with clinical findings and cytomorphology, complementary use of 1) markers of neuroendocrine differentiation, 2) markers confirming epithelial nature, 3) markers of cellular proliferation, 4) transcription factors and hormonal markers, as well as 5) predictive and prognostic markers may be necessary to guide patient management in NETs. The current review summarizes common applications of these immunohistochemical markers when confronted with a potential neuroendocrine neoplasm, and proposes a stepwise algorithmic approach to avoid diagnostic errors in targeted biopsies. Cancer Cytopathol 2016;124:871-84. V C 2016 American Cancer Society.

Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: Report of two cases and review of the literature

“…Tyrosine hydroxylase, a rate‐limiting enzyme in catecholamine synthesis may show immunoreactivity in functional paragangliomas. However, the expression may be weak to negative in parasympathetic or nonfunctional paragangliomas . Other neuroendocrine markers such as CD56, CD57, PGP9.5, are not as reliable as chromogranin and synaptophysin .…”

“…Paragangliomas show the reverse pattern. Immunohistochemical stain S100 is not helpful in discriminating between the two entities because sustentacular cells in both tumors can be positive for this marker . In addition, the staining can be negative if sustentacular cells are not present in a limited cell block such as in case 1.…”

“…However, the expression may be weak to negative in parasympathetic or nonfunctional paragangliomas . Other neuroendocrine markers such as CD56, CD57, PGP9.5, are not as reliable as chromogranin and synaptophysin . Hence, for a peripancreatic/retroperitoneal lesion with neuroendocrine features on FNA, a panel of immunohistochemical stains beyond the usual neuroendocrine markers should be applied.…”

Challenging differential diagnosis of an extra‐adrenal paraganglioma; the role of fine needle aspiration cytology

“…11,12 The most commonly identified structure of paraganglioma cells is the "Zellballen," namely nests of tumor cells surrounded by peripheral capillaries and S-100 positive sustentacular cells. 13 Although tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine biosynthesis, may confirm the diagnosis of a functional paraganglioma, it may be negative in some non-functional paragangliomas. 8 Immunochemistry is of great value to avoid pitfalls; 10 however several important aspects should be kept in mind.…”

“…However, diverse cyto-histologic patterns have been described ranging from angiomatous and sclerosing to small cell variants that resemble other carcinomas. 13 Furthermore, standardized pathological reports according to predefined protocols might be useful in order to avoid misdiagnosis. Synaptophysin is a very sensitive marker, while chromogranin is a highly specific marker for neuroendocrine differentiation.…”