What is the cancer risk associated with Methotrexate (MTX) treatment?

Cancer Risk of Methotrexate

The overall cancer risk associated with low-dose methotrexate (MTX) for inflammatory conditions appears consistent with background population rates, though vigilance for lymphoproliferative disorders is warranted, particularly in rheumatoid arthritis patients. 1

Lymphoma Risk: The Primary Concern

The most significant malignancy concern with MTX involves lymphoproliferative disorders, though the evidence remains contradictory:

Evidence Supporting Minimal Risk

• A long-term study of 248 psoriasis patients (median 7-year follow-up) on low-dose MTX found 10 malignant neoplasms including 2 lymphomas, with rates consistent with expected population incidence. 1
• The authors concluded MTX therapy did not contribute to malignancy development in psoriasis patients. 1

Evidence of Increased Risk

• Methotrexate-associated lymphoproliferative disease (MTX-LPD) is recognized by the World Health Organization classification of lymphoid neoplasms, defined as lymphoid proliferation or lymphoma in MTX-immunosuppressed patients. 1
• Most MTX-LPD cases occur in rheumatoid arthritis patients, many of whom are Epstein-Barr virus-positive. 1
• Critical clinical feature: These lymphoproliferative disorders often reverse spontaneously upon MTX discontinuation. 1, 2
• Eight RA patients experienced spontaneous lymphoma remission after stopping MTX, highlighting the drug's likely causative role. 2

Duration-Dependent Risk

• Lymphoma incidence increases only with high cumulative MTX doses (≥36 months of exposure) when combined with PUVA therapy. 1
• Risk factors for lymphoma development include severe disease activity, intense immunosuppression, genetic predisposition, and latent EBV infection. 2

Skin Cancer Risk

Recent evidence suggests an increased risk of non-melanoma skin cancers with MTX use:

• A 2023 nationwide Danish case-control study found adjusted odds ratios of 1.29 for basal cell carcinoma (BCC), 1.61 for cutaneous squamous cell carcinoma (cSCC), and 1.35 for cutaneous malignant melanoma (CMM). 3
• Dose-response relationship: ORs increased with higher cumulative MTX doses for BCC and cSCC. 3
• Important caveat: When restricting analysis to psoriasis patients only, the associations weakened considerably (OR 1.43 for BCC, 1.18 for cSCC, 1.15 for CMM), suggesting the underlying disease may confound the relationship. 3
• A 2025 review confirms slight concern about increased skin malignancy risk, though no association with other malignancies has been found. 4

Other Malignancies

• MTX showed significant associations with various malignancies in FDA adverse event database analysis, though causality remains uncertain. 5
• Concomitant use of biological DMARDs with MTX further increased risk of breast, ovarian, and lung cancers in RA patients. 5
• Case reports describe rapid progression of previously indolent prostate cancer after MTX initiation, attributed to immunosuppression. 6
• The FDA label notes that non-Hodgkin's lymphoma and other tumors have been reported in patients receiving low-dose oral MTX. 7

Clinical Management Algorithm

For patients starting MTX:

• Obtain baseline assessment for pre-existing malignancies, particularly lymphadenopathy. 1
• Maintain high surveillance for signs/symptoms of lymphoma during treatment. 1, 2
• Monitor for new skin lesions, especially in patients with psoriasis or other risk factors for skin cancer. 3

If lymphoproliferative disorder develops:

• First-line approach: Discontinue MTX and observe for spontaneous remission before initiating anti-lymphoma treatment. 1, 2
• This observation period is advisable when the clinical situation permits. 2

Risk stratification considerations:

• Highest lymphoma risk: RA patients with severe disease, intense immunosuppression, and EBV positivity. 2
• Skin cancer risk appears dose-dependent; consider cumulative exposure when assessing individual risk. 3

Important Caveats

• Disease confounding: The underlying inflammatory condition (particularly RA and psoriasis) independently increases malignancy risk, making attribution to MTX challenging. 1, 3
• Study limitations include potential misclassification of cutaneous T-cell lymphoma as psoriasis in some cohorts. 1
• The FDA label notes that controlled human data regarding neoplasia risk with MTX do not exist, and animal studies show inconclusive results. 7
• Recent evidence emphasizes that concerns about malignancy risk stem largely from high-dose MTX used in cancer chemotherapy, not low-dose regimens for inflammatory conditions. 4