Background

•BCT is defined as surgical excision of the primary tumor with a margin of surrounding normal tissue followed by whole-breast irradiation (WBRT)

•BCT results in long-term cause-specific survival rates greater than 95% for women with DCIS

•WBRT reduces rates of ipsilateral breast tumor recurrence (IBTR), although not survival

•There has been controversy regarding the optimal negative margin width in patients treated with breast-conserving therapy (BCT)… ie there is still no consensus on what constitutes an optimal negative margin width, and as a result~ 1 in 3 women attempting BCT for DCIS undergo re-excision

•Since BCT was established, management has evolved, including with regards to imaging, pathologic evaluation, and the availability of adjuvant endocrine therapy, which have resulted in a decline in IBTR rates

•Due to the lack of consensus regarding adequate negative margins in DCIS and the evolvingmanagement landscape, the Society of Surgical Oncology (SSO), American Society for Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO) convened a multidisciplinary margins panel with the primary question: What margin width minimizes the risk of IBTR in patients with DCIS receiving breast-conserving surgery?

 

Findings / Guideline Recommendations

• A meta-analysis was conducted and included 20 studies with 7,883 patients with DCIS with known margin status and 865 IBTRs. They found the following:

•A positive margin, defined as ink on DCIS, is associated with a significant increase in IBTR. This increased risk is not nullified by the use of WBRT

–In one study, patients with positive margins had a 2x higher IBTR risk despite receiving WBRT, an ~50% were invasive recurrences

•Margins of at least 2 mm are associated with a reduced risk of IBTR relative to narrower negative margin widths in patients undergoing WBRT. The routine practice of obtaining negative margin widths wider than 2 mm is not supported by the evidence.

–The choice of the 2-mm threshold rather than wider than 0 (no ink on tumor) or 1 mm was based on evidence of a statistically significant decrease in IBTR for 2 mm compared with 0 or 1 mm in the frequentist analysis (OR, 0.51; 95% CI, 0.31 to 0.85; P = .01), coupled with weak evidence in the Bayesian model of a reduction in IBTR with the 2-mm distance compared with smaller distances

–Factors felt to be important to consider include assessment of IBTR risk (residual calcifications on postexcision mammography, extent of DCIS in proximity to margin, and which margin is close [i.e. anterior excised to skin or posterior excised to pectoral fascia v margins associated with residual breast tissue]), cosmetic impact of re-excision, and overall life expectancy.

•Treatment with excision alone, regardless of margin width, is associated with substantially higher rates of IBTR than treatment with excision and WBRT, even in predefined low-risk patients. The optimal margin width for treatment with excision alone is unknown but should be at least 2 mm. Some evidence suggests lower rates of IBTR with margin widths wider than 2 mm.

•Rates of IBTR are reduced with endocrine therapy, but there is no evidence of an association between endocrine therapy and negative margin width.

•Multiple factors have been shown to be associated with the risk of IBTR in patients treated with and without WBRT, but there are no data addressing whether margin widths should be influenced by these factors

–Young patient age and tumor factors such as histologic pattern, comedo necrosis, and nuclear grade and size of DCIS; recently, unfavorable gene profile scores have also been associated with IBTR

•Choice of WBRT delivery technique, fractionation, and boost dose should not be dependent on negative margin width. There is insufficient evidence to address optimal margin widths for accelerated partial-breast irradiation (APBI).

•DCIS with microinvasion (DCIS-M), defined as no invasive focus larger than 1 mm in size, should be considered DCIS when determining optimal margin width.

 

Conclusions

•Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.

Introduction

•Surgery is the current treatment for ductal carcinoma in situ (DCIS) because currently there is no way to predict which patients will progress to invasive carcinoma. However, there is growing concern of overdiagnosis (given that many that would have never been detected clinically are detected now due to better screening modalities) and overtreatment

•Partial mastectomy is the treatment of choice for early stage breast cancer. However, there is a 21-25% rate of positive margins and subsequent re-excision (33% by a study of the National Cancer database)

•Thus, there is an opportunity to minimize the burden of surgical treatment of DCIS for a substantial proportion of women if there could be a way to increase the likelihood of complete excision at the time of initial surgery

•Surgeons can use intraoperative pathologic assessment with frozen section or touch preparation to assess breast tissue margins at the time of initial partial mastectomy, and then based on this information they may decide to re-excise additional tissue, potentially preventing the need for future operation

•This study examined the use of intraoperative pathologic assessment for patients undergoing partial mastectomy for DCIS to see if there was any potential effect on subsequent operations in the surgical management of DCIS

 

Findings

•A retrospective cohort study of women diagnosed with DCIS between 1999 and 2007 and undergoing partial mastectomy without lymph node biopsy or dissection was performed examining the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database

•A cohort of 8259 women who underwent partial mastectomy for a DCIS diagnosis was analyzed

•Intraoperative analysis was performed in 26% of cases. Of these, 68% used touch prep, 27% used frozen section, and 5% used both techniques

•Overall, 43% underwent at least one subsequent surgery, either partial mastectomy or mastectomy

•Women who had intraoperative pathology for DCIS were significantly more likely to have tumor grade of not otherwise specified (NOS) (Table 2). No clinically significant variables were found (Of note, >25% of cases had missing observations)

•Among the women with intraoperative pathology, 975 (45%) had subsequent surgery, while among those who did not have intraoperative pathology 2532 (42%) had subsequent surgery.

•Age 80 and older was associated with a lower likelihood of undergoing subsequent surgery

•This may be because the 5 year rate of recurrence in this age group is fairly low, and also surgeons may be more aggressive in their initial resection or more accepting of close or positive margins in elderly patients who are more likely to have multiple comorbidities

•Patient residence in a rural location, poorly differentiated or NOS tumor grade, and tumor size >/= 2cm were significantly associated with undergoing subsequent surgery

•The finding of residence in a rural location was interesting and may be due to those patients receiving more aggressive surgical care due to more advanced disease at time of diagnosis, concern for lack of follow-up, or limited access to radiation therapy

•Intraoperative pathologic assessment did not significantly affect whether or not a subsequent operation occurred after the initial partial mastectomy (Table 3)


Conclusions

•Intraoperative assessment of margins for cases of partial mastectomy performed for DCIS was done in 26% of cases

•However, results of this study showed that routine use of intraoperative pathology was not likely to result in reduction in rates of subsequent surgery

•These findings may have economic implications – Medicare pays about $80 for each intraoperative pathologic assessment, and thus it may not be cost effective to utilize frozen section and/or touch preparation analyses for patients undergoing breast conservation

•Current studies are investigating other possible modalities for reducing the risk of subsequent surgery, including intraoperative mammography and non-invasive optical imaging of tumor margins

Introduction

•Until recently, there was no widely accepted standardized definition of an adequate margin for breast conserving surgery (BCS) for early-stage invasive cancer. This contributed to a significant practice variability in reexcision rates, which reportedly ranged from 2-38% and varied at both the inter and intrainstitutional level as well as at the surgeon level

•There has been considerable debate and controversy regarding the definition of a negative margin, adequate margin widths, and indications for reexcision

•Multiple operations have a number of ramifications, including substantial psychological stress for the patient, increased health care costs, and a potential cosmetic disadvantage, as well as impacting the patient’s decision to opt for a completion mastectomy or even a bilateral mastectomy

•In response to the wide variability in reexcision rates, the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) assembled a multidisciplinary expert panel to provide evidence based consensus guidelines

•A meta-analysis including 33 studies and 28,162 patients was performed, finding that a positive margin (ink on tumor) was associated with at least a twofold increase in ipsilateral breast tumor recurrence (IBTR), thus requiring reexcision, while margins more wide than that did not further decrease the risk of IBTR obviating the need for further excision

•This recommendation did not change for those omitting adjuvant systemic therapies, was not dependent on tumor biology or subtype, young patient age, tumor histology, or the presence of an extensive intraductal component (EIC)

•This study analyzed the rates of reexcision before and after the adoption of the SSO-ASTRO margin guidelines (January 2014) and sought to identify factors associated with reexcision

 

Findings

•Margins were defined as positive if tumor was present at the inked margin, close if </=1 mm, or negative if > 1 mm or when there was no tumor in the separately submitted cavity margins

•Between June 1, 2013, and October 31, 2014, 1205 patients were identified, 504 in the preguideline and 701 in the postguideline adoption groups

•The clinical factors are outlined in Table 1, and the pathologic factors in Table 2

•The reexcision rate declined from 21.4 to 15.1 % (p = 0.006) in the postguideline adoption time period, though the percentage of negative, close, and positive margins did not differ significantly (Table 3)

•85% of patients in the postguideline era did not need reexcision, and the vast majority of those that did need a reexcision needed only 1 additional surgery. Conversion to mastectomy was a rare event, with less than 1% needing or electing for mastectomy after initial attempt at BCS

•The reexcision rate fell for each margin category (negative, close, positive) for invasive and DCIS in the postguideline group

•Factors independently associated with reexcision by univariate and multivariate analysis are shown in Table 5

•EIC, multifocality, positive and close DCIS margins, and positive and close invasive margins were all independent factors associated with increased reexcision

 

Conclusions

•While we know a positive margin is associated with at least a doubling of the risk of an in-breast tumor recurrence (IBTR), increasingly wider margins have not been shown to reduce IBTR

•The SSO-ASTRO margin guidelines were developed in response to a lack of consensus regarding the definition of a negative margin as well as highly variable rates of reexcision among surgeons

•In this study, the authors found a significant decline in overall reexcision rates from 21.4 % (June–December 2013) to 15.1 % (January–October 2014). Close invasive margins were associated with higher rates of reexcision than negative invasive margins in both time periods; however, the effect diminished in the postguideline adoption period

Introduction

•Neoadjuvant systemic therapy for the treatment of breast cancer is increasing. It is used not only as a standard option for patients with early stage disease but also to improve surgical outcomes in previously unresectable or locally advanced breast cancer and to increase breast conservation rates

•Pathologic response includes pathologic complete response (pCR) (defined as absence of disease in the breast and lymph nodes (ypT0/is ypN0 or ypT0 ypN0)) and partial response, such as by the residual cancer burden (RCB) grading system. These give valuable prognostic information for patients and is used as a primary endpoint in clinical trials

•There have been efforts now to standardize pathology in patients receiving neoadjuvant chemotherapy. A single, standardized approach to macroscopic and microscopic pathologic examination would make it possible to provide reliable response information. This approach employs a map of tissue sections to correlate clinical, gross, microscopic, and imaging findings in order to report the presence of pCR versus residual disease

•This review summarizes the challenges that postneoadjuvant systemic therapy surgical specimens pose and how pathologists and the multidisciplinary team can work together to optimize handling of these specimens

 

Discussion

•Changes in the breast tumors after neoadjuvant therapy are complex. The degree of clinical response of breast cancer to neoadjuvant systemic therapy does not correlate well with the degree of pathologic response

•An area of treated tumor may have an obvious tumor bed with prominent fibrosis and inflammatory changes that are grossly evident, while other times the area of tumor may look indistinguishable from normal breast tissue both grossly and microscopically. Thus, the correct area of breast to sample may be difficult to find

•Given this, systematic sampling as opposed to random sampling of representative sections is likely to yield more reproducible results

•Multidisciplinary communication is essential in the neoadjuvant setting, even with just the minimum of clearly labeling the surgical specimen as a postneoadjuvant specimen

•Clip placement at the time of core needle biopsy is very strongly recommended even if mastectomy is planned

•Lymph node status postchemotherapy is a strong predictor of outcome. Therefore, presystemic therapy sentinel lymph node biopsy is not recommended.

•Fine needle aspiration biopsy or core needle biopsy of clinically or radiologically abnormal lymph nodes is strongly recommended before neoadjuvant systemic therapy

•Clip placement into the biopsied LN may help improve the accuracy of sentinel LN biopsy postneoadjuvant systemic therapy

•If a positive lymph node is surgically removed before neoadjuvant systemic therapy, assessment of nodal response in the axilla is unreliable, the RCB score and ypN stage are invalid, and designation as pCR is unreliable

•Interpretation of the histologic findings in the lymph nodes can be difficult because the degree of fibrosis and reaction to a biopsy is very variable and fibrosis or histiocytes may be present in a lymph node without prior treatment or biopsy

•Posttreatment ypN stage classification is the same as for patients who have not received neoadjuvant therapy:  macrometastasis >2 mm, micrometastasis >0.2 mm and </=2 mm, and isolated tumor cells </= 0.2 mm. If micromets or ITCs are present, the response should not be classified as pCR (Figure 2)

•The AJCC Stage 7th edition (2009) introduced the recommendation to estimate the pathologic size of tumors by using mapping techniques of tissue sections. In addition, it recommended pathologic (posttreatment) size pT (ypT) stage should be estimated based on the best combination of gross and microscopic histological findings.

•The posttreatment ypT size is defined as the largest continuous focus of invasive cancer. However, this can be a challenge (see Figure 2)

•In addition to size of residual disease in the breast and LNs, cellularity of the residual tumor should be assessed. The RCB system standardizes cellularity assessment across the entire residual tumor bed (Figure 3)

 

Conclusions

•The pathologist needs the pretreatment size and location of the tumor before evaluating the postneoadjuvant surgical specimen

•Standardized procedures to evaluate the gross specimen are required. A map of the tissue sections related to the gross and imaging findings should be documented. Histopathologic findings should be related to that map. This requires multidisciplinary teamwork from surgeons, radiologists, and pathologists

•The ypT stage defined by largest continuous extent of invasive cancer, the RCB from the dimensions, and cellularity of primary tumor bed and to document multifocality.