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Thyroid
Nodules & Cancer
Update/Overview
Mark A. Lupo, MD, FACE, ECNU
Thyroid & Endocrine Center of
Florida
Objectives
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Thyroid Nodule Evaluation
Role of Ultrasound
FNA Classifications
Management of benign nodules
Management of thyroid cancer
Follow-up of thyroid cancer patients
Nodule Questions
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How to evaluate the nodule?
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US, TSH, Nuclear Scan, FNA ???
What to FNA and how to FNA ???
How do we interpret the FNA?
If surgery, how much?
Is there a non-surgical treatment?
Cancer Questions
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How much initial surgery?
What is the role of pre-operative imaging?
Do we need to give I-131?
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Surveillance for recurrent/persistent disease
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How much? How is the patient prepared?
Ultrasound
Tg levels
Nuclear WBS
TSH suppression goals
Academic Guidelines
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American Association of Clinical
Endocrinologists / Italian Endocrinologists
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National Cancer Institute
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2006
2008
American Thyroid Association
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2006, recently revised in 2009
Epidemiology
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Nodules – extremely common
4% with palpable nodule
 50% of >50 year-olds have nodules on ultrasound
 5-10% of nodules are malignant
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Cancer – increasingly common
37,000 estimated new cases in 2009
 18,000 new cases in 2000
 Much of this is small incidental findings on imaging
 However, there is also an increase in >5cm tumors

Thyroid Nodules
Primary goal is to determine if a
nodule is malignant and needs
surgery, or is benign and does not
need surgery.
History and Physical - Risk Factors
Age <20 or >60 - 80
Prior radiation
Rapid growth
Family history
Hoarseness
Dysphagia
Lymphadenopathy
Tests for Thyroid Nodules

I-123 scan
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Thyroid ultrasound
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FNA biopsy
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TSH
ATA guidelines
THYROID
Volume 19 (11) 2009
© American Thyroid Association
Nuclear Medicine Scans
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VERY limited role in thyroid nodule evaluation
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To identify hot (toxic) nodules
ONLY useful if the TSH is low
Should NOT be ordered as part of the routine
evaluation, even if radiologist recommends it!
NEVER take someone off l-T4 to do a scan

These hypothyroid patients do NOT have a hot
nodule!
Value of Ultrasound in Nodule Evaluation
Ultrasonography altered the clinical management
in 63% of patients (n = 173) referred to the
Thyroid Nodule Clinic at the Brigham and Women’s
Hospital.
Annals Internal Medicine,
2000;133;696
Palpation is NOT accurate in up to
30% of patients with solitary palpable
nodules
• 16% will have no corresponding nodule
•
on US
15% have an additional nonpalpable
nodule >1cm on US
Brander, J Clin Ultrasound 1992; Tan, Arch Intern Med 1995;
Marqusee, Ann Intern Med 2000
What nodules can’t we feel?
Ultrasound vs. Palpation
# Nodules found by US
35
30
25
42%
20
Nodules MISSED by palpation
Nodules FOUND by palpation
50%
15
10
5
94%
0
< 1cm
1-2cm
Nodule size by US
Brander, J Clin Ultrasound 1992
>2cm
Thyroid sonography should be performed in all
patients with one or more suspected thyroid
nodules.
USPSTF Recommendation B
Management guidelines for patients with thyroid nodules and differentiated
thyroid cancer, ATA Task Force, David Cooper, Chair, Thyroid, 2006
Thyroid ultrasound . . . is mandatory when a
nodule is discovered at palpation
European consensus for the management of patients with differentiated
thyroid carcinoma of the follicular epithelium, Eur J Endocrinol 2006
In all patients with palpable thyroid nodules or
MNG, US should be performed
AACE/AME guidelines for clinical practice for the diagnosis and
management of thyroid nodules, Endocrine Pract 2006
Value of Ultrasound in Nodule
Evaluation
Ultrasound evaluation of a nodule imparts to each
nodule a “degree of suspicion” of malignancy.
Ultrasound will aid in FNAB.
Ultrasound will find additional nonpalpable nodules
>1cm in 1 in 7 patients
This information is integrated with the FNA biopsy
results, history and physical examination to decide if
surgery is indicated.
Ultrasound Helps Assess Nodules
However, ultrasound is extremely sensitive
In 101 women with no palpable nodule
Ultrasound revealed 36 with one or more
Nodules.
Brander, et al. Radiology, 1989
Multinodular Thyroid
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Patients with multiple nodules have same risk of
cancer as those with solitary nodules
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The solitary nodule may have increased risk, but the
patient overall is at similar risk
FNA biopsy should be targeted
Dominant nodule
 Nodules with conspicuous ultrasound appearance
 Cold nodule (if TSH low and I-123 scan done)
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Pregnancy and Nodules
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Unless TSH is low, FNA should be performed
during pregnancy
If FNA shows PTC
If grows significantly by 24 weeks, then surgery
during second trimester
 If stable by midgestation or if diagnosed in the
second half of pregnancy, surgery post-partum
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 LT-4 to keep TSH in 0.1-1.0 mU/L
NCI: Thyroid Nodule FNA - Conclusions
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1. All focal 18FDG-PET-avid lesions should undergo
FNA.
2. All hot nodules detected on sestamibi scans should
undergo FNA.
3. Incidentalomas detected by (carotid) US should
undergo a dedicated thyroid sonographic evaluation.
4. Until more data are available, incidentalomas seen on
CT or MRI should undergo a dedicated thyroid
sonographic evaluation.
5. Any nodule with sonographically suspicious features
should be considered for FNA.
6. Lesions with a maximum diameter greater than 1.0-1.5
cm should be considered for FNA.
Diagnostic Cytopathology 36 (6), June, 2008
US Prediction of Thyroid Cancer
Sensitivity Specificity
Microcalcifications
45%
85%
Absence of halo
66%
46%
Irregular margins
64%
77%
Hypoechoic
80%
45%
Increased intranodular flow67%
81%
MicroCa2+ + irreg margin
MicroCa2+ + hypoechoic
Solid + hypoechoic
FNA
30%
28%
73%
92%
95%
95%
69%
84%
Brkljacic J Clin Ultrasound 1994; Takashima J Clin Ultrasound 1994; Rago Euro J Endorinol
1998; Cerbone Horm Res 1999; Leenhardt J Clin Endocrinol Metab 1999; Kim AJR 2002;
Papini J Clin Endocrinol Metab 2002; Cappelli Clin Endocrinol 2006
Selecting Nodules for FNA
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Size and sonographic features
 Society of Radiologists in Ultrasound
Size, sonographic features and clinical history
 American Thyroid Association (‘09 revision)
 FNA <1cm if high-risk history, else >1cm
 American Association of Clinical Endocrinologists
 European consensus
All societies now go beyond size in deciding which nodules
should undergo FNA biopsy.
Nodules >1-1.5cm need careful US evaluation to determine
if FNA biopsy is indicated
Most Nodules >1.5cm should undergo FNA
•
Characteristics Suggestive of Malignant
Nodules
Hypoechoic or heterogeneous nodule
Hypoechoic
Transverse
Longitudinal
This 2 cm nodule shows the typical ultrasound appearance of a
papillary cancer. The nodule is hypoechoic without a “halo”.
At surgery the lesion was not encapsulated and 2 of 3 lymph
nodes were positive.
Heterogeneous
Papillary Carcinoma 1.2 cm
•
Characteristics Suggestive of Malignant
Nodules
Hypoechoic or heterogeneous nodule
• Irregular border
Irregular Border
Transverse
Follicular Carcinoma Characteristics Suggestive of Malignant
Nodules
•
Hypoechoic or heterogeneous nodule
• Irregular border
• Thick wall cyst
CYSTIC PTC
Characteristics Suggestive of Malignant
Nodules
•
Hypoechoic or heterogeneous nodule
• Irregular border
• Thick wall cyst
• Invasion of adjacent tissues
Invasion of Adjacent Tissues
Tr
Invasion of the fibromuscular tissue is
seen near trachea.
Transverse
Longitudinal
Tall cell variant of papillary carcinoma.
Invasion of Adjacent Tissues
Transverse
Longitudinal
Invasion of the posterior capsule of thyroid
Medullary carcinoma
Characteristics Suggestive of Malignant
Nodules
•
•
•
•
•
Hypoechoic or heterogeneous nodule
Irregular border
Thick wall cyst
Invasion of adjacent tissues
Cervical lymphadenopathy
Malignant Lymph Node
Thyroid Nodule with Cervical Lymphadenopathy
Thyroid ultrasound should ALWAYS include evaluation
of the central and lateral neck for abnormal lymph nodes.
Characteristics of Malignant Nodules
•
•
•
•
•
•
Hypoechoic or heterogeneous nodule
Irregular border
Thick wall cyst
Invasion of muscle
Cervical lymphadenopathy
Intranodular vascularity
Intranodular Vascularity
Doppler demonstrates the increased blood flow in this nodule raising the suspicion for malignancy.
Papillary Cancer
Increased vascularity and heterogeneous echotexture
US Prediction of Thyroid Cancer
Sensitivity Specificity
Microcalcifications
45%
85%
Absence of halo
66%
46%
Irregular margins
64%
77%
Hypoechoic
80%
45%
Increased intranodular flow67%
81%
MicroCa2+ + irreg margin
MicroCa2+ + hypoechoic
Solid + hypoechoic
FNA
30%
28%
73%
92%
95%
95%
69%
84%
Brkljacic J Clin Ultrasound 1994; Takashima J Clin Ultrasound 1994; Rago Euro J Endorinol
1998; Cerbone Horm Res 1999; Leenhardt J Clin Endocrinol Metab 1999; Kim AJR 2002;
Papini J Clin Endocrinol Metab 2002; Cappelli Clin Endocrinol 2006
Indications for Ultrasound-Guided FNA
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Nonpalpable nodules
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Small nodules (<1.5 cm)
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Posterior nodules
Cystic (complex) nodules
Obese, muscular, or large frame patient
Dominant nodule in multi-nodular goiter
Previous unsuccessful FNA biopsy
Consider using ultrasound guidance on all aspirations
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FNA versus UG-FNA Biopsies
Inadequate FNA Biopsies
# Patients
Cochand-Priollet
132
Takashimia
327
Danese
9683
Conventional
15 %
UG-FNA
3.8 %
19 %
3.7 %
8.7 %
3.5 %
FNA Procedure
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Simple Outpatient procedure
27 gauge needles
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Core Needle Bx not helpful
Continuous Ultrasound guidance
Local anesthesia optional – seldom needed
2-4 passes per nodule
Onsite adequacy assessment ideal
FNA Results
Cytology
Results (%)
% Malignant
Benign (negative)
65
<1
Malignant (positive)
5
>99
Nondiagnostic
20
<3
Suspicious /
Indeterminate
10
20
Gharib H and Papini E: Endocrinol Metab Clin N Am 36:707, 2007
The Bethesda System:
Relationship to Clinical Algorithms
Category
Risk of
Malignancy (%)
Usual Management
Insufficient for Diagnosis
1-4
Repeat FNA w/ U/S
Benign
<1
Follow
ACUS
~5-10
Repeat FNA
Sus for a Follicular Neo
20-30
Lobectomy
Sus for a Hürthle Cell Neo
20-45
Lobectomy
Suspicious for Malignancy
60-75
Lobectomy or total
thyroidectomy
97-99
Total thyroidectomy
(usually papillary CA)
Malignant
Benign – Follow-up
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Monitor with palpation and ultrasound at 6-18 month
intervals
Routine levothyroxine suppression is not
recommended
Repeat FNA if there is a significant growth
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>20% increase in diameter with a minimum increase in 2 or
more dimensions by at least 2mm
Better yet: a 50% increase in volume
After 2 benign FNAs the chance of missing a
malignancy is extremely low
Benign Nodule Management
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Follow-up US in 6 months, if >50% increase in
volume  repeat FNA (recall 2% false neg rate)
Then follow every 6-18 months or as indicated
NO L-T4 suppression
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Only give L-T4 if TSH elevated
For compressive symptoms
Surgery
 I-131 therapy
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PEI of Thyroid Cysts
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For larger cysts with a pocket of fluid of >4mL
Must have benign FNA prior to PEI
Recurrence after drainage, occurs in >60% pts
Cyst is drained under ultrasound guidance
½ the volume is replaced by 95% ETOH
75% success rate
Risk of extravasation of ETOH  RLN
Follicular Neoplasms
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Includes Follicular & Hürthle lesions/neoplasms
20% are malignant
Additional imaging seldom helpful
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Most undergo lobectomy or thyroidectomy
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I-123 if low TSH
PET studies not conclusive
Frozen section usually not helpful
Does size make a difference? – more concern if >2cm
Future role of molecular markers?
Extent of Surgery for
Follicular and Hürthle Neoplasms
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Surgery becomes a diagnostic procedure
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But only 20% are malignant
Must consider the clinical picture when
recommending lobectomy vs thyroidectomy
Contralateral Nodules
 Compressive Symptoms
 Already Hypothyroid?
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Suspicious for Malignancy
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Confers a 60-75% risk of malignancy
Patients referred for a least a lobectomy
Total Thyroidectomy in some cases
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Mass >4cm, h/o radiation, family history, bilateral
nodules, patient preference
Frozen section may help determine surgical
extent
Pre-operative evaluation of lymph nodes
Preoperative Evaluation of Lateral Compartment
N
LN
Discovery of this right
lateral neck lymph node
changes the surgery to
include modified neck
dissection.
C
Malignant
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Most patients undergo total thyroidectomy
Central compartment dissection is controversial
Must have pre-operative ultrasound
Lateral neck evaluation
 “Mapping” of lymph nodes
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Pre-operative serum markers
Thyroglobulin in PTC – not yet proven useful
 Calcitonin and CEA in MTC – predictive of mets

THE INCIDENCE OF CANCER AND RATE OF FALSE
NEGATIVE CYTOLOGY IN THYROID NODULES > 4 cm
IN SIZE
McCoy KL, Jabbour N, Ogilvie JB, Carty SE, Yim JH
University of Pittsburgh, Pittsburgh, PA
Surgery 2007; 142 (6)
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223 patients with thyroidectomy for a ≥4 cm nodule.
43 patients (19.3%) - thyroid carcinoma on final pathology
34 (15.7%) patients had micropapillary carcinoma.
Preoperative cytology of the ≥4 cm mass read as benign in 71 patients.
false negative rate for cancer - 15.5%
false negative rate for missed follicular lesions of the ≥4 cm (follicular
adenoma, carcinoma and follicular variant of papillary carcinoma) was
33.8%.
32 patients with cytology positive for follicular lesion, 34.4% had thyroid
cancer on final pathology.
THE INCIDENCE OF CANCER AND RATE OF FALSE
NEGATIVE CYTOLOGY IN THYROID NODULES > 4 cm IN
SIZE
McCoy KL, Jabbour N, Ogilvie JB, Carty SE, Yim JH
University of Pittsburgh, Pittsburgh, PA
Surgery. 2007; 142 (6)
Conclusion:
 Thyroid nodules ≥ 4 cm with benign cytology has an
unacceptably high false negative rate and should be
managed with, diagnostic lobectomy to exclude thyroid
malignancy, regardless of FNA results.
Note: 34 (15.7%) patients had micropapillary carcinoma!
Micropapillary Cancer:
Is it Clinical Disease or
Occult pathology?
1) Autopsy series: 6% (3-11%) have an incidental
microcarcinoma (approx 90+% micropapillary)
2) Equal F:M prevalence and no age related increase
3) About 12 million people in USA with micro PTC (est.
6% x 200 million > 25 y/o as of 7/2007 population)
4) Mortality rate for surgically treated microcarcinomas
is 1-2 deaths/1000 pts from multiple large series
5) No difference in malignancy rates for nodules > or <
1-1.5 cm
Micropapillary Cancer:
Is it Clinical Disease or
Occult pathology?
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
PATHOLOGY: 30-50% + have metastatic LNs,
multifocality and extrathyroidal extension
CLINICAL: if NO abnormal LNs (PE or US) at
presentation
 1-2% recurrence rate in lymph nodes1,2,3
 1-2% recurrence rate in residual thyroid tissue or bed1,2
Huge disconnect in high rates of microscopic LN metastases in meticulous
compartment dissections and the rareness of macroscopic, clinically
significant, enlarged or enlarging lymph node recurrence rates
1Ito,
2003
Thyroid 2003;
2Wada,
Ann Surg 2003; 3Chow, Cancer,
Micropapillary Cancer:
Is it Clinical Disease or
Occult pathology?
QUESTIONS:
1) Can we identify microPTC with virulent potential?
2) For micropapillary cancer are there outcomes
predictors for mortality risk and recurrence rates?
Clinical (PE) Lymph Node (LN) Metastases
at Presentation: WORSE Outcome
Local Recurrence
Recurrence (%)
20
Nodal Recurrence
20
LN positive
LN negative
15
15
10
10
p<0.001
5
5
p<0.00
1
0
0
0
5
10
15
20
0
5
10
15
20
Years after initial surgery
Hay, Surgery 1992
Disease-free survival (%)
Ultrasound Detected Lateral LN Metastases
at Presentation: WORSE outcome
US negative LNs
100
US positive LNs
80
60
40
20
p=0.024
0
0
20
40
60
80
100
120 140
Month
s
Ito, Word J Surg 2004
US Detects about 40% of Pathologically
Abnormal LNs
US (-), PATHOLOGY (+) LN Metastases:
NO IMPACT on Outcome
Pts WITH lat neck dissection
survival (%)
Disease-free
100
Pts WITHOUT lat neck dissection
80
60
40
20
p=NS
0
0
20
40
60
80
100
120
140 MONTHS
Ito, Word J Surg 2004
Micropapillary Cancer: Is it Clinical Disease or
Occult pathology?
QUESTIONS:
1) Can we identify microPTC with virulent potential?
2) For micropapillary cancer are there outcomes predictors for mortality
risk and recurrence rates?
ANSWERS:
1) Micropapillary cancers (<1cm) without clinically or sonographically
apparent metastatic lymph nodes almost always remain indolent and
only rarely become clinically significant
2) For < 10 mm nodules with suspicious imaging characteristics, and no
significant medical history (eg familial MTC, PTC) utilize ultrasound to
ascertain presence of clinically relevant lymph nodes and assess risk
status sonographically re: need for UGFNA vs periodic follow-up
3) In everyday practice, may not be so cut and dry. What do you tell
the patient? Perform UGFNA for 1 or more suspicious findings ?
Wada, Ann Surg 2003; Ito, Word J Surg 2004
Differentiated Thyroid Cancer

American Cancer Society estimates 37,000 new cases of
DTC in 2009 and 1,700 deaths
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Mortality rates unchanged over past 50 years

Assumption: Early detection and treatment of cervical
metastases will affect mortality
 This includes optimizing surgical outcomes with
better pre-operative planning and mapping
Role of Pre-Operative Ultrasound
PREOPERATIVE US (prior to thyroidectomy) is being performed more frequently
by physician sonologists and radiologists over the past 5 years
- Lymph nodes detected during preoperative US are categorized by:
1) Imaging characteristics as “benign”, “malignant” and “indeterminate”
2) R & L central location (level VI) and lateral locations (levels II, III, IV and V)
- Preoperative US may change the initial operating procedure up to 14-33%
of the time. UGFNA may be performed for lymph node cytopathology and
Thyroglobulin (Tg) analysis on “indeterminate” nodes
- Lateral compartment adenopathy can be visualized in 70-80% of cases while
central compartment adenopathy is detected in approximately 50% of cases
due to technical difficulties with the thyroid gland in place
Baatenburg, Arch Otolaryngol 1989;115: 689
Kouvaraki, Surgery 2003;134:946
Bruneton, Radiology 1984,152:771
Neck Levels
Pre-Operative Ultrasound
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DTC involves lymph nodes in 20-50%+ of patients .
Pre-op US identifies suspicious nodes in 15-25% of
cases.
Surgical management is altered in the presence of lateral
neck metastases
 Total thyroidectomy
 Lateral neck dissection
Pre-Operative Imaging Alternatives
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Ultrasound evaluation is uniquely operator dependent
Sensitivity of CT, MRI and PET is largely unknown in
this setting however CT may be as sensitive as US
Ultrasound versus CT
 Characteristics of benign/suspicious nodules
 Contrast interference with RAI ablation
 Expense, time and radiation exposure
 Visualization posterior to trachea and TE groove
 Ability to perform US-FNA at the time of US
Pre-Op Ultrasound Map
Prophylactic lateral neck dissection does NOT
improve recurrence free survival for patients
with preoperative US negative for lymph
nodes1
Does lateral neck dissection alter the
outcome for preoperative US positive for
lymph nodes?
1Ito,
World J Surg 2004
Role for Preoperative Ultrasound Nodal Evaluation
460 patients underwent thyroidectomy and modified neck dissection
Recurrence rate
US Neg 3.1%
US Pos 24.8%
Recurrence free survival was significantly worse for patients in whom
ultrasound demonstrated nodes preoperatively1
1Ito,
World J Surg 2005; 2Ito, World J Surg 2004
For “macroscopic” lateral lymph node
metastases, modified neck dissection at time
of initial thyroidectomy improves survival
Noguchi, Arch Surg, 1998 133 276-280
ATA Thyroid Cancer Management
Guidelines

R21. Preoperative neck ultrasound for the contralateral lobe and
cervical (central and bilateral) lymph nodes is recommended for
all patients undergoing thyroidectomy for malignant cytologic
findings on biopsy – Recommendation B

R22. Routine preoperative use of other imaging studies (CT,
MRI, PET) is not recommended – Recommendation E
THYROID, Volume 19 (11),
2009
Thyroid
nodule
Carotid
Metastatic paratracheal lymph node (low R 6)
48yo female with cystic
nodule right lobe (N) and
lymph node in neck (LN)
FNA cytology of nodule and
lymph node negative
Needle washout from
lymph node Tg=24ng/ml
Surgery: FVPTC in N and LN
N
LN
C
Extent of Initial Surgery
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

<1cm solitary cancer  lobectomy or total thyroidectomy
Anything else  total thyroidectomy
Debate regarding central compartment

Central compartment dissection favored if:


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Lateral Neck
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Large tumors +/- extension
US evidence of LN involvment
Only if clinically detectable LNs
Then IIa, III, IV, Vb complete dissection
NO berry picking (isolated/selective lymphadenectomy)
Even if metastatic disease present, removal of thyroid and
locoregional disease facilitates I-131 Rx of metastases
Prophylactic Central
Neck Dissection
Includes lymph nodes from level 6 and
7, including:
pretracheal, prelaryngeal and one
paratracheal nodal basin -usually
ipsilateral to tumor
Level 6 boundaries: superior-hyoid bone,
lateral-carotid arteries, inferior -sternal notch,
deep-prevertebral fascia.
Level 7(aka anterior/superior mediastinal
nodes): sternal notch down to inominate artery
(right) and brachiocephalic vein (left).
Courtesy of Dr. Ralph Tufano.
TSH Suppression




Levothyroxine (preferably brand consistent for
thyroid cancer patients) is part of the thyroid
cancer treatment
High risk patients: TSH < 0.1
Intermediate risk: TSH 0.1-0.5
Low risk: TSH 0.3-2.0 (once disease free)
New Considerations in
I-131 Treatment
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Careful selection of patients likely to benefit
Minimize dose needed to achieve ablation
Recognize risk of secondary cancers
Use of rhTSH to prepare patients
Quality of I-131 rxWBS
Avoidance of iodine contamination
Debate on I-131 indications surrounds PTC

Hürthle and Follicular CA treated with I-131
Post-Operative I-131 Ablation
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Systematic review of English literature
 Endo, Rad onc, Nuc med, Epidemiologic
No randomized, controlled trials available (Level I evidence)
1504 titles/abstracts
228 full text articles
23 met inclusion/exclusion criteria
 Cohort study
 Well-differentiated thyroid cancer
 Bilateral surgery
 RAI within 1 year
 Outcomes
 Mean/median FU > 5 – 10 years
Sawka AM, J Clin Endo Metab 89:3668, 2004
Post-Operative I-131 Analysis
UNADJUSTED ANALYSIS - 23 studies/8280 pts (58% no RAI, 42% RAI)
“Only a long-term randomized controlled
trial may definitively resolve this issue”
25
% 20
No RAI
RAI
50 % reduction
15
55 % reduction
10
5
0
Recurrence
Distant metastases
Sawka AM, J Clin Endo Metab 89:3668, 2004
Post-Operative I-131 Ablation
ADJUSTED ANALYSIS
(prognostic factors and co-interventions)

Mortality (6 studies)

Probably not

5 studies – NS
1 study – 50% reduction


Recurrence (6 studies)
Likely


Largest/longest study (OSU)
3 studies – NS
3 studies – 20-50% reduction

Largest/longest studies
Sawka AM, J Clin Endo Metab 89:3668, 2004
Post-Operative I-131 Ablation

I-131 ABLATION – RISK/BENEFIT
Recurrence - local/regional (10 yr)


Distant metastases (10 yr)


Rx 1000 patients to prevent mets in 10-20 patients
Mortality


Rx 1000 patients to prevent recurrence in 100 patients
Rx 1000 patients – maybe 1-2
Secondary malignancy rate with 131-I Rx

Rx 1000 patients and expect 5-6 excess malignancies
at 10 years (baseline incidence – 45-50/10 yrs, SEER)
Post-Operative I-131 Ablation
RADIOIODINE AND SECONDARY MALIGNANCIES
6841 patients
Mean FU 13 yrs, mean cum 131I 6.0 GBq (162 mCi)
1934 - 1995





Linear dose relationship
20% increased risk/baseline incidence of 2o malignancy
3.7 GBq (100 mCi) lead to 53/10,000 pts excess with solid cancer (4550/10,000 pts background incidence)
3.7 GBq lead to 3/10,000 pts excess leukemia
2.5-2.6 GBq (65-70 mCi) is approximate cut point for association of 2o
malignancies (eg breast, prostate, stomach)
These results strongly highlight the necessity to delineate the
indications of 131I treatment in thyroid cancer patients and to use
in patients in whom clinical benefits are expected
Rubino, Br J Cancer 89:1638, 2003
Risk Stratification for the Likelihood of
Clinically Evident Recurrence From Thyroid Cancer
After Complete Resection of Primary Tumor in Patients
With No Evidence of Distant Metastatic Lesions at Initial Evaluation
Risk Stratification
Intermediate
Factor
Low
Age at diagnosis
Primary tumor size
Histologic finding
Any age
20-60 y
<1 cm
1-4 cm
Classic PTC
Classic PTC
Confined to Thyroid Minimal ETE
Minimal Vascular Invasion
<20 or >60 y
>4 cm
Aggressive Subtype
Gross ETE
Lymph node
Involvement
None apparent
Present or absent
Present
Risk of failing initial
Therapy
Low
Intermediate
High
Modified from Tuttle et al (2,3).
High
Initial Therapeutic Recommendations in Patients With Thyroid Cancer,
Stratified by Risk of Death and Risk of Recurrence
Risk of Death
Risk of Recurrence
Very low
Low
Low
Low
Intermediate
High
Intermediate
High
Intermediate
High
Intermediate
High
Initial Surgery
Lobectomy or Total
Lobectomy or Total
Total
Total
Total
Total
Total
Total
Modified from Tuttle, Endocrine Practice 2008
RRA
TSH Goal
No
0.5-1.5
No
0.5-1.5
Selective 0.1-0.4
Yes
0.1-.04
Most
0.1-0.4
Yes
0.1-0.4
Yes
0.1-0.4
Yes
<0.1
Microscopic Multifocal PTC


New 2009 ATA Guidelines:
I-131 Remnant ablation not recommended for
multifocal cancer when all foci are less than 1cm
in the absence of other higher risk features
Tests Used in Post
-Operative Thyroid Cancer
Post-Operative
Surveillance

131I

Thyroglobulin

Ultrasound
Whole Body Scan
ATA Guidelines
Long-term Follow-up
Diagnosis of Recurrent DTC in
51 of 494 Patients
• 131I Whole Body Scan
• Tg > 2ng/ml (off T4 therapy)
• Tg detectable
“
• Ultrasound
Frasoldati, et al; Cancer 2003
23 (45%)
29 (57%)
34 (67%)
48 (94%)
Limitations of Whole Body Scans





Morbidity of thyroid withdrawal
Expense
Poor sensitivity (60-75%)
“Stunning”
Potential for causing growth?

Withdrawal versus Thyrogen
False Negative Whole Body Scans
Significant Uptake Noted on Subsequent
Post
-treatment scan
Post-treatment
Patients with positive Tg and negative scan
Neg Pre-Rx Scan
Pos Post-Rx Scan
Pacini
17
16
Schlumberger
22
18
Pineda
17
16
All three studies pre-US era. Gave “empiric” RAI for elevated TG.
Causes of False Negative Scans

Diffuse small metastases

Dedifferentiation (loss of NIS symporter)

Iodine contamination.

Insufficient TSH stimulation
Post-operative Ultrasound Evaluation

Both the central compartment and the lateral
compartments of the neck are easily surveyed with
US in the post-op thyroid cancer patient

FNA using US guidance allows both cytology and
analysis for thyroglobulin without regard to
thyroglobulin antibody
Characteristics of Malignant Nodes





Disordered vascularity
Microcalcifications
Cystic Degeneration
Absence of Hilar Line
Hypoechoic Echotexture
From Susan Mandel 2008
Leboulleux JCEM 2007
Ahuja, Clinical Radiology 2001
Sensitivity
Specificity
86%
45%
11%
95%
39%
82%
100%
100%
20%
18%
Thyroglobulin


25% patients have Tg-Ab which interfere w/
immunometric assays
Suppressed Tg <0.3 ideal, but trend/rise is more
clinically important



Detectable levels depend on size of thyroid remnant
Stimulated Tg levels >5-10 should prompt
further investigation and treatment
Measure in same lab and always check antibody
level and TSH level at same time
20-30% of patients have
thyroglobulin antibodies
143 Consecutive Patients with Stage I and II
Papillary Cancer
June 2003-November 2004

41 patients had 1 or more suspicious lymph
nodes and underwent UG-FNA.

14 patients had positive cytology and/or Tg
washout.
Baskin, Thyroid 14:11:2004
Recurrent Cancer Patients
Age/sex
Years
Tg
Tg AB
22 M
50 M
53 F
51 F
36 M
40 M
52 M
54M
48F
32F
43F
57F
71F
54F
1
13
12
20
2
7
5
4
1
18
2
13
15
36
14.2
<0.3
<0.3
<0.3
<0.3
19.
1.8
8
<0.3
0.8
0.6
<0.3
1.3
11.5
+
+
+
-
Cytology FNA-Tg
+
+
+
+
+
+
+
+
+
39.9
24.9
19.8
10.5
67.5
500
443
87.5
24.3
10,936
6.6
237
1.5
2
Avg. Tg
158
Avg. Tg
2.1
What does the future hold?

Will this get easier?
Better US characteristic guidelines on what to FNA
 Better classification of FNA cytology
 Molecular markers to help with indeterminates
 Clarifications on extent of thyroid cancer surgeries
 Clarifications on who to give I-131 for cancer
 Tyrosine Kinase Inhibitors for refractory CA
 Additional cancer markers – TSHR-mRNA
 Non-surgical interventions – Laser, RFA, HIFU

Summary - Nodules




If normal or high TSH  US & possible FNA
Nuclear Scan only if TSH low!
No routine L-T4 suppression
US-FNA is procedure of choice


Core needle is not indicated or helpful
Most benign nodules require observation only
Summary – Cancer




Pre-operative ultrasound to help identify
abnormal lymph nodes
TSH suppression – depends on risk
Recurrence surveillance relies primarily on Tg
levels and careful clinician performed neck US
More careful selection for I-131 treatment
Thank You
Questions?
TSHR m RNA ASSAY

Numerous tumor markers examined over last 10+ yrs
- Serum Tg for postoperative surveillance of thyroid cancer
- BRAF for assessing PTC aggressive behavior
- Tumor tissue and FNAB samples for gene microarray analysis
of thyroid nodules

Thyrotropin receptor (TSHR) mRNA assay
- Thyroid cancer cells express functional TSHR
- TSHR mRNA can be detected from circulating tumor cells
in the bloodstream and be utilized for preoperatively diagnosing
thyroid nodules, thyroid cancer and postoperatively tumor
persistence or recurrence (no interference from TgAB+)
TSHR mRNA ASSAY
CHALLENGES IN THYROID NODULE AND CANCER
DIAGNOSIS
Papillary
Thyroid Cancer
Benign Hyperplastic
Nodule and MNG
VS
Follicular Adenoma
&
Follicular Carcinoma
TSHR mRNA ASSAY

TSHR mRNA is the first circulating molecular marker that
preoperatively distinguishes disease categories
TSHR mRNA/total RNA (ng/ug)
Normal subjects (n=51)
Benign Thyroid Disease (n=119)
New Thyroid Cancer (n=61)
Recurrent Thyroid Cancer (n=27)
0.09
0.43*
1.34*
29.9*
*p<0.05
Gupta et al Clin Chem 2002; 48:1862
Chinnappa et al JCEM 2004; 89:3705
Wagner et al JCEM 2005; 90:1921
Chia et al JCEM 2007;92:468
Milas et al Surgery 2007; 141:137
TSHR mRNA ASSAY
ATA Meeting -2008
251 samples from 176 new, consecutive patients from a
prospectively maintained, IRB approved database.
Values were collected:
• Pre-operatively (n=94)
• Post-operatively following total thyroidectomy (n=64)
• During long-term cancer surveillance (n=60 patients,
n=76 total encounters)
• Benign FNA, not proceeding to surgery (n=17)
Pre-operative TSHR mRNA in Patients with
Thyroid Cancer & Benign Disease 2008
TSHR mRNA level
000
Sensitivity = 67%
100
47
1
10
1
Specificity = 96%
PPV
= 98%
NPV
= 50%
Accuracy = 75%
1 ng/ug
23
23
0.1
Thyroid
Cancer
(N=70)
Benign
Disease
(N=24)
BRAF mutations in papillary
thyroid carcinoma



Ser-Thr kinase in MEK signaling pathway
Activating mutation
 TA substitution at nucleotide 1796 (V600E)
Found in 66% of melanomas


Found in papillary thyroid carcinoma (44%)





Davies, et al. Nature 2003, 417:949417:949-954
Conventional PTC: 60 %
FVPTC: 12%
Tall cell: 77%
Anaplastic carcinoma (24%).
Not identified in FTC, MTC, or benign nodules (n=542)

Review: Xing M. Endocr Relat Cancer. 2005 Jun;12(2):245Jun;12(2):245-62.
Garnett MJ, Marais R.Cancer Cell. 2004 Oct;6(4):313-9.
BRAF mutations in thyroid FNAs

94% concordance with tissue results.





Cohen Y, et al. Clin Cancer Res. 2004 Apr 15;10(8):276115;10(8):2761-5.
Not detected in any benign FNAs (high specificity)
Found in 44% of FNAs with PTC diagnosis
Found in 17% of indeterminate/suspicious FNAs from
PTC and 0% of indeterminate/suspicious FNAs from
benign disease.
Role in clinical management?

Xing M. Endocr Relat Cancer. 2005 Jun;12(2):245-62.
BRAF Mutation Testing of Thyroid FNA Specimens
for Preoperative Risk Stratification in PTC




Association of BRAF mutation in preoperative FNAB
specimens with more extensive disease at surgery and
subsequent poorer clinical outcomes.
In comparison with the wild-type, BRAF mutation strongly
predicted extrathyroidal extension, thyroid capsular
invasion, and lymph node metastasis at the time of surgery.
Over a median follow-up of 3 years PTC
persistence/recurrence was seen in 36% of BRAF mutationpositive cases vs. 12% of BRAF mutation-negative cases
Mingzhao Xing, Douglas P Clark, Haixia Guan, Meiju Ji, Alan PB Dackiw, Kathryn A Carson,
Matthew Kim, Anthony P Tufaro, Paul W Ladenson, Martha A Zeiger, and Ralph P Tufano
J Clin Oncol. 2009 Jun 20;27(18):2977-82
FIG. 3. Kaplan-Meier estimate of recurrence-free probability of PTC in patients with (+) or
without (-) BRAF mutation
Xing, M. Endocr Rev 2007;28:742-762
FIG. 3. Kaplan-Meier estimate of recurrence-free probability of PTC in patients with (+) or without (–) BRAF mutation. A,
Analysis of a multicenter series consisting of 219 cases, mainly Caucasian patients. Log-rank test: 2 = 4.0, P = 0.04. [Adapted
from Xing et al., 2005 (83 ), with permission from The Endocrine Society.] B, Analysis of a Korean series consisting of 203
patients. Log-rank test: 2 = 4.60, P = 0.037.
Copyright ©2007 The Endocrine Society


Iodine Deficiency
Thyroiditis
Hashimotos
 Graves
 Subacute
 Postpartum and Painless



Organification defects
Lymphoma
Goiter




Marie de Medici 1622
Goiter as a symbol of
beauty & status
Common in USA until
1920s with introduction
of ionized salt
Today nodules are much
more common
Classification & Incidence of
Thyroid Cancer
Tumors of Follicular Cell Origin
Differentiated
Papillary 75%
Follicular 10%
Hurthle Cell 5%
Undifferentiated
Anaplastic 5%
Tumors of Parafollicular
Medullary 5%
Other
Lymphoma <1%
Surgical Levels of the Neck
Som et al, AJR 174:837 2003



Arises in thyroid already affected by
Hashimoto’s thyroiditis
Ultrasonographic appearance deeply
hypoechoic.
 Appearance not significantly different than in
Hashimoto’s
 Rapid growth of goiter should raise suspicion
Diagnosis by cytology and flow cytometry
Image courtesy of Woody Sistrunk, MD, FACE
Before the FNA

Clinical Risk Factors for Malignancy
Age <20 or >70 years of age
 Male gender
 History of radiation exposure
 Familial PTC, MTC, Gardners, FAP, MEN
 Symptoms of dysphagia or dysphonia
 Incidental focal PET positive nodule
 Firm/fixed mass with cervical lymphadenopathy

Before the FNA

TSH level
If normal or high  FNA
 If low, consider I-123 scan as “hot” nodules usually
do not require FNA


Ultrasound thyroid and neck
Identify other potentially suspicious nodules
 Identify abnormal lymph nodes
 Ultrasound used to guide FNA
