REVIEW ARTICLE
Histologic Features Predicting Postoperative Crohn’s Disease Recurrence Aude Bressenot, MD* and Laurent Peyrin-Biroulet, MD, PhD†
Abstract: Recurrence of Crohn’s disease (CD) after ileal or colonic resection is common. Many studies have tried to identify predictors of postoperative recurrence (POR) in CD. A wide range of histologic features have been identified, but for most of them, the literature provided conflicting data. In last years, several studies have suggested that histologic findings including inflammatory changes within the enteric nervous system of the resection margin may be associated with CD recurrence. Herein, after briefly summarizing pathophysiology of POR, we review all histological features that have been studied so far: granulomas, histologic appearance at the margin of resection, plexitis, lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. Active disease at the margin of resection, plexitis, lymphatic vessels density, morphological analysis of Paneth cells may predict POR. Most of these histological features await replication in independent studies. Available evidence indicates that histological findings may be taken into account when developing strategies aimed at preventing postoperative CD recurrence. (Inflamm Bowel Dis 2015;21:468–475) Key Words: Crohn’s disease, postoperative recurrence, histologic features
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rohn’s disease (CD) is a chronic disabling and destructive disease.1,2 Despite increased use of immunosuppressive and anti-tumor necrosis factor treatments, approximately half of the patients require surgery within 10 years after diagnosis.2 Three years after surgery, the endoscopic postoperative recurrence (POR) rate increased to 85% to 100%, and symptomatic recurrence occurred in 34% to 86% of patients.1 Surgical resection of the diseased bowel is not curative, and POR remains a significant problem in patients with CD.1 The identification of risk factors may allow targeted strategies to reduce this recurrence rate.1 Since the original report by Crohn et al3 in 1932, many investigators have tried to identify predictors of postoperative CD recurrence. A wide range of clinical and histologic features have been identified, but for most of them, the literature provides conflicting data, partially due to the variable definitions of CD recurrence and methodological discrepancies such as the length and type of follow-up.4,5 Smoking is the strongest risk factor for POR, increasing by 2-fold, the risk of clinical recurrence.1 Previous intestinal resection, penetrating behavior, perianal disease, and extensive bowel disease (.50 cm) are established risk factors for POR.1 Received for publication July 1, 2014; Accepted August 19, 2014. From the *Department of Pathology, University Hospital of Nancy, Vandoeuvrelès-Nancy, France; and †Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France. The authors have no conflicts of interest to disclose. Reprints: Laurent Peyrin-Biroulet, MD, PhD, Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy 54500, France (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000224 Published online 27 November 2014.
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Histological features to predict POR have also been studied. These include granulomas, histologic appearance at the margin of resection, plexitis lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Herein, after reviewing pathophysiology and histologic features predicting POR, we discuss whether histological findings should guide postoperative therapeutic treatment decision in CD.
PATHOPHYSIOLOGY Pathophysiology of POR after ileocecal resection is poorly understood. CD is a heterogeneous disorder caused by a complex interplay of microbial, environmental, immunological, and genetic variables. It seems probable that the same factors which underlie the pathogenesis of CD at its early stages also contribute to recurrence in the postoperative setting.6
Animal Data Understanding of the POR along with effective preventive measures has been limited making an animal model of POR a desirable and essential tool. The model of ileocecal resection in IL-102/2 mice provide a new method to research the postsurgical inflammation and fibrosis in the small intestine and anastomosis.7 Borowiec et al examined the bacterial, local, and systemic immune changes that follow ileocolonic anastomosis in the IL-102/2 mice: ileocolonic anastomosis leads to bacterial changes in the terminal ileum. In the genetically susceptible host, it is associated with small bowel fibrosis and systemic immune alterations with significantly increased interferon gamma secretion by bacterial antigen-stimulated splenocytes and a decreased number of CD11+ cells.8 Inflamm Bowel Dis Volume 21, Number 2, February 2015
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Human Data The site of recurrence in most patients after ileocolonic resection is at the anastomosis and extends into the proximal neoterminal ileum.9 It has been postulated that ileocecal resection removes the ileocecal valve, permitting free reflux of colic contents into the neoterminal ileum, thereby changing the bacterial flora within this region of the small bowel.10,11 D’Haens et al10 studied the effects of intestinal luminal contents into excluded ileum in 3 patients with CD who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy by histology and electron microscopy: intestinal contents trigger POR of CD in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery. To investigate the importance of fecal stream in the pathogenesis of POR in CD, Rutgeerts et al studied 5 patients with CD who had ileal resection. After curative resection and ileocolonic anastomosis, a diverting terminal ileostomy was constructed 25 to 35 cm proximal to the anastomosis thereby excluding the neoterminal ileum, the anastomosis, and the colon from intestinal transit. After 6 months of exclusion, endoscopy of the ileocolon was undertaken and biopsy specimens were taken. Transit was then restored. Six months after reanastomosis, further biopsy specimens were taken. All 5 patients had recurrence of disease, both endoscopically and histologically, at ileocolonoscopy 6 months after reanastomosis. These findings strongly support the view that recurrence of CD in the neoterminal ileum after curative ileal resection is dependent on fecal stream.11 The influence of surgical parameters has been studied in a meta-analysis: there was a trend to a lower number of POR rates in the laparoscopy group, but this technique requires further study in CD to assess whether it may reduce POR.12 Caprilli et al13 showed that patients who have had a resection with end-to-end anastomosis compared with those who have had a resection and other types of anastomosis have a higher risk of recurrence. Scarpa et al14 reported that side-toside anastomosis decreases the clinical POR when compared with end-to-side anastomosis. This may be explained by the wider lumen in the former technique with advantages of delayed anastomotic stenosis, decreased fecal stasis and reduced secondary ischemia.14 The finding that recurrence always takes place in the previously healthy ileum, proximally to the ileocolonic anastomosis, has raised a number of hypotheses regarding the mechanism behind this phenomenon.15 One of the most attractive suggestions has focused on the enteric nervous system.16 This independent well-organized system may provide a pathway along which inflammation could spread proximally.15 Few studies have examined the possible relationship between neuronal inflammation and the development of postoperative CD recurrence. However, many investigators have described changes in neuropeptides in inflamed inflammatory bowel disease tissue, suggesting an inflammatory effect on the enteric nervous system. The precise pathologic role of alterations in 5-hydroxytryptamine,
Postoperative CD Recurrence
neuropeptide Y, glial-derived neurotrophic factor, nerve growth factor, glial fibrillary acidic protein, nitric oxide, and pituitary adenylate cyclase activation peptide localized in the neuronal plexuses of patients with CD remains to be elucidated.17–21 Other factors are incriminated; Vandussen et al showed that high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. The disordered and diffuse abnormal Paneth cell phenotypes are associated with an altered transcriptional signature of immune system activation: the proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles.22
HISTOLOGIC FEATURES PREDICTING POSTOPERATIVE CD RECURRENCE These histological features are summarized in Figure 1.
Granulomas The significance of the granuloma in CD is not clear.23 It is generally assumed to represent a response to the etiological agent.23,24 There are contradictory reports in the literature regarding the impact of identifiable granulomas in the resection specimen on the recurrence.25 Although interobserver agreement for epithelioid granulomas is good, occurrence rates of epithelioid granulomas findings vary across studies, probably as a result of differences in sampling and serial sectioning method.26 In a German referral center of 100 consecutive patients undergoing isolated ileocecal resection for CD, granulomas showed no significant influence on the POR rates,23,27 whereas among 130 patients operated on for CD in Australia, the association of granulomas with recurrence remained significant (P ¼ 0.03).28 In a meta-analysis by Simillis et al,29 comparative studies published between 1954 and 2007 of granulomatous versus nongranulomatous CD were included: granulomatous CD seems to be associated with higher number of recurrences and reoperations and a shorter time to recurrence and reoperation compared with nongranulomatous CD. The number of granulomas found in resected specimen did not influence POR rate.23,30 The role of the granulomas (epithelioid granuloma, isolated giant cells, or microgranulomas) in predicting POR is unknown. VanDussen et al22 showed that abnormal Paneth cell phenotype inversely correlates with granuloma incidence and that high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Because of significant heterogeneity between studies, further studies should be undertaken to confirm these findings.29 Overall, these findings await replication by independent groups.
Histologic Appearance at the Margin of Resection The surgical techniques used in the treatment of CD share a common origin with those used in the resection of gastrointestinal malignancies.31 Several reports have reported that the wide resection of normal bowel uninvolved microscopically www.ibdjournal.org |
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FIGURE 1. Summary of histological features that have been studied for predicting POR in CD. A, Active inflammation in lamina propria (HES ·400). B, Granuloma (HES ·400). C, Chronic inflammation in lamina propria (HES ·100). D, Paneth cells in ileal crypt (HES ·200). E, Lymphatic vessels in submucosae (HES ·200). F, Submucosae plexitis (HES ·400). G, Myenteric plexitis (lymphocyte labeling with CD3 antibody ·400). HES, Hematein– Eosin–Safran.
(radical resection) was associated with a lower recurrence rate than nonradical resection.32–35 However, many studies have shown no difference in the recurrence rates between patients with radical resection and nonradical resection.28,36–39 A large number of published case series and retrospective studies over 50 years (Table 1) have failed to demonstrate a consistent relationship between marginal involvement and recurrence,32,34,35,38,40,41,43,45 despite a number showing an apparent benefit from a disease-free anastomosis.32,34,35,46 Surgical interventions aimed at increasing the likelihood of a disease-free anastomosis have been investigated. A randomized controlled trial demonstrated that extended resection, taking 10 cm of macroscopically healthy proximal ileum, had no benefit over limited resection, where a 2-cm proximal margin was taken, in delaying the need for further surgery.39 The use of frozen-section techniques to provide a rapid histological assessment of disease activity in macroscopically normal bowel and guide the extent of resection has also failed to demonstrate improved outcomes.42 Additionally, there was a poor correlation between the interpretation of frozen sections and permanent sections in this context. More recently, Kinchen et al analyzed 237 bowel resections from patients with CD. They demonstrated that the presence of histologically active disease at the resection margins defined by the presence of acute (neutrophilic) or granulomatous inflammation predicts postsurgical relapse in CD.31 More recently, other histologic criteria have been studied on ileal resection specimen. These studies are summarized in Table 2.
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Plexitis in Proximal Margin of Resection A remarkable pathologic observation is the presence of inflammatory infiltrates associated with both the submucosal and myenteric plexus of patients with CD.16 It remained unknown whether the changes of the enteric nervous system are primary or secondary to inflammation, but the occurrence of lesion in macroscopically uninvolved areas may suggest that they precede mucosal inflammation.16 In last years, several studies have suggested that inflammatory changes within the enteric nervous system of the resection margin could be associated with CD recurrence. The main studies are resumed in Table 2. In a retrospective study, Ferrante et al scored histologically 59 ileocolonic resection specimens from 59 patients 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. Myenteric plexitis was defined by the presence of 1 or several inflammatory cells (lymphocytes, plasmocytes, eosinophils, mast cells) appositioned to or within an enteric ganglion or nerve bundle.15 They demonstrated that inflammatory activity within the myenteric plexitis was significantly associated with postoperative CD recurrence: patients with myenteric plexitis of the proximal resection margin had a higher endoscopic recurrence rate at 3 months (P ¼ 0.008) and at 1 year (P ¼ 0.041).15 In 2009, Sokol et al47 analyzed all consecutive ileocolonic or ileal resection specimens from patients operated for active CD in Lariboisière Hospital (Paris) between 1995 and 2006. Early clinical
Patients, n
Aim of the Study
Type of Recurrence
Studies showing no relationship between histologic appearance at the resection margin and POR Pennington et al40 97 Determination of the influence of Need to resume or increase specific microscopic disease at an anti-inflammatory medication to anastomosis after intestinal control symptoms resection for CD Heuman et al41
67
Hamilton et al42
79
Cooper and Williams43 Adloff et al44
142
58
Kotanagi et al38
100
Fazio et al39
152
Kurer et al45
60
Influence of disease at the margin of resection on the outcome of CD The role of resection margin frozen section in the surgical management of CD
Clinical recurrence
Influence of microscopic disease at the margin of resection on POR in CD Does histologic appearance at the margin of resection affect the POR rate in CD? Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in CD? Assessment of the effect of surgical margin width on POR in CD
Clinical symptoms confirmed by radiological or histological evidence
Clinical recurrence and reoperation
Recurrence within 3 yr
Anastomotic recurrence
Reoperation for recurrent preanastomotic disease
Recommendation for conservative resections for CD: presence or absence of microscopic disease at the anastomosis did not appear to influence POR rates Microscopical involvement does not seem to increase the recurrence rate The findings support conservative resection to achieve grossly uninvolved margins rather than the sacrifice of functional intestine Presence of microscopic disease at the resection margin does not affect recurrence in CD No evidence for adverse influence of residual microscopic disease at the margins of resection Anastomotic recurrence was not associated with any clinical or histological feature or combination of features POR is unaffected by the width of the margin of resection from macroscopically involved bowel. Recurrence rates do not increase when microscopic CD is present at the resection margin Early symptomatic POR of CD remains unpredictable
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The recurrence rates were much lower (14%) when the margins of the resected intestine were free of disease than when microscopic signs of the disease were present (66%)
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Postoperative CD Recurrence
Identify predictors of early Symptomatic disease at 36 mo symptomatic recurrence of CD confirmed histologically after after surgical resection surgery or endoscopy and biopsy or (involvement of resection by radiological evidence of new margin.) mucosal ulceration and/or strictures Studies showing a relationship between histologic appearance at the resection margin and POR 59 Long-term results of surgical Kåresen et al34 treatment
Results
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TABLE 1. Studies on the Relationship Between Histologic Appearance at the Margin of Resection and Postoperative Recurrence in CD
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Histopathological appearance of the resection margins seemed to influence the prognosis, since the presence of ulcers and/or granulomas was correlated with significantly increased recurrence rate The presence of active disease at the resection margin is associated with repeat resection within 5 yr
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Repeat bowel resection with histological confirmation of active CD Re-examination of potential risk of active disease at the resection margin on POR 237
Studies showing a relationship between active disease at the resection margin and POR 207 Features that influence recurrence Lindhagen et al32 after surgical resection of all macroscopically involved bowel
Kinchen et al31
Patients with extensive CD requiring multiple resections with anastomosis, especially when microscopic inflammation is present at the margin, are at very high risk for symptomatic early recurrence Symptomatic recurrent disease within 36 mo Prediction of early symptomatic POR (number of anastomoses, inflammation at the resection margin) 164 Heimann et al46
TABLE 1 (Continued)
Patients, n
Aim of the Study
Type of Recurrence
Results
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recurrence was defined as the reappearance of CD clinical manifestations requiring a specific treatment within 2 years postsurgery. The proximal resection margin was analyzed. Data were available from 171 postoperative follow-up periods in 164 patients with CD. Early clinical recurrence of CD occurred in 28.1%. In multivariate analysis, factors associated with POR were active smoking (hazard ratio [HR] ¼ 1.94; 95% confidence interval [CI], 1.06–3.60; P ¼ 0.033), submucosal plexitis with $3 mastocytes (HR ¼ 1.87; 95% CI, 1.00–3.46; P ¼ 0.048), and a disease-free resection margin ,5 cm (HR ¼ 0.52; 95% CI, 0.27–1.02; P ¼ 0.059).47 In contrast at St Mark’s Hospital, London, the difference of clinical postoperative CD recurrence between patients with or without plexitis in the proximal resection margin did not reach clinical significance: ileocolonic resection specimens from 99 patients with CD were histologically scored for the presence and severity of plexitis. Myenteric plexitis was correlated with immunosuppressive therapy before index surgery.48 Univariate and multivariate analyses were performed to identify predictive factors for plexitis. Preoperative immunosuppressive therapy was not associated with a lesser incidence of plexitis. Twelve of 40 patients (30%) with plexitis and 9 of 54 patients (16%) without plexitis in the proximal resection margin subsequently developed clinical recurrence (median, 10 mo; P ¼ 0.17).48 More recently, Bressenot et al49 performed a retrospective study using the database of the Department of Pathology of Nancy University Hospital. All patients who underwent CD-related resection between 1996 and 2008 were analyzed. The proximal resection margin was analyzed and plexitis was evaluated by counting each cell type (mast cell, plasmocyte, lymphocyte, eosinophil, and neutrophil) in both submucosal and myenteric plexuses. The optimal cutoff value for each cell type was determined by using receiver operating characteristic analysis. Cox proportional hazards regression analysis was used to identify independent predictors of the second CD-related surgery. Sixty-seven patients were included in the study. In multivariate analysis, using Cox proportional hazards regression analysis, early surgical revision after the first ileocecal resection (HR ¼ 9.56; 95% CI, 2.02–45.19; P ¼ 0.0046), the presence of at least 1 eosinophil in the submucosal plexus (HR ¼ 8.02; 95% CI, 1.87–34.47; P ¼ 0.0054), and the presence of more than 6 lymphocytes in the submucosal plexus (HR ¼ 5.84; 95% CI, 1.23–27.65; P ¼ 0.0269) were independently associated with risk of surgical recurrence.49 Type of recurrence is discussed in Table 2. Limitations of these studies include the use of a subjective outcome measure, such as clinical recurrence and the high percentage of missing data.12,47 In the study by Sokol et al,47 because of the retrospective study design, only 61 of 171 patients had a colonoscopy for evaluating endoscopic recurrence. Furthermore, plexitis was evaluated using a semiquantitative scale12 or a priori thresholds.47 In the study of Bressenot et al,49 recurrence was defined as the need for reoperation, which is an objective outcome measure. All 3 studies12,47,49 concluded that the identification of plexitis could be performed routinely with the analysis of proximal margin with routinely staining (Hematein–Eosin–Safran) and immunostaining for lymphocytes labeling in plexus by CD3 antibody47,49 or CD45 antibody.12
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TABLE 2. Studies on Plexitis in Proximal Margin of Resection Predicting POR in CD Patients, n Ferrante et al15
Sokol et al47
59
171
Ng et al48
99
Bressenot et al49
67
Aim of the Study
Type of recurrence
Results
Value of plexitis to predict early postoperative CD recurrence
Endoscopic recurrence at 3 mo and Myenteric plexitis is significantly at 1 yr associated with postoperative CD recurrence Assessment of the predictive value of Early clinical recurrence Submucosal plexitis of $3 mastocytes plexitis for early clinical CD recurrence (reappearance of CD clinical and/or a disease-free margin ,5 cm manifestations requiring are associated with early clinical a specific treatment within 2 yr recurrence postsurgery) Assessment of risk factors for myenteric Clinical recurrence Previous resection and shorter disease plexitis, effect of plexitis on clinical duration are associated with plexitis recurrence and whether preoperative in proximal resection margin medical therapies affect the intensity of plexitis Assessment of the value of submucosal and CD recurrence needing the second Submucosal plexitis of .0 eosinophils myenteric plexis to predicting CD-related surgery and/or .6 lymphocytes in the postoperative surgical recurrence in CD proximal resection margins are predictive of the second surgery in CD
Other histological features that have been studied are summarized in Table 3 and include “lymphatic vessel density” and “morphological analysis of Paneth cells.”
Lymphatic Vessel Density in the Proximal Resection Margin Involvement of the microvasculature and vascular injury,51 together with microvasculature features,52 have been observed in inflammatory bowel disease. Involvement of the intestinal lymphatic system in CD has long been suggested. Early on, pathologists repeatedly pointed out that the microscopic appearance and distribution of lesion suggested lymphatic disease.53 The association of inflammation, granulomas, and tertiary follicles or organs with lymphatic vasculature was recently confirmed in CD.54 Rahier et al50 analyzed lymphatic vessel density of ileal proximal uninflamed section of ileocolonic resection specimens obtained from 28
patients with CD and 10 controls. Patients were divided into 2 groups based on the presence (Rutgeerts score, i3/i4) (R+) or absence (Rutgeerts score, i0/i1) (R2) of endoscopic recurrence 1 year after the surgery. Mucosal lymphatic density greater than 7% predicted the absence of endoscopic recurrence at 1 year, with a sensitivity of 81% and a specificity of 75%.50
Morphological Analysis of Paneth Cells One CD-relevant cell type is the Paneth cell, which is a specialized secretory cell type located at the bases of the crypts of Lieberkühn in the small intestine.55 These cells produce a wide repertoire of antimicrobial peptides, such as lysozyme and a-defensins, to modulate the intestinal microbiome56,57 and are important mediators of the host innate immune response.55,58 VanDussen et al performed a retrospective analysis in 119 patients with CD. Paneth cell analysis made using a previously
TABLE 3. Studies on Lymphatic Vessel Density and Morphological Analysis of Paneth Cells Predicting POR in CD Lymphatic vessel density in the proximal resection margin Rahier et al50 28 Value of lymphatic vessel density in the proximal ileal resection margin at the time of surgery Morphological analysis of Paneth cells 178 Association of specific Van Dussen et al22 phenotypes of Paneth cells with specific subtypes of CD
Endoscopic recurrence at 1 yr
Decreased lymphatic vessel density is associated with high risk of endoscopic recurrence after surgery: mucosal lymphatic vessel density greater than 7% predicted the absence of endoscopic recurrence at 1 yr
Disease recurrence
Histologic analysis of Paneth cells phenotypes can be used to divide patients with CD: high proportions of abnormal Paneth cells are associated with shorter time to disease recurrence after surgery
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developed system for robust, quantitative scoring of Paneth cell phenotype based on high-resolution localization of lysozyme protein.59 They analyzed morphology of Paneth cells on tissues section of proximal margin (terminal ileum). A high proportion of abnormal Paneth cells are defined by more than 20% of abnormal Paneth cells.22 The scoring is made from a minimum of 200 Paneth cells.22 High proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery.22
CONCLUSIONS Some histological features could predict POR in CD: active disease (inflammation of intestinal wall), plexitis, lymphatic vessel density in the proximal resection margin, and morphology of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. A therapeutic strategy based on a risk stratification of patients, with further treatment stepup and adjustment if relapse occurs on the basis of ileocolonoscopy, is recommended in clinical practice.60 Histological criteria might be used to identify patients at risk of POR when developing such preventive strategies.60 Hence, pathologists should be aware of these findings and systematically assess them in the proximal resection margin even though most of these histological features await replication in independent studies. Large prospective studies are required before systematical recommendation for adapting preventive strategies according to these histological features in CD.
ACKNOWLEDGMENTS Author contributions: A. Bressenot wrote the first draft of the article; L. Peyrin-Biroulet contributed to editing of the article and supervised the work.
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11. Rutgeerts P, Goboes K, Peeters M, et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet. 1991; 338:771–774. 12. Rosman AS, Melis M, Fichera A. Metaanalysis of trials comparing laparoscopic and open surgery for Crohn’s disease. Surg Endosc. 2005;19:1549–1555. 13. Caprilli R, Corrao G, Taddei G, et al. Prognostic factors for postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Dis Colon Rectum. 1996;39:335–341. 14. Scarpa M, Ruffolo C, Bertin E, et al. Surgical predictors of recurrence of Crohn’s disease after ileocolonic resection. Int J Colorectal Dis. 2007;22: 1061–1069. 15. Ferrante M, de Hertogh G, Hlavaty T, et al. The value of myenteric plexitis to predict early postoperative Crohn’s disease recurrence. Gastroenterology. 2006;130:1595–1606. 16. Geboes K, Rutgeerts P, Ectors N, et al. Major histocompatibility class II expression on the small intestinal nervous system in Crohn’s disease. Gastroenterology. 1992;103:439–447. 17. Geboes K, Collins S. Structural abnormalities of the nervous system in Crohn’s disease and ulcerative colitis. Neurogastroenterol Motil. 1998;10:189–202. 18. di Mola FF, Friess H, Zhu ZW, et al. Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease. Gut. 2000;46:670–679. 19. Belai A, Boulos PB, Robson T, et al. Neurochemical coding in the small intestine of patients with Crohn’s disease. Gut. 1997;40:767–774. 20. Steinkamp M, Geerling I, Seufferlein T, et al. Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells. Gastroenterology. 2003;124:1748–1757. 21. Cornet A, Savidge TC, Cabarrocas J, et al. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn’s disease? Proc Natl Acad Sci U S A. 2001;98:13306–13311. 22. VanDussen KL, Liu T-C, Li D, et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn’s disease. Gastroenterology. 2014;146:200–209. 23. Chambers TJ, Morson BC. The granuloma in Crohn’s disease. Gut. 1979; 20:269–274. 24. Mitchell DN, Rees RJ, Goswami KK. Transmissible agents from human sarcoid and Crohn’s disease tissues. Lancet. 1976;2:761–765. 25. Yamamoto T. Factors affecting recurrence after surgery for Crohn’s disease. World J Gastroenterol. 2005;11:3971–3979. 26. Heresbach D, Alexandre JL, Branger B, et al. Frequency and significance of granulomas in a cohort of incident cases of Crohn’s disease. Gut. 2005; 54:215–222. 27. Glass RE, Baker WN. Role of the granuloma in recurrent Crohn’s disease. Gut. 1976;17:75–77. 28. Anseline PF, Wlodarczyk J, Murugasu R. Presence of granulomas is associated with recurrence after surgery for Crohn’s disease: experience of a surgical unit. Br J Surg. 1997;84:78–82. 29. Simillis C, Jacovides M, Reese GE, et al. Meta-analysis of the role of granulomas in the recurrence of Crohn disease. Dis Colon Rectum. 2010; 53:177–185. 30. Denoya P, Canedo J, Berho M, et al. Granulomas in Crohn’s disease: does progression through the bowel layers affect presentation or predict recurrence? Colorectal Dis. 2011;13:1142–1147. 31. Kinchen J, Rajaratnam K, Kingston G, et al. The Presence of Microscopic Disease at the Resection Margins Predicts Post-Surgical Relapse in Crohn’s Disease. Gastroenterology. 2012;142:S-189–S-190. 32. Lindhagen T, Ekelund G, Leandoer L, et al. Recurrence rate after surgical treatment of Crohn’s disease. Scand J Gastroenterol. 1983;18: 1037–1044. 33. Shivananda S, Hordijk ML, Pena AS, et al. Crohn’s disease: risk of recurrence and reoperation in a defined population. Gut. 1989;30:990–995. 34. Kåresen R, Serch-Hanssen A, Thoresen BO, et al. Crohn’s disease: longterm results of surgical treatment. Scand J Gastroenterol. 1981;16:57–64. 35. Wolff BG, Beart RW Jr, Frydenberg HB, et al. The importance of diseasefree margins in resections for Crohn’s disease. Dis Colon Rectum. 1983; 26:239–243. 36. Chardavoyne R, Flint GW, Pollack S, et al. Factors affecting recurrence following resection for Crohn’s disease. Dis Colon Rectum. 1986;29:495–502. 37. Wettergren A, Christiansen J. Risk of recurrence and reoperation after resection for ileocolic Crohn’s disease. Scand J Gastroenterol. 1991;26: 1319–1322.
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38. Kotanagi H, Kramer K, Fazio VW, et al. Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in Crohn’s disease? Retrospective analysis of 100 cases. Dis Colon Rectum. 1991;34:909–916. 39. Fazio VW, Marchetti F, Church M, et al. Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg. 1996;224:563–571; discussion 571–573. 40. Pennington L, Hamilton SR, Bayless TM, et al. Surgical management of Crohn’s disease. Influence of disease at margin of resection. Ann Surg. 1980;192:311–318. 41. Heuman R, Boeryd B, Bolin T, et al. The influence of disease at the margin of resection on the outcome of Crohn’s disease. Br J Surg. 1983;70:519–521. 42. Hamilton SR, Reese J, Pennington L, et al. The role of resection margin frozen section in the surgical management of Crohn’s disease. Surg Gynecol Obstet. 1985;160:57–62. 43. Cooper JC, Williams NS. The influence of microscopic disease at the margin of resection on recurrence rates in Crohn’s disease. Ann R Coll Surg Engl. 1986;68:23–26. 44. Adloff M, Arnaud JP, Ollier JC. Does the histologic appearance at the margin of resection affect the postoperative recurrence rate in Crohn’s disease? Am Surg. 1987;53:543–546. 45. Kurer MA, Stamou KM, Wilson TR, et al. Early symptomatic recurrence after intestinal resection in Crohn’s disease is unpredictable. Colorectal Dis. 2007;9:567–571. 46. Heimann TM, Greenstein AJ, Lewis B, et al. Prediction of early symptomatic recurrence after intestinal resection in Crohn’s disease. Ann Surg. 1993;218:294–298; discussion 298–299. 47. Sokol H, Polin V, Lavergne-Slove A, et al. Plexitis as a predictive factor of early postoperative clinical recurrence in Crohn’s disease. Gut. 2009; 58:1218–1225.
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48. Ng SC, Lied GA, Kamm MA, et al. Predictive value and clinical significance of myenteric plexitis in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1499–1507. 49. Bressenot A, Chevaux J-B, Williet N, et al. Submucosal plexitis as a predictor of postoperative surgical recurrence in Crohn’s disease. Inflamm Bowel Dis. 2013;19:1654–1661. 50. Rahier JF, De Beauce S, Dubuquoy L, et al. Increased lymphatic vessel density and lymphangiogenesis in inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34:533–543. 51. Colombat M, Imbert A, Bruneval P, et al. Giant cell arteritis localized to the colon associated with Crohn’s disease. Histopathology. 2001;38:21–24. 52. Hamilton MI, Dick R, Crawford L, et al. Is proximal demarcation of ulcerative colitis determined by the territory of the inferior mesenteric artery? Lancet. 1995;345:688–690. 53. Van Kruiningen HJ, Colombel JF. The forgotten role of lymphangitis in Crohn’s disease. Gut. 2008;57:1–4. 54. Sura R, Colombel JF, Van Kruiningen HJ. Lymphatics, tertiary lymphoid organs and the granulomas of Crohn’s disease: an immunohistochemical study. Aliment Pharmacol Ther. 2011;33:930–939. 55. Stappenbeck TS. Paneth cell development, differentiation, and function: new molecular cues. Gastroenterology. 2009;137:30–33. 56. Salzman NH, Ghosh D, Huttner KM, et al. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature. 2003;422:522–526. 57. Salzman NH, Hung K, Haribhai D, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010;11:76–83. 58. Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. 2010;26:547–553. 59. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259–263. 60. Vuitton L, Koch S, Peyrin-Biroulet L. Preventing postoperative recurrence in Crohn’s disease: what does the future hold? Drugs. 2013;73:1749–1759.
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Histologic Features Predicting Postoperative Crohn’s Disease Recurrence Aude Bressenot, MD* and Laurent Peyrin-Biroulet, MD, PhD†
Abstract: Recurrence of Crohn’s disease (CD) after ileal or colonic resection is common. Many studies have tried to identify predictors of postoperative recurrence (POR) in CD. A wide range of histologic features have been identified, but for most of them, the literature provided conflicting data. In last years, several studies have suggested that histologic findings including inflammatory changes within the enteric nervous system of the resection margin may be associated with CD recurrence. Herein, after briefly summarizing pathophysiology of POR, we review all histological features that have been studied so far: granulomas, histologic appearance at the margin of resection, plexitis, lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. Active disease at the margin of resection, plexitis, lymphatic vessels density, morphological analysis of Paneth cells may predict POR. Most of these histological features await replication in independent studies. Available evidence indicates that histological findings may be taken into account when developing strategies aimed at preventing postoperative CD recurrence. (Inflamm Bowel Dis 2015;21:468–475) Key Words: Crohn’s disease, postoperative recurrence, histologic features
C
rohn’s disease (CD) is a chronic disabling and destructive disease.1,2 Despite increased use of immunosuppressive and anti-tumor necrosis factor treatments, approximately half of the patients require surgery within 10 years after diagnosis.2 Three years after surgery, the endoscopic postoperative recurrence (POR) rate increased to 85% to 100%, and symptomatic recurrence occurred in 34% to 86% of patients.1 Surgical resection of the diseased bowel is not curative, and POR remains a significant problem in patients with CD.1 The identification of risk factors may allow targeted strategies to reduce this recurrence rate.1 Since the original report by Crohn et al3 in 1932, many investigators have tried to identify predictors of postoperative CD recurrence. A wide range of clinical and histologic features have been identified, but for most of them, the literature provides conflicting data, partially due to the variable definitions of CD recurrence and methodological discrepancies such as the length and type of follow-up.4,5 Smoking is the strongest risk factor for POR, increasing by 2-fold, the risk of clinical recurrence.1 Previous intestinal resection, penetrating behavior, perianal disease, and extensive bowel disease (.50 cm) are established risk factors for POR.1 Received for publication July 1, 2014; Accepted August 19, 2014. From the *Department of Pathology, University Hospital of Nancy, Vandoeuvrelès-Nancy, France; and †Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France. The authors have no conflicts of interest to disclose. Reprints: Laurent Peyrin-Biroulet, MD, PhD, Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy 54500, France (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000224 Published online 27 November 2014.
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Histological features to predict POR have also been studied. These include granulomas, histologic appearance at the margin of resection, plexitis lymphatic vessel density in proximal margin of resection, and morphological analysis of Paneth cells. Herein, after reviewing pathophysiology and histologic features predicting POR, we discuss whether histological findings should guide postoperative therapeutic treatment decision in CD.
PATHOPHYSIOLOGY Pathophysiology of POR after ileocecal resection is poorly understood. CD is a heterogeneous disorder caused by a complex interplay of microbial, environmental, immunological, and genetic variables. It seems probable that the same factors which underlie the pathogenesis of CD at its early stages also contribute to recurrence in the postoperative setting.6
Animal Data Understanding of the POR along with effective preventive measures has been limited making an animal model of POR a desirable and essential tool. The model of ileocecal resection in IL-102/2 mice provide a new method to research the postsurgical inflammation and fibrosis in the small intestine and anastomosis.7 Borowiec et al examined the bacterial, local, and systemic immune changes that follow ileocolonic anastomosis in the IL-102/2 mice: ileocolonic anastomosis leads to bacterial changes in the terminal ileum. In the genetically susceptible host, it is associated with small bowel fibrosis and systemic immune alterations with significantly increased interferon gamma secretion by bacterial antigen-stimulated splenocytes and a decreased number of CD11+ cells.8 Inflamm Bowel Dis Volume 21, Number 2, February 2015
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Human Data The site of recurrence in most patients after ileocolonic resection is at the anastomosis and extends into the proximal neoterminal ileum.9 It has been postulated that ileocecal resection removes the ileocecal valve, permitting free reflux of colic contents into the neoterminal ileum, thereby changing the bacterial flora within this region of the small bowel.10,11 D’Haens et al10 studied the effects of intestinal luminal contents into excluded ileum in 3 patients with CD who had undergone a curative ileocolonic resection with ileocolonic anastomosis and temporary protective proximal loop ileostomy by histology and electron microscopy: intestinal contents trigger POR of CD in the terminal ileum proximal to the ileocolonic anastomosis in the first days after surgery. To investigate the importance of fecal stream in the pathogenesis of POR in CD, Rutgeerts et al studied 5 patients with CD who had ileal resection. After curative resection and ileocolonic anastomosis, a diverting terminal ileostomy was constructed 25 to 35 cm proximal to the anastomosis thereby excluding the neoterminal ileum, the anastomosis, and the colon from intestinal transit. After 6 months of exclusion, endoscopy of the ileocolon was undertaken and biopsy specimens were taken. Transit was then restored. Six months after reanastomosis, further biopsy specimens were taken. All 5 patients had recurrence of disease, both endoscopically and histologically, at ileocolonoscopy 6 months after reanastomosis. These findings strongly support the view that recurrence of CD in the neoterminal ileum after curative ileal resection is dependent on fecal stream.11 The influence of surgical parameters has been studied in a meta-analysis: there was a trend to a lower number of POR rates in the laparoscopy group, but this technique requires further study in CD to assess whether it may reduce POR.12 Caprilli et al13 showed that patients who have had a resection with end-to-end anastomosis compared with those who have had a resection and other types of anastomosis have a higher risk of recurrence. Scarpa et al14 reported that side-toside anastomosis decreases the clinical POR when compared with end-to-side anastomosis. This may be explained by the wider lumen in the former technique with advantages of delayed anastomotic stenosis, decreased fecal stasis and reduced secondary ischemia.14 The finding that recurrence always takes place in the previously healthy ileum, proximally to the ileocolonic anastomosis, has raised a number of hypotheses regarding the mechanism behind this phenomenon.15 One of the most attractive suggestions has focused on the enteric nervous system.16 This independent well-organized system may provide a pathway along which inflammation could spread proximally.15 Few studies have examined the possible relationship between neuronal inflammation and the development of postoperative CD recurrence. However, many investigators have described changes in neuropeptides in inflamed inflammatory bowel disease tissue, suggesting an inflammatory effect on the enteric nervous system. The precise pathologic role of alterations in 5-hydroxytryptamine,
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neuropeptide Y, glial-derived neurotrophic factor, nerve growth factor, glial fibrillary acidic protein, nitric oxide, and pituitary adenylate cyclase activation peptide localized in the neuronal plexuses of patients with CD remains to be elucidated.17–21 Other factors are incriminated; Vandussen et al showed that high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. The disordered and diffuse abnormal Paneth cell phenotypes are associated with an altered transcriptional signature of immune system activation: the proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles.22
HISTOLOGIC FEATURES PREDICTING POSTOPERATIVE CD RECURRENCE These histological features are summarized in Figure 1.
Granulomas The significance of the granuloma in CD is not clear.23 It is generally assumed to represent a response to the etiological agent.23,24 There are contradictory reports in the literature regarding the impact of identifiable granulomas in the resection specimen on the recurrence.25 Although interobserver agreement for epithelioid granulomas is good, occurrence rates of epithelioid granulomas findings vary across studies, probably as a result of differences in sampling and serial sectioning method.26 In a German referral center of 100 consecutive patients undergoing isolated ileocecal resection for CD, granulomas showed no significant influence on the POR rates,23,27 whereas among 130 patients operated on for CD in Australia, the association of granulomas with recurrence remained significant (P ¼ 0.03).28 In a meta-analysis by Simillis et al,29 comparative studies published between 1954 and 2007 of granulomatous versus nongranulomatous CD were included: granulomatous CD seems to be associated with higher number of recurrences and reoperations and a shorter time to recurrence and reoperation compared with nongranulomatous CD. The number of granulomas found in resected specimen did not influence POR rate.23,30 The role of the granulomas (epithelioid granuloma, isolated giant cells, or microgranulomas) in predicting POR is unknown. VanDussen et al22 showed that abnormal Paneth cell phenotype inversely correlates with granuloma incidence and that high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Because of significant heterogeneity between studies, further studies should be undertaken to confirm these findings.29 Overall, these findings await replication by independent groups.
Histologic Appearance at the Margin of Resection The surgical techniques used in the treatment of CD share a common origin with those used in the resection of gastrointestinal malignancies.31 Several reports have reported that the wide resection of normal bowel uninvolved microscopically www.ibdjournal.org |
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FIGURE 1. Summary of histological features that have been studied for predicting POR in CD. A, Active inflammation in lamina propria (HES ·400). B, Granuloma (HES ·400). C, Chronic inflammation in lamina propria (HES ·100). D, Paneth cells in ileal crypt (HES ·200). E, Lymphatic vessels in submucosae (HES ·200). F, Submucosae plexitis (HES ·400). G, Myenteric plexitis (lymphocyte labeling with CD3 antibody ·400). HES, Hematein– Eosin–Safran.
(radical resection) was associated with a lower recurrence rate than nonradical resection.32–35 However, many studies have shown no difference in the recurrence rates between patients with radical resection and nonradical resection.28,36–39 A large number of published case series and retrospective studies over 50 years (Table 1) have failed to demonstrate a consistent relationship between marginal involvement and recurrence,32,34,35,38,40,41,43,45 despite a number showing an apparent benefit from a disease-free anastomosis.32,34,35,46 Surgical interventions aimed at increasing the likelihood of a disease-free anastomosis have been investigated. A randomized controlled trial demonstrated that extended resection, taking 10 cm of macroscopically healthy proximal ileum, had no benefit over limited resection, where a 2-cm proximal margin was taken, in delaying the need for further surgery.39 The use of frozen-section techniques to provide a rapid histological assessment of disease activity in macroscopically normal bowel and guide the extent of resection has also failed to demonstrate improved outcomes.42 Additionally, there was a poor correlation between the interpretation of frozen sections and permanent sections in this context. More recently, Kinchen et al analyzed 237 bowel resections from patients with CD. They demonstrated that the presence of histologically active disease at the resection margins defined by the presence of acute (neutrophilic) or granulomatous inflammation predicts postsurgical relapse in CD.31 More recently, other histologic criteria have been studied on ileal resection specimen. These studies are summarized in Table 2.
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Plexitis in Proximal Margin of Resection A remarkable pathologic observation is the presence of inflammatory infiltrates associated with both the submucosal and myenteric plexus of patients with CD.16 It remained unknown whether the changes of the enteric nervous system are primary or secondary to inflammation, but the occurrence of lesion in macroscopically uninvolved areas may suggest that they precede mucosal inflammation.16 In last years, several studies have suggested that inflammatory changes within the enteric nervous system of the resection margin could be associated with CD recurrence. The main studies are resumed in Table 2. In a retrospective study, Ferrante et al scored histologically 59 ileocolonic resection specimens from 59 patients 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. Myenteric plexitis was defined by the presence of 1 or several inflammatory cells (lymphocytes, plasmocytes, eosinophils, mast cells) appositioned to or within an enteric ganglion or nerve bundle.15 They demonstrated that inflammatory activity within the myenteric plexitis was significantly associated with postoperative CD recurrence: patients with myenteric plexitis of the proximal resection margin had a higher endoscopic recurrence rate at 3 months (P ¼ 0.008) and at 1 year (P ¼ 0.041).15 In 2009, Sokol et al47 analyzed all consecutive ileocolonic or ileal resection specimens from patients operated for active CD in Lariboisière Hospital (Paris) between 1995 and 2006. Early clinical
Patients, n
Aim of the Study
Type of Recurrence
Studies showing no relationship between histologic appearance at the resection margin and POR Pennington et al40 97 Determination of the influence of Need to resume or increase specific microscopic disease at an anti-inflammatory medication to anastomosis after intestinal control symptoms resection for CD Heuman et al41
67
Hamilton et al42
79
Cooper and Williams43 Adloff et al44
142
58
Kotanagi et al38
100
Fazio et al39
152
Kurer et al45
60
Influence of disease at the margin of resection on the outcome of CD The role of resection margin frozen section in the surgical management of CD
Clinical recurrence
Influence of microscopic disease at the margin of resection on POR in CD Does histologic appearance at the margin of resection affect the POR rate in CD? Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in CD? Assessment of the effect of surgical margin width on POR in CD
Clinical symptoms confirmed by radiological or histological evidence
Clinical recurrence and reoperation
Recurrence within 3 yr
Anastomotic recurrence
Reoperation for recurrent preanastomotic disease
Recommendation for conservative resections for CD: presence or absence of microscopic disease at the anastomosis did not appear to influence POR rates Microscopical involvement does not seem to increase the recurrence rate The findings support conservative resection to achieve grossly uninvolved margins rather than the sacrifice of functional intestine Presence of microscopic disease at the resection margin does not affect recurrence in CD No evidence for adverse influence of residual microscopic disease at the margins of resection Anastomotic recurrence was not associated with any clinical or histological feature or combination of features POR is unaffected by the width of the margin of resection from macroscopically involved bowel. Recurrence rates do not increase when microscopic CD is present at the resection margin Early symptomatic POR of CD remains unpredictable
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The recurrence rates were much lower (14%) when the margins of the resected intestine were free of disease than when microscopic signs of the disease were present (66%)
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Identify predictors of early Symptomatic disease at 36 mo symptomatic recurrence of CD confirmed histologically after after surgical resection surgery or endoscopy and biopsy or (involvement of resection by radiological evidence of new margin.) mucosal ulceration and/or strictures Studies showing a relationship between histologic appearance at the resection margin and POR 59 Long-term results of surgical Kåresen et al34 treatment
Results
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TABLE 1. Studies on the Relationship Between Histologic Appearance at the Margin of Resection and Postoperative Recurrence in CD
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Histopathological appearance of the resection margins seemed to influence the prognosis, since the presence of ulcers and/or granulomas was correlated with significantly increased recurrence rate The presence of active disease at the resection margin is associated with repeat resection within 5 yr
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Repeat bowel resection with histological confirmation of active CD Re-examination of potential risk of active disease at the resection margin on POR 237
Studies showing a relationship between active disease at the resection margin and POR 207 Features that influence recurrence Lindhagen et al32 after surgical resection of all macroscopically involved bowel
Kinchen et al31
Patients with extensive CD requiring multiple resections with anastomosis, especially when microscopic inflammation is present at the margin, are at very high risk for symptomatic early recurrence Symptomatic recurrent disease within 36 mo Prediction of early symptomatic POR (number of anastomoses, inflammation at the resection margin) 164 Heimann et al46
TABLE 1 (Continued)
Patients, n
Aim of the Study
Type of Recurrence
Results
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recurrence was defined as the reappearance of CD clinical manifestations requiring a specific treatment within 2 years postsurgery. The proximal resection margin was analyzed. Data were available from 171 postoperative follow-up periods in 164 patients with CD. Early clinical recurrence of CD occurred in 28.1%. In multivariate analysis, factors associated with POR were active smoking (hazard ratio [HR] ¼ 1.94; 95% confidence interval [CI], 1.06–3.60; P ¼ 0.033), submucosal plexitis with $3 mastocytes (HR ¼ 1.87; 95% CI, 1.00–3.46; P ¼ 0.048), and a disease-free resection margin ,5 cm (HR ¼ 0.52; 95% CI, 0.27–1.02; P ¼ 0.059).47 In contrast at St Mark’s Hospital, London, the difference of clinical postoperative CD recurrence between patients with or without plexitis in the proximal resection margin did not reach clinical significance: ileocolonic resection specimens from 99 patients with CD were histologically scored for the presence and severity of plexitis. Myenteric plexitis was correlated with immunosuppressive therapy before index surgery.48 Univariate and multivariate analyses were performed to identify predictive factors for plexitis. Preoperative immunosuppressive therapy was not associated with a lesser incidence of plexitis. Twelve of 40 patients (30%) with plexitis and 9 of 54 patients (16%) without plexitis in the proximal resection margin subsequently developed clinical recurrence (median, 10 mo; P ¼ 0.17).48 More recently, Bressenot et al49 performed a retrospective study using the database of the Department of Pathology of Nancy University Hospital. All patients who underwent CD-related resection between 1996 and 2008 were analyzed. The proximal resection margin was analyzed and plexitis was evaluated by counting each cell type (mast cell, plasmocyte, lymphocyte, eosinophil, and neutrophil) in both submucosal and myenteric plexuses. The optimal cutoff value for each cell type was determined by using receiver operating characteristic analysis. Cox proportional hazards regression analysis was used to identify independent predictors of the second CD-related surgery. Sixty-seven patients were included in the study. In multivariate analysis, using Cox proportional hazards regression analysis, early surgical revision after the first ileocecal resection (HR ¼ 9.56; 95% CI, 2.02–45.19; P ¼ 0.0046), the presence of at least 1 eosinophil in the submucosal plexus (HR ¼ 8.02; 95% CI, 1.87–34.47; P ¼ 0.0054), and the presence of more than 6 lymphocytes in the submucosal plexus (HR ¼ 5.84; 95% CI, 1.23–27.65; P ¼ 0.0269) were independently associated with risk of surgical recurrence.49 Type of recurrence is discussed in Table 2. Limitations of these studies include the use of a subjective outcome measure, such as clinical recurrence and the high percentage of missing data.12,47 In the study by Sokol et al,47 because of the retrospective study design, only 61 of 171 patients had a colonoscopy for evaluating endoscopic recurrence. Furthermore, plexitis was evaluated using a semiquantitative scale12 or a priori thresholds.47 In the study of Bressenot et al,49 recurrence was defined as the need for reoperation, which is an objective outcome measure. All 3 studies12,47,49 concluded that the identification of plexitis could be performed routinely with the analysis of proximal margin with routinely staining (Hematein–Eosin–Safran) and immunostaining for lymphocytes labeling in plexus by CD3 antibody47,49 or CD45 antibody.12
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TABLE 2. Studies on Plexitis in Proximal Margin of Resection Predicting POR in CD Patients, n Ferrante et al15
Sokol et al47
59
171
Ng et al48
99
Bressenot et al49
67
Aim of the Study
Type of recurrence
Results
Value of plexitis to predict early postoperative CD recurrence
Endoscopic recurrence at 3 mo and Myenteric plexitis is significantly at 1 yr associated with postoperative CD recurrence Assessment of the predictive value of Early clinical recurrence Submucosal plexitis of $3 mastocytes plexitis for early clinical CD recurrence (reappearance of CD clinical and/or a disease-free margin ,5 cm manifestations requiring are associated with early clinical a specific treatment within 2 yr recurrence postsurgery) Assessment of risk factors for myenteric Clinical recurrence Previous resection and shorter disease plexitis, effect of plexitis on clinical duration are associated with plexitis recurrence and whether preoperative in proximal resection margin medical therapies affect the intensity of plexitis Assessment of the value of submucosal and CD recurrence needing the second Submucosal plexitis of .0 eosinophils myenteric plexis to predicting CD-related surgery and/or .6 lymphocytes in the postoperative surgical recurrence in CD proximal resection margins are predictive of the second surgery in CD
Other histological features that have been studied are summarized in Table 3 and include “lymphatic vessel density” and “morphological analysis of Paneth cells.”
Lymphatic Vessel Density in the Proximal Resection Margin Involvement of the microvasculature and vascular injury,51 together with microvasculature features,52 have been observed in inflammatory bowel disease. Involvement of the intestinal lymphatic system in CD has long been suggested. Early on, pathologists repeatedly pointed out that the microscopic appearance and distribution of lesion suggested lymphatic disease.53 The association of inflammation, granulomas, and tertiary follicles or organs with lymphatic vasculature was recently confirmed in CD.54 Rahier et al50 analyzed lymphatic vessel density of ileal proximal uninflamed section of ileocolonic resection specimens obtained from 28
patients with CD and 10 controls. Patients were divided into 2 groups based on the presence (Rutgeerts score, i3/i4) (R+) or absence (Rutgeerts score, i0/i1) (R2) of endoscopic recurrence 1 year after the surgery. Mucosal lymphatic density greater than 7% predicted the absence of endoscopic recurrence at 1 year, with a sensitivity of 81% and a specificity of 75%.50
Morphological Analysis of Paneth Cells One CD-relevant cell type is the Paneth cell, which is a specialized secretory cell type located at the bases of the crypts of Lieberkühn in the small intestine.55 These cells produce a wide repertoire of antimicrobial peptides, such as lysozyme and a-defensins, to modulate the intestinal microbiome56,57 and are important mediators of the host innate immune response.55,58 VanDussen et al performed a retrospective analysis in 119 patients with CD. Paneth cell analysis made using a previously
TABLE 3. Studies on Lymphatic Vessel Density and Morphological Analysis of Paneth Cells Predicting POR in CD Lymphatic vessel density in the proximal resection margin Rahier et al50 28 Value of lymphatic vessel density in the proximal ileal resection margin at the time of surgery Morphological analysis of Paneth cells 178 Association of specific Van Dussen et al22 phenotypes of Paneth cells with specific subtypes of CD
Endoscopic recurrence at 1 yr
Decreased lymphatic vessel density is associated with high risk of endoscopic recurrence after surgery: mucosal lymphatic vessel density greater than 7% predicted the absence of endoscopic recurrence at 1 yr
Disease recurrence
Histologic analysis of Paneth cells phenotypes can be used to divide patients with CD: high proportions of abnormal Paneth cells are associated with shorter time to disease recurrence after surgery
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developed system for robust, quantitative scoring of Paneth cell phenotype based on high-resolution localization of lysozyme protein.59 They analyzed morphology of Paneth cells on tissues section of proximal margin (terminal ileum). A high proportion of abnormal Paneth cells are defined by more than 20% of abnormal Paneth cells.22 The scoring is made from a minimum of 200 Paneth cells.22 High proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery.22
CONCLUSIONS Some histological features could predict POR in CD: active disease (inflammation of intestinal wall), plexitis, lymphatic vessel density in the proximal resection margin, and morphology of Paneth cells. Granulomas and chronic inflammation at the margin of resection do not seem to predict POR in CD. A therapeutic strategy based on a risk stratification of patients, with further treatment stepup and adjustment if relapse occurs on the basis of ileocolonoscopy, is recommended in clinical practice.60 Histological criteria might be used to identify patients at risk of POR when developing such preventive strategies.60 Hence, pathologists should be aware of these findings and systematically assess them in the proximal resection margin even though most of these histological features await replication in independent studies. Large prospective studies are required before systematical recommendation for adapting preventive strategies according to these histological features in CD.
ACKNOWLEDGMENTS Author contributions: A. Bressenot wrote the first draft of the article; L. Peyrin-Biroulet contributed to editing of the article and supervised the work.
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