Evidence-based clinical practice guidelines for management of colorectal polyps.

BACKGROUND: The Japanese Society of Gastroenterology (JSGE) published ''Daicho Polyp Shinryo Guideline 2014'' in Japanese and a part of this guideline was published in English as "Evidence-based clinical practice guidelines for management of colorectal polyps" in the Journal of Gastroenterology in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version. METHODS: The guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references. RESULTS: The professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas). CONCLUSIONS: After evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.

Japan Gastroenterological Endoscopy Society guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection.

Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also several types of precarcinomatous adenomas. It is important to establish practical guidelines wherein preoperative diagnosis of colorectal neoplasia and selection of endoscopic treatment procedures are appropriately outlined and to ensure that actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society compiled colorectal endoscopic submucosal dissection/endoscopic mucosal resection guidelines by using evidence-based methods in 2014. The first edition of these guidelines was published 5 years ago. Accordingly, we have published the second edition of these guidelines based on recent new knowledge and evidence.

JGES guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection.

Colorectal endoscopic submucosal dissection (ESD) has become common in recent years. Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also many types of precarcinomatous adenomas. It is important to establish practical guidelines in which the preoperative diagnosis of colorectal neoplasia and the selection of endoscopic treatment procedures are properly outlined, and to ensure that the actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with the guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society has recently compiled a set of colorectal ESD/endoscopic mucosal resection (EMR) guidelines using evidence-based methods. The guidelines focus on the diagnostic and therapeutic strategies and caveat before, during, and after ESD/EMR and, in this regard, exclude the specific procedures, types and proper use of instruments, devices, and drugs. Although eight areas, ranging from indication to pathology, were originally planned for inclusion in these guidelines, evidence was scarce in each area. Therefore, grades of recommendation were determined largely through expert consensus in these areas.

Evidence-based clinical practice guidelines for management of colorectal polyps.

BACKGROUND: Recently in Japan, the morbidity of colorectal polyp has been increasing. As a result, a large number of cases of colorectal polyps that are diagnosed and treated using colonoscopy has now increased, and clinical guidelines are needed for endoscopic management and surveillance after treatment. METHODS: Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Ten specialists for colorectal polyp management extracted the specific clinical statements from articles published between 1983 and September 2011 obtained from PubMed and a secondary database, and developed the CQs and statements. Basically, statements were made according to the GRADE system. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid. RESULTS: The professional committee created 91CQs and statements for the current concept and diagnosis/treatment of various colorectal polyps including epidemiology, screening, pathophysiology, definition and classification, diagnosis, treatment/management, practical treatment, complications and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumor/carcinoma). CONCLUSIONS: After evaluation by the moderators, evidence-based clinical guidelines for management of colorectal polyps have been proposed for 2014.

Current status of endoscopic resection strategy for large, early colorectal neoplasia in Japan.

BACKGROUND: Conventional endoscopic resection (CER) for early colorectal neoplasia (CRN) is widely accepted as a minimally invasive treatment. Endoscopic submucosal dissection (ESD) was developed in Japan to resect larger lesions, but ESD was not covered by the Japanese national health insurance until April 2012. In addition, treatment strategies vary considerably among medical facilities. To evaluate the current situation in Japan regarding endoscopic treatment of CRNs measuring ≥20 mm, we conducted a prospective multicenter study at 18 medium-volume and high-volume specialized facilities in cooperation with the Japan Society for Cancer of the Colon and Rectum (JSCCR). METHODS: The JSCCR conducted a multicenter, observational study of all patients treated by CER and ESD of CRNs measuring ≥20 mm. RESULTS: From October 2007 to December 2010, CERs and ESDs were performed on 1,845 CRNs (CERs 1,029; ESDs 816). Lesions diagnosed as protruded, flat, and depressed totaled 541, 1224, and 48, respectively. En bloc resection rates and mean procedure times for CER/ESD were 56.9%/94.5% (P < 0.01) and 18 ± 23 min/96 ± 69 min, respectively. The average ESD procedure time was 129 ± 83 min in the ≥40-mm group. As lesion size increased, the CER en bloc resection rate decreased significantly (trend P < 0.01), but the ESD en bloc resection rate remained over 93%. Perforation and delayed bleeding rates of CER/ESD were 0.8%/1.6% (P < 0.05) and 2%/2.2% (P = 0.3), respectively. CONCLUSIONS: The en bloc resection rate for ESD was significantly higher than for CER, although complication rates were fairly low. Despite a longer procedure time, safety of colorectal ESD has improved in various facilities in Japan. However, ESD for lesions measuring ≥40 mm must be performed by experienced endoscopists due to the longer procedure time.

Genomic copy number of a carcinogenic single nucleotide polymorphism at 8q24 in non-risk allele colorectal cancer associated with insulin growth factor 2 receptor expression.

BACKGROUND AND AIM: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC. METHODS: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype. RESULTS: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P = 0.012). There was neither a diabetes- nor a fat metabolism-related gene that was significantly associated with CRC cases with the risk allele at 8q24. CONCLUSIONS: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC.

Increased risk for CRC in diabetic patients with the nonrisk allele of SNPs at 8q24.

BACKGROUND: Colorectal cancer (CRC) oncogenesis was considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. METHODS: A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at 11 known single nucleotide polymorphisms (SNPs). TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. RESULTS: Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (odds ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.0015). Non-insulin-dependent diabetes mellitus (DM), a higher body mass index at age 20, and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and DM had a 1.66-fold higher risk ratio than the cohort of major allele patients without DM. CONCLUSIONS: We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G allele at the 8q24 rs6983267 SNP; however, a major T allele SNP could more clearly reveal a correlation with CRC specifically when DM is present.

Mild inflammation accelerates colon carcinogenesis in Mlh1-deficient mice.

OBJECTIVE: Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. METHOD: Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1(-/-)), Mlh1 heterozygous (Mlh1(+/-)) and wild-type (Mlh1(+/+)) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, beta-catenin and p53. RESULTS: Male and female Mlh1(-/-) mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1(+/-) and Mlh1(+/+) mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of beta-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. CONCLUSION: Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.

Clinical and pathological prognostic indicators with colorectal mucinous carcinomas.

BACKGROUND/AIMS: Colorectal mucinous carcinomas are considered to have a worse prognosis than typical adenocarcinomas. To evaluate the prognostic relevance of a series of clinical and pathological variables, patients with colorectal mucinous carcinomas were studied retrospectively. METHODOLOGY: Ninety-eight patients who underwent surgery for colorectal mucinous carcinomas were included in this study. We firstly examined whether signet-ring cell carcinomas exhibited worse prognosis than the other mucinous carcinomas. Prognostic factors were then analyzed by both univariate and multivariate analysis for 70 patients who underwent complete resection. RESULTS: The overall five-year survival rate was 44%. Amount of signet-ring cells was a non-significant indicator of poor prognosis. For the cases whose cancers were completely resected, four parameters (liver metastasis, lymph node involvement, vessel involvement, spread beyond the bowel wall) were significantly related to prognosis on univariate analysis. With the multivariate analysis, liver metastasis and spread beyond the bowel wall were independent variables. CONCLUSIONS: This study reaffirmed the importance of liver metastasis and spread beyond the bowel wall for prediction of prognosis with colorectal mucinous carcinomas for cases who undergo complete resection. In addition, the presence of signet-ring cells is a non-significant indicator of a poor prognosis.

Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis.

Membrane arachidonic acid is converted by cyclooxygenase (COX) into prostaglandin (PG) G(2) and then to PGH(2) which is subsequently metabolized to PGE(2) by PGE synthase (PGES). Both COX-1 and COX-2 play critical roles in intestinal polyp formation, whereas COX-2 is also expressed in cancers of a variety of organs. Likewise, inducible microsomal PGES (mPGES-1) is expressed in several types of cancer, although its role in benign polyp formation has not been investigated. We demonstrated recently that most COX-2-expressing cells in the polyps are stromal fibroblasts. Here we show colocalization of COX-1, COX-2 and mPGES in the intestinal polyp stromal fibroblasts of Apc(Delta 716) mice, a model for familial adenomatous polyposis. Contrary to COX-2 that was induced only in polyps >1 mm in diameter, COX-1 was found in polyps of any size. In polyps >1 mm, not only COX-2 but also mPGES was induced in the stromal fibroblasts where COX-1 had already been expressed. Although polyp number and size were markedly reduced in COX-1 (-/-) or COX-2 (-/-) compound mutant Apc mice, both COX-2 and mPGES were induced in the COX-1 (-/-) polyps, whereas COX-1 was expressed in the COX-2 (-/-) polyps. We found also in human familial adenomatous polyposis polyps that COX-2 and mPGES were induced in the COX-1-expressing fibroblasts. On the basis of these results, we propose that COX-1 expression in the stromal cells secures the basal level of PGE(2) that can support polyp growth to approximately 1 mm, and that simultaneous inductions of COX-2 and mPGES support the polyp expansion beyond approximately 1 mm by boosting the stromal PGE(2) production.

Intratumoral heterogeneity of genetic changes in primary colorectal carcinomas with metastasis.

PURPOSE: To elucidate the intratumoral distribution of genetic changes, surgically resected colorectal carcinomas were investigated regarding their loss of heterozygosity in the regions of tumor suppressor genes and the mutation of ras genes. METHODS: Full-thickness fresh tumor slices from 23 colorectal carcinomas were removed and divided into multiple specimens, which were then submitted separately for DNA and histopathological analyses. The loss of heterozygosity was analyzed in 23 primary carcinomas and 9 metastasized carcinomas by the use of restriction fragment-length polymorphism markers on chromosome 1p, 5q, 17p, 18q, and 22q. RESULTS: Intratumoral heterogeneity was identified in 11 of 23 primary carcinomas (47.8%) and we could successfully map the regional genetic variation. In both stages I and II, 1 of 5 cases (20%); in stage III, 3 of 6 cases (50%); and in stage IV, 6 of 7 cases (85.7%) were heterogeneous. With respect to venous invasion positive primary carcinomas, hepatic metastasis occurred in 75% (6/8) of the heterogeneous carcinomas, whereas hepatic metastasis occurred in only 12.5% (1/8) of homogeneous carcinomas. CONCLUSION: The present results suggest that the existence of intratumoral heterogeneity, which may reflect genetic instability, may thus play a role in the enhancement of aggressive progression and the metastasis of colorectal carcimomas.

Cyclooxygenase-2 expression in fibroblasts and endothelial cells of intestinal polyps.

Cyclooxygenase-2 (COX-2), the inducible COX isozyme, plays a key role in intestinal tumorigenesis. We have demonstrated recently that COX-2 protein is induced in the polyp stroma near the intestinal luminal surface in the Apc(Delta716) mouse, a model for human familial adenomatous polyposis, and stimulate tumor angiogenesis. However, the precise cell types that express COX-2 are still to be determined. By immunohistochemical analysis, here we show that the majority of COX-2-expressing cells in the intestinal polyps of Apc(Delta716) mice are fibroblasts and endothelial cells. Furthermore, the COX-2-expressing cells in human familial adenomatous polyposis polyps are also fibroblasts and endothelial cells. In contrast, bone marrow-derived cells such as macrophages and leukocytes express little COX-2 protein in the intestinal polyps. These results clearly indicate that fibroblasts and endothelial cells play important roles in polyp expansion by expressing COX-2, resulting in tumor angiogenesis.