A new type of minocycline-induced cutaneous hyperpigmentation

Abstract

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.

The histopathology of subcutaneous minocycline pigmentation

“…Cases that stain for melanin and calcium have been described. 6 Analysis of cutaneous minocycline pigmentation by mass spectroscopy indicates high levels of iron, and, to some degree, calcium. Radiographic microscopic techniques have confirmed that the clinical coloration is a result of a minocycline derivative chelated with iron that is stored within the lysosomes of macrophages.…”

Minocycline Toxicity: Case Files of the University of Massachusetts Medical Toxicology Fellowship

“…Increasing cumulative dose is a risk factor for this type of discoloration, often involving collective doses of more than 100 g [15]. Tissue sections of skin stain positive for Perls' stain (indicating iron) as well as FontanaMasson stain (indicating the presence of melanin) [10,15]. Electron microscopy of these same samples demonstrates membrane-bound pigment collections.…”

“…Since its initial use in the 1960s, there have been reports of discoloration of various body tissues in both animals and humans. Unfortunately, the insidious onset of pigmentation delays patient selfrecognition of the problem, and the variability in patterns of pigmentation encumbers physician recognition [10]. Theories explaining patterns of pigmentation include drug complexes with iron, enhancement of melanocytes, and direct oxidation of drug resulting in pigmented metabolites [11].…”

“…Other types of pigmentation (each separate entity at various points referred to as type IV) have been described as either blue-gray discoloration of scarring on the back (histologically unique from type I) or bluish pigmentation of the lips [10,19].…”

A Case of Melanoacanthoma: Immunohistochemical Staining Using VECTOR® NovaRED(TM) to Distinguish Melanocytes from the Cutaneous Pigment

“…This novel chromogen stains melanocytes red, which then can be differentiated from surrounding brown-colored melanin-laden keratinocytes. It has also been used in the cases to detect the micrometastases of melanoma or histopathological classification of minocycline-induced cutaneous hyperpigmentation 8,9 . Two cases of melanoacanthomas have been reported in Korean literature, but to our knowledge there is no reported case of staining using this novel chromogen VECTOR Ⓡ NovaRED TM 10,11 .…”