fna cytology of the thyroid - puzzlepix · ultrasound guided fna •full clinical details...
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FNA cytology of the thyroid
Gabrijela Kocjan, FRCPath
Head of Diagnostic Cytopathology
University College London
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Cytopathology of the thyroid
• The bigger picture
• Bird’s eye view of FNA diagnosis
• Classify we must
• Do we agree? Actual or virtual slides?
• What is non-diagnostic? Atypical?
• Are cysts benign or non-diagnostic?
• When to repeat and how many times?
• Will genes help?
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The most commonly occurring papillary thyroid
cancer in the United States is now a
microcarcinoma in a patient older than 45 years
• Estimated cases of thyroid cancer in USA – 2010:
– New cases: 44,670
– Deaths: 1,690
• SEER database 1974-2006
– Diagnosis of PTC has shifted 30yrs – 40-50 yrs
�Until 1999 < 45 yrs
�After 1999 >45 yrs
– Largest increase in <1.0 cm PTC
• Increase in small tumor detection but presentation at higher stage has doubled
Hughes et.al .Thyroid 2011
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Ultrasound guided FNA
•Full clinical details
•Details of the
aspiration procedure
•The site of the
abnormality
•The site of sampling
ROSE in one stop clinic ideal but not always
possible
Make technically optimal samples
Information needed
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SAME Cancer Rates for Solitary and
Multiple Thyroid Nodules
Definition FNA Cancer rate
of nodularity technique1 nodule MNG
McCall/USA scan/histo palpation 17% 13%Belfiore/Italy scan palpation 5% 5%Cochand/France scan/US US 13% 14%Sachamedchi/USA scan palpation 8% 10%Marqusee/USA US US 7% 9%Papini/Italy US US 9% 6%Barroeta /USA US US 52% 47%
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SAME Cancer Rates for Solitary and
Multiple Thyroid Nodules
Definition FNA Cancer rate
of nodularity technique1 nodule MNG
McCall/USA scan/histo palpation 17% 13%Belfiore/Italy scan palpation 5% 5%Cochand/France scan/US US 13% 14%Sachamedchi/USA scan palpation 8% 10%Marqusee/USA US US 7% 9%Papini/Italy US US 9% 6%Barroeta /USA US US 52% 47%
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Aim of FNA thyroid:
To reduce surgery for benign nodules
Patient with thyroid nodule
Excision No excision
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cells
colloid
Bird’s eye view of thyroid FNA
Cell /colloid ratio is a crucial factor in deciding the nature of the lesion
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cells
colloid
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cells
colloid
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cells
colloid
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cells
colloid
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cells
colloid
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cells
colloid
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cells
colloid
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colloid
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Description RCPath/BTA (UK)
BSRTC(Bethesda)
USANon-diagnostic for
cytological diagnosis
Thy1 Cystic lesion
(Thy1c)
I.Cyst fluid
only
Non-neoplastic/benign
Thy2Thy2c
Colloid cystII .
Neoplasm possible /Atypia of undetermined
significance
Thy3a III. or follicular lesion of
undetermined significance
Neoplasm possible/ suggesting follicular
neoplasm
Thy3fIV. Follicular
neoplasm or suspicious for a follicular neoplasm or
Hürthle cell (oncocytic) type
Suspicious of malignancy
Thy4 V.
MalignantThy5
VI.
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colloid
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colloid
II
I
III
IV
V
VI
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Kocjan G, Cochand-Priollet B, et al. Cytopathology 2010:21:86-92
1. Agreement about the need for
standardization of thyroid FNA
2. The majority favoured a translation of
the local terminology to Bethesda as
the first step towards a unified
nomenclature
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Non-diagnostic– BETHESDA I (Thy 1)
• Not of adequate epithelial cellularity
– FNA of solid lesions should have at least six groups of 10 thyroid
follicular epithelial cells across all the submitted slides
• Cystic lesion fluid specimens which do not reach the epithelial
cell adequacy criterion , contain macrophages but without
abundant colloid ( Thy 1c)
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Non-diagnostic– BETHESDA I (Thy 1)
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Non-neoplastic – Bethesda II (Thy 2)
Normal thyroid tissue Thyroiditis Hyperplastic nodules
Colloid nodules ( 6 groups
of 10 cells)
Cystic fluid with adequate
epithelium
Cystic fluid with colloid and
macrophages, Thy 2c
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Architectural ‘atypia’ Sparse colloid Sparsely cellular samples
Focal cytological
changes
A compromised
specimen
Atypical ‘cyst lining
cells’
Atypia of uncertain significance-
Follicular lesion of uncertain significance–
BETHESDA III (AUS/FLUS) (Thy3A)
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Follicular hyperplasia
Oncocytic adenoma
Follicular adenoma Follicular adenoma
Follicular carcinoma
Follicular neoplasm possible-
BETHESDA IV ( Thy 3f)
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Suspicious of malignancy –
BETHESDA V (Thy4)
Suspicious of malignancy, features do not allow confident diagnosis of malignancy
Thy 4 reports should be discussed at the thyroid
multidisciplinary meetings
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Lipid rich variant of
follicular carcinomaFVPC
Suspicious of malignancy –
BETHESDA V (Thy4)
Specimens of low cellularity and mixed cell types (normal and atypical)The tumour type suspected should be clearly stated , and will often be papillary carcinoma
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Suspicious of malignancy
BETHESDA V (Thy4)
Hyalinising trabecular
adenoma
Papillary carcinomaFollicular variant of
papillary carcinoma
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Medullary caPapillary ca
lymphoma
Anaplastic ca
Malignant – BETHESDA VI (Thy5)
Thy 5 reports should be discussed at the thyroid
multidisciplinary meetings
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• 6 observers, all experienced in thyroid FNA, members of RCPath working group
• 200 thyroid FNA slides from routine practice
• Circulated by post to each participant
• 1 or 2 slides per case
• Results collated
Am J Clin Pathol 2011;135:852-859
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Interobserver Agreement for THYROID FNA
reporting using UK RCPAth classification
Kocjan G et al. Am J Clin Pathol 2011;135:852-859
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Interobserver Agreement for
Combined Reporting Categories
relative to clinical managementConservative management BTSRTC 1-3 Surgical management TBSRTC 4-6
Thy1-Thy3a Thy3f-
Thy4Thy5
•Distinguishing non-neoplastic and neoplastic disease •The use of FNA classification is very helpful in providing clarity in clinical management of thyroid lesions
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Comparison between the microscopic and
digital interobserver agreement in
reporting thyroid cytology
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colloid
II
69%
I
4%
III
4%
IV
14%
V
2%
VI
7%
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UK RCPath BETHESDA Diagnostic category Risk of
cancer (%)
Terminology Risk of cancer (%)
Clinical management
Thy1/Thy1cNon-diagnostic for cytological diagnosisUnsatisfactory
I. Non-diagnostic
1-4
Reaspirate suspicious areas under US guidance at least 3 months after initial FNA
Thy2/Thy2cNon-neoplastic ()/Benign
II.Benign 0−3Clinical follow-up at 6-8 months intervals for 3 to 5 years
Thy 3aNeoplasm possible – atypia/non-diagnostic /Atypia of undetermined significance or follicular lesion of undetermined significance
III.Atypia of
undetermined significance or follicular lesion of undetermined significance
5−10
If TSH low consider iodine 123 scan. Repeat FNA in 3 to 6 months with US guidance
Thy3fNeoplasm possible - suggesting
follicular neoplasm /Follicular
neoplasm or suspicious for a follicular neoplasm
IV.Follicular
neoplasm or suspicious for a follicular neoplasm
20-45
Surgical consultation
Thy 4Suspicious of malignancy
V.Suspicious of
malignancy 60−75
Surgical consultation
Thy5 Malignant VI.Malignant 97−100 Surgical consultation
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PPV of malignant diagnosis for different thyroid FNA reporting categories
Total number with
F/U available
Neoplastic
( adenoma or
carcinoma)
Malignant
Thy 3a 10 50% 40%
Thy 3f 47 53% 36%
Thy4 9 77% 66%
Thy5 33 100% 100%
Lobo C et al. Acta Cytologica 2011 ;55:499-506
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UK RCPath BETHESDA Diagnostic category Risk of
cancer (%)
Terminology Risk of cancer (%)
Clinical management
Thy1/Thy1cNon-diagnostic for cytological diagnosisUnsatisfactory
? I. Non-diagnostic ? Reaspirate
suspicious areas under US guidance at least 3 months after initial FNA
Thy2/Thy2cNon-neoplastic ()/Benign
? II.Benign 0−3Clinical follow-up at 6-8 months intervals for 3 to 5 years
Thy 3aNeoplasm possible – atypia/non-diagnostic /Atypia of undetermined significance or follicular lesion of undetermined significance
40**small number
of cases f/u available
III.Atypia of
undetermined significance or follicular lesion of undetermined significance
5−15 If TSH low consider iodine 123 scan. Repeat FNA in 3 to 6 months with US guidance
Thy3fNeoplasm possible - suggesting
follicular neoplasm /Follicular
neoplasm or suspicious for a follicular neoplasm
28 IV.Follicular
neoplasm or suspicious for a follicular neoplasm
20-45 Surgical consultation
Thy 4Suspicious of malignancy
64f/u not
available in more than half
V.Suspicious of
malignancy 60−75
Surgical consultation
Thy5 Malignant 100 VI.Malignant 97−100 Surgical consultation
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Comparison of thyroidectomies in 2005 and 2010
thyroidectomies 2005-2006
thyroidectomies 2010-2011
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
benign lesionsmalignant lesions
58.93%
41.07%
47.22%52.78%
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Proportion of malignant lesions diagnosed
preoperatively in 2005 and 2010
Malignant lesions
Cytologicaldiagnosis
0
5
10
15
20
25
30
35
40
2005-20062010-2011
23
38
3
32
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Thyroid FNA and Adequacy
– Frequently low cellularity samples
• Cystic lesions
• Poor quality sampling by inexperienced aspirators
• Vascular targets - sample prone to dilution by blood
• Colloid rich lesions
– Well differentiated carcinomas are composed of
cells similar in appearance to “benign” follicular
cells
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Cystic change
Colloid goitre
Papillary ca
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colloid
II
54-77%
I
5-24%
III
0.7-18%
IV
1.5-9.7%
V
1.3-4.4%
VI
2-7%
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Goal of Adequacy Assessment
• Reduce “false negative” diagnoses arising
from insufficient sampling
– If adequacy criteria work:
– If adequacy criteria fail:
Malignancy rate in
“Inadequate” cases
Malignancy rate in
“Adequate” / Benign
cases
Greater
than
Malignancy rate in
“Inadequate”
cases
Malignancy rate in
“Adequate” / Benign
cases
Equal to
or less than
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Epithelial Quantitation
• Adequacy is defined by a number of epithelial
cells
– Less than a magical number inadequate
– More than a magical number adequate
• On a conceptional level, this seems logical
– But in practice, it has limitations
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Epithelial Quantitation
• Most commonly quoted criterion:
“at least 6 groups of benign follicular cells are required, each group composed of at least 10 cells.”
• Is referenced to:
– Goellner et al. Acta Cytol 1987;31:587-590
– Grant CS, et al. Surgery 1989;106:980-985
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Epithelial Quantitation
• Goellner et al. Acta Cytol 1987;31:587-590 (Mayo Clinic group)
– Palpation guided• 25 G needle / 1-4 passes / direct smears (fluid – Millipore filter) /
alcohol fixed / Pap stained
– “Adequate” if 5 to 6 groups of 10+ epithelial cells
• Colloid without cells is “non-diagnostic”
• “To be considered adequate for interpretation, our rule of thumb requires five to six groups……”
– 6,346 FNA in study
– 21% “non-diagnostic” (1,299 cases)
• 9.1% “non-diagnostic” excised (118 cases)
• 8.5% of the cases excised had carcinoma on biopsy (10 cases)
– 0.8% of “non-diagnostic” had carcinoma on biopsy considering all cases
– 65% “benign” (4,103 cases)
• 3.2% “benign” excised (130 cases)
• 6.2% of the cases excised had carcinoma on biopsy (8 cases*)
– 0.2% of “benign” had carcinoma on biopsy considering all cases
* 5 papillary ca, 1 Hürthle cell ca, 1 parathyroid ca, 1 lymphoma
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Epithelial Quantitation
• Goellner et al. Acta Cytol 1987;31:587-590 (Mayo Clinic group)
– Palpation guided• 25 G needle / 1-4 passes / direct smears (fluid – Millipore filter) /
alcohol fixed / Pap stained
– “Adequate” if 5 to 6 groups of 10+ epithelial cells
• Colloid without cells is “non-diagnostic”
• “To be considered adequate for interpretation, our rule of thumb requires five to six groups……”
– 6,346 FNA in study
– 21% “non-diagnostic” (1,299 cases)
• 9.1% “non-diagnostic” excised (118 cases)
• 8.5% of the cases excised had carcinoma on biopsy (10 cases)
– 0.8% of “non-diagnostic” had carcinoma on biopsy considering all cases
– 65% “benign” (4,103 cases)
• 3.2% “benign” excised (130 cases)
• 6.2% of the cases excised had carcinoma on biopsy (8 cases*)
– 0.2% of “benign” had carcinoma on biopsy considering all cases
* 5 papillary ca, 1 Hürthle cell ca, 1 parathyroid ca, 1 lymphoma
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When to report Thy 1c and Thy 2c
The sample is in keeping with fluid from a cystic colloid nodule but there are no/too few epithelial cells
for confirmation’ Thy2c
‘the sample is in keeping with fluid from a cyst but there are no epithelial cells or colloid to confirm cyst type’.
Thy1c
Risk of malignancy 5 to 37% (estimated mean 15%)Majority are papillary carcinomas
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Should cyst contents lacking epithelial cells
be considered adequate?
– Features that DO NOT distinguish benign from malignant
• Amount of cyst fluid
• Macroscopic (gross) appearance of fluid
• Presence of macrophages, blood, protein, “inflammatory” cells (cyst contents)
– Features that DO distinguish benign from malignant
• Abnormalities in epithelial cellsJaragh et. al. Cancer Cytopathol. 2009;117:305-310
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Is there a difference between acellular
FNA and FNA with cyst contents?
– Histologic follow-up on non-diagnostic thyroid
FNA from complex thyroid cysts– 11.1% rate of malignancy on non-diagnostic FNA from
complex cysts
»Acellular FNA (n=15) – 6.6%
»Cyst contents FNA (n=21) – 14.3%
Not
statistically
different
García-Pascual et. al. Endocr 2011;39:33-40
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Does the presence of colloid define an FNA as adequate?
– Goellner et al. Acta Cytol 1987;31:587-590 / Grant et al. Surgery 1989;106-908-986
• Colloid without cells is “non-diagnostic”
– The Bethesda system
• “Abundant colloid” lacking epithelial cells is benign
– When is it abundant?
– When is it colloid? - Problem with liquid based preparations
» Loss of colloid through the filter
» Less easily recognized
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How soon to repeat FNA?
• No difference in false-positive interpretations
between early and late repeats
• Repeat aspiration for cystic ND nodules is only
recommended for those lesions with
concerning ultrasonographic features
Singh RS, Wang HH: Acta Cytol 2011; 55:544–548.
The rationale for waiting 3 months is based on the
unproven concern that the interpretation of an aspiration
obtained after a shorter interval might be confounded by
an exuberant repair reaction
Ali SZ, Cibas ES: New York, Springer, 2010.
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The management of the patient with a repeatedly
Non diagnostic thyroid FNA
How many times should FNA be repeated?
Jo,VY.Acta Cytologica 2011;55:539–543
57/834 UNDERWENT SURGERY
21% Malignancy identified histologically after a single
NON DIAG FNA
20% After 2 or more repeatedly NON DIAG FNA
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Ohori ,P.N.et al.Acta Cytologica 2011;55:492–498
0.7-18%Probability of a malignant
diagnosis
6–48%
ATYPIA OF UNCERTAIN SIGNIFICANCE – BETHESDA III ( AUS/FLUS) (Thy3A)
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incidence (<7%)
risk of malignancy (5–15%)
Targets for AUS/FLUS stated in the
BSRTC guidelines
Ohori ,P.N.et al.Acta Cytologica 2011;55:492–498
Review of the literature revealed institutional differences in:
•technical aspects• interpretation and application of criteria•analysis of outcome data•clinicopathologic interactions
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.Differential diagnosis of thyroid nodules using
FNAC and oncogene mutation screening:
Are we ready?
Lesions of ‘uncertain’ nature
– ‘suspicious for malignancy’
– ‘suspicious for follicular neoplasm,
– ‘suspicious for oncocytic neoplasm’
– ‘follicular lesions of undetermined significance
(FLUSs)/atypia of undetermined significance
Melillo RM, Santoro M, Vecchio G.F1000 Med Rep. 2010 Aug 19;2:62
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Specificity of BRAF Detection in Thyroid FNAC
Direct nucleotide (Sanger) sequencing Real time PCR
Marina N. Nikiforova and Yuri E. Nikiforov.Molecular Diagnostics and Predictors in Thyroid
Cancer. THYROID Volume 19, Number 12, 2009
PTC=99.8%
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Combined cytology and molecular testing
• Cytological diagnosis of PTC alone 56/90
(62.3%)
• BRAF V600E mutation/ cytology suspicious
8/32 (56.2%)
• Cytology combined with BRAF V600E 74/90
(82.2%)
Marchetti I, Lessi F, Mazzanti CM, Bertacca G, Elisei R, Coscio GD, Pinchera A,
Bevilacqua,G. A morpho-molecular diagnosis of papillary thyroid carcinoma: BRAF V600E
detection as an important tool in preoperative evaluation of fine-needle aspirates.
Thyroid. 2009 Aug;19(8):837-42
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Combined cytology and molecular
testing
• Molecular testing
– 60% sensitive for malignancy
• Cytology
– 100% specific for malignancy
– 40% sensitive for malignancy
• Molecular analysis and cytology
– 80% sensitivity
Ohori NP, Nikiforova MN, Schoedel KE, et al. Contribution of molecular testing to
thyroid fine-needle aspiration cytology of ‘follicular lesion of undetermined
significance/ atypia of undetermined significance. Cancer Cytopathol 2010,
118:17-23.
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RAS, RET/PTC, and PAX8/PPARgamma mutations also
contribute substantially to cancer diagnosis
• In addition to BRAF mutation, which has been
studied most extensively, detection of RAS, RET=PTC,
and PAX8=PPARg mutations also contribute
substantially to cancer diagnosis
Marina N. Nikiforova and Yuri E. Nikiforov.Molecular Diagnostics and Predictors in Thyroid
Cancer. THYROID Volume 19, Number 12, 2009
FISHReal time PCR
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Copyright ©2010 The Endocrine Society
Cantara, S. et al. J Clin Endocrinol Metab. 2010;95:1365-1369
Correlation between results of cytology, molecular biology
on cytological samples, and final histology
The future
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Molecular analysis of thyroid nodules
• BRAF, RAS, RET/ PTC, and PAX8/PPARg mutations (correlation
with cytology, surgical pathology, and clinical follow-up)
• The presence of a mutation was a strong
indicator of malignancy with specificity of
almost 100%
• BRAF, RET/PTC, and PAX8/PPARg mutations
were always associated with carcinomas
• RAS mutations were found in FA in a few cases, but
never in hyperplastic nodulesNikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecular testing for mutations in
improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol
Metab 2009, 94:2092-8.
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ATA Guidelines
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Adeniran ,A .J.Acta Cytologica 2011;55:570–575
Sensitivity 59.3%Specificity 100%
PPV 100 %
NPV 65.6%
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Acta Cytologica 2011;55:563–569
‘…..it contributes little to reducing
equivocal
cytomorphologic findings …’
•none of AUS/FLUS cases BRAF pos
•3 of 17 suspicious for malignancy
Correlation of BRAF status and PTC histology
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•direct sequencing
•single-strand conformational
polymorphism analysis
•dual priming oligonucleotide-
based multiplex PCR direct
DNA sequencing
•PCR-restriction fragment
length polymorphism
•LightCycler PCR with allele-
specific fluorescent probe
melting curve analysis
•pyrosequencing
A variety of methods to detect the
presence of BRAF mutations
Example of a lesion yielding a negative result by standard sequencing but a positive
result by LNA-PCR sequencing
Colanta et al. Acta Cytologica 2011;55:563–569
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Commercial test
Bethesda system
Benign
AUS/FLUS
Neoplasm
Suspicious
Malignant
Nondiagnostic
Indeterminate
Benign
Suspicious
Molecularclassifier
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Acta Cytologica 2011;55:576–583
The method detects 0.01% BRAF mutant DNA in
the presence of 99.99% WT DNA
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Acta Cytologica 2011;55:584–589
Metabolomic profiles from tissue, particularly from FNAB cytology samples,
have the potential to be used in conjunction with current diagnostics
to help guide the clinical management of patients with thyroid nodules.
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Conclusions
• Cell colloid ratio most important in dg
• Classifications are reproducible,
actually and virtually
• Aim is less surgery for benign disease
• Atypical/FLUS should be kept at <7%
• 15% cysts are malignant
• Repeated non diagnostic samples do
not exclude malignancy
• Molecular tests will help but they need
to be standardised
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Abstract submission closes 20th May