VARYING DEGREES O F MALIGNANCY I N 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 independence 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 a t 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. G R E E N O U G H
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 Massachusetts 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 o n 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 photomicrographs.
I n 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. I n 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 :
455
D E G R E E S O F MALIGNANCY I N CANCER O F T H E BREAST
.~
I
Class
Class
Class
Class
1. ....
2. . . . .
3. . ...
4.. . . .
I
Pathology
Milch Differentiation
Moderate I)ifferent,i:it,ion
Slight Differentiation
Highly h1align:mt
I
I
6 c:1ses
19 "
43 ' I
22 ' i
60 yo
1cures
9 **
10
47 7'0
23 c:h
()?7
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 herewith.
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 ~ i i i ( > sA8
, pcir (sent
_____
-
A ( h u p (glanth riot iiivolvcd)
C C h u p (glands involvrd)
1 1 cases
8
fdSt'S
__
9 cure5
4 CIIres
-
1-
82'i
50 c/'o
TABLE 2
c'lwss '.'--Mecliuir~ Mnlignuttcy
33 rases-11 mires, X3 per cent
..
-~~ _ _ _ _ _ _ _
A Group (glands not involved). . . . . . . . , .
C Group (gl:trrds involved). .
, , ,
. .. . . ...
7 c:~scs
3 cures
20 ciiscs
S ciires
43 (4,
31 yo
TAHLE 3
('lass 3-High Mnligiiaiuy
21 c a s e s 4 cures, 0 per cent
_
_~
._____
-___
0 cures
0 Cllres
456
ROBERT B. GREENOUGH
For the purpose of this study only 73 cases were taken, representing all of the cases of cancer of the breast in the 1918-19191920 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 i t is admittedly 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 internal 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 advanced cases of the lowest grade of malignancy.
These facts are surely of importance if they can be confirmed.
DEGREES O F MALIGNANCY I N CANCER O F THE B R E A S T
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. I n the attempt to determine the
relative importance of these different factors the specimens were
further studied and a value ( A B C ) 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 iiadenocarcinoma.” 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-lenomedullary, adeno-scirrhous, etc., because it was felt that the
adenomatous arrangement of the cells indicated a degree of
differentiation.
T4HLE
=____-
,$deKlO-t)’i)t’
Medullary
Hcrrrhons
_
11
4
_
47 (‘ascs
44 C B s e S
51 cases
I
~
~
17 ciiws
14 cures
17 riires
1
I
-_
I
~
36 yo
31%
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 T T ( I T L ( I Y ~ ) I E ~ ~
18 cxscs showctl marked &no. . . . . , . , , . . . , . , . . . . 8 cures
55 ciiws showed no ttdcno. . . . . . . . , . . , . , . . , . , . . . . .16 cures
44y4
2s yo
I n this case the relatively favorable significance of the adenoma feature is more resdily‘recognized.
30
_
_
458
ROBERT B . GREENOUGH
__-
_ _
8 . Sinall
13. Rledlulrl
c‘. 1,itrgr
AH-B~’-.~b(’Val\
___ -_ ~B . Mcdium
(I.
Large
AH-BC-AH(’.
_ _ _
-~
~
x c:1scs
__
A . Srrinll
~
lllg \I/(>
_________
28 (‘L1Ht!S
1‘4 r:1ses
23 c:Lsc%
1r i i i m
12 “111 CS’
5 wrcs
:3 (*iir(’s
_-~__~_~__________~_____
11 cases
(icures
30 CUSCS
9 rurcs
4 cures
5 (vises
V:iryiiig sin‘
27 r a m
5 cures
_____
EN/,
43‘/b
l:3f (,
~
54‘/0
30%
80‘/,
18f/o
459
D E G R E E S O F MALIGNANCY I N CANCER O F THE B R E A S T
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:
9
TABLE
-~
- -~
-4. Slight
B. Moderate
VnrzrLfaonan S i z r of
_-~
~______
37 cnseb
20 cascs
('ill9
__ -___
17 cures
7 cures
High degree
TABLE
10
Vnriafionin Sixr of hTitclei
~~
~
~~
A . Slight . . . . . . . . . . . . . . . . . . . .
H. >loderate. . . . . . . . . . . . . . . . . .
('. High tlcgrcc. . . . . . . . . . . . . . . .
11 cases
50 cases
8 rases
I n 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.
11
I€ y prrch ro tna t i s rii
TAIILE
.......
A . Slight.. . . . . . . . . . . . . . . . . . . .
B. Moder:ite.. . . . . . . . . . . . . . . . .
C". High degree., . . . . . . . . . . . . . .
32 cases
40 cases
1 casr
~
13 cures
11 curcs
0 curcs
~
-
27:;
~
I n 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.
12
Mitosis
TABLE
A. Slight.. . . . . . . . . . . . . . . . . . . .
8.Moderate.. . . . . . . . . . . . . . . . .
C. High dcgrrc. . . . . . . . . . . . . . . .
35 cases
32 cases
6 cases
18 cures
6 cures
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. I t 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, i t has been
determined that this resistance to transplantation can be enhanced 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 experimental 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 inflammation 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 a n 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 a n 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 roundcell infiltration, however, does not seem to be the case.
TABLE 13
Rotmil-cell Znjltration,
-~
....
___
A . Slight., . . . . . . . . . . . . . . . . . . .
R. Moderate.. . . . . . . . . . . . . . . . .
C. High tlcgree. . . . . . . . . . . . . . . , I
~ _ _
17 cures
55 cases
13 cases
5 cases
I n 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
.I
A . Slight.. . . . . . . . . . . . . . . . . . . .
B . Modcrnte.. . . . . . . . . . . . . . . . .
C. High degree.. . . . . . . . . . . . . .
60 cases
6 cases
7 cases
1
19 cures
0 cures
5 cures
31%
0%
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 vascular 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Of different degrre
......................
.57 eases
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
c.
c
.*
4
CASE
3.2.
. I D E N 0 .\HRAN;UEMENT.
Marked secretion. Few mitoses.
hledinm hyptwhromatiarn. Metiiiim malignancy. Death.
Marked variation.
PLATE V.
CASE 47. A D E N 0 A R R 4 N G E M E N T SLIGHT.
Variation marked. Secretion medium. Hyperand mitosis nxtrked. High malignancy.
chromntism
Cancer in lartation. Death.
PLATE 1-1.
c;
13
J
PLATE IX.
CASE 16. ADENO.\I~RANGEMENT-XONE.
No secretion. Variation marked. Mitosis and hyperchromatism
High mdignancy. Plcomorphic. Death.
marked.
DEGREES OF MALIGNANCY IN CANCER OF THE BREAST
463
should be of assistance in estimating the value of therapeutic
measures.
3. I n 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) M A C C ~ R TW.
Y , C.: Surg. Gynec. and Obst., 1914, xviii, 284. Sce d s o 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) h l A m z L o F F , 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.