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Cancer Medicine Oct 2021Epstein-Barr virus (EBV) is detected in a variety of B-cell lymphomas (BCLs) and B-cell lymphoproliferative disorders (B-LPDs). Immunodeficiency has been considered to... (Review)
Review
BACKGROUND
Epstein-Barr virus (EBV) is detected in a variety of B-cell lymphomas (BCLs) and B-cell lymphoproliferative disorders (B-LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV BCLs and B-LPDs. The PD-1/PD-L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T-cell function. We now consider PD-L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism.
METHODS
We reviewed articles of EBV BCLs and B-LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD-L1 IHC.
RESULTS
Based on PD-L1 IHC, we consider that EBV BCL and B-LPD can be classified into three types: "immunodeficiency", "immune escape", and "immunodeficiency + immune escape" type. The immunodeficiency type includes EBV diffuse large BCL (DLBCL) of the elderly, EBV sporadic Burkitt lymphoma, EBV mucocutaneous ulcer, and methotrexate (MTX)-associated B-LPD. The immune escape type includes EBV classic Hodgkin lymphoma (CHL) and EBV DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX-associated LPD and a minor subset of EBV DLBCL of the elderly.
CONCLUSIONS
Recently, good results have been reported for immune check-point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD-L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.
Topics: Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoproliferative Disorders; Male; Middle Aged; Primary Immunodeficiency Diseases; Tumor Escape
PubMed: 34387382
DOI: 10.1002/cam4.4198 -
Pathobiology : Journal of... 2013Posttransplant lymphoproliferative disorder (PTLD) involves uncommon, severe complications following the transplantation of solid organs, bone marrow and stem cells.... (Review)
Review
Posttransplant lymphoproliferative disorder (PTLD) involves uncommon, severe complications following the transplantation of solid organs, bone marrow and stem cells. Despite comprising mainly lymphoid proliferations that are predominantly driven by lymphotropic Epstein-Barr virus (EBV) infections, PTLD often displays substantial morphologic heterogeneity that can pose diagnostic challenges. With the steady increase in transplantations accompanied by potent immunosuppressive therapy, it is important to heighten awareness of this entity among clinicians and pathologists. In comparison to systemic PTLD, cases that primarily manifest in the central nervous system (CNS) are reported to be more severe and to exhibit unique characteristics. So far, only isolated cases and small series have been reported describing CNS involvement in PTLD. In this article, we review the current knowledge, focusing on the histopathological features of primary CNS lymphoproliferative disorders following organ transplantation.
Topics: Brain; Diagnosis, Differential; Humans; Lymphoproliferative Disorders; Organ Transplantation
PubMed: 24013167
DOI: 10.1159/000347225 -
American Journal of Transplantation :... May 2012Posttransplant lymphoproliferative disorder (PTLD) is a major complication of solid-organ transplantation. With human immunodeficiency virus infection (an analogous... (Comparative Study)
Comparative Study
Posttransplant lymphoproliferative disorder (PTLD) is a major complication of solid-organ transplantation. With human immunodeficiency virus infection (an analogous immunosuppressive state), elevated kappa and lambda immunoglobulin free light chains (FLCs) in peripheral blood are associated with increased risk of lymphoma. To assess the role of B-cell dysfunction in PTLD, we measured circulating FLCs among Canadian transplant recipients, including 29 individuals with PTLD and 57 matched transplant recipients who were PTLD-free. Compared with controls, PTLD cases had higher kappa FLCs (median 1.53 vs. 1.07 times upper limit of normal) and lambda FLCs (1.03 vs. 0.68). Using samples obtained on average 3.5 months before PTLD diagnosis, cases were more likely to have polyclonal FLC elevations (i.e. elevated kappa and/or lambda with normal kappa/lambda ratio: odds ratio [OR] 4.2, 95%CI 1.1-15) or monoclonal elevations (elevated kappa and/or lambda with abnormal ratio: OR 3.0, 95%CI 0.5-18). Strong FLC-PTLD associations were also observed at diagnosis/selection. Among recipients with Epstein-Barr virus (EBV) DNA measured in blood, EBV DNAemia was associated with FLC abnormalities (ORs 6.2 and 3.2 for monoclonal and polyclonal elevations). FLC elevations are common in transplant recipients and associated with heightened PTLD risk. FLCs likely reflect B-cell dysfunction, perhaps related to EBV-driven lymphoproliferation.
Topics: Adolescent; Adult; Antibodies, Viral; B-Lymphocytes; Case-Control Studies; Child; Child, Preschool; DNA, Viral; Female; Herpesviridae; Herpesviridae Infections; Humans; Immunocompromised Host; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Infant; Lymphoproliferative Disorders; Male; Middle Aged; Organ Transplantation; Predictive Value of Tests; Prognosis; Young Adult
PubMed: 22300426
DOI: 10.1111/j.1600-6143.2011.03954.x -
The American Journal of Surgical... Mar 2023Primary cutaneous marginal zone lymphoproliferative disorder (PCMZL) and primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (CD4 + TLPD) are...
Overlapping Features of Primary Cutaneous Marginal Zone Lymphoproliferative Disorder and Primary Cutaneous CD4 + Small/Medium T-Cell Lymphoproliferative Disorder : A Diagnostic Challenge Examined by Genomic Analysis.
Primary cutaneous marginal zone lymphoproliferative disorder (PCMZL) and primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (CD4 + TLPD) are indolent lymphoproliferative disorders. However, cases with overlapping features can be challenging. We identified 56 CD4 + TLPD and 38 PCMZL cases from our pathology archives. Clinical, morphologic, and immunophenotypic features were reviewed. Polymerase chain reaction for immunoglobulin (IG) and T-cell receptor gamma (TRG) gene rearrangements were analyzed. Next-generation sequencing studies were performed on 26 cases with adequate material, 19 with CD4 + TLPD, and 7 with PCMZL. CD4 + TLPD presented mostly (91%) as solitary lesions, located in the head and neck area (64%), while PCMZL occurred mostly in the upper extremity (47%) and trunk (34%). Lesions were sometimes multiple (40%) and recurrences (67%) were more common. Cases of PCMZL had an increase in reactive CD3 + T cells, with frequent programmed cell death protein 1 expression, whereas cases of CD4 + TLPD often contained abundant reactive B cells. Twenty-five cases were identified as having overlapping features: 6 cases of PCMZL were clonal for both IG and TRG; 11 cases of CD4 + TLPD were clonal for IG and TRG and 6 cases of CD4 + TLPD had light chain-restricted plasma cells. By next-generation sequencing, 23 variants were detected in 15 genes, with PCMZL more likely to show alterations, most commonly affecting TNFAIP3 and FAS, altered in 5 cases. Both entities have an indolent clinical course with response to conservative therapy and management, and warrant interpretation as a lymphoproliferative disorder rather than overt lymphoma.
Topics: Humans; Lymphoma, B-Cell, Marginal Zone; Skin Neoplasms; Skin; Lymphoproliferative Disorders; Genomics
PubMed: 36598455
DOI: 10.1097/PAS.0000000000001984 -
PloS One 2022Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative...
BACKGROUND
Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative disorder (PTLD). EBV DNAemia has not been analyzed on a continuous scale in this population.
METHODS
All children ≤ 18 years of age who underwent SOT at a single center between January 1, 2007 and July 31, 2018 were included in this retrospective study. Transplant episodes in which PTLD occurred were compared to transplant episodes without PTLD. Multivariable logistic regression was used to identify factors associated with the development of EBV DNAemia and maximum height of EBV DNAemia. A Cox proportional hazards model was used to calculate hazard ratios for time to PTLD.
RESULTS
Of 275 total transplant recipients and 294 transplant episodes, there were 14 episodes of PTLD. Intestinal and multivisceral transplant were strongly associated with PTLD (p = 0.002). Risk factors for the development of EBV DNAemia include donor and recipient positive EBV serologies (p = 0.001) and older age (p = 0.001). Maximum level of EBV DNAemia was significantly associated with development of PTLD (p<0.0001). Every one log (log10) increase in the maximum level of EBV DNAemia was associated with a more than doubling of the hazard on developing PTLD (HR: 2.18, 95% CI 1.19-3.99).
CONCLUSIONS
Transplant type was strongly associated with development of PTLD in pediatric SOT recipients. EBV serologies and age were associated with the development of EBV DNAemia and height of DNAemia. High levels of EBV DNAemia were strongly associated with an increased hazard for PTLD.
Topics: Child; Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Transplant Recipients; Retrospective Studies; DNA, Viral; Lymphoproliferative Disorders; Organ Transplantation
PubMed: 36256635
DOI: 10.1371/journal.pone.0269766 -
The Oncologist Nov 2021We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant...
Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database.
BACKGROUND
We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods.
MATERIALS AND METHODS
Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method.
RESULTS
We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65).
CONCLUSION
Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD.
IMPLICATIONS FOR PRACTICE
This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoproliferative Disorders; Registries; Research Design; Risk Factors
PubMed: 34506688
DOI: 10.1002/onco.13969 -
Cytometry. Part B, Clinical Cytometry Nov 2018The CLLflow score was recently suggested as an improvement over the Moreau score (MS) for the diagnosis and classification of B-cell lymphoproliferative disorders...
BACKGROUND
The CLLflow score was recently suggested as an improvement over the Moreau score (MS) for the diagnosis and classification of B-cell lymphoproliferative disorders (B-LPD).
METHODS
We determined the CLLflow score in peripheral blood or bone marrow of a series of cases with an inconclusive immunophenotype, including samples with a MS of 3 (n = 52) and CD5-positive with a score of 2 (n = 38). As controls, B-LPD with a MS of 0-1 (n = 95), CD5-negative score 2 (n = 24), and score 4-5 (i.e., chronic lymphocytic leukemia [CLL], n = 166) were included.
RESULTS
The CLLflow score was positive (suggestive of CLL) in all CLL cases and negative in all MS <2, regardless of CD200-positivity, which occurred in 31% (29/95) of cases. The CLLflow score was positive in 71%, 29%, and 8% of samples with a MS 3, CD5-positive score 2, and CD5-negative score 2, respectively.
DISCUSSION
Our results suggest that the CLLflow is useful in the differential diagnosis of cases with inconclusive immunophenotype. © 2018 International Clinical Cytometry Society.
Topics: Flow Cytometry; Humans; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders
PubMed: 29316199
DOI: 10.1002/cyto.b.21623 -
The Oncologist 2011Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic... (Review)
Review
Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti-IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antiviral Agents; Castleman Disease; Herpesvirus 8, Human; Humans; Interleukin-6; Lymphoproliferative Disorders; Molecular Targeted Therapy; Rituximab; Signal Transduction
PubMed: 21441298
DOI: 10.1634/theoncologist.2010-0212 -
Cancer Treatment and Research... 2021While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available... (Review)
Review
GOAL OF THE REVIEW
While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available preventative measures to light and prompt more research to be done with ultimate goal of developing an individualized prevention plan for each patient based on risk factors and available screening tools.
INTRODUCTION
Transplant surgery offers patients with end-stage renal disease a longer life expectancy with help of immunosuppressive therapies. Nonetheless, life-long immunosuppression comes at a cost of post-renal transplant malignancies, which have become the leading cause of morbidity in this patient group.
DISCUSSION
Post-renal transplant cancers can develop through either de novo, by donor-related transmission, or recurrence of recipient's pre-transplant cancer. While immunosuppressive therapy is considered to be the leading cause, weakened immunosurveillance of neoplastic cells and inadequate immune response against oncogenic viruses also plays an important role. The most common cancers seen in renal transplant patients are skin cancers and post-transplant lymphoproliferative disorder (PTLD). Risk factors for skin cancers have are ultraviolet light, human papilloma virus infection, and use of cyclosporin and azathioprine. Numerous viral infections have been associated with transplant-related malignancies post-transplant.
CONCLUSION
While lowering of immunosuppressive therapy remains the treatment of choice, it may lead to graft failure. Given some of the presented malignancies have modifiable risk factors and options for screening, clinical outcomes can be improved. Limiting skin exposure, dermatologic screening, and prophylactic retinoids can help lower the incidence rate of skin malignancy. Endoscopic screening for renal transplant patients can help identify gastric adenocarcinoma early and improve survival rates. Some of the post-transplant malignancies have been responsive to anti-viral treatment.
Topics: Early Detection of Cancer; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Risk Factors; Skin; Skin Neoplasms; Transplant Recipients; Tumor Escape; Ultraviolet Rays
PubMed: 33338850
DOI: 10.1016/j.ctarc.2020.100283 -
Internal Medicine (Tokyo, Japan) Jun 2019Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of... (Review)
Review
Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of MTX-LPD are diverse, little attention is paid to endobronchial involvement. We herein describe two patients with MTX-LPD who presented with parenchymal pulmonary tumors and endobronchial involvement of LPD; one had lymphomatoid gramulomatosis and the other LPD. The patients had no tumors adjacent to the endobronchial lesions. The endobronchial findings included multiple protruded mucosal lesions covered with white material, which was pathologically consistent with LPD. Recognition of the findings may help in making an earlier diagnosis of MTX-LPD in appropriate settings.
Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Bronchial Diseases; Bronchoscopy; Female; Humans; Lymphoproliferative Disorders; Male; Methotrexate; Middle Aged; Tomography, X-Ray Computed
PubMed: 30713318
DOI: 10.2169/internalmedicine.2109-18