Evaluation of the routine use of E-cadherin immunohistochemistry in the typing of breast carcinomas: results of a randomized diagnostic study.

AIMS: Invasive lobular carcinoma (ILC) has distinct morphology and association with loss of E-cadherin function. It has special clinical and imaging features, and its proper recognition is important. Following a recent proposal, we tested the value of the routine use of E-cadherin immunohistochemistry (IHC) in recognizing ILC. METHODS AND RESULTS: Five pathologists with experience in breast pathology from four Hungarian institutions histotyped 1001 breast cancers from diagnostic core biopsies or excision specimens randomly assigned to haematoxylin and eosin (HE) diagnosis first, followed by E-cadherin IHC; or to immediate HE and E-cadherin-based diagnosis. Of 524 cases with HE diagnosis, 73(14%) were deemed uncertain. E-cadherin made the initial histological type change in 14/524 cases (2.7%), including three with confident HE-based type allocation. Use of E-cadherin immunostaining was considered useful in 88/477 cases (18%) with immediate dual assessment, and typing uncertainty went down to 5% (25/477 cases), but was not zero. Collective assessment of 171 uncertain, difficult, nonclassical cases resulted in consensus diagnosis in most cases, but 15 cases were still doubtful as concerns their proper histological type. CDH1 gene sequencing was attempted and successful in 13; pathogenic genetic alterations were identified in seven cases. CONCLUSIONS: The routine use of E-cadherin IHC decreases the uncertainty in typing and improves the typing accuracy at the cost of potentially redundant additional immunostains. Furthermore, this procedure does not exclude uncertainty due to E-cadherin-positive ILCs, which are occasionally difficult to confidently label as ILC, especially when the growth pattern is not classic.

Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma.

Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.

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.

Chromoendoscopy in Combination with Random Biopsies for Patients with Pathogenic CDH1 Mutations Undergoing Endoscopic Surveillance.

OBJECTIVES: Germline mutations in the CDH1-gene are identified as the cause of 30-40% of cases of hereditary diffuse gastric cancer, an autosomal-dominant inherited cancer predisposition syndrome. Given this high risk of developing diffuse gastric cancer, carriers of a pathogenic CDH1 germline mutation are advised to undergo prophylactic gastrectomy. For patients preferring conservative management, endoscopic surveillance is recommended. The detection of diffuse gastric cancer using white light endoscopy, however, remains challenging. METHODS: Patients with pathogenic CDH1 mutation underwent (chromo)endoscopic surveillance or endoscopy prior to surgery. Biopsies were taken at suspicious sites identified by chromoendoscopy. In addition, endoscopically normal areas were assessed with mapping biopsies. Detection rates from endoscopic biopsies (mapping vs. targeted) and gastrectomy specimen were then compared. RESULT: Between 11/2015 and 12/2020, ten patients from four families with a known CDH1 germline mutation had a total of n = 24 endoscopies with n = 518 total biopsies being examined. Three patients were diagnosed with GC during the study period. These patients all had suspicious chromoendoscopic lesions (= detection rate 100%). In two of three patients who had suspicious chromoendoscopic lesions, signet cell carcinoma was also detected in mapping biopsies and multiple additional cancer foci were identified in the gastrectomy specimen. CONCLUSION: Chromoendoscopy facilitated detection of gastric carcinoma foci in CDH1 mutation carriers. Chromoendoscopy identified all patients with gastric cancer, but not all cancer foci present in these patients. We conclude that for patients opting against prophylactic total gastrectomy, the addition of chromoendoscopy to white light could be used to enhance diagnostic reliability of endoscopic surveillance.

Mutational separation and clinical outcomes of TP53 and CDH1 in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a deadly tumor with the fifth highest occurrence and highest global mortality rates. Owing to its heterogeneity, the underlying mechanism of GC remains unclear, and chemotherapy offers little benefit to individuals. AIM: To investigate the clinical outcomes of TP53 and CDH1 mutations in GC. METHODS: In this study, 202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected. A total of 490 genes were identified using target capture. Through t-test and Wilcoxon rank-sum test, somatic mutations, microsatellite instability, and clinical statistics, including overall survival, were detected, compared, and calculated. RESULTS: The mutation rates of 32 genes, including TP53, SPEN, FAT1, and CDH1 exceeded 10%. TP53 mutations had a slightly lower overall occurrence rate (33%). The TP53 mutation rate was significantly higher in advanced stages (stage III/IV) than that in early stages (stage I/II) (P < 0.05). In contrast, CDH1 mutations were significantly associated with diffuse GC. TP53 is related to poor prognosis of advanced-stage tumors; nevertheless, CDH1 corresponds to a diffuse type of cancer. TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms. CONCLUSION: Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

BACKGROUND: Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC). METHODS: Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed. RESULTS: Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy. CONCLUSIONS: PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

Hereditary Diffuse Gastric Cancer-Update Based on the Current Consort Recommendations.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020.

Surgery for Hereditary Diffuse Gastric Cancer: Long-Term Outcomes.

INTRODUCTION: Gastric cancer is inherited as an autosomal dominant condition in hereditary diffuse gastric cancer (HDGC). The gene associated with HDGC is an E-cadherin gene CDH1. At the time of initiation of this study, it was estimated that 70% of patients who inherited the CDH1 gene mutation would develop gastric cancer. We hypothesized that the rate of signet ring cell cancer in asymptomatic patients with CDH1 mutations may be higher than anticipated and that the surgery could be conducted with acceptable short-term and long-term complications suggesting that the quality of life with the surgery is acceptable. METHODS: We prospectively studied the role of total gastrectomy in symptomatic and asymptomatic patients with CDH1 mutations. A total of 43 patients with mutations of the CDH1 gene were studied prospectively, including 8 with symptoms and 35 without symptoms. Total gastrectomy was recommended to each. Quality of life was assessed in patients who underwent prophylactic gastrectomy. Proportions are compared with Fisher's exact test. RESULTS: In total, 13 (30%) asymptomatic patients declined surgery. Total gastrectomy was performed in 8 symptomatic patients and 22 asymptomatic patients of whom only 3 asymptomatic patients (14%) had endoscopically proven signet ring cell cancer preoperatively, while 21 of 22 (95%) had it on final pathology (p = 0.05). Each asymptomatic patient was T1, N0, while seven out of eight symptomatic patients had T3-T4 tumors and six had positive lymph nodes. None had operative complications or operative death. The median follow-up was 7 years. Five (63%) symptomatic patients died, while only one (95%) prophylactic patient died of a non-gastric cancer- or surgery-related issue (p = 0.05). A total of 15 prophylactic patients had long-term follow-up. Each had significant weight loss (mean 23%) but all had a normal body mass index. In total, 40% had bile reflux gastritis controlled with sucralfate. Each returned to work and, if given the choice, said that they would undergo the surgery again. CONCLUSIONS: Total gastrectomy is indicated for patients who have an inherented CDH1 mutation. Endoscopic screening is not reliable for diagnosing signet ring cell stomach cancer. If patients wait for symptoms, they will have a more advanced disease and significantly reduced survival. Operative complications of prophylactic gastrectomy are minimal, and long-term quality of life is acceptable.

Frequency of CDH1 Germline Mutations in Non-Gastric Cancers.

Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.

Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review.

Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.

[Hereditary diffuse gastric cancer : case serie of 8 patients from a single family and literature review]. / Cancer gastrique diffus héréditaire. Série de 8 patients appartenant à une même famille et revue de la littérature.

Hereditary diffuse gastric cancer is a form of gastric cancer associated, in about 40 % of cases, with a germline mutation of the CDH1 gene. The management of patients with a pathogenic mutation of this gene is based on total prophylactic gastrectomy because, until proven otherwise, endoscopic monitoring is insufficient. We report a series of eight patients with pathogenic CDH1 mutation who underwent total prophylactic gastrectomy in our centre.

Le cancer gastrique diffus héréditaire est une forme de cancer gastrique associé, dans 40 % des cas environ, à une mutation germinale du gène CDH1. La prise en charge des patients porteurs d'une mutation pathogène de ce gène repose sur la gastrectomie totale prophylactique car, jusqu'à preuve du contraire, la surveillance endoscopique est insuffisante. Nous rapportons une série de huit patients porteurs d'une mutation pathogène de CDH1 ayant bénéficié d'une gastrectomie totale prophylactique dans notre centre. Mots-clés : Gastrectomie prophylactique - Cancer gastrique diffus héréditaire - Mutation CDH1.

Clinical spectrum and pleiotropic nature of CDH1 germline mutations.

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype-phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin's pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Histologic and immunohistochemical differences between hereditary and sporadic diffuse gastric carcinoma.

We aimed to identify histopathologic features unique in hereditary diffuse gastric cancer (HDGC) by comparing with its sporadic counterpart (SDGC). 11 patients with confirmed CDH1 mutation who were found to have HDGC in a prophylactic total gastrectomy were collected. Median age of HDGC patients was 39 years (range 24-57). All HDGC cases had intramucosal signet ring cell carcinoma. Twenty-three invasive tumor foci from 7 patients with HDGC were available for ancillary studies, and we evaluated each focus separately. Almost all foci (20/23) showed two distinct tumor cell populations, namely, large signet ring cells and small signet ring cells. The large cells were located just beneath the surface epithelium and were positive for mucicarmine and pCEA, while the small cells were found in the deeper lamina propria and were mostly negative for mucicarmine and pCEA. A subset of small cells (6 foci from two resected stomachs) showed poorly differentiated morphology with p16 positivity. All other tumor cells with well-differentiated signet ring cell morphology were negative for p16. In contrast, 18 of 20 SDGCs were positive for p16. In addition, all HDGCs were negative for CDX2, while 19 of 20 SDGCs were positive. We propose that there are three distinct tumor cell populations in HDGC: well-differentiated large cells, well-differentiated small cells, and poorly differentiated small cells, and that the latter group with aberrant p16 expression may represents a more aggressive phenotype. The absence of CDX2 in HDGC suggests that it may develop along a carcinogenetic pathway different from that of SDGC.

Linear-Stapled Side-to-Side Esophagojejunostomy with Hand-Sewn Closure of the Common Enterotomy After Prophylactic and Therapeutic Total Gastrectomy.

After total gastrectomy, anastomosis-related complications such as leak or stricture can be highly morbid. Between July 2005 and December 2015, a linear-stapled side-to-side esophagojejunostomy with hand-sewn closure of the common enterotomy (modified Orringer technique) was used for Roux-en-Y reconstruction after prophylactic total gastrectomy in 22 germline CDH1 mutation carriers and after therapeutic total gastrectomy in 18 patients diagnosed with gastric adenocarcinoma. All operations were performed by the same surgeon. No patient in either cohort developed a clinically evident anastomotic leak, one patient (2.5%) developed a contained radiographic leak that healed without intervention, and one patient (2.5%) developed an anastomotic stricture treated by endoscopic dilatation 7 months after operation. These rates were lower than radiographic leak and stricture rates in a comparison group of 32 patients who received a completely hand-sewn esophagojejunostomy (6.3 and 3.1%, respectively). Here, we describe how to perform the linear-stapled esophagojejunostomy anastomosis.

ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast.

E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion. Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC). However, little is known about genomic differences between ILC with and without a CDH1 alteration. Therefore, we analyzed whole genome sequencing data of 169 ILC cases from The Cancer Genome Atlas (TCGA) to address this deficiency. Our study shows that CDH1 gene was altered in 59.2% (100/169) of ILC. No significant difference was identified between CDH1-altered and -unaltered ILC cases for any of the examined demographic, clinical or pathologic characteristics, including histologic grade, tumor stage, lymph node metastases, or ER/PR/HER2 states. Seven recurrent mutations (PTEN, MUC16, ERBB2, FAT4, PCDHGA2, HERC1 and FLNC) and four chromosomal changes with recurrent copy number variation (CNV) (11q13, 17q12-21, 8p11 and 8q11) were found in ILC, which correlated with a positive or negative CDH1 alteration status, respectively. The prevalence of the most common breast cancer driver abnormalities including TP53 and PIK3CA mutations and MYC and ERBB2 amplifications showed no difference between the two groups. However, CDH1-altered ILC with an ERBB2 mutation shows a significantly worse prognosis compared to its counterparts without such a mutation. Our study suggests that CDH1-altered ILC patients with ERBB2 mutations may represent an actionable group of patients who could benefit from targeted breast cancer therapy.