Evidence Summary

Thyroid Cancer: Screening

May 09, 2017

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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By Jennifer S. Lin, MD, MCR; Erin J. Aiello Bowles, MPH; Selvi B. Williams, MD, MPH; and Caitlin C. Morrison, MPH

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in JAMA on May 9, 2017.

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Importance: The incidence of detected thyroid cancer cases has been increasing in the United States since 1975. The majority of thyroid cancers are differentiated cancers with excellent prognosis and long-term survival.

Objective: To systematically review the benefits and harms associated with thyroid cancer screening and treatment of early thyroid cancer in asymptomatic adults to inform the US Preventive Services Task Force.

Data Sources: Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1966 through January 2016, with active surveillance through December 2016.

Study Selection: English-language studies conducted in asymptomatic adult populations.

Data Extraction and Synthesis: Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted to pool surgical harms.

Main Outcomes and Measures: Thyroid cancer morbidity and mortality, test accuracy to detect thyroid nodules or thyroid cancer, and harms resulting from screening (including overdiagnosis) or treatment of thyroid cancer.

Results: Of 10,424 abstracts, 707 full-text articles were reviewed, and 67 studies were included for this review. No fair- to good-quality studies directly examined the benefit of thyroid cancer screening. In 2 studies (n = 354), neck palpation was not sensitive to detect thyroid nodules. In 2 methodologically limited studies (n = 243), a combination of selected high-risk sonographic features was specific for thyroid malignancy. Three studies (n = 5894) directly addressed the harms of thyroid cancer screening, none of which suggested any serious harms from screening or ultrasound-guided fine-needle aspiration. No screening studies directly examined the risk of overdiagnosis. Two observational studies (n = 39,211) included cohorts of persons treated for well-differentiated thyroid cancer and persons with no surgery or surveillance; however, these studies did not adjust for confounders and therefore were not designed to determine if earlier or immediate treatment vs delayed or no surgical treatment improves patient outcomes. Based on 36 studies (n = 43,295), the 95% CI for the rate of surgical harm was 2.12 to 5.93 cases of permanent hypoparathyroidism per 100 thyroidectomies and 0.99 to 2.13 cases of recurrent laryngeal nerve palsy per 100 operations. Based on 16 studies (n = 291,796), treatment of differentiated thyroid cancer with radioactive iodine is associated with a small increase in risk of second primary malignancies and with increased risk of permanent adverse effects on the salivary gland, such as dry mouth.

Conclusions and Relevance: Although ultrasonography of the neck using high-risk sonographic characteristics plus follow-up cytology from fine-needle aspiration can identify thyroid cancers, it is unclear if population-based or targeted screening can decrease mortality rates or improve important patient health outcomes. Screening that results in the identification of indolent thyroid cancers, and treatment of these overdiagnosed cancers, may increase the risk of patient harms.

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The incidence of detected thyroid cancer cases has been rising in the United States for both men and women, from 4.9 cases per 100,000 persons in 1975 to 14.3 cases per 100,000 persons in 2014.1 However, mortality rates have remained stable at about 0.5 per 100,000 persons per year.2 Differentiated thyroid cancer generally has a very good prognosis and accounts for about 90% of all cases of thyroid cancer.3 Within this category, papillary thyroid cancer accounts for about 70% to 80% of thyroid cancer cases, and follicular cancer accounts for 10% to 15%. The 10-year overall survival rates for papillary and follicular thyroid cancer are 93% and 85%, respectively, for all stages of the disease.4

Screening for thyroid cancer can be performed with neck palpation, ultrasonography, or both. Screening may have the potential for early detection of malignant thyroid nodules that could make treatment more effective, with less harm, than if administered later. However, screening also may result in overdiagnosis (identification of a thyroid malignancy that likely would not have caused symptoms or death during a patient's lifetime), because it can detect very small or indolent tumors that might never affect a person's morbidity or mortality.5,6

No professional medical society recommends population-based screening for thyroid cancer. South Korea appears to be the only country that regularly practices screening for asymptomatic thyroid cancer using ultrasound; this practice arose opportunistically as an add-on option for persons undergoing sanctioned screening through an organized cancer screening program initiated in 1999.7 This article reports the findings from a systematic review conducted to assist the US Preventive Services Task Force (USPSTF) in its process of updating its 1996 "D" recommendation (screening asymptomatic adults or children for thyroid cancer by neck palpation or ultrasound is not recommended).

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Scope of Review

This review addressed 5 key questions (KQs) as shown in Figure 1. Additional methodological details regarding search strategies, detailed study inclusion criteria, quality assessment, excluded studies, and description of data analyses, as well as detailed results, are publicly available in the full evidence report available at http://www.ncbi.nlm.nih.gov/books/NBK447370/.

Data Sources and Searches

MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials were searched to locate primary studies that informed the KQs and that were published from January 1966 through January 2016 (eMethods in the Supplement). The database searches were supplemented with expert suggestions and by reviewing reference lists from existing relevant systematic reviews. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched for ongoing trials. Since January 2016, we continued to conduct ongoing surveillance through article alerts and targeted searches of high-impact journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted in December 2016. No studies were identified that would substantively change this review's interpretation of findings or conclusions.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles against the specified inclusion criteria for studies of thyroid cancer screening, diagnostic accuracy, or treatment in screen-relevant or asymptomatic adults. Discrepancies were resolved through consensus and consultation with a third investigator.

For screening questions (KQ1 through KQ3), any studies of asymptomatic adult populations were included, either those at general risk (eg, unselected) or those with prior personal history of radiation exposure. Populations were excluded if they were selected based on high radiation exposure due to environmental disasters, inherited genetic syndromes associated with a high risk for developing thyroid cancer, or a personal history of thyroid cancer. Diagnostic accuracy studies of palpation or ultrasound had to include a reference standard (ultrasound for detection of nodules on palpation; histopathology results from fine-needle aspiration or surgery for detection of cancer on ultrasound), applied to both screen-positive and screen-negative persons (eg, all or a random subset of screen-negative persons). For screening effectiveness (KQ1), any patient health outcome of reduced morbidity or mortality associated with thyroid cancer was included. For test performance (KQ2), cancer detection rates and measures of diagnostic accuracy (eg, sensitivity, specificity, positive and negative predictive values) were included. For harms of screening (KQ3), direct harms of palpation and ultrasound, subsequent harms of diagnostic fine-needle aspiration, and measures of overdiagnosis were included. For overdiagnosis, studies that compared screened vs unscreened groups were sought. Studies that examined the increasing incidence of thyroid cancers, studies of the incidence and natural history of thyroid nodules and cancers, and autopsy studies were not included but are summarized in the Discussion section.

For treatment questions (KQ4 and KQ5), any studies of thyroid surgery (complete thyroidectomy, near-total thyroidectomy, lobectomy), with or without lymph node dissection or with or without radioactive iodine ablation, were included. Studies of chemotherapy, external beam radiation, and other nonsurgical ablative treatment other than radioactive iodine were excluded. To approximate the treatment of screen-detected cancers, treatment studies including persons with metastatic disease or anaplastic thyroid cancers were excluded. For treatment benefit (KQ4), studies had to have a control group (eg, untreated, surveillance, delayed treatment). To assess the benefit of treatment, the patient health outcomes of recurrence, mortality, and quality of life were considered. For treatment harms (KQ5), studies were not required to include a control group for direct procedural harms (eg, hypoparathyroidism, recurrent laryngeal nerve palsy) but needed a control group for other types of harms (eg, second primary malignancies from radioactive iodine therapy). The evolution of standard of care for the diagnostic workup (eg, use of ultrasound-guided fine-needle aspiration) and treatment of thyroid cancer over time has resulted in a change in the case mix of patients getting surgery with or without lymph node dissection or radioactive iodine therapy, as well as improvements in surgical techniques and radioactive iodine administered activity (doses) over time. To identify the most applicable evidence, studies conducted before 1990 and single-surgeon case series were excluded.

Data Extraction and Quality Assessment

Two reviewers independently critically appraised all articles that met inclusion criteria using the USPSTF design-specific quality criteria9 supplemented by the Newcastle Ottawa Scales for cohort and case-control studies10 and by QUADAS (Quality Assessment of Diagnostic Accuracy Studies) and QUADAS II for studies of diagnostic accuracy11,12 (eTable 1 in the Supplement). Poor-quality studies (those with a single fatal flaw or multiple important limitations that could invalidate results) were excluded from this review. Disagreements about critical appraisal were resolved by consensus and, if needed, consultation with a third independent reviewer. One reviewer extracted key data from included studies; a second reviewer checked the data for accuracy. Tables generally included details on study design and quality, setting and population (eg, country, inclusion criteria, age, sex, race/ethnicity, risk factors for thyroid cancer), screening and treatment details, reference standard or comparator details (if applicable), length of follow-up, and outcomes (eg, cancer yield, diagnostic accuracy, cancer morbidity, mortality, and harms).

Data Synthesis and Analysis

For each KQ, the number and design of included studies, summary of results, consistency and precision of results, reporting bias, summary of study quality, limitations of the body of evidence, and applicability of the findings were summarized. Findings were synthesized by KQ, screening test (eg, palpation, ultrasound) or treatment (eg, type of surgery, radioactive iodine therapy), and type of outcome. Because of the limited number of studies and the clinical heterogeneity of studies, the analyses were largely descriptive.

Random-effects meta-analyses were conducted using the restricted maximum likelihood estimation method to estimate the harms of surgical treatment of thyroid cancer (permanent hypoparathyroidism and permanent recurrent laryngeal nerve palsy). In subgroup analysis when the number of studies was less than 5, a fixed-effects model was used. The presence and magnitude of statistical heterogeneity were assessed among pooled studies using the I2 statistic. Visual inspection of plots stratified or ordered by key study characteristics accounting for clinical heterogeneity among studies was conducted to see if these characteristics affected rates of surgical complications. Key study characteristics included the type of surgery (eg, partial or total thyroidectomy with or without lymph node dissection; type of lymph node dissection), case mix of patients (eg, histology of thyroid cancer, average tumor size, average age), setting (eg, country, year), and type and definition of outcome (eg, criteria for permanent harm). It was not possible to evaluate associations of surgical complications with study quality (because all studies were fair quality) or surgical experience (because experience and surgical volume were not reported in individual studies). Funnel plots and the Egger linear regression method were used to examine whether the distribution of the effect sizes was symmetric with respect to effect precision. Significance threshold was 2-sided P = 0.05. All analyses were performed using R version 3.2.2 (R Project for Statistical Computing).

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A total of 10,424 unique abstracts and 707 full-text articles were reviewed (Figure 2). Of these, 67 unique studies were included: 10 studies of screening test performance (n = 203,718), 3 studies of screening harms (n = 5894), 2 studies of treatment benefits (n = 39,211), and 52 studies of treatment harms (n = 335,091).

Screening Effectiveness or Accuracy

Key Question 1. Compared with not screening, does screening adults for thyroid cancer lead to a reduced risk of thyroid-specific morbidity or mortality, reduced all-cause mortality, and/or improved quality of life?

No studies met the inclusion criteria for KQ1. No randomized clinical trials or controlled clinical trials evaluated the effect of thyroid cancer screening on patient morbidity or mortality compared with no screening. Two cohort studies that compared screened individuals vs a comparator group did not meet inclusion criteria for KQ1.13,14

Key Question 2. What are the test performance characteristics of screening tests for detecting malignant thyroid nodules in adults?

Ten fair-quality studies (n = 203,718) met the inclusion criteria for KQ2 (Table 1). Only 2 studies (n = 354) reported on diagnostic accuracy of palpation to detect nodules16,17 and 2 (n = 243) on diagnostic accuracy of ultrasound to detect cancer.18,19 The majority of studies that examined the diagnostic accuracy of ultrasound to detect thyroid cancer were not (or were not reported to be) conducted in screening populations and were excluded. Therefore, evidence to inform the true diagnostic accuracy of screening using neck palpation or ultrasound to detect thyroid cancer is limited. Among the included studies, 4 reported on cancer yield from screening for thyroid cancer using palpation plus follow-up ultrasound,14-17 another 4 on cancer yield from screening using ultrasound only,18-21 and 2 from the1980s on cancer yield from screening of adults with a history of childhood irradiation.22,23 Cancer yield results are not discussed in this manuscript but are included in the full evidence review.

Two studies (n = 354) conducted by the same investigator, evaluating a single examiner in Finland in the late 1980s, found that neck palpation was not sensitive to detect thyroid nodules in adults.16,17 Only one of these studies reported the diagnostic accuracy of palpation for all screened persons.16 In that study of randomly selected adults (n = 253), an abnormal result from neck palpation (thyroid nodule or diffuse enlargement of the thyroid) was found in 5.1% of participants, whereas an abnormal result from ultrasound was found in 27.3%. The sensitivity and specificity of palpation to detect thyroid nodules (size not reported) were 11.6% (95% CI, 5.1%-21.6%) and 97.3% (95% CI, 93.8%-99.1%), respectively.16 In the other study of women presenting for screening mammography (n = 101), palpation results were reported for the 36 patients with abnormal ultrasound examination results; the sensitivity of palpation to detect nodules in persons with an abnormal ultrasound result was 27.8%.17

In 2 methodologically limited studies conducted in South Korea (n = 243), screening with ultrasound was very sensitive to detect thyroid malignancy and can be specific for thyroid malignancy when using selected high-risk sonographic features (Table 2).18,19 Both studies were conducted by the same investigators from 2004 to 2007 but had different study designs. The better-quality study prospectively examined the diagnostic accuracy of screening for thyroid cancer by ultrasound in 113 women referred for fine-needle aspiration (among 2079 screened). Seventy-seven of the analyzed women had 1 or more high-risk sonographic characteristics (presence of microcalcifications, irregular shape, ill-defined or microlobulated margin, marked hypoechogenicity, taller-than-wide orientation), and 36 had probable benign ultrasound findings but were referred for fine-needle aspiration by the radiologist or by request of their outpatient clinician.18 Among these 113 women, 53 were diagnosed with papillary thyroid cancer. The sensitivity and specificity of having 1 or more malignant features on screening ultrasound were 94.3% (95% CI, 84.3%-98.8%) and 55.0% (95% CI, 41.6%-67.9%), respectively.

The other study was a retrospective analysis of 130 asymptomatic persons selected from 1009 persons who underwent fine-needle aspiration based on ultrasound findings (from 16,352 persons who referred themselves to thyroid cancer screening).19 The study sample included 58 of 150 lesions (38.7%) classified by fine-needle aspiration results as malignant (all papillary thyroid cancer) and 82 of 823 (10.0%) classified as benign, for a total of 140 nodules in 130 persons. Among these 140 nodules, the sensitivity and specificity of having 2 or more high-risk sonographic characteristics (presence of microcalcifications, spiculated margin, marked hypoechogenicity, taller-than-wide orientation or irregular shape, solid) were 94.8% and 86.6%, respectively (95% CI values could not be calculated). The studies did not follow up on the majority (n = 18,188) of screened individuals who were not referred for fine-needle aspiration; therefore, the potential false-negative cases are unknown, and estimates of sensitivity are likely overestimated.

Harms of Screening

Key Question 3. What are the harms of screening adults for thyroid cancer?

Three studies (n = 5894) met inclusion criteria for KQ3 (Table 3). No studies examined the harms of thyroid cancer screening with palpation or ultrasound, and no studies directly examined the effect of overdiagnosis in a screened vs unscreened group. A number of other study designs may indirectly inform the clinical importance and magnitude of overdiagnosis in thyroid cancer screening; these studies are summarized in the Discussion section. Overall, there is limited evidence to evaluate the potential harms of screening for thyroid cancer, including harms of diagnostic follow-up fine-needle aspiration. One US study (n = 400) found that 24.0% of persons who had undergone fine-needle aspiration of a thyroid nodule did not meet the Society of Radiologists in Ultrasound recommendation for fine-needle aspiration.24 Two fair-quality retrospective studies (n = 5494) evaluated the harms of fine-needle aspiration of thyroid nodules, including hospitalization, postprocedural hematoma, and needle tract implantation.25,26 These studies did not suggest serious harms to patients from ultrasound-guided fine-needle aspiration.

Benefits of Treatment

Key Question 4. Does treatment of screen-detected thyroid cancer reduce thyroid-specific mortality or morbidity, reduce all-cause mortality, and/or improve quality of life?

Two unique observational studies (n = 39,211) reported in 5 articles27-31 met inclusion criteria for KQ4 (Table 4). No trials were designed to evaluate if earlier treatment or treatment of screen-detected, well-differentiated thyroid cancer results in better patient outcomes compared with observation (ie, delayed or no treatment). Because of major limitations in the designs of included studies (eg, lack of adjustment for confounders), it is uncertain if earlier or immediate treatment vs delayed or no surgical treatment improves patient outcomes for papillary carcinoma or papillary microcarcinoma. One retrospective observational study using US Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2005 compared survival rates of persons treated (surgery with or without radioactive iodine therapy) or not treated for papillary thyroid cancer.27 A total of 35,663 persons were analyzed; only 440 (1.2%) had not been treated. Overall, untreated persons had a slightly worse 20-year survival rate compared with treated persons (97% [95% CI, 96%-100%] vs 99% [95% CI, 93%-100%], P < 0.001). One prospective study conducted from 1993 to 2013 in Japan examined the recurrence of disease and the survival rate for persons with papillary microcarcinoma who opted for immediate surgery vs those who opted for observation or active surveillance.28-31 From 1993 to 2004, 1395 persons were analyzed, 340 of whom opted for observation with surveillance ultrasound.28 Thirty-two percent (n = 109) who opted for observation ultimately had surgery. After approximately 6 years of follow-up, 2 persons in the immediate surgery group and no persons in the observation group had died. An additional 2153 persons were diagnosed with papillary microcarcinoma from 2005 to 2013; of these, 1179 opted for active surveillance and 974 opted for immediate surgery.31 Only 8% (n = 94) who opted for observation ultimately had surgery. After approximately 4 years of follow-up, no patients in either group developed distant metastases or died from thyroid cancer. In both studies, there were several statistically significant differences between groups; known and potential confounders between treated patients and patients receiving delayed treatment or no treatment were not adjusted for, which limits the ability to compare the effect of treatment on patient outcomes.

Harms of Treatment

Key Question 5. What are the harms of treating screen-detected thyroid cancer?

Fifty-two studies (n = 335,091) met inclusion criteria for KQ5. There were 36 studies (n = 43,295 [64 study groups]) of surgical harms, 32 studies (n = 15,811) of permanent hypoparathyroidism (hypocalcemia),31-62 28 studies (n = 20,125) of permanent recurrent laryngeal nerve palsy (vocal cord paralysis),31,32,34,36-42,44-61,63 2 studies (n = 19,438) of surgical mortality,64,65 and 15 studies (n = 27,533) of other major surgical harms.31,36,37,40,43,44,46,56-58,60,61,64-66 The majority of studies of surgical harms were retrospective observational studies, ranging from 76 to 13,854 persons. The main operations evaluated were total or partial thyroidectomy, with or without lymph node dissection (unilateral, bilateral, or not specified; and prophylactic, therapeutic, or not specified).

Permanent harm was generally defined as an adverse outcome persisting beyond 6 months. There was large variation in the rate of permanent hypoparathyroidism attributable to total or partial thyroidectomy without lymph node dissection: the 95% CI of the pooled estimate (15 study groups) was 2.12 to 5.93 events per 100 operations (I2 =73%) (Figure 3). The rate of permanent hypoparathyroidism from thyroidectomy with lymph node dissection was more varied: the 95% CI for unilateral neck dissection (10 study groups) was 0.84 to 4.04 events per 100 operations (I2 = 73%), and the 95% CI for bilateral neck dissection (9 study groups) was 1.20 to 9.56 events per 100 operations (I2 = 91%) (Figure 4). However, the high degree of statistical heterogeneity may limit the validity of these estimates. The rate of hypoparathyroidism did not seem to vary by year, setting, country, study-level proxies for more advanced tumors, indication for lymph node dissection, or definition of permanent outcomes. Statistical testing suggested biased estimates due to smaller studies, such that smaller studies reported fewer events.

In contrast, there was little variation in the rates of permanent recurrent laryngeal nerve palsy due to thyroidectomy, with or without lymph node dissection. The 95% CI for recurrent laryngeal nerve palsy from thyroidectomy without lymph node dissection (14 study groups) was 0.99 to 2.13 events per 100 operations (I2 =13%) (Figure 5). Estimates were similar for thyroidectomy with lymph node dissection (33 study groups) (Figure 6).

Sixteen studies (n = 291,796) reported harms of radioactive iodine therapy. Eight studies with overlapping populations addressed the risk of second primary malignancies,67-74 6 (n = 830) addressed the permanent adverse effects on salivary glands,75-80 1 (n = 8946) focused on hyperparathyroidism,81 and 1 (n = 18,850) examined reproductive harms82 (Table 5). Three of the 8 studies examining risk of second primary malignancy due to radioactive iodine therapy used SEER data, none of which reported the indication for or the dose of radiation from radioactive iodine therapy.67,69,74 Two SEER studies using similar study methods (ie, years studied, definition of second primary malignancy, number of years of follow-up, reference cohort, outcome measures) found that persons who received radioactive iodine therapy for papillary or follicular thyroid cancer had an excess absolute risk of 11.9 to 13.3 cancers per 10,000 person-years compared with a reference cohort.67,69 The third SEER study had a different study aim and thus did not report the number of excess cancers by radioactive iodine exposure status.74

Nonetheless, this study did not find an association between exposure to radioactive iodine therapy and second primary malignancy using a standardized incidence ratio. However, this study was not limited to differentiated thyroid cancers, included thyroid cancer as a second primary malignancy, and had shorter follow-up for assessment of second primary malignancy. Five smaller studies not conducted in the United States also examined the incidence of second primary malignancies in persons with differentiated thyroid cancer being treated or not treated with radioactive iodine therapy.68,70-73,83 These studies generally reported the cumulative radiation doses in GBq units. Radiation doses in clinical practice vary and generally correspond to the indication for radioactive iodine therapy, such that lower doses (1.11 GBq) are used for ablation and higher doses (up to 5.5 GBq) are used for adjuvant therapy for known or suspected residual disease.84 Study results are difficult to compare, given differences in study design, populations, radiation doses, and outcomes. Overall, they demonstrate that use of radioactive iodine is generally associated with an excess risk of second primary malignancy across a range of doses used in clinical practice.

One retrospective study79 and 5 prospective studies (n = 830) assessed the permanent harms of radioactive iodine therapy on the salivary glands.75-78,80 The studies were generally small, and the mean radiation dose from radioactive iodine ranged from 1.1 to 5.3 GBq. The most common adverse effect of radioactive iodine on the salivary glands was xerostomia (dry mouth), which ranged from 2.3% to 35%. Dry mouth can adversely affect quality of life and vocal function and increase the risk of dental disease.

 

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A summary of evidence for all KQs is presented in Table 6. No trials or well-designed observational studies evaluated the net benefit of thyroid cancer screening. Very limited studies evaluated the true screening accuracy of palpation or neck ultrasound. Ultrasound is very sensitive to detect thyroid nodules, and studies in screening and nonscreening populations have demonstrated that specific high-risk sonographic characteristics can improve sensitivity and specificity for thyroid malignancy.84-86 Although there was no evidence of serious direct harms from screening and diagnostic follow-up with fine-needle aspiration, screening can result in overdiagnosis; SEER data have demonstrated that almost all persons diagnosed with papillary thyroid cancer receive treatment, so there is the potential of adverse effects from unnecessary treatment. No studies evaluated if treatment of screen-detected cancers compared with symptomatic cancers improves patient health outcomes. It is unclear if immediate surgery, compared with active surveillance, improves patient health outcomes for small or well-differentiated thyroid cancers. Although thyroidectomy is considered a relatively benign operation, permanent hypoparathyroidism and recurrent laryngeal nerve palsy are not uncommon. Additionally, treatment with radioactive iodine is independently associated with a small increase in second primary malignancies, as well as permanent adverse effects on the salivary gland, such as dry mouth.

To accurately estimate the magnitude or effect of overdiagnosis, studies must compare screened and unscreened groups.87 However, this review found no trials or observational studies comparing thyroid cancer screening with no screening. However, there are ecologic data on the trend of incidence and mortality of thyroid cancer, autopsy data, and limited natural history data to suggest that overdiagnosis of thyroid cancer is a problem. Multiple studies have shown an increase in the incidence in thyroid cancer detection over time, with no change in the mortality rate.1,7,27,88-90 Several studies by Davies and Welch1,27,90 have used SEER data to estimate the incidence of thyroid cancer and cancer-related mortality in the United States since the 1970s. The absolute increase in the incidence of thyroid cancer from 1975 to 2009 in the United States was 9.4 (95% CI, 8.9-9.9) cases per 100,000 persons, of which 9.1 (95% CI, 8.6-9.6) cases per 100,000 persons were papillary cancers.1 Data from other countries have shown similar findings. Data from the Cancer Incidence in Five Continents database showed steady increases in thyroid cancer incidence in 12 selected countries from 1960 to 2007, primarily due to an increase in papillary carcinoma diagnoses.88 South Korea has had an organized cancer screening program since 1999.7 Although the program did not officially include thyroid cancer screening, physicians frequently offered thyroid screening with ultrasound for a small additional cost. The rate of thyroid cancer diagnoses increased from 5 cases per 100,000 persons in 1993 to 70 cases per 100,000 persons in 2011.7

Autopsy studies have provided additional evidence on overdiagnosis of thyroid cancer. A 2014 review by Lee et al91 summarized 15 studies published between 1969 and 2005 on latent thyroid cancer discovered at autopsy. Of 8619 thyroid glands obtained at autopsy, 989 (11.5%) were positive for papillary thyroid carcinoma. The proportion of papillary thyroid cancers varied widely, from 1.0% to 35.6%. Studies describing the natural history of thyroid nodules and malignancies also lend evidence to the problem of overdiagnosis of thyroid cancer. Durante et al92 described a 5-year follow-up of 992 patients with benign thyroid nodules (0.4 to 4 cm). In 686 patients (69%), the size of the nodules remained stable; in 184 (18.5%), the size of 1 or more nodules decreased; and in 153 (15.4%), the size of 1 or more nodules increased by 20% or more (the groups were not mutually exclusive, because some persons had more than 1 nodule). No studies had follow-up of benign nodules beyond 5 years. The studies included in this review, as well as other studies, demonstrate the slow-growing nature of thyroid tumors and the low potential for recurrence or mortality due to papillary tumors and microcarcinomas.27,29,93-95 However, data on the survival of patients who never receive treatment are very limited.

Limitations

This evidence review focused on screening practices relevant to general US practice in adults and therefore did not include studies primarily focused on cohorts exposed to high doses of radiation via environmental disasters or treated with radiation for childhood cancers. Additionally, it did not systematically review the diagnostic accuracy of ultrasound to detect thyroid cancer in nonscreening populations. The review of harms was limited to those directly related to surgery or radioactive iodine therapy (eg, excluded harms from suppressive doses of thyroxine). Older studies of harms were excluded because over time surgery, radioactive iodine doses, and the case mix of persons undergoing treatment have changed.

Although population-based screening trials for thyroid cancer are unlikely, trials or well-designed observational studies to address the benefit of screening in higher-risk populations (eg, those with a personal history of irradiation or a family history of differentiated thyroid cancers) would be helpful to understand if there is any role for screening for thyroid cancer. Given the indolent nature of many thyroid cancers and the risks associated with treatment, trials or well-designed observational studies examining the benefit of early treatment vs observation or surveillance for patients with (smaller) well-differentiated thyroid cancers are also needed. The net benefit of screening hinges on minimizing overdiagnosis and overtreatment; therefore, for screening to be of benefit, studies are needed to determine which set of prognostic indicators predict aggressive vs indolent disease.

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Although ultrasonography of the neck using high-risk sonographic characteristics plus follow-up cytology from fine-needle aspiration can identify thyroid cancers, it is unclear if population-based or targeted screening can decrease mortality rates or improve important patient health outcomes. Screening that results in the identification of indolent thyroid cancers, and treatment of these overdiagnosed cancers, may increase the risk of patient harms.

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Accepted for Publication: January 23, 2017.

Author Contributions: Dr Lin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This research was funded under contract number HHSA-290-2012-00015-I-357 EPC4, Task Order 4, from the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project: Jennifer Croswell, MD, formerly at the Agency for Healthcare Research and Quality; current and former members of the US Preventive Services Task Force who contributed to topic deliberations; Gunjan Tykodi, MD (Kaiser Permanente Washington Health Research Institute), for expert consultation; Todd Hannon, MLS, and Smyth Lai, MLS (Kaiser Permanente Research Affiliates Evidence-based Practice Center), for creating and conducting the literature searches; Elizabeth L. Hess, MS (Kaiser Permanente Research Affiliates Evidence-based Practice Center), for editorial assistance; and Ning X. Smith, PhD, and Brittany Burda, DHSc (Kaiser Permanente Research Affiliates Evidence-based Practice Center), for assistance with meta-analyses. USPSTF members, expert consultants, and peer reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 4 invited content experts (Louise Davies, MD, School of Medicine at Dartmouth; Hyeong Sik Ahn, MD, Korea University School of Medicine; Edward G. Grant, MD, Keck School of Medicine, University of Southern California; and Mike Tuttle, MD, Memorial Sloan Kettering Cancer Center) and 3 federal partners (National Cancer Institute; Centers for Disease Control and Prevention; and the National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes, Endocrinology, and Obesity Branch). Comments were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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Figure 1 is an analytic framework that depicts the five Key Questions (KQs) described in the Methods section. Specifically, it illustrates the following questions: (1) Compared with not screening, does screening adults for thyroid cancer lead to a reduced risk of thyroid-specific mortality or morbidity, reduced all-cause mortality, and/or improved quality of life? (2) What are the test performance characteristics of screening tests for detecting malignant thyroid nodules in adults? (3) What are the harms of screening for thyroid cancer in adults? (4) Does treatment of screen-detected thyroid cancer reduce thyroid-specific mortality or morbidity, reduce all-cause mortality, and/or improve quality of life? (5) What are the harms of treating screen-detected thyroid cancer?

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depticted by linkages that relate interventions and outcomes. Further details are available in the USPSTF procedure manual.8

 

Text Description

Figure 1 is an analytic framework that depicts the five Key Questions (KQs). It illustrates the following questions: 1) Compared with not screening, does screening adults for thyroid cancer lead to a reduced risk of thyroid-specific mortality or morbidity, reduced all-cause mortality, and/or improved quality of life? 2) What are the test performance characteristics of screening tests for detecting malignant thyroid nodules in adults? 3) What are the harms of screening adults for thyroid cancer? 4) Does treatment of screen-detected thyroid cancer reduce thyroid-specific mortality or morbidity, reduce all-cause mortality, and/or improve quality of life? 5) What are the harms of treating screen-detected thyroid cancer?

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Figure 2 is a flow chart that summarizes the search and selection of articles. There were 11,687 citations identified through literature databases. An additional 178 citations were identified from outside sources, such as reference lists and suggestions from peer reviewers. After duplicates were removed, 10,424 unique citations were screened at the title/abstract stage. The full text of 707 citations were examined for inclusion for one or more of the eight Key Questions, or for contextual questions.

KQ indicates key question.

 

Text Description

Figure 2 is a flow chart that summarizes the search and selection of articles. There were 11,687 citations identified through literature databases. An additional 178 citations were identified from outside sources, such as reference lists and suggestions from peer reviewers. After duplicates were removed, 10,424 unique citations were screened at the title/abstract stage. The full text of 707 citations were examined for inclusion for one or more of the eight Key Questions, or for contextual questions. Of these, 67 unique studies were included: 10 studies of screening test performance (Key Question 2), 3 studies of screening harms (Key Question 3), 2 studies of treatment benefits (Key Question 4), and 52 studies of treatment harms (Key Question 5).

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Figure 3 is a forest plot depicting the event rate of permanent hypoparathyroidism by type of thyroidectomy. There is large variation in the rate of permanent hypoparathyroidism due to total or partial thyroidectomy without lymph node dissection (15 study arms): the 95% CI of the pooled estimate ranges from 2 to 6 events per 100 surgeries (I2=73%).

Tumor size indicates calculated mean tumor size. Size of the data markers indicates the weight used to calculate the pooled estimate. NR indicates not reported.

 

Text Description

Figure 3 is a forest plot depicting the event rate of permanent hypoparathyroidism by type of thyroidectomy (total or partial). There is large variation in the rate of permanent hypoparathyroidism due to total or partial thyroidectomy without lymph node dissection (15 study arms): the 95% CI of the pooled estimate ranges from 2 to 6 events per 100 surgeries (I2=73%).

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Figure 4 is a forest plot depicting the event rate of permanent hypoparathyroidism stratified by unilateral, bilateral, and laterality not specified. The rate of permanent hypoparathyroidism from thyroidectomy with lymph node dissection is varied (I2=73%), with the 95% CI for unilateral neck dissection (10 study arms) ranging from 1 to 4 events per 100 surgeries and the 95% CI for bilateral neck dissection (9 study arms) ranging from 1 to 10 events per 100 surgeries (I2=91%).

Tumor size indicates calculated mean tumor size. Size of the data markers indicates the weight used to calculate the pooled estimate. NR indicates not reported.

 

Text Description

Figure 4 is a forest plot depicting the event rate of permanent hypoparathyroidism stratified by type of lymph node dissection (unilateral, bilateral, and laterality not specified). The rate of permanent hypoparathyroidism from thyroidectomy with lymph node dissection varied (I2=73%), with the 95% CI for unilateral neck dissection (10 study arms) ranging from 1 to 4 events per 100 surgeries and the 95% CI for bilateral neck dissection (9 study arms) ranging from 1 to 10 events per 100 surgeries (I2=91%).

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Figure 5 is a forest plot depicting the event rate of permanent recurrent laryngeal nerve palsy from surgery stratified by type of thyroidectomy. There is little variation in the rates of permanent recurrent laryngeal nerve palsy due to thyroidectomy, with or without lymph node dissection. The 95% CI for recurrent laryngeal nerve palsy from thyroidectomy without lymph node dissection (14 study arms) was 1 to 2 events per 100 surgeries (I2=13%).

Tumor size indicates calculated mean tumor size. Size of the data markers indicates the weight used to calculate the pooled estimate. NR indicates not reported.

 

Text Description

Figure 5 is a forest plot depicting the event rate of permanent recurrent laryngeal nerve palsy from surgery stratified by type of thyroidectomy (total or partial). There is little variation in the rates of permanent recurrent laryngeal nerve palsy due to thyroidectomy, with or without lymph node dissection. The 95% CI for recurrent laryngeal nerve palsy from thyroidectomy without lymph node dissection (14 study arms) was 1 to 2 events per 100 surgeries (I2=13%).

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Figure 6 is a forest plot depicting the event rate of permanent recurrent laryngeal nerve palsy from surgery stratified by lymph node dissection. There is little variation in the rates of permanent recurrent laryngeal nerve palsy due to type of lymph node dissection. The 95% CI for recurrent laryngeal nerve palsy from unilateral thyroidectomy (8 study arms) was 0 to 1 events per 100 surgeries and the 95% CI for bilateral neck dissection (7 study arms) ranged from 1 to 2 events per 100 surgeries.

Tumor size indicates calculated mean tumor size. Size of the data markers indicates the weight used to calculate the pooled estimate. NR indicates not reported.

 

Text Description

Figure 6 is a forest plot depicting the event rate of permanent recurrent laryngeal nerve palsy from surgery stratified by lymph node dissection (unilateral, bilateral, laterality not specified). There is little variation in the rates of permanent recurrent laryngeal nerve palsy due to type of lymph node dissection. The 95% CI for recurrent laryngeal nerve palsy from unilateral thyroidectomy (8 study arms) was 0 to 1 events per 100 surgeries and the 95% CI for bilateral neck dissection (7 study arms) ranged from 1 to 2 events per 100 surgeries.

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Sourcea Screening Method Country (Recruitment Years) Study Design Mean Age, y Screened: Total No. Screened: Women, No. (%) Reported: Diagnostic Accuracy Reported: Cancer Yield
Average-Risk Population
Suehiro,15 2006 Palpation Japan (1989-2005) Retrospective 49 46,433 20,895 (45b)   ✔
Brander et al,16 1991 Palpation Finland (1989-1990) Prospective 35 253 129 (51) ✔ ✔
Brander et al,17 1989 Palpation Finland
(1988)		 Prospective 52 101 101 (100) ✔ ✔
Ishida et al,14 1988 Palpation Japan (1980-1986) Prospective NR 152,651 152,651 (100)   ✔
Kim et al,18 2010 Ultrasonography South Korea (2005-2007) Prospective 43 2079 43 (100) ✔  
Kim et al,19 2008 Ultrasonography South Korea (2004-2006) Retrospective 53 16,352 10,956 (67) ✔  
Lee et al,20 2003 Ultrasonography South Korea (2003) Prospective 43 697 697 (100)   ✔
Chung et al,21 2001 Ultrasonography South Korea (1997-1998) Prospective 47 1401 1401 (100)   ✔
High-Risk Population
Ron et al,22 1984 Palpation + diagnostic follow-upc Israel
(NR)		 Prospective 29 443 217 (49)   ✔
Shimaoka et al,23 1982 Palpation + diagnostic follow-upd United States (1977-1980) Prospective 39 1500 960 (64)   ✔

Abbreviation: NR=not reported
a All studies were of fair quality.
b Percentage of examination visits that were women (calculated).
c Diagnostic follow-up consisted of technitium-99m thyroid scan and thyroid function tests.
d Diagnostic follow-up consisted of iodine 123 thyroid scan, blood tests, and indirect laryngoscopy.

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Sourcea Analytic Sample, No. Characteristic Sensitivity, % (95% CI) Specificity, % (95% CI)
Kim et al,18 2010 113 persons ≥1 of following characteristics 94.3 55.0
Microcalcification 34.0 (21.5-48.3)b 83.3 (71.5-91.7)b
Irregular shape 88.7 (77.0-95.7)b 63.3 (49.9-75.4)b
Taller-than-wide shape 67.9 (53.7-80.1)b 80.0 (67.7-89.2)b
Ill-defined or microlobulated margin 86.8 (74.7-94.5)b 68.3 (55.0-79.7)b
Marked hypoechogenicity 52.8 (38.6-66.7)b 86.7 (75.4-94.1)b
Kim et al,19 2008 140 nodulesc ≥2 of following characteristics 94.8 86.6
Microcalcification 70.7 (57.3-81.9) 98.8 (93.4-99.8)
Taller-than-wide or irregular shape 55.2 (41.5-68.3) 89.0 (80.2-94.8)
Spiculated margin 48.3 (35.0-61.8) 97.6 (91.4-99.6)
Marked hypoechogenicity 55.2 (41.5-68.3) 96.3 (89.7-99.2)
Solid 93.1 (83.3-98.0) 51.2 (39.9-62.4)

a Both studies were of fair quality. Both studies report accuracy only among patients who had at least 1 study-defined malignant ultrasound characteristic, providing no follow-up on the majority (n = 18,188) of screened individuals who did not have these characteristics.
b Calculated confidence intervals.
c Reported in 130 persons.

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Sourcea Country (Recruitment Years) No. of Women/Total (%) Mean Age, y Study Aim Outcome
Hobbs et al,24 2014 United States (2010-2011) 332/400 (83) 55 To determine the proportion of thyroid nodules undergoing ultrasound-guided fine-needle aspiration that do not meet Society of Radiologists in Ultrasound recommendations from 2005b Persons undergoing fine-needle aspiration not meeting Society of Radiologists in Ultrasound recommendations: 96/400 (24.0%)
Abu-Yousef et al,25 2011 United States (2006-2007) 413/582c (71) 56 To determine whether there is a significantly increased incidence of bleeding complications from ultrasound-guided fine-needle aspiration of neck masses in patients receiving antithrombotic or anticoagulant therapy (compared with patients not receiving therapy) Major complications (hospitalization or intervention required): 0/582 (0%)
Postprocedural hematoma: 5/582 (0.9%)d
Ito et al,26 2005 Japan (1990-2002) NR/4912 (NR)e NRe To investigate the relationship between needle tract implantation of papillary thyroid cancer and clinicopathological characteristics Tumor implantation: 7/4912 (0.14%)

Abbreviation: NR, not reported.
a All studies were of fair quality and retrospective design.
b Fine-needle aspiration is appropriate for nodules that have a maximum diameter of 1 cm or larger and have microcalcifications; nodules that are 1.5 cm or larger and are solid or have coarse calcifications; nodules that are 2 cm or larger and are mixed solid and cystic; and nodules with substantial growth since the prior ultrasound.
c For thyroid masses only.
d Difference in incidence of hematomas between persons who were receiving antiplatelet or anticoagulant therapy vs persons not receiving therapy not statistically significant.
e Data reported for 10 persons with outcomes: mean age 65 years and 90% women.

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Sourcea Country (Recruitment Years) Study Design Histology Groupb No. of Women/Total (%) Mean Age, y Follow-Up, Mean (Range), y No. of Thyroid Cancer–Specific Deaths/Total (%) Thyroid Cancer–Specific Survival, % (95% CI)
Davies and Welch,27 2010 United States (1973-2005) Retrospective observational Papillary Intervention 27,122/35,223 (77) 46 7.6 (0-32) 161/35,223 (0.45) 20-y survival:
99 (93-100)
10-y survival:
Treatment recommended:
99.5 (99.4-99.6)c
Comparator 356/440 (81) 51 5.9 (0-31) 6/440 (1.4)
Treatment recommended: 4/216 (1.9)c
Treatment not recommended: 1/165 (0.6)c
(P = 0.10 for recommended vs not recommended)		 20-y survival:
97 (96-100)
10-y survival:
Treatment recommended: 98.1 (95.9-100)c
Treatment not recommended: 99.3 (97.8-100)c
Intervention vs. comparator P = 0.06 P <0.001 P <0.001 P = 0.09 20-y survival:
P <0.001
Oda et al,31 2016
Ito et al,30 2014d
Ito et al,28 2010
Ito et al,29 2003		 Japan (1993-2004) Prospective observational Papillary microcarcinomas Intervention 960/1055 (91) 52 6.3 (0.08-15.3) 2/1055 (0.2) NR
Comparator 313/340 (92) NR 6.2 (1.5-15.6) 0/340 (0) NR
Japan (2005-2013) Prospective observational Papillary microcarcinomas Intervention 857/974 (88) 55e 3.9 (1.0-9.7)e 0/974 (0) NR
Comparator 1038/1179 (88) 57e 3.9 (1.0-9.7)e 0/1179 (0) NR

Abbreviation: NR = not reported.
a All studies were of fair quality.
b Intervention group received surgical treatment; comparator or control group received no (immediate) surgical treatment.
c Subset of population (1988-2005) that had treatment recommendation as a variable and refers to Surveillance, Epidemiology, and End Results classification: recommended indicates recommended to be treated; not recommended, not recommended to be treated.
d This study reports recurrence in the observation group.
e Median.

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Sourcea Country (Recruitment Years) Study Design No. Women, No. (%) Mean Age, y Reported: Second Primary Malignancy Reported: Salivary Gland Harms
Hakala et al,70 2015 Finland
(1981-2002)		 Retrospective observational 910 746 (82) 49 ✔  
Khang et al,71 2015 South Korea, (1976-2010) Retrospective observational 2468 2073 (84) 46 ✔  
Lin et al,72 2015 Taiwan
(2000-2008)		 Prospective observational 10,361 10,361 (100) 46 ✔  
Seo et al,73 2015 South Korea (2008-2013) Retrospective observational 211,360 173,315 (82) 48 ✔  
Lang et al,68 2012
Lang and Wong,83 2011		 Hong Kong (1971-2009) Retrospective observational 895 725 (81) 47 ✔  
Iyer et al,69 2011 United States (1973-2006) Retrospective observational 37,176 NR NR ✔  
Brown et al,67 2008 United States (1973-2002) Retrospective observational 28,286b 21,497 (76) 42c ✔  
Ronckers et al,74 2005 United States (1973-2000) Prospective observational 29,456 22,092 (75) 43c ✔  
Ryu et al,80 2015 South Korea
(2010)		 Prospective observational 160 130 (81) 49   ✔
Jeong et al,77 2013 South Korea (2003-2006) Prospective observational 213 194 (91) 47   ✔
Grewal et al,79 2009 United States (1995-2003) Retrospective observational 262 173 (66) 45   ✔
Ish-Shalom et al,76 2008 Israel (NR) Prospective observational 40 40 (100) 48   ✔
Hyer et al,75 2007 United Kingdom (NR) Prospective observational 76 57 (75) 51   ✔
Solans et al,78 2001 Spain
(1990-1995)		 Prospective observational 79 68 (86) 46   ✔d
Wu et al,82 2015e United States (1999-2008) Retrospective observational 18,850f 18,850 (100) 47    
Lin et al,81 2014g Taiwan
(1997-2008)		 Retrospective observational 8946 7246 (81) 44    

Abbreviations: NR, not reported.
a Lin et al study82 was of good quality; all other studies were of fair quality.
b Total number included in the radioactive iodine analysis, 28,286; total N for study, 30,278.
c Median.
d Study also reported dry eyes.
e Study reported adverse reproductive outcomes related to birth rate and median time to first delivery as serious harms.
f Total cohort included 25,333 persons; the reproductive outcomes subset included 18,850 women.
g Study reported hyperparathyroidism as a serious harm.

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Test or Intervention No. Studies (Design) Summary of Findingsa Body of Evidence Limitationsb Quality Applicability
KQ1: Effectiveness
NA 0 No trials have evaluated effect of screening for thyroid cancer on patient morbidity or mortality. NA NA NA
KQ2: Diagnostic Accuracy
Palpation 2 (prospective diagnostic accuracy [n=354])
4 (prospective and retrospective cohort [n=201,027])		 Neck palpation not sensitive (11.6% to 27.8%) in detecting nodules compared with ultrasound.
Yield of cancers ranged from 0 to 4.3 per 1000 persons. Yield of cancers in adults with history of irradiation ranged from 0 to 11.3 cancers per 1000 persons.		 Two small studies reported diagnostic accuracy, 1 study did not follow up all persons with neck palpations. No evidence of reporting bias. Fair Poor: diagnostic accuracy studies are old and use a single examiner in Finland.
Ultrasound 2 (prospective/retrospective diagnostic accuracy [n=243]) 2 (prospective and retrospective cohort [n=2094]) Using any 1 of several malignant sonographic characteristics can be highly sensitive (94.3%) for detecting cancers; using a combination (≥2) of these characteristics can be both highly sensitive (94.8%) and specific (86.6%). Yield of cancers ranged from 9.2 to 30.3 cancers per 1000 persons. Two small studies reported diagnostic accuracy, neither of which followed up with the majority of screened individuals, such that the reported sensitivities are likely overestimates. No evidence of reporting bias. Fair Fair: both diagnostic accuracy studies conducted in South Korea by the same investigators, 1 of which included women only.
KQ3: Screening Harms
Ultrasound 1 (retrospective cohort [n=400]) 24% of persons underwent fine-needle aspiration of a nodule that did not meet the Society of Radiologists in Ultrasound criteria for fine-needle aspiration. Only 1 study. Fair Poor: single-institution; standards for referral to fine-needle aspiration have changed.
Ultrasound-guided fine-needle aspiration 2 (retrospective cohort [n=5494]) One study (n=4912) observed 7 cases of needle tract implantation of papillary thyroid cancer with fine-needle aspiration. It is unclear what effect, if any, this had on patient outcomes. One study observed hematomas but no major bleeding complications requiring hospitalization from fine-needle aspiration. One study for each type of harm; possible reporting bias. Fair Fair: both single-institution studies.
KQ4: Treatment Benefit
Surgery 2 (prospective and retrospective cohort [n=39,211]) US SEER data demonstrate that, overall, untreated persons with papillary thyroid cancer had a slightly worse 20-y survival rate (97%) than treated persons (99%) (P <0.001).
One Japanese study found no deaths in persons with papillary microcarcinoma who opted for ultrasound observation compared with 2 deaths in persons who opted for immediate surgery.		 Studies were not designed to evaluate the comparative benefit of treatment vs no or delayed treatment. Lack of adjustment for confounders such that it is unclear if differences in survival are due to differences in treatment vs case mix of persons. No evidence of reporting bias. Fair to poor Fair: US study includes persons treated in 1970s and 1980s; Japanese study includes persons with papillary microcarcinoma.
KQ5: Treatment Harms
Surgery 36 (prospective and retrospective cohort [n=43,295]) The rate of permanent hypoparathyroidism varied widely; best estimates were between 2 to 6 events per 100 thyroidectomies and were more variable with lymph node dissection. The rate of recurrent laryngeal nerve palsy was less variable, estimated at 1 to 2 events per 100 operations (with or without lymph node dissection). Possible publication bias for hypoparathyroidism but not recurrent laryngeal nerve palsy outcomes. Reasons for the wide variation in estimates is unclear. Fair Fair: indication for type of surgery and case mix of patients going on to surgery have changed over time.
Radioactive iodine 16 (prospective/retrospective cohort [n=291,796])c Treatment with radioactive iodine for differentiated thyroid cancer is associated with a small increase in primary second malignancies: approximately 12 to 13 excess cancers per 10,000 patients. Smaller studies demonstrate an association of excess cancer at clinically used doses. Other commonly reported permanent harms from radioactive iodine include dry mouth, ranging from 2.3% to 35% of persons. Differences in study designs and variable reporting on radiation doses limits undertanding of the magnitude and precision around risk of second primary malignancies. No evidence-reporting bias for commonly reported adverse outcomes. Fair Fair: indication and radiation dose of radioactive iodine have changed over time.

Abbreviations: NA=not applicable; SEER=Surveillance, Epidemiology, and End Results.
a Includes consistency and precision.
b Includes reporting bias.
c Calculated sample size includes only the largest study using SEER data so as to avoid double-counting studies with overlapping populations.

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