Treatment of Palmoplantar Keratoderma With Continuous Infusion 5-Fluorouracil
A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy with 5-fluorouracil (5-FU) for his inherited punctate palmoplantar keratoderma (PPK). His father also had this skin disorder, which coincidentally cleared after 2 courses of chemotherapy consisting of 5-FU and cisplatin to treat his lung cancer, prompting the patient to undergo this trial of therapy. After the patient's first course of a 5-day continuous infusion (CI) of 5-FU (1000 mg/m2 per day), the lesions on his hands and feet regressed by approximately 80%. However, after completion of each course, the lesions seemed to reappear to some degree. The patient desired to pursue further therapy; therefore, CI 5-FU at a dose of 250 mg/m2 per day (500 mg/d) was instituted, while pyridoxine was avoided in the hope of causing a hand-foot syndrome that may provide some long-term benefit. After receiving a 12-week course of therapy of CI 5-FU at 250 mg/m2 per day, his lesions were approximately 95% improved, with only a few minute punctate keratoses remaining. At follow-up nearly 4 years later, the lesions remain 90% cleared.
At his 1-month follow-up, the patient was pleased that the lesions over his hands and feet had regressed remarkably after only one treatment. The oncologist and patient agreed that the lesions had been reduced by approximately 80%. Laboratory tests disclosed the following values: a white blood cell count of 5400/mm3, a hemoglobin level of 15.5 g/dL, and a platelet count of 194,000/mm3. It was clearly reiterated to the patient again that there was no evidence to suggest that treatment with intravenous 5-FU was effective, despite encouraging results.
After 2 courses of CI 5-FU at 1000 mg/m2 per day for 5 days, the patient desired to pursue further treatment because after each course the lesions seemed to grow back to some degree, though they remained about 75% improved. Because the patient was adamant about pursuing further therapy, CI 5-FU was dosed at 250 mg/m2 per day in the hope that he might develop some hand-foot syndrome, which may lead to long-term benefits. The full course of treatment would require several weeks; thus, a port-a-cath was surgically placed and connected to an infusion pump that administered 5-FU continuously.
After a 12-week therapeutic regimen of 250 mg/m2 per day of CI 5-FU, the patient's lesions were approximately 95% cleared and, for the most part, were unapparent. He had no significant side effects from the 5-FU other than mild cheilosis. Two months later, the lesions had not returned. At follow-up nearly 4 years later, the dermatologist rated the lesions as being 90% cleared; however, the patient believes that the lesions are 100% cleared with only scar tissue remaining. The Figure demonstrates the effectiveness of treatment.
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The patient has experienced one adverse effect since the time 5-FU was initiated, ie, an increased dermatologic sensitivity to non–glycerin-based soaps and shampoos. However, by switching to glycerin-based products, the problem disappeared. Although it is not known whether treatment with 5-FU was the sole culprit of this problem, the timing of treatment and onset of the sensitivity suggest an association.
Comment
In 1879, Davies-Colley described punctate PPK as "disseminated clavis of the hands and feet."3,8 Punctate PPK also is referred to as keratosis punctata palmaris et plantaris or Buschke-Fischer-Brauer disease.6,9 Although the incidence in the United States is unknown, the reported incidence for this rare genodermatosis is 1.17 per 100,000 people in Croatia.10 Hereditary PPK is autosomal dominant and usually develops when a patient is between 12 and 30 years of age.3,11 Punctate PPK presents with abundant hyperkeratotic papules on the palms and soles that are irregularly distributed. The papules tend to be asymmetric, vary greatly in size, and occur more frequently over pressure points, causing pain in many cases.3,6,9 To our knowledge, there have been no cases of spontaneous remission in patients with inherited PPK.
For years, retinoid therapy has represented the treatment of choice for severe inherited keratodermas.12 Treatment of punctate PPK, specifically, usually consists of topical retinoids or calcipotriol to soften the keratoses, and systemic retinoid therapy, if warranted. Although topical tretinoin (vitamin A acid) has been proven to be effective in many keratinizing dermatoses, Muller et al13 revealed that topical tretinoin 0.1% cream was not effective in palmar-plantar hyperkeratosis. In the early 1980s, Bergfeld et al1 demonstrated that oral isotretinoin, a vitamin A analogue, was effective in treating a variety of keratinizing disorders, including one case of punctate keratoderma. Despite the "antikeratolytic" effects of isotretinoin, disease relapse occurred with a reduced retinoid dose and symptoms fully recurred after therapy was discontinued. Oral retinoid therapy is not a cure; therefore, treatment must be continued indefinitely to maintain results.
Topical 5-FU has been used to treat actinic keratoses and basal cell carcinomas.14,15 Osman et al5 reported a case of "spiny keratoderma of the palms and soles" that responded well to 5-FU 5% cream. Recently, a study performed by Levy et al16 suggested that 5-FU 0.5% cream compared with 5-FU 5% cream is equally effective, is associated with less toxicity and may actually be more specific to the affected area of skin in which the cream is applied. These conclusions, though counterintuitive, stem from higher concentrations of 5-FU found in the skin following application of the 0.5% cream compared with the 5% cream. This data is applicable for actinic keratoses; however, it is not clear whether PPK would require higher concentrations of topical 5-FU. The patient in our case, as previously mentioned, experienced only minimal response with topical 5-FU 5% cream. To our knowledge, there has been no evidence that associates systemic 5-FU therapy for treatment of PPK.
