Mixed neuroendocrine-nonneuroendocrine neoplasms of the gastrointestinal system: An update

Abstract

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the digestive tract are a rare heterogeneous group of tumors that present many challenges in terms of diagnosis and treatment. Over the years, the diagnostic criteria, classification, and clinical behavior of these tumors have been the subjects of ongoing debate, and the various changes in their nomenclature have strengthened the challenges associated with MiNENs. This review is performed to provide an understanding of the key factors involved in the evolution of the designation of these tumors as MiNEN, highlight the current diagnostic criteria, summarize the latest data on pathogenesis and provide information on available treatments. Moreover, this work seeks to increase the awareness about these rare neoplasms by presenting the clinicopathological features and prognostic factors that play important roles in their behavior and discussing their different regions of origin in the gastrointestinal system (GIS). Currently, the MiNEN category also includes tumors in the GIS with a nonneuroendocrine component and epithelial tumors other than adenocarcinoma, depending on the organ of origin. Diagnosis is based on the presence of both morphological components in more than 30% of the tumor. However, this value needs to be reconfirmed with further studies and may be a limiting factor in the diagnosis of MiNEN by biopsy. Furthermore, available clinicopathological data suggest that the inclusion of amphicrine tumors in the definition of MiNEN is not supportive and warrants further investigation. The diagnosis of these tumors is not solely based on immunohistochemical findings. They are not hybrid tumors and both components can act independently; thus, careful grading of each component separately is required. In addition to parameters such as the metastatic state of the tumor at the time of diagnosis and the feasibility of surgical resection, the aggressive potential of both components has paramount importance in the choice of treatment. Regardless of the organ of origin within the GIS, almost MiNENs are tumors with poor prognosis and are frequently encountered in the elderly and men. They are most frequently reported in the colorectum, where data from molecular studies indicate a monoclonal origin; however, further studies are required to provide additional support for this origin.

Keywords: Gallbladder; Gastrointestinal system; Liver; Mixed adeno neuroendocrine carcinoma; Mixed neuroendocrine–nonneuroendocrine neoplasms; Pancreas.

Figure 1

Examples of histopathological and immunohistochemical findings in gastrointestinal mixed neuroendocrine-nonneuroendocrine neoplasms. A: Gastric mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN) composed of a NET (lower left) intermingled with an adenocarcinoma (x 400); B: Colonic MiNEN constituted from a neuroendocrine carcinoma and an adenocarcinoma (x 200); C. Diffuse immunostaining with synaptophysin in the neuroendocrine component of a colonic MiNEN (x 200); D: The adenocarcinoma component of this MiNEN shows diffuse positivity with CK20 (x 400).

Figure 2

Histopathological pitfalls in the diagnosis of mixed neuroendocrine-nonneuroendocrine neoplasms of the pancreas. A: A ductal adenocarcinoma of the pancreas surrounding and invading an islet in the background of chronic pancreatitis (x 200). The islet has regular contours despite an invasion; B: A neuroendocrine tumor of the pancreas with entrapped two ductulus without atypia. Such areas should be evaluated carefully to avoid a misdiagnosis of mixed neuroendocrine-nonneuroendocrine neoplasms (x 200).

Figure 3

Acinar carcinoma of the pancreas. A: The tumor is composed of cells that demonstrate the presence of monomorphic nuclei, sometimes forming minute lumens. Tumor cells are in a monolayer with basally located nuclei and have a granular eosinophilic cytoplasm (x 400); B: Bcl-10 expression with higher staining in the apical portion of tumor cells (x 400).