Is dysplasia visible during surveillance colonoscopy in patients with ulcerative colitis?

Objective. Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer. It was widely believed that dysplastic lesions are invisible on colonoscopy and can only be detected by random biopsies, as 95% of dysplastic lesions occur in flat colonic mucosa indistinct from surrounding tissue. The aim of this study was to determine whether dysplasia is visible during routine surveillance colonoscopy by evaluating only patients who had dysplasia without overt carcinoma. Material and methods. The medical records, endoscopy and pathology databases were systematically reviewed between 1997 and 2004 at the University of Pennsylvania Health System. Patients with inflammatory bowel disease and dysplasia were identified and their medical charts reviewed. Results. Of the 113 patients with colonic dysplasia confirmed by pathology at our center, 102 (90%) had UC. Forty-nine of the 102 (48%) patients with UC underwent colonoscopic evaluation prior to dysplasia detection. This group was selected as our study cohort. Overall, 72 macroscopic abnormalities were detected at 49 colonoscopies, including 55 polypoid lesions, 12 areas of ulceration, 3 areas of nodularity, 1 irregular hemicircumferential lesion and 1 area of stricture. Overall, 58 dysplastic sites were detected; 51 were macroscopically visible (87.9%) and 7 were macroscopically invisible (12.1%). Conclusions. Most of the dysplasia in UC is endoscopically visible, but further prospective evaluation of a large number of patients is needed to validate the current observations. Our findings have the potential to modify current recommendations for surveillance biopsies in UC if validated by prospective studies.     

SURVEILLANCE FOR DYSPLASIA AND COLITIC CANCER BY MAGNIFYING COLONOSCOPY IN PATIENTS WITH ULCERATIVE COLITIS

The aim of this study was to evaluate the macroscopic appearance and pit pattern of colitic cancer and dysplasia associated with ulcerative colitis (UC) by conventional and magnifying colonoscopy. Twelve lesions of dysplasia in nine patients and five colitic cancers in four patients were observed by magnifying colonoscopy. On conventional colonoscopy, most colitic cancers and dysplasias were protruded lesions. However, flat lesions were observed only in dysplasia, not in colitic cancer. All colitic cancers and 83% (10/12 lesions) of dysplasias presented reddish surface. On magnifying colonoscopy, most lesions of colitic cancer and dysplasia showed III_S to III_L or III_L to IV or IV type pit patterns. Tumorous pits associated with colitic cancers and dysplasias were similar to those seen in sporadic colorectal cancers and adenomas. Magnifying colonoscopy is expected to facilitate the qualitative diagnosis of colitic cancer and dysplasia associated with ulcerative colitis and to improve the efficiency of targeted biopsy.     

SURVEILLANCE BY MAGNIFYING ENDOSCOPY IN PATIENTS WITH ULCERATIVE COLITIS

Background: Patients with total or left‐sided ulcerative colitis (UC) for more than 10 years have an increased risk of colon cancer. We studied usefulness of magnifying chromoendoscopy for the surveillance of dysplasia and colitic cancer associated with UC. Methods: From April 2003 through February 2004, 39 patients who had total or left‐sided UC for at least 7 years were prospectively enrolled in an endoscopic surveillance program, including target biopsy. All patients were examined by chromoendoscopy and magnifying endoscopy. Sites showing abnormal mucosal surface patterns or pit patterns suggestive of dysplasia underwent biopsy. Results: Of the 39 patients, 26 had total UC and 13 left‐sided UC. The mean time elapsed since the onset of UC was 16.2 ± 5.9 years. Disease activity at examination was remission in 22 patients, mild in 15, and moderate in two. Dysplasia was diagnosed in two patients (three lesions), dysplastic changes were suspected in two (two lesions), and sporadic adenoma was diagnosed in four (five lesions). On endoscopic examination, dysplasia appeared as flat elevated lesions with types IIIl and IV pit patterns. Resected specimens showed low‐to‐high‐grade dysplasia. The four patients presenting with a type III to IV mucosal pit pattern during remission were evaluated as sporadic adenoma on pathological findings. Conclusions: A combination of chromoendoscopy and magnifying endoscopy is useful for the detection of dysplasia and colitic cancer in patients with UC.     

AUTOFLUORESCENCE IMAGING COLONOSCOPY IN ULCERATIVE COLITIS: COMPARISON WITH CONVENTIONAL AND NARROW‐BAND IMAGING COLONOSCOPY

Autofluorescence imaging (AFI) endoscopy is a procedure to demonstrate gastrointestinal neoplasia and inflammation as colored areas distinct from the surrounding normal tissue. In the present pilot study AFI colonoscopy findings in patients with ulcerative colitis (UC) were analyzed. Ten patients with UC were examined using conventional colonoscopy, followed by AFI colonoscopy and narrow band imaging (NBI) colonoscopy. Images under AFI colonoscopy were classified into high AF (green or white) and low AF (magenta). NBI colonoscopy determined vasculature, either into regular, irregular or obscure mucosal vascular pattern. A total of 48 colorectal segments were assessed with the three modes of colonoscopy. The AF was high in 100% of the segments with normal mucosa or with quiescent disease and in 44% of the segments with active mucosa (P < 0.001). Mucosal vascular pattern under NBI was obscure more frequently in low‐AF segments than in high‐AF segments (P < 0.001). Inflammatory infiltrate was more severe and crypt distortion was more frequent in the latter than in the former (P < 0.001). There were trends towards more frequent obscure vascular pattern and more severe inflammation in active segments with low AF than in those with high AF mucosa. These findings suggest that AF status determined by AFI colonoscopy may be a clue for subclassification of active UC.     

Villous, hypermucinous mucosa in long standing ulcerative colitis shows high frequency of K-ras mutations.

BACKGROUND: K-ras mutation is one of the first genetic alterations in classical colorectal carcinogenesis. AIMS: To investigate the role of K-ras mutations in carcinogenesis, in long standing ulcerative colitis. METHODS: A total of 161 microdissected and 100 DNA samples from 13 patients were analysed for K-ras codons 12 and 13 mutations by means of a combination of enriched polymerase chain reaction amplification and temporal temperature gradient electrophoresis. RESULTS: K-ras mutations were found in 21/161 (13%) microdissected samples in 7/13 large bowels (16 and five in codons 12 and 13, respectively), and in 10/100 (10%) mucosal DNA samples (six and four, respectively). One of four patients with six adenocarcinomas had a K-ras mutation in a carcinoma, as well as one of two patients with large dysplasia associated lesion or mass (DALM). Eight of 13 (61%) areas with villous architecture and large, distended goblet cells, had a K-ras mutation, which was significantly more frequent than in low grade dysplasia (one of 23, 4%) but did not reach significance versus high grade dysplasia (four of 14, 28.5%). K-ras mutations were found in one of 20 (5%) flat lesions indefinite for dysplasia, two of 14 (14%) in non-villous, hypermucinous mucosa, and in one of 57 flat areas negative for dysplasia. CONCLUSION: The highest K-ras mutation frequency was found in villous, hypermucinous mucosa. We suggest that this entity should be investigated further as a potential risk lesion for cancer development. It may represent a pathway directly from non-classical dysplasia to cancer, not previously described.     

Detection of colonic dysplasia by light-induced fluorescence endoscopy: a pilot study

Light-induced fluorescence endoscopy (LIFE) has been shown to differentiate between normal mucosa and dysplastic lesions, and dysplastic lesions of the colon occult to routine white-light colonoscopy may thus be visualized by LIFE. We compared the sensitivity and specificity of LIFE to routine white-light colonoscopy in patients with colonic dysplasia. In a pilot study 20 patients with colonic adenoma, inflammatory bowel disease, or with a history of colon cancer were screened for colonic dysplasia during routine colonoscopy. Forty-two sites of mucosal abnormalities regarded as suspicious for dysplasia during white-light colonoscopy were additionally examined with a prototype LIFE system. Biopsies were taken from all 42 colonic sites. The LIFE images were classified as positive or negative for dysplasia. Sensitivity and specificity were calculated by correlating positive and negative findings to the histopathological results. Histopathology detected 21 adenomas with low-grade dysplasia and one with high-grade dysplasia. All dysplastic lesions were found by routine white-light endoscopy. The specificity of conventional white-light endoscopy was 80%. Of the 22 dysplastic lesions 20 were detected by LIFE (sensitivity 91%). The specificity of LIFE was 90% (two false-positive results). LIFE combined with conventional endoscopy may thus improve the detection of colonic dysplasia. Accepted: 17 December 1998     

High-grade dysplastic adenoma-like mass lesions are not an indication for colectomy in patients with ulcerative colitis

Objective. The management of high-grade dysplasia (HGD) in polypoid lesions in patients with ulcerative colitis (UC) is not well characterized. The purpose of this study was to characterize the clinical course of patients with HGD in adenoma-like dysplasia-associated lesion or masses (DALMs) in the absence of any synchronous flat dysplasia. We hypothesize that colectomy is not warranted in patients who undergo complete excision of adenoma-like DALMs with HGD in UC. Material and methods. Pathology and clinical databases were systematically searched for the presence of dysplastic lesions in inflammatory bowel disease from 1997 to 2004. Patients with UC who had adenoma-like DALMs were identified, and a subset with HGD lesions was defined as our study cohort. Results. A total of 102 patients with UC were identified. Thirty of them (29%) had adenoma-like DALMs without synchronous flat dysplasia; 9 of these patients (30%) had HGD in these lesions. Thirty-two surveillance colonoscopies were performed in this cohort (mean 3.6 colonoscopies/patient). The patients were followed for a mean of 76.5 months (52–99 months). Three out of 9 patients (33%) had colectomy. None of the patients in this cohort was detected to have carcinoma in surveillance biopsies and/or in the resection specimens. Conclusions. Our data suggest that the presence of HGD in DALMs does not warrant colectomy. Continued close observation is suggested in this patient cohort after complete excision of polyps. Further prospective evaluation of this patient population is merited.     

窄带光成像肠镜下黏膜血管形态对溃疡性结肠炎患者肠上皮增殖的预测价值

目的探讨窄带光成像(NBI)肠镜下溃疡性结肠炎(UC)患者不同黏膜血管形态(MVP)分型对UC患者肠上皮增殖的预测价值。方法选择2012年12月1日至2015年1月31日在北京协和医院就诊且接受NBI肠镜检查的42例UC患者,采集所有患者普通白光和NBI模式下119个结直肠病变的图像,并至少取1块病变组织用于病理学分析。根据随机数字表法将所有内镜图像随机分配至1位内镜医师(副主任医师),对肠黏膜组织的MVP分型和梅奥内镜评分(MES)做出判断。采用结肠炎组织学评分标准对肠黏膜炎症程度进行0~4级评分,根据免疫组织化学染色结果分析判断黏膜上皮Ki-67表达分布和表达程度。采用Student-Newman-Keuls(SNK)-q检验和Spearman相关分析进行统计学分析。结果UC患者的NBI肠镜下MVP分为清晰型、模糊型和消失型,根据黏膜表面腺管形态,消失型又分为隐窝开口亚型和绒毛亚型。NBI模式下MVP分型与普通白光模式下MES标准呈正相关(r=0.80,P<0.001)。MVP模糊型、消失型、消失型隐窝开口亚型、消失型绒毛亚型病变的Ki-67染色指数均高于MVP清晰型病变(30.3±12.8、45.9±12.5、45.5±12.1、46.3±13.1比15.6±7.3),差异均有统计学意义(SNK-q检验,均P<0.001);MVP消失型、消失型隐窝开口亚型、消失型绒毛亚型病变的Ki-67染色指数均高于MVP模糊型病变,差异均有统计学意义(SNK-q检验,均P<0.001)。NBI肠镜下不同MVP分型与Ki-67表达分布呈正相关(r=0.49,P<0.001)。组织学炎症程度为2、3、4级的Ki-67染色指数高于1级(28.8±10.9、40.2±11.6、49.5±10.3比17.1±8.4),差异有统计学意义(SNK-q检验,均P<0.001);组织学炎症程度为3、4级的Ki-67染色指数高于2级,组织学炎症程度为4级的Ki-67染色指数高于3级,差异均有统计学意义(SNK-q检验,均P<0.001)。Ki-67表达分布与组织学炎症程度呈正相关(r=0.56,P<0.001)。结论NBI肠镜下MVP分型可间接预测UC患者肠上皮增殖活性,肠上皮增殖活性可能与黏膜炎症程度密切相关。     

窄带光成像肠镜下黏膜血管形态对溃疡性结肠炎患者肠上皮增殖的预测价值

目的探讨窄带光成像(NBI)肠镜下溃疡性结肠炎(UC)患者不同黏膜血管形态(MVP)分型对UC患者肠上皮增殖的预测价值。方法选择2012年12月1日至2015年1月31日在北京协和医院就诊且接受NBI肠镜检查的42例UC患者,采集所有患者普通白光和NBI模式下119个结直肠病变的图像,并至少取1块病变组织用于病理学分析。根据随机数字表法将所有内镜图像随机分配至1位内镜医师(副主任医师),对肠黏膜组织的MVP分型和梅奥内镜评分(MES)做出判断。采用结肠炎组织学评分标准对肠黏膜炎症程度进行0~4级评分,根据免疫组织化学染色结果分析判断黏膜上皮Ki-67表达分布和表达程度。采用Student-Newman-Keuls(SNK)-q检验和Spearman相关分析进行统计学分析。结果UC患者的NBI肠镜下MVP分为清晰型、模糊型和消失型,根据黏膜表面腺管形态,消失型又分为隐窝开口亚型和绒毛亚型。NBI模式下MVP分型与普通白光模式下MES标准呈正相关(r=0.80,P<0.001)。MVP模糊型、消失型、消失型隐窝开口亚型、消失型绒毛亚型病变的Ki-67染色指数均高于MVP清晰型病变(30.3±12.8、45.9±12.5、45.5±12.1、46.3±13.1比15.6±7.3),差异均有统计学意义(SNK-q检验,均P<0.001);MVP消失型、消失型隐窝开口亚型、消失型绒毛亚型病变的Ki-67染色指数均高于MVP模糊型病变,差异均有统计学意义(SNK-q检验,均P<0.001)。NBI肠镜下不同MVP分型与Ki-67表达分布呈正相关(r=0.49,P<0.001)。组织学炎症程度为2、3、4级的Ki-67染色指数高于1级(28.8±10.9、40.2±11.6、49.5±10.3比17.1±8.4),差异有统计学意义(SNK-q检验,均P<0.001);组织学炎症程度为3、4级的Ki-67染色指数高于2级,组织学炎症程度为4级的Ki-67染色指数高于3级,差异均有统计学意义(SNK-q检验,均P<0.001)。Ki-67表达分布与组织学炎症程度呈正相关(r=0.56,P<0.001)。结论NBI肠镜下MVP分型可间接预测UC患者肠上皮增殖活性,肠上皮增殖活性可能与黏膜炎症程度密切相关。     

SUBTLE VILLOUS CHANGES DETECTED AT ENDOSCOPY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Dysplastic areas in flat mucosa in patients with inflammatory bowel disease (IBD) are difficult to detect at endoscopic examination. We describe the endoscopic and clinicopathological characteristics of colorectal mucosa with subtle villous changes (SVC) detected by endoscopy and chromoscopy in patients with IBD. The present study consists of 18 IBD patients. The age at onset of the disease, duration and extent of disease, endoscopic features, and clinical follow up were noted. Of the 18 patients, 12 had ulcerative colitis and six had Crohn's colitis. The mean duration from onset of disease to the detection of SVC was 25.4 years (range 4–50 years). All patients had extensive colitis. All SVC areas were present in colorectal segments having absent vascular pattern and decrease or loss of normal folds. Mucosal redness was frequently observed. Following indigo carmine dye spraying the SVC were characterized by a subtle villous surface resembling small intestinal mucosa. Biopsies taken from SVC areas showed dysplasia in nine of the 18 patients (50.0%): LGD in seven and HGD in two. SVC can be identified with endoscopy and chromoscopy. The endoscopic identification of SVC areas may increase the accuracy in detecting epithelial dysplasia in biopsies from patients with IBD.     

Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis

BACKGROUND & AIMS: Long-standing ulcerative colitis has long been recognized as a risk factor for colorectal cancer, but there is still no universal consensus on the optimal management of ulcerative colitis patients with low-grade dysplasia in flat mucosa. Some authorities favor prompt colectomy, whereas others recommend continued surveillance. The purpose of our study was to determine the frequency with which flat low-grade dysplasia in ulcerative colitis progresses to advanced neoplasia (high-grade dysplasia or colorectal cancer) and whether specific variables could predict such progression. METHODS: We reviewed the medical histories, colonoscopic findings, and surgical and pathology reports of 46 patients with ulcerative colitis diagnosed with flat low-grade dysplasia on a surveillance colonoscopy. The rates of neoplastic progression, as well as the frequency of advanced neoplasia, were tabulated. We correlated progression with several clinical and colonoscopic variables: the number of biopsy samples positive for flat low-grade dysplasia, the duration and anatomic extent of disease, patient age, and medication use. RESULTS: Among these 46 patients, there were 7 cases of colorectal cancer, 5 of which were stage II or higher. Unexpected advanced neoplasia occurred in 4 of 17 (23.5%) patients who underwent colectomy for flat low-grade dysplasia. On an actuarial basis, the rate of neoplastic progression was 53% at 5 years. No clinical features predicted progression to advanced neoplasia. Cancers, including 2 at advanced stages, developed despite frequent follow-up surveillance examinations. CONCLUSIONS: A finding of flat low-grade dysplasia during ulcerative colitis surveillance is a strong predictor of progression to advanced neoplasia. Early colectomy should be recommended for such patients.     

Ulcerative colitis with overexpression of p53 preceding overt histological abnormalities of the epithelium

A 53-year-old man with a 22-year history of ulcerative colitis(UC) (pancolitis), had an ulcerating rectal tumor. Resection of the rectum and sigmoid colon was performed. Pathology showed an expansive ulcerating adenocarcinoma tumor (type 2) invading the adventitia against a background of UC in a resolving phase. Dysplasia was also found in granular and flat mucosa adjacent to the invading carcinoma. Immunostaining for p53 showed diffuse positivity in both the carcinoma and dysplasia, and also in the mucosa with indefinite dysplasia or no dysplasia neighboring the dysplasia and carcinoma. Mapping of neoplasms and the area with p53 protein overexpression showed that the grade of dysplasia increased as the lesion approached the invasive carcinoma and that the mucosa with dysplasia was surrounded by mucosa without dysplasia or indefinite for dysplasia, but with p53 protein overexpression. In some areas without dysplasia showing p53 overexpression, there was significant morphometric enlargement of the area and diameter of the nucleus p53 Immunostaing is a good marker for assessing the genetic alterations that precede histological abnormalities and for diagnosing carcinoma in UC. Objective findings such as p53-protein overexpression and morphometric values should be used to evaluate cytological abnormalities in UC, as well as in common colorectal cancer.     

Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis

BACKGROUND AND AIM: Although molecular mechanisms underlying ulcerative colitis (UC)-associated neoplasms have been studied for years, understanding of these mechanisms remains incomplete and no good predictable marker for development of colonic neoplasms in patients with UC has been established. The aim of this study was to assess if microsatellite instability (MSI) contributes to the development of colonic neoplasms in patients with UC. METHODS: We have examined MSI in chronic inflamed and neoplastic colonic mucosa of UC patients. We have also obtained serial biopsied colonic tissues retrospectively 2-12 years before the final diagnosis from patients with high level MSI (MSI-H+) UC-associated neoplasms, and analyzed MSI using them at different periods. RESULTS: Eight of 12 UC-associated colon cancers (67%), four of six UC-associated high grade dysplasias (67%), and two of six UC-associated low grade dysplasias (33%) revealed MSI-H+ phenotypes. In contrast, 15 of 59 lesions (25%) in inflamed UC mucosa without colonic neoplasm revealed MSI-H +. Interestingly, all four patients with MSI-H+ phenotypes at the final diagnosis of UC-associated colon cancer or dysplasia had already had MSI-H+ at the stage of chronic colitis, 2-12 years before the final diagnosis. CONCLUSION: These results support the notion that MSI contributes to the carcinogenesis of UC-associated neoplasms, and indicate that this analysis in inflamed colonic mucosa at surveillance colonoscopy is useful for identifying UC patients who have high risk for neoplastic progression.     

溃疡性结肠炎窄带光成像肠镜下黏膜血管形态对炎症和血管生成的预测价值

目的探讨窄带光成像(narrow-band imaging,NBI)肠镜下溃疡性结肠炎(ulcerative colitis,UC)患者不同黏膜血管形态(mucosal vascular pattern,MVP)分型对UC患者肠黏膜炎症和血管生成的预测价值。方法2012—2015年在北京协和医院就诊的42例UC患者被纳入研究并接受NBI肠镜检查,NBI模式下对存在病变的肠段进行图像采集,并至少活检1块组织用于病理学分析。所有NBI图像经2位内镜医师讨论达成一致后,对MVP做出分型。采用结肠炎组织学评分标准对黏膜炎症程度进行0~4级的分级评分;血管内皮标记CD31免疫组织化学染色后,通过每视野血管计数对微血管密度进行定量分析;根据免疫组织化学结果对黏膜血管内皮生长因子(vascular endothelial growth factor,VEGF)的表达程度进行半定量分析。所有组织学指标由同一位不知道具体内镜相关资料的病理医师进行评价。结果42例UC患者的119处结肠或直肠肠段根据NBI肠镜下MVP分型标准,其中34处肠段被定义为清晰,58处肠段被定义为模糊,27处肠段被定义为消失。NBI肠镜下MVP分型与黏膜炎症程度之间具有显著的相关性(r=0.824,P<0.001)。MVP从清晰型、模糊型至消失型,黏膜的微血管密度(P<0.001)和VEGF表达水平(P<0.001)均呈现出显著递增的趋势。黏膜活检组织的微血管密度和VEGF表达水平之间存在显著的正相关(r=0.961,P<0.001)。结论NBI肠镜下MVP分型可以预测UC患者的黏膜炎症程度和血管生成水平。     

Diagnosis and management of dysplasia in patients with inflammatory bowel diseases

Patients with ulcerative colitis and Crohn's colitis face an increased lifetime risk of developing colorectal cancer. Factors associated with increased risk include long duration of colitis, extensive colonic involvement, primary sclerosing cholangitis, a family history of colorectal cancer, and, according to some studies, early disease onset and more severely active inflammation. Although prophylactic proctocolectomy can essentially eliminate the risk of cancer, most patients and their physicians opt instead for a lifelong program of surveillance. This entails regular medical follow-up, management with antiinflammatory and putative chemopreventive agents, and periodic colonoscopic examinations combined with extensive biopsy sampling throughout the colon. The main objective of regular colonoscopy is to detect neoplasia at a surgically curative and preferably preinvasive stage, i.e., dysplasia. An initial screening colonoscopy should be performed 7-8 years from disease onset or immediately in patients with primary sclerosing cholangitis. Surveillance should then continue annually or biennially so long as no dysplasia is found or suspected. Biopsy specimens are graded pathologically as negative, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or invasive cancer. The diagnosis and grading of dysplasia can be very challenging and should be confirmed by an expert pathologist whenever intervention or a change in management is contemplated. If 1 or more biopsy specimens are indefinite for dysplasia, colonoscopy intervals should be reduced. A patient with low- or high-grade dysplasia found in a discrete adenoma-like polyp, but nowhere else, can be safely managed with polypectomy and accelerated surveillance. However, dysplasia of any grade found in an endoscopically nonresectable polyp and high-grade dysplasia found in flat mucosa are both strong indications for proctocolectomy. Evidence further suggests that the same may be true even of low-grade dysplasia in flat mucosa. Chromoendoscopy holds promise for facilitating the endoscopic detection of neoplasia. The clinical application of newer molecular methods to detect neoplasia, particularly gene microarrays and stool DNA testing, also deserve further study.     

Telomere shortening in the colonic mucosa of patients with ulcerative colitis

Telomere length in human somatic cells gradually decreases with the number of cell divisions and is regarded as a marker of somatic cell turnover. Mucosal cells of the affected colon show rapid turnover in individuals with active ulcerative colitis (UC). Telomere length was determined by Southern blot analysis of terminal restriction fragments (TRFs) from the colonic mucosa of 17 patients with UC in remission, two of whom showed dysplasia, and 17 control subjects without colitis. For each individual, mean TRF length was compared between rectal mucosa and unaffected cecal mucosa. The mean TRF length of the rectal mucosa was significantly less than that of cecal mucosa in UC patients (7.87 ± 0.36 kb versus 8.77 ± 0.21 kb; P = 0.0015, Wilcoxon signed rank test), whereas no significant difference was detected in the control subjects. The extent of telomere shortening was 10.6 ± 3.35% in UC patients, compared with 0.8 ± 0.64% in noncolitis controls (P = 0.0024, Mann-Whitney U-test). Four UC patients, two of whom had dysplasia, showed telomere shortening of more than 20% in the rectal mucosa. These observations suggest that telomere shortening in the colonic mucosa of individuals with UC may represent the history of mucosal inflammation during disease of long duration, and that it may contribute to aneuploidy in UC. (Received May 6, 1997; accepted Sept. 26, 1997)     

MINUTE FINDINGS DETECTED BY MAGNIFYING COLONOSCOPY IN ULCERATIVE COLITIS

In order to detect flat‐type dysplastic and cancerous lesions associated with longstanding ulcerative colitis, it is important to understand the minute findings detected by magnifying colonoscopy in active and quiescent stage of ulcerative colitis. The severity of mucosal findings by magnifying colonoscopy could be categorized as follows: polypoid mucosal tag which has severe ulceration and hemorrhage; coral‐reef‐like appearance which has coarse or nodular mucosa with ulcerations; minute defect of epithelia which has minute or shallow depressions surrounded by edematous mucosa; small yellowish spots which has minute whitish or yellowish coats; villi‐like appearance which has shaggy appearance like small intestinal villi; and regularly arranged crypt opening which has round shaped and regularly arranged crypt.     

Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis

BACKGROUND: Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. Cyclooxygenase (COX)-2 inhibitors are known to suppress sporadic colorectal cancer, but it is unknown whether selective COX-2 inhibitors exhibit a preventive effect in UC-associated neoplasia. This study investigated the preventive effect of nimesulide, a selective COX-2 inhibitor, on colorectal carcinogenesis in an experimental model of murine UC. METHODS: Chronic colitis was induced in mice by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% DSS for 7 days and then distilled water for 14 days). The mice were killed 120 days after the completion of the fourth cycle. The mice were divided into the following five groups: group A served as a disease control; group B received a diet mixed with 400 p.p.m. of nimesulide during the whole period; group C received nimesulide during the four cycles of DSS administration (active phase); group D received nimesulide for 120 days from the end of the fourth cycle (remission phase); group E received no agents including DSS and served as a normal control. RESULTS: The incidence of dysplasia and/or cancer was 28%, 15%, 11.8%, 6.7% and 0% in groups A-E, respectively. In group D, nimesulide significantly suppressed the occurrence of dysplasia and/or cancer (P < 0.05). Strong COX-2 expression was detected by immunohistochemistry in cancer and dysplastic lesions while diffusely weak COX-2 expression was also found in the residual colon (i.e. lesion-free colon). The mucosal concentration of prostaglandin E(2) was significantly lower in groups B and D than in group A. CONCLUSIONS: The administration of the selective COX-2 inhibitor nimesulide (especially during the remission phase) exerts a suppressive effect on the development of dysplasia and/or cancer in a murine model of DSS-induced colitis. These findings may have relevance to long-standing UC in humans.     

Difference in the clinical characteristic and prognosis of colitis-associated cancer and sporadic neoplasia in ulcerative colitis patients

BackgroundAlthough various studies have been conducted on colitis-associated cancer (CAC), few have assessed the differences in the clinical and endoscopic features, treatment, and prognosis of CAC and sporadic neoplasia (SN) in the inflamed mucosa of ulcerative colitis (UC) patients.AimsTo compare the characteristics of CAC and SN within the previously or currently inflamed mucosa.MethodsBetween 1997 and 2017, we retrospectively analyzed the endoscopic chart data of 348 colonic lesions from 266 UC patients. Non-dysplastic lesions and lesions located outside the inflamed mucosa were excluded. The diagnosis of CAC or SN was confirmed by conventional histopathological and immunohistochemical evaluation of p53 and Ki67.ResultsIn total, 74 patients with CAC (97 lesions) and 46 with SN (58) were enrolled. The proportions of patients with a younger age of onset of UC, with chronic persistent UC, and with severe inflamed mucosa were significantly higher in the CAC group. In the SN group, no flat lesions were found, whereas 26% of the lesions in the CAC group were flat. Sixteen patients died during a median follow-up of 6.1 years (interquartile range (IQR) 1.8–11.1)in the CAC group, whereas 1 patient died during a median follow-up 3.2 years(IQR 1.4–4.6) in the SN group. Mortality from colorectal cancer was significantly higher (P = 0.015) in the CAC group (12/68; 17.6%) than in the SN group (1/44; 2.3%). The 5-year survival rate was 100% in the SN group and 97% in the CAC group for lesions located in the mucosa or submucosa.ConclusionRecognizing differences in the characteristics of CAC and SN within the inflamed mucosa is critical to avoid unnecessary total colectomy in patients with SN.     

Predicting Mucosal Proliferation in Ulcerative Colitis by Assessing Mucosal Vascular Pattern Under Narrow Band Imaging Colonoscopy

Background: Proliferative abnormalities are believed to represent an early phase of colorectal carcinogenesis. Narrow band imaging (NBI) colonoscopy allows visual assessment of the mucosal vascular pattern (MVP) without dyeing. The aim of this study was to investigate the predictive value of MVP for mucosal proliferation in ulcerative colitis (UC).Methods: A total of 119 colorectal lesions were analyzed from 42 patients with UC who underwent NBI colonoscopy. Both the MVP and the Mayo endoscopic score (MES) were assessed. The mucosal inflammation was histologically graded using a colitis score. The proliferation marker Ki-67 was assessed by immunohistochemical staining.Results: The results showed that MVP correlated well with the MES (r = 0.796, P < .001). There was moderate correlation between the distribution of Ki-67 staining and MVP (r = 0.492, P < .001), and the Ki-67 labeling index increased with the orderly patterns of MVP (P < .001). An expansion of Ki-67 staining upward from the crypt base may be caused by active inflammation.Conclusion: MVP based on NBI colonoscopy can predict mucosal proliferation which is associated with inflammation in patients with UC.