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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.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2‐step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN‐2B) plus interferon‐β (IFNβ); (ii) SVN‐2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN‐2B plus IFNβ. The primary endpoint was progression‐free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty‐three patients were randomly assigned to receive SVN‐2B plus IFNβ (n = 30), SVN‐2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B‐specific CTLs were found to be increased in the SVN‐2B plus IFNβ group by tetramer assay. Among patients who participated in Step 2, those who had received SVN‐2B plus IFNβ in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN‐2B plus IFNβ did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN‐2B plus IFNβ vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).

Background Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. Methods We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. Results The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. Conclusions The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Although primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) causes various symptoms depending on the tumor region, there has been no previous report of PCNS-PTLD in the cerebellopontine angle that was diagnosed due to peripheral facial nerve palsy. We herein report a case involving a 62-year-old man with PCNS-PTLD in the cerebellopontine angle who was diagnosed due to peripheral facial nerve palsy. The reduction of immunosuppressive therapy, whole-brain radiotherapy, intrathecal chemotherapy, and rituximab were effective in treating this patient. Physicians should therefore be mindful that PCNS-PTLD can cause peripheral facial nerve palsy in renal transplant recipients.

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.

Patient: Male, 27 Final Diagnosis: Secondary syphilis Symptoms: Fever • loss of appetite • neck mass • night sweats • weight loss Medication: Oral amoxicillin Clinical Procedure: Lymph node biopsy Specialty: Infectious Diseases Objective: Challenging differential diagnosis Background: Syphilis is a sexually transmitted disease caused by the pathogen Treponema pallidum. Prevalence continues to rise, especially among men who have sex with men (MSM). Due to changes in patterns of sexual activity, manifestations of the disease are highly variable. Case Report: A 27-year-old male visited the hospital for a low-grade fever and tender 5-cm mass in the right side of his neck. His right tonsil was swollen and covered with a white coating. Levofloxacin was prescribed, but ineffective. The patient’s levels of liver function enzymes increased gradually. Systemic magnetic resonance imaging (MRI) revealed bilateral cervical lymphadenopathy with right predominance, a right pulmonary nodule, and a periportal lymph node, suggestive of malignant lymphoma. However, a biopsy of the right cervical lymph node showed nonspecific inflammation. Preoperative rapid plasma reagin (RPR) and T. pallidum latex agglutination (TPLA) tests were positive. The patient was MSM and reported oral sex with many sexual partners. A diagnosis of secondary syphilis was made. Oral amoxicillin was effective, and all symptoms other than periportal lymph node resolved. Conclusions: Tonsillitis, cervical lymphadenopathy, and lung lesions can be manifestations of secondary syphilis. A detailed history, pathology, and serology are crucial for diagnosis.

Aims Indolent T-lymphoblastic proliferation (iT-LBP) is a non-clonal benign condition showing extrathymic proliferation of T-lymphoblasts positive for CD3, CD4, CD8, and TdT. Isolated iT-LBP has been observed, but the majority of iT-LBP have been seen in conjunction with other disorders including Castleman disease, hepatocellular carcinoma, follicular dendritic cell tumors, angioimmunoblastic T-cell lymphoma, myasthenia gravis, and acinic cell carcinoma (ACC). The clinical course of iT-LBP is indolent, and no therapy is usually required. A major concern is misdiagnosis for T-lymphoblastic lymphoma, and a correct diagnosis of iT-LBP often requires not only pathological analysis but also a cautious monitoring of the clinical course. The aim of this report is to broaden knowledge of this yet not well recognized entity to pathologists and physicians Methods and Results We report a case of iT-LBP concomitant to ACC, along with a literature review of all 14 cases of iT-LBP reported to date Conclusions iT-LBP should always be considered as a differential diagnosis of T-lymphoblastic lymphoma as the two disorders show extremely resembling traits. This article is protected by copyright. All rights reserved.

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 48-year-old man was admitted due to marked leukocytosis. Bone marrow examinations resulted in a diagnosis of Philadelphia (Ph) chromosome-positive chronic myeloid leukemia. One month later, massive muscle and bone invasion by leukemic cells was detected. After induction chemotherapy, he complained of a headache and visual loss, which was caused by a leukemic infiltration in the central nervous system. After temporary remission in response to chemotherapy, the disease relapsed in the form of an intracranial tumor. The unusual t(14;22)(q24;q11.2) translocation of the Ph-chromosome and the significant increase in monocytes observed might have contributed to the unique and aggressive clinical course.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN‐2B), a 9‐mer antigenic peptide encoded by survivin, and an SVN‐2B peptide vaccine‐based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN‐2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN‐2B peptide vaccination and 6 who had not, as negative controls. The expression of immune‐related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme‐linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN‐2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN‐2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor‐specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

Previous worldwide epidemiological studies on lymphoid leukemia and/or lymphoma (LL/L) had considerable bias because of difficulty in covering all clinical departments of hospitals in a restricted area (population base). These studies may not have reflected the actual number of newly diagnosed cases (incidence) strictly, or the true LL/L subtype frequencies. We searched all cases of newly diagnosed LL/L in Miyagi Prefecture over a 5-year period, including those that were discovered as LL/L sorely after autopsy. We registered the actual number of 2098 cases in the prefecture and calculated an accurate incidence rate (17.8 per 100,000 persons). Additionally, we identified more realistic and detailed frequencies of LL/L subtypes including the leukemic phase of some lymphomas. As Miyagi Prefecture is an area in which the population dynamics are relatively stable and representative of Japan, the result of our epidemiological study can be used as the first representative index of LL/L for Japan.

Mucormycosis is an opportunistic infection occurring in immunocompromised hosts with hematological malignancies. Mortality due to mucormycosis in patients with hematological malignancies is high. However, the clinical symptoms of mucormycosis are poorly characterized, and diagnosis is difficult due to the lack of specific culture or serological markers or antigens. We present two cases in which nested polymerase chain reaction with specific primers was used in the serum of patients with hematological malignancies.

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin lymphoma that proliferates in body cavities without detectable masses. PEL is universally associated with human herpes virus-8 (HHV-8) infection and has an aggressive prognosis. Recently, an HHV-8-unrelated PEL-like lymphoma that usually occurs in elderly individuals and follows a more indolent prognosis has been reported, and it is treated as a disease distinct from PEL. However, its pathogenesis and prognostic factors have not been sufficiently clarified. In PEL-like lymphoma accompanied by Epstein-Barr virus (EBV) infection, latent infection types are not mentioned in the literature. Herein, we report the case of an 85-year-old Japanese man with pericardial PEL-like lymphoma who showed good improvement in condition for 24 months after pericardiocentesis without chemotherapy. Serological test results were positive for EBV capsid antigen and EBV nuclear antigen 2 (EBNA2), but negative for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. The disease phenotype and EBV infection mechanism were immunohistochemically investigated by the cellblock prepared from pericardial effusion. Atypical cells were positive for CD20, CD30, CD45, BCL2, MUM1, EBNA2, latent membrane protein 1, and EBV-encoded RNA (on in situ hybridization), but negative for CD3, CD5, CD10, CD138, cytokeratin AE1/AE3, and HHV-8. Accordingly, this case was considered to be a B-cell activated phenotype with a type III latent EBV infection. Type III latent EBV infection is unusual in PEL.

Plasmablastic lymphoma (PBL) is a rare AIDS-related malignancy with a poor prognosis. Little is known about this entity, and no standard treatment regimen has been defined. To establish an adequate treatment strategy, we investigated 24 cases of PBL arising in human immunodeficiency virus-positive individuals. Most of the patients were in the AIDS stage, with a median CD4 count of 67.5/µL. Lymph nodes (58 %), gastrointestinal tract (42 %), bone marrow (39 %), oral cavity (38 %), and CNS (18 %) were the most commonly involved sites. Histology findings for the following were positive at varying rates, as follows: CD10 (56 %); CD30 (39 %); CD38 (87 %); MUM-1 (91 %); CD138 (79 %); EBER (91 %); and LMP-1 (18 %). There was a marked increase in patients in 2011–12, and the cases found in that period appeared to be more aggressive, showing a higher rate of advanced-stage PBL. Fourteen cases were treated with CHOP, while the others were treated with more intensive regimens, including bortezomib and hematopoietic stem cell transplantation. The overall median survival time was 15 months. A CD4 count of >100/µL at diagnosis and attaining complete remission in the first-line chemotherapy were associated with better outcomes (P = 0.027 and 0.0016, respectively). Host immune status and chemosensitivity are associated with improved prognosis in PBL.

We report the case of a 35-year-old woman with chronic active Epstein-Barr virus (EBV) infection (CAEBV). She underwent allogeneic bone marrow transplantation (BMT) from an unrelated male donor and achieved a complete response. However, her CAEBV relapsed one year after BMT. EBV-infected cells proliferated clonally and revealed a 46XY karyotype. In addition, the infecting EBV strain differed from that detected before BMT. These findings indicated that her disease had developed from donor cells. This is the first report of donor cell-derived CAEBV that recurred after transplantation, suggesting that host factors may be responsible for the development of this disease.

Umbilical cord blood transplantation (CBT) is widely accepted, but one critical issue for adult patients is a low engraftment rate, of which one cause is haemophagocytic syndrome (HPS). We aimed to identify the contribution of HPS to engraftment failure after CBT, following preparative regimens containing fludarabine phosphate, in 119 patients (median age, 55 years; range; 17-69 years) with haematological diseases. Graft-versus-host disease prophylaxis comprised continuous infusion of a calcineurin inhibitor with or without mycophenolate mofetil. Of the 119 patients, 20 developed HPS within a median of 15 d (cumulative incidence; 16.8%) and 17 of them did so before engraftment. Donor-dominant chimaerism was confirmed in 16 of 18 evaluable patients with HPS. Despite aggressive interventions including corticosteroid, ciclosporin, high-dose immunoglobulin and/or etoposide, engraftment failed in 14 of 18 patients. Of these 14 patients, four received second rescue transplantation and all resulted in successful engraftment. Overall survival rates significantly differed between patients with and without HPS (15.0% vs. 35.4%; P < 0.01). Univariate and multivariate analysis identified having fewer infused CD34(+) cells as a significant risk factor for the development of HPS (P = 0.01 and 0.006, respectively). We concluded that engraftment failure closely correlated with HPS in our cohort, which negatively impacted overall survival after CBT.

金沢大学医薬保健研究域医学系, Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P

Transient elastography (TE) is a novel, non-invasive imaging technique for measuring liver stiffness (LS). It is considered to be useful for predicting the severity of fibrosis and the risk of cirrhosis or hepatocellular carcinoma. However, the association between the presence of diffuse regions of increased cell density in the liver and elevated LS values has not been assessed. We experienced a case in which a mature T-cell neoplasm had invaded the liver, but the infiltrating lesion was not detected by contrast-enhanced computed tomography (CT) or fluorodeoxyglucose positron emission tomography/CT scans. Instead, the tumor’s presence was indicated by the change in the patient’s TE-derived LS values after chemotherapy. At diagnosis liver dysfunction was detected in a biochemical examination, and mean LS value was as high as 25.4 kPa [interquartile range (IQR): 0.3, success rate (SR):100%]. After chemotherapy, the patient’s mean LS value fell to 4.3 kPa (IQR: 0.8, SR:100%). A follow-up pathological investigation demonstrated that proliferating abnormal T-cells were no longer present in the patient’s liver. This is the first report to describe the use of LS data to support a diagnosis of liver infiltration by tumor cells exhibiting a portal and sinusoidal distribution pattern rather than a focal pattern. Elevated TE-derived LS values should lead to hepatic tumor infiltration being considered during initial examinations or a suspicion of recurrence during follow-up examination of lymphoma patients who achieve complete remission, even when radiological investigations do not detect abnormalities in the liver.

A 46-year-old man presented with a high-grade fever, multiple lymphadenopathies, hepatosplenomegaly and human immunodeficiency virus (HIV) seropositivity, without severe immunosuppression. We suspected human herpesvirus-8 (HHV-8)-associated multicentric Castleman's disease (MCD) based on the results of a physical examination and laboratory investigations, including bone marrow aspiration. However, the patient died eight days after admission due to multiorgan failure. An autopsy revealed MCD and lymphoma cell infiltration in multiple organs. The final diagnosis was large B-cell lymphoma (LBCL) arising in HHV-8-associated MCD. This case illustrates the potential for LBCL in HHV-8 MCD in HIV-infected patients with hepatosplenomegaly and lymphadenopathy without severe immunosuppression and highlights the clinical significance of bone marrow aspiration.

Acute graft-versus-host disease (GVHD) occurring within 100 days post-transplant is one of critical factors influencing prognosis in transplant recipients. Among cases of GVHD of the gastrointestinal (GI) tract, GVHD rarely affects the upper GI. In this study, we retrospectively examined the frequency of upper GI GVHD and diagnostic accuracy.From among 868 patients who underwent allogeneic hematopoietic stem cell transplantation at our hospital between January 2005 and June 2012, 115 of whom underwent biopsy for upper GI symptoms. The endoscopic findings and histologic diagnosis from these 115 patients were retrospectively analyzed.GVHD was histologically diagnosed in 85 patients overall (9.8% of all 868 transplant recipients). Although gastric mucosal exfoliation was not commonly observed, this endoscopic finding when used as a diagnostic predictor had both a specificity and positive predictive value (PPV) of 100%. When using redness, luster, and mucosal change as predictors, specificity and PPV were relatively high, suggesting that these gastric endoscopic findings are useful in the diagnosis of upper GI GVHD. Among the duodenal endoscopic findings, erosion as a diagnostic predictor had both a high specificity and PPV. The biopsy results often lead to a diagnosis of GVHD even in cases judged to be endoscopically normal.Among the gastric endoscopic findings, mucosal exfoliation, although rare, and redness, luster, and mucosal change are likely to be useful diagnostic predictors of upper GI GVHD. GVHD was frequently diagnosed in patients with endoscopically normal duodenum, suggesting that biopsies are important for definitive diagnosis.

The patient was a 73-year-old male who came to our hospital with a chief complaint of pain and swelling of the left side of his jaw. Computed tomography revealed a mass in his left gingiva but no bone destruction. No lesions were observed at any other sites, and an incisional biopsy was performed on the gingival mass on the left side. Histologically, the mass was a diffuse large B-cell lymphoma (DLBCL), and it was CD20-positive, and CD5-negative, CD10-negative, surface immunoglobulin-negative, and Epstein-Barr virus-encoded RNA (EBER)-negative. A serum Human immunodeficiency virus (HIV)-antibody test was negative. A complete remission was achieved after 6 courses of systemic combination chemotherapy, and the complete remission has been maintained for approximately 3 years. According to the literature, primary gingival DLBCL have a high Ki-67-positive rate and many of the cases are stage I and international prognostic index low-risk. However, HIV patients have a high EBER-positive rate and a high risk of developing a CD20-negative, CD138-positive plasmablastic lymphoma, and they have a poor prognosis. By contrast, limited-stage primary gingival lymphomas whose data can be used have been rare in human immunodeficiency virus-negative patients, and only 12 cases, including our own, have ever been reported. Many of the patients have been around 65 years of age, and all of the cases have been CD20-positive, CD138-negative DLBCLs, and the CD5-negative, Epstein-Barr virus-positive rate has been low, with most cases having been non-germinal-center B-cell-like. The prognosis for relapse-free survival has been favorable.

Background Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. Methods A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985–2012 were retrospectively reviewed. Clinical data were collected from patient medical records. Results Mean CD4 counts of patients were 77.0 cells/μL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/μL in naïve patients (ART (−) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (−) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (−) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (−) patients (1.5%; P = 0.026). Conclusions The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (−) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (−) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.

The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naive patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein–Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.

An 85-year-old man presented with pain and numbness in the left buttock, and physical examination revealed an approximately 7 cm mass extending from the first to the third sacral vertebrae; biopsy of the mass led to the diagnosis of CD10-negative, BCL6-weakly positive, MUM1-positive, non-germinal center (non-GC) type diffuse large B-cell lymphoma (DLBCL). Furthermore, serological testing showed negative results for Epstein-Barr virus (EBV) infection, and fluorescence in situ hybridization (FISH) revealed a MYC translocation. Radiographs showed no remarkable osteolytic bone destruction, and the patient was staged with Stage IAE. After 8 cycles of rituximab therapy and 6 cycles of CHOP therapy, complete remission has been maintained until now, approximately 1 year after the treatment. Primary sacral lymphoma is very rare, with only 6 reported cases, including the present one. A review of the reported cases revealed that the disease predominantly affects elderly men, is usually non-GC-type DLBCL and stage IAE, measures approximately 2-7 cm in diameter in general, and does not show early recurrence after chemotherapy or chemoradiotherapy. There is no report in the literature yet of primary sacral DLBCL with MYC translocation, and this is the first case report. On the other hand, 35 cases of CD10-negative DLBCL with MYC translocation, including the present one, have been reported, and a review of the reported cases showed that the disease predominantly affects Asians, middle-aged or elderly men, shows positivity for either BCL6 or MUM1 and negativity for EBV, and has a high international prognostic index and poor prognosis.

The incidence of Hodgkin lymphoma (HL) is paradoxically increasing in the combination anti-retroviral therapy (cART) era. However, there has been no nationwide survey of human immunodeficiency virus (HIV)-associated HL (HIV-HL) in Japan. We retrospectively examined the clinical characteristics and outcomes of 19 newly diagnosed HIV-HL patients at 11 HIV/AIDS and hematology regional hospitals in Japan between 1991 and 2010. At the time of HL diagnosis, 79 % of patients were receiving cART. All the patients, but one received HL diagnoses in the cART era. The median CD4+ cell count at HIV-HL diagnosis was 169/μl. Mixed-cellularity classical Hodgkin lymphoma was the most common subtype occurring in 68 % of the patients; 89 % of the patients were positive for Epstein–Barr virus. Of these 19 patients, 84 % were in advanced stages, with bone marrow involvement observed in 47 % of the patients; 58 % had extranodal sites. All the treated patients were given cART concurrent with HL therapy. The complete remission rate of the treated patients was 87 %. The median OS of the entire cohort was 17 months. These results suggest that the characteristics of HIV-HL in Japan are more aggressive than those of non-HIV-associated HL in Japan, but standard chemotherapy is effective and feasible.

ALK-positive large B-cell lymphoma is a rare subtype of lymphoma, and most cases follow an aggressive clinical course with a poor prognosis. We examined an ALK-positive large B-cell lymphoma case showing an anti-ALK immunohistochemistry pattern distinct from those of 2 known ALK fusions, CLTC-ALK and NPM-ALK, for the presence of a novel ALK fusion; this led to the identification of SQSTM1-ALK. SQSTM1 is an ubiquitin binding protein that is associated with oxidative stress, cell signaling, and autophagy. We showed transforming activities of SQSTM1-ALK with a focus formation assay and an in vivo tumorigenicity assay using 3T3 fibroblasts infected with a recombinant retrovirus encoding SQSTM1-ALK. ALK-inhibitor therapies are promising for treating ALK-positive large B-cell lymphoma, especially for refractory cases. SQSTM1-ALK may be a rare fusion, but our data provide novel biological insights and serve as a key for the accurate diagnosis of this rare lymphoma.

Although allogeneic hematopoietic stem cell transplantation has recently been applied to patients with myelofibrosis with reproducible engraftment and resolution of marrow fibrosis, no data describe the outcomes of umbilical cord blood transplantation. We describe 14 patients with primary (n = 1) and secondary myelofibrosis (n = 13) who underwent reduced-intensity umbilical cord blood transplantation. Conditioning regimens included fludarabine and graft-versus-host disease prophylaxis composed cyclosporine/tacrolimus alone (n = 6) or a combination of tacrolimus and mycophenolate mofetil (n = 8). Thirteen patients achieved neutrophil engraftment at a median of 23 days. The cumulative incidence of neutrophil and platelet engraftment was 92.9% at day 60 and 42.9% at day 100, respectively. Posttransplantation chimerism analysis showed full donor type in all patients at a median of 14 days. The use of umbilical cord blood could be feasible even for patients with severe marrow fibrosis, from the viewpoint of donor cell engraftment.

Signaling through the Notch1 receptor has a pivotal role in early thymocyte development. Gain of Notch1 function results in the development of T-cell acute lymphoblastic leukemia in a number of mouse experimental models, and activating Notch1 mutations deregulate Notch1 signaling in the majority of human T-cell acute lymphoblastic leukemias. Notch2, another member of the Notch gene family, is preferentially expressed in mature B cells and is essential for marginal zone B-cell generation. Here, we report that 5 of 63 (approximately 8%) diffuse large B-cell lymphomas, a subtype of mature B-cell lymphomas, have Notch2 mutations. These mutations lead to partial or complete deletion of the proline-, glutamic acid-, serine- and threonine-rich (PEST) domain, or a single amino acid substitution at the C-terminus of Notch2 protein. Furthermore, high-density oligonucleotide microarray analysis revealed that some diffuse large B-cell lymphoma cases also have increased copies of the mutated Notch2 allele. In the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors show increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B-cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers.

Primary adrenal lymphoproliferative disorder (LPD) is an extremely rare disease that is widely known to be associated with methotrexate (MTX) use in patients with rheumatoid arthritis (RA). A 70-year-old man was incidentally found to have a tumor at the dorsal part of the liver in a medical check-up. He had a history of RA treated with MTX. Abdominal ultrasonography demonstrated a low echoic mass (30 mm in diameter) at the dorsal part of the liver, located close to the inferior vena cava. Preoperative differential diagnoses included intrahepatic cholangiocarcinoma, adrenal tumor, and hepatic malignant lymphoma, but no definitive diagnosis was reached. On exploratory laparotomy, the tumor seemed to be derived from the right adrenal gland and adhered tightly to segment 7 of the liver. Therefore, right adrenectomy with partial resection of segment 7 of the liver was performed. Pathological findings revealed diffuse inflammatory cell infiltration with a population of small atypical lymphoid cells, with positive immunohistochemical evidence for Epstein–Barr virus (EBV). Final diagnosis was primary adrenal iatrogenic EBV-positive LPD, classified as “other iatrogenic immunodeficiency-associated LPDs: Hodgkin-like lesions.” In this report, we described the possibility of the spontaneous healing of MTX-associated LPD (MTX-LPD) before treatment and the importance of doubting MTX-LPD and doing immunostaining to necrotic tissue. To our knowledge, this is the first reported case of MTX-related EBV-positive LPD, Hodgkin-like lesion, of the unilateral adrenal gland in patient with RA.

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.

Background Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they are very rare. This study evaluated clinical and histopathological characteristics of duodenal GISTs to identify factors useful in predicting prognosis for patients with these tumors. Methods A retrospective study was performed on 20 patients who had undergone surgery between 1987 and 2009 for duodenal GISTs. Clinical, histopathological, and immunohistochemical data were evaluated. Survival analyses were conducted using Kaplan-Meier estimates. Results In 12 patients (60%), duodenal GISTs were diagnosed incidentally. Eight cases (40%) were classified as high risk grade GISTs. Skeinoid fibers (SkF), which are eosinophilic globular hyaline deposits in the extracellular interstitium of the tumor, were found in 12 patients. Skeinoid fibers were not recognized in 8 cases, and these included 3 cases (37.5%) where tumors recurred after surgery and the patient died. Tumors without SkF were larger (81 ± 92 vs. 23 ± 8 mm, P < 0.001) and had a higher mitotic count (224.0 ± 336.6 vs. 0.0 ± 0.0 /50 high-power field, P < 0.001) than those with SkF. Survival time was shorter in patients with tumors lacking SkF (52.9 ± 50.7 vs. 108.9 ± 86.5 months, P = 0.019). Conclusions We have identified clinical and histopathological characteristics that were useful in predicting the prognosis of patients with duodenal GISTs. In this study, 60% of the tumors were found incidentally, SkF were not recognized in tumors from 40% of patients, and all cases of post-operative tumor recurrence and death occurred in this subgroup of patients.