Psoriatic arthritis with acral lentiginous melanoma: role for methotrexate?

A 50-year-old male with psoriatic arthritis since 20 years and on methotrexate since 12 years developed an asymptomatic black patch over his right sole of two years duration. On examination, patient had scaly plaque over the body and extremities with severe mutilating arthropathy of distal joints. There was a hyperpigmented patch over the right sole with surface and color irregularities. A possible diagnosis of acral lentiginous melanoma was made which was confirmed by biopsy. Methotrexate can induce malignancies due to immunosuppression. Here, we present a patient of psoriatic arthritis on long term methotrexate developing malignant melanoma.

What was known?

Immunosuppressants can induce malignancy.

Introduction

Psoriasis is a chronic distressing disorder of the skin affecting 2% of the world population and more debilitating is when it licks the joints causing psoriatic arthritis. Methotrexate has been widely used in the treatment of psoriasis, especially psoriatic arthritis, pustular psoriasis, and erythroderma. Methotrexate is known to be highly effective for psoriasis, allowing patients to resume normal life activities. Methotrexate and other immunosuppressives can induce various malignancies. Development of malignancies is common in psoriatic patients treated with PUVA therapy. Here, we report a case of psoriasis with arthritis on weekly methotrexate developing acral lentiginous melanoma over the sole after 12 years.

Case Report

A 50-year-old male with psoriatic arthritis since 20 years on methotrexate, since 12 years on and off with a cumulative dose of 1080 mg, developed an asymptomatic black lesion over his right sole near the instep since 2 years which was gradually increasing in size over last 6 months. No h/o bleeding or ulceration of the lesion. He was a known hypertensive and diabetic. On examination, patient had pallor and right inguinal lymph nodes were enlarged and firm in consistency.

Examination of right sole revealed a hyperpigmented plaque of 3 × 5 cm with surface and border irregularities [Figure 1]. There was no scaling, ulceration, bleeding or induration. Multiple hyperpigmented macules were present over both soles varying in size from 0.3 × 0.3 cm to 1 × 1 cm. There were also multiple discrete and confluent erythematous papules and plaques over thighs, forearm, arms and trunk. Scalp showed scaly plaques. There was subungual hyperkeratosis in all nails. Oral mucosa revealed a black pigmentation.

Figure 1

Blackish patch with border and surface irregularities over the right sole

Examination of musculoskeletal system revealed swan neck deformity of left lateral 3 fingers and right 4 fingers and Boutennaire deformity of left index finger, proximal dislocation of middle toes bilaterally. There was swelling and deformity of both knee joints. With all these findings, we made a provisional diagnosis of psoriasis with mutilating type of psoriatic arthropathy with acral lentiginous melanoma.

Investigations showed an ESR of 130, rheumatoid factor was negative, but C-reactive protein was positive. SGOT was slightly elevated and cytology from the knee joint aspiration was sterile and predominantly composed of neutrophils. Excision biopsy of the blackish plaque revealed epidermis with junctional activity and nests of cells of melanoma cells containing melanin in dermis consistent with malignant melanoma Clark level-III with no involvement of the circumferential deep margin [Figures 2 and 3]. Another biopsy from the smaller hyperpigmented macule on the sole was unremarkable. Lymph node biopsy from right inguinal lymph node showed only reactive hyperplasia.

Figure 2

Epidermis with junctional activity. Dermis composed of nests of cells containing melanin (H and E, ×100)

Figure 3

Melanoma cells (H and E, ×400)

Lesion was completely excised with a margin of 2 cm and chemotherapy with Inj. Dacarbazine 300 mg infusion for 4 days every month was given for 6 months. Lesions completely subsided [Figure 4] and there were no signs of relapse or metastases till date.

Figure 4

Healed scars after surgical removal of melanoma. There are also multiple hyper-pigmented macules

Discussion

Malignant melanoma is an enigmatic and lethal malignancy of melanocytes. Early identification and surgical excision of invasive melanomas are curative. The incidence of melanomas is increasing from 1 in 1500 in 1935 to 1 in 50 by 2010, but the survival rate is increasing. The cause for the increase in incidence may be due to various environmental factors like the exposure to UV radiation and various immunosuppressives. The survival rate is increased probably because of early identification and prompt treatment.

Acral lentiginous melanoma comprises of almost 50% of all melanomas on darker skinned people, i.e., about 1- 2 million/annum mainly on sole of the foot as observed in our patient. Generally growth of these melanomas is very slow and tends to recur because of failure to excise suffice normal skin laterally. The role of methotrexate in causing malignancies in psoriatic patients is difficult to assess and is controversial.

Analysis of a series of 205 psoriatic patients treated with methotrexate for periods of 2 to 7 years showed no increase in the incidence of internal tumors over a matched population control. Logically, one would not expect methotrexate to be carcinogenic, since unlike most cytotoxic drugs, it neither reacts chemically with nor is incorporated into nucleic acids.[1] But, there are reports of sudden onset of an aggressive CTCL occurring in a 36- year- old patient with psoriasis who was on methotrexate.[2] Hsiao et al.[3] also reported a 50- year- old Taiwanese male with severe psoriasis on methotrexate developing large B cell lymphomas with immunoblastic morphology.

There are various reports of melanoma occurring in patients of rheumatoid arthritis on methotrexate. Krathen et al. reviewed literature on PubMed to evaluate and summarize the risk of cutaneous malignancy in patients of psoriasis, psoriatic arthritis, and rheumatoid arthritis who were on various immunosuppressives.[4] He concluded that methotrexate increases the risk of malignant melanoma. Patel et al. reviewed the risk of malignancy associated with therapies for psoriasis and concluded that long term PUVA therapy is one with the most increased risk of cutaneous squamous cell carcinoma and malignant melanoma. Methotrexate, cyclosporine are associated with increased risk of lympho- proliferative disorders, and biologicals like TNF-α inhibitors are associated with increased risk of non- melanoma skin cancers and hematological malignancies.[5] There are also reports of malignant melanoma in psoriatic patient treated with TNF- α antagonists.[6] Barth D et al. reported two patients of psoriasis with fumaric acid developing malignant melanoma.[7] In an extensive study by Buchbinder et al., a 3-fold risk of developing melanoma was noted in rheumatoid arthritis patients treated with methotrexate.[8] There was also a 3-fold increase in lung cancer and 5-fold increase in Non-Hodgkin's lymphoma compared with the general population. They also observed a 2.5-fold increased cancer when methotrexate was combined with cyclophosphamide but no increased risk with azathioprine.

A novel protein MIA (Melanoma Inhibitory Activity), a small 11KDa protein of 131 amino acids encoded by a single gene or chromosome 19, whose serum concentrations when increased indicate degree of metastasis in melanoma patients. But, it is also expressed in developing and mature cartilage and was also found to be elevated in patients with destructive joint diseases like rheumatoid and psoriatic arthritis.[9] Therfore, interpretation of serum levels of MIA in suspected metastatic malignant melanoma in such patients should be done judiciously.

Here, we present a case of psoriasis with psoriatic arthritis on long- term methotrexate developing acral lentiginous melanoma, which was completely treated with wide excision and chemotherapy. The association of methotrexate and psoriasis developing malignant melanoma may be coincidental or therapy- related. Most of the reports conclude that there is definitely role for methotrexate in development of malignancies.

What is new?

Methotrexate probably inducing acral lentiginous melanoma in a patient with psoriatic arthritis.