Differentiated thyroid carcinoma (DTC), including papillary and follicular thyroid carcinoma, accounts for approximately 90% of thyroid cancers. The approach to the management of DTC has been based on retrospective analysis, expert opinion and experience, and the main difficulty in developing treatment guidelines is the lack of Level I evidence and prospective randomized studies. The overall survival rate of DTC is over 95%, but the high survival rate is accompanied by potential risks of treatment, such as salivary gland damage due to radioiodine, recurrent cancer and atrial fibrillation, and osteoporosis due to excessive TSH suppression. Nearly one-third of patients with DTC will relapse or survive with tumors for many years and are at risk of death. The current status of treatment for radioiodine resistant patients is also not ideal. The cost of recurrence assessment in thyroid cancer survivors is enormous. Therefore, the focus of clinical research in DTC should concentrate limited resources on closely focusing on high-risk patients and providing the most effective and cost-efficient treatment options. Studying the prognostic characteristics of DTC and emphasizing risk stratification are essential to determine appropriate treatment options.
1. Molecular genetics of DTC diagnosis and risk stratification
The most common mutated gene in DTC is BRAF, and about 45% of papillary thyroid cancers have BRAF gene mutations. Mutant BRAFV600E was found to be associated with clinical features of DTC, such as thyroid cancer invasion, lymph node metastasis, advanced tumor stage with recurrence and high mortality. The diagnosis of FNA in thyroid nodules suffers from insufficient specimen volume and difficult to confirm cytologically. When cytology is uncertain, BRAF mutation analysis can be used to identify cancer cells and follicular adenoma cells, which improves the accuracy of diagnosis without false positives and can reduce repeat biopsies and unnecessary surgery; it can also be used as a risk marker to guide the extent of surgical resection and monitoring of recurrence. Whether it is the diagnosis of thyroid cancer before surgery or the monitoring of recurrence, TSH receptor gene is also a more specific marker for thyroid cancer.
2.Treatment of DTC
(1) Surgical treatment
The first radical surgery for DTC is the main treatment and the most important factor affecting the prognosis. CT, MRI and 18FDG-PET are more sensitive than ultrasound in diagnosing thyroid cancer, and laryngoscopy can help to evaluate the extra-glandular involvement of thyroid. Recurrent or metastatic lesions should be resected radically if possible, but the extent of surgical resection should take into account the risk of death. Increasing the extent of resection in the initial surgery improves survival in high-risk patients, and subtotal or total thyroidectomy in low-risk patients reduces their recurrence rate. Traditional subtotal thyroidectomy is not suitable for the treatment of thyroid cancer. Lobectomy of one thyroid gland is limited to papillary thyroid cancer with very small tumors, low risk, isolated lesions, and N0 confined to a single lobe of the gland. Total or near-total thyroidectomy should be performed if the tumor is 1 to 1.5 cm in diameter, if there are also nodules in the opposite lobe thyroid, if there are local or distant metastases, if there is a history of radiation exposure to the head and neck or if there is a family history of DTC in first-degree relatives or if the patient is older than 45 years old. Some patients may require reoperation to remove multiple lesions or to create conditions for later 131I treatment if the lesions cannot be diagnosed preoperatively and are diagnosed as malignant after unilateral thyroidectomy. In the case of papillary thyroid cancer with multiple lesions, the incidence of cancer in the contralateral glandular lobe is higher than that of a single lesion in the ipsilateral lobe. Ablation of the remaining thyroid gland with 131I is not recommended as an alternative to secondary surgery because of the uncertainty of its long-term outcome.
The chance of cervical lymphatic metastasis of papillary thyroid cancer can be as high as 20%-90%. Those who are clinically or imaging suspected or diagnosed with cervical lymphatic metastasis should undergo cervical lymphatic dissection, which can reduce recurrence and mortality. Papillary thyroid carcinoma should be routinely dissected in region VI, but it is still controversial whether region VI dissection is beneficial. Follicular thyroid cancer may not be cleared in zone VI. The complications of zone VI clearance can be significantly reduced by operator’s experience.
(2) Radioactive iodine therapy
The dose and indications of 131I ablative therapy are controversial. 131I ablative therapy significantly reduces the recurrence rate and mortality of DTC, and many large series of retrospective studies specifically support 131I ablative therapy for high-risk DTC, including stage III-IV patients, all stage II patients younger than 45 years old, and some stage II patients older than 45 years old. years of age in some stage II patients, especially those with multiple foci, lymph node metastases, extrathyroidal or vascular infiltration and/or high malignancy. Recent literature does not suggest that 131I ablative therapy is beneficial for low-risk papillary thyroid cancer. Although 131I ablation therapy is relatively safe, its acute and chronic complications increase with cumulative dose, such as salivary gland damage, nasolacrimal duct obstruction, and secondary tumors. Therefore, it is important to weigh the pros and cons of repeated 131I treatment. There is no absolutely safe dose of 131I, nor is there a maximum cumulative dose that cannot be used. Usually 30 mCi and 100 mCi of 131I show the same ablation success rate, but there is a tendency that the higher the dose, the higher the success rate. For the purpose of ablation, the smallest radiation dose (30mCi~100mCi) should be selected for ablation treatment. For patients with microscopic residual cancer foci or higher histological malignancy, higher dose 131I (100mCi~200mCi) ablation treatment should be performed. If the presence of residual normal thyroid gland cannot be accurately determined before ablation treatment, low-dose 131I (1 mCi~3 mCi) or 123I scan should be used.
Ablation of residual thyroid tissue requires TSH stimulation, and uncontrolled studies have shown that TSH greater than 30 mU/L is accompanied by increased tumor uptake of 131I. A single exogenous TSH stimulation test suggests that maximum stimulation of thyroid cells is achieved at TSH levels between 51 mU/L and 82 mU/L. Discontinuing thyroid hormone (L-T4) for 3 weeks can increase TSH to more than 30 mU/L in more than 90% of patients. Therefore, those undergoing 131I therapy need to stop L-T4 for at least 3 weeks, or switch to T3 therapy for 2 to 3 weeks and then stop T32 for 2 weeks, and then measure TSH to determine if it is time for treatment (TSH 30mU/L).
Thyroid ablation therapy can also be performed after recombinant human TSH (rhTSH) stimulation. Whether to discontinue L-T4 or rhTSH stimulation therapy, there are no randomized controlled studies. Although most observations suggest that rhTSH stimulation therapy leads to stabilization and improvement, the application of rhTSH has been reported to not only not help to clear metastatic lesions but even to enlarge the tumor. It is now believed that rhTSH stimulation therapy can be used selectively in certain patients, such as those who are potentially at risk from hypothyroidism after drug discontinuation, those with pituitary lesions where TSH cannot be elevated or those whose disease worsens with delayed treatment. Lithium has been found to increase iodine uptake in tumor tissue by a factor of 2. However, it is uncertain whether lithium treatment can significantly improve the prognosis of patients treated with 131I.
A whole-body scan approximately 1 week after 131I ablation therapy may reveal 10% to 26% of new metastatic lesions. The newly identified lesions are mainly located in the neck, lungs and mediastinum, which may change the tumor stage in approximately 10% of patients and affect the clinical management of 9% to 15% of patients.
If imaging is negative a fixed dose of 131I therapy (100 mCi to 200 mCi) should be administered, and after treatment a whole body 131I scan can localize up to 50% of the lesions capable of surgery. Those with inoperable lesions found on the scan after the above treatment and with significant reduction after treatment should repeat treatment until the tumor is eradicated or no longer responds to 131I. For those who cannot localize the lesion after 131I treatment with 100mCi~200mCi, 18FDG-PET should be considered, especially for those with Tg of 10mg/~20mg/L or more in unstimulated state. Those with elevated Tg, negative systemic 131I scan, and negative imaging need only periodic imaging and Tg examination.
(3) TSH suppression therapy
TSH stimulation increases the expression of thyroid cell-specific proteins and promotes cell growth. Inhibition of TSH deprives TSH-stimulated DTC cells of growth and may reduce tumorigenesis and death. Clinical inhibition of TSH with supraphysiologic doses of L-T4 treatment reduces thyroid cancer recurrence. A multifactorial analysis showed that the degree of TSH suppression was an independent predictor of recurrence, and sustained TSH suppression of 0.05 mU/L was associated with longer recurrence-free survival than TSH maintained at 5.00 mU/L or higher. Studies by the National Thyroid Cancer Treatment Research Collaborative have shown that suppression of TSH below 0.1 mU/L improves the prognosis of patients with high-risk thyroid cancer (stages III, IV), but low-risk patients (stage I) do not receive the benefit of TSH suppression therapy. Therefore, it is recommended that TSH should be kept below 0.10 mU/L for a long time in cases with long-standing tumors and no specific contraindications. High-risk patients who are clinically cured should be considered to maintain TSH at 0.10 mU/L to 0.50 mU/L for 5 to 10 years. The side effects of L-T4 therapy are mainly subclinical hyperthyroidism, such as angina pectoris and atrial fibrillation in patients with ischemic heart disease, and increased risk of osteoporosis in postmenopausal women.
(4) Radiation therapy and chemotherapy
Radiation therapy is rarely used in the treatment of thyroid cancer. Age 45, extra-glandular infiltrative growth of thyroid cancer visible to the naked eye at surgery, large residual lesions, or microscopic residual lesions that are inoperable or 131I ablation is ineffective can be considered for radiotherapy. Chemotherapy has no adjuvant effect on DTC. Adriamycin is the most widely studied cytotoxic agent for the treatment of advanced metastatic thyroid cancer, but the clinical results are poor. Adriamycin may have a radiosensitizing effect on some thyroid cancers, and may be considered as a concurrent treatment for some locally progressive tumors treated with radiation.
(5) Management of local recurrence of DTC
Local recurrence and cervical lymphatic metastasis should be removed surgically. Since microscopic lymph node metastasis is much more common and extensive than metastasis detected by imaging, ipsilateral Ⅳ zone clearance and modified II-V zone clearance are recommended for recurrent lesions. Surgery plus 131I therapy and radiation therapy are recommended for tumor invasion of the upper airway and gastrointestinal tract. Surgery ranges from tumor exclusion to resection of the involved airway or esophagus, but only palliative surgery is performed for those who cannot be treated radically. For patients with symptoms of asphyxia or coughing up blood, laser treatment may be performed prior to radical surgery or palliative treatment. 131I may be used for palliative resection of localized lesions or for adjuvant treatment of residual or suspicious lesions in the tracheal digestive tract. Although 131I has shown significant efficacy in treating most patients, the optimal dose for treatment remains controversial. It is generally believed that the higher the total radiation dose activity taken up by the tumor tissue, the better the prognosis.
(6) Management of DTC distant metastases
The treatment of DTC distant metastases should be based on the following principles: ① Patients with distant metastases have a higher mortality rate, but individual prognosis depends on the location, number, tumor load and age of metastases; ② The improvement of survival rate is related to the responsiveness to surgery and 131I treatment; ③ Although there is no evidence to improve survival rate, certain interventional treatment can significantly alleviate the patient’s condition or reduce the disability rate; ④ The value of empirical The value of interventional therapy should be weighed against the potential toxicity; ⑥ Treatment of specific metastatic areas must take into account the patient’s physical status as well as other lesion site conditions.
Treatment of patients with pulmonary metastases should consider the size of the metastatic lesion, its affinity for 131I, and the stability of the metastatic lesion. Small pulmonary metastases should be treated with 131I, and as long as the metastases respond to 131I treatment they should be treated every 6 to 12 months with a high rate of complete remission. The dose and frequency of 131I treatment for pro-131I large nodal lung metastases must be individualized, depending on the response of the metastases to treatment, whether they progress during treatment, the patient’s age, the size of the metastases, the presence of other metastases and the feasibility of other treatments. Treatment should be repeated if the lung metastases shrink and serum Tg decreases. There is no effective systemic therapy for pulmonary metastases that do not absorb iodine, and PET-positive pulmonary metastases respond poorly to 131I therapy. Pneumonia and fibrosis are rare complications of high-dose 131I therapy, and 131I therapy should be limited in cases of pulmonary fibrosis.
Complete surgical resection of isolated and symptomatic bone metastases improves survival and should be considered in patients 45 years of age. 131I treatment of pro-iodine bone metastases improves survival. Treatment of painful but unresectable bone metastases should be individualized or combined, including 131I ablation, radiation therapy, intravenous diphosphonates, and arterial embolization, most of which can relieve cancerous bone pain. The swelling of bone metastases can cause severe pain, fracture or neurological complications, and glucocorticoids should be used during radiation therapy to reduce the enlargement of the mass that may be caused. The treatment for patients with asymptomatic bone metastases that do not respond to 131I therapy and do not endanger surrounding vital structures is inconclusive.
CNS metastases are mainly seen in advanced elderly patients and have a poor prognosis. CNS metastases should be completely removed surgically regardless of 131I uptake, as this can significantly prolong survival. If surgery is not possible, radiation therapy should be performed, and whole brain and spinal cord radiation is feasible for multiple metastases. The central nervous system metastases with polyiodine may also be considered for 131I treatment, but radiation therapy and concomitant glucocorticoids should be administered before 131I treatment to reduce the possible TSH-mediated tumor enlargement and the inflammatory response caused by 131I treatment afterwards.
3. The role of postoperative staging on risk assessment
Because of the clinical value of pTNM staging in predicting mortality of thyroid cancer, pTNM staging is still recommended for standardized assessment of DTC. To address the limitations of pTNM staging, many clinicopathological staging with more accurate grading of risk factors have emerged, but none of them has absolute superiority, among which MACIS staging (metastasis, age, complete resection, invasion and size) has certain advantages.
4.Follow up and monitoring of DTC
(1) Assessment of recurrence risk
Patients with DTC have a high risk of recurrence (2/3 patients recurred in the first 10 years), therefore, lifelong follow-up is required. The follow-up program mainly depends on the assessment of the risk of recurrence, which can be divided into 3 levels according to the risk of recurrence. Low risk: tumor is excised, no local infiltration, no local and distant metastases after initial surgery and ablative treatment, no tissue features of higher malignancy and vascular infiltration, and no 131I uptake except in the thyroid bed when 131I scan is performed. Intermediate risk: At the time of initial surgery, the tumor is microscopically visible to infiltrate the soft tissues surrounding the thyroid gland, or has vascular infiltration, or has a higher degree of histological malignancy. High risk: At the time of initial surgery, tumor invasion into the surrounding tissues is visible to the naked eye, the tumor is not completely excised, there is distant metastasis or there is iodine uptake outside the thyroid bed after ablative treatment of the residual thyroid tissue. Patients with total or near-total thyroidectomy and underwent thyroid ablation therapy can be considered to have complete tumor remission if there is no clinical manifestation of tumor, no tumor confirmed by imaging, and negative serum Tg in TSH suppression state or after stimulation.
(2) Evaluation method with radiation
Thyroglobulin (Tg) measurement
Serum Tg measurement is an important method to monitor residual thyroid tissue or recurrence. The detection of serum Tg after total thyroidectomy and ablative treatment signifies the presence of follicular cell-derived tissue, most likely residual or recurrent. Serum Tg assay is highly sensitive and most sensitive after discontinuation of L-T4 or rhTSH stimulation, but its specificity has to be weighed. More than 95% of DTC and their metastatic lesions are Tg positive. Tg expression is higher in DTC than in poorly differentiated thyroid cancer, a feature that helps to differentiate DTC from medullary, undifferentiated and non-thyroidal carcinomas. Serum Tg measurement is less sensitive for small cervical lymphatic metastases and poorly differentiated tumors. rhTSH stimulation with Tg above 2 ng/mL is a sensitive indicator for monitoring tumor persistence. Serum Tg measurement under TSH suppression and neck ultrasonography should be performed during the initial follow-up after total or near-total thyroidectomy and 131I ablation therapy in low-risk patients. Low-risk patients with no positive neck findings and negative serum Tg at 6 months after ablation therapy should undergo neck and chest imaging to look for metastases if serum Tg can be measured in the unstimulated state 12 months after ablation therapy, or if it was negative and becomes positive, or if Tg rises by 2 ng/mL or more after stimulation. Patients with non-total DTC or total excision without ablation should be considered for recurrence if serum Tg rises by 2ng/L or continues to rise during follow-up.
Tg assessment is also clinically relevant for the diagnosis of tissue specimens, particularly for washout of biopsy specimens of non-thyroidal neck masses or lymph node enlargement. Rinse fluid Tg measurement appears to be independent of Tg antibodies and the main problem currently is the lack of a standard threshold.
There are several technical limitations to Tg immunoquantification, including sensitivity, imprecision and ‘hook influence’. Assays should be standardized and preferably performed in the same laboratory using the same method. Clinical concerns should be raised about interference from Tg antibodies leading to false negatives, and therefore, serum Tg antibodies should be quantified. Currently, the sensitivity of clinical serum Tg assessment is 1 ng/mL, and improvements in immunoassay techniques can result in a sensitivity of 0.1 ng/mL. The clinical need is to determine the impact of undetectable or low levels of Tg on long-term prognosis despite L-T4 treatment.
Imaging
Cervical ultrasound is the method of choice for the diagnosis of cervical lymphatic metastases, with the advantages of no radiation exposure, high sensitivity and the potential to aid in the evaluation of suspicious lesions in FNA. Even when serum Tg cannot be measured after TSH stimulation, ultrasonography may still detect cervical lymphatic metastases. In low-risk patients, the combined application of stimulated Tg and ultrasonography has proven to be the most accurate diagnostic method for identifying persistent tumors, avoiding the need for diagnostic radioiodine whole-body scans. Ultrasonography of the neck should be performed every 6 months after surgery for thyroid bed and cervical lymph node enlargement, and annually thereafter for 3-5 years depending on the patient’s risk of recurrence and Tg level. CT is helpful in detecting pulmonary metastases. 18FDG-PET is an emerging and important tool for localizing tumor recurrence. 18FDG-PET positive patients have a poorer prognosis because 18FDG-PET positivity is associated with dedifferentiation and increased metabolic activity.
5. Emerging therapies and clinical trials
Most patients with DTC are adequately treated with surgery and cautious use of 131I ablation. For a small proportion of patients with recurrent and metastatic tumors that are life-threatening, experimental therapies should be considered. Some phase II clinical trials that build on the understanding of the molecular mechanisms of DTC pathogenesis are already in the clinical evaluation phase. Mitogen-activated protein kinase (MAPK) and angiogenesis inhibitors are hot topics of research. Other early studies that have been initiated include tyrosine kinase inhibitors, RAS, RAF and MEK kinase inhibitors, COX2 inhibitors, retinoids that activate PPARγ/RXR heterodimers, protease inhibitors that inactivate tumors, histone deacetylase inhibitors and demethylating agents. In conclusion, these therapies may offer a ray of hope in the future for patients with life-threatening lesions that have failed to respond to conventional treatments.