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collagenous colitis in inflammatory bowel disease
Journal Pre-proof Clinicopathological significance of lymphocytic collagenous colitis in inflammatory bowel disease
colitis/
Lin Yuan, Tsung-Teh Wu, Vishal Chandan, Yajue Huang, Lizhi Zhang PII:
S0046-8177(19)30193-5
DOI:
https://doi.org/10.1016/j.humpath.2019.09.014
Reference:
YHUPA 4941
To appear in:
Human Pathology
Received date:
8 August 2019
Revised date:
10 September 2019
Accepted date:
11 September 2019
Please cite this article as: L. Yuan, T.-T. Wu, V. Chandan, et al., Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease, Human Pathology(2019), https://doi.org/10.1016/j.humpath.2019.09.014
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© 2019 Published by Elsevier.
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Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease Lin Yuan1, Tsung-Teh Wu2, Vishal Chandan3, Yajue Huang2, and Lizhi Zhang2* Pathology Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, China1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN,
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USA2
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Department of Pathology, University of California, Irvine Medical Center, Irvine, CA,
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USA3
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* Corresponding author:
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Lizhi Zhang, MD
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Mayo Clinic, Division of Anatomic Pathology Hilton 11, 200 1st St. SW
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Rochester, MN, 55905
Email: [email protected] Phone: 1-507-293-1393 FAX: 1-507-284-1599
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Abstract Patients with inflammatory bowel disease (IBD) may occasionally present with lymphocytic colitis/collagenous colitis (LC/CC) either before or after the onset of IBD. Although a few reports have described a small number of such cases, the relationship between these two disorders is still unclear. We evaluated 27 patients
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with diagnosis of either ulcerative colitis (UC) or Crohn’s disease (CD) and LC/CC. Clinical, endoscopic, and pathological features were reviewed. 10 patients with initial
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diagnoses of LC (n=2)/CC (n=8) evolved into UC (n=7) or CD (n=3) after a median
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interval of 14 months (range, 2-44 months). Among these, 4 patients with LC/CC
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evolving into IBD also had recurrent CC in a quiescent phase of IBD. Seventeen
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patients with initial diagnosis of UC (n=11) or CD (n=6) developed LC (n=6)/CC
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(n=11) after a median interval of 108 months (range, 15-548 months). IBD patients with initial presentation of LC/CC were significantly older than those who developed
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LC/CC after onset of IBD (66.5 vs.34.0 years old, p=0.001). The interval time between LC/CC to IBD was significantly shorter than that of IBD to LC/CC (14 vs. 108 months, p=0.007). Quiescent UC with superimposed CC was the most common pattern (n=8). Patients with CD had shorter interval time to develop LC/CC than UC patients, although it was not statistically significant (60.5 vs. 139 months, p=0.14). Endoscopically, most of patients started with LC/CC had unremarkable findings, but 11 of 17 patients who developed LC/CC after IBD showed quiescent chronic colitis. Histologically, LC/CC patients with diagnosis of IBD, either before or after, more frequently show active inflammation. Chronicity was more commonly 2
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seen in biopsy of LC/CC patients with a history of IBD. Our study found that IBD patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time and frequent active inflammation in initial LC/CC. These findings suggest that LC/CC maybe a spectrum of IBD as the initial presentation in a subset of older IBD patients. On the other hand, IBD patients can develop LC/CC associated
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with chronic mucosal injury many years after the onset of IBD (typically with >10 years interval time while patients are in remission phase), for which these two
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processes seem unrelated to each other.
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Key Words: Lymphocytic colitis, Collagenous colitis, Microscopic colitis,
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inflammatory bowel disease, Crohn’s disease, Ulcerative colitis
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INTRODUCTION Lymphocytic colitis (LC) and collagenous colitis (CC) are two main forms of microscopic colitis (MC), which are different from inflammatory bowel disease (IBD) in epidemiology, etiology, clinical presentation, endoscopic appearance, and pathological features. IBD consists of two different diseases, ulcerative colitis (UC)
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and Crohn’s disease (CD), and it is relatively well defined since it was initially described in the latter half of the 19th century (1). UC and CD usually have an early
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onset at 20~40 years old, although there is a second peak incidence among
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middle-aged men (2, 3). The typical clinical symptoms of UC and CD are bloody
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diarrhea, rectal bleeding, abdominal pain, fever, and weight loss, which vary with
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different phase and extent of disease progression. Endoscopically, UC and CD present
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diffuse inflammation and ulcerations in active phase, and quiescent colitis and scars in inactive phase. The classic microscopic finding is chronic active colitis with ulcers
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and crypt architecture distortion, and non-necrotizing granulomas in CD. On the other hand, LC and CC are relatively newly described entities in late 20th century (4, 5). LC/CC is more commonly seen in older females, with a rate peak in the sixth or seventh decade of life (6). Patients with LC and CC most commonly present with chronic watery diarrhea clinically, with normal or almost normal colonoscopy. The hallmark feature of LC is increased surface and crypt lymphocytes, and thickened subepithelial collagen band in CC. Although there are some case reports that have described patients with LC/CC evolving into UC/CD later in life, or vice versa (7-30), the correlation between 4
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LC/CC and IBD has not been well defined, and the histologic features of these patients in either LC/CC or IBD have seldom been described in detail. In this study, we sought to describe the clinical and pathological features in patients with LC/CC either before or after onset of IBD, and to evaluate the clinicopathological significance of LC/CC in IBD.
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MATERIALS AND METHODS Study population
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Patients with both established diagnosis of IBD and LC/CC between 1988 and 2018
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were identified from the surgical pathology files at the Mayo Clinic, Rochester, MN.
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Clinical information including patients’ age at first diagnosis, gender, history, initial
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and second symptoms (including extraintestinal manifestations), treatment, and follow
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up information were collected by reviewing the patients’ clinical charts. Endoscopic reports were also reviewed. The features such as extent of the disease, erythema,
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edema, friability, granularity, an abnormal vascular pattern, and frank ulcerations were recorded, which were recognized as abnormal findings for LC/CC patients. The study was approved by the Mayo Clinic Rochester Institutional Review Board. Histologic analysis All slides of biopsy specimens were reviewed by two pathologists (Y.L and L.Z), and the original diagnoses were confirmed. The histological diagnostic criteria for LC is defined as increased intraepithelial lymphocytes (IELs, >20 per 100 surface epithelial cells) in a normal/near normal architecture mucosa, accompanied with surface epithelial injury and increased lamina propria mixed mononuclear cell infiltrates. For 5
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collagenous colitis, a thickened subepithelial collagen band was present accompanied with other morphologic characteristics seen in LC, although maybe with less prominent IELs. The diagnosis of UC or CD was confirmed by histology in conjunction with clinical, endoscopic, and radiologic findings. Histologic features were evaluated in detail on the hematoxylin and eosin
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(H&E)-stained slides, including: 1) surface epithelial injury, including epithelial degeneration, mucin depletion, cytoplasmic hypereosinophilia, and epithelial
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flattening; 2) IELs, including the presence of intraepithelial lymphocytes in surface
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and crypts (recorded as the number per 100 epithelial cells, n/100 ECs, at the area
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with the most prominent infiltrate), and IELs >20/100 ECs was considered as
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abnormal; (31) 3) subepithelial collagen bands, defined as thickened subepithelial
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collagen layer with entrapped inflammatory cells and capillaries; 4) lamina propria inflammation, defined as significantly increased infiltrates of mixed lymphocytes,
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plasma cells and/or eosinophils in the lamina propria; 5) basal lymphoplasmacytosis, defined as increased lymphoplasmacytic infiltrates that separate the base of the crypts from the muscularis mucosae; 6) basal lymphoid aggregates, referred to lymphoid aggregates basally located in the lamina propria or submucosa; 7) lamina propria neutrophilic infiltrate; 8) cryptitis; 9) crypt abscesses; 10) erosion; 11) ulceration; 12) increased eosinophils, defined as eosinophils＞50/high power field in lamina propria (32), and/or eosinophilic cryptitis (intraepithelial eosinophils＞10/100 ECs), and/or eosinophilic abscess (intraluminal eosinophils gathering); 13) granulomas; 14) crypt architecture distortion, including crypt atrophy (defined as decreased crypts divided 6
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by the increased inflammatory cells and separated from the muscularis mucosae), crypt foreshortening, irregular spacing of crypts, irregular size of crypts, crypt branching or budding, loss of crypt parallelism, villiform surface contour; 15) Paneth cell metaplasia in left colon and Paneth cell hyperplasia in right colon (>5/10 crypts) (33); and 16) pseudopyloric metaplasia and other metaplasia.
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Statistical analysis The t-test was used for comparison of continuous variables, such as patients’ age of
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onset of initial diagnosis, interval time between two diagnoses et al. For comparison
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of histological features between different groups of patients, chi square test and Fisher
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exact test were used.
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RESULTS
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Clinical and endoscopic findings
Among 2533 patients with the diagnoses of IBD (UC or CD) between 1988 and 2018,
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39 cases with an additional diagnosis of LC/CC before or after IBD were identified. Twelve cases were excluded due to equivocal histological findings or insufficient clinical data. The remaining 27 qualified cases were included in this study and are summarized in Table 1. The cases were separated into two main patterns according to the disease evolvement, i.e., LC/CC to IBD or IBD to LC/CC. Interestingly, two tertiary patterns were identified in a small number of cases: LC/CC recurrence after initial LC/CC evolving into IBD (n=4) and conversion between LC and CC after IBD (n=3). Each pattern was then divided into subgroups based on the specific diseases as shown in the 7
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Table 1. The clinical and endoscopic features of 27 cases were summarized in Table 2. The median age of all patients at first diagnosis was 46 (15-76) years, and 62 (20-78) years at second diagnosis. The median interval time between two diagnoses was 44 (2-548) months. The median follow-up time was 53 (0-190) months after the second diagnosis.
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52% (14/27) patients had complete resolution after treatment for the second diagnosis. 19% (5/27) patients got partial remission, with reduced symptoms and slightly
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abnormal endoscopy. Persistent symptoms happened in 15% (4/27) patients, and 22%
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(6/27) patients had surgery for treatment of IBD.
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Patients with the pattern of LC/CC to IBD
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This pattern included 10 patients with initial diagnosis of LC/CC and then developed
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IBD after 14 (2~44) months (Tables 1 and 2). The median age of the patients at initial diagnosis of LC/CC was 66.5 (31~76) years. Among them, CC evolved into UC or
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CD (n=8) was the most common pattern, while only 2 patients who initially presented as LC and then had UC. No patients evolving from LC to CD were identified in our cohort. Five patients who developed UC from CC showed increased diarrhea/bloody diarrhea (5/5), abdominal pain (3/5), and weight loss (1/5) clinically, with pan-colitis (4/5), diffuse inflammation in left colon (1/5) and hemorrhagic ulceration (2/5) under endoscopy. Two patients (2/5) underwent pan-proctocolectomy due to refractory UC eventually. Three patients who developed CD from CC presented with increased diarrhea with abdominal pain (2/3) and weight loss (1/3), with endoscopic findings of ulceration (1/3), diffuse colitis (1/3), and ileitis (1/3). The 3 CD patients had total 8
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remission after treatment. Two female patients diagnosed as LC at first and then developed UC after 12 (6-18) months.
One of them developed severe colitis
resistant to steroid and underwent pan-proctocolectomy 15 days after diagnosis of UC. The other patient also developed CC with watery diarrhea 17 months after UC remission.
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Patients with the pattern of IBD to LC/CC 17 patients with diagnosis of IBD (11 UC, 6 CD) had a second diagnosis of LC
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(n=5)/CC (n=12) long after their onset of IBD (Tables 1 and 2). The median age at the
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onset IBD diagnosis was 34 (15-70) years, which was significantly younger than the
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patients with pattern 1 (66.5, 31-76 years) (p=0.001). The interval time between two
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diagnoses was 108 (15-548) months, which was significantly longer than that of
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patients with pattern 1 (14, 2-44 months), (p=0.007). Among the 11 UC patients, 8 eventually evolved into CC within a median period
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of 113 (16-282) months. They all underwent a typical flare of UC with bloody diarrhea, abdominal pain with/without weight loss, and endoscopic pan-colitis, then developed CC. 6 patients had watery diarrhea at onset of CC, while 2 patients was asymptomatic and were diagnosed on the surveillance biopsy. Three of them were endoscopically normal or almost normal, while the other 8 showed granularity and ulceration under colonoscopy. Two of the 8 UC patients had total remission after treatment of CC, 3 of them had persistent symptoms of mild diarrhea (partial resolution), and 3 underwent pan-proctocolectomy due to refractory recurrent UC. Three UC patients developed LC after a median time of 462 (108-548) months, and 9
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they were all early-onset of UC at the age of 23 (21-33) years old with typical symptoms. 2 of them presented with watery diarrhea and the other one was asymptomatic. Two of them had abnormal endoscopic findings at the time of LC with patchy reduced vascular pattern and sigmoid colon scar. Two of the 3 patients then developed CC after onset of LC within 17 and 49 months respectively. In follow-up,
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one patient presented persistent CC in recent biopsy, and the other 2 patients had total remission with normal endoscopy.
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For the 6 CD patients, 3 developed LC after 37 (1-152) months, and the other 3
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were diagnosed with CC after 77 (48-196) months. All of them had symptomatic
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LC/CC, and 3 of them also had normal endoscopy. In follow-up, for the 3 CD patients
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developed LC, one had ileocecal resection due to obstruction and had total remission
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after treatment of LC; one with history of arthritis and pancreatitis evolved into CC 7 months after the onset of LC; the other one who received right hemicolectomy due to
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perforation showed poor response to treatment and had persistent CD flare. For the 3 CD patients who developed CC, one had total remission and the other two had mild symptoms with partial remission. Patients with the tertiary patterns: LC/CC to IBD and then to LC/CC or conversion between LC and CC after IBD Seven patients had the tertiary pattern with the third diagnoses of LC/CC representing either recurrent LC/CC after IBD (n=4) or conversion between LC and CC (n=3), as shown in Table 3. The interval time between the second diagnosis and the third diagnosis in all 7 patients was 25 (10-55) months. Six of them eventually had CC, and 10
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one patient converted CC to LC after 11 months. There were only two patients with symptoms at the onset of LC/CC, and the others were found by surveillance of IBD. At the last follow-up (median 33, 7-72 months), all 6 CC patients reached complete resolution, and the one patient with conversion from CC to LC underwent surgical treatment due to refractory to steroid.
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Histologic features The histologic findings in the colonic biopsy when the diagnoses of LC/CC were
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made, either before or after IBD, are summarized in Table 4. The biopsy sites of 10
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LC/CC patients who evolved into IBD were 9 from random colon and 1 from left
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colon. In 17 patients who developed LC/CC after IBD, the biopsy sites were 15 from
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Active inflammatory changes
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random colon and 2 from left colon (Figure 1).
Active inflammatory changes, which refer to neutrophilic infiltrate, erosion, or
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ulceration, present at the onset of LC/CC were identified in total 70% (19/27) of patients, including 6/10 (60%) patients with LC/CC before IBD and 13/17 (76.4%) patients who had LC/CC after IBD diagnosis (Table 4). There was no statistical difference in the incidence of active inflammation in two groups (p=0.42). The active inflammatory changes were focal or patchy in all cases and were only present in less than 3 crypts per biopsy in all of the LC/CC patients. Chronic mucosal injury changes More than half (56%, 15/27) patients had chronic mucosal injury changes on the biopsy at the time of diagnoses of LC/CC, either before or after onset of IBD (Table 11
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4). No granulomas were identified in all cases. Patients starting with IBD then developed LC/CC (82%, 14/17) more frequently showed chronicity than those with initial onset of LC/CC (30%, 3/10, p=0.01). In the 10 patients with LC/CC initially, none of them had crypt architectural distortion, Paneth cell metaplasia in left colon and/or hyperplasia in right colon, or pseudopyloric metaplasia. All of the crypt
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Histologic features of LC/CC in the tertiary pattern
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architectural distortion changes were focal and mild.
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Mild active inflammation such as focal lamina propria neutrophilic infiltration and
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focal cryptitis was seen in 5 of 7 cases (4 CC and 1 LC) (Figure 2). Chronic mucosal
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injury changes were identified in all 7 cases, including increased eosinophils (n=6),
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crypt architecture distortion (n=5), basal lymphoid nodules n= (5), Paneth cell metaplasia in left colon and/or hyperplasia in right colon (n=5), diffuse mixed
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lymphoplasmacytic infiltrate within lamina propria (n=4), and basal lymphoplasmacytosis (n=3).
DISCUSSION Both LC/CC and IBD represent inflammatory disorder of colon; however, they are two distinct entities which are essentially different in all aspects. In our study, the incidence of LC/CC in IBD patients is approximately 1% (27 of 2533). This is slightly lower than the rates in previous reports, in which two multi-center studies showed the incidences of 1.9% (44/2324) (26) and 2.6% (6/229) (29) respectively. 12
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Even though LC/CC occurring either before or after the onset of IBD is a rare event among IBD population, it is still important for clinicians and pathologists to realize this disease pattern to avoid confusion and inadequate management.
There are two main disease patterns: LC/CC to IBD or IBD to LC/CC. Most previous
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reports studied the pattern of LC/CC developing after IBD, and the most common disease evolvement pattern is CC occurring after a long history of UC. Jegadeesan et
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al reported a case series of 6 patients with UC subsequently evolving to CC (2) or LC
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(4), with initial diagnosis age at 18-65 years and interval time of 8-30 years between
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first and second diagnosis (30). Wickbom et al identified 30 IBD (21 UC, 9 CD) cases
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developed LC/CC after a median of 20 years and only 1 CC patient developed CD
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after 6 years (29). And the literature review in this report revealed additional 27 cases, 14 IBD to LC/CC with 1-39 years of interval, 13 LC/CC to IBD with 0.5-21 years of
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interval (29). Li et al identified 13 patients diagnosed with LC/CC at median age of 60 years and then evolved into IBD after median duration of 23 months (26). Our study showed similar findings that LC/CC occurring after IBD is more common than LC/CC evolving into IBD. Ten of the 27 patients were initially diagnosed as LC/CC and then had IBD after a median interval time of 17.7 months with the median initial onset age of 66.5 years. And the other 17 patients with IBD who were diagnosed at relatively younger age (median age, 34 years old) developed LC/CC in a quiescent phase after much longer interval time (median, 108 months). The results indicate that IBD patients with initial presentation of LC/CC tend to occur in older age and with 13
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shorter interval time.
On the other hand, our study also revealed a tertiary pattern, in which some patients had a third diagnosis of LC/CC or conversion between LC and CC. We found that 4 patients with LC/CC evolved into IBD and then were diagnosed with CC during
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follow-up. This pattern was only reported in a single case who had LC evolving into UC and then developed CC (34). The time between LC/CC to IBD was 14 months,
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similar to the interval time in all patients with LC/CC to IBD. However, the median
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interval time between IBD to CC was much shorter than the group with LC/CC
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developed just after IBD (25 months versus 108 months, p<0.01). Most of them were
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asymptomatic. Microscopically, besides features of CC, focal active inflammation and
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chronic mucosal injury were also seen. CC after IBD may be considered as recurrence of LC/CC, but the nature of this disease evolving pattern is unclear, and further study
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is warranted. The additional 3 cases showed conversion between LC and CC during IBD (2 LC to CC and 1 CC to LC). The time interval between the conversions was from 11-49 months. Conversion between LC and CC rarely occurs in non-IBD setting (35, 36). 18% conversion rate in our series (3/17) seems very high. The co-existing IBD complicates the disease presentation. One possible explanation is that the conversion between LC and CC is probably not uncommon, and the higher incidence in IBD population may be because of more frequent colonoscopy during IBD surveillance so that the disease progression is better monitored.
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Nearly all patients (92%, 25/27) in the current study had typical symptom of watery diarrhea at onset of LC/CC either before or after the diagnosis of IBD, and most of the IBD patients had symptomatic onset of LC/CC in the quiescent phase of IBD. Only 2 patients diagnosed with LC/CC in quiescent phase of IBD by surveillance were asymptomatic. Such clinical presentations are similar to the cases in the literatures (7,
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14, 26, 27, 29). Thus, it has been suggested that LC/CC should be considered in the patients with IBD if there is chronic watery diarrhea without endoscopic relapse of
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IBD. However, IBD can relapse after the development of LC/CC. We found 2 CD
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patients with CD relapse after treatment of CC. Wickbom et al reported that 8 of 30
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patients with sequential diagnosis of IBD and LC/CC had clinical recurrence of IBD
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after onset of LC/CC (29). A case with LC/CC and UC transforming back and forth
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during the entire disease course was also reported (26). Of note, endoscopic examination is important in this situation. Typically, endoscopic findings are normal
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in patients with LC/CC as the initial presentation; however, 65% (11 of 17) of cases with LC/CC developing in quiescent phase of IBD showed abnormal endoscopic findings with quiescent colitis appearance, including reduced vascular pattern and scar. Erythema, granularity, and even focal ulceration could occur in few cases.
One strength of the current study is the detailed microscopic examination. Although the diagnosis of LC/CC is mainly relied on histologic findings (35, 37, 38), the previous reports were largely clinically based, and detailed pathological features were seldom described. It has been reported that IBD-like features were not uncommon in 15
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LC/CC patients, but none of these LC/CC patients developed IBD in the follow-up period (39). In this report, neutrophilic cryptitis or crypt abscesses, surface erosion, Paneth cell metaplasia, or even crypt architectural irregularity could be seen in 2.5% to 44% patients with LC/CC, and the most common features were Paneth cell metaplasia (CC: 44%, LC: 14%) and focal areas of neutrophilic inflammation (CC:
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30%, LC: 38%) (39). In our study, we found that 70% (19/27) of cases had active inflammation on the biopsy with LC/CC either before (60%, 6/10) or after (76%,
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13/17) IBD diagnosis, and the most frequent features were lamina propria neutrophilic
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infiltration, followed by cryptitis, crypt abscess, and erosion (Table 4). This is more
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frequent than what was described in the previous study (39). Although the presence of
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active inflammation in LC/CC was reported to be significantly related to antibiotic
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use (39), this phenomenon was not observed in the current study. Chronic mucosal injury was also commonly seen in LC/CC patients in our study (56%, 15/27),
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especially in cases with LC/CC developing after IBD (82%, 14/17), which was more frequent than those with LC/CC as the initial presentation (30%, 3/10, p=0.01). The findings of chronicity in our study were also significantly more common than the previous report with non- IBD setting (8.7%, 13/150) (39). In addition, we also found that Paneth cell metaplasia was more frequently observed in CC than in LC either before or after onset of IBD, but such difference was not seen in the LC/CC patients with no IBD in the previous report (39).
In conclusion, our study found that LC/CC can occur either before or after onset of 16
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IBD. Patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time, and unremarkable endoscopy at the onset of LC/CC. These findings may suggest that LC/CC maybe a spectrum of IBD as the earliest presentation in a subset of late-onset IBD patients. On the other hand, IBD patients can develop LC/CC many years after the onset of IBD (typically >10 years while
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patients are in quiescent phase), in which these two processes seem unrelated to each other. Morphologically, LC/CC in patients with IBD more frequently has IBD-like
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changes such as active inflammation and chronicity in biopsy.
Wilks S. Morbid appearances in the intestine of Miss Bankes. London Medical Gazette
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Journal Pre-proof 26. Li J, Yan Y, Meng Z, Liu S, Beck PL, Ghosh S, et al. Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria. Dig Dis Sci. 2017;62(10):2755-67. 27. Megna B, Saha S, Wald A, Agni R, Matkowskyj KA, Caldera F. Symptomatic Microscopic Colitis Atop Quiescent Inflammatory Bowel Disease: A Case Series. ACG Case Rep J. 2017;4:e124.
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28. Calabrese C, Fabbri A, di Febo G. Colitis evolving into ulcerative colitis. Gut.
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2005;54(9):1347-8.
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29. Wickbom A, Bohr J, Nyhlin N, Eriksson A, Lapidus A, Munch A, et al. Microscopic colitis in
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patients with ulcerative colitis or Crohn's disease: a retrospective observational study and
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review of the literature. Scand J Gastroenterol. 2018;53(4):410-6.
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30. Jegadeesan R, Liu X, Pagadala MR, Gutierrez N, Butt M, Navaneethan U. Microscopic colitis: is it a spectrum of inflammatory bowel disease? World J Gastroenterol.
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2013;19(26):4252-6.
31. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, et al. European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis. 2013;7(10):827-51. 32. Yantiss RK. Eosinophils in the GI tract: how many is too many and what do they mean? Mod Pathol. 2015;28 Suppl 1:S7-21. 33. Simmonds N, Furman M, Karanika E, Phillips A, Bates AW. Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in children. BMC Gastroenterol. 2014;14:93. 34. Zhang C, Zhao Z, Osman H, Watson R, Nalbantoglu I, Lin J. Differential expression of 20
Journal Pre-proof miR-31 between inflammatory bowel disease and microscopic colitis. Microrna. 2014;3(3):155-9. 35. Giardiello FM, Lazenby AJ. The atypical colitides. Gastroenterol Clin North Am. 1999;28(2):479-90, x. 36. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients. Gut. 2004;53(4):536-41.
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37. Jawhari A, Talbot IC. Microscopic, lymphocytic and collagenous colitis. Histopathology.
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1996;29(2):101-10.
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38. Bohr J, Olesen M, Tysk C, Jarnerot G. Collagenous and lymphocytic colitis: a clinical and
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histopathological review. Can J Gastroenterol. 2000;14(11):943-7.
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39. Ayata G, Ithamukkala S, Sapp H, Shaz BH, Brien TP, Wang HH, et al. Prevalence and
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significance of inflammatory bowel disease-like morphologic features in collagenous and
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lymphocytic colitis. Am J Surg Pathol. 2002;26(11):1414-23.
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FIGURE LEGENDS Figure 1. Pathologic features of lymphocytic colitis/collagenous colitis (LC/CC) in
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patients with ulcerative colitis/Crohn disease (UC/CD). An example case of CC (a)
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evolving into UC (b) after 8 months. Note the cryptitis in CC. An example case of LC
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(c) evolving into UC (d) after 18 months. Note the crypt abscess in LC. An example
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case of CD (e) evolving into LC (f) after 12 years. Note the mild crypt architecture
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change in LC. An example case of UC (g) evolving into CC (d) after 11 years. Note
CC.
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the mild crypt architectural change, basal plasmacytosis, and Paneth cell metaplasia in
Figure 2. Pathologic features in cases with recurrent lymphocytic colitis/collagenous colitis (LC/CC) after ulcerative colitis (UC) evolving from LC/CC. In this case, focal cryptitis is present at the onset of LC (a). UC was diagnosed 6 months later (b) and then CC was recognized 17 months later. Note the cryptitis and mild crypt architectural change in CC (c).
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Table1. Clinical features of 27 cases with both LC/CC and IBD
Onset age of initial diagnosis (years)
Interval time (months)
Number of cases
Gender(F/M)
(median/average, range)
(median/average, range)
LC/CC→IBD
10
6/4
66.5/63 (31-76) *
14/17.7 (2-44) #
LC→UC
2
2/0
69.5/69.5 (64-75)
12/12 (6-18)
CC→UC
5
2/3
69/64.8 (47-76)
13/20 (3-44)
CC→CD
3
2/1
62/55.7 (31-74)
15/17.7 (2-36)
17
13/4
34/37.8 (15~70) *
UC→LC
3
2/1
UC→CC
8
6/2
CD→LC
3
2/1
CD→CC
3
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23/26 (21~33)
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IBD→LC/CC
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Patterns
3/0
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462/373 (108~548)
36/38 (15~70)
113/139 (16~282)
24/28 (21~39)
34/67 (15~152)
62/58.7 (46~68)
77/106 (44~196)
#
*p=0.0011 age of disease onset of LC/CC→IBD vs. IBD→LC/CC; p=0.007 interval time of LC/CC→IBD vs. IBD→LC/CC.
108/162 (15~548) #
Journal Pre-proof Table 2. Clinical-endoscopic features of LC/CC patients before or after IBD onset.
LC/CC
CD
IBD→
UC→
→C
→L
CD→
LC/CC
LC
C
C
CC
(Total)
→U
CC→
CC→
C
UC
CD
0/2
0/5
0/3
0/10
1/3
1/3
0/3
0/3
2/17
presentations
0/2
0/5
0/3
0/10
2/3
6/8
1/3
2/3
11/17
Extent
Left colon
0/2
1/5
0/3
1/10
0/3
1/8
0/3
1/3
2/17
Right colon
0/2
0/5
0/3
0/10
0/3
0/8
0/3
0/3
0/17
pan-colon
0/2
1/5
0/3
1/10
3/3
7/8
2/3
2/3
14/17
Random colon
2/2
3/5
3/3
8/10
0/3
0/8
1/3
0/3
1/17
1/2
2/5
3/3
0/2
0/5
0/3
persistent
1/2
2/5
Surgery
1/2
time
12
Asymptomatic LC/CC
→IBD
UC
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LC
(Total)
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Abnormal endoscopic
remission
6/10
3/3
2/8
2/3
1/3
8/17
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Outcome
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Complete
0/10
0/3
3/8
0/3
2/3
5/17
0/3
3/10
0/3
3/8
1/3
0/3
1/17
2/5
0/3
3/10
0/3
3/8
0/3
0/3
3/17
47
88
35
93
35
6
31
36
(0-190)
(49-9
(2-84
(3-5
(22-6
(2-97)
7)
)
4)
3)
Partial remission
(months)
(0-24
(31-12
(10-19
)
3)
0)
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after second diagnosis
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Follow-up
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Symptoms
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Journal Pre-proof Table 3. Clinical features of 7 cases with a tertiary pattern
Patterns
Number of cases
Gender (F/M)
Onset age of initial diagnosis (years) (median/average, range)
Interval time between 1st and 2nd diagnosis (months) (median/average, range)
Interval time between 2st and 3rd diagnosis (months) (median/average, range)
14/17.5 (6-36)
25/28.8 (10-55)
4
2/2
63/64.5 (58-74)
UC→LC→CC
2
2/0
28/28 (23-33)
UC→CC→LC
1
1/0
34
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LC/CC→IBD→CC
25
285/285 (108-462)
33/33 (17-49)
188
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Journal Pre-proof Table 4. Histologic features in biopsy of patients with lymphocytic or collagenous colitis before or after onset of inflammatory bowel disease LC/CC→IBD
IBD→LC/CC
Total
(n=10)
(n=17)
(n=27)
Lamina propria neutrophils
6/10
13/17
70% (19/27)
Cryptitis
5/10
13/17
67% (18/27)
Crypt abscess
1/10
5/17
22% (6/27)
Erosion
1/10
3/17
15% (4/27)
Ulceration
0/10
1/17
4% (1/27)
Pseudomembrane formation
1/10
Histologic feature
Active inflammatory
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changes
4% (1/27)
12/17
56% (15/27)
1/10
8/17
33% (9/27)
0/10
2/17
7% (2/27)
1/10
6/17
26% (7/27)
0/10
14/17
52% (14/27)
0/10
11/17
41% (11/27)
Pseudopyloric metaplasia
0/10
1/17
4% (1/27)
Granulomas
0/10
0/17
0% (0/27)
Diffuse mixed lymphoplasmacytic infiltrate within
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0/17
3/10
Basal lymphoid aggregates Increased eosinophils mucosal
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Crypt architecture distortion
Paneth cell metaplasia in left colon (hyperplasia in right colon)
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injury changes
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Chronic
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Basal lymphoplasmacytosis
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lamina propria
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Journal Pre-proof Highlights
A single institute experience of the significance of lymphocytic colitis/collagenous colitis (LC/CC) in inflammatory bowel disease (IBD).
Approximately 1% of IBD patients may have LC/CC patterns either before or after the diagnosis of IBD.
IBD patients with initial presentation of LC/CC tend to occur in older age, with
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IBD patients can also develop LC/CC associated with chronic mucosal injury
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many years after the onset of IBD (typically with >10 years).
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shorter interval time and frequent active inflammation in initial LC/CC.
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Figure 1
Figure 2
colitis/
Lin Yuan, Tsung-Teh Wu, Vishal Chandan, Yajue Huang, Lizhi Zhang PII:
S0046-8177(19)30193-5
DOI:
https://doi.org/10.1016/j.humpath.2019.09.014
Reference:
YHUPA 4941
To appear in:
Human Pathology
Received date:
8 August 2019
Revised date:
10 September 2019
Accepted date:
11 September 2019
Please cite this article as: L. Yuan, T.-T. Wu, V. Chandan, et al., Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease, Human Pathology(2019), https://doi.org/10.1016/j.humpath.2019.09.014
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
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Clinicopathological significance of lymphocytic colitis/collagenous colitis in inflammatory bowel disease Lin Yuan1, Tsung-Teh Wu2, Vishal Chandan3, Yajue Huang2, and Lizhi Zhang2* Pathology Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, China1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN,
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USA2
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Department of Pathology, University of California, Irvine Medical Center, Irvine, CA,
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USA3
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* Corresponding author:
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Lizhi Zhang, MD
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Mayo Clinic, Division of Anatomic Pathology Hilton 11, 200 1st St. SW
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Rochester, MN, 55905
Email: [email protected] Phone: 1-507-293-1393 FAX: 1-507-284-1599
1
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Abstract Patients with inflammatory bowel disease (IBD) may occasionally present with lymphocytic colitis/collagenous colitis (LC/CC) either before or after the onset of IBD. Although a few reports have described a small number of such cases, the relationship between these two disorders is still unclear. We evaluated 27 patients
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with diagnosis of either ulcerative colitis (UC) or Crohn’s disease (CD) and LC/CC. Clinical, endoscopic, and pathological features were reviewed. 10 patients with initial
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diagnoses of LC (n=2)/CC (n=8) evolved into UC (n=7) or CD (n=3) after a median
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interval of 14 months (range, 2-44 months). Among these, 4 patients with LC/CC
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evolving into IBD also had recurrent CC in a quiescent phase of IBD. Seventeen
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patients with initial diagnosis of UC (n=11) or CD (n=6) developed LC (n=6)/CC
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(n=11) after a median interval of 108 months (range, 15-548 months). IBD patients with initial presentation of LC/CC were significantly older than those who developed
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LC/CC after onset of IBD (66.5 vs.34.0 years old, p=0.001). The interval time between LC/CC to IBD was significantly shorter than that of IBD to LC/CC (14 vs. 108 months, p=0.007). Quiescent UC with superimposed CC was the most common pattern (n=8). Patients with CD had shorter interval time to develop LC/CC than UC patients, although it was not statistically significant (60.5 vs. 139 months, p=0.14). Endoscopically, most of patients started with LC/CC had unremarkable findings, but 11 of 17 patients who developed LC/CC after IBD showed quiescent chronic colitis. Histologically, LC/CC patients with diagnosis of IBD, either before or after, more frequently show active inflammation. Chronicity was more commonly 2
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seen in biopsy of LC/CC patients with a history of IBD. Our study found that IBD patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time and frequent active inflammation in initial LC/CC. These findings suggest that LC/CC maybe a spectrum of IBD as the initial presentation in a subset of older IBD patients. On the other hand, IBD patients can develop LC/CC associated
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with chronic mucosal injury many years after the onset of IBD (typically with >10 years interval time while patients are in remission phase), for which these two
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processes seem unrelated to each other.
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Key Words: Lymphocytic colitis, Collagenous colitis, Microscopic colitis,
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inflammatory bowel disease, Crohn’s disease, Ulcerative colitis
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INTRODUCTION Lymphocytic colitis (LC) and collagenous colitis (CC) are two main forms of microscopic colitis (MC), which are different from inflammatory bowel disease (IBD) in epidemiology, etiology, clinical presentation, endoscopic appearance, and pathological features. IBD consists of two different diseases, ulcerative colitis (UC)
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and Crohn’s disease (CD), and it is relatively well defined since it was initially described in the latter half of the 19th century (1). UC and CD usually have an early
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onset at 20~40 years old, although there is a second peak incidence among
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middle-aged men (2, 3). The typical clinical symptoms of UC and CD are bloody
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diarrhea, rectal bleeding, abdominal pain, fever, and weight loss, which vary with
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different phase and extent of disease progression. Endoscopically, UC and CD present
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diffuse inflammation and ulcerations in active phase, and quiescent colitis and scars in inactive phase. The classic microscopic finding is chronic active colitis with ulcers
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and crypt architecture distortion, and non-necrotizing granulomas in CD. On the other hand, LC and CC are relatively newly described entities in late 20th century (4, 5). LC/CC is more commonly seen in older females, with a rate peak in the sixth or seventh decade of life (6). Patients with LC and CC most commonly present with chronic watery diarrhea clinically, with normal or almost normal colonoscopy. The hallmark feature of LC is increased surface and crypt lymphocytes, and thickened subepithelial collagen band in CC. Although there are some case reports that have described patients with LC/CC evolving into UC/CD later in life, or vice versa (7-30), the correlation between 4
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LC/CC and IBD has not been well defined, and the histologic features of these patients in either LC/CC or IBD have seldom been described in detail. In this study, we sought to describe the clinical and pathological features in patients with LC/CC either before or after onset of IBD, and to evaluate the clinicopathological significance of LC/CC in IBD.
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MATERIALS AND METHODS Study population
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Patients with both established diagnosis of IBD and LC/CC between 1988 and 2018
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were identified from the surgical pathology files at the Mayo Clinic, Rochester, MN.
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Clinical information including patients’ age at first diagnosis, gender, history, initial
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and second symptoms (including extraintestinal manifestations), treatment, and follow
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up information were collected by reviewing the patients’ clinical charts. Endoscopic reports were also reviewed. The features such as extent of the disease, erythema,
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edema, friability, granularity, an abnormal vascular pattern, and frank ulcerations were recorded, which were recognized as abnormal findings for LC/CC patients. The study was approved by the Mayo Clinic Rochester Institutional Review Board. Histologic analysis All slides of biopsy specimens were reviewed by two pathologists (Y.L and L.Z), and the original diagnoses were confirmed. The histological diagnostic criteria for LC is defined as increased intraepithelial lymphocytes (IELs, >20 per 100 surface epithelial cells) in a normal/near normal architecture mucosa, accompanied with surface epithelial injury and increased lamina propria mixed mononuclear cell infiltrates. For 5
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collagenous colitis, a thickened subepithelial collagen band was present accompanied with other morphologic characteristics seen in LC, although maybe with less prominent IELs. The diagnosis of UC or CD was confirmed by histology in conjunction with clinical, endoscopic, and radiologic findings. Histologic features were evaluated in detail on the hematoxylin and eosin
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(H&E)-stained slides, including: 1) surface epithelial injury, including epithelial degeneration, mucin depletion, cytoplasmic hypereosinophilia, and epithelial
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flattening; 2) IELs, including the presence of intraepithelial lymphocytes in surface
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and crypts (recorded as the number per 100 epithelial cells, n/100 ECs, at the area
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with the most prominent infiltrate), and IELs >20/100 ECs was considered as
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abnormal; (31) 3) subepithelial collagen bands, defined as thickened subepithelial
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collagen layer with entrapped inflammatory cells and capillaries; 4) lamina propria inflammation, defined as significantly increased infiltrates of mixed lymphocytes,
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plasma cells and/or eosinophils in the lamina propria; 5) basal lymphoplasmacytosis, defined as increased lymphoplasmacytic infiltrates that separate the base of the crypts from the muscularis mucosae; 6) basal lymphoid aggregates, referred to lymphoid aggregates basally located in the lamina propria or submucosa; 7) lamina propria neutrophilic infiltrate; 8) cryptitis; 9) crypt abscesses; 10) erosion; 11) ulceration; 12) increased eosinophils, defined as eosinophils＞50/high power field in lamina propria (32), and/or eosinophilic cryptitis (intraepithelial eosinophils＞10/100 ECs), and/or eosinophilic abscess (intraluminal eosinophils gathering); 13) granulomas; 14) crypt architecture distortion, including crypt atrophy (defined as decreased crypts divided 6
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by the increased inflammatory cells and separated from the muscularis mucosae), crypt foreshortening, irregular spacing of crypts, irregular size of crypts, crypt branching or budding, loss of crypt parallelism, villiform surface contour; 15) Paneth cell metaplasia in left colon and Paneth cell hyperplasia in right colon (>5/10 crypts) (33); and 16) pseudopyloric metaplasia and other metaplasia.
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Statistical analysis The t-test was used for comparison of continuous variables, such as patients’ age of
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onset of initial diagnosis, interval time between two diagnoses et al. For comparison
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of histological features between different groups of patients, chi square test and Fisher
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exact test were used.
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RESULTS
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Clinical and endoscopic findings
Among 2533 patients with the diagnoses of IBD (UC or CD) between 1988 and 2018,
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39 cases with an additional diagnosis of LC/CC before or after IBD were identified. Twelve cases were excluded due to equivocal histological findings or insufficient clinical data. The remaining 27 qualified cases were included in this study and are summarized in Table 1. The cases were separated into two main patterns according to the disease evolvement, i.e., LC/CC to IBD or IBD to LC/CC. Interestingly, two tertiary patterns were identified in a small number of cases: LC/CC recurrence after initial LC/CC evolving into IBD (n=4) and conversion between LC and CC after IBD (n=3). Each pattern was then divided into subgroups based on the specific diseases as shown in the 7
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Table 1. The clinical and endoscopic features of 27 cases were summarized in Table 2. The median age of all patients at first diagnosis was 46 (15-76) years, and 62 (20-78) years at second diagnosis. The median interval time between two diagnoses was 44 (2-548) months. The median follow-up time was 53 (0-190) months after the second diagnosis.
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52% (14/27) patients had complete resolution after treatment for the second diagnosis. 19% (5/27) patients got partial remission, with reduced symptoms and slightly
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abnormal endoscopy. Persistent symptoms happened in 15% (4/27) patients, and 22%
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(6/27) patients had surgery for treatment of IBD.
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Patients with the pattern of LC/CC to IBD
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This pattern included 10 patients with initial diagnosis of LC/CC and then developed
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IBD after 14 (2~44) months (Tables 1 and 2). The median age of the patients at initial diagnosis of LC/CC was 66.5 (31~76) years. Among them, CC evolved into UC or
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CD (n=8) was the most common pattern, while only 2 patients who initially presented as LC and then had UC. No patients evolving from LC to CD were identified in our cohort. Five patients who developed UC from CC showed increased diarrhea/bloody diarrhea (5/5), abdominal pain (3/5), and weight loss (1/5) clinically, with pan-colitis (4/5), diffuse inflammation in left colon (1/5) and hemorrhagic ulceration (2/5) under endoscopy. Two patients (2/5) underwent pan-proctocolectomy due to refractory UC eventually. Three patients who developed CD from CC presented with increased diarrhea with abdominal pain (2/3) and weight loss (1/3), with endoscopic findings of ulceration (1/3), diffuse colitis (1/3), and ileitis (1/3). The 3 CD patients had total 8
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remission after treatment. Two female patients diagnosed as LC at first and then developed UC after 12 (6-18) months.
One of them developed severe colitis
resistant to steroid and underwent pan-proctocolectomy 15 days after diagnosis of UC. The other patient also developed CC with watery diarrhea 17 months after UC remission.
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Patients with the pattern of IBD to LC/CC 17 patients with diagnosis of IBD (11 UC, 6 CD) had a second diagnosis of LC
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(n=5)/CC (n=12) long after their onset of IBD (Tables 1 and 2). The median age at the
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onset IBD diagnosis was 34 (15-70) years, which was significantly younger than the
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patients with pattern 1 (66.5, 31-76 years) (p=0.001). The interval time between two
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diagnoses was 108 (15-548) months, which was significantly longer than that of
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patients with pattern 1 (14, 2-44 months), (p=0.007). Among the 11 UC patients, 8 eventually evolved into CC within a median period
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of 113 (16-282) months. They all underwent a typical flare of UC with bloody diarrhea, abdominal pain with/without weight loss, and endoscopic pan-colitis, then developed CC. 6 patients had watery diarrhea at onset of CC, while 2 patients was asymptomatic and were diagnosed on the surveillance biopsy. Three of them were endoscopically normal or almost normal, while the other 8 showed granularity and ulceration under colonoscopy. Two of the 8 UC patients had total remission after treatment of CC, 3 of them had persistent symptoms of mild diarrhea (partial resolution), and 3 underwent pan-proctocolectomy due to refractory recurrent UC. Three UC patients developed LC after a median time of 462 (108-548) months, and 9
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they were all early-onset of UC at the age of 23 (21-33) years old with typical symptoms. 2 of them presented with watery diarrhea and the other one was asymptomatic. Two of them had abnormal endoscopic findings at the time of LC with patchy reduced vascular pattern and sigmoid colon scar. Two of the 3 patients then developed CC after onset of LC within 17 and 49 months respectively. In follow-up,
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one patient presented persistent CC in recent biopsy, and the other 2 patients had total remission with normal endoscopy.
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For the 6 CD patients, 3 developed LC after 37 (1-152) months, and the other 3
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were diagnosed with CC after 77 (48-196) months. All of them had symptomatic
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LC/CC, and 3 of them also had normal endoscopy. In follow-up, for the 3 CD patients
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developed LC, one had ileocecal resection due to obstruction and had total remission
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after treatment of LC; one with history of arthritis and pancreatitis evolved into CC 7 months after the onset of LC; the other one who received right hemicolectomy due to
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perforation showed poor response to treatment and had persistent CD flare. For the 3 CD patients who developed CC, one had total remission and the other two had mild symptoms with partial remission. Patients with the tertiary patterns: LC/CC to IBD and then to LC/CC or conversion between LC and CC after IBD Seven patients had the tertiary pattern with the third diagnoses of LC/CC representing either recurrent LC/CC after IBD (n=4) or conversion between LC and CC (n=3), as shown in Table 3. The interval time between the second diagnosis and the third diagnosis in all 7 patients was 25 (10-55) months. Six of them eventually had CC, and 10
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one patient converted CC to LC after 11 months. There were only two patients with symptoms at the onset of LC/CC, and the others were found by surveillance of IBD. At the last follow-up (median 33, 7-72 months), all 6 CC patients reached complete resolution, and the one patient with conversion from CC to LC underwent surgical treatment due to refractory to steroid.
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Histologic features The histologic findings in the colonic biopsy when the diagnoses of LC/CC were
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made, either before or after IBD, are summarized in Table 4. The biopsy sites of 10
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LC/CC patients who evolved into IBD were 9 from random colon and 1 from left
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colon. In 17 patients who developed LC/CC after IBD, the biopsy sites were 15 from
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Active inflammatory changes
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random colon and 2 from left colon (Figure 1).
Active inflammatory changes, which refer to neutrophilic infiltrate, erosion, or
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ulceration, present at the onset of LC/CC were identified in total 70% (19/27) of patients, including 6/10 (60%) patients with LC/CC before IBD and 13/17 (76.4%) patients who had LC/CC after IBD diagnosis (Table 4). There was no statistical difference in the incidence of active inflammation in two groups (p=0.42). The active inflammatory changes were focal or patchy in all cases and were only present in less than 3 crypts per biopsy in all of the LC/CC patients. Chronic mucosal injury changes More than half (56%, 15/27) patients had chronic mucosal injury changes on the biopsy at the time of diagnoses of LC/CC, either before or after onset of IBD (Table 11
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4). No granulomas were identified in all cases. Patients starting with IBD then developed LC/CC (82%, 14/17) more frequently showed chronicity than those with initial onset of LC/CC (30%, 3/10, p=0.01). In the 10 patients with LC/CC initially, none of them had crypt architectural distortion, Paneth cell metaplasia in left colon and/or hyperplasia in right colon, or pseudopyloric metaplasia. All of the crypt
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Histologic features of LC/CC in the tertiary pattern
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architectural distortion changes were focal and mild.
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Mild active inflammation such as focal lamina propria neutrophilic infiltration and
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focal cryptitis was seen in 5 of 7 cases (4 CC and 1 LC) (Figure 2). Chronic mucosal
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injury changes were identified in all 7 cases, including increased eosinophils (n=6),
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crypt architecture distortion (n=5), basal lymphoid nodules n= (5), Paneth cell metaplasia in left colon and/or hyperplasia in right colon (n=5), diffuse mixed
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lymphoplasmacytic infiltrate within lamina propria (n=4), and basal lymphoplasmacytosis (n=3).
DISCUSSION Both LC/CC and IBD represent inflammatory disorder of colon; however, they are two distinct entities which are essentially different in all aspects. In our study, the incidence of LC/CC in IBD patients is approximately 1% (27 of 2533). This is slightly lower than the rates in previous reports, in which two multi-center studies showed the incidences of 1.9% (44/2324) (26) and 2.6% (6/229) (29) respectively. 12
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Even though LC/CC occurring either before or after the onset of IBD is a rare event among IBD population, it is still important for clinicians and pathologists to realize this disease pattern to avoid confusion and inadequate management.
There are two main disease patterns: LC/CC to IBD or IBD to LC/CC. Most previous
of
reports studied the pattern of LC/CC developing after IBD, and the most common disease evolvement pattern is CC occurring after a long history of UC. Jegadeesan et
ro
al reported a case series of 6 patients with UC subsequently evolving to CC (2) or LC
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(4), with initial diagnosis age at 18-65 years and interval time of 8-30 years between
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first and second diagnosis (30). Wickbom et al identified 30 IBD (21 UC, 9 CD) cases
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developed LC/CC after a median of 20 years and only 1 CC patient developed CD
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after 6 years (29). And the literature review in this report revealed additional 27 cases, 14 IBD to LC/CC with 1-39 years of interval, 13 LC/CC to IBD with 0.5-21 years of
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interval (29). Li et al identified 13 patients diagnosed with LC/CC at median age of 60 years and then evolved into IBD after median duration of 23 months (26). Our study showed similar findings that LC/CC occurring after IBD is more common than LC/CC evolving into IBD. Ten of the 27 patients were initially diagnosed as LC/CC and then had IBD after a median interval time of 17.7 months with the median initial onset age of 66.5 years. And the other 17 patients with IBD who were diagnosed at relatively younger age (median age, 34 years old) developed LC/CC in a quiescent phase after much longer interval time (median, 108 months). The results indicate that IBD patients with initial presentation of LC/CC tend to occur in older age and with 13
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shorter interval time.
On the other hand, our study also revealed a tertiary pattern, in which some patients had a third diagnosis of LC/CC or conversion between LC and CC. We found that 4 patients with LC/CC evolved into IBD and then were diagnosed with CC during
of
follow-up. This pattern was only reported in a single case who had LC evolving into UC and then developed CC (34). The time between LC/CC to IBD was 14 months,
ro
similar to the interval time in all patients with LC/CC to IBD. However, the median
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interval time between IBD to CC was much shorter than the group with LC/CC
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developed just after IBD (25 months versus 108 months, p<0.01). Most of them were
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asymptomatic. Microscopically, besides features of CC, focal active inflammation and
na
chronic mucosal injury were also seen. CC after IBD may be considered as recurrence of LC/CC, but the nature of this disease evolving pattern is unclear, and further study
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is warranted. The additional 3 cases showed conversion between LC and CC during IBD (2 LC to CC and 1 CC to LC). The time interval between the conversions was from 11-49 months. Conversion between LC and CC rarely occurs in non-IBD setting (35, 36). 18% conversion rate in our series (3/17) seems very high. The co-existing IBD complicates the disease presentation. One possible explanation is that the conversion between LC and CC is probably not uncommon, and the higher incidence in IBD population may be because of more frequent colonoscopy during IBD surveillance so that the disease progression is better monitored.
14
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Nearly all patients (92%, 25/27) in the current study had typical symptom of watery diarrhea at onset of LC/CC either before or after the diagnosis of IBD, and most of the IBD patients had symptomatic onset of LC/CC in the quiescent phase of IBD. Only 2 patients diagnosed with LC/CC in quiescent phase of IBD by surveillance were asymptomatic. Such clinical presentations are similar to the cases in the literatures (7,
of
14, 26, 27, 29). Thus, it has been suggested that LC/CC should be considered in the patients with IBD if there is chronic watery diarrhea without endoscopic relapse of
ro
IBD. However, IBD can relapse after the development of LC/CC. We found 2 CD
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patients with CD relapse after treatment of CC. Wickbom et al reported that 8 of 30
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patients with sequential diagnosis of IBD and LC/CC had clinical recurrence of IBD
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after onset of LC/CC (29). A case with LC/CC and UC transforming back and forth
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during the entire disease course was also reported (26). Of note, endoscopic examination is important in this situation. Typically, endoscopic findings are normal
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in patients with LC/CC as the initial presentation; however, 65% (11 of 17) of cases with LC/CC developing in quiescent phase of IBD showed abnormal endoscopic findings with quiescent colitis appearance, including reduced vascular pattern and scar. Erythema, granularity, and even focal ulceration could occur in few cases.
One strength of the current study is the detailed microscopic examination. Although the diagnosis of LC/CC is mainly relied on histologic findings (35, 37, 38), the previous reports were largely clinically based, and detailed pathological features were seldom described. It has been reported that IBD-like features were not uncommon in 15
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LC/CC patients, but none of these LC/CC patients developed IBD in the follow-up period (39). In this report, neutrophilic cryptitis or crypt abscesses, surface erosion, Paneth cell metaplasia, or even crypt architectural irregularity could be seen in 2.5% to 44% patients with LC/CC, and the most common features were Paneth cell metaplasia (CC: 44%, LC: 14%) and focal areas of neutrophilic inflammation (CC:
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30%, LC: 38%) (39). In our study, we found that 70% (19/27) of cases had active inflammation on the biopsy with LC/CC either before (60%, 6/10) or after (76%,
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13/17) IBD diagnosis, and the most frequent features were lamina propria neutrophilic
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infiltration, followed by cryptitis, crypt abscess, and erosion (Table 4). This is more
re
frequent than what was described in the previous study (39). Although the presence of
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active inflammation in LC/CC was reported to be significantly related to antibiotic
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use (39), this phenomenon was not observed in the current study. Chronic mucosal injury was also commonly seen in LC/CC patients in our study (56%, 15/27),
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especially in cases with LC/CC developing after IBD (82%, 14/17), which was more frequent than those with LC/CC as the initial presentation (30%, 3/10, p=0.01). The findings of chronicity in our study were also significantly more common than the previous report with non- IBD setting (8.7%, 13/150) (39). In addition, we also found that Paneth cell metaplasia was more frequently observed in CC than in LC either before or after onset of IBD, but such difference was not seen in the LC/CC patients with no IBD in the previous report (39).
In conclusion, our study found that LC/CC can occur either before or after onset of 16
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IBD. Patients with initial presentation of LC/CC tend to occur in older age, with shorter interval time, and unremarkable endoscopy at the onset of LC/CC. These findings may suggest that LC/CC maybe a spectrum of IBD as the earliest presentation in a subset of late-onset IBD patients. On the other hand, IBD patients can develop LC/CC many years after the onset of IBD (typically >10 years while
of
patients are in quiescent phase), in which these two processes seem unrelated to each other. Morphologically, LC/CC in patients with IBD more frequently has IBD-like
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changes such as active inflammation and chronicity in biopsy.
Wilks S. Morbid appearances in the intestine of Miss Bankes. London Medical Gazette
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1.
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31. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, et al. European consensus on the histopathology of inflammatory bowel disease. J Crohns Colitis. 2013;7(10):827-51. 32. Yantiss RK. Eosinophils in the GI tract: how many is too many and what do they mean? Mod Pathol. 2015;28 Suppl 1:S7-21. 33. Simmonds N, Furman M, Karanika E, Phillips A, Bates AW. Paneth cell metaplasia in newly diagnosed inflammatory bowel disease in children. BMC Gastroenterol. 2014;14:93. 34. Zhang C, Zhao Z, Osman H, Watson R, Nalbantoglu I, Lin J. Differential expression of 20
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lymphocytic colitis. Am J Surg Pathol. 2002;26(11):1414-23.
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FIGURE LEGENDS Figure 1. Pathologic features of lymphocytic colitis/collagenous colitis (LC/CC) in
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patients with ulcerative colitis/Crohn disease (UC/CD). An example case of CC (a)
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evolving into UC (b) after 8 months. Note the cryptitis in CC. An example case of LC
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(c) evolving into UC (d) after 18 months. Note the crypt abscess in LC. An example
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case of CD (e) evolving into LC (f) after 12 years. Note the mild crypt architecture
na
change in LC. An example case of UC (g) evolving into CC (d) after 11 years. Note
CC.
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the mild crypt architectural change, basal plasmacytosis, and Paneth cell metaplasia in
Figure 2. Pathologic features in cases with recurrent lymphocytic colitis/collagenous colitis (LC/CC) after ulcerative colitis (UC) evolving from LC/CC. In this case, focal cryptitis is present at the onset of LC (a). UC was diagnosed 6 months later (b) and then CC was recognized 17 months later. Note the cryptitis and mild crypt architectural change in CC (c).
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Table1. Clinical features of 27 cases with both LC/CC and IBD
Onset age of initial diagnosis (years)
Interval time (months)
Number of cases
Gender(F/M)
(median/average, range)
(median/average, range)
LC/CC→IBD
10
6/4
66.5/63 (31-76) *
14/17.7 (2-44) #
LC→UC
2
2/0
69.5/69.5 (64-75)
12/12 (6-18)
CC→UC
5
2/3
69/64.8 (47-76)
13/20 (3-44)
CC→CD
3
2/1
62/55.7 (31-74)
15/17.7 (2-36)
17
13/4
34/37.8 (15~70) *
UC→LC
3
2/1
UC→CC
8
6/2
CD→LC
3
2/1
CD→CC
3
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-p re
23/26 (21~33)
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IBD→LC/CC
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Patterns
3/0
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462/373 (108~548)
36/38 (15~70)
113/139 (16~282)
24/28 (21~39)
34/67 (15~152)
62/58.7 (46~68)
77/106 (44~196)
#
*p=0.0011 age of disease onset of LC/CC→IBD vs. IBD→LC/CC; p=0.007 interval time of LC/CC→IBD vs. IBD→LC/CC.
108/162 (15~548) #
Journal Pre-proof Table 2. Clinical-endoscopic features of LC/CC patients before or after IBD onset.
LC/CC
CD
IBD→
UC→
→C
→L
CD→
LC/CC
LC
C
C
CC
(Total)
→U
CC→
CC→
C
UC
CD
0/2
0/5
0/3
0/10
1/3
1/3
0/3
0/3
2/17
presentations
0/2
0/5
0/3
0/10
2/3
6/8
1/3
2/3
11/17
Extent
Left colon
0/2
1/5
0/3
1/10
0/3
1/8
0/3
1/3
2/17
Right colon
0/2
0/5
0/3
0/10
0/3
0/8
0/3
0/3
0/17
pan-colon
0/2
1/5
0/3
1/10
3/3
7/8
2/3
2/3
14/17
Random colon
2/2
3/5
3/3
8/10
0/3
0/8
1/3
0/3
1/17
1/2
2/5
3/3
0/2
0/5
0/3
persistent
1/2
2/5
Surgery
1/2
time
12
Asymptomatic LC/CC
→IBD
UC
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LC
(Total)
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Abnormal endoscopic
remission
6/10
3/3
2/8
2/3
1/3
8/17
re
Outcome
-p
Complete
0/10
0/3
3/8
0/3
2/3
5/17
0/3
3/10
0/3
3/8
1/3
0/3
1/17
2/5
0/3
3/10
0/3
3/8
0/3
0/3
3/17
47
88
35
93
35
6
31
36
(0-190)
(49-9
(2-84
(3-5
(22-6
(2-97)
7)
)
4)
3)
Partial remission
(months)
(0-24
(31-12
(10-19
)
3)
0)
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after second diagnosis
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Follow-up
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Symptoms
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Journal Pre-proof Table 3. Clinical features of 7 cases with a tertiary pattern
Patterns
Number of cases
Gender (F/M)
Onset age of initial diagnosis (years) (median/average, range)
Interval time between 1st and 2nd diagnosis (months) (median/average, range)
Interval time between 2st and 3rd diagnosis (months) (median/average, range)
14/17.5 (6-36)
25/28.8 (10-55)
4
2/2
63/64.5 (58-74)
UC→LC→CC
2
2/0
28/28 (23-33)
UC→CC→LC
1
1/0
34
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na
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re
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ro
of
LC/CC→IBD→CC
25
285/285 (108-462)
33/33 (17-49)
188
11
Journal Pre-proof Table 4. Histologic features in biopsy of patients with lymphocytic or collagenous colitis before or after onset of inflammatory bowel disease LC/CC→IBD
IBD→LC/CC
Total
(n=10)
(n=17)
(n=27)
Lamina propria neutrophils
6/10
13/17
70% (19/27)
Cryptitis
5/10
13/17
67% (18/27)
Crypt abscess
1/10
5/17
22% (6/27)
Erosion
1/10
3/17
15% (4/27)
Ulceration
0/10
1/17
4% (1/27)
Pseudomembrane formation
1/10
Histologic feature
Active inflammatory
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changes
4% (1/27)
12/17
56% (15/27)
1/10
8/17
33% (9/27)
0/10
2/17
7% (2/27)
1/10
6/17
26% (7/27)
0/10
14/17
52% (14/27)
0/10
11/17
41% (11/27)
Pseudopyloric metaplasia
0/10
1/17
4% (1/27)
Granulomas
0/10
0/17
0% (0/27)
Diffuse mixed lymphoplasmacytic infiltrate within
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0/17
3/10
Basal lymphoid aggregates Increased eosinophils mucosal
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Crypt architecture distortion
Paneth cell metaplasia in left colon (hyperplasia in right colon)
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injury changes
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Chronic
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Basal lymphoplasmacytosis
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lamina propria
26
Journal Pre-proof Highlights
A single institute experience of the significance of lymphocytic colitis/collagenous colitis (LC/CC) in inflammatory bowel disease (IBD).
Approximately 1% of IBD patients may have LC/CC patterns either before or after the diagnosis of IBD.
IBD patients with initial presentation of LC/CC tend to occur in older age, with
ro
IBD patients can also develop LC/CC associated with chronic mucosal injury
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re
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many years after the onset of IBD (typically with >10 years).
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of
shorter interval time and frequent active inflammation in initial LC/CC.
27
Figure 1
Figure 2