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Ductal Carcinoma of the Breasts
Path. Res. Pract. 187,62-67 (1991)
Ductal Carcinoma of the Breast! An Analysis of Proportions of Intraductal and Invasive Components A. Matsukuma and M. Enjoji Second Department of Pathology, Faculty of Medicine, Kyushu University, Japan
S. Toyoshima Clinical Laboratory of Kitakyushu City Kokura Hospital, Japan
SUMMARY One hundred and ninety patients with mammary ductal carcinoma were studied to evaluate the correlation of proportions of intraductal and invasive tumor growth to histologic and immunohistochemical features. Initially, attempts were made to divide the cases into 6 groups according to the proportion of extraductal invasive areas within the whole tumor. It has been found that ductal carcinoma could be divided, on this criterion, into 2 groups. One comprised tumors in which invasive areas made up less than 20% ofthe tumor, the other included those with invasive areas exceeding 20%. In the former, intraductal and invasive components exhibited a lower grade of nuclear and tumor component and a higher incidence of cells with CEA immune positivity. The latter manifested higher grades in both intraductal and invasive components and a lower incidence of CEA positive cells. Many of the latter tumors had a solid or comedo-like growing pattern of the intraductal component. There was a significant difference in the prognosis between the two categories. We conclude that like intraductal carcinomas, invasive ductal carcinomas with a predominant intraductal component should be considered a lower grade malignancy.
Introduction Ductal carcinoma is the most common type in mammary carcinoma. It includes non-invasive and invasive tumors, depending on the presence or absence of extraductal stromal invasion. The World Health Organization suggested that, among invasive ductal carcinomas (IDC), tumors in which the amount of the intraductal carcinoma is at least four times greater than that of the invasive component would carry a more favorable prognosis than other invasive ductal carcinomas with a wider expansion of growth. These particular tumors have been differentiated from others as an invasive ductal carcinoma with a This study is supported in part by a grant from the Japanese Breast Cancer Society. 1
0344-0338/91/0187-0062$3.50/0
predominant intraductal component (IDC with PIC)8. There have been, however, only few comprehensive studies on the clinicopathologic significance of proportions of intraductal and invasive growth of ductal carcinoma of the breast? We investigated possible correlations between extraductal invasiveness and other parameters in an attempt to clarify the heterogeneous nature of ductal carcinoma with a propensity toward extraductal invasion. Material and Methods The material examined consisted of 17 non-invasive intraductal carcinomas and 173 invasive ductal carcinomas (IDC), including 28 cases of IDC with PIC. All patients were women who © 1991 by Gustav Fischer Verlag, Stuttgart
Ductal Carcinoma of the Breast . 63 had been treated with standard or modified radical mastectomy between 1974 and 1983. In no patient there was a bilateral breast tumor. Clinical histories, descriptions of gross features and histologic slides of the mastectomy specimens and preoperative biopsy materials were available for all patients. The average number of histologic sections examined for the primary tumor was 6.0 per case. All sections were stained with hematoxylin and eosin. The maximum diameter of the tumor was measured grossly on the cut sections and confirmed or corrected by histologic slides. According to the proportion of extraductal invasive area to the whole tumor, the cases could be separated into 6 groups: intraductal carcinoma (17); invasive ductal carcinoma (IDC) with an invasive component in minimal to 20% (28); IDC with a 20-50% invasive component (11); IDC with a 50-80% invasive component (17); IDC with an 80-100% invasive component (84); and pure invasive carcinoma without any intraductal component (33 cases). The second group was considered to be comparable to the IDC with PIC of the WHO classifications. These groups were studied with regard to clinical and pathologic features such as age of the patients, size of the tumor, tumor grade of invasive component, histologic pattern and nuclear grade of intraductal component, lymph node metastasis and clinical outcome. Tumor grade of the invasive component and nuclear grade of the intraductal component were assessed by the systems of Bloom and Richardson 2 and Black et al. I, respectively. Tumor grade I indicates a well-differentiated lesion and grade III a poorly differentiated one, categorizing an intermediate lesion between the two as grade II. In 10 of the 28 with IDC with PIC, the extent of stromal invasion was too slight to evaluate the grade. Nuclear grade of intraductal component was classified into low, intermediate and high. The histologic pattern of intraductal component was classified into micropapillary, papillary, cribriform, comedo and solid types S,6.
Representative sections from the 149 cases were examined immunohistochemically for carcinoembryonic antigen (CEA), using the avidin-biotin-peroxidase complex (ABC) method. The mouse monoclonal anti-CEA antibody was purchased from Zymed (San Francisco, CA, USA), the nonspecific cross-reacting antigen (NCA) absorbed polyclonal rabbit anti-CEA antiserum was from Milab (Malmo, Sweden) and the non-absorbed polyclonal rabbit antiserum was from Dakopatts (Copenhagen, Denmark). Avidin and biotin reagents were obtained from Vector Laboratories (Vectasin ABC Kit PK-4001, 4002, Burlingame, CA, USA). The reactivities of the intraductal and invasive components were assessed separately in each case. The status of regional lymph node involvement was classified after the General Rules for Clinical and Pathological Recording of Breast Cancer formulated by the Japanese Breast Cancer Society: no, no metastases; nl alpha, positive in less than 3 axillary or interpectoral nodes; n I beta, positive in more than 4 axillary or interpectoral nodes; n2, positive in subclavicular nodes; n3, positive in supraclavicular nodes. Involvement of parasternal nodes was categorized as nl beta for cases with tumors in the median half of the breast and n2 for cases with tumors in the lateral half of the breast 4• Statistical analyses were performed using the chi-square contingency tables and Fisher's exact probability test. The KaplanMeyer method was used to calculate the post-operative survival rate and to determine whether the difference was statistically significant.
Results
Patients ranged from 23 to 80 years of age with a mean of 51.7. There was no significant difference in age of the
Table 1. Mean tumor size and histologic patterns of intraductal component related to the proportion of extraductal invasive growth Degree of invasion No of cases Intraductal
17
Mean size ± SD 4.3 ± 2.9
Mp
Pap
3
2
Histologic patterns Cri Com 5
Sol 2
5
'--------v---'
10 (58.8) IDC with PIC
28
5.2 ± 2.7
5
6
7 (41.2) 9
20 (71.4) 20-50%
11
4.5 ± 1.9
0
2
2
6 8 (28.6)
3
6
0
'--------v---'
5 (45.5) 50-80%
17
3.4 ± 2.6
3
1
6 (54.5) 4
7
8 (47.1) 80-100%
84
3.5 ± 2.3
6
5
9 (52.9) 23
34 (40.5) Pure invasive Total
33
2.4 ± 1.5
190
3.7 ± 2.4
Mp = Micropapillary, Pap group.
157
17 (10.8)
16 (10.2)
= Papillary, Cri = Cribriform, Com = Comedo, Sol = Solid. -
2
32
18 50 (59.5)
44 (28.0)
56 (35.7)
24 (15.3)
Figures in brackets show % of cases in each
64 . A. Matsukuma and M. Enjoji and S. Toyoshima
patients by different proportions of invasive component. Table 1 shows the mean size of tumors and histologic patterns of the intraductal component by different proportions of the invasive component. There was a tendency toward smaller tumor size in cases with a greater proportion of invasive growth and it probably reflected that invasive growth could lead to form palpable lesions more easily than intraductal spreading growth. Regarding the histological patterns of intraductal growth, one pattern was often combined with others in the same case, particularly in those with an extensive intraductal growth. These cases were classified on the basis of dominant pattern. Approximately 70% (30/45) of cases with intraductal carcinoma or IDC with PIC showed evidence of a micropapillary, papillary or cribriform growth, while in about 60% (65/112) of those with greater areas of invasion, there was a comedo or solid growth of the intraductal components. This difference in the pattern of intraductal growth was statistically significant (p < 0.01). Table 2 shows the nuclear grade of intraductal component of IDC with different proportions of invasion. Approximately 70% (30/45) of the cases with non-
invasive carcinoma and IDC with PIC had low-grade nuclei (Fig. 1). On the other hand, over 70% (79/112) of the cases with more widely invasive tumors showed intermediate or high-grade nuclei (Fig. 2). This difference
Table 2. Nuclear grade of intraductal component related to proportion of extraductal growth Degree of InvaSion
No of cases
Nuclear grade Low
Intraductal carcinoma IDC with PIC 20- 80% 80-100% Fig. 1. Intraductal carcinoma growing in a cribriform pattern. The tumor cells have low-grade nuclei (H & E, X 290).
Total
Intermediate
High
17
12 (70.6)
4 (23.5)
1 (5.9)
28 28 84
18 (64.3) 9 (32.1) 24 (28.6)
10 (35.7) 14 (50.0) 44 (52.4)
0 5 (17.9) 16 (19.0)
157
63 (40.1)
72 (45.9)
22 (14.0)
Figures in brackets show % of cases in each group.
Ductal Carcinoma of the Breast . 65
was again statistically significant (p < 0.01). No highgrade nuclei were observed in 77 cases with the intraductal components arranged in a micropapillary, papillary or cribriform pattern. Nineteen (33.9%) of the 56 with a comedo intraductal component and 3 (12.5%) of the 24 cases with a simply solid intraductal component had high-grade nuclei. Table 3 shows the tumor grade of the invasive component. More than 50% of cases ofIDC with PIC were of low tumor grade (grade I), while about 80% (112/145) of those with a greater invasion were of intermediate or high tumor grade (Fig. 3). The difference in the tumor grade between the former with IDC with PIC and the latter was also statistically significant (p < 0.01). In addition, there was a close correlation between nuclear grade of intraductal component and tumor grade of invasive component in each case. Cases showing low-grade nuclei in their intraductal components usually revealed well-differentiated features in their invasive areas and vice versa.
Table 3. Tumor grade of invasive component related to proportion of extraductal invasive growth Degree of InvaSion IDC with PIC 20- 80% 80-100% Pure invasive Total
No of cases 18 28 84 33 163
Tumor grade Grade I
Grade II
Grade III
10 6 21 6
7 18 43 21
1 4 20 6
(55.6) (21.4) (25.0) (18.2)
43 (26.4)
(38.9) (64.3) (51.2) (63.6)
89 (54.6)
(5.6) (14.3) (23.8) (18.2)
31 (19.0)
Figures in brackets show % of cases in each group.
The results of immunoreactivity to monoclonal antiCEA antibody and to NCA absorbed polyclonal antiserum were much the same (Table 4). Significantly, the tissues with an intraductal carcinoma and IDC with PIC were more frequently composed of intraductal (p < 0.01) and invasive (p < 0.05) components positive for CEA than were those ofIDC with greater invasion (Fig. 4). Reactivity to monoclonal antibody and absorbed antiserum depended on the nuclear grade of the intraductal component and on the tumor grade of the invasive component. Thirty-six (73.5%) of the 49 with intraductal components having low-grade nuclei, 35 (57.4%) of the 61 with intermediate grade nuclei and 3 (18.8%) of the 16 with high grade nuclei were CEA positive with the monoclonal antibody. Use of non-absorbed CEA antiserum showed an even higher incidence of positivity in tumors of all grades but no grade-dependency. Lymph node status is summarized in Table 5. Metastases in cases of intraductal carcinoma were never observed. Five cases of IDC with PIC had less than three positive nodes in the axilla. In all these cases, there was a stromal invasion measuring over 8 mm in the largest diameter. As the proportion of invasive component Table 4. CEA positivity of intraductal and invasive component Degree of in- No of cases m-antibody vasion (Zymed)
p-antiserum (NCA-absorbed, Milab)
Intraductal carCInoma
Duct 13
12/13 (92.3)
12/13 (92.3)
IDC with PIC Duct 22 Inv 11
21/22 (95.5) 9/11 (81.8)
21/22 (95.5) 8/11 (72.7)
20- 80% InvaSIOn
Duct 23 Inv 23
10/23 (43.5) 8/23 (34.8)
10/23 (43.5) 8/23 (34.8)
80-100% invasion
Duct 68 Inv 70
31/68 (45.6) 29/70 (41.4)
35/68 (51.5) 35/70 (50.0)
Pure invasive Inv Fig. 3. Photomicrograph of an invasive ductal carcinoma showing more than 80% stromal invasion. Note high-grade nuclei of the intraductal component and of the poorly differentiated invasive component (grade III) (H & E, X 210).
20
9/20 (45.0)
9/20 (45.0) (%)
m-antibody = Monoclonal antibody, p-antiserum = Polyclonal antiserum, Zymed = San Francisco, CA, USA, Milab = Malmo, Sweden, Duct = Intraductal component, Inv = Invasive component.
66 . A. Matsukuma and M. Enjoji and S. Toyoshima Table 5. Regional lymph node involvement related to proportion of extraductal invasive growth Degree of invasion Intraductal carcinoma IDC with PIC 20- 80% 80-100% Pure invasive Total n 1a
No of cases
nOn 1a n 1b n 2 n 3 % n+
17 28 28 84 33
17 0 23 5 17 6 44 17 27 4
0 0 2 11 0
0 0 3 9 2
0 0 0 3 0
0 17.9 39.3 47.6 18.2
190
128 32
13
14
3
32.6
= n 1 alpha, n 1b = n 1 beta.
invasive component (p < 0.05 and p < 0.001, respectively). However, there was no significant difference in the survival rate between those with 20-80% invasion and those with over 80% of invasion. Discussion
~Yl~'
, ", ~"V.:r" ~: .
~
'~,
I·
,j
.
(,,,~ .' t'
." Fig. 4. In a case of invasive ductal carcinoma with a predominant intraductal component, both intraductal and invasive components were CEA positive, as examined by a monoclonal antibody. Nuclei of the intraductal component are graded low and the invasive component is well differentiated (grade I) in this IDC with PIC (ABC immunostain, x 40).
Silverberg and Chitale studied a series of 267 mammary carcinomas inclusive of both intraductal and infiltrating duct types and found no axillary nodal metastases and no tumor-related deaths among patients with pure intraductal carcinoma. However, in patients with tumors of a minimal (less than 10%) stromal invasion there was a low but significant incidence of metastases and mortality. In tumors with increasing proportions of invasive growth, there was a progressive increase both in nodal metastases and mortality? More recently, Patchefsky et al. pointed out the heterogeneous nature of intraductal carcinomas, as noted in their study on 55 intraductal carcinomas, includ100%
A B
C
t.:I
Eo<
<
increased, more distant and a greater number of nodes were involved. Pure invasive ductal carcinoma showed a low incidence of metastasis probably because of the smaller size of the tumor, as given among the data in Table 1. Of the 190 patients studied, 12 were lost to follow-up, 29 died of recurrent disease, 12 died of other diseases and 3 died of undetermined causes. In 22, tumor-related death occurred within 5 years and the other 7 died between 5 and 10 years after surgical treatment. Three patients now have a recurrence. There were neither tumor-related deaths nor recurrent disease among patients with an intraductal carcinoma and IDC with PIC. The 10-year survival rates were 84.1 % in those with invasive component in 20-80% of the entire tumor and 75.1 % in those with over 80% of these components (Fig. 5). There were significant differences in the survival curves between those with less than 20% invasion and those with 20-80% or over 80%
~
.-l
<
:>
....
50%
:>
~
::> en
5
10
SURVI VAL (years)
Fig. 5. Survival of patients with mammary ductal carcinoma according to the proportion of invasive growth; A.less than 20% invasion (intraductal carcinoma and IDC with PIC), B. 20-80% invasion, C. more than 80% invasion. There were significant differences in the survival curves between A and B (p < 0.05) and A and C (p < 0.001), and no significant differences between B and C.
Ductal Carcinoma of the Breast . 67 ing cases with microinvasion which had been detected by clinical signs, mammographic examination or incidental to benign diseases. They found differences in the biologic character of intraductal carcinomas with the histologic types and stressed that comedocarcinomas had a higher incidence of microinvasion and a higher nuclear grade than did carcinomas of other histologic types. If all ductal carcinomas arising in mammary ducts were in a constant progression toward extraductal invasion, there would be a wide spectrum of proportions of intraductal components and the proportions of intraductal growth should be distributed rather uniformly from 100% (intraductal carcinoma) to 0% (pure invasive carcinoma). Nevertheless, the number of cases with 10-89% invasion in one study? (42/267) and that of the cases with 20-80% invasion in our study (28/190) were smaller than expected. Many of the cases (197/267 in the former and 117/190 of the latter series) were included in categories of tumors with extensive stromal invasion (over 90% in the former and over 80% in the later series) at the time of diagnosis. Such a disproportion in the distribution of cases of intraductal and invasive components suggested that ductal carcinomas can be divided into two main categories, depending on the propensity to extraductal invasion. One tends to extraductal invasion from the early phase of development and the other retains in situ or intraductal growth to a considerable extent before stromal invasion occurs. In most of our patients with IDC with PIC, the features of the tumor were essentially similar to those seen in an intraductal carcinoma, particularly in histologic pattern and nuclear grade of intraductal component. These tumors also presented an invasive component with less aggressive features. Cases with a greater proportion (more than 20%) of invasive component, however, showed significantly different features in both invasive and intraductal components. More than 80% of the tumors characterized by a comedo or by a solid growth pattern within the ducts had more than 20% areas of stromal invasion. High-grade nuclei were observed almost exclusively in those with the two growth patterns, comedo or simply solid, except for cases of intraductal carcinoma and IDC with PIC. These two patterns of intraductal growth seem to give rise to extraductal invasion. There have been conflicting data about the correlation between the presence of CEA and the grade of tumor differentiation in carcinomas of the breast3,9, 10. Walker found that a grade-dependency was evident for the CEA positivity of tumors, determined by using an antiserum after absorption of NCAlo. We used three different antibodies and the monoclonal antibody and NCAabsorbed antiserum showed a similar degree of staining,
thereby confirming that the presence of CEA was dependent primarily on tumor differentiation. A cross-reaction of NCA misinterpreted as CEA positivity in some studies may explain some of the discrepant results. The immunoreactive status noted in the present study also revealed that intraductal carcinoma and IDC with PIC have common features. Based on the above findings, it is considered that intraductal carcinoma and IDC with PIC are one particular category of mammary carcinoma with a low-grade malignancy, and a latent or early phase of stromal invasion has to be considered. Mammographic detection of tumors during such a phase may explain the recent increase in the incidence of intraductal carcinoma and IDC with PIC. The current study shows that the definition of IDC with PIC, as classified by the World Health Organization, was appropriate for delineating particular tumors that can safely be treated by simple mastectomy with axillary node dissection. References I Black MM, Opler SR, Speer FD (1955) Survival in breast cancer cases in relation to the structure of the primary tumor and regional lymph nodes. Surg Gynecol Obstet 100: 543-551 2 Bloom HjG, Richardson WW (1957) Histological grading and prognosis in breast cancer: A study of 1409 cases of which 359 have been followed for 15 years. Br j Cancer 11: 359-377 3 Cohen C, Sharkey FE, Shulman G, Uthman EO, Budgeon LR (1987) Tunor-associated antigens in breast carcinomas: Prognostic significance. Cancer 60: 1294-1298 4 japanese Breast Cancer Society (1989) General Rules for Clinical and Pathological Recording of Breast Cancer. 10 ed. Kanehara, Tokyo (Japanese) 5 Patchefsky AS, Schwartz GF, Finkelstein SD, Prestipino A, Sohn SE, Singer jS, Feig SA (1989) Heterogeneity of intraductal carcinoma of the breast. Cancer 63: 731-741 h Rogers LW (1987) Carcinoma in situ (CIS). In: Page DL, Anderson Tj (Eds) Diagnostic Histopathology of the Breast, 157-192. Churchill Livingston, New York 7 Silverberg SG, Chitale AR (1973) Assessment of significance of proportions of intraductal and infiltrating tumor growth in ductal carcinoma of the breast. Cancer 32: 830-837 R Sobin LH (1981) Histological Typing of Breast Tumours. 2ed. World Health Organization, Geneva 9 Wahren B, Lidbrink E, Wallgren A, Eneroth P, Zajicek j (1978) Carcinoembryonic antigen and other tumor markers in tissue and serum or plasma of patients with primary mammary carcinoma. Cancer 42: 1870-1878 10 Walker RA (1980) Demonstration of carcinoembryonic antigen in human breast carcinomas by immunoperoxidase technique. j C1in Pathol 33: 356-360
Received january 31, 1990 . Accepted March 31, 1990
Key words: Breast carcinoma - Ductal carcinoma - Stromal invasion - Intraductal carcinoma M. Enjoji MD, the Second Department of Pathology, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, japan
Ductal Carcinoma of the Breast! An Analysis of Proportions of Intraductal and Invasive Components A. Matsukuma and M. Enjoji Second Department of Pathology, Faculty of Medicine, Kyushu University, Japan
S. Toyoshima Clinical Laboratory of Kitakyushu City Kokura Hospital, Japan
SUMMARY One hundred and ninety patients with mammary ductal carcinoma were studied to evaluate the correlation of proportions of intraductal and invasive tumor growth to histologic and immunohistochemical features. Initially, attempts were made to divide the cases into 6 groups according to the proportion of extraductal invasive areas within the whole tumor. It has been found that ductal carcinoma could be divided, on this criterion, into 2 groups. One comprised tumors in which invasive areas made up less than 20% ofthe tumor, the other included those with invasive areas exceeding 20%. In the former, intraductal and invasive components exhibited a lower grade of nuclear and tumor component and a higher incidence of cells with CEA immune positivity. The latter manifested higher grades in both intraductal and invasive components and a lower incidence of CEA positive cells. Many of the latter tumors had a solid or comedo-like growing pattern of the intraductal component. There was a significant difference in the prognosis between the two categories. We conclude that like intraductal carcinomas, invasive ductal carcinomas with a predominant intraductal component should be considered a lower grade malignancy.
Introduction Ductal carcinoma is the most common type in mammary carcinoma. It includes non-invasive and invasive tumors, depending on the presence or absence of extraductal stromal invasion. The World Health Organization suggested that, among invasive ductal carcinomas (IDC), tumors in which the amount of the intraductal carcinoma is at least four times greater than that of the invasive component would carry a more favorable prognosis than other invasive ductal carcinomas with a wider expansion of growth. These particular tumors have been differentiated from others as an invasive ductal carcinoma with a This study is supported in part by a grant from the Japanese Breast Cancer Society. 1
0344-0338/91/0187-0062$3.50/0
predominant intraductal component (IDC with PIC)8. There have been, however, only few comprehensive studies on the clinicopathologic significance of proportions of intraductal and invasive growth of ductal carcinoma of the breast? We investigated possible correlations between extraductal invasiveness and other parameters in an attempt to clarify the heterogeneous nature of ductal carcinoma with a propensity toward extraductal invasion. Material and Methods The material examined consisted of 17 non-invasive intraductal carcinomas and 173 invasive ductal carcinomas (IDC), including 28 cases of IDC with PIC. All patients were women who © 1991 by Gustav Fischer Verlag, Stuttgart
Ductal Carcinoma of the Breast . 63 had been treated with standard or modified radical mastectomy between 1974 and 1983. In no patient there was a bilateral breast tumor. Clinical histories, descriptions of gross features and histologic slides of the mastectomy specimens and preoperative biopsy materials were available for all patients. The average number of histologic sections examined for the primary tumor was 6.0 per case. All sections were stained with hematoxylin and eosin. The maximum diameter of the tumor was measured grossly on the cut sections and confirmed or corrected by histologic slides. According to the proportion of extraductal invasive area to the whole tumor, the cases could be separated into 6 groups: intraductal carcinoma (17); invasive ductal carcinoma (IDC) with an invasive component in minimal to 20% (28); IDC with a 20-50% invasive component (11); IDC with a 50-80% invasive component (17); IDC with an 80-100% invasive component (84); and pure invasive carcinoma without any intraductal component (33 cases). The second group was considered to be comparable to the IDC with PIC of the WHO classifications. These groups were studied with regard to clinical and pathologic features such as age of the patients, size of the tumor, tumor grade of invasive component, histologic pattern and nuclear grade of intraductal component, lymph node metastasis and clinical outcome. Tumor grade of the invasive component and nuclear grade of the intraductal component were assessed by the systems of Bloom and Richardson 2 and Black et al. I, respectively. Tumor grade I indicates a well-differentiated lesion and grade III a poorly differentiated one, categorizing an intermediate lesion between the two as grade II. In 10 of the 28 with IDC with PIC, the extent of stromal invasion was too slight to evaluate the grade. Nuclear grade of intraductal component was classified into low, intermediate and high. The histologic pattern of intraductal component was classified into micropapillary, papillary, cribriform, comedo and solid types S,6.
Representative sections from the 149 cases were examined immunohistochemically for carcinoembryonic antigen (CEA), using the avidin-biotin-peroxidase complex (ABC) method. The mouse monoclonal anti-CEA antibody was purchased from Zymed (San Francisco, CA, USA), the nonspecific cross-reacting antigen (NCA) absorbed polyclonal rabbit anti-CEA antiserum was from Milab (Malmo, Sweden) and the non-absorbed polyclonal rabbit antiserum was from Dakopatts (Copenhagen, Denmark). Avidin and biotin reagents were obtained from Vector Laboratories (Vectasin ABC Kit PK-4001, 4002, Burlingame, CA, USA). The reactivities of the intraductal and invasive components were assessed separately in each case. The status of regional lymph node involvement was classified after the General Rules for Clinical and Pathological Recording of Breast Cancer formulated by the Japanese Breast Cancer Society: no, no metastases; nl alpha, positive in less than 3 axillary or interpectoral nodes; n I beta, positive in more than 4 axillary or interpectoral nodes; n2, positive in subclavicular nodes; n3, positive in supraclavicular nodes. Involvement of parasternal nodes was categorized as nl beta for cases with tumors in the median half of the breast and n2 for cases with tumors in the lateral half of the breast 4• Statistical analyses were performed using the chi-square contingency tables and Fisher's exact probability test. The KaplanMeyer method was used to calculate the post-operative survival rate and to determine whether the difference was statistically significant.
Results
Patients ranged from 23 to 80 years of age with a mean of 51.7. There was no significant difference in age of the
Table 1. Mean tumor size and histologic patterns of intraductal component related to the proportion of extraductal invasive growth Degree of invasion No of cases Intraductal
17
Mean size ± SD 4.3 ± 2.9
Mp
Pap
3
2
Histologic patterns Cri Com 5
Sol 2
5
'--------v---'
10 (58.8) IDC with PIC
28
5.2 ± 2.7
5
6
7 (41.2) 9
20 (71.4) 20-50%
11
4.5 ± 1.9
0
2
2
6 8 (28.6)
3
6
0
'--------v---'
5 (45.5) 50-80%
17
3.4 ± 2.6
3
1
6 (54.5) 4
7
8 (47.1) 80-100%
84
3.5 ± 2.3
6
5
9 (52.9) 23
34 (40.5) Pure invasive Total
33
2.4 ± 1.5
190
3.7 ± 2.4
Mp = Micropapillary, Pap group.
157
17 (10.8)
16 (10.2)
= Papillary, Cri = Cribriform, Com = Comedo, Sol = Solid. -
2
32
18 50 (59.5)
44 (28.0)
56 (35.7)
24 (15.3)
Figures in brackets show % of cases in each
64 . A. Matsukuma and M. Enjoji and S. Toyoshima
patients by different proportions of invasive component. Table 1 shows the mean size of tumors and histologic patterns of the intraductal component by different proportions of the invasive component. There was a tendency toward smaller tumor size in cases with a greater proportion of invasive growth and it probably reflected that invasive growth could lead to form palpable lesions more easily than intraductal spreading growth. Regarding the histological patterns of intraductal growth, one pattern was often combined with others in the same case, particularly in those with an extensive intraductal growth. These cases were classified on the basis of dominant pattern. Approximately 70% (30/45) of cases with intraductal carcinoma or IDC with PIC showed evidence of a micropapillary, papillary or cribriform growth, while in about 60% (65/112) of those with greater areas of invasion, there was a comedo or solid growth of the intraductal components. This difference in the pattern of intraductal growth was statistically significant (p < 0.01). Table 2 shows the nuclear grade of intraductal component of IDC with different proportions of invasion. Approximately 70% (30/45) of the cases with non-
invasive carcinoma and IDC with PIC had low-grade nuclei (Fig. 1). On the other hand, over 70% (79/112) of the cases with more widely invasive tumors showed intermediate or high-grade nuclei (Fig. 2). This difference
Table 2. Nuclear grade of intraductal component related to proportion of extraductal growth Degree of InvaSion
No of cases
Nuclear grade Low
Intraductal carcinoma IDC with PIC 20- 80% 80-100% Fig. 1. Intraductal carcinoma growing in a cribriform pattern. The tumor cells have low-grade nuclei (H & E, X 290).
Total
Intermediate
High
17
12 (70.6)
4 (23.5)
1 (5.9)
28 28 84
18 (64.3) 9 (32.1) 24 (28.6)
10 (35.7) 14 (50.0) 44 (52.4)
0 5 (17.9) 16 (19.0)
157
63 (40.1)
72 (45.9)
22 (14.0)
Figures in brackets show % of cases in each group.
Ductal Carcinoma of the Breast . 65
was again statistically significant (p < 0.01). No highgrade nuclei were observed in 77 cases with the intraductal components arranged in a micropapillary, papillary or cribriform pattern. Nineteen (33.9%) of the 56 with a comedo intraductal component and 3 (12.5%) of the 24 cases with a simply solid intraductal component had high-grade nuclei. Table 3 shows the tumor grade of the invasive component. More than 50% of cases ofIDC with PIC were of low tumor grade (grade I), while about 80% (112/145) of those with a greater invasion were of intermediate or high tumor grade (Fig. 3). The difference in the tumor grade between the former with IDC with PIC and the latter was also statistically significant (p < 0.01). In addition, there was a close correlation between nuclear grade of intraductal component and tumor grade of invasive component in each case. Cases showing low-grade nuclei in their intraductal components usually revealed well-differentiated features in their invasive areas and vice versa.
Table 3. Tumor grade of invasive component related to proportion of extraductal invasive growth Degree of InvaSion IDC with PIC 20- 80% 80-100% Pure invasive Total
No of cases 18 28 84 33 163
Tumor grade Grade I
Grade II
Grade III
10 6 21 6
7 18 43 21
1 4 20 6
(55.6) (21.4) (25.0) (18.2)
43 (26.4)
(38.9) (64.3) (51.2) (63.6)
89 (54.6)
(5.6) (14.3) (23.8) (18.2)
31 (19.0)
Figures in brackets show % of cases in each group.
The results of immunoreactivity to monoclonal antiCEA antibody and to NCA absorbed polyclonal antiserum were much the same (Table 4). Significantly, the tissues with an intraductal carcinoma and IDC with PIC were more frequently composed of intraductal (p < 0.01) and invasive (p < 0.05) components positive for CEA than were those ofIDC with greater invasion (Fig. 4). Reactivity to monoclonal antibody and absorbed antiserum depended on the nuclear grade of the intraductal component and on the tumor grade of the invasive component. Thirty-six (73.5%) of the 49 with intraductal components having low-grade nuclei, 35 (57.4%) of the 61 with intermediate grade nuclei and 3 (18.8%) of the 16 with high grade nuclei were CEA positive with the monoclonal antibody. Use of non-absorbed CEA antiserum showed an even higher incidence of positivity in tumors of all grades but no grade-dependency. Lymph node status is summarized in Table 5. Metastases in cases of intraductal carcinoma were never observed. Five cases of IDC with PIC had less than three positive nodes in the axilla. In all these cases, there was a stromal invasion measuring over 8 mm in the largest diameter. As the proportion of invasive component Table 4. CEA positivity of intraductal and invasive component Degree of in- No of cases m-antibody vasion (Zymed)
p-antiserum (NCA-absorbed, Milab)
Intraductal carCInoma
Duct 13
12/13 (92.3)
12/13 (92.3)
IDC with PIC Duct 22 Inv 11
21/22 (95.5) 9/11 (81.8)
21/22 (95.5) 8/11 (72.7)
20- 80% InvaSIOn
Duct 23 Inv 23
10/23 (43.5) 8/23 (34.8)
10/23 (43.5) 8/23 (34.8)
80-100% invasion
Duct 68 Inv 70
31/68 (45.6) 29/70 (41.4)
35/68 (51.5) 35/70 (50.0)
Pure invasive Inv Fig. 3. Photomicrograph of an invasive ductal carcinoma showing more than 80% stromal invasion. Note high-grade nuclei of the intraductal component and of the poorly differentiated invasive component (grade III) (H & E, X 210).
20
9/20 (45.0)
9/20 (45.0) (%)
m-antibody = Monoclonal antibody, p-antiserum = Polyclonal antiserum, Zymed = San Francisco, CA, USA, Milab = Malmo, Sweden, Duct = Intraductal component, Inv = Invasive component.
66 . A. Matsukuma and M. Enjoji and S. Toyoshima Table 5. Regional lymph node involvement related to proportion of extraductal invasive growth Degree of invasion Intraductal carcinoma IDC with PIC 20- 80% 80-100% Pure invasive Total n 1a
No of cases
nOn 1a n 1b n 2 n 3 % n+
17 28 28 84 33
17 0 23 5 17 6 44 17 27 4
0 0 2 11 0
0 0 3 9 2
0 0 0 3 0
0 17.9 39.3 47.6 18.2
190
128 32
13
14
3
32.6
= n 1 alpha, n 1b = n 1 beta.
invasive component (p < 0.05 and p < 0.001, respectively). However, there was no significant difference in the survival rate between those with 20-80% invasion and those with over 80% of invasion. Discussion
~Yl~'
, ", ~"V.:r" ~: .
~
'~,
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,j
.
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." Fig. 4. In a case of invasive ductal carcinoma with a predominant intraductal component, both intraductal and invasive components were CEA positive, as examined by a monoclonal antibody. Nuclei of the intraductal component are graded low and the invasive component is well differentiated (grade I) in this IDC with PIC (ABC immunostain, x 40).
Silverberg and Chitale studied a series of 267 mammary carcinomas inclusive of both intraductal and infiltrating duct types and found no axillary nodal metastases and no tumor-related deaths among patients with pure intraductal carcinoma. However, in patients with tumors of a minimal (less than 10%) stromal invasion there was a low but significant incidence of metastases and mortality. In tumors with increasing proportions of invasive growth, there was a progressive increase both in nodal metastases and mortality? More recently, Patchefsky et al. pointed out the heterogeneous nature of intraductal carcinomas, as noted in their study on 55 intraductal carcinomas, includ100%
A B
C
t.:I
Eo<
<
increased, more distant and a greater number of nodes were involved. Pure invasive ductal carcinoma showed a low incidence of metastasis probably because of the smaller size of the tumor, as given among the data in Table 1. Of the 190 patients studied, 12 were lost to follow-up, 29 died of recurrent disease, 12 died of other diseases and 3 died of undetermined causes. In 22, tumor-related death occurred within 5 years and the other 7 died between 5 and 10 years after surgical treatment. Three patients now have a recurrence. There were neither tumor-related deaths nor recurrent disease among patients with an intraductal carcinoma and IDC with PIC. The 10-year survival rates were 84.1 % in those with invasive component in 20-80% of the entire tumor and 75.1 % in those with over 80% of these components (Fig. 5). There were significant differences in the survival curves between those with less than 20% invasion and those with 20-80% or over 80%
~
.-l
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....
50%
:>
~
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5
10
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Fig. 5. Survival of patients with mammary ductal carcinoma according to the proportion of invasive growth; A.less than 20% invasion (intraductal carcinoma and IDC with PIC), B. 20-80% invasion, C. more than 80% invasion. There were significant differences in the survival curves between A and B (p < 0.05) and A and C (p < 0.001), and no significant differences between B and C.
Ductal Carcinoma of the Breast . 67 ing cases with microinvasion which had been detected by clinical signs, mammographic examination or incidental to benign diseases. They found differences in the biologic character of intraductal carcinomas with the histologic types and stressed that comedocarcinomas had a higher incidence of microinvasion and a higher nuclear grade than did carcinomas of other histologic types. If all ductal carcinomas arising in mammary ducts were in a constant progression toward extraductal invasion, there would be a wide spectrum of proportions of intraductal components and the proportions of intraductal growth should be distributed rather uniformly from 100% (intraductal carcinoma) to 0% (pure invasive carcinoma). Nevertheless, the number of cases with 10-89% invasion in one study? (42/267) and that of the cases with 20-80% invasion in our study (28/190) were smaller than expected. Many of the cases (197/267 in the former and 117/190 of the latter series) were included in categories of tumors with extensive stromal invasion (over 90% in the former and over 80% in the later series) at the time of diagnosis. Such a disproportion in the distribution of cases of intraductal and invasive components suggested that ductal carcinomas can be divided into two main categories, depending on the propensity to extraductal invasion. One tends to extraductal invasion from the early phase of development and the other retains in situ or intraductal growth to a considerable extent before stromal invasion occurs. In most of our patients with IDC with PIC, the features of the tumor were essentially similar to those seen in an intraductal carcinoma, particularly in histologic pattern and nuclear grade of intraductal component. These tumors also presented an invasive component with less aggressive features. Cases with a greater proportion (more than 20%) of invasive component, however, showed significantly different features in both invasive and intraductal components. More than 80% of the tumors characterized by a comedo or by a solid growth pattern within the ducts had more than 20% areas of stromal invasion. High-grade nuclei were observed almost exclusively in those with the two growth patterns, comedo or simply solid, except for cases of intraductal carcinoma and IDC with PIC. These two patterns of intraductal growth seem to give rise to extraductal invasion. There have been conflicting data about the correlation between the presence of CEA and the grade of tumor differentiation in carcinomas of the breast3,9, 10. Walker found that a grade-dependency was evident for the CEA positivity of tumors, determined by using an antiserum after absorption of NCAlo. We used three different antibodies and the monoclonal antibody and NCAabsorbed antiserum showed a similar degree of staining,
thereby confirming that the presence of CEA was dependent primarily on tumor differentiation. A cross-reaction of NCA misinterpreted as CEA positivity in some studies may explain some of the discrepant results. The immunoreactive status noted in the present study also revealed that intraductal carcinoma and IDC with PIC have common features. Based on the above findings, it is considered that intraductal carcinoma and IDC with PIC are one particular category of mammary carcinoma with a low-grade malignancy, and a latent or early phase of stromal invasion has to be considered. Mammographic detection of tumors during such a phase may explain the recent increase in the incidence of intraductal carcinoma and IDC with PIC. The current study shows that the definition of IDC with PIC, as classified by the World Health Organization, was appropriate for delineating particular tumors that can safely be treated by simple mastectomy with axillary node dissection. References I Black MM, Opler SR, Speer FD (1955) Survival in breast cancer cases in relation to the structure of the primary tumor and regional lymph nodes. Surg Gynecol Obstet 100: 543-551 2 Bloom HjG, Richardson WW (1957) Histological grading and prognosis in breast cancer: A study of 1409 cases of which 359 have been followed for 15 years. Br j Cancer 11: 359-377 3 Cohen C, Sharkey FE, Shulman G, Uthman EO, Budgeon LR (1987) Tunor-associated antigens in breast carcinomas: Prognostic significance. Cancer 60: 1294-1298 4 japanese Breast Cancer Society (1989) General Rules for Clinical and Pathological Recording of Breast Cancer. 10 ed. Kanehara, Tokyo (Japanese) 5 Patchefsky AS, Schwartz GF, Finkelstein SD, Prestipino A, Sohn SE, Singer jS, Feig SA (1989) Heterogeneity of intraductal carcinoma of the breast. Cancer 63: 731-741 h Rogers LW (1987) Carcinoma in situ (CIS). In: Page DL, Anderson Tj (Eds) Diagnostic Histopathology of the Breast, 157-192. Churchill Livingston, New York 7 Silverberg SG, Chitale AR (1973) Assessment of significance of proportions of intraductal and infiltrating tumor growth in ductal carcinoma of the breast. Cancer 32: 830-837 R Sobin LH (1981) Histological Typing of Breast Tumours. 2ed. World Health Organization, Geneva 9 Wahren B, Lidbrink E, Wallgren A, Eneroth P, Zajicek j (1978) Carcinoembryonic antigen and other tumor markers in tissue and serum or plasma of patients with primary mammary carcinoma. Cancer 42: 1870-1878 10 Walker RA (1980) Demonstration of carcinoembryonic antigen in human breast carcinomas by immunoperoxidase technique. j C1in Pathol 33: 356-360
Received january 31, 1990 . Accepted March 31, 1990
Key words: Breast carcinoma - Ductal carcinoma - Stromal invasion - Intraductal carcinoma M. Enjoji MD, the Second Department of Pathology, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, japan