A study published in the journal JAMA Surgery demonstrated the benefits of using fluorescence-guided imaging to assess margins in head and neck cancer. Researchers at Vanderbilt University Medical Center found that leveraging data collected both during surgery (in vivo) and after the tumor’s removal (ex vivo) can help guide surgeons in achieving a negative margin in cancer resection. 

A margin refers to the areas around the tumor being removed. The desirable outcome is to complete surgery with a negative margin, indicating that no cancer was found at the edge of the resection. A positive margin indicates that cancer cells remain in the tissue, which increases the risk of recurrence and reduces the chance of survival. 

To assess those margins, surgeons may use fluorescent agents administered to the patient’s tissue. Systemically infused agents have been shown to differentiate cancerous and healthy tissue with high accuracy. 

“Our research found that the use of fluorescence imaging both internally and externally can improve surgeons’ ability to precisely and safely excise tumors,” said Shravan Gowrishankar, MD, a research fellow in the Department of Otolaryngology-Head and Neck Surgery and the study’s first author. “This research seeks to illuminate methods of leveraging fluorescence imaging to achieve negative margins, particularly for deep resections, which often prove difficult.” 

The researchers defined two classifications of margins: the superficial or mucosal margin refers to the area uninvolved with the tumor but surrounding its surface, while the deep margin refers to the 4 to 5 millimeters of healthy tissue beyond the tumor’s most invasive points, or the depth of normal tissue between the tumor edge and the cut surface of the specimen. 

“Currently, it’s easier to achieve negative mucosal margins than deep margins,” said corresponding author Eben Rosenthal, MD, chair of the Department of Otolaryngology-Head and Neck Surgery and Barry and Amy Baker Professor of Laryngeal, Head and Neck Research. “Deep margins aren’t able to be assessed as easily because surgeons must rely on estimation of the distance from the tumor to guide the resection. 

“We sought to improve methods of achieving negative margins across the board because estimation isn’t good enough where patient safety is concerned.” 

The assessment of deeper margins is further confounded during surgery by tissue retraction and the presence of blood, which can obscure the view of the surgeon. And while autofluorescence — a process by which naturally occurring chemicals in the tissue can absorb light of a particular wavelength and reemit it at a different wavelength — can help surgeons assess mucosal margins, deeper margins are impossible to assess via this process because the light does not penetrate beyond a millimeter. 

To assist in ensuring a negative margin in a deep resection, surgeons can use fluorescence imaging techniques. Mapping tumors after resection can provide data on how close the margins are to the surface of the deep resection, and intraoperative in vivo fluorescence imaging can reveal areas of residual disease in the tumor bed. In combination, the information provided by both methods of fluorescence imaging can guide further examination and sampling to help achieve fuller resection of the deep margin. 

While both methods in combination are critical to achieving better outcomes in surgery, said Gowrishankar, ex vivo imaging devices have certain advantages over in vivo hardware. 

“While the data we get from in vivo imaging is valuable, it’s largely qualitative because of variance in ambient light in the operating room,” said Gowrishankar. “Ex vivo imaging is more precise because we can seal out external light in a controlled environment to measure fluorescence intensity and guide our assessment of deep margins.” 

In ex vivo imaging, fluorescence intensity increases the closer the tumor tissue approaches the cut surface of the tumor specimen, and data from this measurement can be used to create a sort of “heat map” measuring the relative depth of the tumor across the entire specimen. By using this imaging technique, surgeons can more precisely detect the reach of cancer cells in the tissue and perform precise resections. 

“Mucosal margins are easy enough to detect during surgery without fluorescent agents, but those agents are critical in helping us close the gap with deep margins,” said Rosenthal. “Missed deep margins contribute to the majority of positive margins after resection, which in turn contribute to negative health outcomes for patients. Large-scale adoption of these techniques will have a meaningful impact on the health of patients who undergo surgery to remove cancerous tumors.” 

Additional authors from Vanderbilt University Medical Center include: 

• Jennifer Choe, MD, PhD, assistant professor of Medicine in the Division of Hematology Oncology 

• Alexander Langerman, MD, SM, FACS, associate professor of Otolaryngology-Head and Neck Surgery 

• Kyle Mannion, MD, FACS, associate professor of Otolaryngology-Head and Neck Surgery 

• Aviva S. Mattingly, MD, MS, VTOPS/R25 Research Resident 

• Sarah L. Rohde, MD, MMHC, associate professor of Otolaryngology-Head and Neck Surgery and division director of Head and Neck Oncologic Surgery 

• Robert Sinard, MD, FACS, professor of Otolaryngology-Head and Neck Surgery 

• Hidenori Tanaka, MD, PhD, visiting assistant professor of Otolaryngology-Head and Neck Surgery 

• Michael Topf, MD, MSCI, assistant professor of Otolaryngology-Head and Neck Surgery. 

This research was supported by the National Cancer Institute, part of the National Institutes of Health (grants R01CA279249, R01CA239257, R01CA266233 and R01CA238686). 

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