Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders.

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

The first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma that deteriorated after COVID-19 vaccination.

This is the first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma (EBV + MZL) with an other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) (methotrexate [MTX]-associated LPD) that deteriorated after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. This case had a unique immunophenotype. A 71-year-old female patient with rheumatoid arthritis receiving MTX presented with fatigue 1 week after the SARS-CoV-2 vaccination. She was hospitalized due to hepatorenal dysfunction and pancytopenia. Computed tomography revealed systemic lymphadenopathy. Her physical condition deteriorated, and the patient died. The autopsy revealed systemic lymphadenopathy comprising medium-sized atypical lymphocytes and scattered Hodgkin/Reed-Sternberg (H/RS)-like cells. An immunohistochemical examination showed that atypical lymphocytes were positive for CD79a and MUM-1 and some were positive for CD20 and IRTA-1. H/RS-like cells were immunoreactive for CD30 and CD15 and ringed by T cells. Both cell types were positive for EBV-encoded small RNA. The majority of H/RS-like cells were positive for CD20, whereas a small number of CD3-positive cells were admixed. We herein presented the first autopsy case of EBV + MZL that deteriorated after the SARS-CoV-2 vaccination.

Complete remission of aggressive Epstein-Barr virus-positive diffuse large B-cell lymphoma following withdrawal of tacrolimus and low-dose anticancer drugs.

A 66-year-old woman who had received tacrolimus for more than 11 years was admitted with high fever, generalized lymphadenopathy, and persistent gastrointestinal bleeding. Histopathological evaluation of the lymph nodes and colonic mucosa confirmed the diagnosis of Epstein-Barr virus-positive diffuse large B-cell lymphoma. After discontinuation of tacrolimus, the lymphoma did not improve, and low-dose chemotherapy was introduced, which resulted in a recovery of lymphocyte counts and induction of complete remission. Low-dose anticancer treatments that suppress tumor growth while awaiting normal lymphocyte recovery for several weeks may be a useful therapeutic option even for aggressive lymphomas that develop during immunosuppressant therapy.

[RS3PE syndrome with angioimmunoblastic T-cell lymphoma early after the start of immunosuppressive therapy].

A 75-year-old man visited our Collagen Disease Department because of a fever, edema in the lower legs, and arthralgia. He presented with peripheral arthritis of the extremities and was negative for rheumatoid factor, leading to a diagnosis of RS3PE syndrome. A search for malignancy was performed, but no obvious malignant findings were found. After starting treatment with steroid, methotrexate, and tacrolimus, the patient's joint symptoms improved, but after five months, enlarged lymph nodes throughout the body were observed. A lymph node biopsy revealed a diagnosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders/angioimmunoblastic T-cell lymphoma (OI-LPD/AITL). After discontinuation of methotrexate and follow-up, no lymph node shrinkage was observed, and the patient had strong general malaise, so chemotherapy was started for AITL. After the start of chemotherapy, the patient's general symptoms improved quickly. RS3PE syndrome is a polyarticular, rheumatoid factor-negative, polyarticular synovitis with symmetric dorsolateral hand-palmar symmetric indentation edema that occurs mainly in elderly patients. It is also noted as a paraneoplastic syndrome, with 10%-40% of patients having malignant tumors. When our patient was diagnosed with RS3PE syndrome, a search for malignancy was performed, but there were no findings suggestive of malignant disease. However, after methotrexate and tacrolimus administration was started, the patient developed rapid lymph node enlargement, and the pathology showed AITL. The possibility of AITL as an underlying disease and RS3PE syndrome as a paraneoplastic syndrome, or conversely, OI-LPD/AITL associated with immunosuppressive therapy for RS3PE syndrome is considered. We herein report this case, as sufficient recognition is required for a proper diagnosis to be made and treatment of RS3PE syndrome to be performed.

Primary central nervous system other iatrogenic immunodeficiency-associated lymphoproliferative disorders presenting as extraosseous plasmacytoma with a progressive clinical course: A case report and literature review.

Other iatrogenic immunosuppressive-associated lymphoproliferative disorders (OIIA-LPDs) rarely occur in the central nervous system (CNS). Additionally, they almost always present as lymphoma and withdrawal by cessation of immunosuppressive treatment. We report a case of primary CNS OIIA-LPD that presented as extraosseous plasmacytoma (EP) with a progressive clinical course in spite of immunosuppressive treatment cessation. A 78-year-old man with a history of rheumatoid arthritis (RA) presented with a month-long headache. Magnetic resonance imaging showed mass lesions in the left temporal lobe, left middle fossa, and intradural cervical spine. The left temporal lesion was resected and diagnosed as EP histologically, and OIIA-LPD presented as plasmacytoma integrally due to his history of immunosuppressive treatment using tacrolimus for RA. Despite immunosuppressive treatment cessation, OIIA-LPD lesions did not regress but, on the contrary, showed a progressive clinical course. Considering his advanced age and renal dysfunction, postoperative treatment with radiation and moderate chemotherapy using prednisolone were administrated. Subsequently, the disease state stabilized, and the patient had a Karnofsky performance status score of 90 for 6 months; however, the tumor recurred with meningeal dissemination, and he died 8 months after treatment. Types of OIIA-LPD onset as EP and its progressive clinical course resistant to cessation of immunosuppressive treatment are rare. Moreover, this OIIA-LPD disease state worsened despite its radiosensitivity. We believe the progressive clinical course of this OIIA-LPD case with its high cell proliferation is similar to Epstein-Barr virus negative plasmablastic lymphoma, which could lead to a poor outcome.

[Regression of diffuse large B-cell lymphoma after discontinuation of salazosulfapyridine].

An 81-year-old man with a 3-year history of salazosulfapyridine (SASP) therapy for rheumatoid arthritis (RA) presented with pulmonary infiltrates and underwent computed tomography-guided biopsy. The histopathological and immunohistochemical evaluation confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL). He was recommended chemotherapy, which he refused. Due to the possibility of other iatrogenic immunodeficiency-associated lymphoproliferative disorders, SASP therapy was discontinued. SASP therapy withdrawal led to near-complete resolution of the lung infiltration shadows, and the serum soluble interleukin 2 receptor level returned to the normal range. This is the first report of a case of remission of DLBCL, following SASP therapy withdrawal in a patient with RA.

Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein-Barr virus infection: a case report and review of the literature.

BACKGROUND: Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear. CASE PRESENTATION: We report the first case of Epstein-Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD. CONCLUSION: MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.

Treatment of rheumatoid arthritis after regression of lymphoproliferative disorders in patients treated with methotrexate: a retrospective, multi-center descriptive study.

OBJECTIVES: To identify the optimal treatment for rheumatoid arthritis (RA) after the regression of lymphoproliferative disorders (LPDs). METHODS: The subjects were 232 patients with RA who developed LPD between 2000 and 2017 at seven hospitals participating in the LPD-WG study. Kaplan-Meier and Cox proportional regression analyses were performed to determine the factors associated with the rate of LPD relapse and the retention of biological disease-modifying antirheumatic drugs (bDMARDs). RESULTS: Treatment for RA was resumed in 138 patients after spontaneous regression of LPD after the discontinuation of methotrexate and in 52 patients after chemotherapy for LPD (persistent-LPD). LPD relapses occurred in 23 patients. Not DMARDs use but Hodgkin's lymphoma was identified as a risk factor for LPD relapse. In 88 RA patients treated with bDMARDs [tocilizumab, 39 patients; abatacept 20 patients; tumor necrosis factor inhibitor, 29 patients], the one-year retention rate was 67.8%. The risk factors for discontinuation of bDMARDs were persistent-LPD, non-diffuse large B-cell lymphomas (non-DLBCL), and a high clinical disease activity index (CDAI). Tocilizumab showed the highest retention rate among bDMARDs, particularly in DLBCL. CONCLUSION: Although any bDMARD could be used in patients after LPD regression, effectiveness and risk for relapse should be carefully assessed for each LPD subtype.

[Oral Mucosal Diffuse Large B-cell Lymphoma Caused by Long-term Oral Methotrexate:Report of One Case].

A case of primary oral mucosal diffuse large B-cell lymphoma(DLBCL)due to long-term use of methotrexate(MTX)for the treatment of rheumatoid arthritis(RA)was admitted to the Department of Hematology,Fujian Medical University Union Hospital.We analyzed and discussed the clinical features,diagnosis and treatment,and prognosis of specific malignant lymphoma induced by MTX in this RA patient.Our purpose is to improve the awareness and knowledge of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of clinicians and pathologists.This study provides a new reference for the clinical diagnosis and treatment of MTX-associated DLBCL.

Primary Skeletal Muscle Peripheral T-cell Lymphoma: An Autopsy Case Report and Review of the Literature.

Primary skeletal muscle lymphoma is extremely uncommon, and there have only been eight previous case reports on primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). We herein report an autopsy case of a 71-year-old woman with PSM-PTCL, NOS, who had a 24-year history of systemic sclerosis treated with immunosuppressive drugs. A post-mortem examination revealed infiltration of lymphoma cells positive for T-cell markers, cytotoxic markers, and p53. This case was considered to be one of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD). This is the first case categorized under both PSM-PTCL, NOS, and OIIA-LPD.

Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment.

OBJECTIVES: Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. METHODS: We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. RESULTS: LPD patients were categorized into two groups: patients who regressed spontaneously (n = 19) and those who needed chemotherapy (n = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. CONCLUSIONS: Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.

Primary Central Nervous System T-cell Lymphoma as Methotrexate-associated Lymphoproliferative Disorders: Case Report.

We report a rare case of primary central nervous system (CNS) lymphoma as methotrexate-associated lymphoproliferative disorders (MTX-LPD). A 75-year-old woman who had been treated for rheumatoid arthritis (RA) with MTX for 3 years was admitted to our hospital complaining of unsteady gait, nausea, and vomiting. T2-weighted image of magnetic resonance imaging (MRI) showed multiple high intensity mass-like lesions including right lateral, frontal and temporal lobes, and right cerebellar hemisphere. We performed surgical biopsy, and the pathological and immunohistochemical examinations identified T-cell lymphoma. The tumor regressed and the symptoms were resolved soon after MTX withdrawal. Primary CNS lymphoma due to MTX-LPD is a rare disease and only eight cases including ours are reported.

Primary cutaneous diffuse large B-cell lymphoma, leg type, in a patient with rheumatoid arthritis undergoing etanercept therapy.

An 84-year-old woman, who was diagnosed with rheumatoid arthritis (RA) and was treated with methotrexate and, subsequently, etanercept (ETN) for 6 years, presented with rapidly progressing painful cutaneous mass on the right medial malleolus. The patient was eventually diagnosed with primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). ETN therapy was promptly discontinued expecting spontaneous regression of the lymphoma, which was thought to have developed as other iatrogenic immunodeficiency-associated lymphoproliferative disorders. However, no tumour regression was noted. Chemoimmunotherapy was subsequently initiated, which resulted in partial remission. PCLBCL-LT rarely occurs in patients with RA. Here, we report the first case of PCLBCL-LT that developed in a patient with RA receiving ETN therapy.

Methotrexate-associated Hodgkin Lymphoma in a Patient with Rheumatoid Arthritis Successfully Treated with Brentuximab Vedotin in Combination with Doxorubicin, Vinblastine, and Dacarbazine (BV+AVD).

A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL.

Methotrexate-associated lymphoproliferative disorder demonstrating composite lymphoma of EBV-negative diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders induced by immunosuppressive drugs, such as methotrexate (MTX-LPD), exhibit numerous pathological findings. We report the case of an 81-year-old Japanese woman diagnosed with MTX-LPD exhibiting two distinct pathological features from two different sites. Excisional biopsy of the left cervical lymph node revealed EBV-negative diffuse large B-cell lymphoma and biopsy of a pharyngeal ulcer revealed EBV-positive mucocutaneous ulcer. She was treated using an R-CHOP regimen and maintained complete remission for years. This case demonstrates the heterogeneous pathology of MTX-LPD and suggests the necessity of multiple biopsy.

[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.

[Primary central nervous system methotrexate associated lymphoproliferative disorders in a patient with rheumatoid arthritis].

We report on a 52-year-old woman with rheumatoid arthritis (RA) who developed methotrexate associated lymphoproliferative disorders (MTX-LPD) in the central nervous system (CNS) in the course of immunosuppressive therapy for RA. The patient was admitted because of monoplegia in her left hand. She had been receiving methotrexate (MTX) for her RA for several years and etanercept had also been introduced because of a worsening of the arthritis six months before admission. Brain MRI revealed multiple lesions with enhancement scattered throughout both hemispheres. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography showed abnormal accumulation suggesting malignancy in the right frontal lobe where abnormal enhancement was observed on the MRI. A brain biopsy was performed at the identified site and it confirmed diffuse large B-cell lymphoma (DLBCL). We therefore diagnosed her as MTX-LPD. According to previous reports, most MTX-LPD cases tend to show regression after the cessation of MTX. However, our case showed no regression and even needed chemotherapy. The patient had a poorer prognosis than previous cases and died 17 months after the onset. Although it is an uncommon complication, particularly in the CNS, MTX-LPD should be considered as a critical differential diagnosis if a patient receiving MTX develops central nervous system lesions. Immediate medical intervention including brain biopsy is required.

Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature.

A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report.