Optimal Imaging Methods to Reduce Repeat Surgery in Invasive Breast Cancer

Background Breast cancer is the most common type of cancer in Denmark with approximately 4700 new cases each year, with an increased incidence during the last decades. Almost 70% of the patients are treated with breast conserving surgery (BCS) and breast irradiation. Unfortunately, 5.9 % of the patients treated with BCS will experience local recurrence after 9 years. The strongest predictor for local recurrence is a positive pathologic resection margin. Therefore it is important intraoperatively to be able to evaluate the margin width of the resected specimen precisely. The challenge during BCS is to remove the primary invasive breast cancer, with negative resection margin, free of invasive tumor and DCIS, Ductal Carcinoma In Situ. Some have concluded that lack of accurate imaging especially of the DCIS is the main reason for positive margins and repeat surgery, as the DCIS often, but not in all cases, contains microcalcifications that can be detected on mammography (x-ray of the breast). Consequently, 17%-25% of the patients will need a second or a third surgery. Repeat surgery has been associated with higher surgical risk, poorer cosmetic outcome, and increased psychological and economic burden for both patients and the society. Finding an optimal imaging method to obtain adequate resection margins close to or during BCS that can reduce the number of repeat surgeries, is therefore strongly needed.

Definition of resection margin status

A safe macroscopic surgical resection margin is, according to the Danish Breast Cancer Group´s (DBCG) guidelines, defined as a margin width ≥ 5mm minimizing the risk of leaving residual tumor. In many institutions in Denmark, a perioperative evaluation of the tumor is performed as a macroscopically assessment by a pathologist. This is a ressource demanding procedure and X-ray of the specimen is used instead. A radiological, positive resection margin is defined as a margin width of 0 mm, that leads to a re-excision during the same surgical procedure, and additional breast tissue is removed at the exact same area of the patient's breast. This procedure aims to avoid the discomfort of a repeat surgery. The perioperative radiological assessment of the resection margins is afterwards confirmed microscopically, where a positive margin at our institution is defined as "tumor on ink", meaning tumor cells in the inked resection margin with 0 mm to the margin. A positive margin will trigger a repeat surgery, either a new BCS or a mastectomy where the whole breast is removed. For DCIS, a margin-width of less than 2 mm is considered positive, and the patient will be offered repeat surgery according to guidelines. A distance from the invasive carcinoma to the resection margin of < 2 mm, but not "on the ink" is surgical considered sufficient and the patient will according to DBCG guidelines, not require a repeat surgery, but will instead be offered additional boost to the subsequent radiotherapy. The result of the final histopathology is, however, not available until 7 workdays after the initial BCS. Guidance of a more optimal perioperative methods to evaluate the resection margins during BCS would, therefore, be highly desirable, and could potentially lead to a decreased rate of repeat surgery and hence save several patients from the discomfort of a second surgical procedure.

Intraoperative imaging methods for margin assessment

Various methods to assess resection margins have been investigated such as frozen section analysis, imprint cytology, macroscopically evaluation and imaging with x-ray, micro-CT scanning or ultrasound of the resected tumor margins. All have, however, their limitations, either because they are time consuming, or simply because they are not accurate enough to predict resection margin status. The imaging modality X-ray has been reported in several studies to have a high specificity, predicting negative margins up to 95%, but unfortunately a low sensitivity of only 21%. That means that the method is particularly good to predict a negative margin. The X-ray is less sensitive when it comes to predict a positive resection margin, with the final histopathology as a reference method. The lower sensitivity is due to the fact, that x-ray has difficulties, when it comes to detect the breast tumor in a very dense normal breast tissue, most common for young women. The X-ray evaluation also has the disadvantage of only delivering a 2D solution to a 3D problem. The other imaging method currently in use is ultrasound that has a high sensitivity of 80% but a low specificity of 59% to predict positive resection margins (Ramos M. et al).