Thyroid nodules are a common clinical condition. Epidemiological studies have shown that 5% of women and 1% of men living in non-iodine deficient areas have palpable thyroid nodules.
In 1996, the American Thyroid Association (ATA) issued guidelines for the treatment of thyroid nodules and thyroid cancer, and in the past decade, much more recent evidence has emerged regarding the diagnosis and treatment of thyroid nodules and differentiated thyroid cancer. In response, the ATA appointed a task force to review the current clinical management strategies for these two diseases and to develop new clinical guidelines based on evidence-based medicine.
A thyroid nodule is an isolated, palpable lesion within the thyroid gland that can be distinguished from the surrounding thyroid tissue by ultrasound. Some palpable lesions do not have corresponding imaging abnormalities, while other nonpalpable thyroid nodules are readily detected on ultrasound or other imaging analysis that reveals anatomical structures. Nonpalpable nodules are as likely to be malignant as palpable nodules of the same size.
In general, only nodules >1 cm in diameter should be evaluated because they are potentially malignant. Serum thyroid stimulating hormone (TSH) levels should be checked when ultrasound findings are suspicious, when the patient has a history of head and neck radiation exposure, or when there is a positive family history of thyroid cancer, also at 1 cm in diameter.
If TSH is low, a radionuclide thyroid scan should be performed to determine whether the nodule is functional, isofunctional (“warm nodules”), or nonfunctional. Functional nodules are rarely malignant, so cytologic evaluation of such nodules is not necessary.
If serum TSH is not suppressed, a diagnostic thyroid ultrasound should be performed, which will help to clarify such questions as whether there is indeed a nodule consistent with a palpable lesion, whether the cystic portion of the nodule is >50%, and whether the nodule is located posterior to the thyroid.
The latter two conditions can reduce the accuracy of fine needle aspiration biopsy (FNA). FNA is recommended even if TSH is elevated because the rate of malignancy in normal thyroid tissue is similar to that of nodules in tissue involved in Hashimoto’s thyroiditis. Serum thyroglobulin levels are elevated in most thyroid disorders, but this indicator is neither sensitive nor specific for thyroid cancer. Serum calcitonin is a meaningful indicator, and routine testing of serum calcitonin may improve the overall survival of patients with parathyroid cell hyperplasia and medullary thyroid cancer by providing early detection.
Serum calcitonin >100 pg/ml in unstimulated cases suggests the possibility of medullary thyroid cancer.
FNA is the most accurate and cost effective method for the evaluation of thyroid nodules. Traditionally, FNA biopsies are classified into 4 categories: undiagnosed, malignant, indeterminate (or suspicious for neoplasia), and benign. Indeterminate refers to biopsy results that do not meet specific existing diagnostic criteria, in which case a repeat biopsy under ultrasound guidance is required. Some cystic nodules that remain undiagnosed based on cytologic findings during repeated biopsies are likely to be diagnosed as malignant at the time of surgery.
The risk of malignancy in multiple thyroid nodules is the same as in isolated nodules. Ultrasonography should be performed to determine the morphology of the multiple nodules. If only the “dominant” nodule or the largest nodule is biopsied by needle aspiration, thyroid cancer may be missed.
If the ultrasound shows a solid nodule with microcalcifications, hypoechogenicity, and an abundant blood supply between the nodules, the nodule is likely to be malignant. Even if a thyroid nodule is diagnosed as benign, patients need to be followed up because the false negative rate of FNA can be as high as 5%, and this is a small but not negligible group of patients.
Benign nodules become smaller in diameter, while malignant nodules increase in size, albeit slowly. Nodule growth itself is not an indication for malignancy, but it is an indication for re-biopsy. Initial treatment of differentiated thyroid cancer The fundamental treatment of differentiated thyroid cancer is to:
1. To remove the primary tumor, the lesions that have spread outside the thyroid envelope and the involved cervical lymph nodes.
2. To reduce the rate of disability associated with treatment and disease.
3. To perform precise staging of the tumor.
4. Facilitate the administration of 131I radiotherapy at the appropriate time after surgery.
5.It is convenient for physicians to precisely monitor the recurrence of the disease in the long term after surgery.
6.It is beneficial to control the risk of tumor recurrence and metastasis to the minimum.
Standard pathological examination shows that 20% to 50% of patients with differentiated thyroid cancer (especially papillary carcinoma) have cervical lymph node involvement, even if the primary tumor is small or confined to the thyroid gland.
Postoperative ultrasonography may detect suspicious lymph nodes in the neck in 20% to 31% of patients, and surgical planning may be altered as a result. Accurate staging of the tumor is essential to determine prognosis and guide treatment, however, unlike other tumors, the presence of metastases does not mean that the primary site of differentiated thyroid cancer cannot be removed. Metastases are sensitive to 131I radiation therapy, so even if metastases are present, the primary thyroid tumor and the surrounding tissues that may be involved should be removed during initial treatment.
The surgical options for thyroid cancer include lobectomy, subtotal thyroidectomy [removal of most of the visible thyroid tissue with only a small amount of tissue (about 1 g) attached to the laryngeal recurrent nerve into the cricothyroid muscle] and total thyroidectomy (removal of all visible thyroid tissue). Subtotal thyroidectomy with preservation of the posterior thyroid tissue (>1 g) on the side of the lesion is not suitable for the treatment of thyroid cancer.
Subtotal or total thyroidectomy is recommended in the following cases
①Tumor diameter >1 cm;
②There is a thyroid nodule on the opposite side of the tumor;
(iii) local or distal metastasis;
④Patients with history of head and neck radiotherapy;
⑤ First-degree relatives with a history of differentiated thyroid cancer. Patients who are older (>45 years old) have a higher recurrence rate, and the above-mentioned procedure is also recommended. Local lymph node metastasis is present in 20% to 90% of patients with papillary thyroid cancer at the time of diagnosis, while the metastasis rate is lower in patients with other types of tumors. Bilateral central (zone VI) lymph node dissection can improve survival and reduce the rate of lymph node recurrence. If the thyroid lobe is removed due to undiagnosis or if a non-diagnostic biopsy confirms a malignant lesion, a total thyroidectomy should be performed. For patients with multiple thyroid cancers, total thyroidectomy should be performed to ensure complete excision of the lesion and to prepare for 131I radiotherapy.
American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM Staging
Postoperative staging of thyroid cancer can be used to:
① Determine the individual prognosis of patients with differentiated thyroid cancer;
(2) To guide postoperative adjuvant therapy, including 131I radiotherapy and TSH suppressive therapy, to reduce recurrence and mortality of patients;
(iii) To determine the timing and frequency of follow-up and to provide more intensive follow-up for high-risk patients;
④Help patients communicate better with their physicians. The AJCC/UICC classification system based on TNM parameters is applicable to all types of tumors, including thyroid cancer, because it provides an efficient and convenient way to describe the extent of tumors (Table 1). This classification scheme takes into account a number of predictors of regression, the most significant of which are the presence of distant metastases, patient age, and tumor extent.
The TNM staging system for differentiated thyroid cancer defines
T1 Tumor diameter ≤2 cm
T2 Primary tumor diameter of 2-4 cm
T3 Primary tumor >4 cm in diameter, confined to the thyroid gland or with a small amount of extension outside the thyroid gland
T4a Tumor spreads beyond the thyroid envelope and invades the subcutaneous soft tissue, larynx, trachea, esophagus or laryngeal nerve
T4b Tumor invades the prevertebral fascia or encases the carotid artery or mediastinal vessels TX Primary tumor of unknown size, but does not extend outside the thyroid gland
N0 No lymph node metastasis
N1a Tumor metastasis to zone VI [pre-tracheal, paratracheal and anterior laryngeal (Delphian) lymph nodes]
N1b Tumor metastasis to unilateral, bilateral, contralateral cervical or superior mediastinal lymph nodes NX No intraoperative evaluation of lymph nodes
M0 No distant metastases
M1 distant metastases
MX No distant metastases evaluated
Staging Patients aged 2 ng/ml should undergo neck and chest imaging, such as neck ultrasound and thin-section (5-7 mm) spiral CT of the chest, to detect metastases. Although intravenous iodine is helpful in identifying tumor metastases, enhanced scans with iodine should be avoided if radioactive iodine therapy is planned within a few months of the examination. If the scan is negative, surgical treatment may cure the disease, but empirical radioiodine therapy (100-200 mCi) should also be considered after surgery. There are few studies of chemotherapy for patients with advanced iodine-resistant differentiated thyroid cancer. Doxorubicin at moderate doses (60-75 mg/m2 every 3 weeks) is effective in more than 40% of patients (mostly partially effective or stabilizing), but its duration of action is uncertain.
OUTLOOK
Surgery and radioiodine therapy as described in this guideline can treat most patients with differentiated thyroid cancer, but there are a few patients with rapidly growing, extensively metastatic, or even life-threatening tumors for whom experimental therapy may be indicated. The current understanding of the molecular and cytologic pathogenesis of thyroid cancer has led to the clinical evaluation of several targeted therapies, including oncogene inhibition, growth or apoptosis regulation, inhibition of angiogenesis, immunomodulation, and gene therapy.