Papillary thyroid cancer in black thyroid: a case report and literature review

Introduction

Black thyroid refers to overall black discoloration of the thyroid gland. It was first reported in humans in 1976, and is a rare finding, usually discovered incidentally during surgery (1). More than 250 cases of black thyroid have been reported in literature (2). This phenomenon results from the prolonged usage of tetracycline antibiotics, antidepressants, or lithium, which can cause the accumulation of dark brown or black pigments in thyroid follicular cells (3).

Minocycline [2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S-(4alpha,4a alpha,5a alpha,12a alpha))] is a semi-synthetic antibiotic in the tetracycline family and is generally used as a treatment for acne vulgaris (4). It has been reported to cause pigmentation in various tissues, including the skin, nails, oral mucosa, teeth, eyes, bones, cardiac valves, coronary vessels, substantia nigra, and atherosclerotic plaques (5). Pigmentation can occur more frequently in patients who have taken minocycline for more than one year at cumulative doses of >100 g, although the duration of minocycline use prior to black thyroid discovery varies from 27 days to 20 years (6,7). The causal relationship between minocycline and black thyroid has been attributed to the drug reacting with thyroid peroxidase, producing a black, insoluble, nonfluorescent pigment (8).

The impact of minocycline on the black thyroid has often been reported to be harmless. It occasionally presents with neck swelling, thyroiditis, and benign thyroid neoplasms (9,10). Meanwhile, several studies have reported cases of carcinoma in minocycline-induced black thyroids. However, a causal relationship between them has not yet been demonstrated (6,11).

In this report, we present the case of a patient with papillary thyroid cancer (PTC) who was incidentally found to have black thyroid during surgery. In the past two years, the patient has been taking minocycline as a treatment for rosacea. We present the following case in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-22-482/rc).

Case presentation

Patient

A 29-year-old woman presented to a hospital after noticing a palpable lymph node (LN) at the left neck level V and was referred to our hospital because of a suspicious nodule in the left thyroid with cervical lymphadenopathy. Fine needle aspiration biopsies (FNAB) were performed in the thyroid nodule and the largest suspicious LN in the left neck level IV, which were confirmed as ‘atypia of undetermined significance (Bethesda category III)’ with focal features suggestive of PTC and ‘metastatic PTC’, respectively. She had a medical history of anxiety disorder and depression that was treated with benzodiazepines and a selective serotonin reuptake inhibitor for 10 years. She had been suffering from severe acne and rosacea for the past two years, and had been taking isotretinoin and minocycline for 19 months. She did not have any history of thyroid disease or irradiation exposure, and had no family history of thyroid cancer.

Physical examination of the neck revealed a hard LN at the left level V. Laboratory serum test results, including complete blood count, electrolytes, and thyroid function, were normal. Cervical ultrasonography showed a solid, hypoechoic, irregular nodule with microcalcifications in the upper posterior portion of the left thyroid. The lesion measured 0.9 cm in the longest diameter on the longitudinal view, showing no capsular invasion. Multiple punctate echogenic foci were observed in the entire left lobe and isthmus. Suspicious LNs were noticed in the left neck levels III, IV, V, and VI, with the largest LN at neck level IV measuring 1.6 cm in diameter.

To further evaluate the metastases in the retropharyngeal or superior mediastinal regions, and the lung, a thoracocervical 64-slice computed tomography (CT) scan with intravenous contrast was performed. CT scan showed an approximately 0.8 cm-sized, ill-defined, low-density lesion in the left thyroid and multiple enlarged LNs with contrast enhancement in the left neck levels III, IV, V, and VI. None of the radiologic findings suggested pulmonary metastasis.

Thyroid surgery

The patient underwent total thyroidectomy with left central compartment neck dissection (CCND), and left modified radical neck dissection (MRND). A black thyroid was identified during thyroidectomy (Figure 1). After thyroidectomy, CCND and left MRND were performed by dissecting LNs at left neck levels IIA, III, IV, Vb, and VI. During level IV dissection, we noticed a similar black discoloration in the adipose tissue of the lower neck level IV specimens (Figure 1). After surgery, the patient was informed of the black thyroid. The patient was administered 88 mcg of levothyroxine from postoperative day 1 and had an uneventful postoperative recovery.

Figure 1 Specimens resected from the thyroid gland and cervical lymph nodes. White arrows indicate black discoloration.

Pathology

Gross examination of total thyroidectomy with CCND and left MRND specimens revealed an entirely dark brown-colored thyroid weighing 23 mg (Figure 2A). Several foci of the thyroid parenchyma showed brown pigmentation with a few macrophages (Figure 2B,2C). The serial section revealed a calcified white-yellow lesion in the left upper pole, measuring 0.7 cm × 0.6 cm × 0.4 cm (Figure 2A). On staining with hematoxylin and eosin (H&E), PTC with classic papillary structure, nuclear pleomorphism, nuclear membrane irregularity, and chromatin clearing were identified. No pigmentation was observed in the tumors (Figure 2D). On conducting further molecular studies, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation [Ch 7q34, exon 15, V600E point mutation (c.1799T>A)] and telomerase reverse transcriptase (TERT) promoter mutation (Ch 5p15.33, TERT C228T, C250T point mutation) were not detected. The LN specimen included 12 of 38 LNs confirmed to be metastatic carcinomas without extranodal extension, and the largest metastatic deposit size measured up to 1.6 cm. The serial section revealed no brown pigments in the metastatic LNs, normal LNs, or background adipose tissue (Figure 3). According to the 8^th edition of the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) classification system, the pathological stage was determined as T1aN1bM0, stage I.

Figure 2 Histopathological findings of thyroid and PTC. (A) Gross examination of the thyroid gland and tumor. An ill-defined, calcified, white-yellow mass indicates a PTC (red arrow). (B) Thyroid parenchyma with brown pigment (blue arrows). H&E staining (×200). (C) Thyroid parenchyma with other brown pigments (blue arrows). H&E staining (×200). (D) PTC. Papillary structures with atypical cells showing nuclear pleomorphism, nuclear membrane irregularity, and chromatin clearing. H&E staining (×40). PTC, papillary thyroid cancer; H&E, hematoxylin and eosin.

Figure 3 Histological findings of metastatic LNs. (A) Central LN. H&E staining (×40). (B) Lateral LN. H&E staining (×40). LN, lymph nodes; H&E, hematoxylin and eosin.

Radioactive iodine (RAI) treatments after surgery

Adjuvant RAI ablation treatment was indicated for the patient owing to the lymphatic invasion of the tumor, and N1 disease with 1.6 cm in the largest dimension, which were intermediate risk factors for disease recurrence according to the 2015 American Thyroid Association (ATA) risk stratification system. One month after cessation of levothyroxine medication and exogenous stimulation with recombinant human thyroid-stimulating hormone (TSH), she received RAI ablation treatment by administration of 150 mCi I-131 with no adverse events. A whole-body scan (WBS), following therapeutic RAI ablation, showed residual uptake in the thyroid bed alone (postoperative 2 months).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The black thyroid is an unusual and incidental finding during surgery or autopsy. Diagnosing a black thyroid using FNAB is unreliable and extremely rare. Black or brown pigmentation has been scarcely reported, and mimicking factors and other differential diagnoses should also be considered (12,13). Our patient’s FNAB result for the thyroid nodule was atypia of undetermined significance, with no evidence of pigmentation. In our patient, black thyroid was found incidentally during surgery, similar to previous reports (14).

The cause of this condition can be determined by examining the patient’s medications and other medical conditions. Minocyline-induced black thyroid has been occasionally reported since it was first described in 1967 in animal trials (15). Antidepressants, including lithium and tricyclic antidepressants, have been found to correlate with black thyroid (16). Other differential diagnoses should also be investigated, such as hemochromatosis, ochronosis, cystic fibrosis, ceroid storage disease, bruising and hemorrhage (13). Our patient had a medical history of long-term anxiety disorder with depression, but she did not take antidepressants containing lithium or tricyclic antidepressants. We recognized that the patient was on minocycline for 19 months, to treat acne and rosacea, which is a drug highly associated with the production of black pigmentation in the thyroid.

Minocycline-induced black thyroid is often identified as a harmless condition. It is usually asymptomatic and has no role in thyroid dysfunction (9). However, several reports have described accompanying symptoms of neck swelling, thyroiditis, thyroid dysfunction, and benign thyroid neoplasms (9,10,17,18).

Since black thyroid is mostly discovered during surgery, multiple cases of thyroid cancer in black thyroid have been consistently reported. The incidence of thyroid cancer in black thyroid ranges from 30% to 65% (11,19,20). Previous studies have reported that Caucasians have a significantly higher incidence of thyroid cancer in black thyroid than other ethnicities. No significant differences were observed in sex or age distribution (11,20).

In the pathological aspect, decreased pigmentation of malignant cells compared to the surrounding tissue is interestingly common in cases of black thyroid with PTC (9). In our case, the pigmentation was found only in the thyroid parenchyma, but not in the thyroid tumor. Pigmentation was also not found in the metastatic LNs, normal LNs, or background adipose tissue. This is consistent with the previous reports.

Although the causal relationship between minocycline-induced black thyroid and thyroid cancer has not been proven, few studies have identified a significantly higher incidence of thyroid cancer in black thyroid glands than in non-black thyroid glands (11,20). PTC was most frequently observed in black thyroids. Other thyroid malignancies, including follicular and Hürthle cell carcinomas, were less frequently found in black thyroids.

When evaluating the correlation between black thyroid and PTC aggressiveness, these studies yielded diverse results regarding tumor size. No significant differences were found in tumor multifocality (11,20). None of the previous studies have yet evaluated the association between black thyroid and LN metastasis of PTC.

Owing to the relative scarcity of data, the clinical relevance of black thyroid in thyroid cancer remains unclear. Previous reports on higher incidence of PTC in black thyroid can be a comprehensible finding, since the recognition of black thyroid predominantly occurs during surgery. Spared pigmentation in malignant tumors compared to surrounding tissue and the unproven carcinogenic activity of minocycline still raise questions on their relationships (9,21). Thus, proper treatment strategy has not yet been established. Despite the possible selection bias and different methodologies, the higher incidence of thyroid cancer in black thyroid warrants precise evaluation of the effect of minocycline-induced black thyroid on thyroid malignancy. Since our patient was the first case of minocycline-induced black thyroid with PTC at our institution, determining their relationship was not possible. Further evaluation with a larger number of subjects is necessary.

From the patient’s perspective, black pigmentation in other organs should be considered. Macroscopically, black discoloration was observed not only in the thyroid gland but also in the surrounding adipose tissue. Currently, no other foci of pigmentation have been found in our patient, but black discoloration can occur in any organ (7). Moreover, even with no proven association between black thyroid and malignancy, cessation of minocycline medication and careful follow-up studies are recommended. After surgery, the patient agreed to the cessation of minocycline medication, and the follow-up evaluations were planned in 6 months after RAI treatment.

Conclusions

Herein, we report a case of PTC with cervical LN metastases in a black thyroid. Consistent with previous reports, our patient’s minocycline use was the most plausible cause of black thyroid. It was discovered incidentally during surgery for thyroid cancer. In our case, black discoloration was also seemingly observed in the surrounding adipose tissue of the neck level IV. Pathologic examination identified brown pigmentation in the thyroid parenchyma, but not in the thyroid tumor, LNs, or surrounding adipose tissues. Even with obscure clinical implications of minocycline-induced black thyroid in PTC, higher incidence of PTC in black thyroid can warrant the avoidance of prolonged (>1 year) minocycline use. In the absence of adequate evidence, prolonged minocycline users should ideally undergo routine thyroid assessment to identify possible malignancy.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-22-482/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-22-482/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-482/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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