In Vivo Optical Detection of Dysplasia in Barrett’s Esophagus with Endoscopic Light Scattering Spectroscopy

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Introduction

The incidence of adenocarcinoma of the esophagus is increasing more rapidly than any other type of carcinoma in the United States . Almost 100% of cases occur in patients with Barrett’s esophagus (BE) , a benign condition in which metaplastic columnar epithelium replaces the normal squamous epithelium of the esophagus. Although the prognosis of patients diagnosed with adenocarcinoma is poor, the chances of successful treatment increase significantly if the disease is detected at the dysplastic stage. The surveillance for dysplasia of patients with BE is challenging in three respects. First, dysplasia in nonnodular BE is not visible during routine endoscopy . Thus, numerous systematically located biopsy specimens are taken in a prescribed pattern. Although systematic, this procedure is referred to in the literature as “random,” and we will also use this term. Second, the histopathologic diagnosis of dysplasia is problematic because there is poor interobserver agreement on the classification of a particular specimen, even among expert gastrointestinal pathologists . Third, reliance on histology imposes a time delay between endoscopy and diagnosis, requiring patient recall if disease is discovered as opposed to prompt treatment during surveillance.

Once BE has been identified, most gastroenterologists will enroll the patient in an endoscopy/biopsy surveillance program, presuming that the patient is a candidate for ablative therapy should low-grade or high-grade dysplasia be detected. Although the cost effectiveness of this type of surveillance program has not been validated in prospective studies, the lack of such studies does not preclude its potential usefulness. Patients with BE who have esophageal carcinoma detected as part of such a surveillance program are more likely to have curable disease and have an improved 5-year survival as compared with those whose cancer was detected outside of a surveillance program.

Dysplasia in the gastrointestinal tract is defined as neoplastic epithelium confined within an intact basement membrane. Dysplasia in BE can be classified as low or high grade, based on the criteria originally defined for dysplasia in inflammatory bowel disease . Low-grade dysplasia (LGD) is defined primarily by cytological abnormalities, including nuclear enlargement, crowding, stratification, hyperchromasia, mucin depletion, and mitoses in the upper portions of the crypts. These abnormalities extend to the mucosal surface. High-grade dysplasia (HGD) is characterized by even more pronounced cytological abnormalities, as well as glandular architectural abnormalities including villiform configuration of the surface, branching and lateral budding of the crypts, and formation of the so-called back-to-back glands. When there is any doubt as to the significance of histological abnormalities because of inflammation, ulceration, or histological processing artifacts, the findings may be classified as “indefinite for dysplasia” (IND) in order to prevent unnecessary clinical consequences.

Not all patients with BE progress to adenocarcinoma. The majority live their entire lives without undergoing malignant or neoplastic transformation. Others demonstrate a rapid progression to carcinoma and will die of esophageal cancer if it is not diagnosed and treated in a timely manner. Several recent attempts at identifying molecular markers that can predict which patients with BE will progress to esophageal cancer have not been proven effective in clinical trials. For example, anti-p53 antibodies have been shown to develop in patients with BE and adenocarcinoma, and may predate the clinical diagnosis of malignancy .

At the present time, the standard of care for surveillance of patients with BE remains debated. Although periodic endoscopic surveillance of patients with BE has been shown to detect carcinoma in its earlier stages, surveillance has significant limitations. Dysplastic and early carcinomatous lesions arising in nonnodular BE are not visible macroscopically; therefore, surveillance requires extensive random biopsies of the esophagus and histologic examination of the excised tissue for dysplasia. Random biopsy is prone to sampling error (missed dysplastic lesions) and significantly increases the cost and risk of surveillance. There is also significant interobserver disagreement between pathologists in diagnosing dysplasia. A large 10-year observational study in 409 patients with BE published in the British Medical Journal concluded that the current random biopsy endoscopic surveillance strategy has very limited value.

Optical imaging offers great promise for the detection and characterization of precancers in the esophagus. Endoscopic laser-induced fluorescence (LIF) spectroscopy based imaging is believed to measure the abnormal concentrations of certain endogenous fluorophores such as porphyrins in malignant tissue. Promising results for esophagus have been obtained by Vo-Dinh et al. , von Holstein et al. , Stepp et al. , Messmann et al. , Braichotte et al. , and Georgakoudi et al. . Another native contrast optical imaging approach, optical coherence tomography (OCT), is a method that provides two-dimensional cross-sectional images of the gastrointestinal tract. Like endoscopic ultrasound, OCT provides true anatomic images corresponding to the layers of the gastrointestinal tract , however, by using light the resolution of OCT is nearly 10-fold finer than that of high-frequency endoscopic ultrasound. Recently, Tearney et al. used high-speed OCT technology, termed optical frequency domain imaging (OFDI), to demonstrate the feasibility of a large area imaging of the entire distal esophagus in patients . Fujimoto et al. demonstrated the feasibility of using endoscopic ultra-high resolution optical coherence tomography (UHR OCT) to locating esophageal adenocarcinoma. Wax et al. developed an interferometric light scattering technique called angle-resolved low-coherence interferometry (a/LCI) capable of measuring nuclear morphology as a function of depth in epithelial tissue and demonstrated its ability to detect nuclear atypia in esophageal dysplastic epithelial tissues. Bigio et al. developed a minimally invasive diagnostic light scattering technique called elastic scattering spectroscopy (ESS) and applied it to detect early cancer in colon , bladder , and esophagus . The study in esophagus demonstrated that ESS has the potential to target conventional biopsies in Barrett’s surveillance saving significant endoscopist and pathologist time.

Over a decade ago, we pioneered a new diagnostic optical technique, biomedical light scattering spectroscopy (LSS), and demonstrated that LSS can measure subcellular nuclear morphology in esophageal tissue in vivo and be directly correlated with histopathology . Clinical feasibility of LSS for detection of epithelial precancers (dysplasia) in several organs was later demonstrated and then extended to large field-of-view imaging . Recently, we demonstrated that LSS can be employed to scan an entire esophagus during routine endoscopy, successfully guiding biopsy and detecting and mapping sites of invisible dysplasia missed by the current standard of care .

This article reviews the principles of LSS and describes application of endoscopic LSS for detecting invisible dysplasia in BE during routine clinical procedures.

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