The Sentinel Margin: Intraoperative Ex Vivo Specimen Mapping Using Relative Fluorescence Intensity

Abstract

Purpose: Despite major advancements in surgical oncology, the positive margin rate for primary head and neck cancer resection remains around 15%-30%. In particular, the deep surface margin is the most challenging to adequately assess. Inadequate margins are directly correlated to poor survival, and as such, mitigation of these rates is critical to improve patient outcomes. We have developed an ex vivo imaging strategy that utilizes fluorescence intensity peaks (relative to background signal) of an injected anti-EGFR antibody conjugated to a fluorescent probe to locate potential close or positive margins on the deep surface of the resected tumor specimen. Experimental Design: Twelve patients with head and neck cancer scheduled for surgery received systemic administration of a tumor-specific contrast-agent (panitumumab-IRDye800CW). After surgical resection, the tumor specimen was imaged using a fluorescence imager. The three highest fluorescence intensity-peaks on the deep surface of the specimen were isolated and correlated to histology to determine the margin distance at these regions. Results: Relative fluorescence peak intensities identified the closest margin on the deep surface of the specimen within 2.5 minutes. The highest intensity peak consistently (100%) detected the closest margin to the tumor. The difference in tumor margin distance between the first and second highest fluorescence intensity peak averaged 2.1 AE 1.4 mm. The tumor-margin difference between the second and third highest peak averaged 1.6 AE 0.6 mm. Conclusions: Fluorescence intensity peaks can identify the region on the specimen where tumor is closest to specimen's edge on the deep surface. This technique could have broad applications in obtaining adequate margins in oncological surgery.

Intraoperative Molecular Imaging for ex vivo Assessment of Peripheral Margins in Oral Squamous Cell Carcinoma

“…Second, by generating an immediate intraoperative image available to the surgeon and pathologist, it improves the surgeon's ability to remain oriented to which areas are sampled for FSA and aids with the accurate, targeted re-resection from the wound bed if required. The proposed approach has previously been described by our team for targeting the closest tumor margin on the deep surface (15). The term "sentinel margin" was first introduced to designate the closest margin, which may or may not be positive but will be the margin most at risk.…”

“…To decrease interference of interpatient variables such as dose, infusion-to-surgery window, epidermal growth factor receptor (EGFR)-expression and other biological factors, patients were used as their own internal control by comparing high fluorescence regions to low fluorescence regions on the same specimen as was previously described and validated in our deep sentinel margin mapping study (15).…”

“…Leveraging this technology in the current study, we propose a novel methodology for rapid, objective, and reproducible identification of the closest margin on the peripheral mucosal surface of the resected tumor specimen, termed the "sentinel margin." We have previously demonstrated that the sentinel margin strategy can be applied to evaluate the deep surface of the surgical specimen, and here we focus on the mucosal margin (15).…”

Intraoperative Tumor Assessment Using Real-Time Molecular Imaging in Head and Neck Cancer Patients

“…7,8 Both targeted and nontargeted imaging agents have been shown to be effective for identification of ex vivo tumor specimen and tumor margins with millimeter resolution. [9][10][11] However, these ex vivo modalities do not provide real-time in situ feedback of the primary tumors within the surgical field. 12 Real-time, tumor-specific molecular imaging could assist the surgeon in intraoperative clinical decision-making.…”

Endoscopic Fluorescence‐Guided Surgery for Sinonasal Cancer Using an Antibody‐Dye Conjugate

“…26 We and others have reported the feasibility and potential clinical benefits of FGS using antibody dye-based imaging for patients with solid tumors. 10,11,[13][14][15][16][17][18][27][28][29][30][31] Combining FGS with the advantages of a minimally invasive, endoscopic approach may hold the potential to reduce morbidity while ensuring adequate oncologic outcomes. However, this has yet to be further investigated and validated in large prospective trials.…”