• Cell reprograming
• Mixed adeno-neuroendocrine cancer
• Mixed adenocarcinoma and neuroendocrine carcinoma
• Mixed neuroendocrine and non-neuroendocrine neoplasm
• Tumor plasticity

• MINENs
• gastric cancer
• neuroendocrine tumours
• prognosis
• treatment

• mixed neoplasm
• mixed neuroendocrine-nonneuroendocrine neoplasm
• neuroendocrine
• pancreas

• gastric adenocarcinoma
• metastasectomy
• multidisciplinary team
• neuroendocrine differentiation
• oligometastasis
• pembrolizumab

• Incidence
• Mixed neuroendocrine non-neuroendocrine neoplasms
• Nomogram
• Prognostic factors
• Survival

• Humans
• Incidence
• Prognosis
• Reproducibility of Results
• Calibration
• Lymphatic Metastasis
• Neuroendocrine Tumors/epidemiology
• Nomograms
• SEER Program

• MANEC
• MiNEN
• Mixed pancreatic tumors
• Neuroendocrine

• Humans
• Immunohistochemistry
• Neuroendocrine Tumors/diagnosis
• Neuroendocrine Tumors/pathology
• Pancreas/pathology
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/pathology
• Prognosis

• Gastric Adenocarcinoma
• MANEC
• Mixed Adenoneuroendocrine Carcinoma
• Sister Mary Joseph Nodule
• Umbilical Mass

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–nonneuroendocrine neoplasms
• Mixed adeno neuroendocrine carcinoma
• Gastrointestinal system
• Liver
• Pancreas
• Gallbladder

• Adenocarcinoma
• Aged
• Biopsy
• Gastrointestinal Tract/pathology
• Humans
• Male
• Neuroendocrine Tumors/diagnosis

Mixed adeno-neuroendocrine carcinomas (MANEC) is a rare pathological diagnosis characterized by the presence of both adeno-carcinomatous and neuroendocrine differentiation with each component comprising 30% of the tumor. This literature review is aimed at the extraction of all existing clinical studies and reviews on colorectal MANEC so as to ensure that a suitable chemotherapeutic regimen is chosen to improve survival outcomes and prognosis of the disease. Parallel search strategies were employed to extract past 10 years articles from PubMed, PubMed Central and Google Scholar databases. A total of 30 records consisting of one clinical trial, five retrospective cohort studies, one case control study, one case series, 16 case reports and six review papers were shortlisted. Chemotherapeutic regimens that were administered as an adjuvant and a neoadjuvant therapy were analyzed with their survival outcomes. The overall survival rate of those administered with neoadjuvant and adjuvant therapy can be as high as 57.4% and 69%, respectively. Multiple chemotherapeutic regimens were employed in colorectal MANEC and superiority of one regimen over the other can’t be established. Any drug or combination of drugs that is responsive against either of the MANEC components is found to be effective against the tumor. However, excellent responsiveness has been found with 5-fluorouracil regimens as a neoadjuvant therapy and platinum-based combinations as an adjuvant therapy. XELOX, streptozocin and S1 regimens also prove to be drugs of choice in aggressive and metastasized disease conditions. Our analysis allows for improved chemotherapeutic management of individuals with colorectal MANEC and establishes an increased potential for use of streptozocin therapy in the clinical setting. However, newer drugs like amrubicin require further research prior to describing its efficacy in colorectal MANEC.

• adjuvant
• colorectal
• management
• manec
• neoadjuvant
• treatment

The incidence of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is low. To improve our understanding of this rare tumor type and optimally guide clinical treatment, associated risk factors, clinical manifestations, and prognosis must be explored.

To identify risk factors that influence the prognosis of patients with gastroenteropancreatic MiNEN (GEP-MiNEN).

We retrospectively analyzed the clinical data of 46 patients who were diagnosed with GEP-MiNEN at the First Affiliated Hospital of Bengbu Medical College (Anhui, China) between January 2013 and December 2017. Risk factors influencing the prognosis of the patients were assessed using Kaplan-Meier curves and cox regression models. We compared the results with 55 randomly selected patients with gastroenteropancreatic GEP neuroendocrine tumors, 47 with neuroendocrine carcinomas (NEC), and 58 with poorly differentiated adenocarcinoma.

Among the 46 patients with GEP-MiNEN, thirty-five had gastric tumors, nine had intestinal tumors (four in the small intestine and five in the colon and rectum), and two had pancreatic tumors. The median age of the patients was 66 (41-84) years, and the male-to-female ratio was 2.83. Thirty-three (71.7%) patients had clinical stage III and IV cancers. Distant metastasis occurred in 14 patients, of which 13 had metastasis to the liver. The follow-up period was 11-72 mo, and the median overall survival was 30 mo. Ki-67 index ≥ 50%, high proportion of NEC, lymph node involvement, distant metastasis, and higher clinical stage were independent risk factors affecting the prognosis of patients with GEP-MiNEN. The median overall survival was shorter for patients with NEC than for those with MiNEN (14 mo vs 30 mo, P = 0.001), but did not significantly differ from those with poorly differentiated adenocarcinoma and MiNEN (30 mo vs 18 mo, P = 0.453).

A poor prognosis is associated with rare, aggressive GEP-MiNEN. Ki-67 index, tumor composition, lymph node involvement, distant metastasis, and clinical stage are important factors for patient prognosis.

• Mixed neuroendocrine non-neuroendocrine neoplasm
• Mixed adenoneuro-endocrine carcinoma
• Prognosis
• Gastro-entero-pancreatic tract

• Aged
• Aged, 80 and over
• Carcinoma, Neuroendocrine
• China/epidemiology
• Female
• Humans
• Intestinal Neoplasms/epidemiology
• Intestinal Neoplasms/therapy
• Male
• Neuroendocrine Tumors/epidemiology
• Neuroendocrine Tumors/therapy
• Pancreatic Neoplasms/epidemiology
• Prognosis
• Retrospective Studies
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/therapy

• MANEC
• MiNEN
• classification
• mixed neuroendocrine and non-neuroendocrine neoplasm
• prognosis

• Mixed adenoneuroendocrine carcinoma (MANEC)
• ampulla of Vater
• immunohistochemistry
• mixed tumour

• Mixed adenoneuroendocrine carcinoma
• Neoadjuvant chemotherapy
• Neuroendocrine carcinoma
• Stomach