VARYING DEGREES OF MALIGNANCY IN CANCER OF THE BREAST ROBERT 13. GREENOUGH BOSTON Differences in the degree of malignancy of malignant tumors have been recognized by pathologists for many years. Indeed, Virchow’s original conception of a malignant tumor was one composed of cells, derived from the tissue cells of the individual, but differing from the normal cells in the rapidity and independ- ence of their growth. Hansemann (1) carried this idea somewhat further and intro- duced the word “anaplasia” to indicate the process by which cancer cells came to differ from the normal type cell of the body tissue concerned. Anaplasia involves a loss of differentiation and an increase of reproductive power, so that the anaplastic cell fulfils only in abortive fashion, if at all, its normal function, such as secretion or keratinization; while it shows by increased number of mitotic figures, and especially by the irregularity and abnormality of its nuclear chromatic elements and figures, the increase in rapidity of cell division and of cell growth which is characteristic of malignancy. X number of attempts have been made to grade the malig- nancy of different breast tumors by distinguishing their histo- logical characteristics, such as adenocarcinoma, medullary, scirrhus, colloid, etc. ; but with the exception of adenocarcinoma and colloid, these divisions have proved of little value in prognosis. There the matter rested till 1921, when, under the influence of MacCarty (2) of the Mayo Clinic, Broders published a paper suggesting the classification of cancer tissue according to the degree of malignancy, as estimated by loss of differentiation and increase of reproductive characteristics. Broders (3) studied a large series of cases of cancer of the lip, 453 454 ROBERT B. GREENOUGH classified the malignancy of the tumors in accordance with MacCarty's suggestions and checked the clinical results against this classification. The results aniply justified the principle of classification, and further studies of cancer of other situations have been made, notably cancer of the skin (Broders) (3), cancer of the cervix (Martzloff) (4), and cancer of the fundus of the uterus (Mahle) (5). During the past year I have been interested in studying the material of a series of cases of cancer of the breast at the Massa- chusetts General Hospital during the years 1918, 1919, and 1920. This material was collected by Dr. W. H. Davis of Boston as part of a collective investigation for the College of Surgeons, and I am indebted to him for his help on the records, and to Dr. James Homer Wright and Ilr. C'hanning Simmons of Boston for their interest and assistance in the study of the pathological material, as well as to Dr. Ai.$2. Steele of Boston for the photo- micrographs. In November 1924 this series of cases of breast cancer was reported at the meeting of the Southern lCIedical Association in New Orleans, with a brief discussion of the value of pre-operative and post-operative X-ray treatment as they were then employed at the Massachusetts General Hospital. In the hope that a factor of importance in this discussion might be developed by a more detailed study of the pathological material, the micro- scopic specimens were collected and reviewed under their original pathological enumeration by Dr. Simmons and myself without knowledge of the clinical history and the results. Attention was especially directed to the retention or loss of the adenomatous arrangement of the tumor cells around an open space, to the evidences of secretory activity (vacuoles) in the cell proto- plasm, and to the nuclear changes, hyperchromatism, number of mitoses and especially irregular mitoses, and variations in size and form of the cell and nucleus (pleo-morphism). Four classes were distinguished, from low to high malignancy. The class number was then entered on the clinical records and the cards sorted with the following results : DEGREES OF MALIGNANCY IN CANCER OF THE BREAST 455 .~ I Pathology I I I Class 1. Milch Differentiation 6 c:1ses 1 cures 60 yo Class 2. Moderate I)ifferent,i:it,ion 19 " 9 ** 47 7'0 Class 3. Slight Differentiation 43 'I 10 23 c:h ()?7 Class 4.. Highly h1align:mt 22 'i 0 /C These figures appeared so well to justify the correctness of the assumption that the degree of malignancy could be determined by the histological appearances of the original tumor that a more detailed study of the material was made and is presented here- with. The disadvantage of recognizing four classes as compared with the relative simplicity of making only three groups was at once apparent, arid it was determined to review the material again and reclassify into three groups: high, medium, and low malignancy. This was done again by me without reference to the clinical history or to the first classification, and was repeated independently under the same conditions by Dr. James Homer Wright. We differed materially on seven cases, but after dis- cussion we were able to eliminate these differences and come to substantial agreement. The results were as follows: TAIILI~: 1 C'ln,s I-Lour JIalrgrturicy 19 c:ws-l3 ~iii(>s,A8 pcir (sent _____ - __ - A (hup (glanth riot iiivolvcd) 11 cases 9 cure5 82'i C Chup (glands involvrd) 8 fdSt'S 4 CIIres 1-50 c/'o TABLE 2 c'lwss '.'--Mecliuir~ Mnlignuttcy 33 rases-11 mires, X3 per cent ..-~ ~_______ A Group (glands not involved). , . 7 c:~scs 3 cures 43 (4, C Group (gl:trrds involved). , , , . 20 ciiscs S ciires 31 yo TAHLE 3 ('lass 3-High Mnligiiaiuy 21 cases4 cures, 0 per cent -_____~._____ 0 cures 0 Cllres 456 ROBERT B. GREENOUGH For the purpose of this study only 73 cases were taken, repre- senting all of the cases of cancer of the breast in the 1918-1919- 1920 series which were subjected to radical complete operation, of which we had a satisfactory microscopic slide from the original tumor and a knowledge of the end result. By radical complete operation we mean the removal in one piece of the breast, the skin over the breast, the pectoralis major and minor, the axillary contents, and the deep fascia from clavicle to epigastrium and from sternum to latissimus. It will be noted that in these tables the cases have been arbitrarily divided into two groups: (A) those in which the lymph nodes were proved by pathological examination to be free from disease (23 in number), and (C) those in which cancer was found in the axillary lymph nodes (50). The cases free from axillary involvement gave 12 cures, or 52 per cent, while those with axillary involvement gave 12 cures, or 24 per cent. This is the accepted method of estimating the extent of disease in cases of cancer of the breast, but it is admit- tedly inaccurate for the reason that tumors in the upper or inner hemisphere of the breast may extend through the lymphatics and involve the nodes above the clavicle or in the anterior mediastinurn before the axillary nodes are affected. It is prob- able also that metastasis by the blood stream occurs occasionally and produces metastases in the bones, the lungs, and other in- ternal organs before disease of the axilla can be recognized. The most striking facts presented by these three tables, how- ever, are (1) that nearly one third of these cases of breast cancer were of so malignant a character that not a single surgical cure of the disease was obtained; (2) that cases of such low degree of malignancy occur as to merit hope of cure in 68 per cent of all cases, and that in early favorable cases of this disease without axillary involvement as high a percentage of curability as 82 per cent may be expected; (3) that cases of medium degree of malignancy give a percentage of cures of only 33 per cent, and that in the early and favorable cases of this group the prospect of cure is not quite so good (43 per cent) as even the more ad- vanced cases of the lowest grade of malignancy. These facts are surely of importance if they can be confirmed. DEGREES OF MALIGNANCY IN CANCER OF THE BREAST 457 The pathological classification of these specimens, however, can hardly be reduced to rule of thumb, but rests upon the estimate of the individual observer and the weight he is inclined to give to a number of different factors. In the attempt to determine the relative importance of these different factors the specimens were further studied and a value (ABC)given to each of ten factors, as follows: The common histological characteristics of carcinoma of the breast are usually expressed by the pathologist as “medullary, ” ‘‘ scirrhous,” or ii adenocarcinoma.” It is generally admitted, however, that this classification is somewhat arbitrary, and that appearances of adenocarcinoma in one place and either scirrhous or medullary, or both, in neighboring areas, may often be found in the same specimen and make an exact classification quite impossible. X statement of the general features of each speci- men was attempted, however, under such terms as ac-leno- medullary, adeno-scirrhous, etc., because it was felt that the adenomatous arrangement of the cells indicated a degree of differentiation. T4HLE 4 =____- __~~II~__-~-_ ,$deKlO-t)’i)t’ 47 (‘ascs 17 ciiws 36 yo Medullary 1 44 CBseS I 14 cures 1 31% Hcrrrhons 1 51 cases 17 riires 33(/& The results, however, indicate that the differences are not sufficient to be of moment, or that other factors outweighed the adenonia factor in the end results. There were, however, 18 cases in which the adenomatous arrangement of the cells of the tumor was so pronounced as to warrant the use of the term adenocarcinoma (without qualification).