Neuroendocrine Liver Metastasis—a Specific Set of Markers to Detect Primary Tumor Sites

Abstract

The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters.

The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors—An Overview of the Latest Classifications

“…The major limitation of ISL1 is its lack of expression in neuroendocrine neoplasms of the small intestine and the appendix [ 24 ]. However, combined with other neuroendocrine markers, it may be used to exclude the small intestine as the primary site of a metastatic NEC [ 25 ]. The great sensitivity of secretogranin (SECG) expression in NETs and NECs in several organs, including colorectal NENs where chromogranin A is typically negative, has also been documented.…”

How to Manage Small Intestine (Jejunal and Ileal) Neuroendocrine Neoplasms Presenting with Liver Metastases?

“…As shown recently [ 30 ], the site of the primary NEN may be based on biopsy specimens of the liver applying a specific set of immunohistochemical markers. Positive staining for CDX2 was documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs.…”

Second-Generation Neuroendocrine Immunohistochemical Markers: Reflections from Clinical Implementation

“…It has been noted that ISL1, INSM1 and SECG also may exhibit tissue-specific patterns, thus potentially facilitating the proper identification of the primary site ( Table 1 ) [ 17 ]. While most NETs/NECs are positive for ISL1, small intestinal and appendiceal NETs recurrently display negativity for this marker, while being positive for INSM1 and SECG [ 17 , 39 ] ( Figure 3 ). Similarly, pheochromocytomas and abdominal paragangliomas may be ISL1 and INSM1 positive, but are most often negative for SECG [ 17 ] ( Table 1 , Figure 1 ).…”