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 reconsider the current clinical management strategies for these two 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. Generally speaking, 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 functional, isofunctional (“warm nodules”), or nonfunctional. Functional nodules are rarely malignant; therefore, 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 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 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 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 biopsy results are classified into 4 categories: inconclusive, 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 are consistently undiagnosed on the basis of 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 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, 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.Facilitate the appropriate timing of 131I radiotherapy after surgery. 5.It is convenient for physicians to accurately 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 131I 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 with only a small amount of tissue (approximately 1 g) around the area 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 indicated for the treatment of thyroid cancer. Subtotal or total thyroidectomy is recommended if: (i) the tumor is >1 cm in diameter; (ii) there is a thyroid nodule on the opposite side of the tumor; (iii) there is local or distal metastasis; (iv) the patient has a history of head and neck radiation therapy; (v) the patient has a first-degree relative with a history of differentiated thyroid cancer. Patients who are older (>45 years old) have a higher recurrence rate and the above mentioned procedures are 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 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 guide postoperative adjuvant therapy, including 131I radiotherapy and TSH suppressive therapy, to reduce the recurrence rate and mortality of patients; ③ determine the timing and frequency of follow-up and more intensive for high-risk patients follow-up; 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 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. In staged patients with an age of 2 ng/ml, neck and chest imaging, such as neck ultrasound and thin-section (5-7 mm) spiral CT of the chest, should be performed to detect metastases. Although intravenous iodine can help to distinguish tumor metastases, enhanced scans with iodine should be avoided if radioactive iodine therapy is planned for several 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 its duration of action is uncertain. The surgery and radioiodine therapy 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. 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, including: oncogene inhibition, growth or apoptosis regulation, inhibition of angiogenesis, immunomodulation, and gene therapy.