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Prognostic value of prominent DCIS component in the breast-conserving therapy of stage I and II invasive ductal breast cancer
The Breast (1999) 8, 72-16 0 1999 Harcoun Brace & Co. Lfd
ORIGINAL ARTICLE
Prognostic value of prominent DCIS component in the breast-conserving therapy of stage I and II invasive ductal breast cancer Separovic V, SarCeviC B, SeparoviC R, OreSiC V, Nola N, Vrdoljak M and KruSlin B University Hospital for Turnours, Ilica 197, Zagreb, Croatia S U M MA R Y. The aim of this study was to determine the presence and histological grade of prominent ductal carcinoma in situ (DCIS) and the relationship between the histological grade of DCIS and the grade of invasive ductal carcinoma of the breast to local recurrence and survival. We have analysed 175 patients with stage I and II invasive ductal breast carcinoma who underwent breast-conserving therapy in the period 1987-1994. Patients were divided into those with carcinomas showing prominent DCIS (74 patients), and those with tumours without a DClS component (101 patients). Ten patients developed recurrences and were treated by hormonal and/or chemotherapy. Local recurrence was observed in 2 (2%) patients without, and in 8 (10.8%) patients with prominent DCIS (x*=12.954, P
statistically a significantly increased rate of local recurrences in cancers with prominent DCIS.‘,5 However, there are many types of intraductal carcinoma. There is already evidence in the literature to suggest that certain types of DCIS are more likely to progress to invasive carcinoma than others.“’ It has been shown that the type of DCIS associated with stage I and II invasive ductal carcinoma of the breast is significantly associated with both disease-free and overall survival.7 In this study, a recently proposed classification of DCIS based on cytonuclear and architectural differentiation has been applied.’ Clinical studies of conservation therapy indicate that there are differences in the incidence of recurrence related to the histological type of DCIS.6~s~‘o In this study, we have analysed 175 patients with stage I and II invasive ductal breast carcinoma and determined the presence and histologic grade of any intraductal component and its relationship to local recurrence and overall survival. We have also studied the relationship between the DCIS type and the grade of any invasive carcinoma.
INTRODUCTION The use of breast-conserving therapy has become a widely accepted option for the treatment of early-stage breast cancer. Breast-conserving therapy refers to the use of limited breast resection to remove the primary tumour combined with axillary lymph node dissection, followed by breast irradiation. The lo-year rate of local recurrence following breast-conserving therapy is in the range 8--20%. It has been shown that increasing the size of breast resection may diminish the risk of local recurrence but this can have an adverse impact on cosmetic outcome.‘.* Some studies have shown that rates of local recurrence depend on criteria for patient selection, the presence and extent of cancer involvement at the margins of resection and the presence of ductal carcinoma in situ (DCIS) within and around the invasive cancer.lA An extensive intraductal component within the cancer is defined as the simultaneous presence of a prominent amount of intraductal carcinoma within the primary tumour and intraductal carcinoma clearly extending beyond the infiltrating margin of the tumour or present in grossly normal adjacent breast tissue. Some studies have shown
MATERIALS
Address correspondence to; Boio KruSlin, MD, PhD, Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000 Zagreb, Croatia. Tel.: 385-l-4566 869; Fax: 389-l-4683 829 Presented Maastricht,
in part at the XVI The Netherlands,
AND METHODS
Tumours from patients with stage I and II primary invasive ductal carcinoma of the breast diagnosed between 1987-1994 at the University Hospital for Tumours, Zagreb, Croatia were reviewed. The data were analysed during
European Congress of Pathology, August 31-September 4, 1997
72
Prognostic value of prominent DCIS component December 1996. All patients underwent breast-conserving therapy, consisting of a complete excision of the tumour and an axillary lymph node dissection, followed by radiotherapy. One hundred and seventy-five cases of invasive ductal carcinoma of the breast were included in this study. This group represents a subset of 256 consecutive patients treated with breast conserving therapy for invasive breast carcinoma measuring up to 4 cm.“,” In our series all patients underwent radiotherapy. After surgery the breast was irradiated with lateral and medial tangential portals. The treatment was performed by X-ray energies of 6 MV. Radiation doses of 50 Gy were delivered to the entire breast over 5 weeks (2-Gy dose daily). Irradiation of axillary and supraclavicular lymph nodes was performed in patients who had tumours larger than 2 cm and had axillary lymph node metastases. Doses of 50 Gy were delivered in 25 daily fractions (2-Gy). Ipsilateral internal mammary lymph nodes were irradiated in patients with tumours located in inner quadrants which were either larger than 2 cm or had axillary lymph node metastases. The treatment was performed by a combination of electron beam (16 MeV) and X-rays (6 MV) to doses of 50 Gy (25 daily fractions). Forty-one patients who were lost from follow-up were excluded from this study. Material of 40 tumours was not appropriate or available for pathologic analyses. These patients were not included in the study. Hematoxylin & eosin stained sections of tumours were reviewed independently by two pathologists. All tumours analysed in this study were submitted in their entirety for histology and serially examined except for samples taken for hormone receptor analysis. The total number of sections ranged from lo-50 depending on gross and histologic features of specimens, mammographic findings and results of frozen sections. The sections were taken from the anterior, posterior, medial and lateral aspects of each specimen. These were blocked sagitally to assess margins. In cases with positive margins re-excision was performed. A prominent intraductal component within the cancer is defined as either 1. DCIS present as a prominent component of the tumour (generally this corresponds to 25% or greater of the tumour) and the presence of DCIS in the grossly normal adjacent breast tissue or two diffuse DCIS with foci of invasive cancer.“,” DCIS was classified into three groups according to recently described criteria.” The classification is based on nuclear morphology and on polarization of cells (architectural differentiation). Thus, tumours with very pleomorphic nuclei and no evidence of polarity of cells around intercellular spaces were classified as poorly differentiated; those with less pleomorphic nuclei and definite. but often focal or inconspicuous polarization, as intermediately differentiated, and lesions composed of cells with monomorphic uniform nuclei with prominent polarization of cells as well-differentiated. When more than one type of DCIS was present, the tumour was classified according to
73
the least differentiated component. The grade of the invasive tumour was taken from the original surgical biopsy report. Grading of the invasive component was carried out according to the Nottingham modification of the Bloom and Richardson system proposed by Elston.“,14 Diagnosis and date of recurrence were determined according to the criteria of Hayward et al.15 Local recurrence was defined as detection of cancer in the parenchyma and/or skin of the treated breast occurring before or simultaneously with the discovery of distant metastasis. The follow-up period was between 20 and 120 months with a median of 62 months. Survival, both disease-free and overall, was calculated using the method of Kaplan and Meier.lh
RESULTS There were 101 (57.7%) tumours without a prominent DClS component and 74 (42.3%) tumours with prominent DCIS. Amongst tumours with a prominent DClS component there were 10 (13.5%) which were well differentiated, 36 (48.7%) were of intermediate differentiation and 28 (37.8%) were poorly differentiated. Local recurrence was more common in patients with carcinomas showing a prominent DCIS component; 8 of 74 (10.8%) cases compared with 2 of 101 (2%) tumours without prominent DClS, a statistically significant difference (x*=12.954, PC 0.005).Local recurrences were observed in 0 of 10 patients with well-differentiated DCIS, 2 of 36 (5.5%) patients with intermediately differentiated DCIS and 6 of 28 (21.4%) patients with poorly differentiated DCIS. The difference between tumours without prominent DCIS and those with poorly differentiated DCIS was statistically significant (x2=8.798, P-c0.005).However, the difference in local recurrence between tumours based on DCIS type was not statistically significant. The clinical and pathologic features of patients are shown in Table 1. The relationship between DCIS type and survival is shown in Figure 1. Table 1 prominent
Presentation characteristics of 175 patients DCIS component of grade I, II and III
Mean (year) Range (year)
Age Nodal
status
Tumour
size
Follow-up Recurrences
Negative Positive Mean Range Maximum (Mts) Median (Mts)
with and without
a
Without DCIS
DCIS grade I
DCIS grade II
DCIS grade III
(rr=lOl) 54.4 28-84
(it’lo) 5x.2 45-77
(n=36) 55.2 37-86
(n=28) 50.0 33-64
83 18
9 I
23 13
15 13
I .4 0.4-3.5
I .4 0.b2.s
1.7 0.74.0
2.1 o.w.0
1 I3 60
116 68
101 55
120 62
2
0
2
6
74
The Breast 0
Complete
+
Censored
0.0 -0.1 10
PO
30
40
50
60
70
Time
80
90
100
110
120
130
(months,
Fig. 1 Kaplan-Meier plots for overall survival for patients cancer with and without prominent DCIS component.
with breast
Disseminated metastatic disease occurred in 9 patients without a prominent DCIS component varying from 6 to 24 months (mean 14) after diagnosis, and in two patients with a prominent DCIS component of intermediately differentiated type, 20 and 24 months after presentation, respectively. We have analysed the correlation between histologic type of prominent DCIS component and histologic grade of invasive ductal breast carcinoma (Table 2). There was a highly significant correlation between DCIS type and the grade of the invasive component of the tumour (x*=73.77, P< 0.001, DF=4). Well-differentiated DCIS was usually associated with a grade I tumour, intermediately differentiated with grade II, and poorly differentiated was associated in half with grade II and half with grade III invasive carcinomas. During follow-up 6 patients with tumours without a prominent DCIS component died 25-50 months after diagnosis. Three patients died from disease, and three from unrelated causes. Four patients with tumours showing a prominent DCIS component died due to disease from 24-65 months after presentation (two with well-differentiated, one with moderately differentiated and one with poorly differentiated DCIS). These differences were not statistically significant (x*=3.73 1, P= 0.2921). DISCUSSION In this study we have examined the association between the presence of a prominent DClS component and the risk of Table 2 component
The relationship and histologic
between degree grade of invasive Grade
of differentiation carcinoma
of invasive
cancer
of DCIS
DCIS type Well differentiated Intermediately differentiated Poorly differentiated
I 10 2 1
II 32 10
III 2 17
Total 10 36 28
Total
13
42
19
74
(%)
(%)
local recurrence of a tumour after breast conserving therapy. We found that in patients with invasive ductal breast cancer with a prominent intraductal component the risk of recurrence was significantly higher than for patients without prominent DCIS. In this study prominent intraductal component was determined according to the criteria of Holland et a1.4,9However, according to Schnitt et al. the degree of prominent DCIS component within the tumour and adjacent breast tissue was categorized as absent when no ducts were involved, slight when comprising less than 25% of the tumour area, moderate when comprising 25-50%, and marked when comprising greater than 50% of the tumour area and adjacent breast parenchyma.’ Furthermore, we have investigated the relationship between various types of DCIS and local recurrences as well as with overall survival. We found that patients with DCIS of poorly differentiated type have a significantly higher risk of local recurrence. None of the patients with DCIS of well-differentiated type developed local recurrence in the period of follow-up. A similar observation has been reported by Lampejo et a1.7 There are many classifications of DCIS.6X8X9,‘7-2’ In the past DCIS has been divided into five major groups: comedo, solid, cribriform, papillary and micropapillary.’ DCIS has also been divided into two major type: noncomedo and comedo DCIS, the former being associated with a lower risk of subsequent development of invasive carcinoma than the latter.6,7,8.22However, criteria used for these classifications were poorly defined and were based mainly on architectural pattern and the presence or absence of necrosis, In our study, a recently proposed classification, based on cytonuclear features and architectural pattern was used.’ This classification has also been used in other studies comparing various DCIS types with the mammographic appearance of DCIS, the growth pattern, and distribution of DCIS within the breast and with biological features, including proliferation, steroid-hormone receptor status and oncoprotein expression.7.‘9.23-25Several studies have shown that poorly differentiated DCIS typically lacks oestrogen and progesterone receptors, has a high proliferative rate, exhibits aneuploidy, shows c-erbB-2, ~53 and bcl-2 abnormalities and frequently has new vessel formation in the adjacent stroma.23-25In contrast, well-differentiated DCIS is usually oestrogen and progesterone receptor positive, rarely shows c-erbB-2, ~53 and bcl-2 positive immunostaining, and has a low proliferative activity. Intermediately differentiated DCIS shows characteristics that are intermediate between those of poorly and well-differentiated DCIS.23-25 Conservative surgery and radiation therapy is a widely accepted option in the treatment of early-stage invasive breast cancer.2.5.7,10-12,20.26 The well-known factors for local recurrence are failure to completely excise the tumour and a mammographic pattern of widespread suspicious microcalcifications shown to represent DCIS.*,‘,” The major un-
Prognostic value of prominent DCIS component resolved factors for local recurrence are the extent of breast resection, the presence of a prominent intraductal component within the cancer, and the presence and extent of cancer involvement at the margins of resection.‘.2*3.5,7.‘03”The importance of free margins for the prediction of local recurrence is stressed by many authors including Silverstein’s recent work which has tried to integrate different elements of extent, grade and margins.‘7~‘8However, various methods for assessing completeness of excision have been proposed. Our margins were blocked sagitally and sections from anterior, posterior, medial and lateral aspects of the specimen were examined. Recently, some authors have suggested examination of shaved margins, but the relationship between shaved and inked margins remains unclear.‘” However, the relatively high rate of local recurrence in patients with negative margins, in spite of radiotherapy, shows that the pathological finding of free margins does not ensure no risk of recurrence.‘” The 1O-year rate of local recurrence following breast-conserving therapy is reported to be between 8 and 20%. Recurrence rates for tumours without a prominent DCIS component have been reported by some to be significantly lower than for turnouts with prominent DCIS.‘~‘.‘” It has also been suggested that the type of the DCIS component of the infiltrating carcinoma might be predictive of outcome.7-Y Our results suggest that local recurrences occur significantly more commonly in tumours with a prominent DCIS component and in tumours with poorly differentiated DCIS when compared with tumours without a prominent DCIS component. This difference is present by five years. However, we have failed to find significant differences between various grades of DCIS. This could be due to two factors: first, a relatively short follow-up period or secondly, a relatively small number of cases in our series. We have found a close relationship between degree of differentiation of the invasive and DCIS components of a breast carcinoma as reported by others.’ We believe that the presence of a poorly differentiated prominent DCIS component should be considered as an unfavourable prognostic factor in the development of local recurrences after breast conserving therapy.
3.
4.
5.
6.
7.
8.
9.
IO.
1 I. 12.
13.
14.
15. 16. 17.
18. 19.
20.
Acknowledgement Excellent technical appreciated.
assistance
of Mrs Renata
Periz
should
be cordially
21.
22.
References 1. Schnitt S J, Connoly Pathologic predictors breast cancer treated 53: 1049-1057. 2. Vicini F A, Eberlein resection for patients
J L, Harris J R, Hellman S, Cohen R B. of early local recurrence in Stage I and II by primary irradiation therapy. Cancer 1984;
23.
24. T J, Connolly J L et al. The optimal extent of with Stages I or II breast cancer treated with
75
conservative surgery and radiotherapy. Ann Surg 1991: 214: 200-205. Holland R, Connolly J L, Gelman R et al. The presence of an extensive intraductal component following a limited excision correlated with permanent residual disease in the remainder of the breast. J Clin Oncol 1990; 8: 113-l 18. Silverberg S Cl, Chitale A R. Assesment of proportions of intrdductdl and infiltrating tumor growth in ductdl carcinoma of the breast. Cancer 1973; 32: 830-837. Holland R, Veling S H J, Mravunac M. Hendriks JHCL. Histologic multifocality of Tis, TI-2 breast carcinomas. Implications for clinical trals of breast-conserving therapy. Cancer 1985; 56: 979-990. Page D L, Anderson T J. Carcinoma in situ (CIS). In: Page D L. Anderson T J (eds). Diagnostic histopathology of the breast. London: Churchill Livingstone, 1987, pp 157-192. Lampejo 0 T, Barnes D M. Smith P. Millis R R. Evaluation of infiltrating ductal carcinomas with a DCIS component: correlation of the histologic type of the in situ component with grade of the infiltrating component. Semin Diagn Pathol 1994; II: 215-222. Lagios M D, Margolin F R, Westdahl P R et al. Mammographicallydetected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 1989; 63: 618-624. Holland R, Peterse J L. Millis R R et al. Ductal carcinoma in situ: A proposal for a new classification. Semin Diagn Pathol 1994: II: 167-180. Macmillan R D. Purushotam A D. George W D. Local recurrence after breast-conserving surgery for breast cancer. Br J Surg 1996: 83: 149-155. OreSiC V. Petrinec Z, Stanec M, Vrdoljak D V. Breast conserving surgery: a ten-year experience. Libri Oncol 1997. 26: 47-50. SarEeviC B, Separovic V, KruSlin B. Prognostic value of prominent DCIS component in the breast-conserving therapy of stage I and II invasive ductal breast cancer. Pdthoi Res Pratt 1997: 193: 372 (Abstract). Elston C W. Grading of invasive carcinoma of the breast. In: Page D L. Anderson T J (eds). Diagnostic histopathology of the breast. London: Churchill Livingstone. 1987. pp 157-192. Frierson H F Jr. Wolber R A. Berean K W et al. Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Path01 1995: 103: 195-198. Hayward J L. Melon J W, Stewart H J. Assesment of response and recurrence of breast cancer. Semin Oncol 1978: 5: 445450. Kaplan E L, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 45748 I. Eusebi V, Feudale E, Foschini MP et al. Long-term follow-up of in situ carcinoma of the breast. Semin Diagn Path01 1994; I I : 223-235. Azzopardi J G. Problems in Breast Pathology. Philadelphia: WB Saunders 1979. Bellamy C 0 C, McDonald C. Salter D M. Chetty U, Anderson T J. Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Hum Path01 1993; 24: 16-23. Sinn H P, Oelmans A, Anton H W. Die1 1 J. Metastatic potential of small and minimaly invasive breast carcinomas. Virchow Arch 1994; 425: 237-241. Douglas-Jones A G, Gupta S K, Attanoos R L et al. A critical appraisal of six modern classifications of ductal carcinoma in situ of the breast (DCIS): Correlation with grade of associated invasive cancer. Histopathology 1996; 29: 397-409. Scott M A, Lagios M D. Axelsson K et al. Ductal carcinoma in situ of the breast: reproducibility of histological subtype analysis. Hum Pathol 1997; 28: 967-973. Schnitt S J, Connolly J L. Classification of ductal carcinoma in situ: striving for clinical relevance in the era of breast conserving therapy. Hum Path01 1997: 28: X77-880. Zafrani B. Leroyer A, Fourquet A et al. Mammographically-detected ductal in situ carcinoma of the breast analyzed with a new classification. A study of 127 cases: Correlation with estrogen and
16
The Breast
progesterone receptors, ~53 and c-erbB-2 proteins, and proliferative activity. Semin Diagn Path01 1994; 11: 208-214. 25. Engels K, Fox S B, Whitehouse R M et al. Distinct angiogenic patterns are associated with high-grade in situ ductal carcinomas of the breast. J Path01 1997; 181: 207-212. 26. National Institutes of Health (NIH). Concensus Development Conference statement: treatment of early stage breast cancer. JAMA 1991; 265: 391-394. 27. Silverstein M J. Predicting residual disease and local recurrence in patients with ductal carcinoma in situ. J Nat1 Cancer Inst 1997; 89: 1330-1331.
28. Silverstein M J, Lagios M D, Martin0 S et al. Outcome after invasive local recurrence in patients with ductal carcinoma in situ of the breast. J Clin Oncol 1998; 16: 1367-1373. 29. Guidi A J, Connolly J L, Harris J R, Schnitt S J. The relationship between shaved margin and inked margin status in breast excision specimens. Cancer 1997; 79: 1568-1573. 30. Veronesi U, Salvadori B, Luini A et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials in 1,973 patients. Eur J Cancer 1995; 31A: 1574-1579.
ORIGINAL ARTICLE
Prognostic value of prominent DCIS component in the breast-conserving therapy of stage I and II invasive ductal breast cancer Separovic V, SarCeviC B, SeparoviC R, OreSiC V, Nola N, Vrdoljak M and KruSlin B University Hospital for Turnours, Ilica 197, Zagreb, Croatia S U M MA R Y. The aim of this study was to determine the presence and histological grade of prominent ductal carcinoma in situ (DCIS) and the relationship between the histological grade of DCIS and the grade of invasive ductal carcinoma of the breast to local recurrence and survival. We have analysed 175 patients with stage I and II invasive ductal breast carcinoma who underwent breast-conserving therapy in the period 1987-1994. Patients were divided into those with carcinomas showing prominent DCIS (74 patients), and those with tumours without a DClS component (101 patients). Ten patients developed recurrences and were treated by hormonal and/or chemotherapy. Local recurrence was observed in 2 (2%) patients without, and in 8 (10.8%) patients with prominent DCIS (x*=12.954, P
statistically a significantly increased rate of local recurrences in cancers with prominent DCIS.‘,5 However, there are many types of intraductal carcinoma. There is already evidence in the literature to suggest that certain types of DCIS are more likely to progress to invasive carcinoma than others.“’ It has been shown that the type of DCIS associated with stage I and II invasive ductal carcinoma of the breast is significantly associated with both disease-free and overall survival.7 In this study, a recently proposed classification of DCIS based on cytonuclear and architectural differentiation has been applied.’ Clinical studies of conservation therapy indicate that there are differences in the incidence of recurrence related to the histological type of DCIS.6~s~‘o In this study, we have analysed 175 patients with stage I and II invasive ductal breast carcinoma and determined the presence and histologic grade of any intraductal component and its relationship to local recurrence and overall survival. We have also studied the relationship between the DCIS type and the grade of any invasive carcinoma.
INTRODUCTION The use of breast-conserving therapy has become a widely accepted option for the treatment of early-stage breast cancer. Breast-conserving therapy refers to the use of limited breast resection to remove the primary tumour combined with axillary lymph node dissection, followed by breast irradiation. The lo-year rate of local recurrence following breast-conserving therapy is in the range 8--20%. It has been shown that increasing the size of breast resection may diminish the risk of local recurrence but this can have an adverse impact on cosmetic outcome.‘.* Some studies have shown that rates of local recurrence depend on criteria for patient selection, the presence and extent of cancer involvement at the margins of resection and the presence of ductal carcinoma in situ (DCIS) within and around the invasive cancer.lA An extensive intraductal component within the cancer is defined as the simultaneous presence of a prominent amount of intraductal carcinoma within the primary tumour and intraductal carcinoma clearly extending beyond the infiltrating margin of the tumour or present in grossly normal adjacent breast tissue. Some studies have shown
MATERIALS
Address correspondence to; Boio KruSlin, MD, PhD, Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000 Zagreb, Croatia. Tel.: 385-l-4566 869; Fax: 389-l-4683 829 Presented Maastricht,
in part at the XVI The Netherlands,
AND METHODS
Tumours from patients with stage I and II primary invasive ductal carcinoma of the breast diagnosed between 1987-1994 at the University Hospital for Tumours, Zagreb, Croatia were reviewed. The data were analysed during
European Congress of Pathology, August 31-September 4, 1997
72
Prognostic value of prominent DCIS component December 1996. All patients underwent breast-conserving therapy, consisting of a complete excision of the tumour and an axillary lymph node dissection, followed by radiotherapy. One hundred and seventy-five cases of invasive ductal carcinoma of the breast were included in this study. This group represents a subset of 256 consecutive patients treated with breast conserving therapy for invasive breast carcinoma measuring up to 4 cm.“,” In our series all patients underwent radiotherapy. After surgery the breast was irradiated with lateral and medial tangential portals. The treatment was performed by X-ray energies of 6 MV. Radiation doses of 50 Gy were delivered to the entire breast over 5 weeks (2-Gy dose daily). Irradiation of axillary and supraclavicular lymph nodes was performed in patients who had tumours larger than 2 cm and had axillary lymph node metastases. Doses of 50 Gy were delivered in 25 daily fractions (2-Gy). Ipsilateral internal mammary lymph nodes were irradiated in patients with tumours located in inner quadrants which were either larger than 2 cm or had axillary lymph node metastases. The treatment was performed by a combination of electron beam (16 MeV) and X-rays (6 MV) to doses of 50 Gy (25 daily fractions). Forty-one patients who were lost from follow-up were excluded from this study. Material of 40 tumours was not appropriate or available for pathologic analyses. These patients were not included in the study. Hematoxylin & eosin stained sections of tumours were reviewed independently by two pathologists. All tumours analysed in this study were submitted in their entirety for histology and serially examined except for samples taken for hormone receptor analysis. The total number of sections ranged from lo-50 depending on gross and histologic features of specimens, mammographic findings and results of frozen sections. The sections were taken from the anterior, posterior, medial and lateral aspects of each specimen. These were blocked sagitally to assess margins. In cases with positive margins re-excision was performed. A prominent intraductal component within the cancer is defined as either 1. DCIS present as a prominent component of the tumour (generally this corresponds to 25% or greater of the tumour) and the presence of DCIS in the grossly normal adjacent breast tissue or two diffuse DCIS with foci of invasive cancer.“,” DCIS was classified into three groups according to recently described criteria.” The classification is based on nuclear morphology and on polarization of cells (architectural differentiation). Thus, tumours with very pleomorphic nuclei and no evidence of polarity of cells around intercellular spaces were classified as poorly differentiated; those with less pleomorphic nuclei and definite. but often focal or inconspicuous polarization, as intermediately differentiated, and lesions composed of cells with monomorphic uniform nuclei with prominent polarization of cells as well-differentiated. When more than one type of DCIS was present, the tumour was classified according to
73
the least differentiated component. The grade of the invasive tumour was taken from the original surgical biopsy report. Grading of the invasive component was carried out according to the Nottingham modification of the Bloom and Richardson system proposed by Elston.“,14 Diagnosis and date of recurrence were determined according to the criteria of Hayward et al.15 Local recurrence was defined as detection of cancer in the parenchyma and/or skin of the treated breast occurring before or simultaneously with the discovery of distant metastasis. The follow-up period was between 20 and 120 months with a median of 62 months. Survival, both disease-free and overall, was calculated using the method of Kaplan and Meier.lh
RESULTS There were 101 (57.7%) tumours without a prominent DClS component and 74 (42.3%) tumours with prominent DCIS. Amongst tumours with a prominent DClS component there were 10 (13.5%) which were well differentiated, 36 (48.7%) were of intermediate differentiation and 28 (37.8%) were poorly differentiated. Local recurrence was more common in patients with carcinomas showing a prominent DCIS component; 8 of 74 (10.8%) cases compared with 2 of 101 (2%) tumours without prominent DClS, a statistically significant difference (x*=12.954, PC 0.005).Local recurrences were observed in 0 of 10 patients with well-differentiated DCIS, 2 of 36 (5.5%) patients with intermediately differentiated DCIS and 6 of 28 (21.4%) patients with poorly differentiated DCIS. The difference between tumours without prominent DCIS and those with poorly differentiated DCIS was statistically significant (x2=8.798, P-c0.005).However, the difference in local recurrence between tumours based on DCIS type was not statistically significant. The clinical and pathologic features of patients are shown in Table 1. The relationship between DCIS type and survival is shown in Figure 1. Table 1 prominent
Presentation characteristics of 175 patients DCIS component of grade I, II and III
Mean (year) Range (year)
Age Nodal
status
Tumour
size
Follow-up Recurrences
Negative Positive Mean Range Maximum (Mts) Median (Mts)
with and without
a
Without DCIS
DCIS grade I
DCIS grade II
DCIS grade III
(rr=lOl) 54.4 28-84
(it’lo) 5x.2 45-77
(n=36) 55.2 37-86
(n=28) 50.0 33-64
83 18
9 I
23 13
15 13
I .4 0.4-3.5
I .4 0.b2.s
1.7 0.74.0
2.1 o.w.0
1 I3 60
116 68
101 55
120 62
2
0
2
6
74
The Breast 0
Complete
+
Censored
0.0 -0.1 10
PO
30
40
50
60
70
Time
80
90
100
110
120
130
(months,
Fig. 1 Kaplan-Meier plots for overall survival for patients cancer with and without prominent DCIS component.
with breast
Disseminated metastatic disease occurred in 9 patients without a prominent DCIS component varying from 6 to 24 months (mean 14) after diagnosis, and in two patients with a prominent DCIS component of intermediately differentiated type, 20 and 24 months after presentation, respectively. We have analysed the correlation between histologic type of prominent DCIS component and histologic grade of invasive ductal breast carcinoma (Table 2). There was a highly significant correlation between DCIS type and the grade of the invasive component of the tumour (x*=73.77, P< 0.001, DF=4). Well-differentiated DCIS was usually associated with a grade I tumour, intermediately differentiated with grade II, and poorly differentiated was associated in half with grade II and half with grade III invasive carcinomas. During follow-up 6 patients with tumours without a prominent DCIS component died 25-50 months after diagnosis. Three patients died from disease, and three from unrelated causes. Four patients with tumours showing a prominent DCIS component died due to disease from 24-65 months after presentation (two with well-differentiated, one with moderately differentiated and one with poorly differentiated DCIS). These differences were not statistically significant (x*=3.73 1, P= 0.2921). DISCUSSION In this study we have examined the association between the presence of a prominent DClS component and the risk of Table 2 component
The relationship and histologic
between degree grade of invasive Grade
of differentiation carcinoma
of invasive
cancer
of DCIS
DCIS type Well differentiated Intermediately differentiated Poorly differentiated
I 10 2 1
II 32 10
III 2 17
Total 10 36 28
Total
13
42
19
74
(%)
(%)
local recurrence of a tumour after breast conserving therapy. We found that in patients with invasive ductal breast cancer with a prominent intraductal component the risk of recurrence was significantly higher than for patients without prominent DCIS. In this study prominent intraductal component was determined according to the criteria of Holland et a1.4,9However, according to Schnitt et al. the degree of prominent DCIS component within the tumour and adjacent breast tissue was categorized as absent when no ducts were involved, slight when comprising less than 25% of the tumour area, moderate when comprising 25-50%, and marked when comprising greater than 50% of the tumour area and adjacent breast parenchyma.’ Furthermore, we have investigated the relationship between various types of DCIS and local recurrences as well as with overall survival. We found that patients with DCIS of poorly differentiated type have a significantly higher risk of local recurrence. None of the patients with DCIS of well-differentiated type developed local recurrence in the period of follow-up. A similar observation has been reported by Lampejo et a1.7 There are many classifications of DCIS.6X8X9,‘7-2’ In the past DCIS has been divided into five major groups: comedo, solid, cribriform, papillary and micropapillary.’ DCIS has also been divided into two major type: noncomedo and comedo DCIS, the former being associated with a lower risk of subsequent development of invasive carcinoma than the latter.6,7,8.22However, criteria used for these classifications were poorly defined and were based mainly on architectural pattern and the presence or absence of necrosis, In our study, a recently proposed classification, based on cytonuclear features and architectural pattern was used.’ This classification has also been used in other studies comparing various DCIS types with the mammographic appearance of DCIS, the growth pattern, and distribution of DCIS within the breast and with biological features, including proliferation, steroid-hormone receptor status and oncoprotein expression.7.‘9.23-25Several studies have shown that poorly differentiated DCIS typically lacks oestrogen and progesterone receptors, has a high proliferative rate, exhibits aneuploidy, shows c-erbB-2, ~53 and bcl-2 abnormalities and frequently has new vessel formation in the adjacent stroma.23-25In contrast, well-differentiated DCIS is usually oestrogen and progesterone receptor positive, rarely shows c-erbB-2, ~53 and bcl-2 positive immunostaining, and has a low proliferative activity. Intermediately differentiated DCIS shows characteristics that are intermediate between those of poorly and well-differentiated DCIS.23-25 Conservative surgery and radiation therapy is a widely accepted option in the treatment of early-stage invasive breast cancer.2.5.7,10-12,20.26 The well-known factors for local recurrence are failure to completely excise the tumour and a mammographic pattern of widespread suspicious microcalcifications shown to represent DCIS.*,‘,” The major un-
Prognostic value of prominent DCIS component resolved factors for local recurrence are the extent of breast resection, the presence of a prominent intraductal component within the cancer, and the presence and extent of cancer involvement at the margins of resection.‘.2*3.5,7.‘03”The importance of free margins for the prediction of local recurrence is stressed by many authors including Silverstein’s recent work which has tried to integrate different elements of extent, grade and margins.‘7~‘8However, various methods for assessing completeness of excision have been proposed. Our margins were blocked sagitally and sections from anterior, posterior, medial and lateral aspects of the specimen were examined. Recently, some authors have suggested examination of shaved margins, but the relationship between shaved and inked margins remains unclear.‘” However, the relatively high rate of local recurrence in patients with negative margins, in spite of radiotherapy, shows that the pathological finding of free margins does not ensure no risk of recurrence.‘” The 1O-year rate of local recurrence following breast-conserving therapy is reported to be between 8 and 20%. Recurrence rates for tumours without a prominent DCIS component have been reported by some to be significantly lower than for turnouts with prominent DCIS.‘~‘.‘” It has also been suggested that the type of the DCIS component of the infiltrating carcinoma might be predictive of outcome.7-Y Our results suggest that local recurrences occur significantly more commonly in tumours with a prominent DCIS component and in tumours with poorly differentiated DCIS when compared with tumours without a prominent DCIS component. This difference is present by five years. However, we have failed to find significant differences between various grades of DCIS. This could be due to two factors: first, a relatively short follow-up period or secondly, a relatively small number of cases in our series. We have found a close relationship between degree of differentiation of the invasive and DCIS components of a breast carcinoma as reported by others.’ We believe that the presence of a poorly differentiated prominent DCIS component should be considered as an unfavourable prognostic factor in the development of local recurrences after breast conserving therapy.
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Acknowledgement Excellent technical appreciated.
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