Hepatosplenic T-Cell Lymphoma in an Adolescent Patient after Immunomodulator and Biologic Therapy for Crohn Disease

Abstract

INTRODUCTION The risk of malignancy as a complication of Crohn disease has been well described (1-3). In addition to the established risk of colorectal cancer associated with inflammatory bowel disease, extraintestinal malignancies such as lymphoma have been reported. Areas of intestine with chronic inflammation resulting from mucosal injury may undergo malignant change secondary to accelerated cell turnover. Furthermore, the use of immunomodulatory treatments such as azathioprine and its metabolite 6-mercaptopurine (6MP) and biologic agents such as infliximab may affect immune surveillance, contributing to the development of lymphoma. The biologic agent infliximab, a tumor necrosis factor-α inhibitor, is becoming a therapeutic mainstay for refractory Crohn disease and is often used in conjunction with more traditional immunomodulatory therapy. This case represents the first report of lymphoma in a pediatric patient with Crohn disease undergoing treatment with infliximab and 6MP. CASE REPORT The patient was a 17-year-old female with ileocolonic Crohn disease complicated by perianal fistulae and growth failure. The patient's disease was diagnosed at the age of 12 years, and was initially treated with oral prednisone, hydrocortisone and mesalamine enemas, oral mesalamine and metronidazole. Seven months after diagnosis, 6MP was added because of persistent diarrhea and weight loss. Before the initiation of 6MP, the patient had normal liver enzymes. The patient developed increased hepatic transaminases 15 months after starting 6MP. Her daily dose was reduced from 75 mg to 50 mg (2.3 mg/kg per day to 1.6 mg/kg per day) orally, and her hepatic transaminases returned to normal. She did, however, have subsequent intermittent elevations in her liver enzymes until the diagnosis of lymphoma. The patient had multiple hospital admissions for disease exacerbations requiring intravenous corticosteroids. Forty-seven months after diagnosis, therapy with infliximab (5 mg/kg) was initiated, consisting of infusions at 0, 2 and 6 weeks with subsequent maintenance doses administered at intervals ranging from 5 to 8 weeks based on symptoms. Twenty-seven months after initiation of infliximab therapy, the patient developed fever, malaise and right upper quadrant abdominal pain. Physical examination was significant for hepatosplenomegaly. Laboratory evaluation was notable for a serum alanine aminotransferase of 690 IU/L, aspartate aminotransferase of 523 IU/L, alkaline phosphatase of 296 IU/L, gamma glutaryl transpeptidase of 119 IU/L, total protein of 8.7 g/dL, albumin of 3.7 g/dL, total immunoglobulins of 2060 mg/dL and leukocyte count of 3900/m L. Hemoglobin, platelet count, and total and conjugated bilirubin were normal. Autoimmune hepatitis serology revealed a positive anti-nuclear antibody (>1:1280) with negative anti-liver kidney microsomal and anti-smooth muscle antibodies. Evaluation for infectious etiologies included hepatitis A, B, and C, cytomegalovirus, Epstein-Barr virus, and Bartonella serologies. A computed tomography scan of the abdomen showed splenomegaly with enlargement of the portal vein. A liver biopsy was performed, and the patient was given a presumptive diagnosis of autoimmune hepatitis. Medications at this time included mesalamine 3 g daily, 6MP 50 mg daily and infliximab every 5 to 8 weeks. The patient was started on prednisone and infliximab infusions were continued as required to control her inflammatory bowel disease, but 6MP and mesalamine were temporarily discontinued because of concerns that these agents were exacerbating the hepatitis. Despite initiating therapy with prednisone and discontinuing 6MP and mesalamine, the hepatic transaminases remained increased, and the patient was evaluated at our institution for a second opinion. On review of the original liver biopsy, marked clustering of atypical lymphocytes with irregular, frequently angulated nuclei and one or two prominent nucleoli was noted within the sinusoids and especially around the central veins with parenchymal collapse (Figure 1). Immunohistochemistry performed on paraffin sections revealed that the atypical lymphoid infiltrate stained positively for CD2, CD43, TIA-1 and beta-F1, supporting a diagnosis of a malignant T-cell lymphoma of alpha-beta type. The cells were negative for CD20, CD68, lysozyme, CD34, myeloperoxidase and granzyme B. Cytogenetics showed the presence of isochrome 7q and trisomy 8, typical of hepatosplenic T-cell lymphoma. Additionally, in situ hybridization for Epstein-Barr virus was negative, not supporting the diagnosis of an immunosuppression-related lymphoproliferation such as that seen after organ transplant. A repeat liver biopsy was performed, as was bone marrow aspiration. The bone marrow aspiration was unremarkable, but the repeat liver biopsy was histologically and immunohistochemically identical with the first. By the time the diagnosis was made, the patient had received a total of 20 5 mg/kg doses of infliximab during a 29-month period and had received 50 to 75 mg (1.3 to 2.3 mg/kg per day) of 6 MP daily for 4.5 years. The patient received a course of neoadjuvant chemotherapy in preparation for bone marrow transplant. Her course was complicated by pancytopenia and sepsis, and she died 3 months after diagnosis. Autopsy was not performed.FIG. 1: A. The needle liver biopsy is characterized by a marked centrilobular clustering of atypical T-lymphocytes, obliterating the vein, with hemorrhage and collapse of the surrounding parenchyma. Atypical T-lymphocytes are also scattered throughout the sinusoids (Hematoxylin-eosin, ×100) B. A higher power view demonstrates the atypical lymphoid infiltrate in the pericentral area and infiltrating surrounding sinusoids (Hematoxylin-eosin, ×400).DISCUSSION Comprising fewer than 5% of peripheral T-cell lymphomas, hepatosplenic T-cell lymphoma is a rare neoplasm characterized histologically by lymphoid infiltrates within the liver, spleen and bone marrow (4,5). Of approximately 100 identified cases, the majority express the γδ T-cell receptor gene rearrangement. Only 18 cases expressing the αβ T-cell receptor have been reported (6-8). Clinical presentation includes hepatosplenomegaly, fever, weight loss and malaise in the absence of peripheral lymphadenopathy. The tumor is extremely aggressive, and overall median survival with maximal therapy is less than 1 year. Cases of this type of lymphoma in immunocompromised patients have been described after organ transplant (9). Review of the existing literature reveals a case of hepatosplenic T-cell lymphoma of the γδ subtype in a 35-year-old male patient with Crohn disease treated with azathioprine (10). The patient had been diagnosed with Crohn disease at the age of 20 years and had been treated with 5-aminosalycilates and intermittent steroids for 10 years and azathioprine for 5.5 years. He presented with hepatosplenomegaly, malaise and night sweats. The patient completed six cycles of chemotherapy, had a splenectomy and bone marrow transplantation and died of a subphrenic abscess postoperatively. Colorectal cancer is a recognized complication of inflammatory bowel disease. The development of other malignancies, specifically lymphomas, in patients with Crohn disease is also well documented, raising the issue of whether these patients are at an increased risk for lymphoma even in the absence of immunomodulatory therapy compared with the general population. Despite initial evidence suggesting that patients with Crohn disease may have an increased baseline risk of lymphoma, a retrospective cohort study of nearly 17,000 patients with inflammatory bowel disease concluded that there is no increased disease-related risk of lymphoma (11). However, the increased risk of lymphoma in Crohn disease conferred by azathioprine and 6MP remains controversial. Overall, long-term data on lymphoma in this patient population is lacking (12,13). Accepting the possibility of a minimally increased risk, formal decision analysis has demonstrated increased quality-adjusted life expectancy for patients with Crohn disease who use azathioprine for the maintenance of remission and that treatment benefits outweigh lymphoma risk (14). Further, the benefits of azathioprine therapy are particularly significant in younger patients, who have a lower baseline risk of developing lymphoma. Recent case reports link therapy with infliximab and the development of lymphoma (15). A retrospective review of 500 patients treated with infliximab reveals that nine patients developed a malignancy during therapy with infliximab; one malignancy was a Hodgkin's lymphoma (16). The rate of malignancy of 1.5% noted in this study is comparable to that of 1% in the ACCENT I trial, which found the risk of malignancy to be no higher than expected in the general population (17). Of the nine malignancies in this recent study, there was one case of Hodgkin's lymphoma and one case of non-Hodgkins lymphoma. Both patients who developed lymphoma were male, aged 70 years and 55 years, and they also had undergone concomitant immunosuppression with azathioprine. One patient received three infusions of infliximab during 5 months, and the other received four infusions over a 6-year period. Immunosuppression-related lymphoproliferations, which are associated with Epstein-Barr virus and behave similarly to post-transplant lymphoproliferative disorder, may develop in patients who have not undergone organ transplantation but are otherwise immunosuppressed. Epstein-Barr virus-positive lymphomas have been found with minimally increased frequency in patients with inflammatory bowel disease undergoing therapy with azathioprine or 6MP (18). Epstein-Barr virus-positive lymphomas have not been reported in patients with inflammatory bowel disease treated with infliximab, and in the short term, infliximab does not appear to alter Epstein-Barr viral load in patients with Crohn disease (19). Nevertheless, the entity of immunosuppression-related lymphoma should be excluded in all patients with inflammatory bowel disease who develop lymphoma and are receiving infliximab or other forms of immunosuppression because therapy for this condition rests on cessation of immunosuppression. In summary, we describe a pediatric patient with Crohn disease who developed hepatosplenic T-cell lymphoma after therapy with 6MP and infliximab. Although an exceedingly rare complication, the presence of hepatosplenomegaly and laboratory abnormalities in the context of immunomodulatory and biologic therapy should raise the index of suspicion for malignancy, especially in light of the growing number of pediatric patients maintained on infliximab and immunomodulators such as 6MP. As the duration of treatment with immunosuppressive agents in patients with childhood-onset inflammatory bowel disease may span decades, increased vigilance for long-term consequences such as malignancy is warranted. Formal mechanisms for following large cohorts of these patients should be developed. Acknowledgment: The authors would like to acknowledge Lawrence J. Burgart, MD, for his contribution to this report.