The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence

Background & Aims: Early ileocolonoscopy allows detection of recurrence after surgically induced remission of Crohn’s disease (CD). Unequivocal histologic markers predicting recurrence have not been identified. We assessed the predictive value of neural lesions for early endoscopic CD recurrence and long-term reintervention risk. Methods: Ileocolonic resection specimens from 59 patients with CD and 21 control patients were histologically scored for typical inflammatory bowel disease lesions, neural hypertrophy, and presence and severity of inflamed ganglia and nerve bundles. Endoscopic recurrence was determined at 3 months in all patients and at 1 year in 32 patients as part of 2 prospective clinical trials. Results: Myenteric plexitis of the proximal resection margin was present in 32 patients with CD (54%) in absence of surrounding inflammation. Patients with this feature had a higher endoscopic recurrence (Rutgeerts score ≥2) at 3 months (75% vs 41%; odds ratio, 4.36; 95% confidence interval, 1.44–13.23; P = .008) and at 1 year (93% vs 59%; odds ratio, 9.80; 95% confidence interval, 1.04–92.70; P = .041) and had a trend toward an earlier reintervention (mean, 7.00 vs 5.30 years; P = .174). The severity of myenteric plexitis in the proximal resection margin correlated with the severity of endoscopic recurrence at 3 months (r = 0.334, P = .010) and 1 year (r = 0.560, P = .001). Myenteric plexitis was the only consistent predictor of endoscopic recurrence. Conclusions: The presence of myenteric plexitis in proximal margins of ileocolonic resection specimens is predictive of early endoscopic CD recurrence. Background & Aims: Early ileocolonoscopy allows detection of recurrence after surgically induced remission of Crohn’s disease (CD). Unequivocal histologic markers predicting recurrence have not been identified. We assessed the predictive value of neural lesions for early endoscopic CD recurrence and long-term reintervention risk. Methods: Ileocolonic resection specimens from 59 patients with CD and 21 control patients were histologically scored for typical inflammatory bowel disease lesions, neural hypertrophy, and presence and severity of inflamed ganglia and nerve bundles. Endoscopic recurrence was determined at 3 months in all patients and at 1 year in 32 patients as part of 2 prospective clinical trials. Results: Myenteric plexitis of the proximal resection margin was present in 32 patients with CD (54%) in absence of surrounding inflammation. Patients with this feature had a higher endoscopic recurrence (Rutgeerts score ≥2) at 3 months (75% vs 41%; odds ratio, 4.36; 95% confidence interval, 1.44–13.23; P = .008) and at 1 year (93% vs 59%; odds ratio, 9.80; 95% confidence interval, 1.04–92.70; P = .041) and had a trend toward an earlier reintervention (mean, 7.00 vs 5.30 years; P = .174). The severity of myenteric plexitis in the proximal resection margin correlated with the severity of endoscopic recurrence at 3 months (r = 0.334, P = .010) and 1 year (r = 0.560, P = .001). Myenteric plexitis was the only consistent predictor of endoscopic recurrence. Conclusions: The presence of myenteric plexitis in proximal margins of ileocolonic resection specimens is predictive of early endoscopic CD recurrence. The vast majority (50%–70%) of patients with Crohn’s disease (CD) will require a partial bowel resection in the course of their disease, and most of them will ultimately experience a postoperative recurrence.1Sachar D.B. 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Immunohistochemical approach of the enteric glia in patients with Crohn’s disease (abstr).Gastroenterology. 1996; 110: A889Google Scholar Until now, it remained unknown whether the changes of the enteric nervous system are primary or secondary to inflammation, but the occurrence of lesions in macroscopically uninvolved areas may suggest that they precede mucosal inflammation. Moreover, these findings may indicate a neuronal pathway for the spreading of inflammation and may explain the high incidence of CD recurrence postoperatively.34Geboes K. Rutgeerts P. Ectors N. Mebis J. Penninckx F. Vantrappen G. Desmet V.J. Major histocompatibility class II expression on the small intestinal nervous system in Crohn’s disease.Gastroenterology. 1992; 103: 439-447Crossref Scopus (101) Google Scholar, 38Costa F. Manghetti M. Mumolo M.G. Ciancia E.M. Bongioanni P. Bianchi G. Bellini M. Tumino E. Marchi S. Maltinti G. Immunohistochemical approach of the enteric glia in patients with Crohn’s disease (abstr).Gastroenterology. 1996; 110: A889Google Scholar Based on these data, we investigated the relationship between the presence and severity of neuronal lesions in CD resection specimens in both proximal and distal margins and the occurrence of early postoperative endoscopic lesions and both symptomatic and surgical recurrence of CD. Moreover, we investigated the value of standard histologic and clinical parameters to predict early postoperative CD recurrence in addition to the neuronal lesions in a well-defined and controlled patient population. All 59 patients with CD (29 men and 30 women; mean age, 33.86 ± 11.90 years) participated in one of 2 formerly published postoperative CD recurrence prevention trials, either with metronidazole versus placebo39Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Google Scholar or with ornidazole versus placebo.40Rutgeerts P. Van Assche G. Vermeire S. D’Haens G. Baert F. Noman M. Aerden I. De Hertogh G. Geboes K. Hiele M. D’Hoore A. Penninckx F. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2005; 128: 856-861Abstract Full Text Full Text PDF Scopus (349) Google Scholar The diagnosis of CD was based on clinical, radiologic, and endoscopic examination and histologic findings. All patients included in the present study had been randomized to placebo and did not receive any anti-inflammatory treatment during the first year after their ileocolonic resection. In the 2 placebo-controlled studies, all relevant clinical parameters had been recorded, including smoking habit and C-reactive protein level at the time of surgery. Our control population consisted of 10 oncology patients (5 men and 5 women; mean age, 72.96 ± 12.82 years) who underwent an ileocolonic resection for a cecal carcinoma and 11 patients (6 women and 5 men; mean age, 39.36 ± 16.50 years) with ulcerative colitis (UC) undergoing a proctocolectomy for severely active inflammation. The resection specimens of all 69 ileocolonic resections and 11 proctocolectomies were analyzed by 2 pathologists (K.G. and G. De Hertogh) blinded to the postoperative evolution of each patient. For each sample, about 8 different full-thickness, transversely taken sections were examined from 3 different parts of the bowel: from the ileal and the colonic margin and from the pathologic terminal ileum or colon itself. In the affected bowel fragment, the presence of granulomas, fibromuscular obliteration, and both neural hyperplasia and neural hypertrophy were assessed. The severity of neural hyperplasia was described subjectively. Neural hypertrophy was graded based on the dimensions of the submucosal nerve bundles. Nerve bundles with a diameter ≤0.06 mm were defined as normal (nht0), from 0.07 to 0.11 mm as mild neural hypertrophy (nht1), from 0.12 to 0.30 mm as moderate neural hypertrophy (nht2), and with a diameter ≥0.30 mm as severe neural hypertrophy (nht3). Some examples are shown in Figure 1. In both resection margins, we investigated typical inflammatory bowel disease (IBD) lesions, such as inflammatory infiltrates, crypt abscesses, architectural alterations, granulomas, erosions, and ulcers. Special attention was given to the enteric nervous system, and Auerbach’s plexus and the submucosal plexus were assessed independently. The numbers of ganglia (defined as an accumulation of neuronal cell bodies and glial cells, with at least one neural cell body) and nerve bundles (individual axons surrounded by perineurium) were counted. Plexitis was defined as the presence of one or more inflammatory cells (eosinophils, lymphocytes, plasmocytes, mast cells, or granulocytes) appositioned to or within an enteric ganglion or nerve bundle. Plexitis was graded based on the appearance of the most severely inflamed ganglion or nerve bundle in the available tissue. The plexitis was graded mild (pl1) if this ganglion or nerve bundle contained <4 inflammatory cells, moderate (pl2) if containing 4–9 cells, or severe (pl3) if containing ≥10 cells. In case several sections were available from proximal or distal resection margins, all were examined; however, for each margin, only the section with the most severe myenteric plexitis was used for further analysis. Some examples are shown in Figure 2. In 4 patients with CD, the distal resection margin was not available. The wall thickness ratio was defined as the ratio of the wall thickness in the pathologic involved terminal ileum to that of the macroscopically uninvolved proximal resection margin. Interobserver disagreement was solved by joint revision of the case at a multiheaded microscope. Endoscopic recurrence was studied in all 59 patients with CD by ileocolonoscopy with at least 4 ileal biopsy specimens 3 months after surgery. In 32 patients (ornidazole study), a second ileocolonoscopy was performed after 12 months. The endoscopic findings were scored by means of a formerly reported recurrence score4Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn’s disease.Gastroenterology. 1990; 99: 956-963Crossref Scopus (1434) Google Scholar in the course of the placebo-controlled trial (Table 1). Significant endoscopic recurrence was defined as a Rutgeerts score of i2 or higher.Table 1Endoscopic Recurrence ScoreGradeDescription of endoscopic lesionsi0Absence of any lesions at the site of anastomosis and in the neoterminal ileumi1≤5 Aphthous ulcers (<5 mm)i2>5 Aphthous ulcers with normal mucosa between the lesions, or skip lesions, or lesions confined to the ileocolonic anastomosis (<1 cm in length)i3Diffuse aphthous ileitis with diffusely inflamed mucosai4Diffuse inflammation with already larger ulcers (≥5 mm), nodules, and/or narrowingAdapted from Rutgeerts et al.4Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn’s disease.Gastroenterology. 1990; 99: 956-963Crossref Scopus (1434) Google Scholar Open table in a new tab Adapted from Rutgeerts et al.4Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn’s disease.Gastroenterology. 1990; 99: 956-963Crossref Scopus (1434) Google Scholar Clinical postoperative recurrence data and the need for medical rescue treatment or reintervention were also available from the trials. In 5 of 59 patients with CD, some follow-up data could not be traced. SPSS 12.0 software (SPSS Inc, Chicago, IL) was used for appropriate statistical methods. Both univariate (χ2 and independent t test) and backward Wald multiple regression analysis were performed to look for possible predictors of early postoperative recurrence (endoscopic, clinical, and surgical). Correlations were calculated using the Spearman rank correlation test, and P < .05 was considered statistically significant. Fifty-nine patients with CD were included in this study: 27 from the metronidazole study39Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Google Scholar and 32 from the ornidazole study.40Rutgeerts P. Van Assche G. Vermeire S. D’Haens G. Baert F. Noman M. Aerden I. De Hertogh G. Geboes K. Hiele M. D’Hoore A. Penninckx F. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2005; 128: 856-861Abstract Full Text Full Text PDF Scopus (349) Google Scholar Eleven other patients from these former postoperative recurrence prevention trials had to be excluded, because they had stopped the placebo treatment before the end of the study (2 patients), some pathologic sections were missing (2 patients), or they declined the postoperative endoscopies (7 patients). Clinical characteristics of the 59 patients with CD are summarized in Table 2.Table 2Patient CharacteristicsFemale/male (%)30/29 (51)Mean age at diagnosis (y)25.61 ± 9.93Mean duration before first ileocolonic resection (y)4.39 ± 5.01Mean age at indicator resection (y)33.86 ± 11.90Previous ileocolonic resection (%)19/59 (32)Location (Vienna classification70Gasche C. Scholmerich J. Brynskov J. D’Haens G. Hanauer S.B. Irvine E.J. Jewell D.P. Rachmilewitz D. Sachar D.B. Sandborn W.J. Sutherland L.R. A simple classification of Crohn’s disease report of the Working Party for the world congresses of gastroenterology, Vienna 1998.Inflamm Bowel Dis. 2000; 6: 8-15Google Scholar) (%) Ileal34/59 (58) Ileocolonic24/59 (41) Colonic0/59 (0) Upper1/59 (2)Behavior (Vienna classification70Gasche C. Scholmerich J. Brynskov J. D’Haens G. Hanauer S.B. Irvine E.J. Jewell D.P. Rachmilewitz D. Sachar D.B. Sandborn W.J. Sutherland L.R. A simple classification of Crohn’s disease report of the Working Party for the world congresses of gastroenterology, Vienna 1998.Inflamm Bowel Dis. 2000; 6: 8-15Google Scholar) (%) Inflammatory5/59 (8) Stenotic20/59 (34) Perforating34/59 (58)C-reactive protein level at moment of surgery >5 mg/L (%)18/30 (60)Smoking status at surgery (%) Never smoker23/59 (39) Past smoker5/59 (8) Active smoker31/59 (53)Preoperative medication (%) Mesalamine49/53 (92) Corticosteroids37/53 (70) Immunomodulators7/53 (13) Biologic therapeutic agents0/53 (0) Open table in a new tab All 70 patients with IBD had typical IBD lesions in the affected bowel segment, and in all 11 patients with UC the inflammation extended down to the level of the myenteric plexus. The pathologic features of both patients with CD and control patients are summarized in Table 3. Two patients with CD had microscopic involvement of the proximal resection margin. In one of these, macroscopic involvement was evident at surgery. Fibromuscular obliteration, neural hypertrophy, and granulomas were found in 93%, 75%, and 59% of patients with CD, respectively, whereas these features were absent in both control groups.Table 3Pathologic FeaturesCDUCCecal carcinomaResection specimen Wall thickness ratio2.34 ± 0.77Not relevantNot relevantAffected bowel fragment (%) Fibromuscular obliteration55/59 (93)0/11 (0)0/10 (0) Neural hypertrophyaNeural hypertrophy graded nht1 in 22, nht2 in 12, and nht3 in 10 patients with CD.44/59 (75)0/11 (0)0/10 (0) Granulomas35/59 (59)0/11 (0)0/10 (0) Submucosal plexitis44/52bIn 7 patients with CD, submucosal plexitis in the affected bowel fragment was not accessible due to massive neural hyperplasia. (85)8/11cPlexitis was present in 8/11 cases with UC but always in areas of so-called “proportionate” transmural inflammation. (73)0/10 (0) Myenteric plexitis52/59 (88)8/11cPlexitis was present in 8/11 cases with UC but always in areas of so-called “proportionate” transmural inflammation. (73)0/10 (0)Proximal resection margin (%) Typical IBD lesionsdTypical IBD lesions: inflammatory infiltration, crypt abscesses, erosions, ulcers, architectural alterations, or granulomas.2/59 (3)0/11 (0)0/10 (0) Submucosal plexitis7/59 (12)0/11 (0)0/10 (0) Myenteric plexitis32/59 (54)0/11 (0)0/10 (0)Distal resection margineFor 4 patients with CD, the distal resection margin was not available. (%) Typical IBD lesionsdTypical IBD lesions: inflammatory infiltration, crypt abscesses, erosions, ulcers, architectural alterations, or granulomas.1/55 (2)Not relevant0/10 (0) Submucosal plexitis1/55 (2)Not relevant0/10 (0) Myenteric plexitis3/55 (5)Not relevant0/10 (0)a Neural hypertrophy graded nht1 in 22, nht2 in 12, and nht3 in 10 patients with CD.b In 7 patients with CD, submucosal plexitis in the affected bowel fragment was not accessible due to massive neural hyperplasia.c Plexitis was present in 8/11 cases with UC but always in areas of so-called “proportionate” transmural inflammation.d Typical IBD lesions: inflammatory infiltration, crypt abscesses, erosions, ulcers, architectural alterations, or granulomas.e For 4 patients with CD, the distal resection margin was not available. Open table in a new tab In all patients with a cecal carcinoma, neuronal inflammation was absent. In contrast, plexitis was diagnosed in the submucosal or myenteric plexus of the affected terminal ileum in 88% and 85% of patients with CD, respectively. In 7 patients with CD, the presence of submucosal plexitis could not be assessed properly because of massive neural hyperplasia and architectural distortion. In 8 of 11 patients with UC with severely active inflammation, we found both myenteric and submucosal plexitis in the affected colonic segment. But, in contrast to our CD cases, this was only in areas of so-called “proportionate” transmural inflammation, that is, with the densest inflammatory infiltrate in the mucosa and around ulcers and decreasing density toward the serosa. The other 3 UC cases had no plexitis. A median of 14 myenteric ganglia (range, 6–32) and 9 submucosal ganglia (range, 5–