IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).

The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

Total Versus Subtotal Gastrectomy for Distal Gastric Poorly Cohesive Carcinoma.

BACKGROUND: Gastric poorly cohesive carcinoma (PCC) in advanced stages has a poor prognosis. Total gastrectomy (TG) remains the common treatment for distal gastric PCC, but subtotal gastrectomy (SG) may improve quality of life without compromising outcomes. Currently, no clear recommendation on the best surgical strategy for distal PCC is available. This study aimed to compare overall survival (OS) and disease-free survival (DFS) at 5 years for patients with antropyloric PCC treated by total versus subtotal gastrectomy. METHODS: A large retrospective European multicenter cohort study analyzed 2131 patients treated for gastric cancer between 2007 and 2017 by members of the French Association of Surgery (AFC). The study compared a group of patients who underwent TG with a group who underwent SG for antropyloric PCC. The primary outcomes were 5 year OS and DFS. RESULTS: The study enrolled 269 patients: 140 (52.0%) in the TG group and 129 (48.0%) in the SG group. The baseline characteristics and pTNM stage were similar between the two groups. According to Dindo-Claven classification, the patients treated with TG had more postoperative complications than the patients treated with SG (p < 0.001): grades I to IIIa (77.1% vs 59.5%) and grades IIIb to IVb (14.4% vs 9.0%). No difference in 5-year OS was observed between TG (53.8%; 95 % confidence interval [CI], 43.2-63.3%) and SG (53.0%; 95% CI, 41.4-63.3%) (hazard ratio [HR], 0.94; 95% CI, 0.68-1.29). The same was observed for 5-year DFS: TG (46.0%; 95% CI, 35.9-55.5%) versus SG (45.3%; 95% CI, 34.3-55.6%) (HR, 0.97; 95% CI, 0.70-1.34). CONCLUSIONS: At 5 years, SG was not associated with worse OS and DFS than TG for distal PCC. Surgical morbidity was higher after TG. Subtotal gastrectomy is a valuable option for distal PCC gastric cancer.

Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells.

Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.

USP51/ZEB1/ACTA2 axis promotes mesenchymal phenotype in gastric cancer and is associated with low cohesion characteristics.

poorly cohesive (PC) gastric cancer (GC) (PC-GC) is a distinct histological subtype of GC and is defined as a tumor consisting of isolated or small clusters of tumor cells with poorly differentiated and metastatic characteristics. According to multiple studies, PC-GC is intrinsically heterogeneous, with mesenchymal variants being the most aggressive. However, to date, the molecular mechanisms associated with PC-GC are still not fully understood. This study investigated the role of the USP51/ZEB1/ACTA2 axis in promoting GC metastasis. Single-cell sequencing revealed that E-box binding homeobox 1 (ZEB1) expression was significantly increased in a subpopulation of low-adherent cells and was an independent prognostic factor in GC patients. Furthermore, the bulk transcriptome analysis revealed a significant positive correlation between Ubiquitin Specific Peptidase 51 (USP51), ZEB1, and Actin Alpha 2 (ACTA2), and our data further confirmed that all three were highly co-localized in PC-GC tissues. According to the findings of in vitro and in vivo experiments, USP51 was able to maintain ZEB1 expression to promote ACTA2 transcription, thereby activating the mesenchymal phenotype of GC cells and promoting tumor metastasis. Moreover, USP51 could recruit and activate stromal cells, including M2-like macrophages and fibroblasts, through cancer cells. Clinical data suggested that overexpression of USP51 predicts that patients have difficulty benefiting from immunotherapy and is associated with immune-exclusion tumor characteristics. Collectively, the findings of this study shed light on a key mechanism by which elevated USP51 expression induces Epithelial-mesenchymal transition (EMT) in GC cells, hence facilitating GC cell proliferation, survival, and dissemination. In this view, USP51/ZEB1/ACTA2 may serve as a candidate therapeutic target against GC metastasis.

Molecular profile of poorly cohesive gastric carcinoma with special reference to survival.

BACKGROUND: Patients with poorly cohesive gastric carcinoma (PCC) are known to have poor survival. However, detailed molecular biology of PCC has not been elucidated, except for mutations in CDH1 and RHOA. Additionally, the molecular profiles of signet-ring cell carcinoma (SRC) have not been fully investigated. We aimed to investigate the association between molecular profiles and survival in PCC and PCC subtypes. METHODS: The present study included 455 patients with gastric adenocarcinoma underwent radical gastrectomy. Whole-exome sequencing and gene expression profiling were conducted. Patients were classified according to the WHO classification as PCC or non-PCC, with PCC being further classified into SRC, combined, and PCC not-otherwise-specified (NOS). Clinicopathological factors and survival were compared with molecular profiles. RESULTS: Of the patients, 159 were classified with PCC, while 296 were classified with non-PCC. Among PCC, 44 were classified with SRC, 64 with combined, and 51 with PCC-NOS. Mutations in CDH1 and RHOA were remarkably more frequent in PCC than in non-PCC. PCC had worse overall survival (OS) and disease-specific survival (DSS) compared to non-PCC. For PCC, the SRC group had good OS and DSS, whereas PCC-NOS classification with CDH1 mutations was associated with extremely poor survival. In the PCC-NOS and combined groups, patients with mutations in the extracellular domain 1 of CDH1 had poor survival. CONCLUSIONS: Our findings suggest that PCC has poorer survival than non-PCC. Accumulation of CDH1 and RHOA mutations are unique profiles in PCC. Among PCC, CDH1 mutations may play a crucial role in the survival of non-SRC PCC.

Clinicopathological analysis of a type of "low grade" poorly cohesive gastric adenocarcinoma not otherwise specified with a good prognosis.

Poorly cohesive carcinoma not otherwise specified (PCGCA-NOS) is regarded in the most recent WHO classification as a high-grade malignancy; however, some cases may be associated with a relatively good prognosis. We have studied a series of 115 cases of PCGCA-NOS and were able to identify low-grade features in 14 cases based on three morphological manifestations. Immunohistochemical staining, EBER in situ hybridization, Feulgen staining and flow cytometry were employed. Among the 115 cases of PCGAC-NOS, 14 cases met the criteria of "low grade", accounting for 12.2 %. The "low grade" cases exhibited more shallow invasion and less lymph node metastasis (both P < 0.05); showed less frequent expression of MUC5AC, E-cadherin and p53 (all P < 0.05). Moreover, "low grade" PCGAC-NOS had a lower proliferative index(P < 0.001). We also found that the DNA content was lower in the "low grade" group, and aneuploidy was not detected in the "low grade" group, which was sharply different from the control group (50 %). Last, "low grade" PCGAC-NOS had a more favorable prognosis. A small subset of PCGAC-NOS cases have a low grade nature, and the clinicopathological features, immunophenotypes, and cytogenetics of these "low grade" cases differ from those of traditional PCGAC-NOS.

Clinicopathological characteristics and prognosis of poorly cohesive cell subtype of gastric cancer.

BACKGROUND: The new World Health Organization (WHO) classification of gastric cancer includes a histological subtype of poorly cohesive carcinoma (PCC), which includes signet-ring cell (SRC) phenotype. We aimed to examine the concordance between preoperative clinical and postoperative histological diagnoses according to the 2010 WHO histological subtypes and to compare the prognoses of these subtypes. METHODS: The study cohort comprised 665 patients who underwent gastrectomy from 2005 to 2019. Histological subtypes were classified into PCC-NOS (non-signet ring cell subtype), SRC, and non-PCC, which were defined by the predominant component in accordance with the 2010 WHO classification of gastric cancer. The concordance of clinical and pathological diagnosis was examined and clinicopathological characteristics and survival outcome of the three subtypes compared. RESULTS: The cancers of 443 patients (66.7%) were classified as non-PCC, of 112 patients (16.8%) as PCC-NOS, and of 110 patients (16.5%) as SRC predominant subtypes. Significant differences in sex, age, tumor location, size, macroscopic type, and pathological TNM category (all P<0.05) were found. The concordance rate of preoperative and postoperative histological subtypes was significantly lower for poorly cohesive than other subtypes (P<0.0001). Preoperative stage tended to be underestimated for PCC-NOS subtype and these patients had poorer overall survival than those with the other two subtypes (P=0.005). Multivariate logistic regression analysis of overall survival showed that WHO histological subtype (PCC-NOS vs. non-PCC/SRC, HR: 1.64, 95% CI: 1.18-2.29, P=0.0034) was a significant independent prognostic factor. CONCLUSION: Our results suggest that poorly cohesive carcinoma subtypes have different biological characteristics and prognoses.

FGFR2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma.

BACKGROUND: Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. METHODS: Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. RESULTS: Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. CONCLUSIONS: FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

[Poorly cohesive gastric carcinoma. Validity of using the term; translation variants]. / Kartsinoma zheludka iz plokho stseplennykh kletok. Pravomochnost' ispol'zovaniya termina i varianty perevoda.

Gastric cancer is one of the leading causes of cancer morbidity and mortality worldwide. It is common practice to use two classification systems: the Lauren classification system and the WHO classification of tumors in the morphological study of gastric carcinomas. Since 2010, the WHO classifications have included the term "poorly cohesive carcinoma", which refers to all diffuse forms of gastric cancer, including signet ring cell carcinoma and other subtypes. Despite this, the term has not been widely used in the world community, and it is almost not found in Russian literature. Only recently, after the publication of the 5th edition of the WHO classification (2019), there have been review articles where the term is used, but its name can be translated into Russian in different ways: poor-, weak -, low-adhesive, discogesive. The paper analyzes the Pubmed and Elibrary databases in order to find out the frequency of using various designations for diffuse gastric carcinoma, justifies the use of the term «poorly cohesive carcinoma¼, and proposes a variant of the term interpretation in Russian.

The amount of signet ring cells is significantly associated with tumour stage and survival in gastric poorly cohesive tumours.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether the amount of signet ring cells (SRCs) affects clinicopathological characteristics and prognosis of poorly cohesive (PC) gastric tumours. STUDY DESIGN: One hundred seventy-three patients with PC tumours treated at three European centres from 2004 to 2014 were reclassified in three categories: (a) pure SRC cancers (SRC1) (≥90% SRCs); (b) PC carcinoma with SRC component (SRC2) (>10%, <90% SRCs); (c) PC carcinoma not otherwise specified (SRC3) (≤10% SRCs). RESULTS: The percentage of SRCs was inversely related to the pT stage (Spearman's ρ = -0.174, P < .001) and the number of positive nodes coded as a continuous variable (P = .009). Five year cancer-related survival was significantly higher (58%, 95% confidence interval [CI]: 36%-75%) in SRC1 compared with SRC2 (39%, 95% CI: 28%-50%) and SRC3 (38%, 95% CI: 22%-53%), (P = .048). In multivariable analysis, the impact of PC categories on cancer-related survival was significant when controlling for sex, age, pT, pN, and curativity (hazard ratio [HR] of sSRC2 vs SRC1 = 2.08, 95% CI: 1.01-4.29, P = .046; HR of SRC3 vs SRC1 = 2.38, 95% CI: 1.05-5.41, P = .039). CONCLUSION: The percentage of SRCs was inversely related to tumour aggressiveness, with long-term survival significantly higher in SRC1 compared with SRC2 and SRC3 tumours.

[Changes in the classification of malignant colon epithelial neoplasms. (WHO, 2019, 5th edition)]. / Novoe v klassifikatsii zlokachestvennykh epitelial'nykh opukholei tolstoi kishki. (VOZ, 2019, 5-e izdanie).

There are not many changes compared to 2010 in WHO classification (2019) of colon adenocarcinomas. Cribriform comedo-type adenocarcinoma (ICD-O code: 8201/3), spindle cell carcinoma (8032/3), squamous cell carcinoma (8070/3) are excluded; carcinoma with a sarcomatoid component (8033/3), poorly cohesive carcinoma (8490/3) and adenoma-like adenocarcinoma (8262/3) were added. The important histological characteristics in the conclusion should indicate the presence of lymphatic invasion, intra- and extramural vascular invasion, perineural invasion, grading, «tumor budding¼ and the immune microenvironment. In the 5th edition of the classification a large section has been added regarding molecular diagnostics and molecular prognostic factors of colorectal cancer. Correspondence was found between two different classifications based on two different approaches: genomic (according to DNA analysis) and transcriptomic (according to RNA analysis). According to the genomic classification two large groups of colorectal cancer are distinguished: hypermutated and non-hypermutated cancers that correspond to molecular pathways with the development of microsatellite and chromosomal instabilities, respectively. The section of neuroendocrine tumors did not undergo significant changes. It is not recommended to use the term «carcinoid¼ to refer to a neuroendocrine tumor G1, that is, the term «carcinoid¼ is excluded.

Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma.

BACKGROUND AND AIMS: Clinicopathological characteristics of gastric cancer (GC) are changing, especially in the West with a decreasing incidence of distal, intestinal-type tumours and the corresponding increasing proportion of tumours with Laurén diffuse or WHO poorly cohesive (PC) including signet ring cell (SRC) histology. To accurately assess the behaviour and the prognosis of these GC subtypes, the standardization of pathological definitions is needed. METHODS: A multidisciplinary expert team belonging to the European Chapter of International Gastric Cancer Association (IGCA) identified 11 topics on pathological classifications used for PC and SRC GC. The topics were debated during a dedicated Workshop held in Verona in March 2017. Then, through a Delphi method, consensus statements for each topic were elaborated. RESULTS: A consensus was reached on the need to classify gastric carcinoma according to the most recent edition of the WHO classification which is currently WHO 2010. Moreover, to standardize the definition of SRC carcinomas, the proposal that only WHO PC carcinomas with more than 90% poorly cohesive cells having signet ring cell morphology have to be classified as SRC carcinomas was made. All other PC non-SRC types have to be further subdivided into PC carcinomas with SRC component (< 90% but > 10% SRCs) and PC carcinomas not otherwise specified (< 10% SRCs). CONCLUSION: The reported statements clarify some debated topics on pathological classifications used for PC and SRC GC. As such, this consensus classification would allow the generation of evidence on biological and prognostic differences between these GC subtypes.

Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes.

AIMS: Genome-wide next-generation sequencing has revealed several driver mutations and has allowed the establishment of a molecular taxonomy of gastric cancer. However, there are few detailed studies on the mutational spectrum of poorly cohesive gastric carcinoma. Thus, this study aim to investigate its mutation profile based on clinicopathological characteristics. METHODS AND RESULTS: Herein, we analysed the mutational pattern of 77 genes in a cohort of 91 patients with poorly cohesive carcinoma by using targeted sequencing, and evaluated the clinicopathological significance of the various mutations based on histological pattern, either signet ring cell (SRC) or other types of poorly cohesive carcinoma (not otherwise specified) (PCC-NOS). Panels of seven (PIK3CA, CDH1, PTEN, RHOA, HDCA9, KRAS, and ATM), three (PIK3CA, CTNNB1, and KRAS) and two (HDCA9 and IGF1R) genes were associated with a diffuse infiltrative growth pattern, lymphovascular invasion, and perineural invasion, respectively. Furthermore, PDGFRB mutations were associated with a favourable prognosis, whereas MET mutations were associated with a poor prognosis. The PCC-NOS-predominant type was associated with a greater depth of invasion, lymph node metastasis and poorer prognosis than the SRC-predominant type. Mutations in TP53, BRAF, PI3CA, SMAD4 and RHOA were associated with PCC-NOS. Interestingly, RHOA-mutated gastric cancers showed a distinct morphology, as they were characterised by a superficial SRC or tubular component and a deep invasive PCC-NOS component with desmoplasia. CONCLUSIONS: Taken together, our findings demonstrate that gastric poorly cohesive carcinomas show several mutational patterns associated with specific clinicopathological characteristics, and particularly show distinct morphological findings when associated with RHOA mutation.

CT Perfusion evaluation of gastric cancer: correlation with histologic type.

OBJECTIVES: To prospectively evaluate if the perfusion parameters of gastric cancer can provide information on histologic subtypes of gastric cancer. METHODS: We performed preoperative perfusion CT (PCT) and curative gastrectomy in 46 patients. PCT data were analysed using a dedicated software program. Perfusion parameters were obtained by two independent radiologists and were compared according to histologic type using Kruskal-Wallis, Mann-Whitney U test and receiver operating characteristic analysis. To assess inter-reader agreement, we used intraclass correlation coefficient (ICC). RESULTS: Inter-reader agreement for perfusion parameters was moderate to substantial (ICC = 0.585-0.678). Permeability surface value of poorly cohesive carcinoma (PCC) was significantly higher than other histologic types (47.3 ml/100 g/min in PCC vs 26.5 ml/100 g/min in non-PCC, P < 0.001). Mean transit time (MTT) of PCC was also significantly longer than non-PCC (13.0 s in PCC vs 10.3 s in non-PCC, P = 0.032). The area under the curve to predict PCC was 0.891 (P < 0.001) for permeability surface and 0.697 (P = 0.015) for MTT. CONCLUSION: Obtaining perfusion parameters from PCT was feasible in gastric cancer patients and can aid in the preoperative imaging diagnosis of PCC-type gastric cancer as the permeability surface and MTT value of PCC type gastric cancer were significantly higher than those of non-PCC. KEY POINTS: • Obtaining perfusion parameters from PCT was feasible in patients with gastric cancer. • Permeability surface and MTT were significantly higher in poorly cohesive carcinoma (PCC). • Permeability surface, MTT can aid in the preoperative imaging diagnosis of PCC.

Poorly cohesive gastric cancer with increased epithelial­mesenchymal transition is associated with a poor prognosis.

The present study examined the surgical outcome and prognosis of patients with poorly cohesive carcinoma (PCC), and characterized the molecular pathological factors, epithelial-mesenchymal transition (EMT) and interstitial signals of the disease. A total of 281 patients who underwent gastric cancer (GC) surgery between April 2015 and August 2020 were included. Furthermore, tissue samples from another 197 patients with GC who underwent surgery between 1999 and 2003 were assessed using a tissue microarray. Preoperatively treated cases and endoscopic submucosal dissection cases were excluded, and multiple blocks containing the invasion region were collected for tissue microarray. For tissue microarray analysis, the clinicopathological factors of protein wnt3a (wnt3a), leucine-rich repeat-containing G-protein coupled receptor 5, transforming growth factor-ß-induced, phosphorylated serine/threonine-protein kinase mTOR and E-cadherin expression were collected as EMT markers. The results of the surgical case evaluation and tissue microarray indicated that PCC was more common in younger patients and women, as the ratio of women to men was higher in the PCC group compared with that in the non-PCC group. However, none of the results revealed that the prognosis was worse in all patients with PCC compared with the non-PCC group. Furthermore, in the tissue microarray study, PCC samples exhibited significantly decreased expression of the cell adhesion molecule E-cadherin, suggesting enhanced EMT, which activates wnt3a signaling. PCC with increased EMT was significantly associated with a poor prognosis.

Influence of Tumor Stroma on the Aggressiveness of Poorly Cohesive Gastric Carcinoma.

Tumor-stroma crosstalk promotes the adaptation of cancer cells to the local microenvironment and sustains their growth. We assessed the quantitative and qualitative impact of intralesional stroma on clinic-pathological features and the prognosis of poorly cohesive gastric cancer (PCGC) variants. Tissue microarrays including 75 PCGC specimens were immunostained for cytokeratin 8/18 and α-smooth muscle actin to assess the relative proportion of neoplastic cells versus stromal components and the cases were subsequently divided into stroma-rich (SR) and stroma-poor (SP) tumors. Stromal status is significantly associated with the depth of tumor invasion. Patient survival rate was found to be higher in the SP compared to the SR tumor group and, hence, abundant stroma was identified as a significant risk factor in univariable analysis but had no independent prognostic impact. We also investigated the mRNA levels of KRT8 and the associated transcriptional signatures using the molecular data of 82 PCGC cases divided into KRT8-high and KRT8-low groups. KRT8-high tumors were enriched in proteins localized in the extracellular compartment and their expression levels correlated with longer survival in the KRT8-high group and shorter overall survival in the KRT8-low group. Comprehensively, we find that relative intralesional stromal content is a marker of aggressiveness in PCGC tumors and that extracellular proteins characterize functionally and clinically different PCGC subgroups.

Poorly Cohesive Carcinoma of the Nonampullary Small Bowel: A Rare Cause of Recurrent Small Bowel Obstruction.

Poorly cohesive carcinoma (PCC) is an uncommon neoplasm characterized by tumorous cells exhibiting a lack of adhesion. PCC has been reported rarely in the small intestine other than at the ampulla of Vater. We present a 40-year-old man with recurrent abdominal pain and small bowel obstruction. Imaging revealed an abnormal appearing distal small bowel, with only nonspecific mucosal changes discovered on antegrade and retrograde enteroscopy. On subsequent diagnostic laparoscopy, an ileal mass was found and resected with histopathology showing PCC with signet ring formation. This is an aggressive cancer with a worse prognosis than other small bowel adenocarcinomas.

Clinicopathological features and cancer transcriptomic profiling of poorly cohesive gastric carcinoma subtypes.

Gastric poorly cohesive carcinoma (PCC) manifests with a diffuse pattern and diverse tumor cell morphologies, often indicating a more unfavorable prognosis. Recent consensus has reclassified PCC based on the proportion of signet-ring cells (SRCs) in tumors for research purposes. The two most distinct subtypes, poorly cohesive carcinoma not otherwise specified (PCC-NOS) and signet-ring cell carcinoma (SRCC), are characterized by less than 10% and more than 90% SRCs, respectively. However, research comparing the clinicopathological and transcriptomic differences between these subtypes remains limited. In this study, we conducted a comparative analysis of clinicopathological features in 55 advanced-stage PCCs, consisting of 43 PCC-NOS and 12 SRCC cases. Subsequently, 12 PCC-NOS and 5 SRCC cases were randomly selected for initial cancer-related gene expression profiling and pathway enrichment analysis using the GeoMx digital spatial profiler, followed by validation in a separate validation group comprising 16 PCC-NOS and 6 SRCC cases. These transcriptomic findings were then correlated with tumor morphology and clinicopathological data. PCC-NOS cases exhibited larger tumor size, a higher prevalence of pathological N3 disease, and a worse 1-year progression-free survival rate compared to SRCC cases. Clustering of PCC-NOS and SRCC was successfully achieved using the GeoMx Cancer Transcriptome Atlas. Among all studied genes, only MMP7 showed differential expression, with its overexpression significantly associated with the PCC-NOS subtype, increased perineural invasion, and earlier disease progression. Pathway analysis revealed significantly enriched pathways in PCC-NOS related to vesicle-mediated transport, adaptive immune systems, oncogenic signaling, and extracellular matrix organization, while SRCC displayed significant enrichment in pathways associated with respiratory electron transport and the cell cycle. In conclusion, this study compares and correlates clinicopathological features and transcriptomic data between PCC-NOS and SRCC at advanced stages, employing the latest consensus classification and a novel platform for analysis.

Gastroesophageal signet ring cell carcinoma morbidity and mortality: A retrospective review.

BACKGROUND: Upper gastrointestinal (GI) signet ring cell carcinomas (SRCC) confer a poor prognosis. The benefit of operative intervention for this patient group is controversial in terms of overall survival. AIM: To investigate factors relating to survival in patients with upper GI SRCC. METHODS: A retrospective, tertiary, single-centre review of patients who were diagnosed with oesophageal, gastroesophageal junction and gastric SRCC was performed. The primary outcome was to compare mortality of patients who underwent operative management with those who had nonoperative management. Secondary outcomes included assessing the relationship between demographic and histopathological factors, and survival. RESULTS: One hundred and thirty-one patients were included. The one-year survival for the operative group was 81% and for the nonoperative group was 19.1%. The five-year survival in the operative group was 28.6% vs 1.5% in the nonoperative group. The difference in overall survival between groups was statistically significant (HR 0.19, 95%CI (0.13-0.30), P < 0.001). There was no difference in survival when adjusting for age, smoking status or gender. On multivariate analysis, patients who underwent surgical management, those with a lower stage of disease, and those with a lower Charlson Comorbidity Index (CCI) had significantly improved survival. CONCLUSION: Well-selected patients with upper GI SRCC appear to have reasonable medium-term survival following surgery. Offering surgery to a carefully selected patient group may improve the outcome for this disease.

Systematic review of risk factors, prognosis, and management of colorectal signet-ring cell carcinoma.

BACKGROUND: Colorectal signet-ring cell carcinoma (CSRCC) is a rare clinical entity which accounts for approximately 1% of all colorectal cancers. Although multiple studies concerning this specific topic have been published in the past decades, the pathogenesis, associated risk factors, and potential implications on treatment are still poorly understood. Besides the low incidence, historically confusing histological criteria have resulted in confusing data. Nevertheless, the rising incidence of CSRCC along with relatively young age at presentation and associated dismal prognosis, highlight the actual interest to synthesize the known literature regarding CSRCC. AIM: To provide an updated overview of risk factors, prognosis, and management of CSRCC. METHODS: A literature search in the MEDLINE/PubMed database was conducted with the following search terms used: 'Signet ring cell carcinoma' and 'colorectal'. Studies in English language, published after January 1980, were included. Studies included in the qualitative synthesis were evaluated for content concerning epidemiology, risk factors, and clinical, diagnostic, histological, and molecular features, as well as metastatic pattern and therapeutic management. If possible, presented data was extracted in order to present a more detailed overview of the literature. RESULTS: In total, 67 articles were included for qualitative analysis, of which 54 were eligible for detailed data extraction. CSRCC has a reported incidence between 0.1%-2.4% and frequently presents with advanced disease stage at the time of diagnosis. CSRCC is associated with an impaired overall survival (5-year OS: 0%-46%) and a worse stage-corrected outcome compared to mucinous and not otherwise specified adenocarcinoma. The systematic use of exploratory laparoscopy to determine the presence of peritoneal metastases has been advised. Surgery is the mainstay of treatment, although the rates of curative resection in CSRCC (21%-82%) are lower compared to those in other histological types. In case of peritoneal metastasis, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should only be proposed in selected patients. CONCLUSION: CSRCC is a rare clinical entity most often characterized by young age and advanced disease at presentation. As such, diagnostic modalities and therapeutic approach should be tailored accordingly.