Painful Leg Ulcers: A Misdiagnosed Case Report With Literature Review

Leg ulcers are a common symptom in patients with vascular disease. Ninety-five percent of chronic leg ulcers are due to ischemia, stasis, neurotrophic conditions, and other conditions, such as vasculitis, hypertension, and syphilis.¹ The following case report presents an uncommon cause for a leg ulcer, which was initially suspected to be a vascular disease.

Case Report

A 56-year-old man was admitted to the authors’ department with painful leg ulcers of 3 months duration. Upon examination, 12 ulcerations ranging from 10 mm² x 10 mm² to 50 mm² x 50 mm² located on the left malleolus, tibia, and the dorsal aspect of the feet and calves were found (Figure 1). Exuding ulcers were shallow with diffuse edges. Generalized edema with brown pigmented, scaly surrounding skin was noted, but there was no bone, tendon, ligament or muscle involvement. Brown discoloration of fingernails and diffuse hyperpigmentation over the entire body was present (Figure 2).
Medical history indicated that the patient had been taking a medication for 3 years to treat chronic granulocytic leukemia, which was well controlled. All 12 ulcers were initially treated with therapies including wound dressings, antibiotics, and surgical debridement, but there was no healing in any of the other ulcers. All laboratory data, including white blood cell count, platelet count, biochemical values, and blood glucose level were normal. Coombs and HIV tests were negative. A histological examination of the malleolar ulcer edge (taken from the largest ulcer [50 mm² x 50 mm²]) found papillary dermal edema, vessel hyalinization, and perivascular lymphocytic inflammation with no vasculitis. No malignancy was seen (Figure 3). Arterial and venous angiography was performed and arterial sclerosis/stenosis, varicose veins, and deep venous thrombosis was not found. Lymphadenography was normal.
All 12 leg ulcers were fully cured 2 weeks after discontinuation of hydroxyurea and no ulceration was present at 1-year follow up.

Discussion

The most common leg ulcers are ischemic, stasis, and neurotrophic. More than 95% of chronic leg ulcers fit into 1 of 3 recognized categories: 1) some rare reasons, such as vasculitis, hypertension, and syphilis may produce leg ulcers; 2) leg ulcerations vary in clinical features. Ischemic ulcers are usually caused by arterial sclerosis or stenosis. The ulcers are quite painful, and nocturnal ischemic rest pain in the distal forefoot is typical and was relieved with pain medication; 3) stasis ulcers caused by venous hypertension are located within the gaiter area, most commonly near the medial malleolus. It is usually larger than the other type of ulcers and is irregular in outline yet shallower with a moist granulating base and is always surrounded by a zone of inflammation and “stasis dermatitis,” described as induration, dermatitis, and hyperpigmentation.⁴ A middle degree of pain can be relieved by elevating the leg. Neurotrophic ulcers are completely painless. They are deep and indolent and are often surrounded by chronic inflammatory reaction and callus.⁵ Typically, these ulcers are located over pressure points or calluses. The patient usually has long-term diabetes with neuropathy characterized by patchy hypoesthesia, and diminished positional sense and vibratory perception.¹ Against the interlacements of these clinical features, the patient in the present case presented with extreme painful ulcerations, but did not report the typical ischemic rest pain characteristic of ischemic ulcers. The patient was not elevating or lowering the leg for pain relief. The location and depth of his ulcers was not characteristic of a stasis ulcer or a neurotrophic ulcer. In addition, most patients with common leg ulcers described above often heal with therapy, such as intermittent elevation, topical wound dressings, oral antibiotics, and surgical debridement after underlying diseases have been controlled. This case was received 3 months after the start of those treatments, all of which were not effective. In addition, all of the evidence from image examination did not support the diagnosis of vascular diseases, and other laboratory tests did not reveal that the patient had any specific infectious diseases, such as AIDS or syphilis. Blood glucose levels ruled out diabetes mellitus as a cause of the ulcers. This information suggested that a misdiagnosis was made, and prompted the authors to consider other possible reasons.
A retrospective inquiry and re-review of the patient’s medical history was performed. The patient informed the authors that for 3 years he had been taking hydroxyurea for chronic granulocytic leukemia. This was of great interest in correctly diagnosing the problem.
It has been recognized that hydroxyurea is an effective treatment for cancer since the 1960s.⁶ The most common indications for hydroxyurea therapy are chronic myeloproliferative disorders and acute myelogenous leukemia. Hydroxyurea is typically well tolerated and has a relatively low toxicity profile.⁷ However, dermatitis associated with long-term hydroxyurea therapy, which is characterized by skin atrophy, hyperpigmentation, alopecia, scaling, and nail changes has been reported.⁸ Leg ulceration following hydroxyurea therapy is less common. The first report of hydroxyurea-related skin ulcers was in 1985.⁹ In 1986, Montefusco and colleagues¹⁰ described 17 patients with hydroxyurea-related leg ulcers and found complete resolution after hydroxyurea therapy was discontinued. Best et al¹¹ identified 14 cases of extremely painful hydroxyurea-induced leg ulcers. The most common ulcer site was the malleolus, tibial, and dorsal aspect of the feet and calves. In most cases the patients had multiple ulcers. More importantly, all ulcers healed after discontinuation of hydroxyurea treatment and ulcers developed after treatment was restarted.^10,11 This observation strongly documented the relationship between hydroxyurea therapy and cutaneous leg ulceration.
Histologically, the typical changes of hydroxyurea-induced ulcers are pseudoepitheliomatous hyperplasia and epidermal spongiosis at the ulcer border. Endothelial cell swelling, edema, and thickening of blood vessel walls are prominent in the dermis. Perivascular lymphocytic inflammation without vasculitis is commonly seen.¹¹ Therefore, histological examination shows no diagnostic value, as shown in the present case.
The extent and size of the ulcers does not correlate with the dosage amount of hydroxyurea administered.¹¹ However, no consistent correlation between the dose or duration of hydroxyurea therapy and the occurrence of ulcers has been reported,¹⁰ as described in the present case, where the patient had been on medication with hydroxyurea for 3 years, but presented with ulcers of only 3-months duration.
The diagnosis of a hydroxyurea-induced leg ulcer is difficult because most patients do not develop leg ulcers until after long-term use of hydroxyurea. The ulcer is associated with severe pain and is resistant to almost all traditional wound care treatment.¹¹ The clinical features of hydroxyurea-induced ulcer include extreme pain, brown discoloration of nails, and diffuse hyperpigmentation. These indicators may help distinguish these ulcers from other types of leg ulceration. The only effective treatment is discontinuation of hydroxyurea. Ulcers will reoccur if hydroxyurea is re-administered.¹¹ These characteristics are identical with those found in the present case, and the patient’s leg ulcers were fully healed 2 weeks after hydroxyurea administration was discontinued. At 1-year follow up, the patient did not present with any leg ulceration.

Conclusion

This case further confirms that longstanding hydroxyurea therapy can result in chronic painful leg ulcers, which responds only after discontinuation of hydroxyurea. It is important for clinicians to inquire about a patient’s current medication. Our misdiagnosed case indicates that other factors, aside from vascular disorders and syphilis, may induce chronic leg ulcerations. Therefore, the authors suggest that clinicians always consider an uncommon cause for a long-term leg ulcer that presents in the patient who has been administered medication.