The Influence of Patient Age on Thyroid Nodule Formation, Multinodularity, and Thyroid Cancer Risk.

ORIGINAL

ARTICLE

The Influence of Patient Age on Thyroid Nodule Formation, Multinodularity, and Thyroid Cancer Risk Norra Kwong, MD, Marco Medici,MD, PhD, Trevor E. Angell, MD, Xiaoyun Liu, MD, Ellen Marqusee, MD, Edmund S. Cibas, MD, Jeffrey F. Krane,MD, PhD, Justine A. Barletta, MD, Matthew I. Kim, MD, P. Reed Larsen, MD, and Erik K. Alexander, MD Thyroid Section, Division of Endocrinology, Hypertension and Diabetes (NK, MM, TEA, XL, EM, PRL, MIK, EKA), and Department of Pathology (ESC, JFK, JAB). The Brigham & Women’s Hospital and Harvard Medical School, Boston, MA Submitted: June 24, 2015

Introduction: Though advancing age is known to influence the formation of thyroid nodules, the precise relationship remains unclear. Furthermore, it is uncertain if age influences the risk any thyroid nodule may prove cancerous. Aim: To determine the impact of patient age on nodule formation, multinodularity, and risk of thyroid malignancy. Method: We conducted a prospective cohort analysis of consecutive adults (ages 20 –95 years) who presented for evaluation of nodular disease from 1995–2011. 6,391 patients underwent ultrasound and FNA of 12,115 nodules ⱖ1 cm. Patients were divided into six age groups and compared using sonographic, cytologic, and histologic endpoints. Result: The prevalence of thyroid nodular disease increases with advancing age. The mean number of nodules at presentation increased from 1.5 in the youngest cohort (ages 20 –30) to 2.2 in the oldest cohort (⬎70 years old; P ⬍ 0.001), demonstrating a 1.6% annual increased risk for multinodularity (OR 1.02, P ⬍ 0.001). In contrast, the risk of malignancy in a newly identified nodule declined with advancing age. Thyroid cancer incidence per patient was 22.9% in the youngest cohort, but 12.6% in the oldest cohort (OR 0.972, P ⬍ 0.001), demonstrating a 2.2% decrease per year in the relative risk of malignancy between ages 20 – 60, which stabilized thereafter. Despite a lower likelihood of malignancy, identified cancers in older patients demonstrated higher risk histological phenotypes. While nearly all malignancies in younger patients were well-differentiated, older patients were more likely to have higher risk PTC variants, poorly differentiated cancer, or anaplastic carcinoma (P⬍0.001). Conclusion: With advancing age, the prevalence of clinically relevant thyroid nodules increases while the risk such nodules are malignant decreases. Nonetheless, when thyroid cancer is detected in older individuals, a higher risk histological phenotype is more likely. These data provide insight into the clinical paradox that confronts physicians managing this common illness.

hyroid nodular disease is a common adult illness, with published prevalence ranging between 26%– 67% (1– 8). While most nodules are benign, 8%–15% will prove malignant (9, 10). Therefore, accurate differentia-

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tion between benign and malignant nodules is important and has long been a focus of investigation. Preoperatively, no single clinical, radiologic, or molecular finding has proven perfectly predictive of malignant disease. In lieu of

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received August 5, 2015. Accepted October 7, 2015.

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doi: 10.1210/jc.2015-3100

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Age, Multinodularity, and Thyroid Cancer Risk

this, clinicians collectively integrate multiple variables to improve cancer risk assessment (11). Though there is increasing reliance upon sonographic and cytologic interpretation (9, 12), such interpretations also exhibit significant inter-rater variability (13, 14). While inter-rater variability does not detract from their importance, such findings do support the integration of other secondary risk factors. One such risk factor is patient age, which in contrast is objective and not limited by such variability. Therefore it has long been considered a potentially attractive addition to any risk stratification scheme. While epidemiologic analyses have demonstrated a positive association between thyroid nodule formation and advancing patient age (1, 3–5), the specifics of this relationship are poorly defined. Does this risk increase in a linear fashion or demonstrate a threshold effect? And perhaps most importantly, does age modify the risk that a newly detected thyroid nodule is malignant? This latter question has long been subject to debate. Some argue that age influences thyroid cancer risk in a bimodal fashion, with increasing cancer risk among nodules detected in both younger (⬍30 years) and older (⬎70 years) patients (15), but this idea has been challenged by recent investigation (16, 17). However, in these studies, limited followup, lack of routine sonographic evaluation, and sampling bias prevent a definitive conclusion. Additionally, the type and extent of malignancy may differ in younger vs older populations, and may influence diagnostic and therapeutic decisions. Though thyroid cancer prevalence may be lower in a given age group, the risk of patient morbidity and mortality may still prove greater if such malignancies are more aggressive. In support of this, data confirm an increased risk of thyroid cancer recurrence and disease specific mortality in older (⬎45 years) individuals (18 –20). Thus, to determine the impact of patient age on thyroid cancer risk, one needs to examine both cancer prevalence and the aggressivity of the malignancy. Beginning in 1995, we initiated a prospective, structured data collection of all patients referred to the Brigham & Women’s Hospital for thyroid nodule care. All patients were evaluated in a uniform fashion, integrating clinical, radiologic, cytologic, histopathologic, and surgical evaluation as part of a team-based approach. Our database now depicts the presentation and care of over 6000 consecutive patients with more than 12 000 thyroid nodules. Together, this large, unbiased database provides opportunity to clarify the relationship of patient age to thyroid nodular disease.


Materials and Methods Data from all euthyroid adult patients (ages 20 –95 years) evaluated at the Brigham & Women’s Hospital Thyroid Nodule Clinic between 1995 and 2011 were collected and analyzed as part of a prospective cohort analysis. Patients with a suspected thyroid nodule underwent sonographic evaluation and, when indicated, ultrasound-guided fine needle aspiration (UG-FNA). Ultrasound examination was performed by a BWH radiologist with specific thyroid expertise. For each nodule, size (length, width, and depth) and cystic component (solid, 25%–75% cystic, ⬎75% cystic) were collected as reported at the time of the initial study. Subjects were classified as having a solitary nodule when only one nodule ⱖ 1 cm was present or having a multinodular gland when two or more nodules each ⱖ 1cm were detected. For each subject, age at time of first UG-FNA and the total number of nodules ⱖ 1cm were documented. Consistent with clinical recommendations contemporary to the study period, UG-FNA was generally recommended for all noncystic nodules ⱖ 1cm. UG-FNA was performed with a 25gauge needle following local anesthesia. Typically two to four passes from different areas of the nodule constituted a single aspiration. Samples were processed by the ThinPrep 2000 system (Holigic Corp, Marlborough, MA), and reviewed by a BWH cytopathologist. All aspirates were classified following the Bethesda System for Reporting Thyroid Cytopathology (21). All therapy and follow-up monitoring were standardized depending on cytological result. When FNA cytology was “positive for malignant cells/malignant” or “suspicious for carcinoma (SUSP)”, patients were typically advised to undergo near-total thyroidectomy. Usually, lobectomy was advised for patients with cytology “Suspicious for a Follicular Neoplasm (SFN)” or “Suspicious for a Hurthle Cell Neoplasm (SHCN)”. If cytology demonstrated “atypia of undetermined significance (AUS)“, clinical recommendations were for repeat FNA cytology evaluation, lobectomy (especially if the nodule(s) was large or high risk sonographic features were noted), or more recently, repeat FNA with molecular testing using the Afirma gene expression classifier (GEC; n ⫽ 13). Finally, patients with ”nondiagnostic“ cytology were advised to undergo repeat UG-FNA within 6 months. For those patients with benign nodules, follow-up was generally recommended in 12–24 months pending clinical and sonographic risk assessment. For the purposes of investigating thyroid nodule formation and multinodularity among different age groups, we investigated all nodules ⱖ 1cm identified with ultrasound examination in the entire cohort of 6653 patients. To determine the risk of malignancy in different age groups, nodules were classified as malignant following histologic interpretation, or rarely (⬃3%) when cytology was “positive for malignant cells” but no subsequent surgery occurred because of unique clinical circumstances. Nodules were classified benign when any of the following were confirmed: a) benign UG-FNA cytology (68%), b) benign histopathologic interpretation (16%), c) ⬎75% cystic parenchyma (6%), d) functionality on thyroid scintigraphy (“hot” nodule; 3%), or if e) very low risk sonographic characteristics (eg, spongiform appearance; 5%) or clinic characteristics (eg, ⬎50% reduction in nodule volume during follow up; 2%) were noted as supported by recent American Thyroid Association guidelines (22). A very small proportion of patients (⬍4%) was lost to follow up before final pathologic diagnoses could be made, though initial sonographic data was available. Incidental in-


doi: 10.1210/jc.2015-3100

trathyroidal microcarcinomas (⬍1cm) separate from the primary lesion commonly detected postoperatively upon histopathologic review were not considered malignant for this investigation (23). Histopathology was classified using the Tumor Node Metastasis [TNM] System recommended by American Joint Committee on Cancer (AJCC) (24). All subjects were grouped into one of six age groups as follows: age 20 –29 years, age 30 –39 years, age 40 – 49 years, age 50 –59 years, age 60 – 69 years, or age ⱖ 70 years. For each group, we then determined the mean number of thyroid nodules ⱖ 1cm per patient, the proportion of patients with multinodularity, the proportion of nodules proven cancerous, and the type of malignancy. For the purpose of further analysis, those with a diagnosis of malignancy were further categorized by their histological subtype as having either well-differentiated thyroid carcinoma (papillary or follicular carcinoma) or high-risk thyroid carcinoma (anaplastic, medullary, poorly differentiated or distant metastatic carcinoma). Logistic regression analyses were used for statistical comparison, and corrected by gender. Statistical analysis was performed using SPSS version 22 (SPSS IBM, New York), and P-values ⬍ 0.05 were considered significant. Approval from the Brigham & Women’s Hospital Office of Human Subjects Research was granted to perform this investigation.


Table 1.

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Baseline patient and nodule characteristics.

Patient characteristics: (n ⴝ 6391) Sex: Female Male Age: Mean Range Decile Cohorts: 20 –29 yr 30 –39 yr 40 – 49 yr 50 –59 yr 60 –70 yr ⬎ 70 yr Nodules characteristics: (n ⴝ 12 115) Maximal diameter Mean Range Cystic content ⬍25% cystic 25%- 75% ⬎75% Unknown

5447 (85%) 943 (15%) 47.4 yr ⫾ 10.8 yr 20 –95 yr n ⫽ 420 (7%) n ⫽ 908 (14%) n ⫽ 1475 (23%) n ⫽ 1606 (25%) n ⫽ 1209 (19%) n ⫽ 773 (12%)

2.1 cm ⫾ 1.1 cm 1.0 –12.0 cm n ⫽ 8975 (74%) n ⫽ 2007 (16%) n ⫽ 1070 (9.5%) n ⫽ 63 (0.5%)

Results From 1995 to 2011, there were 6653 consecutive euthyroid patients evaluated at the Brigham & Women’s Hospital Thyroid Biopsy Clinic. Of these, 262 subjects were excluded due to absence of nodule ⱖ 1cm (n ⫽ 79) or patient age ⬍ 20 years (n ⫽ 183). This resulted in a final study population of 6391 patients with 12 115 nodules. As shown in Table 1, the population was predominantly female (85%) with a mean age of 47.4 years. Thyroid nodule size averaged 2.1 cm (⫾1.1 cm) and the majority were solid. Less than 1% of our study cohort had previous exposure to ionizing neck irradiation during childhood, or harbored a family history of medullary thyroid carcinoma. In this total population referred for initial evaluation of nodular disease, an average of 1.9 clinically relevant thyroid nodules was detected per patient. However, when stratified by age, the extent of nodularity increased in a linear fashion (Figure 1). Patients 20 –29 years old had an average of 1.55 nodules ⱖ 1cm, while patients ⱖ 70 years old had an average of 2.21 nodules ⱖ 1cm (P ⬍ .001), representing a 43% increase in the total number of thyroid nodules between these two groups (P ⬍ .001). The prevalence of multinodularity similarly increased with advancing age (Figure 1). With each successive age group, the relative risk for multinodularity increased by 1.6% (OR 1.022; P ⬍ .001). The oldest cohort (⬎70 years) demonstrated a 30% higher absolute risk of multinodularity compared to the youngest cohort (56% vs 26% respectively; P ⬍ .01).

We next investigated the association between patient age at nodule evaluation and malignancy risk. Of the 1018 (15.9%) patients diagnosed with thyroid cancer during this 16 year period, 988 (97%) were confirmed by surgical histology, while 30 (3%) were based on positive FNA cytology without thyroidectomy. Notably, the risk that a nodule was cancerous decreased with advancing age (P ⬍ .001) as shown in Figure 2a. For patients ages 20 –29 years, 30 –39 years, 40 – 49 years, 50 –59 years, 60 – 69 years, and ⬎ 70 years, the cancer prevalence was 22.9%, 21.8%, 17.1%, 13.0%, 13.7%, and 12.6%, respectively (P ⬍ .001). For comparison, when malignancy rate was analyzed ‘per-nodule’, the youngest cohort (20 –29 years) demonstrated a 14.8% malignant risk per nodule at diagnosis in comparison to 5.6% in the oldest cohort (⬎ 70 years; P ⬍ .01). Between the ages of 20 to 60 years, each advancing year was associated with a 2.2% reduction in the relative risk any newly evaluated thyroid nodule was malignant in a patient (OR 0.972, P ⬍ .001). This risk of malignancy stabilized after age sixty. To determine the type and extent of thyroid cancers in this study, all histopathologic diagnoses were reviewed for those nodules that underwent resection (n ⫽ 988). We categorized all malignancies as either well-differentiated thyroid carcinoma (papillary or follicular carcinoma) or high-risk thyroid carcinoma (anaplastic, medullary, poorly differentiated or distant metastatic carcinoma). Table 2 and Figure 2b show the distribution of well-differentiated vs high-risk carcinomas by age deciles. The


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mained poorly defined, with conflicting findings (15–17). Our data depict a large-scale, prospective analysis examining this relationship in unselected consecutive patients presenting for thyroid nodule evaluation in which standardized, high frequency ultrasound evaluation and UG-FNA of nearly all relevant nodules were performed. Our findings confirm an increased prevalence of thyroid nodules and multinodularity with advancing age, but importantly document a reduced risk such nodules will prove cancerous with advancing age. However, thyroid cancer is nonetheless detectable in ⬃12%-13% of older individuals, and when detected is significantly more likely to be of higher risk disease. Anaplastic, poorly differentiated, medullary, and distant metastatic carcinoma were more likely in patients presenting with nodular disease over age 60. Even among those Figure 1. Left axis depicts the mean number of thyroid nodules(⬎1 cm) in each age cohort. Right axis depicts the proportion of patients with multinodularity (2 or more nodules each ⬎ 1 with well-differentiated PTC, higher cm) in each age cohort risk variants such as tall-cell PTC proportion of thyroid carcinoma with high-risk histology were similarly more common in increased with advancing age, ranging from 0% in the older patients. Together, our data emphasize a clinical youngest cohort to 16% of carcinomas detected in the paradox facing affected patients and their physicians. oldest cohort (P ⬍ .001). This increase was most pro- While thyroid nodules are more common and more likely nounced in patients ⬎ 40 years, where a 7.0% increase in benign in older individuals (leading many to support a relative risk of high-risk carcinoma was detected annually conservative strategy of noninvasive evaluation), this (OR 1.073; P ⬍ .001). Next, we analyzed all patients with study also demonstrates that thyroid cancers in older papapillary thyroid carcinoma (PTC) (n ⫽ 851), seeking to tients are more likely to be aggressive and thus early idencompare specific histologic PTC variants at diagnosis. In tification may prove critical for optimal outcome. this analysis, diffuse sclerosing PTC was disproportionOur series investigated 6391 patients over a 16 year ately detected at higher rates in younger patients, with the period in which nearly all aspirated nodules ⱖ 1 cm were majority under age 50 years at diagnosis. In contrast, classified as benign or malignant. We acknowledge that a higher risk variants of PTC such as tall cell variant were small proportion of nodules lacked precise cytologic or more commonly detected in older patients (Table 3). As a small minority of nodules were persistently non- histologic results. In our cohort, a few were persistently diagnostic (⬍3%) or had indeterminate cytology without nondiagnostic. Such nodules, however, were primarily definitive histology (⬃4%), we sought to determine if cystic and have been followed over time without incident these nodules were equally distributed among all age co- leading us to conclude that there is a very high likelihood horts thus avoiding any sampling bias. Such cases were of benignity. A separate small cohort was cytologically widely distributed among all age cohorts, without a sta- indeterminate, though lost to follow-up or further intervention. Most such nodules were cytologically AUS or FN. tistically significant association (P ⫽ .46). We cannot refute the argument that a small proportion of these nodules would prove malignant (10). However, Discussion subanalysis of this cohort demonstrates a similar distriUntil now, the influence of patient age on thyroid nodular bution throughout all age cohorts thus making it signifidisease, multinodularity, and thyroid cancer risk has re- cantly unlikely to impact our conclusions. In contrast, we


doi: 10.1210/jc.2015-3100


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true, this practice would likely increase the proportion of thyroid cancer in the older cohort, suggesting that our findings may be even stronger than observed. Why more thyroid nodules form but are less likely to be malignant with advancing age remains unclear. Oncogenic mutations have been shown to be causative for most thyroid carcinomas (28, 29). Though unproven, mutations are similarly believed to be responsible for benign nodular formation and growth (30, 31). Understanding which genetic mutations associate with benign vs malignant disease, while also better defining a potential multihit hypothesis or the impact of separate epigenetic factors, will be important areas for future research. It has long been known that older age portends a worse prognosis among those diagnosed with thyroid cancer (9, 18). Our data suggest some of the attributable risk is due to more advanced thyroid cancer and higher risk histology at time of diagnosis. Others argue that a poorer response to conFigure 2. a. Patient age and risk a thyroid nodule ⬎ 1 cm will prove malignant when presenting ventional therapy in older compared for initial evaluation. b. Patient age and the proportion of identified malignancies representing high-risk, aggressive disease (Anaplastic, Medullary, Poorly Differentiated, or Distant Metastatic to younger patients with similar disCarcinoma). ease burden may also underlie this difference. Regardless, these findbelieve the broad inclusion of all consecutive thyroid nodings support a complex genotype-phenotype relationship ules evaluated over 17 years in a real-world setting allows likely to be better deciphered in the decades ahead. the most accurate translation of these data into daily pracIn summary, these data substantially expand our untice. Our study population appears highly comparable to derstanding of thyroid nodular disease in the adult popthose previously (25–27) reported and confirms that most ulation by showing that advancing age clearly increases patients referred for nodular disease are female, middle the risk of thyroid nodule formation though decreases the aged, and typically present with a solid, ⬃2cm nodule. Importantly, these data do not describe the prevalence risk such identified nodules will be malignant. Ironically, of thyroid nodularity in a general population, as this in- these associations are inversely related. Given a cancer vestigation was not designed as a screening study. All pa- risk ⬎ 20% in young adults with substantial longevity tients in this study were referred to the clinic because of a ahead, it is arguable that nearly all clinically relevant thyknown or suspected thyroid nodule. Given the observed roid nodules (especially if solid) should be evaluated with increase in nodularity with age, and the increasing use of UG-FNA in this population. In contrast, one potential cross sectional studies in older patients, one might expect strategy for older adults may include ultrasound evaluathis cohort to represent the largest proportion of patients. tion with sonographic risk stratification, thereafter purInterestingly, patients over age 70 only represented 12% suing UG-FNA for nodules identified as sonographically of the referral cohort. One explanation for this finding is intermediate or high risk. Importantly, older patients with that many older patients with thyroid nodules may simply nodular disease must be informed that higher-risk thyroid have been followed conservatively (9), as the risk of any cancer is nonetheless possible, and continued monitoring potential therapy may outweigh the benefits. However, if of any nodularity is therefore necessary. As we seek to


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Table 2. Thyroid Cancer among 988 patients with histological confirmations, stratified by age cohort. The proportion of well-differentiated thyroid carcinoma (Papillary or Follicular carcinoma) vs. high-risk thyroid carcinoma (Anaplastic, Medullary, Poorly differentiated, or distant metastatic carcinoma) are shown. Type of Malignancy: Age Cohort:

20 –29 yr

# patients (n)

420

# malignant (n; %)

93 (22%)

Well-Differentiated

High Risk Thyroid

Thyroid Carcinoma (n; %)† 93 (100%) 79 PTC

Carcinoma (n;%)†

14 FTC 30 –39 yr

908

191 (21%)

187 (97.9%) 170 PTC 17 FTC

40 – 49 yr

1475

246 (17%)

240 (97.6%) 224 PTC 16 FTC

50 –59 yr

1606

204 (13%)

195 (96.0%) 178 PTC 17 FTC

60- 69 yr

1209

163 (13%)

142 (87.1%) 128 PTC

14 FTC ⬎70 yr

773

94 (12%)

79 (84.0%) 72 PTC 7 FTC

0 (0%) 0 Anaplastic/poorly diff 0 MTC 0 Distant metastatic Carcinoma 4 (2.1%) 2 Anaplastic/poorly diff 1 MTC 1 Distant metastatic Carcinoma 6 (2.4%) 2 Anaplastic/poorly diff 3 MTC 1 Distant metastatic Carcinoma 9 (4.4%) 2 Anaplastic/poorly diff 4 MTC 3 Distant metastatic Carcinoma 21 (12.9%) 12 Anaplastic/poorly diff 1 MTC 8 Distant metastatic Carcinoma 15 (15.9%) 9 Anaplastic/poorly diff 1 MTC 5 Distant metastatic Carcinoma

WDTC: well-differentiated thyroid carcinoma, PTC: Papillary thyroid carcinoma, FTC: follicular thyroid carcinoma, Anaplastic/poorly diff: anaplastic or poorly differentiated thyroid cancer, MTC: Medullary thyroid carcinoma. DMC: distant metastatic carcinoma † P ⬍ 0.001 for trend .

optimize the individualized care for affected patients, multivariable diagnostic algorithms should include patient age in addition to nodule size, sonographic characteristics, and other historical risk factors known to modify cancer risk.

Acknowledgments All authors report no disclosures relevant to this work. The research was supported by the NIH T32 DK007529 training grant.

Address all correspondence and requests for reprints to: Erik K. Alexander, MD, Chief, Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 75 Francis Street, PBB-B4. Room 415, Boston, MA 02 115, 617–732-4148 (phone), 617–264-6346 (fax), Email: [email protected] – Preferred method of contact. Address all reprint requests to: Erik K. Alexander, MD (address above) Disclosure and Funding Statement: All authors report no disclosures relevant to this work. The research was supported by the NIH T32 DK007529 training grant.


doi: 10.1210/jc.2015-3100


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Table 3. Variants of Papillary Thyroid Carcinoma (PTC) in 851 patients with histologically confirmed papillary thyroid cancer. Age Cohort:

Papillary Thyroid Carcinoma (n)

Classical variant

Follicular variant

Tall cell variant

Diffuse sclerosing variant

20 – 29 yr 30 – 39 yr

79 170

N (%) 28 (35) 73 (43)

N (%) 47 (59) 86 (51)

N (%) 0 (0) 0 (0)

N (%) 3 (4) 7 (4)

40 – 49 yr

224

89 (40)

113 (50)

11 (5)

6 (3)

50 – 59 yr

178

59 (33)

106 (59)

10 (6)

1 (1)

60 – 69 yr

128

39 (30)

71 (55)

8 (6)

0 (0)

⬎70 yr

72

16 (22)

45 (63)

4 (6)

1 (1)

This work was supported by .

References 1. Brander A, Viikinkoski P, Nickels J, Kivisaari L. Thyroid gland: US screening in a random adult population. Radiology. 1991;181:683– 687. 2. Acar T, Ozbek SS, Acar S. Incidentally discovered thyroid nodules: frequency in an adult population during Doppler ultrasonographic evaluation of cervical vessels. Endocrine. 2014;45:73–78. 3. Reiners C, Wegscheider K, Schicha H, Theissen P, Vaupel R, Wrbitzky R, Schumm-Draeger PM. Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees. Thyroid : official journal of the American Thyroid Association. 2004;14:926 –932. 4. Bartolotta TV, Midiri M, Runza G, Galia M, Taibbi A, Damiani L, Palermo Patera G, Lagalla R. Incidentally discovered thyroid nodules: incidence, and greyscale and colour Doppler pattern in an adult population screened by real-time compound spatial sonography. Radiol Med. 2006;111:989 –998. 5. Guth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest. 2009;39:699 –706. 6. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Annals of internal medicine. 1997;126:226 –231. 7. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med. 1994;154:1838 –1840. 8. Rago T, Chiovato L, Aghini-Lombardi F, Grasso L, Pinchera A, Vitti P. Non-palpable thyroid nodules in a borderline iodine-sufficient area: detection by ultrasonography and follow-up. J Endocrinol Invest. 2001;24:770 –776. 9. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–1214.

Other variants: N (%) - specifics 1 (1) 1 Cribriform 4 (2) 1 Columnar 1 Macrofollicular 2 Oncocytic 5 (2) 1 Cribriform 2 Oncocytic 1 Solid 1 Warthin Tumor like 2 (1) 1 Macrofollicular 1 Solid 10 (8) 1 Columnar 1 Clear cell 1 Macrofollicular 5 Oncocytic 2 Solid 6 (8) 2 Macrofollicular 4 Oncocytic

10. Yassa L, Cibas ES, Benson CB, Frates MC, Doubilet PM, Gawande AA, Moore FD, Jr., Kim BW, Nose V, Marqusee E, Larsen PR, Alexander EK. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer. 2007;111: 508 –516. 11. Alexander EK. Approach to the patient with a cytologically indeterminate thyroid nodule. J Clin Endocrinol Metab. 2008;93:4175– 4182. 12. Durante C, Costante G, Lucisano G, Bruno R, Meringolo D, Paciaroni A, Puxeddu E, Torlontano M, Tumino S, Attard M, Lamartina L, Nicolucci A, Filetti S. The natural history of benign thyroid nodules. JAMA. 2015;313:926 –935. 13. Cibas ES, Baloch ZW, Fellegara G, LiVolsi VA, Raab SS, Rosai J, Diggans J, Friedman L, Kennedy GC, Kloos RT, Lanman RB, Mandel SJ, Sindy N, Steward DL, Zeiger MA, Haugen BR, Alexander EK. A prospective assessment defining the limitations of thyroid nodule pathologic evaluation. Ann Intern Med. 2013;159:325–332. 14. Moon WJ, Jung SL, Lee JH, Na DG, Baek JH, Lee YH, Kim J, Kim HS, Byun JS, Lee DH, Thyroid Study Group KSoN, Head, Neck R. Benign and malignant thyroid nodules: US differentiation–multicenter retrospective study. Radiology. 2008;247:762–770. 15. Belfiore A, LA Rosa GL, Padova G, Sava L, Ippolito O, Vigneri R. The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area. Cancer. 1987;60:3096 – 3102. 16. Rago T, Fiore E, Scutari M, Santini F, Di Coscio G, Romani R, Piaggi P, Ugolini C, Basolo F, Miccoli P, Pinchera A, Vitti P. Male sex, single nodularity, and young age are associated with the risk of finding a papillary thyroid cancer on fine-needle aspiration cytology in a large series of patients with nodular thyroid disease. European journal of endocrinology / European Federation of Endocrine Societies. 2010;162:763–770. 17. Bessey LJ, Lai NB, Coorough NE, Chen H, Sippel RS. The incidence of thyroid cancer by fine needle aspiration varies by age and gender. The Journal of surgical research. 2013;184:761–765. 18. Mazzaferri EL. Papillary thyroid carcinoma: factors influencing prognosis and current therapy. Semin Oncol. 1987;14:315–332. 19. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 1990;71:414 – 424.


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20. Grebe SK, Hay ID. Follicular cell-derived thyroid carcinomas. Cancer Treat Res. 1997;89:91–140. 21. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009;19:1159 –1165. 22. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer; Thyroid 2015 (released publically June, 2014 via oral symposium). 23. Ito Y, Miyauchi A, Inoue H, Fukushima M, Kihara M, Higashiyama T, Tomoda C, Takamura Y, Kobayashi K, Miya A. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010;34:28 –35. 24. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–1474. 25. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351:1764 –1771.


26. Sherman SI. Thyroid carcinoma. Lancet. 2003;361:501–511. 27. Mandel SJ. A 64-year-old woman with a thyroid nodule. JAMA. 2004;292:2632–2642. 28. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676 – 690. 29. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013;381: 1058 –1069. 30. Beaudenon-Huibregtse S, Alexander EK, Guttler RB, Hershman JM, Babu V, Blevins TC, Moore P, Andruss B, Labourier E. Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid. 2014;24:1479 –1487. 31. Liu RT, Hou CY, You HL, Huang CC, Hock L, Chou FF, Wang PW, Cheng JT. Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 2004;14: 616 – 621.


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Thyroid nodule.

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Bethesda Categorization of Thyroid Nodule Cytology and Prediction of Thyroid Cancer Type and Prognosis.

Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution.

Is age associated with risk of malignancy in thyroid cancer?

Associations between thyroid function and mortality: the influence of age.

Management of the single thyroid nodule.

Thyroid nodules and evaluation of thyroid cancer risk.

Primary thyroid schwannoma masquerading as a thyroid nodule.

Thyroid Ultrasound Pitfalls: Esophageal Fibrovascular Polyp Mimicking Thyroid Nodule.

Ectopic thyroid nodule in the esophagus.

Thyroid dysfunction, thyroid hormone replacement and colorectal cancer risk.

Rapid thyroid nodule growth is not a marker for well-differentiated thyroid cancer.

Accuracy of thyroid nodule sonography for the detection of thyroid cancer in children: systematic review and meta-analysis.

Thyroid gland. BMI may predict risk of papillary thyroid cancer.

Thyroid Nodule Imaging, Status and Limitations.

Lipoma of neck mimicking thyroid nodule.

Thyroid cancer in black thyroid glands: the effect of age and race.

Images in Endocrine Pathology: Parasitic Nodule of Thyroid in Neck of Patient with Family History of Papillary Thyroid Carcinoma.

Influence of iodine on the formation of 27S and larger iodoproteins in rat thyroid follicles.