The evaluation and
management of thyroid
nodules
Ryan Hungerford, MD, ECNU
Providence Medical Center
May 3rd, 2011
Marie de Medici
By Peter Paul Rubens, 1622
Goiter considered
fashionable
Thyroid glands are beautiful
• In 1656, Thomas Wharton, English physician
and anatomist, is credited with naming the
thyroid gland:
• “glandulae thyroideae”…
– whose purpose is to beautify the
neck…particularly in females to whom for this
reason a larger gland has been assigned.”
Well, maybe
some goiters
aren’t quite as
attractive!
Thyroid Nodules
Benign (92-96%)
• Adenomas (Follicular or
Hurthle cell)
• Focal thyroiditis
• Thyroid, parathyroid, or
thyroglossal cysts
• Thyroid hemiagenesis
• Postsurgical or postradioiodine
remnant hyperplasia
• Rare: teratoma, lipoma,
hemangioma
Malignant (4-8%)
• Well-differentiated (96%)
– Papillary
– Follicular (includes Hürthle)
– Medullary
• Undifferentiated (3%)
– Anaplastic
• Miscellaneous (1%)
– Lymphoma, SCC, metastatic
carcinoma, etc.
Thyroid cancer
• In general, thyroid cancer is a slow-growing, treatable,
often curable, disease with a low mortality rate*
– ~98% 10-year mortality for PTC
• Unfortunately, recurrences are common and a nonnegligible number of patients will experience:
– Progressive disease with regional spread to cervical or
mediastinal lymph nodes
– Pulmonary or skeletal metastases
– Cerebral metastases
– Death (often from respiratory failure)
• In 2010:
– 44,670 people were diagnosed with thyroid cancer
– 1,690 people died
*does not apply to poorly-differentiated
cancer, such as anaplastic thyroid ca
Thyroid cancer incidence is rising1,2
1975
• Incidence
2007
• Incidence
– 4.85 cases per 100,000
• Mortality
– 11.99 cases per 100,000
• Mortality
– 0.55 deaths per 100,000
– 0.47 deaths per 100,000
2.4 fold increase in thyroid
cancer incidence
1Davies.
JAMA 2006;295:2164.
2NCI Surveillance, Epidemiology
and End Results (SEER)
RED= rising
incidence
Data from the National
Program of Cancer
Registries (NPCR) and
National Cancer Institute
using SEER database.
Conclusions: the increased incidence of
thyroid cancer is due to “overdiagnosis”
of subclinical disease
49% of the increased incidence
attributable to small (<1cm)
papillary thyroid cancers
1Davies.
JAMA
2006;295:2164.
There is more to this story…
• If the higher incidence is exclusively
attributable to detection…
• then it would be expected that only the
number of patients with smaller tumors and
early-stage disease would be increasing.
Larger, more aggressive tumors:
Incidence also rising
Morris study (Am J Surg 2009)
• SEER database since 1983
• Tumors >4cm
– All showing rising incidence
– About 5% annual % ↑
• Extrathyroidal extension
– 0.8 per 100,000 (1983)
– 1.7 per 100,000 (2006)
Chen study (Cancer 2009)
• SEER database since 1983
• Increased incidence in
localized, regional and
distant stage tumors
• Rates of distant mets have
risen from 4% to 9%
• Lymph node mets
– 1.0 per 100,000 (1983)
– 2.9 per 100,000 (2006)
Increasing thyroid cancer incidence not
just “overdiagnosis” of subclinical disease!
<1cm
1.0-2.9cm
3.0-3.9cm
>4cm
1.0-2.9cm
3.0-3.9cm
>4cm
Female
<1cm
Male
Chen. Cancer
2009;115:3801.
Thyroid nodules: epidemiology
• In the United States, 4 to 7% of the adult population have a
palpable thyroid nodule
– ~100-150 million Americans have thyroid nodules (u/s + P)
– 300,000 new nodules identified in 2010!
– Incidental discovery increasing1 with widespread use of CT, MRI,
carotid u/s, PET 2
• More common in women, and increased incidence with age
– If you are a 60 y/o female, there is a 50% chance you have a
thyroid nodule
– By some estimates, it is more common to have a nodule than to
not have a nodule!
• Only 1 of 20 clinically identified nodules is malignant
1Am
J Neuroradiol 1997;18:1423.
2 J Nuc Med 2006;47:609.
Case #1: “They found a nodule in my
thyroid gland”
• 50 year old female presents for evaluation of
neck pain following whiplash from a car
accident
• CT scan of the neck was performed
• Radiology report:
– “Right thyroid lobe contains an ill defined nodule
which is inadequately evaluated by this
examination. Malignancy cannot be ruled out and
a dedicated US study is recommended.”
• Now what?
Basic approach to a thyroid nodule
1.
2.
3.
4.
5.
History
Physical
Neck Ultrasound
TSH
Decision to FNA based upon above data
Perform a good history
Emphasis: thyroid cancer risk factors
•
Relevant family history
– First degree relative with thyroid cancer
•
The “sister factor”
Especially a sibling (6x ↑ risk) or a sister if you are female (11x ↑ risk)
– Family history of multiple endocrine neoplasia (MEN) 2, Carney complex, Cowden’s syndrome
•
Age and gender
– Male gender and extremes of age (<14 or >70) associated with ↑ risk of malignancy
•
Radiation exposure
– History of childhood head and neck irradiation (acne, tonsils, thymus, tinea capitis, etc.)1
– History of BM transplantation with whole body irradiation
– Exposure to ionizing radiation from fallout (in childhood or adolescence), i.e. Chernobyl
•
Relevant symptoms
–
–
–
–
Rapid growth of nodule (if palpable) or palpable cervical lymph nodes
Hoarseness
The three “Ds”: dysphagia, dyspnea, dysphonia
Symptoms of thyrotoxicosis (palpitations, tremor, etc.) more s/o toxic nodule
1Otolaryngol
Head Neck
Surg 1996;115:403.
Prevalence of malignancy in relation to patients' age in years
increased prevalence in patients at the extremes of age
Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301
Nuclear fallout
• Chernobyl, 1986
• Estimated that 60% of
nuclear fallout landed in
Belarus
• Thyroid cancer
incidence rose
dramatically, remains
elevated to present day
>6,000 cases of thyroid cancer
diagnosed as of 2005 among
children/adolescents exposed
in Belarus, Ukraine, Russia
The developing thyroid gland is
very sensitive to radiation
Chernobyl incident
USA Today, April 26th, 2011
Perform a focused physical examination
emphasis: lymph nodes
• Examine neck for palpable nodule(s) and
enlarged cervical lymph nodes
– Particular concern if fixed, hard mass
• Palpation vs. ultrasound
– ~40% of nodules >2cm are MISSED by palpation!1
– Using ultrasound, about 15% of patients will have an
additional non-palpable nodule >1cm, and 15% will
have no nodule at all!2
• For most patients with known or suspected
thyroid nodules, the physical examination is not
particularly useful!
1Brander
2Tan
et al. J Clin Ultrasound 1992;20:37.
GH et al. Arch Intern Med 1995;155:2418.
Covered so far….
1. History
2. Physical
3. Neck Ultrasound
4. TSH
5. Decision to FNA based upon above data
ATA thyroid cancer guidelines
2009;Thyroid;19:1167.
Screening ultrasound not
appropriate for fatigue,
hypothyroidism, or
elevated TPO antibodies
AACE/AME/ETA Thyroid Nodule
Guidelines, Endocr Pract. 2010;16(Suppl 1)
Nodule features by Ultrasound
More likely benign
• Iso- or Hyperechoic
• Smooth borders
• Halo
• Uninterrupted Peripheral or
“eggshell” calcifications
• Low vascularity
• Soft (elastic)
More likely malignant
• Hypoechoic
• Irregular borders
• No halo
• Microcalcifications
• tall>wide
• High vascularity
• Hard (not elastic)
There is no single pathognomic
finding that confirms
malignancy or benignity.
Normal thyroid gland
Normal thyroid
Colloid artifact
Benign cyst
Well-defined borders
Irregular
borders
Microcalcifications
Microcalcifications
Hypoechoic
Taller than wide
Hypoechoic
Hypervascular
Not a cyst! This is a
parathyroid adenoma
PTH dropped from 31040 after removal
Nodule features by Ultrasound
More likely benign
• Hyperechoic
• Smooth borders
• Halo
• Uninterrupted Peripheral or
“eggshell” calcifications
• Low vascularity
• Soft (elastic)
More likely malignant
• Hypoechoic
• Irregular borders
• No halo
• Microcalcifications
• tall>wide
• High vascularity
• Hard (not elastic)
Ultrasound Elastography
• Malignant lesions are associated with changes in
the mechanical properties of a tissue
• Elastography is a dynamic technique that uses
ultrasound to provide an estimation of tissue
stiffness by measuring the degree of distortion
under the application of an external force
• Has been used to differentiate cancer from
benign lesions in prostate, breast, pancreas, LNs
• Now being applied to thyroid nodules
92 consecutive patients who underwent surgery for solitary thyroid nodules
-all underwent standard thyroid ultrasound, standard risk assessment
-Elastography was performed for all nodules
-nodules “scored” based on how “ELASTIC” they are
Rago. J Clin Endocrinol
Metab 2007;92:2917-2922.
Elasto study findings
• 92 cases, all proceeded to surgery, known histologic diagnosis
– 34% malignant
– 66% benign
• Elastography
– Score 1-2 identified in 49 patients: all benign
– Score 3 identified in 13 patient: 1 malignancy, 12 benign
– Score 4-5 identified in 30 patients: all malignant
• Conclusions
– If your thyroid nodule is very elastic (score 1-2), it is most likely benign
– If your thyroid nodule is very firm (score 4-5), it is most likely cancer
• Elastography is of tremendous clinical value, particularly when
added to other standard US sonographic features
– Limitations: can’t be used on cystic/solid nodules or calcified nodules
Rago. J Clin Endocrinol
Metab 2007;92:2917-2922.
Elastic:
Score 1
Hard:
Score 5
Should I do any lab testing for a
thyroid nodule?
•
TSH for everybody!
– If low, don’t biopsy! (To be reviewed in next few slides)
•
TPO and TG antibodies usually NOT necessary
– But, TPO abs may help determine the explanation for other sonographic findings (ex:
Hashimoto’s)
– ↑ TG abs associated with thyroid cancer, hypothesis: thyroid inflammation is tumorigenic or
abnormal TG expressed by tumor cells triggers immune response
•
A
serum
TSH
is
Elevated in Medullary Thyroid Cancer (3-5% of thyroid malignancies) and C-cell hyperplasia
and may help detect MTC at an earlier stage
indicated
inscreening
all inpatients
Some recommend
universal calcitonin
patients with nodules
with thyroid nodules
Calcitonin
–
–
•
•
•
•
American Thyroid Association (2009) guidelines: recommendation I
AACE, AME, European Thyroid Association: “consider”
Always measured if family history of MTC or MEN2
Thyroglobulin
– Not useful, no relationship to thyroid malignancy
– Universal consensus among all professional societies (ATA, AACE, AME, ETA)
– Do NOT measure!
AACE/AME/ETA Thyroid Nodule
Guidelines, Endocr Pract.
2010;16(Suppl 1).
ATA guidelines for management of
thyroid nodules and thyroid cancer,
Thyroid, 2009;19(11):1167.
Why is the TSH so useful?
• It helps determine if the
nodule is likely to be a
“toxic” adenoma
– These are autonomous,
hyperfunctioning nodules,
aka “hot” nodules
– They are [almost] always
benign!
– Thus, FNA is usually*
unnecessary
– If the TSH is low, patient
should be sent for a
radionuclide study first
and/or referred to endo
Important: thyroid uptake and scan
is not appropriate for MOST
patients with thyroid nodules!
*if nodule is smaller (<1.5 or so) with
suspicious features, FNA may still be indicated
Does TSH correlate with risk of
malignancy in a patient with a nodule?
• Prospective study of 1,183 patients with
palpable thyroid enlargement
• All had FNA and/or surgery
• TSH measured at presentation, then
compared to FNA and/or surgical findings
Boelaert K. J Clin Endocrinol
Metab 2006;91(11):4295.
Risk of thyroid cancer increases as TSH rises
Boelaert, K. et al. J Clin Endocrinol
Metab 2006;91:4295-4301
Estimated probability of malignancy in 40 y/o
female with a solitary thyroid nodule
Why?
TSH
Risk of cancer_
TSH has a trophic effect on thyroid cancer
0.3
8%
growth, likely mediated by TSH receptors on
0.5
8.4%
tumor cells.
1.0
9.4%
TSH suppression is an independent
predictor
3.0
14.6%
of relapse-free survival from differentiated
5.0
21.9%
thyroid cancer.
6.0
26.4%
Boelaert, K. et al. J Clin Endocrinol
Metab 2006;91:4295-4301
Test: true or false?
• The larger the nodule, the more likely it is to
be cancer.
• A patient with a solitary nodule is more likely
to have cancer than a patient with multiple
nodules (multinodular goiter).
• Treatment with levothyroxine will shrink
thyroid nodules.
Nodule features by Ultrasound
More likely benign
• Hyperechoic or isoechoic
• Smooth borders
• Halo
• Uninterrupted Peripheral or
“eggshell” calcifications
• Low vascularity
• Soft/elastic
More likely malignant
• Hypoechoic
• Irregular borders
• No halo
• Microcalcifications
• tall>wide
• High vascularity
• Hard/not elastic
No mention of size!
Malignancy rate was not
lower (was actually higher) in
nodules <1cm
520 consecutive thyroid nodules evaluated from 2003-2006.
Group 1: subcentimeter nodules (N=247)
Group 2: supracentimeter nodules (N=273)
Ultrasound and FNA for all patients; malignant or suspicioussurgery
Berker. Thyroid
2008;18:603-608.
Size does not predict risk of malignancy
US guided FNA in 402 pts
with non-palpable nodules
Nodule 10 mm
Nodule >10 mm
9.1% cancer
7.0% cancer
Papini E et al. J Clin Endocrinol
Metab 2002:87:1941-1946
Cancer risk: Solitary vs Multiple
Cohort
n
McCall et al
442
(1986 U.S.)
Cochand-Priolett et al 132
(1994 France)
Sachmechi et al
443
(2000 U.S.)
Marqusee et al
156
(2000 U.S.)
Papini et al
494
(2002 Italy)
Deandrea et al
420
(2002 Italy)
Frates et al
1,985
(2006 U.S.)
Imaging
modality
Scan/Hx
FNA
Cancer risk
as %
Single
Multiple
Palpation
17
13
Scan/US
US guided
13
14
NM Scan
Palpation
8
10
US
US guided
7
9
US
US guided
9
6
US
US guided
6
7
US
US guided
14.8
14.9
Levothyroxine to shrink nodules
• Systematic review of 6 highest quality RCT
evaluating the efficacy of LT4 suppressive therapy
(>50% vol reduction)
• 5 of 6 studies: no statistically significant benefit,
though a trend toward nodule volume reduction
was seen
The use of LT4 to
• It is possible that a subgroup of patients, not
thyroid
nodules
identifiable shrink
based on
pre-treatment
characteristics,
benefit
hascould
fallen
out of favor
• Must consider potential skeletal and cardiac risks
of TSH suppression
Gharib. N Engl J Med 1987;317:70.
Castro. J Clin Endocrinol Metab 2002;87:4154.
Gharib. Ann Intern Med 1998;128:386.
Post test
• The larger the nodule, the more likely it is to
be cancer. False
• A patient with a solitary nodule is more likely
to have cancer than a patient with multiple
nodules (multinodular goiter). False
• Treatment with levothyroxine will shrink
thyroid nodules. False
Fine needle aspiration (FNA)
• Most accurate, cost-effective means to assess
The objective
of the
FNA
risk of malignancy
in a thyroid
nodule
• Highly accurate
in identification
malignancy
is to select
patientsofwho
– Sensitivity ~95%
highersurgery
willorneed
– Specificity ~85% or higher
– Note: false negatives (FNA positive for malignancy,
but negative histologic findings) do occur (~5%),
but are relatively uncommon
• In general, FNA findings are very reliable
The biopsy (FNA):
How it’s done
• Simple in-office procedure
–
–
–
–
Some use local anesthesia (1% Lidocaine), I do not
Patient prepped with alcohol (“clean,” not sterile, procedure)
Usually 25-27g needle, perpendicular or parallel approach
2 passes, sometimes 3-4, more usually does not ↑ diagnostic yield
• Most patients report minimal or no pain
– Bruising, bleeding rare (can be done on coumadin)
– Infection almost unheard of (case reports outside U.S.)
– Patient can go home or back to work, call if swelling
• Post-procedure
– Aspirate smeared on slides, sent to pathology
– Some endocrinologists stain slides (Diff-Quik) and assess adequacy by light
microscopy prior to sending slides to pathology, and repeat the procedure if
insufficient cellular material
– I do this for every FNA
Pathology Findings
• Benign (~65-70%)
• Indeterminate (~10-20%)
– Atypia or follicular lesion “of undetermined
significance”
– Follicular or Hürthle cell neoplasm
• Malignant or suspicious for malignancy (~5%)
• Non-diagnostic (aka insufficient) (10-15%)
Gharib, Papini. Endocrinol Metab
Clin North Am 2007;36:707.
When should FNA be performed?
• >5mm if high risk history (regardless of sonographic features)
– Family history of thyroid cancer, especially MTC
– Calcitonin >100pg/mL
– History Indication
of external beam
irradiation
or ionizingon
radiation
to the neck as
for
FNA
depends
the
a child or adolescent
– Prior hemithyroidectomy
with malignancy
clinical risk factors
and sonographic
– 18FDG avidity
on PETof
scanning
features
the nodule and cervical
• 1-2cm depending on presence or absence of suspicious sonographic
lymph
nodes
features (microcalcifications,
hypoechogenic,
etc.)
• ≥2cm if spongiform, >50% cystic, no suspicious sonographic
features
• A couple exceptions:
– NEVER if purely cystic, regardless of size
– ALWAYS if abnormal cervical lymph nodes
ATA guidelines for management of
thyroid nodules and thyroid cancer,
Thyroid, 2009;19(11):1167.
Important conclusions: The decision to perform FNA can NOT be
made without a focused medical history and can NOT be made
without high quality ultrasonography with lymph node evaluation.
AACE/AME/ETA Thyroid Nodule
Guidelines, Endocr Pract. 2010;16(Suppl 1)
Lymph node evaluation
• Presence of malignant-appearing lymph nodes
dramatically alters FNA threshold
• Many sonographers are not comfortable with
detailed LN evaluations, it is not currently part of the
sonographer training curriculum
• If pathologic LNs are identified, this changes the
surgery!
Thyroid, 2009;19(11):1167.
ECNU
• “Endocrine Certification
in Neck Ultrasound”
• Recognized by the
American Institute of
Ultrasound in Medicine
(AIUM), the preeminent
national accreditation
body for u/s practices
Why can’t we just FNA all nodules?
• Diagnostic possibilities from FNA
–
–
–
–
Non-diagnostic (insufficient)
Benign
Indeterminate, follicular neoplasm
Malignant or suspicious for cancer
• When FNA is performed,
depending on quality of cytology,
there is a 10-30% chance that the
patient will be sent for surgery
• The majority of “indeterminate”
cytology findings turn out to be
benign by histology
Massive numbers of people would be
subjected to surgery, most unnecessarily
The future is now (2011)
•
Genetic mutations associated with thyroid cancer have been identified
–
–
–
–
–
–
•
Molecular analysis
–
–
–
–
•
BRAFV600E, RAS, RET/PTC, Pax8-PPARɣ, galectin-3
Presence or absence provides useful information regarding malignancy risk
American Thyroid Association: “may be considered” for indeterminate cytology on FNA1
Just not enough data for a stronger recommendation
Until now
We can test for all of these mutations from DNA and RNA isolated from a single FNA pass,
have results back in a week2
High-dimensionality genomic data3
mRNA expression analysis used to measure 200,000+ transcripts from thyroid nodule samples
Potential to classify a nodule “benign” with high certainty (96% NPV!!)
Confirmatory studies underway, available in 3 states currently, but should be available soon 4
Clinical applicability
– Use of these advanced tests in those individuals found to have indeterminate FNA findings,
thus allowing greater certainty in determining if nodule is benign
– Could save thousands of people from unnecessary surgery
1ATA
thyroid nodule guidelines, 2009.
2www.asuragen.com
3Chudova. J Clin Endocrinol Metab 2010;95:1-9.
4www.veracyte.com
Back to case #1
•
•
•
•
50 y/o female
Incidental discovery of nodule on CT scan
A neck ultrasound is performed
This is what is found
2.1 cm nodule
clear borders
isoechoic, halo
Biopsy?
Not enough info!
Now biopsy?
Don’t forget about the Hx/PE/TSH
• History
– Palpitations for 3 months
– Weight loss of 8 lbs
– Slight tremor of hands, feels anxious
• Exam
– palpable R thyroid mass, no lymphadenopathy
• TSH 0.05
• Now what?
Send patient for
123I scan!
Case #2: incidental nodule by CT
• History
– No fam hx of thyroid ca, MEN2
– No history of neck irradiation
– Patient can’t feel nodule
• Exam
– You feel nothing
• TSH 1.9
• Ultrasound
– Solid nodule, measures 1.1cm
– Isoechoic, + halo, minimal
blood flow
– Normal-appearing lymph nodes
• Now biopsy?
NO.
This nodule can
be followed.
Case #3: incidental nodule by CT
• History
– Sister has thyroid cancer
– No history of neck irradiation
– Patient can’t feel nodule
• Exam
– You feel nothing
• TSH 1.9
• Ultrasound
– Solid nodule, measures 1.1cm
– Isoechoic, + halo, minimal
blood flow
– Abnormal lymph node (see
next slide)
Case #3: incidental nodule by CT
Now biopsy?
YES!
This is a high risk
patient.
*FNA decision would
have been different
without all the data!
Summary: thyroid nodule workup
Thyroid nodule
identified by
palpation or
imaging
History,
physical, TSH
TSH normal
or high
TSH low
Non
functioning
Follow
Suspicious
sonographic
features and/or high
risk history?
Hyperfunctioning
Evaluate and
treat for
hyperthyroidism
Diagnostic US
No
I-123 scan
Yes
FNA
Summary
• Thyroid cancer incidence is rising nationally and
in Oregon, for uncertain reasons
• Thyroid cancer is generally a treatable disease
with an excellent prognosis
• All known or suspected thyroid nodules require a
high quality U/S with lymph node assessment
• Serum TSH, family history, and sonographic
lymph node assessment are vital components to
proper w/u
• Most nodules do not need FNA, it depends on
above risk factors, time is on your side!
Thank you!
Further questions?
• 541-776-2003 (office)
• 801-540-1523 (cell)
• Please call with questions!
• For this topic or other endocrine topics