Breast conserving surgery (BCS) is common practice for unifocal ductal carcinoma in situ (DCIS) less than 4 cm in size, but the extent of tumor free margin width around DCIS necessary to minimize recurrence is unclear.
Breast conserving surgery (BCS) is common practice for unifocal ductal carcinoma in situ (DCIS) less than 4 cm in size, but the extent of tumor free margin width around DCIS necessary to minimize recurrence is unclear.
Clinical and pathologic details were recorded from all patients with pure DCIS < 4 cm in size, treated with BCS between 1978 and 1997. Histologic margins were measured by using an ocular micrometer. Patients with clear margins (> 1 mm) were divided up into 3 groups for analysis based on margin of normal tissue excised: 1.1–5 mm, 5.1–10 mm, and 10.1–40 mm.
There were 66 patients with close margins (≤ 1 mm), of which 25 cases (37.9%) recurred. The recurrence rates for the 3 clear margin groups ranged from 4.5–7.1%. Median followup was 47 months (range 12–197 mos). Risk of recurrence in the group with close margins was greater than the subgroups with clear margins (P < 0.001); no differences in recurrence was seen between the individual subgroups with clear margins. Nuclear Grade 3 was predictive of recurrence (P = 0.03). Following excision alone, the recurrence rate was 18.6%, compared with 11.1% when radiotherapy was given as adjuvant therapy. Women with clear margins following excision had a recurrence rate of only 8.1%.
After BCS for DCIS, close margins were associated with a high risk of local recurrence. Radiotherapy did not compensate for inadequate surgical clearance. Cancer 2001;91:9–16. © 2001 American Cancer Society.
Ductal carcinoma in situ (DCIS) of the breast is a premalignant condition that occurs in about 30 % of screen detected breast cancers.1–3 Despite increased awareness of DCIS, the optimum management of DCIS remains controversial.2–4 Mastectomy is considered to be overtreatment for most cases of DCIS; however breast-conserving surgery (BCS) is complicated by a high rate of tumor recurrence. Price et al.5 reported that up to 30% of patients develop recurrent disease following BCS for DCIS within 15 years, and of these about 50% will have invasive cancer.
Prospective, randomized, controlled trials, the National Surgical Adjuvant Breast and Bowel Project B-17 (NSABP B-17), and NSABP Project B-24 (NSABP B-24) concluded that radiotherapy and tamoxifen should be given to all patients following BCS for DCIS.6–8 In NSABP B-17, only patients with clear margins were included; however, the NSABP B-17 definition of a clear margin was any margin in which no tumor was seen on the resection margin. NSABP B-24 allowed patients who had involved margins to be included in their study. Pathologic review of both studies revealed that complete excision with clear margins was associated with a lower tumor recurrence rate.6, 9 Thus, to our knowledge, there are no trials that have considered the role of adjuvant therapy when clear margins have been obtained around DCIS.
Margin status is a key prognostic factor, and if the margins are greater than 10 mm, a Silverstein study10 has claimed that radiotherapy is not required. Margin status is the most important predictor of recurrence, as we have previously reported.11 Margin width is an important factor in predicting the risk of tumor recurrence following BCS.12–15 However, there remains no agreement on what constitutes an optimal excision margin width, so the patient is left with a small risk of recurrence but a cosmetically acceptable result from BCS. It has been demonstrated that 43% of patients have residual disease following BCS when the margins are less than 1 mm.16 To our knowledge, few studies have examined explicitly the resection margin and recurrence rate after BCS.10, 17 We and others previously have advocated a margin width of 10 mm.13, 14, 17 However, in practice, it often is difficult to judge the degree of margin clearance when excising the tumor, particularly when there is no microcalcification on initial mammography; therefore, regularly achieving a goal of a 10 mm all around margin is difficult. The purpose of the current study was to determine the necessity for such an excision margin in breast conserving surgery for DCIS.
Patients diagnosed with only DCIS and treated with BCS between 1978 and 1997 at the Breast Unit of the University Hospital of South Manchester were identified. Additional inclusion criteria were a maximum tumor diameter of 40 mm, histologic slide availability for review if the margin width was not declared in the report, and a minimum follow up of 1 year. Clinical and pathologic data were obtained from the medical records of the patients, and, since 1993, data collection has been prospective. There were 70 patients with DCIS treated before 1993 and 145 after 1993.
Women with palpable DCIS had their diagnoses confirmed by fine-needle aspiration cytology or by stereotactic core biopsy and mammography. Patients with tumors less than 4 cm in greatest dimension were offered a wide local excision with a goal of obtaining clear margins and cavity shavings.
Nonpalpable DCIS was detected by screening mammograms performed at the Nightingale Breast Screening Center at the University Hospital of South Manchester. Patients whose mammograms displayed microcalcification or a suspicious mass lesion were referred for a surgical opinion. During the early part of the current study, preoperative stereotactic fine-needle aspiration cytology was in its infancy, and most cytologic results were inadequate for diagnosis; therefore, most patients proceeded to diagnostic needle localization biopsy. The excised specimens were orientated with ligaclips and subjected to two-dimensional compression radiography to check for an adequate excision. If microcalcifications appeared close to the radiologic margin or were transected, then further shavings were taken from the appropriate margin of the cavity.
From 1992 to 1997, patients with screen-detected DCIS treated by BCS were given the choice of entering the United Kingdom DCIS trial. In this trial, patients were randomly assigned to 1 of 4 treatment arms: tamoxifen 20 mg daily for 5 years; radiotherapy, tamoxifen and radiotherapy; and observation only. Radiotherapy treatment consisted of a tangential pair of megavoltage fields (4, 6, or 8 MV) to encompass the breast. A tumor dose was used of 40 Gy (expressed at a point in the midplane of the fields, 1.5 cm anterior to the posterior edge of the fields) in 15 fractions over 3 weeks.
Postoperatively, women were reviewed clinically every 3 months for 1 year, every 6 months for the next 2 years, and annually thereafter. All women underwent annual two-view mammography. Palpable and impalpable lesions suggestive of recurrence were investigated according to unit protocol. If the recurrence was DCIS then patients were recommended to have a total mastectomy, and if an invasive recurrence was found, then a total mastectomy and axillary clearance were recommended. Recurrence was defined as an ipsilateral DCIS or invasive ductal carcinoma, confirmed histologically.
Histologic examination of excised specimens followed a standard protocol. The main specimens and cavity shavings were measured and painted with India ink prior to serial sectioning at 4 mm intervals along the long axis of the specimen, and three-dimensional reconstruction was perfomed by the pathologist to obtain an accurate measurement of tumor size and margin width. All histologic margin widths were measured using an ocular micrometer.
Histologic margin status of the main specimen was defined as follows: clear, DCIS > 1 mm from any inked margin of excision; close, DCIS ≤ 1mm from any inked margin of excision; and involved, DCIS at any inked margin of excision. Women who had either involved margins or cavity shavings underwent another excision in an attempt to excise completely all DCIS. A failure to achieve pathologic clearance or the presence of histologic multifocality led to a recommendation of mastectomy.
Statistical analysis was performed using SPSS software (SPSS, Chicago, IL) by the CRC Department of Computing and Biomathematics at the Paterson Institute for Cancer Research. Univariate analysis was based on the Kaplan–Meier model, and multivariate analysis was performed using a Cox regression model to examine the relative contributions of five categorical variables (margin width, nuclear grade, comedonecrosis, tumor size, and adjuvant therapy). A significance level of 5% was used throughout.
In the period January 1978 to December 1997, 244 patients had breast conservative surgery for DCIS. After excluding women with microinvasive DCIS (n = 31), and undeclared margin width with no slides available for review (n = 8), 205 patients remained for study. Their mean age at diagnosis was 56 years (range, 19–82 yrs). However, for analysis, the age range was divided into 4 groups (< 49, 50–59, 60–69, and > 70). The median time of followup for all 205 patients was 47 months (range, 12–197mos).
Screening detected most of the cases of DCIS (192 of 205, 93.6%). The main abnormal mammographic finding was localized microcalcification (183 of 205, 89.2%). A mammographic mass was present in the other patients (22 of 205, 10.8%). One hundred sixty-four (80%) mammographic lesions were considered impalpable, and 41 (20%) were palpable.
Initial treatment was needle localization biopsy in 154 patients (75.2%), and 51 (24.8%) patients had an open biopsy. Another excision was performed on 65 (31.7%) of these patients either because they had involved margins confirmed by histology (n = 32) or because clear or close margins with positive (DCIS present) shavings were found as shown in Table 1.
|Total||205||102 (49.8%)||32 (15.6%)||71 (34.6%)|
|Total||205||139 (67.8%)||0||66 (32.2%)|
Histopathology revealed pure comedo DCIS in 41 patients (20%), noncomedo in 73 (35.6%), and a mixture of comedo and noncomedo in 91 (44.4%). Therefore, comedo DCIS was present in 132 of the 205 (64.4%) patients.
Nuclear grade was predominantly Grade 3 (126 of 205, 61.5%). Grade 2 (55 of 205, 26.9%) and Grade 1 were less frequent (24 of 205, 11.9%). Nuclear Grade 3 distributions among the margin adjuvant therapy groups and margin width groups are shown in Table 2.
|Plus DXT||11||1||0||1 (9.1)|
|Plus tamoxifen||33||3||1||4 (12.1)|
|DXT & tamoxifen||6||1||0||1 (16.7)|
|Close||37||15||3||18 (48.7)||< 0.001|
The median size of DCIS lesions at initial surgery was 13 mm (range, 2–40 mm). However, for analysis, the size range was divided into 4 groups (0–10, 11–20, 21–30, and 31–40 mm).
Sixty-six patients (32.2%) had close margins (≤ 1 mm). Patients with clear margins were divided into 3 groups for analysis based on distance to the nearest margin: 1.1–5 mm (89 of 205, 43.4%), 5.1–10 mm (28 of 205, 13.7%), and 10.1–40 mm (22 of 205, 10.7%).
Postoperatively, 129 patients (62.9%) received no adjuvant therapy, 49 (23.9%) received tamoxifen therapy alone, 18 (8.8%) received radiotherapy, and 9 (4.4%) received a combination of tamoxifen and radiotherapy. The effect of margin status in the different adjuvant therapy groups is shown in Table 3.
|Excision only||Close||43||14||3||17 (39.5)||< 0.001|
|Excision & radiotherapy||Close||6||2||0||2 (33.3)||0.23|
|Excision & tamoxifen||Close||15||5||0||5 (33.3)||< 0.05|
|Excision, radiotherapy & tamoxifen||Close||2||1||0||1 (50)||0.48|
Overall, there were 32 recurrences (32 of 205, 15.6%). Twenty-five of 66 (37.9%) patients in whom the margin width was ≤ 1 mm (close) had a recurrence compared with 4 recurrences out of 89 (4.5%) patients whose margin widths were 1.1–5 mm (3.5%), 2 recurrences out of 28 (7.1%) patients whose margin widths were 5.1–10 mm, and 1 recurrence out of 22 (4.5%) patients whose margin widths were 10.1–40 mm. Of the 7 recurrences in the groups with clear margins (> 1 mm), 4 patients had DCIS with margins of 4, 5, 5.5, and 6 mm, and 3 patients had invasive recurrences with margins of 4, 5, and 17 mm.
Factors significantly relating to recurrence on univariate analysis were close margin width (log rank X2 = 42.51, 3 degrees of freedom [v = 3], P < 0.001) and nuclear Grade 3 (log rank X2 = 6.89, v = 2, P = 0.03), but age (log rank X2 = 5.78, v = 3, P = 0.12), the presence of comedonecrosis (log rank X2 = 3.98, v = 2, P = 0.14), tumor size (log rank X2 = 5.08, v = 3, P = 0.17), and adjuvant therapy (log rank X2 = 0.36, v = 3, P = 0.95) were not.
Cox regression analysis demonstrated a significantly higher risk of recurrence in the group with close margins compared with the subgroups who had clear margins (P < 0.001). There were no significant differences in recurrence between the different groups who had clear margins and had been divided into groups according to their margin widths (see Figure 1).
A subset analysis of the women with clear margins (n = 139) did not show nuclear Grade 3 as significant in predicting recurrence (log rank X2 = 4.79, v = 2, P = 0.09).
Twenty-six of the recurrences were pure DCIS (81%), and 6 (19%) recurrences were invasive ductal carcinoma within DCIS. Most (30 of 32, 93.8%) recurrences presented asymptomatically (including all recurrent DCISs) and were detected by annual mammographic surveillance at a median time of 20 months (range, 6–109). Twelve ipsilateral recurrences were detected at the first annual mammogram, 9 at the second, 3 at the third, 2 at the fourth and fifth, 3 at the sixth, and 1 at the ninth annual mammogram.
Of the 6 invasive recurrences (Table 4), the median grade was Grade 3 [range, 2–3, Grade 2 (n = 1), Grade 3 (n = 5)]; the original DCIS grades had the same distribution. The sole Grade 2 invasive recurrence had a close margin at the initial excision. The median size was 12 mm (range, 7–24) and median Stage I (range, I–III; only 1 of 6 had nodal metastases). All had abnormal mammograms showing microcalcification, and two patients had a mass lesion at the initial biopsy site. There was one patient who had a recurrence initially with an invasive inflammatory carcinoma, and, a year later, she developed bony metastases and subsequently died.
|Margin width (mm)|
|0.1–1||66||22||3||25 (37.9)||< 0.001|
|Plus DXT||18||2||0||2 (11.1)|
|Plus tamoxifen||49||5||0||5 (10.2)|
|DXT & tamoxifen||9||1||0||1 (11.1)|
|Tumor size (mm)|
During the study period, there were two cases of histologically confirmed carcinoma of the contralateral breast; one was DCIS, and the other was invasive. There were two deaths of which one was related to breast cancer (0.5%), and the remaining death was due to a cardiac cause.
Excision margins greater than 1 mm regardless of width of clearance were associated with a low recurrence rate. Adjuvant radiotherapy and/or tamoxifen did not compensate for close excision margins (≤ 1 mm). Nuclear Grade 3 was associated with an increase in recurrence, particularly invasive cancer. Eighty-one percent of recurrences were localized DCIS and easily treated by further surgery with no compromise to patient survival.
Although the current study did not have control groups and had a small study population relative to the NSABP B-17, NSABP B-24, and the Silverstein study series,6, 8, 10 the data from our study series does raise important issues concerning the need for careful pathologic assessment of margin width, which will determine the necessity of adjuvant therapy following BCS for DCIS. The largest amount of data has been collected prospectively, and meticulous histologic assessment of the specimens has enabled accurate analysis of the factors that affect recurrence: nuclear Grade 3 and a close margin width (≤ 1 mm).
Two separate groups have advocated no adjuvant therapy after BCS when the excision margins are 10 mm or greater.10, 17 Both of these studies were prospective and not controlled; however, particular emphasis was placed on a meticulous standardized method of pathologic processing and margin width assessment of the specimens. In the Nottingham study series, patients who did not have a minimum 10 mm margin width on initial surgery were offered mastectomy or another excision to achieve this wide margin. The recurrence rate for 108 BCS patients in the Nottingham study series was 30% with a median follow-up of 8 years. Silverstein6, 8, 10 reported that if excision clearance margins were 10 mm or greater, then no radiotherapy or tamoxifen was required, regardless of nuclear grade, tumor size, or the presence or absence of comedonecrosis. The overall recurrence rate for this group of patients was 5% at 8 years of followup.
Following excision alone, factors that predicted for recurrence were a close margin width and nuclear Grade 3. The importance of meticulous attention to pathologic margins to prevent local recurrence is clear.
The use of adjuvant therapy in terms of radiotherapy, tamoxifen, and radiotherapy and tamoxifen for all patients following BCS for DCIS is unclear. To our knowledge, there have been three published prospective randomized trials to date on the role of adjuvant therapy following BCS for DCIS: the NSABP B-17, NSABP B-24, and EORTC 10853 trials.6, 18, 19 NSABP B-17 concluded that all patients should receive radiotherapy, and NSABP B-24 concluded that all patients should receive radiotherapy and tamoxifen after BCS. Even though the EORTC 10853 trial showed a significant reduction in ipsilateral DCIS and invasive recurrence but not contralateral invasive cancer, their study concluded that a selection policy for the use of radiotherapy should be adopted as some patients may be at such high risk of recurrence that they should have a mastectomy, and some patients may be at such low risk of recurrence that they should have a local excision only.19
When the NSABP B-17 study began in 1985, and the EORTC 10853 trial in 1986, the belief then was that DCIS was a single disease entity, and, hence, the study asked a single question of whether radiotherapy after BCS for DCIS results in fewer recurrences. We now know that DCIS is, in fact, a heterogeneous disease comprised of different types of DCISs that have different risks of recurrence.20 NSABP B-17 and EORTC 10853 provide evidence that radiotherapy does reduce recurrences after BCS, but they do not provide information on which groups of patients will or will not benefit from radiotherapy.21
The NSABP B-17 pathologic analysis has been criticized because it was a retrospective analysis of only 58% of their patients, and it used inadequate mammographic and pathologic analyses, particularly of margins. One of the criteria for patient entry into their study was a clear margin. The study protocol used by the NSABP B-17 defined a clear margin as a tumor that had not been transected and only a few collagen fibers or fat cells between the tumor and the inked margin were required to designate the margin clear.7 In their initial paper published in 1993, the recurrence rate for the excision only group was 20.9% and 10.4% for the excision and radiotherapy group. Median followup was 43 months,7 similar to the followup time in the current study. The number of their cases with close margins by our definition (≤ 1 mm) is unknown. Their recurrence rates for excision only and excision and radiotherapy were similar to the current study rates (18.6% for excision only, and 11.1% for excision and radiotherapy), but when margins were clear after excision alone in the current study, we obtained a recurrence rate of 8.1% that implied that the higher recurrence rate in the NSABP B-17 study must have been related to close margins.
An important question is whether radiotherapy is indicated if excision margins are clear. In the updated NSABP B-17 report, only the presence of comedonecrosis predicted recurrence; it is noteworthy that margin width was no longer a predictor of recurrence in contradistinction to their initial 1993 report.22, 23 Radiotherapy given to women with margins less than 1 mm reduces recurrence from 58% to 30%; however, this still is an unacceptably high recurrence rate.10 We accept that the numbers in the adjuvant therapy groups from this series are too few for meaningful statistical analysis, but 3 of 8 women who had close surgical margins and were given radiotherapy recurred with DCIS.
Our experience is that adjuvant therapy is unlikely to compensate for inadequate margin clearance. Adjuvant radiotherapy given as 40 Gy in 15 fractions over 3 weeks currently is accepted practice in the United Kingdom for both DCIS and invasive ductal carcinoma (IDC), and the evidence suggests that this is equivalent to 50–60 Gy over 5–6 weeks.24, 25
Radiotherapy is expensive and accompanied by serious morbidity in some patients. A recent overview of adjuvant radiotherapy for breast carcinoma showed a marked increase in deaths due to vascular events, particularly in patients older than 50 years who had a low risk of recurrence.26 In the EORTC 10853 trial, there was a significant increase in contralateral breast carcinoma in their radiotherapy group.19 Radiotherapy can be avoided if meticulous pathologic examination of margin width is carried out and if another excision is performed when margins are close.
The NSABP B-24 demonstrated a decrease in invasive recurrences in women treated with adjuvant tamoxifen and radiotherapy despite involved margins. The decrease in ipsilateral invasive breast carcinoma recurrences in the NSABP B-24 was counterbalanced by an increased risk of endometrial cancer, deep vein thrombosis, and pulmonary embolism in women taking tamoxifen, thus reducing the overall benefit of tamoxifen therapy. The NSABP B-24 study showed no decrease in ipsilateral DCIS recurrences. Over 70% of mammographically detected DCISs are of the comedo subtype, which are predominantly nuclear Grade 3, estrogen receptor (ER) negative, and, as the NSABP B-24 study showed, are unlikely to respond to tamoxifen. in We have reported that, in an in vivo DCIS model, epithelial proliferation and apoptosis in ER negative DCIS are unaffected by estrogen stimulation or antiestrogen therapy (Faslodex®).27
We recognize that the NSABP B-17, NSABP B-24, and EORTC 10853 studies are prospective controlled randomized trials, whereas we report a prospective study without controls. Nonetheless, careful examination of pathologic margins may identify women who have a low risk of recurrence and who, therefore, can avoid radiotherapy.
For margin widths > 10 mm and < 1 mm with no adjuvant treatment, the recurrence rates from our study series (4.5% and 37.9% respectively) compare well with the Silverstein study series (2.2% and 33.3%). However, when comparing intermediate margin widths of the current study with the Silverman studies, the recurrence rate in our study series is 8.1%, and it was 18.5% in the Silverstein studies. This difference may be because of a shorter mean length of followup in our study series (47 mos vs 86 mos).10
Residual disease has been associated with close or involved margins.14, 28 The recurrence rate in our series of patients with a close margin was 37.9%. These patients had mammographically detected and impalpable tumors. Twelve of the 25 were identified within 12 months of followup. All recurrences, except for one, occurred at or near the site of the original biopsy and had similar or identical histopathologic features. These observed recurrences probably were residual disease rather than true recurrences, and when these 12 recurrences were excluded from the analysis, close margin width and nuclear Grade 3 still were the only significant factors to predict recurrence.8, 10 In most cases, mammographically detected recurrence is residual disease, whereas symptomatic disease indicates progression to invasive disease.29 Whereas patients with Grade 1 or 2 DCIS and clear margins did not suffer recurrence in our study series, Grade 3 DCIS produced Grade 3 invasive carcinomas thus indicating the need for particular attention to pathologic margin status in Grade 3 DCIS. Selective treatment for DCIS is as necessary as it is in invasive cancer. Cases of Grade 1 DCISs have been reported to recur as Grade 1 invasive carcinomas and Grade 3 DCISs as Grade 3 invasive carcinomas.30 Over 60% of DCIS lesions are Grade 3.20 If adjuvant therapy is selected by grade and ER status, then patients with Grade 1 ER positive DCIS would be given tamoxifen without radiotherapy, whereas patients with high grade DCIS would have radiotherapy alone.
We have an aggressive biopsy policy for all new microcalcifications detected on annual mammography with the aim of identifying recurrences at an early (i.e., DCIS) stage rather than at a late stage (i.e., IDC). The ratio of 4:1 for DCIS:IDC recurrence has been constant for the last 4 years of followup, although we accept that further recurrence may occur with longer followup.
Surgery should ensure clear margins first before adjuvant treatment for DCIS is proffered. We now do not advise a second surgical excision or adjuvant therapy in patients who have nuclear Grade 1 and 2 DCIS with clear margins and negative shavings. Wider margins do not appear to reduce recurrence but do compromise the cosmetic result. If cosmesis is poor after BCS, then the patient may benefit from a mastectomy and breast reconstruction.
The impact upon patients of local recurrence following BCS for DCIS sometimes is mitigated by high rates of survival, freedom from distant metastases, and freedom from chest wall recurrences.12, 29 The development of invasive disease or overall survival from breast carcinoma are the important endpoints upon which to focus rather than upon DCIS recurrence.
The presence of DCIS close to the excision margins requires a second excision, and radiotherapy does not compensate for inadequate surgical clearance. Clear margins (> 1 mm) associated with nuclear Grade 3 require radiotherapy. Careful pathologic assessment of surgical margins is critical to determine the risk of recurrence. The question of whether DCIS excised with clear margins requires adjuvant radiotherapy and tamoxifen has not been answered by the NSABP B-17 and NSABP B-24 studies. A prospective, randomized, and controlled trial with a distinct definition of a clear margin and a standardized method of measuring margin width is warranted to determine the need for adjuvant radiotherapy and tamoxifen after BCS for DCIS.
The authors thank Dr. Brian Magee for his assistance in this study.