Microscopic Colitis and Colorectal Neoplastic Lesion Rate in Chronic Nonbloody Diarrhea

ORIGINAL ARTICLE

Microscopic Colitis and Colorectal Neoplastic Lesion Rate inChronic Nonbloody Diarrhea: A Prospective, Multicenter StudyGian Eugenio Tontini, MD, PhD,*,† Luca Pastorelli, MD, PhD,*,‡ Luisa Spina, MD, PhD,*Federica Fabris, MD, PhD,§ Barbara Bruni, MD,k Claudio Clemente, MD,k Germana de Nucci, MD,*Flaminia Cavallaro, MD,* Stefano Marconi, MD,¶ Markus F. Neurath, MD, PhD,†

Helmut Neumann, MD, PhD,† Milena Tacconi, MD,§ and Maurizio Vecchi, MD*,‡

Background: Lymphocytic and collagenous colitis are emerging as common findings in subjects undergoing colonoscopy for chronic non-bloodydiarrhea (CNBD). Data concerning microscopic colitis (MC) are still limited and affected by controversial epidemiological evidences. Recent converginglines of evidence suggest that MC correlates a lower risk of colorectal neoplasia. Accordingly, we prospectively assessed MC prevalence in a multicentercohort of subjects submitted to colonoscopy for CNBD, thereby defining whether MC influences the risk of colorectal neoplasia.

Methods: Consecutive patients with CNBD of unknown origin underwent pan-colonoscopy with multiple biopsies. The prevalence of neoplasticpatients in MC was compared with that observed in negative CNBD subjects.

Results: Among 8006 colonoscopy, 305 subjects were enrolled for CNBD. Patients with CNBD were more likely to be women than men (odds ratio ¼1.5; P ¼ 0.001). Histopathology detected high prevalence of MC (16%) with a clear predominance of collagenous colitis (70%). A striking age-dependent rise in MC-associated risk was observed, depicting outstanding differences among varying age groups, as in the number needed to screen1 new case. Gender distribution was balanced within MC patients (Female/Male ¼ 1.5/1), especially among lymphocytic colitis (Female/Male ¼ 1.2/1).MC patients were negatively associated with the risk of neoplastic polyps compared with negative CNBD subjects (odds ratio ¼ 0.22; P ¼ 0.035).

Conclusions: MC is the first cause of CNBD in subjects submitted to colonoscopy. Multiple biopsies are strongly recommended, even in the case ofuneventful endoscopic inspection, especially for age $40 years. MC has a reduced risk of colorectal neoplasia, suggesting that this model of chronicinflammation plays a protective effect against colorectal carcinogenesis.

(Inflamm Bowel Dis 2014;20:882–891)

Key Words: microscopic colitis, collagenous colitis, colonoscopy, chronic nonbloody diarrhea, colorectal cancer

M icroscopic colitis (MC) is an inflammatory and idiopathiccause of chronic or recurrent watery diarrhea characterized

by specific microscopic changes in the large-bowel mucosal layerwith minor and sporadic abnormalities revealed by standard video

colonoscopy.1 The diagnosis rests on specific histological findingsin colonic biopsies from symptomatic patients demonstratingeither lymphocytic colitis (LC) or collagenous colitis (CC).2

These 2 entities have specific histopathological clusters, enablinga distinct diagnosis in more than 90% of MC.3 Symptomaticpatients not fulfilling the histological criteria or indistinguishablefrom LC and CC may have “incomplete MC”.2,3 Despite noso-logic and histological distinction, LC and CC have similar epide-miological and clinical profiles, as different expressions ofa single underlying disease process that interacts with various setsof environmental and host-related stimuli.4–6 Diagnosis of MC ismostly made in older adults presenting with chronic non-bloodydiarrhea (CNBD). Ten percent of patients may refer additionalgastrointestinal symptoms such as nocturnal motions, inconti-nence, bloating, mild-to-moderate abdominal pain, and slightweight loss.1,2,6 Interestingly, population-based studies from theU.S. Olmsted County, as from Northern and South Europe haveshown a sharp rising incidence of both LC and CC during the last2 decades.7–9 Whether this figure reflects an improved diagnosisof these endoscopically uneventful entities, or represents a truerise, is still unknown. Although the growing physicians’ aware-ness would have revealed the hidden part of the “iceberg” with

Received for publication January 9, 2014; Accepted February 12, 2014.

From the *Gastroenterology and Digestive Endoscopy Unit, IRCCS PoliclinicoSan Donato, San Donato Milanese, Italy; †Department of Medicine I, University ofErlangen-Nuremberg, Erlangen, Germany; ‡Department of Biomedical Sciences forHealth, University of Milan, Milano, Italy; §Gastroenterology and Digestive Endos-copy Unit, Istituti Clinici Zucchi, Monza, Italy; kPathology and Citodiagnostic Unit,IRCCS Policlinico San Donato, San Donato Milanese, Italy; and ¶Medical Depart-ment, Chiesi Farmaceutici SpA, Parma, Italy.

Stefano Marconi is employee as MD at the Medical Department of ChiesiFarmaceutici SpA (Parma, Italy). Gian Eugenio Tontini has gained a grant from theItalian Group for the study of IBD (IG-IBD) supporting his research works at theDepartment of Medicine I, University of Erlangen-Nuremberg. The remainingauthors have no conflicts of interest related to this work to disclose.

Supported in part by an unconditioned grant from Chiesi Farmaceutici SpA(Parma, Italy).

Reprints: Gian Eugenio Tontini, MD, PhD, Gastroenterology and DigestiveEndoscopy Unit, IRCCS Policlinico San Donato, Via Morandi 30, San DonatoMilanese 20097, Italy (e-mail: [email protected]).

Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc.

DOI 10.1097/MIB.0000000000000030

Published online 27 March 2014.

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a widespread use of random colonic biopsies,5,7,10,11 a greaterexposition to disease-related factors such as drugs consump-tion12–14 or smoking habit15–17 could have led to a further spreadof the disease. MC patients are more likely to be women thanmen. Nonetheless, the literature depicts large differences amongdifferent countries, varying between 1 and 9 female cases for eachmale case.3,18–24

In recent years, MC is emerging as a common findingamong subjects undergoing colonoscopy and biopsy sampling forCNBD, resulting in 10%–20% of cases with a striking age-dependent rise.18,21,25–28 In contrast, other endoscopic cohortsreported lower diagnostic yields (1.1%–1.3%), raising questionsabout the cost-effectiveness of random biopsies in unselected sub-jects with CNBD.3,29

Indeed, our knowledge about MC epidemiology is stilllimited and affected by controversial evidences. Moreover, noprospective study has so far evaluated this topic in the Italianpopulation. In addition, very recent data have shown a strongnegative association between MC and colorectal adenoma,suggesting the presence of a protective effect played by thesechronic inflammatory disorders, rather than the result of repeatedcolonoscopic inspections for chronic unexplained diarrhea.3,30 Toour knowledge, there is no study designed to untangle this issue.

Accordingly, the aim of this prospective multi-center studywas, first, to assess the prevalence, and the main demographicfeatures of MC in subjects with CNBD consecutively enrolled forcolonoscopy in a metropolitan area of Northern Italy; second, todetermine whether the presence of MC influence the risk ofcolorectal neoplasia compared with non-MC subjects similarlyenrolled for CNBD.

METHODS

PatientsThe study was approved by the local Ethical Committee

(Ethics Committee Protocol number n. 2316, ASL Milano-2,April 2009) and was conducted according to the declaration ofHelsinki.

All Patients referred for complete colonoscopy from May2010 to April 2013 with all the following inclusion criteria wereprospectively and consecutively enrolled:

• CNBD of unknown origin, defined by more than 3 looseor liquid nonbloody stools per day, for a minimum of 4consecutive weeks.28,31,32 All patients presenting with anestablished diagnosis concerning such a complaint orwith one of the following known conditions wereexcluded: celiac disease, lactose intolerance, inflamma-tory bowel disease (IBD), gastrointestinal cancer, HIV,solid organ or bone marrow transplantation, intestinalischemia, positive stool examinations for ova parasites,Clostridium difficile toxin A, Salmonella spp., Shigellaspp., Campylobacter, and Yersinia.

• Complete colonoscopy with a clear description and imageproof of cecum or terminal ileum visualization.

• Boston Bowel Preparation Scale score’s $ 6 with at least2 points for each macro-segment (i.e., rectum plus leftside colon, transverse colon plus left and right flexures,right colon).33

• No history of large-bowel surgery.

Patients included in this study were submitted to thegastroenterologist by primary care providers or by other special-ists throughout Northern Italy. Two patients out of 3 were livingin the metropolitan area of Milan.

Endoscopic ProcedureAll colonoscopies were performed by experienced endo-

scopists, using high-definition or high-resolution endoscopy sys-tems (processors: EPKi and EPK1000; Pentax, Tokyo, Japan andEvis Exera II; Olympus, Tokyo, Japan). A conscious intravenoussedation with constant monitoring of vital signs was appliedadministering midazolam hydrochloride alone (2.5–7.0 mg) or incombination with pethidine hydrochloride (50–100 mg) accordingto the local standard protocol.

All patients had given their written consent for thecolonoscopy examination under conscious sedation with biopticalsampling before the procedure, in agreement with the localprotocols.

Initially, the endoscope was advanced into the colon. Onwithdrawal, we collected at least 3 large biopsies (9-mm diameterof opened jaws, Radial Jaw 4 Biopsy Forceps; Boston scientific,Natick, MA) of grossly normal mucosa from right colon, leftcolon, and rectum to improve diagnostic accuracy and detect bothdiffuse and patchy signs of microscopic inflammation.2,34,35 Addi-tional samples were obtained from terminal ileum and from anymacroscopic finding detected in the course of the endoscopic pro-cedure according to international guidelines.35–37

During colonoscopy, all polyps were resected and retrieveddistinctly. Bioptic specimens and retrieved polyps were separatedaccording to segment provenience and immediately fixed in 4% ofbuffered formalin for subsequent histopathological analysis.

Histopathological AnalysisBiopsy specimens and resected polyps were processed in the

Pathology and Citodiagnostic Unit at I.R.C.C.S. Policlinico SanDonato. Identical sectioning and staining procedures were followedfor each specimen. Slides were always reviewed and interpreted by2 dedicated subspecialty-trained gastrointestinal pathologists, whoshared a common approach to biopsy evaluation. Pathologistsdiagnosed MC according to established standard of care outlined inliterature.2,6,38 Briefly, MC shows a lymphoplasmacellular infiltratein lamina propria; an increased presence CD3 T-lymphocytic infil-tration into the epithelium is also common for both entities butmore characteristic for LC. The criteria for LC diagnosis includedincreased infiltrate of intraepithelial lymphocytes (IEL), defined bymore than 20 intraepithelial lymphocytes per 100 surface epithelial

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cells, in an architecturally normal colonic mucosa accompanied bysurface epithelial disarray and mixed inflammatory infiltrate in lam-ina propria. Conversely, a broad subepithelial collagen band.10 mm in thickness is the hallmark of CC. The term incompleteMC is used when the intraepithelial lymphocytes invasion and thesubepithelial collagen layer did not reach the critical features toentirely fulfill the diagnostic criteria for LC or CC (i.e., focalinvolvement).2,3 Based on current international guidelines, we clas-sified the resected polyps in “adenoma,” “non-neoplastic serratedlesions,” and “neoplastic serrated lesions.”39–41

Data SourceData sources of the study were the endoscopic, clinical, and

histopathology reports of the Gastroenterology and DigestiveEndoscopy Units of 2 different Hospitals in the metropolitan areaof Milan: the IRCCS Policlinico San Donato from May 2010 toApril 2013 and the Istituti Clinici Zucchi from May 2010 toOctober 2011. All patients’ records were deidentified before beingincluded in this analysis, and no direct contact with either patientsor providers was made.

Statistical AnalysisThe statistical analysis was carried out using Microsoft

Excel (Microsoft, 2007 Computer Software; Microsoft Excel.Redmond, WA) and the statistical software GraphPad InStat 3(GraphPad Software, Inc., San Diego, CA).

The primary outcome measure was the prevalence of eachsubtype of MC in the study population. The analysis focused onage and gender distribution. Differences in age among patientswere compared using Wilcoxon–Mann–Whitney two-tailed test forindependent data, whereas differences in gender were comparedusing the two-tailed Fisher’s exact test. The x2 approximationwas performed instead of Fisher’s exact test only when numberswere too large.

The additional primary outcome measure was the preva-lence of each histologic type of resected lesion observed in MCpatients compared with non-MC subjects similarly enrolled forCNBD. To avoid the influence of other potential risk factors ofcolorectal cancer, the last group included consecutive subjectswhose endoscopic and histopathological workup was negativealso for IBD and eosinophilic colitis. Varying frequencies ofpatients with or without colorectal neoplasia were comparedbetween MC and negative CNBD subjects using the two-tailedFisher’s exact test, thereby calculating odds ratios (ORs) and their95% confidence intervals according to the per-patient analysis.

RESULTS

Study Population EnrollmentAmong 8006 subjects undergoing pan-colonoscopy (4226

men, 3780 women), we prospectively and consecutively evaluated305 patients submitted for CNBD with no established diagnosisconcerning this symptom (175 women; median age, 63 6 16.6;

range, 18–97 yr and 130 men; median age, 56.5 6 19.4; range,18–88 yr).

Two hundred sixty-five of them, 151 women and 114 men,fulfilled the inclusion criteria and were enrolled for furtherstatistical analysis (CNBD group). Among the 40 excludedsubjects (24 women and 16 men), 7 had a poor bowel preparationand 33 did not strictly fulfill the biopsy protocol.

Endoscopic and Histopathological Work-upMatching clinical history and results yielded during the

endoscopic and the histopathological work-up, each enrolledpatient with CNBD has been classified as (I) positive for MC,(II) positive for macroscopic disorders affecting ileocolonic tract, or(III) characterized by a full negative diagnostic work-up (Table 1).

Patients Positive for MCThe diagnostic criteria for the diagnosis of MC were satisfied

in 43 patients: 26 women and 17 men. Among them, 13corresponded to LC (7 women), whereas 30 to CC (19 women).No incomplete MC was detected (Table 1).

Patients Positive for Macroscopic DisordersDetected During Endoscopy

In 59 subjects, the ileocolonic examination reported macro-scopic disorders depicting a potential clinical correlation with theirsymptoms (Table 1). Eight subjects had a large adenocarcinoma (4women and 4 men: median age, 74.5 6 14.3 yr; range, 41–85 yr),whereas 51 presented signs of mild-to-moderate inflammatory dis-orders (27 women and 24 men: median age, 596 21.9 yr, range, 18–97 yr). According to histopathology, these macroscopic inflamma-tory disorders were further classified as unspecific inflammatory le-sions (17 cases, mostly suspicious for drugs-induced colitis), newIBD diagnosis (11 Crohn’s disease and 6 ulcerative colitis), divertic-ulosis with peridiverticular inflammation (13 cases), eosinophiliccolitis (2 cases characterized by patchy hyperemic lesions), and pseu-domembranous colitis (1 case). Two additional patients with patchy,mild, inflammatory lesions were further diagnosed as MC. Onepatient diagnosed as CC showed an oozing bleeding point withoutvascular or ulcerative lesion, surrounded by hyperemic mucosaplaced in the descending colon; 1 patient with LC had a mild, patchyhyperemia in the left colon. According to the histopathology, these 2patients were not included within the group defined as “macroscopicbowel disorders” but in the MC group (Fig. 1).

Patients with a Full NegativeDiagnostic Work-up

In 163 patients (94 women and 69 men), endoscopic andhistopathological evaluations were negative for both MC andmacroscopic lesions (Table 1). Indeed, these patients couldpresent minor endoscopic noninflammatory findings, includingcolorectal polyps and uncomplicated diverticulosis. No clinicalfollow-up was designed to evaluate whether these patients obtainedsymptom remission or eventually got a diagnosis of other disordersconsistent with their complaints, such as irritable bowel syndrome

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or colonic diverticular disease. Figure 1 depicts the prevalence ofeach diagnosis resulting by the colonoscopy and histopathologicalevaluation in subjects with CNBD.

Statistical Analysis

MC PrevalenceThe prevalence of MC among subjects receiving colono-

scopy and histopathological evaluation for CNBD was equal to16.2%, where 11.3% were CC and 4.9% LC. The number neededto screen one new diagnosis of MC was equal to 6.2 subjectsusing the per-protocol analysis and to 7.1 subjects with theintention to screen analysis (i.e., including 40 subjects rule-outaccording to the inclusion criteria). In our study population, MC

and CC represented the diseases with the highest diagnostic rate(Table 1; Fig. 1).

When we considered only CNBD with no reliable lesiondetected during colonoscopy, defined as “macroscopic disorders-free,”MC prevalence was equal to 20.9% (14.6% CC and 6.3% LC) witha number needed to screen equal to 4.8 subjects (per-protocol analy-sis). Additional statistical analysis focused on age distribution andgender arrangement among the above-mentioned study groups.

Age DistributionTo determine whether the age could influence the risk of

MC, first, we compared the median ages among subjects with orwithout MC, and then we analyzed the risk associated to thediagnosis of MC according to different age groups. The median

TABLE 1. Gender and Age Distribution of Enrolled Patients According to Endoscopic and Histological Results

Gender Patient Number Age, Median 6 SD Age Range

CNBD group Overall 265 59 6 18.1 18–97

Women 151 (57%) 61 6 16.5 18–97Men 114 (43%) 54 6 19.4 18–86

Full negative work-up Overall 163 54 6 16.6 18–86

Women 94 (57.7%) 55.5 6 15.1 18–86

Men 69 (42.3%) 51 6 18.2 18–83

Macroscopic disorders Overall 59 61 6 21.6 18–97

Women 31 (52.5%) 71 6 19.3 18–97

Men 28 (47.5%) 55.5 6 22.5 18–86

MC Overall 43 67 6 15 21–86Women 26 (60.5%) 70.5 6 14.4 32–86

Men 17 (39.5%) 67 6 16.1 21–82

CC Overall 30 68.5 6 14.1 32–86

Women 19 (63.3%) 72 6 14.5 32–86

Men 11 (36.7%) 67 6 13.2 41–82

LC Overall 13 66 6 17.4 21–83

Women 7 (53.8%) 65 6 14.4 45–83

Men 6 (46.2%) 70.5 6 21.9 21–82

FIGURE 1. Prevalence of each diagnosis resulting by the colonoscopy and histopathological evaluation in subjects with CNBD.



age of the MC group (67 6 15 yr) was significantly higher thanthose observed in the CNBD group (59 6 18.1 yr, P ¼ 0.002)and in the group with a full negative diagnostic work-up (54 616.6 yr, P , 0.001). No difference was detectable comparing themedian age between MC group and patients with macroscopiclarge-bowel lesions at colonoscopy (61 6 21.6 yr, P ¼ 0.122),as well as comparing CC (68.5 6 14.1 yr) and LC (66 6 17.4 yr;P ¼ 0.606).

Focusing on the diagnostic rate of MC in different agegroups, we observed that the prevalence of MC increased over theyears both in the CNBD group and in the macroscopic disorders-free group (Fig. 2). Within CNBD group, the rate of new diag-nosis of MC showed a first peak at 60 to 70 years and a secondmore valuable climax among older than 80 years (Fig. 2).

To determine whether these age-related features werestatistically significant in our population without fragmenting thepopulation in many small groups of age, we analyzed theprevalence of MC comparing the frequencies observed betweenyounger (,) and older ($) with respect to each of the followingages: 40, 50, 60, 70, and 80 years. Among CNBD aged,40 years,the rate of MC diagnosis was 3.8%, whereas within-subjects aged$40 years, the prevalence of MC was equal to 19.2%. This age-dependent rise was also confirmed in subjects aged $50 years(21.3%), $60 years (22.9%), $70 years (25.3%), and $80 years(42.9%) when compared with youngers (7.3%, 9.7%, 12.6%, and13.9%, respectively). These differences were statistically significantand associated to reliable values of OR (Table 2).

Consistently, the number needed to screen one new case ofMC in the CNBD group was equal to 26 subjects among thoseyounger than 40 years but only to 2.3 in those aged $80 years(per-protocol analysis; Table 2).

In the subgroup analysis based on subjects with CNBD andno macroscopic colonic disorder (formerly defined as macroscopic

disorders-free), MC prevalence confirmed this statistically signifi-cant rise at every age’s step (Table 2).

Gender ArrangementIn MC group, the female gender was more represented than

male gender (60.5%) with a ratio equal to 1.5 female for everycase male. CC group presented the highest proportion of femalepatients (63.3%, female/male ¼ 1.7/1), whereas within LC, thegender distribution had a substantial balance (53.6% females,female/male ¼ 1.2/1). The statistical comparison between CCand LC gender distribution showed no significant difference(OR related to female gender ¼ 1.3; CI, 0.7–1.7; P ¼ 0.736).

In CNBD group, as in patients with a full negative work-up,the women population was also prevalent (57%, female/male ¼1.3:1 and 57.7%, female/male ¼ 1.4:1, respectively). The statis-tical comparison focused on gender distribution in CNBD group,and MC or CC groups did not show any significant difference(MC: OR, 1.2; CI, 0.7–2.0; P ¼ 0.737 and CC: OR, 1.3; CI,0.6–2.6; P ¼ 0.558).

In the overall endoscopic survey including 8006 consecu-tive pan-colonoscopy, women accounted for the 47.2% ofpopulation (female/male ¼ 1/1.1). These data were used to deter-mine whether the female sex was associated with an increased riskfor CNBD or MC and CC. The statistical comparison betweengender distribution observed in the MC or CC group and in theendoscopic survey of 8006 subjects showed no significant differ-ence (MC: OR, 1.7; CI, 0.9–3.1; P ¼ 0.111 and CC: OR, 1.9; CI,0.9–4.1; P ¼ 0.112). Thus, according to our endoscopic survey,the female population had a risk of MC or CC comparable withthat observed in men.

Then, we compared the gender distribution between theCNBD group and the overall endoscopic population of 8006subjects. In this case, the female sex showed a statistically

FIGURE 2. Age-dependent rise of MC prevalence in CNBD and macroscopic disorders-free subjects.



significant correlation with CNBD group, resulting in an ORequal to 1.5 (CI ¼ 1.2–1.9, P ¼ 0.001). Thus, among overallsubjects screened with pan-colonoscopy, women had a risk ofCNBD 1.5-fold greater than men.

To determine whether the above-reported age-dependent riseof MC could differently affect women and men, we performeda separate analysis of the MC prevalence among different agegroups for male and female subjects. This analysis was based onCNBD group and confirmed a statistically significant age-dependent rise of MC prevalence in both the male and the femalepopulation (P , 0.05; data not reported in table). To further con-firm these data, we used the Fisher’s exact test to compare thewomen prevalence of MC with that observed in men for eachage groups (i.e., younger than 40, 50, 60, 70, 80 yr and aged$40, $50, $60, $70, and $80 yr). Again, the statistical analysisshowed no significant difference (P . 0.1; data not reported intable), thereby confirming that men and women presenting CNBCshared a comparable age-dependent rise of MC risk.

Colorectal Lesion Detection Rate Accordingto Histopathological Analysis

Overall, 55 colorectal lesions were detected in 38 subjects.In MC group, we found 2 adenomas with low-grade dysplasia:

1 associated with CC and 1 with LC. No serrated lesion or invasivecancer was identified in MC group (Table 3).

Non-MC group embedded 201 CNBD subjects with pan-colonoscopy and negative histopathological work-up for MC, IBD,and eosinophilic colitis (115 women: median age, 58 6 17.3 yr;range, 18–87 yr). One additional patient with a nonretrieved neo-plastic lesion (histology based on biopsy sample only) was excludedfrom this group. In non-MC group, median age was significantlylower compared with MC group (58 6 17.3 versus 67 6 15 yr;P , 0.001), whereas no difference was found about gender distri-bution (female/male ratio, 1.5 versus 1.3, respectively; P . 0.1)(Table 4). In non-MC group, we identified and retrieved 53 colorectallesions in 36 subjects (17 women: median age, 70.5 6 14.2 yr;range, 21–85 yr) and 12 of them were diagnosed with multiplelesions. Histopathology showed 35 low-grade dysplasia in 22 sub-jects, 1 high-grade dysplasia and 8 invasive cancers in as manypatients (4 women: median age, 74.5 6 14.3 yr; range, 41–85 yr).Four colorectal lesions were diagnosed as hyperplastic polyps, 2 asmixed hyperplastic–adenomatous polyps and 2 as serrated adenomas.No serrated cancer or sessile serrated lesion was found (Table 3).Median age of non-MC patients positive either for overall colorectalneoplasia or colorectal cancer only was statistically comparable withthat of MC group (P ¼ 0.869 and P ¼ 0.3, respectively).

TABLE 2. MC Prevalence According to Different Age Groups in Subjects with CNBD and in the MacroscopicDisorders-free Subgroup

Age Groups OR 95% CI P

Age $ 40 yr Age , 40 yr

Patients number MC/CNBD (MDF) 41/213 (169) 2/52 (37)

Number needed to screen with CNBD (MDF) 5.2 (4.1) 26 (18.5)

MC prevalence among CNBD (MDF) 19.2% (24.3%) 3.8% (5.4%) 5.0 (4.5) 1.2–20 (1.1–17.7) 0.006 (0.012)



Number needed to screen with CNBD (MDF) 4.7 (3.6) 13.7 (10.9)MC prevalence among CNBD (MDF) 21.3% (27.7%) 7.3% (9.2%) 2.9 (3.0) 1.4–6.3 (1.4–6.4) 0.003 (0.001)



Number needed to screen with CNBD (MDF) 4.4 (3.6) 10.3 (7.5)

MC prevalence among CNBD (MDF) 22.9% (27.5%) 9.7% (13.4%) 2.4 (2.1) 1.3–4.3 (1.1–3.7) 0.004 (0.016)



Number needed to screen with CNBD (MDF) 3.9 (3.2) 7.9 (6.0)MC prevalence among CNBD (MDF) 25.3% (31.1%) 12.6% (16.6%) 2.0 (1.9) 1.2–3.4 (1.1–3.2) 0.016 (0.024)



Number needed to screen with CNBD (MDF) 2.3 (1.2) 7.2 (5.4)

MC prevalence among CNBD (MDF) 42.9% (81.8%) 13.9% (18.4%) 3.1 (4.5) 1.7–5.5 (2.9–6.7) 0.002 (,0.001)

MDF, macroscopic disorders-free subgroup. The table reports the number needed to screen according to the per-protocol analysis.



The overall prevalence of patients with neoplastic colorec-tal lesions was 4.6% in MC group and 17.9% in the control group.This difference was statistically significant (Table 4).

DISCUSSIONThis study showed that among Northern Italian patients

undergoing colonoscopy for CNBD, the prevalence of MC is highand mostly represented by CC. Consistently, the number ofcolonoscopies needed to name 1 new diagnosis of MC was equalto 6.2 in the overall population with CNBD. Moreover, MC andCC represented the most common causes of watery diarrhea insubjects submitted to pan-colonoscopy by general practitioners orgastroenterologists after having variably ruled out alternativediagnosis (Table1; Fig. 1). These data clearly confirm the value ofmultiple colorectal biopsies in subjects with chronic diarrhea,even in the case of an uneventful endoscopic examination.

Previous studies focused on the impact of histopathologicalanalysis and multiple colorectal random biopsies in patientsundergoing colonoscopy for CNBD have shown wide differencesregarding MC detection rates. In one large retrospective surveyfrom Sweden (1018 subjects), MC was identified in 10% of

patients and in almost 20% of those older than 70 years.8

Recently, a prospective endoscopic study from Spain based onpatients undergoing colonoscopy for CNBD of unknown originfound 1 new case of MC in 12% of the overall population and in22% of subjects over 70 years.18 By contrast, 2 large endoscopiccohorts reported much lower diagnostic yields (1.1%–1.3%), rais-ing questions about the cost-effectiveness of random biopsies inunselected subjects with CNBD.3,29

Compared with the current literature, our results present 2main additional peculiarities. First, our population depicts onlya slight female predominance among CC, and a substantialbalance within LC, so that the prevalence of MC, CC, or LCbetween genders is statistically comparable (Table 1). These datacorrespond to the lowest women-to-men ratio observed so far inWestern Countries (female:male ratio: 2.8–7.9 in CC and 1.6–5.0in LC), where female gender is widely recognized as a major riskfactor for MC, especially for collagenous entities.1,3,7,8,20,24,42,43

However, in 1995, a review of all published cases of lymphocyticand CC showed no significant difference in sex of patients witheither disease44 and, consistent with our result, even the afore-mentioned endoscopic cohort from Spain failed to detect relevantdifferences related to gender.18 Taken together, these data seem to

TABLE 3. Colorectal Lesions Detection Rate According to Histopathological Analysis

Per-lesion Analysis Per-patient Analysis

MC Non-MC MC Non-MC

Adenoma Low-grade dysplasia 2 35 2 22

High-grade dysplasia 0 1 0 1

Cancer 0 8 0 8Non-neoplastic serrated lesions Hyperplastic 0 4 0 3

Sessile serrated 0 0 0 0

Neoplastic serrated lesions Mixed 0 3 0 2

Serrated adenomas 0 2 0 2

Serrated cancer 0 0 0 0

Total 2 53 2 36

Multiple colorectal lesions were found and retrieved in 12 controls; one of them had a hyperplastic and a serrated adenoma.

TABLE 4. Neoplastic Colorectal Lesions Among MC and Non-MC Subjects with CNBD

MC Non-MC OR 95% CI P

Screened patients 43 201 — — —

Age, median 6 SD 67 6 15 58 6 17.3 NA NA ,0.001

Gender distribution (M/F) 17/26 86/115 1.14 0.58–2.24 0.736

Neoplastic patients 2 (4.6%) 36 (17.9%) 0.22 0.05–0.97 0.035

NA, not available.



shrink the impact of hormonal host-related factors, musing ona more pivotal role played by environmental risk factors. In thisrespect, the main limit of our survey is the lack of sufficientclinical data for a statistical analysis focused on the identificationof potential risk factors such as drugs consumption and smokinghabit.2,12–17

Second, unlike previous large population-based studies, whichhave reported similar prevalence for LC and CC,1–3,7,8,19–21,42 in ourpopulation, mainly constituted by subjects living in Milan metropol-itan area, we observed a clear predominance of collagenous over LC,harboring the presence of disease-specific environmental drivers(Table 1; Fig. 1). However, surveys from rural areas or developingcountries entirely indicated the LC as the most recurrent entity,hinting the presence of some microbiological/environmental triggerspotentially switching MC histotype.18,45–49

Consistent with literature,1–3,14,18 our data clearly detaileda striking age-dependent rise of MC prevalence showing outstand-ing odds among different age groups, as in the number needed toscreen only 1 new patient affected (Table 2; Fig. 2). Among adultsyounger than 40 years with CNBD, the rate of MC was low andthe number needed to screen 1 new case was considerable. Bycontrast, after the 40th year of age, MC prevalence increased up to19%, outlining a 5-fold greater risk and a more satisfying numberneeded to screen. This feature spread over time in our population,showing its highest expression in older than 80 years, when MCprevalence was equal to 43%, and a new case of MC almost everyother colonoscopy with biopsies was observed. Notably, thisstriking age-dependent rise in prevalence was apparent in bothmen and women population.

Finally, despite the limited sample size, patients with MCdisplayed a lower risk of neoplastic colorectal lesions comparedwith CNBD negative subjects (Tables 3 and 4). Recently, 2 largeretrospective studies have lead to similar results comparing therisk of colorectal neoplasia between MC and healthy subjects.3,30

It has been postulated that chronic diarrhea could lead colitispatients to repeated colonoscopies; thus, colonoscopies and poly-pectomies performed before the inclusion in the study may par-tially explain this circumstance.3 To avoid such a recall bias andto balance the exposition to prior endoscopic polypectomies, thispilot study was specifically designed a priori to compare the prev-alence of colorectal lesions between CNBD subjects with MC andwithout MC. Accordingly, patients with IBD and eosinophiliccolitis were also excluded. Furthermore, in those patients withrepeated colonoscopies during our study, we have only consid-ered the results of the first examination.

A wealth of experimental and clinical data indicates thatinflammation possesses protumorigenic activities; accordingly, inpatients with long history of IBD, disease severity and extend arerecognized as major risk factors for the development of intestinalepithelial neoplasia.50,51 Nevertheless, some evidence does not fitinto this general pattern.52,53 A marked chronic inflammatory con-dition such as psoriasis is not associated with an increased risk ofdeveloping skin cancer.54 Inflammatory cells can destroy tumorcells, in addition to normal tissue cells.52,53 Cellular effectors of

inflammation such as NF-kB are important constituents of thelocal environment of tumors as play an important role in deter-mining the balance between the pro- and anti-tumorigenic prop-erties of macrophages.52 Evidence indicates that NF-kB has anincreased activity in the colonic mucosa of patients with MC.55

Taken together, these data suggest that the inflammatory path-ways underling MC may result in a protective effect against colo-rectal carcinogenesis. Nonetheless, this study was underpoweredto definitively substantiate this issue. In patients negative for MCwith colorectal neoplasia, both age and gender distribution werefound comparable to those of patients with MC; however nomultivariate analysis or case-control designed with matched con-trols was performed to rule-out the influence of other risk factors.Therefore, we believe that the lower risk of colorectal neoplasticlesions observed in MC should be further confirmed in largersurveys and follow-up studies.

Some additional remarks regarding this study should bealso taken into account. In contrast to studies with a population-based design, our analyses are focused on an endoscopic cohort,thereby yielding prevalence’s rates per colonoscopic patientsrather than per living population. In this setting, the impact ofMC should be weighed against the colonoscopy demand forCNBD resulting from other conditions. Accordingly, advancedelderly is characterized by low rate of functional disorders andIBD, therewith matching the impressive prevalence of MCobserved among older, especially in the case of uneventful endo-scopic examination (Table 2; Fig. 2). Unfortunately, the heterog-enous provenience of many enrolled subjects has limited theavailability of reliable clinical retrospective and follow-up data,whereby hampering the possibility to match the diagnosis of MCwith the presence of environmental risk factors. For the samelimitation, we also failed to collect the final diagnosis of thosepatients with a negative endoscopic and histological work-up. Inthese cases, we hypothesized the functional origin of the diarrheawith putative diagnosis of irritable bowel syndrome or colonicdiverticular disease; indeed, the lack of clinical follow-up datashould be taken into account when analyzing the results. Finally,not all the patients with CNBD who underwent ileocolonoscopy hadreceived a complete clinical work-up to systematically rule-out anyunderlying disorders; consequently, we cannot exclude the presenceof additional comorbidities involved in the onset of CNBD.

Besides providing data on microscopic colitides, this multi-center endoscopic survey reveals other interesting cues regardingpatients with CNBD (Fig. 1). A considerable amount of inflamma-tory lesions detected during colonoscopy showed histological pat-terns compatible with drug-induced disorders. Similarly to MC,these conditions affecting both adult and elderly patients are notyet completely understood and allegedly overlooked.34 Moreover,the diagnosis of 8 colorectal invasive cancer within 305 patientssubmitted for CNBD should raise concerns. Most national andinternational guidelines do not recognize chronic watery diarrheaas a “red flag” symptom for colorectal cancer. However, the secondEuropean Panel on the Appropriateness of Gastrointestinal Endos-copy (EPAGE II) confirmed the appropriateness of diagnostic



colonoscopy for diarrhea of .4-week duration in patients aged.50 years with recent-onset chronic diarrhea or for any patientswith such a complaint in association with alarm symptoms.28

In conclusion, in a multicenter population of consecutivepatients from Northern Italy referred to colonoscopy for CNBD,we detected a relatively high prevalence of MC with a clearpredominance of collagenous entities. A striking age-dependentrise in MC-associated risk was also observed, while genderarrangement resulted substantially balanced, especially amongpatients with LC. MC was negatively associated with the risk ofcolorectal neoplasia compared with negative subjects withCNBD. This evidence suggests that the inflammatory pathwaysunderlying MC may play a protective role against the develop-ment of colonic neoplasia; thus, as opposite of the processesoccurring in other chronic disorders of the gastrointestinal tract,such as IBD, Helicobacter pylori–related gastritis and gastro-esophageal reflux disease. Moreover, we have shown the role ofcolonoscopy in subjects with CNBD, which allowed for severalnew diagnoses of MC, IBD, drug-related colitis and invasivecancer, pointing out the added-value provided by the multiplebiopsy protocol, particularly in the case of uneventful endoscopicinspection and in subjects older than 40 years of age.

ACKNOWLEDGMENTSThe authors are in debt with Dr. A. N. Fardowza, Dr.

P. Lagoussis, and Dr. D. Bona who contributed to the acquisitionof endoscopic data at IRCCS Policlinico San Donato.

Author contributions: Study concept and design, acquisi-tion of data, analysis and interpretation of data, drafting of themanuscript, critical revision of the manuscript for important intel-lectual content: G. E. Tontini and L. Pastorelli; acquisition ofdata, analysis and interpretation of data: L. Spina, F. Fabris,C. Clemente, B. Bruni, G. de Nucci, F. Cavallaro; study conceptand design, technical support for acquisition of data: criticalrevision of the manuscript for important intellectual content:S. Marconi; M. F. Neurath, and H. Neumann; study conceptand design, acquisition of data, critical revision of the manuscriptfor important intellectual content: M. Tacconi; study concept anddesign, analysis and interpretation of data, drafting of the man-uscript, critical revision of the manuscript for important intellec-tual content, study supervision: M. Vecchi.

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Microscopic Colitis and Colorectal Neoplastic Lesion Rate in Chronic Nonbloody Diarrhea

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