No ink on tumor

Approximately 25% of patients with invasive carcinoma and one‐third of those with DCIS undergo re‐excision, 

With approximately half of the re‐excisions performed in patients with negative margins, defined as no ink on tumor.

This is done in the belief that a larger negative margin improves patient outcomes.

The appropriate negative margin width for women undergoing breast‐conserving surgery for both ductal carcinoma in situ (DCIS) and invasive carcinoma is controversial. 

Consensus guidelines support a negative margin, defined as no ink on tumor, for invasive carcinoma treated with breast‐conserving therapy. 

Because of differences in the growth pattern and utilization of systemic therapy, a margin of 2 mm has been found to minimize the local recurrence risk for women with DCIS undergoing lumpectomy and radiation therapy (RT).

Wider negative margins do not improve local control for DCIS or invasive carcinoma when they are treated with lumpectomy and RT. 

Thr routine practice of performing additional surgery to obtain a wider negative margin is not supported by the literature.

The only defined microscopic margin width in the prospective randomized trials that established the safety of BCT in invasive carcinoma was no ink on tumor, the margin definition in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 study.

Margin measurement is an inexact science.

 Approximately half of re‐excisions are performed in patients with negative margins, defined as no ink on tumor, in the belief that a larger negative margin improves patient outcomes. 

Margin width is dependent on multiple factors, including: the number of sections examined, and the technique of margin assessment as perpendicular, shaved, or cavity margins, the defined margin when ink tracks through the irregular fatty surface overlying the tumor, and the use of specimen‐compression devices for radiography. 

When comparing measurements of the anterior‐posterior diameter of breast specimens in the operating room and the pathology laboratory, 46% of the specimen height was lost by the time of measurement in the pathology laboratory, indicating the potential for error in determining margins.

The use of specimen‐compression devices increases these discrepancies in diameters.

It is theoretically estimated that 3000 sections would be required to completely examine the margin surfaces of a spherical lumpectomy specimen.

A negative margin does not guarantee the absence of residual tumor in the breast, and suggests a negative margin  indicates  that the residual tumor burden in the breast is low enough that it is likely to be controlled with radiotherapy.

Ink markings are used to define the margin surface can be seen at various distances from the tumor edge because of the irregular nature of the specimen surface and ink tracking through the breast fat: making reproducible measurements of the margin width difficult.

The rate of local recurrence (LR)  varies with the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status.

Local recurrence is lowest among patients with HR+, HER2– tumors and highest among those with triple‐negative tumors, regardless of whether the treatment includes BCT or mastectomy.

Among those with HR+, HER2– tumors, the risk of LR also varies significantly with the ((21‐gene Recurrence Score)).

LR can be observed even among the smallest cancers (microinvasive, T1a,b),16 and this indicates that this is a fundamental tumor characteristic and not one that is acquired over time. 

Five years of adjuvant tamoxifen reduces the risk of LR by approximately 50%.

Newer  endocrine therapies, such as the use of aromatase inhibitors and more prolonged treatment durations, provide further risk reductions.

Conventional cytotoxic chemotherapy in women younger than 50 years reduces the relative risk of LR to 0.63 in comparison with no treatment.

The  use of trastuzumab provides a further relative risk reduction of 0.47.

Studies of LR outcomes for HER2+ patients in  those undergoing BCT, the 3‐year rate of LR was 7% before the use of adjuvant trastuzumab, and it decreased to 1% in the period immediately after the adoption of trastuzumab.

A positive margin in HER2 + breast cancer defined as ink on tumor, is associated with a significant increase in LR risk and warrants consideration for additional surgery.

In a meta‐analysis that included 33 eligible studies and more than 28,000 women with early‐stage breast cancer. A positive margin was associated with increasing LR, odds ratio for positive margins versus negative margins, 2.44.

There isn no evidence of a decreased LR risk with negative margin widths increasing from 1 to 2 to 5 mm.

A negative margin reduces the risk of LR; however, increasing the size of a negative margin is not significantly associated with an improvement in local control.

A negative margin of no ink on tumor optimizes local control and that the routine practice of obtaining a more widely negative margin than no ink on tumor is not indicated.

Young age and triple‐negative cancers are both independent risk factors for local recurrence, but the available evidence indicates that it is the tumor biology, not the extent of surgical excision, that is associated with a worse outcome because LR rates are similar among women in these high‐risk groups treated with BCT or mastectomy.

In a series examining margin width and local recurrence (LR) among women with triple‐negative breast cancer found no difference in 5‐year LR rates between margins ≤ 2 mm and margins > 2 mm (4.7% and 3.7%, respectively.

extensive intraductal componentkk (EIC) was associated with an increased risk of LR30; however, more recent reports of patients with 

An extensive intraductal component positive margin tumors subsequently excised to negative margins have local recurrence rates similar to rates of those without an extensive intraductal component.

No ink on tumor is an adequate negative margin to avoid re‐excision.

DCIS has a 10‐year cause‐specific mortality rate under 1% after breast conserving surgery.

Optimizing local control in DCIS is important because half of all LR events are invasive cancers with an associated increased risk of breast cancer–specific mortality.

Surveys of surgeons and radiation oncologists report significant heterogeneity regarding what constitutes an acceptable margin width for DCIS treated with BCT, which ranges from no ink on tumor to > 1 cm.

Multicentric DCIS is uncommon.

DCIS within one quadrant may be extensive, with 46% of the lesions measuring > 3 cm in one study.

90% of poorly differentiated lesions of DCIS grow continuously, 70% of well‐differentiated lesions had a multifocal, skip pattern, with 82% of skip lesions measuring between 0 and 5 mm, and only 8% having skip lesions > 10 mm. 

A small negative margin may lie within a skip lesion and may be associated with a substantial residual tumor burden.

Approximately 55% to 70% of women with DCIS treated with lumpectomy receive adjuvant RT.

20% to 50% of DCIS patients receive adjuvant endocrine therapy.

For women with DCIS treated with lumpectomy and RT, the optimal margin is that which leaves a subclinical volume of residual microscopic disease within the breast that can likely be controlled by RT. 

The proportion of women with DCIS treated by excision alone ranges from 17% to 44%.

It is suggested that a margin of 1 cm or greater negated the benefit of RT;  but  findings have not been replicated in subsequent studies.

In a study of 1374 women undergoing excision alone, margin width was significantly associated with LR, with 10‐year LR rates ranging from 41% with a positive margin to 16% with a > 1 cm margin.

In a multivariate analysis incremental increases in margin width were associated with decreasing LR risk.

In contrast, after 12 years of follow‐up in the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network E5194 trial, which included women with low‐ to intermediate‐grade DCIS ≤ 2.5 cm in size or high‐grade DCIS ≤ 1 cm in size treated with excision alone and with a negative margin of at least 3 mm, no significant relation between the margin widths of < 5 mm, 5 to 9 mm, and ≥ 1 cm was observed.52.

There are cohorts of DCIS low‐risk patients undergoing excision alone who have low local failure rates with a range of negative margin widths.

Re‐excision or RT for DCIS is multifactorial, with the margin width being one factor that may affect the decision for further risk‐reducing therapy. 

Other factors: age, the size of the DCIS, the tumor grade, the margin width, and the patient’s comfort with recurrence risk are all taken into consideration when the decision is made to omit RT or return to the operating room.

No uniform negative margin width is routinely associated with a low recurrence risk among women with DCIS treated with excision alone.

The odds of LR are reduced by more than 50% with a negative margin versus a positive margin.

With respect to a positive margin, significant reductions were seen for all negative margin widths.

When a 2 mm margin was compared with a smaller negative margin, a nonsignificant trend toward a decrease in LR is observed.

No additional benefit is  seen for margins greater than 2 mm.

DCIS treated with BCT, and both found that close margins (< 2 mm) were not inferior to wider negative margins among women treated with RT.

The invasive cancer margin guideline endorses no ink on tumor, whereas the DCIS guideline states that 2 mm is an optimal margin. 

The behavior of microinvasive carcinoma is more similar to the behavior of DCIS than invasive cancer and that the use of systemic therapy is more similar to that seen in DCIS. 

Invasive cancer with associated DCIS, whether an extensive intraductal component or lesser amounts, should be managed according to the invasive guideline, as the biology of the invasive cancer is the primary determinant of outcome, and the majority of patients will receive systemic therapy. 

For  invasive and in situ breast carcinomas, the margin status is one of a number of factors affecting LR risk, and the tumor biology rather than an arbitrary anatomic margin cutoff is the major determinant of LR. 

For invasive breast cancer, the data support obtaining a negative margin, defined as no ink on tumor, and do not identify an additional benefit for more widely clear margins. 

In patients with DCIS receiving RT, a margin of 2 mm minimizes LR, but larger margins do not provide added benefit. 

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