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Pigmentary disorders are recognized adverse effects of the semi-synthetic tetracycline derivative antibiotic, minocycline. Three distinct types of minocycline-induced cutaneous pigmentation have been described. Type I, blue-black pigmentation confined to sites of scarring or inflammation on the face; Type II, blue-grey circumscribed pigmentation of normal skin of the lower legs and forearms; and Type III, diffuse muddy brown pigmentation of normal skin accentuated in sun-exposed areas. We report two patients with acne vulgaris with a fourth type of minocycline-induced cutaneous pigmentation. They presented with circumscribed blue-grey pigmentation within acne scars confined to the back. Histology showed pigment within dendritic cells, and extracellularly throughout the dermis. Histochemistry identified a calcium containing melanin-like substance. Iron was absent. Immunohistochemistry confirmed some pigment-containing cells to be macrophages. Electron microscopy demonstrated electron-dense granules, free and membrane-bound, within macrophages and fibroblast-like cells. Energy-dispersive X-ray analysis confirmed the presence of calcium. Iron was absent. This fourth type of cutaneous minocycline hyperpigmentation may be a variant of Type I, but based on clinical, pathological and microanalytical differences, appears to be a new entity. The pigment may be a drug metabolite-protein complex chelated with calcium, or an insoluble minocycline-melanin complex. We propose a classification of cutaneous minocycline pigmentation based on clinico-pathological criteria.

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Papulonecrotic tuberculid (PNT), a form of cutaneous tuberculosis (TB), is uncommon in children. We identified eight children (six girls and two boys) with PNT. Their ages ranged from 19 to 139 months (median 47.5 months, mean:64.75 months). Skin lesions had been present for 2-24 weeks (median: 4 weeks) before diagnosis. All patients displayed scattered papulo- and/or pustulonecrotic lesions on the limbs, and the ears were involved in six patients. Lesions healed with varioliform scars. Associated pulmonary TB was present in seven patients. Additional clinical findings included fever (n = 4), hepatomegaly (n = 4), lymphadenopathy (n = 3), phlyctenular conjunctivitis (n = 3), and splenomegaly (n = 2). Histology of eight biopsies showed ulceration (n = 6), dermal necrosis (n = 6) (follicle-centered in two), granulomatous inflammation (n = 6) (palisading granuloma-like in three), superficial and deep infiltrate of lymphocytes (n = 7), erythrocyte extravasation (n = 7), and subepidermal edema (n = 3). Vasculitis was not a feature. A Ziehl-Neelsen stain was negative in all. Glycosaminoglycans were not increased. Immunohistochemistry found a predominance of T lymphocytes, macrophages, a few antigen-presenting cells, and no B lymphocytes, consistent with a type IV hypersensitivity reaction. Polymerase chain reaction (PCR) performed on deparaffinized tissue identified M. tuberculosis DNA in one biopsy. All patients received combination anti-TB treatment for 6 months. Six patients were compliant and were followed up for 6-30 months. Skin lesions and pulmonary TB healed in all. PNT in children resembles the adult form, but phlyctenular conjunctivitis and associated TB are more common, scrofuloderma and concomitant erythema induratum of Bazin are unusual, and vasculitis is not found. In cases where M. tuberculosis DNA can be confirmed with PCR, papulonecrotic TB is perhaps the more appropriate nomenclature.

Erythema induratum of Bazin is a tuberculid that is strongly associated with tuberculosis. Clinically, erythema induratum of Bazin show recurrent tender subcutaneous nodules that occur mainly on the calves of women with tuberculin hypersensitivity. Previous studies have not documented the histopathologic spectrum of erythema induratum of Bazin in detail. We identified two major histopathologic groups in 19 of 20 skin biopsies obtained from 20 patients with well-documented erythema induratum of Bazin. Six cases (group I) showed focal septolobular panniculitis in close association with a single muscular artery or small vessel with primary neutrophilic vasculitis. Thirteen cases (group II) revealed diffuse septolobular panniculitis with primary neutrophilic vasculitis of either large or smaller vessels. Both groups showed varying combinations and degrees of acute and chronic inflammation, coagulative and caseation-like necrosis, and granulomatous inflammation. Poorly developed granulomas predominated, but mixed, palisading, and lipophagic granulomas also occurred. Inflammation and necrosis were more extensive in group II. Erythema induratum of Bazin may show predominantly acute suppurative or granulomatous panniculitis. Immunostaining showed S100+ antigen-presenting cells, macrophages, and T-lymphocytes. B-lymphocytes were rare. The presence of primary vasculitis and granulomas suggests that types III and IV hypersensitivity reactions play a role in the pathogenesis or erythema induratum of Bazin. The latter remains a clinicopathologic diagnosis, but awareness of the heterogeneous histopathologic spectrum of EIB will ensure a timely diagnosis and institution of antituberculous treatment.

The tuberculids are hypersensitivity reactions to Mycobacterium tuberculosis (MTB) and include papulonecrotic tuberculid (PNT), lichen scrofulosorum, erythema induratum of Bazin (EIB), and phlebitic tuberculid. Papulonecrotic tuberculid displays papulonecrotic lesions mostly on the extensor surfaces of the limbs. Histopathology shows necrosis, granulomatous inflammation (GI), and occasionally vasculitis, usually in the superficial dermis. Erythema induratum of Bazin shows nodulo-ulcerative lesions on the posterior aspect of the legs. Histopathology reveals a septolobular panniculitis, necrosis, GI, and vasculitis. The Mantoux test is strongly positive and associated tuberculosis (TB) may be present in both conditions. MTB cannot be demonstrated with a Ziehl-Neelsen (ZN) stain or cultured. The polymerase chain reaction has demonstrated MTB DNA in PNT (50%) and EIB (25%). The tuberculids respond to full anti-TB treatment. We document four patients with nodules on the legs in whom the pathologic changes were situated in the deep dermis and adjacent subcutaneous fat. Nodular tuberculid (NT) is regarded as a suitable term for these lesions. All patients were female. Their ages were 19 months, 12 years, 17 years, and 5 years. All patients presented with nodules on the limbs. These nodules were approximately 1 cm in diameter, dull red or bluish-red, and nontender. Ulceration was not present. The number of nodules varied from a few to many. The Mantoux test was strongly positive in all the patients. Associated pulmonary TB was present in two patients. Histopathology showed GI (n = 4), vasculitis (n = 2), and coagulative necrosis (n = 2). A ZN stain was negative in each case. All patients received anti-TB treatment for 6 months [rifampicin (n = 4), isoniazid (n = 4), pyrazinamide (n = 4), and ethambutol (n = 2)]. At 12 months follow-up, skin and pulmonary lesions had resolved in all. Nodular tuberculid should be distinguished from arthropod bites and papular urticaria, dermal erythema multiforme, evolving vasculitis, evolving folliculitis, and erythema nodosum. Histopathologically NT should be distinguished from other causes of granulomatous vasculitis and GI with or without necrosis. In children with nodules on the limbs unresponsive to routine treatment, skin biopsy should be done to exclude NT. Nodular tuberculid represents a hybrid between PNT and EIB with characteristic clinicopathologic features and should be included in the classification of cutaneous TB.

Papular urticaria is the result of hypersensitivity (id-reaction) to bites from certain insects such as mosquitoes gnats, fleas, mites, and bedbugs. Papular urticaria is common in childhood and is characterized by symmetrically distributed pruritic papules and papulovesicles. Scratching causes erosions and ulcerations. Pyoderma is common. Lesions occur in crops. The histopathologic features of papular urticaria are inadequately documented. In a prospective study we recorded the histopathologic features of 30 patients (female, 18; male, 12) with papular urticaria. Their ages ranged from 6-343 months (median = 21 months, mean = 37.73 months). Features that presented in more than 50% of cases included mild acanthosis, mild spongiosis, exocytosis of lymphocytes, mild subepidermal edema, extravasation of erythrocytes, a superficial and deep mixed inflammatory cell infiltrate of moderate density, and interstitial eosinophils. We recognized lymphocytic (n = 4), eosinophilic (n = 9), neutrophilic (n = 7), and mixed (n = 9) subtypes. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections from 10 cases and revealed abundant T-lymphocytes (CD45RO, CD3) and macrophages (CD68) in all cases. B-lymphocytes (CD20) and dendritic antigen-presenting cells (S100) were absent. Direct immunofluorescence staining was conducted on cryostat-prepared sections from 26 specimens. Deposition of IgA, IgG, IgM, C3, and fibrin could not be demonstrated. The histopathologic differential diagnosis of papular urticaria includes other spongiotic dermatitides, pityriasis lichenoides et varioliformis acuta, the pruritic papular eruption of human immunodeficiency virus disease, and papulonecrotic tuberculid. Papular urticaria with marked spongiosis and a dense inflammatory cell infiltrate cannot be reliably distinguished from arthropod bites on clinical and histopathologic grounds. The present study provides morphologic and immunohistochemical evidence that a type I hypersensitivity reaction plays a central role in the pathogenesis of papular urticaria. The putative antigen remains undetermined.

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