BORDER-LINE BREAST TUMORS

Transcription

1 BORDER-LINE BREAST TUMORS JOSEPH COLT BLOODGOOD (From the Surgical Pathological Laboratory of the Department ojsurgerg of Johns Hoplcins University and Hospital 3 A brief introduction to this subject appeared recently in International Contributioqs to the Study of Cancer, published in honor of James Ewing (Annals of Surgery 93: 235, 1931), but lack of space forbade a full presentation there of either text or illustrations. This paper should be read in connection with Dr. William S. Halsted's address on "A Clinical and Histological Study of Certain Adenocarcinomas of the Breast," delivered before the American Surgical Association in New Orleans, in April 1898 (Trans. Am. Surg. Assoc. 16: 144, 1898; Ann. Surg. 28: 557, 1898). Although he had seen a few border-line tumors at that date, Halsted does not include them in his paper, but presents chiefly the duct type of adenocarcinoma. In 1921 the present writer published a study of the non-encapsulated cystic adenomas (Arch. Surg. 3: 445, 1921). In none of the cases presented there as benign has there been, on further ten years' observation, any evidence of recurrence, malignant involvement of the remaining breast, or death from cancer. The microscopic diagnoses, therefore, appearing in that paper are identical with the diagnoses to-day. Every pathologist responsible for frozen-section diagnosis of fresh material from the breast in the operating room should be familiar with the photomicrographic reproductions in that journal. Some of them are again reproduced here. These sections and others were submitted to numerous pathologists in 1915, the majority of whom diagnosed the border-line lesions as malignant. In the microscopic demonstrations in the Surgical Pathological Laboratory in the Johns Hopkins Hospital in June and December 1930 and in April 1931, the majority of pathologists reversed the decision of the former group and rendered a diagnosis of benign growth. A good minority, however, still 'Supported by the Garvm, the Chemical Foundrttion, and the Bloodgood Research Funds. 103

2 104 JOSEPH COLT BLOODGOOD looked upon these sections of border-line breast tumors as suspicious of malignancy. It is suggested that the readers of this article go carefully over the illustrations first. They are far more important than the text. In the diagnosis of lesions of the breast before operation we must depend largely upon palpation, though in some instances inspection reveals characteristic changes. In the skin, for example, we may have dimpling, redness and other discolorations, metastasis, pig-skin, and edema; in the nipple, irritation, retraction (congenital, permanent, and intermittent), discharge, scab, ulcer, or even complete destruction. The palpable tumor itself may be visible, or movement of the patient's arm up and down may reveal changes in the nipple, skin, and breast. Masses in the axilla may be seen as well as felt. Lesions of the breast may be divided into clinically benign, clinically malignant, and clinically doubtful or border-line tumors. The first problem in diagnosis, then, is a clinical one. The first question is: Shall an operation be performed? Benign Conditions for Which Operation is Not Indicated: As more and more women are correctly informed and there is less delay in seeking advice after a warning by some sign or symptom in the breast, the number of patients in the clinically benign group increases rapidly. Records before the writer show an increase from a single case in 1897 to almost 100 in The clinical group in which operation has been decided against, and in which malignancy can be excluded with practically no risk, has in thirty-three years increased from less than one to more than seventy per cent. When the average duration of symptoms is decreased from three months to less than one month, there will be a greater increase, and the number of patients will be still further augmented when more women have been taught the importance of the periodic survey. One decides against operation, after one or more examinations, when there is no defmite single tumor in the breast of a woman over twenty years of age, and no other sign or symptom to indicate that the patient runs more risk of cancer than any other woman of her age who is unaware of symptoms referable to the breast, and when, on examination of the breast by palpation, inspection and transillumination (Cutler)-which is becoming more and more important-nothing abnormal can be made out. This latter

3 BORDER-LINE BREABT TUMORS 105 group is increasing as the breasts are included in every complete study of a female patient who enters a clinic because of symptoms elsewhere in the body, or for the annual protective examination. Clinically Benign Tumors: In the decade before 1900, in Halsted's surgical clinic in Johns Hopkins Hospital, among the definitely palpable tumors of the female breast, 80 per cent were malignant and 20 per cent were benign. With rare exceptions, benign tumors were clinically benign; a few were clinically malignant (3 to 5 per cent). With very rare exceptions, malignant tumors were also clinically malignant. The records of the laboratory since 1925 show that benign lesions now outnumber the malignant, and that almost one-half of the malignant tumors seen are clinically benign and must be explored for gross or microscopic diagnosis before their malignant nature is established with certainty. There is still among the benign tumors an appreciable percentage that are clinically malignant and should be explored if one would save the patient's breast. Border-line breast tumors in the clinical group are those in which, no matter what the signs and symptoms may be, one is still uncertain as to definite malignancy. In this group-becoming larger every year-exploration should be done. Clinicalll~ Malignant Tumors: Even before the advent of radium and deep x-ray treatment, surgeons recognized malignant conditions of the breast for which they concluded operation promised neither cure nor relief. Experience with x-rays and radium has influenced many surgeons to try irradiation first in definitely malignant tumors of the breast which appear to be in the very late stage, in which the possibility of complete removal is questionable. In this sense there is a border-line group even among the malignant tumors of the breast. Here there is as yet great difference of opinion, largely to be explained by the varying experience of operators, pathologists, and radiotherapeutists. Personally, I have not had enough experience to speak with authority as to the choice of procedures in this late and very malignant group-irradiation without operation or preoperat'ive irradiation, irradiation with deep x-rays, with radium packs, or with radium needles. If women with breast tumors continue to come under observation in my clinic, as they are doing, earlier and earlier after the first warning symptom, my life will not be long enough for the accumulation of sufficient experience to determine what to do for 8

4 106 JOSEPH COLT BLOODGOOD these clinically malignant tumors in the late and advanced stage. At present I would at least give them the benefit of irradiation first, since, with rare exceptions, as far as my experience goes, they are more comfortable when no operation is performed. This decision rests upon the nature of the breast tumor itself, palpation of the glands in the axilla and of the supraclavicular glands, and the presence or absence of involvement of the chest or mediastinum. With metastasis to the skin, it is wiser to use irradiation first and then operate, unless the metastatic growth is too extensive. Metastasis to bone is not a contraindication to surgery, but if the vertebrae are involved, it is wise to give irradiation first. Our experience with the new supervoltage tube is still too limited to warrant any statement here. Border-line Tumors. The majority of border-line tumors are clinically benign, and the tumor is either explored to obtain a frozen section, or completely excised and then bisected. To-day, whether or not the lesion is grossly cancer a frozen section should be made before a decision is reached as to the extent of operation -removal of the tumor only or the complete operation for cancer. Unfortunately, this is not the whole problem. A large number of surgeons with experience in the gross appearance of benign and malignant tumors of the breast are unable, in this border-line group, to determine whether the tumor which they bisect, or cut into, is malignant or benign. The same is true of the pathologist responsible for frozen-section diagnosis in the operating room. The most important question in every operating room is what to do when both the surgeon and the pathologist are in doubt. I have restudied every border-line tumor observed during the thirty-seven years of my experience. The records, the sections, the final results are all available. In 1915 sections of practically all these border-line tumors were submitted to the most experienced pathologists and surgical pathologists in six great cities of this country. In every instance the majority vote favored malignancy, and the complete operation was advised. The cases in the chronic cystic mastitis group were reported in 1921 (Archives of Surgery 3: 445, 1921). In June 1930, in the microscopic demonstration in the surgical pathological laboratory of the Johns Hopkins Hospital and University, the same sections which had been submitted to pathologists in 1915 were shown to the attending pathologists, and the majority vote favored benignancy. In not a single one

5 BORDER-LINE BREAST TUMORS 107 of these border-line tumors, diagnosed as benign or malignant in 1915 and followed since then, had cancer developed, irrespective of whether the operation consisted of removal of the tumor only, removal of the breast, or the complete operation for cancer. Up to 1915 the border-line cases which had been diagnosed as cancer and in which the complete operation had been performed, had been included among the cases of cancer of the breast without axillary metastases. The ultimate five-year cures, when the axillary glands showed no microscopic metastasis, amounted to 85 per cent. Excluding the border-line group, this figure fell to 70 per cent. In the border-line group there were no recurrences or deaths from cancer, except in a few instances in which, after five or more years, a cancer developed in the remaining breast. Kilgore of San Francisco, working on the breast material in the surgical pathological laboratory, found that a woman whose breast has been removed for definite cancer runs at least a 10 per cent chance of developing cancer in the other breast if she lives five or more years. Our follow-up of the women in whom one breast had been removed for doubtful tumors showed that the probability of cancer in the remaining breast was even less than in a similar number of women of the same ages who still had both breasts, from one of which a benign tumor had been removed. There have been received for diagnosis in the surgical pathological laboratory at Johns Hopkins, beginning about 1895, and in largely increasing numbers since 1920, breast tumors from surgeons and pathologists throughout the country. Up to 1920 the majority of the breast tumors sent for diagnosis were cancers; in many instances the complete operation had not been performed. Since 1920 the number of cancer cases has decreased, and since 1925, with rare exceptions, the tumors belong to the border-line group. In December 1930 we presented for diagnosis further borderline breast tumors to a group of about sixty pathologists, many of whom had been present at the previous microscopic demonstration in June. The diagnoses of the border-line breast sections were identical with those in June; the majority were right, and the actual percentage voting benign, especially among those who had been present at the previous demonstration, was larger. On the basis of this experience, it seems justifiable to draw up a working rule for surgeons and pathologists. Givgn a surgeon of average experience in the naked-eye diagnosis of breast tumors

6 108 JOSEPH COLT BLOODGOOD and a pathologist with equal experience in frozen-section diagnosis, neither of whom is certain whether a lesion is cancer or not, what is the safest thing to do? At present I am of the opinion that it is justifiable to remove the tumor only and to submit the sections to a number of pathologists qf larger experience, if possible. If the majority vote favors malignancy, the complete operation may follow. If not, the breast can be saved. This decision finds still greater justification in those clinics where the percentage of benign conditions for which operation is not indicated is greater than forty, the percentage of clinically benign or doubtful tumors is almost equal to the percentage of clinically malignant growths, and the hopeless cases approach 10 per cent or less. As the number of early breast tumors seen increases, the number that should be explored for frozen-section diagnosis also increases. We will be able to persuade more and more women to report immediately for examination if they have confidence in the judgment of the surgeon and pathologist. They must have the assurance that they will not be subjected to operation unless palpation or transillumination indicate its necessity, and that the complete operation for cancer will not be done unless it is justified by frozen section. In the article previously referred to, in the Archives of Surgery, sixty microscopic pictures of border-line tumors appeared-breast lesions suggesting cancer or apparently resembling cancer, but in which the follow-up disclosed no evidence of malignancy. I have waited ten years since the publication of that monograph before making this second contribution. During this study every effort has been made to compare the sections of the border-line cases which we believed to be benign with border-line cases which we concluded were malignant, and with sections of fully developed cancer of the breast. With rare exceptions, all the breast cases in the laboratory have been followed to date, and the cause of death has been pretty accurately ascertained. It seems justifiable, on the basis of this long experience, repeated microscopic studies, and accurate knowledge of the final results, to conclude that the element of error is small. Of this we are certain-in the cases in which the breast has been saved after the removal of a benign or border-line tumor, the incidence of cancer over a period of thirty years has been no greater than in a similar number of women of identical age observed during the same period. The remarkable feature is that in the

7 BORDER-LINE BREAST TUMORS 109 few breasts in which definite cancer formation occurred after a tumor had been removed, the second growth was not in the border-line group. In two instances-one an encapsulated tumor, the other a non-encapsulated tumor-the microscopic picture was distinctly malignant. The complete operation was not performed in the first of these cases because the tumor was, grossly, definitely encapsulated. The cancer developed some four years later in another part of the breast. In the second case, the section showed a very rare type of cylindroma. Since he had removed it with a good margin, the operator felt that it was safe to rest there. The formation of a scirrhous carcinoma was discovered in a routine annual examination some four years later. The complete operation was then performed. The axillary glands were not involved, and the patient lived more than five years without recurrence. In two other cases-one of my own and one of my colleague, Dr. Bevan of Chicago-areas of chronic cystic mastitis were removed. In Bevan's case the cyst was larger than a twenty-five cent piece, in mine smaller than a ten-cent piece. In neither were the sections considered suspicious of malignancy. Dr. Bevan informed me that in his patient recurrence was observed within a few months and the result was fatal. In my case recurrence took place after four and one-half years in a different part of the breast. At the complete operation the glands were found not to be involved. The patient died of metastasis to the brain after five years. In another case we have been unable to obtain the sections of the original tumor, which were lost. Both the operator and the pathologist, however, were of the opinion that the lesion was benign-a non-encapsulated area of chronic cystic mastitis. Rapid recurrence took place in the scar, the recurrent tumor being an undoubted cancer. Unfortunately, in the past, the larger number of border-line tumors have ultimately been treated by the complete operation for cancer. Some have been clinically malignant, and the radical operation has been performed without an exploratory incision. In others the gross appearance of the non-encapsulated area, or the diffuse involvement of the breast, did not impress the operator as malignant, but the pathologist later concluded that the lesion was either actually malignant or sufficiently suspicious to justify the complete operation. There has been in these cases almost every combination of operative treatment. When the glands have been removed, no

8 110 JOSEPH COLT BLOODGOOD metastases have been found, and, as has been stated above, the follow-up has produced no clinical evidence that the original tumor was malignant. When we study those cancers of the breast about which pathologists are in complete agreement as to the interpretation of the microscopic section; in which the complete operation has been performed with or without exploratory incision; in which the axillary glands have shown no involvement, and the patients have been followed five years, we never see 100 per cent cures. Only in the border-line group are 100 per cent cures to be found. When the actual sections of border-line tumors are mixed with sections of undoubted cancer-comedo or duct cancer, colloid cancer, scirrhous and medullary carcinoma, cancer cysts, cancer in intracystic papilloma-the experienced pathologist will have no difficulty in separating the border-line from the distinctly benign cases. But the same pathologist, meeting the border-line case in the operating room, when the tumor is not encapsulated and the section is not from the wall of a blue-domed cyst or an intracystic papilloma, hesitates and fears cancer. One of two things happens -either the surgeon is advised to perform the complete operation at once, or the wound is closed and sections of the tumor are restudied in the laboratory or perhaps submitted to one or more colleagues, usually with the final decision that complete operation is the safer procedure. As this border-line group 'is steadily on the increase, it seems imperative, through the publication of extensively illustrated studies, and by the help of frequent microscopic demonstrations in medical centers, to offer an opportunity for surgical pathologists to become familiar with its varying microscopic pictures, in the hope that more breasts can be saved with as little risk as when the complete operation is unnecessarily performed. To repeat, the problem is a clinical one or one of gross pathology, but the final decision in cases subjected to operation must ultimately be founded on the frozen section expertly cut, properly stained, and accurately interpreted in the operating room. CLINICAL, GROSS, AND MICROSCOPIC PICTURES Fully developed cancer (microscopic) in the breast, as a rule, is first observed as a single palpable lump without any clinical evidence of malignancy. When the lump is explored at this stage, the cancer may have the exact gross appearance of a clinically

9 BORDER-LINE BREAST TUMORS 111 malignant cancerous lump for which the complete operation is usually performed without exploration. When we group all malignant tumors of the breast together, both sarcomas and carcinomas, we find that, with the rarest exceptions, from the pre-microscopic era until to-day, these malignant tumors have been recognized by their gross fresh appearance. Furthermore, when sections of fully developed cancer are submitted to pathologists of ordinary training, opinion as to their malignancy is uniform. Similarly, fully developed encapsulated adenomas of the fibrous and intracanalicular myxomatous type were recognized as benign by Velpeau and the surgical pathologists before the days of the microscope. To-day the majority of operators having an average experience with breast tumors, when they encounter a typically encapsulated breast nodule of moderate size, remove it, save the breast, and are interested in its pathology only when someone less experienced informs them of the presence of an area suggestive of malignancy in this clinically benign encapsulated tumor appearing to the naked eye as an adenoma. As long as women waited one year or more after feeling a definite lump in the breast, a cancer was clinically malignant by the time it was first observed by the surgeon, and the complete operation could be performed on clinical signs alone. The pathologic study was postoperative. This same state of affairs existed in regard to encapsulated adenomata, while in all types of mastitis coming under observation, healed, with abscess formation, or after rupture, a sinus was present. Inflammatory lesions now and then were seen before reaching the stage of abscess or sinus formation, when they were clinically malignant. These early cases of mastitis before the stage of abscess or sinus formation, may be associated with a retracted nipple or red and adherent skin, and not infrequently have they been diagnosed as cancer and subiected to complete operation, their inflammatory nature being discovered only later in the laboratory. Fully developed cancer and the majority of encapsulated adenomas present no difficulties in diagnosis, either grossly or in frozen or permanent section. Mastitis, however, of any type, if observed soon after onset is less easily differentiated from malignant disease. It begins with an area of induration in the breast, without changes in the nipple or skin. When explored, it shows none of the usual signs of tuberculous or pyogenic inflam-

10 112 JOSEPH COLT BLOODGOOD mation-there is no pus, no caseation. It suggests rather diffuse, acute carcinoma. Under the microscope the inflammatory reaction has so dest'royed the basement membrane and the normal appearance of the lobule, that it is fair to say that there is a microscopic suggestion of malignancy. A very large number of border-line tumors difficult to distinguish from malignant tumors, are actually chronic cystic mastitis. This may come under observation as a single tumor and, when explored, prove to be a cyst or a non-encapsulated area not unlike a benign adenoma. It was the border-line cases of this group that were presented in 1921 in the article already referred to, in Archives of Surgery. The solid encapsulated benign tumors of the breast are: fibro-adenoma, myxadenoma (intracanalicular myxoma), cystic adenoma, cysts with intracystic papillomas, solid dermoids and lipoma, with a few other rare types, as pure myxoma, fibroma, and calcified tumors. The non-encapsulated benign tumors, as a rule, represent areas of chronic cystic mastitis, ranging from simple adenoma to,zdvanced types of cystic and papillary-cystic adenoma. Any form of mastitis may appear as a single non-encapsulated tumor and not as a diffuse process. Even lactation hypertrophy may persist for years and appear later as a non-encapsulated tumor of the breast. Nodules in the hypertrophied breast of puberty or in diffuse virginal hypertrophy may present themselves clinically as single definite tumors, appearing grossly as non-encapsulated areas. The benign cysts of the breast are most frequently associated with chronic cystic mastitis. The cyst most frequently explored is a single tumor which, when cut down upon, has a blue dome, and, when opened, clear or cloudy contents and a smooth wall. When the cyst is excised with a zone of surrounding breast tissue, the latter may show any of the various stages of chronic cystic mastitis. Fully two-thirds of the cases of chronic cystic mastitis operated on up to 1921 belonged to the blue-domed cyst type. In the past ten years we have been recognizing more frequently shotty breasts, lumpy breasts, and breasts with dilated ducts beneath the nipple, thus reducing operations for chronic cystic mastitis fully 25 per cent. The types of chronic cystic mastitis which still demand exploration are the blue-domed cysts and the non-encapsulated adenomas. These single definite lesions must

11 BORDER-LINE BREAST TUMORS 113 be explored whether palpation of the remaining breast tissue and the other breast shows them to be shotty or lumpy, or with palpable worm-like masses beneath the nipple. The next most common cyst is the galactocele, whose milky contents distinguish it at once from cancer. There is, however, a cyst of the galactocele type seen in chronic cystic mastitis, which, while it grossly resembles the galactocele, is unaccompanied by any evidence of lactation hypertrophy in the surrounding tissue. The blue-domed cyst, the cyst of the galactocele type, and the galactocele in the lactating breast have fresh appearances so distinctive that they should never be confused with malignancy. When, however, the walls of these cysts are examined in frozen section in the operating room, the number of border-line pictures discovered is in direct proportion to the inexperience of the pathologist. The same is true of the now common intracystic papilloma. Its contents may be bloody. The pedicle, growing from the cyst wall, may be distinct. That there is no cellular infiltration of the cyst beneath the pedicle, may easily be made out with the naked eye. Yet when the papilloma is studied microscopically in frozen section by a pathologist who has had only rare opportunities of observing such tumors, the diagnosis is usually one of malignancy or probable malignancy. In more than half of the benign intracystic papillomas a microscopic diagnosis of cancer has been made, and in most of these the complete operation for cancer has been performed. A true cancer cyst will never be overlooked if a frozen section is made of its wall. In the early years the most experienced surgical pathologists overlooked the rare cancer cyst with the smooth wall but bloody contents. Now every operator and pathologist should know that this type of hemorrhagic cyst without papilloma, but with bloody contents, is invariably malignant. Surgeons and pathologists who have been studying their material systematically and thoroughly during the last twenty-five years are beginning to realize that any of the various benign lesions of the breast may come under observation and be explored when the frozen section reveals a border-line microscopic picture. The next important thing to remember is that, with very rare exceptions, this border-line microscopic picture is simply a variant of benignancy and not one of malignancy.

12 114 JOSEPH COLT BLOODGOOD As has already been said, up to 1900, in the surgical clinic of Johns Hopkins Hospital, the percentage of malignant tumors was eighty. To-day the proportion of benign lesions in the operative group is more than one-half, while formerly it was less than one-fifth. With this change the number of microscopic pictures difficult of differentiation, either in the frozen section in the operating room, or later in permanent sections, is increasing so rapidly as to constitute one of the most important problems in surgery of the breast-the problem of whether the tumor alone should be removed or the complete operation for cancer performed. While the actual percentage of benign lesions of the breast coming under observation in the clinically malignant stage is so small that if all of these patients were subjected to the complete operation for cancer, the number of unnecessary complete operations would still not be large, we are beginning to learn, nevertheless, thak it is most satisfactory to be able to pick out this group, explore the tumor, and differentiate the benign from the possibly malignant as indicatjed both by fresh appearance and frozen section. Encapsulated adenomas are most frequently observed in the breasts of women from sixteen to twenty years of age, though tumor masses of this type have occurred at every age up to fifty. Cystic adenoma is much less frequent than are encapsulated tumors of fibro-adenomatous or intracanalicular myxomatous type. Grossly and histologically the encapsulated cystic adenoma resembles an area of chronic cystic mastitis or non-encapsulated cystic adenoma. As stated above, however, the encapsulated cystic adenoma is encountered more frequently in young women, while the non-encapsulated form, with rare exceptions, comes under observation during the cancer age. For this reason, the encapsulated cystic adenoma, even though it may show areas suggestive of cancer under the microscope, has not been so often subjected to the complete operation for cancer as the non-encapsulated growth. The intracystic papilloma, in which the papilloma fills the cyst cavity, is another type of encapsulated tumor, but this has the gross and microscopic appearance of cancer more often than the encapsulated cystic adenoma. The largest number of border-line tumors presenting difficulties of differentiation from cancer are found among the cystic ade-

13 BORDER-LINE BREAST TUMORS 115 nomas, encapsulated and non-encapsulated, the intracystic papillomas, in which the papilloma fills the cyst cavity, areas of chronic cystic mastitis in the walls of benign blue-domed cysts, and in breasts the seat of diffuse chronic cystic mastitis of the Schimmelhusch type. The following cases, with the accompanying illustrations are Patient aged fifty, tumor of ten years' durat,ion. This section might also represent the adenomatous stage of chronic cystic mastitis. It should be compared with Fig. 8, which illustrates an irregular adenomatous area. selected chiefly for their contribution to the microscopic diagnosis. Although some gross illustrations are shown, this study must be looked upon as primarily a microscopic one. The first cystic adenoma was observed in the Johns Hopkins Clinic in J. H. H. (Path. 431), a white female, aged thirtythree, unmarried, gave a history of a small tumor appearing in the left breast six years before, about five and one-half months

14 116 JOSEPH COLT BLOODGOOD after a single trauma. The original pain and tenderness from the trauma had disappeared in a few days. When first observed, the tumor was the size of a five-cent piece. It had disappeared and reappeared one year before the patient was seen in the Johns Hopkins Clinic. No definite clinical description of the tumor is available, except that it was benign. The pathological report describes it as consisting of dense fibrous tissue containing many FIQ. 2A. MICROSCOPIC DRAWING FROM SECTION OF AN ENCAPSULATED BENIGN TUMOR REMOVED IN PATH. 294 This was interpreted as early malignant (adenocarcinoma). small and larger cysts lined by epithelium and a good deal of normal breast, as shown in Fig. 1. The record shows that in 1890 this tumor was recognized as clinically benign; that on removal it was considered grossly benign, and in the pathological department the section was interpreted as benign. It is unfortunate that there was no follow-up. The second case (Path. 294), seen at Johns Hopkins in 1894, illustrates the removal of a benign tumor of the breast which, on gross examination, was looked upon as benign, because it was encapsulated. The tumor was riddled with many minute cysts,

15 BoRDER-LINE BREAST TUMORS n7 in some of which intracystic papillomas were recognized. In spite of this, when the tumor was studied microscopically (by Dr. Halsted and the writer) it seems to have been regarded as suspicious of malignancy, since the complete operation for cancer was performed. The axillary glands showed no involvement, and the patient was followed for twenty years. No further trouble in either breast was observed. This would be interpreted today as an irregular adenomatous area with a tendency to ectasia or the formation of solid, non-malignant adenoma. This section is practically normal breast tissue with an increase of fibrous stroma. The patient was an unmarried woman of thirty-three with a discharge from the nipple and a palpable tumor the size of a five-cent piece, of a year's duration, clinically considered benign. For the further history of the case see the text. Figure 2a is a drawing of the most malignant area of this tumor, and Fig. 2b of a more fibrous area. Reviewing this case to-day, I cannot understand why it was interpreted as suspicious of malignancy. This note appears in the record: "When the section was first made, we did not correctly interpret this histological picture (Figs. 2a and 2b) and thought it might be adeno-

16 118 JOSEPH COLT BLOODGOOD carcinoma." It is important to state that the breast removed at the complete operation was the seat of chronic cystic mastitis, both grossly and microscopically. My original description of the breast reads as follows: "One sees numerous minute cysts varying in size from the head of a pin to a pea; the contents are dark brown, viscid fluid; the ducts near the nipple are also dilated." The patient was thirty-three years old and unmarried. The symptom of onset was a mucopurulent, bloody discharge from the nipple, which had continued for one year. The tumor was no larger than a five-cent piece and was situated to the right of the nipple. There was very little pain and only slight growth n few months FIG. 3. BISECTED ZONE OF BREAST SHOWING ENCAPSULATED TUMOR BURIED IN FIBROUS BREAST TISSUE, WITH SCANTY ADENOMATOUS AREAS. PATH The case is described in the text. One can recognize in the photograph the cystic or spongy appearance of the tumor. This was diagnosed clinically and grossly as benign and the patient was well nine years after operation. Case of Dr. Callender. before the patient was first seen. In spite of its nearness to the nipple, there was no retraction and no change had occurred in the skin. The natural diagnosis of intracystic pfipilloma was made. The tumor was removed. It is described as 2.5 by 3 cm., not distinctly encapsulated, but irregular in shape and buried in fat and breast tissue. On section three distinct cysts could be recognized, 5 mm. in diameter, each containing s papillomatous growth; other cysts were without papillomata; the stroma about the cyst was fibrous. Yet, in t'he description of the microscopic sections, there is no note of finding intracystic papilloma. The sections have faded, and the only microscopic evidence we have is shown in Figs. 2a and 2b, which were drawn as the most characteristic areas: (a) suspicious of malignancy and (b) benign. To-day

17 BORDER-LINE BREAST TUMORS 119 we would describe Fig. 2n as an irregular adenomatous area with beginning solid adenoma, but as showing nothing suspicious of malignancy. The clinical and the gross description in this case would suggest that we were dealing with multiple intracystic papillomas in which each minute cyst was filled with a papilloma. The patient lived twenty years without further trouble in either breast. Figure 3 (Path ) shows a bisected zone of breast, in which one can see a distinctly encapsulated tumor surrounded by breast tissue and make out that the tumor contains many minute cysts, while the surrounding breast is fibrous, with only here and Note typicai cystic adenoma surrounded by fatty and fibrous breast with here and there a senile lobule or duct. there an elevated dot of an adenomatous lobule. Figure 4 is a photograph of a section of a distinctly benign cystic adenoma from this breast. Yet it may be observed that there is not a very distinct capsule. It would have been difficult to enucleate the tumor. The zone of breast is fatty and fibrous, with here and there an atrophic breast lobule or duct. Figure 5 is a low-power photomicrograph of an area in the tumor and its margin. Dr. Callender, by whom this specimen was referred, and his pathologist were of the opinion that the tumor was benign but desired confirmation, as they had removed the tumor only. This patient has had no trouble in either breast almost nine years since operation.

18 120 JOSEPH COLT BLOODGOOD The patient in this case was at the cancer age-thirty-fourand gave a history of two lactations, ten and thirteen years before. Two nodules had been observed one year without change in size. This favors a non-malignant lesion. The larger nodule was the size of a ten-cent piece, the other the size of a pea. Both were removed. The smaller specimen measured 1 cm. in diameter. Grossly only fat with some breast tissue could be made out. Under the microscope normal adenomatous nodules were found, FIG. 5. LOW-POWER VIEW OF AREA FROM SECTION SHOWN IN FIG. 4. PATH Note contrast of tumor area and fatty breast tissue. See Fig. 3 for gross appeurunce. two dilated ducts, and one small epithelium-lined cyst. The larger nodule is shown in Fig. 3. When we compare Fig. 5, studied in 1922, with Fig. 2a, misinterpreted in 1894, we must fairly conclude that in the earlier case the picture may be a little more suggestive of malignancy, and that, even to-day, it might prove difficult of diagnosis to some pathologists. The next case has been selected as perhaps the best illustration of the gross and microscopic pictures of a benign cystic adenoma,

19 FIG. 6. HALF OF BISECTED TUMOR WITH SURROUNDING ZONE OF BREAST, REMOVED ON A CLINICAL AND GROSS DIAGNOSIS OF BENIGNANCY IN PATH For microscopic illustrations see Figs For details of case see text. Case of Dr. Howard A. Kelly.

20 122 JOSEPH COLT BLOODGOOD which should be differentiated without difficulty from malignancy. The specimen (Path. 2568) was sent to the laboratory by Dr. Howard A. Kelly in This patient was unmarried and had had a tumor in the breast for ten years. The growth had been slow. The tumor was situated in the lower and outer quadrant, and measured about 3 cm. in diameter, that is about the size of a fifty-cent piece. There were no clinical signs of malignancy. This is a low-power drawing of the area marked I11 in Fig. 7. When Dr. Kelly removed the tumor with a zone of breast tissue and bisected it, he found it distinctly encapsulated, as shown in Fig. 6. This photograph of a drawing made from the tumor after fixation in alcohol shows clearly the relation between the encapsulated tumor and the surrounding zone of breast tissue. Figure 7, a drawing of a section of the tumor, is a remarkable picture of diffuse chronic cystic mastitis of the Schimmelbusch type in which adenomatous areas (111) and cystic-adenomatous areas (IV) predominate, while intracystic-papillomatous areas (VI) are infrequent. These areas are reproduced in Figs. 8, 9, and 11, while

21 Fro. 9. CYSTIC ADENOMATOUS AREA IN BENIGN ENCAPSULATED CYSTIC ADENOMA SHOWN IN FIG. 6. PATH This is a low-power drawing of the area marked IV in Fig. 7. FIG. 10. SMALL CYST WITH REMAINS OF EPITHELIAL LINING AT X FROM ENCAPSULATED BENIGN CYSTIC ADENOMA SHOWN IN FIG. 6. PATH This is a low-power drawing of area marked V in Fig

22 124 JOSEPH COLT BLOODGOOD Fig. 10, corresponding to V in Fig. 7, shows the remaining epithelial lining (at X).in one of the larger cysts. These pictures-figs. 8, 9, 10, and 11-represent the unit microscopic pictures of cystic adenoma, whether encapsulated or non-encapsulated, and of diffuse chronic cystic mastitis. Microscopic variants are accounted for by changes in the irregular adenomatous areas, either to solid adenomatous areas, large and FIG. 11. BENIGN PAPILLARY CYBTADENOMA FROM AREA VI IN FIG. 7, BENIGN ENCAPSULATED CYSTIC ADENOMA. PATH small, or to cysts of different sizes with epithelial lining of different types, or to larger solid adenomatous areas, or to papillary cystadenomatous areas. This case was previously reported in Surgery, Gynecology and Obstetrics in Figure 12 (Path ) shows a section which was sent to me in by Dr. C. S. Butler, pathologist of the U. S. Naval Medical School. I examined the section without having seen the gross specimen or knowing the age of the patient, and concluded that it was suspicious of malignancy, and without further knowledge of the case was inclined to advise the radical operation for cancer.

23 BORDER-LINE BREAST TUMORS 125 In 1915, when this same section was submitted to a group of pathologists, the majority regarded it as suspicious of malignancy. At microscopic demonstrations in June and December 1930, when a lantern slide of the section was shown, the. majority present favored a benign diagnosis. The operator in this case had diagnosed the lesion as benign both preoperatively and, at operation. The tumor was distinctly encapsulated and when bisected showed This tumor, removed in 1911, had been observed nine months, and was diagnosed before and at operation as benign. There was no further operation, and the patient was well sixteen years later. Case of Drs. Butler and Ley. grossly no evidence of malignancy, though the patient was at the cancer age-thirty-eight. The tumor had been observed for nine months but had not grown recently. This patient was well in 1927, sixteen years after removal of the tumor only. Figures 13 and 14 (Path ) show sections of tumor, a piece of which was sent to me by Dr. M. L. Casey of Rochester, N. Y., in The patient, a whioe female twenty-one years of age, gave a history of injury several months before the appearance 9

24 FIGS. 13 AND 14. SECTIONS OF TUMOREFERRED BY DR. M. L. CASEY IN PATH Fig. 14 (below) is from the area marked X in Fig. 13. See text. 126

25 BORDER-LINE BREAST TUMORS 127 of the tumor, which had been present two months. The operator had removed the tumor with a zone of breast tissue and sent part of it to Dr. Casey, who was inclined to consider it as malignant. From the piece sent to the laboratory, I could not make out definite encapsulation; many minute cysts could be clearly seen, some filled with intracystic material, but there was no gross evidence of cancer. A diagnosis of benign cystic adenoma was favored and no further operation advised. The patient was traced for many years, during which t'here was no recurrence. Figure 13 is a low-power photomicrograph, showing almost every type of cyst with epithelial lining and intracystic papillomatous growth. At X the wall of the cyst seams broken, and this area was studied under a higher power (Fig. 14). This section was diagnosed by a minority of pathologists in 1915 as suspicious of malignancy. Even in 1930 a few pathologists were inclined to the diagnosis of possible malignancy. The age of the patient, however-only twenty-one-almost excludes the possibility of a malignant tumor of the breast, and this was confirmed by the follow-up.

26 128 JOSEPH COLT BLOODGOOD Figures 15 and 16 show sections of an encapsulated tumor removed by the late Dr. John B. Roberts of Philadelphia. The patient was but twenty years of age, the tumor had been present but a few months, was distinctly encapsulated, and could have been enucleated from the surrounding normal breast. It was removed, however, with a zone of breast. This was in December The tumor only was removed and there was no recurrence. 1912, nineteen years ago. After the wound had been closed and the patient sent to her room, the pathologist reported that the tumor was microscopically a cancer and that he felt that a more extensive operation should be done. On account of the age of the patient and the distinct encapsulation, however, Dr. Roberts postponed decision until he had submitted the section to twelve pathologists. I received a small piece of the tumor, which had the gross appearance of a cystic adenoma or an area of chronic cystic mastitis. From a study of the sections (Figs. 15 and 16) I concluded that it was a benign cystic adenoma with areas of

27 For details of case, see text. 129

28 130 JOSEPH COLT BLOODGOOD papillary cystadenoma. Of the twelve pathologists who studied the sections only four agreed with the diagnosis of a benign tumor, while eight favored malignancy. For this reason, a month after the first operation Dr. Roberts removed the scar and a small zone of the surrounding breast, though not enough to produce any mutilation. Microscopic sections showed no evidence of the original tumor in the remaining breast and no signs of malignancy. When these sections were submitted to a group of pathologists in 1915 the majority still voted in favor of malignancy but when lantern slides from these sections were thrown on the screen at the microscopic demonstration in December 1930, the majority favored benign adenoma. This patient had no recurrence in the scar and no difficulty with either breast. Figures 17 and 18 (Path ) are photomicrographs from slides of a breast tumor sent me by Dr. Francis Carter Wood in May The patient was a woman fifty years of age. The tumor was small, freely movable and, when exposed, encapsulated. A frozen section diagnosis was so doubtful that the axillary nodes were explored. The nodes which were excised, however, showed no new growth. '(The tumor is in my opinion," wrote Dr. Wood, "unquestionably carcinoma. There has been no recurrence in a year. What interested me in this case was that despite every evidence of active growth the cells remain pretty well confined to the inside of the alveoli. There was a large amount of blood in the alveoli, although none had ever been noted from the nipple. The lymphocytic infiltration about the alveoli is also interesting and, to my mind, suggestive of malignancy." In 1915 nine out of ten pathologists voting on this case favored carcinoma; only one considered the growth benign. This patient has had no recurrence since. Here, therefore, is an example of a distinctly encapsulated tumor which is microscopically cancer. Sections from the breast tumor shown in Figs. 19 and 20 (Path ) were sent to me by the late Charles H. Peck of New York in December I was informed that the patient was a girl of eighteen years and that the tumor in the lower hemisphere of the left breast was a little larger than a five-cent piece and of two years' duration. It had exhibited slight increase in size recently. At operation it was found to be not distinctly encapsulated, but circumscribed. From its fresh appearance, Dr. Peck was of the opinion that it was benign. I had never seen

29 For detaik of case, see text. 131

30 132 JOSEPH COLT BLOODGOOD a malignant tumor in the breast of a girl of eighteen, and the tumor (Fig. 19) impressed me, also, as a benign cystic adenoma or an area of chronic cystic mastitis of the Schimmelbusch or RBclus type. While the little area shown in Fig. 20 might at first be looked upon as suspicious of malignancy, it represents a microscopic picture not infrequently found in cystic adenoma and in the Schimmelbusch type of chronic cystic mastitis. This section, when submitted to pathologists, always causes a dilemma, and the majority, when they do not know the age of the patient, still express an opinion of malignancy. When the patient was last heard from there had been no recurrence. This tumor differs clinically, grossly, and microscopically from encapsulated adenoma only in the absence of a distinct capsule, the area being simply a part of the breast. Many of these cases have been subjected to the complete operation for cancer. Of the 350 cases of chronic cystic mastitis reported by me in the Archives of Surgery in 1921, 18 were of the non-encapsulated cystic adenomatous type-less than 6 per cent. The number has since increased to additional cases in ten years. Figure 3 is a fairly good example of the gross appearance of the majority of cases of encapsulated and non-encapsulated cystic adenoma, irrespective of the age of the patient, the duration of the tumor, or the condition of the surrounding breast. Figure 21 (Path. 2627) is a photographic copy of a painting of an encapsulated cystic adenoma made more than twenty-five years ago. It was unusual on account of the size both of the tumor and of some of the individual cysts. It should be compared with Fig. 6, a photograph of a pen-and-ink sketch of another encapsulated cystic adenoma, and Fig. 3, the actual photograph of the hardened specimen showing tumor and breast. None of these, however, give the actual fresh appearance of 'the tumor. As a matter of fact, this is quite impossible to reproduce. Fortunately the microscopic appearance can to a very large extent be preserved in the fixed section and reproduced in the photomicrograph. Figure 22 (Path. 3965) is a reproduction of a section through a breast the seat of diffuse chronic cystic mastitis of the Schimmelbusch type made more than twenty-nine years ago, showing (1) an area of cystic adenoma combined with papillary cystadenoma, microscopically almost identical with sections taken from the

31 BORDER-LINE BREAST' TUMORS 133 tumors in Figs. 3 and 21; (2) an area which was looked upon as cancer and which stood out grossly as a definite circumscribed area, and (3) practically normal breast, as shown in Fig. 1, which represents.a non-cystic area in Fig. 21. As will be observed, the disease involved a quadrant or hemisphere. A small cyst may be seen in the normal breast tissue. The gross appearances shown in Figs. 3, 6, 21, and 22 picture The tumor was of ten years' duration. The specimen was sent to the writer more, than twenty-five years ago by Dr. Howard A. Kelly. There was no recurrence. Compare this with Fig. 22. as clearly as possible the usual gross appearance of an encapsulated adenoma, a non-encapsulated cystic adenoma, and diffuse chronic cystic mastitis of the Schimmelbusch or RBclus type. In 1906 I used the term senile parenchymatous hypertrophy to describe this picture. I now know that the conditionis not senile; it is, however, certainly parenchymatous, and it may be an hypertrophy. All the evidence points to the conclusion that it is a pathological change due to an exciting cause not unlike pregnancy, which is the cause of the lactation hypertrophy that begins in the breast shortly

32 134 JOSEPH COLT BLOODGOOD after conception and may persist in spots for years after lactation has ceased. These non-encapsulated areas of cystic adenoma may appear clinically as a single tumor which, on palpation, cannot be distinguished from any other type of encapsulated or non-encapsulated tumor of the breast, benign or malignant. Apparently the most important thing to learn is the microscopic appearance of these benign and border-line tumors, as revealed by frozen sections in the operating room. These cases are, Clinically the breast illustrated here was "shotty." The breast only was removed. Twenty years later the other breast was removed. The first diagno~is was adenocarcinoma in chronic cystic, mastitis (at X). Papillary cystadenomatous areas, a cyst in normal breast, and normal breast tissue are seen. This is the best illustration of this disease in the literature. however, so rare, and it takes so long to learn from operating room experience alone, that, unless the pathologist has an opportunity to acquire this microscopic knowledge from verified cases from the experience of others, he must of necessity advise complete operation in a large number of cases which we now know are just as benign as the definitely encapsulated adenoma and the nonencapsulated areas which are microscopically distinctly nonmalignant. As stated in the introduction, this seemed until recently to be the safer course if there was any doubt as to the

33 BORDER-LINE BREAST TUMORS 135 benignancy of the breast tumor. The evidence which we have now accumulated, however, indicates strongly that a surgeon of considerable experience in gross pathology and a pathologist of equal experience in frozen section diagnosis in the operating room run no risk, in these border-line cases, in excising the tumor together with a zone of breast tissue, closing the wound, and referring the sections to more experienced surgical pathologists for confirmation. Unfortunately, this formerly led, in the majority of instances, to the complete operation. But in the past few years an increasing number of breasts have been saved without risk to the patient. It has seemed to the writer that the best way of presenting this sub~cthece is by the reproduction of microscopic illustrations of cases in which the result is known. In none of these cases, either of encapsulated or non-encapsulated cystic adenoma, has there been recurrence on the operated side, regardless of the nature of the operation. A comparison of follow-up resultsafter five, ten, or twenty years-in this group of encapsulated and non-encapsulated cystic adenoma of the border-line type, even including those cases which were quite suspicious microscopically of cancer, and in an equal number of fully developed cancer cases, will reveal a distinct difference. The incidence of cancer in the remaining breast in the cancer group is fully 10 per cent, while the incidence of cancer in the opposite breast in the borderline group is identical with the incidence of cancer in women who have had no previous trouble with either breast. The largest number of our patients living today more than thirty years after the complete operation for cancer, many of them over eighty years of age, belong in this border-line group of cases originally diagnosed as cancer and recorded until 1915 as cured cancer cases. Figures illustrate a Johns Hopkins Hospital case (Path. 1210) observed in In this case the complete operation for cancer was performed by Dr. Halsted because of retraction of the nipple. At the age of fifty-two, four years after the menopause, the lump in the left breast had been observed ten years. There had been no difficulty in five lactations. The tumor had grown slowly in the first year to the size of a hickory nut (five-cent piece) and had then remained quiescent for nine years. In the nine months before the patient was seen there had been a slight increase in size and the tumor had been painful. At admission it was the size of a fifty-cent piece, felt like an irregular area of induration,

34 136 JOSEPH COLT BLOODGOOD but was distinctly more lobulated (like a mulberry) than like an area of mastitis or cancer. Dr. Halsted thought that there was slight atrophy of the subcutaneous fat. When this case was seen, it impressed us as a rare example of an early malignant tumor, and the complete operation was performed. The glands were not involved. The patient lived thirteen years, and died at the age of seventy-five of apoplexy. The photograph shown in Fig. 23 is of an alcohol specimen after some years of hardening. Even to-day this non-encapsulated area looks more like a zone of lactation hypertrophy than an orea This tumor was clinically malignant. See text and Figs of cancer of any type. It was described at the time as circumscribed in some places, infiltrating in others, and was pictured as composed of large cellular alveoli divided by fibrous trabeculae. The retraction of the nipple was produced by one of these trabeculae, between the-nipple and the tumor. There were no definite cysts, dilated ducts, or comedos. The fresh appearance suggested to me at that date a cancer or n solid intracystic papilloma. The microscopic sections (Figs ) were diagnosed as adenocarcinoma cysticum without metastasis to the glands. Figure 24, first interpreted as an area of cystic adenocarcinoma, is now interpreted as papillary cystadenoma. Such an area is a not uncommon finding in encapsulated benign cystic adenoma of

35 The majority of pathologists diagnosed this tumor as malignant in 1915, as benign in

36 135 JOSEPH COLT BLOODGOOD the breast at any age, even under twenty. The picture is a characteristic one of benign intracystic papilloma, whether the papilloma fills the cyst or not. It is a microscopic picture that is confusing even to the most experienced pathologist. There are distinct areas in which the basement membrane of the duct or acinus is gone and the epithelial cells are free in connective tissue. There may be no lymphoid-cell granulation tissue, as in Fig. 24, or it may be very evident, as in Fig. 27. Note the marked chronic mastitis with lymphoid granulation tissue about the epithelia1 nests. The majority of pathologists are stiil suspicioua of cancer in this section. Figure 25 shows an area of benign cystic adenoma which no experienced pathologist would diagnose as even suspicious of malignancy. Yet, here and there can be seen the beginnings of small papillomata. When these little intrapapillomat~us growths continue, the picture in Fig. 24 will be reproduced, and the pressure of the growing cells or some external trauma will break the basement membrane and an appearance resembling cancer will be produced. To-day we are not sure enough of the actual mor-

37 BORDER-LINE BREAST TUMORS 139 phology of the benign and the malignant epithelial cell in the breast to differentiate from the cells only, especially the benign epithelial cell and the grade I cancer cell. With cancer cells of grades I11 or IV, we do not need the morphology of the cell to tell us that the lesion is malignant. It would be very helpful, however, to have a differential stain to distinguish grade I and I1 cancer cells from benign cells. Figure 26 shows a third area of the tumor shown in Fig. 23. FIG. 27. SECTION OF TUMOR SHOWN IN FIG. 23. PATH The majority of pathol~gist~s still look upon this area as suspicious of malignancy. However, the glands were not involved, and the patient died thirteen years after operation, at the age of seventy-five, of apoplexy. Here we see epithelium-lined cysts of various sizes with varying degrees of proliferation and degeneration; small intracystic papillomas; well staining nests of epithelial cells without a distinct basement membrane surrounded by lymphoid-cell stroma-histologically cancer, morphologically either not cancer or grade I cancer. Figure 27 shows still another part of this tumor. The lymphoid-cell inflammatory reaction observed here is unusual for

38 140 JOSEPH COLT BLOODGOOD cancer, being more common in mastitis. Nevertheless, there are many epithelial nests in the fibrous stroma and in the lymphoid-cell areas that have no baqement membrane. If there were but a single case like this, or if the complete operation for cancer had always been performed for such cases, we would be more and more inclined still to consider this an early malignant tumor of the breast. But when, in thirty-seven years of continuous and repeated study, we have never found involved glands in the axilla FIG. 28. GROSSPECIMEN OF A CLINICALLY BENIGN BREASTUMOR EXPLORED IN 1015 AND D~AQNOSED CANCER ON GROSS APPEARANCE. PATH Complete operation was performed. The glands were not involved. The patient is living, with no recurrence, sixteen years later. See Figs. 29 and 30 for microscopic pictures. with breast tumors of this microscopic appearance; when similar microscopic areas are found in encapsulated and non-encapsulated tumors in which only the area has been removed without a single example of recurrence, and when, in addition, such areas are found in tumors removed from the breasts of women under twenty years of age, one begins to suspect that this is not cancer, and that in these cases it would be just as safe to confine the operation to the removal of the tumor, as when the tumor is encapsulated and microscopically benign. Figures (Path ) illustrate a case seen by the writer in St. Agnes Hospital, in 1915, a clinically benign tumor of thirty-two years' duration in a woman aged forty-two. The gross diagnosis at operation was cancer, and the complete operation for cancer was performed. The permanent sections do not show cancer, and the patient is well in 1931, sixteen years later.

39 BORDER-LINE BREAST TUMORS 141 When I bisected this tumor, shown in Fig. 28, I was surprised to find that it had the appearance of cancer. It felt and cut like cancer; it cupped on section; there were 'he fine dots and lines so characteristic of the surface of carcinoma of the breast. However, nothing could be expressed from the surface. Surprised to find that a tumor of thirty-two years' duration in a woman of fortytwo, present since ten years of age and exhibiting no growth, could be malignant, I had frozen sections made at once (this was FIG. 29. SECTION FROM TUMOR SHOWN IN FIG. 28, DIAGNO~ED AB BENIGN NON- ENCAPSULATED CYSTIC ADENOMA WITH AREAS OF PAPILLARY CYBTADENOMA AND POSSIBLY RESIDUALACTATION. PATH Today the majority of pathologists diagnose this as benign. See also Fig. 30. not then a routine procedure in St. Agnes Hospital). The microscopic sections (Figs. 29 and 30) picture a distinctly benign tumor. Figure 29 shows areas of cystic adenoma, a few of solid duct adenoma, and a small area of papillary cystadenoma. Figure 30, a high-power photomicrograph of the papillary cystadenomatous area in Fig. 29, shows a typically benign papillary cystadenoma, somewhat resembling an area of old lactation. This was the first time, after an experience of twenty-two 10

40 142 JOSEPH COLT BLOODGOOD years, that I had encountered a benign tumor with the gross appearance of cancer. Within the next week I explored a nonencapsulated area in a breast that had the distinct appearance of a gumma and not of cancer, but in which the frozen section showed cancer. There was positive metastasis to the basal glands in the axilla, and the patient died six years later with symptoms of internal metastasis. After these two experiences I introduced Fro. 30. SECTION FROM TUMOR SHOWN IN FIGS. 28 AND 29, DIAGNOSED AS I'APILLARY CYSTADENOMA WITH POSSIBILITY OF RESIDUAL LACTATION HYPERTROPHY. PATH The majority of pathologists diagnose this as benign. frozen-section diagnosis as a routine in the operating room. Now, after sixteen years' observation, I feel confident that the evidence accumulated proves the necessity of this. The danger is not so much of overlooking cancer and not performing the immediate complete operation as of performing the complete operation for cancer when the lesion is really benign. In a restudy of the history of the case shown in Figs. 28, 29, and 30, I find the patient positive t,hat there was a distinct lump in the right breast at the age of ten years and for some years after

41 BORDER-LINE BREAST TUMORS 143 that, that this lump gave no trouble when she nursed her two children twenty-two and ten years before operation, that the lump had been distinct in or near the same spot as the earlier lump for a number of years. It was not much larger than a five-cent piece, and felt smooth, like a cyst. Otherwise both breasts were normal. Clinically benign tumors of long duration, often give great digiculty in diagnosis, both gross and microscopic. Before the educational effort began in 1913 to instruct women concerning the danger of delay after feeling a lump in the breast, the majority of tumors of the breast in our records of more than three years' duration came under observation with practically the same symptoms as those of shorter duration. These symptoms were pain, rapid growth of the tumor, involvement of the skin, discharge from, retraction of, or ulceration of the nipple. At that time the majority of these tumors of more than two years' duration were malignant. Since 1913, however, the majority of tumors of long duration are apt to be benign. This is explained by the fact that the patients have come to the clinic not because of recent symptoms on the part of the tumor, but because of recent knowledge that it is dangerous to watch an evident lump in the breast. The majority of these tumors of long duration present the gross appearance of an encapsulated nodule. When not encapsulated, as in Fig. 28, they may suggest malignancy. Unfortunately, when studied microscopically, either in frozen or permanent sections, these tumors of long duration, both non-encapsulated and encapsulated, present difficulties of diagnosis, the majority belonging to the border-line group. Malignancy in a breast tumor cannot be excluded because of its known long duration. So far, in my experience, the most helpful clinical evidence against malignancy is the age of the patient-under twenty-five years. It is quite possible that women themselves will eventually relieve the surgeon and pathologist of this dilemma by ceasing to delay three years or more after feeling a lump, before seeking advice. The tumor shown in Figs. 31 and 32 (Path. 1147) was observed by Halsted at Johns Hopkins in In this instance the small tumor was clinically benign. At exploration it was found to be a non-encapsulated tumor, a part of which Dr. Halsted recognized as malignant, the other part as benign cystic adenoma. The sections (Figs. 31 and 32), when submitted to pathologists in 1915, were uniformly diagnosed as malignant, and at the microscopic demonstrations in June and December 1930, no pathologist of

42 144 JOSEPH COLT BLOODGOOD experience interpreted the lantern slides other than as definitely malignant. Sections similar to or identical with those pictured are to be found in scirrhous carcinoma, whether the tumor is small or large, whether circumscribed or infiltrating, whether of short or long duration. The epithelial cells in the small nests (Fig. 32) are somewhat different morphologically from similar nests found in border-line benign tumors. Some of the cells are grade I, FIG. 31. BREABT TUMOR EXPLORED BY HALBTED IN 1895, DIAGNOSED FROM FREBH G~oss APPEARANCE ~8 CANCER IN NON-ENCAPSULATED CYGTIC ADENOMA. PATH The complete operation was done; the glands were not involved. The patient lived thirty years and died of cancer of the liver. All pathologists agree on a diagnosis of cancer in this case. For high-power pilotomicrograph see Fig. 32. others possibly grade 11. Certainly, if one finds an area in a breast tumor resembling the area in Fig. 32, the complete operation should be performed. In this case there was no metastasis to the glands, and the patient lived thirty years. She died in 1925 of cancer of the liver. How shall this death from cancer of the liver be interpreted? Our statistical studies fail to record another example of cancer of the liver observed thirty years after a free interval following

43 BORDER-LINE BREAST TUMORS 145 operation for cancer of the breast. It may be possible, however. We have one example in which there was an absolutely free interval of twenty years after the complete operation for a cancer of the breast with involvement of axillary glands. The recurrence in this case was a small affair in the mid-axilla, encircling and binding the axillary vessels and brachial plexus, manifested first by lymphedema, and then by symptoms of nerve pressure with All pathologists diagnosed this area cancer in spite of the fact that the major part of the tumor is cystic adenoma, the glands were not involved, and the patient lived thirty years after the complete operation and died of cancer of the liver. loss of power. The axilla was explored and distinct evidence of gross and microscopic cancer was found. There were no symptoms of malignancy elsewhere, though there was no x-ray study and no autopsy. Another patient, who is living today, underwent complete operation in 1895 for a colloid cancer of the breast with axillary metastasis. After a free interval of about twenty years, a mass appeared beneath the inner third of the clavicle. When this was explored, in 1915, a colloid cancer mass was found which so

44 146 JOSEPH COLT BLOODGOOD involved the vessels and nerves that it could not be completely removed. The only evidence of cancer today, fifteen years since the second operation, is beginning loss of sensation and motion in the muscles of the arm. This patient has had almost continuous x-ray treatment since The case pictured in Figs. 31 and 32 is the first example of a definite cancer of the breast in the remains of an apparently benign tumor. The study of this tumor suggested the origin of cancer in a non-encapsulated area of the breast resembling a cystic adenoma or a zone of chronic cystic mastitis. In our forty years' experience with a very large number of malignant tumors this combination is rare in spite of the greatly increased number of early tumors, benign and malignant, now being observed. The case shown in Figs. 33, 34 and 35 (Path. 1734) was observed by Halsted in The clinical diagnosis was benign tumor of the breast. The gross diagnosis was benign non-encapsulated cystic adenoma. The tumor was first removed and then, after one month of intensive microscopic study with a final diagnosis of adenocarcinoma, the complete operation was performed. The glands showed no metastasis. The patient was followed sixteen years with no evidence of recurrence. Microscopically the tumor was a small non-encapsulated cystic adenoma; many minute cysts, containing brown-gray material and milky fluid predominated. The fresh appearance is probably best pictured in Fig. 22. The cysts were smaller than those seen in Fig. 21, and were more distinct than those seen in Fig. 3, which shows an encapsulated cystic adenoma. This is a picture with which we are becoming more and more familiar as we have more experience with chronic cystic mastitis. Such areas predominate in disease of the Schimmelbusch and RBclus type. Here a quadrant, a hemisphere, or the entire breast is the seat of a diffuse, nonencapsulated cystic adenoma. At first fluid covers the surface of the cut section; the fluid varies in color-gray, brown, yellow, white; rarely, if ever, is it distinctly bloody, though there is no reason why it should not be. Also, in chronic cystic mastitis, especially of the shotty or Schimmelbusch type, there is often a discharge from the nipple, resembling the contents of t,he cysts and ducts in the area of involvement. Distinct discharge of blood from the nipple, with rare exceptions, is associated with a papilloma in a duct near the nipple. The amount of blood has no relation to the size of the papilloma.

45 FIGS. 33 AND 34. SECTIONS OF NON-ENCAPSULATED TUMOR DIAGNOSED IN 1897 AN BENIGN; LATER, ON MICROSCOPJC STUDY, AS ADENOCARCINOMA. PATH This is an example of solid adenoma which must be distinguished from duct cancer. 147

46 148 JOSEPH COLT BLOODGOOD The microscopic pictures shown in Figs. 33 and 34, we were not familiar with in 1897, when no one had had much experience with chronic cystic mastitis and everyone was influenced by the papers,of RBclus and Schimmelbusch and regarded areas such as that shown in Fig. 33 as adenocarcinoma. We now know that areas \ similar to or identical with those shown in Figs. 33 and 34 are never associated with metastasis to the axilla or death from cancer. FIG. 35. SECTION FROM CASE SHOWN IN FIGS. 33 AND 34. PATH The majority of pathologists diagnosed this as benign. Observe dilated duct filled wit,h proliferating cells, destruction of basement membrane beneath proliferating cells of duct, and marked lymphoid-cell granulation tissue about the duct. Such areas are quite frequently found in the zone of breast surrounding the blue-domed cyst and have probably been cut through with the knife when this zone was removed and the breast saved. I have never observed a recurrent cancer in such a breast. In the Archives of Surgerg for November 1921 (Fig. 59, page 502) is shown a microscopic section from the wall of a blue-domed cyst which resembles Fig. 33. The patient from whom this bluedomed cyst was removed, in 1920, has had no recurrence to date, eleven years since operation.

47 BORDER-LINE BREAST TUMORS 149 In Fig. 33 we see chiefly large solid duct adenomata. In Fig. 34 the adenomatous areas are smaller and seem to have some relation to a large duct; there are a few cysts, a few small papillary cystadenomata, and lymphoid-cell infiltration in the stroma. In Fig. 35, from another part of the tumor shown in Figs. 33 and 34, we see a dilated duct and periductal mastitis; in the duct proliferating and degenerating cells are seen; above the duct, cystic This is a gross non-encapsulated cystic adenoma not unlike that in Fig. 21. The glands were not involved. The majority of pathologists are still suspicious of malignancy here. The minority diagnosed this section as benign-chronic mastitis in cystic adenoma. adenoma. The majority of pathologists in 1915 considered Fig. 33 as indicating malignancy. They reversed their decision in Figure 36 (Path. 2145) is taken from a specimen sent to the laboratory in The complete operation for cancer had been performed. The patient was well in 1930, thirty-two years later. The figure represents the area most suspicious of malignancy in the left breast, which was removed. When this section and the history were presented to the pathologists in 1915, the diagnoses were about evenly divided between benign and malignant. The

48 150 JOSEPH COLT BLOODGOOD stellate masses of cells in the fibrous stroma are the areas which aroused suspicion. These consist largely in a lymphoid-cell reaction around remains of ducts or acini. The picture is a common one in chronic interstitial mastitis, which may be found in any breast at autopsy or operation, whether the breast is the seat of cancer or not. In spite of its common occurrence, this condition always creates a dilemma when observed in a piece excised for diagnosis at operation, or in a breast tumor, encapsulated or not, which is otherwise benign. Pathologists responsible for diagnosis in the operating room, and also for permanent sections in the laboratory, must attempt to gain experience in the microscopic appearance of tissue outside the diseased area, both during operation and postoperatively. This was forcefully illustrated recently during an operation upon a sinus in the chin leading to a piece of dead bone. There was nothing about the sinus itself to suggest malignancy. It had remiined after an operation four years before for a recent basal-cell cancer. First a small sequestrum was removed, then a zone of skin, and then granulation tissue. It would be difficult to imagine basal cancer cells remaining dormant for a period of four years after operation, during which there had been no irradiation. Yet most of the students in the pathological group studying the frozen sections interpreted stellate areas of lymphoid-cell granulation tissue in scar tissue, similar to the areas shown in Fig. 36, as basal-cell cancer areas. Some of these students had had from one to five years' experience in interpreting sections. The more experienced members of the pathological group agreed that this was scar tissue. The case shown in Fig. 36 (Path. 2145) has been selected to illustrate why Schimmelbusch and RBclus before 1900, and the present writer in 1906, concluded that chronic cystic mastitis, especially of the Schimmelbusch and RBclus type, might be a precancerous lesion. These conclusions were incorrect, inasmuch as they were based upon diagnosing areas in chronic cystic mastitis as cancer. Later studies have convinced a minority of students that the areas formerly called cancer are not cancer, but simply variants in the microscopic pictures of an epithelial activity in the breast of a non-pregnant or non-lactating female which may be observed at almost any age. As our experience accumulates, as more conservative operations are performed and more cases followed, the end-results confirm the very rare association of

49 BORDER-LINE BREAST TUMORS 151 cancer with chronic cystic mastitis, at least of the type that brings the patients under observation with pain, tumor, discharge from the nipple, or even retraction of the nipple, usually of the intermittent type. The lump may be single or multiple. When it is multiple both breasts are usually involved. In the case illustrated in Fig. 36 (Path. 2145) the operator performed the complete operation for cancer on the left breast more.than thirty-three years ago. The report received in the laboratory described a tumor in the upper and outer quadrant of the breast, clinically benign. This tumor was a small nonencapsulated area, in which there were numerous cysts from 1 to 2 cm. in diameter, not unlike that shown in Fig. 21. The cysts were buried in a dense fibrous stroma, and contained a brownish fluid. Microscopic sections showed every type of chronic cystic mastitis. Figure 36 represents the most malignant area. Of nine pathologists to whom it was submitted, only one diagnosed adenocarcinoma. I looked upon it then, in 1898, as a localized area of senile parenchymatous hypertrophy, a term I used in my publication in Eight months later a lump was removed from the remaining right breast. We do not know its pathology. In 1906 the hospital from which this specimen had been sent eight yeare before referred to the laboratory nodules from the skin above the left clavicle which had been diagnosed as skin metastases. The original diagnosis recorded in that hospital was cancer of the left breast. These nodules proved to be fibromas. It must be remembered that the glands in the axilla at the time of the first operation had shown no metastasis. Fortunately we have been able to follow this case ever since. No further skin nodules have appeared, and there has been no trouble with the right breast in the thirty-three years since the operation. In the long pathological report, containing the original descriptions of this case and the remarks of associates in the laboratory through all these years, it is found that many of the pathologists voting the section benign advised removal of the breast. I wrote about this case in 1898 as follows: "I believe it would be difficult to distinguish it (the tumor) from cancer and a complete. operation would be the wisest procedure." Dr. Sydney Cone of Baltimore, then associated with me in the laboratory, recorded

50 152 JOSEPH COLT BLOODOOOD the same conclusion. The chances are that the same condition was present in the right breast, which was only locally removed. The operator, therefore, who took no risk with the left breast did so with the right. Figures 37 and 38 (Path ) are from a case observed in The tumor was excised and twenty-four hours later, on the microscopic diagnosis of cancer, the oomplete operation was performed. The axillary glands showed no metastasis, and the The complete operation was done. The glands were not involved. Nineteen years later the patient was free from recurrence. The majority of pathologists today diagnose this as benign cystic adenoma, with areas of papillary oystadenoma at X. See Fig. 38. patient was well in 1930, nineteen years later. This lump was brought to me by the operator himself within twelve hours after the operation. I referred the section to Dr. Welch and we both gave the opinion that it was suspicious of cancer in an area of senile parenchymatous hypertrophy and advised the complete operation. However, when we study the sections to-day (Figs. 37 and 38), with the added experience of nineteen years, we find no microscopic evidence of malignancy. I have the vote of the

51 BORDER-LINE BREAST TUMORS 153 pathologists in 1915 before me. Eight recorded carcinoma and advised complete operation. None voted benign. In 1930, at the microscopic demonstrations, when the lantern slide was projected, the majority voted benign. Figure 37 is from the most suspicious area. The area at X was interpreted as adenocarcinoma, the earliest stage in senile parenchymatous hypertrophy. We now know that such areas are very common in the breast, and we have no proof that they bear FIG. 38. SECTION FROM CASE SHOWN IN FIG. 37. PATH In upper right corner note the cyst lined by a single layer of columnar epithelium; then zones of irregular adenoma, some slightly cystic; lower left, solid adenoma in dilated duct. The majority of pathologists to-day diagnose this as benign. any more relation to cancer than any other epithelial element in the parenchyma. Ewing views them as sweat gland inclusions. Figure 38, from the same breast, was diagnosed in 1915 as benign by the majority of pathologists. We see the wall of an epithelium-lined cyst, then a zone of solid small adenoma, then a large solid adenoma. This is a very common microscopic picture in the wall of a blue-domed cyst, as is Fig. 37. The patient in this case (Figs. 37 and 38) was twenty-seven years old and had observed a small tumor in the mid-zone of the

52 154 JOSEPH COLT BLOODGOOD lower outer quadrant for ten days. She was married, but had had no pregnancies. There were no other signs or symptoms present except the tumor. We have no notes on the gross pathology, except that the tumor was non-encapsulated and could not be enucleated. Frozen sections made at that time were looked upon as suspicious of malignancy, but the husband of the patient, a surgeon, would not permit the complete operation without consultation and verification. Later we received pieces of the breast and glands from the second operation. The glands were negative for cancer; there was evidence, as one would expect, of chronic cystic mastitis in the breast: chiefly adenomatous areas, but a few adenocystic areas just as suspicious of cancer as the one illustrated in Fig. 37. This was in Many of us at that time were beginning to feel that if there was a large blue-domed cyst in the breast, there was very little danger of cancer. But when the lesion, either a single non-encapsulated area or a diffuse area, resembled the Schimmelbusch or RBclus type, which I had described in 1906 as senile parenchymatous hypertrophy, the possibility of cancer was considered greater, and for a number of years after 1911 there were very few surgeons or pathologists who, although willing to restrict the operation for the blue-domed cyst, were willing to do this for the other types of chronic cystic mastitis. In 1921 I could report 210 cases of the blue-domed cyst type and 140 cases of other types. Of these 140, only 31 were gross and microscopically of the Schimmelbusch or RBclus type; 22 cases belonged to the readily recognized picture of diffuse dilatation of the ducts beneath the nipple; 87 cases should have been recognized clinically as lumpy breasts and not subjected to operation. In about onefourth, or 20 cases, there were clinically single definite tumors, and at operation non-encapsulated areas composed chiefly of adenomatous hypertrophy, with and without cystic areas, that is, areas that should be recognized, at least in the frozen section, as benign. Figures 39 and 40 (Path ) are sections from a clinically benign non-encapsulated tumor which was removed in After careful microscopic study I advised the complete operation for cancer, which was done three months later. The glands were not involved. This patient remained free from any signs of recurrence to 1927, sixteen years after operation. To-day, if frozen sections from a breast tumor resemble Figs. 39 and 40, we know that it would be safe to save the breast.

53 BORDER-LINE BREAST TUMORS 155 This patient was a young woman, aged twenty-six and unmarried. She had had pain and a lump in the breast for two months. The tumor felt circumscribed, but at operation it was found to be diffuse. In it the operator found a few cysts. The specimen, received by us in alcohol, consisted of firm white breast tissue surrounded by fat. In the breast tissue we could recognize a few cysts. Grossly it did not impress me as cancer, but resembled the breast of a young girl at puberty. At a period, Fro. 39. SECTION FROM A CLINICALLY BENIGN NON-ENCAPSULATED TUMO REMOVED FROM THE BREAST OF A WOMAN AGED TWENTY-SIX. PATH The section shown here was diagnosed in 1911 as malignant or suspicious of malignancy; the complete operation was performed; the glands were not involved. There was no recurrence after sixteen years. For high-power photomicrograph,see Fig. 40. however, when the majority of the students of diseases of the breast agreed with Schimmelbusch and Rhclus, my conclusion was that the picture suggested the beginning of carcinoma in Schimmelbusch's disease. Three months later, when I performed the complete operation, I found in the remaining breast tissue the same gross and microscopic appearance as in the zone first removed. There is no note on the other breast until I examined the patient many years later, when it was normal. I am quite confident

54 156 JOSEPH COLT BLOODGOOD that to-day we would have recognized, clinically, a bilateral lesion, and probably no operation would have been performed. We now know that twenty-six is not too young for any type of chronic cystic mastitis. One of the cases reported in my article in the Archives oj Surgery for November 1921 (Fig. 55, page 498) was an example of diffuse chronic cystic mastitis at the age of twenty-three. The majority of pathologists in 1915 diagnosed this as malignant adenoma; in 1930 the majority diagnosed it as benign. Such areas of irregular solid adenoma are frequently seen in the walls of blue-domed cysts, in all types of chronic cystic mastitis, in fibroadenoma, and in traumatic mastitis. This patient had operations on both breasts. It is now more than fifteen years since operation, and the breasts are normal. I have before me the votes of eleven pathologists who examined the section shown in Fig. 39 and 40 in Dr. McCallumls laboratory in New York in Five voted malignant and advised the complete operation; six voted benign, but advised the removal of the breast. In the case illustrated in Figs. 41 and 42 (Path ) Dr. Rogers of Jacksonville, Florida, removed the breast in February

55 BORDER-LINE BREAST TUMORS His clinical and gross diagnosis was benign. When I wrote him that Dr. Welch agreed with me that the sections were sufficiently suspicious to justify the diagnosis of malignancy and the complete removal of the scar, muscles, and axilla, he answered that he would give the patient this advice and would perform the complete operation if she desired it, but he would not change his diagnosis. A month later the tissue removed at the second FIG. 41. SECTION OF NON-ENCAPSULATED CYSTIC ADENOMA DIAGNOSED AS BENIGN IN PATH The complete operation was done. The glands were not involved. The patient is free from recurrence nineteen years later. For high-power photomicrograph see Fig. 42. operation was sent to us. The glands showed no metastasis. This patient is well in 1931, nineteen years later. She is forty-nine years old, and a few years ago observed a disappearing tumor in the remaining breast. The high and low-power photomicrographs (Figs. 41 and 42) illustrate two points on which RBclus and Schimmelbusch based their diagnosis of malignancy-the heaping up of the proliferating epithelial cells, the change in morphology, and the partial, or in places complete, disappearance of the basement membrane. This is histological cancer. We observe it in the parenchyma in 11

56 158 JOSEPH COLT BLOODGOOD tuberculous and lactation mastitis, in old encapsulated adenomas with increased fibrous stroma and often calcification. I have a section like it from a typically encapsulated tumor of the breast in which only the tumor was removed (see Fig. 20). In Figs. 41 and 42 we might conclude that we have an area of unresolved lactation. Perhaps we have! The patient was thirty years old; the tumor of two months' duration having been first observed two months after lactation. The majority of pathologists still diagnose this as malignant. Such areas have been observed in benign encapsulated adenoma, in the walls of blue-domed cysts, and in resolving chronic lactation mastitis. In the tumor first sent to us papillary-adenocystic areas (Figs. 41 and 42) predominated. In other areas every stage of the Schimmelbusch type of disease was present. My notes made then about the suspicious areas read as follows: "The basal membrane has disappeared in many lobules, and the epithelial cells begin to infiltrate the stroma. About these lobules there is more lymphoidcell infiltration. Perhaps the lymphoid-cell granulation tissue was responsible for the destruction of the basement membrane, and

57 BORDER-LINE BREAST TUMORS 159 not the epithelial cell." In the remaining breast there was no evidence of residual lactation hypertrophy, nor were there any areas resembling the malignant areas of the first piece of tissue removed. This patient has been pregnant on two occasions since, and normal lactation has occurred in the remaining breast. The patient whose case is illustrated in Fig. 20 was only eighteen, and there was no history of lactation or pregnancy. Sections like those shown in Figs. 20, 41, and 42 are unusual The tumor only was removed, but following study of this section and the one in Fig. 44 the complete operation for cancer was done. This was in The glands were not involved. The patient was followed four years without recurrence. The majority of pathologists to-day diagnose this as benign papillary cystadenoma. in benign tumors of any type and are not found in malignant tumors. We found them incidentally in, the wall of a blue-domed cyst (Archives of Surgery 3: 516, 1921) after excision of the cyst in 1910, the patient being free from trouble twenty years later in We may find a similar picture in diffuse Schimmelbusch's disease (see Fig. 76, p. 519, Archives of Surgery, November 1921), and it has been found in another non-encapsulated cystic adenoma (see Fig. 77, page 520, Archives of Surgery, November 1921).

58 160 JOSEPH COLT BLOODGOOD We cannot explain why these areas are not malignant. It seems justifiable, however, to confine the operation to the removal of the tumor when such areas are found in the frozen section. The one found in the wall of the blue-domed cyst, referred to above, was not observed until some weeks after operation in the routine sections. The complete operation was not done, nor the breast removed. In the other cases the diagnosis of adenocarcinoma was made and ultimately the complete operation was performed. FI~. 44. SECTION FROM CASE SHOWN IN FI~. 43. PATH The majority of pathologists to-day are suspicious of the very cellular area in the lower half of the picture. The sections shown in Figs. 43 and 44 (Path ) were taken from a breast removed by Dr. Ramey of El Paso, Texas, in May On my advice he did the complete operation with skin grafting about two weeks later. He was able to follow the patient four years, during which time there were no signs of recurrence. The axillary glands were not involved. Grossly minute cysts were seen in the breast tissue. In one portion of the tissue from which the sections shown in the photomicrographs were taken, there was a non-encapsulated area which had all the appearance of cancer, as illustrated in Fig. 28. This patient was

59 BORDER-LINE BREAST TUMORS 161 forty-eight years of age and had no children. Pain and tumor had been present in the breast for six months. The tumor was the size of a twenty-five-cent piece and clinically benign. After removing the breast, Dr. Ramey bisected the area of the tumor and thought, as we did, that it was malignant. Figure 43 shows a distinctly benign condition, of the papillary-cystadenomatous type; it was the solid area of cells in the wall of a small cyst shown in Fig. 44 that led to an interpretation of malignancy. We are FIG. 45. SECTION OF TUMOREMOVED FROM LEFT BREAST OF PATIENT WITH NODULES IN BOTH BREASTS. PATH This was diagnosed as benign in There was no recurrence after removal of the tumor only. See Figs. 46 and 47 for sections of tumor in right breast. Case of Dr. Francis Carter Wood. beginning to be quite familiar with areas such as that shown in Fig. 44 as benign. Similar areas are pictured in my article in the Archives of Surgery. The photomicrographs shown in Figs. 45, 46, and 47 (Path. 1409) are from sections sent to me by Dr. Francis Carter Wood from St. Luke's Hospital in New York, in April 1913, seventeen years ago. Figures 46 and 47 are from a nodule removed from the right breast, after which the breast, but not the axilla, was

60 162 JOSEPH COLT BLOODGOOD excised. The section shown in Fig. 45 is from a nodule removed from the left breast and is distinctly microscopically benign. The operator was Dr. Walton Martin. Dr. Wood always held to his opinion that the condition was benign. He wrote: '(I feel that the tumor is still within the non-malignant limits, and that only a very slight local operation is required to make the patient perfectly safe." Apparently I was not so certain. I wrote to him as follows: "We are dealing here either with multiple cystic FIG. 46. TUMOREMOVED FROM RIQHT BREAST OF PATIENT SHOWN IN FIG. 45. PATH This was diagnosed as benign in 1913 and the breast only was removed. The majority of pathologists diagnose this picture even to-day as suspicious of cancer. See Fig. 47. adenoma or bilateral senile parenchymatous hypertrophy. For practical purposes it does not make any difference. Both have the same tendency to become malignant. I believe that the removal of the breast (right) was justified in this case, and I am inclined to the opinion that if this woman is over thirty the opposite breast should be excised." I was informed in 1930 by Dr. Wood that this left breast, which was not removed, had given no further trouble.

61 BORDER-LINE BREAST TUMORS 163 Figure 47 is from the specimen removed from the right breast at the first operation; Fig. 46 from the remaining right breast at the second operation; Fig. 45 from the left breast, which was not completely removed. The right breast showed diffuse evidences of chronic cystic mastitis. It is interesting to note that in 1913 Dr. Wood had no suspicion of the area pictured in Fig. 47. The majority of pathologists to whom the section shown in Fig. 47 has been submitted for diagnosis have expressed the opinion that FIG. 47. HIGH-POWER PHOTOMICROGRAPH OF AREA SHOWN IN FIG. 46. PATH This was diagnosed by Dr. Francis Carter Wood as "still within the non-malignant limits." The majority of pathologists are still of the opinion that this is histological cancer. The patient is well seventeen years after removal of breast only. it was malignant. Since this time I have found such areas in old, very fibrous adenomas with and without calcification. Figure 45 is typical of benign Schimmelbusch's disease, showing cystic and papillary-cystic areas with no change in the basement membrane. In Fig. 46 we have largely solid adenomatous areas, a few papillarycystadenomatous areas, and some small epithelium-lined cysts. Many pathologists would be suspicious of this section. Figure 47 must be looked upon as histologically cancer-the

62 164 JOSEPH COLT BLOODGOOD basement membrane is gone, and the cells are morphologically similar to cancer cells. The question is: how are we to distinguish such areas from cancer? It is areas such as this and that shown in Fig. 46 that influenced Schimmelbusch, RBclus, myself, and others, to the conclusion that there was a larger per cent of cancer in Schimmelbusch's disease than in the normal breast and other types of chronic cystic mastitis, but none of us at that time- Only the breast was removed. See Fig. 49. The patient has had no trouble after twelve years. nor since-has seen any cases with metastasis to the glands, recurrence, or death from metastasis to prove this point. A photomicrograph (Fig. 48) and sections (Path ) were sent to me by Dr. Haythorn of Pittsburgh, with the following note: In 1915 Dr. Gaub of Pittsburgh palpated what he called an acute nodular condition of the breast. One nodule was removed with a diagnosis of benign chronic cystic mastitis. In 1918, three years later, because of the recurrence of symptoms, the breast was removed. Dr. Haythorn was suspicious of cancer in the area

63 BORDER-LINE BREAST TUMORS 165 shown in Fig. 48. Figure 49 represents the predominant type and the most suspicious areas in the seven slides referred to me. At that time my conclusions were that the lesion was benign. There was no evidence of malignancy in the chronic cystic mastitis. There is no note on the remaining breast, and there is no history, but up to 1930 the patient had remained well, a period of fifteen years since the first operation and twelve years since the second. FIG. 49. PHOTOMICROQRAPH OF SECTION SHOWN IN Fra. 48. PATH The majority of pathologists diagnosed this as benign. Sections like those shown in Figs. 48 and 49 do not indicate even the removal of the breast. Fig. 49 shows an area of irregular solid adenoma. Fig. 48 has, in addition, cysts. Figures 50, 51, and 52 (Path ) are from a case in which the patient is free from all signs of recurrence ten years after the complete operation for a tumor of the right breast, but is suffering considerably from lymphedema. I am of the opinion that had the frozen section been properly interpreted at the operation in 1921, this patient would now have two breasts and no lymphedema. Figure 50 is a photograph of the entire section and corresponds with the frozen section taken at the time of the operation. In the upper periphery normal breast lobules may be observed. Below

64 166 JOSEPH COLT BLOODGOOD this is a zone of small and large cysts and small and large papillary cystadenomatous areas. Figure 51 is a medium-power photomicrograph of some areas of mastitis, epithelium-lined cysts, and a few papillary cystadenomas, while Fig. 52 is a clear picture of a small intracystic papilloma. It was this latter area that influenced the pathologist at the operation in 1921 to advise the complete operation for cancer. The glands were not involved. FIG. 50. PHOTOMICROGRAPH OF ENTIRE SECTION OF A CLINICALLY BENIGN TUMOR REMOVED IN 1921 AND DIAGNOSED CANCER FROM THE ~ECTIONS SHOWN IN FI AND 52. PATH Complete operation was performed. The glands were not involved. There had been no recurrence ten years after operation. This low-power photomicrograph shows numerous cysts, numerous intracystic papillomas, irregular adenomtttous areas--chronic mastitis. There was no indication for removal of more than the tumor. I saw this patient when she was but twenty-three years old, in 1913, and removed a non-encapsulated tumor from the right breast. I have previously reported her case in the Archives qf Surgery (3: 495, 1921). Figure 14 in that report pictures the gross non-encapsulated area of breast the seat of adenomatous puberty hypertrophy. Figure 32 in the same article pictures the microscopic appearance. Later this patient married and bore two children, with both of whom lactation was normal. Nineteen years

65 BORDER-LINE BREAST TUMORS 167 later a second tumor was felt in the same breast (right), but not near the scar. A complete operation was performed (Fig. 50). Dr. Charles F. Geschickter is now making a restudy of benign and malignant intracystic papillomatous tumors of the breast. Complete cancer operations for benign tumors have been far too many. The tumor is often mistaken for cancer from its gross appearance or the microscopic section. There should be no difficulty, except in very rare instances, in making the differential diagnosis from the frozen section. Multiple intracystic papillomas in the breast, when they can be differentiated microscopically from cancer, should not be considered an indication for removal of the breast, especially in younger women. The danger of malignancy in a papillomatous cyst has been exaggerated, and, as will be shown by Dr. Geschickter, when cancer has occurred, it has quite frequently not originated in the preexisting papillomatous cyst, but has been of independent origin. When the cyst is filled by the papilloma and the cyst wall is very thin, differentiation between the benign and the malignant is often difficult.

66 168 JOSEPH COLT BLOODGOOD In Fig. 53 (Path ) a small tumor is shown with a very thin capsule buried in fat. Its fresh appearance suggested a colloid cancer. As shown by the photograph, the complete operation was performed in this case. The photomicrographs shown in Figs. 54, 55, and 56 correspond to frozen sections made at the time of operation. When I looked at the frozen sections I FIG. 52. HIGHER-POWER PHOTOMICROGRAPH FROM AREA SHOWN IN FIG. 50: TYPICAL BENIGN INTRACYST~C PAPILLOMA, OR PAPILLARY CYSTADENOMA. PATH Such pictures are too frequently diagnosed malignant or ~uspicious of malignancy. Many breasts are unnecessarily sacrificed for this lesion. felt that we were dealing with a papilloma of benign type filling a cyst. This is best shown in Fig. 54-observe the arrangement along the cyst wall-but when one looks at further sections (Figs. 55 and 56) there is a suggestion of malignancy, in that in places the basement membrane is not clear, though the morphology of the cell nests is that of benign tumor or grade I cancer. There is no evidence grossly or in the frozen section of any infiltration of cells outside the cyst wall. However, if these were cancer cells, metastasis would be possible.

67 BORDER-LINE BREAST TUMORS 169 This patient was seventy-two years old. The tumor, the size of a ten-cent piece, had been present a few weeks. It felt like a cyst and appeared like a cyst on transillumination. However, I have observed a small colloid cancer which on palpation and transillumination was exactly like a benign blue-domed cyst. Operation was performed under rectal avertin anesthesia. As the FIG. 53. T. TUMOR AND ZONE OF FATTY TISSUE FIRST REMOVED AFTER FROZEN-SECTION DIAGNO~I~; B. BREAST AND TISSUE REMOVED AFTER REMOVAL OF TUMOR AND ZONE OF FATTY TISSUE. PATH For details of this case see text. See also Figs breast was small, the patient thin and in good condition, it took but a moment's additional time to remove the breast, as shown in Fig. 53. The glands showed no metastasis. The wound was closed without grafting, and recovery was uncomplicated. Had I operated under local anesthesia, I am inclined to the opinion that, after a careful microscopic study of the frozen sections, I would have confined the operation to the removal of the tumor and a

68 170 JOSEPH COLT BLOODGOOD small zone of fat. With avertin, however, the anesthetic period could not be shortened and the'patient, therefore, ran the same risk whether the operation were short or long. When we look over the records of similar cases, we find that the complete operation has been the rule. In 1907, twenty-four years ago, Dr. Halsted explored a small tumor of two months' duration in the breast of a woman aged forty-four. Clinically, Note the fibrous cyst wall and fat beyond and absence of breast parenchyma; the heaped-up epithelium lining the cyst; the fine communications between the cyst wall and the intracystic tumor composed of stems of connective tissue containing vessels and covered with low-type benign columnar epithelium. See also Figs. 55 and 56. there were no signs of cancer, but after dividing the tumor, Dr. Halsted rendered a diagnosis of colloid cancer and performed the complete operation. This patient is well and free from recurrence in Dr. Porter described the tumor in this case as circumscribed, granular, with many minute cysts, and drops of fluid. He was unable to decide between non-encapsulated cystic adenoma and early cancer. The breast contained a number of minute cysts and dilated ducts. I described the section as typical of

69 BORDER-LINE BREAST TUMORS 171 Schimmelbusch's disease, that is, a non-encapsulated area of chronic cystic mastitis of papillary cystadenomatous type. The glands showed no metastasis. There was no microscopic evidence of colloid material. The tumor grossly and in the microscopic sections did not have the distinct capsule of an intracystic papilloma as shown in Figs. 53 and 54. As we go over the breast material again in 1929, 1930, and This illustrates the relation between the intracystic tumor and the cyst wall. first frozen section there was an appearance of colloid material. See text. In the 1931, as we did in 1915 and in 1921, we find an increasing number of border-line tumors. As frozen sections are being employed more and more in the operating room, the figures suggest that there are even more complete operations for cancer than when the surgeon depended upon gross diagnosis only. Formerly, however, operation was done in two stages. The surgeon considered the exposed area from the gross appearances to be benign, and either removed only the tumor or the breast, according to his individual practice. Later the pathologist reported the tumor

70 172 JOSEPH COLT BLOODGOOD malignant or suspicious of malignancy, and the complete operation was performed. To-day, when frozen sections are the rule in the operating room, the great majority of patients are protected from an incomplete operation when cancer is actually present. The problem now is to protect the women who have been educated to report to their physicians the moment anything unusual is observed in the breast against unnecessary loss of the breast, while at the FIG. 56. HIGH-POWER PHOTOMICROQRAPH FROM AREA SHOWN IN FIG. 54, TO ILLUSTRATE THE BENIGN MORPHOLOGY OF THE PROLIFERAT~NG EPITHELIAL CELLB AND THEIR RELATION TO THE STROMA. PATH. 442'36 The majority of pathologists even to-day are suspicious of malignancy in areas resembling this and too many breasts are sacrificed on the diagnosis of adenocarcinoma. In this case the complete operation was unnecessary (see Fig. 53). same time not increasing the risk of women with early malignant tumors. Through all the years, from 1889 until to-day, there have always been a certain number of border-line tumors which for one reason or another have been treated by the removal of the tumor only or the breast only, so that we have been able to compare over periods of from five to thirty-nine years the results of the three types of operation-removal of the tumor only,

71 BORDER-LINE BREAST TUMORS 173 removal of the breast only, and the complete operation for cancer. The glands, of course, have never been microscopically involved in these cases. The ultimate results, have been identical, that is, the absence of an increased frequency of cancer in the remaining breast. This is even more suggestive to-day than ever before. If one hundred cases of cancer are followed five years or more, in at least ten the other breast becomes the seat of cancer, while in the This was diagnosed by the pathologist as cancer seven and one-half years ago. A second pathologist diagnosed it as benign. No operation was done beyond removal of the tumor, and there has been no recurrence. The majority of pathologists diagnose this as benign encapsulated cystic adenoma. same number of women with benign or border-line tumors the risk of cancer in the other breast is practically the same as that which every woman runs of having breast cancer-less than 2 per cent. In 1923, seven and one-half years ago, an experienced surgeon and former student of mine sent me a piece of a breast tumor (Path ) which he had persuaded himself to remove in his office, because it was small and clinically benign. After removal of

72 174 JOSEPH COLT BLOODGOOD the tumor, its gross appearance made him fear cancer, and his pathologist diagnosed the tumor as cancer. From the study of the sections shown in Figs. 57 and 58, we interpret)ed the pictures as benign and called it a non-encapsulated cystic adenoma, and no further operation was performed. This patient reported in August of 1930 that she was well. We also thought that we could detect some areas of residual lactation in the sections. The age of the patient was thirty-three. The tumor had been felt two years before, when her youngest child was three years old, and had varied in size-suggesting benignancy. It was smaller than a twenty-five cent piece, and freely movable. Readers of this article who are specially interested in the microscopic diagnosis of breast tumors are urged to study and re-study the photomicrographs illustrating my article appearing ten years ago in the Archives of Surgery (3: 445, 1921). Every case there reported and illustrated has been followed, and in not a single in-

73 BORDER-LINE BREAST TUMORS 175 stance has it been necessary to revise the diagnosis, nor has a single case diagnosed as benign developed any evidence of malignancy in relation to the breast. Many of these cases, in 1915, were diagnosed carcinoma, of the adenocarcinoma type, without metastasis to the glands. The removal of these cases from the group of cancer of the breast without axillary metastasis decreased the fiveyear cures from more than 85 per cent to less than 70 per cent. Even to-day many surgical pathologists do not agree with our position that the peculiar pictures to be found among the illustrations in the Archives of Surgery, and many reproduced here, are benign. Cheatle and Cutler, for example, in their recent book on Tumors of the Breast2 (p. 106) reproduce the illustration of diffuse chronic cystic mastitis of the non-encapsulated cystadenomatous type, appearing as Fig. 22 (p. 134) of this article. Their legend, however, speaks of a breast containing multiple cysts with "carcinoma in the area at C." As a matter of fact, as stated above, this is in my opinion the best illustration of the gross appearance of a breast the seat of a disease first known as RBclus' or Schimmelbusch's disease, and since known under many titles, the latest being Sir Lenthal Cheatle's "cystiphorous desquamative epithelial hyperplasia." My own choice, in brief Anglo-Saxon, is '(shotty breast." The most prominent microscopic feature of t,his remarkable hyperplasia of the breast is the presence of minute intracystic papillomas. In 1906 my studies, because of mistaken microscopic diagnosis, were in agreement with Schimmelbusch and RBclus, that this form of chronic cystic mastitis showed evidence of potential cancer, and that the proper procedure was the removal of both breasts. Further experience reversed that view. In the past ten years we have records of 30 new operative cases and almost 200 examples of clinically shotty breasts that have not been subjected to operation, but to a yearly follow-up and examination. We have no evidence that the breast the seat of chronic cystic mastitis is more likely to develop cancer than any other breast. In spite of all our studies, there is no definite indication of any cause to explain the occurrence of cancer of the breast, except that its incidence is greater in the female than in the Published in London by Edward Arnold & Co.; in the United States and Canada by J. B. Lippincott Co., Chapter VII, devoted to chronic cystic mastitis, presents in the most forcible manner the views of Schimmelbusch and RBclus and those who regard this epithelial activity of the breast as a precancerous lesion and who advise at least the removal of one or both breasts.

74 176 JOSEPH COLT BLOODGOOD male, that it is rarely seen between twenty-five and thirty, and that, with few exceptions, it begins in one breast in a single area. The breast may be the seat of lactation either during or after pregnancy, or it may show changes which may be present in any breast in which cancer never develops. Repeated studies have failed to reveal any evidence, clinical, gross, or microscopic, which justifies the removal of one or both breasts not the seat of cancer, to protect the patient from possible future cancer. As more women present themselves to physicians and surgeons and at diagnostic clinics, either because of symptoms referred to the breast, or for annual or semi-annual physical examination, the incidence of a definite tumor will recede from more than 99 per cent to less than 20. To differentiate the larger number for which operation is not indicated is a new and difficult problem for the medical profession. The physical examination of the breast should be as precise and thorough as that now developed for the chest. The essential features are inspection, palpation, and transillumination, combined with the proper interpretation of ages under twenty-five and such signs as irritation and discharge from the nipple, retraction of the nipple, swelling of the arm, palpable glands in the axilla, shotty breast, lumpy breast, worm-like tumors beneath one or both nipples, pain tenderness, and unilateral or bilateral hypertrophy. When exploration of a zone of breast is indicated, the diagnosis rests in the majority of instances upon the frozen section made and studied during operation, or upon a permanent section when the operator is of the opinion that it is justifiable, after the removal of the specimen, to wait for further microscopic study before deciding as to malignancy or suspicious malignancy and the necessity of a more complete operation.