Methotrexate-associated Lymphoproliferative Disorder Research Articles

Regression of Necrotic Lesions after Methotrexate Withdrawal in Patients with Methotrexate-Associated Lymphoproliferative Disorders: A Retrospective CT Study.

This retrospective study investigated whether necrotic lesions detected on a computed tomography (CT) scan are more regressive than non-necrotic lesions after methotrexate withdrawal in patients pathologically diagnosed with methotrexate-associated lymphoproliferative disorders (MTX-LPD). In total, 89 lesions extracted from 24 patients on CT scans were included in the analysis. All patients had been evaluated for the presence of necrosis within lesions via CT scan upon first suspicion of MTX-LPD (baseline CT scan). The percentage lesion size reduction between the baseline and initial follow-up CT scan was calculated. The association between necrosis within lesions and size changes was estimated via linear regression analyses using both crude and adjusted models. Necrosis was significantly more common in extranodal lesions (27 out of 30 lesions, 90%) than in nodal lesions (9 out of 59 lesions, 15%, p<0.001). In the crude model, the regression of necrotic lesions was 58.5% greater than that of non-necrotic lesions; the difference was statistically significant (p<0.001). Additionally, the longest diameter of necrotic lesions at the baseline CT scan was significantly greater than that of non-necrotic lesions (p<0.001). Based on the adjusted model, necrotic lesions showed 49.3% greater regression than non-necrotic lesions (p=0.017). Necrosis detected on a CT scan was found to be an independent predictor of regression after MTX withdrawal in patients with MTX-LPD.

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.

Hepatic and lung methotrexate-associated polymorphic lymphoproliferative disorders arising during postoperative follow-up of renal cell carcinoma: a case report

IntroductionMethotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult.Case presentationA 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed.ConclusionMethotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered.

Cardiac Sarcoidosis treated with non-steroidal immunosuppressive therapy

Abstract Background Non-steroidal immunosuppressive therapy is a potential treatment strategy for cardiac sarcoidosis. However, due to the lack of robust evidence, it is not recommended as an established treatment option in the guideline. Purpose The purpose of the study is to demonstrate the clinical outcome of the patients with cardiac sarcoidosis using non-steroidal immunosuppressive therapy in a retrospective registry entitled ILLUMINATE-CS (ILLUstration of the Management and prognosIs of JapaNese pATiEnts with Cardiac Sarcoidosis). Methods Of an entire cohort of 512 patients, 26 who received immunosuppressive therapy other than steroids were recruited for the analysis. The clinical outcome included all-cause death, fatal ventricular arrhythmic event (FVAE), and worsening heart failure with hospitalization. Results The reasons to use non-steroidal immunosuppressant were increased fluorodeoxyglucose (FDG) accumulation on the heart suggesting worsened inflammation (n = 13), side effects of steroid (n = 7), ventricular tachycardia or frequent ventricular premature contraction (n=4), complete atrioventricular block (n = 2), worsened symptom relating to non-cardiac sarcoidosis including neuro and pulmonary sarcoidosis (n = 2), and the other reason (n = 2), with some overlapping. Used non-steroidal immunosuppressants were comprised of methotrexate (n = 20, 6.9 ± 2.1 mg/week), cyclosporine (n =2, 75 or 100 mg/day), cyclophosphamide (n = 2, 25 or 50 mg/day), and azathioprine (n = 3, 100 mg/day in each). Side effects of non-steroidal immunosuppressant were observed in six cases and included one with methotrexate-related interstitial pneumonia, one with a methotrexate-associated lymphoproliferative disorder, one with septic coxitis with methotrexate, one with methotrexate-induced acute kidney injury, one with methotrexate-induced hepatic dysfunction, and one with azathioprine-induced anemia. After the addition of a non-steroidal immunosuppressant, steroids could be reduced in 14 cases of 26 cases with a median maintenance dose of 5 (interquartile range of 5–17) mg, although no cases stopped steroids. Of 13 cases who started non-steroidal immunosuppressant for the increased FDG uptake, decreased FDG uptake was observed in seven cases at the follow-up scan. Clinical outcome events were observed in 11 cases (42.3%). Detected events included all-cause death in five cases (19.2%), FVAE in four cases (15.4%), and worsening heart failure with hospitalization in five cases (19.2%), with some overlapping. Conclusions Non-steroidal immunosuppressive therapy may be a possible treatment option for patients who are not stabilized using sole steroid therapy or who suffer from the side effects of steroids.

Key CT and MRI findings of drug-associated hepatobiliary and pancreatic disorders.

Obtaining an imaging diagnosis of various hepatobiliary and pancreatic disorders caused by certain drugs can often be challenging. Familiarity with these conditions may improve diagnostic accuracy and patient management. This review aimed to describe the imaging findings of drug-associated hepatobiliary and pancreatic disorders and identify suggestions for obtaining a correct diagnosis. We focused on relatively common disorders or those that can present with characteristic imaging findings, such as drug-induced acute hepatitis, sinusoidal obstruction syndrome, focal nodular hyperplasia-like lesions, hepatocellular adenoma, pseudocirrhosis, chemotherapy-associated steatohepatitis, amiodarone deposition in the liver, secondary iron overload, drug-induced pancreatitis, pancreatic enlargement after epoprostenol therapy, ceftriaxone-associated gallbladder pseudolithiasis, immune-related adverse events, and methotrexate-associated lymphoproliferative disorders.

Methotrexate-associated lymphoproliferative disorder in the thyroid gland of a patient with chronic thyroiditis.

Methotrexate-associated lymphoproliferative disorder in the thyroid gland of a patient with chronic thyroiditis.

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.

Hepatic Superscan in Methotrexate-Associated Lymphoproliferative Disorder.

A 60-year-old man on methotrexate for treatment of adult-onset Still disease presented with acute onset of fever, pancytopenia, and deranged liver function. Besides FDG-avid lesions in spleen and skeleton, his 18F-FDG PET/CT study showed diffuse and intense uptake in the liver with significantly suppressed heart and brain activity (reminiscent of a hepatic superscan). Subsequent biopsy confirmed the diagnosis of methotrexate-associated lymphoproliferative disorder.

Methotrexate-associated Lymphoproliferative Disorder Presenting as an Ulcer With Tendon Exposure on the Dorsum of the Hand: A Case Report and Literature Review

Introduction. MTX-LPD is a complication that occurs during MTX treatment. Skin lesions in MTX-LPD are often subcutaneous nodules with occasional necrosis and ulceration. Although MTX-LPD regression is frequently observed upon discontinuation of oral MTX treatment, delayed diagnosis of MTX-LPD with associated ulceration may lead to ulcer enlargement and the need for surgical procedures such as skin grafts. Case Report. A 74-year-old female was diagnosed with RA and administered MTX for 3 years and 8 months. The patient presented with a 2-month-old ulcer on the dorsum of the hand. The ulcer size was 6.5 cm × 5 cm, and it was surrounded by an embankment tumor measuring 7 cm × 6 cm. Although a definitive diagnosis could not be made based on the biopsy specimen, excision of the ulcer-containing mass confirmed MTX-LPD diagnosis. MTX was discontinued, and free-flap reconstruction was performed 3 weeks after the first surgery. The postoperative period was uneventful, and MTX-LPD recurrence was not observed 10 months after the second surgery. Conclusion. Although MTX-LPD with ulceration is rare, it should be considered in cases of refractory ulcers in patients with RA. The discontinuation of MTX based on early MTX-LPD diagnosis is critical to avoid surgical procedures such as skin grafts and flap reconstruction.

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder.

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (1H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient's 1H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.

Methotrexate-Associated Lymphoproliferative Disorder With Gingival Swelling

A 63-year-old Japanese man being treated for pemphigus vulgaris with methotrexate (MTX) presented with a fever of unknown origin. His only symptom at onset was mild gingival swelling. Suspected to have gingivitis, he was followed for 1 month. After that, he presented with cervical lymphadenopathy, dysphagia, and bicytopenia, and a diagnosis of MTX-associated lymphoproliferative disorder (MTX-LPD) was finally made by gingival biopsy. He had spontaneous remission after the withdrawal of MTX. When MTX-treated patients complain of fever and oral lesions, even if the oral lesions present as mild gingival swellings, physicians should consider MTX-LPD and perform a diagnostic biopsy.

FDG-PET/CT imaging parameters for predicting spontaneous regression of methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis

In this study, we investigated the usefulness of FDG-PET/CT for predicting spontaneous regression in methotrexate-associated lymphoproliferative disorder (MTX-LPD). Twenty patients with rheumatoid arthritis who were diagnosed with MTX-LPD were enrolled in the study. These patients were divided into those who showed spontaneous regression (SR group: ten patients) and those who received chemotherapy after discontinuation of MTX (CTx group: ten patients). Between-group differences in potential biomarkers were compared, including clinical markers at the onset of LPD [serum LDH and interleukin 2 receptor (sIL-2R)], change in absolute number of peripheral lymphocytes (ΔALC) over follow-up, and the FDG-PET/CT-derived parameters of maximum standardized uptake value (SUVmax), mean SUV (SUVmean), peak SUV (SUVpeak), sum of the metabolic tumor volume (MTVsum), and sum of total lesion glycolysis (TLGsum). The levels of sIL-2R, MTVsum, and TLGsum were significantly lower in the SR group than in the CTx group. In addition, ΔALC was higher in the SR group. In conclusion, MTV and TLG values measured by FDG-PET/CT may be suitable for use as predictors of SR in patients with MTX-LPD.

Histopathological and Clinical Features of Methotrexate-Associated Lymphoproliferative Disorders and Post-Transplant Lymphoproliferative Disorders

Objective: To study histopathological and clinical features of methotrexate-associated lymphoproliferative disorders (MTX-LPD) and post-transplant lymphoproliferative disorders (PTLD).Material and Methods: A retrospective study on 30 cases of MTX-LPD and 2 cases of PTLD from 2006 to 2021.Results: By histopathology, the MTX-LPD group had 21 cases of lymphoma (MTX-Lymphoma) and 9 cases of reactive changes (MTX-Reactive). The PTLD group included diffuse large B-cell lymphoma and polymorphic PTLD (1 case each). The distinctive findings in MTX-Lymphoma and PTLD were association with Epstein-Barr virus (EBV) (8/12 cases, 66.7%) and CD30 positivity (13/18 cases, 72.2%). The MTX-LPD group had median MTX dosage of 10 mg/week, median MTX cumulative dosage of 2,613.75 mg, and median duration of MTX usage of 2,186 days. The 14 MTX-LPD and PTLD patients has median duration to response after the varied interventions of 47 days and the time to the first complete remission (CR) of 126 days. The MTX-Reactive patients had a significantly higher absolute lymphocyte count, younger median age, fewer B symptoms, higher rate of single site involvement, less extranodal involvement, shorter duration to response, less time to enter CR, and higher CR rate than the MTXLymphoma patients (p &lt; 0.05).Conclusion: Histopathology in MTX-LPD and PTLD patients can vary from reactive changes to lymphoma. EBV study and CD30 immunostaining help identify MTX-LPD and PTLD. History of MTX usage and other causes of immunodeficiency should be considered before diagnosing lymphoma. MTX discontinuation or reduction of immunosuppressant dosage are recommended before administrating combined chemotherapeutic agents in unresponsive cases.

A case series of different courses of methotrexate-associated lymphoproliferative disease with pulmonary involvement

Lymphoproliferative Disorder (LPD) is a complication of Methotrexate (MTX) therapy. Several cases of Methotrexate-Associated Lymphoproliferative Disorder (MTX-LPD) have been reported. However, pulmonary lesions in MTX-LPD are rare. Image findings of MTX-LPD show various patterns. Pneumocystis pneumonia and interstitial pneumonia, which have complex courses, have been reported in MTX-treated patients with lung diseases other than MTX-LPD. Furthermore, the treatment course of MTX-LPD differs from those of other lung diseases and could vary across patients. Here in, we discuss the importance of an accurate MTX-LPD diagnosis through detailed examination and treatment priority depending on the severity of underlying diseases and complications.

9p24.1 Genetic Alteration and PD-L1 Expression Are Characteristic of De Novo and Methotrexate-associated Epstein-Barr Virus-positive Hodgkin Lymphoma, But Not Methotrexate-associated Hodgkin-like Lesions.

Although the alteration of the 9p24.1 chromosome locus and PD-L1 overexpression is found in nodular sclerosis classic Hodgkin lymphoma, whether these aberrations occur in CHL and Hodgkin-like lesion (HLL) of methotrexate-associated lymphoproliferative disorder (MTX-CHL and MTX-HLL) is unknown. We compared the clinicopathologic features, the genomic status of the 9p24.1 locus and PD-L1 expression in a series of 34 patients including 17 with Epstein-Barr virus-positive de novo CHL, 7 with MTX-CHL, 10 with MTX-HLL using an immunofluorescence in situ hybridization method and immunohistochemistry. The proportions of cells with 9p24.1 genetic alteration in CD30-positive Hodgkin/Reed-Sternberg cells of de novo CHL, MTX-CHL and MTX-HLL were 55%, 68%, and 24%, respectively. The positive rates of PD-L1 measured by immunohistochemical H-scores of de novo CHL, MTX-CHL and MTX-HLL were 142±38, 157±75, and 70±42, respectively. Alteration of the 9p24.1 gene and expression of PD-L1 protein were correlated with all 3 diseases (correlation coefficient, 0.731). Both alteration of the 9p24.1 gene and overexpression of PD-L1 protein were observed in Epstein-Barr virus-positive de novo CHL and MTX-CHL but not in MTX-HLL. In conclusion, MTX-CHL has similar pathogenesis-like de novo CHL, but MTX-HLL seems to be a different disease from de novo CHL and MTX-CHL.

A Case of Methotrexate-Associated Lymphoproliferative Disorder That Required to be Differentiated from Parotid Gland Cancer

A Case of Methotrexate-Associated Lymphoproliferative Disorder That Required to be Differentiated from Parotid Gland Cancer

A Case of Methotrexate-associated Lymphoproliferative Disorder in the Corner of the Mouth

A Case of Methotrexate-associated Lymphoproliferative Disorder in the Corner of the Mouth

PD-L1 expression is associated with the spontaneous regression of patients with methotrexate-associated lymphoproliferative disorders.

BackgroundMost patients with methotrexate‐associated lymphoproliferative disorder (MTX‐LPD) show diffuse large B‐cell lymphoma (DLBCL) or classic Hodgkin lymphoma (CHL) types. Patients with MTX‐LPD often have spontaneous remission after MTX discontinuation, but chemotherapeutic intervention is frequently required in patients with CHL‐type MTX‐LPD. In this study, we examined whether programmed cell death‐ligand 1 (PD‐L1) expression levels were associated with the prognosis of MTX‐LPD after MTX discontinuation.MethodsA total of 72 Japanese patients diagnosed with MTX‐LPD were clinicopathologically analyzed, and immunohistochemical staining of PD‐L1 was performed in 20 DLBCL‐type and 24 CHL‐type MTX‐LPD cases to compare with the clinical course.ResultsPD‐L1 was expressed in 5.0% (1/20) of patients with DLBCL‐type MTX‐LPD, whereas it was expressed in 66.7% (16/24) of the patients with CHL‐type MTX‐LPD in more than 51% of tumor cells. Most CHL‐type MTX‐LPD patients with high PD‐L1 expression required chemotherapy owing to exacerbations or relapses after MTX discontinuation. However, no significant differences in clinicopathologic findings at diagnosis were observed between PD‐L1 high‐ and low‐expression CHL‐type MTX‐LPD.ConclusionPD‐L1 expression was significantly higher in patients with CHL‐type than DLBCL‐type MTX‐LPD, suggesting the need for chemotherapy in addition to MTX discontinuation in CHL‐type MTX‐LPD patients to achieve complete remission. No association was observed between PD‐L1 expression levels and clinical findings at diagnosis, suggesting that PD‐L1 expression in tumor cells influences the pathogenesis of CHL‐type MTX‐LPD after MTX discontinuation.

Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma: A Reappraisal of 23 Japanese Patients Based on EBV Association and PD-L1 Expression in Tumor Cells.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

The first case of methotrexate‐associated lymphoproliferative disorder presenting as follicular T‐cell lymphoma

This is the first case of follicular T-cell lymphoma (FTCL) presenting as methotrexate-associated lymphoproliferative disorders (MTX-LPDs). A 69-year-old man treated rheumatoid arthritis with methotrexate presented with cervical swelling, hoarseness and fever. Imaging studies revealed multiple lymphadenopathy and lymphoma was suspected. Lymph node biopsy was performed to confirm the diagnosis. Pathologically, the lymph node was composed of atypical lymphocytes with a follicular growth pattern and area of necrosis. Immunohistochemical examination showed the atypical lymphocytes were positive for CD3, CD4, programmed cell death protein 1, and inducible T-cell co-stimulator. These findings are consistent with FTCL. During hospitalization, the patient's fever subsided and cervical lymphadenopathy improved, probably due to discontinuation of MTX. Here we presented the first case of FTCL presenting as MTX-LPDs. The T-cell phenotype MTX-LPDs are relatively rare and accounts for only 3.4%-6.3% of all MTX-LPD cases. Therefore, detailed clinicopathological features have not been clarified sufficiently. It is hoped that similar cases should be accumulated and studied to better understand the clinical and pathological features of this condition.