As the description of 2019 WHO Classification of Tumors of digestive tumors, the term “MiNEN” was defined as neoplasms composed of morphologically recognizable neuroendocrine and non-neuroendocrine components, each constituting at least 30% of the tumor volume . Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in this WHO classifications. Most of them are usually mixed ductal adenocarcinoma with neuroendocrine carcinoma (NEC), but the combination of NET G3 and IPMN are rarest. In our report, we describe a case of concomitant IPMN with associated invasive carcinoma and NET (MiNENs) of the pancreas.
The most common tumors of the neoplasms in pancreas are IPMN and more and more attentions are attracted to its unique features and malignant. It can be subclassified into three subtypes including gastric, intestinal, and pancreatobiliary by their predominant cell differentiation pattern. In clinical, about 70% IPMNs are gastric-type which usually occurs in branch ducts and most of them are low-grade lesions. The second most common type of IPMN is intestinal-type, which accounts about 20% of cases and usually involves in the main duct. They often present high-grade lesions and even an associated invasive carcinoma. Pancreatobiliary-type of IPMN typically occurs in the main pancreatic duct and often are high-grade lesions . According to the histology and the results of immunohistochemistry, the intraductal lesions in our case were identified as intestinal-type IPMN with associated invasive carcinoma which was positive for the markers of intestinal differentiation such as CDX2, MUC2 and MUC5AC, and negative for MUC6 and EMA (pancreatobiliary-type IPMN).
Due to the high index of Ki-67 and mitoses in this case, another key point of identification was that the neuroendocrine component in the tumor was NET G3 or NEC. Comparing with NEC, NET is with higher rates of avidity on somatostatin receptor scintigraphy (SRS), lower Ki67, poorer responses to platinum base chemotherapy, and longer survival. Histologically, NET G3 is a high grade and well-differentiated NEN with moderate atypia, often presenting organoid patterns and less necrosis. However, NECs usually shows flaky or trabecular pattern with high heterogeneity. Necrosis is easy to be discovered. But in many cases, it is difficult to distinguish them only from morphology. Fortunately, some markers may help us make a right judgment. Primary NET G3 almost always have no damage in TP53 and RB1, and reveals loss expression of DAXX and ATRX. However, NECs have a mutation of TP53 and RB1, showing p53 nuclear accumulation and lack expression of RB1 expression and SMAD4. The Ki-67 proliferation index of NECs is commonly > 60–80%. Anymore, the expression of SSTR2A in NET is always higher than that in NEC. In our cases, the tumor presented a well-differentiated organoid growth in histopathology. In immunohistochemistry, p53 showed as a wild type and RB1 is intact. SSTR2A was strongly expressed (2++) in a membranous pattern. The Ki-67 proliferation index was about 50%. Based on the data above, we made a final diagnosis of MiNENs (NET G3 and IPMN with associated invasive carcinoma).
Although the histology origins of IPMN and NET seems different, the associations between them have been described in the several literatures. In most cases, IPMN and NET were apparently self-governed and probably represented two different neoplasms. In molecular, about 40% of NETs occurs somatically inactivation of MENI gene . About 40% of NETs have mutation in DAXX or ATRX [6, 7]. There are also showed NETs also showed HlF1A, VHL, TSC2 and PTEN alterations [8–10]. On the other hand, IPMNs frequently harbour mutations in KRAS, GNAS and RNF43[11, 12]. Missense mutations of TP53 can occurs in high-grade IPMNs or invasive carcinomas associated with IPMN . Anymore, loss of SMAD4 occurs uncommonly in the invasive carcinomas associated with IPMN . While, in some reports both the two components shared KRAS and GNAS mutations, which were common in IPMNs and are often not appeared in pancreatic NET, indicating that the NET might originate from IPMN [11,12]. Moreover, Alterations of the CDKN2A and CCND1genes have also been found in both NETs and IPMNs [15–17]. In our case, in some area the two components were distinct, but in some area, they were intermingled. Unfortunately, the NGS of the two components in our case were not detected. Further analyses the molecular alterations of the IPMN and NET should be done in our next study.
In conclusion, we share a rare case of MiNEN which consists NET G3 and IPMN with associated invasive carcinoma, and expect that this very rare association, still of unknown molecular basis, should be kept in mind.