Dermatologic side effects of hydroxyurea are fairly common and include hyperpigmentation, scaling, erythema and desquamation of the face and hands, and partial alopecia [7]. A less well-described and less well-characterized complication is leg ulcers.

We present clinical observations documenting a strong association between hydroxyurea therapy and cutaneous ulceration of the legs. Retrospective review of the medical records of patients registered at the Mayo Clinic, Rochester, Minnesota, identified 14 patients who had leg ulcers related to hydroxyurea therapy.

Case Reports

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Patient 1

A 69-year-old man with a history of polycythemia vera and an associated transient ischemic attack received 1.5 g of hydroxyurea daily. After 3 years of continuous therapy, he developed a painful, indolent ulcer of the right posterior calf. Various topical wound dressings, enzymatic debridement, and oral antibiotics failed to heal the ulcer. When the hydroxyurea dosage was increased to 2 to 2.5 g/d, the ulcer increased in size to 3 x 3 cm. Hydroxyurea treatment was discontinued when its association with the ulcer was identified. The ulcer healed over the course of 3.5 months, and the patient had no further difficulties until 3 years later, when hydroxyurea treatment was restarted by a physician who was not convinced of the original diagnosis of hydroxyurea-induced cutaneous ulceration. Four months after therapy was reinitiated, the patient developed multiple painful ulcers on both ankles (Figure 1). Treatment was again discontinued, and the cutaneous ulcers completely resolved within 6 months.

View larger version (75K): [in this window] [in a new window]   Figure 1. Hydroxyurea-induced ulcer. Top. Shallow, polyangular, punchedout ulceration on the left lateral malleolus of a patient receiving hydroxyurea treatment. Note the porcelain-colored scar from a healed ulcer. Bottom. Photoµgraph of a skin biopsy specimen from the border of a typical hydroxyurea-induced ulcer. Note the papillary dermal edema, vessel hyalinization, and perivascular lymphocytic inflammation. (Hematoxylin and eosin; original magnification, x40.).

Patient 2

A 41-year-old woman with an undifferentiated myeloproliferative disorder and a history of portal venous thrombosis had received hydroxyurea therapy for 9 years without complications, but she developed an extremely painful ulcer over the left lateral malleolus while she was receiving 1.5 g of hydroxyurea daily. Treatment with pentoxifylline, aspirin, warfarin, and leg elevation was unsuccessful. Hydroxyurea therapy was subsequently discontinued, and anagrelide therapy was initiated. The ulcer resolved within 2 months. Several months later, hydroxyurea therapy was restarted at a dosage of 1.5 g/d because of gastrointestinal intolerance of anagrelide. Cutaneous ulcers developed within 4 months and persisted for the ensuing 4 years while the patient was receiving hydroxyurea therapy.

Results

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Fourteen patients with hydroxyurea-induced leg ulcerations were identified through review of the medical records of 115 patients with various myeloproliferative diseases and leg ulcers who had been treated with hydroxyurea during the previous 16 years (1980 to 1995). This period extended back beyond the first report of hydroxyurea-associated leg ulcers, which was published in 1986 [8]. It would have been preferable to identify all patients treated with hydroxyurea at our institution, but this was not possible because our clinical database does not index patients by medication use. Detailed medical histories of 8 women and 6 men, including the 2 patients described above, were reviewed. The Table 1 summarizes the clinical and morphologic features and clinical course of hydroxyurea-related skin ulcers in these 14 patients. The average age of patients at diagnosis was 65 years (range, 41 to 74 years). Hydroxyurea was administered to treat polycythemia vera (5 patients), essential thrombocythemia (2 patients), agnogenic myelogenous metaplasia (2 patients), chronic granulocytic leukemia (4 patients), and an incompletely characterized myeloproliferative disorder (1 patient). One patient had diabetes mellitus, and 6 had hypertension. Noninvasive arterial and venous vascular studies were done in 7 patients, and no specific vascular causes were identified that might explain the persistent ulcers.

Cutaneous ulcers were typically located near the malleoli but were occasionally found over the tibia, on the dorsal aspect of the feet, and on the calves. Of the 18 malleolar ulcers in our 14 patients, 10 (55.6%) were over the medial malleolus and 8 (44.4%) were over the lateral malleolus. A representative cutaneous ulceration is shown in the top panel of the (Figure 1). The ulcers were usually extremely painful. Multiple ulcers were seen in 9 patients (64%). When treatment was discontinued, the hydroxyurea dosage ranged from 1 to 2.5 g/d. The average cumulative dose of hydroxyurea before ulcers developed was 3.2 kg (range, 1.4 to 5.5 kg). The duration of hydroxyurea treatment ranged from 2 to 15 years (mean, 6.1 years).

The cutaneous ulcers completely resolved in 12 patients after cessation of hydroxyurea treatment. Two patients had skin grafting to expedite healing. Patient 4 had an indolent ulcer for 1 year, after which time the hydroxyurea dosage was decreased from 1.5 to 0.5 g/d. Ulcer healing ensued within 5 months. Patient 8 also had improvement after the hydroxyurea dosage was decreased from 2 to 1 g/d. However, this dosage was subsequently increased to 2.5 g/d. The original ulcer markedly worsened over the ensuing 4 months, and new ulcers appeared over both malleoli. Hydroxyurea treatment was discontinued. A fatal myocardial infarction that occurred 2 weeks later prevented further assessment.

Discussion

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Hydroxyurea is typically well tolerated and has a relatively low toxicity profile [9]. However, substantial cutaneous side effects have been seen; these include diffuse hyperpigmentation, brown discoloration of nails, acral erythema, photosensitization, fixed drug eruption, alopecia, oral ulceration, and stomatitis [9]. A poikilodermatous dermatomyositis-like skin eruption with atrophy, erythema, and scaling has also been reported [7]. Another ill-defined dermatologic side effect is cutaneous ulceration during hydroxyurea administration. Montefusco and colleagues [8] described 17 patients who had hydroxyurea-related leg ulcers and found complete resolution (14 patients) or marked improvement (3 patients) after hydroxyurea therapy was discontinued. Another study [10] described 4 patients with hydroxyurea-induced skin ulcers that eventually resolved with diligent wound care.

We describe 14 patients in whom cutaneous leg ulcers developed while the patients were receiving long-term treatment with hydroxyurea. Our findings indicate that even with meticulous wound care, resolution of the ulcers usually requires discontinuation of hydroxyurea treatment. Extensive attempts to initiate wound healing before discontinuation of treatment included the use of topical and systemic antibiotic therapy, pentoxifylline, hyperbaric oxygen, warfarin, prednisone, Unna vascular boots, and topical wound dressings. None offered significant clinical benefit.

Several mechanisms of action have been described for hydroxyurea, including inactivation of the enzyme ribonucleotide reductase with subsequent inhibition of cellular DNA synthesis and cell death in S phase [11]. In the skin, basal keratinocytes are the most actively replicating cells of the epidermis, and damage to keratinocytes by cytotoxic chemotherapeutic agents is one of the most common pathologic alterations seen in chemotherapy-induced reactions [12]. With sustained damage to basal keratinocytes, epidermal atrophy may become prominent [7]. Hydroxyurea has other effects on mammalian cells, including damage due to free-radical nitroxide intermediates and inhibition of DNA repair [11].

Hydroxyurea-induced cutaneous ulcers often occur over the malleoli. One explanation for this localization may be mechanical injury and trauma. In addition, the latency to onset, indolent behavior, and eventual healing after therapy is discontinued all suggest that the mechanism for cutaneous toxicity involves chronic and progressive but reversible cytologic damage. Cellular injury accumulates to the extent that repair mechanisms can no longer regenerate viable, normal-functioning epidermis, stromal cells, or endothelium and tissue damage and ulcers therefore develop [11].

Histologic examination shows nondiagnostic changes. A typical histologic photoµgraph of a hydroxyurea-induced ulcer is shown in the bottom panel of the (Figure 1). At the ulcer border, pseudoepitheliomatous hyperplasia and epidermal spongiosis are seen. In the dermis, endothelial cell swelling, edema, and thickening of blood vessel walls are prominent. Perivascular lymphocytic inflammation without vasculitis is common. In chronic lesions, focal hyalinization of blood vessel walls and intraluminal deposition of fibrinoid material directly beneath the ulceration are seen. These findings resemble the cutaneous occlusive vasculopathy seen in livedoid vasculitis. At later stages, dermal fibrosis develops.

No consistent correlation between the dose or duration of hydroxyurea therapy and the occurrence of ulcers has been reported previously [8]. On the other hand, although we observed the development of ulcers over a range of hydroxyurea dosages, the extent and size of the ulcers did correlate with the amount of hydroxyurea administered in two patients. One patient had resolution of the ulcers when the dosage was decreased to 500 mg/d. In addition, long-term hydroxyurea therapy lasting at least 2 to 3 years was generally required before the ulcers occurred.

The clinical experience summarized here confirms and further clarifies the association between hydroxyurea therapy and the development of chronic leg ulcers. Our observations also show that patients who had previously had hydroxyurea-induced leg ulcers again developed painful, indolent ulcers when hydroxyurea treatment was resumed. This drug challenge confirms that hydroxyurea was the cause of the cutaneous ulcerations. If ulceration of the legs develops while a patient is receiving hydroxyurea, therapy with the drug often needs to be discontinued; hydroxyurea should be avoided if an alternate agent can be identified.

Drs. Daoud and Pittelkow: Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Petitt: Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.