Florence-Sydney Breast Biopsy Study- Sensitivity of Ultrasound-guided Versus Freehand Fine Needle Biopsy of Palpable Breast Cancer

Report
Florence–Sydney Breast Biopsy Study: sensitivity of ultrasound-guided versus
freehand fine needle biopsy of palpable breast cancer
N. Houssami
1,2
, S. Ciatto
1
, D. Ambrogetti
1
, S. Catarzi
1
, G. Risso
1
, R. Bonardi
1
, and L. Irwig
2
1
Centro per lo Studio e la Prevenzione Oncologica, Florence, Italy;
2
Screening and Test Evaluation Program, School of
Public Health, University of Sydney, NSW, Australia
Key words: breast cancer, fine needle aspiration biopsy (FNAB), sensitivity, ultrasound-guidance
Summary
Background. Fine needle aspiration biopsy (FNAB) is widely used in the diagnosis of breast cancer. It is unknown
whether, for palpable cancers, ultrasound-guided FNAB is more accurate than freehand FNAB, and practice varies
between physicians, services and countries.
Methods. From consecutive women attending a major cancer centre in Florence, we prospectively recruited
subjects who had a definitely palpable lump which was solid on ultrasound and suspicious of malignancy (n ¼ 102).
All subjects were investigated using both ultrasound-guided and freehand FNAB (one aspirate with each method).
Radiologists skilled in both sampling techniques performed all clinical examinations and aspirations, and for each
subject the same radiologist obtained both FNAB samples. Sequence of aspiration method was randomised.
Cytological interpretation was blinded to method of sampling. Comparative sensitivity (and insufficiency) for
FNAB using the two methods was calculated in all cancers (n ¼ 97).
Results. Ultrasound-guided FNAB resulted in 13.6% (5–22%) less insufficient aspirates than freehand FNAB
(v
2
¼ 7.58; p ¼ 0.006). When insufficient aspirates are included and considered as negative, ultrasound-guided
FNAB has a 14.6% (5.8–23%) or a 16.5% (7.6–25.4%) significantly better sensitivity than freehand FNAB (for
cytology 3–5 positive or cytology 4–5 positive respectively). When insufficient aspirates are excluded from the
analysis, ultrasound-guided FNAB has a 1.4% ()1.2 to 3.9%) or a 2.6% ()2.5 to 7.8%) higher sensitivity than
freehand FNAB (for cytology 3–5 positive or cytology 4–5 positive respectively) but this difference in the sensitivity
of the two methods is not statistically significant.
Conclusion. Our data suggest that ultrasound-guided FNAB has better sensitivity than freehand FNAB in pal-
pable breast cancer, which is predominantly an effect of a significant reduction in insufficient aspirates, but in part
an effect of ‘upgrading’ cytological classification of cancers.
Introduction
Fine needle aspiration biopsy (FNAB) has been used in
breast diagnosis for several decades and shown to be an
accurate test [1–4] with relatively low cost and no sig-
nificant complications. Although the use of core biopsy
has progressively complemented or even replaced
FNAB [5], especially in the screen-detected setting,
FNAB continues to be widely used in pre-operative
biopsy of symptomatic breast tumours. The use of
ultrasound guidance to perform FNAB is essential for
non-palpable lesions, and is often used for palpable le-
sions in dedicated breast centres. However, to date,
there is no evidence that ultrasound-guided FNAB of
masses that are definitely palpable results in an incre-
mental gain in accuracy relative to freehand sampling.
There is no consensus amongst breast experts with re-
gards to this issue, although imaging experts may
advocate ultrasound-guidance irrespective of lesion
palpability. Variations in practice exist in different
countries and in settings where breast FNAB is per-
formed independently of imaging or outside of dedi-
cated breast centres. Variations in FNAB practice are
also partly related to whose role it is to perform FNAB
of palpable masses (the pathologist, the radiologist, the
surgeon, or the breast clinician) and are not based on
evidence. Adding to this controversy is the potential
financial incentive in some countries, according to
whether fine needle biopsy is performed with or without
ultrasound-guidance depending on tumour palpability.
We hypothesised that real-time sonographic visuali-
sation of needle sampling of palpable tumours may
confer diagnostic benefit on the basis of two mecha-
nisms. First, by specifically targeting the lesion and
confining the needle sampling to within the tumour mass
it may avoid sampling from the surrounding tissue, thus
preventing ‘dilution’ of the specimen. Second, it may
provide technical efficiency in obtaining the sample, thus
reducing insufficient aspirates. We conducted a study to
establish the comparative sensitivity of FNAB per-
Breast Cancer Research and Treatment (2005) 89: 55–59 Ó Springer 2005
formed freehand with that of ultrasound-guided FNAB
in women with palpable suspicious breast tumours.
Methods
The study was conducted prospectively from March
2001 to December 2003. Subjects were women with
clinically palpable breast lumps attending a major Ital-
ian cancer centre on the basis of self-referral, clinical
referral, or screen-detected findings. From consecutive
women we included subjects who had palpable lumps
which were: definitely palpable, shown to be solid on
ultrasound, and warranting FNAB on the basis of
clinical or imaging suspicion. In the study centre, judi-
cious use of FNAB and/or core biopsy is based on the
expected likelihood of malignancy. Palpable solid mas-
ses are usually investigated with FNAB if they are
considered to have suspicious features, and thus to have
a high likelihood of malignancy; solid masses with be-
nign features that warrant investigation are generally
sampled with core biopsy or FNAB. On the basis of
these eligibility criteria, our subjects would therefore
have a high pre-test probability of breast cancer. Eligible
subjects were invited to participate in the study, and
verbal informed consent was obtained by the radiologist
performing the assessment. Women who had breast
prostheses were not recruited into the study.
Each subject underwent freehand FNAB (one aspi-
rate only) as well as ultrasound-guided FNAB (one
aspirate only). The order (sequence) of performing the
two sampling methods was randomised using a coin toss
technique by the participating radiologist, who also
performed the clinical examination. Current FNAB
practice in the study centre is tailored to the logistics of
the clinic, and FNAB of palpable masses may be done
by the radiologist freehand or with ultrasound guidance
depending on availability of an ultrasound unit where
the patient is being examined. All FNAB sampling was
performed by one of five radiologists with established
and ongoing experience in both freehand and ultra-
sound-guided FNAB (each radiologist had over 5 years
experience with each method), and the same radiologist
performed the two sampling methods for each case. All
sampling was performed using a 21 gauge needle and
with remote controlled (automatic aspirator) suction,
with the sampling operator directly handling the needle,
which is standard practice in the study centre. Within
subjects the same sampling conditions were strictly
maintained for both sampling methods.
FNAB specimens were prepared and reported in line
with the centre’s standardised reporting protocols, by
one of six cytopathologists. Participating pathologists
were blinded to the sampling methods, but were aware
that two samples were provided for each subject.
Cytology was reported using a standardised categorical
scale of 1–5 widely used in reporting breast cytology
[6–8]. Data collected included sequence of sampling
method, lesion size based on maximum diameter on
ultrasound, and cytology result for each sampling method.
Final histological diagnosis was obtained in all subjects.
Data analysis
The sensitivity and the adequacy of FNAB performed
with and without ultrasound guidance was compared
using McNemar’s v
2
test for paired proportions with a
continuity correction. The 95% confidence interval for
the difference between paired proportions was calcu-
lated [9]. Comparative sensitivity of FNAB using the
two sampling methods was calculated using different
thresholds for classifying results as positive or negative.
We used SAS (version 8.2) for cross-tabulation of data
and for logistic regression modelling. We examined
whether tumour size had an effect on the difference in
sensitivity (and the likelihood of insufficiency) of the two
sampling methods using logistic regression and taking
account of the paired data using generalised estimating
equations [10]. We examined insufficiency in relation to
aspirator. We calculated sensitivity for each test
according to the sequence of performing the sampling
method.
Results
There were 97 malignant lesions sampled in 93 subjects
(two subjects with bilateral cancer and two subjects with
multicentric cancer), and nine subjects had benign
pathology. The mean age in subjects was 63 years
(range: 37–91 years). Invasive ductal cancer (invasive
ductal NOS, and mixed invasive ductal and lobular)
comprised the majority of our series (81.5%). The
remaining histological types were: invasive lobular
(8.3%), medullary (2.1%), tubular (2.1%), mucinous
(2.1%), cribriform (2.1%), and other invasive breast
cancers (2.1%). The absence of ductal carcinoma in situ
from this series reflects our subject inclusion criteria.
Mean tumour size was 18.1 mm (range 10–40 mm).
Because the number of subjects who had benign
pathology in our series was small (n ¼ 9) we did not
calculate specificity.
Comparative sensitivity of freehand and ultrasound-
guided FNAB using different thresholds for considering
results as positive or negative is presented in Table 1. In
the study centre, FNAB cytology reported as category 3
(atypical) would be considered as positive (in that it
would be further investigated), but we have presented
comparative sensitivity using different thresholds for
considering results as positive or negative to allow for
variations in clinical practice. When insufficient aspi-
rates are included and considered as negative, ultra-
sound-guided FNAB has a 14.6% (5.8–23%) or a 16.5%
(7.6–25.4%) significantly better sensitivity than freehand
FNAB (Table 1). When insufficient aspirates are ex-
cluded from the analysis, ultrasound-guided FNAB has
a 1.4% ()1.2 to 3.9%) or a 2.6% ()2.5 to 7.8%) higher
N Houssami et al. 56
sensitivity than freehand FNAB but this difference in
the sensitivity of the two methods is not statistically
significant (Table 1). Absolute sensitivity (proportion of
all cancers with category 5 cytology) was 10.3% (2–
18.6%) higher for ultrasound-guided FNAB than for
freehand FNAB (v
2
¼ 4.5; p ¼ 0.03), but this was
mainly due to differences in insufficient aspirates.
Ultrasound-guided FNAB resulted in 13.6% (5–22%)
less insufficient aspirates than freehand FNAB
(v
2
¼ 7.58; p ¼ 0.006) (Table 1).
Logistic regression analysis showed that tumour size
did not have a significant effect on the difference in the
sensitivity of the two sampling methods ( p ¼ 0.14) and
there was no evidence of interaction between method of
sampling and tumour size ( p ¼ 0.9). Tumour size,
however, had an effect on the difference in the proba-
bility of an insufficient result between the two sampling
methods ( p ¼ 0.015). There was no significant aspirator
(or radiologist) effect on the difference in the probability
of an insufficient result ( p ¼ 0.09). That is, comparing
the two FNAB sampling methods, the likelihood of an
insufficient result was not significantly influenced by
aspirator. However, for individual FNAB methods,
insufficiency rates varied significantly between aspirators
(v
2
ð3Þ
¼ 8.44; p ¼ 0.04) for freehand FNAB only.
Consistent with randomisation of sampling se-
quence, freehand FNAB was performed first in 50.5% of
subjects, and ultrasound-guided FNAB was performed
first in 49.5%of subjects. Sequence of sampling had little
effect on the sensitivity or the adequacy of ultrasound-
guided FNAB: sensitivity was approximately 94.0%
whether ultrasound-guided FNAB was performed first
or second in sequence; insufficiency rate was 4.2% for
first in sequence and 6% for second in sequence. Esti-
mates for freehand FNAB differed according to se-
quence of performing the sampling but the differences
were not statistically significant. Freehand FNAB had a
sensitivity of 83.3% when performed as second in sam-
pling sequence and a sensitivity of 75.5% when per-
formed as first in sequence, which was a non-significant
difference of 7.8% (95% CI: )8 to 24%) and was largely
due to differences in insufficiency. Freehand FNAB had
an insufficiency rate of 24.5% when performed as first
method, and an insufficiency rate of 12.5% when per-
formed as second method, which was a non-significant
difference of 12% (95% CI: )3 to 27%).
Discussion
This paper focuses on palpable breast cancer, and shows
that FNAB is more sensitive when performed using
ultrasound guidance. This effect is largely achieved
through a significant reduction in insufficient aspirates
when FNAB is performed with ultrasound guidance.
This is an important finding since insufficiency is a major
reason for the increasing abandonment of FNAB in
breast diagnosis. It is also important since freehand
FNAB of palpable breast masses is widely practised in
various settings.
In an overview of breast FNAB sensitivity was re-
ported to be 87% (range: 78–98%) [11]. It may therefore
be argued that the sensitivity of freehand FNAB in our
study, when insufficient cytology is included as a nega-
tive test result in the analysis, is relatively low (although
within the reported range). We emphasise that our data
present comparative sensitivity for each sampling
method using one aspirate (one sample) only obtained
with each technique. These data cannot be taken to be
indicative of the true sensitivity of FNAB (where more
Table 1. Comparative sensitivity, and adequacy, of ultrasound-guided and freehand FNAB
Classification of cytology result as positive
(negative)
Ultrasound-guided
FNAB sensitivity
Freehand FNAB sensitivity Difference in sensitivity
(95% CI)
Insufficient cytology included in analysis
Categories 3–5 positive 93.8% 79.4% 14.6% (5.8–23%)
(1–2 negative) v
2
= 8.45 ( p = 0.004)
Categories 4–5 positive 89.7% 73.2% 16.5% (7.6–25.4%)
(1–3 negative) v
2
= 10.2 ( p = 0.001)
Insufficient cytology excluded from analysis
Categories 3–5 positive 98.8% 97.4% 1.4% ()1.2 to 3.9%)
(2 negative) v
2
= 0 ( p = 1)
Categories 4–5 positive 93.4% 90.8% 2.6% ()2.5 to 7.8%)
(2–3 negative) v
2
= 0.25 ( p = 0.6)
Absolute sensitivity
Proportion of all cancers with category 5
cytology
66.0% 55.7% 10.3% (2.0 to 18.6%)
v
2
= 4.5 ( p = 0.03)
Insufficiency/inadequacy rate
IR = % (number) of all
cancers with category 1 cytology
Ultrasound-guided
IR = 5% (5/97)
Freehand IR = 18.6%
(18/97)
Difference in IR )13.6%
()5 to )22%) v
2
= 7.58
( p = 0.006)
Ultrasound-guided versus freehand breast needle biopsy 57
than one aspirate may be taken) and cannot be com-
pared to sampling using multiple aspirates which is
known to improve specimen yield. It is possible that the
common practice of obtaining more than one FNAB
sample may eliminate any difference in accuracy be-
tween the two sampling techniques (i.e. may overcome
the incremental gain in accuracy obtained with the use
of ultrasound-guidance). Were this the case, this does
not invalidate our findings since ultrasound-guidance
would allow a faster and more efficient FNAB proce-
dure, with less samples required (and therefore less dis-
comfort to the patient) and a lower number of smears to
be read.
The clinical question our study addresses relates to
tumours that are readily palpable. Tumours that are
vaguely or inconsistently palpable, or palpable within
nodular tissue or surrounding tissue reaction, were not
included. We feel that it would not have been appro-
priate to include this category of tumours in our study
since tumours that are difficult to palpate clinically
should always be sampled with image guidance to en-
sure that the lesion is appropriately targeted.
It is possible that radiologists participating in our
study may be more skilled at ultrasound-guided FNAB
or may have a preference for ultrasound-guided sam-
pling, and it may be argued that this has caused the
difference in insufficient aspirates in our data. While we
acknowledge this potential limitation, we point out that
the radiologists in our study are experienced with free-
hand FNAB and continue to practice both freehand and
ultrasound freehand FNAB in their work setting (about
30–40% of palpable masses are sampled freehand in the
study setting). Our analyses of insufficiency did not
show a statistically significant radiologist (aspirator)
effect on the difference in the probability of an insuffi-
cient result (comparing the two methods). However, we
did find significant variations in insufficiency rates be-
tween aspirators for freehand FNAB only. It is possible,
then, that ultrasound-guidance may minimise the effect
of inherent differences in aspirator skills. That is,
ultrasound-guidance may reduce operator-related vari-
ations in FNAB acquisition, potentially ‘equalising’
adequacy of aspirates. Future studies should explore this
aspect of our findings, using a larger sample of subjects,
and more aspirators with varying FNAB experience.
We did not find a sampling sequence effect with
ultrasound-guided FNAB, but for freehand FNAB
sensitivity was higher (predominantly due to lower
insufficiency) when freehand was performed second in
the sampling sequence – this was not statistically sig-
nificant. This unexpected finding may be due to chance.
Another possibility is that when freehand FNAB sam-
pling is performed following on from ultrasound-guided
sampling, there is a ‘flow-on’ effect from the prior
aspiration. This may be a physical effect (increased cel-
lular discohesion from the ultrasound-guided aspira-
tion) or an information effect whereby the aspirator has
retained an image of the lesion (gained from the ultra-
sound-guided aspiration) which then assists the freehand
sampling.
It may be argued that ultrasound-guided FNAB
cannot be performed in all settings, as ultrasound is not
always available and/or aspirators may not be skilled in
ultrasound-guided biopsy. However, we feel that clini-
cal and imaging correlation is mandatory in contem-
porary diagnosis of breast diseases, and ultrasound
should always be accessible wherever differential diag-
nosis of breast abnormalities is being undertaken. In
addition, skills in ultrasound-guided biopsy may be
acquired by clinicians of varying disciplines.
Our paper has presented the first evidence on the
comparative sensitivity of ultrasound-guided and free-
hand FNAB in women with palpable breast cancer. We
used a paired study design that allows comparison
within subjects, thus maintaining patient and tumour
variables constant for both sampling methods. Cyto-
logical interpretation of FNAB was blinded to the
method of acquiring the sample. Future studies should
examine this issue using a similar methodology to our
study, but including women with benign findings to al-
low calculation of specificity as well as sensitivity.
However, it would be reasonable to assume that the
improvement in adequate aspirates (achieved with the
use of ultrasound-guidance) would not adversely affect
specificity. That is, a reduction in insufficient aspirates
would not be expected to cause false positive cytology.
Where a judgement is made to use FNAB in the
diagnosis of clinically palpable breast cancer, the use of
ultrasound-guidance may improve sensitivity by reduc-
ing insufficient FNAB aspirates. The evidence from this
study should assist in guiding policy and practice in
sampling of suspected breast cancer.
Acknowledgements
Dr Houssami was partly supported by National Health
and Medical Research Council grant no. 211205 to the
Screening and Test Evaluation Program. We thank all
the Florence women who participated in this study.
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Address for offprints and correspondence: Dr Nehmat Houssami,
Screening and Test Evaluation Program, School of Public Health,
University of Sydney, NSW 2006, Australia; Tel.: +61-2-9351-5994;
Fax: 61-2-9351-5049; E-mail: nehmath@health. usyd.edu.au
Ultrasound-guided versus freehand breast needle biopsy 59
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