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

• DOI: 10.1097/mpg.0000000000000532
• Publication Date: 2014-08-20T10:52:52Z
• Authors: Dror S. Shouval; Christen L. Ebens; Ryan Murchie; Katelyn McCann; Raja Rabah; Christoph Klein; Aleixo M. Muise; Scott B. Snapper
• Keywords: Pancolitis; Failure to Thrive

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine (1,2) and loss-of-function mutations in IL-10 or the receptor (IL-10R) have been implicated as common cause of infantile inflammatory bowel disease (IBD) (3–6). These patients typically present first months life with severe colitis, perianal disease, folliculitis, and, on occasion, arthritis, are classically refractory to various immunosuppressive agents. Hematopoietic stem cell transplantation (HSCT) has shown be curative, but not available for all (4–6). The long-term risks IL-10R deficiency unclear; however, B-cell lymphomas recently reported untransplanted young children known diagnosis (7). Here we report discovery patient who presented IBD an infant developed mature lymphoma adolescence. Through our interNational Early Onset Pediatric Cohort Study/Care-for-Rare Alliance were referred 15-year-old female history IBD. She bloody diarrhea anal fissures weeks life, failure thrive anemia requiring several blood transfusions by 6 months, rectovaginal fistula at 8 age. Endoscopic evaluation revealed pancolitis, distal colonic stricture, pseudopolyps; biopsies demonstrated patchy areas cryptitis, ulcerations, lymphocytic infiltration. Her was resistant medications including steroids aminosalicylates 5 years, Imuran next 3 combination anti-tumor necrosis factor antibodies methotrexate more years. Persistent symptoms led partial colectomy colostomy age years subtotal colectomy, Hartmann pouch construction, permanent ileostomy. Despite these interventions, continued experience fistulizing disease. At 12 2 right-sided abdominal pain hepatosplenomegaly. Blood tests mild thrombocytopenia, hyperuricemia, abnormal liver (Table 1). An computed tomography showed hepatosplenomegaly multiple focal lesions accompanied enlarged mesenteric lymph nodes, confirmed hypermetabolic positron emission scan (Fig. Liver biopsy CD20-positive, Epstein-Barr virus (EBV)-encoded RNA-negative small round blue cells leading large lymphoma. successful initial treatment cyclophosphamide, vincristine, prednisone, ritixumab, cytarabine, doxorubicin well intrathecal methotrexate, hydrocortisone, remission maintained only time relapse 15, salvage chemotherapy rituximab, ifosfamide, carboplatin, etoposide initiated consolidation autologous HSCT being considered referral.TABLE 1: Laboratory results presentation diffuse lymphomaFIGURE Imaging histology A, Abdominal showing (arrow pointing representative lesion) (B). C, Hematoxylin eosin staining (×40) numerous tumor cells.We performed functional testing freshly isolated peripheral mononuclear obtained from her father served healthy control. Our flow cytometry-based assay measures IL-10–induced phosphorylation signal transducer activator transcription (STAT3), which downstream receptor; IL-6–induced STAT3 serves internal positive While patient's IL-6–dependent intact, IL-10–dependent completely abrogated 2A), suggesting abnormalities signaling components. Targeted sequencing IL10R genes novel compound heterozygous IL10RB (NM_000628.4) comprising variant exon (c. 172 A>G; p. S58R) serine arginine substitution, predicted PolyPhen analysis highly deleterious, 611 G>A; W204X) stop codon 2B). Additional assays monocytes this patient, other IL-10R–deficient patients, demonstrating increase proinflammatory macrophage function defect generation published (2). Because would ineffective given broad requirement hematopoietic compartment, allogeneic HSCT. Four after matched unrelated transplantation, fully engrafted without any signs active colitis recurrence, resolving.FIGURE 2: Identification loss IL10RB. Functional assessing using cytometry. Peripheral control cultured stimuli (unstim.) 20 ng/mL 30 minutes. Stimulation IL-6 because it also induces phosphorylation. Cells then fixed, permeabilized, stained pSTAT3 (phosphorylated STAT3). B, heterozygote mutations.DISCUSSION health transplanted unknown. Although lack suitable donors cost, complexity, potential morbidity mortality prevent its widespread use. here had that surgical age-developed gene 15 altered plan A recent study Neven et al (7) association between In their report, 5/14 (36%) IL10RA did undergo HSCT-developed involving spleen, liver, bone, Tumor analyses characteristics EBV-negative containing monoclonal germinal center B Two additional cases EBV-positive elsewhere (5). precise mechanism how leads development unclear yet might related impaired immune surveillance. effective surveillance infiltrating CD8+ T cells. expressed response IL-10, increased interferon-γ granzyme secretion enhanced antitumor activity (8). Granzyme expression reduced Further support role finding dominant negative STAT3, molecule IL-10R, can develop (9). Finally, although postulated tumorigenesis may result thiopurine and/or antibody exposure (10–12), such contribution among subjects described remote tumors exposed suppression conclusion, case highlights critical importance pursuing presenting missed obviously delay appropriate curative intestinal inflammation places great risk developing This emphasizes parents remain elusive even Clinicians should aware complication pursue early course. Autologous therapy chemotherapy-refractory offered concomitant excluded. If feasible, steps implemented detection tumors. Gene replacement approaches, field evolves, warranted patients.