Bleomycin

Abstract

A 29-year-old male with AIDS was treated with bleomycin and vincristine for visceral Kaposi's sarcoma. Three days later, he developed two distinct eruptions simultaneously. One eruption was characterized by tender, erythematous, edematous plaques and nodules on the palmar and dorsal surfaces of the hands, forearms, and elbows. The other consisted of grouped, erythematous, hyperpigmented streaks on the trunk, buttocks, and extremities. The patient subsequently received a second treatment consisting of vincristine with adriamycin, without bleomycin, and no cutaneous effects were seen. Diagnoses of flagellate erythema and acral nodular eruption secondary to bleomycin were made and confirmed histopathologically. To our knowledge, this is the first report of two cutaneous side effects of belomycin appearing simultaneously in a patient with AIDS.

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Case Report

The patient was a 29-year-old Hispanic male diagnosed with AIDS in 1992. He was admitted to Bellevue Hospital with a 6-week history of right upper quadrant pain, and a 3-week history of nausea, vomiting, and diarrhea. Medications at the time of admission included isoniazid, pyrazinamide, rifampin, ethambutol, trimethoprim-sulfamethoxazole, acyclovir, fluconazole, omeprazole, sucralfate, and multivitamins.

On physical examination, the patient was a thin male in no apparent distress with normal vital signs and bright red blood per rectum. His skin was dry and ichthyotic with multiple hyperpigmented macules and scattered excoriations. Laboratory studies were significant for a CD4 count less than 10 cells/[mm.sup.3].

[FIGURE 1 OMITTED]

Esophageal gastroduodenoscopy revealed Kaposi's sarcoma (KS) involving greater than one-half of the gastric wall. A treatment regimen consisting of bleomycin 14 mg (following a 1 mg test dose) and vincristine 1 mg was initiated. Thiethylperazine 10 mg, diphenhydramine 25 mg, and acetaminophen 650 mg were given to him for prophylaxis. No adverse effects were noted in the first 24 hours and the patient was discharged.

Two days later, the patient developed tender, erythematous, edematous plaques and nodules on the palmar and dorsal surfaces of the hands, forearms, and elbows (Figure 1). Simultaneously, grouped, erythematous, hyperpigmented streaks appeared on the trunk, buttocks, and extremities, but spared the face (Figure 2). The patient complained of increasing pruritus, but denied fever, chills, diarrhea, headache, and ocular symptoms.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Biopsies were taken from a streak on the back and from a plaque on the dorsum of the hand. Histopathologic changes in both lesions were consistent with a drug eruption; namely, a superficial perivascular and interstitial infiltrate comprised mostly of eosinophils with few melanophages with no apparent organisms (Figure 3). Subsequently, the patient received a course of vincristine and adriamycin without bleomycin and had no cutaneous side effects. Taken together, the clinicopathologic findings strongly suggested flagellate erythema and nodular acral eruption secondary to bleomycin.

Discussion

Bleomycin is an antitumor antibiotic that was originally extracted from Streptomyces verticullus, a fungus found in Japanese soil. (1) It consists of a mixture of 2 copper-chelating glycoproteins that induce DNA double-strand breaks by forming free radicals in the presence of molecular oxygen and iron. (2) It is used in the treatment of germ cell tumors of the testis and ovary, squamous cell carcinomas of the head and neck, malignant lymphomas, and Kaposi's sarcoma. (1-6)

Bleomycin distributes to all tissues, but is quickly inactivated by an aminohydrolase. Levels of the hydrolase are lower in certain tissues, such as lung and skin; therefore, these sites have prolonged exposure to the drug and are subject to its sustained effects, both beneficial and toxic. (2) The most serious side effect of bleomycin is a devastating pulmonary fibrosis, which has been reported to be lethal in 1% of affected patients. (3,4) This toxicity has an unknown pathogenesis, appears to be dose related, and is seen primarily in patients over 70 years old. (4,7) The lungs are affected functionally, but do not show any change radiographically. (7) Dermatologic changes include cutaneous eruptions (to be described later), alopecia, stomatitis, and nail alterations. Nail changes are non-specific and include brittleness, Beau's lines, onycholysis, and onychomadesis. The fingertips may reveal thickening of the nail bed, dark cuticles, and gangrene. (8) Additional adverse effects of Bleomycin include constitutive symptoms (nausea, vomiting, fever) and, on rare occasions, bronchospasm. In patients with AIDS, bleomycin may cause a dose related hematological toxicity, specifically a grave neutropenia that restricts dosages and necessitates close monitoring of blood cell counts. (4-6)

Among the cutaneous eruptions caused by bleomycin is a peculiar hyperpigmented flagellate erythema. This reaction was first described by Moulin et al in 1971 as linear streaks measuring approximately 10 cm in length and criss-crossing one another in a pattern reminiscent of flagellation scars. (7) In 1973, Cohen et al studied 6 patients treated with bleomycin and observed eruptions that included linear hyperpigmentation on the torso, diffuse pigmentation overlying the joints of the hands and knees and indurated nodules on the hands. (9) Other reports have also documented the appearance of erythematous tender macules, nodules, or patches on various body surfaces. (10) None of the patients described to date have had the acral indurated nodules and linear hyperpigmentation concurrently. (7,9,10) Interestingly, an eruption similar to the flagellate dermatitis caused by bleomycin has been reported to occur in certain individuals after ingestion of Shiitake mushrooms. (11)

A review of the literature led us to divide bleomycin induced cutaneous eruptions into two main patterns of reaction: (1) acral infiltrative and (2) truncal pigmentary (Table 1). In contrast to the majority of patients who present with a single reaction pattern, our patient developed both acral infiltrative lesions and truncal pigmentary changes simultaneously. On the forearms, elbows, and surfaces of the hands, he had erythematous, edematous plaques and nodules; on the trunk, buttocks, and extremities, he had flagellate erythema and hyperpigmented streaks.

While little is known about the mechanism by which bleomycin induces an acral infiltrative eruption, various mechanisms have been proposed to explain the hyperpigmented flagellate erythema. In general, existing hypotheses implicate alterations in the function of either epidermal cells (specifically keratinocytes or melanocytes) (12-16) or fibroblasts. (17) The majority of authors, however, contend that the eruption is actually a type of dermatographic response (12,18,19) These authors suggest that scratching in response to pruritus causes increased extravasation of drug into the skin. (20) Although linear eruptions in dermatology are often attributed to external factors, almost all attempts to reproduce these flagellate lesions by scratching during bleomycin therapy have failed. In one study, a patient even continued to develop new lesions in locations away from those being scratched. (21)

Interestingly, skin toxicity due to bleomycin has been described in the setting of radiation recall. (22) A patient who received radiation therapy for cutaneous Kaposi's sarcoma and was subsequently treated with bleomycin developed erythema, desquamation, and subsequent hyperpigmentation on surfaces previously irradiated. Notably, the lesions were most severe on areas that had received the highest dose of radiation. (22) This observation implies that certain injuries to the skin may predispose it to cutaneous toxicity from bleomycin. Consistent with this hypothesis is a case report of a patient who developed hyperpigmentation occurring in newly formed striae distensae. (23) The patient was receiving a combination of chemotherapy with bleomycin and prednisone and developed hyperpigmented striae subsequent to rapid weight gain. (23)

Flagellate erythema with hyperpigmentation, therefore, could be a form of "scratching recall toxicity" in which lesions appear in areas traumatized prior to, but not during, therapy. This hypothesis could be tested by scratching certain sites before administering bleomycin or carefully noting areas of recent scratching or excoriation prior to starting therapy.

In conclusion, we divide the cutaneous eruptions of bleomycin into two main patterns, acral infiltrative and truncal pigmentary, and report the simultaneous occurrence of both in a single patient with AIDS. While we do not attempt to explain the etiology of the acral nodular lesions, we speculate that the mechanism of flagellate pigmentation may involve a form of "scratching recall toxicity," similar to the well described entity of radiation recall toxicity.

References

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Maryann Mikhail, Mark Eichenbaum MD, Eric Gerstenfeld MD, Julie Duquette MD, Miriam Keltz Pomeranz MD, David Polsky MD PhD

The Ronald O. Perelman Department of Dermatology, New York University Medical Center, New York, NY

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