What is the management approach for a patient on methotrexate (MTX) with lung cavitary lesions, liver mass, and adrenal mass?

Management of Methotrexate-Associated Lymphoproliferative Disorder

Immediately discontinue methotrexate and observe for spontaneous regression of the cavitary lung lesions, liver mass, and adrenal mass, as this clinical presentation is highly consistent with methotrexate-associated lymphoproliferative disorder (MTX-LPD), which frequently regresses without chemotherapy after drug withdrawal. 1, 2, 3

Immediate Actions

• Stop methotrexate immediately upon recognition of this pattern of multiorgan masses in a patient on chronic MTX therapy 1, 2, 3
• Obtain tissue diagnosis through biopsy of the most accessible lesion (lung or liver) to confirm lymphoproliferative disorder and assess for Epstein-Barr virus (EBV) positivity 1, 2, 4
• Check complete blood count with differential, comprehensive metabolic panel including liver function tests and albumin, and renal function 5, 6
• Test for EBV serology and perform EBV-encoded small RNA (EBER) in situ hybridization on biopsy specimens 2, 4

Diagnostic Considerations

This presentation strongly suggests MTX-associated lymphoproliferative disorder rather than primary malignancy or infection. The key distinguishing features include:

• Multiple organ involvement (lungs, liver, adrenal gland) in a patient on chronic MTX therapy 1, 2, 3
• Cavitary lung lesions are characteristic of lymphomatoid granulomatosis, a specific subtype of MTX-LPD 1
• MTX-LPD is a recognized complication of immunosuppression, particularly associated with EBV reactivation 5, 2, 4

The American Academy of Dermatology specifically warns about the risk of lymphoma (especially EBV-associated B-cell lymphoma) in patients with psoriasis treated with methotrexate, supporting the importance of maintaining high clinical suspicion for these complications 5

Observation Period After MTX Withdrawal

Adopt a "watch and wait" approach for 4-8 weeks after stopping methotrexate before initiating chemotherapy, as spontaneous regression is well-documented:

• Case reports demonstrate complete resolution of large tumors (up to 8 cm) in lungs, liver, spleen, kidneys, and adrenal glands within 1-3 months after MTX cessation alone 1, 2, 3
• One patient had an 8 cm cavitary lung tumor plus liver and splenic masses that completely regressed without lymphoma treatment 1
• Another patient had a 3 cm renal mass with multiple pulmonary nodules that spontaneously resolved after MTX withdrawal 3
• Repeat imaging (CT chest/abdomen/pelvis) at 4 weeks and 8 weeks to document response 1, 3

Adjunctive Therapy During Observation

• Consider short-term corticosteroids (methylprednisolone 125 mg IV daily for 1 week, then taper) if the patient has systemic symptoms like fever or significant organ dysfunction 4
• Ensure adequate folate supplementation during the observation period 5, 6
• Monitor for signs of infection given the immunosuppressed state 5

When to Proceed with Chemotherapy

Initiate lymphoma-directed chemotherapy only if:

• No regression or progression of lesions after 8-12 weeks of observation 1, 3
• Development of life-threatening complications (respiratory failure, liver failure, adrenal crisis) 2
• Biopsy shows high-grade aggressive lymphoma histology that is unlikely to regress spontaneously 1, 4

Critical Pitfalls to Avoid

• Do not assume this is metastatic cancer and rush to chemotherapy without considering MTX-LPD and allowing time for spontaneous regression 1, 3
• Do not restart methotrexate even if the rheumatoid arthritis flares, as this will cause recurrence of the lymphoproliferative disorder 1, 4
• Do not dismiss necrotic tissue on biopsy as non-diagnostic—specifically request immunostaining for EBV even in necrotic specimens, as this can establish the diagnosis 2
• Do not overlook the adrenal mass as incidental—primary adrenal MTX-LPD, though extremely rare, has been reported and follows the same regression pattern 2

Long-term Management

• After complete regression, select alternative disease-modifying therapy for the underlying rheumatoid arthritis that does not include methotrexate 1, 4
• Continue surveillance imaging every 3-6 months for the first year to ensure no recurrence 4
• The prognosis is excellent with complete regression and no recurrence reported in cases managed with MTX withdrawal alone 1, 3, 4