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CORRESPONDENCE
Year : 2013  |  Volume : 9  |  Issue : 3  |  Page : 500-503

Bleomycin induced flagellate erythema: Revisiting a unique complication


1 Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication8-Oct-2013

Correspondence Address:
Ahitagni Biswas
Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.119358

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 > Abstract 

Bleomycin induced flagellate dermatitis is a rare and unique adverse effect. With the declining use of bleomycin, this complication is becoming increasingly infrequent in common clinical practice. We herein describe a case of a 22-year-old Indian male with Hodgkin's lymphoma, Ann Arbor stage IIBEX developing flagellate dermatitis following 1 st cycle of chemotherapy with ABVD regimen. The diagnostic dilemma in the illustrative case underscores the importance of awareness and prompt identification and treatment of this dermatological toxicity in limiting morbidity in patients undergoing bleomycin based combination chemotherapy. In patients having severe rash, bleomycin should be expeditiously discontinued. Omission of bleomycin does not compromise the treatment outcome in the majority of patients with Hodgkin's lymphoma.

Keywords: Bleomycin, dermatitis, erythema, flagellate


How to cite this article:
Biswas A, Chaudhari PB, Sharma P, Singh L, Julka PK, Sethuraman G. Bleomycin induced flagellate erythema: Revisiting a unique complication. J Can Res Ther 2013;9:500-3

How to cite this URL:
Biswas A, Chaudhari PB, Sharma P, Singh L, Julka PK, Sethuraman G. Bleomycin induced flagellate erythema: Revisiting a unique complication. J Can Res Ther [serial online] 2013 [cited 2019 Nov 19];9:500-3. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/500/119358


 > Introduction Top


Bleomycin is an antibiotic antitumor agent first developed in Japan by Umezawa in 1966. [1] It is derived from Streptomyces verticillus. Cytotoxic effect results from generation of activated oxygen-free radicals, which cause single and double-stranded DNA break and eventual cell death. Bleomycin is commonly used in Hodgkin's lymphoma, germ cell tumor, squamous cell carcinoma of head and neck, gynecological system and skin. It is also used as a sclerosing agent for pleurodesis in recurrent malignant pleural effusion.

Bleomycin induced toxicities are more pronounced in lungs and skin due to low concentration of the metabolizing enzyme-bleomycin hydrolase in these organs. [2] The spectrum of bleomycin induced dermatological toxicity includes Raynaud's phenomenon, hyperkeratosis, nail bed changes, peeling of skin on palmar and planter surface, digital gangrene and pigmentary alterations. [3],[4] Flagellate erythema is a less common but unique toxicity of bleomycin with a reported incidence of 8-20% in available literature. [3],[4] Flagellate erythema was first reported as an adverse effect of bleomycin in 1970 by Moulin et al. [5] However, with the declining use of bleomycin, this unique reaction has become infrequent in common clinical practice. [3]

We herein provide an overview of the clinical presentation, pathophysiology, histopathological features and treatment options of this dermatological toxicity by citing the case of a 22-year-old Indian male with Hodgkin's lymphoma, Ann Arbor stage IIBEX developing flagellate dermatitis following his 1 st cycle of chemotherapy with ABVD regimen.


 > Case Report Top


A 22-year-old man presented to our clinic with symptoms of dry cough, shortness of breath, bilateral neck swelling, and significant weight loss for the last 4 months. He did not have any preexisting dermatological disorder or allergic condition. On examination, bilateral supraclavicular lymph nodes were found to be enlarged (2 × 1 cm). Whole body 18-F fluorodeoxyglucose positron emission tomography/ computed tomography ( FDG PET-CT) study showed enlarged bilateral cervical (level IV), bilateral supraclavicular, prevascular, precarinal, left internal mammary, left anterior diaphragmatic lymph nodes with increased FDG uptake. A large anterior mediastinal mass (10.5 × 9.2 × 9.6 cm) with increased radiotracer uptake (standardised uptake value SUV max 18.7) was noted. There was evidence of left pleural thickening with multiple FDG avid pleural based nodules [Figure 1]a-d. Computed tomography (CT) guided biopsy from mediastinal mass showed features of Hodgkin's lymphoma, mixed cellularity. Large cells were immunopositive for CD 15 and CD 30 but negative for leucocyte common antigen (LCA), CD 3 and Bob-1. Bone marrow biopsy showed no evidence of lymphoma deposit. Serum lactate dehydrogenase (LDH) was noted to be 309 units/l. The final diagnosis was made as Hodgkin's lymphoma, mixed cellularity, stage IIBEX.
Figure 1: Baseline PET (a) and PET-CT (b-d) images of the patient, showing FDG avid (SUVmax-18.7) anterior mediastinal mass (a-c, arrow), FDG avid cervical nodes (a, b, arrowheads) and FDG avid pleural based left lung nodule (d, arrow). Interim PET (e) and PET-CT (f-h) images, showing reduction in size and uptake (SUV max-3.6) of the anterior mediastinal mass (e-g, arrow) as well as the pleural based nodule (h, arrow). The cervical nodes were not visualised (e, f). When compared to baseline PET-CT, interim PET-CT findings were suggestive of residual disease with partial response to chemotherapy

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The patient was planned for 6 cycles of systemic chemotherapy with ABVD regimen (Inj. Adriamycin - 25 mg/m 2 , Inj. Bleomycin - 10 IU/m 2 , Inj. Vinblastine - 6 mg/m 2 , and Inj. Dacarbazine - 375 mg/m 2 IV day 1 and day 15 q 4 weeks) followed by consolidation radiotherapy. Interim assessment by whole-body PET-CT was planned after 3 cycles. Four days following the first dose of chemotherapy, he developed erythematous, pruritic, papular lesions in the flexor aspect of right forearm. There was no perceptible relief with antihistaminics and lotio calamine. Subsequently, the lesions generalized to face, trunk, buttock, bilateral upper and lower extremity, and increased in severity. There was evidence of dermatographia. Erythematous pruritic papules cropped in the interdigital clefts and groin. There was no evidence of mucosal involvement or systemic upset. He was referred to the Department of Dermatology where a clinical diagnosis of scabies was made. Scrapings from the papules in the interdigital cleft however, did not reveal scabies mite. Following local application of 1% permethrin, the lesions increased in severity. Papules started coalescing to form erythematous plaque and pruritus increased in intensity. Lesions at this stage resembled flagellate erythema and bleomycin was considered the putative agent [Figure 2]. Skin biopsy showed basal vacuolization, mild spongiosis and moderately dense mixed inflammatory infiltrate with presence of eosinophils in the superficial dermis [Figure 3]. No atypical Reed Sternberg cells were identified. Given the clinical presentation and drug history of the patient these histomorphological features were compatible with bleomcyin-induced flagellate erythema reaction. Eosinophilia (22%) was noted on differential leucocyte count. He was started on oral and topical steroid. Bleomycin was omitted from the chemotherapy regimen (from cycle IIB onwards). There was marked symptomatic improvement within a week and lesions decreased in severity (by ~80%). Post-inflammatory hyperpigmentation was noted to be minimal. Interim PET-CT after 3 cycles of systemic chemotherapy showed a reduction in size and uptake (SUVmax-3.6) of the anterior mediastinal mass as well as the pleural based nodule. The cervical nodes were not visualized. When compared to baseline PET-CT, interim PET-CT findings were suggestive of residual disease with partial response to chemotherapy [Figure 1]e-h. The patient has been planned for 3 more cycles of chemotherapy with adriamycin, vinblastine and dacarbazine (AVD) regimen followed by re-evaluation by whole-body PET-CT imaging.
Figure 2: Bleomycin induced flagellate dermatitis with linear erythematous streaks involving the (a) upper back, (b) buttocks, (c) left arm, (d) right arm and (e) multiple erythematous papules involving the interdigital clefts and dorsum of both hands

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Figure 3: Photomicrograph (a × 400) and (b × 100) of skin biopsy shows basal vacuolization, mild spongiosis and moderately dense mixed inflammatory infiltrate with presence of eosinophills in superficial dermis. No atypical Reed Sternberg cells were identified

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 > Discussion Top


Bleomycin induced flagellate erythema is a rare drug rash where the patient appears to have been whipped over multiple body area. [6] Erythematous, linear, intermingled streaks are formed by rows of adjoining firm papules. [3] Though majority of cases seem to be preceded by a prodrome of generalized pruritus, there are few reports describing the lesions as nonpruritic. [7] There might be evidence of punctuate hemorrhage and pustules. [3] There is no characteristic distribution-lesions can be located in face, trunk, and extremities. [3] However, there have been some reports highlighting the predominance of lesions over bony prominence. [8] Dermatographia is present in a limited extent and the role of scratching in producing the linear shape of the lesion is debated. [3] As the rash becomes less erythematous, affected areas become deeply pigmented. These hyperpigmented areas may persist up to 6 months. [6],[9]

This characteristic rash may appear following administration of bleomycin by any route: intravenous, intramuscular, topical and has been reported even after intrapleural administration of the drug for management of malignant pleural effusion. [6] This rash may appear several hours to 2 months after the onset of administration of bleomycin. [7],[8] Though initially believed to be associated with cumulative bleomycin dosage, several reports attest to the fact that this rash is indeed dose independent and can manifest after administrations of variable dose of bleomycin ranging from 5 IU to 465 IU. [3],[8] In a compendium of 24 individual cases from 20 reports by Ziemer et al., [8] males and females were found to be equally affected. However, in patients developing flagellate dermatitis early (within 72 h of administration of bleomycin), there was a female preponderance (6/7) and majority of them had received low dose of bleomycin (5-15 IU) for Hodgkin's lymphoma. Patients developing flagellate dermatitis 1 week after the administration of bleomycin were mostly males (9/12) who had received a relatively higher dose (30-465 IU) for solid malignancies. The authors hypothesized that B symptoms like fever and night sweat in patients of Hodgkin's lymphoma receiving bleomycin may act as a trigger for exanthem leading to early-onset flagellate dermatitis.

Histological features of this unique dermatitis are rather non-specific and have been nicely summarized by Ziemer et al. in their report. [8] Common histological changes include inconspicuous epidermal or spongiotic dermatitis, superficial lymphocytic infiltrate with neutrophil and eosinophilic granulocytes, dermal edema, melanophages in papillary dermis and epidermal hyperpigmentation. Occasionally necrotic keratinocytes and vacuolar degeneration at dermo-epidermal junction may be discerned. Focal acantholysis and leucocytoclasia are rare histopathological findings. Histological changes depend on the stage of evolution of skin lesions and the site of biopsy (central versus peripheral).

The plausible mechanisms for this adverse effect include localized increase in melanogenesis, pigmentary incontinence secondary to inflammation, alterations in normal pigmentation patterns, and toxic effects of the drug itself, inducing neutrophilic eccrine hidradenitis. [10] Histological and ultra-structural studies indicate that bleomycin reduces the epidermal turnover, resulting in a prolonged contact between melanocytes and keratinocytes. [7],[10] Takeda et al. [11] localized bleomycin hydrolase in the subcorneal layer of epidermis. It is likely that bleomycin hydrolase is expressed in human epidermis but is not able to degrade the drug efficiently. Toxic cutaneous concentration of bleomycin might be the most probable explanation for this skin eruption. [8] It is further speculated that linear pigmentation may be caused by scratching, which induces subclinical local vasodilatation by a dermographic mechanism resulting in excessive local accumulation of bleomycin. [4]

Flagellate dermatitis has also been reported in patients receiving other chemotherapeutic agents like peplomycin, a bleomycin derivative and docetaxel. [12],[13] Flagellate dermatitis can also occur in association with consumption of shiitake mushroom, dermatomyositis, adult-onset Still's disease and infection with human immunodeficiency virus. [6],[8] Both bleomycin and consumption of shiitake mushroom may cause flagellate dermatitis at a low dose. However, there is no longstanding post-inflammatory hyperpigmentation or systemic effect associated with the latter. [8]

Occurrence of bleomycin induced flagellate dermatitis mandates prompt institution of treatment with antihistaminics and topical and oral corticosteroid. [8] Severe rash requires discontinuation of bleomycin. [3],[8] Exclusion of bleomycin in the retrospective analysis of large cohort of patients of Hodgkin's lymphoma initially treated with bleomycin containing regimen did not interfere with overall therapeutic success. [14] The German Hodgkin Study Group (GHSG) HD13 trial is investigating whether bleomycin and dacarbazine can be omitted from the ABVD regimen by comparing 2 cycles of ABVD, AV, ABV, or AVD followed by 30 Gy involved field radiotherapy (IFRT) in patients of early stage favorable Hodgkin's lymphoma. Re-exposure to bleomycin may cause recurrence of rash and should be avoided. [6],[9] Permanent post-inflammatory hyperpigmentation in the affected area is not uncommon. [3]

In the illustrative case, the rash appeared 4 days after the institution of ABVD chemotherapy and did not respond to conservative management. A presumptive diagnosis of scabies was made based on certain clinical findings - erythematous papules in interdigital cleft, intense pruritus and underlying immunosuppression. However, when the patient did not respond to antiscabetic treatment and the lesions worsened, the diagnosis was revised as bleomycin induced flagellate dermatitis. Omission of bleomycin from the chemotherapy regimen and administration of oral and topical corticosteroids led to dramatic clinical improvement. The diagnostic dilemma in the index case highlights the importance of awareness and prompt identification and treatment of this dermatological toxicity in limiting morbidity in patients undergoing bleomycin based combination chemotherapy.


 > Conclusion Top


Bleomycin induced flagellate dermatitis is a rare and unique adverse effect. With the declining use of bleomycin, this adverse effect is becoming increasingly infrequent in everyday clinical practice. This underscores the importance of awareness of this dermatological toxicity in patients undergoing bleomycin based combination chemotherapy. In patients having serious rash, bleomycin should be expeditiously discontinued. Omission of bleomycin does not jeopardize the therapeutic success in the majority of patients with Hodgkin's lymphoma.

 
 > References Top

1.Umezawa H. Bleomycin and other antitumor antibiotics of high molecular weight. Antimicrob Agents Chemother (Bethesda) 1965;5:1079-85.  Back to cited text no. 1
    
2.Lazo JS, Humphreys CJ. Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc Natl Acad Sci U S A 1983;80:3064-8.  Back to cited text no. 2
    
3.Chen YB, Rahemtullah A, Breeden E, Hochberg EP. Bleomycin-induced flagellate erythema. J Clin Oncol 2007;25:898-900.  Back to cited text no. 3
    
4.Rubeiz NG, Salem Z, Dibbs R, Kibbi AG. Bleomycin-induced urticarial flagellate drug hypersensitivity reaction. Int J Dermatol 1999;38:140-1.  Back to cited text no. 4
    
5.Moulin G, Fière B, Beyvin A. Cutaneous pigmentation caused by bleomycin. Bull Soc Fr Dermatol Syphiligr 1970;77:293-6.  Back to cited text no. 5
    
6.Fyfe AJ, McKay P. Toxicities associated with bleomycin. J R Coll Physicians Edinb 2010;40:213-5.  Back to cited text no. 6
    
7.Vuerstaek JD, Frank J, Poblete-Gutiérrez P. Bleomycin-induced flagellate dermatitis. Int J Dermatol 2007;46:3-5.  Back to cited text no. 7
    
8.Ziemer M, Goetze S, Juhasz K, Elsner P. Flagellate dermatitis as a bleomycin-specific adverse effect of cytostatic therapy: A clinical-histopathologic correlation. Am J Clin Dermatol 2011;12:68-76.  Back to cited text no. 8
    
9.Mowad CM, Nguyen TV, Elenitsas R, Leyden JJ. Bleomycin-induced flagellate dermatitis: A clinical and histopathological review. Br J Dermatol 1994;131:700-2.  Back to cited text no. 9
    
10.Al-Khenaizan S, Al-Berouti B. Flagellate pigmentation: A unique adverse effect of bleomycin therapy. Eur J Dermatol 2011;21:146.  Back to cited text no. 10
    
11.Takeda A, Nonaka M, Ishikawa A, Higuchi D. Immunohistochemical localization of the neutral cysteine protease bleomycin hydrolase in human skin. Arch Dermatol Res 1999;291:238-40.  Back to cited text no. 11
    
12.Araki Y, Tamura K, Seita M. Side effects of peplomycin. Gan To Kagaku Ryoho 1986;13:2446-50.  Back to cited text no. 12
    
13.Tallon B, Lamb S. Flagellate erythema induced by docetaxel. Clin Exp Dermatol 2008;33:276-7.  Back to cited text no. 13
    
14.Canellos GP, Duggan D, Johnson J, Niedzwiecki D. How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 2004;22:1532-3.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]


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1 Bleomycin
Reactions Weekly. 2013; 1478(1): 11
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