Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients

Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

Role of IgG4 serology in identifying common orbital lymphoproliferative disorders

AIM： To explore the role of IgG4 serology in identifying common orbital lymphoproliferative disorders, METHODS： Eighty -one patients with orbital lymphoproliferative diseases were treated in the Department of Ocular Oncology, Beijing Tongren Hospital, Capital Medical University between September 2010 and December 2012. Serum IgG4 levels were measured in 46 cases of idiopathic orbital inflammatory pseudotumor （IOIP）, 17 benign lymphoepithelial lesion （BLEL）, 12 cases of orbital mucosa-associated lymphoid tissue （MALT）, and 6 cases of diffuse large B-cell lymphoma （DLBL） using immuno-scatter turbidmetry （ISTM）.RESULTS： The frequency of elevated IgG4 levels in patients with IOIP, BLEL, MALT, and DLBL was 30.43% （14/46）, 76.47% （13/17）, 8.33% （1/12）, and 0.00 （0/6）, respectively. Among the patients with elevated serum IgG4 levels, all IgG-IOIP patients were male, and 92.31% of the IgG4-BLEL patients were female （12/13）. The mean serum IgG4 level of IgG4-1OIP patients was lower than that of individuals with IgG4-BLEL, but the variation in serum IgG4 levels was larger in IgG4-1OIP than IgG4- BLEL patients. Only one case of IgG4-MALT with elevated serum IgG4 levels had a medical history 〉10y, which was significantly longer than the MALT patients with normal serum IgG4 levels. There was no significant elevation of serum IgG4 levels in patients with DLBL. CONCLUSION： Detecting serum IgG4 levels plays an important role in the differential diagnosis of orbital lymphoproliferative diseases.

Infectious complications during immunochemotherapy of posttransplantation lymphoproliferative disease–can we decrease the risk? Two case reports and review of literature

BACKGROUND Post-transplant lymphoproliferative disease(PTLD)is a heterogeneous group of diseases that develop after solid organ and hematopoietic stem cells transplantation related to intensive immunosuppression regimen,T-cell depletion and Epstein-Barr virus infection.Despite the improvement in the management of PTLD,the prognosis remains poor.Here we report the management of two transplanted patients with PTLD and infections during immunochemotherapy(ICTH).CASE SUMMARY Of 65-year-old woman 11 years after kidney transplantation(first case)presented with diffuse large B-cell lymphoma(DLBCL)CS III and started ICHT according to R-CHOP protocol.Despite the secondary prevention of neutropenic fever,the patient developed grade 4 neutropenia with urinary and pulmonary tract infections after the fifth cycle.ICTH was continued in reduced doses up to 7 cycles followed by involved-field radiation therapy of the residual disease.The second case presents a 49-year-old man,8 years after liver transplantation due to cirrhosis in the course of chronic hepatitis B,who started ICTH for DLBCL Burkitt-like CS IV.The patient received four cycles of ICTH according to RCODOX/R-IVAC protocol,with reduced doses.In both cases initially undertaken reduction of immunosuppression was ineffective to prevent infectious complications.Despite one incomplete ICHT treatment due to recurrent infections,both our patients remain in complete remission.CONCLUSION Reduction of immunosuppression and the doses of chemotherapeutics may be insufficient to prevent infectious complications during ICTH in PTLD patients.

CD8-positive indolent T-Cell lymphoproliferative disorder of the gastrointestinal tract:A case report and review of literature

BACKGROUND Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract(ITLPDGI),a primary tumor forming in the gastrointestinal(GI)tract,represents a rarely diagnosed clonal T-cell disease with a protracted clinical course.CASE SUMMARY This report presented a 45-year-old male patient with a 6-year history of anal fistula and a more than 10-year history of recurrent diarrhea who was not correctly diagnosed until the occurrence of complications such as intestinal perforation.Postsurgical histopathological analysis,combined with hematoxylineosin staining,immunohistochemistry and TCRβ/γ clonal gene rearrangement test,confirmed the diagnosis of CD8+ITLPD-GI.CONCLUSION Individuals with this scarce lymphoma frequently show non-specific symptoms that are hard to recognize.So far,indolent CD8+ITLPD-GI has not been comprehensively examined.The current mini-review focused on evaluating indolent CD8+ITLPD-GI cases based on existing literature and discussing future directions for improved differential diagnosis,detection of genetic and epigenetic alterations,and therapeutic target identification.

EBV-associated lymphoproliferative disease post-CAR-T cell therapy

Epstein–Barr virus(EBV)-associated lymphoproliferative diseases(EBV-LPDs)are common complications that occur after solid organ transplantation or allogeneic hematopoietic stem-cell transplantation(HSCT).However,their occurrence and treatment post-chimeric antigen receptor-modified T(CAR-T)cell therapy has not been reported.Two patients had been diagnosed with EBV-positive aggressive B-cell lymphoma and experienced relapses after multiple lines of treatment.After receiving CAR-T cell therapy in tandem with autologous HSCT,the patients achieved complete remission.However,with a median time of 38.5 months after CAR-T cell therapy,B-cell-derived EBV-LPDs were diagnosed,and they were relieved through the administration of immune checkpoint inhibitor or B-cell-depleting agents.Collectively,our report suggests that EBV-LPDs may represent a long-term adverse event after CAR-T cell therapy,especially in patients who previously had EBV-positive disorders,and they can be resolved by immune normalization strategy or B-cell depleting therapy.

Pulmonary lymphomatoid granulomatosis in a 4-year-old girl:A case report

BACKGROUND Pulmonary lymphomatoid granulomatosis(PLG)is a lymphoproliferative disease associated with Epstein-Barr viral infection occurring mainly in adults and rarely in children.It is characterized by multiple pulmonary nodules.Its diagnosis depends on lung biopsy findings.Most patients are immunodeficient,and it commonly presents in children undergoing chemotherapy for leukemia.We report the case of a child with PLG caused by a mutation in the macrophageexpressed gene 1(MPEG1),suggesting possible PLG occurrence in children undergoing treatment for pulmonary nodular lesions.CASE SUMMARY This study reports a case of PLG without apparent immunodeficiency,suggesting the possibility of this disease occurrence during the treatment of pulmonary nodular lesions in children.Initially,the cause was assumed to be an atypical pathogen.Following conventional anti-infective treatment,chest computed tomography findings revealed that there were still multiple nodules in the lungs.Additionally,the patient was found to be infected with the Epstein-Barr virus.Histopathological examination of the resected lung revealed lymphoproliferative lesions with necrosis.Small lymphocytes,plasma cells,and histiocytes were observed in the background,although Reed-Sternberg cells were absent.Immunohistochemical staining[CD20(+),CD30(+),and CD3(+)]and EBV-encoded small RNA1/2 in situ hybridization of small lymphocytes revealed approximately 200 cells/high-power field.Whole exon sequencing of the patient revealed a mutation in the MPEG1.The patient was eventually diagnosed with PLG and transferred to the Department of Pediatric Oncology for bone marrow transplantation.CONCLUSION As PLG is rare and fatal,it should be suspected in clinical settings when treatment of initial diagnosis is ineffective.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders:beyond chemotherapy treatment

Post-transplant lymphoproliferative disorder(PTLD)is a rare but life-threatening complication of both allogeneic solid organ(SOT)and hematopoietic cell transplantation(HCT).The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma.Most commonly,PTLDs are Epstein-Barr virus(EBV)positive and result from loss of immune surveillance over EBV.Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different,resistance to treatment is unique,and there are specific concerns for organ toxicity.While recipients of HCT have a limited time during which they are at risk for this complication,recipients of SOT have a lifelong requirement for immunosuppression,so approaches that limit compromising or help restore immune surveillance are of high interest.Furthermore,while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy,the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms.Therefore,reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib,reduced dosing of standard chemotherapeutic agents,and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored.Here,we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.

Identification of a new isoform of the murine Sh2d1a gene and its functional implications

Signaling lymphocytic activation molecule （SLAM）-associated protein （SAP） is a Src homology （SH） domain 2-containing in- tracellular adaptor protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells. SAP protein is encoded by the SH2DIA gene located on the X chromosome. Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease （XLP）, a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr vi- rus and impaired humoral immunity. Normal individuals express several functional and non-functional isoforms of SAP as a result of alternative splicing. In this study, we identify a cryptic exon in the murine Sh2dla gene. At the mRNA level, the new isoform of SAP （SAP-2） that includes this new exon is widely expressed in lymphoid tissues by C57BL/6 and 129 strains of inbred mice. SAP-2 accounts for approximately 1%-3% of total SAP transcripts, and it is dynamically regulated during lym- phocyte activation. At the protein level, the SAP-2 isoform is a 144 amino-acid protein. Compared to the dominant 126 ami- no-acid SAP-I isoform, the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding. Our functional analysis in vitro indicates that SAP-2 is a non-functional isoform due to decreased protein stability. Thus, both human and mouse have multiple SAP splice isoforms that may or may not function. Modulation of relative propor- tions of these isoforms is potentially a mechanism whereby cells can regulate SAP-mediated biological activities.