May 2005

Fig.4

Fig.5

Diagnosis: Methotrexate UV recall

Pathology:
Two punch biopsies of the left buttock were taken. Histopathologic examination revealed marked spongiosis with intraepidermal vesiculation, keratinocyte necrosis and scattered dyskeratotic cells in the superficial stratum spinosum (Figs. 4 & 5). Neutrophils, lymphocytes, and histiocytes were seen within the vesicles (Fig. 5). There was also a perivascular lymphohistiocytic infiltrate with neutrophils. GMS and Gram stain showed no stainable organisms. No interface dermatitis was seen.

Discussion:
Methotrexate (MTX) has been associated with many mucocutaneous side effects including stomatitis, transient alopecia, and phototoxic dermatitis. Rarely, it has been associated with reactivation of a prior sunburn. This phenomenon, termed methotrexate recall, is characterized by dusky erythema, bullae, desquamation and pain in areas of previously ultraviolet-induced sunburn; it is often more intense than the original photoreaction. As in the case of our patient, this rash often spares chronically exposed areas on the face, neck, and arms.

The mechanism of this UV recall phenomenon is unknown. MTX is an antimitotic and immunosuppressive agent that inhibits dihydrofolate reductase to terminate DNA synthesis. It is hypothesized that MTX inhibits local mononuclear cell response and DNA synthesis in the previously solar damaged basal keratinocytes, delaying healing and increasing inflammation.

It differs from radiation recall because the radiation recall reaction can occur at any time after radiation exposure, whereas MTX-induced UV recall seems to occur only after a UV exposure 2-8 days prior to MTX treatment. This patient differs from other case reports of MTX UV recall in that she did not have any recent sunburn episode and her rash did not occur until more than three weeks after her last UV exposure and not until after the third dose of MTX.

There is no standard treatment for MTX-induced UV recall. Leukovorin rescue has been used to prevent toxicity associated with high dose methotrexate, such as bone marrow suppression, stomatitis, renal and hepatic toxicity. Leukovorin is a reduced form of folic acid and supplies the necessary cofactor that is blocked by methotrexate (a folate antagonist). However, leukovorin rescue does not appear to prevent sunburn reactivation from MTX. Wet dressings and topical steroids may provide some relief. The inflammation generally subsides gradually and in most case studies, did not recur with subsequent doses of MTX. However, Guzzo, et al reported a case where a burn was reactivated with MTX, resolved, and was then reactivated twice more with his two subsequent weekly doses of MTX. After withholding the MTX for one week, there were no more recurrences.

1. Fitzpatrick's Dermatology in General Medicine, 5th ed. (Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI eds.). New York: McGraw-Hill, 1999. p 1646.
2. Khan, AJ et al. Methotrexate and the Photodermatitis Reactivation Reaction: A Case Report and Review of the Literature. Cutis. 2000; 66:379-82.
3. Korossy KS, et al. Methotrexate reactivation of sunburn reaction. Arch Dermatol. 1981; 117:310-11
4. Corder, MP et al. Failure of Leukovorin rescue to prevent reactivation of a solar burn after high dose methotrexate. Cancer. 1976; 37: 1660-2
5. Jaffe N. Reactivation of a solar burn with high-dose methotrexate and citrovorum rescue [letter]. Cancer. 1976; 38:1036-7.
6. Guzzo C, et al. Recurrent recall of sunburn by methotrexate. Photodermatol, Photoimmunol, Photomed. 1995; 11:55-6.

This case was presented by Drs. Caroline Halverstam, Margaret Mann, Helen Kim-James and Michael Heffernan