Is Thyroid Cancer Increasing in Incidence and Aggressiveness?

Thyroid cancer incidence has continuously increased in recent decades, more than any other malignancy. According to the Surveillance, Epidemiology, and End Results (SEER) database, in the period 1980-2016, the incidence rate in the United States increased from 2.39 to 7.54 per 100 000 in men and from 6.15 to 21.28 per 100 000 in women (1). The increase in incidence is global, involving high- and low-income countries, regardless of variable diagnostic practices, ethnic characteristics, and environmental differences (2).

A higher detection rate due to more sensitive and diffuse diagnostic practices certainly contributes to this increase, allowing the emergence of small and indolent tumors that are irrelevant to patients’ health and survival and that previously would have gone undiagnosed. Stable thyroid cancer-related mortality rate, at approximately 0.5 cases per 100 000 inhabitants, was believed to support an “apparent” increase in thyroid cancer incidence.

However, in recent decades, thyroid cancer has been diagnosed at an earlier stage (indicated by the progressive prevalence of small tumors) and is more efficaciously treated (indicated by the overall survival at 5 years, which increased from 92.1% in 1975-1977 to 98.5% in 2009-2015) (1). Early diagnosis and better treatment reduce cancer mortality: a steady death rate could be the final result of increasing mortality compensated by the decreasing trend due to improved medical procedures. Moreover, because of the indolent nature of most thyroid cancers, an increased incidence will influence mortality only decades later. Some recent data suggest, indeed, that this phenomenon is occurring. In many countries (3), although not all (4), thyroid cancer-related mortality is increasing: for instance, a 1.1% increase per year was reported in the United States in the period of 1994-2013 (5).

An important contribution to better clarify the relationship between thyroid cancer incidence and mortality comes from the California cancer registry. Analyzing 69 684 thyroid cancer patients with 2562 related deaths, both an increasing incidence trend and an increasing incidence-based mortality were observed in the last 18 years (2000-2017) (6). The increase in incidence (average annual percent change 4%) was irrespective of sex, ethnicity, tumor size, stage (excluding distant cancers) and histotype (excluding follicular tumors). The incidence of tumors larger than 4 cm and of anaplastic cancers, which are very unlikely to have been undetected in the past, was also increased.

During the same period, also the incidence-based mortality for thyroid cancer increased. The overall increase was 1.7% per year, which was more pronounced in aged patients and, for papillary tumors, in patients in the advanced stage, as expected.

These new epidemiological, biological and clinical data from a large source independent from the SEER program strongly suggest that a “true” biological increase is contributing to the overall rise of thyroid cancer incidence and that thyroid cancer-related mortality has also been increasing in recent years.

These Observations Raise Three Major Questions

• 1) Can we identify the relative contribution of the “apparent” and the “true” components of the increasing thyroid cancer incidence?

At present, this subdivision is not possible because each component will variably contribute in different settings, depending on the socioeconomic conditions and medical procedures at local level (for the “apparent” part) and from the environmental factors and genetic characteristics of the population (for the “true” part).

• 2) Why is the thyroid cancer incidence increasing when the incidence of most cancers is stationary or even decreasing?

The “apparent” increase should have curbed down in recent years because of the progressive emptying of the large reservoir of occult and clinically irrelevant tumors and the worldwide increased attention to overdiagnosis. However, this has not occurred; it is too early to evaluate the significance of the stabilizing trend reported in California in 2015-2017 (6). The “true” increase in incidence, therefore, might become more prevalent. Increased exposure to radiation, increased iodine intake, and dietary factors such as nitrates have been blamed (2), but many other factors might be responsible, considering that in recent decades the industrialized lifestyle and the agroindustrial procedures have exposed the population to thousands of chemicals with unknown carcinogenicity. Heavy metals, for instance, have sharply increased in the environment because of their current use in daily life. These compounds may affect the thyroid function and morphology through different mechanisms. Chronic exposure of human stem/precursor thyroid cells to the heavy metal tungsten at high-normal environmental concentrations causes mitogenic and genotoxic effects typical of malignant transformation (7). These in vitro effects are not seen in mature thyrocytes but are present in thyrocytes differentiated from exposed stem/precursor cells, indicating the development of a thyroid cell population with a propensity for malignant transformation. This kind of stage-specific effect is compatible with the observation of increased mortality in youngest generations, born in the 1960s (4), the first exposed to the increasing pollution of expanding westernized life in the prenatal and early life period.

• 3) Why is the incidence-based mortality increasing despite improvements in early diagnosis and treatments?

The most plausible explanation is that a subset of thyroid cancers has become faster growing, more extensively invading and spreading at distances. Changes in the tumor molecular profile may produce this effect. The significant increase observed in recent years in the prevalence of the BRAF^V600E mutation, which is associated with worse papillary thyroid cancer outcomes, is consistent with this possibility (6).

In addition to directly affecting malignant cell biology, however, the environment may have detrimental effects on the thyroid cancer outcome also through indirect mechanisms, influencing patient immunology and the tumor immune microenvironment, favoring the evasion of tumor cells from the immunological control (8).

In conclusion, more research is needed to identify causes and mechanisms that promote thyroid cancer initiation and progression. In addition to novel therapies with molecular targeted drugs and immunological agents, more attention should be given to the risk factors in the environment, in order to arrange preventive measures able to reduce the thyroid cancer worldwide burden.

Acknowledgments

Financial Support: R.V.’s research is supported by a grant from the Associazione Italiana Ricerca sul Cancro (AIRC) Foundation (n0.19897),

Additional Information

Disclosure Summary: The Authors have nothing to disclose.

References