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10.1245/ASO.2005.03.021
Annals of Surgical Oncology 12:881-885 (2005)
© 2005 Society of Surgical Oncology
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Original Article

The Consequence of Multiple Re-Excisions to Obtain Clear Lumpectomy Margins in Breast Cancer Patients

Tehillah S. Menes, MD1, Paul Ian Tartter, MD, FACS1, Ira Bleiweiss, MD2, James H. Godbold, PhD3, Alison Estabrook, MD, FACS1 and Sharon Rosenbaum Smith, MD1

1 The Comprehensive Breast Center, 425 West 59th Street, Suite 7A, New York, New York 10019
2 Department of Pathology, Mount Sinai Medical Center, Gustave L. Levy Place, New York, New York 10029
3 Department of Community and Preventive Medicine, Mount Sinai Medical Center, Gustave L. Levy Place, New York, New York 10029

Correspondence: Address correspondence and reprint requests to: Paul Ian Tartter, MD, FACS; E-mail: paultartter{at}yahoo.com.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Microscopically clear lumpectomy margins are critical for optimizing local control with breast conservation for cancer. Re-excisions are often necessary to achieve clear surgical margins. Factors that contribute to nonnegative margins and necessitate re-excision may increase the risk of local recurrence.

Methods: Patients who were treated with breast conservation for breast cancers were identified from a prospective database maintained by one of the authors. Factors associated with local recurrence were evaluated in 459 consecutive patients with attention to the number of re-excisions required to obtain clear margins.

Results: Twenty-eight patients (5%) developed local recurrences at a mean follow-up of 78 months. In multivariate analysis, local recurrence was most significantly associated with the omission of radiotherapy (19% vs. 5%; relative risk [RR], 3.64; 95% confidence interval, 1.6–8.2), followed by young age (52 vs. 58; 95% confidence interval, –.83 to –10.6 years) and the number of re-excisions required to obtain clear margins (none, 4%; one, 7% [RR, 2.05; 95% confidence interval, .86–4.89]; two or more, 17% [RR, 5.20; 95% confidence interval, 1.44–18.8]). Tumor size, the number of involved nodes, pathology, and adjuvant chemotherapy were not significantly related to local recurrence.

Conclusions: The risk of local recurrence after breast conservation for breast cancer increases progressively with the number of re-excisions needed to achieve clear margins. Patients in whom the cancer is fully excised with clear margins in the first excision will have less of a chance of local recurrence compared with patients who need further re-excision to achieve clear margins.

Key Words: Breast cancer • Lumpectomy • Margins • Local recurrence


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Survival after lumpectomy with radiotherapy for early breast cancer is comparable to that after mastectomy. Mastectomy is superior to breast conservation only because local recurrences are less frequent. Breast conservation involves compromises between optimal local control and cosmesis, expense, and inconvenience. Adjuvant radiotherapy is widely recognized as the most important factor for reducing local recurrence; generally the associated inconvenience and expense of radiation are tolerable, and cosmesis is not compromised. Clear microscopic margins are also necessary for optimal local control, and for many patients this means the inconvenience and added expense of an additional trip to the operating room to re-excise a close or involved margin. Cosmesis can be compromised depending on the size of the breast relative to the cavity created by the lumpectomy and re-excision(s).

Re-excision to obtain clear margins reduces the risk of local recurrence in patients with close or positive margins,1–3 but patients often have nonnegative margins after re-excision, and they are confronted with the choice of mastectomy or additional re-excisions to attempt to clear the margins. Because in most studies patients with clear margins after re-excision have higher rates of local recurrence than patients with clear margins without re-excision,1,3 additional attempts to attain clear margins may be associated with higher rates of local recurrence. We studied the factors influencing local recurrence in a large number of patients with long follow-up treated with breast conservation, 36 of whom required 2 or more re-excisions to obtain clear margins.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients who underwent lumpectomy for invasive breast cancer between 1973 and 1998 at the Mount Sinai Medical Center in New York were identified from a prospective database maintained by one of the authors. Patients were entered prospectively, and the interval from diagnosis to last follow-up or to local or distant recurrence was updated annually. Data collected included age, invasive tumor size, pathology, presence of extensive intraductal carcinoma, first and final margin status, nodal involvement, radiotherapy, and chemotherapy. The study population consisted of 459 patients who had breast-conserving therapy with clear margins and for whom at least 5 years of follow-up was available.

Patients underwent lumpectomy for ductal carcinoma-in-situ or lumpectomy with axillary node dissection for invasive cancers. Tumor size in patients with both invasive and in situ cancer is the largest dimension of the invasive component measured microscopically and was determined by one of the authors (I.B.). Since 1996, lumpectomy specimens have been labeled with silk sutures to maintain the orientation of the specimen, and the specimens are inked with six different colors to keep track of the medial, lateral, anterior, posterior, superior, and inferior margins. Patients who underwent re-excision for nonnegative margins had directed re-excision of the walls of the lumpectomy cavity that corresponded to the nonnegative sides of the lumpectomy specimen. Before 1996, specimens were not oriented, and patients who underwent re-excision had complete re-excision of all of the walls of the lumpectomy cavity. Margins were considered clear when no invasive or noninvasive disease was within a millimeter of the margin, close if within a millimeter, and positive if at the inked margin.1 This has been the institutional policy since 1996. The 61 carcinomas that presented as calcifications on mammography and underwent re-excision had preradiation mammography to exclude residual calcifications.

Adjuvant radiotherapy for most patients was given as an external beam of 45 Gy to the entire breast followed by a 15-Gy boost to the lumpectomy bed. Generally, chemotherapy was given to premenopausal patients with nodal involvement or with tumors >2 cm and to postmenopausal women with estrogen receptor–negative tumors >2 cm. Chemotherapy was cyclophosphamide and 5-fluorouracil with doxorubicin or methotrexate.

Data were analyzed with SPSS statistical software (SPSS Inc., Chicago, IL). The significance of differences in continuous variables was evaluated by using Student’s t-test, and the significance of differences in categorical variables was evaluated by using the {chi}2 test. The Cox proportional hazards model was used to evaluate the significance of each potential risk factor for local recurrence. The 5-year risk of local recurrence was calculated with the Kaplan-Meier method, and the significance of the differences was evaluated by the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The 459 patients ranged in age from 27 to 87 years (mean, 58 years). Most (n = 251; 55%) presented with clinical findings, and 45% (n = 208) presented with mammographic abnormalities. Eighty-two percent (n = 350) of the cancers were infiltrating ductal carcinoma, 10% (n = 172) were ductal carcinoma-in-situ, and 8% (n = 37) were infiltrating lobular carcinoma. The invasive cancers ranged in size from <1 mm to 70 mm, with a mean of 14 mm. The margin of the first excised specimen was negative for 46% (n = 210), close for 10% (n = 47), positive for 15% (n = 68), and unknown for 29% (n = 135). A total of 439 re-excisions were performed in 229 patients. Axillary lymph nodes were examined in 352 (77%) of the 459 patients and were positive in 95 (24%). Axillary nodes were examined in 11 patients with ductal carcinoma-in-situ, and none was positive. Ninety percent (n = 412) received radiotherapy, and 30% (n = 137) received chemotherapy.

The longest follow-up was 242 months, and follow-up averaged 75 months. Twenty-eight (6%) of the 459 patients had local recurrences. In multivariate analysis, local recurrence was significantly related to omission of radiotherapy (P < .001), young age (P = .029), and the number of re-excisions necessary to obtain clear margins (P = .042; Fig. 1Go, Table 1Go).


Figure 1
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  		FIG. 1. Local recurrence–free survival in relation to the number of re-excisions.

 

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  		TABLE 1. Multivariate analysis with local recurrence as the dependent variable
 
The most significant variable associated with local recurrence was omission of radiotherapy. The 5-year cumulative risk of local recurrence without radiotherapy was 18.4%, compared with 3.8% with radiotherapy (P = .0001; Table 2Go). Radiation also increased the interval between surgery and local recurrence from 26 to 52 months.


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  		TABLE 2. Five-year cumulative risk of local recurrence
 
Younger patients experienced the highest rates of local recurrence. The local recurrence rate for the 137 women <50 years of age was 6.6%, compared with 2.6% in the 322 women ≥ 50 years (P = .0842; Table 2Go). The mean age of patients with local recurrences was 52 years, compared with 58 years for patients who did not have a local recurrence. The mean interval between operation and local recurrence was also longer in the older patients: 55 months for patients >50 years and 19 months for patients <50 years.

Patients who underwent two or more re-excisions also experienced a higher rate of local recurrence. The 5-year cumulative risk of local recurrence for the 22 patients who required ≥2 re-excisions was 13.4%, compared with 5.6% for the 210 patients who had one re-excision and 3.5% for the 209 patients who had none (P = .0149 for ≥2 vs. 0 re-excisions; P = .0705 for 1 vs. 2 re-excisions; P = .3845 for 0 re-excisions vs. 1 re-excision). The mean interval between operation and local recurrence for patients with two or more re-excisions was 30 months, compared with 54 months with one re-excision and 40 months without re-excision.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These results indicate that local recurrence after breast-conservation treatment for breast cancer is more frequent when re-excisions are required to obtain clear margins, when adjuvant radiotherapy is omitted, and in young patients. Omission of radiotherapy has also been previously associated with higher rates of local recurrence after breast conservation.4 The addition of radiotherapy to surgical extirpation of the tumor generally reduces the risk of local recurrence by 3- to 4-fold.

High rates of local recurrence after breast conservation have repeatedly been noted in young patients,5–7 perhaps in part because such women often have more poorly differentiated, estrogen receptor–negative, aneuploid tumors with higher S phases than their older counterparts. Invasive tumor size, margin status, and nodal involvement have not been related to the high local recurrence rate in young women.

The progressively increasing risk of local recurrence with additional re-excisions to obtain clear margins has not been previously appreciated. We noted that the risk of local recurrence increased progressively with the number of re-excisions from 3.5% without re-excision to 5.6% with one re-excision and to 13.4% with two or more re-excisions to obtain clear margins. This relationship was statistically significant after consideration for age and treatment with radiation. This finding is not inconsistent with previous studies of variables influencing local recurrence after breast conservation.1,3,8 Local recurrence is generally lowest in patients who have clear margins after their first procedure and higher in patients with initially nonnegative margins who are converted to clear margins by re-excision. This relationship has not been found to be statistically significant previously because of the small numbers of patients studied1,3 or the short follow-up time3 or because large numbers of disease recurrences were counted as new primary tumors rather than local recurrences.8 We could find no reference to patients having two or more re-excisions—the group with the highest risk of local recurrence in our study.

The assessment of surgical margins is problematic. The surgeon labels the lumpectomy specimen to orient the pathologist. The shape and borders of the cancer and the tissue around it make the definition by the surgeon and correlation with the pathologist imprecise.9 Margin assessment may further be complicated in wire-localized cases by the significant flattening of the specimen by compression radiography before it reaches the pathology suite, thus making clear margins appear closer.10 Re-excision for positive margins often yields no residual disease, whereas additional cancer is often found at re-excision for close margins. When margin assessment is not precise, re-excising cannot be perfect, especially if it is performed only for the involved margin and not by resecting the entire cavity. Because assessment of the surgical margins consists of sampling, even if all the tissue removed is embedded into paraffin blocks, the microscopic margin status serves as a marker for the amount of residual cancer: clear margins correlate with lower rates of residual disease, and multiple positive margins correlate with higher rates of residual disease and, hence, higher local recurrence rates.11,12 The necessity for re-excision of nonnegative margins indicates a higher risk of local recurrence because it reflects more extensive disease with a higher risk of local recurrence.

Our results indicate that the risk of local recurrence progressively increases with the number of re-excisions required to obtain clear margins. Achieving clear margins on primary excision is superior to achieving clear margins after re-excision. Patients with nonnegative margins who are contemplating returning to the operating room for re-excision or mastectomy should be aware of the higher risk of local recurrence when re-excision is necessary to obtain clear margins.


   ACKNOWLEDGMENTS
 
Supported by The Martin Feuer Education Fund.

Received for publication March 15, 2004. Accepted for publication June 6, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Tartter PI, Kaplan J, Bleiweiss I, et al. Lumpectomy margins, re-excision, and local recurrence of breast cancer. Am J Surg 1999;179:81–5.
  2. Smitt MC, Nowels KW, Zdeblick MJ, et al. The importance of lumpectomy surgical margin status in long term results of breast conservation. Cancer 1995;76:259–67.[CrossRef][Medline]
  3. Anscher MS, Jones P, Prosnitz LR, et al. Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy. Ann Surg 1993;218:22–8.[Medline]
  4. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomized trials. Lancet 2000;355:1739–40.[CrossRef][Medline]
  5. Gajdos C, Tartter PI, Bleiweiss IJ, Bodian C, Brower ST. Stage 0 to stage III breast cancer in young women. J Am Coll Surg 2000;190:509–15.[CrossRef][Medline]
  6. Kim SH, Simkovich-Heerdt A, Tran KN, et al. Women 35 years of age or younger have higher locoregional relapse rates after undergoing breast conservation therapy. J Am Coll Surg 1998;187:1–8.[CrossRef][Medline]
  7. Kollias J, Elston CW, Ellis IO, et al. Early-onset breast cancer—histopathological and prognostic considerations. Br J Cancer 1997;75:1318–23.[Medline]
  8. Gibson GR, Lesnikoski B, Yoo J, Mott LA, Cady B, Barth J Jr. A comparison of ink-directed and traditional whole-cavity re-excision for breast lumpectomy specimens with positive margins. Ann Surg Oncol 2001;8: 693–704.[Abstract/Free Full Text]
  9. Carter D. Margins of "lumpectomy" for breast cancer. Hum Pathol 1986;17:330–2.[Medline]
  10. Graham RA, Homer MJ, Katz J, et al. The pancake phenomenon contributes to the inaccuracy of margin assessment in patients with breast cancer. Am J Surg 2002;184: 89–93.[CrossRef][Medline]
  11. Wazer DE, Schmidt-Ullrich RK, Schmid CH, et al. The value of breast lumpectomy margin assessment as a predictor of residual tumor burden. Int J Radiat Oncol Biol Phys 1997;38:291–9.[CrossRef][Medline]
  12. Neuschatz AC, DiPetrillo T, Steinhoff M, et al. The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast. Cancer 2002;94:1917–24.[CrossRef][Medline]



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