MTP: Thyroid Nodules

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2 Canadian Endocrine Update MTP: Thyroid Nodules Deric Morrison MD, FRCP, ECNU Assistant Professor, Division of Endocrinology and Metabolism, Western University April 2014

3 Faculty/Presenter Disclosure Faculty: Deric Morrison Relationships with commercial interests:* Grants/Research Support: NONE Speakers Bureau/Honoraria: NONE Consul8ng Fees: NONE Other: NONE

4 Disclosure of Commercial Support This program has received financial support from Eli Lilly/ Boehringer Ingelheim, Novo Nordisk, Pfizer, Sanofi, Astra/BMS, Merck, Novartis, Serono/EMD, Jannssen in the form of an Unrestricted Educational Grant This program has not received in-kind support from any commercial organization

5 Objectives

6 Thyroid Nodules 3 Questions: Is it (are they) malignant? Is it (are they) autonomous? Is it (are they) compressing local structures?

7 Thyroid Nodule 19 year old was seen in clinic today regarding thyroid nodules. PAST MEDICAL HISTORY: None MEDICATIONS: None DRUG ALLERGIES: None THYROID NODULES: Asymmetric goitre noted on physical exam in September 2013.

8 What Else No dysphagia, stridor or hoarseness. Aware of the thyroid nodule on the left, not bothered by it No Family History Thyroid Cancer No personal radiation exposure

9 Thyroid Nodule PHYSICAL EXAMINATION: Blood pressure today was 108/62 mmhg. No cervical lymphadenopathy. Thyroid normal on the right, very large on the left. No tremor or tachycardia, extraocular movements were normal.

10 Investigations? Thyroid Function: TSH = 0.52 (Normal )

11 Thyroid Nodule REAL-TIME CLINIC ULTRASOUND: The right lobe and isthmus were normal in size, echogenicity and vascularity. There was very minimal normal left lobe tissue. Left nodule 6.0 x 3.3 x 4.2 cm. Mostly solid isoechoic with a small cystic area laterally. There were no sonographic risk factors No abnormal lymph nodes in neck levels I-VI

14 Next Step?

15 FNA Cytology Diagnosis Follicular Neoplasm

16 Bethesda Cytology

17 Bethesda System Cytology Diagnos8c Category Risk of Cancer (NB local variability) Insufficient/Unsa7sfactory 1-10% Repeat Usual Management Benign 0-3% Clinical follow up Atypia/Follicular LESION of Undetermined Significance Follicular ( or Hurthle Cell) NEOPLASM 10-45% Atypia = variability in risk. Consider surgery for atypia % Repeat? Close monitoring? Hemi? Consider clinical and imaging findings Rule out molecular markers? Hemi? Close monitoring? Specific molecular markers? Suspicious for malignancy 60-75% Total? Hemi? Sensi7vemolecular markers? Posi7ve for malignancy 97-99% Total +/- Neck dissec7on, stage with neck US or CT

18 Indeterminate/Intermediate Risk Intermediate Risk of Malignancy Follicular neoplasm (15-30% chance of cancer) Follicular cell predominance, > 50% microfollicular Most are nodular hyperplasia or follicular adenoma Can t rule out follicular or follicular variant of papillary If Follicular Neoplasm: Radioactive iodine uptake and scan showing the nodule is hot may help risk stratify. Not recommended unless TSH is low (Low yield)

19 Repeat Biochemistry TSH = 0.33 (January Normal range for this lab is ). Next Step?

20 Patient asks: Is there any way I can avoid surgery?

21 Options Monitoring? Already 6 cm US features? Molecular markers? Which? Radioiodine uptake and scan Only If TSH is low, but wait second TSH was low

23 Management Options

24 Thyroid nodule + Low TSH Nodule detected TSH is next test If TSH is low radioactive iodine scan is next test Hot/Hyperfunctioning nodule about same risk of malignancy as a nodule with a benign result on FNA cytology No biopsy needed, but follow as one would a benign biopsy and consider biopsy if growth or worrisome features

25 Autonomous Nodules ATA Guidelines. Thyroid. Volume 19, Number 11, 2009

26 Radioactive Iodine Scan (Scintigraphy) hcp:// medicine.html

27 Normal

28 Thyroid Nodules IS IT MALIGNANT?

29 Thyroid Cancer Epithelial cell derived» Well differen8ated Papillary (>85%) Follicular (<10%) Hurthle cell/oxophyllic (~3%)» Poorly differen7ated» Anaplas7c Medullary (C-cell derived) Lymphoma Metastases

30 Epidemiology Thyroid Cancer 4-15% of nodules About twice as high: Man vs. Woman Child vs. Adult

31 Epidemiology Yearly Incidence of Thyroid Cancer in U.S. 3.6 per in per in 2002 Mostly due to Papillary Thyroid Cancer (PTC) Mostly < 2cm in diameter, 50% <1cm Increasing faster than any other cancer

32 Epidemiology At least partially related to increased use of neck U/S + biopsy 6-13% of US autopsy specimens <1 cm PTC In Finland it s up to 36% Statistically significant of tumors > 5 cm. Incidence of regional + distant metastases ~15% of all DTCs are aggressive Including some <1 cm

33 Thyroid Nodules l Risk factors include l Younger/older patients (<20 / >60) l l l l l Male Exposure to radiation during childhood Hoarseness, dysphagia, stridor or rapidly growth (Rapid) Nodule Growth Physical exam characteristics: (hard, fixed nodule, vocal cord paralysis, lymphadenopathy) - Higher TSH = (slightly) higher risk of malignancy - Risk of malignancy is similar in patients with single vs multiple nodules

34 Clinical Evaluation Risk factors for malignancy Family history Differen7ated (papillary, follicular) Thyroid Cancer (DTC) Medullary Thyroid Cancer (MTC) - Calcitonin Mul7ple Endocrine Neoplasia 2 (MEN2) MEN2A - MTC/Pheo/Hyperparathyroidism MEN2B - MTC/Pheo/Neuromas Familial Polyposis Syndromes

35 Palpation l Nodules Missed - <1cm l 94% - 1-2cm l 50% - >2cm l 42% l Brander. J Clin US l Thyroid US should be performed in all with known or suspected nodules - ATA Level A Recommenda7on

36 Ultrasound Screening l Not recommended unless: - External radia7on in childhood - History of familial thyroid cancer - Prior history of thyroid cancer - Hyperparathyroidism l 2 birds, one surgery

37 Ultrasound hcp:// thyroidcancersurvivor.wordpress.com/ category/thyroid- nodule/

38 Thyroid Nodules ATA Guidelines. Thyroid. Volume 19, Number 11, 2009

39 Ultrasonography of Thyroid Nodules ATA Guidelines. Thyroid. Volume 19, Number 11, 2009

40 Microcalcifications l Suggestive of Papillary Cancer - Psammoma Bodies

41 Microcalcifications

42 Vascularity l More = Higher Risk - None (Grade 1) - Peripheral (Grade 2) - Internal (Grade 3 and 4)

43 Taller Than Wide, Invasion, Irregular Borders l Increased Risk Tall Wide

44 Irregular borders, Extra thyroidal extension, microcalcifications

45 Other Risk Factors l Abnormal Cervical Lymph nodes l Increasing Size

47 Reassuring Ultrasound

48 Cystic Nodules

49 Purely Cystic Nodule Biopsy not indicated Options: Do nothing Drain fluid 60-90% reaccumulate Remove surgically if bothersome Ethanol injec7on Not widely available

50 Halo, isoechoic, hyperechoic

54 Author Conclusions Using only + Microcalcifications or combination of both >2 cm and solid as indications for biopsy estimated risk of cancer in those not biopsied is ~0.5% May reduce number of biopsies by as much as 90%. 20 year survival of DTC is > 97% Ongoing surveillance is unlikely to be beneficial as risk for cancer remains low at 10 years.

55 Pitfalls This does not take into account unusual, but very concerning US features: Abnormal lymphadenopathy Evidence of invasion beyond thyroid capsule Clinical risk factors: Family history Radia7on exposure as a child

56 Weaknesses This is a retrospective study. A prospective study would be better Prospective data is lacking in general and many of the current recommendations are based on retrospective data.

57 Calcitonin? Insufficient to recommend for or against Consider if any suspicion of family history of medullary Consider if non-diagnostic biopsy and planning to ultrasound monitor Especially if large, and/or worrisome features

58 Future? (Present in the USA) Molecular markers BRAF, RAS, RET/PTC, PAX8- PPARγ or galec7n 3 May help predict malignancy in indeterminate nodules Prevalence varies by popula7on Any 1 marker may not be adequate Microarray gene analyses seem promising

59 Molecular Markers Alexander EK, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. June 25, 2012 Afirma: Negative predictive values within the indeterminate cytology categories similar to having a benign cytology. i.e. may be able to follow much like would a benign cytology nodule. Contrast with BRAF, RET/PTC, RAS, PAX8/ PPARG panel where positive predictive value is high. i.e. In pa7ent going for surgery for indeterminate result do total thyroidectomy, consider central neck dissec7on, but can t rule out cancer with a nega7ve result.

60 Next Generation Sequencing ThyroSeq: Simultaneous detec7on of muta7ons in 284 hotspots of 12 genes with muta7ons that are found in thyroid cancer Improvements expected to improve sensi7vity and specificity in dis7nguishing benign and malignant samples from indeterminate cytology nodules

61 Serum MiRNAs

63 Editorial Problems: High rate of diagnos7c hemithyroidectomy Onen benign If cancer is detected comple7on is necessary Possible solutions: Molecular markers? US features? Elastography? Monitoring in selected pa7ents?

64 Summary Nodule Evaluation History + Physical + TSH TSH low Radioiodine Uptake/Scan Treatment of hyperthyroidism TSH not low Ultrasound Pure Cyst nothing, drain, surgery (EtOH) Complex or Solid Consider biopsy >1.5 cm» Smaller if high risk history, or ultrasound features» Larger if cys7c component

65 Summary Biopsy Results Non-diagnostic Repeat Benign U/S q 6-18 months, then q 3-5 years Consider repeat biopsy if >20% in 2 dimensions or >50% volume Malignancy or Suspicious Surgery (Rule in markers?) Indeterminate (Follicular, Hurthle, Atypia) Hemi vs Monitoring for Follicular/Hurthle Neoplasm RAI if TSH low? Molecular markers? Repeat? RAI? U/S features? Monitoring?

Evaluation and Management of Thyroid Nodules. Nick Vernetti, MD, FACE Palm Medical Group Las Vegas, Nevada

Evaluation and Management of Thyroid Nodules Nick Vernetti, MD, FACE Palm Medical Group Las Vegas, Nevada Disclosure Consulting Amgen Speaking Amgen Objectives Understand the significance of incidental