Cases of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the urinary system are rare, and reports of primary MiNENs in the ureter are lacking. Herein, we present the case of a 71-year-old man who presented with painless gross hematuria and weight loss. Contrast-enhanced abdominal computed tomography (CT) revealed a tumor, comprising small cell neuroendocrine carcinoma (SCNEC) and adenocarcinomatous components, attached to the ureter. The SCNEC components were strongly positive for synaptophysin, CD56 and INSM1 and adenocarcinomatous components were strongly positive for CDX2 and cytokeratin 20, respectively. Four weeks post-surgery, the patient received four cycles of cisplatin-based chemotherapy; the 7-month follow-up CT confirmed that he was healthy without disease recurrence. The occurrence of MiNEN in the ureter with SCNEC and adenocarcinomatous components is extremely rare, wherein histopathological and immunohistochemical features aid in the diagnosis MiNEN. With its aggressive nature, MiNEN can only be effectively treated by early diagnosis and radical surgery.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are rare tumors recently characterized by the presence of both neuroendocrine and non-neuroendocrine components within the same tumor tissue. Although MiNEN found their place in the WHO classification for various organs, this composite tumor in the head and neck region remains exceptionally rare. We present a case of primary oral MiNEN in a 64-year-old male located on the left side of lower gingiva. Biopsy raised suspicion of neuroendocrine carcinoma (NEC) and the patient underwent partial mandibulectomy. The resected specimen showed two distinct components of NEC and squamous cell carcinoma (SCC) with the confirmation of immunohistochemical markers. There has been no sign of recurrence nor metastasis 6 years after the surgery. In addition, we have conducted a review of published cases with potential relevance to this entity, resulting in five cases. The diverse terminology reinforces the need for a standardized classification system of oral/head and neck MiNENs.

BACKGROUND: Mixed neuroendocrine and non-endocrine neoplasms (MiNENs) are challenging to diagnose and manage clinically. The current understanding of MiNENs\' pathobiology, molecular mechanisms, and management is incomplete. Though microsatellite instability (MSI) is known to impact carcinogenesis, reports examining MSI mechanisms for MiNENs are rare.
METHODS: We report an unusual colonic MSI-MiNEN uncovered in an 89-year-old woman and the review of the literature.
RESULTS: Pathologic inspection revealed a high-grade carcinoma composed of tumor cells with neuroendocrine histologic traits and immunophenotype intermixed with mucin-containing signet ring-like cells arranged in nested and micronodular patterns. Loss of MLH1 and PMS2 mismatch repair proteins was detected in tumor cells. INSM1 immunostaining highlighted about 50% of the tumour, further reinforcing the MiNEN diagnosis. Next-generation sequencing identified multiple carcinogenic mutations. Because of the advanced stage of the tumor and its adhesion to the adjacent organs, surgical resection was aborted; immunotherapy was initiated. The tumor is in remission 30 months following initiation of treatment, and the patient remains asymptomatic.
CONCLUSIONS: This unique MSI MiNEN was characterized by its immunohistochemical and molecular signatures and illustrated how correctly diagnosing MSI can strongly improve a patient\'s outcomes.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are a peculiar entity that can occur throughout the whole gastrointestinal trait, and pancreatic localization is rare. Their main characteristic is the presence of at least a neuroendocrine and an epithelial component, each accounting for at least 30% of the tumour mass. The presence of epithelial ductal component defines adeno-MiNEN. We report a case of a 59-year-old woman affected by pancreatic adeno-MiNEN with challenging diagnosis and successfully treated. A systematic literature review and pooled analysis was also performed, aiming to define the management and outcomes of pancreatic adeno-MiNEN. Out of 190 identified records, 15 studies including 28 patients affected by pancreatic-adeno-MiNEN were included in the analysis. Pancreatic adeno-MiNEN occurred mainly in males (82.8%) and at a mean age of 61.7 (range: 24-82) years. Pre-operative diagnosis was possible only in 14.2% of cases. At presentation, the majority had already advanced disease (TNM stage III (53.8%) and stage IV 19.3%). Adjuvant therapy was performed in 55% of patients, and the tumour recurrence rate was in 30% of cases. Median disease-free survival (DFS) was 12 months (range: 0-216 months) with a 5-year DFS of 16.6%, while the median overall survival (OS) was 12 months (range: 0-288 months) with a 5-year OS of 23.5%. Pancreatic adeno-MiNENs are rare; as they have very heterogenous behaviour, they are rarely diagnosed preoperatively and have poor prognosis. Treatment of localised MiNEN still relies on radical surgical resection, which seems essential to achieve a good oncological prognosis. International registry on MiNEN is necessary to improve the knowledge on this rare tumour and to improve its outcomes.

Amphicrine phenotype in medullary thyroid carcinoma (MTC) is a rare phenomenon characterized by tumor cells that show both endocrine differentiation (calcitonin secretion) and exocrine differentiation (mucin production and secretion). Not much is known about the pathobiology of amphicrine MTCs. This report undertook a case-based review approach by discussing the cytological, histopathological, and ultrastructural features of this rare enigmatic entity, expanding on the radiological and novel MUC immunohistochemistry findings from a 28-year-old MEN2B syndrome patient with C cell hyperplasia and multifocal MTC with amphicrine features. The patient had widespread hematogenous metastases at presentation. MUC immunoexpression analysis revealed evidence of micro-lumina formation, and unique to-date unreported expression patterns of MUC1, MUC5AC, and MUC6 in an amphicrine subtype of MTC. Review of the literature identified five other MTC cases with well-documented amphicrine features. Of these six cases, two were associated with MEN2B syndrome, and four had metastatic disease. Follow-up was available in three patients, and two died of disease. Recognition of this rare subtype of MTC may be of clinical interest given their frequent link to MEN2B syndrome and biological aggressiveness.

Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) of the pancreas is a rare entity, and obtaining a preoperative diagnosis is difficult. We present a 70-year-old man in whom the possibility of MiNEN was successfully discovered preoperatively by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). Immunostaining revealed positive results for the neuroendocrine markers chromogranin A and synaptophysin. We considered the possibility for MiNEN before surgery. He underwent distal pancreatectomy with splenectomy. Immunohistochemical examination of the tumor cells showed a wide range of positivity for trypsin as well as for chromogranin A and synaptophysin. Considering that ≥ 30% tumors ware positive for both acinar and neuroendocrine markers, the patient was diagnosed with MiNEN. MiNEN is a malignant tumor that requires early detection and treatment but is a rare disease for which no method has been established. We found that EUS-FNA and immunostaining are effective diagnostic methods for MiNEN.

BACKGROUND: Mixed adeno-neuroendocrine carcinomas (MANEC) are a subgroup of mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) described as mixed neoplasms containing dual neuroendocrine and non-neuroendocrine components. The aim of this study was to appraise the prevalence of MANEC in the lower gastrointestinal (GI) tract and provide reliable estimates of survival.
METHODS: A systematic review was undertaken in accordance with PRISMA guidelines using PubMed, Embase, Cochrane Library of Systematic Review, Web of Science, and Scopus databases, and a Bayesian hierarchical survival pooled analysis was performed.
RESULTS: Of 182 unique records identified, 71 studies reporting on 752 patients met the inclusion criteria. Mean age was 64.2 ± 13.6, with a male-to-female ratio of 1.25. Overall, 60.3% of MANEC were located in the appendix, 29.3% in the colon, and 10.4% in the anorectum. More than a quarter (29%) of patients had stage IV disease at diagnosis, with higher prevalence in appendiceal than colonic and anorectal primaries. More than 80% had a high-grade (G3) endocrine component. Of the 152 patients followed up for a median of 20 months (interquartile range limits, 16.5-32), median overall survival was 12.3 months (95% credible interval [95%CrI], 11.3-13.7), with a 1.12 [95%CrI, 0.67-1.83] age-adjusted hazard ratio between metastatic and non-metastatic MANEC. Stage IV disease at diagnosis was more prognostically unfavorable in cases of colonic compared to anorectal origin.
CONCLUSIONS: MANEC is a clinically aggressive pathological entity. The results of this study provide new insights for the understanding of tumor location within the lower GI tract and its prognosis in terms of overall survival.

BACKGROUND: The majority of gastrointestinal tumors are adenocarcinomas. Rarely, there are other types of tumors, such as acinar cell carcinoma, and these are often called pancreatic-type acinar cell carcinomas. Among these tumors, some are differentiated into neuroendocrine components. A few of them are MiNENs.
METHODS: The patient was an 80-year-old male who was referred to our hospital for treatment of a pedunculated gastric tumor. It was 5 cm in diameter and detected in the upper gastric body with upper GI endoscopy conducted to investigate anemia. In the biopsy, although hyperplasia of gastric gland cells was noted, no tumor cells were found. Retrospectively, the diagnosis was misdiagnosed. An operation was arranged because bleeding from the tumor was suspected as a cause of anemia and because surgical resection was considered to be desirable for accurate diagnosis. Hence, laparoscopic and endoscopic cooperative surgery was performed. In the pathological examination, several types of epithelial cells that proliferated in the area between the mucosa and deep inside the submucosa were observed. These consisted of acinar-glandular/trabecular patterns and solid. A diagnosis of pancreatic-type acinar cell carcinoma of the stomach with NET G2 and G3 was made based on characteristic cellular findings and the results of immunostaining tests. Each of them consisted of more than 30% of the lesion; a diagnosis of pancreatic-type mixed acinar neuroendocrine carcinoma (pancreatic-type MiNEN) of the stomach or a type of gastric MiNEN was obtained. Anemia was resolved after the operation, and the patient was discharged from the hospital without perioperative complications.
CONCLUSIONS: Pancreatic-type ACC of the stomach that is differentiated into neuroendocrine tumors is very rare. Hence, we report this case along with a literature review.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.