Cutaneous methotrexate-related lymphoproliferative disorderL98.8

Methotrexate-induced (benign/cutaneous) proliferation of lymphoid cell systems caused primarily by B cell proliferates, but also proliferates in which T cells and/or NK cells predominate. Diagnosis is based on a combination of clinical symptoms, histopathology and immunohistopathology, as well as specific EBV diagnostics (EBV-PCR, EBV-EBER in situ hybridization).

The cause of the MTX-induced variant is long-term systemic therapy with MTX, which is based on artificial immunosuppression. Patients with rheumatoid arthritis, psoriatic arthritis, dermatomyositis, lupus erythematosus and other systemic diseases are mainly affected.

Methotrexate(MTX) is a commonly used antimetabolic agent. Long-term MTX treatment. It can lead to MTX-associated lymphropoliferative diseases (MTX-LPD). This is reversible in 80% of cases. It occurs at extranodal sites in 50% of cases. Extranodally, MTX-LPD is associated with pseudolymphoma-like skin proliferations, lung infestation, gastrointestinal infestation (Toyonaga H et al. 2019) and, more rarely, osteonecrosis of the jawbone. B-cell proliferates are present in most cases. In up to 80% of cases, these are EBER-positive on tissue immunostaining, which indicates EBV activation under immunodepression. A rare variant of MTX-LPD is T-cell MTX-LPD. Epstein-Barr virus (^EBV+ ) tumor cells are rarely detected in MTX-associated T-cell LPD (MTX-T-LPD).

MTX-LPD in association with skin manifestations: thromboembolism-like patchy, also nodular, flat protuberant red surface inlays or also ulcerated, painless plaques and nodules.

Favorable course: 80% of lesions heal after discontinuation of MTX therapy within a period of several months.

MTX-LPD:

• A 71-year-old Japanese man with rheumatoid arthritis had been treated with MTX for 6 years. He noticed the appearance of red surface intact plaques, including ulcerated plaques on both lower legs for 6 months and a two-week history of high fever and fatigue. Skin samples showed that medium-sized atypical lymphocytes were positive for CD3, CD4, CD30, CD56 and in situ hybridization for EBV-encoded RNA. Four months after discontinuation of MTX, the skin lesions had disappeared.

MTX-LPD in association with non-cutaneous lesions:

• MTX-LPD in association with osteonecrosis of the jaw: A 74-year-old man with RA who had been treated with MTX for 7 years developed osteonecrosis of the jaw combined with submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated with MTX for 21 years and presented with osteonecrosis of the jaw. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years.

1. Claudino WM et al. (2016) Methotrexate-associated primary cutaneous CD30-positive cutaneous T-cell lymphoproliferative disorder: a case illustration and a brief review. Am J Blood Res 6:1-5.
2. Furudate K et al. (2028) Methotrexate-Related Lymphoproliferative Disorder in Patients With Osteonecrosis of the Jaw: A 3-Case Report and Literature Review. J Oral Maxillofac Surg 76:97-111.
3. Hashimoto K et al. (2015) Methotrexate-associated lymphoproliferative disorders of the tongue developing in patients with rheumatoid arthritis: a report of 2 cases and a review. Oral Surg Oral Med Oral Pathol Oral Radiol 119:e1-5.
4. Kudoh M et al. (2024) Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. Oral Surg Oral Med Oral Pathol Oral Radiol 118:e105-110.
5. Nocco S et al. (2025) Primary Cutaneous Methotrexate-Associated T-Cell Lymphoproliferative Disorder in the Setting of Autoimmune Disease: A Case Series and Review of the Literature. Am J Dermatopathol 47:145-152.
6. Omori I et al. (2021) Cutaneous methotrexate-related T-cell lymphoproliferative disorder with CD4, CD30, CD56, EBV-positive tumor cell infiltration: a case illustration and a brief review. Am J Blood Res 11:163-167
7. Tirado-Sánchez A et al. (2018) Nodular Lymphangitis (Sporotrichoid Lymphocutaneous Infections). Clues to Differential Diagnosis. J Fungi (Basel) 4:56.
8. Toyonaga H et al. (2019) Methotrexate-associated lymphoproliferative disorder in the stomach and duodenum: a case report. BMC Gastroenterol 19:62.