Hydroxyurea ulcers of unusual location: a case report and review of literature

Hydroxyurea is a cytotoxic drug that has been utilized for several decades to treat various hematologic conditions, particularly polycythemia vera. It presents with diverse side effects, including dermatological manifestations, ranging from skin xerosis to hyperpigmentation, dermatomyositis-like lesions, and shows even a potential association with premalignant processes (actinic keratosis) and non-melanoma cancers (squamous, basal cell, Merkel, and oral tumors).

We present the case of a 74-year-old man diagnosed with polycythemia vera 6 years ago after two routine blood tests revealed thrombocytosis and polycythemia, separated by a year. The patient did not report splenomegaly or other symptoms. The rest of the blood test results were within normal limits. Peripheral blood smear showed no abnormalities. Janus Kinase-2 (JAK-2) mutation (V617F) was present. A narrow biopsy confirmed increased cellularity, especially in megakaryocytes, consistent with polycythemia vera. Finally, karyotype analyses were normal.

Subsequently, the patient was started on treatment with hydroxyurea 500 mg every 12 h and acetylsalicylic acid 100 mg every 24 h. It led to a rapid improvement and becoming asymptomatic with better routine controls. However, 3 years after initiating treatment, the patient developed edema and tumefaction in both hands, along with numerous painful ulcers on the palm and dorsal aspects of the hand.

Initially, the condition was attributed to chilblains due to the cold, and avoidance of exposure was recommended. Since there was no improvement, the patient was referred to a rheumatologist, who considered it as part of the underlying disease and provided symptomatic treatment. Ultimately, the patient was referred to dermatology.

On examination, several well-defined ulcers (seven or eight on the dorsal side and two or three on the palmar side) were observed. The ulcers were minimally painful to touch, with a crusty surface. In addition, the patient presented small erythematous, violaceous papules on the back of the hands and pigmentation at the nail level (Figure 1).

Figure 1:

Suspecting ulcers due to prolonged treatment with hydroxyurea, a punch biopsy was performed and discontinuation of the drug was advised. In the biopsy, an epidermal hyperplasia with reparative changes, fibrosis, and reparative changes was observed, consistent with a nonspecific ulcer. The histology did not show any evidence of perniosis or malignancy. The patient was started on second-line treatment with ruxolitinib 10 mg every 12 h, which resulted in rapid improvement, leaving a remnant after 1 month of treatment and complete disappearance of the lesions after 2 months of treatment (Figure 2).

Figure 2:

Hydroxyurea (hydroxycarbamine) is a pharmacological agent that has been used since the mid-20th century to treat various hematologic conditions, including polycythemia vera, chronic myeloid leukemia, and sickle cell anemia^[1].

Among its potential adverse effects (hematologic, infections, gastrointestinal, hepatic, renal, neurologic, pulmonary, etc.), cutaneous side effects are reported. Half a century ago, Kennedy et al. reported several of these effects in a series of 20 patients treated with hydroxyurea for chronic myeloid leukemia, including partial alopecia, increased pigmentation, scaling, nail changes, facial and hand erythema^[2].

Furthermore, Daoud proposed the term “hydroxyurea dermopathy” exclusively to patients with associated hematologic malignancy, characterized by an erythematous, crusty rash with lichenoid papules resembling Gottron's sign in dermatomyositis, primarily on the dorsum of the fingers^[3].

It has also been associated with premalignant processes (actinic keratosis) and non-melanoma cancers (squamous, basal cell, Merkel, and oral tumors)^[4].

In a 2012 review, Latagliatata et al. found that mucocutaneous toxicity during HU treatment is more common than expected and may manifest with various clinical features. Furthermore, it often necessitates a permanent discontinuation of the drug, and only partial resolution is reported to occur in approximately 25% of patients^[5].

Among the cutaneous side effects are ulcers, which were first described by Stahl and Silber in 1985^[6]. The prevalence of hydroxyurea-induced ulcers ranges between 3.5% and 5% in large cohort studies^[7,8]. In a recent review by Quattrone et al., ulcers were found to be more frequent in women, with a mean age of 62.7 years, and predominantly occurred in hematologic patients (polycythemia vera and chronic myeloid leukemia)^[9].

These ulcers typically exhibit a well-defined border with a surrounding whitish or erythematous halo and a dry superficial crust. They are often clinically painful^[8,10].

Although most ulcers due to hydroxyurea are located in the lower limbs, some cases have been described in the upper body, including the hands, as observed in our clinical case^[11,12].

Histopathologic findings in hydroxyurea-induced ulcers vary and may include leukocytoclastic vasculitis, lymphocytic infiltration, thrombi formation, vessel wall thickening, dermal fibrosis, and hyperkeratosis^[9].

However, the diagnosis is primarily clinical and is corroborated by discontinuing the medication, leading to improvement rates of over 90%. Other treatment options include local debridement^[13], the use of healing materials like dextranomer^[6], vasodilators such as prostaglandins E1 and I2^[14], topical antibiotic treatments^[15], and enzymatic debridement materials like collagenase^[16].

Through this clinical case, we aim to highlight a relatively common adverse effect, albeit with a very atypical presentation, associated with a drug widely used in the field of hematology: hydroxyurea. Knowledge of these effects is crucial for hematologists to ensure adequate patient care.