Papillary Thyroid Cancer

Changing Thyroid Cancer Incidence

The incidence of thyroid cancer in the United States has tripled over the past three decades, the majority of which is due to small papillary thyroid carcinomas. This trend has also been noted in many other countries across Europe, Asia, Oceania, and South America. The incidence is rising in both genders and across all age groups, including children and adolescents. Fortunately, in the United States, the incidence rates may be stabilizing, though it remains to be seen if the plateau will persist ( Figure 19.1 ).

Although the incidence of thyroid cancer has risen in recent times, PTC remains a relatively rare tumor, representing only 3.1% of all new cancer cases. It is estimated that 56,870 new cases were diagnosed in 2017, and 2010 deaths were attributed to thyroid cancer during this period. In spite of the recent upward trend in thyroid cancer incidence, mortality rates remain stable, suggesting a significant proportion of new cases represent overdiagnosis. Indeed, there is a large reservoir of undiagnosed disease with thyroid cancer identified in up to 36% of cases of autopsy studies, a prevalence that is more than 1000-fold higher than the rates of disease that are clinically diagnosed in the general population ( Figure 19.2 ). Further support of the role of increased diagnostic scrutiny in the uptrend is revealed by the numbers of small cancers detected: 87% of newly diagnosed cancers are 2 cm or smaller and 49% are < 1 cm. However, it should be noted that several studies have determined that thyroid cancers of all sizes are on the rise, suggesting that overdiagnosis is not solely to blame for increased incidence (see Chapter 17 , Differentiated Thyroid Cancer Incidence).

Exposure to Radiation

Exposure to ionizing radiation during childhood has been the most extensively studied causative factor in the development of thyroid cancer. Factors that increase the risk for developing PTC after radiation exposure include female gender, radiation for childhood cancer (rather than benign conditions), and a family history of thyroid cancer. In one study, younger age at exposure and dose of radiation administered significantly influenced the risk of development of cancer.

Polybrominated Diphenyl Ethers

Some have proposed a potential role of polybrominated diphenyl ethers (PBDEs) in the development of thyroid cancer. These ubiquitous flame retardants may be found in plastics, electrical appliances, televisions, computers, building supplies, foams, carpets, and upholstery. PBDEs and their metabolites may accumulate in human tissues and bear a striking structural similarity to thyroxine. These compounds have been shown to be potent endocrine disrupters, with thyroid and estrogen effects being the most common. Although there has been no direct link between an increased risk of thyroid cancer and PBDEs, their increased oncogenic potential in other tissues has made them an attractive candidate for further study in thyroid cancer.

Obesity

Obesity and overweight were linked to nearly 18% of all cancer cases and 16% of cancer deaths in 2014. Several studies have identified a significantly higher risk of thyroid cancer in overweight and obese patients. The inflection point in the incidence of thyroid cancer occurred in the mid-1970s; there was a similar change in the trend for obesity rates in the United States just a few years prior. Over time the slopes of these two conditions have remained nearly parallel. Consequently, some have posited a potential causal relationship, although the mechanism is elusive.

Obesity affects the secretion of adipokines by adipose tissue, including increased leptin and decreased adiponectin. Through complex molecular signaling, these adipokines interact with key factors in carcinogenesis, including cell proliferation, angiogenesis, and antiinflammatory cytokines. Further studies are necessary to delineate the role of obesity in the development of thyroid cancer, particularly as the incidence of obesity continues to climb throughout Europe, North America, and Asia.

Hereditary Syndromes

The majority of thyroid cancers are sporadic; however, approximately 5% of nonmedullary thyroid cancers are hereditary. These hereditary cases have been divided into two groups: those tumors associated with a familial cancer syndrome, such as familial adenomatous polyposis, Gardner syndrome, Cowden disease, Carney complex type 1, or Werner syndrome; and those with thyroid tumors as the primary feature, such as familial nonmedullary thyroid cancer (see Chapter 30 , Familial Nonmedullary Thyroid Cancer).

Tumor Histology

Numerous histologic variants of PTC have been described based on architectural or cellular features. Acknowledgement of the tumor subtype is important, as it can contribute to the risk stratification of individual tumors. The classic variant of PTC and the follicular variant of PTC (FVPTC) are associated with very favorable outcomes. More concerning histologic subtypes include tall cell, hobnail variants, and, perhaps to a lesser extent, columnar cell; these tumors tend to present at an older age and with more advanced disease than is seen in classic PTC (see Chapter 41 , Surgical Pathology of the Thyroid Gland). These more aggressive histologic variants also are associated with worse recurrence-free and disease-specific survival rates.

Tumor Size

Primary tumor size is closely associated with the outcome of PTC, including both 10-year recurrence and cancer-specific mortality rates. Cancer-specific mortality rates increase incrementally from 2% for tumors < 1 cm to 19% for tumors > 8 cm. Furthermore, larger tumors are associated with a higher rate of locoregional and distant metastases.

Multifocality

Patients with PTC have a 32% to 45% chance of cancer elsewhere in the ipsilateral or contralateral lobe. Tumor multifocality is also found frequently in papillary thyroid microcarcinomas (PMCs). Multifocal disease increases the risk of recurrence, particularly in patients who have had a lobectomy. With the current trend to performing lobectomy for the majority of low-risk cancers, some have raised concerns about the potential for increased recurrence rates. Indeed, some patients may develop recurrence in the remaining contralateral lobe, necessitating completion thyroidectomy at a later date. Fortunately, it is the minority (7% at 10 years of follow-up) of patients who will require such an intervention. A large, long-term follow-up study of patients undergoing lobectomy for PTC, 14.6% of whom had multifocal disease, demonstrated a recurrence-free 20-year survival rate of 95% in the opposite lobe, 91% for lymph node (LN) recurrence, and a disease-specific survival rate of 97.8%. Predictors of recurrence or worse disease-specific survival were age, primary tumor > 4 cm, and clinically apparent LNs, suggesting that properly selected patients will have an excellent prognosis after lobectomy of PTC.

The implications of tumor multifocality on survival are controversial. Some studies have determined that multifocal disease does not increase the risk of disease-specific mortality. However, when distinguishing unilateral multifocal from bilateral disease, other studies have demonstrated that survival was lower for bilateral tumors.