DIAGNOSIS: Black thyroid syndrome, a.k.a. Melanosis Thyroidi due to Minocycline therapy DISCUSSION Minocycline-induced black thyroid (MIBT) is a rare condition that was first described in 1967 by Benitz et al. in the thyroidal tissues of laboratory animals. 1 It was not documented in the thyroid glands of humans until nearly 10 years later when Attwood et al. reported a single case at autopsy in a man with bronchiectasis and emphysema treated antemortem with twice daily minocycline for one year. 2 A tetracycline-derived, semisynthetic broad-spectrum antibiotic, minocycline was first used clinically in 1967. It is used most commonly to treat long-term acne vulgaris but also can be used to treat other bacterial infections such as pneumonia, urinary tract infections, skin infections, and methicillin-resistant Staphylococcus aureus infections as may be seen in osteomyelitis. 3 Pigmentation as a side effect of minocycline therapy has not only been seen in the thyroid gland but has also been documented in the skin, oral mucosa, bone, nail beds, heart valves, and teeth. 4,5 Since the original MIBT publication, the literature cites approximately 60 total cases, some following minocycline exposures as short as 12 days in duration. 6 Pathologic examination of aMIBT reveals characteristic gross features, including the eponymous charcoal black coloring in a full-thickness distribution from the capsular layer throughout the entire thyroid parenchyma. Neither gland enlargement (goiter) nor nodularity of the thyroid is specifically associated with the pigment deposition. Histol- ogy reveals intracytoplasmic accumulation of “dust like” granules most oftenwithin follicular epithelial cells or tissue macrophages. The differential diagnosis includes iron and ochronotic pigment depositions. Iron accumulation within the thyroid can be seen in patients with hemosiderosis ei- ther due to primary or secondary hemochromatosis. Iron, however, typically manifests grossly as a ruddy or maroon discoloration and will stain positively with iron stains such as Prussian blue. Ochronotic pigment is a black-appearing pigment that accumulates in tissue in association with the autosomal recessive condition of ochronosis. It, however, displays refractile properties under polarized light and has yet to be published within the thyroid gland. 7 The nature of the black pigment in MIBT remains de- bated. Considerations have included lipofuscin, melanin, neuromelanin, a melanin-like substance, or simply oxida- tive byproducts of minocycline. 8 Several mechanisms for the accumulation of black pigment in thyroid tissue have been hypothesized, but the most reliable consensus seems to center around the fact that minocycline is a competitive inhibitor of thyroid peroxidase and thereby, becomes itself oxidized. 6,9 Clinically, MIBT has long been thought to be a harmless phenomenon without clinical ramifications. However, in some recent literature reviews, MIBT has been suggested
as a potential marker for thyroid carcinoma. In one such 2001 study of 28 reported MIBT cases by Birkedal et al.,11 of the MIBT patients (39%) also had papillary carcinoma. 5 With an additional case of MIBT, in conjunction with pap- illary carcinoma to report, Bruins et al., in 2007, make the comparative remark that the observed incidence of thyroid cancer inMIBT patients approached 40%while the observed incidence of thyroid cancer in the general population ap- proximated 0.003% or 3/100,000. 10 In 2010, six additional patients withMIBT and carcinoma were added to the litera- ture, leading to published recommendations that clinicians attend differently to thyroid glands with black pigmentation. Recommendations also endorsed a more comprehensive pathologic examination of MIBT thyroidectomy specimens, including submission of a greater number of blocked sec- tions per specimen for histopathology. 11,12 And finally in 2011, in an effort to establish the malignant potential of black thyroid syndrome, Kandil et al. conducted a retrospective chart review of more than 400 patients who underwent thyroid surgery for nodular lesions. The authors calculated a 15% incidence of MIBT (63/433) and found significantly more malignancy in the MIBT group than the non-MIBT group [50.8% vs. 29.8%, p<0.002]. Conversely, benign le- sions were statistically more likely in the non-MIBT group than those with black thyroid syndrome. 12 The current case demonstrates the classic features of minocycline-induced black thyroid syndrome (MIBT), sometimes known as a Melanosis thyroidii. Histology was characteristic, and iron stains were negative. There was no evidence of malignancy on multiple histologic sections submitted. The diagnosis was made incidentally at the time of autopsy. There is currently an additional need for case reporting of MIBT in order to establish any causal link between pigmentation and the development of malignancy. A longtime believed harmless phenomenon, MIBT should be reconsidered by clinicians across disciplines as further mechanisms of possible carcinogenesis are explored. In the meantime, the current literature supports a more thorough pathologic examination of these surgical specimens than once previously recommended. ACKNOWLEDGEMENTS The authors would like to gratefully acknowledge the support of the Orleans Parish Coroner’s Office: Dr. Frank Minyard and Chief Investigator JohnGagliano for providing the case material for this report. REFERENCES 1. Benitz KF, Roberts GK, Yusa A. Morphologic effects of minocycline in laboratory animals. Toxicol Appl Pharmacol 1967;11:150–170. 2. Attwood HD, Dennett X. A black thyroid and minocycline treatment. Br Med J 1976;2:1109–1110. 3. http://www.nlm.nih.gov/medlineplus/druginfo/meds/ a682101.html (Accessed March 14, 2014) 4. Treister NS, Magalnick D, Woo SB. Oral mucosal pigmentation
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