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Langerhans cell histiocytosis (LCH) is a rare disease primarily occurring in children, and commonly involves the bone and skin; gastrointestinal tract involvement is notably rare. The incidence and significance of gastrointestinal lesions in adult LCH are unclear; thus, we aimed to investigate adult Japanese cases of LCH and clarify the features of gastrointestinal involvement. We gathered clinical information on 43 Japanese cases of adult LCH and analyzed patient backgrounds, affected organs, features of the gastrointestinal lesions, and the clinical courses. Thirteen patients underwent endoscopic examinations: an upper gastrointestinal endoscopy alone in 5, lower gastrointestinal endoscopy alone in 3, and both in 5 patients. A gastric lesion (one case), colonic lesion (one case), and both gastric and rectal lesions (one case) were detected. The three cases of gastrointestinal involvement also exhibited nongastrointestinal multisystem LCH lesions and showed no gastrointestinal symptoms or increased uptake on positron emission tomography. Endoscopy revealed small erosions without specific features; histological examinations were required for diagnosis. These three cases were treated with chemotherapy, comprising vinblastine/prednisolone, methotrexate, and daily 6-mercaptopurine, for 36 weeks; in two cases, the clinical condition remained stable for several years post-treatment. One case showed recurrence 1 year 7 months after treatment, and chemotherapy was re-administered. No case with single-system disease exhibited gastrointestinal involvement. Although gastrointestinal LCH lesions are rare, they were more common than expected in our cases of multisystem LCH. However, these lesions were relatively small and did not affect the patients’ clinical courses.

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

Epstein-Barr virus (EBV) reactivation causes serious diseases in immunocompromised hosts, such as acquired immunodeficiency syndrome (AIDS). We report on a case of plasmablastic lymphoma (PBL) with hemophagocytic lymphohistiocytosis (HLH).A-53-year-old Japanese man was diagnosed with PBL and AIDS. In addition to combined antiretroviral therapy, HyperCVAD (cyclophosphamide, doxorubicin, vincristine, prednisone)/high-dose methotrexate + cytarabine was initiated immediately. Partial remission was attained with chemotherapy. However, the patient developed HLH and died despite intensive therapy. Autopsy findings suggested that PBL was controlled, and immunosuppression appeared to cause fatal infection. The patient showed high titers of EBV viral-capsid antigen (VCA)-IgG (1:2560) on PBL diagnosis and high EBV-DNA levels throughout the clinical course. Moreover, EBV-DNA was detected in the fraction of CD8-positive cells, which strongly supports the pathogenesis of EBV-associated HLH.Our report highlights the importance of EBV control in patients with EBV-positive AIDS lymphoma. EBV not only behaves as the etiologic pathogen of PBL but also can be a trigger of HLH, the fatal complication. Careful follow-up of the EBV status should be performed, and if needed, preemptive anti-EBV therapy should also be considered to prevent EBV-associated complications such as HLH.

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

A 67-year-old woman presented with a swelling on both sides of the neck. Biopsy of an enlarged cervical lymph node on the left side and flow cytometric analysis revealed CD56-positive CD4(+)CD8(+) abnormal NK/T cells. A Southern blot analysis of the cervical lymph node biopsy specimen showed a human T-cell leukemia virus type 1 provirus DNA monoclonal band. Based on these findings, the patient was diagnosed with CD56-positive adult T-cell leukemia/lymphoma. After five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, the general condition of the patient gradually declined, indicating resistance to treatment, and approximately 9 months after the onset of symptoms, the patient died. CD56 is recognized as an unfavorable prognostic marker in cases of acute myeloid leukemia with t(8;21), acute promyelocytic leukemia, and anaplastic large cell lymphoma. Only eight cases of CD56-positive adult T-cell leukemia/lymphoma have been reported so far in the literature. Most of these cases were in the advanced stage at diagnosis and had poor outcomes. It appears that the correlation between CD56 expression and outcomes in patients with adult T-cell leukemia/lymphoma should be clarified by investigating a larger number of cases in the future.

Dear Editor, The clinical courses of patients with malignant lymphoma are sometimes complicated with the occurrence of another type of lymphoma. Comorbid lymphoma can occur in the form of transformation, composite lymphoma, ormultiple primary lymphomas. Here, we present a patient with Waldenstrom’s macrogloblinemia/lymphoplasmacytic lymphoma (WM/LPL) who was subsequently diagnosed with adrenal diffuse large B cell lymphoma (DLBCL). A 69-year-old Japanese male was referred to our hospital for a work-up of positron emission tomography (PET)-avid bilateral adrenal nodular lesions, incidentally noticed at a yearly health check (Fig. 1a). The image study was not suggestive of neoplastic involvement of other organs, including the lymph nodes and spleen. An increased serum IgM (4184 mg/dl) with a monoclonal component was documented. Bone marrow examination revealed a collection of small lymphoid cells and plasma cells (Fig. 1b). They were immunohistochemically positive for CD20 and kappa and negative for CD5, CD10, CD23, and cyclin D1. CD38 was positive in the plasma cells and negative in the lymphoid cells. TheMIB-1 index was less than 5%.MYD88 L265Pmutation was detected by polymerase chain reaction (PCR) and gene sequence techniques. He was diagnosed with WM/LPL. Although the level of IgM was gradually increasing, he was observed without treatment because of the absence of symptoms related to WM/LPL. The PET finding of adrenal lesions showed no remarkable change 3 months later. He presented with severe general malaise 10 months after the diagnosis of WM/LPL. A blood examination showed surges in the values of lactate dehydrogenase (700 IU/l) and soluble interleukin-2 receptor (11,200 U/ml), and computed tomography (CT) revealed an obvious enlargement of the adrenal lesions (Fig. 1c). Unilateral CT-guided biopsy was performed, and the invasion of large lymphocytes with nuclear debris was documented (Fig. 1d). These lymphocytes were positive for CD20 and MUM1 and negative for CD5, CD10, BCL2, BCL6, and EBER-ISH. The MIB-1 index was approximately 95 %. A split signal of c-myc was not observed by fluorescence in situ hybridization assay. Based on this combination of findings, we diagnosed adrenal DLBCL with probable bilateral involvements. Six cycles of R-CHOP (rituximab, doxorubicin, vincristine, cyclophosphamide, and prednisolone) resulted in a complete response. In order to clarify the clonal relatedness betweenWM/LPL and DLBCL, we carried out an analysis of immunoglobulin heavy chain (IGH) clonality with specimens of bone marrow and adrenal gland using commercially available PCR-based kits (Invivoscribe Technologies, San Diego, CA) [1]. The PCR products underwent direct sequencing and were analyzed by IMGT/V-QUEST [2]. The resultant sequence data showed that WM/LPL cells utilized rearranged the VH4-39 gene whereas DLBCL cells utilized rearranged the VH1-46 gene. There have been just a few reports on the concomitant occurrence of WM/LPL and DLBCL [3]. In such cases, DLBCL can either be clonally related or unrelated to WM/ LPL [4–7]. While the transformation of WM/LPL into DLBCL has been recognized, the coincidence of different * Sumito Shingaki shinpth2@tmd.ac.jp

Dear Editor, Eosinophilic gastroenteritis is characterized by symptoms such as abdominal pain, diarrhea, nausea, and marked eosinophilic infiltration into the gastrointestinal tissue. Several reports have shown that eosinophilic gastroenteritis occurred in patients after hematopoietic stem cell transplantation (HSCT) [1–3]. We herein report an adult case with myelodysplastic/ myeloproliferative disease, unclassifiable (MDS/MPD-U) that subsequently developed eosinophilic gastroenteritis after allogeneic bone marrow transplantation (BMT). A 46-year-oldmanwithMDS/MPD-U received azacitidine treatment. Thereafter, he underwent allogeneic BMT from a human leukocyte antigen-matched sibling donor with a conditioning regimen comprising 12 Gy of total body irradiation and high-dose cytarabine because the response to azacitidine was gradually lost. Prophylaxis for graft-versus-host disease (GVHD) consisted of intravenous cyclosporine and shortterm methotrexate. The patient had evidence of grade II acute GVHD of the skin, which required no steroid treatment. On day 122, he developed watery diarrhea with colicky abdominal pain under oral cyclosporine (100 mg/day). A colonoscopic examination revealed mucosal edema, erosion, and shallow ulceration in the cecum to the ascending colon and from the sigmoid colon to the rectum (Fig. 1a). A histological examination of several biopsy specimens of the colon revealed intense infiltration of eosinophils in the lamina propria (Fig. 1b). Based on these findings, the patient was diagnosed with eosinophilic gastroenteritis. His abdominal symptoms were resolved under fasting conditions without any treatment. Follow-up colonoscopy showed complete resolution of the eosinophilic infiltration of random biopsy specimens of the colon. He has not experienced a recurrence of eosinophilic gastroenteritis 1 year after the initial episode. Gastrointestinal complications after allogeneic HSCT can arise due to various causes, such as regimen-related toxicity, GVHD, and infection. In our patient, the histological characteristics of GVHD, such as apoptosis and destruction of crypt epithelial cells, and lymphocyte infiltration of the epithelium and lamina propria, were almost never found in the biopsy specimens of the colon. In addition, the histological findings showed negative immunostaining for cytomegalovirus (CMV). These findings indicated that the diagnosis of intestinal GVHD and CMV colitis could be excluded for our patient. The diagnosis of eosinophilic gastroenteritis is based on the clinical symptoms and histological findings, including eosinophilic infiltration in one or more areas of the gastrointestinal tract, defined as 20 or more eosinophils per high-power field [4]. These findings are compatible with those of our patient. The majority of cases of eosinophilic gastroenteritis have a history of allergy, hypereosinophilia, and elevated serum IgE levels. Therefore, eosinophilic gastroenteritis is closely related to allergic disease [5]. Although our patient and his donor did not have any past history of allergy or hypereosinophilia, the serum IgE level was slightly elevated to 191 IU/mL (upper limit of normal, 173 IU/mL) at the time of the diagnosis of eosinophilic gastroenteritis. In addition, fasting conditions without steroid treatment resulted in improved symptoms in our patient, suggesting that a food allergy might have been associated with the eosinophilic gastroenteritis. This case * Takaaki Konuma tkonuma@ims.u-tokyo.ac.jp

Background and aims Spontaneous gastric perforation in the absence of chemotherapy is extremely rare. The authors encountered a case of spontaneous perforation of primary gastric lymphoma. Case presentation A 58-year-old man visited the authors’ hospital with acute severe epigastralgia. A large amount of free gas and a fluid collection around the stomach were noted on an abdominal computed tomography scan. The results of imaging studies indicated a perforated gastric ulcer, and a distal gastrectomy was performed. There was a large perforation about 50 mm in diameter in the anterior wall of the middle part of the stomach body. Microscopically, the full thickness of the gastric wall was diffusely infiltrated by a population of large atypical lymphoid cells. The lymphoid nature of these cells was indicated by the strongly positive immunohistochemical staining for CD20 and CD10. This confirmed the diagnosis of a germinal center B-cell-like type of diffuse large B cell lymphoma. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone were administered after the operation. Results and conclusion Gastrectomy should be considered if a giant ulcer with necrotic matter on the ulcer floor is seen on upper gastrointestinal endoscopy because of the possibility of gastric perforation. If upper gastrointestinal endoscopy shows a finding similar to the abovementioned one during chemotherapy, dose reduction of chemotherapy or gastrectomy should be considered.