2012-02-07 20:16:57 UTC

The Changing Paradigm of Endoscopy and Pathology

Sept. 14, 2010

Michael B. Wallace, MD, MPH

Michael B. Wallace, MD, MPH

Professor and Chair, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL  


Since the first flexible endoscopic examination of the gastro-intestinal tract in 1957, excisional biopsy and endoscopic examination have been tightly linked. The ability to remove tissue, virtually without pain, and to make precise diagnoses of inflammation and neoplasia with pathological examination has driven much of the advancement in our understanding of gastrointestinal diseases, particularly cancer. This paradigm is rapidly changing.

Since the early days of microscopy in the 17th and 18th century, modern pathology relies on its core instrumentation, the microscope, with high-powered, high-resolution lenses, which allow optical inspection of cellular structure. Until recently, this has been the exclusive domain of ex vivo microscopy. Over the past three to four years, endoscopic flexible optical instruments have reached a level of magnification, resolution, and in conjunction with specific staining methods, contrast to directly visualize cellular and sub-cellular structures similar to that of ex vivo microscopy.

These endoscopic optical instruments began with simple magnification systems, which achieved magnification of 40- to 100-fold. Optical magnification up to 400-fold was integrated into moderate endoscopes in Japan in the 1990s, and together with the use of topical and vital stains, increased the ability to see detailed mucosal structures such as colonic pit patterns as well as variable contrast uptake between normal and neoplastic cells. Most recent advances in endoscopic optical imaging reach the threshold of 1,000-fold magnification and less than one micron resolution, on par with most traditional ex vivo microscopes.

The standard endoscopes now available use high-definition optics with optical filtering or color enhancement methods (e.g., narrow band imaging (NBI), Fujinon intelligent color enhancement and iScan), which substantially improve the contrast between normal and disease tissues. Recent advances extend the ability to directly visualize cells and subcellular structures. The most commonly used and commercially available technology in this field is confocal laser endomicroscopy (CLE). The instruments are either integrated into commercially available endoscopes or probes, which can be passed through the accessory channel of endoscopes (pCLE). CLE allows direct imaging of cells, nuclei, stromal tissue, and in the case of pCLE, blood flow.

Several other related technologies combine high magnification/high resolution, allowing imaging of broad fields of tissue at extremely high resolution and magnification. The two most promising of these technologies, although still in the research phase, are optical coherence tomography and optical frequency domain imaging.

How will these technologies be integrated into our practice and affect our valuable interaction with pathologists? The most common reason we perform excisional biopsy is to characterize colorectal polyps. Ex vivo microscopy, by distinguishing between neoplastic versus non-neoplastic polyps, stratifies a patient’s risk of colorectal cancer (CRC). Seminal studies have shown that patients who have neoplastic polyps are at greater risk for progression to CRC, and that removal of these polyps reduces this risk. Thus, the main reason that we perform ex vivo examination is to distinguish between a low-grade neoplastic polyp, such as a tubular adenoma, and a low-grade hyperplastic polyp. Other purposes include distinguishing between grades of neoplasia or a tubular adenoma versus a high-grade adenoma or a cancer, as these typically require more invasive therapies and closer surveillance.

Perhaps the greatest impact of new in vivo optical systems is in colorectal polyps. Currently, more than 14 million colonoscopies are performed yearly in the U.S. and polyps are detected in at least half of these. More than one third of polyps are non-neoplastic, usually small distal hyperplastic polyps. Of the neoplastic polyps, more than 90 percent are small low-grade adenomas. Typically less than 5 percent of polyps had advanced histologic features such as a villous component, and less than 1 percent of all polyps detected had invasive carcinoma.

Numerous large-scale multicenter trials have shown that modern endoscopic systems,  such as high-definition endoscopy with contrast enhancement methods, can accurately distinguish — at least in a significant proportion of polyps — between hyperplastic and neoplastic polyps and — particularly in the case with zoom-chromoendoscopy or NBI — can distinguish between low-grade and high-grade adenomas and cancers. This ability has led to the proposal that some polyps, namely those with classic features of low-grade adenomas or hyperplasia, do not require ex vivo pathologic confirmation (figures 1 and 2). In the so-called diagnosis-and-discard strategy, small polyps would be resected and discarded after an in vivo optical diagnosis.1 Surveillance intervals would be guided based on the in vivo optical diagnosis. This concept has not yet been tested in a prospective clinical trial; however, each of the components necessary to estimate its efficacy have been well published, including the accuracy of polyp classification, the subsequent accuracy of proposed surveillance intervals and estimation of the clinical impact of the small percentage of misclassified lesions. The major advantage of the diagnosis-and-discard strategy would be to reduce the overall cost of colon cancer screening without negatively impacting quality.

Another proposed strategy involves leaving hyperplastic polyps in situ. This would likely be restricted to small distal hyperplastic polyps, which are widely accepted to have low malignant potential. Recent studies suggest that larger, proximal hyperplastic polyps have some malignant potential, particularly those with CPG island methylation phenotype. This strategy has the potential to reduce cost and risk of post-polypectomy complication. Although I frequently encounter some resistance to this concept, the fact is that many endoscopists already follow this concept when large numbers of tiny, classic hyperplastic-appearing polyps are found in the rectosigmoid and left behind, with at most, a biopsy sample of one to two of them.

Another common indication for excisional biopsy is surveillance of neoplasia in Barrett's esophagus and chronic IBD. In this setting, neoplasia is often invisible through traditional endoscopes and thus, extensive, low-yield, random biopsy protocols are utilized to identify patients with neoplasia.

Although ex vivo microscopy has become the reference standard for diagnosing most diseases, it presents significant impediments to effective and efficient clinical care. The most significant of these is the delay between the endoscopic procedure and the ultimate diagnosis. In cases where an endoscopic therapy is indicated, that therapy has to be performed in a separate endoscopy session. A typical situation is the patient with chronic IBD where random biopsy detects neoplastic change, which often prompts a total colectomy. The ability to precisely locate and classify neoplastic tissue in vivo has the potential to dramatically improve the efficiency and methods with which we can treat these conditions.

Perhaps the most likely area for early adoption of these in vivo technologies is in the replacement of random biopsy with optically guided biopsy. Studies from our group and others have already shown that NBI and CLE can detect all, or nearly all, patients with high-grade neoplasia in Barrett’s esophagus while eliminating the majority of random biopsies.2, 3 Similarly, in IBD surveillance, prospective controlled trials have shown that chromoendoscopy with or without CLE can nearly eliminate the need for random biopsy,4 leading the AGA5 and the Crohn’s and Colitis Foundation of America6 to accept optically guided biopsies as an alternative to random biopsy. These approaches should allow more than a 90 percent reduction in the need for biopsy without sacrificing, and in fact increasing, the yield for neoplasia.

Some limitations of this approach should be addressed before they are widely adopted. Prospective clinical trials, particularly in colorectal polyps, are paramount and already underway. Training in image interpretation and documentation of accuracy outside of highly specialized academic centers is needed. Other issues involve how to integrate pathology expertise with endoscopic expertise. Particularly in the area of confocal imaging, our pathology colleagues have been very valuable in developing the criteria for distinguishing between neoplastic and non-neoplastic tissues. In the long run, it is likely that pathologists will play an increasing role in interpretation and in vivo endoscopic images. This will change the structure of how procedures are performed and would require new models of interaction, either at the bedside or via remote image transmission.

There is no doubt that pathologists will continue to play an integral role in the management of gastrointestinal disease, as there are many conditions that are not amenable to in vivo microscopy. However, we should maintain an open mind as to how these new technologies can improve the care of our patients and how we can take full advantage of the expertise brought to the table by both endoscopists and pathologists alike.

  1. Ignjatovic A, East JE, Suzuki N, Vance M, Guenther T, Saunders BP. Optical diagnosis of small colorectal polyps at routine colonoscopy (Detect InSpect ChAracterise Resect and Discard; DISCARD trial): a prospective cohort study. Lancet Oncol 2009 Dec;10(12):1171-8.
  2. Wolfsen HC, Crook JE, Krishna M, Achem SR, Devault KR, Bouras EP, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett's Esophagus. Gastroenterology 2008 Jul;135(1):24-31.
  3. Sharma P, Meining A, Coron E, Lightdale CJ, Wolfsen HC, Bansal A, et al. 1071 Detection of Neoplastic Tissue in Barrett's Esophagus With In Vivo Probe-Based Confocal Endomicroscopy (DONT BIOPCE). Final Results of a Prospective International RCT: Image Guided Versus 4 Quadrant Random Biopsies? Gastroenterology 2010;138(5, Supplement 1):S-155.
  4. Kiesslich R, Goetz M, Lammersdorf K, Schneider C, Burg J, Stolte M, et al. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology 2007 Mar;132(3):874-82.
  5. Farraye FA, Odze RD, Eaden J, Itzkowitz SH, McCabe RP, Dassopoulos T, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010 Feb;138(2):738-45.
  6. Itzkowitz SH, Present DH. Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005 Mar;11(3):314-21.

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