Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.076 on December 8, 2003
Annals of Surgical Oncology 11:59-64 (2004)
© 2004 Society of Surgical Oncology
Breast Cancer in Patients With Residual Invasive Carcinoma is More Accurately Staged With Additive Tumor Size Assessment
S.T. Hollenbeck, MD,
C. Cellini, MD,
P. Christos, MS, MPH,
Y. Varnado-Rhodes, BS,
D. Martins, PA-C,
M. Nussbaum, BS,
M.P. Osborne, MD and
R.M. Simmons, MD
From the Department of Surgery (STH, CC, MPO, RMS) and Department of Public Health (PC), Weill Medical College of Cornell University; and the Strang Weill Cornell Breast Center (YV-R, DM, MN, MPO, RMS), New York, NY.
Correspondence: Address correspondence and reprint requests to: Rache M. Simmons, MD, Strang 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
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ABSTRACT
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Background: Accurate assessment of tumor size for patients with breast cancer undergoing re-excision following breast-conserving therapy is important for appropriate staging and adjuvant treatment. We investigated the accuracy of additive vs. nonadditive size assessment in determining final tumor stage.
Methods: Patients with infiltrating carcinoma in the initial excision and in at least one additional re-excision (re-excision positive; n = 89) had tumor size assessed with additive and nonadditive techniques. This group was compared with patients undergoing re-excision but without identifiable residual carcinoma (re-excision negative; n = 105) regarding rates of lymph node (LN) metastasis.
Results: The re-excision positive patients had a different median final tumor size depending on the size assessment technique used (nonadditive: 1.8 cm; additive: 3.0 cm; P < .0001). Both groups of patients had a median tumor size consistent with T1c staging in nonadditive size assessment. However, re-excision positive patients had a significantly higher incidence of LN metastasis (P < .05) than did re-excision negative patients. Both groups were then separated into T1 and T2 stages and the LN metastasis rates were assessed. Compared with nonadditive size assessment, additive size assessment distributed re-excision positive patients into T stages whereby the LN metastasis rates more closely approximated those of re-excision negative patients (T1, 3% vs. 6% difference; T2, 4% vs. 13% difference).
Conclusions: With regard to LN metastasis, staging for patients with residual invasive carcinoma in re-excision specimens is more accurate with additive tumor size assessment.
Key Words: Breast neoplasm • Positive margins • Re-excision • Tumor size
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INTRODUCTION
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Tumor size is an essential factor when considering treatment strategies and prognosis for patients with invasive breast carcinoma.1–6 The current staging manual from the American Joint Committee on Cancer (AJCC) states that "in cases of multiple tumors in 1 organ the tumor with the highest T category is the one selected" for staging.7 Thus, tumor stage in patients with breast cancer found to have residual invasive carcinoma in re-excision specimens would be determined by a nonadditive size assessment (largest tumor specimen) rather than additive size assessment (largest tumor plus any residual excised tumor). There is evidence to suggest that the use of nonadditive tumor size assessment may result in undertreatment of patients with breast cancer.8 To investigate the importance of size assessment in patients with residual invasive carcinoma found in re-excision specimens, we compared the additive and nonadditive tumor sizes and correlated this with the incidence of lymph node (LN) metastases.
Current practice standards dictate that patients with close or positive margins following breast carcinoma excision should be advised to undergo re-excision in an effort to obtain definitive negative final margins. Numerous studies have highlighted the importance of obtaining negative final margins to decrease local recurrence rates.9–11 The likelihood of finding residual carcinoma in re-excisions performed for positive margins appears to be 38% to 65%, and large tumor size and extensive intraductal components are associated with positive tumor margins.9,12 In this study we investigated the impact of the finding of residual tumor at re-excision on tumor staging.
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MATERIALS AND METHODS
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We reviewed the medical records of 397 female patients followed up at our institution from 1990 to 2002 who underwent multiple surgical excisions. Surgical excisions were defined as and limited to excisional biopsies, lumpectomies, mastectomies, and immediate postmastectomy chest wall excisions. Patients underwent re-excisions for positive or close surgical margins. Positive margins were defined as tumor cells (either focal or extensive) directly at the cut edge of the specimen. Close margins were defined by the presence of tumor cells less than 1 mm from the cut edge of the specimen. Negative margins were defined by a space of greater than 1 mm between tumor cells and the cut edge of the specimen.
In some instances, patients underwent the initial surgical excision at another (outside) institution. An attending pathologist at our institution reviewed all inside and outside specimens. In cases in which the patient was referred with positive margins, the accepting physician at our institution performed the re-excision. In cases in which the patient underwent all treatment at our institution, the same physician performed the initial and all additional re-excisions.
Of these 397 patients, 194 had infiltrating carcinoma in at least one specimen, and these patients comprise the study population. Patients with infiltrating carcinoma in the initial excision and in at least one additional re-excision specimen were defined as the re-excision positive group. In this group of patients, tumor size was determined both nonadditively (the largest diameter of invasive cancer in any specimen) and additively (adding the largest diameter of invasive cancer in all specimens). Patients with infiltrating carcinoma in only the initial excision were defined as re-excision negative, and their tumor size was assessed as the largest single diameter. In all cases, the final margin of excision was negative. The technique used to evaluate the axilla was at the discretion of the operating surgeon and was influenced by a period of combined sentinel LN dissection (SLND) and axillary LN dissection (ALND) to validate SLND at our institution. Following validation, SLND was initially performed in all patients. In cases in which the sentinel LN was positive, a completion ALND was performed. Patient age, tumor characteristics, definitive surgical treatment, and LN status were characterized for each group of patients.
Statistical analyses were performed with Statview software (SAS Institute, Cary, NC). Comparisons were made with Student’s t-test and 
2 analyses. For all statistical comparisons, P values less than or equal to .05 were considered significant.
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RESULTS
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Of the 194 patients with infiltrating carcinoma in the initial excision, 45.9% had residual invasive carcinoma in the re-excision specimen. Thus, 89 patients were defined as re-excision positive and 105 patients were defined as re-excision negative. As expected, in the re-excision positive group, tumor size was larger with additive assessment (t-test, P < .0001) than with nonadditive assessment, with which the median tumor size increased by 1.2 cm (Table 1). Approximately one-half of the re-excision positive patients had negative final margins following two excisions (Table 2). Two-thirds of re-excision positive patients had the largest tumor diameter found at the initial excision, and one-third had the largest tumor diameter found at the second excision. Forty-one patients (46%) had a change in their tumor size stage; the most common change was from T1c to T2. The median time between excisions was 40 days; the longest interval was between the second and third excisions. Sixty-six percent of patients underwent mastectomy for definitive care, whereas the remainder underwent breast-conserving therapy (lumpectomy with radiotherapy).
We then sought to determine which size assessment method (additive or nonadditive) categorized re-excision positive patients more accurately. To investigate this we compared the LN metastasis rates between the re-excision positive group and the re-excision negative group. The characteristics of each group are outlined in Table 3. Both groups had similar distributions of primary histologic subtypes. Additionally, the two groups had similar median ages, percentage of grade 3 tumors, and percentage of estrogen receptor (ER) positive tumors. The re-excision positive group of patients had a higher percentage of grade 2 tumors and tumors with lymphovascular invasion as well as a lower percentage of progesterone receptor (PR) positive tumors.
Axillary evaluation was performed on 96% of re-excision positive patients and 95% of re-excision negative patients. Axillary LN dissection was performed equally in both patient groups; however, the re-excision positive patients had a higher percentage of combined sentinel LN and axillary LN dissection. The overall LN metastasis rates were 38.8% and 23.5% for the re-excision positive and re-excision negative groups, respectively (2, P < .05). Both groups were then separated into T1 and T2 stages and the LN metastasis rates were compared. The re-excision positive patients were grouped two ways: first with nonadditive size assessment and second with additive size assessment. Compared with nonadditive size assessment, additive size assessment distributed re-excision positive patients into T stages whereby the LN metastasis rates more closely approximated those of re-excision negative patients (T1, 3% vs. 6% difference; T2, 4% vs. 13% difference; Fig. 1). These data indicate that for re-excision positive patients the nonadditive size assessment understages, whereas additive size assessment stages more accurately.
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FIG. 1. Lymph node metastasis rates for T1 and T2 patients. Patients who were re-excision positive whose disease was staged with nonadditive versus additive size assessment are compared with those who were re-excision negative.
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DISCUSSION
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The importance of tumor size in the management of breast cancer has been well established.1,13 Increasing tumor diameter has been shown to be an independent predictor of local recurrence4 and survival.1,14 Given the prognostic information gained by tumor staging, clinicians may determine to initiate chemotherapy or postmastectomy radiation on the basis of tumor size.15 Therefore, methods that improve the accuracy of tumor size assessment may impact decisions regarding the use of adjuvant therapy and thus survival.
On the basis of the AJCC staging manual, final tumor size and staging for patients with breast cancer undergoing re-excision is determined by nonadditive rather than additive size assessment. Brenin and Morrow8 have previously evaluated 72 re-excision positive patients regarding LN metastasis rates and found that the use of nonadditive tumor size assessment may result in understaging for this set of patients with breast cancer. These authors also describe the importance of orientation of the re-excision specimen for accurate additive size assessment. Furthermore, studies of patients with multifocal and multicentric breast tumors have demonstrated that additive tumor size assessment results in more accurate staging for this subset of patients.16
On the basis of these studies we evaluated our own group of patients undergoing re-excisions to determine the accuracy of size assessment techniques. We found that for patients with residual invasive carcinoma in re-excision specimens, staging differs significantly according to tumor size assessment technique. Despite having similar median tumor sizes (T1c), with use of nonadditive size assessment the re-excision positive patients had a significantly higher rate of LN metastasis than did the re-excision negative patients. Overall, a similar proportion of patients from both groups underwent at least SLND. A greater percentage of re-excision positive than re-excision negative patients underwent combined SLND and ALND, and thus one might suggest that this contributed to the higher rate of identification of metastatic disease in the re-excision positive group. However, the increased rate of combined SLND and ALND in the re-excision positive cohort is approximately equivalent to the proportion of patients with metastatic disease identified in the axilla who underwent a completion ALND. Therefore, we conclude that nonadditive size assessment understages disease for patients with residual tumor in re-excision specimens.
When positive margins are identified on initial excision, a re-excision is indicated. Although our entire patient population underwent re-excision for close or positive margins, only 46% of these patients had residual invasive carcinoma. In the current series the residual tumor was larger than the first tumor in one-third of cases. Given these data and the observation that positive margins following needle localization biopsy occur in 45% to 83% of cases,17–19 the incidence of a large volume of residual invasive carcinoma could be anticipated in approximately 5% to 10% of cases following needle localization biopsies. Swanson et al.12 state that routine re-excision should not be performed because the finding of residual carcinoma approaches only 50%, even in the setting of positive margins, and that radiotherapy will be effective at local control irrespectively. Yet we show that a large number of patients would have a change in tumor stage, simply on the basis of the finding of residual carcinoma and the additive size assessment tumor staging. Furthermore, there is a well described observation that positive margins are associated with higher rates of local recurrence, even with radiotherapy.9,10 The added knowledge regarding additive tumor size that would be obtained following re-excision further accentuates the need for routine re-excision for positive margins.
Recent 20-year follow-up data from the randomized B-06 trial continue to validate lumpectomy and radiotherapy as appropriate for invasive breast carcinoma.20 However, the success of breast-conserving therapy is dependent on obtaining negative margins at the time of surgical treatment. There are few data regarding the appropriate number of re-excisions for positive margins prior to committing to a mastectomy. From our series we can conclude that each additional re-excision improves the chances of obtaining negative margins. However, this negative margin rate never improved above 80% for any number of excisions following an initial positive margin. Because 66% of re-excision positive patients underwent a mastectomy, vs. 30% of re-excision negative patients, residual invasive carcinoma was predictive of performance of a mastectomy. With use of retrospective data it is difficult to determine the factors that contributed to the decision about when to perform a mastectomy. Certainly, one can assume that tumor characteristics and breast anatomy would play a role in the number of re-excisions prior to mastectomy.
We are currently evaluating characteristics of the initial excision and the re-excision specimens to determine risk factors for residual carcinoma and local recurrence in this setting. While multiple criteria have been associated with positive margins, tumor size appears to be the most important factor for predicting positive margins in multivariate analysis.21,22 Additionally, Wiley et al.23 investigated the timing between first and second excisions and found that as time increases, the likelihood of residual carcinoma decreases, a finding suggesting that the inflammatory response decreases residual disease. However, we found that for patients having residual invasive carcinoma the median time between excisions was 40 days. Patients without residual invasive carcinoma had a median interval of 26 days between excisions. On the basis of our findings, we continue to recommend expeditious re-excision following the documentation of close or positive margins.
The importance of accurate tumor staging is not trivial. In our series, with additive size assessment, 26% of patients would have a clinically significant change in tumor size. Six patients with negative LNs had a change in tumor size from l cm or less to greater than 1 cm. Additionally, 25 patients had a change in tumor staging from T1c to T2 or T3. Seventeen of these patients had negative LNs. Thus, the use of AJCC-recommended staging and failure to consider the residual volume of tumor at re-excision would result in understaging for numerous patients unlikely to receive adjuvant therapy.
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CONCLUSION
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Staging for patients with invasive breast carcinoma found in re-excision specimens (re-excision positive) is generally based on the largest single diameter (nonadditive assessment) of invasive tumor. We have demonstrated that these patients have a higher rate of LN metastasis than expected by nonadditive tumor size assessment. Additive tumor size assessment would enable more accurate staging for these patients on the basis of LN metastasis rates for tumor size.
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ACKNOWLEDGMENTS
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The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.
This project was funded by the Darrow, Finnell, Lahiff, Cadwell, and McElvery Breast Cancer Research Fund.
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FOOTNOTES
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We investigated the importance of finding residual tumor at the time of re-excision in patients with breast cancer. We found that with regard to lymph node metastasis rates, staging for patients with residual invasive carcinoma is more accurate with additive tumor size assessment.
Received for publication March 17, 2003.
Accepted for publication September 16, 2003.
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Factors Associated With Residual Breast Cancer After Re-excision for Close or Positive Margins
Ann. Surg. Oncol.,
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915 - 920.
[Abstract]
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ABSTRACT
INTRODUCTION
