Current approaches to the morphological diagnosis of pancreatic neuroendocrine tumors and prediction of their clinical course based on the analysis of our own database

Aim: Combined clinical and morphological analysis of the pancreatic neuroendocrine tumor (pNET) spectrum according to the new World Health Organization classification: patient distribution, hormonal status, morphological grading, somatostatin receptor 2 (SSR2) and 5 (SSR5) expression, the choice of tissue-specific markers for the differential diagnosis of primary NET in the pancreas based on metastases with unknown primary tumor.Materials and methods: The study was performed with 472 tissue samples from pNETs taken from patients. Morphological analysis consisted of histological and immunohistochemical examination with a panel of antibodies to chromogranin A, synaptophysin, CD56, insulin, glucagon, somatostatin, gastrin, calcitonin, adrenocorticotropic hormone (ACTH), serotonin, pancreatic polypeptide, cytokeratins (CK) of a wide spectrum, CK7 and CK19, p53, Ki-67, SSR 2 and SSR5, PDX-1, Isl-1, and NESP-55.Results: In women, the prevalence of pNETS was 2.3 higher than in men (2.3:1). We were able to identify 299 (63.3%) insulinomas, 134 (28.4%) non-functioning NETs, 28 (5.9%) gastrinomas and 1.8% rare tumors (somatostatinomas, “calcitoninomas” and ACTH-producing). Metastatic tumors were found in 16.5% of the cases. Multiple endocrine neoplasia syndrome type 1 was confirmed in 11.9% of the pNET patients, and in 30.8% of those aged below 30 years. Multiple tumors (2 to 10) were found in 32 patients by the time of the diagnosis or occurred at 7 to 18 years after initial surgery. 28.3% of the tumors were CK19-positive, with 54.4% of them being metastatic. Insulinomas were least prone to metastasizing (5.7% of the cases), with 41.2% of them being CK19-positive. Metastases were found in 70.4, 66.7, 100, and 100% of gastrinomas, “calcitoninomas”, ACTH-producing, and somatostatinomas, respectively, with CK19-positivity found in 85.2, 66.7, 66.7, and 100% of these tumors. SSR2 expression was observed in all gastrinomas and “calcitoninomas”, in 90.5% of “glucagonomas”, 85.7% of PPomas, and 66.7% of somatostatinomas. SSR5 expression was significantly less frequent. 86.3% of the studied tumors were PDX-1-positive: all somatostatinomas, 97.4% of insulinomas, 92.3% of gastrinomas, 83.3% of PPomas, 80% of the non-functioning NETs. PDX-1-negativity was identified in all “calcitoninomas” and in 57.1% of the non-functioning “glucagonomas”. 83.3% and 90.9% of the pNETs were Isl-1 and NESP-55-positive, respectively.Conclusion: Combined morphological and immunohistochemical examination of pNETs allows for the correct diagnosis, assessment of their prognosis and choice of the most effective treatment. The malignancy grade of pNETs depends on the cell immunophenotype and is higher in the cases with co-expression of the markers of neuroendocrine and ductal differentiation (CK19), as well as with ectopic hormonal production