Cord colitis syndrome (CCS) is a recently proposed clinical entity characterized by a persistent diarrheal illness after cord blood transplantation (CBT), which is not caused by GVHD or CMV colitis. CCS is histologically characterized by chronic active colitis with granulomatous inflammation and Paneth cell metaplasia suggesting chronicity. However, the specificity of these pathological features to CCS remains to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with biopsy following allogeneic hematopoietic SCT. None of the patients met the clinical criteria for CCS. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was present in 12/33 (36%) patients with biopsy-proven GVHD, 4/6 (67%) patients with CMV colitis and 2/15 (13%) patients with nonspecific colitis. In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients after CBT and in 11/26 (42%) patients undergoing BMT or PBSCT. These results demonstrate that chronic active colitis with granuloma and Paneth cell metaplasia is not only a specific feature of CCS but also is present in GVHD and CMV colitis, irrespective of stem cell source.
Allogeneic hematopoietic SCT is a potentially curative therapy for various hematologic malignant and non-malignant disorders. Acute GVHD, a donor T-cell-mediated systemic inflammatory condition, remains a major obstacle for wider application of this therapy. A profuse watery diarrhea or hemorrhagic diarrhea after engraftment is a significant cause of illness in patients undergoing allogeneic SCT and is most likely due to acute GVHD and intestinal infection such as CMV colitis.1
Cord blood transplantation (CBT) has been increasingly performed as an alternative to BMT or PBSCT.2, 3, 4, 5 The major advantages of using cord blood (CB) over BM or PBSC include its rapid availability and the requirement for a less stringent criterion for HLA matching between the donor and recipient.5, 6 Recently, Herrera et al.7 proposed a new clinical entity of culture-negative, antibiotic-responsive diarrhea not attributable to any known cause following CBT. This syndrome, designated as cord colitis syndrome (CCS), is histologically characterized by chronic active colitis with granulomatous inflammation and/or Paneth cell metaplasia. However, the specificity of these pathological features to CCS needs to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with a biopsy procedure following allogeneic SCT. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was frequently observed in acute GVHD and CMV colitis after allogeneic SCT, irrespective of stem cell source; this indicates that these were not histological hallmarks of CCS.
Materials and methods
A total of 224 patients underwent allogeneic SCT at Kyushu University Hospital between February 2005 and November 2011. We identified 49 consecutive patients who suffered from diarrhea and underwent diagnostic colonoscopy and biopsy procedure and reviewed their medical records and histology slides. This study was approved by the institutional review board.
Definition of CCS, GVHD and CMV colitis
CCS was defined as a persistent diarrheal illness (duration, >7 days) that occurred following CBT and was not caused by acute GVHD, bacterial (including Clostridium difficile) or viral infection, post-transplant lymphoproliferative disease or another identifiable cause on microbiological and histopathological examination.7 Acute GVHD was diagnosed clinically with histological confirmation on the basis of previously published criteria.8 Pathologically, crypt cell apoptosis or single-cell necrosis with karyorrhectic debris is the most useful marker of acute intestinal GVHD.9, 10 Intranuclear inclusion bodies and eosinophilic cytoplasmic inclusions in epithelial, endothelial and stromal cells are diagnostic for CMV colitis.11 Acute GVHD graded according to the standard criteria was defined as moderate to severe (grades II–IV) disease.8
For histopathological analysis, biopsy samples were fixed in 10% neutral-buffered formalin, embedded in paraffin, sectioned, slide-mounted and stained with hematoxylin and eosin. CMV colitis was examined histologically and immunochemically.12 All samples were reviewed by three pathologists. Pictures from tissue sections were recorded at room temperature using a digital camera (DP72; Olympus, Tokyo, Japan) mounted on a microscope (BX51; Olympus).
A P-value <0.05 was considered statistically significant. Fisher’s exact test and logistic regression analysis was performed using STATA version 8 (STATA Corp., College Station, TX, USA).
In all, 49 patients underwent intestinal endoscopy and biopsy procedures. The patient characteristics are listed in Table 1. Primary diseases included myelodysplastic syndrome/acute myelogenous leukemia (n=19), CML (n=1), ALL (n=6), malignant lymphoma (n=11), adult T-cell leukemia/lymphoma (n=9), plasma cell leukemia (n=1), aplastic anemia (n=1) and primary myelofibrosis (n=1). A total of 21 patients had received conventional preparative regimens comprising either TBI/Cy (n=16) or Bu/Cy (n=6). The remaining 27 cases had received purine analog-based reduced-intensity conditioning regimen comprising either fludarabine (Flu)/Cy (n=2), Flu/Bu (n=12) or Flu/melphalan (n=13). Low-dose TBI (2–4 Gy), antithymocyte globulin and alemutuzumab were administered in 20, 4, and 1 patient, respectively. The sources of stem cells were related PBSCs (n=14), related BM (n=3), unrelated BM (n=22) or unrelated CB (n=10). HLA-matching varied from haploidentical (3/6) to identical (6/6). In all, 17 patients received a cyclosporine-based regimen, and 32 received a tacrolimus-based regimen for GVHD prophylaxis. Moreover, 35 patients received MTX therapy, six received mycophenolate mofetil (MMF) therapy and four received antithymocyte globulin therapy.
We reviewed the medical records and confirmed that the pathological and clinical diagnoses coincided in all patients. The median day of biopsy was 50 days after HSCT (range, 15–506 days).
Neutrophilic granulomas (Figure 1a) were present in 17/28 (61%), 1/1 (100%), 4/5 (80%) and 4/15 (27%) biopsy specimens that were diagnosed as GVHD, CMV colitis, GVHD plus CMV colitis and nonspecific colitis, respectively (Table 2). Paneth cells were morphologically identified by the presence of cytoplasmic eosinophilic granules in hematoxylin- and eosin-stained sections. Paneth cell metaplasia (Figure 1b) was present in 7/28 (25%), 1/1 (100%), 3/5 (60%) and 1/15 (7%) biopsy specimens that were diagnosed as GVHD, CMV colitis, GVHD plus CMV colitis and nonspecific colitis, respectively. Chronic active colitis is histologically characterized by crypt architectural distortion and lymphoplasmacytic infiltrate deep into the crypts.13 Chronic active colitis with neutrophilic granuloma and/or Paneth cell metaplasia, a hallmark of CCS,7 was observed in 9/28 (32%), 1/1 (100%), 3/5 (60%) and 2/15 (13%) biopsy specimens that were diagnosed as GVHD, CMV colitis, GVHD plus CMV colitis and nonspecific colitis, respectively. There is a trend toward more frequent presence of chronic active colitis in patients with GVHD and/or CMV colitis than those with nonspecific colitis (16/39 vs 2/15, P=0.099).
In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients undergoing CBT and in 11/26 (42%) patients undergoing BMT or PBSCT (Table 3). There are no significant differences in the incidence of the chronic active colitis between stem cell sources.
CCS is a recently proposed diarrheal illness that affects recipients of CBT.7 It is important to distinguish this new syndrome from other causes of diarrheal illness that have a similar presentation, in particular GVHD and CMV colitis, because treatment strategies differ a lot between these conditions. Gut biopsies have an important diagnostic role in patients with diarrhea after allogeneic SCT. The histopathological hallmark of CCS is reported to be chronic active colitis associated with neutrophilic granulomas and/or Paneth cell metaplasia, which indicates chronicity of the lesion.13 Herrera et al.7 described that these features were not observed in GVHD or other diarrheal illness after any type of allogeneic SCT. In our study, these features were present in a substantial proportion of patients with GVHD and CMV colitis.
Furthermore, Herrera et al.7 also documented that only 1 patient had histological findings of CCS out of 381 patients who underwent a biopsy in recipients of BMT or PBSCT. Our study clearly confirmed that chronic active colitis with granulomas and/or Paneth cell metaplasia were frequently observed in specimens from patients with acute GVHD and CMV colitis following BMT or PBSCT.
In addition, we found that Paneth cell metaplasia was present in the colon of patients with GVHD or CMV colitis as well. Paneth cells are abundant in the ileum but are occasionally present in the colon of the elderly and some patients with inflammatory bowel diseases (Paneth cell metaplasia).14, 15, 16, 17 Paneth cell metaplasia was observed in affected mucosa but not in unaffected mucosa in these patients and caused by various types of inflammation, suggesting that it occurs nonspecifically in response to chronic inflammation.16, 18 Paneth cells regulate the composition of colonized microbes in the intestine and protect epithelial cells from bacterial invasion.19, 20 We recently demonstrated that Paneth cells are targeted by GVHD, resulting in a subsequent alteration in the intestinal flora.21, 22 Other groups have also demonstrated a dramatic alteration in intestinal microbiota in GVHD, both in mice and in humans.23, 24, 25 Metaplastic Paneth cells can express α-defensins,17, 26 and therefore Paneth cell metaplasia may be a compensatory mechanism for reduced number of Paneth cells in the small intestine and subsequent alteration of the intestinal microbiota. Paneth cell metaplasia is also observed in chronic gastritis in association with Helicobacter pylori infection, suggesting a natural mechanism of adaptation aimed to eradicate bacteria in acid-deficient stomachs.27, 28
MMF is an immunosuppressive agent used for prophylaxis and treatment of GVHD in allogeneic SCT. Diarrhea is a commonly seen side effect of MMF. Selbst et al.29 reported that Paneth cell metaplasia is frequently observed in biopsy specimens from patients with MMF-induced colitis following solid organ transplantation and that the histological changes mimic inflammatory bowel disease or GVHD. In our study, Paneth cell metaplasia was present in three patients receiving MMF therapy and in nine patients not receiving MMF therapy.
These results must be interpreted within the context of study limitations. Our study and the study by Herrera et al.7 lack healthy controls and infectious colitis other than CMV colitis. Biopsy sites may also influence the incidence of Paneth cell metaplasia. Paneth cell metaplasia is occasionally seen in elderly individuals.30 It is more frequently observed at the ascending colon and cecum than at distal sites of elderly individuals and in affected mucosa than in healthy mucosa in patients with inflammatory bowel diseases.16 Nevertheless, our results indicate that the presence of chronic active colitis with granuloma and/or Paneth cell metaplasia is not a specific feature of CCS. Prospective studies of the larger numbers of patients including, particularly, CBT patients are required to evaluate the incidence of chronic active colitis with granuloma and/or Paneth cell metaplasia in CCS, GVHD and other infectious colitis.
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This study was supported by JSPS KAKENHI (21390295 to TT), Health and Labor Science Research Grants (TT) and a grant from Yakult Bio-Science Foundation (Tokyo, Japan) (to TT).
The authors declare no conflict of interest.
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Shimoji, S., Kato, K., Eriguchi, Y. et al. Evaluating the association between histological manifestations of cord colitis syndrome with GVHD. Bone Marrow Transplant 48, 1249–1252 (2013) doi:10.1038/bmt.2013.44
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