Introduction

Germline truncating variants in the CTNNA1 gene, encoding ⍺E-catenin, account for approximately 2% of hereditary diffuse gastric cancer (HDGC) cases. Signet-ring-cell (SRC) / poorly-cohesive (diffuse) gastric cancer (GC) with loss of ⍺E-catenin expression has been reported on a case-by-case basis in carriers of germline CTNNA1 variants. However, there is a knowledge gap regarding the detailed histopathological and immunohistochemical features of CTNNA1-associated GCs.

Aims & Methods

Eleven tumour samples, including six primary GCs and five (peritoneal and nodal) metastases, from nine CTNNA1 truncating carriers fulfilling the 2020 HDGC genetic testing criteria [doi:10.1016/S1470-2045(20)30219-9] were studied. Immunohistochemistry for ⍺E-catenin (clone EP1793Y) was performed on eight samples from seven patients.

Results

Median age at GC diagnosis was 48 years (range:37–75). One case was detected at early stage (pT1a) in a prophylactic total gastrectomy, while the remaining eight were diagnosed at advanced stage (≥pT2), including five with metastatic disease.
The pT1a carcinoma, adjacent to pagetoid spread of SRCs (pTis), showed classic SRCs. Advanced-stage GCs showed predominantly poorly-cohesive morphology with variable SRC component: <5% in five cases, 5–10% in two, and 10–50% in three. In two patients, the SRC proportion increased from 10% in primary tumours to 50% in corresponding metastases. All metastatic sites showed purely poorly-cohesive morphology with prominent desmoplastic stroma. In contrast, primary tumours displayed additional patterns, including nested, trabecular, rosetoid and true microglandular structures.
All tumours demonstrated aberrant ⍺E-catenin expression: complete loss in 63% (5/8) of samples analysed, and faint/incomplete membranous, paranuclear dotted, and/or cytoplasmic staining in the remaining 37% (3/8).

ID

Gender

Source

CTNNA1 variant

Phenotype (age of onset)

TNM Staging

Type of sample

Morphology: % signet ring cells

Morphology: non-poorly cohesive patterns*

Morphology: desmoplastic reaction

αE-catenin expression: membranous

αE-catenin expression: cytoplasmic

αE-catenin expression: dotted

P1

F

France

c.2023C>T (p.Gln675*)

DGC (58)

pT4b/Nx/M1

Peritoneum

<5%

Pseudoglandular (inside vessels)

+++

<5%

<5%

<5%

P2

F

France

c.2023C>T (p.Gln675*)

DGC (40)

pT4a/N3a/M1

Small bowel wall

<5%

No

+++

NA

NA

NA

P4

M

Germany

c.1030del (p.Leu344Cysfs*25)

DGC (48)

≥pT2/≥N1/M0

(1) Stomach biopsy (2) Lymph node metastasis

(1) 5-10% (2) 10-50%

(1) Nested / trabecular / rosetoid / MICROglandular / solid (2) No

(1) No (2) No

(1) 0% (2) 0%

(1) 0% (2) 0%

(1) 0% (2) 0%

P6

M

France

c.543del (p.Lys181Asnfs*7)

DGC (49)

pTx/Nx/M1

Peritoneum

<5%

No

++

0%

0%

0%

P7

M

France

c.543del (p.Lys181Asnfs*7)

DGC (55)

pTx/Nx/M1

Stomach biopsy

<1%

Rosetoid / microglandular / trabecular

No

1%

1%

1%

P8

M

Spain

c.1329delT (p.Asn443Lysfs*5)

DGC (40)

pT4a/N2/M0

Gastrectomy specimen

1-5%

Solid component

++

NA

NA

NA

P10

M

France

c.2056del (p.Glu686Asnfs*36)

DGC (75)

≥pT2/Nx/M1

(1) Stomach biopsy (2) Peritoneum

(1) 5-10% (2) 10-50%

(1) Rosetoid / trabecular (2) No

(1) No (2) ++

(1) 5-10% (2) 0%

(1) 1-5% (2) 0%

(1) 5-10% (2) 0%

P11

F

Germany

c.1175del (p.Asp392Valfs*13)

DGC (45)

ypT3/N0/M0

Gastrectomy specimen

10-50%

No

NA

0%

0%

0%

P12

NA

Germany

c.1175del (p.Asp392Valfs*13)

DGC (37)

pT1a

Prophylactic total gastrectomy specimen

100%

No

No

NA

NA

NA

Conclusion

This is the largest cohort to date characterizing histopathological features and ⍺E-catenin expression in CTNNA1-associated GCs. The morphological diversity observed in primary tumours may represent a diagnostic pitfall in the recognition of HDGC cases. The possible utility of ⍺E-catenin expression as a marker for genetic triage in these cases warrants further investigation.

References

1. van der Sluis L, van Dieren JM, van der Post RS, Bisseling TM. Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review. Hered Cancer Clin Pract. 2024 Oct 8;22(1):21. doi: 10.1186/s13053-024-00293-5. PMID: 39379994
2. Lobo S, Benusiglio PR, Coulet F, Boussemart L, Golmard L, Spier I, Hüneburg R, Aretz S, Colas C, Oliveira C. Cancer predisposition and germline CTNNA1 variants. Eur J Med Genet. 2021 Oct;64(10):104316. doi: 10.1016/j.ejmg.2021.104316
3. Coudert M, Drouet Y, Delhomelle H, Svrcek M, Benusiglio PR, Coulet F, Clark DF, Katona BW, van Hest LP, van der Kolk LE, Cats A, van Dieren JM, Nehoray B, Slavin T, Spier I, Hüneburg R, Lobo S, Oliveira C, Boussemart L, Masson L, Chiesa J, Schwartz M, Buecher B, Golmard L, Bouvier AM, Bonadona V, Stoppa-Lyonnet D, Lasset C, Colas C. First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants. J Med Genet. 2022 Dec;59(12):1189-1195. doi: 10.1136/jmg-2022-108740. Epub 2022 Aug 29. PMID: 36038258.
4. Gullo I, van der Post RS, Carneiro F. Recent advances in the pathology of heritable gastric cancer syndromes. Histopathology. 2021 Jan;78(1):125-147. doi: 10.1111/his.14228. PMID: 33382491.

Introduction

Prophylactic total gastrectomy (PTG) is the definitive treatment for hereditary diffuse gastric cancer syndrome (HDGC). Endoscopic surveillance informs the requirement and optimal timing to surgery. However, endoscopic recognition of early signet ring cell carcinoma (SRCC) remains challenging. In this study, we aimed to develop and prospectively validate a user-friendly diagnostic framework with machine-learning to support endoscopists in accurate identification of early SRCC during surveillance in HDGC individuals.

Aims & Methods

We retrospectively analysed 147 HDGC individuals undergoing endoscopic surveillance to evaluate the diagnostic accuracy of endoscopic criteria (Cambridge criteria), develop a clinical decision tree (cDT) to better apply the criteria based on machine leaning, and investigate its clinical significance. We then prospectively validated cDT in 66 CDH1 pathogenic-variant carriers. The inter-observer agreement and diagnostic accuracy of Cambridge criteria and cDT were assessed through multi-reader multi-case study.

Results

Retrospective analysis of 537 endoscopies showed Cambridge criteria achieved 82.8% (48/58) sensitivity and 78.2% (140/179) specificity for SRCC diagnosis. The presence and number of neoplastic pale areas are independent predictors of higher cancer burden in HDGC individuals. In prospective study, cDT had 77.8% (21/27) sensitivity and 90.7% (49/54) specificity. The cDT significantly improved average sensitivity among non-experts from 66.7% to 72.5% and 87.5%, and among experts from 74.1% to 80.0% and 91.7% (P = 0.03).

Conclusion

We developed and validated a practical endoscopic framework to enhance SRCC assessment during HDGC endoscopic surveillance.

Introduction

Hereditary diffuse gastric cancer (HDGC) associated with CDH1 germline pathogenic variants (PV), carries a high lifetime risk of signet ring cell carcinoma (SRCC). Clinical and molecular events driving progression from early SRCC to advanced cancer are elusive, therefore there is uncertainty to whom and when to recommend risk reducing total gastrectomy (RRTG). We hypothesise a high number of early SRCC lesions (SRCC burden) could be a risk factor for progression to clinical gastric cancer. This study aimed to identify predictors of SRCC burden and provide evidence to modify surveillance intervals.

Aims & Methods

We analyzed data from 53 CDH1 PV carriers who underwent RRTG prospectively recruited between Jan 2006 and Dec 2024 (RRTG dataset) and a separate cohort of 95 CDH1 carriers with ≥2 surveillance endoscopies and 0-2 positive biopsies at baseline (endoscopy dataset). Targeted biopsies (TB) and systematic random biopsies (RB) were obtained using the Cambridge protocol. Multivariable negative binomial regression was used to assess the association of clinical (age, sex, family history, ethnicity, CDH1 variant type) and endoscopic factors (mean number of positive TB and RB per endoscopy) with SRCC burden in RRTG specimens. A logistic regression model with significant predictors was trained to classify patients into low (≤20 foci) and high (>30 foci) cancer burden, validated over 1,000 iterations. Temporal trends in biopsy findings were analyzed using linear mixed-effects models in endoscopy dataset. Surveillance effectiveness at 6- and 12-month intervals was compared in a subset of 38 patients with at least one positive endoscopy followed by subsequent surveillance.

Results

Among 53 RRTG patients (median: 3 surveillance endoscopies over 19 months), 47 (90%) had pT1aN0M0 cancer, and 6 (11%) had pT0N0M0. The mean number of SRCC foci on RRTG specimens was 13, with a median of 33 (IQR: 2-37) and a range of 0 to 273. Among clinical factors, whereas the average number of positive TB (p = 0.001) and RB (p < 0.001) per endoscopy were independent predictors. The model based on endoscopy factors achieved an AUC of 0.88 (0.87, 0.89) for predicting cancer burden under RRTG. No significant trend in biopsy positivity over time was observed (Estimate = 0.0046, p = 0.176). Extending surveillance intervals from 6 to 12 months in patients with low-level positivity did not significantly reduce detection of increased positive biopsies (22% vs. 19%, p = 0.78). Furthermore, using ≥3 positive biopsies as a trigger for recommending RRTG, only 6 patients (16%) met this threshold. The median time after the first positive endoscopy to meeting this criterion was 9 months (95% CI: 0-29) under the 6-month surveillance strategy and 12 (95% CI: 3-33) months under the 12-month surveillance strategies.

Conclusion

Endoscopic surveillance using targeted and random biopsies by experienced endoscopists provides a reliable estimate of SRCC burden in HDGC. Our findings suggest that extending surveillance intervals and delaying surgery in patients with low early SRCC burden is clinically safe.

Introduction

Gastric intestinal metaplasia (GIM) is a known premalignant lesions of gastric cancer (GC). Several factors have been associated with the progression of GC such as family history, smoking and increased BMI. Dietary factors such as the consumption of meat, salt and alcohol are also linked to GC progression. However, the intricate relationship between dietary factors and the progression of GIM remains poorly understood. The aim of this prospective cohort study was to identify dietary factors for GIM progression in a low incidence area.

Aims & Methods

The Progression and Regression of Precancerous Gastric Lesions (PROREGAL) study prospectively included patients with GIM who underwent endoscopic surveillance from September 2009 to February 2024. GIM stage was determined by the Operative Link on Gastric Intestinal Metaplasia (OLGIM) criteria. Disease progression was based on the increase in OLGIM, comparing the baseline score to at least two follow-up (FU) endoscopies. If only one FU endoscopy was conducted, the baseline was compared to this single FU examination. Comprehensive data on family history, lifestyle factors, and dietary habits were collected through structured questionnaires. Helicobacter pylori (H. pylori) infection status was determined by pathology. Multivariate logistic regression analysis was used to determine risk factors.

Results

In total 312 patients were included, with a median FU of 54 months (median age: 61 years, 50.3% male) of which 112 patients (35.9% ) showed GIM progression (7.6% to stage I, 27.6% to stage II, 46.7% to stage III and 18.1% to stage IV), with six patients (1.9%) developing high-grade dysplasia or GC. A positive family history (first or second degree) was present in 103 (30.6%) cases. High dietary salt consumption (OR 1.67; 95% CI 1.05–2.68, P=0.04), meat ≥6 servings per week (OR 1.25; 95% CI 1.07–1.46, P=0.004) smoking (OR 1.76; 95%CI 1.04–2.68), autoimmune gastritis (OR 2.49; 95%CI 1.04–5.83) and having a positive first-degree family member with GC (OR 2.01; 95%CI 1.20–3.52) significantly associated with GIM progression. Factors like fish intake, alcohol consumption, prepared meal consumption, fruit and vegetable intake, autoimmune gastritis (AIG), extensive GIM, vitamin intake, Body Max Index (BMI) and history of H. pylori infection showed no significant association.

Conclusion

Increased consumption of meat and salt is significantly associated with GIM progression, suggesting that dietary risk factors for GIM progression are similar in low-incidence Western countries and high-incidence regions.

References

1. Bray F, Laversanne M, Sung H et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2024; 74: 229-263. doi:10.3322/caac.21834
2. Chen Y-C et al. Global Prevalence of Helicobacter pylori Infection and Incidence of Gastric Cancer Between 1980 and 2022. Gastroenterology 2024; 166: 605-619. doi:10.1053/j.gastro.2023.12.022
3. Shin WS et al. Updated Epidemiology of Gastric Cancer in Asia: Decreased Incidence but Still a Big Challenge. Cancers 2023; 15: 2639. doi:10.3390/cancers15092639
4. Fock KM, Ang TL. Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. Journal of Gastroenterology and Hepatology 2010; 25: 479-486. doi:10.1111/j.1440-1746.2009.06188.x
5. Allemani C, Weir HK, Carreira H et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). The Lancet 2015; 385: 977-1010. doi:10.1016/s0140-6736(14)62038-9
6. Huang RJ, Choi AY, Truong CD et al. Diagnosis and Management of Gastric Intestinal Metaplasia: Current Status and Future Directions. Gut and Liver 2019; 13: 596-603. doi:10.5009/gnl19181
7. Poorolajal J et al. Risk factors for stomach cancer: a systematic review and meta-analysis. Epidemiology and Health 2020; 42: e2020004. doi:10.4178/epih.e2020004

Introduction

Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome characterized by the development of numerous adenomatous polyps in the colon and rectum, with prophylactic colectomy being the standard treatment to prevent disease progression. Recently, endoscopic intensive downstaging polypectomy (IDP) has attracted attention as a novel disease management strategy, particularly for patients with non-dense FAP who refuse or delay surgery. Since IDP requires the resection of numerous polyps, simpler and safer techniques such as hot snare polypectomy (HSP), cold snare polypectomy (CSP), and hot biopsy (HB) are commonly used. However, the effectiveness of these techniques for the treatment of small adenomas in the context of IDP has not been fully evaluated.

Aims & Methods

This study aimed to evaluate the safety and efficacy of CSP compared with HSP and HB in patients with FAP undergoing IDP. This retrospective study included patients with FAP who underwent IDP using only CSP, HSP, or HB at Hiroshima University Hospital between September 2012 and March 2024. Patients were divided into two groups: the CSP group, treated with CSP from October 2022 onward, and the HOT group, treated with HSP and HB between 2012 and September 2022. The primary endpoints were the incidence of adverse events and the treatment duration per polyp. Secondary endpoints included the incidence of immediate and delayed bleeding, perforation, total treatment duration per session, number of polyps removed per procedure, R0 resection rate, and the rate of missed polyps ≥10 mm.

Results

Variables	Total (n=185)	CSP (n=46)	HOT (n=139)	p-value
Treatment duration per procedure (min)	45.9 (22.1)	51.1 (23.2)	44.3 (21.7)	0.06
Polyps removed per procedure	51.6 (52.1)	80.5 (56.8)	42.1 (46.9)	< 0.01
Treatment duration per lesion (min)	1.7 (1.4)	1.3 (1.4)	1.8 (1.3)	0.01
Maximum tumor size per procedure (mm)	5.2 (2.4)	6.0 (2.5)	4.9 (2.4)	< 0.01
Overall adverse events (n (%)) Immediate bleeding (n (%)) Delayed bleeding (n (%)) Perforation (n (%))	14 (7.6) 10 (5.4) 2 (1.1) 2 (1.1)	0 (0) 0 (0) 0 (0) 0 (0)	14 (10.1) 10 (7.2) 2 (1.1) 2 (1.1)	0.03 0.06 0.41 0.41

During the study period, 46 treatment sessions were performed in 24 patients in the CSP group, resulting in the removal of a total of 3,689 polyps. In contrast, 139 treatment sessions were performed in 27 patients in the HOT group, with a total of 5,912 polyps removed. The average number of polyps removed per session was significantly higher in the CSP group (80.5 polyps) than in the HOT group (42.1 polyps) (p < 0.01). Additionally, the treatment duration per polyp was significantly shorter in the CSP group (1.3 minutes) than in the HOT group (1.8 minutes) (p = 0.01). The total treatment duration per session was slightly longer in the CSP group (51.1 minutes) compared to the HOT group (44.3 minutes), although the difference was not statistically significant (p = 0.06). The maximum polyp size was significantly larger in the CSP group (6.0 mm) than in the HOT group (4.91 mm) (p < 0.01). The overall incidence of adverse events was significantly lower in the CSP group. Immediate bleeding occurred in 10 cases (7.2%) in the HOT group but was not observed in the CSP group. Delayed bleeding and perforation were also observed only in the HOT group; however, there were no statistically significant differences between the groups.

Conclusion

This study demonstrated that CSP is a safe and effective option for intensive polyp reduction in patients with FAP. Compared with HSP and HB, CSP enabled the removal of more polyps in a shorter duration and reduced the risk of adverse events.

Clinical Case Summary

Our patient was a 66yr Chinese man who was treated for active Chronic Hepatitis B from 2009 with Lamivudine, Adefovir and then switched to Tenofovir from 2020 with long term undetectable Hepatitis B viral load (HBV VL) and normal Liver function tests. His ultrasound liver was normal and Fibroscan 6.9kpa in 2021. Hepatitis B Surface quantification was 87 IU/ml. ALT 28.
The patient was enrolled in a research trial which randomized him to stopping Tenofovir with close follow up.
At week 4 after stopping Tenofovir, his HBV VL became detectable at 2.53log and ALT 31.
At week 8, his HBV VL increased to 5.55log and ALT 35.
At week 10, HBV VL was 6.85, ALT 384, Bilirubin and INR normal. HBeAg remained negative and the patient remained asymptomatic.
He was promptly restarted on Tenofovir but his ALT continued to rise and peaked at 832 at week 12 before gradually returning to normal as did his Hepatitis B viral load.
At week 13, he developed tingling over his hands and feet.
At week 14, he was admitted for clumsiness with reduced sensation over the feet and hands. He had no other systemic symptoms suggestive of any infections.
Examination revealed subjective reduction in sensation over the distal peripheral limbs. Power was normal but reflexes were absent over the ankles and knees.
MRI brain was normal.
Lumbar puncture showed high CSF protein 0.7gL but normal cell count. Nerve Conduction study (NCS) reported acute inflammatory demyelinating polyneuropathy.
EMG was unremarkable.
A probable diagnosis of GBS was made.
His ALT was down to 304 and HBV VL 3.82 log.
NCS repeated 2 months later and showed similar inflammatory demyelinating polyneuropathy.
NCS repeated 4 months later showed significant improvement which confirmed a diagnosis of GBS
1 year from his first presentation, he recovered fully.
Only 7 cases of Hepatitis B related GBS have been reported in the literature. Our case highlights GBS resulting from Hepatitis B flare

References

none

Introduction

​Endocytoscopy (ECS), an ultrahigh-magnification contact-type endoscopy, enables real-time visualization of gastrointestinal mucosal and neoplastic cells. As a result, ECS enhance diagnostic precision as a form of optical biopsy. However, the reliability of ECS diagnosis is contingent upon adequate staining, which remains a considerable challenge in the stomach due to the abundance of mucus and inflammatory exudates that hinder optimal visualization. Weak vital staining can easily reduce the reliability of ECS diagnosis. Texture and Color Enhancement Imaging (TXI), a digital image enhancement modality developed by Olympus, enhances three key imaging elements—brightness, texture, and color tone—to optimize lesion visualization even under suboptimal staining conditions. Consequently, TXI may augment the diagnostic utility of ECS.

Aims & Methods

The aim of this study was to evaluate whether TXI enhances the diagnostic performance of ECS in early gastric cancer. Twenty-eight patients with 30 gastric cancers scheduled for magnifying endoscopic examination at Nippon Medical School Tama Nagayama Hospital between February 2024 and March 2025 were prospectively enrolled. All ECS procedures were performed with GIF-H290EC (Olympus Co., Tokyo, Japan) and the video processors EVIS X1 (Olympus Co., Tokyo, Japan). For in vivo dyeing, double staining with crystal violet and methylene blue was used. ECS was performed with and without TXI in both cancer and non-cancerous legions. ECS observation is performed by first taking photographs without TXI, and then taking photographs of the same area using the TXI. From each lesion, five ECS images with and without TXI were selected, resulting in a blinded and randomized image catalog (comprising 300 images from 30 gastric cancers and 280 images from 28 non-tumor areas). Two endoscopists independently assessed the images using a numerical rating scale (NRS, 0–10) to evaluate the visibility of nuclear atypia and structural cellular atypia. Diagnostic accuracy was assessed against pathological diagnosis as the gold standard. ECS diagnoses were rendered based on previously established criteria, wherein lesions exhibiting high-grade atypia were classified as cancer (Kaise M, et al. Endoscopy. 2015).

Results

The overall accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for EGC diagnosis by the two endoscopists were 82.5%, 84.3%, 80.7%, 81.3%, and 83.8%, respectively. The rate of interobserver agreement between the two endoscopists was high, with a kappa coefficient of κ = 0.797. Notably, diagnostic accuracy was significantly higher in the TXI images compared to the non-TXI images (85.2% vs. 79.0%, p = 0.0027). While the NRS scores for structural atypia did not differ significantly between the TXI and non-TXI images (4.90 vs. 4.87, p = 0.61), the NRS scores for nuclear atypia were significantly elevated in the TXI images (6.88 vs. 5.88, p < 0.0001).

Conclusion

​The integration of TXI with ECS significantly enhances the visualization of nuclear atypia and improves diagnostic accuracy in the diagnosis of gastric cancer. This synergistic approach facilitates superior optical biopsy capabilities, enhancing its clinical utility in the endoscopic diagnosis of early gastric cancer.

References

Kaise M, Ohkura Y, Iizuka T, Kimura R, Nomura K, Kuribayashi Y, et al. Endocytoscopy is a promising modality with high diagnostic accuracy for gastric cancer. Endoscopy. 2015;47:19–25.