Diagnostic Radiology
Prognostic Factors of Breast Neoplasms· Detected on Screening by Mammography and Physical Examination 1 Stephen A. Feig, M.D., Gordon F. Schwartz, M.D., Rudolph Nerlinger, B.S., and Jack Edeiken, M.D.
A total of 183 neoplasms detected on screening women between the ages of 45 and 64 by mammography and physical examination were analyzed according to multiple histologic parameters. In general, tumors apparent only on mammography should be associated with favorable long-term survival because of their early stage. These .lesions had histologic features indicating significant potential for subsequent metastatic spread. This analysis strongly suggests that mammographic screening of asymptomatic women both above and below 50 years of age can substantially reduce breast cancer mortality. INDEX TERMS:
Breast neoplasms, diagnosis. Breast neoplasms, metastases • Breast neoplasms. staging
Radiology 133:577-582, December 1979
mammography and physical examination have been advocated as means of reducing breast cancer mortality; hence it is crucial to. understand their relative contribution towards this goal. One means of dealing with this problem is through the use of pathologic discriminants related to patient survival. These include lesion size, ratio of infiltrating to intraductal growth, histologic type, histologic grade, per cent tubule formation, lymph vessel invasion, and axillary lymph node metastasis. This paper analyzes results of a breast cancer screening project in terms of these pathologic factors.
B
OTH
z
0
100 90
§....
80
0
w
60
....
50
~
w
I
I
40 30
RESULTS
Histologic Type All 183 lesions were classified by histologic type according to the method of McDivitt et al. (23). Of these lesions, 79 % (145/183) were detected by mammography and 54 % (98/183) by physical examination (Fig. 1). Most
rII
c,
20 10 INVASIVE LOBULAR
INVASIVE OUCTAL
TU8uLAR
iii _J I
i :
MiCRO INVASIVE
IN SITU DUCTAL
IN SITU LOBULAR
ALL CANCERS
DUCTAL
MEAN
Of 17,000 self-selected women between the ages of 45 and 64 years, 183 were found to have breast cancer on screening by xeromammography and/or physical examination. The respective studies were independently evaluated by radiologists and clinical physicians specializing in breast diseases. All biopsies, regardless of initial pathologic diagnosis of benign or malignant disease, were reviewed by a single pathologist. This study represents a more complete biopsy case follow-up than has been previously reported on these patients (12, 13,25).
MAMMOGRAPHY PHYSICAL EXAMINATION
I
NO OF CANCERS
PATIENTS AND METHODS
o ~
70 ~
u
ll:
~
LESION SIZE (CM )
9
113
16
20
15
28
24
09
08
02
10 01
183 18
Fig. 1. Relationship of tumor histology to detection of 183 breast tumors by mammography and/or physical examination. Cancers included in more favorable prognostic groups such as tubular, microinvasive ductal, in situ ductal, and in situ lobular were considerably less likely to be found on physical examination and more likely to be evident on mammography than were all cancers in general.
neoplasms, 113 in our series, were of the invasive ductal variety, but the highest survival rates have been reported in other types with more specific histologic designations, such as in situ ductal (3,8,20,24), micro-invasive ductal (less than 10% invasive growth) (26), and tubular carcinoma (9, 10). These have been associated with five-year survival rates of 96-100 % and account for 51 neoplasms in our study. Among them, detection rates by physical examination were by far the lowest, in the range of 1325 %, whereas mammographic detection rates were 85-93%. We found 10 in situ lobular carcinomas, only four of which were palpable. At this stage, lobular carcinoma 'can be cured by surgery (4). If left untreated, a minority of these
1 From the Departments of Radiology (S.A.F., R.N., J. E.) and Surgery (G.F.S.), Thomas Jefferson University Hospital, Philadelphia, PA. Presented at the Sixty-fourth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, IL, Nov. 26-Dec. 1, 1978. Received Nov. 30, 1978; revision requested Jan. 30, 1979; revision accepted June 26. jr Supported by NIH Contract No. 1-CN-35027 from the National Cancer Institute.
577
STEPHEN
578
o
100
70
l.lJ
60
I-
MAMMOGRAPHY
80
0
i= o
FEIG AND OTHERS
~ PHYSICAL EXAMINATION
90
z
A.
l.lJ
0
50
IZ
40
l.lJ U
a::
l.lJ Q.
30 20
LESION SIZE (CM.)
0-0.5
NO OF CANCERS
41
0.51-1.0 33
11-2.0
2.1-30
59
25
3125
Fig. 2. Relationship of lesion size to detection for 183 breast tumors. The performance of physical examination declines as smaller sized lesions are considered, while detection rates for mammography remain high.
100
0 I?Z1
MAMMOGRAPHY PHYSICAL EXAMINATION
90
z i= o
80
0
w w
I-
70
0
I-
Z
w o
a:: w a..
60
50
40
POSITIVE NODES
0
NO OF CANCERS
121
MEAN LESION SIZE (CM)
1.2
1-3 30 3.0
420 3.5
Fig. 3. Relationship of axillary lymph node metastases to method of detection for 171 tumors. Physical examination did least well for 121 lesions without nodal involvement. In this favorable prognostic category, mammography detected 80 % (97/121) of tumors, but only 40%(48/121) were evident on physical examination.
lesions may develop into infiltrating lobular carcinoma, where survival is less than in infiltrating ductal carcinoma (1,4,22,23). Neoplasms representing infiltrating lobular carcinoma were among the largest in size of all lesions detected and the only group where detection by physical examination exceeded detection by mammography.
Stage of Cancer Development Lesion Size: The correlation between tumor size and prognosis has been repeatedly demonstrated in numerous clinical studies (1,2,5-7, 10, 11, 15,23,31). Patients with smaller lesions have a much greater likelihood of long-term
December 1979
survival. For all 183 tumors the mean tumor diameter measured on pathologic examination was 1.6 em. Very small lesions, such as those of in situ ductal and in situ lobular carcinoma, were usually identified on the basis of microcalcifications when seen on mammography (Fig. 1). Figure 2 illustrates that physical examination becomes decreasingly sensitive in the smaller size ranges. For example, of 41 cancers measuring from 0.5 em down to microscopic diameter, 93% (38/41) were found on mammography but only 20% (8/41) palpated. As indicated in the figure, a number of tumors (even among those measuring more than 2.1 ern) were not seen on mammography. The reason for this finding is that the relative efficacy of detection by mammography and physical examination depends not only on lesion size, but also on location within the breast, breast parenchymal density, and breast size (12). Proportion of Infiltrating to Intraductal Growth: Nearly all breast cancers arise in the ducts and lobules but later may break through the basement membrane to invade the breast stroma (18). Another means of relating prognosis to stage of breast cancer development is based on the work of Silverberg and Chitale (26) who foundthat mortality increased as progressive proportions of infiltrating to intraductal growth were attained. Accordingly, invasion of ductal and lobular tumors in our series was classified as being minimal (0-10%), moderate (10-75%), and maximal (75-100%). For each of these three categories, physical examination was less effective than mammography. The disparity between the modalities was greatest for minimally invasive lesions, less for moderately invasive lesions, showing little additional change with further stromal invasion. Lymphatic Vessel and Lymph Node Involvement: Following stromal invasion, breast cancer may infiltrate the breast lymphatics which drain to the regional nodes. Observation of tumor cells in breast lymphatic vessels has been associated with an increased chance of treatment failure (14). Since lymph flow is continuous, histologic examination can detect the presence of intravascular tumor cells only at a particular moment. This finding was demonstrated on biopsy specimens in 27 of 140 patients in whom sufficient histologic material was available. Of these tumors, mammography detected 81 % (22/27) and physical examination 85% (23/27). Of 113 patients in whom lymphatic vessel invasion could not be found, 77 % (87/113) of tumors were detected by mammography and 54% (61/113) by physical examination. Previous investigators have found prognosis to be best in patients without axillary lymph node metastases, intermediate in those with one to three involved nodes, and worst where four or more nodes are involved (15). When our patients were grouped according to these designations (Fig. 3), physical examination performed slightly better than mammography in the latter two categories, probably because nodal involvement is more readily assessed by palpation than by mammographic visualization. Of 121 tumors without axillary metastases, 80 % (97/121) were
579
PROGNOSTIC FACTORS OF BREAST NEOPLASMS
Vol. 133
90
o
100 MAMMOGRAPHY 90
~ PHYSICAL EXAMINATION ~
i=
e
70
o
L&J
I
II
NO. OF CANCERS
27
93
44
MEAN LESION SIZE (CM)
1.0
1.9
2.0
0
MAMMOGRAPHY
~ PHYSICAL EXAMINATION 90
80
70
z
0
60
IL&J
0
50
L&J
u
a::
L&J
CANCERS S2CM NEGATIVE AXILLARY NODES
MINIMAlCANCERS (WANEBO ET AL)
TOTALNO.OFCANCERS
183
105
MEAN LESION SIZE (CM)
1.7
0.9
59 0.5
40
30
20
PER CENT TUBULE FORMATION NO. OF CANCERS MEAN LESION SIZE (CM)
MINIMAL CANCERS (GALLAGER8MARTIN)
42 0.2
JII:
Fig. 4. Relationship of histologic grade in 164 ductal carcinomas to detection by mammography and physical examination. Mean size of Grade I lesions was approximately half that of those in GradesII or III.Because of their smaller size, Grade I lesions were most likely to be occult to physical examination.
a.
ALL CANCERS
Fig. 6. Detection of breast tumors in various prognostic categories. When these are arranged according to increasing long-term survival (from left to right), relative contribution of mammography increases, whereas that of physical examination decreases.
HISTOLOGIC GRADE
z
20
40
20
I-
30
o
30
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u
10
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o
i= u
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~
L&J
L&J
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0:
0
a.
70 60
~
w
60
L&J
a::
MAMMOGRAPHY PHYSICAL EXAMINATION
I-
I-
lZ
~
80
80
z 0 i=
o
Diagnostic Radiology
0-9
10-B9
90-100
110
23
16
2.1
2.1
0.9
Fig. 5. Relationship of tubule formation to detection of 149 invasive ductal and tubular carcinomas. Accuracy of physical examination is inversely proportional to the per cent tubule formation.
seen on mammography, but only 40% (48/121) could be palpated.
Intrinsic Tumor Factors Histologic Grade: Based on nuclear size, shape, staining, mitoses, and-tubule formation, ductal carcinomas may be classified as Grades I (low), II (moderate), or III (high) malignancy. The validity of such a histologic grading system as a prognostic indicator was established by Bloom (5-7) and subsequently confirmed by other investigators (2, 14,29). Histologic grading is believed to reflect intrinsic tumor aggressiveness. Among early cancers of similar size, Grade I lesions have the least immediate potential for metastatic spread. Of 27 Grade I tumors in our study, 89 % (24/27) were apparent on mammography and 26 % (7/27) on physical examination (Fig. 4). Detection rates by physical examination for Grade II and III lesions were higher than those for Grade I lesions but still less than those obtained by mammography. Tubule Formation: Most invasive ductal carcinomas are characterized by a loss of normal ductal morphology. A minority show well preserved tubules. Tubular carcinoma can be defined as a histologic Grade I invasive ductal carcinoma with 90 % or greater tubule formation. There were 16 such lesions in our study (Fig. 1), and in these cases excellent long-term survival can be expected. Improved survival has also been seen in lesions containing lesser degrees of tubule formation. Several studies indicate that survival may be proportional to the degree of tubule formation (5, 14, 31). Data from our study indicate that accuracy of physical examination decreases with increasing tubule formation. This was most apparent for pure tubular carcinoma where 88 % (14/16) of lesions were found by mammography but only 25 % (4/16) by physical examination (Fig. 5). Tumor Margins: Although several investigators have suggested that neoplasms with a well delimited border on
STEPHEN A. FEIG AND OTHERS
580
100
HISTOLOGIC GRADE 100
90
90 ff)
~
80
~
70
ll: W
III
u
w
Prognostic Factors of Breast Neoplasms· Detected on Screening by Mammography and Physical Examination 1 Stephen A. Feig, M.D., Gordon F. Schwartz, M.D., Rudolph Nerlinger, B.S., and Jack Edeiken, M.D.
A total of 183 neoplasms detected on screening women between the ages of 45 and 64 by mammography and physical examination were analyzed according to multiple histologic parameters. In general, tumors apparent only on mammography should be associated with favorable long-term survival because of their early stage. These .lesions had histologic features indicating significant potential for subsequent metastatic spread. This analysis strongly suggests that mammographic screening of asymptomatic women both above and below 50 years of age can substantially reduce breast cancer mortality. INDEX TERMS:
Breast neoplasms, diagnosis. Breast neoplasms, metastases • Breast neoplasms. staging
Radiology 133:577-582, December 1979
mammography and physical examination have been advocated as means of reducing breast cancer mortality; hence it is crucial to. understand their relative contribution towards this goal. One means of dealing with this problem is through the use of pathologic discriminants related to patient survival. These include lesion size, ratio of infiltrating to intraductal growth, histologic type, histologic grade, per cent tubule formation, lymph vessel invasion, and axillary lymph node metastasis. This paper analyzes results of a breast cancer screening project in terms of these pathologic factors.
B
OTH
z
0
100 90
§....
80
0
w
60
....
50
~
w
I
I
40 30
RESULTS
Histologic Type All 183 lesions were classified by histologic type according to the method of McDivitt et al. (23). Of these lesions, 79 % (145/183) were detected by mammography and 54 % (98/183) by physical examination (Fig. 1). Most
rII
c,
20 10 INVASIVE LOBULAR
INVASIVE OUCTAL
TU8uLAR
iii _J I
i :
MiCRO INVASIVE
IN SITU DUCTAL
IN SITU LOBULAR
ALL CANCERS
DUCTAL
MEAN
Of 17,000 self-selected women between the ages of 45 and 64 years, 183 were found to have breast cancer on screening by xeromammography and/or physical examination. The respective studies were independently evaluated by radiologists and clinical physicians specializing in breast diseases. All biopsies, regardless of initial pathologic diagnosis of benign or malignant disease, were reviewed by a single pathologist. This study represents a more complete biopsy case follow-up than has been previously reported on these patients (12, 13,25).
MAMMOGRAPHY PHYSICAL EXAMINATION
I
NO OF CANCERS
PATIENTS AND METHODS
o ~
70 ~
u
ll:
~
LESION SIZE (CM )
9
113
16
20
15
28
24
09
08
02
10 01
183 18
Fig. 1. Relationship of tumor histology to detection of 183 breast tumors by mammography and/or physical examination. Cancers included in more favorable prognostic groups such as tubular, microinvasive ductal, in situ ductal, and in situ lobular were considerably less likely to be found on physical examination and more likely to be evident on mammography than were all cancers in general.
neoplasms, 113 in our series, were of the invasive ductal variety, but the highest survival rates have been reported in other types with more specific histologic designations, such as in situ ductal (3,8,20,24), micro-invasive ductal (less than 10% invasive growth) (26), and tubular carcinoma (9, 10). These have been associated with five-year survival rates of 96-100 % and account for 51 neoplasms in our study. Among them, detection rates by physical examination were by far the lowest, in the range of 1325 %, whereas mammographic detection rates were 85-93%. We found 10 in situ lobular carcinomas, only four of which were palpable. At this stage, lobular carcinoma 'can be cured by surgery (4). If left untreated, a minority of these
1 From the Departments of Radiology (S.A.F., R.N., J. E.) and Surgery (G.F.S.), Thomas Jefferson University Hospital, Philadelphia, PA. Presented at the Sixty-fourth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, IL, Nov. 26-Dec. 1, 1978. Received Nov. 30, 1978; revision requested Jan. 30, 1979; revision accepted June 26. jr Supported by NIH Contract No. 1-CN-35027 from the National Cancer Institute.
577
STEPHEN
578
o
100
70
l.lJ
60
I-
MAMMOGRAPHY
80
0
i= o
FEIG AND OTHERS
~ PHYSICAL EXAMINATION
90
z
A.
l.lJ
0
50
IZ
40
l.lJ U
a::
l.lJ Q.
30 20
LESION SIZE (CM.)
0-0.5
NO OF CANCERS
41
0.51-1.0 33
11-2.0
2.1-30
59
25
3125
Fig. 2. Relationship of lesion size to detection for 183 breast tumors. The performance of physical examination declines as smaller sized lesions are considered, while detection rates for mammography remain high.
100
0 I?Z1
MAMMOGRAPHY PHYSICAL EXAMINATION
90
z i= o
80
0
w w
I-
70
0
I-
Z
w o
a:: w a..
60
50
40
POSITIVE NODES
0
NO OF CANCERS
121
MEAN LESION SIZE (CM)
1.2
1-3 30 3.0
420 3.5
Fig. 3. Relationship of axillary lymph node metastases to method of detection for 171 tumors. Physical examination did least well for 121 lesions without nodal involvement. In this favorable prognostic category, mammography detected 80 % (97/121) of tumors, but only 40%(48/121) were evident on physical examination.
lesions may develop into infiltrating lobular carcinoma, where survival is less than in infiltrating ductal carcinoma (1,4,22,23). Neoplasms representing infiltrating lobular carcinoma were among the largest in size of all lesions detected and the only group where detection by physical examination exceeded detection by mammography.
Stage of Cancer Development Lesion Size: The correlation between tumor size and prognosis has been repeatedly demonstrated in numerous clinical studies (1,2,5-7, 10, 11, 15,23,31). Patients with smaller lesions have a much greater likelihood of long-term
December 1979
survival. For all 183 tumors the mean tumor diameter measured on pathologic examination was 1.6 em. Very small lesions, such as those of in situ ductal and in situ lobular carcinoma, were usually identified on the basis of microcalcifications when seen on mammography (Fig. 1). Figure 2 illustrates that physical examination becomes decreasingly sensitive in the smaller size ranges. For example, of 41 cancers measuring from 0.5 em down to microscopic diameter, 93% (38/41) were found on mammography but only 20% (8/41) palpated. As indicated in the figure, a number of tumors (even among those measuring more than 2.1 ern) were not seen on mammography. The reason for this finding is that the relative efficacy of detection by mammography and physical examination depends not only on lesion size, but also on location within the breast, breast parenchymal density, and breast size (12). Proportion of Infiltrating to Intraductal Growth: Nearly all breast cancers arise in the ducts and lobules but later may break through the basement membrane to invade the breast stroma (18). Another means of relating prognosis to stage of breast cancer development is based on the work of Silverberg and Chitale (26) who foundthat mortality increased as progressive proportions of infiltrating to intraductal growth were attained. Accordingly, invasion of ductal and lobular tumors in our series was classified as being minimal (0-10%), moderate (10-75%), and maximal (75-100%). For each of these three categories, physical examination was less effective than mammography. The disparity between the modalities was greatest for minimally invasive lesions, less for moderately invasive lesions, showing little additional change with further stromal invasion. Lymphatic Vessel and Lymph Node Involvement: Following stromal invasion, breast cancer may infiltrate the breast lymphatics which drain to the regional nodes. Observation of tumor cells in breast lymphatic vessels has been associated with an increased chance of treatment failure (14). Since lymph flow is continuous, histologic examination can detect the presence of intravascular tumor cells only at a particular moment. This finding was demonstrated on biopsy specimens in 27 of 140 patients in whom sufficient histologic material was available. Of these tumors, mammography detected 81 % (22/27) and physical examination 85% (23/27). Of 113 patients in whom lymphatic vessel invasion could not be found, 77 % (87/113) of tumors were detected by mammography and 54% (61/113) by physical examination. Previous investigators have found prognosis to be best in patients without axillary lymph node metastases, intermediate in those with one to three involved nodes, and worst where four or more nodes are involved (15). When our patients were grouped according to these designations (Fig. 3), physical examination performed slightly better than mammography in the latter two categories, probably because nodal involvement is more readily assessed by palpation than by mammographic visualization. Of 121 tumors without axillary metastases, 80 % (97/121) were
579
PROGNOSTIC FACTORS OF BREAST NEOPLASMS
Vol. 133
90
o
100 MAMMOGRAPHY 90
~ PHYSICAL EXAMINATION ~
i=
e
70
o
L&J
I
II
NO. OF CANCERS
27
93
44
MEAN LESION SIZE (CM)
1.0
1.9
2.0
0
MAMMOGRAPHY
~ PHYSICAL EXAMINATION 90
80
70
z
0
60
IL&J
0
50
L&J
u
a::
L&J
CANCERS S2CM NEGATIVE AXILLARY NODES
MINIMAlCANCERS (WANEBO ET AL)
TOTALNO.OFCANCERS
183
105
MEAN LESION SIZE (CM)
1.7
0.9
59 0.5
40
30
20
PER CENT TUBULE FORMATION NO. OF CANCERS MEAN LESION SIZE (CM)
MINIMAL CANCERS (GALLAGER8MARTIN)
42 0.2
JII:
Fig. 4. Relationship of histologic grade in 164 ductal carcinomas to detection by mammography and physical examination. Mean size of Grade I lesions was approximately half that of those in GradesII or III.Because of their smaller size, Grade I lesions were most likely to be occult to physical examination.
a.
ALL CANCERS
Fig. 6. Detection of breast tumors in various prognostic categories. When these are arranged according to increasing long-term survival (from left to right), relative contribution of mammography increases, whereas that of physical examination decreases.
HISTOLOGIC GRADE
z
20
40
20
I-
30
o
30
L&J
u
10
SO
o
i= u
40
~
L&J
L&J
50
~
0:
0
a.
70 60
~
w
60
L&J
a::
MAMMOGRAPHY PHYSICAL EXAMINATION
I-
I-
lZ
~
80
80
z 0 i=
o
Diagnostic Radiology
0-9
10-B9
90-100
110
23
16
2.1
2.1
0.9
Fig. 5. Relationship of tubule formation to detection of 149 invasive ductal and tubular carcinomas. Accuracy of physical examination is inversely proportional to the per cent tubule formation.
seen on mammography, but only 40% (48/121) could be palpated.
Intrinsic Tumor Factors Histologic Grade: Based on nuclear size, shape, staining, mitoses, and-tubule formation, ductal carcinomas may be classified as Grades I (low), II (moderate), or III (high) malignancy. The validity of such a histologic grading system as a prognostic indicator was established by Bloom (5-7) and subsequently confirmed by other investigators (2, 14,29). Histologic grading is believed to reflect intrinsic tumor aggressiveness. Among early cancers of similar size, Grade I lesions have the least immediate potential for metastatic spread. Of 27 Grade I tumors in our study, 89 % (24/27) were apparent on mammography and 26 % (7/27) on physical examination (Fig. 4). Detection rates by physical examination for Grade II and III lesions were higher than those for Grade I lesions but still less than those obtained by mammography. Tubule Formation: Most invasive ductal carcinomas are characterized by a loss of normal ductal morphology. A minority show well preserved tubules. Tubular carcinoma can be defined as a histologic Grade I invasive ductal carcinoma with 90 % or greater tubule formation. There were 16 such lesions in our study (Fig. 1), and in these cases excellent long-term survival can be expected. Improved survival has also been seen in lesions containing lesser degrees of tubule formation. Several studies indicate that survival may be proportional to the degree of tubule formation (5, 14, 31). Data from our study indicate that accuracy of physical examination decreases with increasing tubule formation. This was most apparent for pure tubular carcinoma where 88 % (14/16) of lesions were found by mammography but only 25 % (4/16) by physical examination (Fig. 5). Tumor Margins: Although several investigators have suggested that neoplasms with a well delimited border on
STEPHEN A. FEIG AND OTHERS
580
100
HISTOLOGIC GRADE 100
90
90 ff)
~
80
~
70
ll: W
III
u
w
