5/16/2018 AACE Pre-Congress Symposium Management of Benign Thyroid Nodules and Goiter

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1 5/16/2018 AACE Pre-Congress Symposium Management of Benign Thyroid Nodules and Goiter Stephanie L. Lee, MD, PhD Professor of Medicine Director, Thyroid Health Center Section of Endocrinology, Diabetes and Nutrition Boston Medical Center

2 Disclosures No relevant disclosures

3 To Discuss: Natural history of BENIGN nodules based on US, cytology or molecular signature Long term management to identify missed malignancy US features Growth Management of MNG beyond US and FNB Imaging Functional studies When to refer for surgery

4 PRACTICAL QUESTIONS ~50-75 million thyroid nodules 500,000 FNB/year 450,000 BENIGN nodules each year HOW DO YOU FOLLOW? % POPULATION Can we STOP surveillance of a nodule after: Benign cytology (One, Two or more biopsies)? Lack of Growth?( 1 year, 2 years, 5 years)? Indeterminate FNB and benign molecular test What do you do with multiple nodules (MNG) % POPULATION Haugen, et al. Thyroid 2016;26:1

5 Case 65 year old female with a palpable thyroid mass 2.5 cm and growing over the last 3 years No radiation history No FH of benign or malignant nodules TSH 1.2 uu/ml US:ATA suspicious (?) 70-90% risk of cancer FNA: Bethesda 2: BENIGN

6 Benign Cytology Has Low Risk of Malignancy Nondiagnostic Benign AUS/FLUS Follicular neoplasm Suspicious for malignancy Malignant 1-4% 0-3% 5-15% 15-30% 60 to 75% 97-99% Median 2.5% (Range 1-10%) Berman & Wartofsky NEJM 2015 False Negative Benign Cytology: 7 Studies with >250 Patients Bethesda System for Reporting Thyroid Cytopathology (2009) Cibas ES et al; AJCP; Gharib Endo Prac 2010;16:468 Berman&Wartofsky NEJM (2015), Chedade Endocrine Pract 2001; Orlandi Thyroid 2001; Oertel Thyroid 2007; Illouz Eur J Endocrinol 2007; Torre Acta Cytologica 2007; Durante JAMA 2005; Kwak Radiology 2010 Rosario Thyroid :1115; Flanagan Am J Clin Pathol 2006;125:698

7 Case With a Bethesda II BENIGN biopsy with a 1-3% false negative rate how should you follow? What is the natural history of a nodule with benign biopsy? Growth is defined as: >50% change in volume or >20% increase at least in two dimensions (minimum 2 mm) in a solid nodule or solid portion of a cystic nodule ATA Guidelines Nodules and Cancer (Cooper 2006 and 2009; Haugen 2016)

8 Growth of Nodules with Benign Cytology Kim: 854 cytologically benign nodules, 4 yr mean fu, mean 3 US Durante: 630 cytologically and 937 sonographically benign nodules in 992 pts, 5 yr fu, annual US exam Haddady 1078 cytology benign nodules, minimum 64 mo fu; avg time to growth 52 months 100% 80% 60% 40% 20% 0% Increase Stable Decrease Kim Durante Haddady Kim Radiology 2014;271:272; Durante JAMA 2015;313:926;Hadday 2015 AACE PP 22-1

9 Nodules and Growth WHICH DO NOT GROW? SMALL and LARGE nodules LESS likely to grow Nodules <1cm less likely to grow than nodules >1cm 3,5 Larger nodules >30mL (~4 cm sphere) less likely to grow 4 WHICH TEND TO GROW? Younger patients 3,5,6 Predominantly solid nodules 2,3 Multinodular glands 5 in low iodine areas Longer follow-up to detect growth 1,3,4,6 GROWTH NOT ASSOCIATED WITH CANCER in all studies Initial Volume (ml) 1 Alexander Ann Intern Med 2003;138:315; 2 Edrogan Clin Endocrinol 2006;65:767; 3 Kim Radiology 2014;271:272; 4 Puzziello J Endocrinol Invest 2014;37:1181; 5 Durante JAMA 2015;313:926, Hadddy AACE 2016

10 Growth is NOT Associated with Cancer Kim Radiology Cytology Benign GROWTH >50% volume 172 Kim Radiology 2014;271:272 1 cancer (0.6%) STABLE 1 cancer --Retrospective study --Mean volume 3.2cm 3 ~ 1.8 cm sphere --4 yr mean follow up --10 cancers/854: 1.1%

11 So our patient has probably 1-3% risk of cancer. If growth is NOT does not predict a MISSED cancer with a Bethesda II benign biopsy, what now?

12 Growth is NOT Associated with Cancer Kim Radiology Cytology Benign Retrospective study Mean volume 3.2cm 3 4 yr mean follow up 10 cancers/854: 1.1% GROWTH >50% volume 172 Suspicious initial US features 55 Kim Radiology 2014;271:272 1 cancer (0.6%) STABLE cancer (0.2%) 8 cancers (15%)

13 Suspicious US features on imaging are best indicator of missed malignancy...

14 Follow up after Bethesda II FNB R23: NEW ATA Recommendation 2015 EVICORE FOR NHP Follow-up of benign thyroid nodules after FNB: 1. Ultrasound (CPT 76536) 6 to 18 months after the initial FNA If nodule size is stable, follow-up ultrasound exam (CPT 76536) can be performed every 3 to 5 years. 2. If evidence of nodule growth, FNA with ultrasound guidance (CPT 76942) should be repeated No recommendations for nodules not biopsied (except < 1 cm) ATA Guidelines Nodules and Cancer (Haugen 2016)

15 Case This patient as an suspicious US appearance and BENIGN FNA Recommend repeat US and biopsy in 6 week-3 months (current recommendations indicate you can do immediate rebiopsy) ATA Guidelines Nodules and Cancer (Haugen 2016)

16 Case 1 Second biopsy: Bethesda 2 Benign Now what?????

17 R23 FU of Nodules with Benign Cytology NEW Recommendation 2015 Sonographic Pattern IF 2 nd US FNA done with benign cytology, repeat US for continued risk of malignancy is no longer indicated Strength of rec Strong Quality of evidence Moderate But personally, I would follow for growth at >18 months 2 years ATA Guidelines Nodules and Cancer (Haugen 2016)

18 Sonographically Benign Nodules Subcentimeter nodules- non-suspicious Spongiform nodule DO NOT MISTAKE MICROCALCs SPONGIFORM SPONGIFORM MICROCALCs

19 What Are Sonographically Benign Nodules? <1 cm in size without suspicious US features Subcentimeter nodules 5 year follow up of 852 nodules <1cm sonographically NONsuspicious (ABSENCE of hypoechogenicity, irregular margins, tall>wide shape, microcalcifications, vascularity) 1 cancer (0.1%) after 5 years diagnosed with new irregular margins and hypoechogenicity on follow up US and no growth Durante JAMA 2015;313:926;

20 Spongiform Nodules are BENIGN (10% of Thyroid Nodules) Moon: 1/52 (1.9%) PTC Bonavita: 0/210 PTC Kim: 0/117 PTC Virman 0/66 PTC Brito Meta-analysis LEE:1 cancer in 445 (0.2%) spongiform nodules 13 studies: 18,288 nodules; average size 15 mm Highest diagnostic Odds Ratio (OR) indicating benign Spongiform OR 12 (95% CI, ) Moon Radiology 2008;247:262; Bonavita AJR 2009;193; Kim AJNR Am J Neuroradiol 2010;31:1961; Virmani AJR 2011;196:891; Brito J Clin Endocrinol Metab 2014;99:1253

21 SONOGRAPHIC APPEARANCE R24 FU of nodules that have not had FNA NEW recommendation 2015 Strength of Rec Quality of Evidence Very low suspicion: <1 cm with no suspicious US <1cm: Do not require routine US surveillance Weak Low SPONGIFORM PURE CYST Routine biopsy is not recommended for all in this category Observation without FNA is a reasonable option

22 MOLECULAR MARKERS BENIGN... Cytologically indeterminate (AUS/FLUS or follicular neoplasm) with benign molecular testing What does this mean?

23 Molecular Tests Reporting NPV for Cytologically Indeterminate Nodules Affirma GSC (phase in August to Fall 2017 to Afirma GSC-improved hurthle detection) Validate with same data set as GEC Sensitivity 91%, Specificity 63% Suspicious : 49% malignancy ThyroSeq V.3 (changed in Fall 2017 improved hurthle detection) Detects 90% malignancies Sensitivity 98.0%, Specificity was 81.8%, Accuracy 90.9% ThyGenX/ThyroMIR: retrospective multicenter Rosetta GX Reveal : limited published data ALL 4 ASSAYS USE A DIFFERENT TECHNOLOGY Alexander NEJM (2012); Nishino Cancer Cyt (2016);Patel Abstract WCTC 2017 Nikiforov Cancer (2014);Nikiforov Thyroid (2015); Nishino Cancer Cyt (2016)

24 Molecular Benign Nodules QUESTIONS THAT STILL NEED TO BE ANSWERED We need more data in real practice with the new tests introduced Fall 2017 What is the cancer rate in indeterminate cytologies with negative molecular testing with long term FU? What is the clinical significance of the pathologies of missed cancers? Afirma and ThyroSeq misses said to be low risk PTCs

25 My Recommendations: Benign Thyroid Nodules NO F/UP Watch 2-3 years Watch CA@6-12 mo Repeat FNB Surgery <1 cm isoechoic or spongiform or cyst >1 cm spongiform or cyst or 2 Bethesda II FNB Bethesda II Initial or subsequent US suspicious feature Molecular marker negative Growing Bethesda II nodule XXX XXX XXX XXX XXX XXXX or XXX for growth

26 What If There Are Multiple Thyroid Nodules? 65 yo woman complaints of 10 years of right side neck enlargement and more recent difficulty swallowing solid foods with a MNG on exam

27 Laboratory Studies Determine thyroid function TSH level and treat if necessary Determine if thyroiditis is the cause of nodularity Thyroid autoantibodies (anti-tpo antibodies) or US Urinary Iodine for special conditions: Recent radiology studies using iodinated contrast dye Medication history of iodine containing medications Amiodarone, seaweed tablets, betadine washes Family history and history of recent immigration from regions of the world with iodine deficiency

28 Evaluation of MNG US evaluated nodules by guidelines Size measurement inaccurate in very large goiters If no nodules, no biopsy If all nodules are sonographically alike, TRANS biopsy the largest nodule Biopsy highest risk nodule, even if not the largest Determine if trach deviation & inferior margin of the goiter can be seen (r/o substernal goiter = thyroid extension inferior to the sternal notch)?? SAG TRANS Diffuse Goiter SAG SAG TRANS MNG: multiple isoechoic nodules 2-4 cm, biopsy of largest x2 negative, referred for surgery MNG: multiple confluent spongiform nodules indistinct margins

29 Clinical Manifestations of MNG Small goiters are asymptomatic With growth the patient may notice: Increase pressure on the trachea and esophagus especially with neck flexion (globus sensation) Cough, dyspnea on exertion and dysphagia depends on which structure is compressed by goiter TRACHEA Common carotid artery ESOPHAGUS Goiter compressing trachea and esophagus

30 Clinical Evaluation of MNG Clinical Scoring of Goiter Grade 0: Impalpable/invisible Grade 1a: Palpable but invisible even in full extension Grade 1b: Palpable in neutral position/visible in extension Grade 2: Visible but no palpation required to make diagnosis Grade 3: Visible at a distance MY ADDTION: Positional stridor MY ADDITION: Pemberton s sign MY ADDITION: SVC syndrome My ADDITION: Voice changes EVAL & SURGERY Wallace Ann Intern Med 125(1996)568

31 Cause of Pemberton s Sign: Indicates MNG Nearly Fills the Thoracic Inlet 2014 Garber s group reported the cause of Pemberton s sign Clavicle moves medially and inferiorly against the goiter in the thoracic inlet obstructing the external JV, IJV and subclavian vein confluence with SVC TRACHEA CLAVICLE TRACHEA THYROID CLAVICLE THYROID ARMS DOWN ARMS UP De Filippis JCEM 2014;99:1949

32 Superior Vena Cava Syndrome From Mediastinal Goiter MNG blocked venous return to SVC Distended external JV Blood returns from head enters chest via cutaneous vessels

33 Evaluation of Goiter with Scintigraphy Thyroid scintigraphy If TSH is suppressed To help determine which nodule(s) are cold to direct FNA Not to determine extent of goiter UNLESS with SPECT/CT (no contrast needed) Not routinely ordered Technetium-99m (99mTc) thyroid scan I-123 scan of toxic MNG

34 Evaluation of Goiter with PFTs Cross-sectional imaging (CT without contrast or MRI) Pulmonary function tests may be used as a functional assessment of dyspnea 59% of substernal goiter have respiratory symptoms 22% Orthopnea and 37% SOB 75.5% of positional SOB is associated with substernal goiter Highly associated with tracheal compression External tracheal compression can be detected in flow-volume loop tracings Exclude pulmonary disease cause of symptoms Shen Arch Surg 2004;139:656; Strang Arch Surg 2012;147:621.

35 Evaluation of Goiter with Esophagram Barium swallow if with significant CERVICAL dysphagia Solid and dry foods (bread and rice) compared to liquid Elderly may have presbyesophagus with tertiary contractions GERD/tracheo-esophagitis make sure sx are not pharyngeal 47% of substernal goiter have dysphagia and 1 yr after surgery 20% continues to have symptoms (p=<0.001) Goiter Tertiary contractions Spasm GERD/esophagitis Lombardi Surgery 2009;146:1174; Greenblatt, W J Surg 2009;33:255

36 CT Evaluation of Goiter Cross-sectional imaging (CT without contrast or MRI) Not for routine evaluation of MNG Evaluation of substernal component for risk of malignancy, nodes Extent of mediastinal goiter into mediastinum Extent of tracheal compression vs. deviation Extent of vascular compression Look for tracheomalacia in the largest goiter and tracheal compression (transient tracheal narrowing with inspiration) Examples of MNG Correlation with Symptoms Randolph Laryngoscope 2011;121:68

37 Back to our case 65 yo woman complaints of 10 years of right side neck enlargement and more recent difficulty swallowing solid foods with a MNG on exam

38 Our case: MNG Was Asymmetric: Tracheal Deviation Without Obstructive Symptoms >30 years of right sided thyroid enlargement. Right lobe: 9.4 (TR) x 7.4 (AP) ; left lobe: normal size thyroid with small spongiform nodules Right lobectomy recommended because of size and dysphagia

39 Substernal Goiter with Tracheal Deviation: Dysphagia to Solid Food Only A B C D AXIAL CT IMAGES Superior to inferior Thyroidectomy for dysphagia and mediastinal growth through cervical incision

40 Massive Substernal Goiter with DOE, Supine Stridor and Cough with Solid Dysphagia CORONAL CT SAG CT AXIAL CT Tracheal deviation and narrowing to 8 mm Resection by cervical incision

41 Critical Tracheal Obstruction 6-7 mm Trachea: Usually Inferior to the Thyroid Bed and Requires Surgery

42 Critical Tracheal Stenosis: Intrinsic Tracheal Stenosis Not from MNG

43 Direct Laryngoscopy Direct laryngoscopy can demonstrate tracheal compression Preoperatively in patients with voice symptoms or prior thyroid/neck surgery 45 yo with h/o bronchitis with acute respiratory arrest from secretions 4 mm tracheal narrowing Before Thyroidectomy After Thyroidectomy

44 Extension of MNG Between the Major Vessels of Thorax: Removed from Cervical Incision for Asthma

45 Substernal MNG Surrounding Carotid Arteries

46 Ectopic or Mediastinal Goiter Thyroid tissue separate from cervical thyroid gland in the anterior mediastinum Embryologic overshoot of thyroid during descent in the neck Often associated with MNG in the cervical thyroid Often a tract of fibrous tissue/thin thyroid tissue leads back to 1 lobe CT >100 Hounsfield units (higher than soft tissue neck) ; immediate enhancement after aortic enhancement with prolonged > 2 min enhancement after contrast Irwin et al Ann Intern Med 1978;89:73; Binder Et al J Compt Assist Tomogr 1980;4:550; Glazer et all. AJR 1982;138L495

47 Thyroid Tissue in Anterior Mediastinum Without Attachment to Right Thyroid Lobe: I-123 Scan With SPECT/CT: No surgery

48 Mediastinal Goiter 10 Years After Graves RAI RX Received 10 mci but never became hypothyroid. Mass found on CXR. No surgery

49 Treatment of Nontoxic Goiter If no clinical, sonographic, cytological suggestion of cancer, management depends on Presence and severity of symptoms Size Location of goiter Extent of compression (not deviation) of trachea Watch for growth development of hyperthyroidism Chen ATA Statement on Optimal Surgical Treatment of Goiter Thyroid 2014;24:181

50 Levothyroxine Treatment of Goiter Levothyroxine therapy Effectiveness is controversial Some favorable and some unfavorable results 7 nonrandomized trials of suppressive therapy for nontoxic goiters 60% of 722 patients had some decrease in goiter size Shrinkage occurred within the first 3 months Diffuse goiters responded better than discrete nodules. Significant risk of TSH suppression Increased risk of atrial fibrillation/angina/mi Adverse effect of bone density, especially in postmenopausal women Chen ATA Statement on Optimal Surgical Treatment of Goiter Thyroid 2014;24:181

51 I-131 Treatment of Nontoxic MNG Radioactive iodine Exclude the risk of malignancy Commonly treat toxic MNG Patients not clinically stable for surgery Several studies from Europe shows safe, effective Better goiter size reduction compared to L-T4 therapy Reduction in MNG by 40% after 1 year and 50-60% after 2-5 yrs Improvement of dyspnea and dypshagia Up to 45% become hypothyroidism Note the high dose of I-131 needed for goiter shrinkage up to 50-60% Usual dose hyperthyroid Graf EJE :2; Huysman Ann Int Med 1994;121:757

52 I-131 Treatment of Goiter 9 randomized controlled trials have shown rhtsh stimulated I-131 RX is more effective than I-131 alone NOT FDA approved in the US rhtsh 0.1 mg the day before RX increases uptake by 2x -4x Higher rhtsh dose may cause hyperthyroidism Usual cancer dose is 0.9 mg/day x 2 Allows more uniform uptake in MNG Decrease total administered dose Increased reduction in size by 2-6 fold than without rhtsh BEFORE AFTER rhtsh INJECTION FastClin Endocrinol 2010;72:411; Graf EJE 2015;172:2.

53 Surgical Treatment of Goiter Surgery Treatment of choice for large, obstructive, substernal nontoxic MNG, increased risk of malignancy and for cosmetic reasons Or minor or no symptoms and continued growth Near total or total thyroidectomy More common complication of hypopara and RLN damage with large sternal goiter and cervical goiter Refer to skilled high volume surgeon Complications for low volume surgeon( <25 /year) is higher than experience surgeon (OR 1.51;p=0.002) Preoperative laryngoscopy if voice symptoms or prior thyroid or anterior neck surgery Chen ATA Statement on Optimal Surgical Treatment of Goiter Thyroid 2014;24:181 Karlie et al Am J Surg 1985;149:283;Adam et al Ann Surg 2014;265:402;Maneck et al Chirug 2017;88:50;.

54 Surgery for Goiter Improves Dyspnea Tracheal compression in 13% of all benign MNG 97% with retrosternal goiter Dyspnea occur in 10-50% MNG that immediately resolves with surgery 76.6% noted marked improvement in snoring Improved dyspnea in 82% with substernal goiter and tracheal compression BUT if >100g goiter; improved dyspnea in 97% after thyroidectomy Narrowing <35% with 60% improvement with dyspnea Narrowing >35% with 98% improvement after surgery Normal cross-sectional area: mm 2 Find normal diameter in adjacent section ( r 2 = 226 mm 2 ) Tracheal compression approximate rectangle 2mmx 8 mm =16mm 2 =70.8% narrowed Chen ATA Statement on Optimal Surgical Treatment of Goiter Thyroid 2014;24:181; Strang Arch Surg 2012;147:621

55 My Recommendations: Benign Euthyroid MNG NO F/UP Watch years Watch mo Surgery Minimally enlarged diffuse goiter, <1cm isoechoic or spongiform nodules XXX Discrete low risk >1 cm nodules with negative FNB XXX Large goiter (sag >6 cm);no trach dev, no symptoms XXX Large goiter, trach deviation, below sternal notch CT and XXX Large goiter, trach narrowing >35% with compressive symptoms XXXX elective Large goiter with extensive substernal extension on CT XXX if medically safe Large goiter with critical narrowing <6-8 mm on CT XXX immediate

56 Summary: Benign Thyroid Nodule and Goiter Risk of cancer in cytologically benign nodules is 3-5% FU of cytology benign nodules Growth is NOT a risk for missed malignancy US features do NOT require FU for CANCER BUT YOU MAY FOLLOW FOR GROWTH Simple cysts >1cm nodules without US suspicious features SPONGIFORM nodules Nodules with 2 benign cytology Initial or subsequent development of suspicious US characteristics are the best predictor of cancer in cytology benign nodules

57 Summary: Benign Thyroid Nodule and Goiter Treatment of large nontoxic goiter depends on size, location, obstruction of trachea and vessels and symptoms Obstructive goiter: noncontrast CT, consider barium swallow Surgery for growing goiter, substernal component if tracheal compression >35% Expeditious thyroidectomy if critical tracheal compression < 6-8 mm Mediastinal goiter can be watched without surgery if no suspicion for malignancy (nuclear scan with I SPECT/CT) Treatment of benign and non-obstructive nodules and goiter Watchful waiting No T4 therapy and not routine use of I-131 Not every thyroid nodule or MNG requires surgery

58 Thank you for your attention! QUESTIONS?