Thyroid Nodules and Cancer Netee Papneja, PGY5
Objectives • Review • Epidemiology of thyroid nodules/cancers • Approach to thyroid nodules • Newer evidence re: indications for biopsy • Molecular characterization of FNA results • Thyroid cancer guidelines
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 ATA guidelines 2009
Etiology of Benign Nodules • Focal thyroiditis • Benign adenomas – follicular and hurthle cell • Thyroid, parathyroid, thyroglossal cysts • Post surgical/radiation remnant hyperplasia • Rare: teratoma, lipoma, hemangioma
Thyroid Nodules • Thyroid cancer which occurs in 5–15% of nodules
Thyroid Cancer – Incidence • Incidence of thyroid cancer is increasing • 1973: 3.6 per 100,000 • 2009: 8.7 per 100,000 • However, mortality rates have stayed the same • ? due to actual increase in incidence or increased detection • Socioeconomic status and increased access to healthcare resources are associated with higher rates of papillary thyroid cancer (US, Canada)
Thyroid Cancer - Incidence • Aim: • examined whether the density of endocrinologists and general surgeons use of US were factors associated with increased incidence of thyroid cancer • Methods: • compared incidence data from SEER database (National Cancer Institute's Surveillance Epidemiology and End Results) from 1999 to 2009 with the density of endocrinologists and general surgeons Udelsman,R.&Zhang,Y.Theepidemicof thyroid cancer in the United States: the role of endocrinologists and ultrasounds. Thyroid http://dx.doi.org/10.1089/thy.2013.
Results: The incidence rates were significantly correlated with the density of endocrinologists (r=0.58, p<0.0001 for males; r=0.44, p=0.0031 for females) and the employment of cervical ultrasonography (r=0.40, p=0.0091 for males; r=0.36, p=0.0197 for females). • Conclusions: • ~ 50% of the DTC epidemic could be explained by ‘overdiagnosis’ • 50% - radiation exposure due to increased use of neck CT scans, chemical exposure and/or obesity Udelsman,R.&Zhang,Y.Theepidemicof thyroid cancer in the United States: the role of endocrinologists and ultrasounds. Thyroid http://dx.doi.org/10.1089/thy.2013.
Thyroid Cancer Risk Factors • Extremes of Age • 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 compared to women (8% vs 4%) • Family history • FHx of a thyroid cancer syndrome (eg, familial polyposis, Carney Complex, MEN type 2) • 10-fold increased risk of thyroid cancer in first degree relatives of thyroid cancer patients Uptodate: ‘’Overview of thyroid nodule formation’’
Thyroid Cancer Risk Factors Clinical signs — • rapid growth, fixation of the nodule to surrounding tissues, new onset hoarseness or vocal cord paralysis, or the presence of ipsilateral cervical lymphadenopathy • Radiation Explosure • most important RF = radiation exposure during childhood • ~25% have thyroid nodules • ~33% have malignant nodules • No evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers
Thyroid cancer risk factors • Radiation exposure - potential sources: • medical uses of radiation (eg, childhood malignancies) • atomic weapons (eg, Nagasaki/Hiroshima, Japan 1945), or nuclear power plant accidents (eg, Chernobyl 1986, Fukushima Daiichi nuclear disaster 2011) • ionizing radiation to treat benign conditions of the head and neck in 1950s
Investigations • Laboratory tests • Serum TSH • If low radionuclide thyroid scan • Either 123I or 99mTc pertechnetate • Otherwise Further evaluation for possible FNA • TSH level correlates to risk of thyroid cancer
Thyroid Cancer and TSH Boelaert K, Horacek J, Holder RL, et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab 2006; 91:4295.
Investigations • Laboratory tests • 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
Investigations • Serum calcitonin • 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) • ATA: Cannot recommend either for or against routine measurement • False-positive results: • hypercalcemia, hypergastrinemia, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, goiter, and chronic autoimmune thyroiditis • prolonged treatment with omeprazole (greater than two to four months), beta-blockers, and glucocorticoids
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
Investigations • Fine-needle aspiration (FNA) • Most accurate and cost effective • 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
ATA FNA Indications High-risk history: History of thyroid cancer in first degree relatives; external beam radiation as a child; exposure to ionizing radiation in childhood or adolescence; prior hemithyroidectomy with discovery of thyroid cancer, 18FDG avidity on PET scanning; MEN2=FMTC-associated RET protooncogene mutation, calcitonin >100 pg=mL. Suspicious features: microcalcifications; hypoechoic; increased nodular vascularity; infiltrative margins; taller than wide on transverse view.
Diagnostic Accuracy of the Ultrasonographic Features for Subcentimeter Thyroid Nodules Suggested by the Revised ATA GuidelinesKIM ET AL, THYROID, Volume 23, Number 12, September 2013 • Purpose: To analyze the diagnostic performance of the ATA guidelines and compared it to that of other modified guidelines. • Methods: • 713 nodules 6-10mm (Yonsei University , Korea) • Frequencies of US features in benign and malignant nodules were compared • Seven modified guidelines were made based on the revised ATA guidelines and from multi- variate analysis results
Modified guidelines • excluded ‘‘increased nodular vascularity’’ • included composition criteria and only solid nodules were considered • excluded the increased nodular vascularity and included solid • included macrocalcification • included macrocalcification and excluded ‘‘increased nodular vascularity’’ • included macrocalcification and only solids • Included macrocalcifications and excluded increased nodular vascularity
Results • Solid composition and macrocalcification were significantly associated with malignancy (p=0.001 and 0.003). • Increased vascularity was not significantly associated with malignant nodules (odds ratio 0.729, p = 0.212). • Among the eight guidelines, the ATA guidelines showed the lowest diagnostic performance (Az = 0.616). • Excluding increased vascuarity and including solid composition +/- macrocalcification to the suspicious US features of the ATA guidelines improved sensitivity (96.6% vs. 97.0%), specificity (26.6% vs. 42.9%), PPV (48.3% vs. 54.7%), and NPV (91.7% vs. 95.2%), thereby resulting in the highest Az value (diagnostic performance) (Az = 0.699, p < 0.001)
Conclusions: • This study suggests that excluding increased vascularity and adding solid composition to the suspicious ultrasonographic features of the ATA guidelines would significantly improve the diagnostic performance in subcentimeter nodules for the identification of malignant lesions.
Risk of Thyroid Cancer Based on Thyroid Ultrasound Imaging Characteristics • Results of a Population-Based Study Rebecca Smith-Bindman, MD; Paulette Lebda, MD; Vickie A. Feldstein, MD; Dorra Sellami, MD; Ruth B. Goldstein, MD; Natasha Brasic, MD; Chengshi Jin, PhD; John Kornak, PhD JAMA Intern Med. Published online August 26, 2013
Risk of Thyroid Cancer Based on Thyroid Ultrasound Imaging Characteristics • Retrospective case control study • 8,806 patients with 11,618 thyroid US at a UCSF facility from January 2000 - March 2005. • patients did not have a diagnosis of thyroid cancer at the time of US • They linked the patients with the California Cancer Registry and identified 105 who were diagnosed with thyroid cancer • The cancer patients were matched with a group of cancer-free control subjects from the same cohort, based on factors such as gender, age and the year of the ultrasound exam
Results: • Only 3 US nodule characteristics were associated with the risk of thyroid cancer— • microcalcifications (odds ratio [OR], 8.1; 95% CI, 3.8-17.3) • size greater than 2 cm (OR, 3.6; 95% CI, 1.7-7.6) • an entirely solid composition (OR, 4.0; 95% CI, 1.7-9.2) • 1 characteristic = sensitivity 88%, high false-positive rate 44%, a low positive likelihood ratio of 2.0 and 56 biopsies will be performed per cancer diagnosed. • 2 characteristics = sensitivity 52%, FPR 7%, the positive likelihood ratio (7.1), and only 16 biopsies performed per cancer diagnosed.
Conclusions: • Using only + microcalcifications or combination of both >2cm AND solid as indications for biopsy, estimated risk of cancer in those not biopsied is only ~0.5% • May reduce unnecessary biopsies by 90% • 20 year survival of DTC is >97% • Ongoing surveillance is unlikely to be beneficial as risk for cancer remains low at 10 years ** Doesn’t take into account lymphadenopathy, invasion beyond thyoird capsule, fHx of Thyroid cancer, or radiation history; was a retrospective study
Management of Indeterminate FNA • 10% to 40% of FNA specimens are cytologically indeterminate. • Indeterminate results = Follicular Lesion of Undetermined Significance (FLUS)/Atypia of Undetermined Significance (AUS) and (suspicious for) Hürthle/Follicular Neoplasm • Risk of malignancy: • FLUS/Atypia: 5-15% • Follicular Neoplasm: 15-30%
FNA – indeterminate results • 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) • 75 to 95 % of patients undergo surgery for what is ultimately confirmed to be benign • increased morbidity, operative risk, and excess cost
FNA – indeterminate results • Improvement in the assessment of indeterminate FNA results may allow better risk stratification • ATA: Recommendation C - Can consider molecular markers to help guide management • e.g. BRAF, RAS, RET/PTC, Pax8-PPAR-gamma, or galectin-3
Molecular Markers • Two approaches to the molecular characterization of FNA results that are commercially available in the United States: • identification of particular molecular markers of malignancy, such as BRAF and RAS mutational status • Use of high density genomic data for molecular classification (an FNA-trained mRNA classifier)
Veracyte Afirma Gene Classifier • GEC assesses gene expression from mRNA from needle washings during a standard FNA procedure • Gene expression is compared against 167 genes Veracyte has previously identified as characteristic of benign and malignant nodules • Reports the nodule as benign or suspicious • Intended as a rule-out test • Analysis most effective in identifying lesions with indeterminate cytology that are highly likely to be benign, therefore avoiding surgery THYROID. Volume 23, Number 2, 2013
Clinical Validity of the Afirma Gene Expression Classifier • A large, multi-center (49 sites - 35% academic / 65% community), prospective clinical validation study published in NEJM in 2012 • “Double-blind” design • patients and physicians blind to molecular result • Molecular lab blind to surgical pathology diagnosis and pathologists unaware of molecular results -Alexander EK, et al. Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology. N Engl J Med. 2012;367:705-715.
Afirma Gene Expression Classifier • Results: • For 265 cytologically indeterminate nodules • overall NPV was 93% • Sensitivity = 92% (7 of 85 cancers, 8%, were incorrectly identified as benign) • Specificity = 52% (48% of benign nodules were incorrectly identified as suspicious) • The risk of malignancy of a GEC benign result is comparable to that of nodule diagnosed as benign by cytopathology (1) 1. Wang CC et al. A Large Multicenter Correlation Study of Thyroid Nodule Cytopathology and Histopathology. Thyroid. 2011;21:243-251
Afirma GEC – Real life experience: • However, findings of study were obtained in a trial where protocol and enrollment are tightly managed. • Understanding how the Afirma GEC performs in a clinical setting remains unclear until recent study published Oct 2013 in JCEM by Erik K. Alexander
E. K. Alexander et al. Multicenter Clinical Experience with the Afirma Gene Expression Classifier. Journal of Clinical Endocrinology & Metabolism, 2013. • Methods: • analyzed all patients who had Afirma GEC testing at 5 academic centers between 2010 –2013. • 339 patients • Results analyzed for pooled test performance, impact on clinical care, and site-to-site variation
Results: • 148 Afirma GEC “Suspicious” • 141 of 148 (95%) surgery recommended • 121 of 148 (82%) surgery performed • Histopathology Malignant: 53 (44%)
174 Afirma GEC “Benign” • 4 of 174 surgery recommended (3 FLUS/1 SUS) • 11 of 174 (6%) surgery performed • Histopathology Malignant: 1/11 = 0.6cm PTC • Initial validation study: 38% indeterminate nodules were benign, however in this study 51% were benign GEC result • Afirma GEC testing after 1st study only recommended for AUS/ FLUS and/or FN cytology; not suspicious. • This study 96% cyto indeterminate samples were AUS/FLUS and/or FN explaining the increased proportion of benign GEC results.
Benign Afirma GEC results: • Only 71/ 174 patients (41%) had documented followup at a mean of 8.5 months following GEC testing • 10/71 – clinical exam followup • 61/71 – repeat US • 11/71 of these patients underwent thyroid surgery (personal preference or compressive symptoms) • 10/ 11 = benign histologically • 1/11 confirmed cancer (1.0cm US nodules which proved a 0.6cm PTC histologically) • Summary: 1/71 GEC benign proved cancerous
Clinical Impact: • 95% of Afirma GEC “suspicious” nodules were referred for thyroid surgery in comparison to only 2% of Afirma GEC “benign” nodules • in an academic clinical setting, a 76% reduction in surgery was observed when the Afirma GEC was applied to patients in whom surgery would otherwise have been typically performed
Results: • current standard of care practice: $12,172 per patient • Using GEC: $10,719 • cost savings due to: less surgeries • GEC test sensitivity was assumed to be 91% • This cost analysis states that only 1.4% of malignant nodules would be missed by the classifier
The Asuragen miRInform Molecular Panel • Panel of molecular tests used to to improve preoperative cytological diagnostic accuracy for indeterminate thyroid nodules • These markers are recommended by the ATA (recommendation rating of "C”) • A rule-in method that is designed to have a high predictive specificity; that is, a positive test is highly associated with malignant histology.