Case Of Lymphoproliferative Disorder Research Articles

Exploring cutaneous lymphoproliferative disorders in the wake of COVID‐19 vaccination

AbstractBackgroundIndividual reports have described lymphoproliferative disorders (LPDs) and cutaneous lymphomas emerging after administration of the COVID‐19 vaccine; however, the relationship between reactions and vaccine types has not yet been examined.ObjectiveDetermine if there are cases of cutaneous LPDs associated with certain COVID‐19 vaccines and their outcomes.MethodsWe analysed PubMed, the Vaccine Adverse Events Reporting System (VAERS), and our database for instances of biopsy‐proven LPDs following COVID‐19 vaccines.ResultsFifty cases of biopsy‐proven LPDs arising after COVID‐19 vaccination were found: 37 from medical literature, 11 from VAERS and two from our institution. Geographical distribution revealed the most cases in the United States, Italy, and Greece, with single cases in Spain, Colombia, Canada, Japan, and Romania. The average age of patients was 53; with a slight male predominance (male‐to‐female ratio of 1.5:1). The Pfizer‐BioNTech vaccine was associated with LPDs in 36/50 (72%) cases, aligning with its 70% share of the global vaccine market. Histopathology revealed CD30+ in 80% of cases. The most prevalent form of LPD was lymphomatoid papulosis (LyP, 30%). All reported cases produced favourable outcomes (either complete or near‐complete remission). Therapeutic approaches ranged from observation to treatment with steroids, methotrexate, or excision.ConclusionLPDs after COVID‐19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self‐limited character.

Differentiating Between Epstein-Barr Virus-positive Lymphoid Neoplasm Relapse and Post-transplant Lymphoproliferative Disorder After Sex-mismatched Hematopoietic Stem Cell Transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), accurate differentiation between donor-derived post-transplant lymphoproliferative disorder (PTLD) and relapse of recipient-derived lymphoproliferative disorder (LPD) is crucial for determining treatment. Conventional diagnostic approaches for PTLD include histopathological examination, flow cytometry, and chimerism analysis of bulk tumor tissue. However, these methods are inconclusive in cases in which the primary disease is an Epstein-Barr virus (EBV)-positive LPD and is of the same lineage as that of the post-HSCT LPD tumor cells. Particularly, in cases where the number of tumor cells in the tissue is low, it is difficult to determine the origin of tumor cells. In this study, we developed a new method to simultaneously detect signals using sex chromosome fluorescence in situ hybridization, immunofluorescence staining, and EBV-encoded small RNA in situ hybridization on a single section of formalin-fixed paraffin-embedded histopathological specimen. The utility of the method was validated using specimens from 6 cases of EBV-positive LPD after sex-mismatched HSCT that were previously difficult to diagnose, including Hodgkin lymphoma-like PTLD that developed after HSCT for Hodgkin lymphoma and recurrence of chronic active EBV infection. This method successfully preserved the histologic structure after staining and allowed accurate determination of tumor cell origin and lineage at the single-cell level, providing a definitive diagnosis in all cases. This method provides a powerful tool for the diagnosis of LPDs after sex-mismatched HSCT.

Somatic Mutational Landscape and Transcriptomic Profiles of Lymphoproliferative Disorders with Epstein-Barr Virus Infection in Activated PI3K Delta Syndrome

Introduction: Germline gain-of-function variants in PIK3CD and PIK3R1 cause activated PI3K delta syndrome (APDS) types 1 and 2, respectively. Lymphoproliferative disorder (LPD) and susceptibility to various infections, including Epstein-Barr virus (EBV), are well-known features of APDS. EBV-associated LPDs are frequently observed in patients with APDS, and oligoclonal LPD might transform malignant lymphoma (ML). However, somatic molecular alterations in LPD and ML are not fully elucidated. Here, we report clinical characteristics and somatic mutational landscape and transcriptomic profiles of LPDs with EBV infection in APDS. Methods: LPD and ML in APDS diagnosed during 2011-2022 were recruited all over Japan. Clinical characteristics and outcomes were analyzed. EBV infection status was analyzed by EBER ISH and RNA sequencing (RNA-seq). Whole-exome sequencing (WES), RNA-seq, and single cell RNA-seq (scRNA-seq) were also performed. Results: Five LPD and 5 ML (borderline ML: n = 2, diffuse large B-cell lymphoma (DLBCL): n = 2, classical Hodgkin lymphoma: n = 1) cases were enrolled. Seven cases were APDS1 and 3 cases were APDS2. The median follow-up period was 2.9 (0.5-8.4) years. LPD cases were treated with rituximab monotherapy (n = 1), prednisolone (n = 3), and hematopoietic cell transplantation (HCT) (n = 1). Rituximab-combined chemotherapy was performed in borderline ML and DLBCL (n = 4) or ABVD regimen in Hodgkin lymphoma cases (n = 1). Sirolimus was used in two ML cases. HCT was performed in 9 cases. Two-year overall survival and event-free survival (events: relapse and death) were 78.8% and 70.0% in total LPDs, respectively, and 60% and 40% in ML cases. EBV was negative in 3 cases and positive in 2 cases of LPD cases, and positive in 4 cases, and negative in 1 case of ML cases. The median of 18 (10-48) and 42 (18-189) somatic variants were detected by tumor/germline pair WES in LPD (n = 5) and ML (n = 7, 2 samples were from the same patient at different time points), respectively. The recurrent variants were identified in ZFHX3 (n = 4), TRPM2 (n = 3), BEND3, CDH23, UBR4, ARAF, TET2, FBXO10, MAP4K1, KMT2C, KMT2D and PIK3R1 (n = 2) in LPD and ML cases. In transcriptome analysis, genes associated with lymphocyte activation including B-cell receptor signaling were upregulated in LPD, cell-cell adhesion, cellular response to TNF, and IL-18 signaling pathway were upregulated in ML samples. We performed correlation analysis to elucidate a relationship between EBV infection status and host transcriptomic profiles using RNA-seq data. Interestingly, in addition to cell-cell adhesion and inflammatory machinery, the upregulated molecules of the p53 pathway and negative regulation of the immune system were correlated with transcripts associated with EBV latency, such as EBNA, LMP-1, and LMP-2. In single-cell transcriptome analysis, LPD sample consisted of two large clusters of T cells and B cells with 10 subsets, and EBV-positive DLBCL sample consisted of one independent large cluster with 9 subsets. In LPD sample, components indicative of the normal lymphocyte differentiation process, including the germinal center, were preserved. The molecules involved in lymphocyte activation were upregulated in LPD subsets. In DLBCL sample, the genes associated with mitotic G2-M phases, chromatin organization and RNA metabolism were upregulated in the subsets in which EBV transcripts were more actively transcribed. Discussion and Conclusions: Our retrospective analysis demonstrated that the outcome of LPD and ML in APDS is not satisfactory. scRNA-seq data revealed that cells in LPD still retain the signature of normal lymph node. However, once transformed with EBV, EBV infection may affect epigenetic machineries including chromatin organizer followed by active RNA transcription involved in cell-cell adhesion, inflammatory machineries, molecules of p53 pathway and negative regulation of immune system in the host genome. As the outcome of ML is inferior to LPD, preemptive HCT would be an option for LPD cases.

Cutaneous lymphoproliferative disorders after COVID-19 vaccination: clinical presentation, histopathology, and outcomes

Individual reports described lymphoproliferative disorders (LPDs) after COVID-19 vaccination; however, the relationship between cases is unexamined. We aim to determine if there are cases of cutaneous LPDs associated with COVID-19 vaccination and their outcomes. We present a review of world literature, vaccine registries, and two unreported cases of LPDs after COVID-19 vaccination. Review of the medical literature, VAERS, and our two cases reveal predominance of Pfizer-BioNTech vaccine, younger patients, and males. All cases resulted in favorable outcomes. Approximately 84% of cases demonstrated CD30+ positivity in their skin biopsies, suggesting that an antigenic trigger may lead to a type IV adaptive immune response, with clonal expansion of CD30+ T-cells and subsequent oncogenic mutational hits eventuating in transient LPDs. LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Natalizumab was associated with EBV negative tumors (P=.023), and EBV positive tumors were associated with improved outcomes (P=.016). Surgical resection was associated with improved outcomes (P=.032), although limited by potential confounding effect. Antiviral treatment (P=.095), rituximab (P=.111), and stem cell transplant (SCT) (P=.198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

P689 Multicenter, cross-sectional, observational study on Epstein–Barr viral infection status and thiopurine use by age group in patients with inflammatory bowel disease in Japan

Abstract Background The Epstein–Barr virus (EBV) infection status in patients with inflammatory bowel disease (IBD), particularly those using thiopurines, may be associated with the risk of lymphoproliferative disorder and hemophagocytic lymphohistiocytosis. This was the first multicenter survey of EBV infection in Japanese patients with IBD (UMIN000033004). Factors related to the EBV infection status were also investigated. Methods This cross-sectional observational study of the EBV infection status in pediatric and adult patients with IBD was conducted at five tertiary institutions in Japan. Serum EBV anti-viral capsid antigen (VCA) IgG, and EBV anti-VCA IgM were measured in 495 patients with IBD□(UC:313 patients, CD:174 patients, IBD-U:8 patients). Patient characteristics (sex, age at diagnosis, age at onset, duration of illness, and disease location), treatments, and blood examination results were obtained from the medical records at each institution. Prior EBV infection was defined as anti-VCA IgM negativity and anti-VCA IgG positivity. Results mong the 495 patients, 56.2% (278/495) were male, and the median age at diagnosis of IBD was 18 years. The median age at the time of the anti-VCA IgG examination was 25 years(range: 0–92 years). Of the 495 patients, 9 were anti-VCA IgM-positive and 354 were anti-VCA IgG-positive (seroprevalence: 72.8%). The proportion of patients with prior EBV infection was 0% for those aged <5 years, <60% for those aged <30 years, and >90% for those aged >30 years. The patients’ current thiopurine use was 37.8% (187/486) for all anti-VCA IgM negative patients and 42.3% (85/201) for anti-VCA IgM negative patients aged <20 years. The proportion of EBV-uninfected patients using thiopurines was 28.4% (52/183) for all patients and 51.8% (44/85) for aged <20 years. Age was significantly associated with anti-VCA IgG seropositivity (p < 0.01, odds ratio: 0.902, 95% confidence interval: 0.880–0.925). No cases of lymphoproliferative disorder, hemophagocytic lymphohistiocytosis, or chronic active EBV infection were reported. Conclusion Approximately 30% of Japanese patients with IBD were EBV-uninfected, including those using thiopurines. Age was a significant factor for anti-VCA IgG seropositivity.

CHRONIC LYMPHOCYTIC LEUKEMIA ARISING IN PATIENT WITH HODGKIN LYMPHOMA TREATED WITH PERIPHERAL BLOOD STEM CELL TRANSPLANTATION -CASE REPORT

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a solid organ, bone marrow or stem cell allograft. The development of PTLDs is usually associated with Epstein-Barr virus (EBV) and the disorder is also termed EBV-associated lymphoproliferative disorder (LPD). The development of PTLD is a rare complication in autologous bone marrow/peripheral blood stem cell transplantation. In the present study, we report a case of   LPD which developed following autologous peripheral blood stem cell transplantation for relapsing Hodgkin's lymphoma. Keywords: CLL, post-transplant lymphoproliferative disorders, Covid 19.  

Epstein-Barr virus status and immunosuppression use in paediatric autoimmune liver disease.

Since azathioprine is associated with lymphoproliferative disorders in Epstein-Barr virus (EBV)-naïve patients with inflammatory bowel disease, guidelines advise avoidance. No recommendations exist for autoimmune liver disease (AILD). To evaluate EBV status and EBV-related complications in paediatric AILD. Single-centre, retrospective, observational study of paediatric AILD. In 245 paediatric patients with AILD, azathioprine was used in 168 (68.6%) and mycophenolate mofetil in 69 (28.2%). EBV status was assessed in 18 (10.7%) prior to azathioprine and 6 (8.7%) MMF. Acute EBV infection was diagnosed in five patients while on immunosuppression, resulting in one transient hepatitis and one persistent hepatitis. There were no cases of lymphoproliferative disorder in native livers. Liver transplantation (LT) was performed in 39 (15.9%) patients, with 8 EBV IgG-negative at LT. Post-LT EBV viraemia developed in 29 (74.4%), first detected at median 26days (IQR, 13-86). EBV IgG-negative recipients had higher peak viraemia (266984IU/mL [IQR, 41108-2429050] v 5333 [IQR, 2036-38770], P=.004) and longer time to peak viraemia (375days [IQR, 251-884] v 70 [IQR, 21-604], P=.04). Early EBV-associated post-transplant lymphoproliferative disorder (PTLD) was diagnosed in two patients, both EBV-IgG negative with prior azathioprine. Real-world data demonstrate that EBV serostatus is not routinely checked before immunosuppression for paediatric AILD. Lymphoproliferative disorder was not diagnosed in those with native livers; however, EBV IgG-negative LT recipients receiving EBV IgG-positive donor organs are at risk of early PTLD. Large multicentre studies with longer follow-up are required to further evaluate the risk.

Multicenter, cross-sectional, observational study on Epstein-Barr viral infection status and thiopurine use by age group in patients with inflammatory bowel disease in Japan (EBISU study).

The Epstein-Barr virus (EBV) infection status in patients with inflammatory bowel disease (IBD), particularly those using thiopurines, may be associated with the risk of lymphoproliferative disorder and hemophagocytic lymphohistiocytosis. This was the first multicenter survey of EBV infection in Japanese patients with IBD. Factors related to the EBV infection status were also investigated. Five tertiary institutions in Japan participated in this study to examine pediatric and adult patients with IBD. Serum EBV anti-viral capsid antigen (VCA) IgG, EBV anti-VCA IgM, and anti-EBV nuclear antigen-antibody were measured in 495 patients with IBD. The patients' information was obtained from their medical records. Prior EBV infection was defined as anti-VCA IgM negativity and anti-VCA IgG positivity (UMIN000033004). The patients' median age was 25years (range 0-92years). Of the 495 patients, nine were anti-VCA IgM-positive and 354 were anti-VCA IgG-positive (seroprevalence: 72.8%). The proportion of patients with prior EBV infection was 0% for those aged < 5years, < 60% for those aged < 30years, and > 90% for those aged > 30years. The proportion of EBV-uninfected patients using thiopurines was 28.4% (52/183) for all patients and 51.8% (44/85) for pediatric patients. Age was significantly associated with anti-VCA IgG seropositivity (p < 0.01, odds ratio: 0.902, 95% confidence interval: 0.880-0.925). No cases of lymphoproliferative disorder, hemophagocytic lymphohistiocytosis, or chronic active EBV infection were reported. Approximately 30% of Japanese patients with IBD were EBV-uninfected, including those using thiopurines. Age was a significant factor for anti-VCA IgG seropositivity.

Younger JAK2V617F+ Individuals with Myeloproliferative Neoplasms Are at Higher Risk of Developing Lymphoproliferative Disorders: A Scoping Review of 214 Patients

Patients with a Ph-negative myeloproliferative neoplasms (MPN) harbor or develop lymphoproliferative disorders (LPD) at a higher rate than general population and a common oncogenic pathway for MPN and LPD has been hypothesized, based on the presence of JAK2 V617F mutation in lymphocytes of patients with the concurrent diseases. Selected therapies for MPN might favor LPD, however, no large scale epidemiologic study ever specifically addressed this issue. We, therefore, conducted a scoping review of published literature in order to sum up the available evidence. We enquired EMBASE, PubMed and Cochrane Library and retrieved 2,064 English language full papers: 83 ones were selected and 62 full texts were definitely analyzed: 2 independent researchers extracted single-patient data for concurrent MPN and LPD cases and references were checked. Single-patient data were retrieved by 50 papers reporting 214 individuals with MPN and LPD: details are reported in Table 1. Half of the reported LPD cases occurred in the follow-up of diagnosed MPN (secondary LPD, sLPD) while 30% of the diagnoses were synchronous and 20% antecedent: indolent LPD occurred in 75% of the patients, while aggressive lymphomas in 8%. As compared with published MPN cohorts (Tefferi et al 2014 Blood), the patients showed a higher male-to-female ratio (1.56), an older age at MPN diagnosis, a lower portion of PV and a higher frequency of JAK2V617F mutation than expected, based on the frequency of PV cases. The patients also showed a high frequency of cytoreductive therapy and a shorter median survival (8 year) than expected. As compared with antecedent or synchronous LPDs, specific epidemiologic features were observed: sLPD cases more frequently occurred in the follow-up of patients with essential thrombocytemia (ET) than polycythemia vera (PV) or myelofibrosis (MF) (p<0.001), which is the probable reason for a lower median age at MPN diagnosis (63 versus 71 years, p<0.001) and a lower male-to-female ratio (1.27 vs 1.96, p=0.18). Nevertheless, V617F JAK2 mutation was harbored by the vast majority of sLPD cases, in particular, 83% of MF patients incurring sLPD carried the mutation (p=0.05). An even more impressive distinguishing feature of sLPD was the higher portion of aggressive lymphomas than reported for antecedent or synchronous LPD (14.1% versus 1.8%; p=0.004). Finally, due to the long time elapsed from MPN to LPD diagnoses, median survival of sLPD (9.6 years) was not significantly different from the overall cohort, but it was still shorter than the expected. A peculiar observation was also made relatively to patients with synchronous diagnosis of LPD and MPN: based on the survival data reported for 46 patients, they showed a sensibly dismal prognosis possibly due to lower intensity of therapeutic approaches, sustained by their old and the lack of therapies being effective both against MPN and LPD.This thorough review of published evidence demonstrates that LPD are relevant clinical events in the history of MPN patients. LPD, including aggressive lymphomas, may occur in the follow-up of younger and/or ET patients, especially those harboring the V617FJAK2 mutation. Prospective interventional studies might not capture the risk of LPD due to the limited size of the studies and the short follow-up. Controlled studies are needed to better refine the target population at high risk of developing LPD in order to support surveillance programs and to avoid therapies (including JAK 2 inhibitors) possibly favoring LPD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)-Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

Evaluation of COVID 19 infection in 279 cancer patients treated during a 90-day period in 2020 pandemic.

BackgroundThe aim of this study was investigation of COVID-19 disease and its outcome in cancer patients who needed treatment, in a 90-day period.MethodsCancer patient who required treatment, were evaluated for potential COVID-19 infection in a 90-day period, starting from beginning of this epidemic in Iran, January, to April 19, 2020. For treatment of solid tumor patients, if they did not have symptoms related to COVID-19, just chest X-ray was requested. If they showed COVID-19 related symptoms, high resolution CT scan of lungs was requested. For hematology cancer patients, PCR test for COVID-19 infection was requested as well. Protection measures were considered for personnel of oncology wards.Results279 Patients were followed up in this 90-day period. No COVID-19 infection was observed in 92 cases of breast cancer, 14 cases of gastric cancer and 12 cases of pancreaticobiliary cancer. However, in 72 cases of colon cancer, 11 cases of lung cancer, 5 cases brain tumors and 12 cases ovarian cancer; 4 cases of COVID-19 were observed. In the hematology cancers group, which included 14 cases of Hodgkin’s disease, 23 cases of lymphoproliferative disorder, 12 cases of acute leukemia and 12 cases of multiple myeloma; 3 cases of COVID-19 were observed.ConclusionPatients with cancer who need treatment can be treated by taking some measures. These measures include observing individual and collective protection principles in patients and health-care personnel, increasing patients’ awareness particularly about self-care behavior, performing a COVID-19 test, and taking a chest X-ray, before the treatment starts

Transbronchial cryobiopsy: an effective tool in the diagnosis of lymphoproliferative disorders of the lung.

IntroductionMalignant lymphoproliferative disorders are rarely observed in the lung and, considering their clinical and radiological heterogeneity, diagnosis is often difficult and may require invasive methods. Transbronchial cryobiopsy has been confirmed as a new tool in the diagnosis of interstitial lung diseases, given its fewer risks and costs compared to surgical approach. This study is aimed at assessing the effectiveness of cryobiopsy in the diagnosis of lymphoproliferative disorders.Materials and methodsAmong 970 consecutive cryobiopsies, performed between January 2011 and June 2018 at Morgagni Hospital of Forlì, Italy, 13 cases of lymphoproliferative disorders were collected.ResultsIn 12 out of 13 cases a precise pathological diagnosis could be reached with the support of immunohistochemistry (IHC) and molecular ancillary studies. In the only case in which cryobiopsy did not lead to a definitive diagnosis, the subsequent surgical biopsy also did not help to clarify the diagnosis. Severe bleeding or pneumothorax did not occur in any case. On average, five biopsies were obtained per case, with a mean total area of 1161 mm2, and only 5 out of 65 specimens were inadequate for diagnosis. Instant freezing did not produce tissue artefacts nor did it affect IHC and molecular tests. In all cases the amount of available tissue was sufficient for all ancillary studies.ConclusionsTransbronchial lung cryobiopsy is safe and effective for diagnosis in patients with suspected pulmonary involvement by lymphoproliferative disorders and it should therefore be considered a valid alternative to surgical biopsy in such cases.

Clinical aspects in patients with rheumatoid arthritis complicated with lymphoproliferative disorders without regression after methotrexate withdrawal and treatment for arthritis after regression of lymphoproliferative disorders

Objectives To identify predictive factors for lymphoproliferative disorders (LPDs) that persist after methotrexate (MTX) withdrawal (Persistent-LPD) and the optimal treatment for rheumatoid arthritis (RA) after LPD regression. Methods Among 3666 patients with RA treated with MTX in our department from 2006 to 2017, 26 cases of LPD that regressed after MTX withdrawal (Regressive-LPD) and 25 cases of Persistent-LPD were compared. Multivariate logistic analysis was performed to identify predictive factors for Persistent-LPD. Retention rates of biological disease-modifying antirheumatic drugs (bDMARDs) were calculated using the Kaplan–Meier Method. Results In Persistent-LPD, the incidence of diffuse large B-cell lymphoma was higher (76%). The overall 2-year survival rate was 83.9%: 95.8% for Regressive-LPD and 71.0% for Persistent-LPD. The International Prognostic Index (IPI) risk classification was useful for predicting Persistent-LPD. bDMARDs were introduced in 38 RA patients after LPD regression. Unadjusted retention rate of bDMARDs in the 51 LPD patients was significantly lower than that in the 1668 non-LPD RA patients in our bDMARD cohort (controls) (p = 0.029). The 1-year retention rates for bDMARDs were 69% and 64% for tocilizumab and abatacept, respectively vs. 46% for TNF-inhibitor (TNFi). Conclusion Risk assessment using IPI predicted Persistent-LPD. After LPD regression, non-TNFi tended to have higher retention rates.

C‐C chemokine receptor 4 expression in CD8+ cutaneous T‐cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment

Patients with aggressive CD8+ cutaneous T-cell lymphomas (CTCLs) progress rapidly and respond poorly to therapy. Confounding treatment planning, there is clinicopathological overlap between aggressive CD8+ CTCLs and other lymphoproliferative disorders (LPDs). Hence, improved diagnostic methods and therapeutic options are needed. The aim of this study was to examine C-C chemokine receptor 4 (CCR4) expression as a diagnostic and therapeutic biomarker in CD8+ CTCLs/LPDs. Forty-nine cases (41 patients) with CD8+ CTCLs/LPDs were examined, including CD8+ mycosis fungoides (MF) (n=14), aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AETCL) (n=8), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (n=7), CD30+ LPDs (n=6), primary cutaneous γδ T-cell lymphoma (GDTCL) (n=6), and others (n=8). Immunohistochemical tissue staining was performed with a CCR4 monoclonal antibody on formalin-fixed paraffin-embedded tissue sections. CCR4 immunostaining was graded as percentage infiltrate, i.e. high (>25%) and low (≤25%), and the results were correlated with clinicopathological diagnoses. CCR4 expression was seen in 69% of the studied cases. Any CCR4 positivity was seen in all CD8+ MF cases, in 83% of CD30+ LPD cases, in 75% of AETCL cases, in 33% of GDTCL cases, and in none of the SPTCL cases. High CCR4 expression was seen in 79% of CD8+ MF cases versus 33% of CD30+ LPD cases, in 17% of GDTCL cases, and in 12.5% of AETCL cases. Patients with more advanced MF stage had higher CCR4 expression. CCR4 immunohistochemistry may be an adjunct in distinguishing advanced CD8+ MF from other CD8+ CTCLs/LPDs. Although CCR4 expression may justify therapeutic targeting of this receptor in CD8+ MF, the role of such therapies in other CD8+ CTCLs/LPDs is not yet clear.

Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders

Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies &amp;gt;100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.

Post-transplant lymphoproliferative disorder manifesting as lymphomatoid granulomatosis: report of two cases and review of the literature highlighting current challenges in pathologic classification

Classification of viral- and immunodeficiency-associated lymphoproliferative disorders continues to evolve. Entities in these categories recognized in the 2016 revision of the World Health Organization Classification of Lymphoid Neoplasms show considerable morphologic overlap, and it is unclear whether the current classification conceptualizes the scenarios in which these lesions arise and how they might be best managed. Here, we report two cases of lymphoproliferative disorders meeting histologic criteria for lymphomatoid granulomatosis that arose following solid organ transplant. In reviewing the clinicopathologic features of these examples and those of similar cases in the literature, we highlight challenges in current classification and opportunities for their refinement.

Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases

Ongoing development of new drugs, as well as novel indications in the treatment of autoimmune diseases leads to the increasing use of immunomodulatory and immunosuppressive drugs. Immunomodulatory agent-related lymphoproliferative disorders are a known and potentially life threatening complication of chronic administration of these drugs, but are less well characterized compared with post-transplant lymphoproliferative disorders. The heterogeneous drug targets, various underlying disease indications, different drug combinations used and relatively low incidence render data collection and interpretation difficult. In this retrospective paper, we describe the clinicopathological characteristics of a larger single-center series of 72 immunomodulatory agent-related lymphoproliferative disorder cases. We divided the cases according to the therapy, administered in the year preceding diagnosis of a lymphoproliferative disorder, in an immunosuppressive drug, an immunomodulatory drug and a combination of immunosuppressive and immunomodulatory drugs group. We observed differences in “time to lymphoproliferative disorder development” with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive-only (p = 0.0031). The proportion of malignant cases in patients receiving immunomodulatory therapy was, however, also significantly lower when compared with the immunosuppressive treated cases (43 vs 88%; p = 0.0184). The immunomodulatory/suppressive agent-related lymphoproliferative disorders were less often associated with the Epstein–Barr virus (EBV) (31 vs 66%; p = 1.829e-05) and the lymphoproliferative disorders incidence in the first year after immunomodulatory/immunosuppressive therapy initiation was lower (18 vs 41%; p = 0.04151)—compared with a published series of 140 post-transplant lymphoproliferative disorder cases from the same center. However, a similar histopathological spectrum from nondestructive, to polymorphic and monomorphic lesions as in post-transplant lymphoproliferative disorders is observed. With increasing use of immunosuppressive and especially immunomodulatory therapy, a higher incidence of immunomodulatory/suppressive agent-related lymphoproliferative disorders is to be expected. Life-long awareness for development of immunomodulatory/suppressive agent-related lymphoproliferative disorders with clinical follow-up and timely biopsies of suspicious lesions is required since these lymphoproliferative disorders arise both early after therapy initiation and many years later. Histopathological confirmation and correct classification is necessary to guide therapy and EBV ISH should be a part of routine pathological diagnostics.

Four cases of lymphoproliferative disorders presenting with methotrexate therapy

Four cases of lymphoproliferative disorders presenting with methotrexate therapy

Methotrexate-related lymphoproliferative disorder in patients with osteonecrosis of the jaw

Patients who are immunodeficient or immunosuppressed are at risk of developing lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD. However, the occurrence of MTX-related LPD causing osteonecrosis of the jaw (ONJ) has rarely been reported. We report a series of three cases of MTX-related LPD in patients with longstanding rheumatoid arthritis who presented with ONJ. A 74-year-old man with rheumatoid arthritis (RA) had received treatment with MTX for seven years before presenting with ONJ and submental lymphadenopathy following dental extraction. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient in our series was a 67-year-old man who had been treated with MTX for more than 15 years. In all three cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (EBV, CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV driven T-cell, B-cell, and Hodgkin-like LPD. All three patients recovered following cessation of MTX and surgical debridement. Although LPD as a cause of ONJ is rare, due to the rise in immunodeficiency disorders and immunosuppressive treatments, the prevalence of this condition may be expected to increase. For this reason, clinicians should be aware of the diagnosis. As this case series has shown, biopsy and diagnostic immunohistochemistry will ensure the correct diagnosis. Because the diagnostic approach used in this case series will distinguish MTX-related LPD from the more familiar condition of Medication-related osteonecrosis of the jaw.