Thyroid Cancer: Best Evidence
Bruce H. Campbell, MD FACS
Division of Head and Neck Surgical Oncology
Guidelines
• American Thyroid Association
• American Association of Clinical Endocrinologists
and American Association of Endocrine Surgeons
• British Thyroid Association and The Royal College
of Physicians
• National Comprehensive Cancer Network
• European Thyroid Association (DTC)
• European Association of Nuclear Medicine (RAI)
Revised American Thyroid Association
Management Guidelines for Patients with
Thyroid Nodules and Differentiated Thyroid
Cancer, November 2009
The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid
Nodules and Differentiated Thyroid Cancer
David S. Cooper, M.D.1 (Chair)*, Gerard M. Doherty, M.D.,2 Bryan R. Haugen, M.D.,3 Richard T. Kloos, M.D.,4
Stephanie L. Lee, M.D., Ph.D.,5 Susan J. Mandel, M.D., M.P.H.,6 Ernest L. Mazzaferri, M.D.,7 Bryan McIver, M.D.,
Ph.D.,8 Furio Pacini, M.D.,9 Martin Schlumberger, M.D.,10 Steven I. Sherman, M.D.,11 David L. Steward, M.D.,12
and R. Michael Tuttle, M.D.13
Abbreviations
•
•
•
•
•
TSH = Thyroid Stimulating Hormone
RAI = Radioactive Iodine
Tg = Thyroglobulin
DTC = Differentiated Thyroid Cancer
PTC = Papillary Thyroid Cancer
Case Report (1) – Initial Evaluation
36-year-old female with slowly growing 2 cm
mass in the right thyroid lobe
No symptoms
Work-up?
Ultrasound: 2 cm cystic mass
Management?
What is the most appropriate next
step?
A. FNA with cytology only
B. FNA with cytology and
thyroglobulin level
C. FNA with cytology and
PTH level
D. No biopsy
0%
A.
0%
0%
B.
C.
0%
D.
Thyroid nodules
• Palpable nodules: 1% - 5% of people
• Ultrasound detected nodules: 19–67%
– Higher in women and elderly
• Thyroid cancer: 5–15% of nodules
– Depends on age, sex, radiation exposure history, family history, and
other factors
• Differentiated thyroid cancer (DTC): 90%
• New Cases in US: 37,200 and increasing
– All of the increase is in papillary carcinoma (PTC)
• Of the rising incidence
– 49% <1 cm
– 87% <2 cm
ATA Guideline Questions
Thyroid nodule assessment
–
–
–
Evaluation of new nodule(s)
Laboratory tests and imaging
Role of FNA
• Follow up of nodules
• Medical therapy
Initial management of DTC
• Preop and Postop Staging
• Surgery for indeterminate nodules
and DTC
• RAI remnant ablation
• Thyroid Stimulating Hormone (TSH)
suppression therapy
• Adjunctive RT and/or
chemotherapy
Long term management of DTC
• Thyroglobulin (Tg) assays
• Ultrasound and other imaging
• TSH suppression
• Metastatic disease
• Management of Tg-positive, scannegative patients
• Adjunctive RT and/or chemotherapy
Directions for future research
Increased Risk
Past History
• Childhood head and neck irradiation
• Total body irradiation for BMT
• Exposure to ionizing radiation from fallout in childhood or
adolescence
• Rapid growth
• Voice weakness
Findings
• RLN paresis
• Lateral cervical lymphadenopathy
• Fixation of the nodule to surrounding tissues
Family History with Increased Risk
Any first degree relative with thyroid carcinoma
Thyroid cancer syndromes
• Cowden’s Syndrome: PTEN gene - Hamartomas and cancers of thyroid (WDTC),
uterus, and breast.
• Familial Adenomatous Polyposis: APC gene – associated with papillary
carcinoma
• Carney complex, Type I: PRKAR1A gene – Cardiac myxomas, hormone over
activity, and tumors (including WDTC)
• MEN 2 (Sipple Syndrome): RET protooncogene
– MEN 2a: MTC, pheochromocytoma, parathyroid adenoma
– MEN 2b: MTC, mucosal neuromas, pheochromocytoma
• Werner Syndrome (premature aging): WRN gene – Multiple disorders and
cancers including thyroid
• Pendred Syndrome: PDS gene - Early-onset SNHL, goiter
FNA Recommendations
Nodule sonographic or clinical features
Recommended nodule threshold size for FNA
High-risk history
Nodule WITH suspicious sonographic features
>5 mm
Strongly recommended (A)
Nodule WITHOUT suspicious sonographic
features
Abnormal cervical lymph nodes
>5 mm
Recommend “neither for or against” (I)
Microcalcifications present in nodule
≥1 cm
Recommended – Evidence (B)
>1 cm
Recommended – Evidence (B)
All
Strongly recommended (A)
Solid nodule
AND hypoechoic
AND iso- or hyperechoic
≥1–1.5 cm
Recommended – Expert opinion (C)
Mixed cystic–solid nodule
WITH any suspicious ultrasound featuresb
≥1.5–2.0 cm
Recommended – Evidence (B)
WITHOUT suspicious ultrasound features
≥2.0 cm
Recommended – Expert opinion (C)
Spongiform nodule
≥2.0 cm
Recommended – Expert opinion (C)
Purely cystic nodule
Regardless of size
NOT Recommended - Evidence (E)
High suspicion [malignancy risk 70-90%]
Solid hypoechoic nodule or solid hypoechoic component of a partially cystic
nodule with one or more of the following features: irregular margins,
microcalcifications, taller than wide shape.
Intermediate suspicion [malignancy risk 10-20%]
Hypoechoic solid nodule without high suspicion features
Low suspicion [malignancy risk 5-10%]
Isoechoic or hyperechoic solid nodule, or partially (> 50%) cystic nodule,
with eccentric solid area without high suspicion features
Very low suspicion [<3%]
Spongiform or partially cystic nodules without high or intermediate
suspicion features
Benign [<1%]
Purely cystic nodules
Slide credit: Brian Haugen, MD (University of Colorado)
Bethesda Classification
Diagnostic Category
Risk of Malignancy (%)
Usual Management
Non-diagnostic; unsatisfactory
1-4%
Repeat FNA - U/S guidance
Benign
0-3
Clinical follow-up
Atypia or follicular lesion “of
undetermined significance”
~5-15%
Repeat FNA
Follicular neoplasm or suspicious
for a follicular neoplasm
15-30%
Surgery
Suspicious for malignancy
60-75%
Surgery
Malignant
97-99%
Surgery
Adapted from: Cibas ES, Ali SZ, Am J Clin Path 2009; 132:658-665
Goals of Initial Therapy of DTC
Remove primary tumor and involved cervical lymph nodes
Minimize treatment-related morbidity
Permit accurate staging of the disease
Facilitate postoperative treatment with radioactive iodine,
where appropriate
• Permit accurate long-term surveillance for disease recurrence
– Implies near-total or total-thyroidectomy
• Minimize the risk of disease recurrence and metastatic spread
– Implies TSH suppression and possible adjuvant therapy for
some patients
•
•
•
•
Case Report (2) – Initial Evaluation
• 45-year-old female with an enlarging 2 cm
thyroid mass
• No symptoms
• Ultrasound shows mixed cystic and solid mass
with microcalcifications
Which of the following tests is always
indicated at this point?
A. CT or MRI
B. PET/CT
C. Thyroid stimulating
hormone (TSH)
D. Thyroglobulin
0%
A.
0%
0%
B.
C.
0%
D.
Preoperative Evaluation for Patient
with Suspicious Cytology
Recommended
NOT recommended
Thyroid Stimulating Hormone (TSH)
CT or MRI
Ultrasound of contralateral thyroid lobe
PET/CT
Ultrasound of neck nodes
Thyroglobulin
FNA of suspicious nodes if it would change
surgical management
Surgical Guidelines (Initial)
Level
Patients with clinical nodal disease
confined to the neck
Therapeutic lateral and/or central neck B
dissection
PTC with clinically uninvolved central
neck lymph nodes, especially for
advanced primary tumors (T3 or T4)
Prophylactic central-compartment
neck dissection (ipsilateral or bilateral)
C
Small (T1 or T2), noninvasive, clinically Near-total or total thyroidectomy
node-negative PTCs and most follicular without prophylactic central neck
cancer
dissection
C
Biopsy-proven metastatic lateral
cervical lymphadenopathy
Therapeutic lateral neck
compartmental lymph node dissection
B
RAI in lieu of completion
thyroidectomy
NOT recommended
D
RAI Recommendations
Level
T4 withdrawal
LT4 withdrawal > 2–3 weeks or LT3 treatment > 2–4 weeks and B
or T3 treatment LT3 withdrawal for 2 weeks. Goal: TSH >30 mU/L. Thyroid
prior to RAI
replacement resumed 2 or 3 days after RAI administration
Thyrogen
(rhTSH)
Remnant ablation performed following thyroxine withdrawal
or rhTSH stimulation
A
Low-dose RAI
30–100 mCi in low-risk patients
B
High-dose RAI
100–200 mCi with residual microscopic disease or more
aggressive tumor histology (e.g., tall cell, insular, columnar cell
carcinoma
C
Pre-RAI lowiodine diet
1–2 week low-iodine diet recommended particularly for those
with high iodine intake
B
Timing of postRAI scan
A post-therapy scan recommended 2–10 days after the
therapeutic dose
B
Adjuvant Management
Level
High-and
intermediate-risk
patients
TSH suppression therapy to maintain TSH below 0.1 mU/L
B
Low-risk patients
+/- RAI
TSH suppression therapy to maintain TSH at or slightly
below normal range (0.1 – 0.5 mU/L)
B
External beam
• Over age 45 with grossly visible extrathyroidal
radiation therapy
extension and high likelihood of microscopic residual
disease
• Patients with gross residual tumor in whom further
surgery or RAI would likely be ineffective
B
Chemotherapy
F
No role for routine use
Case Report (3) – Long-term follow-up
• 35-year-old female treated one year ago for a T1
N1a M0 (Stage I) papillary carcinoma of the right
lobe with total thyroidectomy, RAI, and TSH
suppression
• Undergoes the appropriate follow-up studies
– Thyroglobulin level
– Thyroglobulin antibodies
– Ultrasound
Case Report (3)
• Results:
– Thyroglobulin: 1
– Thyroglobulin antibodies <20
– Ultrasound: 4 mm spherical node with loss of
hilum and some microcalcifications
Next steps?
A. Observation
B. Excisional node biopsy
C. FNA with thyroglobulin
washout
D. MRI with contrast or CT
without contrast
0%
A.
0%
0%
B.
C.
0%
D.
Thyroid Cancer Follow-up
Patient is considered “free of disease,” IF
• No clinical evidence of tumor
• No imaging evidence of tumor
– No uptake outside the thyroid bed on the initial WBS
– No imaging evidence of tumor on a recent diagnostic
scan and neck US
• Undetectable serum Tg levels during TSH
suppression and stimulation in the absence of
interfering antibodies
Post-Treatment Surveillance
Level
Thyroglobulin levels and Tg antibody
measurement
Every 6-12 months after thyroidectomy +/- RAI
A
Thyroglobulin levels and neck ultrasound
“Periodically” for less than total thyroidectomy or
total without RAI
B
Thyroglobulin level after T4 withdrawal
or rhTSH stimulation 12 months after
treatment
•
For low-risk, clinically and U/S negative with TSH
< 0.1.
Follow Tg
A
Cervical ultrasonography
6–12 months and then periodically, depending on
the patient’s risk for recurrent disease and Tg status
B
If a positive result would change management
A
If there is growth or if the node threatens vital
structures.
C
•
•
Ultrasound-guided FNA of suspicious
nodes >5-8 mm
Tg measurement of needle wash-out
Observation of suspicious nodes <5–8
mm
•
Post-Treatment TSH Suppression
Level
Persistent disease
Maintain TSH <0.1 mU/L
indefinitely
B
High-risk and NED
Maintain TSH 0.1 – 0.5 mU/L for
5–10 years
C
Low-risk and NED
Maintain TSH 0.3 – 2 mU/L
B
Low-risk, no RAI,
clinically NED, U/S
negative,
undetectable Tg
TSH may rise into low normal
range (0.3–2 mU/L)
C
Current Thyroid Cancer Trends in the US
Davies L, JAMA Otolaryngol Head Neck Surg. 2014 (Apr);140(4):317-322
Papillary Thyroid Cancer Overdiagnosis and
Overtreatment
Approaches:
• Active surveillance of incidentally identified,
asymptomatic, small PTCs
• Relabeling incidentally identified small thyroid
neoplasms with a term other than “cancer”
• Investigate patient-level patterns of care and
thyroid risk factors that result in a thyroid cancer
diagnosis
Davies L, JAMA Otolaryngol Head Neck Surg. 2014;140(4):317-322
Active Surveillance Trial
Memorial Sloan-Kettering Cancer Center
< 1.5 cm PTCs; confined to gland; no nodes
Ultrasound every 6 mo x 2 years then yearly
80% who are offered the trial opt to
participate
• Preliminary results: 90% with no change at 2
years
•
•
•
•
Jan ‘14 Triological Meeting Debate
Shaha v. Tufano
Ashok Shaha – From Day 1:
• Recognize that nodal mets in PTC occur often and early
• Usually remain subclinical
• All caregivers must understand this
• Can be found incidentally with aggressive screening
• Often watched with active surveillance
• Reserve surgical intervention for progressive disease
-Jan ‘14 Triological Society Meeting
http://ow.ly/yVYHJ
Changes for 2014
New recommendations regarding
• Preoperative ultrasound for all suspicious masses
• Voice/laryngoscopy
• Preoperative CT imaging with contrast for suspected
advanced disease
• Cancers between 1 and 4 cm w/o extrathyroidal extension,
and cN0, the initial surgery can be either total
thyroidectomy (high-risk tumors with nodal mets, requiring
RAI) or thyroid lobectomy (low and medium-risk tumors)
• Consider central neck for advanced disease and N1b
Questions?
[email protected]
Reflections in a Head Mirror www.froedtert.com/reflections
Additional slides regarding decision
making and algorithms
MAJOR FACTORS IMPACTING DECISION MAKING IN
RADIOIODINE REMNANT ABLATION
Expected benefit
Factors
T1
T2
T3
T4
Nx,N0
N1
M1
Decreased risk
Description
of death
1 cm or less, intrathyroidal
No
or microscopic multifocal
1–2 cm, intrathyroidal
No
>2–4 cm, intrathyroidal
No
>4 cm
No
≥45 years old
Yes
Any size, any age, minimal
No
extrathyroidal extension
Any size with gross
Yes
extrathyroidal extension
No metastatic nodes
No
documented
No
>45 years old
Conflicting
data
Distant metastasis present
Yes
Decreased risk of
recurrence
No
May facilitate
initial staging and
follow-up
Yes
RAI ablation usually
recommended
No
Strength of
evidence
E
Conflicting data
Conflicting data
Yes
Yes
Selective use
Selective use
I
C
Conflicting data
Yes
Inadequate data
Yes
Yes
Yes
Yes
Yes
Selective use
B
B
I
Yes
Yes
Yes
B
No
Yes
No
I
Conflicting data
Conflicting data
Yes
Yes
Selective use
Selective use
C
C
Yes
Yes
Yes
A
Surgical Guidelines (Recurrence)
Level
Patients with persistent or recurrent
disease confined to the neck
Therapeutic lateral and/or central neck B
dissection
Subsequent discovery of DTC in lobe
after lobectomy if initial
recommendation would have been for
a total thyroidectomy
Completion thyroidectomy
B
Patients with recurrence in previously
dissected site or after prior EBRT
Limited lateral and/or central neck
dissection
C
Patients with invasion of the
aerodigestive tract
Resection of tumor + RAI +/- EBRT
B
Treatment of Metastases
Level
Benefit of rhTSH therapy + RAI
Unknown
D
RAI-avid pulmonary micrometastases
Treat with RAI every 6-12 months
A
• RAI-avid pulmonary macronodular
metastases
• RAI-avid bone metastases
Treat with RAI (100-200 mCi)
B
Symptomatic bone metastases
EBRT +/- steroids
C
Non-RAI-avid pulmonary disease
Clinical Trials
B-C
• Resectable, isolated symptomatic mets Resect
• Resectable brain metastases
B
Non-resectable brain metastases
C
EBRT

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