Differential Diagnosis of Thyroid Nodules

Marburg Summer School of Thyroid

Cancer Management

Eyal Robenshtok, MD
Endocrinology Institute, Thyroid Cancer Clinic
Rabin Medical Center, Beilinson Hospital
Tel Aviv University
• 58 y.o.

• Levothyroxine 100mcg – 2 years

• Referred to neck ultrasound

Rt. 1.1 cm nodule

FNA?
 Nodules – how common?

Germany: Canada:
32% in women 72% in woman
33% in men 41% in men
>1cm in 12% 21% palpable

Reiners et al. Thyroid 2004 Ezzat et al. Arch Intern Med 1994

Nodules are extremely common

Do an ultrasound → you’ll probably find one
• National screening
Newprogram for cancer
concept:
• In-office ultrasound
Over-diagnosis of
“subclinical” thyroid cancer
Think before an ultrasound

Benign vs. Cancer

Clinically significant cancer?

 Work-up of thyroid nodules

1) Is it functioning?

2) Is it (clinically significant) cancer?

 1) Is it functioning?

• ATA guidelines: Check TSH *

• Low TSH → Thyroid scan

– Toxic adenomas are benign

– FNA: Pitfall - hyperplastic cells

* Toxic adenomas can exist with normal TSH

Görges R et al. Nuklearmedizin 2011

You can start with a thyroid scan

Remember “false positive” with Tc-99
 2) Is it Cancer?

Indications for FNA: according to ultrasound features

High risk ≥1 cm
No FNA under 1 cm
Intermediate risk ≥ 1 cm

Low risk ≥1.5 cm

Very low risk ≥ 2cm or follow-up

 Hypoechoic
± suspicious features

≥ 1 cm
High risk Intermediate risk

Isoechoic / Hyperechoic
no suspicious features

≥ 1.5 cm
Low risk Low risk

Spongiform
No FNA
no suspicious features

≥ 2 cm or follow-up Benign
Very low risk
 Bethesda / Thy
Thy classification

Repeat FNA

Repeat FNA
 What’s next?

• Bethesda I X2 1-4% (up to 20%) 1. Surgery

2. Follow-up
• Bethesda III X2 5-15% (up to 50%)
3. Molecular markers
• Bethesda IV ≈ 30%
4. Scans

• Bethesda V
Molecular markers Nuclear medicine:

1. Afirma 1. Thyroid scan

2. Mutation analysis 2. MIBI

3. microRNA 3. PET/CT
 Molecular markers

• For Bethesda I, III, IV

• Popular in

• Prevent unnecessary surgery

1. Gene expression classifier
• 167 genes
• Requires fresh material – repeat FNA
• Prevents around 50% of surgeries
• Popular

– NPV – 94-95% (real negative)

– PPV – 50% (real positive)
– BRAF

• Expensive - around 3,000$

• “Real world” studies – results not as good
 2. Mutation analysis
• Good at proving cancer (plan surgery)

• Not at excluding cancer – doesn’t prevent surgeries

• Price ≈ 1,500$

• Not popular
“Next generation” mutation analysis

• ThyroSeq® v2
>1000 hotspots of 14 genes
42 types of gene fusions

• NPV – 95-97%
• PPV – 80-85%

• Price: ≈ 3,200$
 3. microRNA
• Stable, can be tested on slides
• Limited number of studies

• Rosetta Gx:
NPV – 91-99%
PPV – 62%

• Price ≈ 3,000$
Molecular markers Nuclear medicine:

1. Afirma 1. Thyroid scan

2. Mutation analysis 2. MIBI

3. microRNA 3. PET/CT
 1. Thyroid scan

Radioiodine

• Hot nodule = benign

Technetium 99 (Tc-99) – Pitfall of false positive

Concentration, no organification
 2. MIBI scan
• Meta-analysis 2013 (21 studies) + several studies since

• Readily available, cost ≈ 200$

Suspicious for cancer

Benign
 Heinzel et al. Eur J Nucl Med Mol Imaging (2014)

• Can prevent 33% of unnecessary surgeries

• Some studies show lower NPV (82%)

Piccardo A et al. Eur J Endocrinol. 2016

• More cost effective that Afirma

 3. 18FDG-PET/CT
• Variable availability, cost, radiation exposure

• Negative FDG-PET/CT in indeterminate nodules – excellent NPV

Merten et al. Thyroid 2017

 Smart use of markers / scans

Only for patients with low to intermediate risk of malignancy

Based on ultrasound + FNA

 Summary
• New approaches and tools

• Think before: Ultrasound

FNA

Molecular markers / scans

• Future: better tools for risk stratification