Diagnosis of breast lesions: fine-needle aspiration cytology

[nadae.benawi]

Diagnosis of breast lesions is routinely performed by the
triple assessment of a specialised surgeon, radiologist
and pathologist. In this setting, fine-needle aspiration
cytology (FNAC) and core needle biopsy (CNB) are the
current methods of choice for pathological diagnosis,
both with their specific advantages and limitations.
Evidence-based literature discussing which of both
modalities is preferable in breast lesion diagnosis is
sparse and there is no consensus among different
specialised breast cancer centres. This study reviews
FNAC and CNB for diagnosing breast lesions, comparing
methodological issues, diagnostic performance indices,
possibilities for additional prognostic and predictive tests
and cost effectiveness. Overall, CNB achieved better
sensitivity and specificity especially in those lesions that
were not definitively benign or malignant, non-palpable
and/or calcified lesions. Although FNAC is easier to
perform, interpretation requires vast experience and even
then, it is more often inconclusive requiring additional
CNB. The authors conclude that overall CNB is to be
preferred as a diagnostic method.
Diagnosis of breast lesions is routinely performed by
the combined assessment of (at least) a specialised
surgeon, radiologist and pathologist, usually
through a multidisciplinary meeting. Fine-needle
aspiration cytology (FNAC) and core needle biopsy
(CNB) are currently widely used methods for
pathological diagnosis, both with their specific
advantages and limitations. Evidence-based literature
discussing which of the modalities is to be
preferred for the diagnosis of breast lesions is sparse
and there seems no real consensus on their place,
even among specialised breast cancer centres,
although some centres tend to favour CNB in
specific cases.1 2 In this article, we will review FNAC
and CNB for breast lesion diagnosis, comparing
methodological issues, diagnostic performance
indices, possibilities for additional prognostic and
predictive tests and cost effectiveness.
DIAGNOSTIC PERFORMANCE INDICES
As for any diagnostic procedure a high negative
predictive value is important to minimise undertreatment;
a high positive predictive value reduces
the risk of overtreatment. Therefore, high sensitivity
and specificity are crucial as they are the key
determinants of both negative and positive predictive
values. The overall sensitivity and specificity of
FNAC and CNB in the classification of breast
lesions depend on variables intrinsic to the technique
as well as related to radiological/clinical and
histological features. Comparison of results of the
different studies on the performance of FNAC and
CNB that have not standardised these parameters
may not be fully possible. Studies comparing the
accuracy of FNAC and CNB within the same
patient population are relatively scarce. Nevertheless,
overall but not invariably, CNB has both higher
sensitivity and specificity than FNAC in diagnosing
benign and malignant lesions (figure 1).3e31 One of
the largest studies so far reported sensitivity, specificity,
positive and negative predictive values of
97.1%, 99.1%, 99.3% and 96.2% for FNAC.21
However, it should be noted that the study included
only definitive benign and malignant lesions,
ignoring the atypical and suspicious categories,
which account for up to 20% of breast lesions in
daily pathology.21 Indeed, Westenend et al8 reported
that the positive predictive value of FNAC for
malignancy was comparable with CNB (ie,
99e100%), but that this rate decreased to 78% for
suspicious lesions (100% for CNB) and was only
18% in case of atypia (80% for CNB). So, in general
CNB achieved higher performance indices when
compared with FNAC across different studies.
PROCEDURAL (DIS)ADVANTAGES
FNAC and CNB are methologically different and
have their own advantages and disadvantages. In
general, FNAC is more suitable for patients on anticoagulants
and for lesions close to the skin, chest
wall, vessels and implant or for very small lesions
and those that are deep seated and difficult to reach.
For accessible, palpable lesions FNAC can be
performed relatively straightforwardly and takes
approximately 5 min in experienced hands. Therefore
and for these cases, FNAC is easier to plan than CNB
in an outpatient clinic. This advantage is often used
as a strong argument in favour of FNAC over CNB,
although it can be (partly) circumvented by optimising
the logistical workflow. As a general feature
of cytology, good quality FNAC depends on the
competence of the aspirator, and its interpretation is
primarily determined by the skills and experience of
the (cyto)pathologist.26 32e34 The main complication
of both FNAC and CNB is pain, the intensity of
which seems to correlate with the diameter of the
needle, but might be influenced significantly by other
factors such as stress.35e38 For both FNAC and CNB,
infection and haematoma formation requiring
medical intervention are rare (0e2%), whereas the
risk of pneumothorax is very rare (<0.05%).13 39e43
DEPENDENCE OF DIAGNOSTIC PERFORMANCE ON
CLINICAL/RADIOLOGICAL FEATURES
The success rate of FNAC for obtaining a definite
(malignant) diagnosis depends both on the
1Department of Pathology,
University Medical Center,
Utrecht, The Netherlands
2Department of Pathology,
Erasmus Medical Center,
Rotterdam, The Netherlands
Correspondence to
Stefan M Willems, Department
of Pathology, University Medical
Center Utrecht, Heidelberglaan
100, 3584 CX Utrecht, The
Netherlands;
s.m.willems-4@umcutrecht.nl
Accepted 27 September 2011
Published Online First
29 October 2011
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palpability and size of the lesion. FNAC has average success rates
of 75e90% for palpable and 34e58% for non-palpable breast
lesions, whereas success rates for CNB were 97% and 94%,
respectively.3 44 45 FNAC has a success rate of only 50% for
lesions less than 10 mm, while CNB is successful in over 90% of
such lesions. Therefore, the success rate of FNAC seems to be
especially low for non-palpable lesions and for those smaller
than 10 mm.46 Accuracy rates for FNAC are also decreased for
large tumours (>4 cm) and calcified lesions are also significantly
associated with a higher rate of insufficient sampling than
masses.45 47e49
DEPENDENCE OF DIAGNOSTIC PERFORMANCE ON
HISTOLOGICAL FEATURES
Apart from radiological and clinical features, diagnostic accuracy
predominantly depends on the morphological diagnosis in
various studies.
(Pre)malignant lesions
An important issue in daily practice is discrimination between
in-situ (eg, ductal carcinoma in situ; DCIS) and invasive lesions.
Although, per definition, cytology is unable to make the claim
of invasion in the strictest sense of the word (ie, invasion
through the basal membrane), several studies reported criteria
to predict invasion on the basis of cytological features. These
include infiltration in fragments of fat, infiltration in fibrous
tissue fragments, proliferation of fibroblasts and elastoid
stromal fragments. The first two features are considered to be
most important, although pre-existent ducts can also be
surrounded by fat in physiological conditions, and over-interpretation
of these criteria has led to false positive cases.50 The
overall sensitivity and specificity of the aforementioned criteria
are, however, low, with 38% of invasive carcinomas showing
none of these criteria, while 29% of DCIS showed at least one.50
In particular, diagnosis of tubular carcinoma and invasive
lobular carcinoma is more difficult on FNAC than on CNB. So,
even with these criteria in hand, it is very difficult to affirm
invasive carcinoma by FNAC whereas it is much easier to do
using CNB. It is worth mentioning that approximately 20% of
patients with a CNB diagnosis of DCIS have invasive carcinoma
in the excision specimen. This proportion varies
according to the gauge of needle.51 CNB is also a more robust
method to distinguish between invasive lobular and invasive
ductal carcinoma, based on histological and immunohistochemical
features. This preoperative distinction may be clinically
relevant for: (1) planning the extent of the surgical
operation especially if they are considering breast-conserving
surgery; (2) considerations regarding neoadjuvant chemotherapy;
and (3) the increased risk of contralateral disease in the
case of invasive lobular carcinoma warranting contralateral
radiological examination (MRI).52e55
High-risk lesions
CNB is an accurate method to diagnose so-called high-risk
lesions such as atypical ductal hyperplasia, lobular carcinoma in
situ, atypical papillomatosis and columnar cell lesions. Recognition
of these lesions is important as they can mimic, and are
often associated with, further advanced lesions, and indicate an
increased risk of invasive cancer during follow-up.56 57 The
increased use of vacuum-assisted biopsies and the intact biopsy
procedure, by which a semi-invasive mini-resection can be
performed, has raised the question of whether an open surgical
excision is always warranted for these lesions.58 The intact
biopsy procedure, which differs from core devices in that it
removes one spheroid specimen rather than smaller cylindrical
cores, can be performed safely and accurately and tends to have
fewer underestimations of DCIS compared with CNB.58 59
Figure 1 Sensitivity (A) and specificity (B) of fine-needle aspiration
cytology (FNAC) and core needle biopsy (CNB) in diagnosing malignant
breast tumours. top bar: CNB; lower bar: FNAC. The sensitivity of FNAC
in different studies (from 35% to 95%) showed more variability and was
generally lower compared with CNB (ranging from 85% to 100%). The
specificity of FNAC (ranging from 48% to 100%) was also generally
lower than CNB (ranging from 86% to 100%).
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Papillary lesions
Papillary lesions comprise a spectrum from benign duct papilloma
to papillary carcinoma. In general, the diagnostic accuracy
of FNAC for papillary lesions is variable but low.60e63 Cytological
features to distinguish between benign and malignant
papillary lesions include papillary fronts, overall cellularity,
epithelial cell balls, single cells (with or without atypia) and
plasmacytoid cells. These criteria are helpful but not unanimous,
and the overall accuracy of FNAC to predict benign from
malignant papillary lesions is poor, especially for diagnosing
malignant lesions.61 The accuracy of CNB in the histological
diagnosis and classification of papillary lesions in the breast is
also moderate. The most difficult differential diagnosis is
between papillary carcinoma in situ and papilloma, especially if
the latter is complicated by florid epithelial hyperplasia, atypical
hyperplasia or carcinoma in situ. Immunohistochemistry has
recently been shown to be helpful as benign papillary lesions can
express high molecular weight cytokeratins (CK5/6, CK14,
34betaE12), are surrounded by myoepithelial cells and show
heterogeneous staining for oestrogen receptor (ER).60 64 65
However, false positive and false negative interpretation cannot
be excluded and surgical (diagnostic) excision for papillary
lesions is recommended, although removal with a vacuumassisted
biopsy device is a reasonable option if there is no atypia
on the core biopsy.
Fibroepithelial lesions
Fibroepithelial lesions of the breast encompass commonly
occurring fibroadenomas and rare phyllodes tumours.66 The
latter can be potentially malignant and require complete excision
with an adequate margin to prevent recurrences.67 The
differential diagnosis between both entities by FNAC is challenging
and is hampered by the shortage of universally accepted
cytological criteria.68 Immunohistochemistry on CNB has
recently been shown to be helpful, although its use in routine
practice is still limited and setting reliable cut-off values is
hampered, for example, for Ki-67, which shows a large overlap
between phyllodes tumour and fibroadenoma.69 Accuracy rates
by FNAC and CNB are moderate to high, respectively.70 71
Regarding the grade of phyllodes tumours, both FNAC and CNB
perform suboptimally. This is mainly due to the heterogeneity
of phyllodes tumours with regard to both stromal cellularity and
(lack of) epithelial atypia. On one hand, sampling areas with
only low cellularity of a relatively large amount of sheets of
epithelial cells with only mild atypia increases the risk of
underestimation of the severity of the lesion. On the other hand,
an epithelial proliferation with mild atypia and limited discohesion
in a FNAC of a histologically unsuspicious fibroadenoma
may result in overestimation of the severity of the lesion.
Normal breast tissue versus benign lesions
As a general rule, a definite benign diagnosis and distinction
between benign and normal breast tissue can be made on CNB.
By comparison, benign and normal lesions are often difficult to
distinguish with FNAC.
Calcifications
The assessment of calcification in a core biopsy is much more
sophisticated than in FNAC, as the calcification can be seen in
the tissue section within the lesion. Moreover, CNB enables
a comparison of the pattern of calcification in the core biopsy
with that seen on the x-ray. This is why in the UK breast
screening programme it is recommended that core biopsy, rather
than FNAC, is used for the assessment of calcification.
ASSESSMENT OF PROGNOSTIC AND PREDICTIVE BIOMARKERS
The increased use of neoadjuvant therapy has prompted the
need for reliable preoperative assessment of histological and
immunohistochemical prognostic and predictive features. For
example, grading of malignant breast tumours is an independent
prognostic factor. Cytological grading on FNAC correlates quite
well with histological grading on CNB and morphometry on
FNAC has been shown to be of some help.72e74 However, as
FNAC cannot reliably discriminate between DCIS and invasive
carcinoma, the value of the cytological grade of a malignant
FNAC remains unclear. Moreover, correlation in grade between
CNB and excision specimens on H&E slides is limited, sometimes
with an underestimation on biopsy, but better concordance
can be obtained with additional immunohistochemical
markers although there is no overall agreement on cut-off
values.75e83 Therefore, despite some centres assessing histological
grade on immunohistochemical/H&E staining, this is not
recommended, neither on FNAC nor on CNB.
In the (neo)adjuvant setting, assessment of ER, progesterone
receptor (PR) and HER2 status is crucial and receptor status is
routinely determined on (preoperative) biopsies in many
pathology laboratories. It is generally accepted that ER, PR and
HER2 can be reliably assessed on CNB but not on FNAC.84 85
The same holds true for proliferation assessment, which is part
of grading and is prognostically very important.86 During the
past decade with the introduction of small molecule inhibitors,
molecular profiling of (breast) tumour samples is increasingly
important. In this respect, it is noteworthy that CNB contains
RNA/DNA in a sufficient amount and of sufficient quality for
molecular testing (eg, arrays), whereas this can be problematical
in the case of FNAC in which the yield is often limited.
COSTS AND SPEED
There is no doubt that the technical costs for a single FNAC is
lower than for CNB. However, the overall costs do not only
depend on the procedural costs of one sampling procedure, but
on the total costs to obtain a reliable definitive diagnosis. In this
respect, CNB might paradoxically even be superior to FNAC, at
least in selected cases. FNAC may be more cost effective for
palpable lesions (with inadequacy rates of <10%), the additional
cost for imaging guidance required for non-palpable lesions
makes this procedure less cost effective in general.18 45 87 Even
with imaging guidance, the rate of insufficient samples yielded
by FNAC varied between 29% and 39%. An interesting study
showed that indefinite diagnosis using FNAC required additional
CNB in 32% (93/289) of cases and additional surgical excision
biopsies in 21% (62/289) of cases versus 1% (2/214) and 15%
(33/214) after CNB, respectively.44 Therefore, although cheaper
as a single sampling procedure, FNAC requires additional
histological tissue sampling (CNB and surgical excision biopsy)
in a significant number of cases due to its lower accuracy. This
stresses the important point that for final accurate diagnosis,
routinely performing FNAC as an initial diagnostic procedure
may be even more expensive than CNB, although these results
need to be confirmed in larger cohorts.
A high quality of patient care stands with a correct diagnosis
as well as the efficacy to come to an optimal plan of treatment.
So, the actual speed to come to a definite diagnosis matters. For
FNAC, a routine MayeGrunwaldeGiemsa staining takes up to
1 h, whereas a so-called Quick-diff enables a diagnosis in only
5 min, which provides a same-day diagnosis. The standard
processing time to get to a histological diagnosis is usually
approximately 24 h. However, ultrafast tissue processing
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procedures now allow an accurate histological diagnosis within
4 h after sampling. FNAC might thus eventually result in a (only
slightly to moderately) faster diagnosis, which is mainly relevant
for patient comfort in the case of a benign diagnosis and no need
for direct further treatment. However, this speed advantage in
diagnosis becomes more relavant in the case of a malignant
diagnosis, which requires discussion in a multidisciplinary team
involving at least a surgeon, radiologist, medical oncologist,
radiation oncologist and pathologist. Although some large
centres can provide a frequent multidisciplinary meeting, which
allows same-day discussion and therapy planning in a one-stop
outpatient clinic in the case of FNAC, this is not an attainable
option for most centres. It is our experience that a window of
36 h after CNB is in most cases sufficient to come to a definite
and reliable diagnosis prior to such multidisciplinary meeting. In
this workup scheme, patients get not only the final diagnosis
but also the treatment plan right after the multidisciplinary
meeting when they return to the outpatient clinic. Therefore, in
the case of a (potentially) malignant breast lesion, the overall
speed advantage of FNAC over CNB is relative. Noteworthy is
that modified core wash cytology has been shown to correlate
well with histology, with a sensitivity and specificity of 97% and
100%, respectively. Combining this technique or imprint
cytology with CNB histology may improve the quick and
reliable diagnosis of malignant breast lesions.88
CONCLUSIONS
The diagnosis of breast cancer is usually accomplished by triple
assessment (surgeon, radiologist and pathologist) in a multidisciplinary
setting. FNAC and CNB are the most commonly used
diagnostic modalities in the morphological diagnosis of breast
tumours. In experienced hands, the sensitivity of FNAC is high,
and not much lower than CNB. The specificity of CNB is,
however, higher as well as the positive predictive value for
suspicious and especially atypical lesions and fibroepithelial
lesions. Also, the inadequacy rate of FNAC for non-palpable
lesions, the incidence of which has increased as a result of widely
used screening programmes, is higher than for CNB. So, the
overall performance indices of CNB are superior to FNAC in the
majority of breast lesions. Ancillary immunohistochemical and
molecular tests are more reliably and more easily performed on
CNB than on FNAC, which is relevant to determine additional
prognostic and predictive markers. Moreover, because of the
increase in (neo)adjuvant treatment options, immunohistochemical
and molecular profiling of individual tumour samples is
increasingly important, especially in this new era of personalised
medicine. Regarding cost effectiveness, the total costs to obtain
a definitive, reliable diagnosis seem to be even higher for FNAC
because of its low accuracy rate, especially for non-palpable and
small lesions. FNAC is fast and therefore might be preferred for
some palpable, probably benign lesions. In the case of (potential)
malignancy, the speed advantage of FNAC over CNB seems
relatively irrelevant in view of the required multidisciplinary
meeting to arrive at a therapy plan. Therefore, taking into
account the benefits and limitations of both techniques (table 1),
we argue that CNB is to be preferred over FNAC for the
diagnosis of breast lesions.
Funding SMW is funded by the Netherlands Organization for Scientific Research
(Rubicon grant 2011/07046/ALW) and the Dutch Cancer Society (clinical fellowship:
2011-4964).
Competing interests None.
Contributors SMW wrote the manuscript. CHMvD and PJvD contributed significantly
to the content and the writing of the manuscript.
Provenance and peer review Not commissioned; externally peer reviewed.
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Table 1 Summary of benefits and limitations of FNAC and CNB
FNAC CNB
Procedural (dis)advantages
Accessibility of deep sites Yes No
Level of experience required High Average
Success rate 60e75% 99%
Complication rate Very low Low
Diagnostic performance dependent on clinical/radiological features
Non-palpable tumours Low High
Palpable lesions High High
Size <10 mm or >40 mm Low High
Diagnostic performance dependent on histological features
Distinction between in-situ and invasive cancer No Yes
Diagnosis of pre-invasive lesions (CCL, ADH) Low High
Diagnosis of papillary lesions Low Moderate
Distinction between fibroadenoma
and phyllodes tumour
Moderate High
Assessment of prognostic and predictive biomarkers
Grading Low Moderate
ER/PR assessment Low High
HER2 assessment Low High
Proliferation assessment Moderate High
DNA/RNA isolation for molecular test Low High
Cost/speed effectiveness
Speed High Moderate
Costs* Very low Low
*Costs: fine-needle aspiration cytology (FNAC) is cheaper as a single procedure but is
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ADH, atypical ductal hyperplasia; CCL, columnar cell lesion; ER, oestrogen receptor; PR,
progesterone receptor.
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< Both have their own advantages and limitations.
< In general and based on overall performance indices, CNB is
to be preferred over FNAC for the diagnosis of breast lesions.
290 J Clin Pathol 2012;65:287e292. doi:10.1136/jclinpath-2011-200410
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