Thyroid Nodules & Cancer Ronen Gurfinkel, PGY4 February 8, 2012

Objectives To review the presentation, investigation and treatment of thyroid nodules To review most recent clinical practice guidelines for thyroid nodules American Thyroid Association (ATA) Guidelines 2009

Background Thyroid nodule Incidentaloma Discrete lesion within the thyroid gland Radiologically distinct from surrounding thyroid parenchyma Incidentaloma Nonpalpable nodules detected on ultrasound or other imaging study Have same risk of malignancy as palpable nodules of same size

Epidemiology Thyroid nodules are very common Palpable nodules 5% of women 1% of men Ultrasound series 19-67% Autopsy series 37-57% The prevalence of nodules increases with age Prevalence in women 1.5-1.7 times higher than men

Epidemiology Prevalence of thyroid nodule by age Age (years) Women (%) 18-25 7.6 4.5 26-30 10.5 6.9 31-35 12.6 8.4 36-40 16.7 9.6 41-45 19.0 11.9 45-50 21.2 13.5 51-55 24.5 15.2 56-65 26.9 17.5

Thyroid Nodules Why do we care? Cosmetic

Thyroid Nodules

Thyroid Nodules Why do we care? Cosmetic Obstruction

Thyroid Nodules This young woman had a rapidly growing left thyroid nodule that compressed her trachea and displaced it to the opposite side.  She also had mild dysphagia.  She had a left hemithyroidectomy.

Thyroid Nodules Why do we care? Cosmetic Obstruction Thyroid cancer

Thyroid Cancer Thyroid cancer occurs in 5-15% of thyroid nodules, and rate depends on risk factors Types of thyroid cancer Differentiated Papillary Follicular Medullary Anaplastic Incidence of thyroid cancer is increasing 1973: 3.6 per 100,000 2009: 8.7 per 100,000 Rise in incidence mostly attributed to papillary thyroid cancer and tumours < 2cm in size

Thyroid Cancer Risk factors Age Sex History of thyroid irradiation Thyroid nodules in children are twice as likely to be malignant In adults, higher rate of malignancy if age > 60 Sex Malignancy rate 2x higher in men as compared to women (8% versus 4%) History of thyroid irradiation ~25% have thyroid nodules ~33% have of nodules are malignant No evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers

Thyroid Cancer Risk factors Size > 4cm Family history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid cancer (MTC) Growing nodule Firm or hard nodule consistency Fixed nodule Cervical lymphadenopathy Persistent hoarseness, dysphonia, dysphagia, dyspnea

Thyroid Nodules - Causes BENIGN (95%) MALIGNANT (5%) Multinodular (sporadic) goitre Papillary carcinoma Hashimoto’s (chronic lymphocytic thyroiditis) Follicular carcinoma Cysts: colloid, simple, or hemorrhagic Minimally or widely invasive Follicular adenomas Hurthle-cell (oxyphilic) type Macrofollicular adenomas Medullary carcinoma Microfollicular or cellular adenomas Anaplastic carcinoma Hurthle-cell (oxyphil-cell) adenomas Primary thyroid lymphoma Macro- or microfollicular patterns Metastatic carcinoma (breast, renal cell, lung, others)

Thyroid Cancer

Thyroid Cancer Prognosis Papillary thyroid carcinoma 30-year survival 95% Follicular thyroid carcinoma 30-year survival 85% Medullary thyroid carcinoma 10-year survival 65% Anaplastic thyroid carcinoma 5-year survival 5% Median survival is 8.1 months

Presentation How do patients with thyroid nodules present? Nodule noted by patient Nodule noted on routine physical Nodule discovered incidentally on imaging Carotid doppler U/S Neck CT 18FDG-PET scan Etc Obstructive symptoms

Evaluation Who should be evaluated? Nodules > 1cm Occasionally, nodules < 1cm Diffuse or focal uptake on 18FDG-PET scan

Evaluation History & Physical TSH Ultrasound Fine-needle aspiration (FNA)

Evaluation Complete history Symptoms of hyperthyroidism Risk factors for malignancy Childhood head and neck irradiation Exposure to ionizing radiation from fallout in childhood or adolescence Family history of thyroid carcinoma or thyroid cancer syndrome in first-degree relative Rapid growth Hoarseness, dysphagia, stridor

Evaluation Physical examination Thyroid gland Size of gland, goitre Does this Patient Have a Goiter? – JAMA 1995 “Goiter ruled out”: normal size on palpation, not visible with neck extended “Goiter ruled in”: large goiter on palpation or lateral prominence > 2 mm “Inconclusive”: all other findings Nodule number, size, consistency, mobility Adjacent cervical lymph nodes Pemberton’s sign

Lateral Thyroid Prominence

A, Enlarged left lobe of the thyroid. A, Enlarged left lobe of the thyroid. B, Marked facial plethora after elevation of both of the patient’s arms. Jukić T , Kusić Z JCEM 2010;95:4175-4175 ©2010 by Endocrine Society

Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg) Serum calcitonin

Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg) If low  radionuclide thyroid scan Either 123I or 99mTc pertechnetate Otherwise  Further evaluation for possible FNA TSH level correlates to risk of thyroid cancer Serum thyroglobulin (Tg) Serum calcitonin

Prevalence of thyroid cancer (%) Thyroid Cancer and TSH TSH (mU/L) Prevalence of thyroid cancer (%) < 0.4 2.8% 0.4 – 0.9 3.7% 1.0 – 1.7 8.4% 1.8 – 5.5 12.3% > 5.5 29.7%

Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg) Can be elevated in most thyroid diseases Insensitive and nonspecific test for thyroid cancer Not recommended as part of the initial evaluation Serum calcitonin

Investigations Laboratory tests Serum TSH Serum thyroglobulin (Tg) Serum calcitonin Evaluated in prospective, nonrandomized studies Screening with calcitonin may detect MTC at an earlier stage (likely present if level > 100 pg/mL) But also detects C-cell hyperplasia and micromedullary carcinoma (clinical significance uncertain) Cannot recommend either for or against routine measurement

Investigations Ultrasound Should be performed in all patients with: Suspected thyroid nodule Nodular goitre Nodule found on other imaging modality

Thyroid Cancer and Ultrasound High Risk Features Low Risk Features Hypoechoic Increased central vascularity Incomplete halo Microcalcifications Irregular borders Taller than wide (transverse view) Suspicious lymph nodes Hyperechoic Peripheral vascularity Complete Halo Comet-tail Large, coarse calcifications

Central Vascularity

Microcalcifications

Irregular Borders

Taller Than Wide

Comet-tail Artifact

Investigations Radionuclide scan If TSH low, 123I or 99mTc pertechnetate should be obtained Hyperfunctioning (hot) nodules are rarely malignant

Investigations Fine-needle aspiration (FNA) Most accurate and cost effective method for evaluating thyroid nodules Sensitivity 76-98%, specificity 71-100% Prior to FNA, only 15% of resected nodules were malignant With FNA, malignancy rate of resected nodules > 50% False positive and non-diagnostic cytology rates lowered with US guidance Non-palpable Posterior location Predominantly cystic

Figure 7a.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. Figure 7a.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. This positioning helps maximize the number of needle-generated reflected echoes perpendicular to the sound wave and is preferred by many operators. (a) Diagram shows insertion of the needle in a plane parallel to that of scanning. (b) US image, obtained with the transducer and needle positioned as in a, depicts the entire length of the needle (arrows) within the nodule. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Figure 7b.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. Figure 7b.  Parallel positioning of the fine-gauge needle for thyroid nodule biopsy. This positioning helps maximize the number of needle-generated reflected echoes perpendicular to the sound wave and is preferred by many operators. (a) Diagram shows insertion of the needle in a plane parallel to that of scanning. (b) US image, obtained with the transducer and needle positioned as in a, depicts the entire length of the needle (arrows) within the nodule. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Figure 8a.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. Figure 8a.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. (a) Diagram shows insertion of the needle in a plane perpendicular to that of scanning. A shorter needle may be used with this option, and it is less likely that the carotid artery or jugular vein may be punctured. (b) US image, obtained as the needle crossed from the skin entry site through the tissues of the neck and into the nodule, shows only the needle tip (arrow) where it intersected with the scanning plane. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Figure 8b.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. Figure 8b.  Perpendicular positioning of the fine-gauge needle for thyroid nodule biopsy. (a) Diagram shows insertion of the needle in a plane perpendicular to that of scanning. A shorter needle may be used with this option, and it is less likely that the carotid artery or jugular vein may be punctured. (b) US image, obtained as the needle crossed from the skin entry site through the tissues of the neck and into the nodule, shows only the needle tip (arrow) where it intersected with the scanning plane. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Figure 9a.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. Figure 9a.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. In aspiration, the needle tip is advanced into various positions in the nodule and moved to and fro while suction is performed (arrow in a). Suction is halted before the needle is removed from the lesion. This procedure is repeated at least five times before the needle is finally withdrawn. In nonaspiration (capillary action), the needle is advanced into the nodule and vigorously moved to and fro while being rotated on its axis until a small amount of cellular material collects inside the needle hub. No suction is performed. This technique is useful in very hypervascular nodules, in which there is a high probability of obtaining a bloodstained specimen that is inadequate for accurate cytologic analysis. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Figure 9b.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. Figure 9b.  Aspiration (a) and nonaspiration (b) techniques for needle biopsy of thyroid nodules. In aspiration, the needle tip is advanced into various positions in the nodule and moved to and fro while suction is performed (arrow in a). Suction is halted before the needle is removed from the lesion. This procedure is repeated at least five times before the needle is finally withdrawn. In nonaspiration (capillary action), the needle is advanced into the nodule and vigorously moved to and fro while being rotated on its axis until a small amount of cellular material collects inside the needle hub. No suction is performed. This technique is useful in very hypervascular nodules, in which there is a high probability of obtaining a bloodstained specimen that is inadequate for accurate cytologic analysis. Kim M J et al. Radiographics 2008;28:1869-1886 ©2008 by Radiological Society of North America

Investigations Fine-needle aspiration Complications Local pain Bleeding or hematoma Infection Vasovagal reaction

Fine-needle Aspiration

Fine-needle Aspiration Purely cystic nodule Any size  No FNA Abnormal cervical lymph nodes Any size  FNA

Fine-needle Aspiration High-risk history > 5mm  FNA Microcalcifications > 1cm  FNA

Fine-needle Aspiration Solid nodule Hypoechoic >1cm  FNA Isoechoic or hyperechoic >1-1.5cm  FNA

Fine-needle Aspiration Mixed cystic-solid Suspicious ultrasound features > 1.5-2cm  FNA No suspicious sonographic features > 2cm  FNA Spongiform nodule

Investigations

Pathology FNA results Historically, FNA cytopathology reports were quite variable In 2007, Bethesda System for Reporting Thyroid Cytopathology was created Recommended the use of 6 general categories Each category associated with a risk of malignancy and linked to a management recommendation

Pathology Bethesda System Categories Nondiagnostic or Unsatisfactory Benign Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) Follicular Neoplasm or Suspicious for a Follicular Neoplasm Suspicious for Malignancy Malignant

Pathology Bethesda System Categories Sample is adequate if: Not obscured (blood, air drying, thick smears, etc) At least 6 groups of benign follicular cells Each group composed of at least 10 cells Above criteria present in at least 2 aspirates Exceptions: Abundant colloid  benign Any atypia Specific diagnosis can be made (eg lymphocytic thyroiditis)

Pathology Bethesda System Categories Nondiagnostic or Unsatisfactory Cyst fluid only Sonographic correlation required to determine malignancy risk Virtually acellular specimen Other Obscurring blood Cloting artifact

Pathology Bethesda System Categories Benign Consistent with a benign follicular nodule Hyperplastic/Adenomatoid nodule Colloid nodule Consistent with lymphocytic (Hashimoto’s) thyroiditis in the proper clinical context Consistent with granulomatous (subacute) thyroiditis Other

Pathology Bethesda System Categories Atypia of Undetermined Significance (AUS) or Follicular Lesion of Undetermined Significance (FLUS) For FNAs that do not easily fit into one of the other categories e.g. prominent population of microfollicles, but not sufficient for diagnosis of follicular neoplasm

Pathology Bethesda System Categories Follicular Neoplasm or Suspicious for a Follicular Neoplasm Follicular carcinomas and adenomas have similar cytomorphologic features Specify if Hürthle neoplasm Considered variant of follicular adenoma or carcinoma by WHO

Pathology Bethesda System Categories Suspicious for Malignancy Used if a malignant diagnosis cannot be made with certainty Suspicious for papillary carcinoma Only 1 or 2 characteristics of papillary carcinoma Abnormalities are focal Sample is sparsely cellular Suspicious for medullary carcinoma Suspicious for metastatic carcinoma Suspicious for lymphoma

Pathology Bethesda System Categories Malignant Papillary thyroid carcinoma Poorly differentiated carcinoma Medullary thyroid carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Carcinoma with mixed features (specify) Metastatic carcinoma Non-Hodgkin lymphoma Other

Pathology Diagnostic Category % of FNAs Nondiagnostic or Unsatisfactory 2-20 Benign 60-70 Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance 3-6 Follicular Neoplasm or Suspicious for a Follicular Neoplasm 5-11 Suspicious for Malignancy 1-7 Malignant 3-7

Pathology

Management

Management Nondiagnostic or Unsatisfactory Repeat FNA with ultrasound guidance Satisfactory specimen in 75% of solid nodules Satisfactory specimen in 50% of cystic nodules On-site cytologic evaluation may improve yield 7% of nodules continue to be nondiagnostic (and may still be malignant) Close observation or surgery (particularly if nodule is solid) is recommended

Management Malignant or Suspicious for malignancy Surgery Malignant: total thyroidectomy Suspicious for malignancy: total thyroidectomy or lobectomy

Management Follicular Neoplasm (not Hürthle cell) Malignancy risk 15-30% If TSH is in low-normal range, can consider 123I thyroid scan If no autonomously functioning nodule seen, lobectomy or total thyroidectomy should be considered Hürthle cell Neoplasm No need for 123I thyroid scan Lobectomy or total thyroidectomy (depending on other risk factors)

Management Benign Immediate diagnostic studies or treatment are not routinely required Follow-up is required Low, but not negligible false-negative rate (up to 5%), especially with larger nodules (greater than 4cm) Repeat US recommended at 6-18 months after initial FNA If nodule is stable in size (<50% increase in volume or <20% increase in 2 dimensions), can increase interval of follow-up If evidence of nodule growth present (>50% increase in volume or >20% increase in 2 dimensions with minimal increase of 2mm) then FNA should be repeated

Management AUS or FLUS Malignancy risk 5-15% Diagnostic accuracy may be improved by considering clinical risk factors The use of 18FDG-PET is not recommended for or against to improve diagnostic accuracy In one study, sensitivity 57%, specificity 50% Can consider molecular markers to help guide management e.g. BRAF, RAS, RET/PTC, Pax8-PPAR-gamma, or galectin-3

Management Molecular markers Haugen et al (International Thyroid Congress, 2010) Developed a molecular classifier using approximately 200 genes Tested classifier to 66 initially indeterminate FNA samples that have underwent surgery and pathology review Sensitivity 95%, specificity 63%, NPV 96% Conclude that this can be used to reduce number of unnecessary surgeries Li et al (JCEM 2011) Created decision making model and used on a hypothetical group of adult patients Showed that using molecular test avoided ¾ of surgeries in indeterminate group and lowered cost of health care

Multiple Nodules Solitary nodules have higher malignancy risk than nonsolitary nodules Patients with multiple nodules have same risk of malignancy as those with solitary nodules Should aspirate nodules > 1cm with suspicious sonographic appearance If TSH is low or low-normal, can use thyroid scintigraphy to direct FNA to iso- or nonfunctioning nodules

Questions?