2 Thyroid Nodules and Goiter

Suggested citation: The Endocrine Society. Endocrine Facts and Figures: Thyroid. First Edition. 2015.

A thyroid nodule is a discrete lesion within the thyroid gland that is palpably and/or sonographically

distinct from the surrounding thyroid parenchyma.39 Thyroid nodules may be solid or fluid-filled cysts and may develop as a result of various conditions, including iodine deficiency and Hashimoto’s thyroiditis. In addition, depending on the method of detection,  thyroid nodules are found in up to 50% of the general population, and are frequently asymptomatic and benign.40

Thyroid nodule classification is used to determine when a FNA should be performed in order to evaluate the composition of the nodule. The Bethesda System for Reporting Thyroid Cytopathology is a standardized reporting system for classifying FNA results comprising 6 diagnostic categories unique characteristics of malignancy and recommendations for clinical management.41

Table 5 shows the risk of malignancy as cited in a recent systematic review and meta-analysis of 41 studies that characterized 29,678 thyroid nodules in total. This study verified and weighted each suspicious and clinical feature of the thyroid nodules.42

Table 5. Risk of malignancy by nodule characteristic and patient history (meta-analysis of 41 studies).
NODULE CHARACTERISTIC OR PATIENT HISTORY INCREASED RISK OF MALIGNANCY (VS. NON-MALIGNANT NODULE)
Height > Width >10 times
Absent halo sign >7 times
Presence of microcalcifications or irregular margins >6 times
Hypoechogenicity or solid structure >5 times
Intranodular vascularization >3 times
Family history of thyroid carcinoma >2 times
Nodule size ≥ 4cm >1.6 times
Single nodule >4 times
History of head/neck irradiation >1.3 times
Male gender >1.2 times

Source: Campanella et al. 201442

A goiter is an enlargement of the thyroid gland itself that may result from a variety of conditions, including hypothyroidism, hyperthyroidism, iodine deficiency, or thyroid tumors; all of which may require specific treatment.43 In addition, a goiter might present itself as a sporadic non-toxic goiter, a benign enlargement of the thyroid in a euthyroid subject living in an iodine-sufficient area, or as either a solitary thyroid nodule or a multi-nodular goiter (MNG), both of which may be toxic or non-toxic, depending on whether they produce an excess of thyroid hormone.44

2.1    Prevalence and Incidence

 2.1.1        Thyroid Nodules

Table 6 summarizes the prevalence of thyroid nodules and goiter reported by US- and international-based studies.  Importantly, reported prevalence values depend on the population studied, for example in iodine-sufficient versus iodine-deficient regions, and the diagnostic method used.45

 Table 6. Estimated prevalence of thyroid nodules and goiter. 
CONDITION DATA SOURCE POPULATION METHOD INCIDENCE RATE PREVALENCE REFERENCE
Non-toxic Thyroid Nodules Framingham Heart Study (1948), US 5,127 subjects free of coronary heart disease 2,845 women, 2,282 men Palpation or previous surgery for thyroid nodules Not reported 4.2% overall; 6.4% in women, 1.5% in men Vander et al. 196846 
Framingham Heart Study, 15 year follow-up (1948 – 1953), US 4,909 survivors of original cohort, initially free of thyroid disease: 2,262 women, 2,247 men Palpation 15-year incidence: 1.4% (1.7% in women, 0.9% in men) 1%, multinodular goiters
Whickham Survey, UK, 20-year follow-up (1972-1992) 1802 survivors of Whickham Survey Antibody assay Not reported 15.5% overall; 8.6% small goiter, 5.9% large goiter Vanderpump et al. 19957
Review (2008), US, 1965 8,641 subjects, age 0–70 years Palpation Not reported 0.47% Dean et al. 200845 
Review (2008), US, 1968 5,127 subjects, age 30–59 years Palpation Not reported 4.2%
Review (2008), US, 1975 2,271 subjects, age 11–18 years Palpation Not reported 1.5%
Review (2008), US, 1977 7,785 subjects, 9–16 years Palpation Not reported 0.2%
Review (2008), England, 1977 2,979 subjects, age 18–75 years Palpation Not reported 3.2%
Review (2008), Finland, 1991 253 subjects, age 19–50 years Palpation Not reported 5.1%
Review (2008), Belgium, 1985 300 subjects, age 0–90 years Ultrasonography Not reported 19%
Review (2008), Finland, 1991 253 subjects, age 19–50 years Ultrasonography Not reported 27.3%
Review (2008), France, 1994 1000 adult subjects Ultrasonography Not reported 34.7%
Retrospective review of adult outpatients (2008 – 2009), US 3077 adults imaged for non-thyroid indications Incidental, contrast-enhanced chest CT Not reported 25.1% Ahmed et al. 20128
Goiter Study of thyroid diseases in iodine-sufficient areas (1998) Adults with sporadic diffuse goiter, in iodine sufficient areas Ultrasonography Not reported 1% to <10% Lind et al. 199814 
Adult females with sporadic diffuse goiter, in iodine sufficient areas Ultrasonography Not reported 5% to 9%
Study of goiter in children (1975), Michigan, Kentucky, Texas and Georgia, US 7,785 children age 9-16 years examined, 377 goitrous children matched with equal number non-goitrous Urinary iodine and creatinine, T4, protein-bound iodine, and plasma inorganic iodide determinations Not reported 6.8% Trowbridge et al. 197515

 

2.2      Demographic Differences

Overall, palpable thyroid nodules are more prevalent in women than men. The results of two large epidemiological studies illustrating these differences are summarized in Table 7.

Table 7. Incidence and prevalence of palpable thyroid nodules by sex.
DATA SOURCE POPULATION METHOD PREVALENCE INCIDENCE REFERENCE
MALES FEMALES MALES FEMALES
Framingham Heart Study (1948), US 5,127 subjects free of coronary heart disease 2,845 women, 2,282 men Palpation 1.5% 6.4% NA NA Vander et al. 196846 ; Dawber et al. 195147
Framingham Heart Study, 15-year follow-up (1948-1953), US 4,909 surviving subjects Palpation 0.5% 4.7% 0.06% 0.11% Vander et al. 196846
Whickham Survey (1972), UK 2779 subjects Palpation 5% 26% NA NA Tunbridge et al. 197748
Whickham Survey, 20-year follow-up (1972-1992), UK 1802 survivors of  Whickham Survey Palpation, Serum TSH, free T4 2% 10.0% NR NR Vanderpump et al. 19957

Abbreviation: NA, not applicable; NR, not reported.

In studies in different US locations, prevalence of nodules detected by microscopic examination at autopsy ranged from 8.2% to 64.5%.17

In a meta-analysis of trials between 1965 and 2012 conducted in 27 countries, the authors chose 143 eligible articles to calculate the effect of gender on goiter prevalence in different age groups and with differing iodine status. They found that goiter is more frequent in females, and the difference is more prominent in iodine-deficient areas. For countries that used the WHO definition for the palpation group, goiter was classified according to WHO criteria. Grade 0: no goiter is found (the thyroid impalpable and not visible on clinical inspection); grade 1: neck thickening is present from enlarged thyroid and palpable, however, not visible in normal position of neck; grade 2: neck swelling, visible when the neck is in normal position, corresponding to enlarged thyroid found in palpation.49

Table 8. Prevalence of goiter by gender and age group (values given as proportion of total).
DATA SOURCE METHOD POPULATION MALES FEMALES
Systematic review and meta-analysis for 27 countries (1965-2012) Palpation
All studies, all countries, all levels of iodine status 470,066 patients, approximately equal males and females, 1–80 years 0.46 0.54
     Grade 1 0.46 0.54
     Grade 2 0.37 0.63
United States US total 0.20 0.80
     Grade 1 0.21 0.79
     Grade 2 0.10 0.90
     Children US children under age 15 0.32 0.68
     Adults US adults 15–90 years 0.08 0.92
Ultrasonography
All countries, all studies Under 15 years 0.58 0.42
15–20 years 0.52 0.48
20 –90 years 0.31 0.69

Source: Malboosbaf et al. 201349

The International Classification of Diseases 9th edition (ICD-9) codes non-toxic uninodular goiter using ICD-9 code 241.0. In 2010, 123,274 US outpatient hospital visits reported ICD code 241.0 as the primary diagnosis and 162,141 visits reported this code as part of any recorded diagnoses, including both primary and secondary cases.50 Similarly, 864,980 physician office visits listed this ICD code as the primary diagnosis, and 1,074,393 visits reported in conjunction with other diagnoses.51 Table 9 presents selected US demographic and clinical breakouts for 2010.50 Similar demographic data based on physician office visits were not available for multinodular goiter.

Table 9. Physician office visit demographics for ICD-9 code 241.0 (nontoxic uninodular goiter) in the US.
GENDER
Male 14.1%
Female 85.9%
ETHNICITY
White 77.1%
Not answered 22.9%
HISPANIC/NON-HISPANIC ETHNICITY
Hispanic 27.4%
Non-Hispanic 71.3%
Not answered 1.3%
PRINCIPAL EXPECTED SOURCE OF PAYMENT 
Private Insurance 73.7%
Medicare 11.4%
Other 5.4%
Not answered 9.5%
AGE
0-9 years 0.0%
10-19 years 14.9%
20-29 years 11.5%
30-39 years 0.0%
40-49 years 9.9%
50-59 years 19.0%
60-69 years 31.8%
70-79 years 2.1%
80+ years 10.9%
NUMBER OF VISITS IN PAST YEAR 
None 0.0%
1-2 40.0%
3-5 8.0%
6+ 26.0%
Not applicable 26.0%

Source: National Ambulatory Medical Care Survey 201050

2.3    Life Expectancy and Mortality

A study of re-biopsy of 66 (11.4%) of 578 patients with initially benign nodules over an 8-year follow-up reported that only one patient was subsequently diagnosed with thyroid malignancy.52 Moreover, evaluation of the long-term status of patients with initially benign FNA cytology, evaluated in the Brigham and Women’s Hospital and Harvard Medical School thyroid nodule clinic between 1995 and 2003, documented only 30 (2.2%) deaths among 1,369 patients, with no deaths attributed to thyroid cancer.53 A recent study that evaluated the diagnostic efficacy of FNA utilizing histological evaluations of tissue samples, found a high correlation between malignancy rates and the predictive results of FNA.54

2.4    Diagnosis, Treatment, and Prescription Trends

Use of imaging technologies, such as ultrasound, CT, and magnetic resonance imaging (MRI), has led to more thyroid nodule diagnosis than in the past, when physical examination was the primary mode of diagnosis. Indeed, studies have reported that nodules are up to 10 times as likely to be detected with ultrasound as compared with physical examination.55

Similarly, from 2006 to 2011, the use of FNA more than doubled, with a 16% annual growth.28 Interestingly, while indeterminate cytology can be found in 15-30% of FNA specimens, retrospective studies have reported that ultrasound-guided FNA procedures yield lower rates of both non-diagnostic and false-negative cytology specimens.61  Moreover, some sources credit FNA biopsies with an increase in the diagnostic yield of cancers at thyroidectomy.55

A retrospective study of patients with FNA biopsy results classified as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) found that 62% of patients were sent directly to surgery, 25% had the FNA biopsy repeated and 13% had neither but remained under observation.56

Table 10 presents data from the Nationwide Inpatient Sample (NIS) and National Survey of Ambulatory Surgery (NSAS) showing an overall increase in thyroidectomies between 1996 and 2006.22

Table 10. Number of thyroidectomies in the US, 1996-2006.
SURGERY TYPE 1996 2006 % INCREASE, 1996-2006
Thyroidectomies 66,864 92,931 39%
Outpatient procedures 19,099 30,731 61%
Inpatient procedures 52,062 62,200 30%

Note: Outpatient denotes a hospital stay of less than 24 hours

Source: Sun et al. 201322

Table 11 summarizes data from a recent study using multiple claims data, reporting an increase in the total number of thyroid surgeries performed in the US due to thyroid nodules between 2006 and 2011.. For all operations during this period, 51% were thyroidectomies and 49% were lobectomies, with 40% being inpatient and 60% outpatient. Trend analysis showed that thyroidectomies increased over this 5-year time period, exceeding lobectomies as a percentage of all thyroid nodule related operations in 2009.28

Table 11.Thyroid nodule surgeries in the US, 2006-2011.
NODULE SURGERY TYPE 2006 2011 % INCREASE, 2006-2011
All nodule surgeries 99,613 130,216 31%
Combined thyroidectomy 45,558 72,344 59%
Inpatient thyroidectomy 22,916 33,611 47%
Outpatient thyroidectomy 22,641 38,733 71%
Combined lobectomy 54,055 57,872 7%
Inpatient lobectomy 21,455 15,625 -27%
Outpatient lobectomy 32,600 42,246 30%

Note: Outpatient denotes a hospital stay of less than 24 hours

Source: Sosa et al. 201328

The aforementioned study also analyzed the yield of malignancy per operation, comparing results using claims data and American Cancer Society (ACS) incidence estimates. From the study calculations, the yield malignancy per operation increased from 30.3% in 2006 to 36.9% in 2011 according to ACS data, whereas claims data suggested no increase in the incidence of malignancy per operation.28

 2.5    Health Outcomes Measures

Table 12 presents data on treatment-based health outcomes for benign thyroid nodules, based on 31 completed randomized controlled trials selected for review through a rigorous evaluation of methodology. In some cases, the number of trial participants was lower than ideal. Importantly, many of these treatment strategies are not routinely available in the US.

Table 12. Effects of levothyroxine and minimally invasive therapies on benign thyroid nodules.
DATA SOURCE THERAPY OUTCOME
Systematic review of 31  studies based on randomized controlled trials up to April 2014 Levothyroxine
(16 trials, n=7083; 780 intervention, 1294 comparator)
Nodule volume reduction of 50% or more in 16% of patients vs 10% of patients receiving no treatment or placebo after 6–24 months of follow-up
Symptoms of hyperthyroidism were apparent in 25% of treated patients vs. 7% of placebo-treated at 12–18 months of follow-up
Percutaneous ethanol injection
(8 trials, 7 using ethanol, 1 using tetracycline)], n=607, 337 intervention, 270 comparator)
Nodule volume reduction of 50% or more in 83% of patients vs 44% of patients receiving cyst aspiration after 1–24 months of follow-up
78% of patients reported improvement in neck compression symptoms after 6–12 months vs. 38% of those in comparator groups
26% of patients reported slight to moderate pain vs 12% of those receiving cyst aspiration only
Laser photocoagulation)/ T4
(2 trials, 50)
After 12 months of follow-up, one study showed a nodule volume reduction of 50% or more in 33% of laser photocoagulation patients vs 0% of T4 patients
Laser photocoagulation(5 trials, n=192, 101 intervention, 91 comparator) 82% of laser photocoagulation patients showed improvements in pressure symptoms after 6–12 months vs. 0% of untreated patients
About 20% of laser photocoagulation-treated patients reported light-to-moderate cervical pain for 48+ hours following treatment
Radiofrequency  ablation
(2 trials; n=70, 50 intervention, 20 comparator
Among radiofrequency patients at 6-month follow-up, mean nodule volume reduction was 76% vs 0% for those untreated; the radiofrequency patients also had fewer pressure symptoms and cosmetic complaints after 12 months of follow-up

Source: Bandeira-Echtler et al. 201457

Studies have attempted to demonstrate the difference in cancer prevalence between single thyroid nodules and MNGs. A systematic analysis of 14 trials found lower prevalence of differentiated thyroid cancer in MNGs of 16.4%, compared with 23.1% among single nodules.58 In a mildly iodine-deficient area (mid/southern Italy) the prevalence of cancer was 20.1% overall, and higher in single nodules (23.1%) than in MNGs (14.4%). By phenotype, single nodules harbored the follicular thyroid cancer phenotype more than twice as frequently as MNGs did (33% vs. 13%).59 For further information about thyroid cancer please refer to the Cancers and Neoplasias Chapter.

In the past two decades, the frequency of thyroid surgery has increased, leading to a debate about how the increase in volume has affected outcomes. For example, Misiakos and colleagues conducted a retrospective analysis of patients age 18-89 years, who underwent thyroid surgery during 1995-1999 (phase 1) and 2000-2005 (phase 2) and found a trend toward increased morbidity during the second phase of the study. In the first phase, 5% had hypocalcemia and 4% had some degree of vocal cord paralysis vs. 8% and 5% in the second phase.60

Table 13 presents data based on the 2003-2009 Nationwide Inpatient Sample showing the effect of factors that have been found to affect the rate of postoperative complications.61 First, surgeon volume defined as number of thyroidectomies performed per year (i.e. low (fewer than 100 per year) or high (100 or more per year). Second, hospital volume or number of thyroidectomies taking place in a given hospital per year (i.e. low (fewer than 42) or high (42 or more)). In addition, the study analyzed the relationship between hospital region and patient demographics.

Table 13. Effect of surgeon volume, hospital volume, race, and household income on the rate of postoperative complications after thyroid procedures, 2003–2009.
WEIGHTED % OF DISCHARGE RECORDS (n= 62,722) POSTOPERATIVE COMPLICATION AMONG PATIENTS PRESENTING COMPLICATIONS (n=10,257) POSTOPERATIVE COMPLICATION AMONG ALL PATIENTS (n=62,722)
SURGEON VOLUME
Low 90.8% 55.4% 17.2%
High 9.2% 3.5% 12.1%
HOSPITAL VOLUME
Low 77.4% 17.7%
High 22.6% 15.1%
RACE
White 71.7% 71.4%
Black 11.5% 12.0%
Hispanic 8.5% 9.2%
Other 8.4% 7.4%
HOUSEHOLD INCOME
<$39,000 20.0% 22.0%
$39,000–$47,999 23.2% 23.5%
$48,000–$62,999 25.1% 25.4%
>$62,999 31.8% 29.1%

Source: Hauch et al. 201462

Table 14 provides data specific to the effect of surgeon volume on in-hospital mortality, postoperative complication, length of stay, and hospital charges derived through a retrospective, cross-sectional analysis of all 2003-2009 discharge information according to the Nationwide Inpatient Sample. This study further characterized surgeon volume as low (fewer than 10 surgeries per year), intermediate (10–99 surgeries per year), and high (100 or more surgeries per year). Interestingly, 57.9% of the procedures were total thyroidectomies for benign conditions, which comprised 60.8% of the total number of thyroidectomies.

Table 14. Effect of surgeon volume on mortality, postoperative complications, length of stay, and hospital charges, for 8 primary thyroid surgical procedures 2003–2009.
IN-HOSPITAL MORTALITY POSTOPERATIVE COMPLICATIONS LENGTH OF STAY >75th PERCENTILE HOSPITAL CHARGES >75th PERCENTILE
SURGEON VOLUME
Low 1.0% 17.7% 29.1% 32.3%
Intermediate 0.1% 14.2% 14.2% 19.3%
High 0.1% 6.4% 7.4% 14.1%

Source: Noureldine et al. 201463

Table 15 presents the effects of ethnicity on a series of variables based on 106,314 procedures, including both thyroidectomies and parathyroidectomies.63

Table 15. Ethnicity-based differences in number of procedures, surgeon volume, overall complications, length of stay and in-hospital mortality, 2003–2009.
PROPORTION OF TOTAL PROCEDURES SURGEON VOLUME OVERALL COMPLICATIONS LENGTH OF STAY (MEAN) IN-HOSPITAL MORTALITY
LOW INTERMEDIATE HIGH
Caucasian 54% 32% 49% 19% 11% 2 days 0.3%
African American 11% 39% 45% 16% 16.8% 4 days 0.8%
Hispanic 7% 38% 50% 13% 13.5% 3 days 0.4%
Asian 3% 24% 51% 24% 12% 2 days 0.5%
Other or Unknown 25% 33% 49% 18% 11.5% 2 days 0.3%

Note: Data is based on the overall number of thyroidectomies and parathyroidectomies.

Source: Noureldine et al. 201463

Table 16 presents data from a retrospective review of over 1000 thyroidectomies in which the length of hospital stay was less than 24 hours (i.e., “outpatient” by Medicare terminology); this analysis shows that, in the hands of an experienced surgeon, outpatient thyroidectomy is safe and reasonable. In addition, a comparative cross-sectional analysis of all cases of thyroid surgery reported in the 2006 National Survey of Ambulatory Surgery and 1996-2006 Nationwide Inpatient Sample not only shows an increase in the total number of thyroidectomies (66,684 in 1996 vs. 92,931 in 2006), but a significant increase of outpatient vs. inpatient procedures. Similarly, this study shows lower per capita charges associated with outpatient procedures as opposed to the inpatient counterpart (Table 17).22

Table 16. Outpatient thyroidectomy (stay in hospital <24 hours) – related complications.
PERCENTAGE OF COMPLICATION AMONG DISCHARGED PATIENTS (n=122)
Symptomatic hypocalcemias 5.2%
Transient recurrent laryngeal nerve injuries 3.7%
Permanent recurrent laryngeal nerve injuries 0.4%
Hematomas 0.19%
Readmissions within 30 days 2.3%

Source: Snyder et al. 201064

Table 17. Increase in outpatient (stay in hospital < 24 hours) vs. inpatient procedures and associated per capita charges.
  OVERALL NUMBER OF PROCEDURES OUTPATIENT PROCEDURES INPATIENT PROCEDURES
PERCENTAGE INCREASE IN PROCEDURES (1996 VS. 2006) 39% 61% 30%
PER CAPITA CHARGES, 2006  – $7,222 $22,537

Source: Sun et al. 201322

Using the 2011-2012 National Surgical Quality Improvement Program database, 8,185 patients who underwent thyroidectomy were identified in each treatment arm. Overall, inpatient thyroidectomy was associated with increased risks of readmission, reoperation, and any complication. The authors cautioned, however, that there are as-of-yet unknown risk factors that may resolve the discrepancy.65

In any thyroid surgery, common comorbidities can have a significant affect. A retrospective cohort study using data from the American College of Surgeons National Surgical Quality Improvement Program from 38,577 thyroidectomy patients between 2005-2010, showed 30-day mortality of 0.06% and 1.49% postoperative morbidity. The risk factors associated with morbidity included hypertension, diabetes, age older than 70 years, malignant thyroid disease, and total as opposed to partial thyroidectomy. Significant predictors of mortality were substernal thyroidectomy, hypertension, diabetes, and age older than 70 years.66

A 20-year review of case histories of patients who had thyroid surgery reported that 20% of patients  developed hyperthyroidism caused by the appearance of hyper-functioning nodules 6-18 years after the initial diagnosis.67 Health outcomes data related to toxicity caused by the presence of nodules will be discussed in the hyperthyroidism section of this chapter.

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