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.

Mixed neuroendocrine–non-neuroendocrine neoplasm of the ampulla of Vater: a case report

“…Multiple biopsies yielded a possible diagnosis of Amp-MiNEN. It has been reported that collecting both component with biopsy or cytology is difficult, and in patients with metastatic disease, biopsies are usually performed from metastases, which are likely to have only one component [ 5 – 7 ]. In addition, the requirement for 30% ≥ proportions of each of the major components for a definitive diagnosis of MiNEN is controversial [ 5 – 7 ].…”

“…It has been reported that collecting both component with biopsy or cytology is difficult, and in patients with metastatic disease, biopsies are usually performed from metastases, which are likely to have only one component [ 5 – 7 ]. In addition, the requirement for 30% ≥ proportions of each of the major components for a definitive diagnosis of MiNEN is controversial [ 5 – 7 ]. Actually, there have been some reports of mixed tumors that did not meet diagnostic criteria for MiNEN because of this 30% threshold, but can be clinically considered MiNEN [ 8 , 9 ].…”

“…If we had used EUS–FNA to assess the enlarged lymph node, we may have realized that the NEC component, rather than the adenocarcinoma, was predominant. Although MiNEN is defined as a single disorder, it is important to recognize that it is a mixed tumor, the components of which behave independently [ 7 ]. Because treatment of only one of the two components can lead to progression of the other, careful consideration should be given to administering neoadjuvant therapy.…”

Gastric mixed neuroendocrine non-neuroendocrine neoplasms

“…Indeed, it has been reported that diagnosing MiNENs solely by quantifying IHC results can lead to terminological inconsistencies and confusion ( 55 ). Therefore, the WHO makes it very evident that these histological findings must be present in each morphological component and that IHC data alone are insufficient for the diagnosis of MiNENs ( 56 ). Another issue that should be considered is the necessity to give a diagnosis of MINENs in cases that do not receive neoadjuvant therapy.…”

Molecular factors, diagnosis and management of gastrointestinal tract neuroendocrine tumors: An update

“…Extensive surgery is not indicated in metastatic disease, especially in high-grade cases. Systemic chemotherapy is advocated in such cases[ 11 ].…”