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Hydroxyurea-induced cutaneous ulcer

Authors: Dr Akshay Flora, Resident Medical Officer, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Dr Ann-Marie Crozier, Medical Director, Hospital in the Home, Sydney Local Health District, Sydney, NSW, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof. Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. September 2020.


Hydroxyurea-induced cutaneous ulcer — codes and concepts
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What is a hydroxyurea-induced cutaneous ulcer?

Hydroxyurea-induced cutaneous ulcer is a painful ulcer on the lower leg of a patient on high-dose long-term treatment with hydroxyurea. Ulcers are the most common adverse cutaneous effect, reported in 9% of patients undergoing hydroxyurea treatment for chronic myeloproliferative disorders.

Hydroxyurea-induced cutaneous ulcer

Who gets a hydroxyurea-induced cutaneous ulcer?

Hydroxyurea-induced cutaneous ulcers develop in middle-aged or elderly patients (median age 67 years) with chronic myeloproliferative disorders actively being treated and maintained on hydroxyurea. A female predominance (61%) has been reported. The most commonly associated myeloproliferative disease reported has been essential thrombocythaemia. Arterial and venous insufficiency may be present, but is not a requirement.

What causes a hydroxyurea-induced cutaneous ulcer?

Hydroxyurea is a cytostatic antimetabolite agent that inhibits ribonucleotide reductase in the S (synthesis) phase of the cell cycle.

A cumulative toxic effect is believed to be involved in the development of the ulcer. Ulcer formation during hydroxyurea treatment is likely to be multifactorial in origin, including due to cytotoxic effects on epidermal basal keratinocytes and vascular endothelial cells, inhibition of collagen formation, and disturbance of the microvascular circulation.

It is not known whether hydroxyurea alone is responsible for the ulcer, or whether the underlying myeloproliferative disorder also contributes to the ulcer formation via effects on arterial and venous circulation leading to tissue ischaemia and delayed wound healing.

Trauma may play an initiating role given the common localisation around the malleoli and pretibial sites.

What are the clinical features of hydroxyurea-induced cutaneous ulcer?

A patient with a hydroxyurea-induced cutaneous ulcer usually has a history of being on hydroxyurea for a few years before the ulcer develops. The median time from starting hydroxyurea treatment to ulcer diagnosis is 60 months. The typical hydroxyurea dose is 1g daily.

  • The ulcer is commonly well-demarcated, round, and painful.
  • The ulcer is usually surrounded by erythema, fibrosis, and cutaneous atrophy.
  • Ulcers may be solitary or multiple, unilateral or bilateral.
  • Atrophie blanche may be present.
  • Ulcers are usually located on the lower limb around the medial or lateral malleolus. Other reported areas include the calf, dorsum of the foot, and toe.

Other dermatological adverse effects of hydroxyurea may be noted.

What are the complications of hydroxyurea-induced cutaneous ulcers?

Secondary bacterial infection of the ulcer is the most common complication. This should be suspected if cellulitis occurs around the ulcer. However, chronic leg ulcers are often colonised by bacteria, and antibiotics are not indicated for localised slough or purulence, which is a sign of bacterial biofilm.

Healing can be delayed or incomplete for hydroxyurea-induced skin ulcers even after cessation of the hydroxyurea.

Analgesia required for the ulcer pain can have adverse effects in this predominantly elderly population.

How is hydroxyurea-induced cutaneous ulcer diagnosed?

The diagnosis of hydroxyurea-induced cutaneous ulcer is clinical, based on history and examination. The patient should be assessed for vascular disease (venous, arterial, or small vessel disease), which can be co-existent.

Histopathological features of hydroxyurea-induced cutaneous ulcer are non-specific and include epidermal atrophy and dermal sclerosis without inflammation.

Diagnosis is often missed or delayed due to the non-specific features.

What is the differential diagnosis for hydroxyurea-induced cutaneous ulcer?

The differential diagnosis of hydroxyurea-induced ulcer includes all forms of chronic leg ulcer. Most leg ulcers involve a component of vascular disease contributing to the development or poor healing of the ulcer.

Stasis ulcer

A venous stasis ulcer is not usually painful. There are associated features of venous stasis including swelling, haemosiderin staining, hyperkeratosis, and lipodermatosclerosis.

Arterial ulcer

An arterial ulcer tends to be painful at night with elevation of the leg. Distal pulses may be reduced or absent.

Diabetic foot ulcer

A diabetic foot ulcer tends to be located over a pressure area such as the heel or tip of a toe in a diabetic patient with peripheral neuropathy and microvascular disease.

What is the treatment for hydroxyurea-induced cutaneous ulcer?

Cessation of hydroxyurea therapy is essential for ulcer healing to occur. Together with wound care, this leads to ulcer resolution in a majority of patients. It is typical of hydroxyurea-induced skin ulcers that healing is not seen with wound care alone.

What is the outcome for hydroxyurea-induced cutaneous ulcer?

Resolution of the ulcer usually occurs within three months of ceasing hydroxyurea, although complete healing may take up to 24 months.

A small proportion of patients experience only partial ulcer healing and improvement in symptoms despite ceasing hydroxyurea.

Patients restarted on hydroxyurea therapy after complete ulcer resolution may quickly redevelop ulcers. These recurring ulcers do not heal until hydroxyurea therapy is ceased again.

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Bibliography

  • Dissemond J, Körber A. Hydroxyurea-induced ulcers on the leg. CMAJ. 2009;180(11):1132. doi:10.1503/cmaj.081042. PubMed Central
  • Malato A, Rossi E, Palumbo GA, Guglielmelli P, Pugliese N. Drug-related cutaneous adverse events in Philadelphia chromosome-negative myeloproliferative neoplasms: a literature review. Int J Mol Sci. 2020;21(11):3900. doi:10.3390/ijms21113900. PubMed Central
  • Romanelli M, Dini V, Romanelli P. Hydroxyurea-induced leg ulcers treated with a protease-modulating matrix. Arch Dermatol. 2007;143(10):1310-13. doi:10.1001/archderm.143.10.1310. PubMed
  • Sirieix ME, Debure C, Baudot N, et al. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol. 1999;135(7):818-20. doi:10.1001/archderm.135.7.818. PubMed

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