Thyroid cancer is the most common endocrine malignancy and its incidence has increased over the past few decades. Most patients with thyroid cancer have an excellent prognosis, but there is a 15% recurrence rate within 10 years after initial treatment and mortality is possible. To date, there are no prospective, well-defined data supporting the use of molecular markers alone to decide the extent of treatment of patients with thyroid cancer or to predict the individual prognosis of these patients. Molecular markers are promising in the development of new targeted therapies particularly for radioiodine-refractory and unresectable thyroid cancers.
Key points
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Molecular testing offers valuable information for the management and prognosis of patients with thyroid cancer by detecting genetic alterations.
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Molecular markers may guide clinicians to assess the individual risk of recurrence and metastasis from thyroid cancer and to tailor the treatment according to that risk stratification.
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B-type RAF mutation has emerged as a possible marker for more aggressive behavior of papillary thyroid cancer; RET/PTC may be a marker of more favorable thyroid tumor behavior.
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There are currently no prospective, well-defined data supporting the use of molecular markers alone to decide on the extent of treatment or to predict the prognosis in patients with thyroid cancer.
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Molecular markers are promising targets for novel therapies and, in particular, for thyroid cancers with aggressive behavior.
Introduction
Thyroid cancer is the most common endocrine malignancy and accounts for approximately 1% of all newly diagnosed cancers. A significant worldwide increase in the incidence of thyroid cancer has been noted over the past few decades. Age-standardized incidence of thyroid cancer in developed countries is estimated to be 9.1 per 100,000 women and 2.9 per 100,000 men. Papillary thyroid carcinoma is almost entirely responsible for the overall increase in the incidence of thyroid cancer in the last several decades. There is also an increase in the incidence of diagnosed thyroid nodules that parallels the rapid increase in the incidence of thyroid cancer. The prevalence of thyroid nodules on physical examination is almost 10% in adults and is detected at a higher rate (up to 70%) in the elderly population if thyroid ultrasonography is used. It is crucial to distinguish cancer from benign thyroid nodules because there is an overall 5% to 10% risk of malignancy in thyroid nodules.
Most of the thyroid cancers are epithelial, follicular cell derived, and the most frequent type is papillary thyroid carcinoma, which constitutes more than 80% of all thyroid malignancies. The second most frequent type of thyroid cancer is follicular thyroid carcinoma, which accounts for 10% to 15% of all thyroid malignancies. Follicular carcinoma most likely originates either from a preexisting benign follicular adenoma or directly, bypassing the stage of adenoma. Medullary thyroid carcinomas, which account for approximately 3% of all thyroid malignancies, develop from the parafollicular C cells of the thyroid gland. Anaplastic and poorly differentiated thyroid carcinomas are rare but represent the most aggressive types, with high mortality. Papillary and follicular thyroid carcinomas, the so-called differentiated thyroid cancers, constitute more than 90% of all thyroid malignancies and they are usually associated with a good prognosis because most have an indolent course. The classic treatment of choice for thyroid cancer is total thyroidectomy with or without radioactive iodine. Despite high disease recurrence rates of up to 20% to 30% in differentiated thyroid cancers, the overall prognosis is still favorable, with a 10-year survival rate of more than 90%. However, surgically inoperable or radioiodine-resistant differentiated thyroid cancers do not yet have an effective treatment and can still cause death.
The prognostic factors favoring recurrence, metastasis, and death from differentiated thyroid cancer include both patient and tumor factors. Among patient factors are age less than 15 years or more than 45 years, male sex, and family history of thyroid cancer. Tumor factors include a primary tumor larger than 2 cm, multifocal cancer, nuclear atypia, tumor necrosis, vascular invasion, extrathyroidal extension, lymph node metastasis, distant metastasis, tall cell and columnar cell variants, and radioiodine resistance. A poor prognosis is most commonly associated with neck recurrence caused by lymph node metastasis or thyroid bed remnant disease and less commonly with distant metastasis.
It can be challenging to assess the individual risk for recurrence and metastasis of thyroid cancer and tailor the treatment according to that risk stratification. However, recent investigations have made progress in understanding the molecular mechanisms of thyroid cancer. These investigations have revealed that thyroid cancers frequently have genetic alterations, and current molecular studies can detect these alterations and offer valuable information for diagnosis, management, and prognosis of patients with thyroid cancer. This article discusses the current use of molecular markers for thyroid cancer from a prognostic and therapeutic perspective.
Introduction
Thyroid cancer is the most common endocrine malignancy and accounts for approximately 1% of all newly diagnosed cancers. A significant worldwide increase in the incidence of thyroid cancer has been noted over the past few decades. Age-standardized incidence of thyroid cancer in developed countries is estimated to be 9.1 per 100,000 women and 2.9 per 100,000 men. Papillary thyroid carcinoma is almost entirely responsible for the overall increase in the incidence of thyroid cancer in the last several decades. There is also an increase in the incidence of diagnosed thyroid nodules that parallels the rapid increase in the incidence of thyroid cancer. The prevalence of thyroid nodules on physical examination is almost 10% in adults and is detected at a higher rate (up to 70%) in the elderly population if thyroid ultrasonography is used. It is crucial to distinguish cancer from benign thyroid nodules because there is an overall 5% to 10% risk of malignancy in thyroid nodules.
Most of the thyroid cancers are epithelial, follicular cell derived, and the most frequent type is papillary thyroid carcinoma, which constitutes more than 80% of all thyroid malignancies. The second most frequent type of thyroid cancer is follicular thyroid carcinoma, which accounts for 10% to 15% of all thyroid malignancies. Follicular carcinoma most likely originates either from a preexisting benign follicular adenoma or directly, bypassing the stage of adenoma. Medullary thyroid carcinomas, which account for approximately 3% of all thyroid malignancies, develop from the parafollicular C cells of the thyroid gland. Anaplastic and poorly differentiated thyroid carcinomas are rare but represent the most aggressive types, with high mortality. Papillary and follicular thyroid carcinomas, the so-called differentiated thyroid cancers, constitute more than 90% of all thyroid malignancies and they are usually associated with a good prognosis because most have an indolent course. The classic treatment of choice for thyroid cancer is total thyroidectomy with or without radioactive iodine. Despite high disease recurrence rates of up to 20% to 30% in differentiated thyroid cancers, the overall prognosis is still favorable, with a 10-year survival rate of more than 90%. However, surgically inoperable or radioiodine-resistant differentiated thyroid cancers do not yet have an effective treatment and can still cause death.
The prognostic factors favoring recurrence, metastasis, and death from differentiated thyroid cancer include both patient and tumor factors. Among patient factors are age less than 15 years or more than 45 years, male sex, and family history of thyroid cancer. Tumor factors include a primary tumor larger than 2 cm, multifocal cancer, nuclear atypia, tumor necrosis, vascular invasion, extrathyroidal extension, lymph node metastasis, distant metastasis, tall cell and columnar cell variants, and radioiodine resistance. A poor prognosis is most commonly associated with neck recurrence caused by lymph node metastasis or thyroid bed remnant disease and less commonly with distant metastasis.
It can be challenging to assess the individual risk for recurrence and metastasis of thyroid cancer and tailor the treatment according to that risk stratification. However, recent investigations have made progress in understanding the molecular mechanisms of thyroid cancer. These investigations have revealed that thyroid cancers frequently have genetic alterations, and current molecular studies can detect these alterations and offer valuable information for diagnosis, management, and prognosis of patients with thyroid cancer. This article discusses the current use of molecular markers for thyroid cancer from a prognostic and therapeutic perspective.
Relevant pathophysiology
Genetic Alteration of Mitogen-activated Protein Kinase Signaling Pathway
The mitogen-activated protein kinase (MAPK) signaling pathway is an intracellular cascade regulating division, proliferation, differentiation, adhesion, migration, and apoptosis in the cell. This pathway also plays a role in survival in response to growth factors, hormones, and cytokines that interact with cell surface receptor tyrosine kinases. Aberrant activation of MAPK pathway has been described in some human malignancies, including thyroid cancer. B-type RAF (BRAF) mutation, RET/PTC rearrangement, and RAS mutation are the common triggers for the activation of the MAPK signaling pathway. When this pathway is activated in the thyroid cells by various growth factors and hormones, a G protein–coupled receptor on the plasma membrane can be activated. This activated G protein RAS then activates the serine/threonine protein kinase RAF. The activation of this cascade has a role in thyroid tumorigenesis by altering some of the cellular functions, which are discussed later.
BRAF Mutation
BRAF is the predominant isoform of the RAF proteins in follicular thyroid cells and is a potent activator of the MAPK signaling pathway. BRAF-induced activation of the MAPK pathway interferes with cellular communication, division, differentiation, proliferation, and apoptosis, and therefore plays a role in several disease processes, such as chronic inflammation and cancer.
BRAF mutation involves nucleotide 1799 and results in a valine-to-glutamate substitution at residue 600 (V600E) of the BRAF protein, and this is the most common genetic alteration in papillary thyroid carcinoma. BRAF mutation is highly prevalent in classic papillary carcinoma and the tall cell variant, whereas it is rare in the follicular variant. The other rare mutation of the BRAF gene results in a lysine-to-glutamate substitution at residue 601 of the BRAF protein. This BRAF (K601E) mutation has been found particularly in the follicular variant of papillary thyroid carcinoma. This article uses BRAF mutation to denote the BRAF(V600E) mutation. Moreover, a chromosomal rearrangement, the AKAP/BRAF rearrangement, has been suggested to be associated with papillary thyroid carcinoma in patients exposed to radiation.
RET/PTC Rearrangement
The RET proto-oncogene is structurally related to tyrosine kinase transmembrane receptors and is involved in glial cell–derived neurotropic factor signaling. RET/PTC rearrangement is a result of a fusion between the 3′ portion of the RET receptor tyrosine kinase gene and the 5′ portion of an unrelated gene. RET/PTC rearrangement can activate the MAPK pathway but the oncogenic effects of this rearrangement in thyroid tumorigenesis require signaling along that pathway in the presence of functional BRAF kinase.
RET/PTC rearrangement has been found to be more common in post-Chernobyl thyroid cancers, and is therefore suggested to be associated with radiation exposure. However, it has also been found in adenomas as well as the other benign tumors of the thyroid gland.
RAS Mutation
The RAS family contains more than 50 small proteins that relay signals from tyrosine kinase receptors and G protein–coupled receptors. RAS is linked to the inner cell membrane and plays a role in the intracellular transduction of signals arising from cell membrane receptors. In its active state, RAS protein activates the MAPK and some other signaling pathways. Mutations in the RAS gene result in formation of a mutant protein that potentially has an oncogenic effect in the development of thyroid cancer. It has been reported that point mutations result in constitutive activation of the RAS protein and lead to the induction of a malignant phenotype, with cell proliferation, invasion, metastasis, and resistance to apoptosis in some human cancers, including thyroid cancer.
PAX8-PPAR Rearrangement
PAX8-PPAR rearrangement results from a translocation that leads to fusion of PAX8 and PPAR genes. PAX8 is a transcription factor regulating the expression of some thyroid-specific genes and proliferation/differentiation of thyroid follicular cells. PPAR is also a transcription factor that is a member of a hormone nuclear receptor family, and it is slightly expressed in normal thyroid tissue. PAX8-PPAR rearrangement has been encountered in follicular thyroid carcinoma and the follicular variant of papillary thyroid carcinoma, and rarely in Hürthle cell thyroid carcinoma. However, the role of this rearrangement in the development of thyroid cancers is not yet clearly understood.
Clinical presentation and examination
Cytologic assessment by fine-needle aspiration biopsy (FNAB) has been the gold standard for diagnosing the behavior of thyroid nodules since the 1980s. More recently, ultrasonography guidance has improved the accuracy of FNAB. Preoperative ultrasonography-guided FNAB has reduced the number of diagnostic surgeries for thyroid nodules that ultimately prove to be benign. However, a recent large multicenter study from the United States showed that up to 26% of FNAB of thyroid nodules were still indeterminate and a median of 34% (range 14%–48%) of patients with indeterminate cytology undergoing surgery had thyroid cancer. Up to a 48% risk of malignancy in indeterminate thyroid nodules is too high to recommend watchful waiting. In 2007, the United States National Cancer Institute sponsored a conference to review cytologic terminology for thyroid lesions in which experts have proposed the Bethesda classification for reporting thyroid cytopathology. By this classification, the indeterminate thyroid nodules are placed into 3 different categories of cytologic diagnosis: (1) atypia of undetermined significance/follicular lesion of undetermined significance, (2) follicular or oncocytic (Hürthle cell) neoplasm/suspicious for follicular or oncocytic (Hürthle cell) neoplasm, (3) suspicious for malignant cells. Predicted probabilities of cancer in these 3 categories are 5% to 15%, 15% to 30%, and 60% to 75%, respectively. Because FNAB cannot provide a definitive diagnosis for indeterminate thyroid nodules, most of these require a diagnostic thyroid lobectomy. However, only 10% to 40% of such nodules ultimately prove to be malignant. If FNAB could reliably give the preoperative diagnosis of these benign nodules, these unnecessary surgeries with expenses and risks would be avoided. Furthermore, once thyroid lobectomy confirms cancer, completion thyroidectomy is usually offered to the patient as a standard of care to minimize the risk of persistent/recurrent disease and to facilitate radioactive iodine therapy. Optimal treatment of choice for such a patient would be an up-front total thyroidectomy if the diagnosis of thyroid cancer could be established by FNAB beforehand.
Cytologic assessment of FNAB remains the best-established diagnostic tool for the evaluation of thyroid nodules, and molecular markers are increasingly being used as adjuncts to cytology to improve diagnosis and to better predict the treatment outcome and prognosis of thyroid lesions. Several molecular markers, alone and in combination, have been studied in FNAB of thyroid nodules and thyroidectomy specimens. This article focuses on the major molecular markers that hold the promise of prognostic value.
Prognostic applications of molecular markers in thyroid cancer
Several molecular markers have been associated with the prognosis of thyroid cancer. Even though some markers are promising, BRAF mutation is the best-defined prognostic marker in molecular thyroid medicine.
BRAF Mutation and Prognosis of Thyroid Cancer
The results of a multicenter study suggest that the presence of BRAF mutation predicts a poorer clinical prognosis in papillary thyroid carcinoma because of the strong association of this mutation with high rates of extrathyroidal extension, lymph node metastasis, advanced disease stage, and recurrent/persistent disease. Several subsequent studies have also confirmed these associations. BRAF mutation has also been associated with loss of radioiodine avidity of recurrent papillary thyroid carcinoma, which makes the disease refractory to radioiodine treatment.
In a 15-year median follow-up study, Elisei and colleagues showed that BRAF mutation correlates with the worst outcome independently from the other clinicopathologic features of the disease. They suggested that these BRAF-positive patients are not only at a higher risk for persistence/recurrence but also for death. A recent international multicenter study also confirmed the strong association of BRAF mutation with mortality of papillary thyroid carcinoma.
Contrary to these reports that BRAF mutation is associated with poor prognosis in papillary thyroid carcinoma, there are studies from Italy, Portugal, and especially from Asia reporting that there is no correlation between the presence of BRAF mutation and high-risk clinicopathologic features, prognosis, or disease-free survival in papillary thyroid carcinoma.
Two Korean studies reported very high (up to 79%) prevalence of BRAF mutations in their cohort of a population with papillary thyroid carcinoma. They found no significant association between the presence of BRAF mutation and tumor size, extrathyroidal extension, multifocality of the tumor, or lymph node metastasis. They therefore proposed that BRAF mutation does not serve as a prognostic factor in Korean patients with classic papillary carcinoma or papillary microcarcinoma, and should not independently alter the management.
RAS Mutation, RET/PTC Rearrangement, PAX8/PPAR Rearrangement, and Prognosis of Thyroid Cancer
Several studies have reported that RAS mutations are associated with thyroid cancer. However, the prognostic value of RAS mutations remains unclear, because these mutations are not specific for thyroid cancer and can occur with a significant prevalence in benign thyroid nodules. RET/PTC rearrangement has been found in classic papillary thyroid carcinoma and has been associated with a high rate of lymph node metastases and lower stage of disease at presentation and is suggested to be a marker of a better prognosis. However, more information is required to confirm whether it is a marker of more favorable behavior of thyroid cancer. The isolated detection of PAX8/PPAR rearrangement is neither diagnostic nor prognostic for follicular thyroid carcinoma but may warrant further diagnostic molecular analysis. The correlation of PAX8/PPAR rearrangement and prognosis in patients with follicular thyroid carcinoma is not yet well-defined.
TERT Promoter Mutations and Prognosis of Thyroid Cancer
In 2013, 2 different studies showed that TERT promoter mutations are highly prevalent in advanced/aggressive thyroid cancers, particularly in those harboring BRAF or RAS mutations. Therefore, TERT promoter mutations may be biomarkers of tumor progression and used as relevant prognostic markers for patients with thyroid cancer in the near future if further studies can validate these initial reports.
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