Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

521

Perspective

The Positive Daniel

Predictive

Value

of Mammography

B. Kopans1

Breast cancer is the leading cause of nonpreventable cancer-associated death among women in the United States. The primary purpose of screening asymptomatic, healthy women for breast cancer is to diagnose it earlier and in so doing reduce the risk of or delay the onset of death from this disease. In addition, detecting cancers when the tumors are smaller benefits many women by permitting the therapeutic option of breast preservation. The importance of mammographic screening is gradually being recognized in the United States, and over the past several years, the number of women screened has increased. Mammography has clearly been shown to be quite sensitive in its ability to detect cancer, but frequently it cannot be used to accurately differentiate benign from malignant lesions [11. Currently, open biopsy is the only accurate way to determine the benign or malignant basis of a mammographic finding, although fine-needle aspiration cytology and core needle biopsy are being explored as alternatives. Preoperative localization of clinically occult abnormalities detected by mammography, followed by excisional biopsy, represents the gold standard. Because of the lack of morphologic specificity, many biopsies done because of mammographic findings are being performed for what prove to be benign lesions. In the United States, the positive predictive value (PPV) of mammography (the number of cancers diagnosed per number of biopsies recommended) has ranged from approximately 15% to 30% [2-7]; in the European trials, it ranged from 30% [8] to 75% [9]. Some of the reasons for such discrepancies have been discussed [1 0]. Nevertheless, as a consequence of the numbers of biopsies that are now being done, and the anticipated increase in biopsies that are likely to accompany largeReceived 1

May 3, 1991;

Department

AJR 158:521-526,

accepted

of Radiology, March

after revision

Massachusetts

October

General

1992 0361-803X/92/1583-0521

scale screening, ing scrutiny.

What Is an Appropriate

32 Fruit St., Boston,

0 American

Roentgen

Positive

Predictive

is under

increas-

Value?

Although a biopsy is an extremely safe procedure, recommendation for a breast biopsy, with the implied possibility of breast cancer, induces high anxiety in patients. The procedure itself results in a loss of productivity during the surgical and recuperative time, creates various degrees of surgical trauma and cosmetic alteration, and generates increased costs for the health care system. It is understandable, and desirable, that attention be directed toward the reduction of surgical procedures for benign changes; however, arriving at an absolute figure for the appropriate PPV is difficult. It is perhaps somewhat ironic that surgeons are now among the critics of the low PPV for mammographically detected lesions [1 1]. Historically, a low PPV for breast biopsies has long been tolerated. In the era before mammography, when the surgeon was determining who should have biopsies, the PPV for the biopsy of palpable lesions was as low as 1 1 % [1 2]. This was tolerated because the presence of a mass was tangible evidence of possibly malignant disease. The psychological impact of a biopsy done because of clinical findings is inherently different from the impact of a biopsy done because of abnormal mammographic findings. The removal of a palpable abnormality that proves to be benign is not considered unnecessary surgery, because the patient and her physician can relate directly to the problem. A mammographically detected lesion, on the other hand, comes as a total surprise to the “healthy” woman and her physician. Its removal must be

14, 1991.

Hospital,

the PPV for mammography

MA 02114. Ray Society

Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

522

KOPANS

completely guided by the radiologist, and when the lesion proves to be benign, it is not unexpected that this would be considered “unnecessary” surgery. This qualitative difference obscures thefact that performing a biopsy ofa palpable lesion is more likely to be unnecessary from a cancer perspective. It has been shown repeatedly that mammographically detected cancers are usually at an earlier stage than those detected by clinical examination [1 3-1 5]. This revelation not only serves as a warning that superficial comparisons of PPV may be misleading but also emphasizes that the appropriate PPv is not an absolute number. When the implications of a biopsy strategy are assessed, PPV cannot be taken out of context but must be evaluated with an understanding of the population in which it occurs. Ultimately, the appropriate PPV depends on what society considers an acceptable falsenegative rate. The decision to perform a biopsy or not follows a receiver operator curve. More cancers will be detected at the cost of increased falsely positive interpretations. Ultimately, if a biopsy were done of everything that was not perfectly normal, the number of cancers diagnosed would be maximized, but the number of women undergoing unnecessary biopsies would likely be unacceptable. Thus, thresholds for intervention are set, but no absolute biopsy rates exist that will be universally accepted.

Positive

Predictive

Value by Itself Can Be Misleading

The same PPV can be found in circumstances with totally different survival implications. It is entirely possible for two radiologists to interpret mammograms with the same PPV, but one can be affecting the death rate by finding small cancers, and the other can be intervening when it is too late to alter the course of the disease. The malignant:benign ratio is relatively meaningless if the threshold criteria used to determine if a biopsy should be done and the characteristics of the cancers found by using those criteria are not known. For example, assume that size is the only criterion used to prompt a biopsy, and one radiologist chooses to do biopsies of lesions that are 1 cm in diameter, whereas another radiologist chooses to wait until a lesion reaches 2 cm. Initially, the first radiologist will diagnose more cancers than the second, because both radiologists will be recommending biopsies of the 2-cm lesions, but the first radiologist will also be doing biopsies of the smaller lesions. Once the first radiologist has eliminated the large cancers, he or she will be diagnosing lesions at the same rate (and PPV) as the second radiologist, but at an earlier time in the growth of the lesions (assuming

a constant

growth

rate). Thus, despite the same PPV, the

first radiologist will more likely on mortalty than the second.

Factors

That

Influence

have

the Positive

a much

Predictive

greater

impact

Value

Sensitivity (the number of cancers detected by mammography divided by the true number of cancers in the population being screened) and specificity (the number of women in the screened population who do not have breast cancer whose mammograms are interpreted as negative divided by the

AJR:158, March 1992

number of women who truly do not have breast cancer) give some indication of the accuracy of a screening program, but they are not sufficient by themselves. Sensitivity and specificity can be misleading, depending on how the “true” number of cancers in the population is measured, and how the “truly” negative women are determined. One measure might count as “missed cancers” only those that are palpable at the time of a normal mammogram. A more accurate number would include those cancers that are diagnosed within 1 year of a normal mammogram (interval cancers). The significance of a specific PPV should be assessed in the light of several other factors. Among these is the number of cancers expected in the particular population being screened (prior probability); the percentage of the population being screened for the first time (the prevalence of breast cancer will be higher than the incidence); the size, histologic type, grade, and stage (lymph node involvement) of the cancers; which cancers are counted as interval lesions; and what percentage of the cancers are ductal carcinoma in situ.

Prior Probabillty

of Cancer

The incidence of breast cancer increases with age. In an average population of women 40-49 years old, the expected annual incidence is approximately one cancer per 1 000; in a population of women 60-70 years old, this rises to two to three cancers per 1 000. It would be anticipated that the PPV of mammography is likely to be higher in an older population just on the basis of this prior probability. In our own recent series of mammographically detected cancers at the Massachusetts General Hospital, the PPV for women age 50 and over was 47%, whereas it dropped to 24% for women under 50. Similar results have been found at Mount Sinai Hospital in New York [1 6]. A higher PPV might be anticipated if the population contains women who are at a higher risk for other reasons (such as those with a family history of breast cancer) in whom a greater number of cancers will develop each year per 1 000 women. Understanding this frame of reference is important. For example, in a particular population, a PPV of 50% may appear successful. If, however, this population has six to seven cancers per 1 000 women per year, and only four to five per 1 000 are being found, then the PPV of 50% suggests that the threshold for biopsy may be too high, because cancers are being missed. A lower PPV may be more desirable if this results in more of the cancers being detected earlier.

Percentage

of Women

Being

Screened

for the First

Time

The PPV is also affected by the percentage of the population being screened for the first time. Numerous normal and benign structures may arouse concern when seen mammographically. In the first year of screening, the radiologist is frequently confronted with potential lesions. These may have been present for many years, but in the absence of previous studies, their significance must be carefully considered, and biopsy is recommended more frequently. When previous studies are available, the stability of a finding can be assessed,

Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

AJR:158,

March

1992

POSITIVE

PREDICTIVE

VALUE

and many biopsies can be avoided. Similarly, because the breast’s appearance is fairly stable over time, a new change, which can be appreciated because of the availability of a previous study, has a higher probability of being malignant. This phenomenon is reflected in the well-organized European trials, in which the PPV in the first year of screening was significantly lower than in the population of women who returned for additional screening in subsequent years and those mammograms could be compared with previous studies.

Size and Stage

of Disease

Size and stage of disease are perhaps the most important factors in assessing the PPV. Staging permits the comparison of tumors by classifying them into groups that behave with some similarity so that prognosis can be estimated and treatments chosen and assessed. Survival from breast cancer is directly linked to the stage of the cancer at the time of detection [1 7]. Women with stage I cancers have a better than 90% 5-year survival [1 8]. When axillary nodes are found to contain tumor or the tumor is larger than 2 cm (stage II), the 5-year survival drops to less than 70%. The prognosis is uniformly poor if metastatic disease is found elsewhere in the body at the time of diagnosis. The randomized controlled trials of the Health Insurance Plan of New York [1 9] and the more recent Swedish twocounty trial [20] confirmed the validity of survival information. Through the randomization process, and by using mortality from breast cancer as the end point, these trials eliminated the effects of lead-time bias and length-bias sampling. Data from the Swedish study further revealed that the reduction in mortality associated with screening was due to the earlier stage of the breast cancers detected [21]. As might be expected with an artificial system, staging is imperfect and cannot be used to accurately group cancers with similar potential. Tumors within the same stage can behave quite differently. The size of the primary tumor is one of the most important predictors of future problems. A longterm follow-up of women with stage I cancers diagnosed at Sloan-Kettering in New York showed that even within stage I, tumors less than 1 cm in diameter had a more favorable prognosis than those between 1 and 2 cm in diameter [22]. A recent study [23] of women whose axillary lymph nodes were free of cancer also indicated the prognostic importance of tumor size. In the Swedish trial, when the tumor was less than 1 cm in diameter, survival was independent of another important prognostic indicator, histologic grade (L. Taber, personal communication). Thus, although 1 cm is an artificial threshold, the detection of invasive lesions smaller than this seems to have important advantages. Such detection is achievable by mammography and is a reasonable screening goal. Among the nonpalpable, screen-detected breast cancers found between 1978 and 1990 at the Massachusetts General Hospital, 57% of the invasive lesions were less than 1 cm in diameter (measured at pathologic examination). Included among the criteria that should be used to assess the significance of PPV should be the size of the cancers detected

OF

523

MAMMOGRAPHY

and, in particular, the percentage of invasive tumors 1 cm or less in diameter. In addition, the percentage of women with lymph nodes that contain cancer should be noted so that the overall distribution of lesions by size and stage can be determined.

Interval

Cancer

Rate

The interval cancer rate, if available, is an important measure of the success of threshold sensitivities. In the Breast Cancer Detection Demonstration Project [24], the cancers that were diagnosed between screenings amounted to almost 20% of the total cancers diagnosed in the population. In the Malmo trial [25], interval cancers accounted for almost 30% of the total cancers diagnosed, suggesting a higher threshold for biopsy (and perhaps, in part, accounting for the failure in that trial to, as yet, show a mortality benefit). A comparison of interval cancer rates gives an indication of the success of thresholds used for intervention-the higher the interval cancer rate, the less successful the screen. A figure that is difficult to obtain in many of the published data is the number of cancers that were interpreted as probably benign but that grew between screenings and were ultimately diagnosed. These are not counted as interval cancers because they remained clinically occult despite their growth. A thorough evaluation of biopsy thresholds and PPV should include this category of clinically occult lesions, of which a diagnosis could have been made sooner but was delayed. These should be distinguished from lesions that are visible in retrospect but were not consciously excluded from biopsy. In the former case, use of a more aggressive biopsy strategy would affect PPV; in the latter, it would have no affect as the tumors were not seen to begin with, and, therefore, no opportunity was missed (only double reading could influence the failure to perceive the lesion).

Percentage

of Ductal

Carcinoma

In Situ

A great deal of controversy still exists about the importance of ductal carcinoma in situ (DCIS) [26]. Many think that this is a precursor of invasive breast cancer; others think that in many women with DCIS, an invasive lesion will never develop. Calcifications are the most common indication of DCIS, but a substantial overlap occurs between the morphologic characteristics of calcifications produced by benign and malignant processes. If biopsies are only undertaken when “classic” fine, linear, irregular calcifications of comedocarcinoma are present, the PPV will be high, but many other cancers may be missed. As DCIS may take 1 0 or more years to become invasive, the failure to diagnose these cancers will not be apparent for many years. In an aggressive screening practice, a significant number of DCIS cases will be found. In our own practice, as well as in that of Sickles and coworkers [27], 30% of cancers detected by mammographic screening are DCIS. Until the natural history of DCIS is better known, we should include these in the

overall

separately.

breast

cancer

statistics

but

classify

the

lesions

524

KOPANS

Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

Lobular carcinoma in situ is even less well understood, and until its true significance is better defined, it should also be classified separately. Most investigators do not include this lesion in breast cancer statistics.

Improving

the Positive

Predictive

Value

A great deal of anxiety is created by the suggestion of a breast abnormality. Reducing the number of “false alarms” is of primary importance in reducing psychological trauma for the patient. Surgery also represents various degrees of physical trauma because the surgical approach to these lesions varies considerably. Although a breast biopsy can be an extremely safe, outpatient procedure done under local anesthesia, some patients and surgeons prefer general anesthesia, despite the attendant increased risk. In addition, the amount of surgery used and the resulting amount of physical trauma sustained by the individual varies widely. Although most of these lesions can be satisfactorily removed in a volume of 5 cm3 or less [28], the reported average amount of tissue removed is more than 40 cm3 [29]. The economic consequences of a breast biopsy cannot be ignored: the more women screened, the more biopsies recommended. The costs of the needle localization and surgery are significant. In Chicago in 1 987, the average cost for needle localization and open biopsy was $2200 [30]. These costs must be factored into the overall cost of screening [31] and ultimately judged in terms of the best use of health-care dollars. We should not lose sight of the fact that early diagnosis is the goal of screening and may save lives. We must also recognize the differences between the health care system’s interests and the advantages and disadvantages for each woman as an individual [32]. As we begin to explore new ways to reduce the number of open biopsies of benign lesions, we should not overlook the fact that a breast biopsy should be among the safest of surgical procedures and that the stakes are quite high for the woman whose diagnosis may be delayed by our attempts to reduce the number of procedures. Although physicians prefer to deny the influence of the present litigious climate, we also cannot overlook the legal consequences of a delayed diagnosis [33]. Efforts to improve the PPV should not be limited to mammographically detected lesions alone. The challenge should also be to surgeons to develop better approaches to the palpable breast lesion. The American College of Radiology with support from numerous other societies and the Centers for Disease Control has developed reporting and data collection systems to be used by individual practices. It is hoped that both will be adopted by those who provide mammography services. The reporting system will help standardize the often confusing analysis of mammograms and, by requiring the radiologist to assign findings into one of five categories, reduce the ambiguous reports that are prevalent. The data base is important to help monitor the success of screening and to assist each practice in assessing the results of its own program. The PPV for each practice must be judged in relation to the type of

AJR:158,

March

1992

cancers detected and their size, grade, and stage. Each practice should establish guidelines and track the results of their biopsy policies. The analysis of mammograms and the resultant recommendation should not be capricious, but should be based on specific, defined criteria. Thresholds for intervention should be delineated and used consistently. By monitoring the results of mammography, specific criteria can be assessed and thresholds adjusted.

How Will Positive

Predictive

Value Be Improved?

Experienced interpreters will help improve the PPV. Sickles [27] has shown in his practice that the most experienced reader has the highest PPV. As more radiologists gain experience, and if they follow up on their patients and learn from the results of biopsies, the level of accuracy will improve. We must become more sophisticated in our selection of lesions that require excision. By organizing our data, as has been done by Moskowitz [34], it should be possible to develop probabilities for various lesions so that the patient and her physician can make an informed decision. We, as radiologists, may be willing to follow up a “low-probability” lesion, but it should be up to the patient to make that decision, and she needs the best estimates that we can provide. Women who are asked to return repeatedly for short-interval follow-up pay a psychological penalty because of uncertainty that is sustamed over many months. A woman should be offered the option of certainty provided by a safe, accurate, and immediate excision should she so desire. New techniques must be developed to reduce the trauma and expense needed to accurately determine the nature of an abnormality. It is time that a modern approach be applied to breast biopsy. Surgeons have, until recently, been uninterested in rethinking the techniques involved in excising nonpalpable breast lesions and have removed far more tissue than was needed for most lesions. Little has been written in the surgical literature about technical approaches to these biopsies. We can only surmise that the lack of discussions among surgeons is due in part to the belief that biopsy of nonpalpable breast lesions is a fairly simple procedure, yet reports in the literature describing failure to remove lesions, complications from wire transection, excessive tissue removal, and complaints about needle positioning belie this. A fairly common attitude among some surgeons is that a large amount of tissue can be removed from the breast without being noticeable. Few surgeons have addressed the question of how much tissue actually needs to be removed, and how the amount can be minimized. There is no reason to remove a large amount of tissue when a lesion is only marginally suspicious. Alternatives to open biopsy, such as fine-needle aspiration cytology and core needle biopsy, are now being explored. Although they should be encouraged, development of new approaches that do not completely remove the lesion suffer from possible sampling error and could potentially result in unfortunate delay in diagnosis in some women. An alternative is for surgeons and radiologists to develop new approaches to the breast biopsy to improve their techniques, minimize

Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

AJR:158,

March

1992

POSITIVE

PREDICTIVE

VALUE

the trauma from an excisional procedure, and reduce the cost of diagnosis. Complete excision eliminates any question of sampling error. Improvements in open biopsy can be made. For example, the vagaries of needle localization and guide placement followed by surgery can be avoided by excising the lesion under indirect visualization while the breast is held in compression in a mammography unit. This could permit the complete excision of a lesion with minimum complexity and trauma. An operating room and all the excess resources currently mobilized would be unnecessary. The size of the incision could be reduced and the volume extracted minimized. Such a procedure could be done expeditiously, and by reducing the volume of tissue removed, recuperation would be hastened. The cost of diagnosis would also be reduced. Alternative approaches to excisional biopsy should be developed. Improved case selection through morphologic analysis may reduce the number of benign biopsies. Lesions with a low probability of being malignant would be segregated into a “probably benign” category and monitored by obtaining mammograms at fixed intervals. In a recent review of lesions classified in this fashion, Sickles [35] found that by using a periodic follow-up instead of biopsy, 1 7 cancers among 3184 lesions had a delayed diagnosis. As almost all were still earlystage lesions by the time of ultimate diagnosis, it appears that harm likely did not occur from this delay (although two were stage II). However, the potential problems with this approach include the patient’s long period of anxiety, and poor compliance during the period of careful monitoring may result in additional delay in diagnosis. In Sickles’s study, by the end of the follow-up period, 35% of patients did not return for examination. Fine-needle aspiration cytology and core needle biopsy, although still experimental in the United States, are promising methods for further reducing the need for unnecessary open biopsies. Fine-needle aspiration cytology has had the greatest evaluation, and in some hands it appears to be very accurate [36-38]. It is, however, operator dependent and somewhat of an art. In addition, it requires a highly skilled cytopathologist to interpret the material. Sampling error is a distinct possibility, and because of the vagaries of the technique, each center should independently establish the efficacy of the procedure [39]. Large-bore core biopsy is likely to become the procedure of choice [40]. Its high degree of mechanization will reduce the learning curve and make it a more transferable technology. The histologic material is more easily interpreted by general pathologists, and significant complications have not yet been reported. Sampling errors will likely occur, but delays in diagnosis can be reduced by using the morphologic appearance of the lesion on mammograms as well as the core sample [41]. By acting on the more suspicious findings as indicated by the two studies, ultimately, false-negatives can probably be kept extremely low. Currently, the only negative concern that has been voiced has come from pathologists, who fear that given only sections of a lesion, and with the loss of cytologic features that are eliminated during the fixation process, breast cancers may be overdiagnosed when core biopsy is used. Further demonstration of the efficacy of these procedures in various settings is needed before either can replace open biopsy.

OF

MAMMOGRAPHY

525

Other imaging technologies should also be studied. MR imaging holds some promise, and a recent positron emission tomography study of breast cancer patients had encouraging results [42].

Conclusions The “appropriate” PPV for mammography cannot be defined in an absolute sense, and an “acceptable” rate will always be subjective. The factors that contribute to PPV and that should be included in any discussion of PPV are summarized in Table 1. In order to reduce the cost of screening (human and economic), the number of cancers diagnosed per biopsy performed should be maximized; but, ideally, this should not be done at the expense of increased false-negative findings. Although breast cancer is a common malignant disease, it fortunately affects only a small percentage of women each year in the large population of women who will be screened. Each case is, therefore, increased in importance. Several approaches for improving the PPV are available. An improved understanding of morphologic differences between benign and malignant lesions may help reduce the number of biopsies of lesions that prove to be benign. Repetitive screening should be encouraged. Stable findings seen on subsequent mammograms have a low probability of being cancer. Fine-needle aspiration and core biopsy should continue to be explored. These less invasive procedures likely will ultimately reduce the number of open biopsies needed for diagnosis. The open biopsy itself should be reevaluated. Approaches that have been used for large, palpable masses in the past are inappropriate for biopsies that rely on imaging guidance. Any radiologist involved in guiding open biopsies knows that the skills of surgeons performing these procedures vary widely. Before accepting a new technique that might result in reduced accuracy and delayed diagnosis, we should try to improve the gold-standard diagnostic technique of excisional

TABLE 1: Data Needed Predictive Value

Age distribution should

to Assess

of the population

be monitored

the

Significance

of Positive

being screened (other risk factors

if possible)

Number of cancers diagnosed per 1 000 women Size distribution of the invasive cancers and the percentage less than 1 cm in diameter Histologic type and grade of cancers Percentage with cancerous nodes Interval cancers (if possible) False-negative mammograms (if possible) Not visible Seen but interpreted as benign and followed up (delayed diagnosis) Visible in retrospect Note-Ideally, the positive predictive value for women being screened for the first time screened before. These data should be tracked in situ. Lobular carcinoma in situ also should included among the cancer statistics.

should

be calculated

separately

and for those who have been separatelyfor ductal carcinoma be followed separately and not

KOPANS

Downloaded from www.ajronline.org by Columbia University on 05/29/14 from IP address 128.59.222.12. Copyright ARRS. For personal use only; all rights reserved

526

biopsy. Accurate needle localization should be required so that tissue removal is minimized. New approaches to minimize the inaccuracies of the open biopsy, such as performing it with the breast held in the mammography unit, should be explored. Tissue diagnosis should become a truly minor procedure so that we can aggressively diagnose early cancers, distinguish benign from malignant lesions with greater cartainty, minimize trauma, and reduce cost.

AJR:158, March 1992

20.

21 .

22.

23.

REFERENCES

24. 25.

1 . Sickles

WA. Mammographic features of 300 consecutive nonpalpable breast cancers. AiR 1986;146:661-663 2. Meyer JE, Kopans DB, Stomper PC, Undfors KK. Occult breast abnermalities: percutaneous preoperative needle localization. Radiology 1984;150:335-337

3. Yankaskas

BC, Knelson MH, Abernathy ML, Cuthno SF, Clark AL. Needle localization biopsy of occult lesions of the breast experience in 199 cases. Invest Radiol 1988;23:729-733 4. Marrujo G, Jolly PC, McClure HH. Nonpalpable breast cancer: needlelocalized biopsy for diagnosis and considerations for treatment. Am J Surg 1986;151 :599-602 5. Poole Gv, Choplin RH, Sterchi JM, Leinbach LB, Myers AT. Occult lesions of the breast. Surg Gynecol Obstet 1986;163: 107-110 6. Rosenberg AL, Schwartz GF, Feig SA, Patchefsky AS. Clinically occult breast lesions: localization and significance. Radiology 1987;162:167-170 7. Meyer JE, Eberlein TJ, Stomper PC, Sonnenfeld MR. Biopsy of occult breast lesions: analysis of 1261 abnormalities. JAMA 1990;263:2341-

BMJ 1988;297:943-949

26. Ketcham AS, Moffat FL. Vexed surgeons, perplexed patients, and breast cancers which may not be cancer. Cancer 1990;65:387-393 27. Sickles EA, Ominsky SH, Sollitto RA, Galvin HB, Monticciolo DL. Medical audit of a rapid-throughput mammography screening practice: methodology and results of 27,1 14 examinations. Radiology 1990;175:323-327 28. Gallagher WJ, Cardenosa G, Aubens JR, McCarthy KA, Kopans DB. Minimal-volume excision of nonpalpable breast lesions. AiR 1989;153:957-961 29. Tinnemans JGM,

1991;157:21-24

16. Hermann GH, Janus C, Schwartz IS, Papatestas A, Hermann DG, Rabinowitz JG. Occult malignant breast lesions in 1 14 patients: relationship to age and presence of microcalciflcations. Radiology 1988;169:321-324 17. Carter CL, Allen C, Hanson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 1989;63: 181-187 18. Fisher B, Redmond C, Fisher E. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N EngI J Med 1985;312:674-682 19. Shapiro S, Venet W, Strax P, Venet L. Periodic screening for breast

Wobbes

T, Hendriks

JHCL,

van der Sluis

RF, Lubbers

EC, do Beer HHM. Localization and excision ofnonpaJpable breast lesions. Arch Surg 1987;122:802-806 30. Dowlatshahi K, Gent HI, Schmidt A, Lolich PM, Bibbo M, Sprenger E. Nonpalpable breast tumors diagnosed with stereotactic localization and fine-needle aspiration. Radiology 1989;170:427-433 31 . Cyrlak D. Induced costs of low-cost screening mammography. Radiology

2343

8. Tinnomans JGM, Wobbes T, Lubbers EC, van der Sluis RF, do Beer HHM. The significance of microcalcifications without palpable mass in the diagnosis of breast cancer. Surgery 1986;99:652-657 9. Tabar L, Gad A. Screening for breast cancer: the Swedish trial. Radiology 1981;138:219-222 10. Kopans DB, Swann CA. Observations on mammographic screening and the false-positive mammograms. AIR 1988;150:785-786 1 1 . Walt AJ. Screening and breast cancer: a surgical perspective. Am Coil Surg 1990;75:6-1O 12. Spivey GH, Perry BW, Clark VA, Coulson AH, Coulson AH. Predicting the risk of cancer at the time of breast biopsy. Am Surg 1982;48:326-332 13. Pagana TJ, Lubbe WJ, Schwartz SM, Sprechini GD. A companson of palpable and nonpalpable breast cancers. Arch Surg 1989;124:26-28 14. Tabar L, Duffy SW, Krusemo US. Detection method, tumor size and node metastases in breast cancers diagnosed during a trial of breast cancer screening. Eur J Cancer Clin Oncol 1987;23:959-962 15. Bassett LW, Uu TH, Giuliano AE, Gold RH. The prevalence of carcinoma in palpable vs impalpable mammographically detected lesions. AiR

cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore: Johns Hopkins University Press, 1988 Tabar L, Fagerberg CJG, Gad A, et al. Reduction in mortality from breast cancer after mass screening with mammography. Lancet 1985;1 :829-832 Tabar L, Gad A, Holmberg L, Ljungquist U. Significant reduction in advanced breast cancer: results of the first seven years of mammography screening in Kopparberg, Sweden. Diagn Imaging Clin Med 1985;54: 158164 Rosen PP, Groshen PE, Kinne DW, Hellman S. A long-term follow-up study of survival in stage I [Ti ,N0,M0] and stage II [Ti Ni MO] breast carcinoma. J Clin Oncol 1989;7:355-366 Rosner D, Lane WW. Should all patients with node-negative breast cancer receive adjuvant therapy? Cancer 1991;68:1482-1494 Baker LH. Breast Cancer Detection Demonstration Project: five-year summary report. CA 1982;32:194-225 Andersson I, Aspegren K, Janzon L, et al. Mammographic screening and mortality from breast cancer: the Malmo Mammographic Screening Trial.

32. 33. 34.

1988;168:661-663 Eddy DM, Hasselblad V, McGivney W, Hendee W. The value of mammography screening in women under 50 years. JAMA 1988;259: 151 2-1 519 Potchen EJ, Bisesi MA, Sierra AE, Potchen JE. Mammography and malpractice. AiR 1991;156:475-480

Moskowitz

M. The predictive

value of certaln mammographic

signs in

screening for breast cancer. Cancer 1983;51 :1007-1011 35. Sickles EA. PeriOdic mammographic follow-up of probably benign lesions: results in 3184 consecutive cases. Radiology 1991;179:463-468 36. Azavedo E, Svane G, Auer G. Stereotactic fine-needle biopsy in 2594 mammographically detected non-palpable lesions. Lancet 1989;1 :10331035 37. Hann L, Ducatman BS, Wang HH, Fein V, Mclntire JM. Nonpalpable breast lesions: evaluation by means of fine-needle aspiration cytology. Radiology 1989;171 :373-376 38. Azavedo E, Svane G, Auer G. Stereotactic fine-needle biopsy in 2594 mammographically detected non-palpable lesions. Lancet 1989;1 :1033-

1036 39. Kopans DB. Fine-needle aspiration of clinically occult breast lesions. Radiology 1989;170:313-314 40. Parker SH, Lovin JD, Jobe WE, et al. Stereotactic breast biopsy with a biopsy gun. Radiology 1990;176:741-747 41 . Dowlatshahi K, Jokich PM, Kluskens LF, Patel A, Economou SG. A prospective study of double diagnosis of nonpalpable lesions ofthe breast. Surg Gynecol Obstet 1991;172:121-124 42. WahI AL, Cody AL, Hutchins GD, MUdgett EE. Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose

analogue

179:765-770

2-[F-18j-fluoro-2-deoxy-D-glucose.

Radiology

1991;