Key words breast lesions - breast diagnostics - touch imprint cytology - core-needle biopsy
Schlüsselwörter Brustläsionen - Brustdiagnostik - Abrollzytologie - Stanzbiopsie
Introduction
The mainstays of breast diagnostics are breast palpation, breast ultrasound and mammography
[1 ]; however the sensitivity and specificity of the individual methods differ. Mammography
is only used as a single method for mammography screening worldwide [2 ]. The increased use of mammograms has led to the frequent detection of breast lesions,
which in turn has led to intense investigation to find the most appropriate algorithm
in their follow-up evaluation. In addition to open excisional biopsy, various cytological
and histological assessment modalities such as fine-needle aspiration cytology (FNAC),
stereotactically guided core-needle biopsy (CNB) or touch imprint cytology (TIC) have
been analysed [3 ].
Although FNAC of the mammary gland with its C-classification has greater importance
in other countries [4 ], stereotactically guided CNB with histological B-classification [5 ] has largely replaced FNAC in Germany [6 ], since the cytological clarification between non-invasive (in situ) and invasive
malignant processes cannot definitely be distinguished [7 ], [8 ], [9 ]. The German interdisciplinary S3-guideline for the diagnosis, treatment and follow-up
of breast cancer therefore stipulates that breast lesions that are suspicious for
malignancy (BI-RADS™ 4/5) should be histologically verified preoperatively [10 ]. In particular it is stated that FNAC should not be employed as the standard method
for diagnostic confirmation of solid breast tumours [10 ]. The histological diagnostic investigation of unclear findings should be carried
out via stereotactically guided CNB, vacuum-assisted biopsy or excision biopsy. CNB
and vacuum-assisted biopsy can be performed mammographically and guided by ultrasound
[10 ]. Improved stereotactic technique has also given rise to the performance of stereotactically-guided
CNB of non-palpable breast lesions [6 ], [11 ], [12 ], [13 ].
Even though FNAC is less sensitive and specific in comparison to the histopathological
assessment of stereotactically guided CNB [3 ], [14 ], [15 ], it is possible to inform the patient about the diagnosis on the same day, thus
avoiding a waiting period which many patients find distressing. Whether TIC taken
from stereotactically guided CNB specimens is suitable for immediate cytological evaluation
and whether it would provide a good compromise between delivering a fast preliminary
result to the patient, at the same time allowing a very sensitive diagnosis with histopathological
assessment, was studied at our department in late 1990s [16 ]. Immediate microscopic evaluation of cytological touch imprints was performed using
stereotactically obtained core needle biopsies from 173 breast tumours in 169 patients.
In contrast to other studies at the time [17 ], [18 ], [19 ], we showed that immediate microscopic evaluation of touch imprints is a less accurate
procedure compared to histological evaluation. We therefore came to the conclusion
that TIC in combination with stereotactically-guided CNB should not be integrated
into our operational procedures.
Demographic developments and greater individualization, as well as a changed entitlement
attitude of patients and changes in the medical economy, continue to stimulate re-evaluation
of each method and its utilization in the patient-oriented and cost effective rendering
of an accurate diagnosis of benign or malignant. TIC promises to be useful in providing
same-day diagnosis for counselling purposes and for planning future surgery. It may
also reduce anxiety in patients with benign lesions and expedite the diagnosis and
assessment of treatment options in patients with breast cancer [20 ], [21 ].
Having addressed the issue of the accuracy of immediate microscopic evaluation of
TIC [16 ], we wanted to re-examine the usefulness of this procedure in light of the present
health care climate of cost containment by incorporating the surgical 15-year follow-up
data and outcome.
Patients and Methods
Patient recruitment and follow-up
From January until December 1996, stereotactically guided CNB was performed on 169
patients with a total of 173 breast lesions at the Department of Gynaecological Radiology,
University Hospital of Erlangen, Germany. The lesions were evaluated histologically
and cytologically.
The 15-year follow-up data of the patients with a benign lesion was collected in 2013
([Fig. 1 ]). Databanks from the Department of Gynaecological Radiology in the Institute of
Radiology as well as the Department of Gynaecology and Obstetrics were surveyed. The
registry office performed a search for patients whose follow-up data could not be
collected using the databanks and these patients were contacted personally.
Fig. 1 Patient recruitment.
Indication and performance of stereotactically guided CNB
The indications for stereotactically guided CNB were:
Clarification of unclear, rather benign, sonographically-definable lesions without
an indication for surgery (BI-RADS™ 4).
Perioperative histological confirmation of a carcinoma with a suspicious sonographically
identifiable lesion for the preoperative planning of the surgical technique or incision
in the case of breast-conserving treatment (BI-RADS™ 5).
The CNB were performed using a CNB instrument from BARD Angiomed™ (now BIP™) by 5
medical doctors supervised by a specialist. The biopsy needles used were 10 cm long
and had a 2.1 mm (14 gauge) diameter. The standard punch depth was defined as 2.2 cm
and the punch speed of the device used by us was 100 km/h.
After a detailed explanation, the patient was correctly positioned for the biopsy.
Oncological aspects were taken into account when choosing the puncture site and direction
so that a carcinoma in the puncture canal could also be removed where possible. Local
anaesthesia of the skin was carried out under sterile conditions. The lesion was targeted
via a coaxial cannula (13 gauge) and the biopsy itself was performed under ultrasound
guidance using a needle guided tangentially to the transducer (7.5 MHz). The position
of the biopsy needle before and after the biopsy was documented. For methodical reasons,
only 2 core biopsy specimens were removed from each respective lesion. After the intervention,
the puncture incision was closed with an adhesive strip and covered with a small dressing.
The patient then applied pressure to the puncture area herself for ca. 30 minutes
to prevent secondary bleeding.
Preparation of the cytological touch imprint specimens
Two TICs were immediately prepared from the tissue cylinders removed under stereotactic
guidance. One specimen was fixed for the subsequent staining according to Papanicolaou,
the other was air dried in preparation for May-Giemsa-Grünwald staining according
to standard procedure. The specimen stained according to Papanicolaou could be assessed
cytologically after 20–45 minutes, the May-Giemsa-Grünwald specimen after 30–90 minutes.
The five categories of the National Health Service breast screening program guidelines
(NHSBSP) were used for reporting the results [22 ]: C1, inadequate; C2, benign; C3, atypia probably benign; C4, probably malignant;
C5, malignant. Imprints categorized as C5 or C4 were considered malignant whilst imprints
classified as C2 or C3 were scored as benign.
Histological evaluation of the tissue cylinders
The tissue cylinders were brought to the local Department of Pathology immediately
after preparation of the touch imprint specimens. Here, one cylinder was prepared
for frozen section analysis and the other was embedded in paraffin according to standard
procedure. The frozen- and paraffin sections were stained with haematoxylin-eosin
stain. Histological assessment of frozen sections can be performed after 10 minutes
and after 4 hours for paraffin sections (automated paraffin embedding).
Statistical analysis
The histology of the surgical specimens was compared with those of the CNB with regard
to sensitivity and positive predictive value. A negative predictive value and specificity
in non-operated, benign lesions was evaluated under the assumption that the histology
of the CNB correlated with the histology of the surgical specimen. The histology of
the CNB was compared with the cytological diagnosis to evaluate the diagnostic value
of TIC compared to the histology of the punch cylinder. False-negative CNB results
from a failed puncture were classified as negative to ensure direct comparison of
the methods.
Results
Study population and histology of the analysed tumours
A total of 173 ultrasound-guided CNB were performed in 169 patients in 1996. The mean
age of the patients was 54 years (minimum 21 years, maximum 92 years); the size of
the lesions ranged from 0.9–1.8 cm, median 1.4 cm.
From a total of 173 lesions, all carcinomas (n = 122) and 5 benign lesions were clarified
surgically and histologically. A surgical breast biopsy was avoided for 46 benign
lesions as the histological result from the CNB was in agreement with the suspected
diagnosis from the complementary breast diagnostics.
Results of the CNB with regard to the surgical specimen histology (1996)
Based on the surgical-histological results, histology of the CNB reached a sensitivity
of 99.2 % and a positive predictive value of 100 % as well as a negative predictive
value of 83.3 % ([Table 1 ]). Assuming that all CNB which were found to be negative were also surgically-histologically
benign, it reached a sensitivity of 99.2 %, a negative predictive value of 98.1 %,
specificity and positive predictive value of 100 %. The diagnostic accuracy was 99.4
and 99.2 % ([Tables 1 ] and [2 ]).
Table 1 Results of the stereotactically-guided core needle biopsies (CNB) with regard to
the surgical specimen histology (n = 125) in 1996.
Positive
Negative
Not assessable
Malignant
119
1
(2)
120
Sensitivity: 99.2 %
Benign
0
5
0
5
Specificity: 100 %
119
6
(2)
125
Positive predictive value: 100 %
Negative predictive value: 83.3 %
Accuracy: 99.2 %
Table 2 Histology of the stereotactically-guided core needle biopsies (CNB) (n = 173) in
1996.
Positive
Negative
Not assessable
Malignant
119
1
(2)
120
Sensitivity: 99.20 %
Benign
0
51
0
51
Specificity: 100 %
119
52
(2)
171
Positive predictive value: 100 %
negative predictive value: 98.1 %
Accuracy: 99.4 %
Results of TIC with regard to the surgical specimen histology (1996)
In assessing the diagnostic value of TIC compared with histology of the CNB, the cytological
results were compared with those of the CNB since cytology can only assess what the
tissue cylinder from the CNB contains. Cytology reached a sensitivity of 77.5 %, specificity
of 95.9 %, positive predictive value of 97.8 % and negative predictive value of 63.5 %
with a diagnostic accuracy of 82.8 % (n = 173, [Table 3 ]). The results of the TIC based on the histology of the surgical specimens are shown
in [Table 4 ].
Table 3 Touch imprint cytology (TIC) of the stereotactically-guided core needle biopsies
(CNB) (n = 173) in 1996.
Positive
Suspect
Negative
Not assessable
Malignant
87
6
27
(2)
120
Sensitivity: 77.5 %
Benign
2
0
47
(2)
49
Specificity: 95.9 %
89
6
74
(4)
169
Positive predictive value: 97.9 %
negative predictive value: 63.5 %
Accuracy: 82.8 %
Table 4 Results of touch imprint cytology (TIC) with regard to the surgical specimen histology
(n = 125) in 1 996.
positive
suspect
negative
not assessable
malignant
87
6
27
(2)
120
Sensitivity: 77.5 %
benign
1
0
4
0
5
Specificity: 80 %
88
6
31
(2)
125
Positive predictive value: 98.9 %
negative predictive value: 12.9 %
Accuracy: 77.6 %
Data from the 15-year follow-up of patients with a benign lesion (2013)
A surgical breast biopsy was avoided in 46 patients with 46 benign breast lesions
as the histological result of the CNB as well as the result of the TIC were in agreement
with the complementary breast diagnostics, and no lesion progression was found at
the 3-, 6- and 12-month follow-up appointments after the interventional procedure.
The 15-year follow-up of the 46 patients took place in 2013 ([Fig. 1 ]); however 3 of these patients had died in the meantime. Other cancers or cardiovascular
failure were present in these patients and breast cancer had not been the reason for
death. Despite intensive research by the registry office and repeated letters, follow-up
was not possible in 3 patients due to frequent changes of address.
Follow-up was carried out on 40 women. One patient underwent surgery after 27 months
on a fibroadenoma with a significant progression in size (> 50 %) which had been confirmed
by histology and TIC. The histopathological result on the other hand showed a benign
fibroadenoma measuring 2.1 × 2.9 × 3.8 cm. Another patient (No. 2) underwent surgical
removal of a lesion, which she had described as being painful at the first diagnosis,
30 months after a diagnosis of “simple mastopathy” was made using CNB and TIC. The
histopathological result was once again “simple mastopathy”, measuring 1.4 × 1.8 × 2.2 cm.
An invasive ductal, poorly differentiated breast cancer (1.3 cm) was detected using
CNB in a third patient, 51 months after the ultrasound intervention. The patient subsequently
underwent stage-appropriate oncological treatment. It should be emphasized that this
very aggressive breast cancer was found 4.65 cm away from the fibroadenoma measuring
1.2 × 1.1 × 0.9 cm which was diagnosed at the time using ultrasound, CNB and TIC.
It remained unchanged and was same size at the time of diagnosis of the invasive ductal
breast cancer.
The fourth patient underwent surgery for an invasive lobular breast cancer 98 months
after the interventional procedure in the area which had been diagnosed as “simple
mastopathy” after CNB and TIC. The histological result was an invasive lobular breast
cancer measuring 1.1 × 0.9 × 1.2 cm, although this was a de novo breast cancer by
definition because the previous intervention had taken place more than 8 years beforehand.
A sensitivity, specificity, positive, negative predictive value and diagnostic accuracy
of 100 % was found for the 40 primary benign lesions verified by CNB and TIC in a
15-year follow-up.
Discussion
In German-speaking countries, the cytological evaluation of suspicious breast lesions
has largely been displaced by histological examination procedures, especially the
stereotactically-guided CNB.
However, the possibility of a rapid cytology-based test on cells obtained from stereotactically-guided
CNB with subsequent histology combines the advantages of both methods. In the present
evaluation, the long-term follow-up of primary benign lesions verified by CNB and
TIC has been presented and showed excellent long-time follow-up.
The histological result of an intervention should preferably be available within a
few days so that the oncological treatment can follow as soon as possible after the
CNB [10 ]. In the 1990s, this approach was not viable in many institutions due to the physical
distance between the clinic and pathology department; however this has changed, especially
through the introduction of certified breast cancer centres. At that time, many hospitals
had an experienced cytologist and ultrasound-guided aspiration cytology reached a
sensitivity of 95 %, specificity of 91 %, and accuracy of 92 % for the fine-needle
aspiration procedure in the hands of the skilled [23 ], [24 ]. The aim of our former investigation [16 ] was to find out to what extent TIC of stereotactically-guided CNB allows a sufficiently
reliable and above all timely diagnosis. The results at that time showed much poorer
sensitivity for cytological evaluation of TIC compared to the histological examination
of the CNB (77.5 vs. 99.2 %). Because this, it was concluded that TIC is not an adequate
method for the assessment of CNB.
Based on the results of our study, it already seemed to us at the time that the stereotactically-guided
CNB was the more reliable method for clarification of mammary tumours, despite the
good cytological results of other research groups.
Towards the end of the 1990s, 100 breast biopsy specimens were examined at the John
Hopkins Bayview Hospital in a comparable study [19 ]. The sensitivity of touch imprints for malignant lesions was 92.3 %, whilst the
specificity of imprints for benign lesions was 98 %. The positive predictive value
of this test is 96 %, whilst the negative predictive value is 96.3 %. The accuracy
of this test is also high at 96.2 %. Although their study demonstrates the accuracy
and concordance of cytological touch imprints, the surgical follow-up data revealed
that there does not appear to be any additive value to rendering a separate diagnosis
on touch imprints of CNB.
A current German study [25 ] which investigated the validity and reproducibility of TIC of CNB in the assessment
of conspicuous breast findings in 158 patients, showed good sensitivity, specificity,
positive predictive value, negative predictive value and overall accuracy for TIC
(99, 100, 100, 94, and 99 %). In addition, inter-observer reproducibility was analysed
und the inter-observer variability was very high (kappa-value of 0.8508; excluding
inadequate imprints, 0.9502). Inadequate cellularity for cytological analysis was
found in 11.4 % (18/158) of findings. They concluded that TIC of CNB specimens of
the breast may be a valid option for providing a diagnosis without delay for a histological
procedure, assuming good quality of the specimen.
This last aspect leads to the limitation of our study in which all evaluable lesions
of the patients, which were considered benign by TIC, did not show malignant deterioration
in our 15-year follow-up. Nonetheless, one could argue that either the target of interest
had been failed by stereotactically guided CNB, or the benign lesion at least camouflaged
a cancerous or precancerous lesion. In one case the histological type of the invasive
breast cancer was an invasive lobular carcinoma. Particularly for this type of histology,
false-negative results seem to be more frequent in other studies [25 ], [26 ]. For benign tumours like fibroadenomas, the evaluation can also be difficult [17 ], [27 ], [28 ]. The cytological appearance of a rapidly-dividing fibroadenoma and papillomatosis
are known to very closely resemble malignant cytology.
It has been suggested that TIC could also serve as a means of verifying the adequacy
of biopsy specimens to optimize the biopsy procedure. Masood et al. [21 ] prospectively evaluated radiologically directed aspiration biopsy of non-palpable
breast lesions and showed that use of a modified non-stereotactic localizing technique
when combined with immediate microscopic evaluation resulted in a lower rate of inadequate
samples (9 %), with a diagnostic accuracy of 96.7 %, sensitivity of 85 %, and specificity
of 100 %. Jacobs et al. [17 ] showed that when immediate evaluation of CNB specimens is important, TIC can potentially
decrease the number of biopsy passes required and provide preliminary diagnoses. Both
studies conclude that touch imprints combined with stereotactic biopsy interpreted
as part of an interdisciplinary approach can provide accurate information and that
discrepancies, false-negative rates and false-positive rates can be reduced if both
the cytological imprints and the cores are combined and diagnosed simultaneously.
However, as mentioned above, Green et al. [19 ] reveal that rendering a separate diagnosis on imprints did not make any significant
contribution. Cytological imprints may be helpful to the radiologist as a tool during
an on-site evaluation; however their study showed that a separate cytological interpretation
is unnecessary.
Conclusion
TIC and stereotactically-guided CNB showed excellent long-term follow-up in our study.
Therefore, the use of TIC to complement CNB can provide an immediate cytological diagnosis
of breast lesions. The potential use of this technique in a certified breast cancer
centre may help allay patient anxiety and expedite the planning of further surgical
management. However, nowadays only few hospitals provide an experienced mammary cytologist
why a nationwide coverage seems to be difficult. The implementation into routine practice
and the limitations have to be evaluated in future studies.
