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

MTX-LPD is a complication that occurs during administration of MTX, an immunosuppressive drug.¹ MTX-LPD was first reported in 1991 by Ellman et al.² Most cases of MTX-LPD involve the lungs, while approximately 25% to 50% of cases involve the skin. Skin lesions are often subcutaneous nodular lesions occasionally associated with necrosis and ulceration.³ Delayed diagnosis of MTX-LPD with ulceration and/or necrosis may lead to ulcer enlargement and the need for surgical procedures such as skin grafts.¹ Therefore, wound care clinicians should be adequately knowledgeable about MTX-LPD as its early diagnosis is vital. This study reports a case of MTX-LPD that caused a skin ulcer leading to tendon exposure on the dorsum of the hand, which was difficult to diagnose and treat.

A 74-year-old female was diagnosed with RA and was administered MTX for 3 years and 8 months (weekly dose, 6 mg–12 mg; overall dose, 2119 mg). The patient visited the dermatology department of the hospital and was diagnosed with an ulcer on the dorsum of the hand associated with RA through a biopsy examination. The ulcer was treated with an ointment but gradually increased in size. 

The patient was referred to the authors’ department more than 2 months after the ulcer enlarged. The ulcer size was 6.5 cm × 5 cm, and it was surrounded by an embankment tumor that measured 7 cm × 6 cm (Figure 1A). Pain in the affected area, edema of the fingers, and flexion failure beyond the metacarpophalangeal joint were observed. Magnetic resonance imaging of the hand showed hyperintensity on T2-weighted images of the dorsum of the hand, which involved the extensor tendons (Figure 1B). First, a mass, including an ulcer, was excised and submitted for pathological examination, and the wound was treated conventionally post-surgery (Figure 2). Pathological examination using hematoxylin-eosin staining showed diffuse proliferation of small to large atypical lymphoid cells. Immunohistochemical examination revealed the presence of CD20-, CD30-, and 50% Ki-67-positive atypical lymphoid cells, and in situ hybridization revealed the presence of EBV-encoded small RNA-positive atypical lymphoid cells (Figure 3). Blood analysis revealed elevated serum sIL-2R (955 U/mL) and EBV-DNA (14×10² copy/µgDNA) levels. 

Based on the pathological diagnosis and medical history, the patient was diagnosed with EBV-positive MTX-LPD; MTX and tacrolimus treatments were discontinued. Three weeks after the first surgery, the wound on the dorsum of the hand was covered with an anterolateral thigh free flap (Figure 4). No postoperative complications were reported. Two months post-MTX and tacrolimus discontinuation, sIL-2R levels improved (377 U/L) and whole-body computed tomography revealed no evident lymphadenopathies or other lesions suggestive of malignancy. Ten months after the second surgery, MTX-LPD recurrence was not observed in the dorsum of the hand (Figure 5).

MTX-LPD is categorized as an iatrogenic complication, and oral administration of MTX should be discontinued upon diagnosis of MTX-LPD.³ Spontaneous regression has been reported in 60% of EBV-positive and 40% of EBV-negative patients with MTX-LPD who discontinued oral MTX treatment.^4,5 Although MTX-LPD regression is often observed within 2 weeks to 3 months post-MTX discontinuation, some cases may require chemotherapy or surgery.^1,3,6 The Table summarizes the patient characteristics of MTX-LPD with skin ulceration cases reported in the literature^1,3,6-10 as well as those of this case. In this case report, MTX was discontinued, and free flap reconstruction was performed within a few days. The postoperative period was uneventful, and MTX-LPD recurrence was not observed. Although it has been reported that skin grafting should be performed at 2 months post-MTX discontinuation,¹ the optimum time period between MTX discontinuation and reconstructive surgery remains unclear. Patients with RA tend to develop infectious diseases due to the use of therapeutic drugs, such as steroids and biologics, in addition to the immunological abnormalities attributed to RA itself. Furthermore, conventional treatment of ulcers with exposed tendons and bones poses a high risk of infection. The patient in this report was diagnosed with MTX-LPD after excision of the ulcer-containing mass, suggesting the need for early reconstructive surgery. Therefore, if the patient’s condition necessitates reconstructive surgery, early surgical treatment post-MTX discontinuation may be beneficial.

A subcutaneous nodule with an ulcer may be difficult to diagnose based on pathologic biopsy examination alone. The ulcer in this case may have had a peculiar morphology not previously reported. Specifically, this ulcer was surrounded by an embankment tumor and appeared to be necrotic from self-destruction of the tumor core. As the patient was initially diagnosed with a rheumatoid nodule, it was assumed that the nodule itself had self-destructed and ulcerated. This is probably because the subcutaneous nodule was not sufficiently extracted during specimen collection. As a result, delayed diagnosis led to ulcer enlargement and tendon exposure, which required free flap reconstruction. This suggests that the possibility of MTX-LPD should always be considered in patients with RA treated with MTX, and careful specimen collection in cases of MTX-LPD associated with ulcers is vital for accurate MTX-LPD diagnosis.

This case report describes 1 case of MTX-LPD. Additional studies and case reports focused on MTX-LPD cases associated with ulceration and/or necrosis that require skin graft or flap reconstruction may be useful in establishing treatment plans and collaboration among different departments for effective treatment.

Although MTX-LPD with ulceration is rare, it should be considered in cases of refractory ulcers in patients with RA. Discontinuation of MTX based on early diagnosis is critical to avoid surgical procedures such as skin grafts and flap reconstruction. Additionally, cooperation within the rheumatology department, as well as with other departments dealing with wound care, is essential for effective treatment.