Etoposide (VP-16) is a semisynthetic podophyllotoxin derivative that is active against a number of solid and hematologic malignancies. Previously reported cutaneous complications include Stevens-Johnson syndrome and radiation recall. We report 4 cases of cutaneous eruptions with distinctive histopathologic changes following etoposide therapy. Diffuse erythematous macules and papules developed 5-9 days after initiation of etoposide therapy and resolved spontaneously within 3 weeks. Histologic examination revealed epidermal maturation disturbances with scattered markedly enlarged individual keratinocytes. These cells had pale cytoplasms and fragmented, haphazardly dispersed nuclear chromatin in a starburst pattern ("starburst cells"). Many keratinocytes showed notable nuclear enlargement with multiple prominent nucleoli. In addition, numerous dyskeratotic cells and basilar mitotic figures in metaphase were present. Some of these changes have been described in condylomata acuminata treated with topical applications of podophyllin, a compound structurally related to etoposide. Starburst cells have not been reported in cutaneous eruptions produced by other chemotherapeutic agents. These cells may represent abnormal mitotic arrest secondary to podophyllin and its related compounds.

A 55-year-old Indian man presented to the dermatology service at The Johns Hopkins Hospital, Baltimore, Md, with a chief complaint of discoloration and thickening of the skin of his axillae, popliteal fossae, the dorsal surface of his toes, and the posterior aspect of his neck. He also complained of a generalized darkening of his complexion. These changes began 12 weeks after starting nicotinic acid, at an oral dose of 500 mg three times a day, for the treatment of hypercholesterolemia. After 16 weeks of treatment with nicotinic acid, his total serum cholesterol value had dropped from 7.24 to 6.10 mmol/L; however, the skin changes were cosmetically unacceptable. His medical history was significant for myocardial infarction and three-vessel coronary artery bypass surgery. He was otherwise in good health, and consultation with his internist revealed no evidence of malignancy or endocrine dysfunction.On physical examination, he had symmetrically distributed, velvety, hyperpigmented plaques in the distribution noted above. The remainder of his physical examination showed normal findings. DIAGNOSIS Acanthosis nigricans induced by treatment of hypercholesterolemia with nicotinic acid.THERAPEUTIC CHALLENGE Treatment of acanthosis nigricans consists primarily of a search for and then treatment of underlying malignancy or endocrinopathy. In most cases of acanthosis nigricans, however, as when induced by nicotinic acid, the condition is solely of cosmetic concern. Acanthosis nigricans following treatment with nicotinic acid resolves on discontinuation of the medication. In treating hypercholesterolemia, however, withdrawal of nicotinic acid results in a rebound increase in the serum cholesterol value. Thus, reversal of nicotinic acid-induced acanthosis nigricans by a method other than medication withdrawal would be advantageous. SOLUTION Because of the hyperkeratotic nature of acanthosis nig¬ ricans, and the favorable response of many other hyper¬ keratotic conditions to topical tretinoin (retinoic acid),1 we attempted a therapeutic trial of tretinoin treatment of pseudo-acanthosis nigricans. The untreated skin of the right axilla served as a control (Fig 1) and was unchanged in clinical appearance over the 2-week trial period. Topical application of 0.1 % tretinoin gel two times daily for 2 weeks to the skin of the left axilla produced a nearly complete resolution of his clinical lesions (Fig 2). Fig 1.-Untreated right axilla at the end of the 2-week trial period, showing velvety, verrucous, hyperplgmented plaques of acanthosis ni¬ gricans. Fig 2.-Skin of the left axilla after topical application of 0.1% tretinoin gel twice daily for 2 weeks, showing clinical resolution of the cutaneous thickening and hyperpigmentation of acanthosis nigricans. Downloaded From: http://archderm.jamanetwork.com/ by a Karolinska Institutet University Library User on 06/02/2015

Pemphigus is an autoimmune disease proved to be mediated by IgG autoantibodies. Skin lesions clinically and histologically identical to pemphigus may occur in patients receiving penicillamine and captopril, but some of these patients lack circulating or tissue-bound autoantibodies. Therefore, we examined the ability of these drugs to produce acantholysis directly in organ explant culture. Human skin explants were prepared from split-thickness graft skin from adults and from neonatal foreskins. Explants were cultured in media containing 0.1 to 200 mmol/L of penicillamine or captopril; parallel drug-free control cultures were also prepared. Acantholysis occurred in all split-thickness graft skin cultures incubated for 72 hours with at least 20 mmol/L of penicillamine and at 24 to 48 hours in those incubated with at least 10 mmol/L of captopril. Acantholysis occurred less frequently in foreskin cultures, being present in 1 (8%) of 12 of those exposed to at least 20 mmol/L of penicillamine and 3 (12%) of 25 of those exposed to at least 10 mmol/L of captopril. None of the parallel drug-free control cultures developed acantholysis. Subcorneal acantholysis, resembling that seen in pemphigus foliaceus, and suprabasilar acantholysis, resembling that seen in pemphigus vulgaris, were induced in vitro. Our results indicate that both drugs can act as ligands and produce acantholysis in organ explant culture in the absence of autoantibody. This ligand-induced acantholysis may also be responsible for induction of the disease in vivo in those patients who lack demonstrable autoantibodies.

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A 61-year-old black woman presented to the dermatology clinic at The Johns Hopkins Hospital, Baltimore, Md, with a 5-year history of a pruritic eruption that flared during the summer, but was present year around. Previous attempts at management with multiple topical steroid preparations had not been successful. Her general health was good except for mild hypertension, which had been treated in the past with hydrochlorothiazide. She was receiving no medication on presentation.