Thyroid tuberculosis: an unexpected diagnosis

Abstract

Mycobacterium tuberculosis (MTB) is an aerobic bacillus responsible for tuberculous infection. The the thyroid gland being affected by MTB is a rare condition. A 71-year-old woman had 6 months of slight cervical discomfort. Her neck ultrasound showed, at the right lobe of the thyroid, a dominant heterogeneous nodule of 18 mm and homolateral lymph nodes with suspicious ultrasonographic features. The patient underwent fine-needle aspiration, the results of which were non-diagnostic (thyroid nodule) and reactive pattern (lymph node). A total thyroidectomy was performed and a lymph node was sampled for extemporaneous examination. Surprisingly, necrotising granulomas were documented. The diagnosis was definitely established by a positive culture of the lymph node tissue and molecular detection of MTB. Pulmonary involvement was excluded and she was started on antituberculous agents. In the absence of systemic, specific complaints or history of exposition, histopathology and culture of MTB remain a key step for the diagnosis.

Background

Mycobacterium tuberculosis (MTB) is an aerobic bacillus responsible for most cases of tuberculous infection. Approximately one-third of the world’s population is estimated to be infected.^{1 2} Tuberculosis (TB) of the thyroid gland is an extremely unusual diagnosis. Its prevalence varies from 0.1% to 0.6% in histologically diagnosed specimens.³ A systematic medical review in 2017 found only seven cases since 2010 in western European countries where TB is non-endemic.⁴ The thyroid gland seems to be relatively resistant to the infection, yet the underlying mechanisms are still not clarified.⁵ The involvement of the gland can be primary or secondary. The secondary TB is more common and the bacillus reaches the gland via hematogenous, lymphatic route or directly from larynx or cervical tuberculous nodes. The primary TB is rare, can be insidious and mimics different pathologies: thyroid tumour, lymphoma, infectious thyroiditis, Graves’ disease, multinodular goitre or bacterial abscess.^6–8 This diagnosis can be easily disregarded, especially in non-endemic countries and if the patient has a primary form, because the clinical and imagological findings can be non-specific. Fine-needle aspiration under ultrasound guidance followed by cytology with acid-fast bacilli staining, histopathological examination with acid-fast bacilli staining or TB culture is the gold standard examination.⁹ We present the case of a 71-year-old woman without systemic symptoms except a palpable cervical mass, which was mistaken for a probable malignant thyroid nodule, that subsequently underwent total thyroidectomy.

Case presentation

The patient, a 71-year-old-woman, was referred to our Endocrinology Outpatient Clinic following a diagnosis of nodular thyroid disease performed 4 months earlier, without symptoms of thyroid dysfunction. The only complaint was cervical discomfort for 6 months. She denied dyspnoea, dysphagia, dysphonia or sore throat. She was medicated for dyslipidaemia and epilepsy.

The patient had no recent travel history and had no known exposure to TB. There was no history of neck irradiation. She denied alcohol or tobacco consumption. The family history was unremarkable, particularly for thyroid diseases.

On physical examination, she had a good general condition, her temperature was 36.8°C, blood pressure was 135/70 mmHg and heart rate was 68 beats per minute. At cervical examination, the thyroid gland was soft, painless and slightly enlarged. A movable, elastic and non-tender nodule of 1.5 cm, at the right superior thyroid lobe, and small enlarged homolateral lymph nodes were identified. No axillary or inguinal lymphadenopathies were identified. Otherwise, examination of her heart, respiratory and abdominal systems was normal.

Investigations

Thyroid blood tests and erythrocyte sedimentation rate were normal. A neck ultrasound showed a slight enlargement of both lobes with a heterogeneous pattern due to bilateral small solid nodules. At the right lobe, there was a solid nodule of 18 mm with heterogeneous echogenicity and multiple calcifications reported as European Thyroid Imaging Reporting and Data System category 4 (EU-TIRADS 4), as well as another two adjacent nodules with the same suspicious characteristics, one with 11 mm and the other with 10 mm in largest dimensions. In addition, multiple adenopathies along the right internal jugular chain, the largest localised at level IV with 24×17×14 mm, were reported. Fine-needle aspiration cytology (FNAC) of both the dominant thyroid nodule and the largest adenopathy was performed; the result was non-diagnostic (Bethesda I) for the former and lymph node with reactive pattern for the latter. The FNAC was repeated for both and the results were similar.

Differential diagnosis

Thyroid TB is rare and may mimic different conditions. Usually, it is not investigated. The clinical presentation may be acute, subacute or even silent. The differential diagnosis in the case of acute presentation includes other infectious conditions.

The patient, presented herein, was asymptomatic except for a slightly cervical discomfort and had a painless thyroid palpation with normal thyroid tests. Thus, the main differential diagnosis was a benign nodular goitre or a carcinoma. The presence of lymph nodes, regarded as suspicious by ultrasonographic criteria, was in favour of the latter hypothesis. Another hypothesis, taking into account the cervical discomfort lasting for 6 months, was a thyroid lymphoma.

Primary thyroid lymphoma is a rare condition, presenting, most of the times, as a rapidly growing cervical mass, frequently associated with cervical lymph nodes. The most common manifestation is the diffuse enlargement of the gland. Although rare, its manifestation can be a single nodule. Usually, it occurs in patients with a previous diagnosis of Hashimoto’s thyroiditis and is associated with systemic B symptoms of lymphoma. The FNAC is the initial diagnostic procedure for thyroid tissue sampling, yet it has low sensitivity, and a cytology with flow cytometry, or a core biopsy with flow cytometry, or immunohistochemical staining is needed to establish the diagnosis. In a number of cases, the diagnosis is histological.¹⁰

The paucity of clinical manifestations and the absence of a history of TB ruled out the suspicion of thyroid TB. Given the clinical suspicion and inconclusive results of FNAC, knowing that the rate of malignancy of Bethesda 1 (non-diagnostic or unsatisfactory) is up to 10%, we decided for a surgery.¹¹ The extension of surgery (hemithyroidectomy vs total thyroidectomy) was discussed with the patient who preferred total thyroidectomy.

Further to the hypotheses presented above, other rare diagnoses such as sarcoidosis might be considered in the differential diagnosis of a patient with a painless form of primary thyroid TB.¹²

Treatment

Owing to a strong suspicion of malignancy with bilateral nodules in this patient, it was decided to perform total thyroidectomy with an extemporaneous examination of a lymph node. Necrotising granulomas were identified in all the three removed lymph nodes. The Ziehl-Neelsen staining (ZNS) was negative. Thyroidectomy was completed without lymph node emptying. Histopathological examination of the thyroid showed tuberculoid-type granulomas with a lymphoid border and central necrosis. However, the ZNS was negative (figure 1). The remaining tissue presented nodular hyperplasia with oncocytic and fibrotic areas. The diagnosis of thyroid TB was established after the positivity of the extemporaneous lymph node cultural examination and molecular detection of MTB by PCR. The patient was referred to a regional centre dedicated to TB treatment. The lung being affected was excluded with a normal thorax radiography and a negative ZNS of expectoration. She accomplished a total of 9 months of treatment with antituberculous agents. During the first 2 months, she underwent a four-drug regimen (rifampicin 120 mg, ethambutol 1 g, isoniazid 50 mg and pyrazinamide 300 mg) and thereafter a two-drug regimen (isoniazid 50 mg and rifampicin 120 mg).

Figure 1.

Photomicrograph showing thyroid gland with multiple epithelioid granulomas, some confluent, with central caseous necrosis and surrounded by a lymphocyte collar. Acid-fast bacilli were not seen using Ziehl-Neelsen staining (H&E, 40×).

Outcome and follow-up

After thyroidectomy, she was started on levothyroxine with the aim to achieve thyroid-stimulating hormone levels within the normal range. Treatment with antituberculous agents was undertaken in a centre of TB diseases and oriented by a pneumologist. She completed the treatment successfully and without any intercurrence after 9 months.

Discussion

According to the WHO, in 2017, more than 6 million notified cases and 120 000 deaths related to TB were registered.¹³ About 5%–10% of infected patients will develop symptoms during their lifetime. Lungs are the primordial organ of affection, corresponding to 90% of the cases. The lymph nodes are the second most common affected organ, followed by other organs such as bones, joints, pleura, central nervous system, peritoneum, pericardium, and gastrointestinal and genitourinary tract.¹⁴ Contrariwise, organs such as heart, pancreas and thyroid are rarely affected. A work from 2009 reviewed all the thyroid specimens from thyroid surgeries performed in a tertiary hospital along 5 years and found a prevalence of thyroid TB in only 0.6%.³ The mechanisms underlying the relative resistance of the thyroid gland to infection are still not totally understood, but factors such as the presence of a capsule, high iodine concentration, bactericidal colloid properties and high vascular and oxygenation supply are possible explanations.¹⁵ According to the literature, the thyroid gland being affected with MBT has a slight female preponderance, and the mean age of onset is around the third or fourth decade of life.⁵

There are five classical forms of clinical presentation: goitre with caseation, cold abscess formation (in the early stages mimicking a solid or cystic thyroid nodule), acute abscess, miliary and chronic fibrosing TB. Thereby, in the rare thyroid involvement of TB infection, the clinical presentation is variable, though most frequently with a subacute manifestation. Sometimes adenopathies are present. The patients can either be asymptomatic or present cervical pain or mass effect symptoms (dysphagia, dysphonia or dyspnoea). When there are other organ involvement, the patients can present associated symptoms or constitutional symptoms traditionally attributable to TB (fever, weight loss, night sweats or anorexia).^{5 16} If the cervical pain is the clinical predominant symptom, the differential diagnosis should consider an infectious form of thyroiditis and subacute granulomatous thyroiditis.¹⁷ In the majority of cases with TB of the thyroid, the patients are euthyroid, yet thyrotoxicosis explained by an increase in thyroid hormone release due to partial parenchyma destruction or hypothyroidism as a consequence of extensive glandular destruction may occur.⁶

Our patient did not have systemic symptoms and only had a minor cervical discomfort. Ultrasonography is the gold standard imaging method for thyroid evaluation. However, in TB infection, the findings are not specific. Since Portugal is not an endemic TB country, combined with non-conclusive ultrasonography findings and clinical presentation, thyroid TB diagnosis was not considered preoperatively. The first hypothesis was of thyroid carcinoma. FNAC is of major importance when a suspicious nodule is found. Findings such as epithelioid histiocytes or giants cells may alert for the diagnosis of TB. Furthermore, the aspirated material can be used for microbiological culture and ZNS. Once more, in the current case, results from FNAC were inconclusive, and due to the clinical suspicion of malignancy, surgery was decided.

In non-endemic countries, the diagnosis of thyroid TB is most of the times histological. The presence of granulomas, constituting epithelioid histiocytes and Langerhans giant cells, with central caseation necrosis and surrounded by lymphocytes is characteristic.^{3 17} However, the presence of granulomas in the absence of TB bacillus may orient for other possible diagnoses such as Quervain’s thyroiditis, sarcoidosis, fungal infections, granulomatous vasculitis or foreign body reaction. The histopathological tissue allows the detection of the bacillus through ZNS, TB culture or molecular examinations (PCR for MBT).

The treatment for thyroid TB is the use of antituberculosis drugs. The duration of treatment varies between 6 and 9 months, depending on the experience of each centre.¹⁷ Surgery is not indicated unless for particular cases such as large abscesses needing drainage. When the diagnosis is disclosed by surgery, in cases where a total thyroidectomy was performed, a treatment for 6–9 months is recommended when other organs are affected. When no other organs, or lymph nodes, are affected, a close follow-up should be performed, but in most cases no drugs are needed. Nevertheless, no consensus has been found when thyroidectomy is used as an isolated treatment. When lobectomy is performed, a 6-month treatment should be performed, even if no more infected organs are identified.^{6 18}

Learning points.

• Thyroid tuberculosis can manifest in various ways mimicking a panoply of other thyroid pathologies.

• Although rare, this diagnosis should be considered, even in non-endemic countries, as differential diagnosis of anterior cervical mass with acute or subacute growth.

• Gold standard examinations for diagnosis are the detection of Mycobacterium tuberculosis by fine-needle aspiration cytology (FNAC) with Ziehl-Neelson staining, culture of tuberculosis or molecular detection with PCR. However, many times, the diagnosis is only reached after surgical resection of the lesion and pathological examination.

• In thyroid lesions suspicious for malignancy on clinical grounds but with non-diagnostic FNAC, ultrasound-guided FNAC, frozen sections (if facility available) or hemithyroidectomy can be considered in order of preference, avoiding radical unnecessary surgeries.

• The treatment is the use of antituberculosis agents (6–9 months depending on other organ involvement). Surgery is a solution for particular conditions such as an abscess requiring drainage.