Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing and remitting inflammation of the colonic mucosa.¹ Over time, patients with long-standing UC face an increased risk of developing colitis-associated neoplasms, most commonly colorectal adenocarcinoma.² By contrast, lymphoma arising in the setting of UC is exceedingly rare and often overlooked.³ Diffuse large B-cell lymphoma (DLBCL) involving the colon may mimic active colitis clinically and endoscopically, making a timely diagnosis challenging. Immunosuppressive therapies are frequently used in moderate- to-severe UC. Hence, distinguishing primary UC inflammation from a superimposed lymphoproliferative process is essential for safe and effective treatment.⁴ This paper presents a case of DLBCL developing on the background of long-standing UC, initially presenting as acute severe ulcerative colitis. This case highlights the importance of repeated biopsies and immunohistochemical staining in patients with persistent or atypical clinical presentations before initiating biologic therapy.

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

A 46-year-old woman with an eight-year history of intermittent rectal bleeding, initially presumed to be hemorrhoidal in origin, had not undergone a colonoscopic evaluation because of the limited access to endoscopic services in her rural locality. Her medical history was otherwise unremarkable, but her paternal grandmother had a history of colorectal cancer. The patient was a lifelong non-smoker, abstained from alcohol, and reported no occupational or environmental exposures, but her spouse was a chronic smoker.

In early 2024, she was diagnosed with UC of moderate severity, based on the clinical symptoms supported by the endoscopic and histopathological findings (Mayo score not recorded). A colonoscopy performed at that time revealed continuous mucosal inflammation extending from the rectum to the sigmoid colon, characterized by erythema, friability, loss of vascular pattern, and superficial ulcerations―typical features of UC. The patient was classified as having left-sided colitis (E2, Montreal classification) based on the extent of the disease. A histological evaluation revealed crypt architectural distortion, crypt abscesses, basal plasmacytosis, and diffuse inflammatory cell infiltration in the lamina propria, consistent with chronic active ulcerative colitis. Management consisted of oral mesalazine (2 g twice daily) and intermittent courses of corticosteroids during the disease flare-up. The patient had never been initiated on thiopurine immunomodulators such as azathioprine or 6-mercaptopurine. She achieved only partial remission, with bowel movements typically two to three times per day, accompanied by intermittent blood-streaked stools. On the other hand, adherence to follow-up was poor, and long-term disease monitoring was suboptimal.

In early 2025, she was admitted with features consistent with acute severe ulcerative colitis (ASUC), including hematochezia (eight to 10 episodes per day), lower abdominal pain, and generalized fatigue. Upon admission, she was hemodynamically stable, with a weight of 50 kg and a height of 162 cm. Her vital signs included a pulse rate of 92 beats/minute, blood pressure of 120/80 mmHg, respiratory rate of 16 breaths/minute, and a temperature of 37°C. A clinical examination revealed pallor and lower abdominal tenderness without peritoneal signs. No hepatosplenomegaly or peripheral lymphadenopathy was noted.

The initial laboratory investigations revealed significant anemia (hemoglobin 78 g/L), elevated inflammatory markers, including C-reactive protein (CRP) at 17.3 mg/L, and an erythrocyte sedimentation rate of 50 mm at one hour and 80 mm at two hours. Additional abnormalities included hypoalbuminemia (3.32 g/dL) and hypokalemia (3.0 mmol/L). Fecal calprotectin was markedly elevated at 800 μg/g, while the serum ferritin level was reduced (14.47 ng/mL). Stool analysis showed no evidence of ova or parasites. The bacterial stool cultures yielded only commensal flora, and Clostridium difficile toxin A/B PCR was negative. Table 1 provides a summary of the laboratory data.

Flexible sigmoidoscopy revealed diffusely inflamed, edematous mucosa in the sigmoid colon and rectum, with multiple deep ulcers (10–15 mm in diameter) covered by pseudomembranous exudates (Fig. 1). An Xpert MTB/RIF assay performed on the mucosal biopsy specimens was negative for Mycobacterium tuberculosis. The initial biopsies revealed features of chronic active colitis consistent with ulcerative colitis, without evidence of cytomegalovirus (CMV) infection as determined by PCR testing performed at that time. Contrast-enhanced abdominal computed tomography revealed concentric mural thickening of the descending colon, sigmoid colon, and rectum with mucosal hyperenhancement, consistent with active inflammation (Fig. 2).

The patient was initiated on intravenous hydrocortisone (100 mg four times daily for seven days), resulting in partial clinical improvement, with a reduction in hematochezia frequency and a decline in CRP to 7.8 mg/L. On the other hand, a clinical relapse occurred upon tapering steroids to methylprednisolone 32 mg/day, with worsening hematochezia and rising CRP to 28 mg/L.

A second flexible sigmoidoscopy with repeated biopsies was performed because of symptom recurrence and the suspicion of CMV reactivation. A histological reassessment showed ongoing chronic active colitis accompanied by scattered atypical lymphoid cells, raising concerns for a lymphoproliferative disorder. PCR testing of the colonic tissue confirmed CMV reactivation with a viral load of 5.4×10⁴ IU/mL, and concurrent serum CMV PCR was 8.0×10¹ IU/mL. The patient was treated with intravenous ganciclovir (5 mg/kg/day) for 10 days, followed by oral valganciclovir (450 mg twice daily) for 21 days. Corticosteroids were gradually tapered during this period. Antiviral therapy led to partial symptom relief, with the bowel movement frequency reduced to four to five times daily and CRP decreasing to 14.8 mg/L. The follow-up serum CMV PCR was negative; tissue PCR was not repeated.

The initiation of infliximab was considered, given the suboptimal clinical response to corticosteroids and completion of antiviral therapy for CMV. Immunohistochemical (IHC) staining was performed on colonic biopsy specimens because of persistent symptoms and the prior histologic identification of atypical lymphoid cells. IHC staining of the colonic biopsy specimens showed diffuse and intense positivity for CD20 and PAX5, confirming the B-cell lineage of the neoplastic cells. In addition, tumor cells exhibited positivity for CD10 and BCL2, suggesting a germinal center B-cell origin. CD5 was positive, a finding occasionally observed in certain DLBCL subtypes, indicating a potential atypical variant of DLBCL. In particular, the Ki-67 proliferation index was approximately 15%, which was relatively lower than typically reported in classical DLBCL, suggesting a less aggressive or possibly indolent variant of the disease. These immunophenotypic features were collectively consistent with a diagnosis of DLBCL, arising in a background of long-standing UC (Fig. 3).

Staging investigations included bone marrow aspiration and biopsy, which showed no evidence of lymphomatous infiltration. Whole-body positron emission tomography-computed tomography revealed intense fluorodeoxyglucose uptake restricted to the colon and rectum (maximum standardized uptake value: 19.79), with no involvement of lymph nodes or other extranodal sites. The disease was classified as primary colonic DLBCL. The patient was referred to the Hematology Department for definitive treatment and was scheduled to initiate systemic chemotherapy with a regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Considering the underlying UC, close multidisciplinary collaboration between hematology and gastroenterology teams was planned to monitor the treatment-related complications and manage potential inflammatory bowel disease (IBD) flares during chemotherapy. The patient was maintained on oral mesalazine as the baseline therapy to control the underlying mucosal inflammation and reduce the risk of chemotherapy-induced disease exacerbation.

Distinguishing a severe flare-up of UC, particularly ASUC, from a superimposed malignancy like a lymphoma can be exceptionally challenging. Both conditions can present with overlapping clinical symptoms, including severe rectal bleeding, abdominal pain, and systemic inflammatory responses.⁵ As observed in the present case, the patient initially presented with symptoms fulfilling the Truelove and Witts criteria for ASUC and showed a partial and transient response to intravenous corticosteroids. This initial response, followed by a relapse upon steroid tapering, further complicated the diagnostic picture.

This case underscores the crucial role of a meticulous histopathological evaluation, particularly the importance of repeated biopsies when clinical evolution deviates from the expected patterns. Initially, biopsy samples showed only chronic active colitis without apparent neoplastic cells. On the other hand, a second biopsy became essential after the partial clinical response and subsequent relapse upon steroid tapering, eventually revealing subtle atypical lymphoid cells. IHC played a pivotal role in establishing a definitive diagnosis, emphasizing its critical value in complex colorectal pathologies. The lymphoma may have already been present at the time of the initial presentation, but was not detected because of sampling limitations or obscuration by intense mucosal inflammation. This patient developed lymphoma without prior exposure to thiopurines or biologic agents, therapies traditionally associated with lymphoproliferative risk in IBD.⁶ Moreover, the concurrent CMV colitis further complicated the clinical presentation, initially masking the underlying lymphoma and illustrating the diagnostic complexity in managing cases of severe UC with incomplete or partial steroid responsiveness.

Although colorectal adenocarcinoma is the most recognized malignancy associated with long-standing UC, an increased risk of lymphoma, though less common, has also been reported.² Several meta-analyses and population-based cohort studies have investigated this association. A recent meta-analysis by Zamani et al. showed that patients with IBD had a 30% higher odds of lymphoma.³ Specifically, a 2024 meta-analysis of Zhou et al. revealed higher incidences of non-Hodgkin’s lymphoma (standardized incidence ratio [SIR]=1.70), Hodgkin’s lymphoma (SIR=3.47), and leukemia (SIR=3.69) in the IBD cohort, with UC patients specifically having a higher incidence of hematologic malignancies (SIR=2.29).⁷

The pathogenesis of lymphoma in UC is likely multifactorial. UC is characterized by persistent mucosal inflammation, which can lead to a chronically stimulated immune system in the colonic mucosa. Over years of inflammation, the continuous turnover and proliferation of lymphocytes increase the likelihood of accumulating oncogenic mutations in B cells.⁸ Furthermore, the role of immunosuppressive therapies commonly used in UC management, such as thiopurines and anti- tumor necrosis factor (anti-TNF) biologics, has been studied extensively.^9,10 In the present case, the patient was managed with oral mesalazine and intermittent corticosteroids, without the long-term use of thiopurine or biologics before the lymphoma diagnosis, suggesting that, although speculative, the chronic inflammation itself, or other yet unidentified factors, may have played a more dominant role. In the present case, the authors do not suggest a definitive causal link between UC and the development of DLBCL. Instead, this paper reports the concurrent occurrence of these two conditions, while acknowledging that the association may be coincidental.

A diagnosis of DLBCL dramatically altered the management plan for this patient, underscoring the critical need for accurate diagnosis before escalating immunosuppressive therapy. Had the underlying lymphoma not been identified, the planned initiation of infliximab for presumed refractory ASUC could have been detrimental. Anti-TNF agents might accelerate lymphoma progression or mask its symptoms by further suppressing the immune system, leading to delayed diagnosis and worse outcomes.¹⁰

Primary colorectal lymphomas are very rare (0.2–1.2% of all colonic malignancies), and DLBCL arising in the colon of UC patients is exceedingly uncommon.¹¹ Suzuki et al. reviewed 10 such cases and reported a striking male predominance (10:1 male-to-female ratio) with a median age of 55 years. Approximately 70% of reported cases had a history of prolonged immunosuppressant therapy (e.g., azathioprine, anti- TNF biologics, or both), and a high proportion of tumors tested were positive for the Epstein–Barr virus. The outcomes have varied: remission was achieved (often with combined surgery and chemotherapy) in approximately half of the reported cases, whereas the others resulted in mortality because of either lymphoma progression or treatment-related complications.¹²

This case emphasizes one important clinical recommendation: clinicians should maintain a high index of suspicion for an underlying or concurrent malignancy in patients presenting with severe UC, particularly those showing an incomplete or partial response upon steroid tapering or displaying atypical clinical features. Before considering escalation to biologic therapy or potent immunosuppressants, a thorough endoscopic evaluation combined with meticulous histological assessment is imperative. Moreover, if the initial biopsy findings are equivocal or inconclusive, repeating endoscopy with additional biopsies is strongly recommended to detect subtle pathological changes, as demonstrated in this patient. IHC staining must be used whenever the histology reveals atypical lymphoid cells, even if scarce, to exclude lymphoma. Although the current guidelines do not explicitly mandate routine IHC analysis for all severe UC biopsies prior to biologic therapy, the practice of excluding malignancies in atypical or partially steroid-responsive cases represents an essential principle of clinical care. The clinical course of this patient serves as an important reminder that cases initially suspected as severe inflammatory flares can, in rare instances, harbor a lymphoma, a life-threatening malignancy necessitating an entirely different therapeutic strategy. In addition, the planned chemotherapy regimen introduces further clinical challenges because of potential gastrointestinal toxicities and the risk of exacerbating the underlying UC. Therefore, close multidisciplinary collaboration between hematologists and gastroenterologists is essential for effectively managing potential complications, such as exacerbations of UC, neutropenia, or opportunistic infections, during chemotherapy.

The primary limitation of this report is its single-case nature, restricting generalizability. In addition, the absence of repeat tissue CMV-PCR after antiviral therapy poses limitations on definitively assessing CMV clearance and its clinical impact.

In conclusion, lymphoma represents a rare but critical complication in long-standing UC patients, requiring meticulous differentiation from severe colitis before initiating biologic therapy. Early histological evaluation, including immunohistochemistry, is essential for making an accurate diagnosis and optimal management.