Methotrexate-induced Skin Necrosis in a Child Receiving Low-dose Methotrexate

Pictures showing necrotic lesions described in the text.

Summary

Methotrexate is an antimetabolite used for treatment of cancer. Although the commonest complications are myelosupression and orointestinal mucositis, skin necrosis has been reported as a side effect. Most cases of skin necrosis have been reported in persons receiving high dose methotexate or with underlying skin diseases. A rare case of skin necrosis in a child receiving treatment for Burkitt lymphoma with a drug combination including low-dose methotrexate is reported and the possible risk factors discussed.

Introduction

Methotrexate is an antimetabolite that inhibits utilization of folic acid by inhibiting dihydrofolate reductase a key enzyme in the generation of reduced folates crucial for the biosynthesis of purines and thymidylic acid.¹ It has been used effectively, most often in drug combinations, for a number of neoplasms such as acute lymphoblastic leukaemia, non-Hodgkin lymphoma and osteosarcoma.² The primary toxic effects of methotrexate are myelosuppresson and orointestinal mucositis, which occur 5-14 days after the drug has been administered.² We report the case of a child treated for Burkitt lymphoma with a regimen containing methotrexate who developed skin necrosis within 14 days of commencement of treatment.

Case Report

The patient was a four-year-old girl who presented at the University College Hospital Ibadan with a month’s history of progressive painless bilateral jaw swelling. Five days before presentation, she developed protrusion of both eyes, which soon resulted in bilateral loss of vision. The illness was associated with weight loss and no history of swelling of any other part of the body. On examination, the patient looked acutely ill, was mildly pale and had obvious bilateral proptosis with no light perception in either eye. There were bilateral, non-tender swellings of the right mandible with intra oral extension, and bilateral swelling of both maxillae with dental malalignment. Other significant findings were lower motor neuron facial nerve palsy involving the right half of the face and hepatomegaly. An abdominal ultrasound scan revealed an enlarged liver containing a hypoechoic mass; biopsy of the right mandibular mass, showed histological features consistent with Burkitt lymphoma and ophthalmologic assessment revealed features of bilateral optic atrophy. Full blood count at diagnosis revealed a haematocrit of 34%, total white blood cell count of 11,000/mm³ (neutrophils 61%, lymphocytes 36%, monocytes 3%) and a platelet count of 114,000/mm³. Serum electrolytes, urea, creatinine, calcium, phosphate, uric acid and liver function tests were within normal limits. Specific treatment was initiated using COM chemotherapy according to INCTR protocol 03-06C. This consisted of cyclophosphamide 1200mg/m², vincristine 1.4 mg/m² and methotrexate 75mg/m² all given intravenously on day 1. She was also given intrathecal methotrexate, 12 mg, on days 1 and 8 respectively and intrathecal cytarabine, 50mg, on day 4. Cerebrospinal fluid cytology was negative for malignant cells. Four days before commencement of chemotherapy she was started on intravenous ciprofloxacin and amikacin for presumed septicaemia and had become afebrile prior to the initiation of chemotherapy.

On day 13 of the first cycle of chemotherapy, necrotic patches were observed on her labia majora, the skin over the lumpar puncture site, and the medial aspect of the infraorbital skin of both eyes adjacent to the medial epicanthi. There was also associated bilateral conjuctivitis. A clinical diagnosis of methotrexate toxicity was made and chemotherapy was stopped. Full blood count performed on the day of appearance of the lesions revealed a haematocrit of 21% (for which she was transfused with blood) and total WBC of 700/mm³ (Neutrophils 78%, lymphocytes 16%, monocytes 6%) and platelet count of 136,000/mm³. Over time, the necrotic patches sloughed off leaving full thickness ulcers at all affected sites and the ulcers adjacent to the medial epicanthi coalesced over the bridge of the nose. The lesions were managed by dressings and healing was almost complete three weeks after. After the Haemogram had returned to normal, chemotherapy was recommenced with methotrexate replaced with Cytarabine. Child remained free of any toxic effect of the new regimen on day 7.

Discussion

There are reports of cutaneous toxicity of methotrexate but most of them have been in adults. Tazi et al³ reported a case of Toxic epidermal necrolysis (TEN) in a nine-year-old child treated for Burkitt lymphoma with a regimen that included high dose methotrexate. Our patient also had Burkitt lymphoma but received low dose methotrexate and had a less extensive but full thickness skin necrosis. Toxic epidermal necrolysis (TEN) is a known cutaneous complication of methotrexate; it is a life-threatening disease characterized by extensive destruction of the epidermis.

Although the ulcers that followed necrosis in our patient were so severe and disfiguring, particularly those of the face, the characteristics of the lesions and non-extensive distribution make TEN an unlikely diagnosis.

Cutaneous ulceration has been reported as a side effect of methotrexate therapy in patients with psoriasis. In addition to the rare occurrence of a toxic epidermal necrolysis-like condition, two different patterns of ulcerations have been described in these patients: one type in psoriatic plaques and the other type in skin uninvolved by psoriasis but affected by other cutaneous pathology, such as stasis dermatitis or scars.4 Cutaneous ulceration has also been reported to complicate methotrexate usage in patients with erythrodermic mycosis fungoides.⁵

Previous reports on methotrexate –induced skin necrosis have indicated that it is dose dependent and therefore observed usually in patients on high dose MTX or changing drug dosages in patients on prolonged methotrexate use. Others have implicated underlying skin disease as a risk factor; methotrexate-induced cutaneous necrosis is said to be rare in patients without underlying skin disease.^{5, 6}

Our patient does not seem to fit into any the risk groups described above since the dose of methotrexate was not high and there was no underlying skin disease. Methotrexate-induced necrosis has been associated with concomitant administration of drugs that interfere with methotrexate excretion by competing for renal tubular secretion such as ciprofloxacin.² Dalle et al reported cases of methotrexate toxicity following administration of ciprofloxacin but their patients received high dose methotrexate unlike our patient.⁷ Therefore, although ciprofloxacin might have predisposed to the reaction seen in our patient, the chances are low. Concomitant use of Amikacin in our patient may also have been a contributory factor in altering the clearance of methotrexate, even though renal function tests remained normal in our patient.²

Conclusion

There is need for clinicians to carefully monitor renal function and consider drug interactions while treating children with methotrexate even when there are no obvious risk factors for toxicity. In African children on treatment for Burkitt lymphoma, cytarabine may be used successfully to substitute for methotrexate in cases of toxicity.⁸

Biobele Brown, Ibadan University, Ibadan, Nigeria

References

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Methotrexate-induced toxic epidermal necrolysis: A case report. International Journal of Medicine and Medical Science Vol. 1(4), pp. 099-101, 2009.
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