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

• CP: Cancer
• CP: Genomics
• evolutionary clonal origins
• gastric mixed adenoneuroendocrine carcinoma
• mixed neuroendocrine tumors
• mixed neuroendocrine-nonneuroendocrine neoplasm
• multi-regional sequencing
• parallel divergence
• phylogenetic construction
• tumor differentiation
• tumor evolution
• whole-genome doubling

• Humans
• Phylogeny
• Microdissection
• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/pathology
• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Genomics

• liver metastasis
• liver transplant
• metastases
• neuroendocrine cancer
• neuroendocrine tumors
• transplant oncology

• Adjuvant chemotherapy
• Gastric cancer
• Gastric mixed neuroendocrine non-neuroendocrine neoplasm
• Microsatellite instability
• Mismatch repair protein

• Clinical challenge
• Molecular landscape
• Pancreatic NETs
• Spatial heterogeneity
• Temporal heterogeneity

• Humans
• Neuroendocrine Tumors/pathology
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Radiopharmaceuticals

A non-ampullary duodenal mixed adenoneuroendocrine carcinoma (MANEC), consisting of a conventional adenocarcinoma and a neuroendocrine carcinoma (NEC), is exceedingly rare. Moreover, mismatch repair (MMR) deficient tumors have recently attracted attention. The patient, a 75-year-old woman with epigastric pain and nausea, was found to have a type 2 tumor of the duodenum, which was diagnosed on biopsy as a poorly differentiated carcinoma. A pancreaticoduodenectomy specimen showed a well-defined 50 × 48 mm tumor in the duodenal bulb, which was morphologically composed of glandular, sheet-like, and pleomorphic components. The glandular component was a tubular adenocarcinoma, showing a MUC5AC-positive gastric type. The sheet-like component consisted of homogenous tumor cells, with chromogranin A and synaptophysin diffusely positive, and a Ki-67 index of 72.8%. The pleomorphic component was diverse and prominent atypical tumor cells proliferated, focally positive for chromogranin A, diffusely positive for synaptophysin, and the Ki-67 index was 67.1%. The sheet-like and pleomorphic components were considered NEC, showing aberrant expression of p53, retinoblastoma, and p16. Notably, all three components were deficient in MLH1 and PMS2. We diagnosed a non-ampullary duodenal MANEC with MMR deficiency. This tumor has a unique morphology and immunohistochemical profile, and is valuable for clarifying the tumorigenesis mechanism of a non-ampullary duodenal MANEC.

• Immunohistochemistry
• Mismatch repair deficiency
• Mixed adenoneuroendocrine carcinoma
• Neuroendocrine carcinoma
• Non-ampullary duodenum
• Tumorigenesis mechanism
• Unique morphology

Gastric neuroendocrine neoplasms (g-NENs) are a rare type of stomach cancer. The three main subtypes have different pathogeneses, biological behaviours and clinical characteristics, so they require different management strategies. This article will provide an overview of g-NENs and highlight recent advances in the field.

Molecular profiling has revealed differences between indolent and aggressive g-NENs, as well as a new somatic mutation responsible for some familial type I g-NENs. Novel biomarkers have been developed which will hopefully improve diagnosis, treatment, risk stratification and follow-up. Patient treatment is also changing, as evidence supports the use of less aggressive options (e.g. endoscopic surveillance or resection) in some patients with more indolent tumours.

g-NEN heterogeneity poses challenges in understanding and managing this rare disease. More basic science research is needed to investigate molecular pathogenesis, and future larger clinical studies will hopefully also further improve treatment and patient outcomes.

A mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) is a recently defined entity that comprises a neuroendocrine tumor (NEN) component and a non-neuroendocrine tumor (nNEN) component. As MiNEN is a recently defined entity, its molecular nature is not well known. Here, we evaluated the clinicopathologic and molecular characteristics of gastrointestinal (GI) MiNENs.

We performed a genomic analysis of 31 samples from 12 GI MiNEN cases using next-generation sequencing. We examined the primary NEN and nNEN components, as well as the metastatic NENs and nNENs. The relationships between the clinical tumor features (component, location, and grade) and their molecular characteristics were examined.

The 12 MiNENs included in the study were found in the stomach (n=10), distal rectum (n=1), and anus (n=1). Primary MiNENs that had NENs as the major component showed a worse clinical outcome than those that had nNENs as the major component. All distant metastatic tumors originating from MiNENs were NENs. In addition, NENs generally carried 1.5 times more gene mutations and copy number variations than nNENs. The ATRX gene deletion and TP53 gene mutation were the most common variants in both components of GI MiNENs.

We have revealed the detailed clinicopathologic and molecular findings with distinguishable alterations of GI MiNENs. To our knowledge, this is the first study to report the ATRX gene deletion in GI MiNENs. The molecular characteristics of GI MiNENs could provide clues to the pathogenic origin and progression of GI MiNENs.

• ATRX
• gastrointestinal
• molecular
• neoplasms
• neuroendocrine
• pathology
• sequence

Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions.

We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes.

Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L, ATM, and BRCA2; amplifications of ERBB2 and MDM2; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of < 10 mutations/Mb.

Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer.

• gastric cancer
• genetics
• neuroendocrine carcinoma
• targeted sequencing

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

• Gastric adenocarcinoma
• Neuroendocrine carcinoma
• Overall survival

• Adenocarcinoma/diagnosis
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Adenocarcinoma/therapy
• Adult
• Age Factors
• Aged
• Carcinoma, Neuroendocrine/diagnosis
• Carcinoma, Neuroendocrine/mortality
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/therapy
• Chemotherapy, Adjuvant
• Female
• Follow-Up Studies
• Gastrectomy
• Gastric Mucosa/diagnostic imaging
• Gastric Mucosa/pathology
• Gastric Mucosa/surgery
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Staging
• Prognosis
• Propensity Score
• Retrospective Studies
• Risk Factors
• Sex Factors
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

• 81802735 National Science Foundation for Young Scientists of China
• QML20191101 Beijing Youth Talent Plan
• 2020-11 Science Foundation of Peking University Cancer Hospital

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) are a group of rare tumors previously known as mixed adenoneuroendocrine carcinomas (MANECs). The neuroendocrine component is high-grade and may consist of small-cell carcinoma or large-cell neuroendocrine carcinoma. The nonneuroendocrine component may consist of adenocarcinoma or squamous cell carcinoma. We report a unique case of a MiNEN with trilineage differentiation: large-cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma. The reported patient presented with symptoms of an upper gastrointestinal bleed and was ultimately diagnosed with a MiNEN with trilineage differentiation. This is the first report of this exceedingly rare tumor type to include next-generation sequencing of the 3 separate tumor entities. In addition, we review the current literature and discuss the role of next-generation sequencing in classifying and treating MiNEN tumors.

• Gastric cancer
• Neuroendocrine neoplasm
• Precision medicine

• Ki67
• MANEC
• NEC
• prognosis

• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/pathology
• Cell Proliferation
• Female
• Humans
• Ki-67 Antigen/genetics
• Male
• Prognosis

• GEP-NENs
• Neuroendocrine cancer
• Neuroendocrine tumor
• Organoids
• Rare disease modeling

The Roux-en-Y gastric bypass is one of the most common procedures currently performed for surgical treatment of patients with severe obesity. Gastric cancer after bariatric surgery is not common, with most of them arising in the excluded stomach. Gastric mixed adenoneuroendocrine carcinomas are a rare type of stomach malignancy, composed of both adenocarcinoma and neuroendocrine tumor-cell components, with the latter comprising at least 30% of the whole neoplasm. In this article, we report a unique case of a mixed adenoneuroendocrine carcinoma with a mixed adenocarcinoma (tubular and poorly cohesive) component arising in the gastric pouch of a patient who underwent previous Roux-en-Y gastric bypass for glycemic control. Since stomach cancer is not usual in patients who have formerly undergone bariatric surgery and symptoms tend to be nonspecific, such diagnosis is often rendered at an advanced stage. Full assessment of these patients when presenting such vague symptoms is critical for an early cancer diagnosis.

• MANEC
• gastric bypass
• gastric cancer
• mixed adenoneuroendocrine carcinomas
• mixed tumor
• neuroendocrine tumors

• ampullary MANEC
• pancreaticoduodenectomy

• Classification
• Combined tumor
• Composite tumor
• Mixed adenoneuroendocrine carcinoma
• Mixed neoplasm
• Neuroendocrine

• Female
• Humans
• Immunohistochemistry
• Male
• Neoplasms, Complex and Mixed/classification
• Neuroendocrine Tumors/classification

We report a case of mixed adenoneuroendocrine carcinoma (MANEC) of stomach with tubular adenoma and well-differentiated neuroendocrine tumor (WD-NET) in the primary tumor in the stomach giving rise to biphenotypic regional nodal metastases. A 35-year-old woman with abdominal pain was found to have a 1.8-cm gastric lesion, diagnosed as WD-NET (intermediate grade) on the biopsy. The resection specimen contained residual WD-NET; there was also a gastric adenoma adjacent to the NET and nodal metastasis with both adeno- and neuroendocrine components. The tumor was classified as MANEC. Of note, the entire gastric tissue was submitted and multiple deeper levels of the adenomatous lesion were examined; no adenocarcinoma was present in the primary lesion. While association of gastric adenoma with neuroendocrine neoplasm is rare, presence of biphenotypic metastasis originating from such a lesion is highly unusual and to the best of our knowledge has not been reported.

• Classification
• Mixed adenoneuroendocrine carcinoma
• Prognosis
• Stomach

• GASTRIC PATHOLOGY
• NEUROENDOCRINE TUMOURS
• SURGICAL PATHOLOGY

To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type. Concentrating on GEP-NECs, we can conclude that survival times are poor, with a median of only 4–16 months depending on disease stage and primary site. Further, this aggressive disease appears to be on the rise, with incidence numbers increasing while survival times are stagnant. Treatment strategies concerning surgery are often undecided and second-line chemotherapy is not yet established. After an analysis of over 2600 articles, we can conclude that there is indeed more empirical literature concerning GEP-NECs available than previously assumed. This unique review is based on 333 selected articles and contains detailed information concerning all aspects of GEP-NECs. Namely, the classification, histology, genetic abnormalities, epidemiology, origin, biochemistry, imaging, treatment and survival of GEP-NECs are described. Also, organ-specific summaries with more detail in relation to disease presentation, diagnosis, treatment and survival are presented. Finally, key points are discussed with directions for future research priorities.

• Ki-67 index
• colo-rectal
• large cell carcinomas
• neuroendocrine carcinomas
• neuroendocrine neoplasms
• neuroendocrine tumours
• oesophagus
• pancreas
• small cell carcinomas
• stomach

• Aged
• Aged, 80 and over
• Carcinoma/genetics
• Carcinoma/metabolism
• Carcinoma/pathology
• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/metabolism
• Carcinoma, Neuroendocrine/pathology
• DNA Repair/genetics
• Female
• Follow-Up Studies
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/pathology
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Multivariate Analysis
• Survival Analysis
• Urogenital Neoplasms/genetics
• Urogenital Neoplasms/metabolism
• Urogenital Neoplasms/pathology

• Aged
• Aged, 80 and over
• Carcinoma, Neuroendocrine/genetics
• Carcinoma, Neuroendocrine/pathology
• DNA Mutational Analysis
• Female
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/pathology
• Humans
• Male
• Middle Aged
• Mutation
• Tumor Suppressor Protein p53/genetics

• GASTRIC PATHOLOGY
• NEUROENDOCRINE TUMOURS
• SURGICAL PATHOLOGY

• Braun enteroenterostomy
• Gastroenterostomy
• Mixed adenoneuroendocrine carcinoma
• Neuroendocrine carcinoma

• carcinoma
• endocrine
• gastroenteropancreatic
• gastrointestinal
• neuroendocrine

AIM: To achieve a better understanding of the origination of neuroendocrine (NE) cells in gastric adenocarcinoma.

METHODS: In this study, 120 cases of gastric adenocarcinoma were obtained. First, frozen section-immunohistochemistrical samples were selected from a large quantity of neuroendocrine cells. Second, laser capture microdissection was used to get target cells from gastric adenocarcinoma and whole genome amplification was applied to get a large quantity of DNA for further study. Third, genome-wide microsatellite abnormalities [microsatellite instability (MSI), loss of heterozygosity (LOH)] and p53 mutation were detected by polymerase chain reaction (PCR)-single-strand conformation polymer- phism-silver staining and PCR-sequencing in order to identify the clonality of NE cells.

RESULTS: The total incidence rate of MSI was 27.4%, while LOH was 17.9%. Ten cases had a highest concordance for the two types of cells. The other samples had similar microsatellite changes, except for cases 7 and 10. Concordant p53 mutations exhibited in sample 4, 14, 21 and 27, and there were different mutations between two kinds of cells in case 7. In case 17, mutation took place only in adenocarcinoma cells. p53 mutation was closely related with degree of differentiation, tumor-node-metastasis stage, vessel invasion and lymph node metastasis. In brief, NE and adenocarcinoma cells showed the same MSI, LOH or p53 mutation in most cases (27/30). In the other three cases, different MSI, LOH or p53 mutation occurred.

CONCLUSION: NE and the gastric adenocarcinoma cells may mainly derive from the same stem cells, but the remaining cases showing different origin needs further investigation.

• Neuroendocrine differentiation
• Clonal analysis
• Gastric adenocarcinoma
• Neuroendocrine cells

• Adenocarcinoma/genetics
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Biomarkers, Tumor/genetics
• Cell Differentiation
• Cell Lineage
• Chi-Square Distribution
• Clone Cells
• Genetic Predisposition to Disease
• Humans
• Kaplan-Meier Estimate
• Loss of Heterozygosity
• Lymphatic Metastasis
• Microsatellite Instability
• Mutation
• Neoplasm Invasiveness
• Neoplasm Staging
• Neuroendocrine Cells/chemistry
• Neuroendocrine Cells/pathology
• Phenotype
• Prognosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Tumor Suppressor Protein p53/genetics

• Aged
• Aged, 80 and over
• Biomarkers, Tumor/metabolism
• Carcinoma, Neuroendocrine/pathology
• Carcinoma, Neuroendocrine/surgery
• Chromogranin A/metabolism
• Female
• Gastrectomy
• Humans
• Immunohistochemistry
• Japan
• Male
• Microscopy, Electron, Transmission
• Middle Aged
• Phosphopyruvate Hydratase/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Synaptophysin/metabolism
• Tumor Suppressor Protein p53/metabolism

Neuroendocrine tumor (NET) in adenoma of the gastrointestinal tract is a rare mixed glandular-endocrine neoplasm and has uncommonly been described mostly in the colon. Histologically, this tumor is composed of a predominant proportion of benign adenomatous component and a small portion of well-differentiated NE component. Only three cases of NET in gastric adenoma have been reported in the literature. We present 4 cases of NET in gastric adenoma mimicking invasive adenocarcinoma. The NETs were 0.62 mm to 4.1 mm in size and located at the basal lamina propria, muscularis mucosa and submucosa. Histologically, NETs consisted of nests, cords, tubules, and clusters of cells that predominantly interposed between the foveolar base without disturbing the overall polyp architecture. The lesions were completely removed by endoscopic submucosal dissection in three cases and in one case, subtotal gastrectomy was performed because endoscopic biopsy was invasive adenocarcinoma. The patients’ clinical course was uneventful without an evidence of recurrence or metastasis. The recognition of NET in gastric adenoma will help avoid potential diagnostic pitfalls masquerading as invasvie adenocarcinomas posed by their infiltrative pattern into submucosa.

• Gastric neuroendocrine tumours
• MANEC
• Trilineage differentiation

• Adenocarcinoma
• Neuroendocine tumors
• Stomach neoplasms

A composite glandular/exocrine-endocrine carcinoma of the gastrointestinal tract is characterized by the co-existence of two adjacent, but histologically-distinct tumors in an organ. Composite glandular/exocrine-endocrine carcinomas are a special type of tumor comprised of common adenocarcinomas and neuroendocrine components that account for at least one-third of the entire tumor area. Composite tumors have been reported in a range of organs, but are relatively rare in the stomach. We report a case of a composite neuroendocrine carcinoma with an adenocarcinoma of the stomach (mixed exocrine-endocrine carcinoma), which was misdiagnosed as a giant submucosal tumor preoperatively based on esophagogastroduodenoscopy and a contrast-enhanced axial computed tomographic scan.

• Composite tumor
• Stomach
• Submucosal tumor

The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types.

The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q).

Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%).

The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis.