Seeing Cancer With the World's Smallest Microscope
Joseph Romagnuolo, M.D., Professor and Director of Clinical Research in MUSC’s Division of Gastroenterology and Hepatology, is the first in the state to use probe-based confocal laser endomicroscopy (pCLE) to visualize dynamic, microscopic images of the gastrointestinal tract that could speed the diagnosis and better target the treatment of patients with a variety of upper gastrointestinal disorders. Marketed as Cellvizio® (Mauna Kea Technologies, Paris, France), pCLE requires three key pieces of equipment: a miniprobe consisting of a fiberoptic bundle, a laser scanning unit, and a computer on which specially designed image-processing software has been installed.
During an endoscopy, if the gastroenterologist observes an abnormality or a suspect lesion, he or she can further investigate in real time by injecting a fluorescein dye and introducing the miniprobe into the operating channel of the endoscope. Once the probe is in contact with the area of interest, a focused low-power laser light can be directed through the fiberoptic bundle, reflecting off of the fluorescein-stained tissue and allowing microscopic-level images to be transmitted back via the probe to a computer monitor. There, they can be watched as real-time video.
The ability to visualize living tissue at the microscopic level in real time represents a remarkable advance for gastroenterologists: “It’s amazing to see the movement of cells within tiny blood vessels in real life—you don’t see that on a pathology image. It’s definitely a ‘wow’ moment for a gastroenterologist,” says Dr. Romagnuolo.
With this technology, gastroenterologists can for the first time explore abnormalities during the endoscopic procedure at the microscopic level to determine whether any cancer cells are present. If the miniprobe reveals cancer or precancerous (dysplastic) cells, the gastroenterologist can ablate those cells during the endoscopy, meaning that a diagnosis can be made and treatment delivered in the same endoscopic session.
The patients most likely to benefit first from this technology are those with Barrett’s esophagus or ulcerative colitis, both of which are premalignant conditions that put patients at higher risk of cancer. A 2011 article validated pCLE-observed microscopic characteristics that could be used to diagnose dysplasia/cancer in Barrett’s esophagus (two or more of the following are needed for diagnosis: a saw-toothed epithelial surface, enlarged cells, pleomorphic cells, glands that are not equidistant or that are unequal in size and shape, goblet cells that are not easily identified).¹ It also reported that the overall accuracy of this technology in diagnosing dysplasia was 81.5% and did not vary significantly between experts and nonexperts who had undergone a structured training session. Although the evidence is strongest for the efficacy of pCLE in diagnosing dysplasia/cancer in Barrett’s esophagus, recent studies show that it has diagnostic sensitivity in ulcerative colitis as well.²
In the past, patients with one of these conditions have had to undergo frequent random biopsies to monitor for potential cancer. These frequent biopsies and the waiting time between biopsy and the receipt of the pathology report took both a physical and emotional toll on patients. With pCLE technology, an abnormality observed during endoscopy can be investigated immediately, sparing the patients days of anxiety. Instead of relying on random biopsies for cancer surveillance, the gastroenterologist can use the miniprobe to identify areas of concern for selective biopsy.
Not only does the technology pave the way for more targeted biopsies that are likely to yield more information with less inconvenience to the patient, it can actually enable a better diagnosis in certain cases, as for example distinguishing whether an indeterminate pancreaticobiliary stricture is benign or malignant. The standard of care is to use endoscopic retrograde cholangiopancreatography (ERCP), a technique combining endoscopy and fluoroscopy, to explore and treat such strictures. In ERCP, contrast dye is injected into the ducts, allowing visualization of the area via X-ray. MUSC is fortunate to have endoscopic ultrasound (EUS) and ERCP with mini-endoscopes (Spyglass,™ Boston Scientific), which can navigate ducts to take tiny biopsies of indeterminate strictures. Both can make a diagnosis in many cases when magnetic resonance imaging and computed tomography are nondiagnostic.
While the ERCP mini-endoscopes have a higher yield for finding cancer cells than the traditional ERCP cytology brush (50%-70% vs 30%), many strictures still remain “indeterminate.” Patients with such indeterminate strictures would likely have few options other than to undergo a high-risk Whipple procedure just to surgically remove any possibility of a missed cancer. In this procedure, large sections of the stomach, bile duct, pancreas, and small intestine are removed, and the remaining portions of the stomach and pancreas as well as the hepatic duct are connected to the jejunum to allow for the passage of food, digestive juices, and bile.
The new pCLE technology allows for better exploration of these strictures and therefore more accurate diagnosis and more targeted therapy. The Cellvizio miniprobe, which fits down the endoscope used in ERCP, is small enough to explore even very small bile ducts and strictures, sending real-time video at the microscopic level instantly to the computer monitor. Such an optical biopsy of the stricture could help clinicians discern whether it is malignant. Only patients with strictures showing signs of malignancy would then undergo the high-risk and highly invasive Whipple procedure. A recent study in 102 patients with indeterminate pancreaticobiliary strictures at five academic centers found that ERCP combined with pCLE had significantly better diagnostic accuracy than ERCP alone (90% vs 73%; P<.001).²
Whether such an optical biopsy could one day replace the traditional biopsy and pathology report requires further study in larger groups of patients monitored over longer periods of time. Although traditional biopsy will likely always remain a definitive diagnostic tool, increased use of pCLE-enabled optical biopsy in specified conditions could reduce the number of biopsies needed and increase their yield by better targeting the tissue sampled. In doing so, pCLE could represent a significant cost saving for institutions and an improved health care experience for patients.
¹ Gaddam S, Mathuyr SC, Singh M, et al. Novel probe-based confocal laser endomicroscopyh criteria and interobserver agreement for the detection of dysplasia in Barret's Esophagus. Am J Gastroenterol2011; 106:1961-1969.
² Rispo A, Castiglione F, Staibano S, et al. Diagnostic accuracy of confocal laser endomicroscopy in diagnosing dysplasia in patients affected by long-standing ulcerative colitis. World J Gastrointest Endosc 2012 Sep 16;4(9):414-420.
³ Meining A, Chen YK, Pleskow D, et al. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc 2011 Nov;74(5):961-968.