Hydroxyurea is a cytostatic agent that serves as the drug of choice in the treatment of myeloproliferative disease. Because it acts during cellular replication (S phase) by blocking ribonucleotide reductase, the conversion of ribonucleotide to deoxynucleotide is inhibited
1,2. Adverse cutaneous effects associated with hydroxyurea have been occasionally described in the literature. Xerosis, diffuse hyperpigmentation, nail discoloration, alopecia, scaling, skin atrophy, skin tumors, lichen planus-like eruptions, and dermatomyositis-like eruptions represent the majority of adverse effects
1,3. In addition, leg ulcers have been noted in association with long-term hydroxyurea administration. Nine percent of patients taking hydroxyurea medication develop this complication
4.
There is still controversy concerning the origin of the cutaneous ulcers-whether they are disease-related or treatment-related. Myeloproliferative disorders can impair cutaneous microcirculation. One theory says that the hyperviscosity resulting from blood dyscrasias may itself be a further risk factor for leg ulceration
5,6. However, ulcerative skin lesions appear after the myeloproliferative disorder is well controlled with hydroxyurea. Furthermore, the lesions disappear after hydroxyurea is discontinued. Paradoxically, the ulcers have been shown to improve when the blood dyscrasia recurs
1. So, in our opinion, hyperviscosity can be ruled out as a major contributor to ulcer formation.
Hydroxyurea treatment induces ulcerative skin lesion formation secondary to direct cytologic damage. Because hydroxyurea kills proliferating cells during the synthesis phase of the cell cycle, keratinocyte and collagen fiber synthesis could be impaired
7. This hydroxyurea-induced compromise of skin formation could cause ulceration if followed by minor trauma, like rubbing in the present case
8. A recent study showed that hydroxyurea can lead to increases in red blood cell volume and a reduction in red blood cell susceptibility to deformation. Therefore, it may cause impaired microcirculation and cutaneous anoxia, which then lead to ulcerative skin lesions and severe pain
9,10. Bader et al
11 proposed some criteria to help in diagnosis and differentiation. First, the duration of treatment should be at least 1 year, and the dose of hydroxyurea should be at least 1 g/day. Most ulcers are found on the malleoli (77%) or in neighboring regions (e.g. the Achilles tendon). Healing is slow (1~9 months) but spontaneous in 85% of patients after discontinuation of hydroxyurea therapy, and when hydroxyurea therapy is resumed, the ulcers do not resolve spontaneously and are difficult to treat. Ulcers are small, and size seems to be correlated with the hydroxyurea dose.
The treatment of choice for hydroxyurea-induced leg ulcers is discontinuation of the drug. Other reported therapies including topical granulocyte macrophage colonystimulating factor (GM-CSF), recombinant human erythropoietin (r-HuEPO), or bilayered bioengineered skin substitute
12. In one report, a patient was successfully treated with prostaglandin E
1 and pentoxifylline while hydroxyurea was continued
13. In the present case, the cutaneous ulcers and xerosis completely healed within 2 months without recurrence, and nail hyperpigmentation gradually improved after hydroxyurea was discontinued.
The present case shows that long-term administration of hydroxyurea can result in ulcerative skin lesions of the lower legs, like other cases that have been reported in Korea
14,15. Because hydroxyurea has long been the treatment of choice for myeloproliferative disorders, the possibility that cutaneous side effects will occur in patients treated with hydroxyurea always exists. Leg ulcers represent 9% of these side effects. Therefore, physicians should not overlook this adverse effect and must perform careful history-taking. In addition, because discontinuation of hydroxyurea can cause a hematologic crisis, a hematooncologist should be consulted, and periodic laboratory examinations should be performed.
and Ho-Suk Sung, M.D.
