VOLUME
32
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NUMBER
14
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MAY
10
2014
JOURNAL OF CLINICAL ONCOLOGY
ONCOLOGY GRAND ROUNDS
Too Much, Too Little, or Just Right? Tumor Margins in Women Undergoing Breast-Conserving Surgery Kelly K. Hunt and Aysegul A. Sahin, The University of Texas MD Anderson Cancer Center, Houston, TX See accompanying article on page 1507 The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. CASE DESCRIPTIONS
Case 1 A 68-year-old woman presented for routine screening mammography, which identified an area of microcalcifications in the left breast upper inner quadrant. Diagnostic mammography revealed a high-density irregular mass measuring 0.8 ⫻ 0.8 ⫻ 0.7 cm with partially obscured margins and associated microcalcifications. Ultrasound confirmed the suspicious mass, and ultrasound-guided core biopsy demonstrated invasive ductal carcinoma with tubular features, low nuclear grade, associated ductal carcinoma in situ (DCIS), and microcalcifications associated with invasive carcinoma. Tumor cells were positive for estrogen receptor (ER) and progesterone receptor (PgR) and were negative for human epidermal growth factor receptor 2 (HER2). The patient underwent segmental mastectomy and sentinel lymph node biopsy with final pathology revealing a 0.8-cm invasive ductal carcinoma and low nuclear grade with focal DCIS component. Invasive tumor was noted within 2 mm of the inked margin with atypical glands present within 1 mm of the inked margin (Fig 1). There was no lymphovascular invasion, and two sentinel lymph nodes were negative for metastatic disease. The margin would be considered negative, but close, with tumor and atypical glands approaching the inked margin. The patient will receive postsurgical radiotherapy and adjuvant endocrine therapy with an aromatase inhibitor. The preoperative imaging, intraoperative assessment with specimen radiograph, and histologic evaluation are all consistent with a unifocal lesion. This margin is considered adequate and we would not recommend re-excision. Case 2 A 62-year-old woman underwent a screening mammogram that demonstrated a mass in the upper inner quadrant of the left breast. Ultrasound confirmed a 1.2-cm mass at 10 o’clock, with a possible small satellite lesion. Core biopsy revealed invasive ductal carcinoma, grade 3, negative for ER, PgR, and HER2. The patient underwent left breast lumpectomy with sentinel lymph node biopsy. Final pathology Journal of Clinical Oncology, Vol 32, No 14 (May 10), 2014: pp 1401-1406
2 mm
Fig 1. Case 1. Invasive and in situ ductal carcinoma extending to within 2 mm of the inked margin. Insert shows higher magnification of both components of the tumor; in situ carcinoma is in the center. Invasive carcinoma infiltrates around in situ carcinoma and into adipose tissue.
revealed invasive ductal carcinoma grade 3 measuring 1.4 cm in greatest dimension. There was marked lymphoplasmacytic infiltration with invasive carcinoma extending to the inked superior margin (Fig 2). DCIS was also present and covered an area of 2 cm extending to the © 2014 by American Society of Clinical Oncology
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500 µm 100 µm Fig 2. Case 2. High-grade invasive ductal carcinoma associated with dense lymphoplasmacytic infiltrate extending to inked margin. There is cautery artifact at the inked margin.
superior and posterior margins. Two sentinel lymph nodes were removed and were negative for metastatic disease. The margins were focally positive with ink on tumor for both invasive carcinoma and DCIS. Adjuvant chemotherapy and radiotherapy are indicated. The preoperative imaging suggested multifocal disease, and intraoperative assessment with specimen radiograph demonstrated tumor close to the margin on at least two sections. Final pathology demonstrates tumor at the inked margin with a lymphoplasmacytic infiltrate making it difficult to be certain whether the tumor has been completely excised. We recommend re-excision of the superior and posterior margins. Case 3 A 54-year-old female underwent a screening mammogram that revealed a new focal asymmetry in the left breast upper hemisphere at 12 o’clock located 7 cm from the nipple. Ultrasound revealed a suspicious hypoechoic mass measuring 1.3 ⫻ 1.0 ⫻ 0.7 cm correlating with the area of mammographic concern. A core biopsy demonstrated invasive ductal carcinoma grade 3. The tumor was ER negative, PgR negative, and HER2 negative. The patient underwent left breast wirelocalized segmental mastectomy with sentinel node biopsy. The pathology revealed invasive ductal carcinoma measuring 2.5 cm in the largest dimension. There was adjacent high-grade, solid-type DCIS with central necrosis. Invasive tumor extended to 1.5 mm from the inked margin at a single focus (Fig 3). The remaining margins were widely free of tumor. Three sentinel lymph nodes were negative for metastatic disease. The patient had a T2N0, high-grade, triple-receptor–negative breast cancer in the left breast with excision revealing tumor close to the inked margin focally in only one section. There was also high-grade DCIS adjacent to the invasive cancer. Adjuvant chemotherapy and radiotherapy are indicated. The preoperative imaging, intraoperative assessment with specimen radiograph, and histologic assessment were all consistent with a unifocal breast cancer that has been completely excised. The possibility of finding 1402
© 2014 by American Society of Clinical Oncology
Fig 3. Case 3. Histologic sections revealed invasive carcinoma with focal myxoid matrix deposition, high nuclear grade, and Nottingham histologic grade 3. There is associated high grade, solid type ductal carcinoma in situ with central necrosis. The invasive tumor measured 2.5 cm in greatest dimension. No lymphovascular invasion was identified. Invasive tumor is noted to be less than 1.5 mm from the inked margin. Inset reveals high-power view of the invasive tumor.
residual tumor in the breast is quite low, and we would not recommend re-excision in this patient. Case 4 A 77-year-old woman had a screening mammogram that revealed a left-breast abnormality. A diagnostic bilateral mammogram revealed an area of architectural distortion measuring 2.4 cm in the posterior region of the left breast, upper outer quadrant at 1 o’clock, 9 cm from the nipple. There were no abnormalities in the right breast. Ultrasound of the left breast identified an area of architectural distortion in the 1 o’clock position, 9 cm from the nipple measuring 2.2 ⫻ 2.2 ⫻ 0.9 cm. There was no evidence of multifocal or multicentric disease. There were scattered fibrocystic changes noted in the remaining left breast. No evidence of regional lymphadenopathy was identified. Ultrasound-guided core biopsy revealed invasive mammary carcinoma with mixed ductal and lobular features grade 2, strongly positive for ER and PgR and negative for HER2. The patient underwent left breast needlelocalized segmental mastectomy, intraoperative lymphatic mapping, and sentinel lymph node biopsy. The pathology revealed invasive carcinoma grade 2 with predominantly lobular features. Invasive tumor was seen throughout the largest dimension of the specimen measuring approximately 7 cm in greatest dimension. Invasive tumor was seen within 0.5 mm of the inked inferior margin and was less than 1 mm from the anterior/superior and the posterior margins (Fig 4). One sentinel lymph node was negative for metastatic disease. In this case the preoperative imaging significantly underestimated the size of the tumor and extent of disease in the breast. On the basis of the preoperative tumor size, hormone receptor status, and age of the patient, consideration was given for surgical excision followed by adjuvant endocrine therapy without the need for radiation. Although there was no ink on the tumor, because of the finding of several close margins and the discrepancy JOURNAL OF CLINICAL ONCOLOGY
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Surgical Margins and Breast Conservation
A
Fig 5. Case 5. Specimen radiograph of the segmental mastectomy specimen sliced from medial (M) to lateral (L). The mass is primarily identified on the second and third slices and the marker clip from the diagnostic biopsy is identified in the fourth slice. Two areas of tumor extending close to the margin are noted by the radiologist (arrows). The dotted circles denote the focus of tumor. A, anterior; I, inferior; P, posterior; S, superior.
intraoperative x-ray evaluation (Fig 5) and sentinel lymph node biopsy. The final pathology revealed invasive ductal carcinoma with lobular features measuring 1.2 cm in maximum dimension. Both invasive and in situ carcinoma extended to within 1 to 2 mm of the inked margin (Fig 6). One sentinel node was positive for a 3-mm metastasis. Two additional sentinel nodes were negative for metastatic disease. The patient had a T1N1 invasive ductal carcinoma with a close but negative margin. Preoperative imaging and intraoperative specimen radiograph are consistent with unifocal disease. She is a candidate for whole-breast radiation and can avoid axillary lymph node dissection. She will receive endocrine therapy with or without chemotherapy. Although there is a close margin, she appears to have unifocal disease that has been completely excised, and we would not re-excise. If the multiple margins for DCIS were less than 1 mm, we would favor re-excision.
B
Fig 4. Case 4. (A) Small clusters of invasive carcinoma extending to within 1 mm of the inked margin. (B) Higher magnification of (A) showing invasive carcinoma cells tracking along the lymphovascular bundle.
between clinical and pathologic tumor size, the likelihood of having residual tumor is high, and we recommend re-excision. Case 5 A 44-year-old woman underwent screening mammography that showed nodularity in the upper outer quadrant of the left breast and the central aspect of the right breast for which additional investigation was recommended. She underwent bilateral diagnostic mammography that showed a 9-mm lobulated mass in the right breast at the subareolar central region. In the left breast, there was a 1-cm irregular mass located at 12 o’clock, 4 cm from the nipple. She then underwent bilateral breast ultrasound, which showed a cyst in the right breast corresponding to the subareolar mass and a mass measuring 0.8 ⫻ 0.7 ⫻ 0.7 cm in the left breast with irregular margins. Ultrasoundguided biopsy of the left breast mass revealed invasive mammary carcinoma, histologic grade 1. There were lobular features and lowgrade DCIS with a cribriform pattern without necrosis. The tumor was ER positive (90%), PgR positive (50%), Ki-67 low (10%), and HER2 2⫹ immunoreactive. The patient underwent lumpectomy with www.jco.org
Case 6 A 41-year-old woman palpated a mass in the upper outer quadrant of the right breast and underwent imaging with diagnostic mammography. This revealed an area of asymmetric tissue in the axillary tail of the breast corresponding to the palpable finding. Ultrasound was performed and it revealed an irregularly shaped, solid mass suggestive of malignancy measuring 1.6 ⫻ 1.3 ⫻ 1.2 cm. Core biopsy of the breast mass revealed high-grade invasive ductal carcinoma that was ER positive (80%), PgR positive (1%), Ki-67 high (40%), and HER2 3⫹ immunoreactive. The patient underwent a right breast segmental mastectomy with sentinel lymph node biopsy. Final pathology revealed a 1.9-cm invasive ductal carcinoma and extensive DCIS with multiple small foci of invasive carcinoma close to the margins. Foci of high-grade DCIS measuring from 0.3 to 3 mm were extending to 1 mm from the inked margin. In addition, there were ducts with marked cautery artifact at the margin (Fig 7). Four sentinel nodes were removed, and one node contained a 0.6-mm metastasis. The patient returned for postoperative assessment and discussion of pathology findings and adjuvant therapy recommendations. The patient had a T1N1mi invasive ductal carcinoma that was ER positive and HER2 positive. Systemic chemotherapy, endocrine therapy, and HER2-directed therapy are indicated. Although the margins were negative, there was invasive and in situ ductal carcinoma extending close to the inked margin in several microscopic foci. In addition, © 2014 by American Society of Clinical Oncology
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A
B
Fig 7. Case 6. Invasive and in situ ductal carcinoma extending close to the inked margin. In addition, there are ducts with marked cautery artifact at the margin (arrow). Although a definitive diagnosis is difficult, these ducts most likely represent in situ carcinoma at the margin.
CHALLENGES IN DIAGNOSIS AND MANAGEMENT
What is an adequate margin for breast-conserving surgery? The literature is replete with studies, largely retrospective, examining different margin widths and breast cancer outcomes, and yet there continues to be debate regarding the need for re-excision when a margin reveals tumor cells within a few millimeters of the inked surface. The case presentations illustrate many of the issues that must be considered when making local therapy decisions for patients with early-stage breast cancer. The goal of breast-conserving therapy is to remove the primary tumor with negative margins but to preserve the shape and size of the breast for an optimal long-term cosmetic outcome. While a floridly positive margin clearly warrants re-excision to lower the risk of in-breast recurrence, the adequacy of a negative margin cannot be determined in isolation and depends on a variety of clinical and pathologic factors, including tumor focality, the extent of affected margins, planned systemic therapy and radiotherapy, and surgical opportunities for re-excision without the need for mastectomy. The case presentations illustrate how patients with early-stage breast cancer vary with respect to age, tumor size, single or multiple foci of invasive cancer on microscopic assessment, extent of associated DCIS, hormone receptor status, HER2 status, and regional lymph node involvement. The decision to perform re-excision for a patient with a positive margin may be straightforward; however, the decision to perform re-excision in a patient with a negative margin requires careful consideration of all the clinical, pathologic, and treatment variables (Table 1).
C
Fig 6. Case 5. (A) Invasive and in situ carcinoma extending close to the inked margin. (B) High magnification of invasive carcinoma component, which shows ductal nuclear features with invasive lobular carcinoma infiltration pattern. (C) High magnification of in situ carcinoma.
SUMMARY OF THE RELEVANT LITERATURE
there were ducts with marked cautery artifact at the margin. Although definitive diagnosis of the tissue at the margin is difficult, these ducts most likely represent in situ carcinoma at the margin. Therefore, we recommend re-excision.
The report by Moran et al1 provides a summary of the Society of Surgical Oncology and American Society for Radiation Oncology consensus guidelines on margins for breast-conserving surgery in patients with stage I and II breast cancer treated with whole-breast irradiation. The authors performed a systematic review of 33
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JOURNAL OF CLINICAL ONCOLOGY
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Surgical Margins and Breast Conservation
Table 1. Reasons to Consider Re-Excision Tumor at the inked margin Significant discrepancy between radiographic and pathologic tumor size with multiple close margins Scattered foci of DCIS or invasive cancer near multiple margins Cautery artifact within ductal tissue at the margin with foci of DCIS or invasive cancer approaching the margin Abbreviation: DCIS, ductal carcinoma in situ.
published studies to assess the impact of margin width on ipsilateral breast tumor recurrence (IBTR). They concluded that positive margins were associated with a two-fold increase in the risk of IBTR when compared with negative margins. By using the definition of no ink on tumor as a negative margin, there was no evidence that wider negative margins reduced the risk of IBTR in patients receiving wholebreast radiation therapy. Establishing consensus on definitions for a negative margin can potentially reduce variability and costs in the care of patients with early breast cancer. There is substantial variability between surgeons and institutions with respect to re-excision rates in patients with negative margins and variation in rates of re-excision for close margins.2 Although many re-excisions are performed for margins of less than 1 mm, one recent study showed that 20% of patients with margins between 1 and 2 mm had re-excision, and there were patients with more than 3-, more than 4-, and more than 5-mm negative margins who underwent re-excision. It seems unlikely that going for such wide negative margins would have a major impact on local failure rates, and it is certain to have an impact on cosmetic outcomes as a result of the volume of normal breast tissue that is removed with this strategy. Although older studies reported IBTR rates in the range of 10% to 15% with long-term follow-up after breast conservation, more current studies demonstrate local failure rates of 5% or less.3 The report by Moran et al1 found the prevalence of IBTR to be 5.3% (interquartile range, 2.3% to 7.6%), with a median follow-up time of 79.2 months across the 33 studies examined. These low local failure rates are likely the result of a number of factors, including improvements in imaging and detection, enhanced pathologic techniques, understanding of biologic subtypes, and improvements in systemic therapy and radiation delivery. In a recent report from the American College of Surgeons Oncology Group Z0010 trial, patients with T1 or T2 breast cancers and negative sentinel nodes undergoing breast-conserving surgery and whole-breast radiation had a local failure rate of 3.2% at 8.4 years median follow-up.4 Although local failures were uncommon, they were associated with reduced overall survival. Use of chemotherapy was associated with a reduction in the rate of both local and locoregional recurrences. Use of endocrine therapy has also been demonstrated to decrease ipsilateral breast tumor recurrence rates in patients with hormone receptor–positive disease. Although the triple-receptor–negative and HER2-positive breast cancer subtypes have been associated with higher local failure rates after breast-conserving surgery and radiation, this is not mitigated by wider margins or more aggressive surgical resection. www.jco.org
SUGGESTED APPROACHES TO MANAGEMENT
Although it is clear that positive margins are associated with higher local failure rates and that local failure is associated with reduced survival, it is not clear that widely negative margins play a role in reducing local failures. The definition of a negative margin has long been debated; however, in the current era, it appears that “no ink on tumor” is sufficient in most cases and re-excision to achieve wider negative margins in all patients is not justified. However, as illustrated in these cases, there are circumstances in which negative margins may still warrant re-excision, for example, when imaging studies underestimate the extent of disease and pathology reveals multiple foci of disease not seen on imaging studies. The surgeon must use clinical judgment and carefully consider what may be achieved by a re-excision to assess for residual disease and at what cost to the optimal cosmetic outcome. Other circumstances include those in which the patient is not anticipating treatment with radiotherapy (eg, elderly patients with ER-positive tumors) or situations in which the patient is unable or unwilling to consider appropriate systemic therapy. Lobular histology and DCIS pose particular challenges for margin assessment and management. In case 4, the patient had what appeared to bea2.4-cmtumoronpreoperativeimagingbuthadatleast7cmofdisease on microscopic assessment of the segmental mastectomy specimen. With numerous foci of disease close to the margin and disease tracking along the lymphovascular bundle, the likelihood of residual disease in the breast is high, and re-excision is warranted to determine whether the cancer has been completely excised. Data are not available to suggest that wider margins result in lower IBTR rates for invasive lobular carcinoma. However, when the extent of the disease is not clearly delineated on the basis of imaging or pathologic assessment, further investigation is important. In case 5, the histology was also consistent with invasive lobular carcinoma, but the imaging and pathology results were concordant in terms of estimated tumor size. In this case, a narrow margin is acceptable because it is unlikely that there is substantial residual disease beyond the margin of resection. Another problematic area is that of extensive intraductal component. Multiple close margins demonstrating DCIS are often cause for concern. When the in situ carcinoma is associated with microcalcifications, specimen radiograph and postoperative mammography are useful for assessing the possibility of residual disease. In cases where the in situ carcinoma is occult on imaging, such as in case 6, it becomes more challenging to know that a negative margin of “no ink on tumor” is truly a negative margin. In case 6, where there were multiple foci of DCIS approaching the margin and there were atypical ducts at the cauterized margin,re-excisionseemsprudent.Thesurgeonneedstohaveagoodway of measuring the target and confirming the targeted excision with pathology and imaging. In the case of invasive lobular carcinoma and extensive in situ component, the target is sometimes more ill-defined making it difficult to assess the adequacy of surgical resection. The evidence does not support wider margins or more extensive surgery on the basis of aggressive biologic subtypes such as triplenegative disease and HER2-positive disease. Although hormone receptor–negative breast cancers appear to be less sensitive to radiation therapy, the use of mastectomy does not result in significantly lower local failure rates.5 It is likely that systemic therapy has the greatest potential to reduce the risk of recurrence and improve breast cancer– © 2014 by American Society of Clinical Oncology
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specific survival. Younger age at breast cancer diagnosis is also associated with more aggressive disease; however, wider negative margins do not appear to significantly reduce the risk for local recurrence over a negative margin (“no ink on tumor”). Studies show higher rates of local failure in younger patients treated with mastectomy when compared with older patients; therefore, striving for wider negative margins with breast conservation does not appear to be justified. Younger patients may be at risk for carrying mutations in the breast cancer– associated genes (BRCA1 and BRCA2), and genetic counseling and genetic testing may be warranted. In the case of a BRCA mutation, breast conservation is not the preferred approach. The surgeon plays a key role in getting the margin just right for patients with early-stage breast cancer. Working closely with the multidisciplinary team proREFERENCES 1. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology–American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol [epub ahead of print on February 10, 2014]
vides the best opportunity for achieving local control, optimal cosmesis, and recurrence-free survival. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
2. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467-475, 2012 3. Cabioglu N, Hunt KK, Buchholz TA, et al: Improving local control with breast-conserving therapy: A 27-year single-institution experience. Cancer 104:20-29, 2005 4. Hunt KK, Ballman KV, McCall LM, et al: Factors associated with local-regional recurrence after a negative sentinel node dissection: Results of the ACOSOG Z0010 trial. Ann Surg 256:428-436, 2012
5. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011
DOI: 10.1200/JCO.2013.54.8388; published online ahead of print at www.jco.org on March 31, 2014
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JOURNAL OF CLINICAL ONCOLOGY
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32
䡠
NUMBER
14
䡠
MAY
10
2014
JOURNAL OF CLINICAL ONCOLOGY
ONCOLOGY GRAND ROUNDS
Too Much, Too Little, or Just Right? Tumor Margins in Women Undergoing Breast-Conserving Surgery Kelly K. Hunt and Aysegul A. Sahin, The University of Texas MD Anderson Cancer Center, Houston, TX See accompanying article on page 1507 The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. CASE DESCRIPTIONS
Case 1 A 68-year-old woman presented for routine screening mammography, which identified an area of microcalcifications in the left breast upper inner quadrant. Diagnostic mammography revealed a high-density irregular mass measuring 0.8 ⫻ 0.8 ⫻ 0.7 cm with partially obscured margins and associated microcalcifications. Ultrasound confirmed the suspicious mass, and ultrasound-guided core biopsy demonstrated invasive ductal carcinoma with tubular features, low nuclear grade, associated ductal carcinoma in situ (DCIS), and microcalcifications associated with invasive carcinoma. Tumor cells were positive for estrogen receptor (ER) and progesterone receptor (PgR) and were negative for human epidermal growth factor receptor 2 (HER2). The patient underwent segmental mastectomy and sentinel lymph node biopsy with final pathology revealing a 0.8-cm invasive ductal carcinoma and low nuclear grade with focal DCIS component. Invasive tumor was noted within 2 mm of the inked margin with atypical glands present within 1 mm of the inked margin (Fig 1). There was no lymphovascular invasion, and two sentinel lymph nodes were negative for metastatic disease. The margin would be considered negative, but close, with tumor and atypical glands approaching the inked margin. The patient will receive postsurgical radiotherapy and adjuvant endocrine therapy with an aromatase inhibitor. The preoperative imaging, intraoperative assessment with specimen radiograph, and histologic evaluation are all consistent with a unifocal lesion. This margin is considered adequate and we would not recommend re-excision. Case 2 A 62-year-old woman underwent a screening mammogram that demonstrated a mass in the upper inner quadrant of the left breast. Ultrasound confirmed a 1.2-cm mass at 10 o’clock, with a possible small satellite lesion. Core biopsy revealed invasive ductal carcinoma, grade 3, negative for ER, PgR, and HER2. The patient underwent left breast lumpectomy with sentinel lymph node biopsy. Final pathology Journal of Clinical Oncology, Vol 32, No 14 (May 10), 2014: pp 1401-1406
2 mm
Fig 1. Case 1. Invasive and in situ ductal carcinoma extending to within 2 mm of the inked margin. Insert shows higher magnification of both components of the tumor; in situ carcinoma is in the center. Invasive carcinoma infiltrates around in situ carcinoma and into adipose tissue.
revealed invasive ductal carcinoma grade 3 measuring 1.4 cm in greatest dimension. There was marked lymphoplasmacytic infiltration with invasive carcinoma extending to the inked superior margin (Fig 2). DCIS was also present and covered an area of 2 cm extending to the © 2014 by American Society of Clinical Oncology
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1401
Hunt and Sahin
500 µm 100 µm Fig 2. Case 2. High-grade invasive ductal carcinoma associated with dense lymphoplasmacytic infiltrate extending to inked margin. There is cautery artifact at the inked margin.
superior and posterior margins. Two sentinel lymph nodes were removed and were negative for metastatic disease. The margins were focally positive with ink on tumor for both invasive carcinoma and DCIS. Adjuvant chemotherapy and radiotherapy are indicated. The preoperative imaging suggested multifocal disease, and intraoperative assessment with specimen radiograph demonstrated tumor close to the margin on at least two sections. Final pathology demonstrates tumor at the inked margin with a lymphoplasmacytic infiltrate making it difficult to be certain whether the tumor has been completely excised. We recommend re-excision of the superior and posterior margins. Case 3 A 54-year-old female underwent a screening mammogram that revealed a new focal asymmetry in the left breast upper hemisphere at 12 o’clock located 7 cm from the nipple. Ultrasound revealed a suspicious hypoechoic mass measuring 1.3 ⫻ 1.0 ⫻ 0.7 cm correlating with the area of mammographic concern. A core biopsy demonstrated invasive ductal carcinoma grade 3. The tumor was ER negative, PgR negative, and HER2 negative. The patient underwent left breast wirelocalized segmental mastectomy with sentinel node biopsy. The pathology revealed invasive ductal carcinoma measuring 2.5 cm in the largest dimension. There was adjacent high-grade, solid-type DCIS with central necrosis. Invasive tumor extended to 1.5 mm from the inked margin at a single focus (Fig 3). The remaining margins were widely free of tumor. Three sentinel lymph nodes were negative for metastatic disease. The patient had a T2N0, high-grade, triple-receptor–negative breast cancer in the left breast with excision revealing tumor close to the inked margin focally in only one section. There was also high-grade DCIS adjacent to the invasive cancer. Adjuvant chemotherapy and radiotherapy are indicated. The preoperative imaging, intraoperative assessment with specimen radiograph, and histologic assessment were all consistent with a unifocal breast cancer that has been completely excised. The possibility of finding 1402
© 2014 by American Society of Clinical Oncology
Fig 3. Case 3. Histologic sections revealed invasive carcinoma with focal myxoid matrix deposition, high nuclear grade, and Nottingham histologic grade 3. There is associated high grade, solid type ductal carcinoma in situ with central necrosis. The invasive tumor measured 2.5 cm in greatest dimension. No lymphovascular invasion was identified. Invasive tumor is noted to be less than 1.5 mm from the inked margin. Inset reveals high-power view of the invasive tumor.
residual tumor in the breast is quite low, and we would not recommend re-excision in this patient. Case 4 A 77-year-old woman had a screening mammogram that revealed a left-breast abnormality. A diagnostic bilateral mammogram revealed an area of architectural distortion measuring 2.4 cm in the posterior region of the left breast, upper outer quadrant at 1 o’clock, 9 cm from the nipple. There were no abnormalities in the right breast. Ultrasound of the left breast identified an area of architectural distortion in the 1 o’clock position, 9 cm from the nipple measuring 2.2 ⫻ 2.2 ⫻ 0.9 cm. There was no evidence of multifocal or multicentric disease. There were scattered fibrocystic changes noted in the remaining left breast. No evidence of regional lymphadenopathy was identified. Ultrasound-guided core biopsy revealed invasive mammary carcinoma with mixed ductal and lobular features grade 2, strongly positive for ER and PgR and negative for HER2. The patient underwent left breast needlelocalized segmental mastectomy, intraoperative lymphatic mapping, and sentinel lymph node biopsy. The pathology revealed invasive carcinoma grade 2 with predominantly lobular features. Invasive tumor was seen throughout the largest dimension of the specimen measuring approximately 7 cm in greatest dimension. Invasive tumor was seen within 0.5 mm of the inked inferior margin and was less than 1 mm from the anterior/superior and the posterior margins (Fig 4). One sentinel lymph node was negative for metastatic disease. In this case the preoperative imaging significantly underestimated the size of the tumor and extent of disease in the breast. On the basis of the preoperative tumor size, hormone receptor status, and age of the patient, consideration was given for surgical excision followed by adjuvant endocrine therapy without the need for radiation. Although there was no ink on the tumor, because of the finding of several close margins and the discrepancy JOURNAL OF CLINICAL ONCOLOGY
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Surgical Margins and Breast Conservation
A
Fig 5. Case 5. Specimen radiograph of the segmental mastectomy specimen sliced from medial (M) to lateral (L). The mass is primarily identified on the second and third slices and the marker clip from the diagnostic biopsy is identified in the fourth slice. Two areas of tumor extending close to the margin are noted by the radiologist (arrows). The dotted circles denote the focus of tumor. A, anterior; I, inferior; P, posterior; S, superior.
intraoperative x-ray evaluation (Fig 5) and sentinel lymph node biopsy. The final pathology revealed invasive ductal carcinoma with lobular features measuring 1.2 cm in maximum dimension. Both invasive and in situ carcinoma extended to within 1 to 2 mm of the inked margin (Fig 6). One sentinel node was positive for a 3-mm metastasis. Two additional sentinel nodes were negative for metastatic disease. The patient had a T1N1 invasive ductal carcinoma with a close but negative margin. Preoperative imaging and intraoperative specimen radiograph are consistent with unifocal disease. She is a candidate for whole-breast radiation and can avoid axillary lymph node dissection. She will receive endocrine therapy with or without chemotherapy. Although there is a close margin, she appears to have unifocal disease that has been completely excised, and we would not re-excise. If the multiple margins for DCIS were less than 1 mm, we would favor re-excision.
B
Fig 4. Case 4. (A) Small clusters of invasive carcinoma extending to within 1 mm of the inked margin. (B) Higher magnification of (A) showing invasive carcinoma cells tracking along the lymphovascular bundle.
between clinical and pathologic tumor size, the likelihood of having residual tumor is high, and we recommend re-excision. Case 5 A 44-year-old woman underwent screening mammography that showed nodularity in the upper outer quadrant of the left breast and the central aspect of the right breast for which additional investigation was recommended. She underwent bilateral diagnostic mammography that showed a 9-mm lobulated mass in the right breast at the subareolar central region. In the left breast, there was a 1-cm irregular mass located at 12 o’clock, 4 cm from the nipple. She then underwent bilateral breast ultrasound, which showed a cyst in the right breast corresponding to the subareolar mass and a mass measuring 0.8 ⫻ 0.7 ⫻ 0.7 cm in the left breast with irregular margins. Ultrasoundguided biopsy of the left breast mass revealed invasive mammary carcinoma, histologic grade 1. There were lobular features and lowgrade DCIS with a cribriform pattern without necrosis. The tumor was ER positive (90%), PgR positive (50%), Ki-67 low (10%), and HER2 2⫹ immunoreactive. The patient underwent lumpectomy with www.jco.org
Case 6 A 41-year-old woman palpated a mass in the upper outer quadrant of the right breast and underwent imaging with diagnostic mammography. This revealed an area of asymmetric tissue in the axillary tail of the breast corresponding to the palpable finding. Ultrasound was performed and it revealed an irregularly shaped, solid mass suggestive of malignancy measuring 1.6 ⫻ 1.3 ⫻ 1.2 cm. Core biopsy of the breast mass revealed high-grade invasive ductal carcinoma that was ER positive (80%), PgR positive (1%), Ki-67 high (40%), and HER2 3⫹ immunoreactive. The patient underwent a right breast segmental mastectomy with sentinel lymph node biopsy. Final pathology revealed a 1.9-cm invasive ductal carcinoma and extensive DCIS with multiple small foci of invasive carcinoma close to the margins. Foci of high-grade DCIS measuring from 0.3 to 3 mm were extending to 1 mm from the inked margin. In addition, there were ducts with marked cautery artifact at the margin (Fig 7). Four sentinel nodes were removed, and one node contained a 0.6-mm metastasis. The patient returned for postoperative assessment and discussion of pathology findings and adjuvant therapy recommendations. The patient had a T1N1mi invasive ductal carcinoma that was ER positive and HER2 positive. Systemic chemotherapy, endocrine therapy, and HER2-directed therapy are indicated. Although the margins were negative, there was invasive and in situ ductal carcinoma extending close to the inked margin in several microscopic foci. In addition, © 2014 by American Society of Clinical Oncology
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A
B
Fig 7. Case 6. Invasive and in situ ductal carcinoma extending close to the inked margin. In addition, there are ducts with marked cautery artifact at the margin (arrow). Although a definitive diagnosis is difficult, these ducts most likely represent in situ carcinoma at the margin.
CHALLENGES IN DIAGNOSIS AND MANAGEMENT
What is an adequate margin for breast-conserving surgery? The literature is replete with studies, largely retrospective, examining different margin widths and breast cancer outcomes, and yet there continues to be debate regarding the need for re-excision when a margin reveals tumor cells within a few millimeters of the inked surface. The case presentations illustrate many of the issues that must be considered when making local therapy decisions for patients with early-stage breast cancer. The goal of breast-conserving therapy is to remove the primary tumor with negative margins but to preserve the shape and size of the breast for an optimal long-term cosmetic outcome. While a floridly positive margin clearly warrants re-excision to lower the risk of in-breast recurrence, the adequacy of a negative margin cannot be determined in isolation and depends on a variety of clinical and pathologic factors, including tumor focality, the extent of affected margins, planned systemic therapy and radiotherapy, and surgical opportunities for re-excision without the need for mastectomy. The case presentations illustrate how patients with early-stage breast cancer vary with respect to age, tumor size, single or multiple foci of invasive cancer on microscopic assessment, extent of associated DCIS, hormone receptor status, HER2 status, and regional lymph node involvement. The decision to perform re-excision for a patient with a positive margin may be straightforward; however, the decision to perform re-excision in a patient with a negative margin requires careful consideration of all the clinical, pathologic, and treatment variables (Table 1).
C
Fig 6. Case 5. (A) Invasive and in situ carcinoma extending close to the inked margin. (B) High magnification of invasive carcinoma component, which shows ductal nuclear features with invasive lobular carcinoma infiltration pattern. (C) High magnification of in situ carcinoma.
SUMMARY OF THE RELEVANT LITERATURE
there were ducts with marked cautery artifact at the margin. Although definitive diagnosis of the tissue at the margin is difficult, these ducts most likely represent in situ carcinoma at the margin. Therefore, we recommend re-excision.
The report by Moran et al1 provides a summary of the Society of Surgical Oncology and American Society for Radiation Oncology consensus guidelines on margins for breast-conserving surgery in patients with stage I and II breast cancer treated with whole-breast irradiation. The authors performed a systematic review of 33
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Surgical Margins and Breast Conservation
Table 1. Reasons to Consider Re-Excision Tumor at the inked margin Significant discrepancy between radiographic and pathologic tumor size with multiple close margins Scattered foci of DCIS or invasive cancer near multiple margins Cautery artifact within ductal tissue at the margin with foci of DCIS or invasive cancer approaching the margin Abbreviation: DCIS, ductal carcinoma in situ.
published studies to assess the impact of margin width on ipsilateral breast tumor recurrence (IBTR). They concluded that positive margins were associated with a two-fold increase in the risk of IBTR when compared with negative margins. By using the definition of no ink on tumor as a negative margin, there was no evidence that wider negative margins reduced the risk of IBTR in patients receiving wholebreast radiation therapy. Establishing consensus on definitions for a negative margin can potentially reduce variability and costs in the care of patients with early breast cancer. There is substantial variability between surgeons and institutions with respect to re-excision rates in patients with negative margins and variation in rates of re-excision for close margins.2 Although many re-excisions are performed for margins of less than 1 mm, one recent study showed that 20% of patients with margins between 1 and 2 mm had re-excision, and there were patients with more than 3-, more than 4-, and more than 5-mm negative margins who underwent re-excision. It seems unlikely that going for such wide negative margins would have a major impact on local failure rates, and it is certain to have an impact on cosmetic outcomes as a result of the volume of normal breast tissue that is removed with this strategy. Although older studies reported IBTR rates in the range of 10% to 15% with long-term follow-up after breast conservation, more current studies demonstrate local failure rates of 5% or less.3 The report by Moran et al1 found the prevalence of IBTR to be 5.3% (interquartile range, 2.3% to 7.6%), with a median follow-up time of 79.2 months across the 33 studies examined. These low local failure rates are likely the result of a number of factors, including improvements in imaging and detection, enhanced pathologic techniques, understanding of biologic subtypes, and improvements in systemic therapy and radiation delivery. In a recent report from the American College of Surgeons Oncology Group Z0010 trial, patients with T1 or T2 breast cancers and negative sentinel nodes undergoing breast-conserving surgery and whole-breast radiation had a local failure rate of 3.2% at 8.4 years median follow-up.4 Although local failures were uncommon, they were associated with reduced overall survival. Use of chemotherapy was associated with a reduction in the rate of both local and locoregional recurrences. Use of endocrine therapy has also been demonstrated to decrease ipsilateral breast tumor recurrence rates in patients with hormone receptor–positive disease. Although the triple-receptor–negative and HER2-positive breast cancer subtypes have been associated with higher local failure rates after breast-conserving surgery and radiation, this is not mitigated by wider margins or more aggressive surgical resection. www.jco.org
SUGGESTED APPROACHES TO MANAGEMENT
Although it is clear that positive margins are associated with higher local failure rates and that local failure is associated with reduced survival, it is not clear that widely negative margins play a role in reducing local failures. The definition of a negative margin has long been debated; however, in the current era, it appears that “no ink on tumor” is sufficient in most cases and re-excision to achieve wider negative margins in all patients is not justified. However, as illustrated in these cases, there are circumstances in which negative margins may still warrant re-excision, for example, when imaging studies underestimate the extent of disease and pathology reveals multiple foci of disease not seen on imaging studies. The surgeon must use clinical judgment and carefully consider what may be achieved by a re-excision to assess for residual disease and at what cost to the optimal cosmetic outcome. Other circumstances include those in which the patient is not anticipating treatment with radiotherapy (eg, elderly patients with ER-positive tumors) or situations in which the patient is unable or unwilling to consider appropriate systemic therapy. Lobular histology and DCIS pose particular challenges for margin assessment and management. In case 4, the patient had what appeared to bea2.4-cmtumoronpreoperativeimagingbuthadatleast7cmofdisease on microscopic assessment of the segmental mastectomy specimen. With numerous foci of disease close to the margin and disease tracking along the lymphovascular bundle, the likelihood of residual disease in the breast is high, and re-excision is warranted to determine whether the cancer has been completely excised. Data are not available to suggest that wider margins result in lower IBTR rates for invasive lobular carcinoma. However, when the extent of the disease is not clearly delineated on the basis of imaging or pathologic assessment, further investigation is important. In case 5, the histology was also consistent with invasive lobular carcinoma, but the imaging and pathology results were concordant in terms of estimated tumor size. In this case, a narrow margin is acceptable because it is unlikely that there is substantial residual disease beyond the margin of resection. Another problematic area is that of extensive intraductal component. Multiple close margins demonstrating DCIS are often cause for concern. When the in situ carcinoma is associated with microcalcifications, specimen radiograph and postoperative mammography are useful for assessing the possibility of residual disease. In cases where the in situ carcinoma is occult on imaging, such as in case 6, it becomes more challenging to know that a negative margin of “no ink on tumor” is truly a negative margin. In case 6, where there were multiple foci of DCIS approaching the margin and there were atypical ducts at the cauterized margin,re-excisionseemsprudent.Thesurgeonneedstohaveagoodway of measuring the target and confirming the targeted excision with pathology and imaging. In the case of invasive lobular carcinoma and extensive in situ component, the target is sometimes more ill-defined making it difficult to assess the adequacy of surgical resection. The evidence does not support wider margins or more extensive surgery on the basis of aggressive biologic subtypes such as triplenegative disease and HER2-positive disease. Although hormone receptor–negative breast cancers appear to be less sensitive to radiation therapy, the use of mastectomy does not result in significantly lower local failure rates.5 It is likely that systemic therapy has the greatest potential to reduce the risk of recurrence and improve breast cancer– © 2014 by American Society of Clinical Oncology
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specific survival. Younger age at breast cancer diagnosis is also associated with more aggressive disease; however, wider negative margins do not appear to significantly reduce the risk for local recurrence over a negative margin (“no ink on tumor”). Studies show higher rates of local failure in younger patients treated with mastectomy when compared with older patients; therefore, striving for wider negative margins with breast conservation does not appear to be justified. Younger patients may be at risk for carrying mutations in the breast cancer– associated genes (BRCA1 and BRCA2), and genetic counseling and genetic testing may be warranted. In the case of a BRCA mutation, breast conservation is not the preferred approach. The surgeon plays a key role in getting the margin just right for patients with early-stage breast cancer. Working closely with the multidisciplinary team proREFERENCES 1. Moran MS, Schnitt SJ, Giuliano AE, et al: Society of Surgical Oncology–American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol [epub ahead of print on February 10, 2014]
vides the best opportunity for achieving local control, optimal cosmesis, and recurrence-free survival. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
2. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467-475, 2012 3. Cabioglu N, Hunt KK, Buchholz TA, et al: Improving local control with breast-conserving therapy: A 27-year single-institution experience. Cancer 104:20-29, 2005 4. Hunt KK, Ballman KV, McCall LM, et al: Factors associated with local-regional recurrence after a negative sentinel node dissection: Results of the ACOSOG Z0010 trial. Ann Surg 256:428-436, 2012
5. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011
DOI: 10.1200/JCO.2013.54.8388; published online ahead of print at www.jco.org on March 31, 2014
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