Lori J. Wirth, MD
Manisha H. Shah, MD
THYROID CANCER diagnoses are increasing at a rate faster than any other malignancy in the United States. In 2017, there will be 56,870 new cases, accounting for 3.4% of all cancers, and 2,010 people will die of thyroid cancer.1 This represents a more than 200% increase in incidence since the 1970s.
There is no doubt that this dramatic rise has been fueled by increased detection resulting from more frequent neck ultrasounds, fine-needle aspirations, and incidental findings on neck imaging performed for other diagnostic purposes. A critical question, however, is this: Is the rise in incidence simply due to the overdetection of small, indolent thyroid cancers that would remain subclinical had they not been detected in the first place, or does it reflect a true increase in thyroid cancers that should represent cause for concern?
Overdiagnosis or True Increase—or Both?
MULTIPLE STUDIES indicate that overdiagnosis is the most significant factor behind this trend. In 2006, analysis of Surveillance, Epidemiology, and End Results (SEER) cancer registry program data by Davies and Welch revealed an increase in thyroid cancer incidence from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002.2 From 1988 to 2002, the increase consisted entirely of cancers ≤ 1 cm in size. Moreover, mortality from thyroid cancer remained stable (approximately 0.5 deaths per 100,000).
Confirming the idea that the rising incidence of thyroid cancer represents an epidemic of diagnosis rather than disease is a recent meta-analysis of autopsy studies over the past 6 decades.3 Data from 42 data sets consisting of 12,834 autopsies indicated that the prevalence of incidental differentiated thyroid cancers remained stable in the period from 1970 to 2007, with a prevalence of approximately 11.2% when whole thyroids were examined.
Yet not all studies have been entirely reassuring. For example, when examining the SEER database for trends in thyroid tumor characteristics from 1980 to 2005, Enewold and colleagues found that although thyroid cancer incidence rose most dramatically in small papillary thyroid cancers ≤ 1 cm, significant increases in papillary thyroid cancers of all sizes were found, including tumors > 5 cm.4
Because advanced-stage thyroid cancers are less likely to be cured, it is difficult to dismiss the clinical significance of these findings. We also may be witnessing a change in the biologic underpinnings of thyroid cancer, as represented by an increasing frequency of known thyroid cancer driver mutations, including those in BRAF and RAS, implying that the change in incidence may be related to changes in disease biology, not just increased detection.5,6
More to the Story Than Overdiagnosis
NOW, WE HAVE new data that indicate the increase in thyroid cancer incidence in the United States cannot be explained by overdiagnosis alone. As reviewed in this issue of The ASCO Post, Lim and colleagues carried out an updated analysis of incidence and mortality among 77,276 thyroid cancer cases from the SEER database diagnosed from 1973 to 2013.7 Thyroid cancer incidence increased at a rate of 3.6% annually.
“There does indeed seem to be mounting evidence of a clinically significant increase in thyroid cancer in our population.”— Lori J. Wirth, MD, and Manisha H. Shah, MD
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The rise was greatest in tumors ≤ 1 cm (at an annual change of 9.3%). Still, the annual percent change of larger tumors > 1 to ≤ 2 cm, > 2 to ≤ 4 cm, and > 4 cm was, respectively, 5.4%, 4.5%, and 6.1%. Moreover, Lim and colleagues found that although mortality due to thyroid cancer was underestimated in the early period of their analysis, from 1994 to 2013, thyroid cancer incidence–based mortality increased 1.1% annually on average. Among patients who died of thyroid cancer, the median time from diagnosis to death was 25 months, though 27% of patients who died of thyroid cancer survived for more than 10 years after diagnosis.
What are the implications of this new study? The increasing incidence of more advanced-stage thyroid cancer, coupled with the increase in death due to thyroid cancer, does indicate that the increase in thyroid cancer incidence over the past 40 years cannot be due only to more frequent identification of patients from an unchanging reservoir of disease. There does indeed seem to be mounting evidence of a clinically significant increase in thyroid cancer in our population.
Is this due to changing environmental exposures leading to more thyroid cancer? As the authors note, the most obvious culprit might be exposure to ionizing radiation. Yet, there is no evidence of an increase in thyroid cancers that harbor “rearranged during transfection” papillary thyroid cancer (RET/PTC) rearrangements, considered a hallmark of radiation-induced disease.6 Other potential environmental factors could include iodine intake or chemical exposure. Another plausible etiology is obesity, which happens to be increasing at a similar rate to that of thyroid cancer.8 Obesity could impact on thyroid carcinogenesis by insulin resistance, thyroid hormone, or estrogen-related pathways. Clearly, more epidemiologic and basic research to identify causal relationships is needed.
Screening Issues
A SECOND important implication of these data relates to screening for thyroid cancer. Recently released U.S. Preventive Services Task Force (USPSTF) recommendations advise against screening for thyroid cancer by either physical examination or ultrasound of the neck.9 The USPSTF found inadequate evidence to support screening based on three factors: (1) the rarity of thyroid cancer, (2) the apparent lack of difference in outcomes between patients who are treated vs those who are monitored, and (3) evidence showing no change in mortality over time. Although the study by Lim and colleagues does not overturn all three arguments against routine thyroid cancer screening, this new evidence of increasing thyroid cancer mortality does suggest that for some patients—ie, those who will die of the disease—early detection and treatment may be critical.
Better Detection Tools Needed
LASTLY, there is a third reason why we should care about thyroid cancer. There is significant concern that overdiagnosis has led to overtreatment, with many patients undergoing surgery and often receiving radioactive iodine for cancers that may never cause them illness. The emphasis has shifted to avoiding treatment in patients who do not need it and establishing programs for safe active surveillance in lieu of treatment.10-12 However, with an increase in more-advanced thyroid cancer and a small but detectable increase in thyroid cancer mortality, while we focus on avoiding unnecessary treatment for patients with small, indolent thyroid cancers, we need to develop better tools to detect small cancers that do need treatment.
Several studies have begun to shed light on the prognostic value of genetic markers in thyroid cancer. For example, when BRAF, RAS, or TERT promoter mutations occur alone in papillary thyroid cancers, there is no meaningful impact on outcomes, whereas coexisting mutations in the TERT promoter with either BRAF or RAS mutation predicts higher thyroid cancer mortality.13,14 One great challenge is to figure out a way to introduce molecular diagnostics into the evaluation of patients who may otherwise be considered suitable for active surveillance, in order to identify patients who may need active treatment instead.
In Summary
THE STUDY by Lim and colleagues shows an increase in incidence and mortality rate of thyroid cancer, including advanced-stage papillary thyroid cancers, in the United States over the past 4 decades. Studies are needed to understand the reasons beyond overdetection underlying this increase and to guide clinicians in choosing between active surveillance or early treatment for individual patients with small thyroid cancers. ■
DISCLOSURE: Dr. Wirth has served as a consultant to Amgen, Blueprint Medicines, Eisai, Loxo Oncology, and Merck. Dr. Shah has served as a consultant to Eisai and Loxo Oncology; she also has received research funding from Eisai, Loxo Oncology, and Merck.
REFERENCES
1. National Cancer Institute: Cancer stat facts: Thyroid cancer. Available at seer.cancer. gov/statfacts/html/thyro.html. Accessed July 18, 2017.
2. Davies L, Welch HG: Increasing incidence of thyroid cancer in the United States, 1973- 2002. JAMA 295:2164-2167, 2006.
3. Furuya-Kanamori L, Bell KJ, Clark J, et al: Prevalence of differentiated thyroid cancer in autopsy studies over six decades: A meta-analysis. J Clin Oncol. September 6, 2016 (early release online).
4. Enewold L, Zhu K, Ron E, et al: Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005. Cancer Epidemiol Biomarkers Prev 18:784-791, 2009.
5. Mathur A, Moses W, Rahbari R, et al: Higher rate of BRAF mutation in papillary thyroid cancer over time: A single-institution study. Cancer 117:4390-4395, 2011.
6. Jung CK, Little MP, Lubin JH, et al: The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. J Clin Endocrinol Metab 99:E276-E285, 2014.
7. Lim H, Devesa SS, Sosa JA, et al: Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA 317:1338-1348, 2017.
8. Ogden CL, Carroll MD, Fryar CD, et al: Prevalence of obesity among adults and youth: United States, 2011-2014. NCHS Data Brief:1-8, 2015.
9. U.S. Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al: Screening for thyroid cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 317:1882-1887, 2017.
10. Ito Y, Miyauchi A, Inoue H, et al: An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg 34:28-35, 2010.
11. Sugitani I, Toda K, Yamada K, et al: Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: Our treatment strategies and outcomes. World J Surg 34:1222-1231, 2010.
12. Haser GC, Tuttle RM, Urken ML: Challenges of active surveillance protocols for low-risk papillary thyroid microcarcinoma in the United States. Thyroid 26:989-990, 2016.
13. Cancer Genome Atlas Research Network: Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676-690, 2014.
14. Shen X, Liu R, Xing M: A six-genotype genetic prognostic model for papillary thyroid cancer. Endocr Relat Cancer 24:41-52, 2017.
