A case of an adverse reaction to topical 5-fluorouracil in irradiated skin

Journal of Drugs in Dermatology, March, 2006 by Thomas Lambert, Kimberly Mullinax, Jennifer Smith

Abstract

A 73-year-old Caucasian male was treated in the dermatology clinic for squamous cell carcinoma (SCC) of the scalp by Mohs micrographic surgery. The patient subsequently received radiation therapy because of possible calvarium invasion. Approximately 2 years later, the patient developed Bowen's disease within the previously irradiated skin flap. The lesion was treated with topical 5-fluorouracil (5-FU) twice daily for 4 weeks, and subsequently developed a 2 x 2 cm full-thickness ulceration with exposed calvarium.

Case Report

A 73-year-old Caucasian male was referred to the dermatology clinic in May 2002 for a 3-month history of a rapidly growing lesion on the scalp. Physical examination revealed a 3.0 x 2.7 cm crateriform nodule without adenopathy on the right parietal scalp. Biopsy of the lesion revealed aggressive squamous cell carcinoma (SCC). The patient was treated with Mohs micrographic surgery, and closure was achieved with a rotational skin flap. Histologically, the tumor was suspicious for extension to the calvarium and the patient was recommended to undergo adjunctive radiation therapy. At his 2-week follow-up, the flap was healing well with minimal pain. Radiation therapy was performed in June 2002 and the patient was lost to further follow-up.

In November 2004, the patient was again referred to the dermatology clinic for evaluation of a 2 x 2 cm erythematous plaque with central crust at the previous operative site that had been present for several months. A shave biopsy of the lesion revealed Bowen's disease. Treatment with 5% 5-FU cream was initiated twice daily for 4 weeks.

Four weeks later, examination revealed a 2.1 x 2.3 cm eschar with mild surrounding erythema at the site of the 5-FU application. The patient complained of minimal pain with no other symptoms. Wound care with Polysporin was instructed with close follow-up.

Two months later, the patient returned with a 2 x 2 cm ulceration that extended to the calvarium (Figure 1). Biopsy specimens from the edge of the ulcer were negative for malignancy, revealing only inflamed scar tissue. An 8 x 3 cm rotational flap was performed that subsequently failed. At his last clinic visit, the ulcer measured 2.8 x 2.0 cm with persistent exposed calvarium. Vinegar soaks (1) have been instituted and the patient will be pursuing further surgical options including a larger rotational flap.

Discussion

5-Fluorouracil (5-FU) is a fluorinated pyrimidine analog that inhibits DNA formation by blocking thymidylate synthetase. To a lesser extent, 5-FU also inhibits RNA formation by competing with metabolites such as uracil for incorporation into a growing RNA strand. These combined actions produce a cytotoxic effect that is most marked in cells which grow rapidly, such as tumor cells. For dermatological use, 5-FU is available in topical preparations which have been found to be effective in the treatment of actinic keratoses, keratoacanthomas, superficial basal cell carcinomas, verruca, (2) and Bowen's disease. (3) The effectiveness of topical 5-FU in these disorders is related to the ability of the agent to penetrate abnormal skin to a greater extent than normal skin. Once applied to abnormal skin, 5-FU induces a cascade of events beginning with painful erythema, then erosions, and finally necrosis of the individual lesions. Normal skin is typically spared. Common adverse effects associated with topical 5-FU occur locally and include burning, crusting, allergic contact dermatitis, erythema, hyperpigmentation, irritation, pain, photosensitivity, pruritus, scarring, rash, soreness, and painful erosions. (4) Notably, erosive dermatitis rarely occurs unless 5-FU application is continued after significant inflammation develops. (5) Topical 5-FU has also been shown to cause chronic mucosal ulcers in a small minority of patients when used to treat vaginal human papillomavirus-associated lesions. (6)

Exposure to ionizing radiation induces both reversible and irreversible changes in the skin, as well as predisposing to radiation-induced skin cancers and ulceration. (7) After almost any exposure to radiation, there will be various mild tissue reactions that will not prevent the skin from returning to an apparently normal condition. (8) They include reversible effects such as erythema, cutaneous irritability, temporary epilation, functional suppression of cutaneous glands, and pigmentation changes that may last weeks. Depending on the amount of radiation, these changes may progress to a more severe acute radiodermatitis (ARD) manifested by intense local inflammation, vesiculation, erosion, and even ulceration. (9)

[FIGURE 1 OMITTED]

Chronic radiodermatitis (CRD) generally occurs years after radiation exposure, and is usually subclinical in the early stages. (10) Clinical signs resemble poikiloderma, including atrophy, partial or complete destruction of cutaneous appendages, telangiectasias, sclerosis of underlying tissue, and pigmentary changes. CRD can sometimes result in irradiation-induced tumors, mainly in sun-exposed areas. (7) The affected skin is very sensitive to minor trauma, which may lead to persistent ulceration that has a very poor tendency to heal. (9) The histopathologic findings of CRD are varied depending on the severity of involvement. CRD may present with epidermal atrophy, loss of rete ridges, dyskeratotic cells, and focal basal vacuolar change. Dermal changes are often prominent as a result of a marked upregulation of collagen synthesis leading to swollen, hyalinized collagen with irregular eosinophilic staining. (11) An almost pathognomonic feature is the presence of giant stellate cells with large nuclei containing clumped chromatin, otherwise known as radiation fibroblasts. (9) Dermal vessels are frequently dilated, decreased in number, and exhibit hyalinization of the vessel wall, resulting in a narrowed lumen. Pilosebaceous units are generally absent, with few scattered eccrine glands. (12) The complete histologic picture can resemble a scar. The ultimate extent of the injury to the skin will vary with the amount of radiation absorbed, with the individual, and with different areas on the body of the same individual. (8)