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1 BREAST CANCER SCREENING Preliminary Report of 207 Biopsies Performed in 4,728 Volunteer Screenees MYRON MOSKOWITZ, MD, PETER RUSSELL, MD, JAMES FIDLER, DARRYL SUTORIUS, MD, EDWARD J. LAW, MD, AND JAN HOLLE, MD, BS Thirty-six carcinomas of the breast were pathologically verified in the first 207 biopsies performed to date on women attending the Breast Cancer Detection Center at The University of Cincinnati. Fifty-three percent of these have been minimal breast cancer, 14 being totally in situ. This is compared with a similar number of breast biopsies performed prior to the opening of the Breast Cancer Project. In the latter group of cases there were 45 carcinomas proven, only 1 of which was in situ, 24 of which were invasive Stage I and 20 Stage I1 or higher. In addition, 65 biopsies demonstrated proliferative disease of varying degrees of severity as compared to a total of 13 in the non screened population. Cancer 36: , ARCINOMA OF THE BREAST CAN FREQUENTLY C be diagnosed radiographically before it is clinically palpable, i.e. while it is occult. It is often implied that the clinically occult carcinoma is either early or small. Neither one of these latter assumptions may be true. The size of the breast, the consistency of the carcinoma, vis a vis the consistency of the breast, and the astuteness of the physical examiner all interplay in determining whether a lesion will be palpable. Furthermore, some so called occult carcinomas are invasive. Once diagnosis is based on the x-ray characteristics of a mass, whether or not that mass is clinically palpable, one is dealing with well established neoplastic disease. In fact, it has been ~uggested ~ that one may be able to predict from the radiographic appearance of these well developed neoplasms how aggressive they are likely to be. Therefore, if early diagnosis is to be emphasized, the detection of merely clinically occult carcinoma is insufficient. Rather must our efforts be concentrated towards detecting the neoplasm at its earliest possible pathologic stage. Ideally, this would be while the lesion is first From the University of Cincinnati College of Medicine, Departments of Radiology, Pathology and Surgery. Supported in part by the N.C.I. Contract 1-CN and The American Cancer Society, DPBC-11. Address for reprints: Myron Moskowitz, MI1 Breast Cancer Detection Center, University of Cincinnati, Logan Hall Basement, Room 5, Cincinnati, OH. Received for publication December 10, developing biochemical abnormalities, at present not possible. The major thrust of our effort should be in detecting breast cancer while totally in an in situ stage, or as close to this stage as possible. As has been pointed OU~,~-@ meticuluous examination of the entire breast affected with carcinoma will frequently reveal a gamut of proliferative disease inclusive of atypical hyperplasias and carcinoma in situ. Prospective st;ldies have likewise established the relationship of atypical hyperplasias and carcinoma in situ to the later development of invasive cancer. Minimal breast cancer is defined as carcinoma of the breast less than 5 mm in size, either completely in situ, or with microinvasion, but without evidence of metastatic disease to the regional lymph nodes. - Others26 have modified this to include lesions with less than 10% microinvasion and negative regional adenopathy. Our efforts in this first year s screening have been directed heavily toward achieving the diagnosis of minimal breast cancer. Although all suggested biopsies have not yet been performed to date, we believe the results of the first 207 biopsies performed indicate some success in this regard. MATERIALS AND DATA This Center is one of 27 centers established jointly with the National Cancer Institute and The American Cancer Society as a demonstration project for the early detection of breast can- 2245

2 2246 CANCER December 1975 Lo1 36 cer. We &re screening 5,000 women per year with physical examination, thermography, and Xeroradiographic mammography. Each patient fills out a detailed clinical history. Women are excluded from the Cincinnati screening project if: 1) they are under 35 years of age; 2) pregnant; or 3) they have been referred by a physician for a specific breast problem, or are currently under the care of a physician for a specific breast problem. These patients are self selected and there is no control group for comparison. Patients come to this Center from a wide radius around metropolitan Cincinnati. Surgery is performed by the physician of the patient's own selection and in the hospital of her choice. Whenever possible, the original biopsy material, paraffin blocks and microscopic slides are obtained for review. Surgical schedules in the major community hospitals are screened weekly and patients scheduled for breast surgery are matched against our rolls. We have been unable to do this routinely for biopsies performed at hospitals distant to our Center. This preliminary report concerns itself with the data from the first 207 biopsies reviewed to date. For comparison purposes, we reviewed consecutive breast biopsy reports from each of three major hospitals of The University Of Cincinnati Medical Center prior to the establishment of an effective screening process. 'The results, summarized in Tables 1 and 2 show a positive biopsy rate of 22 %% malignant lesions (45 out of 200). This is not significantly different from our 36 carcinomas out of 207 biopsies (17.4%). More striking however, is the stage at which the disease was detected in these two series (Table 2 and Fig. 1). In the non-screened group, 20 out of the 45 carcinomas (44%) were '1'~~i.t 1. Cancers Found in Biopsies Performed Screened #36/207 17% Non Srreened #4.5/ r-\hi.k, 2. k'athological Staging of Cancers Iletected Screened Non screened Stage # "0 # Yo In situ I 2.2 hl icroinvasive, less than IO" Stage j3.3 Stage 11 or higher u) w 0 z & 10 a W m s 5 Minimal Slage I Stage n or greater NONSCREENEO 0 SCREENED PATHOLOGICAL STAGE Pic;. 1. Stages of cancers found in screened and nonsrrernrd p~ipulation. 'l'here were 200 biopsies in the nonscreened and 207 biopsies in the screened group. invasive carcinomas with lymph node metastases. In the screened patients, 10 out of the 36 cancers (28%) were invasive cancers with either lymph node involvement or blood vessel invasion. In the non-screened group, 24 out of the 45 cancers (53%) were invasive without lymph node metastases, and all being larger than 1 cm. In the screened group, 7 out of the 36 cancers (19%) were invasive cancers without lymph node spread. There was only one in situ carcinoma described in the non screened group and this was a lobular carcinoma. In the screened group on the other hand, there were 14 in situ carcinomas, 12 of which were predominantly ductal in type and 2 predominantly lobular, and there were 5 carcinomas with less than 10% microinvasion and no lymph node involvement. Fiftythree percent of the detected carcinomas represented minimal breast cancer. There was one histologically benign cystosarcoma phylloides identified in each group. The 36 cancers were found in 34 patients. We have only included more than 1 cancer in a single patient when the disease was proven to be bilateral. Multifocal carcinoma within 1 breast has been regarded as a single carcinoma. Therefore, there have been only 2 patients to date in

3 No. 6 BREAST CANCER SCREENING Moskowitz et al TABLE 3. Pathological Findings in Biopsies Which Were Non-malignant Screened Non screened Pathological diagnosis (No.) (Percent) (No.) (Percent) 1. Hyperplasias (total) a. severe atypical epithelial hyperplasia (borderline Ca. in situ) 4 2 b. atypical epithelial hyperplasia 12 6 c. proliferative disease, papillomatosis Nonproliferative fibrocystic Miscellaneous* c - Totals * Miscellaneous includes fibroadenomas, lipomas, lactating nodules, lymph nodes, fat necrosis, no lesion found and cystosarcoma phylloides (histologically benign) our series in whom carcinoma has been definitely proven by biopsy to be bilateral. A second significant comparison can be seen in Table 3 describing the microscopic findings of biopsies which were non malignant in the screened and non screened groups. In tabulating the pathology results of the 207 biopsy specimens we have examined, an attempt has been made to group them approximately in ascending order of pre-malignant potential, or in the case of obvious malignancies, according to the pathological staging. Miscellaneous, therefore, includes inflammatory lesions, fat necrosis, and fibroadenomas. Non proliferative mammary dysplasias include fibrosclerosis, adenosis, and sclerosing adenosis, apocrine metaplasia, duct ectasia, and cyst formation. Those instances classified as proliferative mammary dysplasias, in addition to showing these former features, show lobular hyperplasia or ductal epithelial hyperplasia, either papillary, (papillomatosis) or non papillary (duct epitheliosis, duct hyperplasia). Nuclear atypia and some disorder in proliferation were used as criteria for classifying cases in category lb Table 3. The criteria used for labeling as carcinoma in situ are essentially those of McDivitt (lobular carcinoma in situ)*' and Gallager (ductal carcinoma in situ).' In the non-screened series, 13 hyperplasias (6.5%) were reported. These were all duct hyperplasia or papillomatosis, no further grading of severity being available. In the screened series, there were 49 examples of proliferative mammary dysplasias, 12 cases showing atypical hyperplasia, and four severely atypical hyperplasias. This represents a total of 65 cases (31%) of proliferative disease in varying degrees of severity out of the 207 specimens reviewed. In both groups the incidence of non proliferative cystic disease is approximately the same. The distribution of the carcinomas per thou- sand patients screened proven by biopsy to date is of some interest (Table 4). It can be seen that there have been 11 cancers proven in the first 1,000 patients, 8 carcinomas proven in the second 1,000, 14 carcinomas proven in the third 1,000. There are no carcinomas yet proven in the fourth 1,000, but 3 have already been proven in the last 1,000 patients screened during the first year of our operation. This apparent discrepancy can readily be explained by the lag occurring between the time biopsy is suggested and the time biopsy is performed, this time being anywhere from 2 weeks to 6 months. At the beginning of our operation, there was a definite hesitancy on the part of the attending physicians to perform biopsies upon lesions which they were unable to palpate. Lesions which were either obvious clinically or at least palpable were more likely to be operated upon soon after discovery. Therefore, we think that the prevalance rate for proven carcinomas is fairly accurately reflected by the first 3,000 patients screened where a tissue diagnosis of carcinoma has been established in 11 patients per thousand screened. There have been 2 patients in our series with bilateral carcinoma, one of which was definitely diagnosed by mammography prior to biopsy, and the other proven by mirror image blind biopsy. In addition to these 2 cases, there have been 6 multifocal carcinomas occurring within TABLE 4. Distribution of Cancers per 1000 Patients Screened No. patients No. Cancers found

4 2248 CANCER December 1975 Vol. 36 the same breast. Twenty-two of the carcinomas which have been proven have been associated with proliferative disease of the breast of varying degrees of severity, while 14 have not had proliferative disease demonstrated (Table 5). The age distribution for the 35 patients with breast cancer, and for those patients with minimal breast cancer shows that in the decades 35-45,8 neoplasms have been proven. Four of these have been minimal breast cancer. In the age group 46-55, 13 cancers have been proven, 7 of which are minimal. In the age group 56-65, 11 carcinomas have been proven of which 6 have been minimal. There have been 4 cases found in women over age 66, 2 of which are minimal. (Table 7). These first 207 biopsies were suggested either by physical examination or by mammography. Table 6 shows the distribution of carcinomas found on the basis of recommendation by each of the modalities. If there was a finding described but biopsy was not suggested by either the physical examiner or the mammographer, we considered this a miss for that modality. If the examiner thought a localized lesion was present, and even if he thought it was benign, but recommended biopsy, it was considered as positive. Physical examination was positive in 21 of the 36 carcinomas, mammography was positive in 27, thermography was positive only in 11. Physical examination and mammography were both positive in 13 patients. Thus there were 14 patients in whom mammography alone detected the carcinoma, and there were 8 patients in whom physical examination alone detected the carcinoma. One carcinoma was detected by mirror image biopsy after an in situ ductal carcinoma was proven on the original suspicious side. There were 2 patients for whom biopsy was suggested on the basis of physical examination and mammography because a dominant mass was seen and/or felt. In both these instances, the dominant mass proved to be benign, cyst in one case and fibroadenoma in the other, but multifocal carcinoma in situ was present in the surrounding area. These probably were serendipituous. A third patient had a suspicious area palpated by one of our examiners and not by another. The patient had a biopsy and a 5 mm TABLE 5. Multicentricity and Atypia Cancers not associated with cellular atypia. Cancers associated with cellular atypia. Cancers associated with non atypical proliferative disorder TABLE 6. Cancers Found by Each Modality No. Percent Physical examination only 8 22% Mammography only 14 38% Both Physical and Mammography 13 38% Mirror Image Biopsy 1 3% Thermography 11 carcinoma was found. In retrospect, the lesion was present on the mammogram but undercalled. DISCUSSION As suggested earlier, in planning the operation of this center the specific purpose was set of detecting minimal breast cancer, preferably in situ whenever possible. It was felt that detection of pathological Stage I carcinoma was acceptable but not preferred. We believe that with removal from the screened population those in situ carcinomas which would later become invasive, it should be possible subsequently to: 1) demonstrate an improvement in the long term overall survival of patients with carcinoma of the breast); and 2) to reduce the incidence of subsequent development of invasive carcinoma in that screened population. Therefore, to achieve the earliest diagnosis possible, we felt justified in suggesting biopsy of minimally suspicious lesions on physical examination, and patients whose mammograms exhibited the secondary signs of carcinoma described by others.3~10~11~13~10~1g~'s~'g We anticipated a positive biopsy rate of 10% which we felt would be acceptable if a significant number of these biopsies proved to be minimal breast cancer. We base this decision on the fact that a frequently reported positive biopsy rate in surgical series based on physical examination alone hovers around the 20% level. 2*16*'3 As can be seen from our results, the anticipated 10% positive biopsy rate was exceeded by 70%, 17% of the 207 biopsies examined being malignant. Only 28% of the carcinomas detected were invasive and later than Stage I. This is compared to 44% of the carcinomas operated on in three hospitals of The University Of Cincinnati Medical Center in 1972 before any significant screening program was in effect. This figure may also be compared with the 56% Stage I1 or greater, carcinomas found in a non mammographically evaluated population as recently reported.' Previously in Cincinnati, carcinoma in situ

5 No. 6 BREAST CANCER SCREENING 9 Moskowitz et al was a rarely or uncommonly diagnosed lesion. From inclusive, 2,921 breasts were removed for cancer. In situ cancer was diagnosed pathologically 16 times. This may have been related more to lack of recognition than a reflection of its true incidence. We believe that a part of this, however, reflects screening of a relatively asymptomatic population. In our series, in situ carcinoma represents 39% of the cancer detected by screening, and minimal breast cancer, including the in situ carcinomas, represents 53% of the cancers detected. Not only are we finding carcinoma at an earlier stage, but the screening process is identifying a larger number of patients with atypical proliferative breast disease who will be at high risk for subsequent development of clinical carcinoma The value of a screening procedure for breast carcinoma which includes mammography has been questioned. Several previous screening studies report a much lower yield for incidence or prevalence of carcinoma of the breast in screened populations. In one series of cases reported from Canada, 1.7 cases of carcinoma per thousand in the age group of were found. O The Israel Cancer Association reported a yield of 0.5 cancers per thousand detected in those women invited to attend a breast cancer center. The same group reported 1.6 cases per thousand in women who presented themselves for examination and 3.3 cases per thousand in those referred by physicians. Forrest, citing the results of screening performed by several other investigators, indicated a range of detection of cancer from.6 cases per thousand to a high of TABLE 7. Distribution of Cancers Found Cancers all &Over stages Minimal carcinoma tection rate of 61.7 cases per thousand in 1,440 women referred for evaluation of symptoms. In a screening series, Strax reports a prevalence rate of 8.3 cases per thousand women examined.26 These figures suggest that in any given closed population, there is a much larger reservoir of carcinoma, clinical, occult or in situ, at any one given point in time than the earlier incidence figures indicate. It is undoubtedly true that any self selected population of women will not represent a random valid cross section of the population. It also seems equally clear that the number of carcinomas existing either in situ or pre-malignant in any population of mature women is much higher than 1, 2 or even 3 cases per thousand. If this postulate is true, we should expect to see in our screened population the following results: 1) In ourjrst 5,000 screenees, the incidence rate of new carcinomas should drop in the second year of screening, and even further in the third year. 2) Subsequent or interval carcinomas should be expected to develop at the highest rate in those women who have been identified by biopsy as having a proliferative disorder of the breast. 3) The detection rate of new carcinomas in the second 5,000 women to be screened should 3.2 cases per thousand. Venet and Stra~~~*~* re- approximate the rate in the first 5,000 screenees. port a detection rate on initial screening of 2.72 cancers per thousand patients examined, and 1.51 cancers per thousand women in follow up screenings. The same group reports 0.84 cancers per thousand as interval cancers not detected during the screening process. The predicted incidence rate of clinically invasive carcinoma of the breast varies from a low of approximately one-half case per thousand at age 35 to a rate of approximately 4 cases per thousand at age However, it has also been estimated that 1 out We are uncertain whether survival figures are valid in deciding whether or not the screening process is effective. We believe this to be so because the definitive surgical procedure appropriate for each pathological stage of the disease is apparently still in doubt. Patients in whom carcinoma has been detected are being treated by a variety of different procedures, varying from lumpectomy to radical mastectomy. Since the disease does seem to be multifocal so frequently, and since the lag time from in situ to invasion of 15 American women will develope breast can- may be failure of local treatment for cer at some time in her life, i.e. 70 cases per thousand (24). Gershon-Cohen reported finding 36 cancers in 4,120 healthy volunteers screened every 6 months over a 10-year period. Dowdy et al. reported a discovery rate of 13.2 cases per thousand in 3,470 women with no breast symptoms.3 This was compared to a deminimal cancer may not be appreciated for years to come. Although this paper is not primarily directed at the therapeutic process, we strongly believe that any therapeutic approach planned must take cognizance of the frequency of bilaterality, multicentricity, and proliferative change within the breast.

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