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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. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical behaviour of signet ring cell histology in gastric cancer has long been a subject of controversy. Recent years have underscored the pressing issue of a lack of a standardised definition for signet ring cell histology, leading to its often-ambiguous placement within broader categories associated with poor prognosis. Conversely, comparisons of signet ring cell gastric cancer have been made against a wide spectrum of non-signet ring cell cases, introducing significant heterogeneity. The primary objective of this literature search and subsequent meta-analysis was to gain a deeper understanding of signet ring cell gastric cancer. Our findings revealed that the prognosis of signet ring cell gastric cancer is intricately tied to the disease stage, yet it is also contingent on the specific comparison group employed. The variability in signet ring cell cancer's clinical behaviour may stem from the absence of a standardised definition. Therefore, it is imperative to work towards a uniform classification system for gastric cancer to enhance clarity and coherence in future research and clinical practice. Background: Conflicting results about the prognostic relevance of signet ring cell histology in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histologies. Methods: A systematic literature search in the PubMed database was conducted, including all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was performed. Results: A total of 2062 studies referring to gastric cancer with signet ring cell histology were identified, of which 262 studies reported on its relationship with clinical information. Of these, 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal metastases in signet ring cell tumours compared to other histotypes was found (especially to undifferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to-moderately differentiated adenocarcinoma. Conclusions: Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications. [ABSTRACT FROM AUTHOR]

Poorly cohesive (PC) gastric cancer (GC) is extremely aggressive in progression, and there is an urgent need to identify the molecular pathways involved. We hypothesized the essential role of the RhoA–YAP axis in these mechanisms. The present observational multicenter retrospective study included 133 patients with PC GC treated at two dedicated European surgical centers between 2004 and 2014. YAP nuclear localization was measured by immunohistochemical (IHC) analysis of tissue biopsies. The complete absence of nuclear reactivity was coded as negative expression; we considered "any positive" as low nuclear expression (>0% but <10% of cells) and high nuclear expression (≥10% of cells). Women represented about half of the present series (52%), and the median age was 64 years (p25–p75 range: 53–75). Neoadjuvant and adjuvant treatments were administered to 10% and 54% of the cases, respectively. Extended systemic lymphadenectomy (D2) was the most common (54%). In nearly all cases, the number of retrieved nodes was ≥15, i.e., adequate for tumor staging (94%). An R0 resection was achieved in 80% of the cases. Most patients were pathological T stage 3 and 4 (pT3/pT4 = 79.0%) and pathological N stage 2, 3a, and 3b (pN2/pN3a/pN3b = 47.0%) at the pathological examination. Twenty patients (15%) presented distant metastases. Five-year overall survival (OS) was significantly higher (p = 0.029) in patients with negative YAP (46%, 95% CI 31.1–60.0%) than in the other patients (27%, 17.5–38.1%). Moreover, when controlling for sex, age, pT, pN, and percentage of signet ring cells in the multivariable analysis, YAP expression was a significant predictor of OS (HR 2.03, 95% CI: 1.18–3.51, p = 0.011). Our results provide new insights into the role of the YAP signaling cascade, as its activation was associated with a worse prognosis in PC GC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Simple Summary: The classification of signet ring cell (SRC) carcinoma has been inconsistent and SRC carcinoma was classified as a subtype gastric cancer of poorly cohesive (PC) carcinoma. SRC and PC gastric carcinomas are morphologically similar but has been suggested to exhibit different biological behavior. We compared clinical and molecular characteristics of SRC and PC carcinomas. SRC and PC carcinomas showed significantly different clinical behavior that SRC carcinoma was associated with favorable clinical factors, suggesting that these subtypes should be classified and treated differently. SRC and PC carcinomas shared common transcriptome expression patterns, however, PC carcinomas showed an increased expression of genes related to cancer progression. Among genes differentially expressed between PC and SRC carcinomas, protein tyrosine phosphatase receptor type M (PTPRM) was overexpressed in PC and related to unfavorable clinical factors. PTPRM was identified as a potential diagnostic and prognostic biomarker for PC carcinoma. Background and aims. Signet ring cell (SRC) and poorly cohesive (PC) gastric carcinomas are morphologically similar but exhibit different biological behavior. We compared the clinical and molecular characteristics of SRC and PC carcinomas. Methods. Diffuse-type gastric cancer (GC) cases were classified into SRC carcinomas (>90% of SRCs), PC carcinomas (<10% of SRCs), and combined PC/SRC carcinomas (≤90% but ≥10% of SRCs). The gene expression patterns in SRC and PC carcinomas were examined by transcriptome and protein immunohistochemistry analyses, and diagnostic and prognostic biomarkers were identified. Results. SRC and PC carcinomas showed significantly different clinical behaviors but shared common RNA expression patterns. PC carcinomas showed an increased expression of genes related to cancer progression. Among genes differentially expressed between PC and SRC carcinomas, protein tyrosine phosphatase receptor type M (PTPRM) was overexpressed in PC and related to unfavorable clinical factors. Conclusion. We found that PC and SRC carcinomas had distinct clinical characteristics and should be classified as different carcinoma types. PTPRM was identified as a potential diagnostic and prognostic biomarker for PC carcinomas and could represent a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background and ObjectivesOnly recently the percentage of signet ring cells (SRCs) in gastric cancer (GC) has been proposed as an independent predictor of survival. High amounts of SRCs have been related to lower recurrence and mortality rates, better prognosis, and favorable clinicopathological features in a poorly cohesive histotype. It is not known what the effect of SRC percentage in mixed-type GC is. We investigate the role of SRCs as a prognostic marker in mixed-histotype GC.MethodsA retrospective analysis was performed through a prospectively maintained database of patients with diagnosed “mixed-type” gastric carcinoma, defined according to 2019 WHO classification. These patients underwent surgery between 1995 and 2016, and their tissue samples were stored in a tissue bank. All slides were analyzed, and patients were divided into three groups according to the percentage of SRCs: “Group 1” (displaying ≤10% of SRCs), “Group 2” (displaying 10% of SRCs), and “Group 3” (displaying ≥90% of SRCs). We compared clinical and pathological features as well as prognostic factors between the different groups.ResultsAmong 164 enrolled patients, 68.9% were male and 31.1% were female (p = 0.612). The mean (±SD) age at diagnosis was 71.4 ± 9.6 years. Ninety-eight (59.7%) patients were classified as “Group 1”, 66 (40.3%) as “Group 2”, and none as “Group 3”. Five-year overall survival was remarkably higher in Group 2 (73.8%) in comparison to Group 1 (35.4%), p < 0.001. Mortality risk was three times higher in patients with ≤10% SRC pattern compared to those with >10% [HR 2.70 (95% CI 1.72–4.24)]. After adjusting according to potential confounding factors, SRC percentage was still an independent predictor of survival.ConclusionsThe proportion of SRCs is inversely related to aggressive behavior and poor prognosis in mixed-type GCs, highlighting the role of SRC amount as an independent predictor of survival.

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. [ABSTRACT FROM AUTHOR]

Frozen section examination of adenocarcinomas with poorly cohesive growth, including signet-ring cell carcinoma, is challenging. Due to their diffuse morphology, the tumor cells may be indistinct and difficult to distinguish from inflammatory or stromal cells. Misdiagnosis may result in significant adverse clinical outcome. We performed a detailed retrospective analysis of such cases to identify features that are helpful to avoid misdiagnosis at the time of frozen section. We reviewed the original frozen section slides from 50 patients with poorly cohesive carcinoma (PCC) including 32 with positive and 18 with negative frozen section slides. Tumor cells and inflammatory cells were evaluated for 17 distinct cytologic and nine architectural or stromal features. Features with 100% specificity and positive predictive value (PPV) for carcinoma included the presence of cells with a single distinct cytoplasmic mucin vacuole, focal gland formation, and perineural invasion. Features with high specificity, sensitivity, PPV, and negative predictive value (NPV) (all > 75%) included irregular nuclear contours, large nuclear size with many nuclei > 4× the size of a small lymphocyte, and disruption/obliteration of normal structures. Other features with high specificity and PPV (both ≥ 85%) but relatively low sensitivity and NPV-included crescent-shaped/indented nuclei, prominent nucleoli, anisonucleosis (> 4:1 difference in nuclear size), multinucleation, and the presence of mitotic figures. We characterized useful histologic features of poorly cohesive carcinoma that may serve to distinguish carcinoma cells from benign inflammatory or stroma cells. Knowledge of the relatively specific features in particular may help surgical pathologists avoid false-negative interpretation resulting in significant clinical morbidity. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Histologic mimics of poorly cohesive gastric carcinoma are uncommon but are important for pathologists to recognize. Here we report 2 cases of a novel histologic pattern mimicking poorly cohesive gastric carcinoma. In both cases, light microscopy revealed sheets of discohesive epithelial cells with prominent mitoses that have high proliferative activity, with a Ki67 proliferation index greater than 70%. One case was diagnosed as poorly cohesive carcinoma at an outside hospital and the other was referred in consultation as atypia of undetermined significance. Reexamination of the hematoxylin–eosin slides revealed morphologic clues that these sheets of discohesive cells represent artifactual extrusion of the highly proliferative neck zone from the surrounding benign mucosa. In contrast to poorly cohesive cancer, this artifact lacks all of the following diagnostic features: nuclear atypia, signet ring cell morphology, and intercellular stroma with infiltrating single cells between glands. Eight and 14 months later, both patients remain cancer free. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV)-associated gastric cancer (GC) is one of four major gastric cancer types and is traditionally considered to be related to lymphoepithelioma-like GC. Few studies have investigated the clinical significance of EBV infection in intestinal/solid type, diffuse (poorly cohesive) type, and lymphoepithelioma-like GC. Methods: A total of 460 GC patients receiving curative surgery were enrolled. The clinicopathological features, genetic alterations and prognoses were compared between patients with and without EBV infection. Results: EBV-positive GC patients (n = 43) had more tumors located in the upper and middle stomach, more common in lymphoepithelioma-like carcinoma, more lymphoid stroma, fewer Helicobacter pylori infections, and higher programmed death-ligand 1 (PD-L1) expression than EBV-negative GC patients. For intestinal/solid type GC, EBV-positive tumors were more likely to be located in the upper and middle stomach, have more lymphoid stroma, fewer Helicobacter pylori infections, higher PD-L1 expression, and more liver metastases than EBV-negative tumors. For diffuse (poorly cohesive) type GC, EBV-positive tumors were more likely to be located in the upper stomach, and have more lymphoid stroma than EBV-negative tumors. For lymphoepithelioma-like GC, EBV-positive tumors had more PI3K/AKT pathway mutations than EBV-negative tumors. Conclusions: Intestinal/solid type GC patients with EBV-positive tumors were associated with higher PD-L1 expression and more liver metastases, while lymphoepithelioma-like GC patients with EBV-positive tumors had more PI3K/AKT pathway mutations. Immunotherapy and targeted therapy may be beneficial for these groups of patients. Routine EBV survey is recommended in GC. [ABSTRACT FROM AUTHOR]