Thyroid Cancer in 2019 and the Questions That Remain Unanswered

Angela M. Leung, MD, MSc

Disclosures

January 28, 2019

Editorial Collaboration

Medscape &

Nearly 54,000 cases of thyroid cancer were diagnosed in 2018, corresponding to 3.1% of all new cases of cancer confirmed during that year.[1] As the 12th leading type of cancer in the United States,[1] thyroid cancer is a relatively rare malignancy.

It is the fastest rising cancer, such that if current trends continue, thyroid cancer is expected to be the fourth most common cancer by 2030.

Thyroid cancer is categorized into four main types—papillary (which accounts for 80% of all thyroid cancers), follicular, medullary, and anaplastic—with each subtype usually corresponding to the aggressiveness of the disease.

Significant advances continue to make this a very active field, and as we enter 2019, there remain some unanswered questions regarding the best diagnostic and management approaches for patients with thyroid cancer.

Let's examine the evidence surrounding the top questions currently facing our patients with thyroid nodules and thyroid cancer.

Why Is Thyroid Cancer on the Rise?

Thyroid cancer diagnoses in the United States have risen an average of 3.1% per year in recent years,[1] consistent with a similar trend worldwide over the past several decades.[2] It is the fastest rising cancer, such that if current trends continue, thyroid cancer is expected to be the fourth most common cancer by 2030.[3]

Some have ascribed this pattern to overdiagnosis of the disease[4,5] (ie, the detection of thyroid cancer resulting primarily from incidental findings of thyroid nodules in the current era of increased radiographic imaging). Most data ascribe the rising number of thyroid cancer diagnoses to the detection of small micropapillary thyroid cancers, which usually do not contribute to increased mortality.[4]

In contrast, others have shown that the substantial increase in thyroid cancer over the past four decades may not be overdiagnosis but a true biological rise in the incidence of thyroid cancer, demonstrated by the increased incidence of advanced-stage micropapillary thyroid cancers that are associated with higher mortality rates.[6]This question remains unresolved. These data present the need to examine this question in other ways, perhaps by rigorous assessment of other datasets obtained from different populations that similarly represent the full spectrum of disease.

What Increases the Risk for Thyroid Cancer?

Thyroid cancers can arise only from thyroid nodules. Because thyroid nodules are quite common (exceeding a 60% lifetime risk[7]) and the overall risk for malignancy is relatively low and stable,[1] it is important to accurately distinguish benign from malignant nodules.

Greater understanding is needed to guide clinicians in determining which nodules are suspicious.

Currently known risk factors for thyroid cancer include ionizing radiation exposure to the head and neck during childhood, and exposure to radiation either from bone marrow transplantation or fallout following a nuclear accident. A genetic basis accounts for only 5%-10% of differentiated thyroid cancers, with the exception of the rare medullary subtype.[8]

Syndromes that predispose an individual to developing thyroid cancer include Cowden disease, familial adenomatous polyposis, Carney complex, Werner syndrome, and for medullary thyroid cancer, multiple endocrine neoplasia types 2A and 2B.

Yet, the field awaits better understanding of the characteristics that predispose certain thyroid nodules to become malignant. Although it is reassuring that most thyroid nodules are benign (only 7%-15% of nodules are malignant[8]), greater understanding is needed to guide clinicians in determining which nodules are suspicious and will require workup and, potentially, surgery.

Current guidelines provide useful recommendations based on a combination of the size of the thyroid nodule and its appearance on ultrasound imaging.[8,9] However, improved knowledge in this area would allow a more accurate assessment of the risks of each thyroid nodule encountered in clinical practice.

What Is the Role of Molecular Markers?

Approximately one quarter of thyroid nodules are classified as cytologically indeterminate. Until the advent of molecular marker testing in the late 2000s, thyroid surgery was historically recommended for the vast majority of patients with these nodules, resulting in unnecessary surgery for the nearly 70% of patients who ended up having benign surgical thyroid pathology.[10]

Molecular marker testing utilizes either DNA, RNA, or microRNA expression profiles to more accurately assess the likelihood of thyroid malignancy within a thyroid nodule. However, these tests are not universally available, can be expensive, and require additional aspirated material.

The field of molecular assessment of thyroid nodules has seen explosive advances in recent years, and further refinements will undoubtedly help guide determining which nodules truly require resection and additional treatment postoperatively.

Do All Thyroid Cancers Require Surgery?

Thyroid cancers have historically been managed with resection of the tumor as either a thyroid lobectomy or a total thyroidectomy.

In recent years, there has been growing interest in monitoring biopsy-proven small papillary thyroid cancers rather than proceeding with surgery.[11] In fact, "active surveillance" has already been successfully established for other cancers, such as prostate cancer.[12]

Published series of nearly 1500 patients followed since the early 1990s in Japan have shown that observation can be a first-line option for select individuals with low-risk papillary thyroid cancer.[13]

In the United States, the concept of active surveillance of thyroid cancer is newer but currently being offered at a small number of centers. In a study of 291 patients at Memorial Sloan Kettering Cancer Center undergoing active surveillance for a median of 25 months (range, 6-166 months), tumor growth of ≥ 3 mm was observed in only 3.8% of the cohort, and no regional or distant metastases occurred during ongoing monitoring.[14]

Pregnancy and younger age at diagnosis appear to be risk factors for progression in those undergoing active surveillance of papillary thyroid cancer.[13]

The ideal combination of factors related to the patient, the tumor, and the monitoring institution to recommend this as a viable option for patients with thyroid cancer remains to be identified.

What Does a Diagnosis of NIFTP Signify?

In 2016, Nikiforov and colleagues[15] published the findings of a provocative study proposing the new classification of a thyroid neoplasm subtype that was highly indolent and associated with an excellent prognosis.

In this study, the tumor aggressiveness in 109 patients with noninvasive encapsulated follicular variant of papillary thyroid carcinoma who were observed for 10-26 years was compared against that in 101 patients with the invasive form, who were observed for 1-18 years.

All of those with the noninvasive form of the tumor were alive with no evidence of disease at final evaluation, whereas five patients with the invasive form developed distant metastases and two died of the disease.

Although the sample size of the study was small, among other limitations, these findings created substantial interest for both patients and the scientific community, ultimately resulting in the reclassification of this entity as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), a neoplastic variant.[16]

How prevalent this diagnosis is, as well as long-term psychosocial implications of being diagnosed with what may be a low-grade thyroid cancer versus a benign neoplasm, remains to be further studied.

What Therapies Are Available for Advanced and Refractory Thyroid Cancers?

One of the most exciting areas in the field of thyroid cancer is the rapidly growing literature surrounding targeted therapies in patients with advanced or refractory tumors.[17]

Traditional treatment of thyroid cancer consists of thyroid surgery followed by radioactive iodine (RAI) ablation in those with intermediate- or high-risk disease.[8] Ongoing research is focusing on how drugs that can target and alter thyroid cancers may more effectively enable greater RAI uptake in those who have non–RAI-avid disease.

Some groups are also investigating how conventional chemotherapy might offer benefit in thyroid cancer patients, including those with anaplastic thyroid cancer.[18] External beam radiation may offer some additional benefit toward local control in some patients with radioiodine-refractory disease.

Novel molecularly targeted therapies are another promising approach to treating individuals with advanced or refractory thyroid cancer. Kinase inhibitors target the activities of thyroid cancers demonstrating certain genetic mutations, and four agents (two for differentiated thyroid cancer and two for medullary thyroid cancer) have been approved for clinical use in recent years.

These multitargeted kinase inhibitors have been demonstrated to improve progression-free survival in patients with structurally progressive, RAI-refractory differentiated thyroid cancer[19] and medullary thyroid cancer,[20] but they are associated with substantial side-effect profiles.

Additionally, immunotherapies (ie, checkpoint inhibitors, which target regulators of the immune system to alter the response to cancer) are increasingly being studied for their potential use in thyroid cancer, although they are associated with various types of endocrine dysfunction, including hypophysitis and thyroiditis.

Ongoing clinical trials and studies will be paramount to assess the long-term efficacy and tolerability of the targeted-therapy drugs in patients with advanced disease who otherwise have few therapeutic options.

Thus, as we enter 2019, many questions remain in the field of thyroid cancer, the answers to which are being actively pursued by investigators and clinicians worldwide. Thyroid cancer is a dynamic and multidisciplinary field; a wide breadth of ongoing research, epidemiologic studies, and clinical trials will be critical to understanding the complex questions related to thyroid cancer management.

Dr Leung serves on the board of directors of the American Thyroid Association (ATA) and is editor-in-chief of Clinical Thyroidology, one of the journals of the ATA.

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