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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 898-900 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.7691
Bleomycin-Induced Flagellate ErythemaMassachusetts General Hospital, Boston, MA A 25-year-old man with a history of mild asthma presented to our hospital's emergency department with persistent dyspnea that was not responsive to his usual inhaler. On further questioning, he also admitted to mild fatigue, a 20- to 30-pound weight loss in the preceding few months, drenching night sweats occurring nightly, and bilateral lower extremity pruritus. Physical examination revealed several 1-cm bilateral axillary lymph nodes, and a palpable 1.5-cm left supraclavicular lymph node. Further evaluation included computed axial tomography (CAT) scan of the chest that showed the presence of a large anterior mediastinal mass measuring 11.4 x 10.3 x 4.6 cm with significant mediastinal, supraclavicular, and axillary lymphadenoapathy. Laboratory studies were notable for a mild microcytic anemia (hemoglobin, 12.5 g/dL), relative lymphopenia (WBC, 9,800/µL with 10% lymphocytes), albumin of 3.8 g/dL, and a significantly elevated erythrocyte sedimentation rate. An excisional biopsy of the palpable left supraclavicular lymph node was performed, and pathologic examination revealed classical Hodgkin's lymphoma, nodular sclerosis type. Abdominal CAT scan did not reveal infradiaphragmatic disease. Positron emission tomography (PET) showed intense fluorodeoxyglucose (FDG) -avid uptake in the mass and in the lymphadenopathy. No PET avidity was seen outside of these nodal areas. The patient was diagnosed with stage IIBX classical Hodgkin's lymphoma. He was started on ABVD chemotherapy (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 325 mg/m2; all were administered intravenously on days 1 and 15) with plans for consolidation with involved-field radiation therapy (IFRT), given the bulky nature of his disease. He was seen back in follow-up on day 7 of cycle 1 of ABVD with significant resolution of all of his systemic symptoms except his bilateral lower extremity pruritus, which had become worse. Physical examination showed the appearance of an erythematous papular rash on his lower extremities, with evidence of dermatographia. Evaluation by dermatology was obtained and a course of systemic antibiotics to treat presumed folliculitis was administered with no success. One week later, new lesions had appeared on his arms, palms, and feet. These were intensely pruritic and more nodular in character (Fig 1). A skin biopsy of a right-arm lesion was taken. He received day 15 of his first cycle of ABVD chemotherapy uneventfully, though significant improvement of the lesions was noted, which coincided with administration of corticosteroids as part of standard prophylactic antiemetic measures. He was seen in follow-up 1 week later with a severe exacerbation of his pruritic symptoms and the new development of angry flagellate erythema across his upper chest and back that were not pruritic in nature (Fig 2). Pathologic examination of the skin biopsy showed perivascular and interstitial lymphoeosinophilic inflammatory infiltrate present in the superficial and deep dermis (Fig 3A). Focally, "flame figures" were identified, consisting of eosinophilic granular material encrusted onto dermal collagen bundles (Fig 3A, inset; level of magnification: 400x). The inflammatory infiltrate extended into the underlying subcutaneous tissue, resulting in an eosinophilic panniculitis (Fig 3B). No atypical Reed-Sternberg cells or variants were identified. The findings were thought to be consistent with a systemic hypersensitivity reaction. Given his clinical history and gross appearance of his lesions, his diagnosis was most compatible with a severe bleomcyin-induced flagellate erythema reaction. Consequently, bleomycin was withheld from his treatment regimen, and he continued on treatment with combination therapy of doxorubicin, vinblastine, and dacarbazine. A PET-CT scan after four cycles showed significant decrease in the size of the mediastinal mass and all sites of lymphadenopathy with no evidence of any FDG-avid uptake. He finished six full cycles of chemotherapy and involved-field radiotherapy as part of combined-modality treatment, and remains in complete remission.
Bleomycin is a chemotherapeutic antibiotic used most commonly in the treatment of Hodgkin's lymphoma, germ cell tumors, and for the sclerosis of recurrent pleural effusions. Toxicities due to bleomycin are most significant in the skin and in the lungs because these organs appear to have lower concentrations of the enzyme that detoxifies bleomycin to a less-toxic metabolite.1 Reported dermatologic adverse effects include Raynaud's phenomenon, hyperkeratosis, nailbed changes, and peeling of the skin on the palmar and plantar surfaces.2 "Flagellate erythema" is a less common cutaneous toxicity of bleomycin, but is one with a strikingly characteristic presentation. Flagellate erythema was first reported as an adverse effect of bleomycin use in 1970.3 Historical studies had quoted an 8% to 20% incidence rate of flagellate streaks of hyperpigmentation; however, with the declining use of bleomycin, this reaction has become much less common in everyday practice. Flagellate erythema is thought to be a reaction specific to bleomycin and is independent of the route of administration or type of malignant disease being treated. Though initially believed to be associated with a cumulative bleomycin dosage, several reports, such as this case, have shown that severe reactions can occur even during the initial doses. Onset of the characteristic lesions can occur anywhere from 1 day to 9 weeks after bleomycin administration.4 Many cases seem to be preceded by a prodrome of generalized pruritus and erythema, which ameliorates when the lesions begin to develop into their most markedly papular and nodular forms. Physical exam usually reveals linear intermingled streaks formed by rows of adjoining firm papules, which can show evidence of punctuate hemorrhages or can be pustular in character. There does not seem to be a characteristic distribution as cases have shown involvement of the face, trunk, and extremities. Dermatographia is present to a limited extent and the role of scratching in producing the linear shape of the lesions has been debated. However, there are clear reports, including this case, which have shown the appearance of linear streaks in the absence of direct trauma. Biopsy of the affected area has shown a spectrum of morphologic findings, including inflammatory oncotaxis,2 urticarial hypersensitivity reaction,4 lymphocytic vasculitis,5 a drug-induced toxic skin reaction,6 and a fixed drug eruption-like reaction.7 The histologic findings in this case of a dermal inflammatory infiltrate containing a significant number of eosinophils overlap with those noted by other authors2,4,5; however, the presence of flame figures and an associated eosinophilic panniculitis have not, to our knowledge, been previously reported in association with bleomycin. The hypothetical mechanism of flagellate erythema is a skin reaction to localized toxic levels of bleomycin,6 though it is unclear which patients are susceptible and why. There is no specific treatment for flagellate erythema, which usually has a self-limited course of several weeks to months as long as bleomycin is subsequently avoided, although permanent hyperpigmentation in affected areas is not unusual. The exclusion of bleomycin, at least in retrospective analyses of large cohorts of patients initially treated with bleomycin-containing regimens, does not appear to influence the overall success of treatment in Hodgkin's lymphoma.8,9 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
REFERENCES
1. Lazo JS, Humphreys CJ: Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc Natl Acad Sci U S A 80:3064-3068, 1983 2. Cortina P, Garrdio JA, Tomas JF, et al: "Flagellate" erythema from bleomycin: With histopathological findings suggestive of inflammatory oncotaxis. Dermatologica 180:106-109, 1990[Medline] 3. Moulin G, Fiere B, Beyvin A: Cutaneous pigmentation caused by bleomycin [in French]. Bull Soc Fr Dermatol Syphiligr 77:293-296, 1970[Medline] 4. Rubeiz NG, Salem Z, Dibbs R, et al: Bleomycin-induced urticarial flagellate drug hypersensitivity reaction. Int J Dermatol 38:140-141, 1999[CrossRef][Medline] 5. Duhra P, Ilchyshyn A, Das RN: Bleomycin-induced flagellate erythema. Clin Exp Dermatol 16:216-217, 1991[CrossRef][Medline] 6. Miori L, Vignini M, Rabbiosi G: Flagellate dermatitis after bleomycin: A histological and immunohistochemical study. Am J Dermatopathol 12:598-602, 1990[Medline] 7. Lindae ML, Hu CH, Nickoloff BJ: Pruritic erythematous linear plaques on the neck and back: "Flagellate" erythema secondary to bleomycin therapy. Arch Dermatol 123:395, 398, 1987[CrossRef][Medline] 8. Canellos GP, Duggan D, Johnson J, et al: How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 22:1532-1533, 2004 9. Martin WG, Ristow KM, Habermann TM, et al: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23:7614-7620, 2005
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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