Adolescents and young adults (AYA) with germline CDH1 variants are at risk of overtreatment when precancer lesions are detected with endoscopic screening. We characterize diffuse-type gastric cancer prevalence and survival in AYA managed with prophylactic total gastrectomy (PTG) or endoscopic surveillance.

Prospective cohort study of 188 individuals aged 39 and younger enrolled from January 27, 2017, to May 1, 2023. Clinicopathological data, prevalence of early gastric signet ring cell (SRC) lesions, advanced gastric cancer diagnoses, and cancer-specific survival were measured.

Among 188 AYA patients, 104 chose surveillance and 67 pursued PTG for management of elevated gastric cancer risk. AYA who enrolled early in the study period and had SRC lesions detected on preoperative endoscopy were more likely to elect for PTG compared with surveillance. SRC lesions were detected on preoperative endoscopy in 48% of patients who subsequently had PTG, and yet nearly all (93%, 62/67) had multifocal SRC (pT1aN0) on final pathology. Median age at enrollment (30 vs 31 years, P = .21), biological sex (P = .17), and median number of family members with gastric cancer (3 vs 4, P = .14) were not different between groups. No patients under surveillance developed advanced cancer or developed cancer recurrence after PTG with a median follow-up of 2.5 years (IQR = 1.6-4.0) from initial endoscopy.

Cancer-specific outcomes were not different in AYA who harbored SRC and were managed with surveillance or PTG. Lack of cancer-specific deaths and low prevalence of advanced gastric cancer underscore the risk of overtreatment of SRC lesions and suggest that active surveillance is warranted.

Development of diffuse-type gastric cancer (DGC) starts with intramucosal lesions that are primarily composed of differentiated, non-proliferative signet ring cells (SRCs). These indolent lesions can advance into highly proliferative and metastatic tumours, which requires suppression of DGC cell differentiation.

Our goal was to identify molecular changes contributing to the progression of indolent to aggressive DGC lesions.

We conducted spatial transcriptomic analysis of patient tumours at different stages of hereditary DGC, comparing transcriptional differences in tumour cell populations and tumour-associated cells. We performed functional analysis of identified changes in a human gastric (CDH1 KO) organoid model recapitulating DGC initiation.

Our analysis reveals that distinct DGC cell populations exhibit varying levels of Wnt-signalling activity, and high levels of Wnt signalling prevent differentiation into SRCs. We identify multiple adaptations during DGC progression that converge on Wnt signalling, allowing tumour cells to remain in an undifferentiated state as they disseminate away from the gastric stem cell niche. First, DGC cells establish a cell-autonomous source for Wnt-pathway activation through upregulated expression of Wnt-ligands and 'secreted frizzled-related protein 2' (SFRP2) that potentiates ligand-induced Wnt signalling. Second, early tumour development is marked by extracellular matrix remodelling, including increased deposition of collagen I whose interactions with DGC cells suppress their differentiation in the absence of exogenous Wnt ligands.

Our findings demonstrate that tumour cell-derived ligand expression and extracellular matrix remodelling sustain Wnt signalling during DGC progression. These complementary mechanisms promote niche independence enabling expansion of undifferentiated DGC cells needed for the development of advanced tumours.

Individuals with a germline pathogenic variant in the CDH1 gene have a lifetime risk of advanced diffuse gastric cancer (DGC) of up to 10.3% and a 37%-52% risk of breast cancer, specifically the lobular subtype. Guidelines recommend prophylactic gastrectomy between ages 18-40 years for those with a family history of DGC. For patients declining surgery or lacking a family history of DGC, annual endoscopic surveillance according to recommended protocols is an alternative. This case reviews the management of a patient with a history of Roux-en-Y gastric bypass followed one year later by a diagnosis of lobular breast cancer due to a germline CDH1 pathogenic variant.

Breast cancer (BC) is a common cancer in females. Spread to the gastrointestinal tract is rare. This is a 61-year-old woman with history of T2N0M0 lobular BC treated 5 years earlier. She underwent endoscopic evaluation for new-onset anemia and was found to have multiple gastric ulcers, a normal-appearing duodenum, and subtle colonic nodules. Targeted and random biopsies of abnormal and normal findings, respectively, showed adenocarcinoma with diffuse immunohistochemical staining compatible with her BC history. This highlights the importance of maintaining a high suspicion index in patients with lobular BC and the utility of random biopsies in such cases.

Prophylactic total gastrectomy (PTG) is performed in carriers of CDH1 pathogenic and likely pathogenic (P/LP) variants and is becoming more frequent with broader use of germline genetic testing. There is an unmet need to standardize care and enhance outcomes among patients undergoing surgery for the prevention of gastric cancer.

This was a retrospective analysis of 150 individuals with germline CDH1 P/LP variants who underwent PTG as part of a prospective natural history study from October 2017 to May 2023. All individuals received multidisciplinary, protocolized care before and after total gastrectomy.

A total of 150 asymptomatic patients with germline CDH1 P/LP variants underwent PTG with the aid of a multidisciplinary enhanced recovery after surgery (ERAS) pathway. This study demonstrated that acute major morbidity (Clavien-Dindo grade of ≥3) was low (17/150 [11.3%]) and that the most common complication was anastomotic leak (11/150 [7.3%]) in the setting of a comprehensive preoperative and postoperative care pathway. Nearly all gastrectomy specimens (132/150 [88.0%]) harbored occult signet ring cell lesions on final pathology. There were no gastric cancer recurrences or gastric cancer-related deaths during the study period, with a median overall follow-up of 36 months (IQR, 24-48) from gastrectomy.

PTG can be performed with low surgical morbidity in a high-volume center. The delivery of patient-centered care by a multidisciplinary team and the application of an ERAS pathway may improve short-term outcomes. However, interventions that can reduce chronic morbidity associated with total gastrectomy warrant further study.

To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13-19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

Gastric signet-ring cell carcinoma (GSRCC) is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis. Studies have shown that early GSRCC has a good prognosis, while advanced GSRCC is insensitive to radiotherapy, chemotherapy or immune checkpoint blockade therapy. With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry, more detailed atlas of tumor microenvironment (TME) in GSRCC and its association with prognosis could be investigated extensively. Recently, two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME, manifested as highly immunosuppressive, leading to high immune escape. The TME of advanced GSRCC was enriched for immunosuppressive factors, including the loss of CXCL13 +-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells. In addition, GSRCC was mainly infiltrated by follicular B cells. The increased proportion of SRCC was accompanied by a decrease in mucosa-associated lymphoid tissue-derived B cells and a significant increase in follicular B cells, which may be one of the reasons for the poor prognosis of GSRCC. By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism, more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Cancer susceptibility syndromes confer an increased lifetime risk of cancer and occur due to germline likely-pathogenic or pathogenic variants in a cancer susceptibility gene. Clinical Genetics services advise patients of ways to manage their future cancer risks, often prefaced with uncertainties due to poor understandings of individualised risk. For individuals/couples whose future offspring are at risk of a cancer susceptibility syndrome, different options are available depending on their preferences and circumstances, including prenatal diagnosis and preimplantation genetic testing. This review provides an overview of the most common cancer susceptibility syndromes, available reproductive options and a genetic counselling framework recommended to support individuals/couples in their decision-making. We describe complexities of decision-making involving moderate penetrance and sex-specific variable penetrance genes and explore associated ethical issues arising in this complex area of medicine.

Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.

A retrieval of relevant literature on hepatic nodular lesions, gastric cancer (GC), and Crohn's disease (CD) was conducted from Chinese and English databases. Meta-analysis was performed using Review Manager 5.4 software and the MIDAS package in Stata 18.0. Results from 11 studies comprising 1847 patients were synthesized. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio with 95% confidence intervals were: 0.91 (0.84-0.95), 0.73 (0.65-0.79), 3.30 (2.60-4.30), 0.13 (0.07-0.23), and 26.00 (12.00-53.00), respectively. Significant statistical heterogeneity was found in sensitivity and specificity (P<0.05), with specificity heterogeneity originating from n, type, and mode (P<0.05). Sensitivity and specificity for n, type, object, and mode were non-heterogeneous (P>0.05). The combined AUC from SROC curve analysis of the 11 studies was 0.85. Deeks' funnel plot asymmetry test yielded a p-value of 0.01, indicating potential bias across studies in the diagnostic odds ratio funnel plot. Fagan's nomogram demonstrated that using CT for diagnostic modeling increased the post-test probability of correctly diagnosing hepatic nodular lesions, GC, and CD from 50.00% to 77.00%. Overall, multi-detector CT shows good diagnostic value for hepatic nodular lesions, GC, and CD, supporting its clinical flexibility based on patient-specific considerations.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

The prognostic factors of diffuse GC patients were screened the prognostic nomogram was constructed, and the prediction accuracy was verified.

From 2006 to 2018, there were 2877 individuals pathologically diagnosed with diffuse gastric cancer; the clinicopathological features of these patients were obtained from the SEER database & randomly divided into a training cohort (1439) & validation cohort (1438).To create prognostic nomograms & choose independent prognostic indicators to predict the overall survival (OS) of 1, 3, & 5 years, log-rank & multivariate COX analysis were utilized & discrimination ability of nomogram prediction using consistency index and calibration curve.

Age, T, N, M, TNM, surgical status, chemotherapy status, & all seven markers were independent predictors of OS (P < 0.05), & a nomogram of OS at 1, 3, & 5 years was created using these independent predictors. The nomogram's c-index was 0.750 (95% CI 0.734 ~ 0.766), greater than the TNM staging framework 0.658 (95%CI 0.639 ~ 0.677); the c-index was 0.753 (95% CI 0.737 ~ 0.769) as well as superior to the TNM staging mechanism 0.679 (95% CI 0.503-0.697). According to the calibration curve, the projected survival rate using the nomogram & the actual survival rate are in good agreement.

Prognostic nomograms are useful tools for physicians to assess every individual's individualised prognosis & create treatment strategies for those with diffuse gastric cancer. They can reliably predict the prognosis for individuals with diffuse gastrointestinal carcinoma.

Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy.

Germline DNA, obtained from peripheral blood, was analysed by NGS.

A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up.

This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.

Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.

Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation.

To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival.

This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers.

Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis.

Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03).

In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome.

Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing.

One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months.

RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome associated with early onset diffuse gastric cancer. Definitive treatment is prophylactic total gastrectomy (PTG) associated with significant morbidity. Studies published from January 2000 to December 2022 reporting clinical, histopathological or health-related quality of life outcomes in HDGC patients undergoing PTG were identified. The study quality was assessed by the "Newcastle-Ottawa scale". Of the 257 articles screened, 21 were selected. A total of 353 patients were examined in 15 studies that reported surgical outcomes. The median age was 42 years old. The median major complication and mortality rates were 19.2% and 0.3%, respectively. The most common complications were wound infection at 4.8% followed by anastomotic leak and pulmonary complications at 4.5% each. Following PTG, 88.6% of patients had early lesions amongst 414 patients. The mean/median number of signet ring cell carcinoma foci in the gastrectomy specimens was from 2 to 78. All cases were stage 1 with no lymph node involvement. There was a wide range of psychosocial effects following PTG closely related to the physical symptoms. It is imperative for patients to receive comprehensive preoperative counselling to make an informed decision and be followed up under the care of a multidisciplinary team.

Deep learning (DL) models perform poorly when there are limited gastric signet ring cell carcinoma (SRCC) samples. Few-shot learning (FSL) can address the small sample problem.

EfficientNetV2-S was first pretrained on ImageNet and then pretrained on esophageal endoscopic images (i.e., base classes: normal vs. early cancer vs. advanced cancer) using transfer learning. Second, images of gastric benign ulcers, adenocarcinoma and SRCC, i.e., novel classes (n = 50 per class), were included. Image features were extracted as vectors using the dual pretrained EfficientNetV2-S. Finally, a k-nearest neighbor classifier was used to identify SRCC. The above proposed 3-way 3-shot FSL framework was conducted in three rounds.

Dual pretrained FSL performed better than single pretrained FSL, endoscopists and traditional EfficientNetV2-S models. Dual pretrained FSL obtained the highest accuracy (79.4%), sensitivity (68.8%), recall (68.8%), precision (69.3%) and F1-score (0.691), and the senior endoscopist achieved the highest specificity of 93.6% when identifying SRCC. The macro-AUC and F1-score for dual pretraining (0.763 and 0.703, respectively) were higher than those for single pretraining (0.656 and 0.537, respectively), along with endoscopists and traditional EfficientNetV2-S models. The 2-way 3-shot FSL also performed better.

The proposed FSL framework showed practical performance in the differentiation of SRCC on endoscopic images, suggesting the potential of FSL in the computer-aided diagnosis for rare diseases.

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC.

This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices.

Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P < .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P = .01), with 43% detected when ≥40 samples were taken.

Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

Germline pathogenic variants in E-cadherin (CDH1) confer high risk of developing lobular breast cancer and diffuse gastric cancer (DGC). The cumulative risk of DGC in CDH1 carriers has been recently reassessed (from 40-83% by age 80 to 25-42%) and varies according to the presence and number of gastric cancers in the family. As there is no accurate estimate of the risk of gastric cancer in families without DGC, the International Gastric Cancer Linkage Consortium recommendation is not straightforward: prophylactic gastrectomy or endoscopic surveillance should be proposed for these families. The inclusion of CDH1 in constitutional gene panels for hereditary breast and ovarian cancer and for gastrointestinal cancers, recommended by the French Genetic and Cancer Consortium in 2018 and 2020, leads to the identification of families with lobular cancer without DGC but also to incidental findings of pathogenic variants. Management of CDH1 carriers in case of incidental findings is complex and causes dilemmas for both patients and providers. We report eleven families (47 CDH1 carriers) from our oncogenetic department specialized in breast and ovarian cancer, including four incidental findings. We confirmed that six families did not have diffuse gastric cancer in their medical records. We discuss the management of the risk of diffuse gastric cancer in Hereditary Lobular Breast Cancer (HLBC) through a family of 11 CDH1 carriers where foci were identified in endoscopic surveillance. We also report a new colon signet ring cancer case in a CDH1 carrier, a rare aggressive cancer included in CDH1-related malignancies.

Recognition of early signet-ring cell carcinoma (SRCC) in patients with hereditary diffuse gastric cancer (HDGC) undergoing endoscopic surveillance is challenging. We hypothesized that probe-based confocal laser endomicroscopy (pCLE) might help diagnose early cancerous lesions in the context of HDGC. The aim of this study was to identify pCLE diagnostic criteria for early SRCC.

Patients with HDGC syndrome were prospectively recruited and pCLE assessment was performed on areas suspicious for early SRCC and control regions during an endoscopic surveillance procedure. Targeted biopsies were taken for gold standard histologic assessment. In Phase I two investigators assessed video sequences off-line to identify pCLE features related to SRCC. In Phase II pCLE diagnostic criteria were evaluated in an independent video set by the investigators blinded to the histologic diagnosis. Sensitivity, specificity, accuracy, and interobserver agreement were calculated.

Forty-two video sequences from 16 HDGC patients were included in Phase I. Four pCLE patterns associated to SRCC histologic features were identified: (A) glands with attenuated margins, (B) glands with spiculated or irregular shape, (C) heterogenous granular stroma with sparse glands, (D) enlarged vessels with tortuous shape. In Phase II, 38 video sequences from 15 patients were assessed. Criteria A and B and C had the highest diagnostic accuracy, with a κ for interobserver agreement ranging from 0.153 to 0.565. A panel comprising these 3 criteria with a cut-off of at least one positive criterion had a sensitivity of 80.9% (95%CI:58.1-94.5%) and a specificity of 70.6% (95%CI:44.0-89.7%) for a diagnosis of SRCC.

We have generated and validated off-line pCLE criteria for early SRCC. Future real-time validation of these criteria is required.

Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy.

In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma.

Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up.

In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants.

Intramural Research Program, National Institutes of Health.

Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in 2 genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. We discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation, and its natural history. Finally, we describe current best practice for the clinical management of HDGC, including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, postoperative quality of life, and the emerging field of HDGC chemoprevention.