Abstract
Limited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN). We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.
Highlights
The 2017 WHO classification of pancreatic neuroendocrine neoplasms (PanNENs) [1] and subsequently the 2019 WHO classification of digestive system tumors [2] stratified highgrade neuroendocrine neoplasms (NENs) into neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC), mainly based on histology and genetic profile [3, 4]
One hundred thirty NETs G3 were identified among 1513 NENs, including 1103 NETs (71%), 255 NECs (17%), and 155 mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) (10%)
In contrast to NETs G3, NETs G1/G2 (739/973, 76%) and MiNENs (120/155, 77%) were more often obtained from primary sites, while NECs were frequent in primary (125/255, 49%) and metastatic sites (130/255, 51%)
Summary
The 2017 WHO classification of pancreatic neuroendocrine neoplasms (PanNENs) [1] and subsequently the 2019 WHO classification of digestive system tumors [2] stratified highgrade neuroendocrine neoplasms (NENs) into neuroendocrine tumor (NET) G3 and neuroendocrine carcinoma (NEC), mainly based on histology and genetic profile [3, 4]. Member of the German Cancer Consortium (DKTK), Munich, Germany. As many NETs G3 presented as metastasis with a clinically unclear origin, the tumors were tested by a panel of markers with known site specificity, e.g., ISLET-1, CDX2, serotonin, and TTF-1. The special aims of this study were to investigate (1) the prevalence of NET G3 regarding origin and metastasis; (2) the characterization
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