Clinical characteristics and long-term prognosis of type 1 gastric neuroendocrine tumors in a large Japanese national cohort.

OBJECTIVES: Optimal management of type 1 gastric neuroendocrine tumors (T1-GNETs) remains unknown, with few reports on their long-term prognosis. This study investigated the clinical characteristics and long-term prognosis of T1-GNETs. METHODS: We reviewed the medical records of patients diagnosed with T1-GNET during 1991-2019 at 40 institutions in Japan. RESULTS: Among 172 patients, endoscopic resection (ER), endoscopic surveillance, and surgery were performed in 84, 61, and 27, respectively, including 27, 77, and 2 patients with pT1a-M, pT1b-SM, and pT2 tumors, respectively. The median tumor diameter was 5 (range 0.8-55) mm. Four (2.9%) patients had lymph node metastasis (LNM); none had liver metastasis. LNM rates were significantly higher in tumors with lymphovascular invasion (LVI) (15.8%; 3/19) than in those without (1.1%; 1/92) (P = 0.016). For tumors <10 mm, LVI and LNM rates were 18.4% (14/76) and 2.2% (2/90), respectively, which were not significantly different from those of tumors 10-20 mm (LVI 13.3%; 2/15, P = 0.211; and LNM 0%; 0/17, P = 1.0). However, these rates were significantly lower than those of tumors >20 mm (LVI 60%; 3/5, P = 0.021; and LNM 40%; 2/5, P = 0.039). No tumor recurrence or cause-specific death occurred during the median follow-up of 10.1 (1-25) years. The 10-year overall survival rate was 97%. CONCLUSIONS: Type 1 gastric neuroendocrine tumors showed indolent nature and favorable long-term prognoses. LVI could be useful in indicating the need for additional treatments. ER for risk prediction of LNM should be considered for tumors <10 mm and may be feasible for tumors 10-20 mm. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) under the identifier UMIN000029927.

Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports.

BACKGROUND: Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. METHOD: In this study we report the clinical courses of three cases with HDGC from a single Japanese family. RESULTS: The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. CONCLUSION: It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

Relationship of early acute complications and insertion site in push method percutaneous endoscopic gastrostomy.

Percutaneous endoscopic gastrostomy (PEG), which is frequently used for nutrition management in patients having difficulty with oral intake, is considered a safe procedure. However, serious complications may occur depending on site of the puncture. This study aimed to clarify whether push method PEG construction at the posterior wall (PW) of the greater curvature (GC) had a higher risk of complications. We retrospectively investigated the relationship between puncture site at the PW of the GC and early acute complications in 540 patients receiving PEG. Early acute complications were defined as bleeding or perforation within 30 days after the PEG procedure. PEG-related complications were observed in 80 patients in total, with early acute complications detected in 42 patients. PEG construction at the PW of the GC in 12 cases exhibited a significantly higher occurrence of early acute complications versus PEG at other sites (41.7% vs. 7.0%, p = 0.001). Further, multivariate analysis revealed PW at the GC to be independently associated with early acute complications (OR 9.59, 95% CI 2.82-32.61; p = 0.0003). It may be desirable to avoid PEG at the PW of the GC. If performed, clinicians should pay careful attention to early acute complications.

[Familial adenomatous polyposis with papillary thyroid cancer:a case report].

The patient is 36-year-old woman who complained of proptosis and was diagnosed as thyroid cancer. The pathologic diagnosis of her resected specimen was papillary thyroid cancer, cribriform morular variant (CMV). Subsequently, she was suspected of having familial adenomatous polyposis (FAP), although she had no family history of it. The diagnosis of FAP was confirmed following colonoscopy, which showed multiple polyps, and the biopsies that revealed multiple adenomas and cancers with APC gene mutation. She underwent restorative proctocolectomy, rectal mucosectomy with ileal pouch anal anastomosis, and ileostomy in our department. Cancer in the adenomas was found in four polyps on histopathological examination. CMV is known to be complicated with FAP. However, the number of reported cases remains few. This case was relatively rare, with an initial diagnosis of FAP because of the coexistence of CMV. In patients with papillary thyroid cancer (CMV type), colonoscopy should be considered because of the possibility of FAP.

Polymorphism at rs9264942 is associated with HLA-C expression and inflammatory bowel disease in the Japanese.

An expression quantitative trait locus (eQTL) single-nucleotide polymorphism (SNP) at rs9264942 was earlier associated with human leukocyte antigen (HLA)-C expression in Europeans. HLA-C has also been related to inflammatory bowel disease (IBD) risk in the Japanese. This study examined whether an eQTL SNP at rs9264942 could regulate HLA-C expression and whether four SNP haplotypes, including the eQTL SNP at rs9264942 and three SNPs at rs2270191, rs3132550, and rs6915986 of IBD risk carried in the HLA-C*12:02~B*52:01~DRB1*15:02 allele, were associated with IBD in the Japanese. HLA-C expression on CD3e+CD8a+ lymphocytes was significantly higher for the CC or CT genotype than for the TT genotype of rs9264942. The TACC haplotype of the four SNPs was associated with a strong susceptibility to ulcerative colitis (UC) but protection against Crohn's disease (CD) as well as with disease clinical outcome. While UC protectivity was significant but CD susceptibility was not for the CGTT haplotype, the significance of UC protectivity disappeared but CD susceptibility reached significance for the CGCT haplotype. In conclusion, our findings support that the eQTL SNP at rs9264942 regulates HLA-C expression in the Japanese and suggest that the four SNPs, which are in strong linkage disequilibrium, may be surrogate marker candidates of a particular HLA haplotype, HLA-C*12:02~B*52:01~DRB1*15:02, related to IBD susceptibility and disease outcome.

Diffuse large B-cell lymphoma of the colon and rectum in a patient with colonic Crohn's disease treated with infliximab and azathioprine.

A 52-year-old woman was treated for colorectal diffuse large B-cell lymphoma (DLBCL) after a prolonged treatment period of azathioprine (AZA) and infliximab (IFX) for Crohn's disease (CD). She had been diagnosed as having colonic CD at the age of 24 years and received AZA from age 29. IFX was added at 47 years of age. She experienced massive hematochezia and anal pain at the age of 52 years and was transferred to our hospital. Endoscopic examination revealed a deep rectal ulcer with arterial bleeding. A stoma constructed at the transverse colon for refractory CD relieved her symptoms. Four months later, computed tomography showed increased thickness of the rectal wall. DLBCL was diagnosed from biopsy specimens of the rectum. Treatment with 6 courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone along with additional radiation therapy for remnant rectal lymphoma has resulted in complete remission for over 5 years. Although colorectal malignant lymphoma coexisting with active CD was rare and the lesions were difficult to detect, intensive therapy for CD helped in the diagnosis and successful treatment of the patient.

Sjögren syndrome-related plasma cell disorder and multifocal nodular AL amyloidosis: clinical picture and pathological findings.

Background: Localized nodular deposits of AL amyloid are seen in different tissues/organs; however, the pathogenesis of this form of amyloidosis remains unclear. Recently, Sjögren syndrome combined with localized nodular AL amyloidosis has been noted. Here, we report Sjögren syndrome cases showing multifocal nodular AL amyloidosis and the followed benign course. Materials and methods: We investigated the clinical pictures and histopathological findings of three cases with both presence of Sjögren syndrome and localized nodular AL amyloidosis, paying a special attention to the distribution of amyloidoma. Results: All three cases were middle-aged females. In two of three cases localized deposits of AL amyloid preceded Sjögren syndrome. Amyloidoma was detected in scalp, eyelid, cheek, larynx, trachea, lung and breast, and around these amyloid-deposited lesions infiltration of plasma cells was seen. Pulmonary amyloidosis was consistently accompanied with parenchymal cystic lesions, but this amyloidosis did not produce any significant respiratory symptoms. Some of large pulmonary amyloidomas showed cavity formation and subsequent shrinkage. In two cases amyloid deposition was found on gastric mucosa. Two cases received small doses of oral prednisone, with no further appearance of amyloidoma. Conclusion: Sjögren syndrome-related plasma cell disorder may be responsible for the formation of this unique multifocal nodular AL amyloidosis.

Correlation of clinicopathological features and LGR5 expression in colon adenocarcinoma.

Colon cancer stem cells (CSCs) are closely related to tumorigenesis and treatment response, and LGR5 is currently the most robust and reliable CSC marker in colorectal cancer (CRC). However, LGR5 expression in CRC tumor budding (TB) is not well understood. We examined the clinicopathological and prognostic significance of LGR5 in CRC TB. LGR5 expression was evaluated by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 55 patient samples of TB in colon adenocarcinoma (CA) selected from the medical archives at our hospital. Patients were stratified into negative and positive LGR5 expression groups. Inflammatory cell infiltration was weaker and histological grade was lower in the LGR5-positive group compared with the LGR5-negative group (P = 0.0407 and P = 0.0436, respectively). There was a significant difference in OS between the LGR5-positive group and LGR5-negative group (log-rank test, P = 0.0088). Cox proportional hazards models revealed that the LGR5-positive group (Overall survival (OS) = 0.37, 95% CI: 0.17-0.79, P = 0.0101) had better OS. LGR5 expression may be affected by inflammatory cell infiltration in the budding area of CA and is an important potential marker of prognosis.

Leucine-rich repeat-containing G-protein-coupled receptor 5 expression and clinicopathological features of colorectal neuroendocrine neoplasms.

LGR5 is expressed in various tumors and has been identified as a putative intestinal stem cell marker. Here we investigated LGR5 expression in colorectal neuroendocrine neoplasms and analyzed the correlation with pathological characteristics. We evaluated the clinicopathological features of 8 neuroendocrine tumor (NET) grade 1 (NET G1), 4 NET Grade 2 (NET G2), and 8 NET Grade 3 (NET G3; also termed neuroendocrine carcinoma, or NEC) cases. We examined LGR5 expression using an RNAscope, a newly developed RNA in situ hybridization technique, with a tissue microarray of the neuroendocrine neoplasm samples. LGR5 staining in individual tumor cells was semi-quantitatively scored using an H-score scale. We also performed a combination of LGR5 RNA in situ hybridization and synaptophysin immunohistochemistry. All cases contained tumor cells with some LGR5-positive dots. For all cases, H-scores showed a positive correlation with nuclear beta-catenin expression. In the NEC group, there was a strong positive correlation between H-score and beta-catenin expression. Our findings suggest that LGR5 may serve as a stem cell marker in NEC, as is the case in colon adenocarcinoma. The positive correlation between H-score and beta-catenin expression suggests that LGR5 expression might be affected by beta-catenin expression in neuroendocrine neoplasms and especially in NEC.

Accuracy of Endoscopic Diagnosis for Mild Atrophic Gastritis Infected with Helicobacter pylori.

BACKGROUND/AIMS: This study examined the accuracy of endoscopic evaluation for determining the Helicobacter pylori infection status in patients with mild atrophy who might not exhibit characteristic endoscopic findings. METHODS: Forty endoscopists determined the H. pylori infection status of 50 randomly presented H. pylori-positive and H. pylorinegative cases on the basis of a list of established findings. RESULTS: The median clinical endoscopy experience was 7 years (range, 1-35 years), including 22 board-certified endoscopists (55%) of the Japan Gastroenterological Endoscopy Society. The mean accuracy rate of endoscopic diagnosis was 67% and was unrelated to experience status (experienced vs. trainee: 69% vs. 65%, p=0.089) and total years of experience (R2 =0.022). The most frequently selected endoscopic findings were regular arrangement of collecting venules (59%), atrophy (45%), and red streak (22%), which had fair accuracy rates of 67%, 65%, and 73%, respectively. By contrast, the accuracy rates of nodularity (89%) and mucosal swelling (77%) were highest. The 20 endoscopists who more frequently identified these findings diagnosed H. pylori infection significantly more accurately than did the other endoscopists (71% vs. 64%, p=0.008). CONCLUSIONS: Careful attention to nodularity and mucosal swelling in patients with mild atrophy may enhance diagnosis, enable prompt treatment, and avoid possible long-term carcinogenesis.

Association between KIR-HLA combination and ulcerative colitis and Crohn's disease in a Japanese population.

Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn's disease (CD). Natural killer cell responses play a crucial role in autoimmune disease through innate immunity, in which killer cell immunoglobulin-like receptors (KIRs) are closely involved. Although the genetic combination of KIRs with their specific HLA class I ligands has been associated with IBD in Caucasians, such KIR-HLA receptor-ligand combinations are not fully understood in the Japanese. We investigated 14 KIR genes along with HLA-Bw and -C ligands in 90 patients with UC and 50 patients with CD and compared them with the characteristics of 325 healthy control subjects. The frequency of HLA-Bw4 was significantly increased in patients with UC (P = 1.3 × 10-6; odds ratio [OR] = 3.39) and CD (P = 0.0065; OR = 2.32) versus controls. The UC group had a significantly higher frequency of KIR2DS3 (P = 0.024; OR = 1.94) and lower frequency of KIR2DS4 (P = 0.019; OR = 0.40) and KIR2DL1-HLA-C2 (P = 0.035; OR = 0.47). The Tel-A/B haplotype was significantly decreased in UC patients (P = 0.0056; OR = 0.49). The frequency of KIR3DL1-HLA-Bw4 was significantly higher in patients with UC (P = 4.3 × 10-6; OR = 3.12) and CD (P = 0.0067; OR = 2.30). In conclusion, HLA-Bw4 and KIR-HLA pairs may play an important role in the genetic susceptibility to IBD in the Japanese.

Resection depth and layer of cold snare polypectomy versus endoscopic mucosal resection.

BACKGROUND: Cold snare polypectomy (CSP) has not undergone sufficient histopathological evaluation. This study aimed to clarify the histopathological features of CSP specimens, including resection depth and layer, as compared with endoscopic mucosal resection (EMR). METHODS: Polyps were recruited retrospectively. Sessile, semi-pedunculated, and 0-IIa polyps of ≤ 9 mm were selected by propensity score matching and classified as either a complete resection or one with an unevaluable/positive (X/+) margin. Resection depth and layer were estimated and the risk factors for an X/+ margin were evaluated. RESULTS: A total of 1072 polyps were enrolled. After matching, 184 polyp pairs were selected. An X/+ margin was seen in 105/184 (57%) vs. 70/184 (38%) CSP vs. EMR specimens (p < 0.001): specimen damage was 53/184 (29%) vs. 30/184 (16%) (p < 0.01) and vertical margin (VM) X/+ was 11/184 (6%) vs. 2/184 (1%) (p < 0.05). Among 193 completely resected specimens, resection depth from the muscularis mucosae in CSP vs. EMR was 76 vs. 338 µm (p < 0.001) and resection layer was the submucosa in 7/79 (9%) vs. 105/114 (92%) (p < 0.001). In multivariate analysis, CSP was a risk factor for procedure-associated VMX/+ [odds ratio (OR) 6.80, 95% confidence interval (CI) 1.33-34.69, p < 0.05]. Sessile serrated adenoma/polyp (SSA/P) was a risk factor for VMX/+ margin in CSP specimens (OR 58.36, 95% CI 7.45-456.96, p < 0.001). CONCLUSIONS: SSA/P and colorectal cancer may not be suitable for CSP adoption.

Development of diffuse large B-cell lymphoma from follicular lymphoma of the duodenum: changes in endoscopic findings during a 6-year follow-up.

A 71-year-old Japanese man was diagnosed as having stage I primary follicular lymphoma (FL) of the duodenum according to Lugano International Conference Classification and began receiving annual checkups. Endoscopic examination disclosed white villi swelling with depressed red mucosal lesions. Biopsy specimens from the area of white villi exhibited histopathological features that met the diagnostic criteria for low-grade FL. The depressed red lesions gradually enlarged over six years of follow-up. A biopsy of the white villi swelling revealed distinct well-circumscribed follicles with attenuated mantles in the lamina propria that were positive for CD20, bcl-2, and CD10. Histological findings from the depressed red lesions at 5.5 years after the initial diagnosis were compatible for FL. However, biopsy specimens 6 months later obtained from the same lesions showed a mixture of larger mononuclear cells. These follicular cells were positive for CD20 and bcl-2, but not for CD10, indicating the presence of diffuse large B-cell lymphoma (DLBCL). This case shows altered endoscopic findings in the course of DLBCL development from FL. When depressed red lesions are detected in the background of white villi swelling, repeated biopsies should be performed from both lesions.

The loop-forming method as a useful technique to rotate the endoscopic insertion tube shaft.

BACKGROUND AND STUDY AIMS: Gastroenterological endoscopists are instructed to bring the target to the 6-o'clock position when they take a biopsy specimen, use a snare, or cut a target organ. This action is performed primarily by rotating the shaft of the endoscopic insertion tube, which can be difficult in some situations when existing endoscopic methods are used. We previously described a method for optimal rotation of the endoscopic insertion tube shaft, called the loop-forming method (LFM). The present study aimed to validate this procedure and confirm the usefulness of the LFM for leftward rotation of the shaft. PARTICIPANTS AND METHODS: The LFM was specifically taught to 28 gastroenterological endoscopists, and the angle of rotation was measured before and after they received instruction in this method. RESULTS: The LFM significantly increased the average angle of leftward rotation from 266° to 327°. Moreover, whereas the instrument channel inlet tended to move away from the right hand of an operator using a conventional endoscopy method, it remained closely accessible to the right hand of an examiner using the LFM. CONCLUSIONS: The LFM has the potential to make endoscopic procedures easier and safer.

Screening to Identify and Eradicate Helicobacter pylori Infection in Teenagers in Japan.

The purpose of this study was to elucidate the prevalence and effect of Helicobacter pylori infection in Japanese teenagers. The study subjects were students ages 16 to 17 from one high school studied between 2007 and 2013. Students who tested positive on this screening examination underwent esophagogastroduodenoscopy and biopsy samples to determine their H pylori status using culture and histology. Cure of H pylori infections was determined by urea breath test. The low rate of prevalence of H pylori infection in present Japanese teenagers makes it possible and cost effective to perform examinations and carry out treatment of this infection in nationwide health screenings of high school students.

Eosinophilic gastroenteritis complicated with Helicobacter pylori infection unresponsive to eradication therapy.

An adolescent girl presented with inappetence. Upper gastrointestinal endoscopy showed rough and cracked mucosa at the gastric antrum with a scarred duodenal ulcer, and a biopsy sample demonstrated abundant eosinophils. We therefore diagnosed the patient as having eosinophilic gastroenteritis. Eradication therapy for Helicobacter pylori (H. pylori) did not improve her symptoms; however, proton pump inhibitor therapy was effective in resolving her chief complaints. There are several reports of eosinophilic gastroenteritis complicated with H. pylori infection in which the association between eradication therapy and the patient's symptoms is unclear. In the present case, the patient's symptoms did not improve with eradication therapy, and there appeared to be no relationship between the two.

Antimicrobial resistance and characteristics of eradication therapy of Helicobacter pylori in Japan: a multi-generational comparison.

BACKGROUND: Eradication of Helicobacter pylori (H. pylori) at a younger age is considered to be effective in preventing gastric cancer. This study assessed the characteristics of eradication therapy in young patients. MATERIALS AND METHODS: We enrolled 1073 patients with H. pylori infection between 2000 and 2013. The subjects were divided into three groups according to age into the young (≤30 years), middle-aged (31-50 years), and elder (≥51 years) groups. We also examined 472 cases to investigate clinical eradication characteristics. RESULTS: The rate of clarithromycin (CAM) resistance was 57.9%, 34.5%, and 35.2% in the young, middle-aged, and elder group, respectively, in 2012-2013 and was significantly higher in the young group than in the elder group (p = .01). Metronidazole (MNZ) resistance was similar among the three groups at each time point. While CAM resistance rose over the study period, MNZ resistance was noted to have decreased of late. The overall initial eradication success rate was 91.9% (95% CI, 89.1-94.1) in our cohort. Eradication efficiency was comparable in the young, middle-aged, and elder group at 94.3% (95% CI, 87.4-97.5), 90.2% (95% CI, 82.9-94.6), and 91.8% (95% CI, 88.1-94.5) respectively. Side effects such as skin rash were observed in 14.8%, 3.9%, and 3.5% of the respective groups. There were significant differences in the incidence of side effects between the young group and other groups (p < .05, respectively). CONCLUSION: Since CAM resistance and the incidence of side effects are higher in young individuals, it is especially important to select eradication regimens based on testing for antimicrobial susceptibility.