Part I. Lecture:
Minimal Breast Lesions - Non-operative diagnosis
With the contribution of the European Community Working Group on Breast Screening Pathology
Part of the report of the working meeting in Leuven, 22-23/04/99
Introduction
The decision about whether to operate on patients with screen-detected mammographic abnormalities involves the correlation of clinical and radiological data and findings from needle aspiration cytology (FNAC) and/or needle core biopsy (NCB). This is best achieved in multidisciplinary meetings where the clinician, radiologist and pathologist (triple assessment) discuss these findings and reach a consensus on the appropriate management of each patient following pre-defined protocols.
Until recently, needle aspiration was the more widely used technique but core biopsy is being used increasingly. There has been much discussion about the relative merits and disadvantages of the two methods.
Core biopsy has several advantages. It is possible to distinguish in situ from invasive carcinomas although, not surprisingly, the technique has greater positive than negative predictive value as the invasive component of a tumor may not always be included in the biopsy. It is easier to diagnose carcinomas with low grade cytological features which are difficult to recognise without architectural interpretation. Specific benign diagnoses can be made and this allows better correlation of clinical, radiological and histological features. Another major advantage is that needle biopsies can be subjected to specimen radiography to ensure that the mammographic abnormality has been sampled. If the relevant calcification is included in the biopsy and is clearly associated with a benign process then an unnecessary operation is avoided.
On the other hand, fine needle aspiration is quicker to perform, does not require local anaesthetic and consequently uses less clinic time. Multiple passes with a needle can increase diagnostic accuracy with both techniques (FNAC and NCB) but is easier to perform with FNAC. Small and impalpable lesions are also generally easier to localise, particularly if imaging is used but localisation of lesions with NCB has improved significantly in recent years. As FNAC is a quicker technique cytopathologists can provide diagnoses in clinics so that triple assessment can be completed in a single visit.
Most pathologists, however, find if easier to interpret NCB and consequently the standards of diagnosis are generally higher except where FNAC is performed in major cytopathology centres.
It is clear that FNAC and NCB are complementary techniques in arriving at a non-operative diagnosis. The efficacy of both methods, however, is heavily dependent on the skill and experience of the operator who is rarely a pathologist, particularly in the case of needle core biopsy.
From "European Guidelines for Quality Assurance in Mammography Screening" 2nd edition, June 1996. A downloadable file can be found at the site of the European commission (Coming from the main site, first choose 'Cancer' then 'Publications'): http://europa.eu.int/comm/dg05/index_en.asp
The results of FNAC are reported according to five categories:
C1 Inadequate
Indicates a scanty or acellular specimen or poor preparation. The designation of an aspirate as "inadequate" is to a certain extent a subjective matter and may depend on the experience of the aspirator and/or the interpreter. Poor cellularity (usually less than five clumps of epithelial cells) is sufficient to declare an aspirate inadequate. Preparative artefacts or excessive blood may also be reasons for rejecting an aspirate as inadequate.
Preparative artefacts include:
- Crush, when too much pressure is used during smearing.
- Drying, when dry smears are allowed to dry too slowly or when wet-fixed smears have been allowed to dry out before fixation.
- Tick smears, when an overlay of blood, protein-rich fluid or cells obscurs the picture, making assessment impossible.
C2 Benign
Indicates an adequate sample showing no evidence of malignancy. The aspirate in this situation is often poorly to moderately cellular and tends to consist mainly of regular duct epithelial cells. These are generally arranged in monolayers and have the characteristics benign cytological features with round, oval, regular, small nuclei. Should cystic structures be a component of the aspirated breast, then a mixture of foamy macrophages with or without regular apocrine cells may be part of the picture. Fragments of fibrofatty and/or fatty tissue are common findings. A positive diagnosis of specific conditions (fibroadenoma, lymph node, ) may be suggested if sufficient features are present to establish the diagnosis with confidence.
C3 Atypia probably benign
All the characteristics of a benign aspirate may be seen as described above. In addition, there are certain features not commonly seen in benign aspirates, including any of the following, alone or in combination:
- Nuclear pleomorphism
- Some loss of cellular cohesion
- Nuclear and cytoplasmic changes resulting from, for example, hormonal influence or treatment effects.
Increased cellularity may accompany the above features. As thus defined, this group would be expected to contain approximately 20% of cases which were subsequently proven to be malignant.
C4 Suspicious of malignancy
The pathologist's opinion is that the material is suggestive but not diagnostic of malignancy. There are three main reasons:
- The specimen is scanty, poorly preserved or poorly prepared, but some cells with features of malignancy are present.
- The sample may show some malignant features without overt malignant cells present. The degree of abnormality should be more severe than in the previous C3 category.
- The sample has an overall benign pattern but with occasional cells showing distinct malignant features.
As thus defined, this group would expected to contain approximately 80% of cases which were subsequently proven to be malignant.
C5 Malignant
Indicates an adequate sample containing cells characteristic of carcinoma or other malignancy.
The interpreter should feel ease in making such a diagnosis. Malignancy should not be diagnosis on the basis of a single criterion but on a combination of features.
Calcification
It is very useful for the radiologist if the pathologist reports the presence of calcification within FNAC specimens when the abnormality is one of mammographic microcalcification. If calcification is present in theses circumstances, the radiologist or multidisciplinary team can be more certain that the lesion has been sampled accurately and that the likelihood of false negative due to an aspiration miss is lower. This may allow the team to advise with greater confidence that the women be routinely recalled or rescreened early rather than subjected to biopsy. It is desirable to specify the type of calcification.
Calcification alone does not discriminate between benign and malignant conditions.
European Guidelines for QUALITY ASSURANCE in Mammography Screening 2nd edition (JUNE 1996)
Quality assurance | ||
Definitions | The following calculations are intended to reflect the quality of the FNAC service as a whole rather than the laboratory component alone. Inadequate FNAC results are not, therefore excluded from the calculations as in some publications. Cytologists wishing to evaluate purely their own accuracy in diagnosis may wish to calculate the figures differently. | |
Absolute sensitivity (C5) | = The number of carcinomes diagnosed as such expressed as a percentage of the total number of carcinomes aspirated. | |
Complete sensitivity (C3, 4 and 5) | = The number of carcinomes that were not definitely negative or inadéquate on FNAC expressed as a percentage of the total number of carcinomes aspirated. | |
Specificity | = The number of correctly identified benign lesions (the number of C2 results minus the number of false negatives) expressed as a percentage of the total number of benign lesions aspirated. | |
Positive predictive value of a C5 diagnosis | = The number of correctly identified cancers (numbers of C5 results minus the number of false positive results) expressed as a percentage of the total number of positive results (C5). | |
Positive predictive value of a C4 diagnosis | = The number of cancers identified as suspicions (number of C4 results minus the number of false suspicions results) expressed as a percentage of the total number of suspicions results (C4). | |
Positive predictive value of a C3 diagnosis | = The number of cancers identified as atypia (number of C3 results minus the number of benign atypical results) expressed as a percentage of the total number of atypical results (C3). | |
Negative predictive value of a C2 diagnosis | = The number of benign cases (including those with no histology) expressed as a percentage of the total number of C2 diagnoses. | |
False negative case | = A case which subsequently turns out (over the next 2 years) to be carcinoma having had a negative cytology result. (This will by necessity include some cases where the cancer was missed rather than misinterpreted in the smears. Furthermore, the interval may vary from one programme to another depending on the screening interval). | |
False positive case | = A case which was given a C5 cytology result but which turns out at open surgery to have a benign lesion (including atypical hyperplasia). | |
False negative rate | = The number of false negative results expressed as a percentage of the total number of carcinomas aspirated. | |
False positive rate | = The number of false positive results expressed as a percentage of the total number of carcinomas aspirated. | |
Inadequate rate | = The number of inadequate specimens expressed as a percentage of the total number of cases aspirated. | |
Suspicious rate | = The number of C3 and C4 diagnoses expressed as a percentage of the total number of cytology results. | |
How to calculate these figures | It is intended that a computer system will be able to calculate these figures automatically from the data in the database cross-referencing with the histology or subsequent outcome and a report derived for quality assurance purposes. | |
CYTOLOGY
QA STANDARD REPORT Total cases screened in period Totalassessed Total FNAC performed |
Cytology
Histology | C5 | C4 | C3 | C2 | C1 | Total |
Total malignant | Box 1 | Box 2 | Box 3 | Box 4 | Box 5 | Box 6 |
Invasive | Box 7 | Box 8 | Box 9 | Box 10 | Box 11 | Box 12 |
Non-invasive | Box 13 | Box 14 | Box 15 | Box 16 | Box 17 | Box 18 |
Total benign | Box 19 | Box 20 | Box 21 | Box 22 | Box 23 | Box 24 |
No histology | Box 25 | Box 26 | Box 27 | Box 28 | Box 29 | Box 30 |
Total C results | Box 31 | Box 32 | Box 33 | Box 34 | Box 35 | Box 36 |
Each box (numbered 1 to 36) of the above table is calculated from the number of FNAC with a C code (C1, C2, etc.) cross-referenced with the worst histology diagnosis. The table and calculations (see below) should be produced for all FNAC tests (headed ALL TESTS) and also for all patients (headed ALL PATIENTS) where if two FNAC records are present the highest C number is taken. Only closed episodes should be used. | ||
From the above table the sensitivity and specificity are then calculated in percentages for each of the categories in the cytology document. (The numbers correspond to BOX NUMBERS in the above table.) | ||
1 ABSOLUTE SENSITIVITY (This assumes that ali unbiopsied C5 results are carcinomas treated non surgically . ) |
= ((1 + 25) : (6 + 25)) x 100 | |
2 COMPLETE SENSITIVITY | = ((1 + 2 + 3 + 25) : (6 + 25))x 100 | |
3 SPECIFICITY (biopsy cases only) |
= (22 : 24) x 100 | |
4 SPECIFICITY (full) (This assumes that all cases of atypia (C3) which are not biopsied are benign.) |
= ((22 + 28) : (24 + 27 + 28 + 29)) x 100 | |
5 POSITIVE PREDICTIVE VALUE
(C5 diagnosis) |
= ((31 - 19) : 31) x 100 | |
6 POSITIVE PREDICTIVE VALUE
(C4 diagnosis) |
= (2 : (32 - 26)) x 100 | |
7 POSITIVE PREDICTIVE VALUE (C3 diagnosis) |
= (3 : 33) x 100 | |
8 NEGATIVE PREDICTIVE VALUE (C2) |
= ((34 - 4) : 34) x 100 | |
9 FALSE NEGATIVE RATE (This EXCLUDES inadequate results) |
= (4 : (6 + 25)) x 100 | |
10 FALSE POSITIVE RATE | = (19 : (6 + 25)) x 100 | |
11 INADEQUATE RATE | = (35 : 36) x 100 | |
12 INADEQUATE RATE FROM CANCERS | = (5 : (6 + 25)) x 100 | |
13 SUSPICIOUS RATE | = ((32 + 33) : 36) x 100 | |
It is recognized that the specificities are approximate and will be more accurate the longer the follow up. | ||
Suggested minimum standards where therapy is partially based on FNAC | Absolute sensitivity (AS) Complete sensitivity (CS) Specificity (SPEC) (as calculated above) Positive predictive value (C5) (+PV) False negative rate (F-) False positive rate (F+ ) Inadequate rate (INAD) Inadequate rate in samples taken from carcinomas Suspicious rate |
> 60% > 80% > 60% (including non-biopsied cases) > 98% < 5 % < 1 % < 25% < 10% < 20% |
These figures will obviously depend on aspiration techniques and the experience and care of the aspirator and will vary widely between units. The figures are interrelated and strategy to improve one figure will affect others.Thus attempts to reduce the inadequate rate will often increase the number of suspicious reports and attempts to improve the specificity will increase the false negative rate and so on. Also, reducing the benign biopsy rate by not sampling the majority of lesions with benign cytology will reduce the specificity where this is based on cases with benign histology rather than on the total. | ||
A high proportion of impalpable cases aspirated in any series is likely to make the figures worse as there is more chance of missing a small area of microcalcification leading to a false negative or inadequate result and more likelihood of aspirating atypical hyperplasia, radial scars and tubular carcinomas, leading to a high level of suspicious or atypical reports. In screening with aspiration of impalpable lesions the results are likely to reveallower values than those achieved in the symptomatic setting. |
The present classification is currently used in United Kingdom. An optional two step procedure for the diagnosis of NCB has been proposed by Prof. Jean-Pierre Bellocq (Hôpital Hautepierre, Strasbourg) and is detailed on a separate sheet. Meeting of the European Community Working Group on Breast Screening Pathology, Leuven, 22-23/04/99.
For the purposes of data recording and quality assurance in breast screening programmes, it is recommended that needle core biopsies are classified on a 5 point scale in a similar fashion to cytological specimens. Some teams may wish to merge categories B3 and B4 as both indicate the need for further action.
It needs to be emphasised, however, that the categories are not the same as the five cytology categories and have different clinical inferences. It is essential that the histological appearances in NCB are compared with clinical and radiological findings in order to ensure that the biopsy is representative.
B1 Uninterpretable or Normal
This may indicate an unsatisfactory biopsy which is uninterpretable because of artefact or composed of stroma only. Biopsies containing normal breast tissue in case where normal appearances are felt to be inconsistent with findings on imaging and clinical examination should be classified in this category.
B2 Benign lesion or Normal
Indicates that the sample contains a benign abnormality. Biopsies exhibiting normal appearances may be included in this category if they are felt to be consistent with the findings on imaging and clinical examination. Involutionary calcification should be classified as benign.
B3 Benign but of uncertain biological potential
Indicates a benign abnormality which is recognised to be associated with an increased risk of developing breast cancer, or is often associated with the presence of in situ or invasive carcinoma. Examples of such lesions include atypical hyperplasia, radial scars,
B4 Suspicious
Indicates that the changes suggestive of in situ or invasive malignancy are present but a categorical diagnosis cannot be made because of artefact or because the appearances are borderline.
B5 Malignant
Categories
a) indicates that in situ carcinoma only is present.
b) indicates that invasive carcinoma is seen
c) indicates that it is not certain whether the carcinoma is invasive or not.
Calcification
Should a needle core biopsy be performed for investigation of suspicious microcalcification, the report should clearly indicate whether microcalcification has been identified in the biopsy and whether it is associated with a specific abnormality. Radiography of the specimen can assist in identification of microcalcification and confirm that its characteristics are the same as those of the mammographic abnormality.
Quality assurance
In assessing performance it is essential to specify whether the performance indicators (e.g. sensitivity, specificity, positive predictive value) related to the histological report alone or to the diagnosis reached after consideration of pathological, radiological and clinical findings.
... | |
Two step diagnosis for needle core biopsies | |
... |
"Crude" histological diagnosis (a) | Group O artefacts |
Group
1 or 2 1 = normal 2 = benign lesion |
Group 3 or
4 3 = benign but of uncertain biological potential 4 = suspicious |
Group 5 malignant |
|
Concordance with radiology (b) |
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no |
yes |
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Definitive result | Non informative | Benign reliable (c) | Risk of malignancy | Malignant | |
Practical attitude | New biopsy (d) | No special follow-up | Resection (for diagnosis and therapy) (e) | Resection (therapeutic) |
(a) This diagnosis is exclusively based on the analysis of the histological specimen, independently of the mammographic or echographic context.
(b) The results are sorted out by comparing the histological image and the radiological image
(c) The degree of reliability of the medical team composed by the pathologist and the radiologist (negative predictive value of the team decision) towards this benign definitive result has to be evaluated periodically.
(d) Depending on the positive predictive value of the radiological image, the alternative option could be a surgical resection (if the PPV is high) or a follow-up (if the PPV is low).
(e) Depending on the positive predictive value of the histological image, the alternative option could be a follow-up (if the PPV is low).
FNAC and NCB: The experience of the CHU Tivoli
Presented in part at the "Autumn meeting of the Belgian Society of Clinical Cytology,10/10/98, Leuven" under the tittle "Use of the European guidelines for FNAC of the breast. Three years experience in the "Centre Hospitalier Universitaire du Tivoli". Daniel Faverly MD, Michaël Galand, Bernard Vanden Heule MD, Department of Pathology, CHU Tivoli, La Louvière, Belgium.
Fine Needle Aspiration Cytology
An internal routine
audit on the performance of FNAC of breast lesions was initiated in the department of
Pathology of the University Hospital Tivoli from October 1995.
The results of 556 FNAC were reported according to the original classification of Wells et
al. (1) and recently published in the European Guidelines for Quality Assurance in
Mammography Screening (2). The aspirates are performed by two experienced gynaecologists
("senologists") and three radiologists specially trained for breast pathology.
The FNAC are received alcohol-fixed and stained with Papanicolaou. All FNAC are examined
by both a cytopathologist and a pathologist, a third reading is systematically done by the
pathologist who is in charge of the weekly clinical meeting. During this meeting, the
clinical and cyto-histological characteristics of the individual cases as well as the
results of breast imaging are discussed by a multidisciplinary team to define a
comprehensive management strategy of the patient. In Table I, the performances of the CHU
Tivoli are compared to the FNAC standards suggested by EC guidelines (2).
Table I. Internal audit in FNAC from 01/10/95 to 07/08/98 |
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Variables |
CHU Tivoli |
EC standards |
Absolute sensitivity |
46% |
> 60% |
Complete sensitivity |
80% |
> 80% |
Full specificity |
72% |
> 60% |
Positive Predictive value C5 |
97% |
> 98% |
False negative rate |
2% |
< 5% |
False positive rate |
2% |
< 1% |
Inadequate rate |
21% |
< 25% |
Inadequate rate from cancers. |
19% |
< 10% |
Suspicious rate |
13% |
< 20% |
In general, the results appear reasonably good but the sensitivity was too low (46% versus >60%) and the rate of inadequate FNAC in case of cancer higher than the EC standards (19% versus <10%). The performances slowly improved with time, if the three years periods are separately considered (Table II: absolute sensitivity from 43% to 57% respectively for the first and third periods). Nevertheless, the rate of inadequate FNAC in cancer cases remains high (17% for the third period).
Table II. Internal audit in FNAC for three years periods |
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Variables |
95-96 |
96-97 |
97-98 |
EC standards |
Absolute sensitivity |
43% |
40% |
57% |
> 60% |
Complete sensitivity |
74% |
82% |
83% |
> 80% |
Full specificity |
70% |
70% |
76% |
> 60% |
Positive Predictive value C5 |
89% |
100% |
100% |
> 98% |
False negative rate |
5% |
0% |
0% |
< 5% |
False positive rate |
5% |
0% |
0% |
< 1% |
Inadequate rate |
21% |
23% |
19% |
< 25% |
Inadequate rate from cancers |
21% |
18% |
17% |
< 10% |
Suspicious rate |
14% |
14% |
10% |
< 20% |
The analysis of the results of FNAC in cancer cases is easier if absolute numbers are considered (Table III).
Table III. Internal audit in FNAC from 01/10/95 to 07/08/98: absolute numbers. |
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Histology |
Cytology |
|||||
C5 |
C4 |
C3 |
C2 |
C1 |
Total C |
|
Malignant |
47 |
39 |
4 |
2 |
24 |
116 |
Benign |
2 |
4 |
9 |
22 |
18 |
55 |
No histo. |
11 |
2 |
13 |
285 |
74 |
385 |
Total |
60 |
45 |
26 |
309 |
116 |
556 |
The unsatisfactory performances are caused by many of FNAC classified as suspicious for malignancy (C4: 39 cases) in case of cancer. We reviewed 36 out of the 39 cases considered as C4. Twenty-one samples are scanty, poorly preserved or hemorragic but some cells with features of malignancy were present. In 6 cases, the FNAC showed some malignant features without overt malignant cells. The 9 remaining samples were reclassified C5 after revision. This review shows that, in our experience, the factor "aspirator" is more determinant on the quality of FNAC than the factor "reader".
In conclusion, this study demonstrates the interest of an internal audit in the evaluation of the performance of FNAC in routine practice. The audit is successful in identifying the weak points of the technique that would have otherwise been obscured by the overall performance of the multidisciplinary team.
Needle Core Biopsy
Only 98 NBC were performed during the three-year period; the majority in 1998. A large proportion of the targeted lesions were smaller than 1.5 cm. Sonography and palpation, when the abnormality could be palpated, guided the NCB sampling for many patients. Two or three cores per case were obtained from 18 or 14 gauge needle and high-speed biopsy gun Bip â . NCB histologic findings were classified according to ECWGBSP guidelines and compared to FNAC performance for the same period.
Table IV Comparison of the performance of FNAC and NCB for the period 01/10/95 to 07/08/98 |
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Variables |
NCB |
FNAC |
EC standards |
Absolute sensitivity |
80% |
46% |
> 60% |
Complete sensitivity |
81% |
80% |
> 80% |
Full specificity |
68% |
72% |
> 60% |
Positive Predictive value B5 and C5 |
100% |
97% |
> 98% |
False negative rate |
5% |
2% |
< 5% |
False positive rate |
0% |
2% |
< 1% |
Inadequate rate B1 and C1 |
21% |
21% |
< 25% |
Inadequate rate from cancers |
14% |
19% |
< 10% |
Suspicious rate B4 and C4 |
1% |
13% |
< 20% |
The performance of NCB in terms of absolute sensitivity (the number of carcinomas in category B5 expressed as a percentage of the total number of carcinomas sampled) appears better than the results obtained with FNAC. This can be explained by the low rate of cases (1%) found in B4 category (suspicious for malignancy). In our experience, the samples obtained from NCB are of better quality than those of the aspirates and allows a more accurate diagnosis. In this preliminary study, the rate of inadequate NCB remains high, comparable to FNAC. A gain in experience of the samplers should improve the performance and diagnostic accuracy of NCB. Technical equipment also have a definitive and important impact on the overall results in using NCB for diagnostic purpose (3).
References
1) Wells C, Ellis I, Zakhour H, Wilson A. Guidelines for cytology procedures and reporting on fine needle aspirates of the breast. Cytopathology 1994; 5:316-334.
2) EC Working Group on Breast Screening Pathology. Cytopathology Guidelines in European Guidelines for Quality Assurance in Mammography Screening. 2nd edition Europe against Cancer; 1996.
3) Rosen PP. Role of cytology and needle biopsy in the diagnosis of breast cancer. In Rosen's Breast Pathology, chapt 48, Lippincott-Raven, 1996.
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