A Rare Adverse Effect of Methotrexate Mimicking Disease Progression in Folliculotropic Mycosis Fungoides: A Case Report

Abstract

Introduction

Cutaneous ulceration is an uncommon adverse effect of methotrexate (MTX). This complication has been rarely described in cutaneous T-cell lymphoma and, to date, has not been reported in folliculotropic mycosis fungoides (FMF).

Case Report

A 66-year-old Thai man with stage IB FMF achieved excellent clinical improvement with low-dose MTX therapy for 13 months. He subsequently developed disseminated erythematous papules, plaques, and necrotic ulcers on the extremities. Laboratory evaluation revealed mild anemia, and microbial cultures were negative. Histopathologic examination demonstrated epidermal dysmaturation with necrotic keratinocytes, infiltration by eosinophils and neutrophils, and atypical lymphocytes with features consistent with FMF – findings suggestive of MTX-induced ulceration rather than tumor progression. Discontinuation of MTX led to dramatic resolution within 2 weeks, after which the patient was transitioned to acitretin, resulting in sustained disease control.

Conclusion

This case highlights MTX-induced cutaneous ulceration as a rare adverse event in FMF that can mimic disease progression. Recognition of the characteristic histopathologic features facilitates accurate diagnosis. Early discontinuation of MTX leads to rapid resolution, underscoring the importance of prompt recognition and management.

Introduction

Methotrexate (MTX) is a widely used systemic therapy for inflammatory and neoplastic dermatologic conditions, including cutaneous T-cell lymphoma (CTCL). Although generally well tolerated, MTX can cause adverse effects, with skin ulceration being a rare but significant complication [1, 2].

Only a few case reports have documented MTX-induced cutaneous ulceration in mycosis fungoides (MF), with no reported cases in patients with folliculotropic MF (FMF), a distinct variant of CTCL [3]. We present a case of a 66-year-old man with FMF who developed drug-related cutaneous ulcers mimicking tumor progression after 1 year of successful MTX therapy. This underscores the importance of recognizing MTX-induced skin ulcers as a potential adverse effect, especially in the context of CTCL. Differentiating this complication from the disease progression of MF is crucial for appropriate management. The patient’s clinical course and histopathologic findings provide insights into the diagnosis and treatment of this rare and not yet widely known complication.

Case Report

A 66-year-old Thai male with arterial hypertension, hyperlipidemia, and hemiplegia due to prior cerebrovascular disease presented with widespread pruritic erythematous patches and plaques on his face, trunk, and extremities. An initial skin biopsy revealed findings consistent with spongiotic dermatitis. Despite extensive treatment for eczema, his condition progressively worsened over 5 years. He developed intractable pruritus, scaly patches, and plaques on his back, extremities, face, and scalp, along with alopecia (Fig. 1a–d). A second biopsy of the scalp revealed psoriasiform epidermal hyperplasia with lymphocytic infiltration and folliculotropism by abnormal small- to medium-sized lymphoid cells. Immunohistochemistry demonstrated CD3 and CD4 positivity and CD20 negativity in the folliculotropic lymphoid cells. CD8 highlighted small lymphocytes, with a CD4:CD8 ratio of approximately 4:1. CD30-positive cells comprised approximately 10% of T cells, findings consistent with FMF (Fig. 2a–f). A staging workup, including complete blood count, comprehensive metabolic panel, peripheral blood flow cytometry, and computed tomography scan of the chest and whole abdomen, showed no evidence of extracutaneous involvement. The patient was diagnosed with stage IB FMF. Oral MTX at a dose of 20 mg weekly was initiated, along with folic acid, antihistamines, gabapentin, and topical corticosteroids. Phototherapy was not feasible due to hemiplegia. The treatment significantly improved his skin lesions and pruritus with no reported adverse effects.

Fig. 1.

Clinical images of FMF at diagnosis. Multiple erythematous to brownish patches and plaques involving the face (a), back (b), and extremities (c, d).

Fig. 2.

Hematoxylin and eosin (H&E) staining revealed folliculotropism by abnormal small- to medium-sized lymphoid cells (a, ×100; b, ×100). Immunohistochemistry demonstrated folliculotropic lymphocytes predominantly positive for CD3 (c) and CD4 (d), with a CD4:CD8 ratio of approximately 4:1 (e) and occasional clusters of CD30-positive cells (f).

After 13 months of MTX therapy, the patient developed new erythematous patches and papules on his arms, rapidly progressing to disseminated erythematous crusted papules, plaques, and necrotic ulcers involving all extremities (Fig. 3a–c) within a week. He denied MTX dosing errors or the use of additional medications. He was afebrile, and the physical examination was otherwise unremarkable, including normal mucosa. The clinical differential diagnosis comprised CTCL progression, secondary lymphoma, cutaneous infection, and eczematous eruption. Laboratory investigations revealed mild anemia (hemoglobin 10.7 g/dL, baseline 13.3 g/dL), a white blood cell count of 4,580/mm³ with 86.7% neutrophils, and a platelet count of 486,000/mm³. Liver and renal function tests were within normal limits. Despite systemic antibiotic therapy, the skin lesions worsened. A biopsy from an ulcerated lesion revealed epidermal dysmaturation, characterized by acanthosis, scattered necrotic keratinocytes, and enlarged pale keratinocytes with large nuclei and prominent nucleoli. The dermis showed a dense band-like infiltrate of small- to medium-sized atypical lymphoid cells, eosinophils, and neutrophils. Epidermotropism and folliculotropism were also observed. Atypical lymphocytes in the epidermis and dermis were strongly positive for CD3 and CD4, with an elevated CD4/CD8 ratio and scattered CD30-positive cells (Fig. 4a–f), consistent with findings from a previous biopsy of FMF. However, the presence of eosinophils and epidermal dysmaturation suggested MTX toxicity. Epstein-Barr virus-encoded RNA in situ hybridization was negative. Cultures for bacteria, fungi, and atypical mycobacteria were negative.

Fig. 3.

MTX-induced skin ulceration. a–c Multiple discrete necrotic nodules and plaques with ulcers on the extremities. d–f Spontaneous regression of lesions 2 weeks after MTX discontinuation.

Fig. 4.

a Sections (H&E) showed epidermal hyperplasia with necrotic keratinocytes and a dense dermal infiltrate of atypical lymphoid cells exhibiting epidermotropism and folliculotropism, admixed with eosinophils (×100). b Epidermal dysmaturation and necrotic keratinocytes suggestive of an MTX-related eruption (×400). Immunohistochemistry demonstrated positivity for CD3 (c) and CD4 (d), with a CD4:CD8 ratio of approximately 4:1 (e) and scattered CD30-positive cells (f).

MTX was discontinued, resulting in spontaneous resolution of skin lesions within 2 weeks (Fig. 3d–f). Acitretin at 10 mg daily was subsequently initiated, leading to a favorable response and well-controlled FMF.

Discussion

Low-dose MTX (5–25 mg/week) is commonly used to treat various dermatologic and rheumatologic conditions, including psoriasis, rheumatoid arthritis, CTCL, bullous pemphigoid, dermatomyositis, systemic lupus erythematosus, and atopic dermatitis [1, 2]. However, MTX has a wide spectrum of side effects, involving gastrointestinal symptoms, bone marrow suppression, hepatotoxicity, nephrotoxicity, and pulmonary complications. Rarely, MTX can cause alopecia, anaphylaxis, oligospermia, photosensitivity, radiation recall, and lymphoproliferative disorders. Although low-dose MTX is generally safe and well tolerated, toxicity can occur with varying severity [1].

MTX-induced cutaneous ulceration is a rare but notable adverse effect, primarily reported in patients with psoriasis [4–6]. Berna et al. [2] reviewed 114 cases of MTX-associated ulcers, most involving psoriasis patients, followed by those with rheumatoid arthritis and MF. The median MTX dose reported was 20 mg/week, with ulcers appearing from days to years after starting MTX. Risk factors include dosing errors, renal impairment, advanced age, and concurrent use of medications that impair renal excretion, such as NSAIDs or folate antagonists like trimethoprim/sulfamethoxazole [1, 6].

MTX-related ulcers may present with localized or generalized erosions, ulcers, bullae, crusted plaques, and necrotic nodules. These lesions can occur on pre-existing skin conditions, particularly psoriasis, or on previously unaffected skin, regardless of underlying dermatologic disease [2, 3, 5, 7, 8]. While oral ulcer is a common manifestation of MTX toxicity, cutaneous ulceration without mucosal involvement is possible, necessitating thorough clinical evaluation [2].

Histologically, MTX-induced ulcers commonly show epidermal dysmaturation, characterized by acanthosis, dyskeratotic, and enlarged pale keratinocytes with pleomorphism or mitotic figures. Dermal findings demonstrate a lymphohistiocytic infiltrate, often with eosinophils and occasional neutrophils [3, 5, 7, 8]. Nonspecific ulcers, vacuolar interface dermatitis, and toxic epidermal necrolysis-like features are not uncommon. Aebischer et al. [7] recently postulated epidermal dysmaturation as a diagnostic clue for MTX-induced skin ulcers, regardless of the underlying condition. In MTX-induced ulcers in MF patients, these histologic changes may coexist with atypical lymphocytes and epidermotropism, as observed in our patient [3, 7].

Cutaneous ulcers can be an early indicator of MTX toxicity, often preceding systemic involvement [4, 8]. Although routine laboratory monitoring is essential during MTX therapy, the ulcers can occur without significant laboratory abnormalities [2, 3, 7]. Moreover, serum MTX levels are often undetectable in cases of toxicity due to the drug’s high intracellular distribution [9, 10].

In our patient, MTX-induced ulceration was initially misdiagnosed due to its rarity and the absence of typical features such as precipitating factors, mucositis, or systemic toxicity. However, biopsy findings revealed epidermal dysmaturation with eosinophils, a hallmark of MTX toxicity, and the rapid resolution of the ulcers upon MTX discontinuation further confirmed the diagnosis, even though MTX levels were not measured in this case.

Previously, MTX-associated ulcers in CTCL have predominantly been reported in patients with erythrodermic MF. Notably, some cases presented without laboratory abnormalities or mucositis, and most patients recovered after MTX discontinuation without leucovorin rescue therapy, paralleling the outcome observed in our FMF patient [3].

In conclusion, we report a case of MTX-induced ulceration in an FMF patient, emphasizing the need to recognize potential MTX cutaneous adverse effects, even without risk factors. Acute skin ulcers in MTX-treated MF patients should raise suspicion for MTX toxicity, requiring careful clinical evaluation, thorough history, and skin biopsy to differentiate from disease progression. Discontinuing MTX typically results in rapid resolution, highlighting the importance of early diagnosis and intervention.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550569).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Surachanee Likittanasombat contributed to case conceptualization and manuscript writing. Manasmon Chairatchaneeboon contributed to pathology interpretation, supervision, and production of the final draft.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data relevant to this manuscript are contained in the publication. Further inquiries can be directed to the corresponding author.