VARYING DEGREES of MALIGNANCY in CANCER of the BREAST Differences in the Degree of Malignancy of Malignant Tumors Have Been Reco

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 introduced 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 malignancy of different breast tumors by distinguishing their histological 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 microscopic 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 protoplasm, 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 discussion 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 probable 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, however, 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 specimen 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).

TABLE 5

‘4 dcnomatoirs A TT(ITL(IY~)IE~~

18 cxscs showctl marked &no. . . . . , . , , . . . , . , . . . . 8 cures 44y4 55 ciiws showed no ttdcno...... , . . , . , . . , . , . . . . .16 cures 2s yo In this case the relatively favorable significance of the ade- noma feature is more resdily‘recognized. 30 458 ROBERT B. GREENOUGH

- __ __- ~ ~ -~______8. Sinall x c:1scs 1riiim EN/, 13. Rledlulrl 28 (‘L1Ht!S 12 “111 C’S 43‘/b c‘. 1,itrgr 1‘4 r:1ses 5 wrcs AH-B~’-.~b(’Val\ lllg \I/(> 23 c:Lsc% :3 (*iir(’s l:3f (, ______

___ -_ ~- ~ _-~__~_~______~_____ A. Srrinll 11 cases (icures 54‘/0 B. Mcdium 30 CUSCS 9 rurcs 30% (I. Large 5 (vises 4 cures 80‘/, AH-BC-AH(’. V:iryiiig sin‘ 27 ram 5 cures 18f/o DEGREES OF MALIGNANCY IN CANCER OF THE BREAST 459

of the nucleus which appears significant. An explanation for the surprising results in the five cases showing large nuclei is not readily found. The importance of variation in the size of the cells and nuclei is further emphasized in the following tables:

TABLE 9 VnrzrLfaonan Sizr of ('ill9 -~- -~ _~______-~ __ -___ -4. Slight 37 cnseb 17 cures B. Moderate 20 cascs 7 cures High degree

TABLE 10 Vnriafionin Sixr of hTitclei

~~ ~ ~~ A. Slight ...... 11 cases H. >loderate...... 50 cases ('. High tlcgrcc...... 8 rases

In each case the high degrees of variation carry with them a serious prognostic influence and are worthy of consideration in the classification of the tumor. Closely associated with V. Hansemann's idea of anaplasia are the conditions of hyperchrornatism and the presence of numerous and irregular mitoses. TAIILE 11

I€ y prrch ro tna tisrii ...... - A. Slight...... 32 cases 13 cures B. Moder:ite...... 40 cases 11 curcs 27:; C". High degree., ...... 1 casr 0 curcs

~ ~ ~ In this table the importance of hyperchromatism is evidenced by the more favorable results which were obtained in the cases which showed only slight hyperchromatism, and in Table 12 the same fact is demonstrated in regard to the number of mitoses. TABLE 12 Mitosis

A. Slight...... 35 cases 18 cures 8. Moderate...... 32 cases 6 cures C. High dcgrrc...... 6 cases 0 cures 460 ROBERT B. GREENOUGH

A high degree of variation in size of cells and nuclei combined with hyperchromatic figures and many and irregular mitoses (a condition commonly spoken of as pleomorphism) is, of course, an indication of a high degree of malignancy and is often met and recognized in other forms of malignant tuniors, notably in osteogenic sarco1na. Such a tumor gives to the observer the irripression of tremendous activity and rapidity of growth and justifies the term of “angry,” a word which is often used in the laboratory to describe the impression made upon the observer. There were five such cases in the series, all in Class 3, and none were cured. Many observers have maintained that there is a positive and definite resistance on the part of the tissues of the body to the growth of cancer. Wherein this resistance lies is as yet not clearly defined. It is probably not a specific substance in the blood serum, although the failure of occasional blood metastases to flourish seems to justify the conclusion that substances in the normal serum are inimical to the growth of cancer cells. From aninial experiments with transplantable tumors, it has been determined that this resistance to transplantation can be en- hanced by preliminary injection of more or less similar tissues and especially embryonic tissues; but even in this case the nature of the resistance or immunity suggests a defensive mechanism against any similar foreign substances introduced from without into the body, rather than a specific protection against cancer growth. When the protective mechanism is in operation in experi- mental animals against artificial transplants of tumor growth, the phenomena observed consist chiefly in a dense round-cell infiltration around the tumor, followed by proliferation of the fixed connective tissue cells, invasion of the transplant by leucocytes, disintegration and absorption, or extrusion by in- flammation of the transplanted foreign tissue (Tyzzer) (6). It is for these reasons that round-cell infiltration frequently observed in human cancer tissue has been held to be an indication of the resistance of the individual to the cancer growth. MacCarty and Broders lay stress on the presence of round-cell DEGREES OF MALIGNANCY IN CANCER OF THE BREAST 461 infiltration and hyalinization of the stroma as indication of the resistance of the individual against the growth of squanious cell carcinoma. Unfortunately we have been unable to confirm this observation in cases of breast cancer. We believe that the resistance of the individual is a fact and a fact of great importance. Indeed, perhaps this resistance or the lack of it is an important factor in the remarkable and historic instances of the frequent occurrence of cancer in certain families, which have given rise to the theory that heredity is of great significance in the etiology of cancer. That this resistance makes itself evident by round- cell infiltration, however, does not seem to be the case.

TABLE 13 Rotmil-cell Znjltration, -~.... ___ ~__ A. Slight., ...... 55 cases 17 cures R. Moderate...... 13 cases C. High tlcgree...... ,I 5 cases

In this table the importance of slight or moderate round-cell infiltration appears to be significant, while in the five cases of round-cell infiltration of high degree, although the results are considerably more favorable, another explanation seems more probable. It is a familiar fact that round-cell infiltration is called forth by the presence of degenerative products in the tissues. If we check the degree of round-cell infiltration against the degenerative phenomena, we find that they run surprisingly parallel. The degree of degeneration itself appears to have little to do with the prognosis. It is of interest to note that V. Hanseiiiann took the view that the round-cell infiltration was not an expression of the resistance of the individual, but rather of the irritant effect of the growth of the particular tumor in the tissues of the host. TABLE 14 Crll Dcgcneration

A. Slight...... 60 cases 19 cures 31% B. Modcrnte...... 6 cases 0 cures 0% C. High degree...... I 7 cases 1 5 cures 70% Degeneration in cancer tissue which is not on the surface and 462 ROBERT B. GREENOUCH exposed to bacterial invasion probably depends chiefly upon the breadth of the columns of cells and the distance of the older and central portions of the columns from the surrounding vascu- lar supply. The degree of round-cell infiltration, however, conforms closely with the degenerative process and it is easier to believe that it is the expression of a natural function of the body in response to the presence of degenerated matter than that it expresses the resistance of the individual to cancer growth. This can be said without denying the fact that a stroma infiltrated with round cells may well be less favorable soil for the growth of cancer than one that is not so infiltrated.

TAULE 1.5 Degeneration and Round Cells Of thc snnic degrec ...... 57 eases Of different degrre ...... 16 cases It has long been recognized that cancer grows as a rule more rapidly in a young woman than in the fibrous breast of a woman of extreme age. TABLE 16 Hyalinizalion . ~__..._____I____ --~ __ -_- A. Slight...... 13. Modernte ...... C. High degree......

This table shows, however, that this consideration is not one of extreme importance. There were only six instances of extreme hyalinization of the stroma, and of these only one was cured, or 16 per cent, a lower percentage than occurred with either slight or moderate degree of hyalinization. We have now considered the several factors that enter into the deterniination of the degree of malignancy of cancer of the breast, and we can summarize as follows: 1. The degree of malignancy of a given case of cancer of the breast can be determined with reasonable accuracy by study of the histgology of the original tumor; and three classes, low, medium, and high malignancy, can be distinguished. 2. Such a classification is of importance in prognosis, and m 3 .*cc. 4

PLATE V. PLATE 1-1.

CASE 3.2. .IDEN0 .\HRAN;UEMENT. CASE 47. ADEN0 ARR4NGEMENT SLIGHT. Marked variation. Marked secretion. Few mitoses. Variation marked. Secretion medium. Hyper- hledinm hyptwhromatiarn. Metiiiim malignancy. Death. chromntism and mitosis nxtrked. High malignancy. Cancer in lartation. Death. c;13 J PLATE IX.

CASE 16. ADENO.\I~RANGEMENT-XONE. No secretion. Variation marked. Mitosis and hyperchromatism marked. High mdignancy. Plcomorphic. Death.

DEGREES OF MALIGNANCY IN CANCER OF THE BREAST 463 should be of assistance in estimating the value of therapeutic measures. 3. In estimating the degree of malignancy of a given tumor, the following factors are of importance: (a) Degree of differentiation, as shown by arrangement of cells around an open gland lumen (adenocarcinoma) ; (b) Degree of secretory activity of cell protoplasm as shown by vacuoles and droplets of mucoid material; (c) Uniformity of size of cells and of nuclei, as opposed to variations in size; (d) Absence or presence of hyperchrornatic changes in nucleus, and few or many mitotic figurcs, and whether irregular or not. (e) High malignancy is shown by cells and nuclei of irregular shape and size without secretory function, and arranged in solid columns, large or small, together with numerous and irregular mitoses and hyperchromatisni. The extreme degree of these features is pleomorphism. (f) h tumor of adenomatous arrangement (adenocarcinoma) with uniform sized cells and nuclei, few mitoses, and absence of hyperchromatism, indicates low malignancy. 4. A high degree of round-cell infiltration appears to indicate a considerable degree of cell degeneration, and is not to he relied upon as an indication of the resistance of the individual to the cancer growth. 5. Hyalinization of the stroma does not indicate active resistance to the tumor growth but is rather a factor of the age or previous condition of the mammary tissue in which the tumor lies. RRE’HRESCEH (1) D. HANSEMANN:Die Mikroskopische Diagnose der bosartigen Gvschwulstc. Berlin, 1897. (2) MACC~RTY,W. C.: Surg. Gynec. and Obst., 1914, xviii, 284. Sce dso Am. J. Rled. Sci., 1919, clvii, 657, and Sistrunk, W. E., and MacCarty, W. C.: Anrials of Surgery, 1922, lx-iv, 61. (3) BRODERS,A. C.: Ann. Surg., 1921, lsxiii, 141. (1) hlAmzLoFF, ki. H.: Johns Hopkins Hosp. Bull., 1923, xxxiv, 141, 181. (5) MAHLE:,A. E.: Surg. Gynec. and Obst., 1923, xxxvi, 385. (6) TYZZEIL,E:. E.: J. Cancer Res., 1916, 1, 125.