CP

D
CPD Clinicopathological case

CED
Clinical and Experimental Dermatology

Longstanding truncal hyperpigmented patches in a young man

T. Bremec, J. Demsar, B. Luzar,* M. Adamic and M. D. Pavlovic
Department of Dermatology and Venereology, University Clinical Centre Ljubljana, Slovenia; *Institute of Pathology, School of Medicine, University of Ljubljana, Ljubljana, Slovenia; and Dermatology Centre Parmova, Ljubljana, Slovenia
doi:10.1111/j.1365-2230.2009.03367.x

Clinical ndings
A 26-year-old man presented with a 2-year history of large hyperpigmented patches. He had been treated for presumed fungal infection with topical antimycotics then with topical corticosteroids, but with no apparent response. The number of lesions had slowly increased over the 2-year period. On physical examination, numerous hyperpigmented patches were seen on the lower back and shoulders, and in the axillae and inguinal folds (Fig. 1a). On

questioning, the patient reported that he experienced a burning sensation and a reddish hue around the patches a few hours after ingestion of acetaminophen (paracetamol). The patient was admitted to the ward and oral provocation with 50 mg of acetaminophen was performed. Two hours after ingestion, burning erythema and slight swelling developed around the hyperpigmented patches (Fig. 1b).

Histological ndings
There was vacuolar degeneration of basal keratinocytes, exocytosis of individual lymphocytes and suprabasal apoptotic keratinocytes in the epidermis, along with a mild perivascular inltrate, composed of lymphocytes, melanophages and eosinophils, within the reticular and mid dermis (Fig. 2). What is your diagnosis?

(a)

(b)

Figure 1 (a) Numerous hyperpigmented patches on trunk and genital area at presentation; (b) erythematous extension of a xed patch appearing a few hours after ingestion of acetaminophen.
Correspondence: Dr Milos D. Pavlovic, Dermatology Centre Parmova, Parmova 53, SI-1000 Ljubljana, Slovenia E-mail: milos.pavlovic@dcp.si Conict of interest: none declared. Accepted for publication 16 December 2008

Figure 2 Epidermis with vacuolar degeneration of basal keratinocytes, exocytosis of individual lymphocytes and a suprabasal apoptotic keratinocyte. Haematoxylin and eosin, original magnication 200.

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2010 The Author(s) Journal compilation 2010 British Association of Dermatologists Clinical and Experimental Dermatology, 35, e56e57

D CP
Clinicopathological case

Diagnosis
Multiple xed drug eruption caused by acetaminophen (Dalmatian dog-like skin eruption).

Discussion
Strict avoidance of all prescription and over-the-counter medications containing acetaminophen (paracetamol) was advised. Since then, the patient has not experienced any episodes of burning or swelling of the lesions. Fixed drug eruption (FDE) is a cutaneous reaction induced by hypersensitivity to drugs. It is relatively uncommon in some areas of the world, but in others it represents the commonest drug reaction; in a recent prospective study from India, it comprised up to 30.5% of all cutaneous drug eruptions.1 The classical presentation of FDE is a solitary, rarely blistering, red patch accompanied by an itching and burning sensation after exposure to the causative drug. It recurs at the same location after re-exposure to the drug. The lesions eventually assume a brownish pigmentation, due to pigmentary incontinence. FDE may be considered a hypersensitivity reaction mediated by T cells recognizing haptenated drug antigens presented by epidermal cells. It was recently shown that the most probable effector cells in established FDE are cytotoxic CD8-positive T cells with natural killer (NK) cell-associated molecules resembling effector cells found in toxic epidermal necrolysis.2 In fully evolved FDE that eventually resolves, high numbers of intraepidermal suppressor CD4+ CD25+ Foxp3+ regulatory T cells counteract the cytotoxic cells and ameliorate the damage. Further, lesional epidermal keratinocytes produce interleukin-15, which is a crucial factor for maintaining viability, prolonged presence and induction of NK cell markers on intraepidermal CD8+ T cells, which will be reactivated once the drug antigen is again presented by keratinocytes.2 Multifocal or extensive FDE is a less common variant of FDE, in which lesions are present at > 1 location. Although often used either alone or in various drug combinations, acetaminophen has relatively rarely been reported as a causative agent of FDE; in a series of patients with FDE, only 3.5% were caused by acetaminophen.1 A multifocal variant of FDE induced by acetaminophen has been described in only a few patients.3 Histologically, FDE resembles erythema multiforme, with an interface dermatitis with lymphocytes at the dermalepidermal junction and degenerative changes of the epithelium with dyskeratosis. Eosinophils are also present. The repetitive nature of the disease is mirrored by the perivascular localization of the pigment and

melanophages around the upper reticular and mid dermal vessels (Figs 1d, 2). The differential diagnosis includes conditions presenting with multiple hyperpigmented patches, such as erythema dyschromicum perstans, erythema multiforme, idiopathic eruptive macular pigmentation, and postinammatory hyperpigmentation. Erythema dyschromicum perstans is believed to be a variety of lichen planus, and unlike the hyperpigmented patches in FDE, macules are usually grey-blue in colour and symmetrically distributed over the trunk, proximal arms, face and neck.4 In inactive lesions, which may clinically resemble FDE, there is no vacuolization of the basal cell layer, and there is a diminished dermal inltrate and an increased number of dermal melanophages. Erythema multiforme is characterized by stereotypical target-like lesions, which may leave postinammatory hyperpigmentation.5 The latter is a consequence of epidermal and or dermal melanin deposition without other distinguishing histological features. Idiopathic eruptive macular hyperpigmentation is an uncommon condition characterized by the presence of asymptomatic hyperpigmented macules involving the face, trunk and arms in children and adolescents.4 The hyperpigmented patches in FDE are usually larger and often involve the lower trunk, including the genital area, as in our patient. This case clearly shows that FDE should be considered in patients who present with multifocal patches of longer duration where they do not readily link the eruption to ingestion of a particular drug. Careful and targeted history-taking is crucial to elicit the right information.

References
1 Raksha MP, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venreol Leprol 2008; 74: 80. 2 Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol 2008; 158: 12308. 3 Hayashi H, Shimizu T, Shimizu H. Multiple fixed drug eruption caused by acetaminophen. Clin Exp Dermatol 2003; 28: 4556. 4 Lapeere H, Boone B, Schepper SD et al. Hypomelanoses and Hypermelanoses. Chapter 73. In: Fitzpatricks Dermatology in General Medicine (Wolff K, Goldsmith LA, Katz SI et al., eds), 7th edn. Available at: http://www.accessmedicine. com/content.aspx?aID=2973170 (accessed 20 December 2008). 5 Roujeau J-C. Erythema multiforme. Chapter 38. In: Fitzpatricks Dermatology in General Medicine (Wolff K, Goldsmith LA, Katz SI et al., eds), 7th edn. Available at: http:// www.accessmedicine.com/content.aspx?aID=2970488 (accessed 20 December 2008).

2010 The Author(s) Journal compilation 2010 British Association of Dermatologists Clinical and Experimental Dermatology, 35, e56e57

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