Clinical diagnosis and treatment of primary thyroid tuberculosis: a retrospective study

ABSTRACT BACKGROUND: Primary thyroid tuberculosis (PTT) is an uncommon type of extrapulmonary tuberculosis, which is caused by Mycobacterium tuberculosis. It does not have specific clinical manifestations, and most cases are diagnosed through postoperative histopathological examination. OBJECTIVE: To evaluate the diagnostic pattern and management strategy among patients with primary thyroid tuberculosis. DESIGN AND SETTING: Retrospective study on patients with primary thyroid tuberculosis in the First Hospital of Jilin University (Changchun, China). METHODS: Between March 2015 and June 2020, nine cases of PTT were diagnosed and treated in the Department of Thyroid Surgery of the First Hospital of Jilin University. Age at diagnosis, primary symptoms, preoperative biopsy, operation method, pathological classification, acid-fast staining test, anti-TB therapy and prognosis were registered in order to explore the appropriate protocol for diagnosis and treatment of this disease. RESULTS: None of the patients was diagnosed with thyroid tuberculosis before surgery. All the patients underwent surgery. Granulomatous changes or caseous necrosis in thyroid tissue were found through postoperative histopathological evaluation. Polymerase chain reaction (PCR) results for Mycobacterium tuberculosis were positive in all patients. Most patients had a good prognosis after surgery and anti-tuberculosis drug therapy. CONCLUSION: PTT is a rare disease. It is important to improve the preoperative diagnosis. Preoperative diagnostic accuracy relies on increased awareness of the disease and appropriate use of preoperative diagnostic methods, such as PCR detection, fine-needle aspiration cytology, acid-fast bacillus culture, ultrasound and blood sedimentation. PCR detection of M. tuberculosis is recommended as the gold standard for diagnosis.


INTRODUCTION
The World Health Organization (WHO) reported in 2009 that there were 9 million new cases of tuberculosis (TB) in the world every year. In 2011, it was estimated that there were about 8.7 million cases worldwide. It can be seen that the incidence of TB remains high and is spreading rapidly throughout the world. 1 Thyroid tuberculosis (TT), also known as tuberculous thyroiditis, can be divided into two types: primary and secondary. Secondary thyroid tuberculosis occurs after infection with tuberculosis in any other parts of the body. Primary thyroid tuberculosis (PTT) is mostly caused by direct infection of the thyroid by Mycobacterium tuberculosis.
Due to the lack of obvious specificity of clinical manifestations, signs and laboratory and imaging examinations, PTT can be easily misdiagnosed clinically.

OBJECTIVE
The objective of this study was to evaluate the diagnostic pattern and management strategy among patients with primary thyroid tuberculosis.

METHODS
In this study, the clinical data of nine patients with PTT who were diagnosed in the Department of Thyroid Surgery of the First Hospital of Jilin University between March 2015 and June 2020 were retrospectively analyzed. Age at diagnosis, primary symptoms, preoperative biopsy, operation method, pathological classification, acid-fast staining test, anti-TB therapy and prognosis were registered in order to explore the appropriate protocol for diagnosis and treatment of this disease.

General data
Between March 2015 and June 2020, nine cases of PTT were diagnosed in the Department of Thyroid Surgery of the First Hospital of Jilin University. There were five women and four men, with a median age of 50 years (range 43-64 years) ( Table 1). None of the nine patients had any history of pulmonary or extrapulmonary TB.

Clinical manifestations
Four of the nine patients were admitted with a self-evident neck mass, and five were admitted because of thyroid nodules (nature to be determined), which had been found through outpatient physical examination. One patient presented with tenderness of the mass, but there was no obvious specific manifestation in the other eight cases. There were none of the common TB symptoms such as low fever, fatigue, night sweats, emaciation or loss of appetite ( Table 1).

Auxiliary examinations
After admission, all patients underwent routine examinations such as thyroid color Doppler ultrasonography, thyroid function tests and computed tomography (CT) scan of the lungs. Thyroid nodules were examined by means of fine-needle aspiration in some patients (3/9).
Thyroid color Doppler ultrasonography showed that five patients were initially suspected of having thyroid malignancy, among whom two cases showed fine-dot calcification inside the thyroid nodule, and one case showed arc calcification at the edge of the nodule (Figure 1). The other four patients tended to be benign.   Another two patients had large masses. A hypothesis of nodular goiter was considered preoperatively, and granulomatous inflammation accompanied by nodular goiter was indicated through rapid intraoperative pathological evaluation. Thus, right lobectomy resection and right near total resection + left partial resection was performed, respectively ( Table 1).

Ethics statement
These studies involving human participants were reviewed and  were followed up for 7-70 months. The disease was found to be not completely controlled in one patient, and there was recurrence of pulmonary TB in another patient. However, no recurrence was seen in the remaining seven patients ( Table 1).

DISCUSSION
PTT is a fairly rare disease and the incidence of all forms of thyroid tuberculosis (TT) is only 0.4%-0.76% in China. 2 Here, we reported nine cases of PTT that we saw within a five-year period in our hospital. PTT is caused by M. tuberculosis infection and occurs when the systemic immune function is weakened. 3 It has been reported that human immunodeficiency virus (HIV) infection or extrapulmonary TB can greatly increase the incidence of PTT, to 45%-75%. 4,5 However, in the nine cases assessed here, there was no HIV infection or extrapulmonary TB, according to the preoperative examinations.
Misdiagnosis and missed diagnosis are common among PTT cases before surgery, and high clinical standards and experience are needed for making the diagnosis. Among our cases, the maleto-female ratio was 4:5 and the median age was 50 years old. These characteristics are not specific and are similar to what is seen regarding the incidence of thyroid disease. PTT is most frequent in the lower right lobe of the thyroid 6,7 and the cases of our study were consistent with this (6/9).
Tuberculous nodules are often accompanied by thyroid adenoma, diffuse goiter, acute abscess and cervical lymph node lesions, and are sometimes manifested as sudden enlargement of the original thyroid nodules. 8 Some cases are accompanied by neck compression symptoms. 9 In a few cases, thyroid damage has been found to be caused by M. tuberculosis or even by thyrotoxicosis or mucoedema. 10 Most researchers believe that the granulomatous type is the most common type in clinical practice, while a few researchers believe that the caseous type is the most common. Among the nine patients with PTT in our study, six were considered to be the granulomatous type; two, the caseous type; and one, the diffuse type.
Many studies have emphasized the importance of ultrasound in making the diagnosis of PTT. Chan et al. 11 described the ultrasound features of a mixed cystic and solid hypoechoic mass in the right lobe.
Kang et al. 12 performed an ultrasound examination on one patient that showed enlargement of the right thyroid gland, with nodules that were mainly anechoic, with some internal echoes and irregular margins. In another patient, the left lobe showed a large, heterogeneous, mostly anechoic lesion with irregular vascular walls and a small amount of internal echo. Yang et al. 13 carried out dynamic ultrasound monitoring on a PTT patient, and the initial ultrasound examination showed an uneven fluid-filled nodule with internal bleeding.
In the present study, all of the nine cases underwent thyroid color doppler ultrasonography, from which five patients were suspected of having thyroid malignancy and four patients tended to be benign. A single ultrasound examination was not specific for PTT in our clinical practice. Yang et al. 13 reported that repeated ultrasound examination during disease progression showed gradual changes when the nodule was solid and hyperechoic with blurred edges.  A B Some research has also described the magnetic resonance imaging (MRI) features of TT. 15  For patients with complications such as abscesses or sinus passages due to TB, drainage or complete thyroidectomy with medication is recommended. This medication should be continued for at least an average of four months after the last operation.
The appropriate follow-up for patients with PTT includes ultrasonography every three months for the first six months, followed by ultrasonography every six months for two years, and then annually thereafter. 17 Among our patients, only one patient underwent total thyroidectomy without anti-TB therapy, and the remaining eight received postoperative anti-TB drug therapy. The follow-up showed no recurrence in any of the patients within follow-up periods ranging from 7 to 70 months.

CONCLUSION
Primary thyroid tuberculosis is a rare thyroid disease and it is easy to misunderstand the diagnosis, thus resulting in delayed treatment. Here, we presented our diagnosis and treatment experiences relating to nine cases that were confirmed as primary thyroid tuberculosis through postoperative histopathological evaluations. We believe that with further accumulation of cases and experience in the future, our understanding of PTT will become enhanced, and the diagnosis and treatment of this disease will be improved.