In 2012, the American Cancer Society released the 2011 American Cancer Incidence and Mortality Survey, which reported 56,460 new cases of thyroid cancer and 1,780 deaths. Although the American Thyroid Association (ATA) and the NCCN Thyroid Clinical Practice Guidelines have established the relevant diagnosis and treatment protocols, there are still many controversial clinical issues such as the choice of treatment for differentiated thyroid cancer due to the relatively good prognosis and the lack of prospective and randomized clinical trial results.
I. Update of NCCN clinical practice guidelines for thyroid cancer
In 2009, ATA made updates on the diagnosis and management of differentiated thyroid cancer, including the initial diagnosis of thyroid nodules, clinical and imaging indications for fine-needle aspiration biopsy, interpretation of cytopathological findings and management of benign nodules. In addition, the 2010 NCCN clinical practice guideline on thyroid cancer was updated in early 2012 to include changes in the staging of differentiated thyroid cancer, surgery and adjuvant therapy.
Choice of diagnostic methods for thyroid nodules
Thyroid nodules are one of the most common body surface masses. Both ATA and NCCN guidelines recommend ultrasound as the first imaging option for patients with first diagnosed thyroid nodules. History, physical examination, thyrotropin (TSH) and 131I imaging are the comprehensive basis for the evaluation of thyroid nodules, and fine needle aspiration cytopathology is an important tool to confirm the diagnosis.
It is well established that among patients with thyroid nodules, males, age <15 or >45 years, history of radiation exposure and family history of thyroid cancer in first-degree relatives are risk factors for thyroid cancer. Patients with these risk factors should be examined in detail and followed up regularly.
Ultrasound examination of the thyroid gland needs to clarify whether the nodules match the clinically detected nodules. nodule size, number, location, morphology, mobility as well as the size, texture, extent and fusion of the cervical lymph nodes should also be described. some features of ultrasound examination suggest the possibility of malignancy of thyroid nodules, such as nodules with mixed echogenicity, abundant blood flow in the nodules, irregular shape, poorly defined borders and fine calcified shadows.
For masses with compression symptoms, giant nodules or retrosternal thyroid nodules, the guidelines also recommend the choice of imaging tests such as CT or MRI.
Laboratory tests and 131I imaging are further methods to determine the functional status of the mass and to assess the possibility of malignancy. It has been found that the higher the TSH level, the higher the risk of developing differentiated thyroid cancer. If TSH is low, 131I imaging should be performed and attention should be paid to the warm and cold nodules therein.
For thyroid nodules suspected to be malignant, the NCCN guidelines recommend preoperative fine needle aspiration to clarify the nature of the nodule and suggest indications for aspiration based on ultrasound. Thyroid nodules outside this indication should be clinically flexible, and excisional biopsy can be considered for patients who are willing to undergo excisional biopsy, especially for patients with high-risk factors and large nodules (>40 cm in diameter).
For non-indicated nodules and benign nodules with fine needle aspiration, ultrasound review after 6 to 12 months is recommended, or at intervals of 3 to 5 years if the nodule is stable within 1 to 2 years. Multiple thyroid nodules are commonly seen clinically. It is recommended to select nodules with high-risk presentation or to select the largest nodule for puncture and to follow up other nodules with ultrasound.
Fine needle aspiration cytology is the best option to clarify the nature of suspicious nodules. The National Cancer Institute classifies thyroid fine needle aspiration findings into six categories: (1) benign; (2) undetermined follicular lesions; (3) follicular or Hurthle cell tumors; (4) suspicious malignancy; (5) malignant, such as papillary, medullary and undifferentiated carcinoma; and (6) insufficient or undiagnosable for diagnosis.
III. Current status of surgical treatment for differentiated thyroid cancer
At present, most of the thyroid diseases in China are treated in the general surgery department of general hospitals. Few patients have used fine needle aspiration to obtain a definite pathological status of thyroid tumor before surgery, and more often, it is clarified by frozen pathological examination during surgery. The surgical approach is also not uniform, as general surgeons in general hospitals often adopt the traditional procedures from the classical textbooks, i.e. unilateral thyroid cancer is treated by unilateral lobectomy, isthmus resection, and contralateral major resection; cervical lymph node dissection is performed only when clinically significant enlarged lymph nodes are found, covering roughly incomplete zones III and IV; and active exposure of the recurrent laryngeal nerve is not advocated. In contrast, head and neck oncologic surgeons at specialty oncology hospitals actively recommend expanding the scope of their procedures to include prophylactic central zone lymph node dissection and total bilateral thyroidectomy.
Despite the controversy, the NCCN and ATA guidelines are consistent in their understanding of the extent of surgical resection. Indications for lobectomy (one lobe and isthmus) include: low risk (low risk of recurrence and metastasis), single nodule <10 cm in diameter, nodule confined to the gland, no vascular invasion, no history of head and neck radiation, and no lymph node invasion on clinical or imaging examination. Indications for total thyroidectomy are any of the following preoperative and intraoperative findings: (1) age <15 or >45 years, (2) history of head and neck radiation, (3) known distant metastases, (4) bilateral nodules, (5) extraglandular invasion, (6) nodule diameter >4.0 cm, (7) cervical lymph node metastases, (8) invasive pathology, and (9) follicular carcinoma. hürthle NCCN, ATA and the literature recommend total thyroidectomy for all thyroid cancers, including children and adults with low risk factors, in order to improve disease-free survival. However, the better prognosis of differentiated thyroid cancer, the uncertain correlation between different procedures and survival rates, and the relatively high number of complications of total thyroidectomy and the high technical requirements for surgeons may be one of the reasons why it is less chosen in China. Since there is still no authoritative treatment protocol for differentiated thyroid cancer in China, whether to perform total or partial thyroidectomy for differentiated thyroid cancer is still a topic of debate, and we expect prospective randomized clinical trials and long-term follow-up to improve the evidence-based approach.
Regarding the regional lymph nodes, the guidelines recommend bilateral lymph node dissection in the central region (VI) and the affected side (II-IV, Vb) if there are positive lymph nodes after total bilateral glandular resection, with the option of lymph node dissection in regions I and Va (especially in cases with high T stage, such as T3 and T4). If the lymph nodes are negative, the choice of prophylactic central zone lymph node dissection should be considered according to their stage and aggressiveness. It has been proved that patients with papillary thyroid cancer without clinical lymph node metastasis (cN0) should also routinely undergo lymph node dissection in the central region, as those with high positive rate of lymph node metastasis in the central region are prone to ipsilateral lymph node metastasis in the lateral cervical region.
Adjuvant therapy for differentiated thyroid cancer
The guidelines suggest that in addition to choosing different surgical treatment options for differentiated thyroid cancer with reference to TNM stage, adjuvant treatments such as TSH suppression, 131I and radiotherapy should also be considered, and the patient’s prognosis should be evaluated in the context of pathological type, surgical margins, lymph node and distant metastasis.
TSH suppression therapy is an important adjuvant measure to reduce the recurrence rate of differentiated thyroid cancer. It is recommended not only for patients after total bilateral thyroidectomy, but also for patients after partial resection and as a treatment modality for metastatic disease. Although precise serum TSH values are not available, guidelines recommend the following criteria: (1) patients with residual lesions or at high risk for initial treatment need to suppress TSH below 0.1 mU/L; (2) patients at low risk but with positive thyroglobulin and normal ultrasonography (abnormal labs but no abnormal imaging) maintain TSH at 0.1 to 0.5
mU/L; (3) low-risk patients with no residual lesions maintain TSH at the low end of the normal range. Patients who have survived several years without disease on review may maintain TSH in the normal range. Also, patients on long-term TSH suppression therapy should take calcium and vitamin D.
Radionuclide 131I can be used as initial treatment for patients at risk of recurrence and as adjuvant therapy in cases with distant metastases. ATA recommends tumors >4.0 cm in diameter, distant metastases, and extra-glandular invasion visible on gross specimens (regardless of tumor size) as indications for treatment. For limited tumors between 1.0 and 4.0 cm in diameter, lymph node metastases or high-risk manifestations should be selected in the context of the clinical situation. Prior to treatment, recombinant human TSH may be used to stimulate isotope uptake or to discontinue thyroxine, and a low iodine diet is recommended during treatment. Studies have shown that the recurrence rate of 131I therapy is lower than that of other adjuvant treatments for tumors ≥1.5 cm in diameter.
There are no prospective studies to confirm the benefit of external radiation therapy. Guidelines recommend external radiation therapy for patients >45 years of age, staging T4 and residual lesions without iodine uptake, with the dose depending on the volume of residual lesions and their response to 131I therapy.
Bisphosphonates and low-molecular kinase inhibitors such as sorafenib and sunitinib can be used for bone metastases and metastases other than the brain, respectively.
V. Follow-up of differentiated thyroid cancer
Post-treatment follow-up includes physical examination at 6 and 12 months after surgery. TSH, thyroglobulin, thyroglobulin antibody test and neck ultrasound are mandatory. If there are no positive findings, the follow-up will be annual thereafter. If there are abnormal findings or if the initial assessment of tumor stage is T3/4 or M1, 131I imaging with recombinant human TSH stimulation must also be considered, and depending on the review (especially thyroglobulin concentration), reoperation, continuous TSH suppression or 131I therapy will be chosen.