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Annu. Rev. Med. 1990.41:117-132. Downloaded from www.annualreviews.org Access provided by Michigan State University Library on 02/16/15. For personal use only.
MAMMOGRAPHY SCREENING FOR BREAST CANCER A. P. M. Forrest, M.D., F.R.C.S., and R. J. Aitken, F.R.C.S.
University Department of Surgery, Royal Infirmary, Edinburgh EH3 9YW, Scotland KEY WORDS:
cancer trials, health care systems, biopsy, pathology, prevention.
ABSTRACT
There is now unequivocal evidence that screening with mammography reduces the mortality of breast cancer. This benefit will best be realized by a national screening program. Such programs require a meticulous organization with dedicated staff who are experienced in the management of screen-detected lesions.
WHY SCREEN The objective of breast screening is to reduce the mortality of breast cancer by detecting tumors before they present symptomatically as a palpable mass in the breast. This goal can be achieved by mammography (soft tissue radiology of the breast). As a basic mammogram can only distinguish between those women with or without a mammographic abnormality, the screening procedure must also include an assessment of the nature of that abnormality in order to determine whether a biopsy is necessary. Also needed is an administrative organization to define the population of women to be screened, to encourage participation, and to monitor not only every stage of the screening process, but also the outcome in terms of the incidence of the disease and its mortality. Organized breast screening has now been introduced in several European countries, including Britain. In this review we concentrate on the factors that influence the implemen tation of such a program. 117 0066-4219/90/0401-0117$02.00
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A MORTAL DISEASE In the Western world, the lifetime odds of developing breast cancer approach 1 in 12. The disease starts in the secreting units of the breast, the duct-lobular units or breast lobules which contain the terminal ductules and their sac-like acinar ends embedded in fine connective tissue (1-3). The epithelium lining these structures may undergo hyperplastic change that can be atypical both in degree and pattern. Malignant transformation leads to the formation of in situ (noninvasive) cancer that histologically may be lobular or ductal, depending upon the cytology and architecture of the lesion. Of the two, ductal carcinoma has a greater potential for invasion and is less likely to affect both breasts (4). It can express mam mographic and/or clinical features, whereas lobular carcinoma in situ is a histopathological finding. Recent autopsy evidence suggests that car cinoma in situ may occur in normal young women more frequently than was previously suspected (5). The change from a normal to a malignant cell involves fundamental genetic processes. So also does the change from a noninvasive to an invasive tumor (6). Once invasive, cancer cells extend into the surrounding
breast tissue and distort its architecture, producing a mass of nondescript cells with some primitive glandular and ductal structures. In a few cases, greater differentiation is seen (cribriform, papillary, and tubular cancers) such tumors have a relatively favorable prognosis (7). Screen-dctected cancers are more commonly of this type (8). Cancer cells invade not only surrounding breast tissue, they also migrate into lymphatics and blood vessels and are swept to regional lymph nodes and systemic sites to form o.:cult micrometastases. It is the microscopic deposits of tumor in essential organs which ultimately develop into the metastatic deposits that cause the patient to die. By definition, noninvasive breast cancer is curable by surgical excision. However, invasive cancer is not. Several long-term followup studies of patients with invasive cancer indicate that the majority of such patients die from metastatic disease (9-12). Many years may intervene between primary local treatment, relapse, and death; even 30 years after local treatment excess mortality still occurs (Figure 1). The time to relapse depends on several factors, of which the growth rate of the tumor is most important. While statistical cure has not been demonstrated, up to one third of women with invasive breast cancer remain free from disease for their normal lifespan following local treatment alone. Either the growth rate of the tumor is exceptionally slow or it had not metastasized. The occurrence of metastases in regional lymph nodes is known to be related to the size
MAMMOGRAPHY SCREENING
1 19
LONG TERM FOLLOW - UP OF 704 PATIENTS WITH BREAST CANCER
1 00
%
survival
70 50
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30 20 stage J &II
10 7
(306 )
6 5 2
o
5
10
15
20
25
30
35
years Figure I
Long-term survival of women with breast cancer [after Brinkley
& Haybittle (9)].
of an invasive tumor (13, 14), and metastases are unlikely to be present if the volume of the tumor is less than 0.125 cm3 (diameter 0.5 cm) (15, 16). The results of the large USA Breast Cancer Detection Demonstration Project suggested that for practical purposes tumors less than I cm in diameter have a favorable prognosis (17). To be successful, screening must not only detect noninvasive cancers but also invasive tumors before they are of palpable size. In the USA, the term "minimal cancer" has been applied to such tumors (18).
MAMMOGRAPHY There is no evidence that population screening by any method other than mammography reduces the mortality from breast cancer. X-rays were first used by the German pathologist Salomon to examine mastectomy specimens ( 19). It was not until 1930 that Warren first applied the technique to living patients, noting its potential diagnostic role (20). However, full utilization of the technique awaited careful radiological-pathological cor relations and the development of a reproducible and practical technique
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(21-24). Dedicated mammography units are now available that, along with film-screen combinations of high sensitivity and resolution, provide excellent images with a low dose of radiation (1.5 mGy per view). The risk of inducing cancer with doses of this level is far less than the benefit of regular mammographic screening (25). Xeromammography, the alter native method of imaging the breast, is not recommended for population screening because of the larger doses of radiation involved. Three s tandard projections are used for mammography: lateral, cranio caudal, and mediolateral-oblique. As the oblique view allows visualization of almost all breast parenchyma on a single film, it can be used alone for the initial screen (26). The efficiency of mammography in detecting breast cancer is defined by its sensitivity (the proportion of those women with breast cancer who have a positive mammographic screen) and its specificity (the , proportion of those women who do not have breast cancer in whom the screening mammogram is negative). Because those with negative mammograms are not further investigated, a precise estimate of sensitivity cannot be made. However, the rate of cancers arising within a defined period of a negative screen (interval cancers) can be used to calculate this. Conventionally this period is 12 months. Sensitivity and specificity are inversely related, their values depending on the threshold of suspicion applied to the test. Estimates for mammography, with or without clinical examination, show a first-round screening vari ation in sensitivity from 78 to 96%, and in specificity from 87 to 97% (25). In well-organized programs of population screening the incidence of false negative and false positive mammograms should not exceed 10%. To achieve the necessary expertise, radiologists participating in screening pro grams in Britain are urged to read screening films from 6000 cases each year (27).
PROOF OF
BENEFIT
It is essential to the success of a b reast screening program that cancers in those invited to be screened are less likely to be invasive and, if invasive, smaller in size than those that present in symptomatic women. However, this does not provide proof of benefit. The survival of women with breast cancer in those offered screening is also prolonged, but this also does not provide proof of benefit. Survival is measured from the date of diagnosis. As this date is advanced by screening, survival time is automatically lengthened, even if the date of death remains the same. This is known as lead-time bias. Cancers that grow rapidly spend a relatively short time in the preclinical
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MAMMOGRAPHY SCREENING
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phase, during which they may be detected by screening. Therefore they are less likely to be detected than the slow-growing cancers, which spend longer in the phase before they are clinically recognized and have a better prognosis. This is known as length bias. A third bias that may affect survival (selection bias) arises because women who accept an invitation to be screened generally belong to a higher socioeconomic group and are more aware of health issues than are those who refuse the invitation (28). These biases can be overcome only by comparing the mortality from breast cancer in two populations of women: those offered screening and those not. Preferably this should take the form of a controlled randomized trial, in which, to eliminate social bias, selection should be by individual, rather than cluster, randomization (29). The less satisfactory alternative is a case-control study, carried out in a population of women offered mammographic screening in which the screening history of women who have died from breast cancer (the cases) is compared with that of age-matched and healthy controls. The methods of assessing the effectiveness of screening have recently been discussed (28, 30). The results of three controlled randomized trials and three case control studies using mortality from breast cancer as the cnd point have now been reported (31-39) (Table 1). In all, the invitation to attend for mammographic screening has reduced mortality from breast cancer. This reduction was significant in all but one of the seven reports (35), but even in the one exception, the result was still compatible with benefit. The randomized trials showing greatest benefit were the Health Insurance Plan (HIP) study conducted by Shapiro and Strax in Greater New York (31, 31) and the two-counties (WE Study) conducted by Tabar and colleagues in Sweden (33, 34); together these studies included 125,000 women over 40 years of age. Over the 7-10-year period after entry to the trial, there were 30% fewer deaths from breast cancer in those offered screening, an effect that in the HIP study has persisted in lesscr degree for 18 years. In Britain a nonrandomized comparison commenced in 1979 in eight National Health Service Districts to determine the effect of (a) screening by annual clinical examination and biennial mammography over a 7-year period, and (b) instruction in breast self-examination supported by a self-referral clinic offering physical and mammographic examination. The effects of both of these factors on the mortality of the disease were com pared to those in control districts not offering any form of screening. The first analysis reported a 20% reduction in mortality in the two screening districts that reached significance only after six years. No reduction of mortality was observed among those offered instruction in breast self examination (40, 41) (Table 1).
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Table 1
tv tv
Latest reports of trials of screening for breast cancer Population
Studies (Ref.)
Response
Cancers
Screening
to initial
detected
physical
interval
invitation
study/cases
Mortality
mammography
(months)
(%)
control
reduction
Screening method,
study/
Age
cases
range
Recruitment
control
(yrs)
years
"l'j
HIP New York (32)
30,131
Two-counties, Sweden (34)
70,090
40-64
1963-1966
40-74
1977-1980
yes
12
67
304
30 if
89
1166
two viewx4
30,565
no single view x 2
::J
30%
Z
610
40-49 yrs 21,088
45-69
1976--1986
21,195
no
18-24
74
558
4%
448
two view x 5 or 6
Comparative 45,841
45-64
1979-1986
yes x 7
12
60
748
14%
(2.57/1000) single view x 4
127,117
24
72
1472 (1.70/1000)
20% corrected
Case control Nijmegen, Holland (37)
34,600
40--64
1976--1981
no
24
85
single view Utrecht, Holland (38)
20,555
50-64
1973-1981
yes
24,813
40-70
1977-1984
no two view x 2
49%
20 6
72
single view x 4 Florence, Italy (39)
26 9
70%
35 30
60
�
trI
@8 yrs
24 if
;.-
30%
295 > 50 yrs
55,985
TEDBC, UK (40)
trI '" ....,
Ro
Randomized
Malmo, Sweden (35)
0 ::c ::c
47%
MAMMOGRAPHY SCREENING
123
In Edinburgh, one of the two screening centers in the above study, the initial work was extended by a controlled randomized trial: 60,000 women were randomized by family doctor practice to be offered screening or to form a control group (42). An analysis of mortality during the seven years since entry to the trial is now under way. From these studies, the following conclusions can be drawn:
Annu. Rev. Med. 1990.41:117-132. Downloaded from www.annualreviews.org Access provided by Michigan State University Library on 02/16/15. For personal use only.
1. The early detection of breast cancer by mammography reduces mor
tality from the disease. 2. The effect of screening is limited to women over 50 years of age, probably because mammography is less sensitive in younger women as a result of the increased density of their breasts. 3. There is no proof that the addition of a physical examination to modern high-quality mammography improves the results of screening. 4. Single medio-Iateral oblique mammography can be used as the sole screening method. There are no prospective studies of the cost effectiveness of single- versus two-view mammography for the basic screen. 5. The optimal frequency for mammographic screening is not known. In the two-counties trial in Sweden, it was 33 months for women over the age of 50 years; in Britain three years are recommended (25). Recent reports on interval cancer rates suggest that 24 months may be pref erable (43). Organized national programs for mammographic screening of target populations of normal women are now being set up in Britain, Holland, Finland and Sweden, and pilot studies are under way in Germany and France. In the USA, a large Demonstration Project involving 280,000 women in 29 centers has been completed (17). THE SCREENING PROCESS
Basic mammographic screening (Figure 2) determines only whether a mammographic abnormality is present or not. It does not diagnose breast cancer; such a diagnosis requires histological examination of the excised lesion. It is neither practicable nor desirable in population screening to perform a biopsy for every mammographic abnormality. A surgical biopsy is not without risk, it causes additional anxiety, and it distorts the breast tissue, which makes subsequent mammograms difficult to interpret (44). To minimize the number of biopsies, one must carefully evaluate the likely nature of a mammographic abnormality. The surgical biopsy and its histopathological assessment comprise the third stage in the screening procedure. Some consider that reaching a
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SCREENING PROCEDURE
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STAGE I
STAGE II
STAGE m
STAGE I'il
,
TREATMENT
Figure 2
The screening process of women invited to a breast cancer screening program.
definitive histopathological diagnosis marks the end point of screening, but because the management of screen-detected cancers requires complex decisions, others include management as part of a comprehensive screening program. The proportion of women recalled for each of the following four steps in programs of high-quality screening is shown in Figure 3. Stage 1: The Basic Screen
The screening mammogram may demonstrate a discrete abnormality (opacity, architectural distortion, or a cluster of microcalcifications), diffuse change (asymmetry of parenchymal tissue, scattered micro calcifications), or an alteration in appearance on successive screens. If a single-view mammogram was the hasic screening method, the radiologist may wish a second view to confirm the presence of the abnormality and further define its nature; some regard this as part of the basic mam mographic screen. If a definite abnormality is present, the woman must return for full assessment.
MAMMOGRAPHY SCREENING
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THE SCREENING PROCEDURE
normal
�
normal
197 -98"10 1
normal
198-99% 1
normal
199.5% I
Figure 3 The recall and referral pattern in women attending a breast cancer screening program.
Stage 2: Assessment
The methods available for assessing a mammographic abnormality include physical examination, magnification mammography, ultrasonography, fine-needle aspiration (FNA), and FNA cytology. A physical examination should be performed early in the assessment procedure. If a mass is pal pable at the site of the mammographic abnormality, and this is so in the majority of screened women, further diagnosis is straightforward. Fine needle aspiration will quickly determine whether the palpable lesion is cystic or solid; if it is solid, cytology will allow a definitive diagnosis 90% of the time. It is important that if cancer is suspected a surgeon should have an opportunity to examine the mass before needle aspiration is performed because the aspiration may distort size and other physical findings. In organized screening programs the aspiration of a cyst may be carried out by the staff of the screening clinic, but it is wise to perform ultrasonography first so that solid lesions are not inadvertently needled. If the mammographic lesion is impalpable, ultrasonography is helpful
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in defining a cyst and in guiding an aspirating needle. Magnification mammograms permit a more detailed evaluation of the edges of an impal pable solid opacity and allow the number and type of microcalcifications to be defined (45). Increasingly, fine-needle aspiration cytology is also being used for the diagnosis of impalpable lesions, this under stereotactic radiological guidance using a computerized simulator (46, 47). Recent reports of the accuracy of this method indicate that, as with a palpable lesion, a cytological report of malignancy allows a therapeutic rather than a diagnostic operation, which will spare the patient a second procedure (48-50). Negative cytology does not exclude cancer; if there is any mam mographic suspicion, a biopsy should be carried out. However, it has been shown that if both mammography and cytology suggest that a lesion is benign, it can safely be left in the breast. In a recent report from Sweden only one of 2005 patients with impalpable lesions, in whom the combined mammographic and cytological diagnosis was of benign disease, have subsequently developed cancer over a period of 1-13 years (48). The efficiency of the assessment determines the biopsy rate and also the proportion of biopsies that are benign. The ratio of benign to malignant tumors in previous studies has varied from 1 : 1 to greater than 1 : 10. A ratio greater than 1 : 3 should prompt a reevaluation of the assessment technique. Reporting 515 localization biopsies for impalpable lesions, we found that patients who had attended the screening clinic and had been assessed at a formal review clinic had significantly fewer biopsies for benign disease than those who had initially been seen at a symptomatic breast clinic and who did not attend a formal review clinic. The rate of benign biopsies per 1000 mammograms was respectively 2.17 and 8.53. In Britain, assessment is being carried out by teams with a radiologist, a surgeon, and a pathologist, who conduct a joint review clinic for women with doubtful mammographic lesions. As the ultimate decision whether to perform a biopsy or not is surgical, the surgeon should assume responsibility for coordinating results and advising and counselling the patient. Stage 3: Biopsy
Palpable lesions requiring biopsy can readily be excised with local anes thesia; for impalpable lesions, a localization procedure is required, which may necessitate a general anesthetic. Various methods of localization have been described. The method most generally used is the hooked wire marker developed by Frank (51, 52), in which a wire is inserted pre operatively, and its position relative to the lesion is checked by mam mography. The use of stereotactic equipment allows the wire to be placed
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MAMMOGRAPHY SCREENING
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with greater accuracy and, if wished, several wires can be placed to demar cate the radiological extent of the lesion. The alternative method is to inject a suspension of carbon particles (50) or a mixture of contrast material and a visible dye (53) that are both radiopaque and visible to the eye. In the operating room an appropriate incision is made, the marker identified, and the appropriate area of breast tissue excised. The surgeon must confirm that the mammographic lesion is contained within the excised tissue. This requires an X-ray of the specimen. In our experience over 95% of lesions are identified in the specimen radiograph on the first attempt. Some advocate frozen section examination to determine whether the lesion is malignant (53), but most consider it inappropriate because of the complexity of interpreting these early lesions and the likelihood of multifocal change (54). As one cannot determine the size of a small cancer from the specimen radiograph, a positive pre-operative cytological diag nosis greatly facilitates the operative procedure, which, as indicated above,
becomes a therapeutic procedure, not just a diagnostic biopsy. In exam ining the specimen, the pathologist will wish to concentrate on the radio logical abnormality. The fresh specimen is sliced, each slice is X-rayed, and appropriate areas are examined histopathologically (52, 55). Many screen-detected lesions are too small to provide tissue for biochemical analysis, but immunocytochemical techniques (e.g. for the estimation of estrogen receptor activity) may be applicable (56). In a population screening program, it is necessary to use standard criteria to describe the nature of the screen-detected lesions. Otherwise the reporting of atypical changes can be inexact. In Britain and elsewhere in Europe, guidelines for the interpretation of screen-detected lesions have been devised and review panels have been established (57, 58). In Britain the surgical member of the assessment team is increasingly being given responsibility for the conduct of biopsies generated from the screening program, particularly those requiring localization. This practice allows review by other members of the team and the accumulation of expertise. Stage 4: Treatment
The final stage in the screening procedure is the management of the screen detected cancer. A woman whose cancer is detected through screening expects to avoid mastectomy; for noninvasive and for small invasive tumors, local excision is now the preferred surgical treatment. Controlled randomized trials are required to determine the extent to which local excision alone is adequate treatment and those patients in whom post operative radical radiation therapy is mandatory. Mastectomy may still be required for certain types of tumors, for example those with multifocal
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FORREST & AITKEN
disease. The indications for adjuvant systemic therapy also require defi nition. Several trials in Europe and in the USA are addressing these questions.
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ORGANIZATION AND QUALITY ASSURANCE The organization of a national population screening program is a massive undertaking. For example, in Britain the target population to be invited for screening (aged 50-64 years) is 4.8 million! The responsibility for organization falls on 14 Regional Health Authorities in England and on the Departments of Health in Wales, Scotland, and Nor-them Ireland. National Advisory Committees have been formed to advise Health Depart ments on the conduct of the service. Throughout the country, women in the target age range are being identified from family practice or health authority registers, and are being sent personal invitations to attend for mammography, either at static or mobile units. Each unit can screen 12,000 women a year. On a 3-year screening cycle, this provides for a population of 40,000 women in the target age group in a total population of half a milli on Mammograms are being processed in the static units and are initially read by radiologists. Women without an abnormality are excluded from further investigation, but those with an abnormality are asked to return for assessment by a multidisciplinary team, as detailed above. The decision on whether a biopsy is required or not is made at a formal assessment clinic. As these multidisciplinary teams are hospital based, they can also provide a service for symptomatic patients. Increasingly, they are also responsible for reviewing biopsy findings and their surgical members for arranging treatment. These arrangements depend upon the wishes of the family doctor, but as they result in better service to the patient, they are gradually leading to the formation of specialist breast units, as has indeed been established in our center in Edinburgh. Operating a program of this magnitude requires trained'personnel, and a number of training centers have been established. It also requires that the quality of all stages of the screening procedure be assured. Standards have been set, and each region employs quality assurance managers who are responsible for maintaining these standards and monitoring per formance. All breast cancers diagnosed and all deaths in the target popu lation will be registered and details of the stage distribution of survival and mortality used to assess the effectiveness of the program. Organization and management of the highest quality are clearly necessary. An claborate computerized records system has been established to record the results, to arrange for recall, and to monitor effectiveness of screening. .
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The success of a screening program depends not only on its quality, but on the compliance of the invited population. Response rates to an invi tation to mammographic screening vary from 64 to 89% (25), and this must be taken into account when assessing the effectiveness of the program. Public education is a vital part of the screening process. The cost of providing a National Screening Service has been based on existing programs in Britain and Holland (25, 59). In terms of quality adjusted life-years gained, its cost lies midway between that of providing service for renal and heart transplantations. The introduction of population screening for breast cancer is greatly facilitated by health care systems organized on a regional or national basis. Mammography performed in an opportunistic and unmonitored manner in a radiologist's office is not a screening program.
RESEARCH Many questions bearing on screening for breast cancer still remain to be answered. In Britain, under the auspices of the UK Coordinating Com mittee for Cancer Research, national studies are at an advanced stage of planning to determine (a) whether single-view oblique or two-view mammography is the more cost-effective for basic screening; (b) whether one or three years is the optimal interval for rescreening; and (c ) whether regular annual mammographic screening of women over 40 years of age confers benefit. The treatment of screen-detected in situ cancer is also being evaluatcd in a controllcd randomized trial. This trial is comparing local excision with and without radiation therapy, and women in each arm are also being randomized for the administration of the antiestrogen tamoxifen versus no systemic therapy. The National Health Service pro gram of breast cancer screening offers a unique opportunity to address issues such as these. ACKNOWLEDGMENTS
We arc grateful to Dr. T. J. Anderson for his advice, and to Mrs. M. Dunn for secretarial assistance. Literature Cited
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R. G. 1975. An atlas of subgross pathol ogy of human breast with special ref erence to possible pre-cancerous lesions. J. Natl. Cancer Inst. 55: 23 1-73 2. Azzopardi, J. G. 1979. Problems in Breast Pathology. London: Saunders
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Lipmann, A. S. Lichter, D. N. Danforth. Philadelphia: Saunders 5. Neilson, M., Thomsen, J. L . , Prindahl, S., Dyreborg, U. , Andersen, J. A. 1987. Breast cancer and atypica among young and middle-aged women: A study of 110 medico legal autopsies. Br. J. Cancer 56: 814-19 6. Editorial. 1989. Metastatic funda mentals. Lancet I: 1052-1054 7. Dixon, J. M., Page, D. L. , Anderson, T. J., Lee, D. , Elton, R. A. , et al. 1985. Long-term survivors after breast car cinoma. Br. J. Surg. 72: 445-48 8. Anderson, T. J., Lamb, J., Alexander, F. , Lutz, W., Chetty, U., et al. 1986. Comparative pathology of prevalent and incident cancers detected by breast screening. Edinburgh Breast Screening Project. Lancet I: 519-23 9. Brinkley, D. M., Haybitt[e, 1. M. 1984. Long-term survival of women with breast cancer. Lancet I: 1118 10. Rutqvist, L. E. , Wallgren, A. 1995. Long-term survival of 458 young breast cancer patients. Cancer 55: 658-65 II. Mueller, c., Ames, F., Anderson, G. D. 1978. Breast cancer in 3558 women; age as a significant determinant in the role of dying and causes of death. Surgery 83: [ 23-32 12. Langlands, A. 0., Pocock, S. J., Kerr, J. R., Gore, S. M. 1979. Long-term sur vival of patients with breast cancer; a study of the curability of the disease. Br. Med. J. 2: 1247-51 13. Tabar, L., Duffy, S. W. , Krusemo, U. B. 1987. Detection method, tumour size and node metastases in breast Cancers diagnosed during a trial of breast screening. Eur. J. Cancer Clin. Oncol. 23: 959-62 14. Ho[mberg, 1. , Ponten, J., Adami, H.-O. 1989. The biology and natural history of breast cancer from the screening per spective. World J. Surg. 13: 25-29 15. Gallager, H. S., Martin, J. E. 1971. An orientation to the concept of minimal breast cancer. Cancer 28: 1505-7 16. Gallager, H. S. 1983. Minimal breast cancer: Results of treatment and the long-term follow-up. In Breast Car cinoma: Current Diagnosis and Treat ment, ed. S. A. Feig, R. McLelland, pp. 291-94. New York: Masson 17. Seidman, H., Gelb, S. K., Silverberg, E., et a1. 1987. Survival Experience in the Breast CancerDetection Demonstration Project. CA 37: 258-90 18. Report of the working group to review the National Cancer Institute-Amer ican Cancer Society Breast Cancer Detection Demonstration Projects.
1979. J. Natl. Cancer Inst. 62: 639709 19. Salomon, A. 1913. Beitrage zur Patho logie und Klinik der Mammar carcinome. Arch. Klin. Chir. 101: 5 73 668 20. Warren, S. L. 1930. Roentgenologic study of breast. Am. J. Roentgenol. Radium Ther. 24: 113-24 21. Leborgne, R. 1951. Diagnosis of tumours of the breast by simple roent genography. Calcifications in carci nomas. Am. J. Roentgenol. Radium Ther. 65: I-II 22. Ingleby, H. , Gershon-Cohen, J. 1960. Comparative Anatomy, Pathology and Roentgenology 0/ the Breast. Phila delphia: Univ. Pennys1vania Press 23. Egan, R. L. 1960. Experience with mam mography in a tumour institution. Evaluation of 1000 studies. Radiology 75: 894-900 24. Gros, C. M. 1963. Les maladies du sein. Paris: Masson 25. Breast Cancer Screening. 1987. Report to the Health Ministers 0/ England, Wales, Scotland and Northern Ireland by a Working Group chaired by Sir Patrick Forrest. Her Majesty's Stationery Office 26. Lundgren, B. 1979. Population screen ing for breast cancer by single view mammography in a geographic region in Sweden. J. Natl. Cancer Inst. 62: 137379 27. The Pritchard Report. 19 88. Guidelines on the establishment 0/ a quality assur ance system/or the radiological aspects 0/ mammography used/or breast screening. Radiation Advisory Committee: Sub committee on quality assurance (The Pritchard Committee) 28. Chamberlain, J. 1985. Secondary pre vention: Screening for breast cancer. Effective Health Care 2: 180-87 29. Alexander, F., Roberts, M. M., Lutz, W., Hepburn, W. 1989. Randomisation by cluster and the problem of social class bias. J. Epidemiol. Commun. llealth 43: 29 36 30. Day, N. E., Williams, D. R. R., Khaw, K. T. 1989. Breast cancer screening pro grammes: The development of a moni toring and evaluation system. Br. J. Can cer 59: 954-58 31. Shapiro, S., Venet, W. , Strax, P., et al. 1982. Ten-to-fourteen-year effect of screening on breast cancer mortality. J. Natl. Cancer Inst. 69: 349-55 32. Venet, W., Shapiro, S. 1986. Final report. Evaluation o/periodic breast can cer screening with mammography and clinical examination. Health Insurance Plan of Greater New York
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MAMMOGRAPHY SCREENING 33. Tabar, L., Fagerberg, C. J. G., Gad, A., Baldetorp, L., Holmberg, L. H., et al. 1985. Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from thc Brcast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet I: 82932 34. Tabar, L., Fagerberg, G., Duffy, S. W., Day, N. E. 1989. The Swedish two county trial of mammographic screening for breast cancer: Recent results and cal culation of benefit. 1. Epidemiol. Commun. Health 43: 107-14 35. Andersson, I., Aspergen, K., Janzon, L., Landberg, T., Lindholm, K., et al. 1988. Mammographic screening and mortality from breast cancer: The Malmo mam mographic screening trial. Br. Med. J. 297: 943--48 36. Verbeek, A. L. M., Hendricks, J. H. C. L., Holland, R., Mravunac, M., Stur mans, F., el a l. 1984. Reduction of breast cancer mortality through mass screening with modern mammography: first results of the Nijmegen project, 1975198!. Lancet I: 1222-24 37. Peters, P. H. M., Verbeek, A. L. M., Hendriks, J. H. C. L., Van Bon, M. J. H. 1989. Screening for breast cancer in Nijmegen. Report of 6 screening rounds 1975-1986. Eur. J. Cancer 4 3: 226-30 38. Collette, H. J. A., Day, N. E., Rombach, J. J., Waard, F. 1984. Evaluation of screening for breast cancer in a non randomised study (the DOM project) by means of a case-control study. Lancet I: 1224-26 39. Palli, D., Rosselli del-Turco, M., Buiatti, E., Carli, S., Ciato, S., et al. 1986. A case-control study of the efficacy of a non-randomised breast cancer screening program in Florence (Italy). Int. J. Can cer 38: 501--4 40. UK Trial of Early Detection of Breast Cancer Group. 198!. Trial of early detection of breast cancer: description of method. Br. J. Cancer 44: 618-27 4!. UK Trial of Early Detection of Breast Cancer Group. 1988. First results on mortality reduction in the UK trial of early detection on breast cancer. Lancel 2: 411-15 42. Roberts, M. M., Alexander, F., Ander son, T. J., Forrest, A. P. M., Hepburn, W., et al. 1984. The Edinburgh ran domised trial of screening for breast can cer: Description of method. Br . J. Can cer 50: 1-6 43. Tabar, L., Fagerberg, G., Day, N. E., Holmberg, L. 1987. What is the optimal interval between mammographic screen-
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ing examinations? An analysis based on the latest results of the Swedish two county breast cancer screening trial. Br. J. Cancer 55: 547-51 Sickles, E. A., Herzog, K. A. 1980. Mammography of the postsurgical breast. Am . J. Roentgenoi. 136: 585-88 Sickles, E. A. 1980. Further experience with microfocal spot magnification mammography in the assessment of clus tered breast microcalcifications. Radi ology 137: 9-14 Bolmgrehn, 1., Jacobson, B., Norden strom, B. 1977. Stereotaxic instrument for needle biopsy of the mamma. Am. J. Roentgenol. 129: 121-125 Denarnaud, Y. , Haehne1, P., Isnard, A., Chaintreuil, J. 1987. Stereotactic breast puncture: New step in breast screening. In Diagnostic Imaging. Miller Freeman Publications Lofgren, M., Andresson, I., Bondeson, L., Lindholm, K. 1988. X-ray guided on fine-needle aspiration for the cytologic
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diagnosis of non-palpable breast lesions. Cancer 61: 1032-1037 Dent, D. M., Kirkpatrick, A. E., McGoogan, E., et al. 1989. Stereotaxic localisation and aspiration cytology of impalpable breast lesions. Clin. Radiol. In press Azavedo, E., Svane, G., Aner, G. 1989. Stereotactic fine-needle biopsy in 2594 mammographically detected non-pal pable lesions. Lancet I: 1033-1035 Frank, H. A., Hall, F. M., Steer, M. L. 1976. Pre-operative localization of non palpable breast lesions demonstrated by mammography. N. Engl. J. Med. 296: 259-60 Chetty, U., Kirkpatrick, A. E., Ander son, T. 1., Lamb, 1., Roberts, M. M., et al. 1983. Localisation and excision of occult breast lesions. Br. J. Surg. 70: 607-10 Simon, N., Lesnick, G. J., Lerer, M. N., Bachman, A. L. 1972. Roent genographic localization of small lesions of the breast by the spot method. Surg. Gynecol. Ohstet. 134: 572-74 Tinnemans, J. G. M., Wobbes, Th., Hol land, R., Hendricks, J. H. C. L., van der Sluis, R. F., el al. 1987. Mammographic and histological correlation of non palpable lesions of the breast and the reliability of frozen section. Surg. Gynaecol. Ohstet. 165: 523-29 Anderson, T. 1. 1989. Breast cancer screening: principles and practicalities for histopathologists. Recent Advances in Histopathology, pp. 43-61 Hawkins, R. A., Sangster, K., Tesdale, A. 1988. The cytochemical detection of
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oestrogen receptors in fine-needle aspi rates of breast cancer: Correlation with biochemical prediction of response to endocrine therapy. Br. J. Cancer 58: 77� 80 57. Pathology Reporting in Breast Cancer Screening. 1989. DraJt guidance. Depart ment of Health and Royal College of Pathologists Working Group. 58. Gad, A. 1988. Screening for breast can cer: examination and reporting of histo pathological preparations. Lancet 2: 953
59. Report. 1988. The costs and effects oj mass screening Jor breast cancer. Dept. of Public Health and Social Medicine, Erasmus Universiteit, Rotterdam; Dept. of Social Medicine/Dept. of Radiology, Katholicke Universitet Nijmegen; Pre venticon/Department of Public Health and Epidemiology, Rijksuniversiteit, Utrecht; Dept. of Medical Sociology, Rijksuniversiteit, Groningen.
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MAMMOGRAPHY SCREENING FOR BREAST CANCER A. P. M. Forrest, M.D., F.R.C.S., and R. J. Aitken, F.R.C.S.
University Department of Surgery, Royal Infirmary, Edinburgh EH3 9YW, Scotland KEY WORDS:
cancer trials, health care systems, biopsy, pathology, prevention.
ABSTRACT
There is now unequivocal evidence that screening with mammography reduces the mortality of breast cancer. This benefit will best be realized by a national screening program. Such programs require a meticulous organization with dedicated staff who are experienced in the management of screen-detected lesions.
WHY SCREEN The objective of breast screening is to reduce the mortality of breast cancer by detecting tumors before they present symptomatically as a palpable mass in the breast. This goal can be achieved by mammography (soft tissue radiology of the breast). As a basic mammogram can only distinguish between those women with or without a mammographic abnormality, the screening procedure must also include an assessment of the nature of that abnormality in order to determine whether a biopsy is necessary. Also needed is an administrative organization to define the population of women to be screened, to encourage participation, and to monitor not only every stage of the screening process, but also the outcome in terms of the incidence of the disease and its mortality. Organized breast screening has now been introduced in several European countries, including Britain. In this review we concentrate on the factors that influence the implemen tation of such a program. 117 0066-4219/90/0401-0117$02.00
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A MORTAL DISEASE In the Western world, the lifetime odds of developing breast cancer approach 1 in 12. The disease starts in the secreting units of the breast, the duct-lobular units or breast lobules which contain the terminal ductules and their sac-like acinar ends embedded in fine connective tissue (1-3). The epithelium lining these structures may undergo hyperplastic change that can be atypical both in degree and pattern. Malignant transformation leads to the formation of in situ (noninvasive) cancer that histologically may be lobular or ductal, depending upon the cytology and architecture of the lesion. Of the two, ductal carcinoma has a greater potential for invasion and is less likely to affect both breasts (4). It can express mam mographic and/or clinical features, whereas lobular carcinoma in situ is a histopathological finding. Recent autopsy evidence suggests that car cinoma in situ may occur in normal young women more frequently than was previously suspected (5). The change from a normal to a malignant cell involves fundamental genetic processes. So also does the change from a noninvasive to an invasive tumor (6). Once invasive, cancer cells extend into the surrounding
breast tissue and distort its architecture, producing a mass of nondescript cells with some primitive glandular and ductal structures. In a few cases, greater differentiation is seen (cribriform, papillary, and tubular cancers) such tumors have a relatively favorable prognosis (7). Screen-dctected cancers are more commonly of this type (8). Cancer cells invade not only surrounding breast tissue, they also migrate into lymphatics and blood vessels and are swept to regional lymph nodes and systemic sites to form o.:cult micrometastases. It is the microscopic deposits of tumor in essential organs which ultimately develop into the metastatic deposits that cause the patient to die. By definition, noninvasive breast cancer is curable by surgical excision. However, invasive cancer is not. Several long-term followup studies of patients with invasive cancer indicate that the majority of such patients die from metastatic disease (9-12). Many years may intervene between primary local treatment, relapse, and death; even 30 years after local treatment excess mortality still occurs (Figure 1). The time to relapse depends on several factors, of which the growth rate of the tumor is most important. While statistical cure has not been demonstrated, up to one third of women with invasive breast cancer remain free from disease for their normal lifespan following local treatment alone. Either the growth rate of the tumor is exceptionally slow or it had not metastasized. The occurrence of metastases in regional lymph nodes is known to be related to the size
MAMMOGRAPHY SCREENING
1 19
LONG TERM FOLLOW - UP OF 704 PATIENTS WITH BREAST CANCER
1 00
%
survival
70 50
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30 20 stage J &II
10 7
(306 )
6 5 2
o
5
10
15
20
25
30
35
years Figure I
Long-term survival of women with breast cancer [after Brinkley
& Haybittle (9)].
of an invasive tumor (13, 14), and metastases are unlikely to be present if the volume of the tumor is less than 0.125 cm3 (diameter 0.5 cm) (15, 16). The results of the large USA Breast Cancer Detection Demonstration Project suggested that for practical purposes tumors less than I cm in diameter have a favorable prognosis (17). To be successful, screening must not only detect noninvasive cancers but also invasive tumors before they are of palpable size. In the USA, the term "minimal cancer" has been applied to such tumors (18).
MAMMOGRAPHY There is no evidence that population screening by any method other than mammography reduces the mortality from breast cancer. X-rays were first used by the German pathologist Salomon to examine mastectomy specimens ( 19). It was not until 1930 that Warren first applied the technique to living patients, noting its potential diagnostic role (20). However, full utilization of the technique awaited careful radiological-pathological cor relations and the development of a reproducible and practical technique
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(21-24). Dedicated mammography units are now available that, along with film-screen combinations of high sensitivity and resolution, provide excellent images with a low dose of radiation (1.5 mGy per view). The risk of inducing cancer with doses of this level is far less than the benefit of regular mammographic screening (25). Xeromammography, the alter native method of imaging the breast, is not recommended for population screening because of the larger doses of radiation involved. Three s tandard projections are used for mammography: lateral, cranio caudal, and mediolateral-oblique. As the oblique view allows visualization of almost all breast parenchyma on a single film, it can be used alone for the initial screen (26). The efficiency of mammography in detecting breast cancer is defined by its sensitivity (the proportion of those women with breast cancer who have a positive mammographic screen) and its specificity (the , proportion of those women who do not have breast cancer in whom the screening mammogram is negative). Because those with negative mammograms are not further investigated, a precise estimate of sensitivity cannot be made. However, the rate of cancers arising within a defined period of a negative screen (interval cancers) can be used to calculate this. Conventionally this period is 12 months. Sensitivity and specificity are inversely related, their values depending on the threshold of suspicion applied to the test. Estimates for mammography, with or without clinical examination, show a first-round screening vari ation in sensitivity from 78 to 96%, and in specificity from 87 to 97% (25). In well-organized programs of population screening the incidence of false negative and false positive mammograms should not exceed 10%. To achieve the necessary expertise, radiologists participating in screening pro grams in Britain are urged to read screening films from 6000 cases each year (27).
PROOF OF
BENEFIT
It is essential to the success of a b reast screening program that cancers in those invited to be screened are less likely to be invasive and, if invasive, smaller in size than those that present in symptomatic women. However, this does not provide proof of benefit. The survival of women with breast cancer in those offered screening is also prolonged, but this also does not provide proof of benefit. Survival is measured from the date of diagnosis. As this date is advanced by screening, survival time is automatically lengthened, even if the date of death remains the same. This is known as lead-time bias. Cancers that grow rapidly spend a relatively short time in the preclinical
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MAMMOGRAPHY SCREENING
121
phase, during which they may be detected by screening. Therefore they are less likely to be detected than the slow-growing cancers, which spend longer in the phase before they are clinically recognized and have a better prognosis. This is known as length bias. A third bias that may affect survival (selection bias) arises because women who accept an invitation to be screened generally belong to a higher socioeconomic group and are more aware of health issues than are those who refuse the invitation (28). These biases can be overcome only by comparing the mortality from breast cancer in two populations of women: those offered screening and those not. Preferably this should take the form of a controlled randomized trial, in which, to eliminate social bias, selection should be by individual, rather than cluster, randomization (29). The less satisfactory alternative is a case-control study, carried out in a population of women offered mammographic screening in which the screening history of women who have died from breast cancer (the cases) is compared with that of age-matched and healthy controls. The methods of assessing the effectiveness of screening have recently been discussed (28, 30). The results of three controlled randomized trials and three case control studies using mortality from breast cancer as the cnd point have now been reported (31-39) (Table 1). In all, the invitation to attend for mammographic screening has reduced mortality from breast cancer. This reduction was significant in all but one of the seven reports (35), but even in the one exception, the result was still compatible with benefit. The randomized trials showing greatest benefit were the Health Insurance Plan (HIP) study conducted by Shapiro and Strax in Greater New York (31, 31) and the two-counties (WE Study) conducted by Tabar and colleagues in Sweden (33, 34); together these studies included 125,000 women over 40 years of age. Over the 7-10-year period after entry to the trial, there were 30% fewer deaths from breast cancer in those offered screening, an effect that in the HIP study has persisted in lesscr degree for 18 years. In Britain a nonrandomized comparison commenced in 1979 in eight National Health Service Districts to determine the effect of (a) screening by annual clinical examination and biennial mammography over a 7-year period, and (b) instruction in breast self-examination supported by a self-referral clinic offering physical and mammographic examination. The effects of both of these factors on the mortality of the disease were com pared to those in control districts not offering any form of screening. The first analysis reported a 20% reduction in mortality in the two screening districts that reached significance only after six years. No reduction of mortality was observed among those offered instruction in breast self examination (40, 41) (Table 1).
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Table 1
tv tv
Latest reports of trials of screening for breast cancer Population
Studies (Ref.)
Response
Cancers
Screening
to initial
detected
physical
interval
invitation
study/cases
Mortality
mammography
(months)
(%)
control
reduction
Screening method,
study/
Age
cases
range
Recruitment
control
(yrs)
years
"l'j
HIP New York (32)
30,131
Two-counties, Sweden (34)
70,090
40-64
1963-1966
40-74
1977-1980
yes
12
67
304
30 if
89
1166
two viewx4
30,565
no single view x 2
::J
30%
Z
610
40-49 yrs 21,088
45-69
1976--1986
21,195
no
18-24
74
558
4%
448
two view x 5 or 6
Comparative 45,841
45-64
1979-1986
yes x 7
12
60
748
14%
(2.57/1000) single view x 4
127,117
24
72
1472 (1.70/1000)
20% corrected
Case control Nijmegen, Holland (37)
34,600
40--64
1976--1981
no
24
85
single view Utrecht, Holland (38)
20,555
50-64
1973-1981
yes
24,813
40-70
1977-1984
no two view x 2
49%
20 6
72
single view x 4 Florence, Italy (39)
26 9
70%
35 30
60
�
trI
@8 yrs
24 if
;.-
30%
295 > 50 yrs
55,985
TEDBC, UK (40)
trI '" ....,
Ro
Randomized
Malmo, Sweden (35)
0 ::c ::c
47%
MAMMOGRAPHY SCREENING
123
In Edinburgh, one of the two screening centers in the above study, the initial work was extended by a controlled randomized trial: 60,000 women were randomized by family doctor practice to be offered screening or to form a control group (42). An analysis of mortality during the seven years since entry to the trial is now under way. From these studies, the following conclusions can be drawn:
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1. The early detection of breast cancer by mammography reduces mor
tality from the disease. 2. The effect of screening is limited to women over 50 years of age, probably because mammography is less sensitive in younger women as a result of the increased density of their breasts. 3. There is no proof that the addition of a physical examination to modern high-quality mammography improves the results of screening. 4. Single medio-Iateral oblique mammography can be used as the sole screening method. There are no prospective studies of the cost effectiveness of single- versus two-view mammography for the basic screen. 5. The optimal frequency for mammographic screening is not known. In the two-counties trial in Sweden, it was 33 months for women over the age of 50 years; in Britain three years are recommended (25). Recent reports on interval cancer rates suggest that 24 months may be pref erable (43). Organized national programs for mammographic screening of target populations of normal women are now being set up in Britain, Holland, Finland and Sweden, and pilot studies are under way in Germany and France. In the USA, a large Demonstration Project involving 280,000 women in 29 centers has been completed (17). THE SCREENING PROCESS
Basic mammographic screening (Figure 2) determines only whether a mammographic abnormality is present or not. It does not diagnose breast cancer; such a diagnosis requires histological examination of the excised lesion. It is neither practicable nor desirable in population screening to perform a biopsy for every mammographic abnormality. A surgical biopsy is not without risk, it causes additional anxiety, and it distorts the breast tissue, which makes subsequent mammograms difficult to interpret (44). To minimize the number of biopsies, one must carefully evaluate the likely nature of a mammographic abnormality. The surgical biopsy and its histopathological assessment comprise the third stage in the screening procedure. Some consider that reaching a
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FORREST & AITKEN
SCREENING PROCEDURE
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STAGE I
STAGE II
STAGE m
STAGE I'il
,
TREATMENT
Figure 2
The screening process of women invited to a breast cancer screening program.
definitive histopathological diagnosis marks the end point of screening, but because the management of screen-detected cancers requires complex decisions, others include management as part of a comprehensive screening program. The proportion of women recalled for each of the following four steps in programs of high-quality screening is shown in Figure 3. Stage 1: The Basic Screen
The screening mammogram may demonstrate a discrete abnormality (opacity, architectural distortion, or a cluster of microcalcifications), diffuse change (asymmetry of parenchymal tissue, scattered micro calcifications), or an alteration in appearance on successive screens. If a single-view mammogram was the hasic screening method, the radiologist may wish a second view to confirm the presence of the abnormality and further define its nature; some regard this as part of the basic mam mographic screen. If a definite abnormality is present, the woman must return for full assessment.
MAMMOGRAPHY SCREENING
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THE SCREENING PROCEDURE
normal
�
normal
197 -98"10 1
normal
198-99% 1
normal
199.5% I
Figure 3 The recall and referral pattern in women attending a breast cancer screening program.
Stage 2: Assessment
The methods available for assessing a mammographic abnormality include physical examination, magnification mammography, ultrasonography, fine-needle aspiration (FNA), and FNA cytology. A physical examination should be performed early in the assessment procedure. If a mass is pal pable at the site of the mammographic abnormality, and this is so in the majority of screened women, further diagnosis is straightforward. Fine needle aspiration will quickly determine whether the palpable lesion is cystic or solid; if it is solid, cytology will allow a definitive diagnosis 90% of the time. It is important that if cancer is suspected a surgeon should have an opportunity to examine the mass before needle aspiration is performed because the aspiration may distort size and other physical findings. In organized screening programs the aspiration of a cyst may be carried out by the staff of the screening clinic, but it is wise to perform ultrasonography first so that solid lesions are not inadvertently needled. If the mammographic lesion is impalpable, ultrasonography is helpful
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in defining a cyst and in guiding an aspirating needle. Magnification mammograms permit a more detailed evaluation of the edges of an impal pable solid opacity and allow the number and type of microcalcifications to be defined (45). Increasingly, fine-needle aspiration cytology is also being used for the diagnosis of impalpable lesions, this under stereotactic radiological guidance using a computerized simulator (46, 47). Recent reports of the accuracy of this method indicate that, as with a palpable lesion, a cytological report of malignancy allows a therapeutic rather than a diagnostic operation, which will spare the patient a second procedure (48-50). Negative cytology does not exclude cancer; if there is any mam mographic suspicion, a biopsy should be carried out. However, it has been shown that if both mammography and cytology suggest that a lesion is benign, it can safely be left in the breast. In a recent report from Sweden only one of 2005 patients with impalpable lesions, in whom the combined mammographic and cytological diagnosis was of benign disease, have subsequently developed cancer over a period of 1-13 years (48). The efficiency of the assessment determines the biopsy rate and also the proportion of biopsies that are benign. The ratio of benign to malignant tumors in previous studies has varied from 1 : 1 to greater than 1 : 10. A ratio greater than 1 : 3 should prompt a reevaluation of the assessment technique. Reporting 515 localization biopsies for impalpable lesions, we found that patients who had attended the screening clinic and had been assessed at a formal review clinic had significantly fewer biopsies for benign disease than those who had initially been seen at a symptomatic breast clinic and who did not attend a formal review clinic. The rate of benign biopsies per 1000 mammograms was respectively 2.17 and 8.53. In Britain, assessment is being carried out by teams with a radiologist, a surgeon, and a pathologist, who conduct a joint review clinic for women with doubtful mammographic lesions. As the ultimate decision whether to perform a biopsy or not is surgical, the surgeon should assume responsibility for coordinating results and advising and counselling the patient. Stage 3: Biopsy
Palpable lesions requiring biopsy can readily be excised with local anes thesia; for impalpable lesions, a localization procedure is required, which may necessitate a general anesthetic. Various methods of localization have been described. The method most generally used is the hooked wire marker developed by Frank (51, 52), in which a wire is inserted pre operatively, and its position relative to the lesion is checked by mam mography. The use of stereotactic equipment allows the wire to be placed
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with greater accuracy and, if wished, several wires can be placed to demar cate the radiological extent of the lesion. The alternative method is to inject a suspension of carbon particles (50) or a mixture of contrast material and a visible dye (53) that are both radiopaque and visible to the eye. In the operating room an appropriate incision is made, the marker identified, and the appropriate area of breast tissue excised. The surgeon must confirm that the mammographic lesion is contained within the excised tissue. This requires an X-ray of the specimen. In our experience over 95% of lesions are identified in the specimen radiograph on the first attempt. Some advocate frozen section examination to determine whether the lesion is malignant (53), but most consider it inappropriate because of the complexity of interpreting these early lesions and the likelihood of multifocal change (54). As one cannot determine the size of a small cancer from the specimen radiograph, a positive pre-operative cytological diag nosis greatly facilitates the operative procedure, which, as indicated above,
becomes a therapeutic procedure, not just a diagnostic biopsy. In exam ining the specimen, the pathologist will wish to concentrate on the radio logical abnormality. The fresh specimen is sliced, each slice is X-rayed, and appropriate areas are examined histopathologically (52, 55). Many screen-detected lesions are too small to provide tissue for biochemical analysis, but immunocytochemical techniques (e.g. for the estimation of estrogen receptor activity) may be applicable (56). In a population screening program, it is necessary to use standard criteria to describe the nature of the screen-detected lesions. Otherwise the reporting of atypical changes can be inexact. In Britain and elsewhere in Europe, guidelines for the interpretation of screen-detected lesions have been devised and review panels have been established (57, 58). In Britain the surgical member of the assessment team is increasingly being given responsibility for the conduct of biopsies generated from the screening program, particularly those requiring localization. This practice allows review by other members of the team and the accumulation of expertise. Stage 4: Treatment
The final stage in the screening procedure is the management of the screen detected cancer. A woman whose cancer is detected through screening expects to avoid mastectomy; for noninvasive and for small invasive tumors, local excision is now the preferred surgical treatment. Controlled randomized trials are required to determine the extent to which local excision alone is adequate treatment and those patients in whom post operative radical radiation therapy is mandatory. Mastectomy may still be required for certain types of tumors, for example those with multifocal
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disease. The indications for adjuvant systemic therapy also require defi nition. Several trials in Europe and in the USA are addressing these questions.
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ORGANIZATION AND QUALITY ASSURANCE The organization of a national population screening program is a massive undertaking. For example, in Britain the target population to be invited for screening (aged 50-64 years) is 4.8 million! The responsibility for organization falls on 14 Regional Health Authorities in England and on the Departments of Health in Wales, Scotland, and Nor-them Ireland. National Advisory Committees have been formed to advise Health Depart ments on the conduct of the service. Throughout the country, women in the target age range are being identified from family practice or health authority registers, and are being sent personal invitations to attend for mammography, either at static or mobile units. Each unit can screen 12,000 women a year. On a 3-year screening cycle, this provides for a population of 40,000 women in the target age group in a total population of half a milli on Mammograms are being processed in the static units and are initially read by radiologists. Women without an abnormality are excluded from further investigation, but those with an abnormality are asked to return for assessment by a multidisciplinary team, as detailed above. The decision on whether a biopsy is required or not is made at a formal assessment clinic. As these multidisciplinary teams are hospital based, they can also provide a service for symptomatic patients. Increasingly, they are also responsible for reviewing biopsy findings and their surgical members for arranging treatment. These arrangements depend upon the wishes of the family doctor, but as they result in better service to the patient, they are gradually leading to the formation of specialist breast units, as has indeed been established in our center in Edinburgh. Operating a program of this magnitude requires trained'personnel, and a number of training centers have been established. It also requires that the quality of all stages of the screening procedure be assured. Standards have been set, and each region employs quality assurance managers who are responsible for maintaining these standards and monitoring per formance. All breast cancers diagnosed and all deaths in the target popu lation will be registered and details of the stage distribution of survival and mortality used to assess the effectiveness of the program. Organization and management of the highest quality are clearly necessary. An claborate computerized records system has been established to record the results, to arrange for recall, and to monitor effectiveness of screening. .
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The success of a screening program depends not only on its quality, but on the compliance of the invited population. Response rates to an invi tation to mammographic screening vary from 64 to 89% (25), and this must be taken into account when assessing the effectiveness of the program. Public education is a vital part of the screening process. The cost of providing a National Screening Service has been based on existing programs in Britain and Holland (25, 59). In terms of quality adjusted life-years gained, its cost lies midway between that of providing service for renal and heart transplantations. The introduction of population screening for breast cancer is greatly facilitated by health care systems organized on a regional or national basis. Mammography performed in an opportunistic and unmonitored manner in a radiologist's office is not a screening program.
RESEARCH Many questions bearing on screening for breast cancer still remain to be answered. In Britain, under the auspices of the UK Coordinating Com mittee for Cancer Research, national studies are at an advanced stage of planning to determine (a) whether single-view oblique or two-view mammography is the more cost-effective for basic screening; (b) whether one or three years is the optimal interval for rescreening; and (c ) whether regular annual mammographic screening of women over 40 years of age confers benefit. The treatment of screen-detected in situ cancer is also being evaluatcd in a controllcd randomized trial. This trial is comparing local excision with and without radiation therapy, and women in each arm are also being randomized for the administration of the antiestrogen tamoxifen versus no systemic therapy. The National Health Service pro gram of breast cancer screening offers a unique opportunity to address issues such as these. ACKNOWLEDGMENTS
We arc grateful to Dr. T. J. Anderson for his advice, and to Mrs. M. Dunn for secretarial assistance. Literature Cited
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