Hydroxyurea-induced leg ulcers: is macroerythrocytosis a pathogenic factor?

Hydroxyurea is a common cancer chemotherapy agent that inhibits ribonucleotide reductase, an enzyme essential to DNA synthesis. It is considered the drug of choice in the treatment of chronic myelogenous leukemia and essential thrombocythemia. The occurrence of leg ulcers have been described in 8.5% of patients receiving continuous treatment with hydroxyurea, but the cause of this complication is unknown. We report two additional patients and suggest that macroerythrocytosis, which occurs in almost all the patients taking hydroxyurea, may be a pathogenic factor. Macroerythrocytosis can be considered as an 'acquired' blood dyscrasia, and similar leg ulcers have long been known to occur with certain hereditary blood dyscrasias, such as sickle cell anemia, thalasemia, and spherocytosis.     

Ulzerationen unter Therapie mit Hydroxyharnstoff

Hydroxyurea is frequently used for therapy of myeloproliferative disorders. One cutaneous side-effect is painful, therapy-resistant ulcers which have bizarre configurations and occur at atypical sites for venous ulcers. Improvement or healing often first occurs when hydroxyurea is discontinued. We report on one patient with essential thrombocythemia and two with polycythemia vera, who developed such ulcers during hydroxyurea therapy. In one case, the ulcers developed shortly after hydroxyurea was started. In addition we give a short overview of the current literature.     

A Hydroxyurea-induced Leg Ulcer

Hydroxyurea is a cytostatic agent that has recently become the drug of choice in the treatment of various myeloproliferative diseases. The cutaneous side effects of hydroxyurea include xerosis, hyperpigmentation, nail discoloration, and scaling. Leg ulcers have only rarely been reported in association with hydroxyurea treatment. A 75-year-old woman presented with leg ulcers, nail discoloration, and xerosis. The leg ulcers were refractory to conventional treatment. She had been taking oral hydroxyurea since being diagnosed with essential thrombocytosis in 2002. Hence, we suspected hydroxyurea-induced leg ulcers and discontinued her hydroxyurea treatment; the ulcers gradually healed thereafter. We present a rare case of hydroxyurea-induced leg ulcers in Korea.     

Hydroxyurea-related leg ulcers in a patient with chronic myelogenous leukemia: a case report and review of the literature

The unusual appearance of extensive skin ulcerations has been reported in patients with chronic myelogenous leukemia (CML) undergoing continuous chemotherapy with hydroxyurea. It is thought that hydroxyurea, an antineoplastic agent with selective cytotoxicity for cells that divide most actively (such as those of the skin), causes these ulcerations through impairment of normal wound healing in areas of common trauma. The most common site of ulcers is the leg, where the ulcers are often extremely painful, with violaceous macules surrounding them, and are associated with extensive edema. On biopsy, histological vascular changes include leukocytoclastic vasculitis, perivascular lymphocytic infiltration, formation of thrombus, swelling of the endothelial cells, and thickening of the vascular walls. We report successful split-thickness skin grafting on hydroxyurea-related leg ulcers after preoperative discontinuation of hydroxyurea treatment in a patient with CML. The possible pathogenesis of hydroxyurea-related leg ulcers is discussed.     

Hydroxyurea-induced genital ulcers and erosions: Two case reports

Hydroxyurea is a chemotherapeutic agent used for myeloproliferative disorders and sickle cell anemia that is well known to cause painful mucocutaneous ulcers, typically involving the legs or mouth. However, genital ulcerations due to hydroxyurea therapy are a rare, and likely underrecognized, adverse effect with only a few cases reported in the literature to date. Ulcers of the lower legs caused by hydroxyurea are associated with a diagnostic delay, and this is likely exacerbated in cases of genital ulceration due to a lack of awareness. Herein we present two cases of painful genital ulceration in patients on hydroxyurea therapy. In the first Case, an 87 year-old male with polycythemia vera developed an ulcer on the scrotum, which was assessed initially through virtual visits during the COVID-19 pandemic, and was refractory to topical and oral antibiotic treatments. The second case was a 79 year-old male with essential thrombocythemia and a history of persistent leg ulcers who developed erosions of the glans penis. Both patients experienced complete resolution within weeks of discontinuing hydroxyurea therapy. In conclusion, genital ulcers and erosions induced by hydroxyrea may be underrecognized in clinical practice, but if identified, withdrawal of hydroxyurea leads to quick resolution of these lesions and the associated pain.     

羟基脲致下肢溃疡一例

报告1例由羟基脲不良反应引起的下肢溃疡。患者女,82岁,既往原发性血小板增多症15年,长期口服羟基脲治疗。5年前出现下肢溃疡。查体可见双踝周多发性浅溃疡伴网状色素减退,周围皮肤肿胀。诊断:下肢溃疡(羟基脲不良反应)。给予布洛芬缓释胶囊、盐酸莫西沙星片口服,生理盐水、硫酸阿米卡星注射液、地塞米松磷酸钠注射液混合后外用,溃疡创面基本愈合,伴白色萎缩。     

Aggressive, extensive, vasculitic leg ulceration associated with hydroxyurea therapy and a fatal outcome

The association of lower leg ulcer development and hydroxyurea therapy in patients with myeloproliferative disorders has been reported previously. In most of these cases the ulcers healed with cessation of the hydroxyurea together with meticulous attention to wound care. We report a patient who developed painful vasculitic ulcers secondary to hydroxyurea on both lower legs whilst on long-term hydroxyurea therapy for idiopathic thrombocytosis. The ulcers extended relentlessly despite stopping hydroxyurea, maximizing topical therapies and starting intensive systemic treatment. We discuss the association of hydroxyurea therapy with the development of painful ulceration.     

Cutaneous ulcerations on hands and heels secondary to long-term hydroxyurea treatment

Hydroxyurea is a chemotherapeutic agent used to treat myeloproliferative disorders and other non-neoplastic conditions. Cutaneous side-effects have been described in long-term therapy with hydroxyurea and include xerosis, hyperpigmentation, skin atrophy, erythema, alopecia, skin tumours and ulceration of the skin, particularly of the legs. We present a 71-year old patient with chronic myelocytic leukemia (CML) who developed extremely painful ulcers on the hands and heels as well as skin tumours while on long-term therapy with hydroxyurea. The ulcers were resistant to therapy but healed three months after discontinuation of hydroxyurea therapy.     

Secondary cutaneous effects of hydroxyurea: possible pathogenetic mechanisms

We report the case of a 73-year-old man who had been on hydroxyurea for essential thrombocythemia since 1988. After 12 years of treatment he developed a symmetrical dermatomyositis-like eruption together with a leg ulceration and five squamous cell carcinomas of the face. The possible pathogenetic mechanisms of these known side effects are discussed.     

Kutane Nebenwirkungen einer Hydroxyurea-Therapie bei Polycythaemia vera

A 68-year-old women with polycythemia vera was treated with hydroxyurea for 8 years and developed painful ulcers on her lower legs, multiple hypertrophic actinic keratoses and a squamous cell carcinoma. After discontinuing hydroxyurea therapy the leg ulcers resolved within 8 weeks. The hypertrophic actinic keratoses and squamous cell carcinoma were treated with cryotherapy and excision, respectively. Hydroxyurea induces a variety of cutaneous side effects such as painful leg ulcers and squamous cell carcinomas. Given the wide variety of adverse cutaneous side effects associated with long-term hydroxyurea therapy, the first step in management is to insure that physicians and patients are aware of the specific risks of this treatment. Patients under hydroxyurea therapy should be monitored closely by dermatologists to early detect and treat the cutaneous side effects.     

Leg ulcers and hydroxyurea: forty-one cases.

BACKGROUND: Hydroxyurea is an antitumor agent used to treat chronic myeloproliferative disorders. Leg ulcerations have been reported in patients undergoing long-term hydroxyurea therapy for myeloproliferative diseases. To better define this dermatological adverse effect of hydroxyurea therapy and to try to understand the pathophysiological process of this disease, we collected medical information for such patients in a multicenter retrospective study. OBSERVATIONS: Forty-one patients (mean age, 67 years) developed leg ulcerations while undergoing hydroxyurea therapy (mean therapy duration, 5 years). The sex ratio was 1, and there was no underlying vascular disease. Hematologic abnormalities were identified. Complete recovery from the ulcerations occurred quickly after withdrawal of treatment in 33 (80%) of the cases. CONCLUSIONS: This longest-reported series of patients confirms the role of hydroxyurea therapy in the onset of leg ulcerations. Healing or improvement requires cessation of treatment. Cutaneous atrophy and impaired wound healing may explain the relationship between hydroxyurea and leg ulcers. In addition, the megaloblastic erythrocytes resulting from the presence of hydroxyurea may circulate poorly through the capillary network. A prospective study in hematologic centers would be valuable.     

Cutaneous manifestations in patients with essential thrombocythemia

In a retrospective study of 268 patients with essential thrombocythemia, related cutaneous manifestations were found in 58 (22%). In 27 cases (10%) the related skin lesions were present at the time of the primary diagnosis of essential thrombocythemia. Hematomas, ecchymoses, petechiae, or purpura occurred in 24 (41%) of the 58 patients. Fifteen patients (26%) had erythromelalgia, in 11 of whom it was the initial complaint. Livedo reticularis, recurrent superficial thrombophlebitis, ischemic complications with gangrene, leg ulcers, or ulcers on the toes were other manifestations. Urticaria occurred in two patients, and Raynaud's phenomenon and necrotizing vasculitis were each observed in one patient. Platelet function may be abnormal, and this was found in 13 of 19 patients studied, 9 of whom had spontaneous platelet aggregation. Knowledge of the cutaneous manifestations in essential thrombocythemia may lead to its earlier detection. Prompt diagnosis of essential thrombocythemia is important because treatment may prevent severe hemorrhagic or thrombotic events.     

Cutaneous manifestations of hydroxyurea therapy in childhood: case report and review

Hydroxyurea is commonly used in the treatment of various myeloproliferative disorders. In conventional pediatric clinical practice, its use is limited to benign hematologic conditions such as sickle cell disease and thalassemia. Long-term hydroxyurea use is associated with various adverse mucocutaneous effects including hyperpigmentation, alopecia, leg ulcers, and lichenoid eruptions. We report a 10-year-old boy with chronic myelogenous leukemia who presented with hyperpigmentation of the skin and nails 3 months after the start of hydroxyurea therapy. Melanonychia of all 20 nails with involvement of all three mucocutaneous areas (skin, nails, and mucosa) at presentation was a unique feature in our patient. With the recently increasing pediatric use of hydroxyurea in a variety of disorders, its benign and not so uncommon cutaneous adverse effects are emphasized here.     

Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease

BACKGROUND: Treatment with hydroxyurea may alleviate the symptoms of sickle cell disease (SCD). Because treatment with hydroxyurea may be responsible for several cutaneous side effects and is often lifelong in patients with SCD, we conducted this study to evaluate the risk of cutaneous adverse reactions in SCD patients treated with hydroxyurea. OBSERVATIONS: Seventeen adult patients with SCD treated with hydroxyurea at one institution were examined by a dermatologist. Hydroxyurea was given for a mean of 3.04 years (range, 0.42-6.5 years). None of the patients had skin cancer, but 5 (29%) had disabling hydroxyurea-induced leg ulcers. Four of these 5 patients had a previous history of SCD ulcer, compared with none of the 12 patients without hydroxyurea-induced leg ulcers (P<.05). The mean age of patients with induced ulcers was 35.8 years and for those without ulcers was 23.5 years (P<.01). CONCLUSIONS: Our rate of hydroxyurea-induced leg ulcers (29%) is higher than that reported for patients with myeloproliferative syndromes (9%). In addition, use of hydroxyurea has induced ulcers mainly in patients with previous SCD ulcers, suggesting that hydroxyurea could act in conjunction with other vascular abnormalities. Careful attention should be required when giving hydroxyurea to patients with SCD with previous ulcers as well as in older patients with SCD.     

Nicorandil-induced leg ulceration without mucosal involvement

We report a case of leg ulceration occurring in a patient without mucosal ulcers, in whom nicorandil appeared to be the main aetiological factor. Having failed to heal on compression therapy, the ulcer rapidly improved and healed after the discontinuation of nicorandil. Most cases of nicorandil-induced ulcers reported in the literature develop on mucosal surfaces, including oral, vulval, perianal and peristomal ulcers. There are rare reports of cutaneous ulceration attributable to nicorandil, occurring concurrently with mucosal ulcers. To our knowledge, this is the first case of nicorandil-induced leg ulceration affecting the skin without mucosal involvement.     

Leg ulceration with associated thrombocytosis: healing of ulceration associated with treatment of the raised platelet count

Thrombocytosis is the cause of various complications in myeloproliferative disorders. We present the case of a 54-year-old woman with chronic myelogenous leukaemia who developed large ulcers on both lower legs that were refractory to standard treatment. As concomitant thrombocytosis persisted despite treatment with hydroxyurea, the new megakaryocyte inhibitor anagrelide (Agrelin^R) was administered and led to normalization of the platelet count within 11 days. The leg ulcers started to heal after 2 weeks and disappeared over a period of 5 months. Our findings argue for a pathogenic role of platelets in the development of leg ulcers in patients with thrombocytosis due to a myeloproliferative disorder.     

Leg ulcers in patients with myeloproliferative disorders: disease- or treatment-related?

Leg ulcers are a relatively frequent problem in patients with myeloproliferative disorders under treatment with hydroxyurea (HU). The pathogenesis is currently unknown and may be multifactorial. Concomitant arterial or venous disease may play a contributing role in the development of these wounds. Vasculitis, cryoglobulinemia and pyoderma gangrenosum should be considered if typical clinical signs are present. We report on 3 patients with myeloproliferative disorders who developed HU-induced leg ulcers and review the literature. HU-induced leg ulcers share clinical features which can help to differentiate them from leg ulcers of other etiologies: occurrence under long-term treatment with HU at a dose of at least 1 g/day, localization in the malleolar region and spontaneous healing when HU is discontinued. We conclude that differentiation between disease-related and treatment-induced leg ulcers can be difficult and may not always be possible. In HU-induced leg ulcers, cessation of the drug typically leads to wound healing. Copyright (R) 2000 S. Karger AG, Basel     

Leg ulcers in essential thrombocythemia

By means of two case reports, essential thrombocythemia is discussed as an uncommon cause of leg ulcers, and the other possible cutaneous manifestations of this disease are briefly outlined.     

Hydroxyurea-induced leg ulcers treated with a protease-modulating matrix

BACKGROUND: The development of painful leg ulcers in the ankle area is a rare and only partially described complication in patients receiving high-dose, long-term hydroxyurea treatment for myeloproliferative diseases. Several reports have described treatments for chronic wound management with this type of lesion. OBSERVATIONS: We describe 2 patients who were diagnosed as having hydroxyurea-induced leg ulcers that were successfully treated with a freeze-dried sponge containing oxidized regenerated cellulose and bovine purified collagen. This dressing is able to modulate the activity of proteases such as plasmin, neutrophil-derived elastase, and matrix metalloproteinase by physically entrapping them and thus inhibiting their activity. CONCLUSION: This case demonstrates that topical application of a matrix metalloproteinase modulator can be a successful and safe treatment option for patients with hydroxyurea-induced recalcitrant leg ulcers.     

Differential proteinase expression by Pseudomonas aeruginosa derived from chronic leg ulcers

Pseudomonas aeruginosa colonizes 20-30% of all venous leg ulcers. Hypothetically, P. aeraginosa could release proteases and cytotoxic substances in the environment of chronic ulcers, thus negatively affecting the wound-healing activity in this patient group. Here we show that P. aeruginosa isolates from leg ulcers exhibit a highly variable expression of the proteinases elastase and alkaline proteinase. We propose that bacterial phenotype should be taken into account in future studies on the clinical outcome of leg ulcers colonized by P. aeruginosa.