Diffuse large-cell lymphoma of B-cell origin and deficient T-cell function in a patient with rheumatoid arthritis

An increased incidence of non-Hodgkin's lymphoma has been described in patients with rheumatoid arthritis. Mechanisms related to abnormal immune regulation have been postulated, but no patients with rheumatoid arthritis and lymphoma have been previously well characterized immunologically. We describe here a patient with long-standing rheumatoid arthritis in whom a B-cell diffuse large-cell lymphoma developed. He was found to have a severe T-cell immunodeficiency and evidence of persistent Epstein-Barr virus infection. Epstein-Barr nuclear antigen was not found to be present within lymphoma cells. The combination of defective T-cell function and persistent Epstein-Barr virus infection may have predisposed this patient with rheumatoid arthritis to the development of a malignant clone of B lymphocytes.     

Bone marrow B-cell clonal expansion in type II mixed cryoglobulinaemia: association with nephritis

OBJECTIVES: To investigate the relationship between the pattern of bone marrow (BM) B-cell expansion and the clinical features of mixed cryoglobulinaemia (MC) syndrome. METHODS: Fifty-five patients with type II MC syndrome were analysed. Their median age was 64 yrs (range 24-82), the median disease duration was 6 yrs (range 1-26) and the mean follow-up after BM analysis was 2.65 yrs (s.d. = 1.33). Peripheral neuropathy was present in 33 patients (60%), nephritis in 14 (25.4%), skin ulcers in 14 (25.4%) and lymphoma or atypical lymphoproliferative disorder (LPD) in 17/55 (30.9%). Anti-HCV antibodies were found in 43/55 patients (78.2%). BM B-cell expansion was evaluated by a semi-nested PCR amplification of the V-D-J region of the IgH genes. RESULTS: A clonal B-cell expansion in the BM was found in 33/55 (60%) patients, while a polyclonal pattern in 22/55 (40%). A BM pattern of clonal B-cell expansion increased the risk of nephritis of about 10 times [odds ratio (OR) = 10.11, CI95%1.52-67.31], if compared to a polyclonal pattern. In contrast, the risk of skin ulcers was decreased in BM clonal cases (OR = 0.09, CI95%0.02-0.49). Overt lymphomas did not emerge from patients with BM monoclonal expansion (without clinical or histopathological features of lymphoproliferation; or with LPD) in a short-term, consistent with the finding that monoclonality was associated with nephritis and not with an underlying, not recognized lymphoma. CONCLUSION: BM clonal B-cell expansion is associated with nephritis in MC syndrome. Particular B-cell clones may be preferentially expanded and may play a pathogenic role in MC nephritis.     

Hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma

OBJECTIVE: As a causative role of hepatitis C virus (HCV) in B-cell lymphoproliferative disorders (LPD) has been suggested by several reports, we investigated the prevalence of HCV infection among patients with LPD at our hospital with the aim of clarifying the clinical features and the outcome for HCV antibody-positive patients with non-Hodgkin's lymphoma (NHL). METHODS: Retrospective chart review. PATIENTS: A total of 123 patients with B-cell LPD (4 with chronic lymphocytic leukemia, 17 with multiple myeloma, and 100 with B-cell NHL), 38 patients with non-B-cell LPD (5 with adult T-cell lymphoma, 8 with Hodgkin's disease, and 25 with non-B-cell NHL) and 516 patients with miscellaneous diseases other than liver diseases or LPD (control) were studied. RESULTS: HCV infection was detected in 17 of 100 patients with B-cell NHL versus none of 25 patients with non-B-cell NHL (p=0.023) and in 34 patients (6.6%) in the control group with miscellaneous diseases (p=0.0011). In HCV-positive B-cell NHL, primary liver involvement was detected in 3 of 17 patients compared to none of 83 HCV-negative patients (p=0.0019). Intermediate-grade lymphoma (Working Formulation) was the most frequent histology. Eleven of 15 HCV-positive patients achieved complete remission after chemotherapy, and 6 of 7 deaths were caused by liver-related diseases. CONCLUSION: The prevalence of HCV infection was higher in patients with B-cell NHL than in those with non-B-cell NHL and the control group. Primary liver involvement and liver-related causes of death were frequent in HCV-positive patients with B-cell NHL.     

Pulmonary non-Hodgkin’s lymphoma developed during long-term methotrexate therapy for rheumatoid arthritis

Methotrexate is effective in treating rheumatoid arthritis (RA). Some reports have discussed the possible association between methotrexate and lymphoma. Here, we report a case of pulmonary non-Hodgkin’s lymphoma (NHL) developed after 11?years’ methotrexate therapy for RA. Biopsy of the pulmonary mass demonstrated a diffuse large B-cell lymphoma. After withdrawal of methotrexate without any other intervention for 4?weeks, a significant reduction in the size of the lymphoma was observed. The causative relationship between methotrexate and pulmonary lymphoma is suggested by the persistent remission after stopping methotrexate therapy.     

Methotrexate-related lymphomatoid granulomatosis: a case report of spontaneous regression of large tumours in multiple organs after cessation of methotrexate therapy in rheumatoid arthritis

We describe a 54-year-old female patient with rheumatoid arthritis (RA) and Sj?gren's syndrome (SS) who presented with right chest pain and a large mass visible in the upper right field of a chest X-ray. Computed tomography (CT) showed multiple tumours in both lungs, the liver, and the spleen. The right lung tumour was 8 cm in diameter with a cavity. Biopsy of the lung and liver revealed lymphomatoid granulomatosis (LG) and diffuse large B-cell lymphoma (DLBCL). These lesions spontaneously regressed after withdrawal of methotrexate without any therapy for the lymphoma. This is the first report of self-limiting LG in a patient, complicated with methotrexate-treated RA.     

Methotrexate-related lymphoproliferative disorder of the stomach in a patient with rheumatoid arthritis: a case of disease regression after methotrexate cessation

We report the case of a 78-year-old woman with methotrexate-related gastric lymphoproliferative disorder (LPD). The patient had a history of rheumatoid arthritis (RA) and had been treated with methotrexate (MTX). Endoscopic examination revealed round elevated lesions in the stomach, and a biopsy specimen showed atypical lymphoid cell proliferation. Immunohistological study found these atypical cells to be positive for L-26 but not for CD3 or EBER. Therefore, we made a diagnosis of MTX-related LPD showing features of diffuse large B-cell lymphoma. Combined positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) showed increased avidity in the stomach in addition to slightly increased FDG-avidity in the mediastinum and left chest wall. We decided not to start chemotherapy but to discontinue administration of MTX, with follow-up using endoscopy and PET-CT. The endoscopic examinations after cessation of MTX demonstrated gradual regression of the elevated lesions. PET-CT 6 months after cessation showed no increased FDG avidity in the stomach. While disease regression was observed in the stomach, the other FDG-avid spots remained unchanged on PET-CT. Therefore, we performed chemotherapy as additional therapy. On PET-CT after chemotherapy, the FDG-avid spots remained unchanged for more than 1 year, and we eventually concluded that they were RA-related inflammatory lesions. In patients with MTX-related LPD, cessation of MTX may be a therapeutic option, but careful follow-up and chemotherapy in accordance with the clinical course are essential.     

Malignant lymphoma associated with rheumatoid arthritis, developing shortly after initiation of oral methotrexate

We report a patient with rheumatoid arthritis (RA) who developed malignant lymphoma of the diffuse large B-cell type in the right submandibular region shortly after initiation of oral methotrexate (MTX). Despite cessation of MTX, the lymphadenopathy did not regress, and only reached complete remission after 3 courses of CHOP therapy followed by irradiation. In this patient highly active RA itself was considered to be the main cause of malignant lymphoma, and MTX might have contributed to the development by modifying the immune system. When RA is highly active, MTX should be used carefully because of the possible development of malignant lymphoma as well as other serious complications.     

Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort

The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient’s report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12–1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00–1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.     

Lymphoproliferative disorders in paediatric rheumatic diseases. A report of two cases

Lymphoproliferative disorders (LPD) are reported with a much lower frequency in children with rheumatic diseases than in their adult counterparts. We describe 2 patients who developed a lymphoma during the course of the disease. The first is a 16-year-old girl diagnosed with systemic juvenile idiopathic arthritis 6 years before who developed a mucosa-associated lymphoid tissue (MALT) lymphoma. The second report involves a boy diagnosed with systemic lupus erythematosus at 9 years of age who developed a Hodgkin's lymphoma 9 years after the disease onset. In spite of the low frequency of LPD in children with rheumatic diseases, these processes do occur.     

Epstein-Barr virus-associated B-cell type non-Hodgkin's lymphoma with concurrent p53 protein expression in a rheumatoid arthritis patient treated with methotrexate

A Japanese male patient received various medications for his long-standing rheumatoid arthritis (stage IV, class II). He developed a mass on the right anterior chest wall after being treated with methotrexate (MTX) for 4 months. A biopsy of the mass showed it to be Epstein Barr virus (EBV)-associated lymphoma of B-cell phenotype stage IE (bulky mass), with positive EBV-encoded small RNAs (EBERs) in situ hybridization, EBV latent membrane protein-1 (LMP-1) negative, EB nuclear antigen-2 (ERNA-2) negative, CD20/L26 (+), CD45RO/UCHL-1 (-). A single band of the joined termini of the EBV genome was demonstrated in DNA extracted from the mass, suggesting a clonal disorder of the mass. Immunostaining of the mass with p53 antibody was also positive. With discontinuation of MTX and administration of chemotherapy, the tumor disappeared but recurred after 3 months. This case suggests that concordant p53 expression and latent EBV infection may play an important role in the pathogenesis of lymphomas arising in patients with rheumatoid arthritis who are immunosuppressed with MTX.     

Malignant Lymphoma Complicating Sjögren's Syndrome

Summary: This report describes a patient with rheumatoid arthritis, Felty's syndrome and Sjögren's syndrome who developed a malignant lymphoma of histiocytic (reticulum cell) type. Serum salivary duct antibodies and the salivary gland histology of Sjögren's syndrome were demonstrated before clinical features of the syndrome appeared. As the lymphoma developed, autoantibodies and rheumatoid factor disappeared from the serum and immunoglobulin levels declined. The successful response to drug therapy was accompanied by a recovery of immunoglobulin levels and return of rheumatoid factor. The spectrum of lymphoproliferation, from benign to malignant, seen in Sjögren's syndrome and the factors that may be important in the malignant transformation are briefly discussed.     

A case of age-related EBV-associated B-cell lymphoproliferative disorder metachronously showing two distinct morphologic appearances, one of a polymorphic disease resembling classical Hodgkin lymphoma, and the other of a large-cell lymphoma

We report a case of age-related EBV-associated B-cell lymphoproliferative disorder (age-related EBV+ B-cell LPD) metachronously showing two distinct morphologic appearances: one of a polymorphic disease resembling classical Hodgkin lymphoma (CHL), and the other of a large-cell lymphoma. A 71-year-old man was admitted to the St. Marianna University Hospital because of fever and generalized lymphadenopathy. Right axillary lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (MCHL). The patient was referred to the Tokyo Medical Center, where he was treated with chemotherapy and obtained CR. One year later, the patient again developed fever and generalized lymphadenopathy. Biopsy of the right cervical mass revealed a diagnosis of diffuse large B-cell lymphoma. The patient was treated with salvage chemotherapies and obtained the second CR. Two years later, the patient developed acute myeloid leukemia (AML). Although CR was achieved with chemotherapy, AML relapsed 5 months later and proved to be refractory. Two and a half years later, the patient developed right cervical lymph node enlargement. The biopsy again revealed diagnosis of MCHL. The patient died 2 months later. On reviewing all of the biopsy specimens, including the findings of immunohistochemistry and in situ hybridization, possibility of CHL was ruled out, because neoplastic giant cells resembling Hodgkin and Reed-Sternberg (HRS) cells were positive for both Oct2 and BOB.1, which has not been reported in CHL. Both HRS-like cells at the time of diagnosis of Hodgkin lymphoma and lymphoma cells at the time of diagnosis of non-Hodgkin lymphoma were positive for CD20 and EBV-encoded small RNAs. This case was finally diagnosed as having age-related EBV+ B-cell LPD. We report the case here as it underscores the difficulty in diagnosing age-related EBV+ B-cell LPDs and also suggests an important role of EBV in the pathogenesis of lymphoid neoplasms.     

Anaplastic large cell lymphoma in a patient with rheumatoid arthritis

It is known that patients with rheumatoid arthritis (RA) have an increased risk for non-Hodgkin’s lymphomas in comparison with the general population. Although increased risk of lymphoma is attributed to the disease activity, the drugs used in the therapy of RA may also cause increased risk of malignancy. Herein, we report on an RA patient who developed non-Hodgkin’s lymphoma after methotrexate therapy and review the literature about it. A 74-year-old man with RA had been treated with low-dose methotrexate and subsequently developed anaplastic large cell lymphoma of the T-cell phenotype. Anaplastic large cell lymphoma has been reported rarely in rheumatoid arthritis.     

Extranodal NK/T-cell lymphoma, nasal type, developed in a patient with rheumatoid arthritis

It is well known that patients with rheumatoid arthritis (RA) have a higher risk of developing malignant lymphoma (ML) than the general population. Most of these lymphomas occur in patients receiving immunosuppressive (IS) agents such as methotrexate (MTX). Spontaneous regression of tumors is often observed after the discontinuation of IS drugs, especially in patients with Epstein-Barr virus-positive lymphoma. Here we encountered an RA patient who developed extranodal NK/T-cell lymphoma, nasal type during treatment of RA with MTX and etanercept. Despite the discontinuation of MTX and etanercept, the tumor did not show any regression. Complete response was achieved after treatment with concurrent chemoradiotherapy. ML of NK-cell origin is extremely rare, while the majority of ML cases associated with RA are of B-cell origin. This report describes extranodal NK/T-cell lymphoma, nasal type case associated with RA. Such cases should be accumulated to evaluate the mechanism of onset and clinical characteristics of NK/T-cell lymphoma associated with RA.     

Clinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis

Abstract

Objective. To investigate the incidence and clinical features of methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPDs) in patients with rheumatoid arthritis (RA).

Patients. In total, 589 RA outpatients were examined at the National Center for Global Health and Medicine in the period from January 1990 to October 2010.

Results. MTX was used in 403 cases, and the duration of follow-up was 2379 person-years. Four patients developed MTX-LPDs; the incidence of MTX-LPDs was calculated as 0.00168/person-year and the standardized incidence as 8.21 (95% CI: 0.16–24.30). The mean total dosage of MTX was 1142 ± 871 mg, and the dosage at LPD onset was 7.4 ± 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX, but who had not progressed to LPDs (3.1 years vs. 12.5 years; P = 0.01). The following LPD subtypes were observed: diffuse large B-cell lymphoma (N = 2); Hodgkin's lymphoma (N = 1); and T-cell lymphoma (N = 1). After withdrawal of MTX, two of these patients showed spontaneous regression of the tumor, one did not have a recurrence, while the other patient relapsed and required chemotherapy.

Conclusion. Our study revealed that MTX-LPDs are not rare complications of RA outpatients. The MTX-LPDs were associated with a relatively shorter RA duration, and half of them showed tumor regression after MTX withdrawal, which suggested an association with MTX. It is important to consider the possibility of MTX-LPD in RA patients who have received MTX.     

Mucosa-associated lymphoid tissue lymphomas in two patients with rheumatoid arthritis on second-line agents, and secondary Sjögren's syndrome

We report two patients with rheumatoid arthritis and secondary Sj?gren's syndrome whose disease was complicated by a mucosa-associated lymphoid tissue (MALT) lymphoma. Although this particular type of lymphoma is associated with primary Sj?gren's syndrome, it has not been described, to our knowledge, in the context of rheumatoid arthritis and Sj?gren's syndrome. The potential causative factors are discussed.     

Spontaneous remission of low-grade B-cell non-Hodgkin's lymphoma following withdrawal of methotrexate in a patient with rheumatoid arthritis: case report and review of the literature

A 69-year-old woman, who had suffered from deforming rheumatoid arthritis since the age of 40 years, had been treated with methotrexate for 3 years. She presented with a 7 week history of neck lymphadenopathy. Biopsy revealed low-grade marginal-zone B-cell non-Hodgkin's lymphoma. Computerized tomography and bone marrow biopsy confirmed stage IIIA disease. Spontaneous complete remission of the lymphoma was achieved 14 months after withdrawing immune suppression with methotrexate.     

Epstein–Barr virus and methotrexate-related CNS lymphoma in a patient with rheumatoid arthritis

Abstract

Patients with rheumatoid arthritis (RA), especially those treated with methotrexate (MTX), might have an increased risk of lymphoproliferative disorders that are associated with Epstein–Barr virus (EBV). We describe a case of EBV-associated central nervous system (CNS) lymphoma (diffuse large B-cell lymphoma) in a patient with RA on a short course of MTX treatment. The neoplastic cells express the B-cell surface markers (CD20, Pax-5 and CD30), and EBV-encoded RNA was demonstrated by in situ hybridization. The patient’s lymphoma did not recur for the 8-year follow-up period after the tumor resection and cessation of MTX. MTX may promote EBV-positive CNS lymphoma in RA patient due to its immunosuppressive properties as well as reactivating latent EBV infection.     

Spontaneous regression of EBV-associated diffuse lymphoproliferative disease in a patient with rheumatoid arthritis after discontinuation of etanercept treatment

We describe the case of a 64-year-old female patient with rheumatoid arthritis (RA), who presented with lymphoproliferative disease (LPD) soon after the administration of etanercept, and regressed very shortly after the withdrawal of it. The occurrence was also associated with the Epstein–Barr virus (EBV) infection. The case of our patient may provide the evidence that etanercept plays an etiologic role in LPD in patients with RA.