Emerging optical methods for surveillance of Barrett's oesophagus

Abstract

The rapid rise in incidence of oesophageal adenocarcinoma has motivated the need for improved methods for surveillance of Barrett's oesophagus. Early neoplasia is flat in morphology and patchy in distribution and is difficult to detect with conventional white light endoscopy (WLE). Light offers numerous advantages for rapidly visualising the oesophagus, and advanced optical methods are being developed for wide-field and cross-sectional imaging to guide tissue biopsy and stage early neoplasia, respectively. We review key features of these promising methods and address their potential to improve detection of Barrett's neoplasia. The clinical performance of key advanced imaging technologies is reviewed, including (1) wide-field methods, such as high-definition WLE, chromoendoscopy, narrow-band imaging, autofluorescence and trimodal imaging and (2) cross-sectional techniques, such as optical coherence tomography, optical frequency domain imaging and confocal laser endomicroscopy. Some of these instruments are being adapted for molecular imaging to detect specific biological targets that are overexpressed in Barrett's neoplasia. Gene expression profiles are being used to identify early targets that appear before morphological changes can be visualised with white light. These targets are detected in vivo using exogenous probes, such as lectins, peptides, antibodies, affibodies and activatable enzymes that are labelled with fluorescence dyes to produce high contrast images. This emerging approach has potential to provide a 'red flag' to identify regions of premalignant mucosa, outline disease margins and guide therapy based on the underlying molecular mechanisms of cancer progression.

Keywords: BARRETT'S OESOPHAGUS; IMAGING.

Figure 1

Imaging of Barrett’s oesophagus (BE). (A) Wide-field imaging is needed to localise neoplastic lesions, identify tumour margins and evaluate for cancer recurrence. White light image shows patches of squamous (SQ) in BE. An area of high-grade dysplasia (HGD) is not visibly distinct. (B) Cross-sectional imaging is needed to assess depth of early cancer invasion (T1a vs T1b). Histology (H&E) shows feature of both SQ and HGD.

Figure 2

Optical properties of tissue. Image resolution improves with shorter wavelengths, and tissue penetration increases with longer wavelengths. Haemoglobin (Hb) dominates absorption of light in the visible (400–700 nm). Water absorption plays a small role in the infrared (IR; >900 nm). The extinction coefficients for Hb (blue), oxyhaemoglobin (HbO₂; red) and water (black) are shown. Fluorophores can be used to improve image contrast, and include Diethylaminocoumarin (DEAC), fluorescein, fluorescein isothiocyanate (FITC; derivative of fluorescein), Cyanine (CY) derivatives (Cy5, Cy5.5), and IR800. AFI, autofluorescence imaging; NBI, narrow band imaging; OCT, optical coherence tomography; OFDI, optical frequency domain imaging; WLE, white light endoscopy.

Figure 3

Novel imaging instruments. (A) Conventional white light endoscopy(WLE) shows squamous (SQ) patches within Barrett’s oesophagus (BE). (B) Fluorescence (F) endoscope shows molecular images of high-grade dysplasia (HGD; high signal) next to SQ (low signal). (C) Scanning fibre endoscope inserted transnasally shows patches of BE. (D) Capsule endoscopy with tethered probe shows cross-sectional image of BE on optical coherence tomography (images courtesy of G. Tearney and M. Gora). (E) Confocal laser endomicroscope (CLE) passes through instrument channel of endoscope to shows optical cross-section of HGD on molecular imaging in vivo. pCLE, probe-based CLE.

Figure 4

Targets for molecular imaging. Cell surface glycans are underexpressed with disease progression in oesophageal cancer (EAC), and can be detected with lectins. Protein targets (epidermal growth factor receptor (EGFR), ERBB2, c-MET, fibroblast growth factor receptors (FGFR) 1 and 2)) that are overexpressed in Barrett’s neoplasia are accessible to imaging with peptides and antibodies. Cyclooxygenase-2 (COX-2) is an intracellular enzyme that is absent in normal cells but increased in neoplasia. Osteopontin (OPN) is a secreted extracellular matrix protein that is highly overexpressed in EAC.

Figure 5

Molecular probe platforms. Various classes of molecular probes have been developed and demonstrated on imaging in vivo in preclinical models and in the clinic. Each class has unique strengths and weaknesses. Biochemical structures of commonly used fluorophores for molecular imaging are shown. FITC, fluorescein isothiocyanate.