Clinical Review & Education
Special Communication
Incidental Thyroid Nodules and Thyroid Cancer Considerations Before Determining Management Ralph P. Tufano, MD, MBA; Salem I. Noureldine, MD; Peter Angelos, MD, PhD
The worldwide incidence of thyroid cancer is increasing substantially, almost exclusively attributable to small papillary thyroid cancers. Increased use of diagnostic imaging is considered the most likely explanation for this reported rise, but other factors may also be contributing. The increase in health care expenditures related to managing these presumably low-risk cancers, without a clear patient benefit, has resulted in a backlash against the early detection of thyroid cancer. Currently, there is no way to confidently predict which incidentally detected thyroid nodule may be the precursor to a more aggressive process. Predictions such as these would require more accurate characterization of the biology of individual thyroid cancers than is currently possible. With time, we might prove our ability to confidently differentiate low-risk from high-risk thyroid cancers, but until that happens, routine screening for thyroid cancer by imaging billed as a “health checkup” should not be performed. However, incidentally detected thyroid nodules should be reported, and a clear medical team management plan should be developed. Our ethical responsibility is to provide patients with objective, evidence-based information about their disease status, not to assume that we know what is best for them by selectively withholding information. In addition, providing patients with psychosocial assistance will help them process the information necessary to make informed decisions that will provide them with the most value when a small thyroid nodule or cancer is incidentally identified. Herein, we summarize the epidemiological data for disease incidence, discuss some controversies in disease management, and outline the key elements and ethical considerations of informed decision making as they apply to managing incidentally detected thyroid nodules and thyroid cancer. JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2015.0647 Published online April 30, 2015.
T
Author Affiliations: Division of Head and Neck Endocrine Surgery, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (Tufano, Noureldine); Department of Surgery, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois (Angelos). Corresponding Author: Ralph P. Tufano, MD, MBA, Division of Head and Neck Endocrine Surgery, Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins School of Medicine, Johns Hopkins Outpatient Center, 601 N Caroline St, Sixth Floor, Baltimore, MD 21287 ([email protected]).
hyroid nodules are extraordinarily prevalent, detected by physical examination in 4% to 7% of the population and by imaging studies in 30% to 67%.1 Although most of these nodules are benign, up to 20% are found to be malignant on excision.2 Autopsy studies have shown that a third of patients who died from reasons other than thyroid conditions were found to have thyroid cancer.3 These cancers were incidentally discovered through interval sectioning of 2 to 3 mm, suggesting that if all thyroid glands were subject to 1-mm-thick cuts, microscopic thyroid cancers would be detected in more than 50% of the population. This occult reservoir of subclinical thyroid cancer has recently reached epidemic proportions with the increased use of imaging studies for diagnostic scrutiny.4-6 However, most patients with these tumors have an excellent prognosis owing to the relatively indolent course that most of these tumors follow.7 These incidental cancer findings may exemplify the epidemiologic term overdiagnosis, the detection of subclinical disease that would have not caused symptoms or death during a patient’s lifetime if left undetected.8,9
cer, shows that the age-standardized incidence of thyroid cancer in womenhasincreasedfrom1.5per100 000in1953to7.5per100 000 in2002,withasimilarrelativeincreaseinmen.IntheUnitedStates,the incidenceofthyroidcancerhasincreasedfrom4.9per100 000in1975 to 14.3 per 100 000 in 2009, making it one of the fastest-growing cancers.12 Infact,itisprojectedthatin2019,theUSrateofpapillarythyroid cancer (PTC) will be 37 per 100 000 women, becoming the third mostcommoncancerinwomenofallagesafterbreastandlungcancer.13 The increases in incidence of thyroid cancer in France, Italy, Croatia, the Czech Republic, Australia, and Canada parallel that seen in the United States.11 In South Korea, the incidence of thyroid cancer in women abruptly increased from 10.6 per 100 000 to 111.3 per 100 000 between 1996 and 2010, making it the most common cancer among South Korean women.14 Conversely, in Japan, China, and Sweden, the increase in incidence has been marginal.11 Variations in incidence were also noted within countries.15 Interestingly, however, the worldwide rise in thyroid cancer incidence has not been accompanied by an increase in disease-specific mortality.10
A Perplexing Rise in Thyroid Cancer
Factors Associated With Increased Incidence of Thyroid Cancer
The worldwide incidence of thyroid cancer has increased substantially over the past 50 years.10 The Cancer Incidence in Five Continents report,11 maintained by the International Agency for Research on Canjamaotolaryngology.com
The precise reasons for the increased incidence of thyroid cancer are difficult to determine. Increased use of diagnostic imaging capable
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
E1
Clinical Review & Education Special Communication
of exposing subclinical disease is considered the most likely explanation for this reported rise.4-6 The location of the thyroid gland places it within the window of many diagnostic imaging studies. Ultrasonography of the neck for parathyroid disease,16 carotid flow evaluation,17 or even in the context of otherwise healthy individuals may reveal an asymptomatic thyroid nodule as small as 2 mm in up to 67% of patients.1 In addition, cross-sectional imaging studies have contributed to a 2.4-fold increase in the reported incidence of thyroid nodules over the past 30 years.18-20 More than half of the cases detected incidentally through imaging can be labeled as low-risk cancers.9,21 The use of ultrasonography for the screening of thyroid cancer has also been considered a contributing factor to its increasing incidence. This is believed to be the key factor in South Korea’s abrupt increase in thyroid cancer incidence. A study based on the 2009 Korean National Cancer Screening Survey revealed that 13.2% of South Koreans underwent thyroid cancer screening with ultrasonography.22,23 The link between imaging studies and increased incidence is supported by a correlation with access to health care, and the incidence is rising more rapidly in countries where health care expenditure is driven by the private sector rather than the public sector.24 A recent analysis of the Surveillance, Epidemiology, and End Results Program (SEER) database showed that the incidence of thyroid cancer was positively associated with sociodemographic markers of health care access, such as college education, white-collar employment, and higher family income.9 Contrary to the hypothesis that diagnostic imaging is the main cause of the increased incidence of small thyroid cancers, the incidence of large thyroid cancers has not declined and is also increasing.25-27 Moreover, higher rates of aggressive PTCs are being detected, including those with extrathyroidal extension and distant metastases.25,28-30 Finally, risk factors not yet identified may also be contributing to this increase in incidence. Studies have suggested that it may be due to high levels of ionizing radiation exposure, which have doubled in the United States since the 1970s, mainly due to increased use of radiographic imaging.31 Moreover, hormonal, nutritional,32 and menstrual and reproductive factors may be causing this surge in incidence.33 The worldwide rise and the differing rates of thyroid cancer between countries suggest that multiple factors may have a role in the incidence and warrant further investigation.
South Korea’s Experience—“a Cautionary Tale” Cancer is the leading cause of death in the republic of South Korea, accounting for almost a third of overall deaths per year.34 In 1999, the government of South Korea initiated a national campaign to improve health and reduce the number of cancer-related deaths by providing screening for breast, cervical, colorectal, gastric, and hepatic cancers free of charge or, for people with above-average income, for a minor copayment. Although thyroid cancer screening was not included in the funded screening program, clinicians frequently offered screening with ultrasonography for an extra charge of approximately $50,35 which provided a profitable outcome for business-focused health care practices.24 The South Korean health care system relies heavily on patients’ direct payment supplemented by private health insurance. In addition, ultrasonography screening is excluded from public health E2
Incidental Thyroid Nodules and Thyroid Cancer
care expenditure and therefore is not regulated by government guidelines. One South Korean reporter portrayed the problem as a mass production of patients for the benefit of the health care industry rather than health care services for the benefit of patients. He described the situation as “doctors selling refrigerators to the Eskimos.”36 Many hospitals, even university-based centers, commercialized health screening programs that included thyroid cancer screening using ultrasonography and cross-sectional imaging.22,23 Almost all of the newly identified thyroid cancers found by screening are subcentimeter PTCs, which studies have shown are typically very slow growing and highly unlikely to cause symptoms, much less death.7,9,21 Nonetheless, 9 of 10 patients diagnosed in South Korea will undergo thyroidectomy, and roughly two-thirds of these will undergo total thyroidectomy. The proportion of patients undergoing thyroidectomy in South Korea for a subcentimeter thyroid cancer has increased from 14% to 56% between 1995 and 2005.37 This scenario of overdiagnosis and overtreatment clearly illustrates the downside of early PTC detection, and serves as a cautionary tale for the rest of the world where the thyroid cancer incidence is surging.35 On March 18, 2014, at a press conference held in the South Korean National Health Insurance Corporation, 8 cancer specialists expressed concern about overdiagnosis of thyroid cancer and suggested that routine screening be banned. Major newspapers reported the story and ran headlines asking “Is thyroid cancer overdiagnosed?”38 There was also widespread broadcast coverage, including special television programs devoted to the issue. South Korea’s Ministry of Health and Welfare is currently working to establish appropriate screening criteria. The final consensus report was scheduled for release in December 2014 but was delayed owing to the inability of the review committee to reach consensus. Many of the committee members benefit financially from screening and so favor such intervention.39 It seems that the establishment of these guidelines may require more time. Currently, the lack of sufficient evidence makes the route to consensus unclear. Moreover, because it is challenging to explain to the South Korean public why early diagnosis and treatment of a common type of cancer could be problematic, screening for thyroid cancer continues to be relevant. In contrast to South Korea’s experience, according to new figures from the Office of National Statistics in England,40 the survival rate for patients with thyroid cancer has worsened in the last year. In England, thyroid cancer is more often diagnosed in the emergency department, when the tumor is often at a more advanced stage, and is not being found early by primary care clinicians. The solution proposed by the British council is to provide physicians there with more screening tools to help them diagnose these cancers as early as possible.41 The question is how will British physicians be able to confidently distinguish small, indolent thyroid cancers from those that would behave more aggressively. Failure to make this distinction and institute clear protocols for surveillance vs intervention may lead the British down the same path as the South Koreans.
Risk-Based Screening—the Happy Medium Recently, the American College of Radiology (ACR) issued a white paper suggesting that radiologists might decide whether or not to
JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
jamaotolaryngology.com
Incidental Thyroid Nodules and Thyroid Cancer
Special Communication Clinical Review & Education
Tailoring the Treatment to the Type of Thyroid Cancer Papillary and follicular thyroid cancers both have favorable prognoses, with mortality rates of 1% to 2% at 20 years for PTC46 and 10% to 20% at 20 years for follicular thyroid cancer.47 In contrast, patients with medullary thyroid cancer have 25% to 50% mortality at 10 years, and most patients with poorly differentiated and anaplastic thyroid cancer die within a year of diagnosis (5-year mortality rate, 90%).47,48 Papillary thyroid cancers are generally perceived as low-risk thyroid cancers47 and are not associated with well-recognized predictors of mortality.49,50 The encapsulated follicular variant of PTC also appears to be associated with a low risk of recurrence.51 Well-differentiated follicular thyroid cancers demonstrating only capsular invasion (without vascular invasion) usually have an excellent prognosis, with recurrence rates of jamaotolaryngology.com
Figure. Different Behaviors and Rates of Growth of Thyroid Cancers That Determine Their Potential to Be Detected by Screening Screening Intervals
Progression Time of Thyroid Cancer
report incidentally found thyroid nodules.42 The ACR assumes that because thyroid cancer is typically an indolent disease, patients will not be harmed by this practice, and when the reported number of incidentally found thyroid nodules is reduced, the corresponding costs of unnecessary procedures are also reduced, as are the risks to the patient from unnecessary surgery. Radiologists believe that they are the ones responsible for the avoidable psychological stigma of cancer in these patients and their lifelong dependency on daily thyroid hormone supplementation.19 However, if radiologists fail to report the incidental finding of thyroid nodules, even with the best of intentions, they deprive patients and their physicians—the 2 key stakeholders in the process of informed decision making—of information needed to make important management decisions. In addition, radiologists have no way to confidently predict which incidentally detected thyroid nodules may be the precursor to a more aggressive process. It is paternalistic for any clinician or payer to presume that increased awareness of a patient’s thyroid nodule will pose harm. Clinicians meet their responsibilities to their patients by focusing on the benefit of each individual patient rather than the interests of society. Clearly, some thyroid cancers become not only symptomatic but deadly, resulting in a consistent 0.5 deaths per 100 000 individuals annually.43 Metastases can, and occasionally do, exist regardless of the size of the primary tumor. Moreover, men are more likely to present with advanced and sometimes fatal disease, which is believed to result from delayed diagnosis.44 While it may be that many thyroid cancers remain indolent, it is also true that the thyroid cancer death rate in the United States is higher than the death rates for Hodgkin lymphoma and testicular, anal, bone and joint, and small-intestinal cancers.43,45 Strategies to reduce the detection and treatment of indolent disease include focusing screening on high-risk populations. An ideal screening program would identify consequential disease that is ideally treated in the early stages; such a program would allow early curative interventions (Figure). Better screening depends on our ability to more accurately characterize the biology of individual thyroid cancers detected; until this can be confidently accomplished screening should not be utilized.
Advanced disease (palliation only) Symptomatic disease (likely curable)
Tumor A
Detectable by screening
Asymptomatic disease Microscopic disease
Overdiagnosis Tumor B Tumor C
Patient’s Lifetime
Tumor A grows rapidly and therefore is not usually detected by screening. This tumor is diagnosed clinically in the interval between screening examinations and has a poor prognosis. Tumor B is capable of metastasizing and progressing into advanced disease, but it grows slowly enough to be detected by screening (*). In most cases, early detection and treatment will result in disease-free survival. Tumor C eventually becomes detectable by screening (*), but it is so indolent that it will never progress to affect the quality of life of the patient. Its detection will result in overdiagnosis and potentially overtreatment. Molecular markers and other objective predictors of an individual patient's tumor behavior might be identified that will allow us to confidently differentiate low-risk (tumor C) from high-risk (tumor A and tumor B) thyroid cancer, but those predictors have not been elucidated yet.
0% to 7%, and can be classified as low-risk tumors.52-54 Encapsulated, minimally invasive follicular thyroid cancer with only minor vascular invasion appears to also have a low recurrence rate, from 0% to 5%.55 Currently, the treatment for all of these low-risk thyroid cancers is surgical removal. Although it is generally accepted that surgery is the standard to eradicate these tumors, there is less agreement about the extent of the surgery (ie, lobectomy vs total thyroidectomy).56 Guidelines from surgical professional societies have provided guidance on the management of these low-risk tumors,47,57 but owing to the broad category into which these lesions fall, coupled with the uncertainty about the proper classification and optimal management of these cancers, many patients receive care similar to that of patients with more aggressive thyroid cancers.56 The rationale for total thyroidectomy in these patients is that there are fewer recurrences with this intervention than with lobectomy.58 Nonetheless, no randomized trials have investigated the advantages of total thyroidectomy over lobectomy for patients with low-risk thyroid cancers. A large observational study based on the SEER database found no survival benefit with more aggressive surgical treatment for those patients with low-risk tumors after controlling for tumor size.59 As clinicians, we should not dismiss incidentally detected small thyroid nodules and small thyroid cancers; rather, we should seek methods to personalize care that will yield the most value to the patient. These methods must be based on objective data and psychosocial support to help both physician and patient process the information necessary to make informed decisions.
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
E3
Clinical Review & Education Special Communication
Incidental Thyroid Nodules and Thyroid Cancer
Table. Active Surveillance Studies in Patients With Low-Risk Thyroid Cancers Patients, No. (%)
Study
Tumor Size Cutoff, cm
Patients, No.
Follow-up Duration
Tumor Growth >3 mm
Subsequent Need for Surgery
Sugitani et al,70 2010
Special Communication
Incidental Thyroid Nodules and Thyroid Cancer Considerations Before Determining Management Ralph P. Tufano, MD, MBA; Salem I. Noureldine, MD; Peter Angelos, MD, PhD
The worldwide incidence of thyroid cancer is increasing substantially, almost exclusively attributable to small papillary thyroid cancers. Increased use of diagnostic imaging is considered the most likely explanation for this reported rise, but other factors may also be contributing. The increase in health care expenditures related to managing these presumably low-risk cancers, without a clear patient benefit, has resulted in a backlash against the early detection of thyroid cancer. Currently, there is no way to confidently predict which incidentally detected thyroid nodule may be the precursor to a more aggressive process. Predictions such as these would require more accurate characterization of the biology of individual thyroid cancers than is currently possible. With time, we might prove our ability to confidently differentiate low-risk from high-risk thyroid cancers, but until that happens, routine screening for thyroid cancer by imaging billed as a “health checkup” should not be performed. However, incidentally detected thyroid nodules should be reported, and a clear medical team management plan should be developed. Our ethical responsibility is to provide patients with objective, evidence-based information about their disease status, not to assume that we know what is best for them by selectively withholding information. In addition, providing patients with psychosocial assistance will help them process the information necessary to make informed decisions that will provide them with the most value when a small thyroid nodule or cancer is incidentally identified. Herein, we summarize the epidemiological data for disease incidence, discuss some controversies in disease management, and outline the key elements and ethical considerations of informed decision making as they apply to managing incidentally detected thyroid nodules and thyroid cancer. JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2015.0647 Published online April 30, 2015.
T
Author Affiliations: Division of Head and Neck Endocrine Surgery, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (Tufano, Noureldine); Department of Surgery, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois (Angelos). Corresponding Author: Ralph P. Tufano, MD, MBA, Division of Head and Neck Endocrine Surgery, Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins School of Medicine, Johns Hopkins Outpatient Center, 601 N Caroline St, Sixth Floor, Baltimore, MD 21287 ([email protected]).
hyroid nodules are extraordinarily prevalent, detected by physical examination in 4% to 7% of the population and by imaging studies in 30% to 67%.1 Although most of these nodules are benign, up to 20% are found to be malignant on excision.2 Autopsy studies have shown that a third of patients who died from reasons other than thyroid conditions were found to have thyroid cancer.3 These cancers were incidentally discovered through interval sectioning of 2 to 3 mm, suggesting that if all thyroid glands were subject to 1-mm-thick cuts, microscopic thyroid cancers would be detected in more than 50% of the population. This occult reservoir of subclinical thyroid cancer has recently reached epidemic proportions with the increased use of imaging studies for diagnostic scrutiny.4-6 However, most patients with these tumors have an excellent prognosis owing to the relatively indolent course that most of these tumors follow.7 These incidental cancer findings may exemplify the epidemiologic term overdiagnosis, the detection of subclinical disease that would have not caused symptoms or death during a patient’s lifetime if left undetected.8,9
cer, shows that the age-standardized incidence of thyroid cancer in womenhasincreasedfrom1.5per100 000in1953to7.5per100 000 in2002,withasimilarrelativeincreaseinmen.IntheUnitedStates,the incidenceofthyroidcancerhasincreasedfrom4.9per100 000in1975 to 14.3 per 100 000 in 2009, making it one of the fastest-growing cancers.12 Infact,itisprojectedthatin2019,theUSrateofpapillarythyroid cancer (PTC) will be 37 per 100 000 women, becoming the third mostcommoncancerinwomenofallagesafterbreastandlungcancer.13 The increases in incidence of thyroid cancer in France, Italy, Croatia, the Czech Republic, Australia, and Canada parallel that seen in the United States.11 In South Korea, the incidence of thyroid cancer in women abruptly increased from 10.6 per 100 000 to 111.3 per 100 000 between 1996 and 2010, making it the most common cancer among South Korean women.14 Conversely, in Japan, China, and Sweden, the increase in incidence has been marginal.11 Variations in incidence were also noted within countries.15 Interestingly, however, the worldwide rise in thyroid cancer incidence has not been accompanied by an increase in disease-specific mortality.10
A Perplexing Rise in Thyroid Cancer
Factors Associated With Increased Incidence of Thyroid Cancer
The worldwide incidence of thyroid cancer has increased substantially over the past 50 years.10 The Cancer Incidence in Five Continents report,11 maintained by the International Agency for Research on Canjamaotolaryngology.com
The precise reasons for the increased incidence of thyroid cancer are difficult to determine. Increased use of diagnostic imaging capable
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
E1
Clinical Review & Education Special Communication
of exposing subclinical disease is considered the most likely explanation for this reported rise.4-6 The location of the thyroid gland places it within the window of many diagnostic imaging studies. Ultrasonography of the neck for parathyroid disease,16 carotid flow evaluation,17 or even in the context of otherwise healthy individuals may reveal an asymptomatic thyroid nodule as small as 2 mm in up to 67% of patients.1 In addition, cross-sectional imaging studies have contributed to a 2.4-fold increase in the reported incidence of thyroid nodules over the past 30 years.18-20 More than half of the cases detected incidentally through imaging can be labeled as low-risk cancers.9,21 The use of ultrasonography for the screening of thyroid cancer has also been considered a contributing factor to its increasing incidence. This is believed to be the key factor in South Korea’s abrupt increase in thyroid cancer incidence. A study based on the 2009 Korean National Cancer Screening Survey revealed that 13.2% of South Koreans underwent thyroid cancer screening with ultrasonography.22,23 The link between imaging studies and increased incidence is supported by a correlation with access to health care, and the incidence is rising more rapidly in countries where health care expenditure is driven by the private sector rather than the public sector.24 A recent analysis of the Surveillance, Epidemiology, and End Results Program (SEER) database showed that the incidence of thyroid cancer was positively associated with sociodemographic markers of health care access, such as college education, white-collar employment, and higher family income.9 Contrary to the hypothesis that diagnostic imaging is the main cause of the increased incidence of small thyroid cancers, the incidence of large thyroid cancers has not declined and is also increasing.25-27 Moreover, higher rates of aggressive PTCs are being detected, including those with extrathyroidal extension and distant metastases.25,28-30 Finally, risk factors not yet identified may also be contributing to this increase in incidence. Studies have suggested that it may be due to high levels of ionizing radiation exposure, which have doubled in the United States since the 1970s, mainly due to increased use of radiographic imaging.31 Moreover, hormonal, nutritional,32 and menstrual and reproductive factors may be causing this surge in incidence.33 The worldwide rise and the differing rates of thyroid cancer between countries suggest that multiple factors may have a role in the incidence and warrant further investigation.
South Korea’s Experience—“a Cautionary Tale” Cancer is the leading cause of death in the republic of South Korea, accounting for almost a third of overall deaths per year.34 In 1999, the government of South Korea initiated a national campaign to improve health and reduce the number of cancer-related deaths by providing screening for breast, cervical, colorectal, gastric, and hepatic cancers free of charge or, for people with above-average income, for a minor copayment. Although thyroid cancer screening was not included in the funded screening program, clinicians frequently offered screening with ultrasonography for an extra charge of approximately $50,35 which provided a profitable outcome for business-focused health care practices.24 The South Korean health care system relies heavily on patients’ direct payment supplemented by private health insurance. In addition, ultrasonography screening is excluded from public health E2
Incidental Thyroid Nodules and Thyroid Cancer
care expenditure and therefore is not regulated by government guidelines. One South Korean reporter portrayed the problem as a mass production of patients for the benefit of the health care industry rather than health care services for the benefit of patients. He described the situation as “doctors selling refrigerators to the Eskimos.”36 Many hospitals, even university-based centers, commercialized health screening programs that included thyroid cancer screening using ultrasonography and cross-sectional imaging.22,23 Almost all of the newly identified thyroid cancers found by screening are subcentimeter PTCs, which studies have shown are typically very slow growing and highly unlikely to cause symptoms, much less death.7,9,21 Nonetheless, 9 of 10 patients diagnosed in South Korea will undergo thyroidectomy, and roughly two-thirds of these will undergo total thyroidectomy. The proportion of patients undergoing thyroidectomy in South Korea for a subcentimeter thyroid cancer has increased from 14% to 56% between 1995 and 2005.37 This scenario of overdiagnosis and overtreatment clearly illustrates the downside of early PTC detection, and serves as a cautionary tale for the rest of the world where the thyroid cancer incidence is surging.35 On March 18, 2014, at a press conference held in the South Korean National Health Insurance Corporation, 8 cancer specialists expressed concern about overdiagnosis of thyroid cancer and suggested that routine screening be banned. Major newspapers reported the story and ran headlines asking “Is thyroid cancer overdiagnosed?”38 There was also widespread broadcast coverage, including special television programs devoted to the issue. South Korea’s Ministry of Health and Welfare is currently working to establish appropriate screening criteria. The final consensus report was scheduled for release in December 2014 but was delayed owing to the inability of the review committee to reach consensus. Many of the committee members benefit financially from screening and so favor such intervention.39 It seems that the establishment of these guidelines may require more time. Currently, the lack of sufficient evidence makes the route to consensus unclear. Moreover, because it is challenging to explain to the South Korean public why early diagnosis and treatment of a common type of cancer could be problematic, screening for thyroid cancer continues to be relevant. In contrast to South Korea’s experience, according to new figures from the Office of National Statistics in England,40 the survival rate for patients with thyroid cancer has worsened in the last year. In England, thyroid cancer is more often diagnosed in the emergency department, when the tumor is often at a more advanced stage, and is not being found early by primary care clinicians. The solution proposed by the British council is to provide physicians there with more screening tools to help them diagnose these cancers as early as possible.41 The question is how will British physicians be able to confidently distinguish small, indolent thyroid cancers from those that would behave more aggressively. Failure to make this distinction and institute clear protocols for surveillance vs intervention may lead the British down the same path as the South Koreans.
Risk-Based Screening—the Happy Medium Recently, the American College of Radiology (ACR) issued a white paper suggesting that radiologists might decide whether or not to
JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
jamaotolaryngology.com
Incidental Thyroid Nodules and Thyroid Cancer
Special Communication Clinical Review & Education
Tailoring the Treatment to the Type of Thyroid Cancer Papillary and follicular thyroid cancers both have favorable prognoses, with mortality rates of 1% to 2% at 20 years for PTC46 and 10% to 20% at 20 years for follicular thyroid cancer.47 In contrast, patients with medullary thyroid cancer have 25% to 50% mortality at 10 years, and most patients with poorly differentiated and anaplastic thyroid cancer die within a year of diagnosis (5-year mortality rate, 90%).47,48 Papillary thyroid cancers are generally perceived as low-risk thyroid cancers47 and are not associated with well-recognized predictors of mortality.49,50 The encapsulated follicular variant of PTC also appears to be associated with a low risk of recurrence.51 Well-differentiated follicular thyroid cancers demonstrating only capsular invasion (without vascular invasion) usually have an excellent prognosis, with recurrence rates of jamaotolaryngology.com
Figure. Different Behaviors and Rates of Growth of Thyroid Cancers That Determine Their Potential to Be Detected by Screening Screening Intervals
Progression Time of Thyroid Cancer
report incidentally found thyroid nodules.42 The ACR assumes that because thyroid cancer is typically an indolent disease, patients will not be harmed by this practice, and when the reported number of incidentally found thyroid nodules is reduced, the corresponding costs of unnecessary procedures are also reduced, as are the risks to the patient from unnecessary surgery. Radiologists believe that they are the ones responsible for the avoidable psychological stigma of cancer in these patients and their lifelong dependency on daily thyroid hormone supplementation.19 However, if radiologists fail to report the incidental finding of thyroid nodules, even with the best of intentions, they deprive patients and their physicians—the 2 key stakeholders in the process of informed decision making—of information needed to make important management decisions. In addition, radiologists have no way to confidently predict which incidentally detected thyroid nodules may be the precursor to a more aggressive process. It is paternalistic for any clinician or payer to presume that increased awareness of a patient’s thyroid nodule will pose harm. Clinicians meet their responsibilities to their patients by focusing on the benefit of each individual patient rather than the interests of society. Clearly, some thyroid cancers become not only symptomatic but deadly, resulting in a consistent 0.5 deaths per 100 000 individuals annually.43 Metastases can, and occasionally do, exist regardless of the size of the primary tumor. Moreover, men are more likely to present with advanced and sometimes fatal disease, which is believed to result from delayed diagnosis.44 While it may be that many thyroid cancers remain indolent, it is also true that the thyroid cancer death rate in the United States is higher than the death rates for Hodgkin lymphoma and testicular, anal, bone and joint, and small-intestinal cancers.43,45 Strategies to reduce the detection and treatment of indolent disease include focusing screening on high-risk populations. An ideal screening program would identify consequential disease that is ideally treated in the early stages; such a program would allow early curative interventions (Figure). Better screening depends on our ability to more accurately characterize the biology of individual thyroid cancers detected; until this can be confidently accomplished screening should not be utilized.
Advanced disease (palliation only) Symptomatic disease (likely curable)
Tumor A
Detectable by screening
Asymptomatic disease Microscopic disease
Overdiagnosis Tumor B Tumor C
Patient’s Lifetime
Tumor A grows rapidly and therefore is not usually detected by screening. This tumor is diagnosed clinically in the interval between screening examinations and has a poor prognosis. Tumor B is capable of metastasizing and progressing into advanced disease, but it grows slowly enough to be detected by screening (*). In most cases, early detection and treatment will result in disease-free survival. Tumor C eventually becomes detectable by screening (*), but it is so indolent that it will never progress to affect the quality of life of the patient. Its detection will result in overdiagnosis and potentially overtreatment. Molecular markers and other objective predictors of an individual patient's tumor behavior might be identified that will allow us to confidently differentiate low-risk (tumor C) from high-risk (tumor A and tumor B) thyroid cancer, but those predictors have not been elucidated yet.
0% to 7%, and can be classified as low-risk tumors.52-54 Encapsulated, minimally invasive follicular thyroid cancer with only minor vascular invasion appears to also have a low recurrence rate, from 0% to 5%.55 Currently, the treatment for all of these low-risk thyroid cancers is surgical removal. Although it is generally accepted that surgery is the standard to eradicate these tumors, there is less agreement about the extent of the surgery (ie, lobectomy vs total thyroidectomy).56 Guidelines from surgical professional societies have provided guidance on the management of these low-risk tumors,47,57 but owing to the broad category into which these lesions fall, coupled with the uncertainty about the proper classification and optimal management of these cancers, many patients receive care similar to that of patients with more aggressive thyroid cancers.56 The rationale for total thyroidectomy in these patients is that there are fewer recurrences with this intervention than with lobectomy.58 Nonetheless, no randomized trials have investigated the advantages of total thyroidectomy over lobectomy for patients with low-risk thyroid cancers. A large observational study based on the SEER database found no survival benefit with more aggressive surgical treatment for those patients with low-risk tumors after controlling for tumor size.59 As clinicians, we should not dismiss incidentally detected small thyroid nodules and small thyroid cancers; rather, we should seek methods to personalize care that will yield the most value to the patient. These methods must be based on objective data and psychosocial support to help both physician and patient process the information necessary to make informed decisions.
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 30, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of Calgary User on 05/26/2015
E3
Clinical Review & Education Special Communication
Incidental Thyroid Nodules and Thyroid Cancer
Table. Active Surveillance Studies in Patients With Low-Risk Thyroid Cancers Patients, No. (%)
Study
Tumor Size Cutoff, cm
Patients, No.
Follow-up Duration
Tumor Growth >3 mm
Subsequent Need for Surgery
Sugitani et al,70 2010
