Fluorescence-Guided Surgery May Soon Extend Beyond Oncology

Improving visualization is key to enhancing surgical precision and optimizing patient outcomes. Fluorescence-guided surgery (FGS) is increasingly used to address pathology while preserving healthy tissue, and emerging technologies are widening potential applications of FGS across surgical specialties.

Fluorescence in Surgery

Scientists have described fluorescence, the emission of light after absorption of radiation, dating back to the mid-16th century. Since the 1940s, this phenomenon has been put to a range of scientific uses, from immunofluorescence to flow cytometry to fluorescence in situ hybridization. Many of these technologies have advanced cellular biology, immunology, and clinical care, particularly in oncology.

In contrast, fluorescence in the OR is relatively straightforward. It involves applying a fluorescent agent (or fluorophore) to tissue during surgery to enhance visualization of structures of interest in real time. Fluorophores can perfuse through tissue or cause specific tissue types to glow, enhancing assessment, excision, and/or reconstruction.

Although the US Food and Drug Administration (FDA) issued the first approval for a fluorescent agent, indocyanine green (ICG), in 1959, surgeons only began routinely using FGS around 2005, after imaging systems emerged to facilitate ICG use. Since then, numerous agents have been developed.¹ The US FGS market is now valued at approximately $100 million.² But use remains limited relative to its potential applications.

Approximately 60% of all FGS usage is oncologic,¹ and most peer-reviewed studies on FGS indexed in PubMed focus on cancer, even though FGS use is possible for a range of indications beyond biopsy and resection, including flap creation, burn assessment, aspects of organ transplant, and more. The reasons for the focus on cancer are historical, biological, and financial—but as laparoscopic and robotic-assisted surgery continue to expand, the opportunity to add FGS to other procedures is growing rapidly.

With the investigation of one new, broadly applicable fluorophore, the options for FGS use may expand even further.

New Way to Visualize Nerves

For Samuel Gold, MD, a urologist completing a fellowship in urologic oncology at Memorial Sloan Kettering Cancer Center in New York, New York, the excitement of investigating the novel fluorescent agent rizedisben lies in its broad use cases.

Dr. Gold and colleagues published a phase I, nonrandomized clinical trial of rizedisben in JAMA Surgery in July 2025.³ His team administered rizedisben to 38 patients undergoing robotic-assisted laparoscopic radical prostatectomy, aiming to establish both safety and an effective dosage. The results revealed effective use at a range of dosages with few adverse events.

In some ways, the study reflects dominant patterns in FGS: It used a fluorescent product in an oncologic procedure. But Dr. Gold is enthusiastic about rizedisben because the fluorophore appears to be one of the first that can illuminate nerve tissue specifically.

“I’ve always been fascinated by how advancements in technology and the subsequent guidelines that might police or embrace those advancements affect the care that’s delivered and the way that patients can access that care,” he explained. “The work that I was doing and continue to do with rizedisben is not just about how we can create a clinical trial protocol to make sure that we are testing efficacy. It’s also: What’s next? How do we make a case for why this is important on a larger scale?”

In the case of rizedisben, the answer is simple. “It’s not engineered to be specific to cancer,” Dr. Gold said.

Instead, rizedisben may enable visualization of nearly any nerve in the body and could be used in any surgery in which locating a nerve and/or avoiding nerve injury is important. “It’s ubiquitous,” Dr. Gold said.

“There are profound clinical and quality-of-life implications to enhancing nerve tissue visualization in surgery, and we are working to explore these in our ongoing efforts,” he added.

If rizedisben reaches the market, its nonspecific nature may position it similarly to ICG, the most common surgical fluorophore. The widespread use of ICG also is attributable to its ability to fluoresce tissue (although not nerve tissue) throughout the body, and its applicability to numerous surgical tasks.

Leakage and Perfusion

Use cases for ICG are somewhat typified by the clinical practice of Steven D. Wexner, MD, FACS, physician executive director and system chief of colorectal surgery for MedStar Health in Washington, DC. His insights also help clarify why FGS is predominantly used in cancer procedures, even though it could aid many other types of surgical care.

Dr. Wexner first used FGS approximately 25 years ago, around the time it became widely available. He explained that a fellow surgeon “brought it in for me to use it on a J-pouch, and I was very impressed by how it basically saved this patient from a permanent ileostomy.”

He rapidly embraced the method and soon became the lead North American investigator for a trial with NOVADAQ Technologies Inc., a now-defunct company then developing new fluorophores. He served as the chief medical officer until its acquisition by Stryker Corporation in 2017 and also has consulted widely with other companies.

As a disclosure of conflicts of interest, he noted consulting roles with Arthrex and Activ Surgical. Dr. Wexner also is the current president of the North American chapter of the International Society for Fluorescence Guided Surgery (ISFGS), through which he has taught surgeons worldwide about FGS.

Although uncommonly well-versed in multiple approaches to FGS, Dr. Wexner mostly uses ICG on his own surgical cases. “I use it routinely in clinical practice for high-risk anastomosis,” he said.

Dr. Wexner emphasized its utility in high-risk colorectal cases, particularly left-sided anastomoses.^4,5 Although he typically completes surgeries creating right-sided anastomoses without fluorescence, left-sided anastomoses are another matter. In those cases, even when anastomoses have passed visual inspection, air leak tests, and other assessments, “I want something else to tell me it’s going to be okay. In fact, if I had three more ways to tell me, I would want to do those things,” he said. “When you have a leak in those anastomoses, it’s just a horrible situation for the patient,” and could involve abscess, sepsis, and/or urgent reoperation.

Citing a recent Lancet study,⁶ he explained why this occurs most typically in oncological procedures: “When you pool all the trials on ICG, it does significantly reduce leak rates in high-risk anastomosis. But high-risk anastomoses mostly occur in cancer cases.”

Dr. Wexner added that additional uses also arise in cancer surgeries: “When you look at the resection rather than anastomosis, the use of ICG shows potential promise to facilitate lateral pelvic node dissection. When operating for both benign and malignant disease, the safety of pelvic dissection can be improved by ICG illumination of the ureters. Thus, FGS has important roles in dissection, resection, and anastomosis.”

Multiple studies have reinforced the functionality of FGS in specialties other than colorectal surgery. For example, another meta-analysis⁷ of 20 studies comparing ICG versus standard assessment in resection of liver cancer found an array of benefits, including significantly reduced intraoperative blood loss and hospital stay duration, halved transfusion rates (odds ratio, 0.50 [95% CI, 0.36–0.70]), and a 41% decrease in complications (odds ratio, 0.59 [95% CI, 0.44–0.79]).⁷

In other words, the combination of specific patient needs and the likelihood of significant benefit to the patient is large enough to compel widespread implementation of ICG in cancer surgery, conditions that may not be met elsewhere.

Targeting Tumors

Another reason that FGS is predominantly used in oncology is technological. The limitation of FGS has always been the nonspecific binding of fluorophores to tissues, which primarily allowed use focused on vascular perfusion.

However, researchers have launched a renaissance by using insights into cancer biology to develop numerous highly specific fluorophores that specifically bind diseased cells. These approaches conjugate photosensitizer molecules with antibodies, proteins, enzymes, or small molecules known to be more highly expressed in tumors than surrounding tissue. When injected, these fluorophores specifically bind cell surface molecules that cause tumors to glow, aiding precise excision and helping ensure margins are microscopically negative.

The work of Sunil Singhal, MD, FACS, chief of thoracic surgery and the William Maul Measey Professor in Surgical Research at Penn Medicine in Philadelphia, Pennsylvania, illustrates this approach. He is both a clinician who uses fluorophores “every day, whenever I do surgeries,” and a researcher leading a team investigating new fluorophores.

Dr. Singhal uses the term “intraoperative molecular imaging,” which uses fluorescent agents to identify tumors via activatable or receptor-specific molecules. “Our main contribution has been developing targeted tracers. We’ve specifically led the field on small molecule methods to target tumors.”

His achievements have been substantial. In 2022, after conducting phase I, II, and III, multi-institutional randomized clinical trials, Dr. Singhal and his team received FDA approval for pafolacianine (Cytalux^®). This fluorophore illuminates a folate receptor present on ovarian cancer and lung cancer in a blue-green or neon-green shade.

Randomized clinical trials^8,9 on pafolacianine established three main benefits, according to Dr. Singhal. “The endpoints are specifically that we can locate tumors that may be hard to find minimally invasively, because you can’t get your fingers in to feel them or they have no obvious indentation on the lung surface. This fluorophore also helped us identify patients who had a positive margin, that is, we had inadvertently cut too close to the cancer. And it helped us find additional cancers called synchronous cancers or occult cancers.”

To date, there is no substantial evidence that it improves disease-free or overall survival, and after completing more than 1,700 lung cancer resections, Dr. Singhal is careful to note that the fluorophore is not necessarily always needed: “There is no magic bullet for everything.”

Nonetheless, he was confident that benefits to the patient arose via use of Cytalux. “There are certain situations where it’s really helpful, such as when a tumor is close to a major blood vessel…I find it’s very useful in sarcoma patients. That’s been really a high yield.”

What’s Next for FGS?

Will rizedisben, with its promise of wide applicability, increase the use of FGS beyond surgical oncology?

That will depend on further investigation by Dr. Gold, who was quick to note that only a phase I trial has been completed and efficacy across clinical settings has yet to be determined. For now, he noted that there are subtleties in rizedisben not yet fully explored.

“What we were seeing is that certain types of tissue would fluoresce green instead of the true signal, blue. We determined that those were more likely to be things like blood vessels or lymphatic ducts. That allowed for some very interesting conversations during the surgery. It might be more effective in certain tissue settings,” he said.

Whatever rizedisben’s outcome, these surgeons expect the use of fluorescence in surgery to continue expanding.

Each noted that the rise of laparoscopic and robotic surgeries plays an important role in FGS expansion. While open surgeries can use FGS, they require dimming the entire OR before handheld fluorescent lights can be applied. In contrast, laparoscopic and robotic systems incorporate cameras that can be easily switched to fluorescent light within the confined operation space, making FGS a quicker, easier option.

In addition, the proliferation of new fluorophores will continue. Dr. Singhal’s laboratory has ongoing research examining multiple fluorophores as part of its mission to advance intraoperative molecular imaging. These investigators are among the many researchers investigating fluorescent agents for surgical and nonsurgical uses.

Dr. Wexner also expects various new dyes to emerge. “The technology coming down the road may be laser imaging or spectral technology, where we can visualize blood flow without a dye. You basically have a laser light that you turn on and off, and you can see the blood supply in the vessel. A variety of people are looking at that avenue.”

Drs. Singhal and Wexner also are on the leading edge of helping surgeons across disciplines use existing FGS approaches. Both say their experience shows that interest comes from surgeons in virtually all disciplines, including many who may not use FGS primarily for cancer procedures.

For his part, Dr. Gold plans to continue his ongoing inquiry into rizedisben. He aims to advance the technology through later-phase clinical trials, FDA approval, and market entry, with the goal of establishing FGS as a standard intraoperative practice across surgical specialties.

M. Sophia Newman is the Medical Writer and Speechwriter in the ACS Division of Integrated Communications in Chicago, IL.

References

1. Van Keulen S, Hom M, White H, Rosenthal EL, Baik FM. The evolution of fluorescence-guided surgery. Mol Imaging Biol. 2023;25(1):36-45.
2. Grandview Research. Fluorescence guided surgery systems market (2024-2030). Published 2024. Available at: https://www.grandviewresearch.com/industry-analysis/fluorescence-guided-surgery-systems-market-report. Accessed March 9, 2026.
3. Gold SA, Pere MM, Assel M, et al. Rizedisben in minimally invasive surgery: A nonrandomized clinical trial. JAMA Surg. 2025;160(8):875-883. 
4. Garoufalia Z, Wexner SD. Indocyanine green fluorescence guided surgery in colorectal surgery. J Clin Med. 2023;12(2):494.
5. Jafari MD, Wexner SD, Martz JE, et al. Perfusion assessment in laparoscopic left-sided/anterior resection (PILLAR II): a multi-institutional study. J Am Coll Surg. 2015;220(1):82-92.e1.
6. Wajahat Mirza, Hania Iqbal, Saeeda Yasmin, et al. Indocyanine green fluorescence-guided perfusion vs. standard assessment to prevent clinical anastomotic leak after colorectal resection: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials with site-specific subgroup analysis. World J Surg Onc. 2025;23:454.
7. Xiong D, Li J, Li L, et al. A meta-analysis of the value of indocyanine green fluorescence imaging in guiding surgical resection of primary and metastatic liver cancer. Photodiagnosis and Photodynamic Therapy. 2025;52:104489.
8. Sarkaria IS, Martin LW, Rice DC, et al. Pafolacianine for intraoperative molecular imaging of cancer in the lung: the ELUCIDATE trial. J Thoracic Cardiovasc Surg. 2023;166(6):e468-e478.
9. Kennedy GT, Azari FS, Singhal S, et al. Surgical impact of pafolacianine-based intraoperative molecular imaging in lobar versus sublobar pulmonary resection. JTCVS Techniques. 2025; 34:219-221.