Diagnostic Challenges in Diffuse Large B-Cell Lymphoma in a Young Liver Transplant Patient with Ulcerative Colitis: A Case Report

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma, accounting for approximately 40% of all malignant lymphoid neoplasms and comprising a morphologically and molecularly heterogeneous group of lymphomas [1]. Age-related immunodeficiency (immunosenescence) has been implicated in the development of lymphoma. The median age of patients with diffuse large B-cell lymphoma is slightly over 70 years [2]. The risk of developing lymphoma increases in patients infected with the Ebstein-Barr virus (EBV, also known as human herpesvirus 4), and any causes of reduced immunity increase the oncogenic potential of the virus [3]. Although the use of immunosuppressive drugs in EBV-positive patients is associated with the risk of progression to lymphoma regardless of immunosenescence, it has been observed that this risk increases significantly only after the age of 50 years [4]. Patients infected with EBV in combination with DLBCL have a higher age distribution, aggressive clinical features, and frequent extranodal involvement, such as the lungs, upper aerodigestive tract, and gastrointestinal tract [5,6]. We present a unique case of a young patient with ulcerative colitis (UC), on immunosuppressive therapy due to liver transplantation, who was diagnosed with DLBCL. The symptoms initially suggested an exacerbation of the underlying disease (UC), which contributed to a delay in DLBCL diagnosis. Moreover, oncological treatment in a patient who treated with immunosuppressants due to liver transplantation is challenging and is associated with a much higher risk of failure [7]. This report describes a 22-year-old liver transplant patient with ulcerative colitis (UC) presenting with ileus and diffuse large B-cell lymphoma (DLBCL).

Case Report

A 22-year-old man was admitted to the Gastroenterology Clinic in August 2021 due to a suspected gastrointestinal obstruction. The patient’s history included a diagnosis of ulcerative colitis (UC) in 2015, and he underwent liver transplantation in 2018 due to liver failure in the course of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). The patient was under the regular surveillance of the Gastroenterology Clinic and Transplantation Clinic. At the time of the admission to the clinic, he reported having severe abdominal pain with moderate cramping and bloating, first observed a few weeks earlier. Due to the character of pain, the patient considered it as a symptom of mild ulcerative colitis course. The symptoms increased gradually, with abdominal bloating and obstruction.

Before being admitted to the hospital, treatment included oral mesalazine 2 g per day as maintenance therapy for ulcerative colitis and immunosuppression with mycophenolate mofetil 1000 mg per day in 2 divided doses and tacrolimus 5 mg in 2 divided doses, which he received after liver transplantation.

On the admission to the Clinic, he was generally in fair condition, with tenderness in the middle and lower abdomen and reduced motility of the large intestine. On the day of admission, laboratory blood tests revealed a slightly elevated CRP value of 17.9 mg/dl (normal range 0.08–3.1 mg/dl), but the other laboratory blood tests (eg, complete blood count with smear, ionogram, renal parameters) revealed no abnormalities, which did not correlate with severe flare-up of ulcerative colitis.

To assess the function of the transplanted liver, an evaluation of the liver panel (AST, ALT, bilirubin, ALP, GGTP), coagulation system panel (INR, PT, APTT), and a proteinogram were performed. These showed no irregularities. At the same time, to clarify the cause of the lack of bowel movements, an X-ray was performed, which showed dilated small-bowel loops measuring up to 40 mm, with fluid levels and radiological features of ileus/sub-ileus (Figure 1). The radiological features of megacolon toxicum were excluded. In the next stage, an abdominal ultrasound was performed, which revealed an enlarged spleen, free fluid in the peritoneal cavity, and a non-characteristic focal lesion in the lower abdomen measuring 80×50 mm with visible vascular flows and a centrally located intestinal lumen suggesting a conglomerate of inflamed intestinal loops.

Due to the splenomegaly and possibility of lymphatic system disease, uric acid and LDH levels were assessed, but they revealed no abnormalities. Stool tests were not conducted due to the inability to obtain an adequate sample for examination. Due to the detection of radiological abnormalities and the medical history, we decided to perform a sigmoidoscopy to assess the severity of the ulcerative colitis. The endoscope was introduced approximately 35 cm from the sphincter line. The examination of the relevant section of the large intestine revealed no evidence of the typical changes associated with active ulcerative colitis, and the endoscopic image was completely normal (Figure 2).

As the patient was on immunosuppressive therapy, there was a risk of opportunistic diseases developing. Confirmation of any of them would allow for precise direction of further diagnostics. Screening tests for antibodies against human immunodeficiency virus type 1, type 2 and the p24 antigen, cytomegalovirus, herpes simplex virus type 1 and 2, and Toxoplasma gondii in the IgM and IgG classes yielded negative results. The serological tests for EBV in the IgM class yielded negative results, whereas those in the IgG class were positive. A qualitative EBV DNA genetic assay identified the presence of the EBV virus.

In the following days, the patient’s general condition declined gradually, and he presented with new symptoms, including increased pain, vomiting, and diarrhea, which were indicative of a permeable obstruction. Furthermore, there was an observable increase in the size of the abdominal girth and cervical lymph nodes. A contrast-enhanced abdominal and pelvic computed tomography (CT) scan was performed, which revealed an irregular mass in the middle pelvis (above the urinary bladder) measuring 150×95×68 mm, which was compressing and modelling the surrounding intestinal loops (Figure 3A, 3B). A similar focal change with a diameter of up to 25 mm was observed around the described mass and in the periaortic space. The image indicated the presence of enlarged lymph nodes forming a conglomerate. A diagnosis of lymphoma was considered.

A consultation was held with a hematologist. An ultrasound of the lymph nodes of the neck and the supraclavicular region was performed to localize the enlarged lymph nodes. The ultrasound examination revealed the presence of enlarged lymph nodes with abnormal structure. The patient was qualified for a neck lymph node biopsy for histopathological evaluation. The biopsy result did not confirm the presence of a proliferative disease of the lymphatic system. The patient was referred for surgical consultation and was qualified for a percutaneous thick-needle biopsy of a conglomerate of lymph nodes in the abdominal cavity. A repeat biopsy demonstrated the presence of an aggressive peripheral B-cell lymphoma, specifically diffuse large B-cell lymphoma (DLBCL). Histopathological images are provided in Figure 4.

Serological tests for hepatitis B and C viruses were evaluated before beginning treatment. Their results were negative. Subsequently, following a consultation with the Transplant Clinic, mycophenolate was discontinued, prednisone at a dose of 20 mg/day was initiated, and the dose of tacrolimus was reduced to 2 mg 2 times daily.

The patient was transferred to the Hematology Clinic for further treatment, where he received a regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy, which was the standard treatment [8,9].

The patient had a significant improvement in overall condition following the initial course of chemotherapy, likely related to the dynamic breakdown of the tumor. He started to eat all meals and the abdominal pain and emesis ceased. Following the fourth cycle of chemotherapy, a positron emission tomography (PET)/CT scan was conducted, which demonstrated complete regression of the abdominal tumor and no enlargement of the lymph nodes, liver, or spleen. Following the sixth cycle of R-CHOP, no evidence of the proliferative process was observed in the PET/CT scan, with complete metabolic remission. The patient is being followed by the Hematology Clinic and is disease-free at 3-year follow-up. The gastrointestinal obstruction was caused by lymphoma and the symptoms were not associated with ulcerative colitis. A detailed timeline of symptom progression and treatment is included in Table 1.

Discussion

This case report emphasizes the necessity for clinicians to evaluate the oncogenesis risk associated with prolonged use of immunosuppressive agents and EBV-seropositive infection status [1,7]. DLBCL is the most common lymphoid malignancy. In Europe, the estimated incidence is approximately 12 cases per 100 000 population per year, with an age-related increase in prevalence. The etiology of the majority of DLBCLs remains unclear. A number of risk factors have been identified as having a proven causal relationship with the disease, including environmental, infectious, immunological, and iatrogenic factors [10]. A comprehensive clinical and physical evaluation, in conjunction with laboratory and imaging studies, is imperative for the diagnosis of lymphoma. Laboratory tests include complete blood count with smear, comprehensive metabolic profile (CMP), LDH, HIV and hepatitis B and C serologies, and proteinogram. Further diagnostic procedures include PET and CT scans to ascertain the stage of the disease, and excisional biopsy of the lymph node [11].

A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported. An EBV infection in patients with IBD can result in several complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD. Additionally, an EBV infection can lead to the progression of lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH), and DLBCL [5,12,13].

The link between immunosuppressive therapy and increased lymphoma risk is well established in solid organ transplantation patients [14,15]. Post-transplant lymphoproliferative disorder (PTLD) is defined as the proliferation of lymphoid cells in an immunocompromised state, caused by immunosuppressive agents that are used following the transplantation of solid organs or allogeneic stem cells. There has been a notable increase in the number of solid organ and stem cell transplants. Concurrently, the risk of graft rejection has diminished with use of more efficacious immunosuppressive agents. A significant disadvantage associated with the prolonged immunosuppression of these individuals is the emergence of a potentially fatal post-transplant lymphoproliferative disorder (PTLD) in up to 20% of transplant recipients [16,17]. The condition was first described by Doak et al (1968) in patients who had undergone solid organ transplantation. A multitude of risk factors increase the probability of a patient developing PTLD. Of these, the most significant are the degree of immunosuppression of T cells and the recipient’s EBV status [18,19]. Immunosupressive therapy and EBV-positive status resulted in development of lymphoma.

Patients with germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) respond well to 6 cycles of R-CHOP therapy, administered every 21 days. Patients with activated B-cells (ABC) respond well to R-CHOP therapy combined with lenalidomide, bortezomib, or ibrutinib. A more aggressive approach involves rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) therapy, followed by methotrexate and leucovorin. Studies have suggested using 6–8 cycles of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) in patients with advanced DLBCL with double translocations. Cytogenetical rearrangement and/or increased numbers of MYC, BCL2, and/or BCL6 copies in large B-cell lymphoma is called double/triple hit lymphoma (DHL/THL) due to molecular, biologic, and clinical similarities. Other regimens include (R-CHOP), bendamustine or cyclophosphamide, doxorubicin, and prednisone (R-CVP) [11,20]. Mycophenolate mofetil was the second immunosuppressive drug beyond tacrolimus added after liver transplantation. It was completely discontinued, and the dose of tacrolimus was reduced. Routinely, when starting oncological treatment, immunosuppressive therapy is always reduced, at least in the initial phases. Moreover, immunosuppressive regimens after liver transplantation allow the possibility of using tacrolimus with a steroid, which is included in the R-CHOP protocol. Mycophenolate mofetil was the second immunosuppressive drug (after tacrolimus) added after liver transplantation. It was completely discontinued, and the dose of tacrolimus was reduced. This is due to both potential interactions and adverse effects [21–23]. The therapeutic challenge was the risk of damage to the transplanted liver. Drugs used in chemotherapy have hepatotoxic potential, which may be an additional difficulty in a patient after liver transplantation, especially in the context of possible weaker repair mechanisms. Nevertheless, our patient’s liver tolerated the treatment well. The coexistence of ulcerative colitis can cause additional difficulties in the case of possible drug-induced colitis [24,25]. No intestinal complications of the hematological treatment were observed in our patient.

There was no correlation between ulcerative colitis and lymphoma. Immunosuppressive treatment was initiated after liver transplantation due to AIH and PSC. EBV infection in patients with IBD and immunosuppressive treatment can lead to development of DLBCL.

The present case was a major clinical challenge for many reasons. After the first symptoms appeared (abdominal pain and bloating), the patient did not immediately seek treatment, thinking that the symptoms were a normal phenomenon related to the periodic exacerbation of ulcerative colitis. Lymphomas are characterized by various and quite often non-specific symptoms, and one of the first can be the mass effect, as in our case, in which the clinical manifestation of lymphoma was related to its compression of the intestines. Since the patient had ulcerative colitis, he and the medical staff were guided first by the suspicion of an exacerbation of the underlying disease.

A similar case with mass effect was described by Deng et al, who presented the case of a young boy with intussusception of the ileum by Burkitt’s lymphoma. He had undergone laparotomy and R-CHOP therapy, with successful outcome [26]. Another case of colonic diffuse large B-cell lymphoma in a liver transplant (OLT) patient was described by Moore et al, describing a case of a 53-year-old man with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed cecal diffuse DLBCL. He was treated with CHOP-R chemotherapy and achieved remission [27]. The literature describes equally interesting cases of mass effect caused by DLBCL, such as pulmonary artery compression symptoms suggesting pulmonary embolism [28].

Because the symptoms of lymphoma are often non-specific and are only noticeable in advanced forms of the disease, screening tests should be considered in certain risk groups.

It seems rational to first determine the EBV status in immunosuppressed patients, including those who underwent liver transplantation. Thus, EBV-negative patients especially should avoid exposure to infection, and infected individuals should continue to undergo surveillance [6,16,29]. Unfortunately, there is no laboratory marker that meets the criteria for screening [22]. Routinely, after liver transplantation, peripheral blood counts and abdominal ultrasound are evaluated regularly, and can be useful in lymphoma screening [22,28]. Unfortunately, in our patient, the results of these tests did not suggest lymphoma at first. Although the results of uric acid and lactate dehydrogenase analysis were normal in the symptomatic phase, the available literature suggests their usefulness in diagnosis of lymphoma. The systematic evaluation of these laboratory parameters could contribute to improved surveillance for early diagnosis of lymphoma [30].

Conclusions

This case emphasizes that clinicians need to consider the risk of oncogenesis associated with the prolonged use of immunosuppressive agents and EBV-seropositive infection status. Screening for EBV before initiating immunosuppressive therapy should be compulsory. EBV-negative patients on immunosuppression must especially avoid EBV infection, while EBV-positive patients must be monitored more closely due to higher oncological risk.