April 28, 2008

Optical Biopsy: Characterizing Tissue While It’s in the Body
By Beth W. Orenstein
For The Record
Vol. 20 No. 9 P. 26

Lung cancer patients face the possibility that it could be more than two months from the time their cancer is first suspected from a chest x-ray or CT or PET scan until their diagnosis is confirmed and treatment begun.

“By the time the patients go through six different appointments and getting this test and that, it could be 70 to 80 days until they are ready to start chemotherapy or radiation,” says Michael J. Simoff, MD, director of bronchoscopy and interventional pulmonology, pulmonary, and critical care medicine at Henry Ford Medical Center in Detroit.

However, Simoff believes that within five to 10 years, optical biopsies could be a reality that shortens the time from diagnosis to treatment. Optical biopsies use the properties of light to provide real-time images of live human tissue. Several optical tools are in development that would allow physicians to make a diagnosis at the time of the biopsy. That, in turn, would help eliminate the bottlenecks that delay patients with confirmed malignancies from receiving appropriate treatments sooner.

“Most of us in pulmonology believe that the more we can reduce the time from the discovery of the abnormality to starting treatment, the more good we are doing for our patients,” Simoff says. As with most cancers, the smaller and more confined the lung lesion is when it is discovered and treated, the better the prognosis.

When imaging reveals a suspicious lung nodule, the traditional way to confirm or dismiss the concern is to take a tissue biopsy and send it to the pathology lab. “Right now, we go in and we take a sample of the tissue where we have a good clinical suspicion of XYZ. Then we put the sample under a microscope and look at its cellular structures,” Simoff says.

A lung biopsy is performed with a bronchoscope, and the pulmonologists hope they hit their target and get good samples from the region of interest, he says. The pathologists then read the stained slides to determine whether it is malignant or benign.

Simoff says he is one of a few researchers worldwide studying optical biopsy methods that will allow physicians to not only locate suspicious nodules but also visualize them and make a diagnosis in real time. He says doing this may change the way lung cancer patients are treated. Radiation oncologists could begin treatments sooner and may also be better able to target, localize, and deliver therapy to confirmed malignancies.

While Simoff is excited about real-time optical biopsies, he cautions that most techniques are in their infancy. “There are very few centers worldwide involved with any of these techniques,” he says. “It is extremely new. While the idea has been around for a long time, we are currently trying to make the ideas into reality, and I am lucky enough to be one of the people involved.”

At this point, there are several optical technologies being explored to improve diagnostic yield. Which one of them will emerge as the best? According to Simoff, “It is too early to say. We just don’t have enough information for me to comment on that yet.”

EBUS-TBNA
One technique that has been available for more than five years and shows promise is endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA). The procedure is performed under local or general anesthesia with a bronchoscope, a thin flexible telescope with a linear ultrasound attached to its tip. The bronchoscope probe is inserted through the patient’s mouth into his or her lungs. The ultrasound on the bronchoscope’s tip provides images of the mediastinum, the region between the two lungs. The procedure appears to permit more and smaller nodes to be sampled compared with TBNA, which is done blindly, notes Simoff.

Simoff says he has been able to access previously inaccessible lymph nodes with EBUS-TBNA. He says the ultrasound technique is particularly effective at diagnosing cancers in lymph nodes that are less than 1 centimeter. Nodes this small are not easily diagnosed by traditional sampling techniques or PET/CT, he says.

From his studies, Simoff has found that 22% of such nodes diagnosed with PET/CT as negative are found to be positive with EBUS-TBNA. He is hopeful that as the technique advances it could help some patients avoid exploratory surgery.

Simoff says EBUS-TBNA, while effective and highly accurate, is underutilized in cancer care today, in part because it takes time for an endoscopist to master the technique. “We have been performing this procedure for the last six or seven years,” he says, “but it is only in the last two to three years that it has really taken off.”

Confocal Fluorescence Microendoscopy
Simoff is also interested in confocal fluorescence microendoscopy, which is in the early stages of development. The Henry Ford Medical Center is one of three sites worldwide currently working to develop a tool that makes confocal microendoscopy a reality in the procedure room.

Confocal microscopy, a laser technology, has the potential to produce high-resolution, blur-free images of thick specimens of living tissue in the lungs at various depths. It works by concentrating on one focal plane at a time and reducing the out-of-focus light from above and below it. A computer reconstructs the images, which are taken point by point rather than projected through an eyepiece. The principle for this kind of microscopy was developed in 1953, but it did not become a standard technique until lasers were developed for it in the late 1980s.

“Confocal microscopy is one way in which we are taking things from the laboratory and moving them into the real world,” Simoff says. “By bringing confocal microscopy into the fiber-optic world, we are able to do it in vivo.”

The equipment is currently capable of producing 5-micron resolution. “The problem is we don’t know exactly what we are looking at yet, and the three centers are working together to collect as much information as possible for the future of making diagnoses,” Simoff says.

Optical Coherence Tomography
Another similar tool is optical coherence tomography. “What it does is it allows us to look deeper into the tissue as well,” Simoff says. “You need 1- to 2-micron resolution to see clearly at a cellular level. Currently we are at 10- to 20-micron resolution with this technology.”

In the near future, Simoff expects that optical coherence tomography systems will incorporate spectral analysis, which will provide chemical clues to the makeup of the tissue in question. “What we hope to do as we continue to improve on the resolution is actually look at the airways in ways that have never been seen before, looking further for submucosal invasion, looking further for making the diagnosis, and hopefully—again, the goal being the optical biopsy—at the time of my procedure, I can tell what is going on,” he says.

Optical biopsies do not lengthen procedure time much. “For us to do a confocal microendoscopy vs. a conventional endoscopic procedure adds five to 10 minutes,” Simoff says. “If you know where you need to go, you can take the tool and place it into that location and get your answer right way.”

At the same time that the diagnostic tools are being developed for optical biopsies, researchers are learning more about various cancers and what markers are present or absent. Their presence or absence can indicate how the cancers may respond to various therapies. “There may be other types of treatments that we will be able to modify for our patients based upon the markers that are there,” Simoff says. “Hopefully, we will be doing optical biopsies at the same time.”

Optical biopsies also could help radiation oncologists to better target the tumor by providing precise mapping techniques, Simoff says. “It is possible that clinicians eventually will be able to apply dosimeters with this technology, too,” he adds.

Moving Forward
Simoff says optical biopsies may seem far off in the future or “something that is not going to be done, but the reality is that within five years at Henry Ford, I hope that we are performing this very thing,” he says. Simoff believes it will take another two to three years to continue to improve the equipment and gain the clinical experience needed. “We need a couple of good studies that ensure we are ascertaining the correct information,” he says. “Once we have that, it’s another couple years to start bringing the equipment into the fold of what’s happening out there.

“We are moving along in each and every one of these technologies so that someday soon we will be able to achieve this goal: the treatment of a solitary pulmonary nodule without surgery,” he adds.

Armin Ernst, MD, chief of interventional pulmonology at Beth Israel Deaconess Medical Center in Boston, is also researching optical biopsy tools. He, too, has no doubt that they will experience dramatic growth over the next five to 10 years. One major advantage to optical biopsies over traditional histological and cytological biopsies is that they could decrease sampling error. “With optical biopsy techniques, you can see in real time what it is you are going to biopsy,” he says.

However, Ernst says that the technique raises many questions, including which specialty will be trained to make the diagnosis when the tissue is in vivo. “We don’t know who should be interpreting the images,” he says. “Traditionally, it is a pathologist who looks at the biopsies. For the most part, what the pathologists are used to looking at is dead tissue taken out of someone’s body. It is stained, it is fixed, and what you’re looking at with an optical biopsy is alive. It’s part of your living body.”

The technique is so new that “obviously there are few people who have experience in what they would be looking at and whether it is the same as a dead piece of tissue,” Ernst says. “So there are lots of things that still need to be figured out before these optical techniques come to the forefront.”

— Beth W. Orenstein is a freelance medical writer and frequent contributor to For The Record. She writes from her home in Northampton, Pa.