Lymphoproliferative disorder risk after methotrexate treatment for rheumatoid arthritis.

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX-LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease-modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL-6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX-LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.

Distinct decrease in peripheral lymphocytes in EBER-positive cases of MTX-LPD.

OBJECTIVES: To determine the clinical characteristics of methotrexate-associated lymphoproliferative disorder (MTX-LPD). METHODS: In this study, 12 RA patients who developed MTX-LPD were assessed. The peripheral blood lymphocyte (PBL) count at the onset of MTX-LPD was compared to that 6 months before the onset, in Epstein-Barr virus-encoded RNA (EBER)-positive and -negative subgroups. We examined the change in the PBL count after MTX withdrawal. In patients with relapsed LPD, changes in the PBL count before relapse were also examined. RESULTS: Regression of LPD after MTX withdrawal was noted in eight patients. In these patients, the PBL count was decreased at the onset of MTX-LPD compared to 6 months before the onset; the decrease was significantly more prominent in EBER-positive patients. In cases of spontaneous regression of LPD, the PBL count recovered quickly after MTX withdrawal. Four of eight patients showed a recurrence of LPD after they improved following MTX withdrawal. These patients also exhibited a decreased PBL count at recurrence compared to 6 months before recurrence. CONCLUSION: A decrease in the PBL count might be involved in the pathogenesis of MTX-LPD, especially in EBER-positive cases and in patients with LPD relapse after MTX withdrawal following initial improvement.

[A methotrexate-associated lympholiferative disorder patient with gastrointestinal perforation].

A 70-year-old woman was diagnosed with chronic rheumatoid arthritis and treated with methotrexate and prednisolone. She visited our hospital to determine the cause of her continuous fatigue and fever for the past three weeks. She consumed no food orally and was provided antibiotics because free air was found on computed tomography (CT). Intraperitoneal small lymphadenopathy and swelling of both adrenal glands was also found on CT, and MTX-associated lymphoproliferative disorder (MTX-LPD) was suspected. Am adrenal gland biopsy showed diffuse large B-cell lymphoma (DLBCL) associated with MTX-LPD. The causes of gastrointestinal perforation with collagen diseases have been reported to be functional gastrointestinal disorders with collagen diseases like amyloidosis, gastrointestinal infections in immunocompromised patients, and side effects of medication, such as steroids or NSAIDs and MTX. MTX-LPD is an uncommon side effect of methotrexate. To ensure its appropriate diagnosis and treatment, it is important to improve the degree of recognition of MTX-LPD, and a prompt response is needed.

Methotrexate-associated lymphoproliferative disease detected as a colorectal mass lesions: a case report.

Methotrexate-related lymphoproliferative disorder (MTX-LPD) is a rare but serious complication that occurs in patients treated with methotrexate (MTX); although MTX-LPD has been reported recently, the incidence in the colon is very low. A 79-year-old woman who had been receiving MTX for 15 years came to our hospital complaining of postprandial abdominal pain and nausea. Computed tomography scan showed the dilation of the small bowel and a tumor in the cecum. In addition, numerous nodular lesions were seen in the peritoneum. Ileal-transverse colon bypass surgery was performed for small bowel obstruction. Histopathological findings of both the cecum and the peritoneal nodules revealed the diagnosis of MTX-LPD. We report MTX-LPD occurring in the colon; it is important to consider MTX-LPD when intestinal symptoms occur during MTX therapy.

Magnetic resonance imaging of methotrexate-related lymphoproliferative disorder with a chief complaint of oral symptoms.

OBJECTIVES: To determine the magnetic resonance imaging (MRI) features of methotrexate-related lymphoproliferative disorder (MTX-LPD) in the oral cavity of a patient with a chief complaint of oral symptoms. METHODS: We included six patients who visited our hospital between November 2014 and November 2019, histopathologically diagnosed with MTX-LPD. All images were examined using 3 T MRI and reviewed by two radiologists. RESULTS: Masses were detected in five cases; all masses demonstrated signal hypointensity and homogeneous signal hyperintensity on T1- and T2-weighted images with fat suppression. Homogeneous enhancement with fat suppression was evident on post-contrast T1-weighted imaging. We performed dynamic contrast-enhanced MRI in three cases and observed early enhancement with a low washout ratio pattern in all cases. Four patients underwent diffusion-weighted MRI and revealed low mean apparent diffusion coefficient (ADC) of 0.57 (range 0.5-0.65) × 10-3 mm2/s. CONCLUSIONS: We reported on the imaging characteristics of six rare cases of MTX-LPD in the oral cavity. Homogeneous hyperintensity on fat-suppressed T2-weighted images and low ADC values are possible features of MTX-LPD. Moreover, MTX-LPD can be differentiated from other carcinomas in the oral cavity.

Pathological Vertebral Fracture Arising From Methotrexate-Associated Lymphoproliferative Disorder in a Patient With Systemic Lupus Erythematosus.

The incidence of lymphoproliferative disorders associated with methotrexate is rising in patients with rheumatoid arthritis. These disorders typically exhibit spontaneous tumor regression upon discontinuation of methotrexate therapy. Spinal lesions associated with these diseases are extremely rare. We present a case of systemic lupus erythematosus in which the patient developed lumbar spine lymphoproliferative disorders secondary to methotrexate therapy, which failed to regress despite discontinuation of the drug, ultimately leading to pathological fracture necessitating posterior spinal fixation. A 60-year-old woman had been diagnosed with systemic lupus erythematosus at the age of 55 years and had been taking prednisolone, hydroxychloroquine, and methotrexate. Throughout the course of her treatment, she experienced recurrent tumefaction and lymph node swelling in various locations. These masses and lymphadenopathy were believed to be potential complications of methotrexate-associated lymphoproliferative disorders, leading to the discontinuation of methotrexate. One month prior to cessation of methotrexate therapy, the patient presented to an orthopedic clinic with lower back pain, and T2-weighted magnetic resonance imaging revealed low signal intensity in the Th10 and L2 vertebrae, initially misdiagnosed as lumbar spinal stenosis. The patient was eventually referred to our department under suspicion of malignant pathology. Computed tomography identified a vertical fracture of the L2 vertebra, which, in conjunction with the imaging results, led to the diagnosis of pathological fracture secondary to methotrexate-associated lymphoproliferative disorder. Following admission to our department, bone biopsy and percutaneous pedicle screw fixation were performed one week later. Pathological examination confirmed the diagnosis of methotrexate-associated lymphoproliferative disorder. Given the possibility of pathological fracture in patients on methotrexate therapy experiencing severe back pain, additional imaging studies should be considered.

Epstein-Barr virus-related diffuse large B-cell lymphoma type methotrexate-associated lymphoproliferative disorders presenting in the adrenal gland.

Introduction: Methotrexate-associated lymphoproliferative disorders appear during treatment with methotrexate as an immunosuppressive drug. However, the mechanism and frequency are still unknown, and the treatment is undefined. Case presentation: A 76-year-old woman was admitted to the hospital with back pain, and magnetic resonance imaging showed a tumor in the right adrenal region. She had received methotrexate for rheumatoid arthritis. Enhanced computed tomography showed a tumor of 90 mm in diameter on the dorsal side of the liver abutting to the inferior vena cava. The preoperative diagnosis was a hepatic invasion of right adrenocortical carcinoma and right adrenalectomy was performed. The histopathological diagnosis was diffuse large B-cell lymphoma. The final diagnosis was methotrexate-associated lymphoproliferative disorders. Conclusion: It is important to consider methotrexate-associated lymphoproliferative disorders before surgery when neoplastic lesions are found in patients taking methotrexate.

Methotrexate-Associated Lymphoproliferative Disease of the Thoracic Spine Misdiagnosed as Metastatic Spinal Tumor: A Case Report.

Methotrexate (MTX) is increasingly used in the treatment of rheumatoid arthritis. Many recent reports have identified MTX-related lymphoproliferative disorder (MTX-LPD) as lymphoma that develops during MTX therapy. However, spinal lesions, which are extremely rare, can be misdiagnosed as spinal metastases or pyogenic spondylitis. Here, we describe a 69-year-old man with rheumatoid arthritis who had MTX-LPD of the thoracic spine. He complained of back pain and weakness in the bilateral iliopsoas muscle. A radiographical assessment by his previous physician revealed the cause to be a spinal tumor. They performed posterior spinal decompression and fixation, and a pathological examination revealed only inflammatory changes, necrosis, and increased collagen fiber growth, with no evidence of malignancy. Nevertheless, magnetic resonance imaging two weeks after the surgery showed an increase in the size of the spinal tumor. When the lesion paralyzed the patient soon afterward, the physician considered that a total en bloc spondylectomy was necessary and referred the patient to our hospital. MTX-LPD was suspected because of a history of MTX administration, and a biopsy, posterior spinal decompression, and fixation were performed again. Following the histopathological diagnosis of the tumor as MTX-LPD, MTX administration was terminated. Three months following surgery, the tumors' removal was confirmed. Because MTX-LPD can be treated with MTX withdrawal, correct diagnoses should be made, and unnecessary treatments avoided.

Methotrexate-associated proliferative disorder in the lower esophagus extending to the gastroesophageal junction: A case report.

A 64-year-old woman was receiving oral methotrexate (MTX) for rheumatoid arthritis (RA) for 15 years. She underwent esophagogastroduodenoscopy because of discomfort in the chest. Endoscopic findings revealed an ulcer in the lower esophagus extending to the gastroesophageal junction (EGJ). The ulcer occupied half of the esophageal lumen and had a sharp and clear margin. Magnifying narrow-band imaging endoscopy revealed the deposition of white plaque, and there were few microvessels in the edge and bottom of the ulcer. Histologic examination of the biopsy specimens from the oral edge of the lesion revealed proliferation of atypical lymphoid cells (immunophenotype results: CD20 [+], CD3 [partially +], CD5 [-], and BCL-2 [-]]. The patient was diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) and was advised to stop MTX intake. After 2 months of stopping MTX, the ulcer was found to be almost regressed and showed signs of healing. MTX-LPD in the lower esophagus extending to the EGJ is extremely rare. This case can help in expanding the understanding of esophageal MTX-LPD.

Successful Treatment of Intracranial Methotrexate-associated Lymphoproliferative Disorder without Epstein-Barr Virus Infection Using Rituximab, Methotrexate, Procarbazine, and Vincristine: A Case Report.

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) occurs in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). MTX-LPD is typically associated with Epstein-Barr virus (EBV) infection and regresses with MTX discontinuation. On the other hand, EBV-negative MTX-LPDs are less common and are more likely to show partial or no regression after MTX discontinuation. There were no standard chemotherapeutic options for refractory MTX-LPD. We present a case of EBV-negative MTX-LPD in the central nervous system (CNS) that was successfully treated with rituximab, methotrexate, procarbazine, and vincristine (R-MPV), followed by reduced-dose whole-brain radiotherapy (rdWBRT), following the same treatment protocol as primary CNS lymphoma. A 59-year-old woman with RA treated with MTX presented with gradually developing staggered gait, memory deficit, and disorientation. Multiple lesions with heterogeneous contrast enhancement were discovered using brain magnetic resonance imaging. The patient was suspected of having MTX-LPD, but discontinuing MTX did not result in regression of the brain lesions. She underwent a biopsy from the left parietal lesion. The tissue was pathologically diagnosed as diffuse large B-cell lymphoma. Furthermore, pathological examination through EBV-encoded ribonucleic acid in situ hybridization demonstrated a lack of EBV infection. She was ultimately diagnosed with EBV-negative CNS MTX-LPD. We applied chemotherapy with R-MPV and rdWBRT. The patient achieved a complete response. In the case of CNS MTX-LPD without EBV infection, chemotherapy with R-MPV followed by rdWBRT may be considered.

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.

Methotrexate-associated lymphoproliferative disorder with histopathological features of histiocytic necrotizing lymphadenitis.

An 84-year-old Japanese woman suffering from rheumatoid arthritis (RA), who had been treated with methotrexate (MTX) for 15 years, was admitted to our hospital for generalised lymphadenopathy, thrombocytopenia, anaemia, elevated aminotransferases, and elevated CRP levels. Pathological findings of cervical lymph node biopsy were compatible with histiocytic necrotising lymphadenitis (HNL). Small lymphocytes positive for Epstein-Barr virus (EBV)-encoded small RNA were detected in the tissue. We suspected a MTX-associated lymphoproliferative disorder (MTX-LPD), withdrew MTX and administered leucovorin (folic acid). The patient's symptoms gradually resolved following discontinuation of MTX. We considered that this patient developed HNL as an MTX-LPD when EBV was reactivated. This is the first case of HNL associated with MTX treatment for RA, which we report here along with clinical course.

A case of resected pulmonary lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder and was incorporated into the WHO classification of Tumours of the Lung, Pleura, Thymus and Heart in 2015. LYG is known to be associated with the host's immune function, and can be caused by some immunosuppressive agents, including methotrexate. A woman in her sixties with an 18-year history of methotrexate treatment for rheumatoid arthritis visited our hospital after detection of an abnormal chest shadow on her radiograph. She had been having anemia and a slight fever. Computed tomography (CT) revealed a 2.9-cm sized nodule in her left lung and hilar adenopathy, which suggested a primary lung carcinoma or an inflammatory lesion. We performed a left upper lobectomy with lymph node dissection for the purpose of diagnosis and treatment. Pathologic findings revealed that the tumor was a grade 3 LYG based on the number of EBV-positive B cells. The patient was treated with two chemotherapy regimens including R-CHOP at another hospital, and survived for four years after resection without recurrence in the lung. It is rare to find a case resected LYG, and the clinical or pathological findings of our case are expected to be extremely helpful in studying this disease and improving the understanding of this disease.

Methotrexate-associated Lymphoproliferative Disorder in the Liver Resembling Hepatocellular Carcinoma Treated with Transarterial Chemoembolization.

Methotrexate-related lymphoproliferative disorder (MTX-LPD) is known to be a side effect of MTX, but its involvement in the liver has been rarely reported. We herein report a 70-year-old woman with autoimmune hepatitis and rheumatoid arthritis who developed multiple liver tumors. We initially considered that she had developed rapid-growing hepatocellular carcinoma (HCC) in the cirrhotic liver based on imaging tests. A tumor biopsy and transcatheter arterial chemoembolization were thus performed. The tumors were then diagnosed as diffuse large B-cell lymphoma pathologically and considered to be MTX-LPD. This case indicates that MTX-LPD should be considered even in cirrhotic patients with liver tumors resembling HCC.

A case of bilateral methotrexate-associated diffuse large B-cell lymphomas of the breasts with unique clinical presentation and outcome.

A 54-year-old woman on methotrexate (MTX) treatment developed reddish skin change in her right breast. Mammography and ultrasound showed no masses in the breasts but bilateral mammary glands presented diffuse lower-level echoes. Only 19 days later, the patient developed bilateral breast masses. Histological examination showed that diffuse large B-cell lymphoma cells spread widely and sparsely in the bilateral breasts in addition to the tumor cell conglomerate, leading to the diagnosis of MTX-associated lympho-proliferative disorders (MTX-LPDs). Withdrawal of MTX resulted in complete disappearance of the left MTX-LPD in 2 months but no regression of the right MTX-LPD. Chemotherapy led to a partial response followed by re-growth of the right MTX-LPD. Re-biopsy of the right MTX-LPD revealed double/triple hit lymphoma. Second-line and later-line chemotherapies caused no regression of the right MTX-LPD. The patient died in a year after the diagnosis of MTX-LPDs. Breast oncologists should note the presence, biology, and diagnostic images of MTX-LPD.

Hepatic methotrexate-associated lymphoproliferative disorders identified by multiple liver tumors: a case report and review of the literature.

BACKGROUND: Methotrexate, an immunosuppressant, is widely used as the standard therapeutic drug for rheumatoid arthritis. With the increasing frequency of use of methotrexate, adverse effects of methotrexate have been reported, one of which is known as methotrexate-associated lymphoproliferative disorders. The etiology of hepatic methotrexate-associated lymphoproliferative disorders remains largely unknown. To date, there have only been ten cases of hepatic methotrexate-associated lymphoproliferative disorders reported in the English literature and a case report is very rare. CASE PRESENTATION: An 82-year-old Japanese man with rheumatoid arthritis treated with methotrexate presented with fever. Contrast-enhanced computed tomography showed multiple hypovascular nodules in his liver, spleen, and lung, and para-aortic lesions. Endoscopic ultrasound-guided fine-needle aspiration biopsy for liver tumors was performed, and pathological results identified cluster of differentiation 20-positive lymphocytes. Discontinuance of methotrexate led to regression of the nodules and a final definitive diagnosis of methotrexate-associated lymphoproliferative disorders was made. CONCLUSIONS: We review 11 reported cases of hepatic methotrexate-associated lymphoproliferative disorders including the present case. Physicians should discontinue methotrexate in patients with rheumatoid arthritis treated with methotrexate when elevated soluble interleukin-2 receptor and hypovascular lesions in contrast-enhanced computed tomography are confirmed considering the possibility of methotrexate-associated lymphoproliferative disorders.

Spontaneous regression of a renal mass and multiple lung nodules after methotrexate cessation.

INTRODUCTION: Methotrexate has been reported to increase the risk of lymphoproliferative disorders. We report a rare case who was clinically diagnosed with methotrexate-associated lymphoproliferative disorders of the kidney. CASE PRESENTATION: A 77-year-old patient with rheumatoid arthritis had taken low-dose methotrexate for 13 years. The patient developed left renal mass 3 cm in size and multiple pulmonary nodules. Initially, renal malignant tumor with lung metastases was considered and the renal biopsy was planned. However, under possible diagnosis of methotrexate-related lymphoproliferative disorder, we withdrew methotrexate treatment at first and then observed spontaneous regression of the tumorous lesions of the kidney and lungs. CONCLUSION: Although methotrexate-related lymphoproliferative disorder in kidneys is very rare, our case advocates the importance of a relevant differential diagnosis of methotrexate-related lymphoproliferative disorder under the setting of long-term treatment of methotrexate for rheumatoid arthritis.

Methotrexate-related lymphoproliferative disorder of the lumbar spine origin presenting with severe low-back pain: case report.

The use of methotrexate (MTX) to treat rheumatoid arthritis (RA) is increasing. Recently, MTX-associated lymphoproliferative disorder (MTX-LPD) has been frequently reported as lymphoma occurring during MTX therapy. The authors report their experience with a relatively rare case of MTX-LPD presenting in the lumbar spine. The patient, a 73-year-old woman who experienced low-back pain while receiving MTX therapy for RA, was suspected of having developed MTX-LPD based on her medical history, images of the L1 vertebra, and transpedicular biopsy results. One week after discontinuing MTX, the patient's low-back pain reportedly improved. The woman was diagnosed with MTX-LPD based on histopathological findings. MTX discontinuation alone coincided with spontaneous tumor regression. Because MTX-LPD can occur in tissues other than lymph nodes, such as in bones and joints, it is a disease that should be considered when diagnosing spinal tumors in patients receiving MTX therapy.

Methotrexate-associated orbital lymphoproliferative disorder in a patient with rheumatoid arthritis: a case report.

PURPOSE: Lymphoproliferative disorders (LPDs) can develop in patients treated with methotrexate (MTX) and usually respond well to MTX withdrawal. Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare type of MTX-LPD. The development of MTX-LPD in the orbit has not been previously described. We here report a case of orbital MALT lymphoma that disappeared after MTX withdrawal in a patient treated with MTX for rheumatoid arthritis. CASE: A 78-year-old woman who complained of swelling of the left upper eyelid had been treated with MTX for >8 years for rheumatoid arthritis. Slit-lamp examination revealed a temporal subconjunctival mass, salmon pink in color, in the left eye. Fundus photographs also suggested the presence of a temporal tumor in the left orbit. [(18)F]Fluorodeoxyglucose positron emission tomography-computed tomography revealed highly integrated lesions in the left inferotemporal orbit and a left external iliac lymph node, a left obturator lymph node, and an inguinal lymph node. Pathologic analysis of a tumor biopsy specimen showed small- and medium-sized lymphocytes positive for CD20, MIB-1, and bcl-2 and negative for CD10, CD3, bcl-1, IgG4, and EBV-ISH. On the basis of these findings, we diagnosed the tumor as MTX-induced MALT lymphoma. The subconjunctival and orbital masses disappeared gradually over 10 months after MTX withdrawal and did not recur within 2 years. CONCLUSION: This case of orbital MTX-LPD suggests that the possibility of MTX-LPD should be considered even for ocular tumors in patients treated with MTX.