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) published 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 reconsider the current clinical management strategies for both diseases and to develop a new version of the clinical guidelines based on the principles of evidence-based medicine.
Thyroid nodules
A thyroid nodule is an isolated, palpable lesion within the thyroid gland that can be distinguished from surrounding thyroid tissue by ultrasonography. 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 have the same probability of malignancy as palpable nodules of the same size. In general, only nodules >1 cm in diameter need to be evaluated because of their potential for malignancy. Serum thyroid stimulating hormone (TSH) levels should be checked when ultrasound findings are suspicious, or when the patient has a history of head and neck radiation exposure, or a positive family history of thyroid cancer, also in response to a 1 cm diameter.
If TSH is low, a radionuclide thyroid scan should be performed to determine whether the nodule is a functional nodule, an isofunctional nodule (“warm nodule”), or a nonfunctional nodule. Functional nodules are rarely malignant, and therefore, cytologic evaluation of such nodules is not necessary. If serum TSH is not suppressed, a diagnostic thyroid ultrasound should be performed, which helps to clarify: 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 in the posterior aspect of 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 and 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 such patients by early detection of parathyroid cell hyperplasia and medullary thyroid carcinoma. Serum calcitonin >100 pg/ml in the unstimulated setting suggests the possibility of medullary thyroid cancer.
FNA is the most accurate and has the highest efficacy ratio for the evaluation of thyroid nodules. Traditionally, FNA biopsy results are classified into 4 categories: inconclusive, malignant, indeterminate (or suspicious for new organisms), 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 are consistently 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 up to 5%, which is a small but not negligible percentage of patients. Benign nodules become smaller in diameter, while malignant nodules increase in size, albeit slowly. Nodule growth itself is not an indication for malignant lesions, but it is an indication for re-biopsy.
Initial treatment of differentiated thyroid cancer
The fundamental treatment of differentiated thyroid cancer is aimed at
1. Removal of the primary tumor site, the diseased tissue that has spread outside the thyroid envelope and the involved cervical lymph nodes.
2. To reduce the rate of disability associated with treatment and disease.
3.Precise staging of the tumor.
4. To facilitate the appropriate timing of I131 radiotherapy after surgery.
5. Facilitate 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.
It is known by standard pathological examination 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 can detect suspicious lymph nodes in the neck in 20% to 31% of patients, and surgical options may be altered as a result. Accurate staging of the tumor is essential both to determine prognosis and to guide treatment; however, unlike other tumors, the presence of metastases does not mean that the primary site of differentiated thyroid cancer cannot be removed. Metastatic foci are sensitive to I131 radiotherapy, therefore, even if metastatic foci are present, the primary thyroid tumor and the surrounding tissues that may be involved should be removed during initial treatment.
Surgical options for thyroid cancer include thyroid lobectomy, subtotal thyroidectomy [removal of most of the visible thyroid tissue, preserving only a small amount of tissue (about 1 g) attached around the site where the recurrent laryngeal nerve enters 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
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 A history of differentiated thyroid cancer in the first-degree relative of the patient. Patients who are older (>45 years old) have a higher recurrence rate, and the above 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 may improve survival and reduce the rate of lymph node recurrence. Total thyroidectomy should be performed when the thyroid lobe is removed due to an undiagnosed diagnosis or when a non-diagnostic biopsy confirms a malignant lesion. Total thyroidectomy should be performed in patients with multiple thyroid cancers to ensure complete removal of the lesion and to prepare for I131 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;
(ii) guide postoperative adjuvant therapy, including I131 radiotherapy and TSH suppressive therapy, to reduce the recurrence rate and mortality of patients;
(iii) To determine the timing and frequency of follow-up visits 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 effective and convenient way to describe the extent of tumors. This classification scheme takes into account a number of predictors of regression, the most meaningful of which are the presence of distant metastases, patient age and tumor extent.
Long-term follow-up of differentiated thyroid cancer
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 help in the effective treatment of patients. 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 predicts the risk of death but not the risk of recurrence of the tumor.
To assess patient prognosis and determine treatment options, 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 visually visible tumors have been removed, the tumor has not invaded local tissues and there are no highly invasive pathological manifestations or invasive vessels. If I131 is used, then there is no I131 uptake outside the thyroid bed when a whole body radioiodine scan (RxWBS) is performed after the initial surgery.
Intermediate-risk patients: Tumor invasion into parathyroid soft tissue visible to the naked eye at the time of initial surgery, or tumor with invasive pathologic manifestations or invasion of blood vessels.
High-risk patients: Tumor invasion into peripheral tissues visible to the naked eye at the time of initial surgery, incomplete tumor resection, distant metastases, or iodine uptake outside the thyroid bed visible on I131 scan after removal of residual thyroid lesions.
Patients who have undergone total or near-total thyroidectomy are considered disease-free if all of the following conditions are present: no clinical evidence of the presence of a tumor, no imaging evidence of the presence of a tumor (no iodine uptake outside the thyroid bed on postoperative whole-body scans, on recent diagnostic scans, and on neck ultrasound), and in the absence of interfering antibodies, no iodine uptake during suppression and stimulation with TSH. Thyroglobulin (Tg) is detected in the absence of interfering antibodies.
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 not known. 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 contrast, another large study showed that disease stage, patient age and the status of I131 treatment were all independent predictors of disease prognosis, while the degree of TSH suppression was not.
If tumor metastases are found during follow-up, I131 therapy is usually not helpful. For tumors invading the upper respiratory and upper gastrointestinal tracts, surgical treatment plus adjuvant therapy [I131 and/or external beam radiotherapy (EBRT)] is recommended. The patient’s outcome is determined by whether the tumor focus can be completely removed with preservation of the patient’s relevant physiological functions and whether the tumor can be removed from the trachea or esophagus that has been superficially invaded. When the tumor invades deeper tissues of the trachea (e.g., directly into the lumen), trachelectomy or pharyngeal esophagectomy is required. Less invasive treatment should be performed 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 symptoms of choking or hemoptysis, laser treatment can be performed prior to radical surgery or palliative care.
Although I131 therapy has shown significant efficacy in many patients, the optimal therapeutic dose has not been determined.
There are three methods of I131 treatment.
① Empirical fixed dose treatment ;
② Determination of the treatment dose by the radiation tolerance of the blood and body and the upper limit of radiation tolerance of a specific amount of tumor;
③ For patients with distant metastases or other special circumstances (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 after using these methods. With the increasing use of radioactive iodine in the treatment of thyroid cancer, 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 system 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 tumor metastases. Without impairing iodine uptake, lithium inhibits the release of iodine from the thyroid gland and, therefore, can contribute to the retention of I131 in normal thyroid tissue and tumor cells. One study found that lithium increases the average radiation dose of I131 by a factor of 2 in tumor metastases that originally released iodine at a faster rate.
If Tg is detected without stimulation, or if Tg >2 ng/ml if stimulated, 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 can help to distinguish tumor metastases, enhanced scans with iodine should be avoided if radioactive iodine therapy is planned to be administered within a few months after 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.
Few studies have been performed on chemotherapy for patients with advanced iodine-resistant differentiated thyroid cancer. Doxorubicin in moderate doses (60-75 mg/m2 every 3 weeks) is effective (mostly partially effective or stabilizing) in more than 40% of patients, but the duration of its effect 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 whose tumors grow rapidly, metastasize extensively, or even become life-threatening, and experimental therapy is available for these patients. Current understanding of the molecular and cytologic pathogenesis of thyroid cancer continues to improve, and a variety of targeted therapies have entered the clinical evaluation phase. These therapies include: oncogene inhibition, growth or apoptosis regulation, inhibition of angiogenesis, immunomodulation, and gene therapy.