U.S. Guidelines for the Treatment of Thyroid Nodules and Differentiated Thyroid Cancer
In our clinical work and online consultation, we often encounter patients asking whether thyroid nodules are benign or malignant. Do thyroid nodules require surgery? Do I have to undergo total thyroidectomy or partial thyroidectomy for thyroid cancer surgery? Do we need 131 iodine treatment after surgery? There are no clear guidelines for these questions.
In 2006, the American Thyroid Association (ATA) appointed a working group to reconsider the current clinical treatment strategies for these two diseases and formulated new guidelines for the treatment of thyroid nodules and differentiated thyroid cancer according to the principles of evidence-based medicine. This latest guideline can provide guidance and reference to our thyroid medical practice, because after all, the United States is a developed country and is ahead of China in medical progress.
I. Thyroid nodules
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. A history of bone marrow transplantation, head and neck radiation or whole body radiation, 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 and relative fixation to the surrounding tissue may also indicate a malignant nodule.
Usually, only nodules >1 cm in diameter should be evaluated, as they may be 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. Serum thyroid stimulating hormone (TSH) levels should be checked for nodules > 1 cm in diameter. 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 to help 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 posterior to the thyroid. The latter two conditions reduce the accuracy of fine-needle aspiration biopsy (FNA). FNA is recommended even if TSH is elevated because the rate of malignancy of nodules 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 diseases, but this indicator is neither sensitive nor specific for thyroid cancer. Serum calcitonin is a meaningful indicator for the early detection of parathyroid cell hyperplasia and medullary thyroid carcinoma, and a serum calcitonin >100 pg/ml without stimulation is indicative of medullary thyroid carcinoma.
Fine needle aspiration biopsy (FNA) is the most accurate and efficient method for evaluating thyroid nodules. Traditionally, FNA biopsy results have been classified as inconclusive, malignant, indeterminate (or suspicious for neoplasia), or benign. Indeterminate means that the biopsy does not meet the specific diagnostic criteria available and requires additional biopsies under ultrasound guidance. Cystic nodules that are consistently undiagnosed on repeated biopsies based on cytologic findings 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. Ultrasound should be performed to determine the morphology of the multiple nodules, and 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 or an abundant blood supply between the nodules, the nodule may be malignant.
Patients diagnosed with benign thyroid nodules need to be followed up, as the false negative rate of FNA can be as high as 5%. Benign nodules become smaller in diameter, while malignant nodules increase in size, possibly slowly. Nodule growth itself is not an indication for malignant lesions, but it is an indication for re-biopsy.
II. Initial treatment of differentiated thyroid cancer
2.1 The fundamental treatment objectives of differentiated thyroid cancer
( 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 treatment and disease-related disability;
(3) Accurate staging of the tumor;
(4) Facilitate postoperative elective 131 iodine therapy;
(5) To facilitate precise monitoring of disease recurrence by physicians in the long term after surgery;
( 6) To minimize the risk of tumor recurrence and metastasis.
2.2 Standard pathological examination shows that 20% to 50% of differentiated thyroid cancer patients (especially papillary carcinoma) have lymph node involvement in the neck. Postoperative ultrasonography can detect suspicious lymph nodes in the neck in 20%-31% of patients, and the surgical plan may be changed accordingly. Unlike other tumors, however, the presence of metastases does not mean that the primary site of differentiated thyroid cancer cannot be removed. Unlike other tumors, however, the presence of metastases does not mean that the primary site of differentiated thyroid cancer cannot be removed.
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 attached to the recurrent laryngeal 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 indicated for the treatment of thyroid cancer.
A subtotal or total thyroidectomy is recommended in the following cases
( 1) Tumor diameter > 1 cm;
(2) The presence of a thyroid nodule contralateral to the tumor;
( 3) local or distal metastases;
(4) Patient has a history of head and neck radiotherapy;
( 5) History of differentiated thyroid cancer in first-degree relatives. The above procedure is recommended for older patients (>45 years) who have a higher recurrence rate. Total thyroidectomy is recommended for patients with undiagnosed thyroid lobe resection or non-diagnostic biopsy that confirms a malignant lesion. For patients with multiple thyroid cancers, total thyroidectomy should be performed to ensure complete excision of the lesion and to prepare for 131 I radiotherapy.
Postoperative staging of thyroid cancer can be used to:
( 1) To determine the prognosis of patients with differentiated thyroid cancer;
(2) To guide postoperative adjuvant therapy, including 131 iodine therapy and TSH suppression therapy, to reduce the recurrence and mortality of patients;
( 3) To determine the timing and frequency of follow-up, and to provide more intensive follow-up for high-risk patients.
3. Long-term follow-up of differentiated thyroid cancer
The goal is to closely monitor patients who may have recurrence in order to detect recurrent lesions as early as possible. The content of follow-up varies depending on the persistence of the lesion or the risk of recurrence. The patient’s prognosis and treatment plan should be assessed according to the risk of recurrence.
Low-risk patients: No local or distant metastases after initial surgical treatment and removal of residual lesions, all visible tumors have been removed, no local tissue invasion and no highly invasive pathology or invasion of blood vessels. If 131 I is used, there is no 131 I uptake outside the thyroid bed at the time of the whole body radioiodine scan (RxWBS) after the initial surgery.
Intermediate-risk patients: At the time of the initial surgery, tumor invasion into 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 resection, distant metastases, or iodine uptake outside the thyroid bed on 131 iodine scan after thyroid remnant removal.
Patients who have undergone total or subtotal thyroidectomy are considered disease-free if all of the following conditions are present: 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, undetectable during suppression and stimulation with TSH In the absence of interfering antibodies, thyroglobulin (Tg) is not detected during TSH suppression or stimulation.
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 thyroid hormone discontinuation or stimulation with recombinant human thyroid stimulating hormone (rhTSH). Small amounts of residual tumor could not be detected by Tg during TSH suppression with thyroid hormone.
Diagnostic whole-body radioiodine scanning (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 without clinical residual tumor foci, undetectable Tg during thyroxine suppression and negative neck ultrasound do not require RxWBS. neck ultrasound is a highly sensitive method to detect 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. It has been suggested that thyroid hormone suppression therapy may reduce the incidence of large clinical adverse events during long-term follow-up of thyroid cancer patients, but the optimal level of thyroid suppression with levothyroxine (LT4) is unknown. Sustained TSH suppression (≤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 131 iodine treatment were independent predictors of disease prognosis, but not TSH suppression.
If tumor metastases are found during follow-up, 131 iodine therapy is usually not helpful. For tumors invading the upper respiratory and upper gastrointestinal tracts, surgical treatment with adjuvant therapy [131 iodine therapy and/or external beam radiation therapy (EBRT)] is recommended. Patient outcome is determined by complete resection of the tumor and preservation of the patient’s relevant physiological functions, as well as the ability to remove the tumor from the superficially invaded trachea or esophagus.
Trachelectomy or pharyngeal esophagectomy is indicated when the tumor invades deeper tissues of the trachea (e.g., directly into the lumen). Less invasive treatment is recommended for patients who cannot be cured, and the use of tracheal stents or tracheotomy may improve the quality of life for such patients. For patients with asphyxia or hemoptysis, laser treatment can be performed prior to radical surgery or palliative care.
Although 131 iodine therapy has been shown to be effective in many patients, the optimal dose of 131 iodine therapy has not yet been determined. 131 iodine therapy is administered in three ways:
(1) Empirical fixed-dose therapy;
(2) Treatment dose determined by blood and body radiation tolerances and the upper limit of radiation tolerance for a given amount of tumor;
( 3) For patients with distant metastases or other special conditions (e.g. renal failure), or those who really need rhTSH stimulation, the dose titration method should be used. As the use of radioactive iodine becomes more widespread in the treatment of thyroid cancer, physicians must better understand the long-term risks associated with its use, such as the effects of the therapy on the salivary glands, the long-term effects on the reproductive system of men and women with curable thyroid cancer, and the risk of secondary diseases such as parotid tumors, gastrointestinal tumors, bladder tumors, and colon cancer after treatment.
The use of rhTSH may not only fail to suppress metastases, but may also accelerate the growth of metastases. Without impairing iodine uptake, lithium inhibits iodine release from the thyroid gland, thus contributing to the retention of 131 I in normal thyroid tissue and tumor cells. It has been found that lithium increases the 131 I radiation dose accumulated in tumor metastases by an average of 2-fold, and that tumors release iodine more rapidly.
If Tg is detected without stimulation, or if Tg > 2 ng/ml is 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 be 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 131 iodine therapy (100-200 mCi) should also be considered after surgery.
Chemotherapy for patients with advanced iodine-resistant differentiated thyroid cancer has been rarely studied. Moderate doxorubicin (60-75 mg/m2 every 3 weeks) is effective (mostly partially effective or stabilizing) in more than 40% of patients, but its duration of action is uncertain.