Work Up & Evaluation of Thyroid Nodules In 2013: State of The Art

Todd McMullen MD PhD FRCSC FACSEndocrine Surgeon

Divisions of General Surgery and OncologyDirector, Division of Surgical Oncology

BC Surgical Oncology Network, Fall Update

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

Overall Prevalence of Thyroid Cancer

SEER Database

Subtypes of Thyroid Cancer

SEER Database

A Sea of Nodules

Nieuwenhuis et al., 2013; Guth et al., 2009; Sosa et al., 2013

• 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

6Schonfeld et al., 2012; Nieuwenhuis et al., 2013; Carpi et al., 2012; Septer S, et al., 2013

• Patients with PTEN mutations and hamartoma tumour syndrome have a30+% risk of thyroid cancer - females>males

• Family history is also an important factor predicting risk and severity

• 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.

Special Patients

• Thyroid cancer is 4X more likely in patients with familial adenopolyposis (FAP) compared to general population

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

• 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

• 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)

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

Risk of Papillary Thyroid Carcinoma in Relatives of Probands

Figure Legend:

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

Bastin et al., J Med Imag and Rad Onc (2009)

Can ultrasound identify a patient at risk of thyroid cancer?

Ultrasound – The Details

Smith-Bindman R, et al., JAMA Intern Med. 2013

9000 patients over 5 years

Size: 2+cm nodule 3X more likely to be malignant than nodule <1 cm

Ultrasound – The Reality

Number of Reported Features

Number of CasesN=336

Percentage of all cases

0 1411 1032 663 194 25 26 3

Ultrasound Feature Frequency of Reporting (%)

Confirmed Cases of Cancer (%)

P value

Microcalcifications 24 77 0.002Solid 40 48 0.008

Irregular margin 14 37 0.002Hypoechoic 36 24 0.18

Intranodular vascularity 11 33 0.97Absent halo sign 5 20 0.59

Ultrasound – The Reality

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 fluid- filled 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

Ali, S. Acta cytologica (2010)

Currently in Edmonton – 75% of reports

• 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 arecost-effective. (Heller M et al. 2012)

Bethesda Criteria: Since 2008

A Second Biopsy or a Second Pathologist?

Olson MT, JCEM 2013

• 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.

3885 thyroid cytological samples reviewed over 4 years

Molecular Testing in Thyroid Investigations

Nikiforov YE et al. 2012; Alexander et al., 2012

• 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

Molecular Testing in Thyroid Investigations.

Nikiforov YE et al. 2011

N=1056

©2011 by Endocrine Society

Technology Makes Life Better?

Technology Makes Life Better?

John Hopkins School of Public Health

Veracyte

Testing benign nodules

If it is benign

Oertel YC et al., 2007; Gharib et al. 2010

• 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

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

• 2nd 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)

Winter Fun!

Thanks to Chrystal and Sam and the BCCA!

Questions?