Thyroid Carcinoma: Epidemiology, Histology, and Diagnosis

The incidence of thyroid cancer has risen in recent years. In the United States, the incidence increased at an annual rate of 5.4% in men and 6.5% in women from 2006 to 2010.¹ Whether this increase represents a true rise in incidence—or early discovery of subclinical disease—is a matter of discussion. Early diagnoses of subclinical disease are also becoming more common throughout the world.² This increase has generated significant interest in the management of thyroid cancer.

Pathophysiology

Thyroid cancer begins in the follicular cell of the thyroid gland. There are 2 types of cells located within the thyroid parenchyma: the follicular cells and the supporting cells (also called the C cells). Cancers derived from follicular cells are generally differentiated thyroid carcinomas (DTC). Although these cancers are not usually aggressive, they can eventually mutate into more aggressive variants.

Thyroid cancer progresses according to a well-defined tumor progression model (Figure 1).³ Approximately 85% of patients present with DTC, and they have an excellent prognosis following treatment. Between 10% and 15% of tumors will mutate into more aggressive variants of thyroid carcinoma (Figure 2). These tumors may present with tall-cell features or as tall-cell thyroid carcinoma, and they have a biologic behavior that requires more aggressive surgical intervention and adjuvant therapy. Notably, these patients could be candidates for novel therapies if their disease is unresectable or refractory to radioactive iodine (RAI).

Figure 1.

Thyroid cancer progresses according to a well-defined tumor progression model. Data from Wreesmann VB et al. Am J Pathol. 2002;161(5):1549–1556.³

Figure 2.

A small proportion (approximately 10%) of papillary carcinomas will undergo progression to more aggressive variants. As the tumor progress to more aggressive variants, it leads to clinical manifestations of progression and increased mortality.

DM, distant metastases; ETE, extrathyroid extension; PTC, papillary thyroid carcinoma.

When the same stimulus that initiated the cancer continues, the tumors may mutate into poorly differentiated carcinomas. Approximately 10% of thyroid cancers may present with these features, and they carry a worse prognosis requiring more aggressive interventions, both surgically and nonsurgically. These cancers are generally refractory to RAI and have a higher risk of cause-specific mortality.

Fewer than 2% of thyroid cancers present as anaplastic carcinomas.⁴ Most mortality in thyroid cancer occurs in patients with anaplastic carcinoma. It is a uniformly fatal cancer.

Etiology

Thyroid cancer has no established etiologic factors, although exposure to radiation has been implicated for several decades. The phenomenon of radiation exposure leading to increased incidence of thyroid cancer was documented following the atomic bomb exposure in Hiroshima and Nagasaki during World War II.⁵ More recently, it was shown after the Chernobyl accident, which was followed by a steep rise in thyroid cancer among children exposed to the radiation fallout.⁶ There is evidence that exposure to low-dose radiation during childhood (such as in patients receiving therapeutic radiation for leukemia/lymphoma) is associated with an increased incidence of thyroid cancer.⁷ There is also evidence to show an increased risk of thyroid cancer in children treated with low-voltage radiation for acne. Although the incidence of thyroid cancer is higher after radiation exposure, the biological behavior of the disease is similar in both radiation-exposed and nonradiation-induced thyroid cancer. Therefore, although radiation exposure is important for triggering the disease, it does not appear to play a role in determining the aggressiveness of the malignancy.

Epidemiology

Thyroid cancer is most frequently encountered in younger age groups.⁸ Across the literature, age at onset appears as a bell-shaped curve, with the highest incidence in the second, third, and fourth decades of life. Within the past 2 decades, however, there has been a rise in the incidence of thyroid cancer during the fourth and fifth decades of life.⁹ The increased diagnoses may be attributable to incidental findings of tumors on imaging studies, such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), performed for other reasons.

In the United States, occult thyroid cancers are reported with an incidence of approximately 10% at autopsy among people who died of other causes.¹⁰ This incidence rises in various geographic regions of the world. In Finland, the autopsy incidence of occult papillary carcinoma is 35%.¹¹ These cancers likely had been present in the thyroid glands of these people throughout a portion of their life, without ever becoming clinically significant. These findings raise a controversial issue regarding whether all thyroid cancers should be diagnosed and treated. Data from the US autopsy study would suggest that there are more than 38 million people unknowingly living with papillary carcinoma. If overdiagnosis and treatment of these subclinical cancers continues, then in years to come, the autopsy incidence of occult thyroid cancers will probably decrease. Whether all thyroid carcinomas need to be treated is currently under debate.

Diagnosis

Typically, thyroid cancer is diagnosed after intrathyroid nodules are discovered on routine imaging (eg, on an MRI performed for a whiplash injury or an ultrasound performed on carotid arteries). The majority of such patients with thyroid cancer have no symptoms at the time of initial diagnosis. When symptoms do arise, they are usually caused by invasion of an adjacent structure by the primary tumor or metastatic progression to a lateral neck lymph node. A minority of patients present with locally advanced thyroid cancer (often poorly differentiated or anaplastic carcinoma). These patients may present with either symptoms of a mass in the neck, a feeling of pressure in the neck, or a choking sensation. Occasionally, patients present with hoarseness caused by paralysis of the vocal cords resulting from invasion of the recurrent laryngeal nerve. Some patients may also experience hemoptysis or airway obstruction from tumors growing into the trachea and compromising the airway. In some patients, the only symptom is a lump in the neck that turns out to be a metastatic lymph node.

A series of tests can be performed to diagnose and assess the primary tumor. The tests most relevant to decision-making in this disease are an ultrasound of the thyroid gland and a fine-needle aspiration biopsy. All other tests are relatively peripheral and subsequent to the establishment of the diagnosis of cancer.

Following confirmation of the diagnosis, and depending on the size and extent of the tumor, further radiologic workup may be necessary. Anatomic imaging studies, such as CT or MRI, are usually required in those patients who have an extensive primary tumor (such as a T3 or a T4 primary tumor) with invasion of adjacent structures or in patients who present with extensive nodal metastases.

Some clinicians believe that a CT scan should not be performed with the contrast dye. Use of iodine-containing contrast dye for imaging studies will delay the administration of RAI treatment, but this delay is not necessarily detrimental to the long-term outcome of the patient. In fact, detailed and accurate anatomic assessment of the primary tumor and its invasion to local structures is crucial for the surgeon to be able to perform a definitive and complete operation and achieve an R0 resection. Thus, when necessary, contrast dye should be used to obtain a good structural study.

Histology

Fortunately, the majority of newly diagnosed thyroid cancers are well-differentiated papillary carcinomas that are easily treatable and highly curable, and they respond well to therapy. In the past 2 decades, more than 80% of patients with newly diagnosed thyroid cancer had tumors less than 2 cm in diameter.⁹ This relatively small size implies that the cancer is at an early stage and associated with an excellent prognosis.

DTC can present with a papillary pattern or a follicular pattern, resulting in a diagnosis of either papillary carcinoma or follicular carcinoma. Most tumors are heterogeneous with both histologies—papillary and follicular— which is why they were formerly referred to as mixed papillary and follicular carcinomas. Current classification, however, is based on the predominance of the histologic pattern. Within DTC, there are variants of papillary carcinoma. For example, a follicular variant of papillary carcinoma is diagnosed when the follicular histology is predominant.

Prognosis

The prognosis in DTC depends on a variety of factors that are related to the patient and the tumor (Figure 3).^12–16 Patient age is an important prognostic factor.^8,17 Patients who are younger (generally considered <45 years) have an improved prognosis compared with older patients. In patients younger than 45 years, the 10-year survival rate is 98% to 99%. In contrast, mortality rates reach 20% to 25% among patients older than 70 years.

Figure 3.

Prognostic factors independently impacting outcomes in differentiated thyroid carcinoma based on multivariate analyses from the Mayo Clinic,^12,14 Lahey Clinic,¹³ the Karolinska Institute,¹⁵ and the Memorial Sloan Kettering Cancer Center (MSKCC).¹⁶

Histologic grade is another important factor for prognosis, with well-differentiated tumors having a better prognosis compared with poorly differentiated tumors.⁸ Similarly, extrathyroid extension is an independent factor impacting outcome.⁸ Patients with minor extension (T3) outside the thyroid gland have a relatively better outcome compared with those who have major extension (T4a) involving the adjacent structures, such as the recurrent laryngeal nerve, the trachea, the larynx, and the esophagus.

Tumor size is also of prognostic value.⁸ With increasing size, the risk of local recurrence starts to rise, which may eventually have a potential negative impact on survivorship. Presence of distant metastases is also an obvious and independent predictor of outcome.

Risk Group Stratification

The identification of prognostic factors led to the development of risk group stratification, which categorizes patients into low-risk, intermediate-risk, and high-risk groups.¹⁸ This stratification allows clinicians to tailor the initial treatment, including the extent of surgery, as well as the need for adjuvant postoperative therapy and the intensity of subsequent follow-up care. The low-risk category consists of patients who are young and female, with intraglandular tumors that are smaller than 4 cm, and who show no evidence of distant metastases (Figure 4). The 5-year survival rate in low-risk patients following treatment is near 100% (Figure 5).⁴ The high-risk category includes patients who are older and male, with extraglandular tumors larger than 4 cm that have a high-grade histology or evidence of distant metastases. These patients require aggressive surgery. There should also be consideration of elective treatment of regional lymph nodes and adjuvant therapies with RAI, external radiation therapy, or newer systemic agents.

Figure 4.

The identification of prognostic factors led to the development of risk group stratification, which categorizes patients into low-risk, intermediate-risk, and high-risk groups. GAMES, grade, age, metastases, extension, size. Based on a multivariate analysis from the Memorial Sloan Kettering Cancer Center.¹⁶

Figure 5.

Disease-specific survival according to risk group stratification according to the GAMES system from the Memorial Sloan Kettering Cancer Center.¹⁶ GAMES, grade, age, metastases, extension, size.

There are 2 groups of patients in the intermediate-risk group category. One group consists of younger patients with tumors that have poor histology or a gross extrathyroid extension. The second group includes older patients with small intrathyroidal differentiated tumors. Management should be tailored to the patient and the tumor in the intermediate group, to avoid overtreating the patient.