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Current Concepts in Pathology
CoCoPath Bulletin vol 1, issue 2
March/April 2015
ULTRASOUND-GUIDED FINE NEEDLE ASPIRATION BIOPSY:
A KEY TOOL FOR THYROID NODULE EVALUATION
The prevalence of thyroid
nodules in North America
ranges from 4-7% in the adult
population, with an annual
incidence of 0.1% (300,000
newly diagnosed nodules per
year). By age 60, about 50% of
all people have a thyroid nodule
detected by either physical
examination or imaging. The
majority of thyroid nodules
(>90%) are benign and do not
cause symptoms. Typically
nodules are detected incidentally
by the patient, during routine
physical examination, on
radiographic imaging for
unrelated reasons, or from
abnormal thyroid function tests.
Most thyroid nodules are
non-functioning, and tests for
thyroid hormones are typically
normal.
HISTORY AND PHYSICAL
EXAMINATION
Once a nodule is discovered, a
complete history and physical
examination is generally
undertaken. Pertinent history
includes a history of childhood
head and neck irradiation,
family history of thyroid
carcinoma, or thyroid cancer
syndrome (e.g., Cowden’s
syndrome, familial polyposis,
Carney complex, multiple
endocrine neoplasia [MEN] 2,
or Werner syndrome). Physical
findings that could suggest
malignancy include solitary
nodule, hardness, fixation of
nodule to surrounding tissues,
vocal cord paralysis, and lateral
cervical lymphadenopathy.
Initial laboratory tests may
include measurement of thyroid
hormone (thyroxine or T4) and
thyroid-stimulating test (TSH).
Unfortunately, it is usually not
possible to determine the
malignant potential of a thyroid
nodule by history, physical
examination and blood tests
alone. Further evaluation
typically requires specialized
testing by ultrasonography and
fine needle aspiration (FNA)
biopsy. FNA has also largely
replaced nuclear thyroid scans as
a first-line method of evaluation.
Current Concepts in Pathology
is a newsletter designed to keep
our clinical colleagues updated on
current topics in the field of
pathology, and how they correlate
with clinical practice.
In this edition, Dr. Risha
Ramdall, one of our
cytopathologists, discusses the
importance of ultrasound-guided
FNA in the evaluation of thyroid
nodules. Also presented is an
abstract on a novel minimally
invasive sampling technique with
TFF3 immunohistochemistry in
the evaluation of patients with
potential Barrett’s esophagus.
CoCoPath:
Nader Shihabi M.D.
Nick Byrne, M.D.
Christine Cesca, M.D.
Jeffrey Curtis, M.D.
Dennis Hwang, M.D.
Barry Latner, M.D.
Rajni Mandal, M.D,
Risha Ramdall, M.D.
CONTRA COSTA PATHOLOGY ASSOCIATES
399 Taylor Blvd, Ste 200, Pleasant Hill, CA 94523 | Office: 925-270-3575 | Fax: 925-270-3589 | www.cocopath.net
Continued from page 1
(Nuclear scans may still be
useful in the setting of
hyperthyroidism, as
hyperfunctioning nodules rarely
harbor malignancy and generally
do not require FNA.)
FINE NEEDLE
ASPIRATION BIOPSY
FNA is the most accurate and
cost-effective method for
evaluating thyroid nodules. No
serious adverse side effects or
seeding of tumor cells in the
needle track have been reported.
When performed by an
experienced physician,
specificity, sensitivity and
predictive value are > 90%.
When combined with
ultrasound imaging and
guidance, studies report lower
rates of non-diagnostic and
false-negative cytology results.
Ultrasound-guided FNA is
preferred for cystic nodules with
a higher likelihood of
non-diagnostic cytology
(>25-50% cystic component)
and nodules with a risk of
sampling error (difficult to
palpate or posteriorly located).
Ultrasound imaging during
FNA not only guides accurate
needle placement directly into a
nodule for optimal sampling,
but provides information about
nodule characteristics (i.e. solid,
cystic, or complex) and its
precise size and location. After
initial examination, the
ultrasound can also be used to
follow patients with benign
nodules to detect growth or
shrinkage over time.
Generally, thyroid nodules greater
than 1 cm are biopsied due to
higher risk of malignancy. In the
presence of 2 or more thyroid
nodules, ultrasound characteristics
are used to determine which
nodule is aspirated. When none of
the nodules have a suspicious
ultrasound appearance, only the
largest nodule is biopsied, with
observation and serial ultrasound
examinations of the other
nodules.
FNA REPORTING
The biopsy report will usually
indicate a diagnosis falling under
one of six categories set forth in
the most recent classification by
the 2007 National Cancer
Institute Thyroid Fine Needle
Aspiration State of the Science
Conference. This expanded
classification standardizes
terminology for thyroid FNA
cytology reporting:
1. Nondiagnostic/ Inadequate
(< 5% of FNA biopsies; 1-4%
risk of malignancy). A repeat
aspiration biopsy with US-guidance
is typically recommended.
2. Benign (60-70% of FNA
biopsies; 0-3% risk of malignancy).
Routine clinical follow-up at 6-18
month intervals is recommended.
3. Follicular Lesion of
Undetermined Significance
(3-6% of all thyroid FNA biopsies;
15% risk of malignancy).
Recommended management
requires clinical correlation.
4. Follicular Neoplasm/Suspicious
for Neoplasm (15-30% risk of
malignancy.) Surgical lobectomy is
typically recommended.
5. Suspicious for Malignancy
(60-75% risk of malignancy.)
Surgical lobectomy or total
thyroidectomy is recommended.
6. Malignant (3-7% of all thyroid FNAs;
97-99% risk of malignancy.) Total
thyroidectomy is recommended.
CONTRA COSTA PATHOLOGY ASSOCIATES
399 Taylor Blvd, Ste 200, Pleasant Hill, CA 94523 | Office: 925-270-3575 | Fax: 925-270-3589 | www.cocopath.net
MOLECULAR DIAGNOSTICS
Over the past decade, several molecular
markers have emerged as possible
diagnostic tools for providing a more
definitive diagnosis for thyroid nodules
with an indeterminate diagnosis on FNA
biopsy. Somatic mutation testing
(BRAF, RAS, RET/PTC and PAX8/PPAR-γ), gene expression profile analysis,
immunocytochemistry (ICC) and
miRNA analysis have all been tested in
indeterminate thyroid lesions with
reasonable success. However, every one
of these markers has its own set of
limitations, and none has yet been
proven to perfectly distinguish benign
from malignant nodules in FNA indeterminate cases. Furthermore, the gold
standard to which these molecular tests
are often measured up against – cytologic
diagnosis – is imperfect, with discordances in up to 14% of cases, even after
independent expert thyroid cytopathologist review. This potential for interobserver variability remains a weakness in
any platform that relies on FNA
diagnosis as its standard.
remains the gold standard for the
evaluation of a thyroid nodule. It is safe,
accurate, and cost-effective, with a
diagnostic accuracy of over 90%.
Clinical management should be guided
by the results of the ultrasound-guided
FNA.
The American Thyroid Association
Guidelines Task Force is currently
reviewing several commercially available
gene expression markers in order to
generate expert consensus guidelines on
when and how to use these platforms.
Given the clear limitations described,
more progress in this technology is
anticipated in the next few years.
References:
SUMMARY
Compared to other diagnostic
modalities at this point in time, FNA
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
Am J Clin Pathol 2009;132:658-665.
Thyroid 2009; Vol 19, Number 11:1167-1214.
J Clin Endocrinol Metab 81:3563–3569.
Thyroid 1998; 8:15–21.
Thyroid 1998;8:283–289.
Diagn Cytopathol 36:425–437.
J Clin Endocrinol Metab 87:1941–1946
J Clin Endocrinol Metab 91:3411–3417.
J Clin Endocrinol Metab 87:4924–4927.
N. Engl. J. Med. 367(8), 705–715 (2012).
Expert Rev Mol Diagn. 2013;13(6):613-623.
April is Head & Neck Cancer and Esophageal Cancer Awareness Month
Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil
factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study.
Ross-Innes CS et al; BEST2 Study Group. (71 collaborators)
PLoS Med. 2015 Jan 29;12(1):e1001780. doi: 10.1371/journal.pmed.1001780. eCollection 2015.
Abstract
BACKGROUND:
Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic
screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study
was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with
immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to
diagnose BE.
METHODS AND FINDINGS:
A case-control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals
comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The
primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with
endoscopy and biopsy. In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were
attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and
patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p <
0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%-83.0%), increasing to 87.2% (95% CI 83.0%-90.6%) for patients with
3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%-94.8%) in 107
patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The
specificity for diagnosing BE was 92.4% (95% CI 89.5%-94.7%). The case-control design of the study means that the results are not
generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure.
CONCLUSIONS:
The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and
inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.
CONTRA COSTA PATHOLOGY ASSOCIATES
399 Taylor Blvd, Ste 200, Pleasant Hill, CA 94523 | Office: 925-270-3575 | Fax: 925-270-3589 | www.cocopath.net
399 Taylor Blvd, Suite 200
Pleasant Hill, CA 94523
www.cocopath.net
March/April 2015
CoCoPath Bulletin