Intramucosal Signet Ring Cell Carcinoma Research Articles

Verrucous gastritis-like lesion in intramucosal Helicobacter pylori-uninfected signet ring cell carcinoma with poorly differentiated adenocarcinoma

In Japan, accessible Helicobacter pylori (Hp) eradication therapy is associated with an increase in the prevalence of gastric cancers (GCs) in Hp uninfected stomachs. Signet ring cell carcinoma (SRCC) is the most common of these GCs. Intramucosal SRCC with poorly differentiated adenocarcinoma (PDA) occurring in Hp uninfected gastric mucosa is rare; furthermore, many Hp uninfected pure SRCCs exhibit discoloration and flat or slightly depressed lesions, and morphological elevation is relatively rare. We report a case of intramucosal SRCC with PDA with an elevated, verrucous gastritis-like lesion in a 57-year-old male patient. In the present case, the PDA area showed dense tumor cell growth and coexisting desmoplastic and fibrotic reactions. Histopathology and immunohistochemical staining identified extensive fibromuscular obliteration with smooth muscle bundles extending from the muscularis mucosa into the lamina propria. The patient underwent curative endoscopic submucosal dissection. The reporting and analysis of such rare cases may lead to a better understanding of the characteristics of advanced Hp uninfected GCs.

Histopathological Findings in Turkish Patients Undergoing Sleeve Gastrectomy: Is Histopathologic Examination of Sleeve Gastrectomy Specimens Clinically Important?

Sleeve gastrectomy (SG) is a widely used surgical method in the treatment of obesity. This study aimed to reveal the histopathological changes in SG materials and to investigate the prevalence of clinically important lesions requiring follow-up. Three hundred five patients' data who underwent SG were analyzed. Cases were divided into three groups as normal, chronic inactive gastritis (CIG), and chronic active gastritis (CAG). Age, gender, and body mass index (BMI) of the three groups and the differences in the gastritis parameters of CIG and CAG groups were compared. Thirty-three patients (10.8%) were in the normal group, 145 (47.5%) were in the CIG group, and 127 (41.6%) were in the CAG group. Preoperative endoscopic examination was performed in all cases, but Helicobacter pylori (HP) treatment was not applied. HP were detected in 39.3%, atrophy in 3.9%, intestinal metaplasia (IM) in 4.9%, and lymphoid follicle (LF) in 30% of the cases. Inflammation, atrophy, IM, LF, and HP were significantly higher in the CAG group. The proton pump inhibitor (PPI)-related changes were seen in 20 cases and it was more frequent in the CIG group. Intramucosal signet ring cell carcinoma was detected in 1 case. Endocrine cell hyperplasia and dysplasia were present in 7 cases with CAG. Multiple grade 1 neuroendocrine tumors were detected in just 1 case. In our SG specimens, HP and clinically important lesions were significantly higher in the CAG group. Pathological examination should be carefully done as the lesions detected in SG specimens can change patient management.

Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study

Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions. For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci. 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%. Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer. UK Medical Research Council.

S3103 A Fleeting Intramucosal Signet Ring Cell Carcinoma of the Stomach: What to Do Next?

S3103 A Fleeting Intramucosal Signet Ring Cell Carcinoma of the Stomach: What to Do Next?

Indolent feature ofHelicobacter pylori-uninfected intramucosal signet ring cell carcinomas withCDH1mutations.

In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. Eighteen patients (aged 29-78years) with DGCs and nine normal subjects (28-77years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5years showed no progression. Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Detection of multiple intramucosal signet-ring cell carcinomas by white-light endoscopy and magnifying endoscopy with narrow-band imaging in a hereditary diffuse gastric cancer patient with a CDH1 germline mutation.

Detection of multiple intramucosal signet-ring cell carcinomas by white-light endoscopy and magnifying endoscopy with narrow-band imaging in a hereditary diffuse gastric cancer patient with a CDH1 germline mutation.

Histopathologic Analysis of Signet-ring Cell Carcinoma In Situ in Patients With Hereditary Diffuse Gastric Cancer.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.

Complete histopathologic examination of risk reduction gastrectomy specimens for CDH1 germline mutation: Is it warranted in routine clinical practice?

AimsCDH1 germline mutation is associated with high penetrance of hereditary diffuse gastric cancer (HDGC). Due to the lack of endoscopically identifiable lesions, routine surveillance is ineffective in the early detection of gastric cancer, and risk-reduction gastrectomy is often recommended. Many academic pathology departments elect to submit the entire gastrectomy specimen for histological examination, which is associated with significantly increased cost, technical and professional time, and turnaround time. MethodsWe present our experience with 5 completely submitted and 2 representatively submitted prophylactic total gastrectomy cases in HDGC patients. ResultsMultifocal intramucosal signet ring cell carcinoma was identified in all cases except one, in which only in situ carcinoma was identified. The tumoral foci (2 to 35 per case; average 14.4) were concentrated in proximal stomach. No submucosal invasion or nodal metastases was seen in any case. The final stage was either stage 0 (pTisN0cM0) or stage 1a (pT1aN0cM0). ConclusionsOur findings are in line with that reported in the literature. Considering that deeply invasive carcinoma is very rare in this situation, and no further treatment is indicated for the vast majority of those patients, complete submission and pathologic examination of the entire stomach provides little additional value for routine clinical management. We propose a two-step approach with targeted submission of the proximal stomach, and subsequent entire submission of the remaining stomach if no intramucosal carcinoma is identified during the initial targeted examination.

Pathological features of total gastrectomy specimens from asymptomatic hereditary diffuse gastric cancer patients and implications for clinical management.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome characterised by multigenerational diffuse gastric cancer, and is mainly caused by germline alterations in the CDH1 gene. Currently, endoscopy has limited diagnostic accuracy, and total gastrectomy (TG) is the treatment of choice for asymptomatic CDH1 carriers. In this study, we aimed to obtain a better understanding of HDGC syndrome by exploring the histopathological findings of TG specimens from asymptomatic HDGC patients. A comprehensive literature review was carried out, searching for TGs performed in asymptomatic HDGC patients. Fourteen unpublished cases, analysed in our institution, were also included. The series encompassed 174 CDH1 carriers. Preoperative endoscopic biopsies were positive in 28.3%. A macroscopic lesion was apparent in 11.7% of TGs. Histopathological analysis revealed intraepithelial lesions and/or intramucosal signet ring cell carcinoma in 87.9% of TGs. When we explored the type of protocol used for handling the specimens, we found that microscopic cancer foci were detected in 95.3% of TGs when a total-embedding protocol (assessment of the totality of gastric mucosa) was applied, and only in 62.5% when no specific protocol was used (P<0.001). Helicobacter pylori infection was found in 23.4% cases. In conclusion, a thorough histopathological examination of gastric mucosa remains the gold standard for detection of cancer foci in HDGC gastrectomy specimens, requiring experienced pathologists for an accurate diagnosis. A better understanding of the natural history of HDGC will enable better clinical management of HDGC patients, particularly regarding the optimal timing for the performance of TG.

Outcomes after Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer

Prophylactic total gastrectomy is the treatment of choice in patients with germline mutation in the CDH1 gene and therefore high risk for hereditary diffuse gastric cancer (HDGC). Minimally invasive techniques have been established in recent years for treatment of gastric cancer. We report findings with 12 patients with proven CDH1 mutation who underwent multidisciplinary treatment between 2013 and 3/2018 in our centre for hereditary tumour diseases, followed by prophylactic total gastrectomy in our department. Data were collected in a prospective hereditary tumour database. Open prophylactic total gastrectomy was performed in 5 patients (between 2013 and 2015) and minimally invasive prospective gastrectomy in 7 patients (between 2015 and 2018). The median age of all patients (7 women and 5 men) was 42 (range: 19 - 60) years. The mean operation time was 291 ± 72 minutes (open: 269 ± 70; minimally invasive: 307 ± 75). Perioperative 60-day mortality and anastomotic leakage rate were 0%. In 3 patients, postoperative complications occurred (according to the Clavien-Dindo classification: one each of grades II, IIIa and IVb, respectively), and therefore 25% morbidity. The average postoperative hospital stay was 14.5 ± 6.2 days (open: 16.2 ± 7.9; minimally invasive: 13.3 ± 5.0). In 10 of 12 patients (83%), foci of intramucosal signet ring cell carcinomas were found in the gastric specimen, in 9patients with multifocal dissemination. There were no cases with advanced carcinomas (≥ pT1b) or lymph node metastases. Patients with suspected high risk for hereditary diffuse gastric cancer should be cared for in a multidisciplinary centre for hereditary tumour diseases. Laparoscopic total gastrectomy is a safe and feasible risk-reducing procedure for patients with CDH1 germline mutation. Therefore, in the absence of contraindications and with available surgical expertise, the minimally invasive operation should be the standard procedure for these patients.

Hereditary gastric cancer

In 1998, Guilford et al. identified the hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline alterations at the CDH1 (E-cadherin) gene. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described. In mutation-positive individuals prophylactic total gastrectomy is recommended. The systematic histological study of prophylactic gastrectomies shows intramucosal signet-ring cell carcinoma and pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. In 2011, a new hereditary gastric cancer syndrome was identified: gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma, characterized by the autosomal dominant transmission of fundic gland polyposis, with areas of dysplasia or intestinal-type GC, restricted to the proximal stomach, with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

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.

A Risk-prediction Model Based on Lymph-node Metastasis for Incorporation Into a Treatment Algorithm for Signet Ring Cell-type Intramucosal Gastric Cancer.

The aim of the study was to develop a reliable and easy-to-use risk-scoring system (RSS) to predict lymph-node metastasis (LNM) and determine the feasibility of endoscopic submucosal dissection for mucosa-confined signet ring cell carcinomas (SRCs). Fewer LNM and better survival rates have been reported for early gastric SRCs compared with other undifferentiated early gastric cancers (EGCs). Data from 1544 patients with mucosa-confined SRCs were reviewed. Stepwise logistic regression analysis determined the independent predictors of LNM. Risk scores were based on the final predictive factors for LNM, and performance was internally validated using a split-sample approach. External validation was also performed in an independent dataset (n = 208) to assess the discriminatory power of the RSS. The overall LNM incidence was 3.8% (57/1544). Three risk factors (tumor size ≥1.7 cm, tumors of elevated type, and lymphatic-vascular involvement) were significantly associated with LNM. These factors were incorporated into the RSS, and were assigned scores ranging from 0 to 4. The area under the receiver-operating characteristic curve for predicting LNM after internal and external validation was 0.68 (95% confidence interval, 0.0793-0.2865) and 0.686 (95% confidence interval, 0.618-0.748), respectively. A score of 2 points was the optimal cut-off value for LNM prediction, and the overall diagnostic accuracy was 96%. LNM were found in 2.9% and 23.8% of the low and high-risk groups of the RSS, respectively. A RSS may help to predict LNM and evaluate endoscopic submucosal dissection feasibility in patients with intramucosal SRC.

Distribution of Lgr5-positive cancer cells in intramucosal gastric signet-ring cell carcinoma.

Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a putative intestinal stem cell marker that is also expressed in various tumors. To analyze its pathological characteristics in mucosal gastric signet-ring cell carcinoma (SRCC), we investigated Lgr5 expression in 35 intramucosal gastric SRCC patients using RNAscope, a newly developed RNA in situ hybridization technique. Lgr5 expression in individual tumor cells was scored semi-quantitatively from 0 to 400. Ki67 was also examined by immunohistochemistry, with a linear arrangement of Ki67-expressing cells present in 20 of 35 cases. This area of Ki67-expressing cells was topographically divided into upper, middle, and lower regions. All cases with linear Ki67 expression patterns also had Lgr5-positive cells arranged in a linear fashion in the lower area-which was distinct from the area of high Ki67 expression. The rate of Ki67 positivity in Lgr5-positive cells was significantly lower than that of Lgr5-negative cells in areas of high Ki67 expression. In intramucosal SRCC, the low mitotic activity of Lgr5-positive cells suggests that they may represent cancer stem cells as seen in other types of stomach carcinomas. Intramucosal SRCC may therefore contain stem cells expressing Lgr5 in the lower area of the lamina propria, akin to normal gastric pyloric mucosa.

Sa1906 Non-Magnifying Narrow-Band Imaging of Small Intramucosal Signet Ring Cell Carcinoma of the Stomach

Sa1906 Non-Magnifying Narrow-Band Imaging of Small Intramucosal Signet Ring Cell Carcinoma of the Stomach

Diagnosis of small intramucosal signet ring cell carcinoma of the stomach by non-magnifying narrow-band imaging: A pilot study.

To examine the efficacy of non-magnifying narrow-band imaging (NM-NBI) imaging for small signet ring cell carcinoma (SRC). We retrospectively analyzed 14 consecutive small intramucosal SRCs that had been treated with endoscopic submucosal dissection (ESD) and 14 randomly selected whitish gastric ulcer scars (control). The strength and shape of the SRCs and whitish scars by NM-NBI and white-light imaging (WLI) were assessed with Image J (NIH, Bethesda). NM-NBI findings of SRC showed a clearly isolated whitish area amid the brown color of the surrounding normal mucosa. The NBI index, which indicates the potency of NBI for visualizing SRC, was significantly higher than the WLI index (P = 0.001), indicating SRC was more clearly identified by NM-NBI. Although the NBI index was not significantly different between SRCs and controls, the circle (C)-index, as an index of circularity of tumor shape, was significantly higher in SRCs (P = 0.001). According to the receiver-operating characteristic analysis, the resulting cut-off value of the circularity index (C-index) for SRC was 0.60 (85.7% sensitivity, 85.7% specificity). Thus a lesion with a C-index ≥ 0.6 was significantly more likely to be an SRC than a gastric ulcer scar (OR = 36.0; 95%CI: 4.33-299.09; P = 0.0009). Small isolated whitish round area by NM-NBI endoscopy is a useful finding of SRCs which is the indication for ESD.

Synchronous appendiceal and intramucosal gastric signet ring cell carcinomas in an individual with CDH1-associated hereditary diffuse gastric carcinoma: a case report of a novel association and review of the literature

BackgroundHereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome associated with mutations of the E-cadherin gene (CDH1). E-cadherin is normally involved in cell-cell adhesion, so it not surprising that individuals with this syndrome are predisposed to develop malignancies with dyshesive morphologies at a young age, such as diffuse (signet ring cell) gastric carcinoma and lobular breast carcinoma. Herein we describe the first reported case of primary appendiceal signet ring cell carcinoma arising in a CDH1-associated hereditary diffuse gastric carcinoma kindred with synchronous primary diffuse gastric carcinoma.Case presentationA 51- year old woman, with known CDH1 mutation carrier status and a prior history of lobular breast carcinoma underwent prophylactic total gastrectomy which revealed multifocal intramucosal signet ring cell carcinoma. An appendectomy was performed at the same time due to a prior episode of presumed appendicitis, with pathologic examination significant for a primary signet ring cell carcinoma of the appendix.ConclusionAs appendiceal signet ring cell carcinoma is exceedingly rare, the occurrence of this neoplasm in this patient, with this particular morphology, provides credence for it being part of the hereditary diffuse gastric carcinoma spectrum of malignancies.

Hereditary gastric cancer

In 1998, Guilford et al. identified the hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline alterations at the CDH1 (E-cadherin) gene. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described. In mutation-positive individuals prophylactic total gastrectomy is recommended. The systematic histological study of prophylactic gastrectomies shows intramucosal signet-ring cell carcinoma and pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. In 2011, a new hereditary gastric cancer syndrome was identified: gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma, characterized by the autosomal dominant transmission of fundic gland polyposis, with areas of dysplasia or intestinal-type GC, restricted to the proximal stomach, with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Neuroendocrine and mucinous differentiation in signet ring cell carcinoma of the stomach: evidence for a common cell of origin in composite tumors

Composite tumors are rare neoplasms containing a mixture of 2 different cellular components present in roughly equal proportions. It is hypothesized that composite tumors arise from a multipotential stem cell with subsequent bidirectional differentiation. We present an unusual composite tumor of the stomach composed equally of signet ring cell carcinoma and low-grade neuroendocrine carcinoma. Twenty-one additional patients with signet ring cell carcinomas of the stomach were studied to determine the prevalence of neuroendocrine differentiation by morphology and immunohistochemistry for synaptophysin and chromogranin A. Immunohistochemistry for mucins 5AC and 2 was performed to assess for divergent differentiation toward foveolar and intestinal mucin phenotypes, respectively, and to evaluate for any potential relationship with neuroendocrine differentiation. We found morphologic evidence of neuroendocrine carcinoma in 4 (19%) of 21 consecutive signet ring carcinomas. E-cadherin immunostaining was subsequently performed on these 4 tumors plus the index case. All 5 tumors demonstrated concordance between the signet ring and neuroendocrine components. There was no distinct relationship to mucin 5AC/mucin 2 profiles, with the exception that all 11 intramucosal signet ring cell carcinomas from 4 patients with germ line cadherin 1 gene mutations were composed exclusively of mucin 5AC+ signet ring cells that lacked intestinal mucin and neuroendocrine differentiation. The concordant E-cadherin status in the neuroendocrine and signet ring cell tumor components and the frequent admixture of mucin 5AC+ cells with foveolar differentiation and mucin 2+ cells with intestinal differentiation may support the hypothesis that composite tumors arise from a common stem cell with bilineage or multilineage differentiation.

E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man

The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by CDH1) to tumor progression is well established. However, CDH1 germ-line mutations predispose to the cancer susceptibility syndrome hereditary diffuse gastric cancer (HDGC), suggesting a role for E-cadherin in tumor initiation. The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated "eHDGC"). Here, we used N-methyl-N-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and cdh1(+/-) mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in cdh1(+/-) mice compared with wt mice. The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear beta-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs confirmed the importance of the second CDH1 hit to the initiation of diffuse gastric cancer. CDH1 promoter hypermethylation has been proposed to be a major second hit in advanced HDGC; however, its contribution to eHDGC was unknown. We thus examined a series of human eHDGC and detected CDH1 promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt CDH1 mRNA levels in the foci and had a monoclonal pattern, consistent with an epigenetic initiation of disease. Together, these findings provide compelling evidence for a deficiency in cell-to-cell adhesion being sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and beta-catenin activation.