Thyroid nodules are a common clinical condition. 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 in 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 anatomic 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. Nodules <1 cm in diameter should also be evaluated 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.
After finding a thyroid nodule, a complete medical history should be collected and a detailed examination of the thyroid gland and adjacent cervical lymph nodes should be performed (Figure 1). Some relevant medical history, such as history of head, neck, or body radiation for bone marrow transplantation, family history of thyroid cancer in first-degree relatives, rapid growth of the mass, and hoarseness, may indicate a malignant nodule. Vocal cord paralysis, enlarged cervical lymph nodes on the same side of the nodule with relative fixation to the surrounding tissues also indicate that the nodule may be malignant.
When a thyroid nodule is >1 cm in diameter, serum thyroid stimulating hormone (TSH) levels should be checked. If TSH is low, a radionuclide thyroid scan should be performed to determine whether the nodule is functional, isofunctional (“warm”), 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 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 and require additional biopsies under ultrasound guidance. 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%, which is small but should not be ignored. 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 basic treatment of differentiated thyroid cancer is aimed at:
1. to remove the primary tumor, the tissue that has spread outside the thyroid envelope, and the involved cervical lymph nodes.
2. to reduce the incidence of disability associated with treatment and disease.
3. To provide precise staging of the tumor.
4. facilitate the administration of 131I radiotherapy at the appropriate time postoperatively.
5. facilitate precise monitoring of disease recurrence by physicians in the long term after surgery.
6. to minimize the risk of tumor recurrence and metastasis.
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 its surrounding tissues 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 if: (1) the tumor is >1 cm in diameter; (2) there is a thyroid nodule on the opposite side of the tumor; (3) there is local or distal metastasis; (4) the patient has a history of head and neck radiation therapy; (5) the patient has a first-degree relative with a history of differentiated thyroid cancer. Older patients (>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.
The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM staging of thyroid cancer can be used to: (1) determine the individual prognosis of patients with differentiated thyroid cancer; (2) guide postoperative adjuvant therapy, including 131I radiotherapy and TSH suppressive therapy, to reduce recurrence and mortality; (3) determine the timing and frequency of follow-up, and provide more intensive follow-up for high-risk patients; and (4) help patients and their families to understand the importance of follow-up. ③ Determine the time and frequency of follow-up to provide more intensive follow-up for high-risk patients; ④ Help 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 goal of long-term follow-up of patients with differentiated thyroid cancer is to closely monitor patients with possible recurrence in order to detect recurrent lesions as early as possible, and early detection of recurrent lesions can facilitate effective treatment. The content of follow-up varies depending on the persistence of the lesion or the risk of recurrence. The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM staging can predict the risk of death but not the risk of tumor recurrence. To assess the prognosis and determine the treatment plan, patients should be classified into 3 levels according to the risk of recurrence:
Low-risk patients: no local or distant metastases after initial surgical treatment and removal of residual disease, all visible tumors have been removed, the tumor has not invaded local tissues and there is no highly invasive pathology or invasion of blood vessels. If 131I is used, there is no 131I uptake outside the thyroid bed on a whole-body radioiodine scan (RxWBS) after the initial surgery.
Intermediate-risk patients: At the time of initial surgery, tumor invasion of the parathyroid soft tissue is visible to the naked eye, or the tumor has invasive pathology or invades blood vessels.
High-risk patients: Tumor invasion into peripheral tissues at the time of initial surgery, incomplete tumor excision, distant metastases, or iodine uptake outside the thyroid bed on 131I scan after thyroid remnant removal.
Patients who have undergone total or subtotal thyroidectomy are considered disease-free if they have all of the following: no clinical evidence of tumor, no imaging evidence of tumor (no iodine uptake outside the thyroid bed on postoperative whole-body scans, recent diagnostic scans, and neck ultrasound), and in the absence of interfering antibodies, no detection of thyroglobulin during TSH suppression and stimulation. In the absence of interfering antibodies, thyroglobulin (Tg) was not detected during TSH inhibition and stimulation (Figure 1).
Measurement of serum Tg levels is an important method for monitoring residual or metastatic lesions and is highly sensitive and specific for thyroid cancer, especially after total thyroidectomy and removal of residual lesions. The test is most sensitive after discontinuation of thyroid hormone or stimulation with recombinant human thyroid stimulating hormone (rhTSH). Detection of Tg during suppression of TSH secretion with thyroid hormone fails to detect small amounts of residual tumor.
Diagnostic RxWBS is the most useful follow-up method when there is no or only a small amount of normal thyroid tissue remaining after treatment. The sensitivity of RxWBS decreases after radioiodine treatment, therefore, low-risk patients with no clinical residual tumor foci, undetectable Tg during thyroxine suppression and negative neck ultrasound do not require RxWBS. neck ultrasound is a highly sensitive method for detecting neck metastases in patients with differentiated thyroid cancer. Sometimes metastases can be detected by neck ultrasound even before serum Tg is detected under TSH stimulation.
The efficacy of thyrotropin suppression therapy is currently controversial. Some studies have shown that thyroid hormone suppression therapy reduces the incidence of large clinical adverse events during long-term follow-up in patients with thyroid cancer, but the optimal degree of thyroid suppression with levothyroxine (LT4) is unknown. Sustained suppression of TSH (≤0.05 mU/L) resulted in longer recurrence-free survival compared with higher TSH levels (≥1 mU/L). In multivariate analysis, the degree of TSH suppression was an independent predictor of tumor recurrence. In another large study, disease stage, patient age, and 131I treatment were independent predictors of disease prognosis, whereas the degree of TSH suppression was not.
If metastases are found during follow-up, 131I therapy is usually not helpful. For tumors invading the upper respiratory and upper gastrointestinal tracts, surgical treatment plus adjuvant therapy [131I and/or external beam radiation therapy (EBRT)] is recommended. The patient’s outcome is determined by whether the tumor foci can be completely removed with preservation of the patient’s relevant physiological functions and whether the tumor can be removed from the superficially invaded trachea or esophagus. When the tumor invades deeper tissues of the trachea (e.g., directly into the lumen), trachelectomy or pharyngeal esophagectomy is required. Less invasive treatment is indicated for patients who cannot be cured, and the use of tracheal stents or tracheotomy for such patients may improve their quality of life. For patients with asphyxia or hemoptysis, laser treatment may be performed prior to radical surgery or palliative care.
Although 131I therapy has shown significant efficacy in many patients, the optimal dose of 131I therapy has not been determined. 131I therapy is administered in three ways: (1) empirical fixed-dose therapy; (2) dose determination by blood and body radiation tolerance and upper limit of radiation tolerance for a specific amount of tumor; (3) dose titration for patients with distant metastases or other special circumstances (e.g., renal failure), or those who really need rhTSH stimulation. For patients with distant metastases or other special conditions (e.g., renal failure), or those who do require rhTSH stimulation, the dose titration method should be used. No studies have been done to compare the regression of these methods. As the use of radioactive iodine in the treatment of thyroid cancer becomes more widespread, physicians must better understand the long-term risks of its use, such as the effects of the therapy on the salivary glands and its long-term effects on the reproductive systems of men and women with curable thyroid cancer, as well as the risk of secondary diseases such as parotid tumors, gastrointestinal tumors, bladder tumors, and colon cancer after treatment.
Instead of suppressing metastases, the use of rhTSH may accelerate the growth of metastases. Without impairing iodine uptake, lithium inhibits the release of iodine from the thyroid gland, thus contributing to the retention of 131I in normal thyroid tissue and tumor cells. One study found that lithium increased the average radiation dose of 131I by a factor of 2 in tumor metastases, which were previously releasing iodine at a faster rate.
If Tg is detected without stimulation, or if Tg >2 ng/ml in stimulated cases, neck and chest imaging, such as neck ultrasound and thin (5-7 mm) spiral CT of the chest, should be performed to look for tumor 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.
Surgery and radioactive iodine therapy, as described in this guideline, can treat most patients with differentiated thyroid cancer, but there are a few patients whose tumors grow rapidly, metastasize extensively, or are even life-threatening, and 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 modulation, inhibition of angiogenesis, immunomodulation, and gene therapy.