Mixed Adenoneuroendocrine Carcinoma Research Articles

Synergizing traditional CT imaging with radiomics: a novel model for preoperative diagnosis of gastric neuroendocrine and mixed adenoneuroendocrine carcinoma

ObjectiveTo develop diagnostic models for differentiating gastric neuroendocrine carcinoma (g-NEC) and gastric mixed adeno-neuroendocrine carcinoma (g-MANEC) from gastric adenocarcinoma (g-ADC) based on traditional contrast enhanced CT imaging features and radiomics features.MethodsWe retrospectively analyzed 90 g-(MA)NEC (g-MANEC and g-NEC) patients matched 1:1 by T-stage with 90 g-ADC patients. Traditional CT features were analyzed using univariable and multivariable logistic regression. Tumor segmentation and radiomics features extraction were performed with Slicer and PyRadiomics. Feature selection was conducted through univariable analysis, correlation analysis, LASSO, and multivariable stepwise logistic. The combined model incorporated clinical and radiomics predictors. Diagnostic performance was assessed with ROC curves and DeLong’s test. The models’ diagnostic efficacy was further validated in subgroup of g-NEC vs. g-ADC and g-MANEC vs. g-ADC cases.ResultsTumor necrosis and lymph node metastasis were independent predictors for differentiating g-(MA)NEC from g-ADC (P < 0.05). The clinical model’s AUC was 0.700 (training) and 0.667(validation). Five radiomics features were retained, with the radiomics model showing AUC of 0.809 (training) and 0.802 (validation). The combined model’s AUCs were 0.853 (training) and 0.812 (validation), significantly outperforming the clinical model (P < 0.05). Subgroup analysis revealed that the combined model exhibited acceptable performance in differentiating g-NEC from g-ADC and g-MANEC from g-ADC, with AUC of 0.887 and 0.823 in the training cohort and 0.852 and 0.762 in the validation cohort.ConclusionA combined model based on traditional CT imaging and radiomic features provides a non-invasive and effective preoperative diagnostic method for differentiating g-(MA)NEC from g-ADC.

Clinical and pathological characteristics of gastric large cell neuroendocrine carcinoma: A report of 2 cases series and literature review.

Gastric large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive neuroendocrine carcinoma that arises from the stomach and with high malignancy. Patients with gastric LCNEC usually have a poor prognosis. The standard treatment plan has not been established and its curative effect is poor. The present study described 2 cases diagnosed with gastric LCNEC and reviewed in depth the literature to improve our understanding more about this uncommon tumor and further to provide more experience to diagnose and treat this disease. The present study reported 2 cases of gastric LCNEC in male patients aged 51 and 73 years old, respectively. Both patients had epigastric discomfort, pain, acid reflux and heartburn. The medical history was unremarkable. The ulcerative lesion located at gastric was examined in the 2 patients by taking the esophagogastroduodenoscopy (EGO), computed tomography (CT) and digital gastrointestinal radiography (GI), that both were suspected gastric malignancy. Endoscopic biopsies of the tumor led to the initial diagnosis of gastric cancer. Postoperative pathological and immunohistochemical examinations of the surgical specimens confirmed that 1 case had mixed adeno-neuroendocrine carcinoma (MANEC) and the other had LCNEC. Both patients underwent surgical resection and received etoposide-cisplatin combination chemotherapy following surgery. The operation was successful. Both patients had uneventful recoveries following surgery, and had been followed-up regularly. The general condition was satisfactory, and no tumor metastasis was observed at present.

Tumor recurrence with disseminated liver metastases in a patient with resected early gastric cancer: a case of mixed adenoneuroendocrine carcinoma (MANEC).

Tumor recurrence with disseminated liver metastases in a patient with resected early gastric cancer: a case of mixed adenoneuroendocrine carcinoma (MANEC).

S2457 Not Another Acute Cholecystitis - A Rare Case of Mixed Adenoneuroendocrine Carcinoma of the Gallbladder

S2457 Not Another Acute Cholecystitis - A Rare Case of Mixed Adenoneuroendocrine Carcinoma of the Gallbladder

Identification of human papillomavirus and Rb/E2F pathway genomic alterations in mixed adeno-neuroendocrine carcinoma.

To investigate the molecular characteristics of Rb/E2F in mixed adeno-neuroendocrine carcinoma (MANEC). The clinicopathological features of MANEC were analyzed. The protein expressions of Rb, p16, and p53 were detected by the immunohistochemical method. The infection status of high-risk human papillomavirus (HR-HPV) was evaluated by in situ hybridization (ISH) and the gene chip method. Thirteen cases of MANEC were divided into four molecular patterns according to Rb protein expression and HPV status. Group 1: A total of eight of the 13 cases showed positive Rb protein expression and lack of HR-HPV expression (8/13, 62%). Rb protein expression with p16 protein deletion and p53 protein abnormal expression was unique to NEC. Group 2: three cases (3/13, 23%) with negative Rb protein expression and lack of HR-HPV expression. Group 3: There was one case (1/13, 8%) with positive expression of Rb protein accompanied by HR-HPV. Group 4: There was one case of Rb protein loss with an HR-HPV-positive status. HR-HPV and Rb/p16/p53 pathway can be associated in MANEC pathogenesis, which provides the research basis for personalized treatment of MANEC.

Does the size of the neuroendocrine-carcinoma component determine the prognosis of gallbladder cancer?

Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.

Distinctive Phenotypic and Microenvironmental Characteristics of Neuroendocrine Carcinoma and Adenocarcinoma Components in Gastric Mixed Adenoneuroendocrine Carcinoma

This study aimed to conduct an in-depth examination of gene expression and microenvironmental profiles of gastric neuroendocrine carcinoma (NEC) and mixed adeno-NEC (MANEC). Tissue microarrays from 55 patients with gastric MANEC (N = 32) or NEC (N = 23) were analyzed using digital spatial profiling (GeoMx DSP, NanoString Technologies). Representative regions of interest were selected from the adenocarcinoma (ADC) portion (ADC-MANEC) and the NEC portion (NEC-MANEC) of the MANEC cores, and pure NEC (pNEC) cores. All regions of interest were separated into epithelial components and stromal components using the masking procedure in the GeoMx platform, followed by transcriptome analysis. Comparison of gene expression between ADC-MANEC and NEC-MANEC/pNEC identified several differentially expressed genes in the epithelial (including PEG10, MAP1B, STMN3, and AKT3) and stromal (FN1, COL1A1, SPARC, and BGN) components. Gene set enrichment analysis revealed that pathways related to the E2F target and G2M checkpoint were more enriched in NEC-MANEC and pNEC than in ADC-MANEC. Deconvolution analysis showed that the microenvironmental profile varied according to histologic differentiation. In ADC-MANEC, intraepithelial infiltrating immune cells were relatively more numerous, whereas fibroblasts in the stroma were more abundant in NEC-MANEC and pNEC. This study confirmed the distinct expression profile of each histologic component of MANEC according to its tumor vs stromal compartment using the DSP platform. Although each component of MANEC shares the same genetic origin, distinctive phenotypes should not be overlooked when managing patients with MANEC. This study provides a useful validation data set for future studies.

MANEC TUMOR OF RECTUM. A RARE CASE SERIES OF 3 PATIENTS AND A LITERATURE REVIEW.

The term Mixed Adeno-Neuro-Endocrine Carcinoma (MANEC) was introduced in 2010 by the WHO Classification of Tumors of the Digestive System. It refers to a neoplasm with dual epithelial and neuroendocrine differentiation, each component representing at least 30% of the tumor. It is an uncommon tumor accounting for < 3% of all colon and rectum malignancies. We report three cases of this extremely rare MANEC of the rectum. All three cases presented with hematochezia, variable constipation, and abdominal pain. They were diagnosed and staged appropriately with colonoscopy, biopsy with immunohistochemistry, and imaging. They underwent an anterior resection with circular stapled anastomoses. Because of the low incidence of this histotype, we reviewed the clinical presentation, diagnostic characteristics, and treatment of MANEC of the colon and rectum.

Sarcopenia and Neuroendocrine Neoplasms.

To summarise the current literature regarding the presence of sarcopenia in patients with neuroendocrine neoplasms (NENs). These are uncommon cancers separated into well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinoma (NECs). For the diagnosis of sarcopenia, there needs to be low muscle strength and low muscle quantity/quality. Five studies exist describing either low muscle strength or low muscle quantity in patients with NETs. The studies used different techniques to analyse muscle strength and muscle quantity, included heterogeneous populations, and performed the analysis at different time points following the diagnosis of the NET. Only 2 studies regarding patients with NECs could be found, both included mainly patients with a mixed adenoneuroendocrine carcinoma (MiNEN) and are, therefore, difficult to interpret for patients with a NEC. The main findings of this review are to describe the presence of sarcopenia in patients with NENs. However, results should be interpreted with caution, and future research should focus on the correct technique, homogenous population and same time point.

Characterization and natural evolution of mixed adeno-neuroendocrine carcinoma of the pancreas

Characterization and natural evolution of mixed adeno-neuroendocrine carcinoma of the pancreas

Smíšený adenoneuroendokrinní karcinom žaludku – kazuistika

Neuroendocrine tumours represent a heterogeneous group of neoplasia arising from different anatomical locations, with approximately 50% of gastrointestinal origin. Main parameters in the evaluation of each case include tumour morphology, mitotic cell count, and Ki-67 index. Mixed adeno-neuroendocrine carcinomas (MANECs) are rare aggressive neoplasms consisting of both adenocarcinomatous and neuroendocrine cells, each component constituting at least 30% of the lesion. Our case represents 77-year-old polymorbid patient who, due to signs of acute bleeding in the upper gastrointestinal tract with anaemic syndrome, underwent a gastroscopic examination for melena with the finding of an ulcer lesion on the front wall of the stomach at the junction of the body and the antrum. The control gastroscopic examinations with biopsies, at first only signs of chronic gastritis with Helicobacter pylori positivity were histologically proven, then fragments of high-grade tubular to tubulovillous adenoma and structures of moderately differentiated tubular adenocarcinoma were found. Histological analysis of the gastric resection showed mixed adeno-neuroendocrine carcinoma with lymphangioinvasion.

S4227 Metastatic Mixed Adenoneuroendocrine Carcinoma Presenting as a Poorly Differentiated Sarcomatoid Neoplasm

S4227 Metastatic Mixed Adenoneuroendocrine Carcinoma Presenting as a Poorly Differentiated Sarcomatoid Neoplasm

Comparison of survival outcomes and survival prediction in patients with primarycolorectal MANEC and primary colorectal SRCC: a population-based propensity-score matching study.

Primary mixed adeno-neuroendocrine carcinoma (MANEC) and primary signet-ring cell cancer (SRCC) are two rare but highly malignant tumors in colorectal cancer. Therefore, we attempted to compare the tumors' survival outcomes, identify risk factors, and ultimately evaluate the prognosis by developing a nomogram. We identified 755 MANEC and 5836 SRCC patients of colorectal cancer. PSM was used to balance the influence of baseline clinical and pathological differences. Kaplan-Meier method was used to compare the prognosis of different pathological grades and AJCC stages. Cox proportional hazards model was used to identify potential prognostic factors for the two groups. Finally, we developed a nomogram and evaluated the feasibility of the model. After PSM, the median OS and CSS of MANEC patients were significantly better than those of SRCC patients in stage III-IV (P < 0.001) but similar in stage I-II. The median OS and CSS of MANEC patients in each pathological grade were also greater than those of SRCC patients. Patients with MANEC and SRCC who underwent lymph node dissection in more than four areas had longer survival time. MANEC patients benefited from postoperative chemotherapy and radiotherapy; among SRCC patients, those who received preoperative and postoperative comprehensive chemotherapy and radiotherapy had benefits in OS and CSS. Both MANEC and SRCC are often diagnosed in advanced stages, highlighting the importance of early screening. Despite the better prognosis of MANEC compared to SRCC, both types of patients require the formulation of personalized treatment strategies based on different risk factors combined with column charts.

Survival Trends and Profiling of Gastric Mixed Adenoneuroendocrine Carcinoma (gMANEC) in the Current Era

Background: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a histopathologic diagnosis with at least 30% each of exocrine and endocrine components. Although prognosis is thought to be driven by the relative exocrine or endocrine dominance, gMANEC has been clinically treated as gastric adenocarcinoma (gAC). The overall survival of gMANEC as compared to gastric neuroendocrine carcinoma (gNEC) or gAC remains undefined. Methods: Using the National Cancer Database, patients with gastric tumors were queried from 2004 to 2016 for gMANEC, gNEC, and gAC histologies. Demographic and clinicopathologic features were recorded. Univariate and multivariate Cox proportional hazards analyses were performed to delineate factors associated with overall survival (OS). Results: Overall, 404 patients diagnosed with gMANEC were identified. Patients had a median age 68 years, were majority male, and predominantly Caucasian. Gastric MANEC was more frequently poorly differentiated (73%vs 52% (gAC) vs 20% (gNEC), P &lt; .001) with lymphovascular invasion (57%vs 38%vs 27%, P &lt; .001) and lymph node involvement (59%vs 49%vs 36%, P &lt; .001); these factors were associated with worse OS on univariable analysis. Finally, tumors &gt;5 cm and lymph node involvement were independent predictors of worse survival. The median OS of patients with gMANEC was 41.5 months. Conclusion: Gastric MANEC and gAC have a similarly dismal prognosis and thus should be continued to treat like gAC. Pathologic nodal metastasis, tumor size and grade are useful prognostic factors.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

Mixed adenoneuroendocrine carcinoma originating from the appendix and colorectum: a comparative analysis of a large population-based database.

As a rare gastrointestinal neoplasm, the demographic, clinicopathological, and prognostic characteristics of mixed adenoneuroendocrine carcinoma (MANEC) remain unclear. The purpose of this study was to evaluate its biological features, survival outcome, and prognostic factors. From the Surveillance, Epidemiology, and End Results (SEER) database, we retrospectively reviewed clinicopathological and survival data of 513 patients who were histopathologically diagnosed with MANEC of the appendix and colorectum bettween 2004 and 2015. The clinicopathological features and survival outcomes of MANEC located at different anatomical locations were compared, and predictive factors for cancer-specific survival (CSS) and overall survival (OS) were assessed. In terms of anatomical distribution of MANEC, the appendix (64.5%, 331/513) was more frequently involved, followed by colon (28.1%, 144/513) and rectum (7.4%, 38/513). The MANEC at different anatomical locations had a distinct clinicopathological characteristic, and colorectal MANEC was significantly associated with more aggressive biological features. The survival outcomes of appendiceal MANEC were significantly better than that of colorectal MANEC (3-year CSS rate 73.8% vs 59.4%, P = 0.010; 3-year OS 69.2% vs 48.3%, P < 0.001). In addition, hemicolectomy had a better survival benefit than appendicectomy for patients with appendiceal MANEC, regardless of lymph node metastasis (P < 0.05). Tumor location, histology gradeIII, tumor size > 2cm, T3-T4 stage, lymph node metastasis, and distant metastasis were independent prognostic factors for patients with MANEC. Tumor location had an important prognostic significance for MANEC. As an uncommon clinical entity, colorectal MANEC had more aggressive biological features and worse prognosis than its appendiceal counterpart. The standard surgical procedure and clinical management strategy for MANEC need to be established.

Clinicopathological characteristics of mixed neuroendocrine-non-neuroendocrine neoplasms in gastrointestinal tract.

In 2019, the World Health Organization (WHO) classification system updated the definition of mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), previously known as mixed adenoneuroendocrine carcinomas (MANECs). The clinicopathological characteristics of this new definition remains to be clarified. We analyzed the clinical data of 43 patients diagnosed with MiNENs in Wuhan Union Hospital from 2011 to 2020 according to the definition of MiNENs proposed in 2019. Among the 43 patients with MiNENs, the top two most common sites were stomach and colon, and 69.8% were males. Nearly half (21/43) of the patients were diagnosed at TNM stage III, and about 53.5% (23/43) of patients were the neuroendocrine neoplasm dominant type. Among the non-neuroendocrine tumor components of 43 MiNENs patients, adenocarcinoma accounted for 95.3% (41/43) and squamous cell carcinoma accounted for 4.7% (2/43)；95.3% (41/43) of the neuroendocrine neoplasm components were neuroendocrine carcinoma (NEC) and 4.7% (2/43) were neuroendocrine tumor (NET). Approximately 60.5% (26/43) neuroendocrine components had a Ki-67 index ≥55%. In addition, we further compared the prognosis of different subtypes of the MiNENs based on the neuroendocrine neoplasm component and non-neuroendocrine neoplasm component, and the results showed that there was no significant difference in survival between different subtypes of MiNENs (P>0.05). MiNENs can exhibit diverse clinicopathological characteristics, and there is no significant difference in prognosis among MiNENs subtypes, indicating that the definition of MiNENs can well summarize the prognosis of this type of tumor.

The other colon cancer: a population-based cohort study of appendix tumour trends and prognosis.

Appendiceal neoplasms are rare subtypes of colorectal tumours that mainly affect younger patients some 20 years earlier than other colon tumours. The aim of this study was to gain more insight into the histological subtypes of this rare disease and include cases previously excluded, such as mucinous neoplasia. The cohort study included 1097 patients from the Munich Cancer Registry (MCR) diagnosed between 1998 and 2020. Joinpoint analysis was used to determine trend in incidence. Baseline demographic comparisons and survival analyses using competing risk and univariate/multivariate methods were conducted according to tumour histology: adenocarcinoma (ADENO), neuroendocrine neoplasia (NEN), mixed adeno-neuroendocrine carcinoma (MANEC), and low- (LAMN) and high-grade mucinous neoplasia (HAMN). Up to 2016 the number of cases increased significantly [annual per cent change (APC)=6.86, p< 0.001] followed by a decline in the following years (APC=-14.82, p= 0.014; average APC=2.5, p= 0.046). Comparison of all patients showed that NEN (48.4%) and mucinous neoplasms (11.6%) had a considerably better prognosis than ADENO (36.0%) and MANEC (3.0%, p< 0.0001). A multivariate analysis within the NEN and ADENO subgroups revealed that further histological classification was not prognostically relevant, while older age and regional tumour spread at diagnosis were associated with a poor prognosis. ADENO histology with high tumour grade and appendectomy only was also associated with poorer survival. Appendiceal neoplasms are histologically heterogeneous; however, this diversity becomes less relevant compared with the marked difference from cancers of the remaining colon. The previously observed increase in cases appears to be abating; fewer cases of appendicitis and/or appendectomies or changes in histopathological assessment may be behind this trend.

Molecular profiling of gastric neuroendocrine carcinomas.

451 Background: Reports of comprehensive genetic analysis of gastric neuroendocrine carcinoma (G-NEC) are limited, and few have described the tumorigenesis of G-NEC. G-NEC usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because these two tumors share common pathogenic mutations and loss of heterozygosity. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis than that of G-NEC with adenocarcinoma. This study aimed to elucidate the tumorigenesis of G-NEC by focusing on the percentage of NEC component, using comprehensive genetic analysis. Methods: Of the 698 patients who had undergone gastrectomy for gastric cancer between January 2014 and March 2019, this study included 13 patients with G-NEC. Comprehensive genetic analysis using whole-exome sequencing, deep sequencing using a target gene panel, and microarray analysis were performed. NEC was classified according to the 2010 WHO classification. G-NEC without an adenocarcinoma component was defined as pure NEC. Results: There were six patients with mixed adeno-neuroendocrine carcinoma (MANEC), four patients with NEC, and three patients with pure NEC. TP53 was detected as the most frequent gene mutation, independent of classification (85%). RB1, ANKRD17, KMT2C, LTBP1, MAATS1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Gene expression analysis showed that six key transcripts of importance in NEC tumorigenesis were upregulated in two patients with pure NEC, while they were downregulated in all six MANEC patients. Conclusions: NEC and MANEC with adenocarcinoma components tend to share common pathogenic mutations, but Pure NEC has different genomic and transcriptomic characteristics than other NECs. This suggests that pure NEC has a different mechanism of tumorigenesis than other G-NECs with adenocarcinoma. This is the first study to present a comprehensive genetic analysis of G-NEC, classified by the percentage of NEC components.

Relationships of tumor differentiation and immune infiltration in gastric cancers revealed by single-cell RNA-seq analyses

Gastric cancers are highly heterogeneous malignant tumors. To reveal the relationship between differentiation status of cancer cells and tumor immune microenvironments in gastric cancer, single-cell RNA-sequencing was performed on normal mucosa tissue, differentiated gastric cancer (DGC) tissue, poorly differentiated gastric cancer (PDGC) tissue and neuroendocrine carcinoma (NEC) tissue sampled from surgically resected gastric cancer specimens. We identified the signature genes for both DGC and PDGC, and found that signature genes of PDGC strongly enriched in the epithelial–mesenchymal transition (EMT) program. Furthermore, we found that DGC tends to be immune-rich type whereas PDGC tends to be immune-poor type defined according to the density of tumor-infiltrating CD8+ T cells. Additionally, interferon alpha and gamma responding genes were specifically expressed in the immune-rich malignant cells compared with immune-poor malignant cells. Through analyzing the mixed adenoneuroendocrine carcinoma, we identified intermediate state malignant cells during the trans-differentiation process from DGC to NEC, which showed double-negative expressions of both DGC marker genes and NEC marker genes. Interferon-related pathways were gradually downregulated along the DGC to NEC trans-differentiation path, which was accompanied by reduced CD8+ cytotoxic T-cell infiltration. In summary, molecular features of both malignant cells and immune microenvironment cells of DGC, PDGC and NEC were systematically revealed, which may partially explain the strong tumor heterogeneities of gastric cancer. Especially along the DGC to NEC trans-differentiation path, immune-evasion was gradually enhanced with the decreasing activities of interferon pathway responses in malignant cells.