Introduction

Primary small-bowel cancer (PSBC), including duodenum, jejunum and ileum, is a relatively uncommon disease. However, the number of cases has been increasing in recent years. Furthermore, since more than half of all PSBCs occurred in the duodenum, cancers of the jejunum and ileum were particularly rare tumors. Few reports have focused on the jejunum and ileum.

Aims & Methods

We analyzed the clinicopathological features and prognosis of PSBC from a large multicenter study conducted in Japan. A total of 2,388 primary small-bowel lesions were collected between January 2008 and December 2017 from 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) in Japan. We excluded 2,032 lesions for the following reasons: site of duodenum, unavailability of patient’s or tumor essential information, histology not consistent with PSBC (such as malignant lymphoma, gastrointestinal stromal tumor, metastasis of PSBC, hamartoma, adenoma, or others), and patients with background diseases such as (Crohn disease, familial adenomatous polyposis, and Peutz-Jeghers syndrome). Because it was more difficult to clearly diagnose Lynch syndrome than other diseases, we did not exclud it in this study. We analyzed the clinicopathological features and the prognosis of PSBC. Clinicopathological features and TNM classification were evaluated according to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma eighth edition (JCCAC).

Results

354 patients with 358 PSBC were enrolled. The average age of enrolled patients was 64.4 years, with 218 males (61.6%). The average tumor size was 49.9 mm, and the rate of PSBC’s site in the jejunum was 66.2%, while in the ileum was 30.4%. Of the 354 enrolled, 19 patients (5.4%) were diagnosed with Lynch syndrome, and 272 (76.8%) had symptoms at the initial diagnosis. Single-balloon endoscopy, double-balloon endoscopy and capsule endoscopy were used for diagnosis in 43 patients (12%), 166 (47%) and 43 (12%), respectively. Surgical resection was the most performed to the 291 patients (82.2%) for treatment and in those 115 patients (32.5%) underwent chemotherapy after surgical resection. In this study, the rate of each stage (0, I, II, III, IV) was 5.3%, 2.5%, 27.0%, 25.8% and 36.2%, respectively. The average follow-up period was 31.0 ± 30.8 months. Among the 217 patients with PSBC in stages 0 to III, there were 51 recurrences. The recurrence rate of each stage was stage 0: 5.3% (1/19), stage I: 11.1% (1/9), stage II: 18.6% (18/97) and stage III: 33.7% (31/92), respectively. The most common site of metastasis at first diagnosis (stage IV) was the peritoneum (55.8%). The 5-year overall survival rate in each stage was 92.3%, 60.0%, 75.9%, 61.4% and 25.5%, while the 5-year disease-specific survival (DSS) rate in each stage was 100%, 75.0%, 84.1%, 59.3% and 25.6%, respectively. The site of PSBC in the jejunum had a significantly lower 5-year DSS rate than that in the ileum (50.8% vs 66.7%, p=0.0418). The patients with symptoms at initial diagnosis had a significantly lower 5-year DSS rate than patients without symptoms (51.2% vs 70.5%, p=0.0416).

Conclusion

We have identified the characteristics and prognosis of PSBC in a large number of patients. 76.8% of patients with PSBC already had symptoms at the initial diagnosis and were often detected at the advanced stage. To improve the prognosis of PSBC, identifying with high-risk patients such as Lynch syndrome and screening should be examined, and the PSBC should be detected and treated in the early stages before symptoms appear.

Introduction

The molecular and clinicopathological features of primary small bowel adenocarcinoma (SBA) are less well understood than those of colorectal and gastric cancers, primarily due to its rarity. Cancer stem cells, a small subpopulation of tumor cells, are capable of initiating tumors and contributing to relapse. However, the clinicopathological significance of cancer stem cell marker expression in SBA remains unclear.

Aims & Methods

To investigate the localization and clinicopathological relevance of stem cell markers in SBA, we conducted immunohistochemical analysis of CD44, CD44v, CD44v9, CD133, Lgr5, β-catenin and E-cadherin using formalin-fixed paraffin-embedded tissue samples from 57 SBA cases. DNA mismatch repair (MMR) status was assessed through immunostaining for MLH1, MSH2, MLH6, and PMS2. We then compared the expression patterns with clinicopathological data, including sex, age, localization, histological type, depth of invasion, lymph node metastasis, distant metastasis, clinical stage, disease-free survival and cancer-specific survival. Correlations between protein expression and prognosis were evaluated using the Kaplan-Meier method and Cox proportional hazards regression analysis.

Results

The mean follow-up period was 52 months (median: 46; range: 4–110 months), during which 19 patients died. Tumor localization was as follows: duodenum (n=24), jejunum (n=28), and ileum (n=5). Histologically, 47 tumors were well differentiated, 6 poorly differentiated, and 4 were mucinous adenocarcinoma. According to the TNM classification, 15 cases were stage I, 18 stage II, 10 stage III, and 14 stage IV. Positive expression rates for each protein were CD44, 54%; CD44v6, 46%; CD44v9, 49%; CD133, 39%; and Lgr5, 37%. Lgr5 expression was significantly correlated with lymph node metastasis, distant metastasis, and advanced TNM stage. It was also associated with reduced membranous β-catenin staining, indicative of Wnt/β-catenin pathway activation. CD44 and its variants were significantly associated with both lymph node metastasis and distant metastasis, as well as abnormal reduced membranous β-catenin staining and E-cadherin staining. CD133 was expressed in 39% of cases but did not correlate with any clinicopathological factors. Notably, its expression was higher in MMR-proficient tumors compared to MMR-deficiency ones. Univariate analysis identified histological type, depth of invasion, lymph node metastasis, CD44, CD44v6, CD44v9, CD133 and Lgr5 expression as significantly associated with cancer-specific survival. In multivariate analysis, both lymph node status (hazard ratio: 16.4) and Lgr5 expression (hazard ratio: 3.7) retained independent prognostic significance. For disease-free survival, univariate analysis using the Cox proportional hazards model revealed that lymph node metastasis, CD44v6 and Lgr5 had significant prognostic value. Multivariate analysis confirmed lymph node metastasis (hazard ratio: 31.2) and Lgr5 expression (hazard ratio: 28.7) as independent predictors of poorer disease-free survival.

Conclusion

Our findings suggest that all analyzed cancer stem cell markers had prognostic relevance in SBA. CD44 and its variant isoforms expression are associated with epithelial-mesenchymal transition. Lgr5 expression is linked to Wnt/β-catenin pathway and is an independent predictor of poor cancer-specific survival and disease-free survival, regardless of lymph node metastasis.

Introduction

Small bowel adenocarcinoma (SBA) are rare, but their incidence is increasing. Early diagnosis of SBA remains elusive, so that about one-third of patients are initially diagnosed with distant metastases. In clinical practice, regimens used for SBA parallel those commonly administered in the adjuvant setting for colorectal cancer, owing to its anatomic proximity. However, genomic profiling of SBA has been shown to be distinct from colorectal cancer through comprehensive analysis of genomic alterations. Therefore, it is vital to establish a distinct chemotherapy regimen for SBA based on its molecular pathological characteristics. Claudin-18 plays a key role in constructing tight junctions and altered claudin-18 expression has been documented in various human malignancies. On the basis of this, both monoclonal antibodies and claudin-18.2-specific chimeric antigen receptor engineered T-cells have been recently developed and employed in several clinical trials, showing promising results in the treatment of advanced gastroesophageal and pancreatobiliary tract cancers. However, little is known about the clinicopathological significance of claudin-18 expression in SBA.

Aims & Methods

To explore the localization of claudin-18 in human SBA tissue and draw comparisons and determine the relationship between their expression and clinicopathological factors, and genomic alterations.
We examined 50 surgical resections from patients with primary SBA for immunohistochemical analyses of claudin-18, CK7, CK20, CD10, CDX2, MUC2, MUC5AC, and MUC6 expression. DNA mismatch repair (MMR) status was defined by immunostaining for all MMR proteins; MLH1, MSH2, MLH6, and PMS2. Both MUC 2 and CD10 are markers of intestinal type tumors, whereas MUC5AC and MUC6 are markers of gastric type tumors. Tissue samples showing both gastric and intestinal phenotypes were classified as gastrointestinal type tumors, whereas those showing neither gastric nor intestinal phenotype expression were classified as null type tumors. In addition, genomic profiling was performed on 31 patients using targeted next-generation sequencing.

Results

Claudin-18 expression was observed in 46% of SBA patients. Claudin-18 expression was positively associated with cytokeratin 7 (P=0.003) and MUC5AC (P=0.020) expression, whereas it was negatively associated with MUC2 (P=0.010), CD10 (P=0.014), and CDX2 (P=0.003) expression. Tumor mucin phenotypes included gastric type (n=9), intestinal type (n=20), gastrointestinal type (n=17) and null type (n=4). Claudin-18 was more frequently expressed in gastric type (100%) than in intestinal type (30%) phenotypes (P=0.001). GNAS mutations (N=4) were found in only claudin-18 positive SBA patients, although the difference was not significant. Claudin-18 expression did not correlate with patient age at diagnosis, patient gender, site, histological type, depth of invasion, lymph node metastasis, distal metastasis, TNM stage, and MMR status. However, claudin-18 expression correlated with worse progression free survival.

Conclusion

Claudin-18 expression is associated with gastric immunophenotype and with worse progression free survival. These findings suggest that claudin-18 may be a potential therapeutic target in certain SBA cases.

Introduction

Small bowel cancers are rare, accounting for less than 5% of gastrointestinal cancers, but their incidence is increasing. Small bowel adenocarcinoma (SBA) accounts for one-third of small bowel cancers, and due to its rarity, scarcedata exist on its molecular and clinicopathological features.According to the stem cell hypothesis, only a very small number of cancer cells in a tumor have the ability to promote its growth and development. Lgr5 is known as a Wnt/β-catenintarget gene, marking normal stem cells in various tissues, including the small and large intestine. Lgr5 expression has been shown to correlate with poor prognosis in colorectal cancer. However, the clinicopathological significance of Lgr5expression in SBA remains unclear.

Aims & Methods

Aims: To explore the localisation of Lgr5 in human SBA tissueand draw comparisons and determine the relationship between their expression and clinicopathological factors and Wnt/β-catenin signaling pathway-related genomic alterations and proteins.
Methods: We examined 50 surgical resections from patients with primary SBA for immunohistochemical analyses of Lgr5, cyclin D1, c-Myc, and β-catenin expression. DNA mismatch repair (MMR) status was defined by immunostaining for all MMR proteins; MLH1, MSH2, MLH6, and PMS2. A comparative investigation was then performed with the clinicopathological data of patients (sex, age, localisation, histological type, depth of invasion, lymph node metastasis, distant metastasis, and clinical stage) and cancer specific survival. In addition, genomic profiling was performed on 31 patients using targeted next-generation sequencing. Correlation between the positive rate for each protein and prognosis was determined by the Kaplan-Meier method and multivariate analysis using the Cox regression.

Results

The average observation period was 53 months (median, 48; range, 4–110 months), and 18 patients died during the analysis. The primary localisation of the tumor was the duodenum (n=20), jejunum (n=25), and ileum (n=5). Forty-onecases were well differentiated; 5, poorly differentiated; and 4, mucinous adenocarcinoma. In terms of TNM classification, 25cases were stage I; 16, stage II; 12 stage III; and 16, stage IV.Lgr5 expression was observed in 38% of SBA patients andcorrelated with lymph node metastasis, distal metastasis, and advancing TNM stage. Lgr5 expression was not associated with DNA mismatch repair status. Lgr5 expression was significantly associated with reduced membranous β-catenin staining, which correspond to an activation of the Wnt/β-catenin pathway in cancer cells. CTNNB1 mutations (N=3) were found in only Lgr5 positive SBA patients, although the difference was notsignificant (P=0.090). APC mutations (N=5) were not associated with Lgr5 expression. Lgr5 expression, lymph node metastasis, and distant metastasis were significantly associated with worse cancer specific survival. In multivariate analysis for cancer specific survival, lymph node metastasis and Lgr5expression retained independent prognostic significance.

Conclusion

Lgr5 expression is associated with an activation of the Wnt/β-catenin pathway and worse cancer specific survival independent of lymph node metastasis in SBA.

Clinical Case Summary

Clinical history / pre-treatment imaging: A 54-year-old male with stage IV rectal adenocarcinoma (pT3N2M1) presented with progressive constipation and hematochezia over the past three months. His history included multiple surgeries for rectal cancer, chemoradiotherapy, and targeted therapy. On admission, he exhibited signs of mechanical small bowel obstruction, including abdominal distension and reduced stoma output. Laboratory tests showed anemia, hypoproteinemia, and elevated inflammatory markers. A contrast-enhanced CT scan revealed small bowel dilatation, pelvic recurrence, and peritoneal metastases, indicating malignant bowel obstruction (MBO).
Treatment options / results: Considering the advanced disease stage, poor nutritional status, and high surgical risk, a minimally invasive intervention was preferred. Digital subtraction angiography (DSA)-guided small bowel decompression was successfully performed. A STIF guidewire and multifunctional catheter were advanced under fluoroscopic guidance, and a decompression tube was placed into the distal jejunum, approximately 210 cm from the duodenojejunal junction. Post-procedure imaging confirmed optimal positioning and effective decompression. The patient experienced significant symptomatic relief, with reduced abdominal distension and improved stoma function. The patient was able to continue palliative chemotherapy with better comfort and improved quality of life.
Conclusion: DSA-guided small bowel decompression is an effective palliative intervention for malignant bowel obstruction. It provides rapid symptom relief and supports continued oncologic management in advanced-stage patients. Minimally invasive techniques should be considered for patients unsuitable for surgical intervention.
We will include the patient's abdominal contrast-enhanced CT images and DSA images in the poster.

Introduction

The role of capsule endoscopy (CE) for the surveillance of small-bowel (SB) cancer in asymptomatic Lynch syndrome (LS) patients has been questioned in recent years, with contradicting results. The overall lifetime risk of SB cancer in this population is around 4-5%, with an age-dependent pattern [1]. Besides, recent data highlight that, depending on the affected path_MMR gene, the frequencies of tumors other than colorectal cancer vary and that affected patients develop subsequent cancers later in life. The aim of this meta-analysis is to evaluate the diagnostic yield (DY) of CE as a screening tool in asymptomatic LS patients.

Aims & Methods

A systematic literature search was conducted in Pubmed, Embase and Web of Science to identify all studies evaluating SB cancer surveillance with CE in asymptomatic LS patients. The primary outcome was the evaluation of the DY of CE in consecutive screening rounds, for both CE-identified pathology and histologically-confirmed pathology (i.e., adenoma or adenocarcinoma). Pooled estimates of DY were calculated from random effects models.

Results

Five studies including 583 patients were identified for data extraction and statistical analysis [2-6] [Table]. The estimated pooled DY for CE-identified pathology was 8% in the first screening round (95% confidence interval [CI] 4-12%) and 6% in the second (95% CI 2-10%). Limiting the analysis to histologically-confirmed pathology, the pooled DY of the second-round screening dropped to 0% (95% CI 0-6%). The time interval between screening rounds was approximately 2 years.
Adenomas were detected in 8 patients (4 males) with a median age of 47.5 years (interquartile range [IQR] 19), while adenocarcinomas were diagnosed in 8 patients (5 males) with a median age of 62.5 years (IQR 17.25). MLH1 was the most involved path_MMR pathogenic variant (9 out of 16 patients), followed by MSH2 and MSH6 (5 and 2 patients, respectively). No adenocarcinomas were detected in MSH6 carriers, as only adenomas were found in 2 patients, with a considerably higher median age than MSH2 and MLH1 adenoma carriers (70.5 years versus 43.5 and 45). No predominance was observed according to the anatomical location (duodenum, n=6; jejunum, n=6; ileum, n=4).

Conclusion

The detection of adenocarcinoma appeared to have a 15-year delay compared to adenomas, supporting a rather slow adenoma to carcinoma transition.
A surveillance strategy starting from the age of 50, with a time interval between procedures lengthened to at least 5 years (instead of 2) could likely be more effective in reducing the burden of advanced disease, both in terms of cost-effectiveness and efficacy. Prospective data may reveal whether a potential SB surveillance might benefit from gene-associated differences in cancer risk, similar to the recent de-escalation of CRC screening recommendations in MSH6 and PMS2 carriers [7].
In conclusion, although the DY of CE is high in detecting SB lesions in LS, the low number of positive examinations eventually resulted in an even lower number of true-positive patients, with a pooled yield proximate to 0%.
The results of this study confirm that SB cancer surveillance with CE with a 2-year interval in asymptomatic LS individuals is not an effective screening strategy.

References

[1] Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020;22:15–25.
[2] Saurin J-C, Pilleul F, Soussan EB, et al. Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome. Endoscopy 2010;42:1057–62.
[3] Haanstra JF, Al-Toma A, Dekker E, et al. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Gut 2015;64:1578–83.
[4] Haanstra JF, Al-Toma A, Dekker E, et al. Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Endosc Int Open 2017;5:E622–E626.
[5] Perrod G, Samaha E, Perez-Cuadrado-Robles E, et al. Effectiveness of a dedicated small bowel neoplasia screening program by capsule endoscopy in Lynch syndrome: 5 years results from a tertiary care center. Ther Adv Gastroenterol 2020;13:1756284820934314.
[6] DeJesse J, Vajravelu RK, Dudzik C, et al. Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome. World J Clin Oncol 2021;12:1023–36.
[7] Peltomäki P, Nyström M, Mecklin J-P, et al. Lynch syndrome genetics and clinical implications. Gastroenterology 2023 Jan 24;S0016-5085(23)00050-1. doi:10.1053/j.gastro.2022.08.058 [Online ahead of print]