Background
Thyroid nodules are a very common condition. Depending on the population studied and the method of detection, thyroid nodules are detected by palpation in 5% of cases and by ultrasound in 30-67% of cases. Although the vast majority of thyroid nodules are benign, 5-20% of nodules are malignant. Therefore, thyroid cancer is very common in the population. Autopsy studies performed in Finland have confirmed these findings, with approximately 1 in 3 patients who died of non-thyroid-related causes having a thyroid tumor.
With the use of imaging techniques, patients with subclinical thyroid tumors are surfacing. Thyroid tumors are now one of the fastest growing diagnoses, with more new thyroid tumors occurring each year in the United States than all leukemia and liver, pancreas, and stomach tumors combined. Although thyroid tumors have a high incidence, they are not a common cause of death. Because of the highly inert course of most thyroid tumors, the vast majority of patients with thyroid tumors have a good prognosis, hence the term “low risk thyroid tumors”.
Several organizations and expert groups have developed guidelines for clinicians and patients for these low-risk tumors. However, due to some uncertainty about the definition, epidemiologic features, and management of these tumors, many patients with aggressive thyroid tumors receive no specific differences in treatment.
New evidence can help to better understand the above status quo or can help to develop targeted solutions. In this article, John C Morris et al. review the available evidence and existing challenges, while also providing an outlook on diagnostic and management options for low-risk thyroid tumors.
Definitions
For thyroid tumors, the most important prognostic predictor is the histologic type of the primary tumor. Papillary thyroid carcinoma and follicular thyroid carcinoma are thyroid tumors that differentiate from follicular cells and account for 90% of all thyroid tumors. Papillary thyroid cancer has a good prognosis, with a 20-year mortality rate of 1-2%. In contrast, follicular carcinoma of the thyroid has a 20-year mortality rate of about 10-20%. Other thyroid cancers, such as medullary thyroid cancer, undifferentiated thyroid cancer, and poorly differentiated thyroid cancer, have a worse prognosis.
The 10-year mortality rate for medullary thyroid cancer is 25-50%. The majority of patients with poorly differentiated thyroid cancer and undifferentiated thyroid cancer experience death within a few years of diagnosis, with a 5-year mortality rate of 90%. Thus, by definition, low-risk thyroid tumors refer to papillary thyroid cancer only.
Predictors for low-risk papillary thyroid cancer are uncommon, such as high-grade and aggressive phenotype, local infiltration, or distant metastasis. Several classification systems incorporating these features have been previously developed and have been used for risk stratification of patients.
Classification systems
The characteristics of low-risk papillary thyroid cancer vary among classification systems. These prognostic scoring and staging systems need to be integrated with histologic information and, in MACIS, with the evaluation of residual lesions after initial surgical resection treatment. Using these systems, 80-85% of papillary carcinomas can be classified as low risk. Although the prognosis of low-risk patients judged by these scoring systems is very good (99% at 20 years), they are not used to predict tumor recurrence.
The American Thyroid Association (ATA), in its clinical guidelines for differentiated thyroid tumors, recommends a three-tiered classification system for predicting disease recurrence that requires real-time assessment of the risk of recurrence and clinical mortality due to thyroid tumors. the ATA details the characteristics of low-risk thyroid tumors as follows.
・ Lesions without local metastasis or distant metastasis or additional thyroid tumor infiltration
・ Histology associated with invasive papillary thyroid tumors, such as high-cell carcinoma, insular carcinoma, and columnar cell carcinoma
・ Removal of all tumors visible to the naked eye (evaluated by surgical report or whole-body radioiodine scan)
・Guidelines also recommend that if radioactive iodine is given, low-risk thyroid tumors will not reintroduce iodine-131 outside the thyroid gland after treatment.
・ Other thyroid associations such as the Latin American Thyroid Association have published similar stratification systems for recurrence.
Delayed risk stratification
Finally, there is debate as to whether the low-risk classification system needs to take into account the effects of initial treatment and the need to re-stratify patients based on the first follow-up (8-12 months). The purpose of this strategy, called delayed risk stratification, is to more accurately assess patients who are misclassified as intermediate or high risk. A retrospective analysis evaluated the predictive value of this strategy and suggested that approximately 50% of patients initially classified as intermediate or high risk were reclassified as low risk at the first follow-up.
A recent retrospective analysis further validated this strategy, and delayed risk stratification in the presence of thyroglobulin antibodies predicted recurrence accurately in this group of patients. The importance of this result is evident in patients with well-differentiated thyroid tumors, as anti-thyroglobulin antibodies are present in 25% of patients.
Although these grading strategies are useful for clinicians and patients in the development of postoperative treatment plans (adjuvant therapy, frequency of therapy, and frequency of follow-up), they are based on conventional clinicopathologic criteria. Ideally, low-risk thyroid tumors should be identified prior to the development of a treatment plan and, in particular, need to be identified prior to radical surgery.
Molecular markers
Molecular markers have the potential to improve the diagnostic accuracy of thyroid nodules and the value of improving risk stratification of thyroid tumors. Two intracellular bypasses play a role in thyroid tumor formation, the MAPK (mitogen-activated protein kinase) bypass and the PI3K-AKT-MTOR (phosphatidylinositol(-3) kinase – protein kinase B – mammalian target protein of rapamycin) bypass. abnormal activation of the MAPK bypass leads to tumor progression, while mutations in the PI3K-AKT-MTOR bypass decrease the expression of tumor suppressor genes. mutations in the PI3K-AKT-MTOR bypass reduce the expression of tumor suppressor genes.
The T1799A BRAF mutation in the MAPK bypass has been used as a prognostic molecular marker to predict aggressive clinicopathological outcomes. In a recent meta-analysis of 2470 patients with papillary thyroid carcinoma, the presence of these mutations increased the risk of tumor recurrence, lymph node metastasis, extrathyroidal lesions, and advanced thyroid tumors with RRs of 1.93, 1.32, 1.71, and 1.70, respectively. the meta-analysis also found that the mutations were not beneficial in predicting distant metastasis.
In a large retrospective multicenter study that included 1890 patients, investigators found that BRAF mutations were associated with significantly increased tumor-related mortality, 5.3% in BRAF mutation-positive patients and 1.1% in BRAF mutation-negative patients, with a median follow-up time of 33 months.
However, after adjustment for clinical and histopathologic characteristics, the significance of these results disappeared, with the vast majority of patients with BRAF mutations still exhibiting a low-risk profile and 95% of deaths in patients with BRAF mutations being associated with papillary thyroid cancer.
Similarly, a recent large retrospective cohort study comparing 429 and 766 patients with papillary thyroid cancer did not find an association between BRAF mutations and tumor multicentricity, lymphovascular infiltration, extra-lymph node lesions, central neck involvement, advanced lesions (stage III-IV), and specific causes of death after distant metastasis.
These results led us to consider whether the presence of BRAF mutations could provide any prognostic value outside of the existing clinical staging system for low-risk thyroid tumors. Investigators are evaluating other markers. For example, the gene encoding the telomerase promoter (TERT) – which has the effect of making telomeres continuously longer – is a marker for whether a thyroid tumor is clinically aggressive and is also associated with disease-specific mortality.
In a retrospective study that included 647 patients with thyroid tumors, investigators found that TERT mutations were associated with disease-specific mortality in patients with papillary thyroid carcinoma, with an HR of 23.8.
TERT mutations were not found in tumors smaller than 25px. Although TERT mutation status and other potential markers (e.g., micro RNA markers and epigenetic changes in oncogenes) can be used in clinical practice to help identify and differentiate between low- and high-risk thyroid tumors, clinicopathologic features are currently the best predictor of mortality and recurrence.
Epidemiology
Thyroid tumors are the most common endocrine tumors, accounting for 2% of all tumors in women and men. Over the past 30 years, the incidence of thyroid tumors has increased worldwide (Figure 1). In the United States, the incidence of well-differentiated thyroid tumors increased from 4.9/100,000 to 14.3/100,000 between 1975 and 2009. Thyroid tumors have become the most common tumor in Korean women.