This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cellini, C. Articles by Simmons, R. Search for Related Content PubMed PubMed Citation Articles by Cellini, C. Articles by Simmons, R.

Factors Associated With Residual Breast Cancer After Re-excision for Close or Positive Margins

From the Department of Surgery (CC, STH) and the Department of Public Health (PC), Weill Medical College of Cornell University, and the Weill Cornell Breast Center (DM, JC, SK, ELaV, EC, RS), New York, New York.

ABSTRACT

Background: Successful breast conservation surgery (BCS) requires complete tumor excision. Margin status of the initial specimen determines the need for additional surgery. We explored factors associated with residual cancer (RC) upon follow-up surgery in patients with close, positive, or undetermined margins following BCS.

Methods: A retrospective analysis of 276 patients with initial close, positive, or undetermined margins who underwent re-excision (RE) or mastectomy was conducted. All initial excisions were intended as definitive procedures. Chi-square analysis was used to identify factors that may predict RC.

Results: Of 276 patients, 87 had close, 168 had positive, and 21 had undetermined margins on initial excision. Of this group, 63% (175/276) had RC upon RE or mastectomy. Of positive-margin patients, 68% had RC, compared with 53% of close-margin and 67% of undetermined-margin patients (P = .006). Tumors 2 cm were more often associated with RC than smaller tumors (70.8% vs. 56.5%; P = .07). This association was strongest in positive-margin patients (P = .04). High tumor grade was associated with RC in all groups. RC linearly increased with the number of involved margins (P = .02). Specimen inking with multiple colors was associated with decreased risk of RC (P = .004).

Conclusions: Over half of patients with involved or undetermined margins had RC upon RE or mastectomy. Positive and undetermined margins were more often associated with RC than close margins. Larger tumor size was associated with RC in patients with positive. Increasing tumor grade suggests a greater chance of detecting RC in all groups. Multiple involved margins led to a greater risk of RC.

Key Words: Breast neoplasm • Positive margins • Re-excision • Residual cancer

Breast conservation therapy (BCT) has been established as an appropriate alternative to mastectomy in early stage invasive cancers as well as ductal carcinoma in situ (DCIS) since the publication of the National Surgical Adjuvant Breast Project (NSABP) B-06 document in 1985.1,2 This treatment allows an acceptable therapeutic result while providing better cosmesis and shorter hospital stay and recovery time. Recent 20-year follow-up data from this trial continues to validate lumpectomy and radiation as appropriate treatment for invasive breast carcinoma and DCIS.2

BCT requires the complete removal of all gross tumor, followed by radiation therapy, thereby necessitating microscopically negative margins for patients undergoing this treatment. In theory, surgeons will use margin status as an indicator of residual disease, and a close or positive margin will be re-excised in an attempt to clear all tumor cells and decrease the risk of local recurrence. However, in practice, many re-excision specimens will be free of residual disease.3 These negative re-excisions do not contribute to local control and perhaps could be avoided. In the current literature, controversy exists regarding the relationship between margin status and local recurrence. Depending on the habitus of the patient, re-excision for close or positive margins can compromise cosmesis as well as increase morbidity and cost. However, at the present time, while the literature suggests that as many as 58% of re-excisions may be negative,4 most practicing surgeons re-excise to achieve negative surgical margins before starting radiation therapy. The ability to predict which patients are at high risk for residual disease would be helpful in recommending further treatment options. We therefore undertook this study to examine the clinical and pathological variables associated with patients who have undergone re-excision for close, positive, or undetermined margins and the presence of residual cancer. The goal of doing so would be to identify a subset of patients who could avoid re-excision surgery with oncologic safety.

MATERIALS AND METHODS

A retrospective analysis of 276 patients diagnosed with breast cancer between 1990 and 2002 was performed. Eighty-three patients underwent a diagnostic procedure (fine-needle aspiration or stereotactic core biopsy) prior to definitive excision; 193 patients had an excisional biopsy with or without needle guidance as both a diagnostic and definitive procedure. All patients had close, positive margins or undetermined margins on the initial surgical excision specimen. Positive margins were defined as tumor cells (either focal or extensive) directly at the cut edge of the specimen. Close margins were defined as tumor cells <1 mm from the cut edge of the specimen. All patients underwent either at least one re-excision of the biopsy cavity or mastectomy for the purpose of eradicating microscopic disease.

The presence of residual cancer in subsequent specimens was noted as documented on pathology reports. Residual disease was defined as the persistence of invasive or intraductal carcinoma in the re-excision or mastectomy specimen. In some cases, initial excision was performed at an outside institution. All subsequent re-excisions or mastectomies were performed at our institution. Outside pathology slides were reviewed by an attending pathologist at our institution. Chi-square analysis was used to identify and compare factors that may be predictive of residual cancer: margin status, tumor size, tumor grade, tumor histology, subtype of ductal carcinoma in situ (DCIS), detection of mass in biopsy specimen by pathologist, method of inking of the initial surgical specimen, method of initial excision (sharp vs. cautery), as well as location of involved margin and number of involved margins per specimens. Patient age was analyzed with Student’s t-test. Statistical analyses were performed with Statview software (SAS Institute, Cary, NC). For all statistical comparisons, a P value less than or equal to .05 was considered significant.

RESULTS

A total of 403 patients with presumed breast cancer were treated with lumpectomy. Of this total, 127 patients were eliminated for at least one of the following reasons: benign histology, negative initial margins, incomplete chart data, and initial treatment was not an open excision. Two hundred seventy-six patients with close, positive, or undetermined margins on initial surgery remained for analysis. Patient and tumor characteristics are described in Table 1. Age ranged from 29 to 78 years, with a median age of 52 and mean age of 54.6 years. To address the involved or undeterminable margin status, 100 patients underwent a mastectomy, while 176 patients had re-excisions performed (Fig. 1). The incidence of residual cancer in the re-excised tissue in all cases was approximately 63% (175/276). Of these patients, 46 had close margins, 115 had positive margins, and 14 had margins that were undetermined upon initial excision. The incidence of residual cancer in the close-margin group was 53% (46/87). In the positive-margin group, 68% (115/168) had residual cancer, while in the undetermined-margin group, 67% (14/21) had residual cancer (P = .006) (Fig. 1).

View larger version (25K): [in this window] [in a new window]   FIG. 1. Treatment course of the 276 patients with positive, close, or undetermined margins after initial excision (ND = undetermined; Mast = mastectomy; RE = re-excision; RC = presence of residual cancer in re-excised or mastectomy specimens).

The number of initially involved margins per specimen linearly correlated with the presence of residual cancer (Fig. 2). As the number of involved margins increased from one to six, the presence of residual cancer increased as well. While 45% of patients with 1 involved margin had residual cancer (22/48), 88.9% of those with 5 or 6 margins involved had residual cancer (8/9; P = .02). The mean numbers of involved margins in patients with and without residual cancer were 2.48 and 1.86, respectively. There did not seem to be any association with location of margin and residual cancer.

View larger version (26K): [in this window] [in a new window]   FIG. 2. Relationship between number of initially involved margins (close, positive, or undetermined) and presence of residual cancer in re-excised or mastectomy specimens. A greater number of margins involved significantly increased the risk of finding residual cancer in re-excised or mastectomy specimens.

Patients who had residual cancer at re-excision had higher tumor grades on average when close, positive, and undetermined margins were combined (55% for grade 1 tumors, vs. 68.5% for grade 2 and higher). When margins were analyzed separately, there was a higher incidence of residual cancer with increasing tumor grade in both the positive-margin group (55% vs. 71%; P = .14) and the undetermined-margin group (0% vs. 88%; P = .007) (Fig. 3). Tumors 2 cm were more likely to be associated with residual cancer than those <2 cm (70.8% vs. 56.5%; P = .07). This association was strongest in the positive-margin group (P = .04) (Fig. 4).

View larger version (25K): [in this window] [in a new window]   FIG. 3. Relationship between initial tumor grade and presence of residual cancer in re-excised or mastectomy specimens. Legend depicts initial margin status (ND = undetermined; = 0%).

View larger version (32K): [in this window] [in a new window]   FIG. 4. Relationship between initial tumor size and presence of residual cancer in re-excised or mastectomy specimens. Legend depicts initial margin status (ND = undetermined; *P = .04).

Younger age at diagnosis carried a higher risk of finding residual cancer at re-excision. When all three groups were examined together, the mean age of patients with residual cancer at re-excision was 53.2 years, compared with a mean age of 55.8 years for those without residual cancer (P = .09). When examined separately, younger age was consistently associated with residual cancer in all three groups but did not reach statistical significance. The method of specimen inking of the initial tumor by the pathologist was associated with the presence of residual cancer at re-excision. Tumors that were analyzed with single ink markings were more often associated with residual cancer than those that were analyzed with multiple colors, with each margin assigned a different color. Tumors in the close-margin group were more likely to have residual cancer at re-excision if analyzed with single ink markings versus multiple markings (72.7% vs. 40.4%; P = .004). Specimens with positive margins showed a similar correlation (P = .09) (Fig. 5).

View larger version (31K): [in this window] [in a new window]   FIG. 5. Relationship between initial method of specimen inking and presence of residual cancer in re-excised or mastectomy specimens. Legend depicts initial margin status (ND = undetermined; *P = .004; + = 0.09; = 0%).

Additional variables analyzed included method of clinical detection, location of tumor, family history, primary and additional histologies, subtype of DCIS, initial surgical dissection (sharp vs. electrocautery), presence of mass upon gross inspection, microscopic involvement of lymph nodes, and type of margin analyzed (posterior vs. superior vs. anterior vs. inferior vs. medial vs. lateral). None of these variables demonstrated a significant correlation with finding residual cancer upon subsequent surgery.

DISCUSSION

Breast conservation surgery combined with radiation therapy has shown to result in survival rates that compare favorably with modified radical mastectomy.1,2 However, the success of breast conservation surgery has generally been thought to be dependent on the adequacy of the excision margins. Numerous studies have looked at the effect of final margins on risk of local failure.3 Negative final margins result in a 5-year risk of local failure in 2% to 8% of cases, while the risk is 0% to 22% for positive margins, 2% to 11% for close margins, and 7% to 16% for unknown margins.3 These findings suggest that eradication of residual cancer would lead to more favorable outcomes. Nevertheless, our study found that the risk of finding residual cancer in re-excised tissue for close or positive margins was 63%. These results are consistent with those in the literature, where the frequency of residual tumors in relumpectomy specimens ranges from 32% to 63%.4 One can suppose from these data that for almost half of all patients undergoing relumpectomy, no increase in cancer control will be achieved from additional surgery. Given that the impact of microscopically involved margins on recurrence and survival is unclear, one must question the value of re-excisions and in some cases total mastectomies performed in an effort to obtain clean margins.

Over the past several years, a number of groups have attempted to correlate the detection of residual cancer at the time of re-excision with a number of possible predictive factors.4–8 Of the number of factors examined, margin status and tumor size and grade were the most commonly noted. A number of studies have found that the likelihood of residual cancer in the breast is related to the status of the initial excision margins.3,4,9 Positive margins, as defined by tumor involving the inked margin, have been associated with residual carcinoma in 38% to 67% of cases. Close- and negative-margin groups are associated with residual carcinoma in 7% to 36% and 0% to 33% of cases, respectively. Margins that were not determined are associated with residual carcinoma in 43% to 48% of cases, more similar to cases with positive margins. Similar numbers have been found in cases of DCIS as well.10–12 Our data show that close, positive, and undetermined margins are associated with residual cancer in 52.8%, 68%, and 67% of cases, respectively. We cannot comment on residual cancer rates in initial specimens with negative margins because patients with clear margins would not routinely undergo a re-excision at our institution. Other series have not shown a significant association between positive margins and residual cancer except when multiple margins are involved.3,4 Our study did show a significant trend toward residual cancer with involvement of multiple margins, although we did not control for margin status.

Our series showed a significant association of residual cancer in re-excision specimen with tumor grade as well as tumor size. Large tumors are prone to have positive margins in lumpectomy specimens, which may lead to an association with residual cancer upon re-excision.4,10,11 Cheng et al.10 illustrated this correlation in their series and found that both margin status and size were independent predictors of residual cancer in patients with DCIS.

Not all studies noted this correlation; this may be due to the variability in tumor grade assignment among institutions as well as the fact that DCIS, given its tendency to be multicentric, can be difficult to measure. In addition, we did not use additive tumor size assessment in terms of tumor staging. We recently reported that patients with residual invasive carcinoma in re-excision specimens are staged significantly differently, depending on tumor size assessment technique. Despite having similar median tumor sizes in nonadditive size assessment, patients with residual cancer had a significantly higher rate of lymph node metastasis than the patients who did not. With use of additive size assessment, tumor staging was more accurate in these patients than for the re-excision-negative patients with regard to lymph node metastasis rates.13

Several studies of breast conservation therapy have shown young age to be associated with increased local recurrence rates, with specific pathologic features and anatomy cited as causes.14,15 With respect to residual tumor risk, margin information may not be interpreted equally across all age groups. Wazer et al.16 found that for positive margins, young age was associated with an increase in risk of finding residual tumor upon re-excision. We were unable to show a significant relationship between age and margin status; however, younger patients did have a consistent trend toward residual cancer, especially in the positive-margin group (P = .1).

We were not able to differentiate between patients with limited disease versus multifocal or extensive disease because of the retrospective nature of this study, in addition to the variability between pathologists’ reports from at least two different institutions. We did not find any difference between histology of the primary tumor and risk of residual disease. For similar reasons, this study was not able to quantitate the amount of residual cancer found in re-excised specimens. This issue is an important one, given that if routine re-excision for involved margin is not mandated, postoperative adjuvant therapy must be able to eradicate what might be left behind. Swanson et al. found a 5% likelihood of significant (>3 mm) residual cancer in re-excised specimens, as did a previous study.17 The degree of residual cancer did not show a significant correlation with the degree of margin involvement.

Radiation can eradicate microscopic disease, and some studies have shown that additional radiation "boosts" to the primary site can increase local control.18 Chemotherapy has also been shown to decrease local failure rates in cases of positive or close margins.19 Ultimately, the answer to the question of how much residual cancer can be adequately controlled by adjuvant therapy has yet to be conclusively determined. If adjuvant radiation can eradicate microscopic disease, then performing a re-excision should lead to removal of an amount of cancer that radiation is not able to handle. This study and those reported in the current literature have not been able to consistently show that a significant amount of residual cancer is being removed.

Ideally, a close cooperative relationship between the surgeon and the pathologist would minimize the rate of margin involvement and re-excisions by enabling clear margins to be obtained at first operation. Standard histological examination of the biopsy specimen involves India ink staining of the entire cut surface, with suture placement for orientation. Although the edges are effectively marked, sutures are removed early in processing, making orientation difficult and possibly leading to re-excision of the whole biopsy bed if a positive margin is found. Some institutions employ a multicolor inking system to mark superior, inferior, lateral, medial, anterior, and posterior surfaces of the cut resection specimen in order to more accurately identify and re-excise involved margins. Our study had 125 patients who had multicolor inking of the initial specimen. These patients were more likely to have all disease removed upon subsequent re-excision. Another benefit of the multicolor system is the significant difference in tissue volume removed when compared with whole cavity re-excision, which is an important consideration in BCS.20 Frozen-section analysis as well as touch-preparation analysis at time of initial surgery are proposed techniques that may allow for ensurance of clear margins while avoiding re-excisions; however, both techniques have varying success as reported in the literature, and neither has been uniformly accepted by surgeons and/or pathologists.21

CONCLUSIONS

In summary, a few factors correlating with residual cancer in re-excised specimens were found. These included larger tumor size, higher tumor grade, younger patient age, positive surgical margins, multicolor specimen inking, and increasing number of involved margins. It is important that surgeons consider these factors and the patient’s individual risk of residual carcinoma in consultation regarding breast cancer surgical management.

ACKNOWLEDGMENTS

Supported by the Darrow, Finnell, Lahiff, Levy, TABC, Cadwell, Faicco, and Villa Breast Cancer Research Funds of NYPH.

FOOTNOTES

Received December 16, 2003; accepted June 28, 2004.

Address correspondence and reprint requests to: Rache M. Simmons, MD, Weill Cornell Breast Center, 425 East 61st Street, 8th Floor, New York, NY 10021; Fax: 212-821-0832; e-mail: rms2002{at}med.cornell.edu.

REFERENCES

1. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985;312:665–73.[Abstract]
2. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233–41.[Abstract/Free Full Text]
3. Swanson G, Rynearson K, Symmonds R. Significance of margins of excision on breast cancer recurrence. Am J Clin Oncol 2002;25:438–41.[CrossRef][Medline]
4. Papa M, Zippel D, Koller M, et al. Positive margins of breast biopsy: Is reexcision always necessary? Surg Oncol 1999;70:167–171.[CrossRef]
5. Kearney T, Morrow M. Effect of reexcision on the success of breast conservation surgery. Ann Surg Oncol 1995;2:303–7.[Abstract]
6. Gwin J, Eisenberg B, Hoffman J. Incidence of gross and microscopic carcinoma in specimens from patients with breast cancer after reexcision lumpectomy. Ann Surg 1993;218:729–34.[Medline]
7. Acosta J, Greenlee J, Gubler K. Surgical margins after needle localization breast biopsy. Am J Surg 1995;170:643–5.[CrossRef][Medline]
8. Jardines L, Fowble B, Schultz D. Factors associated with a positive reexcision after excisional biopsy for invasive breast cancer. Surgery 1995;118:803–9.[CrossRef][Medline]
9. Wazer D, Schmidt-Ullrich R, Schmid C, 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]
10. Cheng L, Al-Kaisi N, Gordon N, et al. Relationship between the size and margin status of ductal carcinoma in situ of the breast and residual disease. J Natl Cancer Inst 1997;89:1356–60.[Abstract/Free Full Text]
11. Neuschatz A, 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]
12. Ratanawichitrasin A, Rybicki L, Steiger E, et al. Predicting the likelihood of residual disease in women treated for ductal carcinoma in situ. J Am Coll Surgeons 1999;188:17–21.[CrossRef][Medline]
13. Hollenbeck S, Cellini C, Christos P, et al. Breast cancer patients with residual invasive carcinoma are more accurately staged using additive tumor size assessment. Ann Surg Oncol 2004;11:59–64.[Abstract/Free Full Text]
14. Nixon A, Neuberg D, Hayes D, et al. Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 1994;12:888–94.[Abstract/Free Full Text]
15. Jacquemier J, Seradour B, Hassoun J, Piana L. Special morphologic features of invasive carcinomas in women under 40 years of age. Breast Dis 1985;1:119–22.
16. Wazer D, Schmidt-Ullrich R, Ruthazer R, et al. The influence of age and extensive intraductal component histology upon breast lumpectomy margin assessment as a predictor of residual tumor. Int J Radiat Oncol Biol Phys 1999;45:885–91.[CrossRef][Medline]
17. Wazer D, Schmidt-Ullrich R, Ruthazer R, et al. Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 1998;40:851–8.[CrossRef][Medline]
18. Bartelink H, Collette L, Fourquet A. Impact of a boost dose of 16 Gy on the local control and cosmesis in patients with early breast cancer: the EORTC "boost vs. no boost" trial. Int J Radiat Oncol Biol Phys 2000;48(Suppl 3):111.
19. Smitt MC, Nowels KW, Zdeblick MJ, et al. The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995;76:259–67.[CrossRef][Medline]
20. Gibson GR, Lesnikoski BA, Yoo J, et al. 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]
21. Singletary S. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002;184:383–93.[CrossRef][Medline]

This article has been cited by other articles:

				J. F. Waljee, E. S. Hu, L. A. Newman, and A. K. Alderman Predictors of Re-excision among Women Undergoing Breast-Conserving Surgery for Cancer Ann. Surg. Oncol., May 1, 2008; 15(5): 1297 - 1303. [Abstract] [Full Text] [PDF]

				D. E. Schiller, L. W. Le, B. C. J. Cho, B. J. Youngson, and D. R. McCready Factors Associated with Negative Margins of Lumpectomy Specimen: Potential Use in Selecting Patients for Intraoperative Radiotherapy Ann. Surg. Oncol., March 1, 2008; 15(3): 833 - 842. [Abstract] [Full Text] [PDF]

				S. Loibl, G. von Minckwitz, G. Raab, J.-U. Blohmer, S. D. Costa, B. Gerber, H. Eidtmann, S. Petrich, J. Hilfrich, C. Jackisch, et al. Surgical Procedures After Neoadjuvant Chemotherapy in Operable Breast Cancer: Results of the GEPARDUO Trial Ann. Surg. Oncol., November 1, 2006; 13(11): 1434 - 1442. [Abstract] [Full Text] [PDF]

				M. F. Dillon, A. D. K. Hill, C. M. Quinn, E. W. McDermott, and N. O'Higgins A Pathologic Assessment of Adequate Margin Status in Breast-Conserving Therapy Ann. Surg. Oncol., March 1, 2006; 13(3): 333 - 339. [Abstract] [Full Text] [PDF]

				D. R. McCready Keeping Abreast of Marginal Controversies Ann. Surg. Oncol., October 1, 2004; 11(10): 885 - 887. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cellini, C. Articles by Simmons, R. Search for Related Content PubMed PubMed Citation Articles by Cellini, C. Articles by Simmons, R.