Iatrogenic Lymphoproliferative Disorders Research Articles

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein–Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Hepatic Hodgkin Lymphoma Presenting as Solitary Hepatic Mass Following Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Patient With Rheumatoid Arthritis

Lymphoproliferative disorders (LPDs) occur frequently in patients with rheumatoid arthritis (RA) under methotrexate treatment. Some LPDs spontaneously regressed after methotrexate discontinuation, but classic Hodgkin lymphoma (CHL)-type LPDs frequently relapse, and chemotherapy is usually required for the treatment. CHL usually spreads in contiguous lymph nodes and then infiltrates in organs at an advanced stage. Thus, hepatic Hodgkin lymphoma (HHL) without lymphadenopathy is extremely rare at diagnosis. We present a case of methotrexate-associated LPDs associated with systemic lymphadenopathy and hepatosplenic mass in a 71-year-old woman with RA under methotrexate treatment over 10 years. Although spontaneous remission occurred after methotrexate discontinuation, she developed HHL presenting as a solitary hepatic mass without lymphadenopathy 3 years after spontaneous regression. She received brentuximab vedotin (BV) combination chemotherapy without bleomycin to avoid pulmonary toxicity. Complete metabolic response was achieved after four courses of BV combination chemotherapy, and the activity of RA was kept to be in remission. Our case suggested that the recurrence lesions of LPDs may present at unexpected site, which is not coincide with the primary site, and BV combination chemotherapy is a promising regimen for limited-stage CHL-type LPDs in patients with RA owing to its anti-lymphoma effect on CHL-type LPDs and a possible targeted therapy for RA. J Med Cases. 2021;12(2):79-83 doi: https://doi.org/10.14740/jmc3636

Epstein Barr Virus Associated B-Cell Lymphomas and Iatrogenic Lymphoproliferative Disorders.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting up to 90% of the population. EBV was first identified as an oncogenic virus in a Burkitt lymphoma cell line, though subsequently has been found to drive a variety of malignancies, including diffuse large B-cell lymphoma (DLBCL) and other lymphoma subtypes. EBV has a tropism for B-lymphocytes and has the unique ability to exist in a latent state, evading the host immune response. In cases of impaired cell mediated immunity, as in patients with advanced age or iatrogenic immune suppression, the virus is able to proliferate in an unregulated fashion, expressing viral antigens that predispose to transformation. EBV-positive DLBCL not otherwise specified, which has been included as a revised provisional entity in the 2016 WHO classification of lymphoid malignancies, is thought to commonly occur in older patients with immunosenescence. Similarly, it is well-established that iatrogenic immune suppression, occurring in both transplant and non-transplant settings, can predispose to EBV-driven lymphoproliferative disorders. EBV-positive lymphoproliferative disorders are heterogeneous, with variable clinical features and prognoses depending on the context in which they arise. While DLBCL is the most common subtype, other histologic variants, including Burkitt lymphoma, NK/T-cell lymphoma, and Hodgkin lymphoma can occur. Research aimed at understanding the underlying biology and disease prevention strategies in EBV-associated lymphoproliferative diseases are ongoing. Additionally, personalized treatment approaches, such as immunotherapy and adoptive T-cell therapies, have yielded encouraging results, though randomized trials are needed to further define optimal management.

Clinical Analysis of Immunodeficiency-Associated Lymphoproliferative Disorders in a Single Institution

BackgroundRecent progress in medicine faces more patients to iatrogenic immunosuppressive state, which increases the risk of following immunodeficiency-associated lymphoproliferative disorders (LPD), such as post-transplant lymphoproliferative disorders (PTLD) which arise after solid organ or hematopoietic stem cell transplantation (HSCT), and other lymphoid proliferations or lymphomas which arise in patients treated with immunosuppressive agents for any reasons. Methotrexate for patients with rheumatoid arthritis (RA) has been the most discussed immunosuppressive agent associated with iatrogenic LPD. Nevertheless, the number of patients treated with other immunosuppressive agents such as biological response modifiers for RA and calcineurin inhibitors after HSCT has recently increased and clinical assessment of iatrogenic-LPD under this recent immunosuppressive setting is still limited. Clinical prognostic factors remain controversial due to the heterogeneity of this disease concept, patients' background and treatment.Methods: A total of 71 patients diagnosed as iatrogenic immunodeficiency-associated lymphoproliferative disorders (PTLD, n=26; other LPD, n=45) over last 20 years in Kyoto University Hospital were reviewed. Cox regression analysis was used to examine the impact of patient characteristics including immunological backgrounds and tumor status on outcomes.Results: Median age at diagnosis of LPD was 63 (range, 3-83; PTLD, 50; other LPD, 66). Regarding the PTLD patients, 12 were recipients of liver transplantation, 8 were of HSCT, 4 were of lung and 2 were of kidney transplantation. Background diseases of the other LPD were RA in 43, systemic lupus erythematosus in 1 and systemic sclerosis in 1. Median time from the initiation of immunosuppressive agents to LPD diagnosis was 82 months (range, 1.5-348.5; PTLD, 35.4; other LPD, 116.5). The number of immunosuppressive agents given at LPD diagnosis was 0 in 1 patient, 1 in 14, 2 in 42, 3 in 12 and 4 in 1 patient. Twenty-nine percentage of those receiving multiple immunosuppressive agents were administered methotrexate in combination with PSL or biological response modifiers. Ann Arbor stage at diagnosis was I in 8 patients, II in 13, III in 20 and IV in 28 patients. Histologic subtypes of PTLD were monomorphic (n=19), polymorphic (n=4), and non-destructive PTLD (n=3). Pathological diagnosis of other LPD were DLBCL (n=20), polymorphic LPD (n=5), classical Hodgkin lymphoma (n=6), Hodgkin-like lesion (n=3), Burkitt lymphoma (n=1), EBV-positive mucocutaneous ulcer (n=3), and other B-cell lymphomas (n=7). EBER in situ hybridization was positive in 38 (63.3%) and systemic EBV reactivation was detected in 17 (43.6%).First line therapy included reduction of immunosuppressive agents without chemotherapy in 33 patients (PTLD, n=4; other LPD, n=29), RTX-containing chemotherapy in 23 (PTLD, n=14; other LPD, n=9), other chemotherapies in 7 (PTLD, n=4; other LPD, n=3), radiation therapy in 2, and no additional treatment in 2 patients.After the first line therapy, complete remission was achieved in 35 patients, partial response in 13, and stable or progressive disease in 14. A total of 4 patients died during the first line therapy. Five-year survival rate was 49.9% (PTLD, 39.0%; other LPD, 54.0%; P=0.101).Multivariate analysis showed that low number of lymphocyte count (< 890/µl, median lymphocyte count) at diagnosis (HR, 5.55; P=0.013), hypoalbuminemia (serum albumin value <3.2 g/dl) at diagnosis (HR, 6.36; P=0.015) and higher IPI (high-risk group vs others, HR, 2.71; n=0.021) were risk factors for poor prognosis. In subgroup analysis for PTLD, low IgG (<825 mg/dl, lowest limiting value of our center) was also an independent prognostic factor for inferior outcome (HR, 15.5; P=0.011).Conclusions: Overall survival of immunodeficiency-associated lymphoproliferative disorders under recent immunosuppressive settings, especially PTLD, was still poor. We found that low number of lymphocyte count could be a new risk factor for poor prognosis, along with known factors as IPI and hypoalbuminemia. Low IgG value was also suggested to be a prognostic factor for inferior outcome in PTLD patients. DisclosuresNishikori:Eisai: Research Funding; Ono Pharmaceuticals: Research Funding.

Spontaneous regression of Epstein-Barr virus-associated lymphoproliferative disorder in a juvenile idiopathic arthritis patient after the discontinuation of methotrexate and etanercept.

A case of a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) since the age of 4 years is reported here. This patient also suffered from multiple congenital anomalies. On long-term treatment with oral methotrexate (MTX) and etanercept, multiple subcutaneous nodules were detected, which were accompanied by increased lactate dehydrogenase and uric acid levels. A biopsy of the largest nodule revealed Epstein-Barr (EB) virus-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified as clinical stage IIIA due to a mediastinal lesion. Immunosuppressive treatment was discontinued immediately, which led to regression of the remaining nodules and normalization of the lactate dehydrogenase levels. The patient was considered to have an iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the World health organization (WHO). To our knowledge, this is the first case report of a JIA patient with EBV-positive DLBCL following the administration of etanercept and methotrexate and spontaneous regression of lymphoproliferation after the discontinuation of antirheumatic treatment.

Iatrogenic lymphoproliferative disorder

Iatrogenic lymphoproliferative disorder

Development of an Epstein-Barr virus-associated lymphoproliferative disorder in a patient treated with azacitidine for chronic myelomonocytic leukaemia

Some chemotherapeutic agents can cause iatrogenic lymphoproliferative disorders. In analogy to what has been observed with other nucleoside analogues such as cladribine and fludarabine, we document the first case of an Epstein-Barr virus-positive, iatrogenic immunodeficiency-associated, lymphoproliferative disease, formally resembling polymorphic post-transplant lymphoproliferative disease in a patient treated with azacitidine (Vidaza) for chronic myelomonocytic leukaemia (CMML). A 78-year-old female patient was diagnosed with CMML in January 2012, and treatment with azacitidine was initiated, which lasted for five cycles from February until June 2012. The patient was hospitalized in June 2012 under the suspicion of pneumonia. Transformation of the CMML was suspected at that time too. During hospitalization, a generalized enlargement of the lymph nodes and the spleen was noticed. The patient rapidly deteriorated and finally died of respiratory insufficiency. At autopsy, an Epstein-Barr virus-associated lymphoproliferative disorder, resembling polymorphic post-transplant lymphoproliferative disease with involvement of the lymph nodes, the spleen and the lung and causing necrotizing pneumonia, was diagnosed. Diagnostic criteria for diffuse large B-cell lymphoma or infectious mononucleosis-like lymphoproliferative disease were not met. This is the first documented case of an azacitidine-associated lymphoproliferative disease, raising awareness for possible not yet known side effects of this drug, which should be kept in mind by oncologists and pathologists.

Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration.

Iatrogenic lymphoproliferative disorders in non-transplantation settings.

Over the last decade, it has become clear that iatrogenic immunodeficiency-related lymphoproliferative disorders can occur in non-transplantation settings. These lymphoproliferative disorders occur predominantly in patients with rheumatologic diseases who are treated with immunomodulatory drugs. Like immunodeficiency-related lymphoproliferations in other settings, these represent a spectrum of lymphoid neoplasms and are frequently associated with Epstein-Barr virus. The distribution of histologic types of iatrogenic lymphoproliferations in non-transplantation settings appears to differ from that seen in other immunodeficiency settings with a probable increase in representation of Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease. Recognition of these immunodeficiency-related lymphoproliferative disorders is important for appropriate patient management.