Acta Radiologica: Therapy, Physics, Biology
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Prognostic Factors in Mammary Carcinoma A. Wallgren, C Silfverswärd & G. Eklund To cite this article: A. Wallgren, C Silfverswärd & G. Eklund (1976) Prognostic Factors in Mammary Carcinoma, Acta Radiologica: Therapy, Physics, Biology, 15:1, 1-16, DOI: 10.3109/02841867609132703 To link to this article: https://doi.org/10.3109/02841867609132703
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A C T A R A D I O L O G I C A OFFICIAL ORGAN O F THE RADIOLOGICAL SOCIETIES O F D E N M A R K , F I N L A N D , NORWAY A N D SWEDEN
Vol. 15 Fasc. 1
THERAPY PHYSICS BIOLOGY
1976 February
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA A. WALLGREN, C. S I L F V E R S Wand ~ D G. EKLUND An extensive literature exists on the prognostic value of various clinical and microscopic factors in carcinoma of the breast. However, few reports deal with the simultaneous influence of multiple factors on the clinical course of the disease. Many prognostic factors wers defined and adapted for multivariate analysis in a previous & SILFVERSWARD 1975). Some of these factors have now been report (WALLGREN analysed with respect to their bearing on the outcome of 581 cases treated with radical mastectomy. Material and Methods Clinical material. In the period 1961 through 1963, 591 women younger than 70 years, who were admitted for treatment of unilateral, invasive carcinoma of the breast, underwent radical mastectomy without previous irradiation or hormone medication. Ten patients, whose available microscopic slides on re-scrutiny showed pure colloid (mucous) carcinoma were excluded from the material, which thus comprised 58 1 radically mastectomized women. All but 9 received postoperative irradiation. The axillary, supraclavicular and ipsilateral parasternal lymph node regions were irradiated in 382 patients; the parasternal and supraclavicular fields From Radiumhemmet (Director: Prof. J. Einhorn) and the Institute of Tumour Pathology (Director: Prof. G. Moberger), Karolinska Sjukhuset, S-104 01 Stockholm, and the Statistical Institution, dniversity of Stockholm, S-113.47 Stockholm, Sweden. Submitted for publication 10 October 1 9 h . Acta Radiologica Therapy Physics Biology 15 (1976) Fasc. I February 1 - 765844
1
2
A. WALLGREN, C. SILFVERSWARD AND G. EKLUND
Table 1 Variables denoting ‘microscopic’stage of the tumours. n = No. of patients Size of tumour (greatest dimension) 1) < 1 cm (n = 33), 2) 1.1 to 2 cm (n = 250), 3) 2.1 to 5 cm (n = 220), 4) > 5 cm (n = 3 3 , 5) multiple tumours or insufficient data (n =41) Axillary node metastases 1) None (n = 296), 2) micrometastases d 2 mm (n = 25), 3) one macrometastasis (n = 78), 4) 2 to 3 macrometastases (n = 112), 5) 4 or more macrometastaw (n = 70) Perinodal growth 1) No metastases (n = 296), 2) metastases without perinodal growth (n = 103), 3) metastases with possible perinodal growth (n = 40),4) metastaseswith evident perinodal growth (n = 79), 5) metastases with massive perinodal growth (n = 63)
only were irradiated in 186 patients without lymph node metastases. Radiation therapy was confined to the axillary region in the 4 remaining cases. Axillary irradiation consisted of 170 to 190 kV roentgen radiation (HVL approximately 1 mm Cu), a dose of 2 400 R being delivered in 6 fractions to one anterior and one posterior field. For parasternal irradiation a short distance 6oCounit was used (EDSMYR& WALSTAM 1963) or a maximum absorbed dose of 4000 rad was administered in 8 fractions over three weeks, using a 12 to 15 MeV electron beam. The supraclavicular region was included in the anterior axillary field or selectively irradiated in the same way as the parasternal region. Surgical or radiologic castration was performed on 154 patients, most of whom had axillary lymph node metastases. The patients were re-examined at regular intervals. After some years the followup was in some cases continued at other hospitals or by letters to the patients. Local recurrences and distant metastases were treated with conventional methods, including hormonal procedures. Patients who died without clinical- or autopsy evidence of distant metastases were regarded as dead from unrelated causes. However, all deaths within a year of the primary treatment or of treatment for local recurrence were classified as malignancy deaths, as were all those that occurred after distant metastases had been detected. There were no deaths in the immediate postoperative period. A contralateral breast malignancy was regarded as a new primary tumour if there were no signs of distant metastases or of spread of tumour over the midline of the chest wall, in accordance with the clinical rules outlined by HAAGENSEN (1971). Five years after the radical mastectomy distant mestastases had been found in 172 patients, 134 of whom had died of their malignancy. Fifteen other patients had died from unrelated causes. A primary tumour of the contralateral breast had appeared in 9 cases. The-f&ezyear survival rate was 76 per cent and the five-year cure rate 70 per cent.
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
3
Table 2 Microscopic primary tumour variables. n = No, of patients
Microscopic classification 1) Infiltrating lobular (n = 80), 2) medullary with lymphoid infiltration (n = 33), 3) ductal: cribriform or papillary (n=51), 4) ductal: comedo type (n=35), 5 ) duct& no further specification (n = 382) Elastosis 3) moderate (n = 113), 4) massive: large confluent 1) None (n = 286), 2) few small areas (n = a), areas (n = 122) Tubule formation 1) Regular (n = 42), 2) moderately regular or small areas with few tubules (n = 82), 3) poor tubule formation or generally few tubules (n = 346), 4) non-tubular carcinoma types (lobular or medullary) (nslll) Lymphoid infiltration , I ) Occasional lymphatic or plasma cells, no focal areas (n =210), 2) small, scattered foci or narrow circumscribing zone (n=204), 3) numerous large foci or wide circumscribing zone (n=121), 4) massive infiltration throughout tumour (n =46) Size of nuclei 1) Small (n = 83), 2) fairly small (n = 163), 3) fairly large (n = 227), 4) large (n = 108) Variability of size of nuclei 1) None (n = 52), 2) slight (n = 225), 3) moderate (n = 227), 4) marked (n = 77) Contour of nuclei 1) Even (n = 91), 2) slightly uneven (n = 285), 3) uneven (n = 167), 4) irregular (n =38) Mitotic frequency 1) Few mitotic figures; no hyperchromatic nuclei (n = 59), 2) occasional mitoses or small numbers of hyperchromatic nuclei (n = 224), 3) moderate frequency or large numbers of hyperchromatic nuclei (n = 196), 4) many mitotic figures (n = 102) Nucleoli 1) Just discernible (n = 203), 2) clearly discernible (n = 197), 3) enlarged (n = 118), 4) prominent (n = 63)
After ten years 222 of the patients had distant metastases, 204 had died of their malignancy and 39 from unrelated causes. A primary contralateral malignant tumour had been found in 20 patients. The ten-year survival rate was 63 per cent and the tenyear cure rate 60 per cent. Microscopy. Sections or paraffin blocks were available from the primary tumour and the axillary lymph nodes in all cases. The surgical specimens had already been examined in a number of laboratories. The sizes and the numbers of the blocks prepared from the primary tumours and also the numbers of excised lymph nodes varied considerably. As part of the postoperative assessment new slides were prepared and wg~-r&iewedat& Institute of Tumour Pathology. These slides, which were
4
A. WALLGREN, C. SILFVERSWhD AND G. EKLUND
Table 3 Clinical variables. n = No.of patients Clinical stage (UICC 1968) 1) Stage I (n =247), 2) stage I1 (n = 172), 3) stage I11 (n = 108). 4) insufficient data (n = 54) Clinical assessment of tumour 1) Greatest dimension d 2 cm, TI (n = 116), 2) greatest dimension 2.1 to 5 cm, T2 (n = 324), 3) greatest dimension > 5 cm,T3 (n = 86), 4) any size, direct skin or chest wall involvment, T4 (n = 13), 5) not palpable or multiple tumours, insufficient data (n = 42) Clinical assessment of lymph nodes 1) None palpable, NO (n = 297), 2) palpable, considered not malignant, N l a (n = 66), 3) palpable, movable, considered malignant, N l b (n-158), 4) fixed nodes, N 2 (n=22), 5) insufficient data (n = 38) Site of primary tumour 1) Lateral (n = 258), 2) central (n = 173), 3) medial (n = 133) 4) insufficient data (n = 17) Duration of signs and symptoms 1) < 1 month (n = 176), 2) 1 to 3 months (n = 138), 3) 3 to 6 months (n = 62), 4) > 6 months (n = 186), 5) insufficient data (n = 19) Age of patient 1) < 45 years (n = 105), 2) 45 to 54 years (n = 21 l), 3) 55 to 69 years (n = 265)
stained by the van Gieson or haematoxylin-eosin methods, were mainly used in this investigation. If available slides were substandard, new sections were prepared. The slides were examined without knowledge of the clinical course in the case. The lymph node sections were not examined at the same time as the sections from the primary tumours. The microscopic variables were grouped as those pertaining to the extent of the malignant process-the ‘microscopic’ stage (Table 1) and features of the primary ‘microscopic’ stage (Table 1) and features of the primary tumour (Table 2). The definitions largely agree with those in the previous investigation (WALLGREN& SILFVERSWKRD). The clinical variables’ are presented in Table 3. Statistical methods. The analyses were performed with five- and ten-year survival as dependent variables. For calculation of survival rates weights were allotted. The weighting for a patient, who died of unrelated causes or in whom a new malignant tumour was detected in the contralateral breast during the uth year of follow-up, was the calculated risk of dying of malignancy within a -0.5 years in relation to the total risk of death from malignancy during the whole follow-up period, i.e. 5 or 10 years. The cumulative incidence (risk) is illustrated in Fig. 1. The weighted number of patients (patients at risk) was used in all the calculations. Automatic in&a&hn detector ( A m ) analysis was described by SONQUIST & MORGAN (1964) and-was further elaborated by SONQUIST et coll. (1971). It is a computer-
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
5
Fig. 1. Cumulative incidence of deaths from malignancy in 581 patients following radical mastectomy. The weights were used to correct the survival rates for those who died from intercurrent causes or in whom a contralateral mammary carcinoma was detected during the period.
based technique by which the original material is divided into mutually exclusive risk groups through a series of dichotomous splits. Each split is made according to the explaining variable, predictor, that most reduces the variance of the dependent variable. At each step it is easy to survey the alternative possibilities of splitting the clinical material. AID analysis was selected as a suitable method for a multivariate procedure, since the dependent variables were of dichotomous type (dead, alive) and because no assumption was necessary concerning a linear model. The introduction of rules for terminating the partitioning process, based on calculation of the risk of artifact divisions (GAVATIN & EKLUND 1972, JEREB & EKLUND1973, AVBN1974) has reduced the danger of overestimating the explanatory value (EINHORN1972) or of being & GEHAN 1974). In the present ‘misled by the vagaries of small numbers’ (ARMITAGE analysis the partitioning process was terminated when any further split would have produced a subgroup with less than 10 individuals or when the difference between subgroups did not reach the 0.05 significance level. Significance was calculated as described by JFXEB & EKLUND(1973) and by AVBN(1974). Microscopic classification and site of primary tumour, consisting of unordered, non-numerical categories were free predictors, which implies that the order of the coded classes could be rearranged during the analysis. All the other predictors were monotonic. Predictors which comprised a number of observations with missing data and the predictor tubule formation, containing the non-numerical category of non-tubular carcinoma types, were each transformed into two predictors in order to retain their character of monotonic variables (GAVATIN & EKLUND1972). The part of the variance of the dependent variable that could be ascribed to the most important split accomplished by each predictor was calculated. This coefficient of &&& $,was converted to the corresponding correlation coefficient, r.
A. WALLGREN, c. SILWERSWARDAND G. EKLUND
6
Table 4 Correlation between predictors and suwival. In the calculation of coefficients it was assumed that each predictor consisted of two classes formed by the most important split of the material in regard to that predictor. The levels of significance are indicated (* p 0.05). F =free predictor Predictor
Correlation with survival, r 0-5 Y-
Years
-0.18*** - 0.18*** - 0.17*** 0.10* -0.10*
-0.21*** -0.22*** -0.20*** 0.11* - 0.09.
N.S. N.S. N.S. N.S. N.S.
N.S.
N.S.
N.S.
-0.30*** - 0.28*** ' -0.28***
-0.31*** -0.33*** -0.24***
N.S.
-0.25*** -0.23*** -0.19*** +0.16*** -0.16*** 0.14** -0.13** -0.10*
-0.23*** - 0.22*** -0.21*** + 0.23*** -0.13** 0.13** - 0.19*** -0.12** - 0.09*
0-10 YWS
5-10
Clinical variables Stage
Assessment of lymph nodes Assessment of tumour Site of primary tumour (F) Age of patient Duration of signs and symptoms Variables denoting microscopic stage Axillary node metastases Perinodal growth Size of tumour Primary tumour variables Tubule formation Mitotic frequency Variability of size of nuclei Elastosis Nucleoli Microscopic classification (F) Contour of nuclei Size of nuclei Lymphoid infiltration
N.S.
-0.13** -0.18*** -0.221'2 -0.14**
N.S. N.S. -0.10* 0.112
N.S. N.S. N.S.
The advantage of r over r8 is that the direction of the correlation is indicated. The coefficients of determination for the total AID analyses, R2,were also calculated. ReSUltS
The correlation coefficients between the predictors and the dependent variables, viz. the five- and ten-year survival for all the 581 patients and the ten-year survival in the 423 who survived for at least 5 years, appear in Table 4. Clinical predictors. Significant correlations with five- and ten-year survival were found for (1) clinical stage, (2) clinical assessment of lymph nodes and (3) clinical assessment of-tumour (Tabk4+-None of the clinical variables was correlated with the
7
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
Table 5 Groups of factors indicating favourable prognosis. AID analysis with five-year survival as dependent variable
No. of patients
Characteristics
No metastases or metastases but no perinodal growth and few or occasional mitoses (Fig. 4) No metastases and tumour size less than 2 cm Markedly or moderately regular tubule formation (Plus massive or moderate elastosis, Fig. 2) Metastases with possible or evident perinodal growth and moderate or massive elastosis (Fig. 4) Clinical assessment T1 and NO or Nla Patients belonging to at leakt one of these groups
survival (per cent)
203 177 124 65
94 94 95
100
47 104
89 94
370
90
Table 6 Percentage of variance of survival attributable to sets of predictors
Set of predictors
Clinical variables Variables denoting microscopic stage Microscopic features of primary tumour All predictors
AID analysis of survival Syears
1oyears
9 15 10 21
6 17 9 21
ten-year survival among patients who were still alive after 5 years (Table 4). A group with favourable five-year survival, 94 per cent, was identified through the AID analysis (Table 5), viz. l a patients with tumours less than 2 cm (Tl) and possibly without malignant lymph nodes (NO or Nla). Their ten-year survival rate was 77 per cent. The lowest survival rates were found for 61 patients in stage 111 with lymph nodes considered to be involved (Nlb or N2). Their five- and ten-year survival rates were 46 and 35 per cent. The variance of the dependent variable attributable to the clinical predictors was 9 per cent for five-year and 6 per cent for tenyear survival (Table 6). Microscopic stage predictors. (1) Size of tumour, (2) axillary node metastases and (3) perinodal growth were all significantly correlated with five- and ten-year survival (Table 4). These predictors accounted for more of the variance of both five- and tenyeaL&a4 @?= Wand I7 per cent) than did the other predictor groups (Table 6).
8
A. WALLGREN, C. SILFVERSWbD AND G. EKLUND
Table 7 Distribution of cases and survival according to some primary tumour predictors. The most important split of the original material by each predictor is indicated by a dividing line
Predictor
Microscopic classification Ductal: cribriform or papillary Infiltrating lobular Medullary with lymphoid infiltration Ductal: no further specification Ductal: comedo type
Distribution Survival (per cent) (Per cent) Jyears loyears
9 14 6 66 6
94 80 78 76 54
85 -
7 14 59 19
95 95 69 79
90
Elastosis None Small areas Moderate Massive
49 10 19 21
71 55 87 90
-
45 -
Mitotic frequency Few mitoses Occasional mitoses Moderate frequency Many mitoses
10 39 34 18
98 83 70 62
95 69 57 44
76
63
Tubule formation Regular Moderately regular
Poor Non-tubular carcinomas
Total
66 75 61 43
84 53 68
60 68 78
Correlation was also found between size of tumour and axillary node metastases and ten-year survival among patients who were still alive after 5 years. A group with 94 per cent five-year survival rate consisted of 177 patients without metastases and with tumours less than 2 cm in diameter (Table 5), their ten-year survival rate was 86 per cent. The same ten-year survival rate was found in the AID analysis for 191 patients without metastases or with micrometastases and with tumours less than 2 cm. A group with 49 per cent five-year survival rate was identified, viz. 135 patients with two or more involved nodes and with possible, evident or massive perinodal growth. Their ten-year survival rate was 32 per cent. The lowest ten-year survival rate, 13 per cent, was found among 38 patients with two or more involved nodes, massive perimdal growth and whose tumours measured more than 2 cm or were multiple.
9
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
76 %
n = 581
TUBULE FORMATION very ar moderately regular
E LASTOS I S
100 %
n = 65
moderate or massive
NAME OF PREDICTOR characteristic 5 year survival rate,% No. af patients, n
n = 235
TUBULE FORMATION poor or non-tubular
84%
n = 170
.
Fig. 2. AID analysis of the prognostic importance of microscopic primary tumour predictors with five-year survival as dependent variable.
Microscopic primary tumour predictors. Except for lymphoid infiltration all the predictors in this category correlated with both five- and ten-year survival (Table 4). Survival in relation to (1) microscopic classification, (2) tubule formation, (3) elastosis and (4)mitotic frequency appears in Table 7.The result of the AID analysis of the prognostic significance of the microscopic primary tumour predictors when five-year survival was the dependent variable is surveyed in Fig. 2. The predictor that accounted for most of the variance was elastosis, but significant partitions of the original material could have been obtained from tubule formation, mitotic frequency, variability of size of nuclei and contour of nuclei. Moderately or very regular tubule formation was associated with high survival rates, and when this microscopic feature was combined with moderate or massive elastosis (65 patients) no deaths from malignancy (Fig. 2, Table 5) had occurred. The explanatory value, R2,was 10 per cent (Table 6). The analysis, however, did not identify any groups with very poor prognosis. When ten-year survival was the dependent variable (Fig. 3), the material was first split according to tubule formation. The predictors mitotic frequency, variability of size of nuclei, elastosis and nucleoli could also have given significant splits. Two groups with favourable prognosis were thus identified. In tumours with markedly or moderately regular tubule formation the ten-year survival rate was 86 per cent, and when there was poor or no tubule formation with scanty mitoses the corresponding F t e was 93 per cent (Fig. 3). No group with very poor prognosis was identifieb-a2-was-9percent (Table 6).
10
A. WALLGREN, C. SILVVERSWARD AND G. EKLUND
TUBULE FORMATION moderately or very regular
86%
n = 124
T O T A L 63 %
M I T O T I C FREQUENCY
n = 581
very few n = 28
93 % TUBULE FORMATION p”r or non-tubular
NAME OF PREDICTOR c h a r o c t e r i st i c 10 year survival rate, % No. of patients, n
MIT OT IC FREQUENCY occarional,moderote number or many n = 429
Fig. 3. AID analysis of the prognostic importance of microscopic primary tumour predictors with ten-year survival as dependent variable.
89 %
n
= 47
E L A S T 05 I S moderote
or massive n = 77
76 % PERINODAL GROWTH
PERINODAL GROWTH
p a r i b l c , evident ormmrivc n=
182
mmsive I
56 %
N A M E OF P R E D I C T O R chorocterirtic 5 year LUWiYal rote,% No. of patients, n
n
= 30
ELASTOSIS none or m a l l
41 %
~ROI
n = 105
Tubule formation and mitotic frequency were related to ten-year survival in the patients who were still alive after 5 years (Table 4). AID analyses with all predictors QS explaining variables. The most important partitioningo€ the wiginat material with both five- and ten-year survival was obtained with the predictors that denoted extent of the disease in axillary lymph nodes.
11
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
DURATION OF SYMPTOMS
53 mmlmr or data insufficient
95% SIZE OF TUMOUR
6 2 cm
83 %
n = 217
"189
SYMPTOMS - DURATION2 cm or multiple
TUBULE FORMATION ".ry
mad.rot.ly npulor or na-tubulor n = 75
0,
78 % T O T A L
63 %
n = 581
TUBULE FORMATION
TUEULE F O R M I T I O N
very or d s r n t e l y regulm
poor
50%
n = 107
2 or more "I
NAME OF PREDICTOR choractsriitic
182 TUBULE FORMATION p" 0,
34%
non-tubulor n = 150
Fig. 5. AID analysis of the prognostic importance of clinical and microscopic predictors with tenyear survival as dependent variable.
When five-year survival was the dependent variable, perinodal growth was the major predictor. It distinguished the cases without metastases, or with metastases but no perinodal growth, from those with metastases and possible, evident or massive perinodal growth (Fig. 4). The AID analysis demonstrated two prognostically favourable groups (Fig. 4, Table 5), viz. without metastases or with metastases but no perinodal growth and with very few or only occasional mitoses (five-year survival rate 94 per cent) and cases with possible or evident perinodal growth and moderate or massive elastosis (89 per cent five-year survival). The poorest survival rate-41 per cent-was found in 105 cases with possible, evident or massive perinodal growth and no or minimal elastosis. Riwas 21 per cent (Table 6). When ten-year survival was substituted for five-year, the material was first split with regard to axillary node metastases (Fig. 5). Cases with 2 or more involved nodes were separated from cases without metastases or with only micrometastases or one macrometastasis. A group with 95 per cent ten-year survival consisted of 89 patients who had had symptoms or signs for more than three months and whose tumours at operation were less than 2 cm in diameter and had produced at most one macrometastasis in the axillary nodes. By contrast, the ten-year survival rate among 150 patients with two or more involved nodes from tumours with poor tubule formation or from non-tubular carcinoma was only 34 per cent (Fig. 5). RBwas 21 per cent (Table 6). ' Thedalpxwitlrlive-year survival as the dependent variable and with various
12
A. WALLGREN, C. SILFVERSWhD A N D G. EKLUND
sets of predictors as explaining variables revealed several groups with high survival rates (Table 5). Of the 581 patients, 370 belonged to at least one of these groups and 90 per cent of them were still alive after 5 years and 78 per cent after 10 years. In the 192 cases with features of at least two of the groups the corresponding,rates were 98 and 88 per cent, respectively. AID analysis was further performed with ten-year survival as the dependent variable and including only those patients who had lived for at least 5 years. Their ten-year survival rate was 83 per cent. Few of the predictors were significantly correlated to that survival (Table 4). Only 7 per cent of the variance of survival could be accounted for.
Discussion Many single features of mammary carcinoma and combinations of a few of these have been demonstrated to influence the outcome, but few reports have appeared in which the prognostic value of multiple factors was simultaneously assessed. ALDERSON et coll. (1971) found from a multiple regression analysis of 15-year survival in patients with operable mammary carcinoma that axillary lymph node metastases, the clinical stage and the size of the tumour were the most important variables independently explaining survival. Other major factors were radiation therapy, which negatively influenced survival, stromal reaction, grade of malignancy and year of treatment. This last variable was positively correlated to survival, i.e. patients who were treated during the later years had higher survival rates than those treated in the earlier years. In order to minimize the time factor, the present analysis was limited to the period 1961 through 1963. Like ALDERSON et coll., it was found that the variables mainly involved in survival were those relating to the extent of the tumour (Table 4, Figs 4, 5). The prognostic influence of the number of involved axillary lymph nodes is well documented in the literature (FISHER& SLACK1970, FISHER et coll. 1975). Since the number of lymph node sections varied considerably within the case series, the estimated numbers of involved nodes probably were too low in some cases. Such underestimation would presumably reduce the value of lymph node involvement as a predictor of prognosis. Perinodal extension of carcinoma has been shown to indicate poor prognosis (HULTBORN & T~RNBERG 1960, MCDIVITTet coll. 1968). In our AID analysis on five-year survival the first split distinguished the cases with possible, evident or massive perinodal growth from those without metastases, or with metastases but no perinodal growth (Fig. 4). The advantage of this predictor over the number of involved nodes is that, whereas the latter may vary as a consequence of the quality of the gross examination of the surgical specimen, nodes with perinodal extension of carcinoma are,most likely to be excised for examination (MCDIVITT et coll.). Tumour - s k i s amother factor of recognized prognostic significance (FISHERet
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
13
coll. (1969). In the present material its explanatory value remained after the material had been split with respect to axillary node metastases (Fig. 5). Tubule formation and mitotic frequency were two important prognostic features of the primary tumours. In contrast to the other microscopic primary tumour predictors, they also exerted a significant influence on the ten-year suririval of the patients who were alive after 5 years (Table 4). Together with ‘irregularity of shape and staining of nuclei’ they are included in the malignancy grading system evolved by SCARFF and BLOOM (SCARFF& TORLONI 1968). Nuclear irregularity was subdivided into the two predictors variability of size and of contour. Both were significantly correlated with five-year survival but not with ten-year survival of patients who where alive after 5 years. Moderate or massive elastosis was found to imply a high five-year survival rate. This is consistent with the finding by SHIVAS & DOUGLAS (1972) of a longer mean survival time in patients who died of mammary tumour when there was gross elastosis. In contrast to FISHER kt coll. (1975), who used slides specifically stained for elastica, diffuse elastosis was not included in the present microscopic grading. Focal areas of elastosis were easily demonstrable in sections stained with van Gieson or haematoxylin-eosin. Elastosis was seen mainly around ducts, but was sometimes visible in the stroma of the tumour. Though in the present investigation elastosis was important as a predictor of five-year survival, it was not significantly correlated with the tenyear survival in patients who had lived for 5 years (Table 4). It seems permissible to assume that moderate or massive degrees of elastosis occur in slowly progressing tumours. Only a few sections from each tumour were examined, however, and the degree of elastosis may have been underestimated in some cases. Relatively few patients, together constituting about 15 per cent of the total series, could be assigned to prognostically distinct groups according to microscopic classification. Pure colloid carcinomas were excluded from the material. Papillary or cribriform appearances in a ductal carcinoma implied a relatively good prognosis (Table 7), as observed also by HAAGENSEN (1971). The small group of comedo carcinoma was found to have a poorer prognosis than other types (Table 7). HULTBORN & T~RNBERG (1960) reported similar findings. In the present material carcinomas were classified as comedo type when the microscopic appearance was that of solid, intraductal growth with central necrosis, irrespective of the relative amounts of the intraductal and the invasive parts. This may explain some of the discrepancy between the present findings and those reported by MCDIVITTet coll. (1968). They found a higher survival rate in comedo carcinoma in a series consisting of predominantly intraductal carcinoma. In medullary carcinoma with lymphoid infiltration the survival rates in the present material were not different from those of other tumour types (Table 7). Like MCDIVITT et coll. it was found that after 5 years few deaths from this type of tumour had occurred. Lymphoid infiltration of the primary tumour was not per se favourable to survival. Indeed, the weak correlation with five-year survival indicated poorer prognosis with
14
A. WALLGREN, C. SlLFVERSWhD AND G. EKLUND
increasing lymphoid infiltration. It has been shown that breast tumours of highgrade malignancy are more likeiy than less malignant tumours to be infiltrated by lymphoid cells (SCHIPIDT 1966, CHAMPION et coll. 1972, FISHER et coll. 1975). On the other hand, some tumours with extensive lymphoid infiltration do better than might be expected (MCDIVITT et coll. 1968). The clinical variables explained little of the variance of survival (Table 6). However, since the selection of the patients for radical surgery was based mainly on the clinical findings, some of the explanatory values of these predictors had already been exploited. The available predictors at the time of radical mastectomy accounted for little of the variance in survival of the patients who were alive after 5 years. Most of the intergroup differences in ten-year rates arose from differences which were already established at 5 years. The explanatory values of the AID analyses were fairly low (Table 6). From the clinical standpoint, however, the possibility of detecting groups of cases in which the outcome may be predicted with a high level of reliability is more important. In contrast to other techniques for multivariate analysis, such as multiple regression, AID analysis leads to a number of subgroups which often are more homogeneous than the original sample with respect to the dependent variable. But since each partitioning represents only one of all the possible splits, the largest possible subgroup with a high or a low value for the dependent variable may remain undetected. The analyses disclosed a number of subgroups with a favourable outcome (Table 5, Figs 2 to 5). The 124 patients with highly or moderately regular tubule formation had 95 per cent five-year and 86 per cent ten-year survival (Table 5, Fig. 3). Of these patients, none with moderate or massive elastosis in the tumour died of the malignancy during the first 5 years after radical mastectomy (Fig. 2). In cases with poor tubule formation or non-tubular type of carcinoma and few mitoses the ten-year survival rate was 93 per cent (Fig. 4). In a group of 89 patients who had had symptoms or signs for more than 3 months, whose tumours did not exceed 2 cm and who had at most one macrometastasis, 95 per cent were still alive after 10 years (Fig. 5). On the other hand, no substantial group with decidedly bad prognosis was revealed. The poorest results were found in 38 patients with 2 or more involved axillary nodes, and massive perinodal growth and whose primary tumours measured more than 2 cm or were multiple. Their ten-year survival rate was 13 per cent. Of 150 patients with two or more involved axillary nodes and tumours with no or poor tubule formation, 34 per cent were alive after 10 years (Fig. 5). The possibility of identifying prognostically distinct groups without the information provided by microscopy of axillary lymph nodes is especially relevant when less radical surgical procedures, such as simple mastectomy or excision of tumour, are contemplated. The present analysis has demonstrated that the clinical predictors and the microscopic features of the primary tumour provide a poor basis for recognizing groups with bad prognosis but permit prediction of a favourable outcome for substantial groups of patients
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
15
SUMMARY The simultaneous prognostic influence of multiple clinical and microscopic features of mammary carcinoma was analysed in 581 women with radical mastectomy. The most important of these features were connected with the extent of the disease in the axillary lymph nodes. In substantial groups of patients, however, a favourable outcome could be predicted from microscopic features of the primary tumour, viz. tubule formation, mitotic frequency and elastosis.
ZUSAMMENFASSUNG Die simultane prognostische Einwirkung von mehreren klinischen Merkmalen und dem mikroskopischen Aussehen des Mammakarzinoms wurde bei 581 Frauen nach radikaler Mastektomie untersucht. Die wichtigsten dieser Parameter waren zur Ausbreitung der Krankheit in den axilliiren Lymphknoten verbunden. In bedeutenden Gruppen von Patienten konnte jedoch eine giinstige Prognose nach dem mikroskopischen Aussehen des Primiirtumors, wie Tubulusformation, Mitosenfrequenz und Elsstosis, vorausgesagt werden.
RBSUMB Sur 581 femmes traitks par mastectomie radicale, les auteurs ont 6tudi6 I’influence pronostique simultank de nombreux caractkres cliniques et microscopiques du cancer du sein. Les plus importants de ces caractbres 6taient en rapport avec l’extension de la maladie dans les ganglions lymphatiques axillaires. Cependant, dans des groupes importants de malades on peut pr6voir un pronostic favorable A partir des caractkres microscopiques de 13 tumeur primitive, en particulier la formation de tubules, la frhuence des mitoses, et I’klistose.
REFERENCES ALDERSON M. R., HAMLIN I. and STAUNTON M. D.: The relative significance of prognostic factors in breast carcinoma. Brit. J. Cancer 25 (1971), 646. ARMITAGE P. and GEHAN A.: Statistical methods for the identification and use of prognostic factors. Int. J. Cancer 13 (1974), 16. AVBNA.: Forslag till losning av signifikansproblemet i AID-analys. (In Swedish.) Research Report. Statistiska Institutionen, Stockholms universitet, Stockholm, 1974. I. W. J. and PRESCOTT R. J.: Histology in breast cancer prognosis. CHAMPION H. R., WALLACE Brit. J. Cancer 26 (1972), 129. F. and WALSTAM R.: Complications in postoperative irradiation of mammary EDSMYR carcinoma. Acta radiol. Ther. Phys. Biol. 1 (1963), 397. EINHORN H. J.: Alchemy in the behavioral sciences. Publ. Opinion Ouart. 36 (1972), 367. FISHER B. and SLACKN.: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg. Gynec. Obstet. 131 (1970), 79. - - and BROSSI. D. J.: Cancer of the breast. Size of neoplasm and prognosis. Cancer 24 (1969), 1071.
FISHER’ E. R., GREGORIO R. M., FISHER B., REDMOND C., VELLIOS F. and SOMMERS S. C.: The pathdlogy of invasive breast cancer. A syllabus derived from findings of the National Surgical,/Adj=gyant m t Project (Protocol No. 4). Cancer 36 (1975), 1. --
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A. WALLGREN, C. SILFVERSWhD AND G. EKLUND
GAVATIN A. and EKLUNDG.: AutQmatic interaction detector (AID) analysis. In: On the role of the viruses in acute infectious diseases of the central nervous system. By B. Skoldenberg. Scand. J. inf. Dis. (1972) Suppl. No. 3, p. 89. HAAGENSEN C. D.: Diseases of the breast. 2nd edition, pp. 449 and 609. W. B. Saunders Company, Philadelphia 1971. HULTBORN K.A. and T~RNBERG B.: Mammary carcinoma. The biologic character of mammary carcinoma studied in 517 cases by a new form of malignancy grading. Acta radiol. (1960) Suppl. No. 196. JEREBB. and EKLUND G.: Factors influencing the cure rate in nephroblastoma. A review of 335 cases. Acta radiol. Ther. Phys. Biol. 12 (1973), 84. MCDIVIITR. W., STEWART F. W. and BERGJ. W.: Tumors of the breast. Atlas of tumor pathology. Second series. Fascicle 2. Armed Forces Institute of Pathology, Washington D. C. 1968. SCARFF R. W. and TORLONI H.: Histological typing of breast tumours. International histological classification of tumours. No. 2. WHO, Geneva 1968. SCHI~DT T.: Breast carcinoma. A histologic and prognostic study of 650 followed-up cases. Munksgaard, Copenhagen 1966. SHIVAS A. A. and DOUGLAS J. G.: The prognostic significance of elastosis in breast carcinoma. J. roy. Coll. Surg. Edinb. 17 (1972), 315. SONQUIST J. A. and MORGAN J. N.: The detection of interaction effects. A report on a computer program for the selection of optimal combinations of explanatory variables. Monograph No. 35. Survey Research Center, Institute for Social Research, The University of Michigan, Ann Arbor, Michigan 1964. - BAKERE. L.and MORGAN J. N.: Searching for structure. Institute for Social Research, The University of Michigan, AM Arbor, Michigan 1971. UICC: TNM classification of malignant tumours, p 39. Geneva 1968. WALLGREN A. and SILFVERSW~~RD C.: Clinical and histological factors of prognostic importance in breast cancer. To be published in Int. J. radiat. Oncol. 1975.
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Prognostic Factors in Mammary Carcinoma A. Wallgren, C Silfverswärd & G. Eklund To cite this article: A. Wallgren, C Silfverswärd & G. Eklund (1976) Prognostic Factors in Mammary Carcinoma, Acta Radiologica: Therapy, Physics, Biology, 15:1, 1-16, DOI: 10.3109/02841867609132703 To link to this article: https://doi.org/10.3109/02841867609132703
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A C T A R A D I O L O G I C A OFFICIAL ORGAN O F THE RADIOLOGICAL SOCIETIES O F D E N M A R K , F I N L A N D , NORWAY A N D SWEDEN
Vol. 15 Fasc. 1
THERAPY PHYSICS BIOLOGY
1976 February
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA A. WALLGREN, C. S I L F V E R S Wand ~ D G. EKLUND An extensive literature exists on the prognostic value of various clinical and microscopic factors in carcinoma of the breast. However, few reports deal with the simultaneous influence of multiple factors on the clinical course of the disease. Many prognostic factors wers defined and adapted for multivariate analysis in a previous & SILFVERSWARD 1975). Some of these factors have now been report (WALLGREN analysed with respect to their bearing on the outcome of 581 cases treated with radical mastectomy. Material and Methods Clinical material. In the period 1961 through 1963, 591 women younger than 70 years, who were admitted for treatment of unilateral, invasive carcinoma of the breast, underwent radical mastectomy without previous irradiation or hormone medication. Ten patients, whose available microscopic slides on re-scrutiny showed pure colloid (mucous) carcinoma were excluded from the material, which thus comprised 58 1 radically mastectomized women. All but 9 received postoperative irradiation. The axillary, supraclavicular and ipsilateral parasternal lymph node regions were irradiated in 382 patients; the parasternal and supraclavicular fields From Radiumhemmet (Director: Prof. J. Einhorn) and the Institute of Tumour Pathology (Director: Prof. G. Moberger), Karolinska Sjukhuset, S-104 01 Stockholm, and the Statistical Institution, dniversity of Stockholm, S-113.47 Stockholm, Sweden. Submitted for publication 10 October 1 9 h . Acta Radiologica Therapy Physics Biology 15 (1976) Fasc. I February 1 - 765844
1
2
A. WALLGREN, C. SILFVERSWARD AND G. EKLUND
Table 1 Variables denoting ‘microscopic’stage of the tumours. n = No. of patients Size of tumour (greatest dimension) 1) < 1 cm (n = 33), 2) 1.1 to 2 cm (n = 250), 3) 2.1 to 5 cm (n = 220), 4) > 5 cm (n = 3 3 , 5) multiple tumours or insufficient data (n =41) Axillary node metastases 1) None (n = 296), 2) micrometastases d 2 mm (n = 25), 3) one macrometastasis (n = 78), 4) 2 to 3 macrometastases (n = 112), 5) 4 or more macrometastaw (n = 70) Perinodal growth 1) No metastases (n = 296), 2) metastases without perinodal growth (n = 103), 3) metastases with possible perinodal growth (n = 40),4) metastaseswith evident perinodal growth (n = 79), 5) metastases with massive perinodal growth (n = 63)
only were irradiated in 186 patients without lymph node metastases. Radiation therapy was confined to the axillary region in the 4 remaining cases. Axillary irradiation consisted of 170 to 190 kV roentgen radiation (HVL approximately 1 mm Cu), a dose of 2 400 R being delivered in 6 fractions to one anterior and one posterior field. For parasternal irradiation a short distance 6oCounit was used (EDSMYR& WALSTAM 1963) or a maximum absorbed dose of 4000 rad was administered in 8 fractions over three weeks, using a 12 to 15 MeV electron beam. The supraclavicular region was included in the anterior axillary field or selectively irradiated in the same way as the parasternal region. Surgical or radiologic castration was performed on 154 patients, most of whom had axillary lymph node metastases. The patients were re-examined at regular intervals. After some years the followup was in some cases continued at other hospitals or by letters to the patients. Local recurrences and distant metastases were treated with conventional methods, including hormonal procedures. Patients who died without clinical- or autopsy evidence of distant metastases were regarded as dead from unrelated causes. However, all deaths within a year of the primary treatment or of treatment for local recurrence were classified as malignancy deaths, as were all those that occurred after distant metastases had been detected. There were no deaths in the immediate postoperative period. A contralateral breast malignancy was regarded as a new primary tumour if there were no signs of distant metastases or of spread of tumour over the midline of the chest wall, in accordance with the clinical rules outlined by HAAGENSEN (1971). Five years after the radical mastectomy distant mestastases had been found in 172 patients, 134 of whom had died of their malignancy. Fifteen other patients had died from unrelated causes. A primary tumour of the contralateral breast had appeared in 9 cases. The-f&ezyear survival rate was 76 per cent and the five-year cure rate 70 per cent.
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
3
Table 2 Microscopic primary tumour variables. n = No, of patients
Microscopic classification 1) Infiltrating lobular (n = 80), 2) medullary with lymphoid infiltration (n = 33), 3) ductal: cribriform or papillary (n=51), 4) ductal: comedo type (n=35), 5 ) duct& no further specification (n = 382) Elastosis 3) moderate (n = 113), 4) massive: large confluent 1) None (n = 286), 2) few small areas (n = a), areas (n = 122) Tubule formation 1) Regular (n = 42), 2) moderately regular or small areas with few tubules (n = 82), 3) poor tubule formation or generally few tubules (n = 346), 4) non-tubular carcinoma types (lobular or medullary) (nslll) Lymphoid infiltration , I ) Occasional lymphatic or plasma cells, no focal areas (n =210), 2) small, scattered foci or narrow circumscribing zone (n=204), 3) numerous large foci or wide circumscribing zone (n=121), 4) massive infiltration throughout tumour (n =46) Size of nuclei 1) Small (n = 83), 2) fairly small (n = 163), 3) fairly large (n = 227), 4) large (n = 108) Variability of size of nuclei 1) None (n = 52), 2) slight (n = 225), 3) moderate (n = 227), 4) marked (n = 77) Contour of nuclei 1) Even (n = 91), 2) slightly uneven (n = 285), 3) uneven (n = 167), 4) irregular (n =38) Mitotic frequency 1) Few mitotic figures; no hyperchromatic nuclei (n = 59), 2) occasional mitoses or small numbers of hyperchromatic nuclei (n = 224), 3) moderate frequency or large numbers of hyperchromatic nuclei (n = 196), 4) many mitotic figures (n = 102) Nucleoli 1) Just discernible (n = 203), 2) clearly discernible (n = 197), 3) enlarged (n = 118), 4) prominent (n = 63)
After ten years 222 of the patients had distant metastases, 204 had died of their malignancy and 39 from unrelated causes. A primary contralateral malignant tumour had been found in 20 patients. The ten-year survival rate was 63 per cent and the tenyear cure rate 60 per cent. Microscopy. Sections or paraffin blocks were available from the primary tumour and the axillary lymph nodes in all cases. The surgical specimens had already been examined in a number of laboratories. The sizes and the numbers of the blocks prepared from the primary tumours and also the numbers of excised lymph nodes varied considerably. As part of the postoperative assessment new slides were prepared and wg~-r&iewedat& Institute of Tumour Pathology. These slides, which were
4
A. WALLGREN, C. SILFVERSWhD AND G. EKLUND
Table 3 Clinical variables. n = No.of patients Clinical stage (UICC 1968) 1) Stage I (n =247), 2) stage I1 (n = 172), 3) stage I11 (n = 108). 4) insufficient data (n = 54) Clinical assessment of tumour 1) Greatest dimension d 2 cm, TI (n = 116), 2) greatest dimension 2.1 to 5 cm, T2 (n = 324), 3) greatest dimension > 5 cm,T3 (n = 86), 4) any size, direct skin or chest wall involvment, T4 (n = 13), 5) not palpable or multiple tumours, insufficient data (n = 42) Clinical assessment of lymph nodes 1) None palpable, NO (n = 297), 2) palpable, considered not malignant, N l a (n = 66), 3) palpable, movable, considered malignant, N l b (n-158), 4) fixed nodes, N 2 (n=22), 5) insufficient data (n = 38) Site of primary tumour 1) Lateral (n = 258), 2) central (n = 173), 3) medial (n = 133) 4) insufficient data (n = 17) Duration of signs and symptoms 1) < 1 month (n = 176), 2) 1 to 3 months (n = 138), 3) 3 to 6 months (n = 62), 4) > 6 months (n = 186), 5) insufficient data (n = 19) Age of patient 1) < 45 years (n = 105), 2) 45 to 54 years (n = 21 l), 3) 55 to 69 years (n = 265)
stained by the van Gieson or haematoxylin-eosin methods, were mainly used in this investigation. If available slides were substandard, new sections were prepared. The slides were examined without knowledge of the clinical course in the case. The lymph node sections were not examined at the same time as the sections from the primary tumours. The microscopic variables were grouped as those pertaining to the extent of the malignant process-the ‘microscopic’ stage (Table 1) and features of the primary ‘microscopic’ stage (Table 1) and features of the primary tumour (Table 2). The definitions largely agree with those in the previous investigation (WALLGREN& SILFVERSWKRD). The clinical variables’ are presented in Table 3. Statistical methods. The analyses were performed with five- and ten-year survival as dependent variables. For calculation of survival rates weights were allotted. The weighting for a patient, who died of unrelated causes or in whom a new malignant tumour was detected in the contralateral breast during the uth year of follow-up, was the calculated risk of dying of malignancy within a -0.5 years in relation to the total risk of death from malignancy during the whole follow-up period, i.e. 5 or 10 years. The cumulative incidence (risk) is illustrated in Fig. 1. The weighted number of patients (patients at risk) was used in all the calculations. Automatic in&a&hn detector ( A m ) analysis was described by SONQUIST & MORGAN (1964) and-was further elaborated by SONQUIST et coll. (1971). It is a computer-
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
5
Fig. 1. Cumulative incidence of deaths from malignancy in 581 patients following radical mastectomy. The weights were used to correct the survival rates for those who died from intercurrent causes or in whom a contralateral mammary carcinoma was detected during the period.
based technique by which the original material is divided into mutually exclusive risk groups through a series of dichotomous splits. Each split is made according to the explaining variable, predictor, that most reduces the variance of the dependent variable. At each step it is easy to survey the alternative possibilities of splitting the clinical material. AID analysis was selected as a suitable method for a multivariate procedure, since the dependent variables were of dichotomous type (dead, alive) and because no assumption was necessary concerning a linear model. The introduction of rules for terminating the partitioning process, based on calculation of the risk of artifact divisions (GAVATIN & EKLUND 1972, JEREB & EKLUND1973, AVBN1974) has reduced the danger of overestimating the explanatory value (EINHORN1972) or of being & GEHAN 1974). In the present ‘misled by the vagaries of small numbers’ (ARMITAGE analysis the partitioning process was terminated when any further split would have produced a subgroup with less than 10 individuals or when the difference between subgroups did not reach the 0.05 significance level. Significance was calculated as described by JFXEB & EKLUND(1973) and by AVBN(1974). Microscopic classification and site of primary tumour, consisting of unordered, non-numerical categories were free predictors, which implies that the order of the coded classes could be rearranged during the analysis. All the other predictors were monotonic. Predictors which comprised a number of observations with missing data and the predictor tubule formation, containing the non-numerical category of non-tubular carcinoma types, were each transformed into two predictors in order to retain their character of monotonic variables (GAVATIN & EKLUND1972). The part of the variance of the dependent variable that could be ascribed to the most important split accomplished by each predictor was calculated. This coefficient of &&& $,was converted to the corresponding correlation coefficient, r.
A. WALLGREN, c. SILWERSWARDAND G. EKLUND
6
Table 4 Correlation between predictors and suwival. In the calculation of coefficients it was assumed that each predictor consisted of two classes formed by the most important split of the material in regard to that predictor. The levels of significance are indicated (* p 0.05). F =free predictor Predictor
Correlation with survival, r 0-5 Y-
Years
-0.18*** - 0.18*** - 0.17*** 0.10* -0.10*
-0.21*** -0.22*** -0.20*** 0.11* - 0.09.
N.S. N.S. N.S. N.S. N.S.
N.S.
N.S.
N.S.
-0.30*** - 0.28*** ' -0.28***
-0.31*** -0.33*** -0.24***
N.S.
-0.25*** -0.23*** -0.19*** +0.16*** -0.16*** 0.14** -0.13** -0.10*
-0.23*** - 0.22*** -0.21*** + 0.23*** -0.13** 0.13** - 0.19*** -0.12** - 0.09*
0-10 YWS
5-10
Clinical variables Stage
Assessment of lymph nodes Assessment of tumour Site of primary tumour (F) Age of patient Duration of signs and symptoms Variables denoting microscopic stage Axillary node metastases Perinodal growth Size of tumour Primary tumour variables Tubule formation Mitotic frequency Variability of size of nuclei Elastosis Nucleoli Microscopic classification (F) Contour of nuclei Size of nuclei Lymphoid infiltration
N.S.
-0.13** -0.18*** -0.221'2 -0.14**
N.S. N.S. -0.10* 0.112
N.S. N.S. N.S.
The advantage of r over r8 is that the direction of the correlation is indicated. The coefficients of determination for the total AID analyses, R2,were also calculated. ReSUltS
The correlation coefficients between the predictors and the dependent variables, viz. the five- and ten-year survival for all the 581 patients and the ten-year survival in the 423 who survived for at least 5 years, appear in Table 4. Clinical predictors. Significant correlations with five- and ten-year survival were found for (1) clinical stage, (2) clinical assessment of lymph nodes and (3) clinical assessment of-tumour (Tabk4+-None of the clinical variables was correlated with the
7
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
Table 5 Groups of factors indicating favourable prognosis. AID analysis with five-year survival as dependent variable
No. of patients
Characteristics
No metastases or metastases but no perinodal growth and few or occasional mitoses (Fig. 4) No metastases and tumour size less than 2 cm Markedly or moderately regular tubule formation (Plus massive or moderate elastosis, Fig. 2) Metastases with possible or evident perinodal growth and moderate or massive elastosis (Fig. 4) Clinical assessment T1 and NO or Nla Patients belonging to at leakt one of these groups
survival (per cent)
203 177 124 65
94 94 95
100
47 104
89 94
370
90
Table 6 Percentage of variance of survival attributable to sets of predictors
Set of predictors
Clinical variables Variables denoting microscopic stage Microscopic features of primary tumour All predictors
AID analysis of survival Syears
1oyears
9 15 10 21
6 17 9 21
ten-year survival among patients who were still alive after 5 years (Table 4). A group with favourable five-year survival, 94 per cent, was identified through the AID analysis (Table 5), viz. l a patients with tumours less than 2 cm (Tl) and possibly without malignant lymph nodes (NO or Nla). Their ten-year survival rate was 77 per cent. The lowest survival rates were found for 61 patients in stage 111 with lymph nodes considered to be involved (Nlb or N2). Their five- and ten-year survival rates were 46 and 35 per cent. The variance of the dependent variable attributable to the clinical predictors was 9 per cent for five-year and 6 per cent for tenyear survival (Table 6). Microscopic stage predictors. (1) Size of tumour, (2) axillary node metastases and (3) perinodal growth were all significantly correlated with five- and ten-year survival (Table 4). These predictors accounted for more of the variance of both five- and tenyeaL&a4 @?= Wand I7 per cent) than did the other predictor groups (Table 6).
8
A. WALLGREN, C. SILFVERSWbD AND G. EKLUND
Table 7 Distribution of cases and survival according to some primary tumour predictors. The most important split of the original material by each predictor is indicated by a dividing line
Predictor
Microscopic classification Ductal: cribriform or papillary Infiltrating lobular Medullary with lymphoid infiltration Ductal: no further specification Ductal: comedo type
Distribution Survival (per cent) (Per cent) Jyears loyears
9 14 6 66 6
94 80 78 76 54
85 -
7 14 59 19
95 95 69 79
90
Elastosis None Small areas Moderate Massive
49 10 19 21
71 55 87 90
-
45 -
Mitotic frequency Few mitoses Occasional mitoses Moderate frequency Many mitoses
10 39 34 18
98 83 70 62
95 69 57 44
76
63
Tubule formation Regular Moderately regular
Poor Non-tubular carcinomas
Total
66 75 61 43
84 53 68
60 68 78
Correlation was also found between size of tumour and axillary node metastases and ten-year survival among patients who were still alive after 5 years. A group with 94 per cent five-year survival rate consisted of 177 patients without metastases and with tumours less than 2 cm in diameter (Table 5), their ten-year survival rate was 86 per cent. The same ten-year survival rate was found in the AID analysis for 191 patients without metastases or with micrometastases and with tumours less than 2 cm. A group with 49 per cent five-year survival rate was identified, viz. 135 patients with two or more involved nodes and with possible, evident or massive perinodal growth. Their ten-year survival rate was 32 per cent. The lowest ten-year survival rate, 13 per cent, was found among 38 patients with two or more involved nodes, massive perimdal growth and whose tumours measured more than 2 cm or were multiple.
9
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
76 %
n = 581
TUBULE FORMATION very ar moderately regular
E LASTOS I S
100 %
n = 65
moderate or massive
NAME OF PREDICTOR characteristic 5 year survival rate,% No. af patients, n
n = 235
TUBULE FORMATION poor or non-tubular
84%
n = 170
.
Fig. 2. AID analysis of the prognostic importance of microscopic primary tumour predictors with five-year survival as dependent variable.
Microscopic primary tumour predictors. Except for lymphoid infiltration all the predictors in this category correlated with both five- and ten-year survival (Table 4). Survival in relation to (1) microscopic classification, (2) tubule formation, (3) elastosis and (4)mitotic frequency appears in Table 7.The result of the AID analysis of the prognostic significance of the microscopic primary tumour predictors when five-year survival was the dependent variable is surveyed in Fig. 2. The predictor that accounted for most of the variance was elastosis, but significant partitions of the original material could have been obtained from tubule formation, mitotic frequency, variability of size of nuclei and contour of nuclei. Moderately or very regular tubule formation was associated with high survival rates, and when this microscopic feature was combined with moderate or massive elastosis (65 patients) no deaths from malignancy (Fig. 2, Table 5) had occurred. The explanatory value, R2,was 10 per cent (Table 6). The analysis, however, did not identify any groups with very poor prognosis. When ten-year survival was the dependent variable (Fig. 3), the material was first split according to tubule formation. The predictors mitotic frequency, variability of size of nuclei, elastosis and nucleoli could also have given significant splits. Two groups with favourable prognosis were thus identified. In tumours with markedly or moderately regular tubule formation the ten-year survival rate was 86 per cent, and when there was poor or no tubule formation with scanty mitoses the corresponding F t e was 93 per cent (Fig. 3). No group with very poor prognosis was identifieb-a2-was-9percent (Table 6).
10
A. WALLGREN, C. SILVVERSWARD AND G. EKLUND
TUBULE FORMATION moderately or very regular
86%
n = 124
T O T A L 63 %
M I T O T I C FREQUENCY
n = 581
very few n = 28
93 % TUBULE FORMATION p”r or non-tubular
NAME OF PREDICTOR c h a r o c t e r i st i c 10 year survival rate, % No. of patients, n
MIT OT IC FREQUENCY occarional,moderote number or many n = 429
Fig. 3. AID analysis of the prognostic importance of microscopic primary tumour predictors with ten-year survival as dependent variable.
89 %
n
= 47
E L A S T 05 I S moderote
or massive n = 77
76 % PERINODAL GROWTH
PERINODAL GROWTH
p a r i b l c , evident ormmrivc n=
182
mmsive I
56 %
N A M E OF P R E D I C T O R chorocterirtic 5 year LUWiYal rote,% No. of patients, n
n
= 30
ELASTOSIS none or m a l l
41 %
~ROI
n = 105
Tubule formation and mitotic frequency were related to ten-year survival in the patients who were still alive after 5 years (Table 4). AID analyses with all predictors QS explaining variables. The most important partitioningo€ the wiginat material with both five- and ten-year survival was obtained with the predictors that denoted extent of the disease in axillary lymph nodes.
11
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
DURATION OF SYMPTOMS
53 mmlmr or data insufficient
95% SIZE OF TUMOUR
6 2 cm
83 %
n = 217
"189
SYMPTOMS - DURATION2 cm or multiple
TUBULE FORMATION ".ry
mad.rot.ly npulor or na-tubulor n = 75
0,
78 % T O T A L
63 %
n = 581
TUBULE FORMATION
TUEULE F O R M I T I O N
very or d s r n t e l y regulm
poor
50%
n = 107
2 or more "I
NAME OF PREDICTOR choractsriitic
182 TUBULE FORMATION p" 0,
34%
non-tubulor n = 150
Fig. 5. AID analysis of the prognostic importance of clinical and microscopic predictors with tenyear survival as dependent variable.
When five-year survival was the dependent variable, perinodal growth was the major predictor. It distinguished the cases without metastases, or with metastases but no perinodal growth, from those with metastases and possible, evident or massive perinodal growth (Fig. 4). The AID analysis demonstrated two prognostically favourable groups (Fig. 4, Table 5), viz. without metastases or with metastases but no perinodal growth and with very few or only occasional mitoses (five-year survival rate 94 per cent) and cases with possible or evident perinodal growth and moderate or massive elastosis (89 per cent five-year survival). The poorest survival rate-41 per cent-was found in 105 cases with possible, evident or massive perinodal growth and no or minimal elastosis. Riwas 21 per cent (Table 6). When ten-year survival was substituted for five-year, the material was first split with regard to axillary node metastases (Fig. 5). Cases with 2 or more involved nodes were separated from cases without metastases or with only micrometastases or one macrometastasis. A group with 95 per cent ten-year survival consisted of 89 patients who had had symptoms or signs for more than three months and whose tumours at operation were less than 2 cm in diameter and had produced at most one macrometastasis in the axillary nodes. By contrast, the ten-year survival rate among 150 patients with two or more involved nodes from tumours with poor tubule formation or from non-tubular carcinoma was only 34 per cent (Fig. 5). RBwas 21 per cent (Table 6). ' Thedalpxwitlrlive-year survival as the dependent variable and with various
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A. WALLGREN, C. SILFVERSWhD A N D G. EKLUND
sets of predictors as explaining variables revealed several groups with high survival rates (Table 5). Of the 581 patients, 370 belonged to at least one of these groups and 90 per cent of them were still alive after 5 years and 78 per cent after 10 years. In the 192 cases with features of at least two of the groups the corresponding,rates were 98 and 88 per cent, respectively. AID analysis was further performed with ten-year survival as the dependent variable and including only those patients who had lived for at least 5 years. Their ten-year survival rate was 83 per cent. Few of the predictors were significantly correlated to that survival (Table 4). Only 7 per cent of the variance of survival could be accounted for.
Discussion Many single features of mammary carcinoma and combinations of a few of these have been demonstrated to influence the outcome, but few reports have appeared in which the prognostic value of multiple factors was simultaneously assessed. ALDERSON et coll. (1971) found from a multiple regression analysis of 15-year survival in patients with operable mammary carcinoma that axillary lymph node metastases, the clinical stage and the size of the tumour were the most important variables independently explaining survival. Other major factors were radiation therapy, which negatively influenced survival, stromal reaction, grade of malignancy and year of treatment. This last variable was positively correlated to survival, i.e. patients who were treated during the later years had higher survival rates than those treated in the earlier years. In order to minimize the time factor, the present analysis was limited to the period 1961 through 1963. Like ALDERSON et coll., it was found that the variables mainly involved in survival were those relating to the extent of the tumour (Table 4, Figs 4, 5). The prognostic influence of the number of involved axillary lymph nodes is well documented in the literature (FISHER& SLACK1970, FISHER et coll. 1975). Since the number of lymph node sections varied considerably within the case series, the estimated numbers of involved nodes probably were too low in some cases. Such underestimation would presumably reduce the value of lymph node involvement as a predictor of prognosis. Perinodal extension of carcinoma has been shown to indicate poor prognosis (HULTBORN & T~RNBERG 1960, MCDIVITTet coll. 1968). In our AID analysis on five-year survival the first split distinguished the cases with possible, evident or massive perinodal growth from those without metastases, or with metastases but no perinodal growth (Fig. 4). The advantage of this predictor over the number of involved nodes is that, whereas the latter may vary as a consequence of the quality of the gross examination of the surgical specimen, nodes with perinodal extension of carcinoma are,most likely to be excised for examination (MCDIVITT et coll.). Tumour - s k i s amother factor of recognized prognostic significance (FISHERet
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
13
coll. (1969). In the present material its explanatory value remained after the material had been split with respect to axillary node metastases (Fig. 5). Tubule formation and mitotic frequency were two important prognostic features of the primary tumours. In contrast to the other microscopic primary tumour predictors, they also exerted a significant influence on the ten-year suririval of the patients who were alive after 5 years (Table 4). Together with ‘irregularity of shape and staining of nuclei’ they are included in the malignancy grading system evolved by SCARFF and BLOOM (SCARFF& TORLONI 1968). Nuclear irregularity was subdivided into the two predictors variability of size and of contour. Both were significantly correlated with five-year survival but not with ten-year survival of patients who where alive after 5 years. Moderate or massive elastosis was found to imply a high five-year survival rate. This is consistent with the finding by SHIVAS & DOUGLAS (1972) of a longer mean survival time in patients who died of mammary tumour when there was gross elastosis. In contrast to FISHER kt coll. (1975), who used slides specifically stained for elastica, diffuse elastosis was not included in the present microscopic grading. Focal areas of elastosis were easily demonstrable in sections stained with van Gieson or haematoxylin-eosin. Elastosis was seen mainly around ducts, but was sometimes visible in the stroma of the tumour. Though in the present investigation elastosis was important as a predictor of five-year survival, it was not significantly correlated with the tenyear survival in patients who had lived for 5 years (Table 4). It seems permissible to assume that moderate or massive degrees of elastosis occur in slowly progressing tumours. Only a few sections from each tumour were examined, however, and the degree of elastosis may have been underestimated in some cases. Relatively few patients, together constituting about 15 per cent of the total series, could be assigned to prognostically distinct groups according to microscopic classification. Pure colloid carcinomas were excluded from the material. Papillary or cribriform appearances in a ductal carcinoma implied a relatively good prognosis (Table 7), as observed also by HAAGENSEN (1971). The small group of comedo carcinoma was found to have a poorer prognosis than other types (Table 7). HULTBORN & T~RNBERG (1960) reported similar findings. In the present material carcinomas were classified as comedo type when the microscopic appearance was that of solid, intraductal growth with central necrosis, irrespective of the relative amounts of the intraductal and the invasive parts. This may explain some of the discrepancy between the present findings and those reported by MCDIVITTet coll. (1968). They found a higher survival rate in comedo carcinoma in a series consisting of predominantly intraductal carcinoma. In medullary carcinoma with lymphoid infiltration the survival rates in the present material were not different from those of other tumour types (Table 7). Like MCDIVITT et coll. it was found that after 5 years few deaths from this type of tumour had occurred. Lymphoid infiltration of the primary tumour was not per se favourable to survival. Indeed, the weak correlation with five-year survival indicated poorer prognosis with
14
A. WALLGREN, C. SlLFVERSWhD AND G. EKLUND
increasing lymphoid infiltration. It has been shown that breast tumours of highgrade malignancy are more likeiy than less malignant tumours to be infiltrated by lymphoid cells (SCHIPIDT 1966, CHAMPION et coll. 1972, FISHER et coll. 1975). On the other hand, some tumours with extensive lymphoid infiltration do better than might be expected (MCDIVITT et coll. 1968). The clinical variables explained little of the variance of survival (Table 6). However, since the selection of the patients for radical surgery was based mainly on the clinical findings, some of the explanatory values of these predictors had already been exploited. The available predictors at the time of radical mastectomy accounted for little of the variance in survival of the patients who were alive after 5 years. Most of the intergroup differences in ten-year rates arose from differences which were already established at 5 years. The explanatory values of the AID analyses were fairly low (Table 6). From the clinical standpoint, however, the possibility of detecting groups of cases in which the outcome may be predicted with a high level of reliability is more important. In contrast to other techniques for multivariate analysis, such as multiple regression, AID analysis leads to a number of subgroups which often are more homogeneous than the original sample with respect to the dependent variable. But since each partitioning represents only one of all the possible splits, the largest possible subgroup with a high or a low value for the dependent variable may remain undetected. The analyses disclosed a number of subgroups with a favourable outcome (Table 5, Figs 2 to 5). The 124 patients with highly or moderately regular tubule formation had 95 per cent five-year and 86 per cent ten-year survival (Table 5, Fig. 3). Of these patients, none with moderate or massive elastosis in the tumour died of the malignancy during the first 5 years after radical mastectomy (Fig. 2). In cases with poor tubule formation or non-tubular type of carcinoma and few mitoses the ten-year survival rate was 93 per cent (Fig. 4). In a group of 89 patients who had had symptoms or signs for more than 3 months, whose tumours did not exceed 2 cm and who had at most one macrometastasis, 95 per cent were still alive after 10 years (Fig. 5). On the other hand, no substantial group with decidedly bad prognosis was revealed. The poorest results were found in 38 patients with 2 or more involved axillary nodes, and massive perinodal growth and whose primary tumours measured more than 2 cm or were multiple. Their ten-year survival rate was 13 per cent. Of 150 patients with two or more involved axillary nodes and tumours with no or poor tubule formation, 34 per cent were alive after 10 years (Fig. 5). The possibility of identifying prognostically distinct groups without the information provided by microscopy of axillary lymph nodes is especially relevant when less radical surgical procedures, such as simple mastectomy or excision of tumour, are contemplated. The present analysis has demonstrated that the clinical predictors and the microscopic features of the primary tumour provide a poor basis for recognizing groups with bad prognosis but permit prediction of a favourable outcome for substantial groups of patients
PROGNOSTIC FACTORS IN MAMMARY CARCINOMA
15
SUMMARY The simultaneous prognostic influence of multiple clinical and microscopic features of mammary carcinoma was analysed in 581 women with radical mastectomy. The most important of these features were connected with the extent of the disease in the axillary lymph nodes. In substantial groups of patients, however, a favourable outcome could be predicted from microscopic features of the primary tumour, viz. tubule formation, mitotic frequency and elastosis.
ZUSAMMENFASSUNG Die simultane prognostische Einwirkung von mehreren klinischen Merkmalen und dem mikroskopischen Aussehen des Mammakarzinoms wurde bei 581 Frauen nach radikaler Mastektomie untersucht. Die wichtigsten dieser Parameter waren zur Ausbreitung der Krankheit in den axilliiren Lymphknoten verbunden. In bedeutenden Gruppen von Patienten konnte jedoch eine giinstige Prognose nach dem mikroskopischen Aussehen des Primiirtumors, wie Tubulusformation, Mitosenfrequenz und Elsstosis, vorausgesagt werden.
RBSUMB Sur 581 femmes traitks par mastectomie radicale, les auteurs ont 6tudi6 I’influence pronostique simultank de nombreux caractkres cliniques et microscopiques du cancer du sein. Les plus importants de ces caractbres 6taient en rapport avec l’extension de la maladie dans les ganglions lymphatiques axillaires. Cependant, dans des groupes importants de malades on peut pr6voir un pronostic favorable A partir des caractkres microscopiques de 13 tumeur primitive, en particulier la formation de tubules, la frhuence des mitoses, et I’klistose.
REFERENCES ALDERSON M. R., HAMLIN I. and STAUNTON M. D.: The relative significance of prognostic factors in breast carcinoma. Brit. J. Cancer 25 (1971), 646. ARMITAGE P. and GEHAN A.: Statistical methods for the identification and use of prognostic factors. Int. J. Cancer 13 (1974), 16. AVBNA.: Forslag till losning av signifikansproblemet i AID-analys. (In Swedish.) Research Report. Statistiska Institutionen, Stockholms universitet, Stockholm, 1974. I. W. J. and PRESCOTT R. J.: Histology in breast cancer prognosis. CHAMPION H. R., WALLACE Brit. J. Cancer 26 (1972), 129. F. and WALSTAM R.: Complications in postoperative irradiation of mammary EDSMYR carcinoma. Acta radiol. Ther. Phys. Biol. 1 (1963), 397. EINHORN H. J.: Alchemy in the behavioral sciences. Publ. Opinion Ouart. 36 (1972), 367. FISHER B. and SLACKN.: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg. Gynec. Obstet. 131 (1970), 79. - - and BROSSI. D. J.: Cancer of the breast. Size of neoplasm and prognosis. Cancer 24 (1969), 1071.
FISHER’ E. R., GREGORIO R. M., FISHER B., REDMOND C., VELLIOS F. and SOMMERS S. C.: The pathdlogy of invasive breast cancer. A syllabus derived from findings of the National Surgical,/Adj=gyant m t Project (Protocol No. 4). Cancer 36 (1975), 1. --
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GAVATIN A. and EKLUNDG.: AutQmatic interaction detector (AID) analysis. In: On the role of the viruses in acute infectious diseases of the central nervous system. By B. Skoldenberg. Scand. J. inf. Dis. (1972) Suppl. No. 3, p. 89. HAAGENSEN C. D.: Diseases of the breast. 2nd edition, pp. 449 and 609. W. B. Saunders Company, Philadelphia 1971. HULTBORN K.A. and T~RNBERG B.: Mammary carcinoma. The biologic character of mammary carcinoma studied in 517 cases by a new form of malignancy grading. Acta radiol. (1960) Suppl. No. 196. JEREBB. and EKLUND G.: Factors influencing the cure rate in nephroblastoma. A review of 335 cases. Acta radiol. Ther. Phys. Biol. 12 (1973), 84. MCDIVIITR. W., STEWART F. W. and BERGJ. W.: Tumors of the breast. Atlas of tumor pathology. Second series. Fascicle 2. Armed Forces Institute of Pathology, Washington D. C. 1968. SCARFF R. W. and TORLONI H.: Histological typing of breast tumours. International histological classification of tumours. No. 2. WHO, Geneva 1968. SCHI~DT T.: Breast carcinoma. A histologic and prognostic study of 650 followed-up cases. Munksgaard, Copenhagen 1966. SHIVAS A. A. and DOUGLAS J. G.: The prognostic significance of elastosis in breast carcinoma. J. roy. Coll. Surg. Edinb. 17 (1972), 315. SONQUIST J. A. and MORGAN J. N.: The detection of interaction effects. A report on a computer program for the selection of optimal combinations of explanatory variables. Monograph No. 35. Survey Research Center, Institute for Social Research, The University of Michigan, Ann Arbor, Michigan 1964. - BAKERE. L.and MORGAN J. N.: Searching for structure. Institute for Social Research, The University of Michigan, AM Arbor, Michigan 1971. UICC: TNM classification of malignant tumours, p 39. Geneva 1968. WALLGREN A. and SILFVERSW~~RD C.: Clinical and histological factors of prognostic importance in breast cancer. To be published in Int. J. radiat. Oncol. 1975.
