Work Up & Evaluation of Thyroid Nodules In 2013: State of The Art BC Surgical Oncology Network, Fall Update Todd McMullen MD PhD FRCSC FACS Endocrine Surgeon Divisions of General Surgery and Oncology Director, Division of Surgical Oncology
Learning Objectives Defining the incidence of thyroid nodules Risk factors for malignancy The role of U/S in predicting malignancy The role of FNA and cytology in predicting malignancy Molecular testing in thyroid disease No disclosures
SEER Database Overall Prevalence of Thyroid Cancer
SEER Database Subtypes of Thyroid Cancer
A Sea of Nodules 8806 patients with 11618 thyroid ultrasounds - 56% had thyroid nodules (2013) German Papillon study - 90 000 people using 7.5 MHz scanners revealed thyroid nodules in 33% of the population (2005) Using a 13 MHz scanner 650 patients, 68% had nodules (2009) 1968 Vander et al., incidence of thyroid nodules about 5% of population In the US Surgical Community (2006-2011) Use of thyroid FNA more than doubled (16% annual growth) Number of thyroid operations increased by 31%. Total thyroidectomies increased by 12%/year Nieuwenhuis et al., 2013; Guth et al., 2009; Sosa et al., 2013
Special Patients Thyroid cancer is 4X more likely in patients with familial adenopolyposis (FAP) compared to general population Patients with PTEN mutations and hamartoma tumour syndrome have a 30+% risk of thyroid cancer - females>males Radiation is a clear risk: Bhatia et al. estimated the cumulative incidence of thyroid cancer to be 4.4% at 30 years after childhood treatment for Hodgkin lymphoma. Family history is also an important factor predicting risk and severity Schonfeld et al., 2012; Nieuwenhuis et al., 2013; Carpi et al., 2012; Septer S, et al., 2013 6
What is/is not Linked to Malignancy Smoking (HR= 0.5) Obesity (HR = 1.7) Benign disease (F, HR = 2.5; M, HR = 4.5) Age Reproductive status Diet Thyroiditis Meinhold et al. 2010; Agate et al. 2012; Kabat et al. 2012; Janovic et al. 2013
Radiation-Induced Risk of Thyroid Cancer Risk is strongest for infants Dental X-rays - the link is weak for normal exposure (1/year)
Familial Risk of Thyroid Cancer Compared to sporadic cancers, familial non-medullary thryoid cancer (FNMTC): - tends to present at a younger age - multicentricity (48% vs. 22%, p=0.01) - lymph nodes (22% vs. 11%, p=0.02) - local invasion (5.4% vs. 0.6%, p=0.007) - higher recurrence rate (24% vs. 12%, p=0.03) 15 families with 2 or more thyroid cancers followed prospectively; 70 yo 90% had nodules, at 20 yo 20% had nodules. In FNMTC, first-degree relatives 10 years or older, including the generation anterior to the index case, should have thyroid screening Meinhold et al., 2010; Mazeh et al., 2013; Kabat et al., 2012; Janovic et al., 2013;Sadowski 2013
From: Establishing a Familial Basis for Papillary Thyroid Carcinoma Using the Utah Population Database JAMA Otolaryngol Head Neck Surg. 2013;():-. doi:10.1001/jamaoto.2013.4987 Figure Legend: Risk of Papillary Thyroid Carcinoma in Relatives of Probands
Other triggers for investigation FDG-avid lesions on PET scans present 2-5X risk compared to non-avid lesions (meta-analysis 34 studies >200 000 patients) Pooled risk of malignancy was 36% Depends also on intensity increasing SUV more likely Much more likely if focal uptake Uptake on MIBG and octreotide scans also indicate increased risk Voice change is sensitive for invasive malignancy (Present in 70% of invasive cases). Approximately 3-6% of all cancer represent disease with nerve/tracheal involvement Treglia et al., 2013; Randolph et al., 2006;
Ultrasound Do it Yourself Can ultrasound identify a patient at risk of thyroid cancer? Bastin et al., J Med Imag and Rad Onc (2009)
Ultrasound The Details 9000 patients over 5 years Size: 2+cm nodule 3X more likely to be malignant than nodule <1 cm Smith-Bindman R, et al., JAMA Intern Med. 2013
Ultrasound The Reality Number of Reported Features 0 141 1 103 2 66 3 19 4 2 5 2 6 3 Number of Cases N=336 Percentage of all cases
Ultrasound The Reality Ultrasound Feature Frequency of Reporting (%) Confirmed Cases of Cancer (%) P value Microcalcifications 24 77 0.002 Solid 40 48 0.008 Irregular margin 14 37 0.002 Hypoechoic 36 24 0.18 Intranodular vascularity 11 33 0.97 Absent halo sign 5 20 0.59
Fine Needle Aspirate (FNA) U/S guided biopsy 5X less likely to miss than by palpation May consider thyroid scan first if TSH suppressed Do not biopsy more than 2 nodules Nodules over 4 cm may need surgery due to FN rate* U/S guided biopsy the role of the pathologist 2% of patients evaluated by a pathologist had a non-diagnostic result 16% of patients had non-diagnostic result if lacking on-site evaluation 40%+ non-diagnostic rate if cystic lesion Cytopathologic evaluation of FNA specimens is cost-effective Simsek et al. 2013; Nasuti et al., 2002
Biopsy Technique: To Aspirate or Not? A combination of capillary and aspiration samplings achieves better diagnostic yields. For cystic nodules - second, after aspiration of the cystic contents of the nodule and exchange of the fluidfilled syringe, US-FNA of the small solid portion of the nodule was performed. Non-diagnostic readings for the core needle biopsies were lower than repeat FNAs (1.6% v 28.1%, p<0.001). AUS/FLUS for core needle biopsies were also lower than that for repeat FNAs (23.6% vs. 39.8%, p<0.001). Krishnappa et al., 2012 Na DG et al. Thyroid 2012
Who Gets a Biopsy? Biopsy 0 to 1.5 cm. May or may not use thyroid scanning. Increasing nodule size impacts cancer risk increasing risk up to 2.0 cm but larger nodules have increased risk of follicular carcinomas The false negative rate of benign nodules >4 cm is 10% (no suspicious U/S features). Kamran SC et al., 2013; Wharry LI et al., 2013
Bethesda Criteria Currently in Edmonton 75% of reports Ali, S. Acta cytologica (2010)
Bethesda Criteria: Since 2008 The new AUS/FLUS category was used more often than recommended (14%) with a higher than expected rate of malignancy (20%). (Broome JT et al. 2011) The BSRTC resulted in more frequent repeat FNAB, fewer thyroidectomies. (Chen JC et al. 2012 ) The fraction of cases suspicious for follicular neoplasm increased from 6.1 to 7.4% (p = 0.0002); surgical follow-up rate increased from 55 to 61% (p < 0.00001), and the histological malignancy rate increased from 22 to 28% (p = 0.03) (Boonaarunnate et al. 2013) Recommendations for repeat FNA (AUS/FLUS) results are cost-effective. (Heller M et al. 2012)
A Second Biopsy or a Second Pathologist? 3885 thyroid cytological samples reviewed over 4 years The BSRTC classification changed 32% of the time Indeterminate rate went down 38% to 28% (P <.000001) Specimens with low cellularity and Hashimoto s thyroiditis most likely to change. Olson MT, JCEM 2013
Molecular Testing in Thyroid Investigations Molecular and IHC markers of malignancy are actively pursued for cytologic testing >3000 articles examining cancer signatures > 25 randomized trials examining mrna and IHC markers of cancer FNA is suitable for IHC and mrna analysis (all you need is ng of tissue) Best studied / accepted - IHC marker for galectin 3 may predict PTC (Bartolazzi., 2008) - BRAF, RAS and RET/PTC mutations - Veracyte mrna analysis - used to define low risk nodules Nikiforov YE et al. 2012; Alexander et al., 2012
Molecular Testing in Thyroid Investigations. N=1056 Nikiforov YE et al. 2011
2011 by Endocrine Society Technology Makes Life Better?
Technology Makes Life Better? Veracyte Testing benign nodules John Hopkins School of Public Health
If it is benign No strong evidence for any follow-up regime Latest guidelines and cohort studies: - If see everyone at least 2X to follow natural history - Reassess in 6-18 months depending on age/duration goiter - Thyroid nodules diagnosed as benign on FNA; if confirmed on repeat aspiration, 98% benign - If grows more than 20% by volume - retest Oertel YC et al., 2007; Gharib et al. 2010
New Paradigms? All U/S should be with 12MHz probe Larger nodules may represent increased risk malignancy Biopsy at 1 or 2 nodules based on i) U/S and ii) size 2 nd review for all FLUS/AUS pathology reports Genetic testing for biopsies defined as FLUS/AUS? BRAF to predict nodal metastases? Which test? You decide. (Cost of Veracyte test $4000)
Thanks to Chrystal and Sam and the BCCA! Questions? Winter Fun!