Hyperpigmented Scar Due to Minocycline Therapy
A 20-year-old woman presented with a heavily pigmented scar on the left lower abdomen following excision of a benign compound nevus. Reexcision showed an organizing scar with pronounced hemosiderinlike pigment deposition and no residual melanocytic lesion. Results of further histopathologic workup showed positive staining with both Perls stain for iron and Fontana-Masson stain. These findings led to further questioning of the patient, which revealed a history of minocycline therapy—information that had not been provided during her initial evaluation. Hyperpigmented scars may result from minocycline ingestion. We present a review of the literature, with particular regard to the possible mechanisms of minocycline hyperpigmentation and the differential diagnosis of hyperpigmented scars.
The duration of treatment and total dose required for minocycline to produce cutaneous pigmentation is difficult to determine. Although data on duration and total dose are often provided in reports, these figures typically reflect the totals at the time the patients present to their physician, rather than the time of actual onset of pigmentation, which is much more difficult to determine. Localized pigmentation at a site of tissue injury does not appear to be directly related to the duration of treatment18 and has been reported to occur as rapidly as 1 to 3 months following the onset of minocycline therapy.16,19 The evidence suggests that the diffuse type of pigmentation is more dependent on total dose and duration of therapy; reported patients have been on minocycline for about 3 years, with total doses ranging from 130 to 144 g.24,25
As generally described, there are differences among the microscopic features of the 3 major types of minocycline pigmentation. In type I, the dermal pigment is present in macrophages and stains positively for iron in a manner similar to hemosiderin.13,16,17 Type II pigmentation stains for iron and also is reactive with Fontana-Masson.10,20,33 Type III pigmentation has shown an increase in basilar melanin and brown-black pigment in macrophages that stains positively with Fontana-Masson and negatively for iron.24 However, staining results are not always distinctive among the 3 types. For example, in our patient's scar and in the inflammatory lesions of Ozog et al19 (examples of type I pigmentation), there was dermal pigment that stained positively both for iron and with the Fontana-Masson method. Patients also may have more than one type of cutaneous minocycline pigmentation. In the case of Pepine et al,25 there were areas of blue-black pigmentation, as well as muddy brown discoloration in sun-exposed areas. Biopsy results showed black pigment deposition in perivascular and periadnexal areas, though it is not entirely clear whether these specimens were obtained from blue-black or muddy brown areas.25 Electron microscopy in cases with blue-gray or blue-black pigmentation has shown electron-dense particles in macrophages or extracellularly. Some intracytoplasmic granules are present within lysosomes, while others, including fine dustlike particles consistent with ferritin, are not bound by lysosomal membranes.10,17,20,25 Energy dispersive x-ray microanalysis has shown that the granules mostly contain iron, with lesser amounts of calcium.21,26
The Fontana-Masson staining method is routinely employed to demonstrate the presence of melanin in tissue sections. Therefore, positivity in instances of minocycline pigmentation has suggested to some that melanin is at least partly responsible for the changes. This idea has been supported by one ultrastructural study showing melanosome complexes in siderosomes in a case of minocycline-related hyperpigmentation.21 However, melanosomes have not been identified in other studies.10 It is reported that iron may give positive reactions with Fontana-Masson staining.20 Furthermore, the black staining of Fontana-Masson results from the action of a reducing substance on ammoniated silver nitrate; that reducing substance is not necessarily melanin.10 The failure of the pigment to bleach, in contrast to the case with melanin, has been used to support the idea that the pigment in question does not contain melanin.10 However, reported results with bleaching have been variable. Successful bleaching or partial bleaching has been observed in examples of cutaneous minocycline pigmentation,19 as well as minocycline pigmentation of the thyroid gland34 and heart valves.32 This also is true of our case, because Fontana-Masson staining became negative when preceded by a bleaching procedure. Because past studies have employed several bleaching agents—hydrogen peroxide and potassium permanganate—and because the concentrations used in bleaching and other technical details are rarely provided, in our view, one cannot rely on the results of bleaching alone as proof of the presence or absence of melanin.
The evidence suggests that most examples of minocycline pigmentation—particularly types I and II—are due to cutaneous deposits of the drug or a metabolite thereof, chelated with iron.10,17,26,35 Clues to the mechanism of pigment deposition are provided by the studies of thyroid pigment by Enochs et al.36 Their in vitro modeling studies using electron paramagnetic resonance spectroscopy suggest that the pigment is a polymer caused by the in vivo oxidation of minocycline by thyroid peroxidase, which produces a melaninlike pigment.36 This pigment also contains significant amounts of iron, tightly bound in situ. A related phenomenon could well occur in the skin. Then, as suggested by Argenyi et al,10 the metabolite could act as a reducing substance, explaining the frequent positivity with the Fontana-Masson stain. It is possible that minocycline also may stimulate melanin production, accounting for the diffuse muddy brown type III pigmentation,17 but further studies are needed to clarify this point. The good news is that minocycline pigmentation resolves after cessation of therapy, though this may be a gradual process.17,19,25,37
Conclusion
