Improvement of Severe Colon Stricture after Rituximab Therapy for Concomitant Mucosa-associated Lymphoid Tissue Lymphoma in a Patient with Ulcerative Colitis

Abstract

Colorectal strictures are uncommon in patients with ulcerative colitis (UC). An extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT) lymphoma is rarely involved in the colon but may be associated with inflammatory bowel diseases. A 41-year-old female with a six-year history of UC presented with a severe stricture of the sigmoid colon that prevented the passage of a colonoscope. A histological examination revealed non-specific inflammation and fibrosis without dysplasia or cancer. Despite conventional treatment, including mesalazine and azathioprine for one year after that visit, the stricture persisted. In addition, diffuse, edematous exudative inflammation and multiple shallow ulcers were observed in the distal rectum, revealing a MALT lymphoma testing positive for CD20, CD43, CD5, and Bcl-2, but negative for CD3, CD10, CD23, and cyclin-D1. Four weekly doses of rituximab were administered. Follow-up colonoscopy performed one month after treatment revealed slight improvement in the rectal lesion without remnant histological evidence of a MALT lymphoma. In addition, the stricture showed marked improvement, and the colonoscope could pass easily through the stricture site. This is the first case report on an improvement of a severe sigmoid colon stricture in a patient with UC after rituximab treatment for a concomitant rectal MALT lymphoma.

INTRODUCTION

Colorectal strictures occur in approximately 1.5–11.2% of patients with ulcerative colitis (UC) and have been reported to be associated with dysplasia and cancer.^1,2 Therefore, appropriate management of a colorectal stricture in patients with UC is critical. Surgery may be indicated for patients with refractory strictures caused by fibrosis rather than active inflammation unresponsive to medical therapy.³

An extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT) lymphoma accounts for approximately 5% of all non-Hodgkin’s lymphoma cases, commonly involving the gastrointestinal tract.^4,5 The stomach is the most commonly involved organ in the gastrointestinal tract, followed by the ileum, cecum, ascending colon, and rectum.^4,5 Therefore, the occurrence of MALT lymphoma in the rectum is a rare condition, but it tends to be high in patients with inflammatory bowel diseases (IBD), such as UC, particularly in those treated with immunosuppressive agents, including azathioprine.^6,7 Despite the advances in the treatment modalities for colonic MALT lymphoma, there is no standardized strategy. Rituximab-based combination chemotherapy or rituximab alone is used widely with successful outcomes.⁸

The authors recently encountered a case of sigmoid colon stricture refractory to conventional treatment that improved markedly after rituximab treatment for MALT lymphoma concomitant with UC; such a condition has not been reported in the literature to the best of the authors’ knowledge. This study was exempted from the review by the Institutional Review Board (IRB) of Kosin University Gospel Hospital (No. 2023-07-029). The requirement for written informed consent was also waived for this case report.

CASE REPORT

A 41-year-old female with UC was referred to the authors’ hospital for the evaluation and treatment of a severe stricture of the sigmoid colon. She had been diagnosed with UC six years earlier and was initially administered 3 g/day of oral mesalazine and 1 g/day of a rectal suppository. Five months earlier, azathioprine at a daily dose of 50 mg was added to her treatment regimen. There was no history of malignancy in her family. She presented with loose stool as well as blood-mixed and mucoid stools 2–3 times per day without abdominal pain and symptoms of incomplete bowel emptying. The initial laboratory tests showed a hemoglobin level of 12.1 g/dL, WBC count of 2,870/mm³, HS-CRP level of 0.066 mg/dL, and fecal calprotectin level of 63.10 μg/g with normal results on other biochemical tests. Stool examinations for parasites and Clostridium difficile were negative. Colonoscopy revealed a severe stricture with a lumen diameter of approximately 6 mm in the sigmoid colon, located 17–19 cm from the anal verge (Fig. 1A). The conventional scope (CF-HQ290L; Olympus, Tokyo, Japan) could not be passed through the stricture. On the other hand, a short, thin scope (GIF-XP260; Olympus) could be passed, but considering the limit of its length, only the mid-transverse colon, 60 cm from the anal verge, could be approached. Therefore, the entire colon could not be examined. The erythematous mucosa, absence of a vascular pattern, slight friability, and a few petechiae with a diffuse, continuous fashion without ulceration were observed from the distal rectum to 40 cm from the anal verge (Fig. 1B), and the more proximal colon showed a normal appearance. The histological examination at the stricture site revealed non-specific inflammation and fibrosis of the lamina propria without dysplasia or cancer (Fig. 2). The abdominal CT scan revealed enhanced wall thickening in the descending and sigmoid colon, as well as a stricture approximately 1 cm in length in the sigmoid colon. The CT findings suggested a benign rather than a malignant stricture, and no significant lymph node enlargement was detected (Fig. 3). The Mayo score of the patient was four. Surgical management of the stricture was initially considered, but she refused. The azathioprine was raised due to concerns about worsening leukopenia. Treatment with biological agents was recommended, but she refused and asked for close observation. During the observation period, she was also treated with a mesalazine enema solution (4 g/day) instead of a suppository, oral mesalazine 4 g/day as an increase in dose, and azathioprine 50 mg/day.

Fig. 1.

Findings of colonoscopy performed at the initial visit. (A) Severe stricture in the sigmoid colon, with a lumen diameter of approximately 6 mm, located 17–19 cm from the anal verge. (B) Erythematous mucosa and absence of the vascular pattern with diffuse, continuous-fashion, but no mucosal break was observed from the distal rectum.

Fig. 2.

Microscopic findings of the mucosa at the stricture site in the sigmoid colon. The mucosa exhibited glandular distortion and fibrous changes in lamina propria (H&E, ×200).

Fig. 3.

Abdominal CT scan at the initial visit. Stricture in the sigmoid colon (white arrows) and enhanced wall thickening are observed. (A) Axial view. (B) Coronal view.

After one year, her laboratory tests showed a hemoglobin level of 12.3 g/dL, WBC count of 2,840/mm³, HS-CRP level of 0.079 mg/dL, and fecal calprotectin level of 62.65 μg/g. Follow-up colonoscopy was performed to evaluate the disease activity and to determine a further treatment strategy. The sigmoid colon stricture persisted, but the gross mucosal disease activity was stable (Fig. 4A). In addition, a new lesion of diffuse, edematous exudative inflammation and shallow ulcers appeared in the distal rectum, 5 cm from the anal verge (Fig. 4B). A histology examination revealed no dysplasia or cancer at the sigmoid stricture area, but atypical lymphocytes diffusely infiltrated the lamina propria and formed lymphoepithelial lesions at the lesion of the distal rectum. Under immunohistochemical staining, CD20, CD43, CD5, and Bcl-2 were positive, and CD3, CD10, CD23, and cyclin-D1 were negative, which is consistent with the rectal involvement of a MALT lymphoma concomitant with UC (Fig. 5A, B). Gastroduodenoscopy showed no involvement of a MALT lymphoma in the upper gastrointestinal tract and no infection with Helicobacter pylori. A systemic evaluation including the following modalities showed no evidence of systemic involvement of lymphoma: a CT scan of the neck, chest, and abdomen; whole-body PET-CT; bone marrow biopsy. An abdomen CT scan of the stricture site showed no significant change compared to the initial CT scan. In addition, the PET-CT scan of the stricture site did not reveal hypermetabolism. Regarding the rectal lesion, it was not evaluable through an abdominal CT scan, but hypermetabolism was detected in the PET-CT scan.

Fig. 4.

Findings of colonoscopy conducted after one year since the first visit. (A) No significant changes in severe stricture in the sigmoid colon, with a lumen diameter of approximately 6 mm, located 17–19 cm from the anal verge. (B) Diffuse, edematous exudative inflammation with shallow ulcers was observed in the distal rectum, 5 cm site from the anal verge.

Fig. 5.

Microscopic findings of rectal mucosa before the rituximab treatment. The rectal mucosa is infiltrated with atypical lymphocytes, revealing small-to-medium-sized nuclei with slightly irregular contours, dispersed chromatin, and inconspicuous nuclei (presented inside the dotted circle) and prominent plasmacytoid differentiation (presented outside the dotted circle) (H&E, ×400).

Four weekly doses of rituximab alone for MALT lymphoma were administered after discontinuing azathioprine, but mesalazine was continued for UC. The follow-up colonoscopy one month after treatment revealed slight improvement in the rectal lesion without remnant histological evidence of a MALT lymphoma (Fig. 6B). In addition, the stricture of the sigmoid colon had improved markedly without histology evidence of dysplasia or malignancy, and the colonoscope (CF-HQ290L; Olympus) could pass easily through the stricture site with an approximate lumen diameter of 20 mm (Fig. 6A). This surprising improvement in the sigmoid stricture was not expected. Follow-up colonoscopy 16 months after treatment showed that the previous stricture of the sigmoid colon was slightly narrower than before (Fig. 6C). On the other hand, the colonoscope (CF-HQ290L; Olympus) could pass through the area. In addition, only mucosal scars remained in the rectal lesion. (Fig. 6D). Histological examinations showed no evidence of dysplasia or malignancy at both the stricture site and the rectal lesion. (Fig. 7A, B). Her UC and MALT lymphoma have been in remission for more than two years since starting the rituximab treatment and regular follow-up with mesalazine-alone therapy.

Fig. 6.

Findings of colonoscopy performed one month (A, B) and 16 months (C, D) after treatment with rituximab. (A) Stricture of the sigmoid colon markedly improved to a lumen diameter of approximately 20 mm. (B) Edematous inflammation with shallow ulcers in the distal rectum, 5 cm site from the anal verge, showing slightly improved nodularity of the lesion. (C) Stricture of the sigmoid colon appeared to be slightly narrower than its condition one month after treatment. (D) Mucosal scar change in the distal rectum, 5 cm site from the anal verge, showing improved edematous inflammation with shallow ulcers.

Fig. 7.

Microscopic findings 16 months after the rituximab treatment. (A) The previous stricture site in the sigmoid colon exhibits glandular distortion of ulcerative colitis, such as intracryptal budding (indicated by an open arrowhead) and crypt rings in rows (indicated by closed arrowheads). (B) The previous mucosa-associated lymphoid tissue (MALT) lymphoma site in the rectum exhibits glandular distortion of ulcerative colitis, such as crypt branching (indicated by an arrow). There is no evidence of malignancy, including MALT lymphoma (H&E, ×400).

DISCUSSION

Colorectal strictures in patients with UC are classified as benign or malignant. According to a study that reviewed 1,156 patients with UC, of 70 cases with a colorectal stricture, 53 were benign, and 17 were malignant.⁹ The authors were concerned with the malignant potential of the stricture in this case, but the results of four biopsies showed no evidence of a malignancy. Although the pathophysiology of the benign stricture has not been fully identified, three hypotheses have been proposed. The first is the development of fibrosis beyond the submucosa. Fibrosis formation is likely associated with the proliferation of myofibroblasts that may be stimulated by basic fibroblast growth factor-positive neutrophils.² Second, inflammation spreading to the muscularis propria. As inflammation progresses, tissue repair induces new tissue formation and scar constitution. This tissue repair process is generally self-limiting. On the other hand, an excessive healing response to inflammatory-induced injury could result in fibrosis and stricture. Rituximab may positively affect the benign stricture in UC by modulating the inflammation process. Third, ischemia and necrotic changes occur during long-duration illness.²

The strategies for managing stricture in patients with UC are not well established, e.g., aggressive treatment for inflammation control or surgical intervention.¹⁰ The development or aggravation of UC after the use of rituximab has been reported in several cases.^11,12 Some animal model studies showed that B cells play a protective role in IBD by controlling the T cell activity and producing interleukin-10.^13,14

In contrast, in a murine model of Crohn’s ileitis in SCID mice, the co-transfer of B cells and CD4 T cells caused more intestinal inflammation than the transfer of CD4 T cells alone, suggesting that B cells worsen colitis. Based on a phase II, placebo-controlled, single-center clinical trial of rituximab involving 24 patients with steroid-resistant active UC, rituximab showed a significant short-term response at week 4 but had no long-term effect for remission.¹⁵ In the present patient, the stricture improved markedly after four weekly doses of rituximab, which were administered to treat concomitant rectal MALT lymphoma. The following reasons were considered. The stricture might have been caused by fibrotic tissue, but it could also have resulted from the excessive accumulation of lymphocytes and recurrent inflammation. Therefore, the rituximab treatment is believed to reduce lymphocytes within the tissue and improve inflammation, potentially improving the stricture. Although further studies are required, rituximab therapy could be cautiously considered for colorectal stricture in patients with refractory UC.

The colorectal involvement of MALT lymphoma is associated with IBD,^6,7,16 but the pathophysiology is unclear. This may be caused by chronic immune stimulation caused by secondary causes, such as bacterial infection. Chronic immune stimulation may trigger B and T cells to accumulate and proliferate. In particular, in the case of abnormal translocation, monoclonal lymphoid proliferation leads to lymphomagenesis.^17,18 Several studies have examined the relationship between the use of azathioprine and the risk of lymphoma development. In a meta-analysis evaluating the risk of lymphoma in patients with IBD who were treated with azathioprine and 6-MP, the study showed that the risk of developing lymphoma is higher in patients who have received an azathioprine treatment for more than one year, are currently using azathioprine, and are under 30 years of age. Consequently, clinicians should be aware of these findings when managing IBD patients.¹⁹

The most common symptoms of colorectal MALT lymphoma are abdominal pain, bloody stools, changes in bowel habits, and weight loss.¹⁶ Colonoscopy usually reveals polypoid lesions or mucosal ulcerations. On the other hand, a MALT lymphoma is relatively difficult to detect in cases of IBD, particularly UC, as in the present case, which reveals mucosal ulcerations and pseudopolyps. In the present patient, the diagnosis was accidental. Usually, the diagnosis of MALT lymphoma is confirmed by a microscopic examination and immunohistochemical staining.¹⁶ Immunohistochemical staining of MALT lymphoma was not clearly defined. Several studies have reported that CD19, CD20, CD22, CD40, and Bcl-2 are expressed in cases of MALT lymphoma, whereas CD3, CD10, CD23, and cyclin-D1 are not.⁴ CD5 is not usually expressed in MALT lymphoma, but few cases expressing CD5 have been reported.²⁰ In this case, although the CD5 status was positive, the results of other markers supported the diagnosis of MALT lymphoma.

In conclusion, this paper reported the first case of a severe sigmoid colon stricture in a patient with UC that was refractory to the conventional UC treatments but showed marked improvement after treatment with rituximab for rectal MALT lymphoma. Physicians need to learn more about MALT lymphoma and colorectal stricture in patients with UC. In addition, when newly developed mucosal irregular lesions with ulceration are observed during a colonoscopy, clinicians should consider the exacerbation of UC and the possibility of a malignancy, including lymphoma, particularly in IBD patients on long-term thiopurine treatment. In such cases, it is advisable to approach a biopsy with caution. Rituximab should be considered a treatment option for a colorectal stricture in cases of treatment-refractory UC. Nevertheless, further studies on using rituximab for treating strictures in patients with refractory UC are needed.