For cancer patients and the surgeons who treat them, tumor margins matter. The amount of malignant tissue left behind after cancer surgery can make a profound difference in overall survival, but sparing healthy tissue while removing as much tumor as possible is limited by the surgeon’s ability to differentiate one from the other.

Now, new optical imaging techniques that deliver fluorescing molecules specifically to tumor targets show promise to allow both surgeons and pathologists to optimize cancer surgery. These intraoperative techniques use fluorescent molecules tagged to a ligand that binds to a target site on malignant cells. Thus, uptake occurs only in the malignant cells, highlighting them for the surgeon and for pathologists assessing margin adequacy.

Dr. Sunil Singhal of the University of Pennsylvania, Philadelphia, has coined the term “optical biopsy” to describe what’s happening during optical imaging-guided surgery. “For so long, we as surgeons have just had our eyes and our hands – and our intuition – to guide us. This technology allows us to really focus our attention where it needs to be in surgery.”

Optical imaging in surgery uses a variety of fluorescing molecules, some of which were originally derived from sources as diverse as scorpions and fireflies. Some of these glow in the visible spectrum, but increasingly, optical imaging techniques are employing molecules that fluoresce when excited by light in the near-infrared spectrum.

Using the near-infrared spectrum, said Dr. Eben Rosenthal, the Anne and John Doerr Medical Director of the Stanford (Calif.) Cancer Center, does two things: it allows for visualization deeper into tissues – up to 1 or 2 cm – and it improves the signal-to-noise ratio that can be a problem in the visual spectrum, where tissue autofluorescence occurs.

Cameras, endoscopes, and surgical microscopes can all be equipped to display the fluorescence and coregister the image with the white-light view the surgeon or pathologist normally sees. Surgeons using optical imaging techniques can usually continue to use the same tools and the same interface they are accustomed to.

Ligands can be small molecules, such as folate, or complex glycoproteins, such as monoclonal antibodies: all will bind selectively to sites on tumor cells. Patients are infused with the fluorescence-tagged ligand complexes before surgery, with timing appropriate to the half-lives of the agents, so infusions may happen the day before or the day of surgery.

For Dr. Rosenthal, using monoclonal antibodies to target tumors for optical imaging techniques affords several advantages. The antibodies are approved by the Food and Drug Administration, with known safety and side effect profiles. The antibodies can be tagged with an FDA-approved fluorescing molecule, allowing an easier approval process for the compound agent. Finally, the epidermal growth factor receptor (EGFR) target of these monoclonal antibodies is well expressed in many target tumor cells, including melanoma, breast, glioma, and colorectal cancers.

Dr. Singhal’s group has been working with fluorescein-tagged folate to identify pulmonary adenocarcinomas and is exploring use of other agents as well. “We like small molecules,” he said. “We can avoid lots of problems with biotoxicity.”

Annexin A2 (ANXA2) is a molecule expressed on the surface of cancer cells but found intracellularly in healthy cells, and it is the target of the chlorotoxin conjugate used by Dr. Jim Olson of Seattle’s Fred Hutchinson Cancer Research Center. Target malignancies may include glioblastoma, medullablastoma, sarcoma, and prostate and intestinal cancers.

Regardless of the target, however, optical imaging techniques may be particularly well suited for tumors occurring in areas where a generous dissection can have potentially devastating consequences, as in the head and neck, and for brain tumors. By giving the surgeon a clear delineation of malignant tissue, optical imaging can help the surgeon strike a balance to achieve the most conservative dissection that still achieves a complete gross dissection of the malignancy.

Achieving gross total dissection during cancer surgery is an important goal, said Dr. Olson. Citing devastating childhood brain tumors such as medulloblastomas and gliomablastomas, he noted that optical imaging can help surgeons avoid leaving behind any bulk areas of tumor, where hypoxic regions and therapy-resistant changes in tumor physiology may reduce the chance for cure. “Surgery is one of the most important elements of curing cancer,” he said. He pointed out that, in children with medulloblastomas, if nearly all tumor tissue is removed, less radiation is needed and survival is improved, even with less radiation – even if very small amounts of cancer remain.

Limitations of these technologies depend, to some extent, on the tissue targets, on substrates used to deliver the fluorescing molecules, and on the fluorescent agents themselves. Even with the enhanced tissue penetration of near-infrared light, the surgeon can really only see a centimeter or two beneath the surface of a solid organ. Said Dr. Singhal, “The basic limitation is that we’re talking about light.” However, if presurgery imaging identifies an area of concern, the surgeon can direct his or her dissection more carefully when the malignant tissue glows during surgery.

Dr. Rosenthal noted that pathologists also are making use of optical imaging to guide their processes. Since only about 5% of most tumor margins are sampled, there is an inevitable chance of sampling error with the resulting potential for a false-negative pathology result. “This technique augments the pathologist’s role and allows for improved biopsy results,” he said. Using image-guided pathology offers a way to test the margins immediately, helping the pathologist ascertain where the surgeon’s attention should be focused. Optical imaging, he said, “will in many ways change and enhance the experience for everybody.”

Dr. Olson, looking forward, asked, “If we can deliver the ability to light up, why can’t we deliver chemotherapy?” He sees an optical imaging future that will make flexible use of ligands to delineate tumors and test drug delivery.

There are many ways optical imaging can improve the practice of cancer surgery, Dr. Rosenthal said. “Historically, surgery has been a hard area to study because it’s so variable.” Following results from optical imaging–guided precision surgery, he said, will allow surgeons to identify and achieve “the right margin for the right cancer.”

Looking to the future, Dr. Singhal said, “it won’t be an either/or scenario. I think there will be multiple targets, multiple agents for this technology. We, as surgeons, have an obligation to our profession to move ahead with this.”