A case of minocycline-induced black thyroid

associated with papillary carcinoma

| Reprints
March 16, 2016
by Kohei Nishimoto, MD, PhD; Yoshihiko Kumai, MD, PhD; Daizo Murakami, MD, PhD; Eiji Yumoto, MD, PhD

Abstract
We report a rare case of black thyroid accompanied by papillary carcinoma in a patient with an
extended history of minocycline treatment. A 78-year-old man was referred to our outpatient clinic
with swelling in his neck. He had been taking minocycline for the previous 2 years and 7 months to
treat chronic perianal pyoderma. Neck ultrasonography and computed tomography demonstrated a
3.5 x 3.7 x 5.0-cm nodule in the left thyroid lobe, and fine-needle aspiration cytology identified it as a
papillary carcinoma. The patient underwent a total thyroidectomy and neck dissection. During the
procedure, a distinct black discoloration of the thyroid parenchyma was observed. Histopathology
confirmed both the black thyroid and the papillary carcinoma. Based on the thyroid gland's
discoloration and the history of minocycline use, the patient was diagnosed with minocycline-induced
black thyroid. He was symptom-free 20 months after surgery.

Introduction
Black thyroid, which is characterized by a black discoloration of the thyroid gland, is a rare condition
that is usually diagnosed incidentally during thyroid surgery or at autopsy. Since Attwood and
Dennett reported the first case of black thyroid in 1976, 1 black discoloration has been considered
pathognomonic of long-term treatment with minocycline. Although black thyroid was long considered
a harmless phenomenon,2,3 it more recently exhibited evidence of malignant potential. 3,4
To the best of our knowledge, only 9 cases of papillary carcinoma associated with minocyclineinduced black thyroid (MIBT) have been previously reported in the literature. 2,3,5-11 Herein we report

a new case of papillary carcinoma associated with MIBT, and we review the literature related to
MIBT.

Case report
A 78-year-old man consulted an otolaryngologist for evaluation of swelling in the anterior neck. He
was diagnosed with a thyroid tumor and referred to our Department of Otolaryngology-Head and
Neck Surgery at the Kumamoto University Hospital in Kumamoto, Japan. According to the patient's
history, a dermatologist had prescribed minocycline at 200 mg/day to treat chronic perianal
pyoderma; the patient had been taking the drug for 2 years and 7 months at the time of our
evaluation.
The patient also had been taking hormone therapy for prostate gland carcinoma for 1 month, and he
had a long history of insulin treatment for diabetes mellitus (his hemoglobin A1c concentration was
8.6%). The patient also had a distant history of treatment for pulmonary tuberculosis 60 years earlier.
On physical examination, remarkable black pigmentation was observed over the patient's entire
face, especially on his forehead and lips (figure 1). Neck ultrasonography and computed tomography
demonstrated a 3.5 x 3.7 x 5.0-cm nodule that contained a small area of calcification in the left
thyroid lobe. The nodule had compressed the trachea on the left side. Fine-needle aspiration
cytology indicated that the nodule was a papillary carcinoma.

Figure 1. At presentation, the black pigmentation

is seen on the patient's face and especially his
forehead and lips.

Laboratory testing revealed that the patient's thyroid function was within normal limits; his free
thyroxine level was 1.19 ng/dl (reference range [RR]: 0.90 to 1.70), his free triiodothyronine
concentration was 2.95 pg/ml (RR: 2.30 to 4.00), his thyroid-stimulating hormone level was 2.80
IU/ml (RR: 0.50 to 5.00), and his serum thyroglobulin value was 156.8 ng/ml (RR: <32.7).
A total thyroidectomy and central lymph node dissection were performed. During the procedure, both
thyroid lobes exhibited a diffuse black discoloration (figure 2, A). The cricoid cartilage and tracheal
rings also showed black discoloration (figure 2, B). The tumor showed no obvious invasion into the
trachea. The excised right lobe was diffusely black, and the left lobe was occupied by a solid tumor,
which had failed to absorb black pigment (figure 3).

Figure 2. A: During thyroidectomy, the thyroid

gland
exhibits
a
distinct
black
discoloration. B: The
cricoid
cartilage
and
tracheal rings also show black pigmentation.

Figure 3. A: Macroscopically, the right lobe is

diffusely black and the left lobe is occupied and
expanded by a solid tumor.B: The tumor (arrows)
has not absorbed black pigment.

Histopathologic examination revealed that the non-neoplastic thyroid parenchyma contained a

diffuse distribution of dark-brown granules in the cytoplasm of the follicular epithelium and colloid
(figure 4, A and B). The granules existed only in the normal thyroid parenchyma and not in the
neoplastic tissue (figure 4, C). The granules were positive on Fontana-Masson staining (figure 4, D);
staining for hemosiderin (Berlin blue stain) was negative. These features suggested that the
discoloration of the thyroid was made by melanin-like pigmentation. The tumor of the left lobe
contained a 2.9 x 4.6-cm papillary carcinoma, and 8 of 10 lymph nodes (1 pretracheal, 3
paratracheal, and 4 perithyroidal on the left side) contained metastatic papillary carcinoma
(pT3pN1aM0, stage III). No local recurrence or distant metastasis was observed during 20 months of
follow-up.

Figure 4. A: The non-neoplastic lesion shows a

brown area in the colloid (H&E; scale bar: 200
m). B: The dark-brown granules are diffusely
distributed in the cytoplasm of the follicular
epithelium and colloid (H&E; scale bar: 50
m). C:The marginal area of the neoplastic lesion
is seen in contact with granules. The cytoplasm
fails to absorb the granules (H&E; scale bar: 50
m). D: The granules are positive on FontanaMasson staining (scale bar: 50 m).

Discussion
The mechanism of hyperpigmentation in black thyroid remains unclear. In fact, there is not even a
precise definition of black thyroid. On histochemical staining, the pigment has typically been
identified as a melanin-like substance or as lipofuscin, a lipid-derived oxidation product of cellular
metabolism.1,5,6
Several studies have demonstrated that pigments naturally accumulate in the thyroid gland with
advancing age. Moreover, Gordon et al reported dark-brown thyroid glands with lipofuscin deposition
in 2 human volunteers (aged 27 and 67 yr) who had never taken minocycline. 12 Conversely, Landas
et al reported that accelerated pigment accumulation is not often found in the thyroid gland without
minocycline treatment.5 In view of this confusion, our literature review focuses on reported cases in
which black discoloration of the thyroid gland with hyperpigmentation occurred after minocycline
administration, and we defined them as MIBTs.
Minocycline is a semisynthetic derivative of tetracycline, and it is commonly used in clinical situations
because it has several pharmacokinetic advantages over other tetracyclines. In addition to its
antibacterial effect, minocycline also exerts an anti-inflammatory effect, and thus it is often used in
the treatment of severe acne.13 On the other hand, minocycline carries a higher risk of severe
adverse effects than do other tetracyclines.
Minocycline administration is often associated with pigmentation, and it has the potential to affect
various organs. Black pigmentation following minocycline administration has been reported on the

skin, nails, teeth, blood vessels, heart valves, and bones. 14 In general, minocycline-induced
pigmentation occurs as a result of long-term use at cumulative doses greater than 100 g; in some
cases, cutaneous or oral mucosal pigmentation may appear regardless of the size of the dose or the
duration of therapy.14
In our case, the patient had been administered a high dose (200 mg/day) of minocycline for 2 years
and 7 months, which calculates to a cumulative dose of approximately 188 g; this might explain the
pigmentation of the skin on the forehead, the tracheal cartilage, and the thyroid gland. Based on the
black discoloration of the thyroid gland and the history of minocycline administration, our patient was
diagnosed with MIBT. The pigments in the thyroid parenchyma outside the tumor were positive on
Fontana-Masson staining and negative on iron (hemosiderin) staining, indicating the presence of
melanin-like granules.15
There are several possible causes of hyperpigmentation other than minocycline administration.
These causes include hemorrhage, hemochromatosis, ochronosis, cystic fibrosis, melanin-producing
medullary carcinoma,16,17 and antidepressant drug administration. 6 Kandil et al retrospectively
studied 433 patients who had undergone thyroid surgery at their institution, and they diagnosed 63
cases (14.5%) as black thyroid based on pathologic examination. 4 However, neither the gross
thyroid color nor any history of minocycline use was mentioned in their report, so the high incidence
of black thyroid led to speculation that these cases also included naturally accumulated pigmentation
or other causes of hyperpigmentation. Among the 49 known cases of MIBT that have been reported
thus far, 10 (including ours) have been diagnosed as papillary carcinoma (20.4%). 2,3,5-11,18
The worldwide incidence of thyroid cancer was estimated in 2008 to be 0.0031%. 19 Burgess and
Tucker studied 1,920 thyroid surgeries and found that they included 121 cases of papillary
carcinoma (6.3%).20 Because of the relatively high frequency of papillary carcinoma among the
reported cases of black thyroid, we initially hypothesized that the MIBTs would possess malignant
potential. However, the frequency may differ depending on the case selection. 7
In addition, no reports have proven a causal relationship between MIBT and papillary carcinoma. In
animal experiments, Gordon et al administered minocycline to 9 rats, 5 dogs, and 6 monkeys for
periods ranging from 1 month to 1 year, and they found that while the animals developed
minocycline-induced pigment, none of their thyroid glands contained a neoplastic lesion. 12
Apart from the thyroid glands, minocycline has not been considered as a cause of cancer in any
other site. In fact, studies have shown that minocycline inhibits ovarian cancer growth in vitro and in
vivo.21Accumulation of additional animal and clinical data is necessary to clarify the causal
relationship between MIBT and malignancy.

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From the Department of Otolaryngology-Head and Neck Surgery, Kumamoto University Graduate
School of Medicine, Kumamoto Japan.
Corresponding author: Kohei Nishimoto, MD, PhD, Department of Otolaryngology-Head and Neck
Surgery, Kumamoto University Graduate School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556,
Japan. E-mail: koheihei@gmail.com