Scrotal ulceration following all-trans retinoic Acid therapy for acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) induces complete remission in most cases of acute promyelocytic leukemia. Toxicity of ATRA has been shown to be mild, consisting of headache, dry skin, dermatitis, and gastrointestinal disorders. We describe a case of scrotal ulceration with ATRA use in a Moroccan patient, an occurrence that has been rarely reported in the medical literature. The pathogenesis of scrotal ulceration remains unknown. Our experience indicates the importance of recognizing genital ulcers associated with ATRA in order that appropriate countermeasures can be taken.

Introduction

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of (15;17) translocation and the resulting PML/RARα fusion proteins. All-trans retinoic acid (ATRA) has been shown to improve the outcome in patients with APL. It induces a complete clinical remission in a high percentage of APL patients. ATRA has been reported to act by inducing the differentiation of leukemic cells into phenotypically mature myeloid cells. Addition of ATRA to cytotoxic chemotherapy has been shown to improve the outcome in patients with APL.[1-3] Adverse effects associated with ATRA include dryness of the skin, xerostomia, chelitis, headache, bone pain, liver dysfunction, and pseudotumor cerebri.[4] A more serious side effect is the ATRA syndrome, which consists of high fever, respiratory distress, and transient pulmonary infiltrates with leukocytosis.[5] Unusual scrotal rashes, including exfoliative dermatitis, Fournier's gangrene, and ulcerations, have only rarely been reported.[6-8] To the best of our knowledge we are reporting the first case of ATRA-induced scrotal ulcerations in a Moroccan patient.

Case Report

A 35-year-old man with no significant past medical history was admitted to our hospital because of fatigue, progressive pallor, gingival swelling and bleeding, and fever of 2 month's duration. He also complained of mild shortness of breath and poor appetite. On physical examination the patient was found to be moderately well nourished. The temperature was 37.8°C, the pulse rate 96/min, the blood pressure 120/80 mmHg, and the respiratory rate 22/min. No jaundice, skin rashes, or petechiae were present. He had no jugular vein dilatation. No superficial lymph nodes could be palpated. He had no thoracic malformations or tenderness. He had normal heart size, with a regular heart rhythm. His abdomen was soft without tenderness. No hepatosplenomegaly was palpated. The vertebral column and the joints of the extremities were normal. No positive nervous system signs were found.

Initial laboratory investigations showed hemoglobin 7.3 g dL (normal range 12–16 g/dL), MCV 83 fL (normal 80–98 fL), total white cell count 2500/L (normal 4000–10,000/L), and platelets 13,000/L (normal 150000–300000/ L). The prothrombin time was 15.6 s (normal 12–14 s), activated partial thromboplastin time was 36 s (normal 25–35 s), fibrinogen was 150 mg/dL (normal 200–400 mg/dL), and fibrin split products were greater than 60 μg/mL (normal <10 μg/mL).

The peripheral smear showed pancytopenia, with atypical cells. Subsequent bone marrow aspirate confirmed the diagnosis of acute promyelocytic leukemia, with cytogenetic analysis revealing the presence of the t (15;17) translocation.

ATRA therapy was initiated at 45 mg/m2 in two divided doses daily, and induction chemotherapy with daunorubicine and cytarabine was introduced 5 days later.

Shortly after starting ATRA, the patient developed fevers as high as 39.5°C. These fevers were ultimately attributed to ATRA after an extensive evaluation, including multiple blood cultures, ruled out other causes. The patient did not have pulmonary complaints or leukocytosis suggestive of retinoic acid-APL syndrome.

Despite treatment with antibiotics and an anti-fungal agent, the high fever continued. No growth of microorganisms was present in any of the cultures and the origin of the fever remained unclear.

On the 17th day of ATRA therapy, the patient developed a 1.5-cm painless, dusky, nonpruritic, superficial scrotal ulcer [Figure 1]. ATRA was discontinued and the patient defervesced within 24 h of stopping the medication. Bacitracin ointment was prescribed as a lubricant and also for prophylaxis of superimposed bacterial infection. The ulcer gradually resolved during the 3 weeks following discontinuation of ATRA. Our patient achieved a complete remission after induction chemotherapy. He received consolidation chemotherapy, and ATRA was resumed during the maintenance phase of his treatment, when it was given for 2 weeks every 3 months. The scrotal ulceration did not recur with the reintroduction of ATRA.

Figure 1

Scrotal ulcer in patient with APL being treated with ATRA

Discussion

The introduction of ATRA, a vitamin A derivative, has revolutionized the treatment and survival of patients diagnosed with APL. By inducing maturation and subsequent apoptosis of APL cells, ATRA therapy alone has led to complete, albeit brief, remissions. Further induction, consolidation, and maintenance chemotherapy is needed to sustain remissions.

ATRA treatment is generally well tolerated. Side effects include fever, headache, dry skin, xerostomia, cheilitis, arthralgia, and hyperlipidemia. A more serious complication is the potentially life-threatening retinoic acid-APL syndrome, characterized by hyperleukocytosis, fever, dyspnea, radiographic pulmonary infiltrates, pleural and/or pericardial effusions, renal failure, and weight gain.[9]

In this report we describe a case of scrotal ulceration with ATRA use, an occurrence that has been rarely reported in the medical literature[679-11] Sun first reported this adverse effect in 1993 in a Chinese patient with severe exfoliative dermatitis and ulceration of the scrotum.[9] The ulcers have usually been observed between the 9th and 22nd days of ATRA treatment and they have been reported to resolve with the use of local or intravenous corticosteroids.[691012] Although the cause of ATRA-induced scrotal ulcerations remains obscure, there are several proposed explanations. The ulcers may result from the release of various cytokines.[6] Tumor necrosis factor-α, interleukin (IL)-1, IL- 6, and IL-8 stimulate peripheral leukocytes and can lead to ulcerations. Moreover, ATRA is reported to directly activate leukocytes by producing superoxide, which can potentially damage tissue. In other reported cases the scrotal ulcerations occurred when the white blood cell count recovered.[1314]

Considering the profound benefit of ATRA therapy, it is reasonable to consider continuing ATRA therapy even when scrotal ulceration develops. Topical corticosteroids and antibiotic ointment to prevent superimposed infection have been used to manage the ulceration and might be beneficial. We chose to temporarily discontinue ATRA because our patient was also having high fevers believed to be secondary to ATRA.

Given their anatomic location and painless nature, some patients may be hesitant about reporting these ulcerations. Therefore, the incidence of these lesions in patients receiving ATRA therapy is probably underestimated. Despite the fact that treatment is most often continued through this cutaneous side effect, it is important for physicians to recognize these ulcers and distinguish them from cutaneous infections or the skin lesions associated with Sweet's syndrome.[15]

We report this case to highlight its rarity and to note that there is no need to stop ATRA therapy; treatment can be continued under cover of steroids and antibiotics. Clinicians should be aware of this distressing complication, especially as ATRA is now being more widely used in the treatment of APL.