Fluorescent Molecular Contrast Agent Shows Glowing Results in Adenocarcinoma

A fluorescent molecular contrast agent accurately identified 92% of lung adenocarcinomas during pulmonary surgery.

Sunil Singhal, MD

A fluorescent molecular contrast agent accurately identified 92% of lung adenocarcinomas during pulmonary surgery, according to data from a recent proof-of-concept study.1These findings, published inThe Journal of Thoracic and Cardiovascular Surgery,introduced a novel strategy for improved surgical resection of lung adenocarcinomas and potentially other types of cancer.

“This approach has a pretty high impact,” said Sunil Singhal, MD, lead investigator of the study and thoracic surgeon in the Department of Surgery, University of Pennsylvania Perelman School of Medicine in Philadelphia, PA. “There’s the clinical aspect of what we found, but there’s also the proof-of principle that this kind of approach could work.”

More than 80,000 individuals undergo pulmonary tumor resection per year in the United States. Currently, histologic analysis is the only way to determine if the tumor is cancerous. Singhal et al sought to investigate whether or not using an optical molecular contrast agent that targets folate receptor (FR)-alpha could accurately identify lung adenocarcinoma cells, which have higher expression of the protein than cells in the normal lung epithelium.

The study included 50 patients who had biopsy-confirmed lung adenocarcinoma and were about to undergo pulmonary resection. Four hours before surgery, a fluorescent molecular contrast agent that binds to FR-alpha was administered intravenously. The primary lesion was located by visual inspection and manual palpation after opening the chest cavity, and the cancerous cells were imaged and photo-documented with a specialized imaging system.

Of the primary lesions, 92% exhibited a green fluorescence that showed a clear demarcation between tumor and normal surrounding tissue. According to Singhal, this could potentially improve quality of the surgery and long-term clinical outcomes.

“The whole goal of this technology is to make surgery more accurate and better for cancer patients,” said Singhal.

In addition, the accumulation of contrast agent within the tumors was sufficient for detection with standard molecular imaging devices, and the imaging methods did not require special techniques or training. According to Singhal, the straightforward nature of this method may help physicians incorporate it into their practice without requiring specialized expertise or expensive equipment.

Use of the fluorescent contrast agent also identified additional lesions that were not detected prior to surgery. In one patient who was initially thought to have a single 2.1-cm lesion in the right upper pulmonary lobe, the fluorescence identified a second pulmonary nodule in that lobe after it was excised. In another patient, the fluorescence detected a metastatic lesion on the parietal surface near the costophrenic sulcus, even though the patient had no signs of metastatic disease prior to surgery. According to Singhal, use of such molecular contrast agents may promote more accurate staging of patients and earlier initiation of appropriate therapies.

“If we start picking up other lesions that we would have typically missed [with the imaging technique], we will detect more people who need chemotherapy up front,” said Singhal.

Targeted molecular contrast agents may also have an application for inspecting and locating nodules during minimally invasive surgery, such as video-assisted thoracoscopic surgery (VATS) and robotic surgery.

“In the future, with improved devices and molecular contrast agents, this approach may reduce the local recurrence rate and improve intraoperative identification of metastatic cancer cells,” said Singhal in a recent press release.2

Furthermore, the technology uses a visible-wavelength fluorophore and does not contain ionizing radiation, making it a safe technique for the patient, surgeon, and operating room personnel. Although one patient developed a mild reaction to the contrast agent, it was easily managed with diphenhydramine.

However, the technology is still undergoing refinement. Four of the tumors, which were later shown to lack FR-alpha expression, did not fluoresce with the contrast agent. Fluorescence was also not detectable in tumors deep beneath the plural surface. This relative lack of penetration is the Achilles heel of the technique, according to Michael I. Ebright, MD, of the Section of Thoracic Surgery, New York-Presbyterian/Columbia University Medical Center in New York, NY, in an editorial commentary.3Nevertheless, Ebright emphasized that the strengths of the study should be seen as a launching pad for further improvement, rather than assessed based on its functionality in the current form.

Singhal agreed that the tool is still undergoing further refinement. He and his colleagues are studying a greater variety of molecular targets for contrast agents and investigating methods that allow the agent to penetrate several centimeters into solid organs. The authors also suggest redesigning the tracer agent for near-infrared capabilities, which would allow detection of nodules buried deep beneath the overlying healthy parenchyma. Nevertheless, Singhal emphasized the proof-of-concept of the recently published fluorescent imaging technology will likely be a valuable addition to existing methods of care for patients with cancer.

“I think we’re defining a whole new field [with this technique],” said Singhal.


1. Okusanya OT, DeJesus EM, Jiang JX, et al. Intraoperative molecular imaging can identify lung adenocarcinomas during pulmonary resection.J Thorac Cardiovasc Surg. 2015;150:28-35.

2. American Association for Thoracic Surgery. Real-Time Imaging of Lung Lesions During Surgery Helps Localize Tumors and Improve Precision.http://www.newswise.com/articles/view/637916/, Accessed August 6, 2015.

3. Ebright MI. Seeing cancer in a new light.J Thorac Cardiovasc Surg.2015;150:8-9.