Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Research Articles

Methotrexate-associated lymphoproliferative disorders: clinical aspects

Methotrexate-associated lymphoproliferative disorders (MTX-LPD) is categorized into other iatrogenic immunodeficiency-associated lymphoproliferative disorders, developing LPD in patients with autoimmune diseases (AIDs) under low dose MTX administration. Two-thirds of MTX-LPDs regresses after MTX withdrawal with the higher incidence in Japanese patients, MTX-LPDs consist of various subtypes of LPDs, the feature of each LPD such as the regressive rate, relapse/regrowth rate, and prognosis, widely varies. The absolute lymphocyte count (ALC) in peripheral blood is suggested to influence LPD development, regression, and relapse/regrowth events. Because various factors might effect the pathogenesis and clinical features of MTX-LPD, careful attention should be paid to assess MTX-LPD.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of B-cell type that develop in patients receiving immunosuppressive drugs other than in the post-transplant setting.

In the current revised 4th edition of the World Health Organization (WHO) classification, ‘other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs)’ is listed in the last section in the chapter on immunodeficiency-associated lymphoproliferative disorders. Oii-LPDs cover a broad spectrum from benign lesions to lymphoma, and correspond to one of the subtypes in the WHO classification for immunocompetent patients.The WHO classification does not clearly indicate the histological subtype of this disease category; however, the framework of subtype classification is similar to the classification of post-transplant lymphoproliferative disorders, and recent studies have attempted to subcategorize Oii-LPDs that fit this unique disease type. In this review, we provide an overview of B-cell-type Oii-LPDs regarding their histopathology and immunophenotype, genetics and clinical behaviors.

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.

Composite Cutaneous Lymphoma (Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder) in a Patient with Rheumatoid Arthritis Treated with Methotrexate: Staging and Evaluation of Response to Therapy with 18F-FDG PET/CT

A 67year old woman with a 10year history of rheumatoid arthritis (RA) treated with methotrexate and prednisone, presented with a 2year history of worsening multiple cutaneous plaques of variable appearance. Two distinct skin lesions were biopsied to reveal a composite cutaneous lymphoma, possibly caused by long term methotrexate therapy. An [18F] fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed to stage the malignancy, and was later repeated to evaluate response to chemotherapy, which guided subsequent management. We present the PET/CT imaging findings of this very rare iatrogenic (methotrexate induced) immunodeficiency-associated lymphoproliferative disorder.

Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Pediatric Patient

It is estimated that approximately 90% of the adult population is infected with the Epstein Barr Virus (EBV). In states of immunosuppression, the disruption in immune regulation can manifest as lymphoproliferative disease that classically presents as a lymphoma. Rarely, EBV-driven lymphoproliferative disease can present as a mucocutaneous ulcer. While this phenomenon is becoming well documented in the adult population, cases affecting pediatric patients are lacking. In this report, we describe a case of a pediatric immunosuppressed patient presenting with an EBV-positive mucocutaneous ulcer. EBV-positive mucocutaneous ulcer in an immunosuppressed patient is an entity within the spectrum of iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) which closely resembles the better-categorized post-transplant lymphoproliferative disorder (PTLD). Though the concept of lymphoproliferative disorders in immunosuppressed patients has been well established, this is a unique case in a pediatric patient.

Methotrexate-Associated EBV-Positive Diffuse Large B-Cell Lymphoma Mimicking Aronj -A Diagnostic Pitfall

Iatrogenic immunodeficiency-associated lymphoproliferative disorders are seen in patients treated with methotrexate. We report a unique case of methotrexate-associated EBV-positive diffuse large B-cell lymphoma (DLBCL) clinically presenting as osteonecrosis of the jaw.

Methotrexate‐related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis

Methotrexate (MTX) is the primary drug used in the management of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. MTX is a strong immunosuppressive agent and has been reported to cause iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). Stomatitis caused by MTX-related cytotoxicity may occur, but gingival MTX-related LPDs are rare. In this article we present a case of gingival MTX-related LPD in a 60-year-old male with RA. The local findings of the gingival ulceration and alveolar bone exposure were similar to those of bisphosphonate-related osteonecrosis of the jaw. However, he had never received bisphosphonate therapy. The biopsy specimen of the gingival lesion was diagnosed as diffuse large B-cell lymphoma with Epstein-Barr virus positivity. Immediate withdrawal of MTX resulted in marked remission of the LPD.

Immunoglobulin rearrangement analysis from multiple lesions in the same patient using next-generation sequencing.

For patients who have multiple lymphomas with discordant pathology, it is relevant to determine whether there is one disseminated lymphoma or two unrelated lymphomas. Patients with disseminated, clonally related lymphomas are usually treated with the most powerful drugs available, while patients with unrelated (primary) lymphomas receive mainly standard first-line therapies. We used next-generation sequencing on the Ion Torrent Personal Genome Machine to characterize the immunoglobulin heavy gene V-D-J rearrangements in two diagnostic tissue samples, including formalin-fixed and paraffin-embedded tissue, of two patients with iatrogenic immunodeficiency-associated Epstein-Barr virus lymphoproliferative disorder, with ulcerative colitis as underlying disease. The immunoglobulin rearrangement sequences obtained by next-generation sequencing revealed undoubtedly clonally related lesions in two tissue biopsies that were taken over time in the first patient, which is concordant with disseminated lymphoma. The other patient showed two clonally unrelated lesions, which is incompatible with clonal dissemination. This information was not inferred from evaluation of the heavy and light chain rearrangements by fragment analysis, which is currently the gold standard. Our study demonstrates the diagnostic application of next-generation sequencing of immunoglobulin rearrangement assessment in pathology for clinical decision-making in patients with several simultaneous or subsequent lymphoproliferations.

Emergence of New lesions upon Treatment failure is an Independent, Negative Prognostic Factor for Patients with Primary Refractory DLBCL

<Introduction>Diffuse large B-cell lymphoma (DLBCL) has an aggressive clinical course and, even in the R-CHOP era, about 10-20% of DLBCL patients (pts) show primary refractory disease. For pts with primary refractory disease, salvage chemotherapy with or without stem cell transplantation (SCT) is generally performed, but even with this treatment, less than half of the pts survive. To elucidate the pts population who require innovative therapy, we retrospectively analyzed the risk factors that lead to an unsuccessful outcome of primary refractory DLBCL.<Patients and Methods>DLBCL pts who received R-CHOP with curative intent were included. Pts with primary mediastinal large B-cell lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma and iatrogenic immunodeficiency-associated lymphoproliferative disorders were excluded. In this study, primary refractory disease was defined as disease progression during first-line immuno-chemotherapy or recurrence within 3 months after completion of the first-line therapy. The primary endpoint was overall survival (OS) after treatment failure, which was assessed using the Kaplan-Meier method. The log-rank test and Cox regression analysis were used to assess the prognostic values of each clinical variable.<Results>From January, 2004 to December, 2013, 440 DLBCL pts were referred to our institute. Among them, 60 pts (20 females and 40 males) were considered to have primary refractory disease (55 with progressive disease and 5 with early relapse). At the time of treatment failure, the median age was 72 (range, 31–90) and 44 pts (73%) showed advanced stage (stage IIIor more) disease. Nineteen (32%) had an ECOG performance status (PS) of 2 or more, and 23 (38%) had a high IPI score. In 31 pts, disease progression was observed at novel sites that had not been detected during the initial evaluation; patients with these sites were designated as "new lesion pts". The remaining 29 pts displayed regrowth of known lesions and were designated as "regrowth pts". Among new lesion pts, 29 displayed extranodal disease. After disease progression, 52 pts received salvage chemotherapy or radiotherapy, and 21 pts achieved a clinical response. Among the 24 patients less than 70 years old, 11 received autologous or allogeneic stem cell transplantation (SCT). After a median follow-up time of 17 months (range, 1–81 months), 39 pts had died of lymphoma. The 1-year OS rate (1y-OS) was 38.8% [95% confidence interval (CI), 25.5-51.8%].Univariate analysis using clinical variables at the time of treatment failure revealed that new lesion pts or patients with an IPI score >3 had a poor 1y-OS rate (p<0.05). The presence of CNS involvement or bulky disease at treatment failure had no effect on OS. In addition, progressive disease before the 4th course of R-CHOP or at a CHOP dose intensity less than half of that actually prescribed had no negative impact on OS. After adjusting for IPI score using multivariate analysis, new lesion pts had an independent, poor prognostic factor for OS (HR, 3.11; 95%CI, 1.34-7.23; p=0.008). The unadjusted 1y-OS of new lesion pts was 11.4% (95% CI, 2.9-26.3%), which was significantly lower than that of regrowth pts, who had a 1y-OS of 65.8% (95% CI, 43.9-80.8%) (HR, 4.4; 95% CI, 2.1-9.3; log-rank, p<0.001). Of 31 new lesion pts, six achieved a clinical response after salvage chemotherapy, but the remission durations were short. Five patients who received SCT died of lymphoma.<Conclusion>Primary refractory DLBCL pts with new lesions, most of which were extranodal sites, have an extremely poor outcome. Disease progression at novel extranodal sites may indicate that the disease has chemotherapy-resistant characteristics. Routine approaches using platinum- or cytarabine-based salvage chemotherapy followed by SCT rarely overcome the progressive nature of the disease, and a novel treatment strategy is required. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Outcome Of Patients With Post Transplant and Immunodeficiency Associated Lymphoproliferative Disorder: The BCCA Experience

BackgroundPost-transplant lymphoproliferative disorders (PTLD) develop in the setting of immunosuppression following solid organ transplant or allogeneic stem cell transplant (alloSCT). Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (‘PTLD-like') can occur with the use of immunosuppressive agents for autoimmune or related disorders. The optimal first-line treatment and risk stratification tool for PTLD remains unclear and rituximab (R) monotherapy is often used following a reduction of immunosuppression (RIS), reserving combination chemotherapy for those failing this initial approach. However, this approach may not be suitable in those with high risk disease. The aim of this study was to review the outcome of patients with PTLD and PTLD-like disease, MethodsUsing the British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database, all patients diagnosed with PTLD and PTLD-like conditions from 1981-2013 were identified, excluding primary CNS lymphoma, low-grade lymphomas and HIV associated lymphomas. Results104 patients were identified: 86 PTLD and 18 PTLD-like. PTLD: Median age 47 y (range 6-71); 64% male; 60% late onset (> 1 year from transplant); 71% extranodal (EN) disease; 14% graft involved; 49% elevated LDH (n=36, missing n=13); 59% PS > 2 (n=45, missing n=10); 60% prior renal transplant. Pathology: 57% EBV positive (n=43, missing n=11); 2% early lesions, 13% polymorphic, 79% monomorphic (83% DLBCL), 1.1% classical Hodgkin lymphoma (CHL) and 4.7% unknown. All patients underwent initial RIS, followed by: observation (n=23, 27%), single agent rituximab (n=37, 43%), anthracycline based combination chemotherapy + R (n= 9 (n=6 + R), 10%), single agent chemotherapy + R (n=8 (n=4 + R), 9%); 4 (5%) were too frail to treat. With a median follow-up for living patients of 4.0 y (range 0.8-16.2 y), the 3-y OS and 3-y TTP were 50% and 48%, respectively. Polymorphic cases had a more favorable outcome compared to monomorphic cases with a 3-y OS of 91% vs. 45% (p=0.029) and a 3-y TTP of 73% vs. 44% (p=0.037). Monomorphic PTLD prognostic factors (n=63): In univariate analysis for TTP, an elevated LDH (p=0.006), poor PS >2 (p=.0012), EN sites > 1 (p=0.005), B symptoms (p=0.0019) and GI (p=0.022), kidney (p=0.009) and hepatic (p<0.00001) involvement were all associated with an inferior TTP. Similarly, elevated LDH (p= 0.028), poor PS (p=0.0001) and kidney involvement (p=0.027) were associated with a poor OS. A high IPI score was associated with an inferior outcome: 3-y OS and 3-y TTP for low (0,1) (n=20), intermediate (2,3) (n=34) and high risk (4,5) (n=14) groups were 69%, 40%, and 21% (p=0.03) and 83%, 28%, and 14% (p<0.0001), respectively. For monomorphic DLBCL cases receiving single agent rituximab (n=29), a higher IPI was also associated with a worse 3-y OS (76%, 64%, and 20%, p=0.018) and 3-y TTP (67%, 27%, and 20%, p=0.03) for the low, intermediate and high risk groups, respectively. PTLD-like: Median age 63 y (range 26-74); 50% male; 51% EN disease; 33% LDH elevated (n=6); 44% PS > 2 (n=7, missing n=2); 92% EBV positive (n= 12, missing n=5). Pathology: 1 polymorphic (6%); 15 monomorphic (83%) (DLBCL n=11, 73%, DLBCL/CHL grey zone lymphoma n=2, 13%), 1 CHL (6%), 1 Hodgkin-like (6%), 1 unknown (6%). The majority of patients had a history of rheumatoid arthritis (n=10, 56%) and had been on treatment with methotrexate (n=10, 56%). The median time from onset of autoimmune disorder to the development of PTLD-like disease was 11 y (0.16-50) and the median duration of drug exposure prior to the development of the PTLD-like disease was 5 y (0.16-15y). All patients underwent RIS, followed by observation (n=6, 32%); single agent rituximab (n=4, 21%); anthracycline based combination chemotherapy + R (n=6, 37%; R, n=4); or single agent chemotherapy + R (n=1, 5.3%); 1 was too frail. With a median follow-up of 4.9 y (range 0.3-17 y), the 3-y TTP and OS were 65% and 77%, respectively. ConclusionFor PTLD, a select group of patients with a low IPI score appear to have high cure rates with single agent rituximab. For those with multiple IPI factors a risk-adapted strategy with earlier use of chemotherapy may be preferred. In the group with PTLD-like disease we observed Hodgkin lymphoma and Hodgkin-like proliferations but also grey zone lymphomas, the latter of which has not been previously reported. Patients with PTLD-like disorders have a more favorable outcome than those with PTLD. Disclosures:Klasa:Roche Canada: Research Funding. Sehn:Roche/ Genentech: Consultancy, Honoraria, Research Funding. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding. Shenkier:Roche Canada: Research Funding. Connors:Roche Canada: Research Funding; F Hoffmann-La Roche: Research Funding. Savage:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding.

Classical Hodgkin Lymphoma Arising in the Setting of Iatrogenic Immunodeficiency

Iatrogenic immunodeficiency-associated lymphoproliferative disorders are rare. A small subset of these lesions resembles classical Hodgkin lymphoma (CHL), but there are few data in the literature about these lesions. We describe 10 patients with autoimmune diseases treated with immunomodulator therapeutic agents who developed CHL. The autoimmune diseases included rheumatoid arthritis (n=5), systemic lupus erythematosus (n=2), dermatomyositis (n=1), autoimmune hepatitis (n=1), and Crohn disease (n=1), and the immunomodulatory therapies were methotrexate, azathioprine, tumor necrosis factor-α inhibitors, and thalidomide alone or in various combinations. The study group included 9 women and 1 man with a median age of 50 years (range, 25 to 77 y). The histologic features supported CHL in all cases with Reed-Sternberg (RS) and Hodgkin (H) cells in an inflammatory cell background, although the neoplasm could only be subclassified in 3 patients: 2 nodular sclerosis and 1 mixed cellularity. Immunohistochemical analysis supported the diagnosis of CHL. In all cases the RS-H cells were CD30. Nine of 10 cases were CD15, whereas CD20 was expressed variably in 4/10 cases. CD45/LCA was negative in 8 cases assessed. In situ hybridization for Epstein-Barr virus-encoded RNA was positive in the RS-H cells in 8/10 cases. The microenvironment of these lesions depicted a predominance of T-regulatory cells and M2 histiocytes. Clinical follow-up data were available for 7 patients, with a median posttreatment period of 27 months (range, 12 mo to 7 y). In all 7 patients immunomodulatory drug therapy was discontinued, and chemotherapy for CHL was administered; 2 patients also received local radiation. All 7 patients achieved complete remission and are alive. We conclude that iatrogenic immunodeficiency-associated CHL is highly associated with Epstein-Barr virus infection, and patients usually have a good outcome after discontinuation of immunomodulatory agents and chemotherapy for CHL.

穿刺吸引細胞診で腺癌と診断された頸部other iatrogenic immunodeficiency-associated lymphoproliferative disordersの１例

穿刺吸引細胞診で腺癌と診断された頸部other iatrogenic immunodeficiency-associated lymphoproliferative disordersの１例

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.

Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies

The 2008 edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes a new diagnostic entity termed "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" highlighting lymphomas arising in patients treated with immunosuppressive agents for autoimmune disorders. The role of antitumor necrosis factor alpha therapy (anti-TNFα) and lymphoma risk in rheumatoid arthritis (RA) patients remains unclear; therefore, the goal of our study was to determine whether anti-TNFα therapy is associated with iatrogenic lymphomas. A meta-analysis of all randomized controlled clinical trials published (2000-2009) in RA patients receiving anti-TNFα therapy was performed. Fourteen studies fulfilled all search criteria and included 2,306 control patients and 5,179 patients treated with anti-TNFα therapy, namely etanercept, adalumimab, and infliximab. Clinical information including the number of patients, age, gender, lymphoma rates, and follow-up time was recorded. The overall rate and rate differences were analyzed using the DerSimonian and Laird method. Of the control group, four (4/2,306, 0.17%) patients developed hematolymphoid neoplasms. Eleven (11/5,179, 0.21%) patients receiving anti-TNFα therapy developed lymphomas. The adjusted overall rates are 0.36 lymphomas per 1,000 person-years in patients who did not receive anti-TNFα therapy versus 1.65 lymphomas per 1,000 person-years in patients who received anti-TNFα therapy. The corresponding 95% confidence interval for this rate difference is (-0.214, 2.79). The adjusted rate difference is 1.29 lymphomas per 1,000 person-years (95% CI, -0.21, 2.8; p value = 0.093). The corresponding p value is p = 0.0928. There is a suggestion of increased lymphomas in the treated group, with the predominant subset being B-cell lymphomas. Since the outcome of lymphoma is rare, it does not reach statistical significance of p < 0.05.

Commentary on the WHO 2008 classification of immunodeficiency-associated lymphoproliferative disorders

The 2008 WHO update of Classification of Tumours of Hematopoietic and Lymphoid Tissues revised the classification of immunodeficiency-associated lymphoproliferative disorders with the aim to better define these heterogeneous entities to better distinguish between reactive and neoplastic lesions, further refine some entities (plasmablastic lymphoma, monomorphic post-transplant lymphoproliferative disorders and other iatrogenic immunodeficiency-associated lymphoproliferative disorders), and introduce a new lymphoma entity (large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease). The purpose of this review is to highlight the changes in the 2008 WHO classification of immunodeficiency-associated lymphoproliferative disorders.

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.

Composite Cutaneous Lymphoma in a Patient With Rheumatoid Arthritis Treated With Methotrexate

Patients with rheumatoid arthritis, whether treated or not with immunosuppressive agents including methotrexate, have an increased risk of lymphoproliferative disorders. Termed "iatrogenic immunodeficiency-associated lymphoproliferative disorders" in the 2008 World Health Organization classification of lymphoid neoplasms, they include Hodgkin and non-Hodgkin lymphomas. Composite lymphomas are rare, particularly in skin, with none reported in immunodeficiency states. We report the case of a 67 year-old woman with a long history of rheumatoid arthritis, on methotrexate treatment, who developed multiple skin lesions exhibiting a malignant infiltrate displaying both B- and T-cell phenotypes and dual clonal gene rearrangement by polymerase chain reaction, consistent with a cutaneous composite lymphoma. The patient received chemotherapy including rituximab with partial response, but the T-cell component recurred. To the best of our knowledge, this is the first case report of a cutaneous composite lymphoma in a patient with an iatrogenic immunodeficiency representing a dual challenge, diagnostic for the pathologist and therapeutic for the hematologist.