Large B-Cell Lymphoma in an Adolescent Patient With Interleukin-10 Receptor Deficiency and History of Infantile Inflammatory Bowel Disease.

Abstract

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine1, 2 and loss of function mutations in IL-10 or the IL-10 receptor (IL-10R) have been implicated as a common cause of infantile IBD3, 4, 5, 6. These patients typically present in the first months of life with severe colitis, perianal disease, folliculitis, and, on occasion, arthritis, and are classically refractory to various immunosuppressive agents. Hematopoietic stem cell transplantation (HSCT) has been shown to be curative, but is not available for all patients4, 5, 6. The long-term risks of IL-10R-deficiency are unclear; however B-cell lymphomas have recently been reported in untransplanted young children with a known diagnosis of IL-10R deficiency7. Here we report the discovery of IL-10R deficiency in a patient who presented with severe IBD as an infant and developed a mature B cell lymphoma in adolescence. Through our interNational Early Onset Pediatric IBD Cohort Study (NEOPICS)/Care-for-Rare IBD Alliance we were referred a 15 year-old female patient with history of infantile IBD. She developed bloody diarrhea and anal fissures in the first weeks of life, failure to thrive and anemia requiring several blood transfusions by 6 months, and a rectovaginal fistula at 8 months of age. Endoscopic evaluation revealed severe pan-colitis, a distal colonic stricture, and pseudopolyps; biopsies demonstrated patchy areas of cryptitis, ulcerations, and lymphocytic infiltration. Her disease was resistant to various medications including steroids and aminosalicylates for the first 5 years, Imuran for the next 3 years, and combination of anti-TNF antibodies and methotrexate for 3 more years. Persistent symptoms led to a partial colectomy and colostomy at 8 months of age and at 5 years of age a subtotal colectomy, Hartmann's pouch construction, and permanent ileostomy. Despite these interventions, the patient continued to suffer from severe perianal fistulizing disease. At 12 years of age the patient presented with two months history of right-sided abdominal pain and hepatosplenomegaly. Blood tests demonstrated mild thrombocytopenia, hyperuricemia and abnormal liver tests (Table 1). An abdominal CT showed hepatosplenomegaly with multiple focal liver lesions accompanied by enlarged mesenteric lymph nodes, all confirmed to be hypermetabolic on PET scan (Figure 1). Liver biopsy revealed CD20 positive, EBV-encoded RNA (EBER)-negative small round blue cells leading to a diagnosis of mature large B cell lymphoma. Despite successful initial treatment with cyclophosphamide, vincristine, prednisone, ritixumab, cytarabine, doxorubicin as well as intrathecal methotrexate, cytarabine, and hydrocortisone, remission was maintained for only two years. At time of relapse at age 15, salvage chemotherapy of rituximab, ifosfamide, carboplatin, and etoposide was initiated and consolidation with autologous HSCT was being considered at the time of referral. Figure 1 Imaging and histology results at time of diagnosis with diffuse large B cell lymphoma Table 1 Laboratory results at presentation with diffuse large B cell lymphoma We performed IL-10R functional testing on freshly isolated peripheral blood mononuclear cells obtained from the patient and her father who served as a healthy control. Our flow cytometry-based assay measures IL-10-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a key transcription factor down-stream of the IL-10 receptor; IL-6-induced STAT3 phosphorylation serves as an internal positive control. While the patient's IL-6-dependent STAT3 phosphorylation was intact, IL-10-dependent phosphorylation of STAT3 was completely abrogated (Figure 2A), suggesting abnormalities in the IL-10 receptor or downstream signaling components. Targeted sequencing of IL10R genes revealed novel compound heterozygous mutations in IL10RB (NM000628.4) comprised of a variant on exon 2 (c. 172 A>G; p. S58R) leading to a serine to arginine substitution, predicted by PolyPhen analysis as highly deleterious, and a variant on exon 5 (c. 611 G>A; p. W204X) leading to a stop codon (Figure 2B). Additional functional assays with monocytes isolated from this patient, as well as other IL-10R deficient patients, demonstrating an increase in proinflammatory macrophage function and a defect in anti-inflammatory macrophage generation and function have been recently published 2. Since autologous HSCT would be predicted to be ineffective in patients with IL-10R deficiency given the broad requirement of IL-10-dependent signalling in the hematopoietic compartment, the patient was referred for allogeneic HSCT. Four months after matched unrelated allogeneic transplantation, the patient is fully engrafted without any signs of active colitis or lymphoma recurrence, and the rectovaginal fistula is resolving. Figure 2 Identification of loss of function mutations in IL10RB