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Shining light on Barrett’s esophagus Expert Rev. Gastroenterol. Hepatol. 3(6), 577–580 (2009)
Luca Quaroni Staff Scientist, Canadian Light Source, Saskatoon SK, S7N 0X4, Canada Tel.: +1 306 657 3577 Fax: +1 306 657 7661 luca.quaroni@ lightsource.ca
Ronghua Zhao Research Scientist, Department of Surgery, University of Saskatchewan, Saskatoon SK, S7N 0W8, Canada Tel.: +1 306 966 7323 Fax: +1 306 966 8026
[email protected]
Alan G Casson Author for correspondence
Professor & Head, Department of Surgery, University of Saskatchewan, Saskatoon SK, S7N 0W8, Canada Tel.: +1 306 966 8641 Fax: +1 306 966 8026
[email protected]
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“…recent epidemiologic studies have now clearly implicated chronic gastroesophageal reflux disease and several lifestyle risk factors, including cigarette smoking, diet and obesity, as significant risk factors for esophageal adenocarcinoma.” Cancer of the esophagus is one of the most frequent malignancies worldwide, with a characteristic geographic variation in incidence [1] . However, over the past 30 years, a marked change in the epidemiology of esophageal malignancy has been reported in many Western populations. While the frequency of esophageal squamous cell carcinoma has remained relatively stable, incidence rates for primary esophageal adenocarcinoma (EADC) and adenocarcinomas involving the esophagogastric junction (cardia) have increased steadily, exceeding that of any other human solid tumor [2–4] . Although the precise reasons for this trend are unknown, recent epidemiologic studies have now clearly implicated chronic gastroesophageal reflux disease (GERD) [5] and several lifestyle risk factors, including cigarette smoking, diet and obesity, as significant risk factors for EADC (reviewed in [6,7]). Primary EADC generally arises from Barrett’s esophagus (BE), an acquired condition predisposed by GERD in which the normal esophageal squamous epithelium is replaced by a specialized metaplastic columnar cell-lined epithelium [8,9] . Progression of BE to invasive EADC is reflected histologically by the Barrett’s metaplasia–d ysplasia–adenocarcinoma sequence. In current clinical practice, the histopathologic finding of dysplasia, particularly high-grade dysplasia (HGD) [10,11] , in esophageal biopsies obtained at endoscopy is still considered the most reliable predictor of malignant progression, and underlies the rationale for endoscopic screening and surveillance [11,12] . However, accurate grading of dysplasia is still somewhat subjective and, as a consequence, inter- and intra-observer variation amongst histopathologists remains high [13] .
10.1586/EGH.09.43
Several critical molecular genetic and epigenetic alterations have also now been reported at various stages of esophageal adenocarcinogenesis (reviewed in [14–16]), providing further insight into esophageal tumor biology. However, as GERD and BE are relatively frequent in the general population, and only a fraction of individuals ever develop EADC [17] , it is likely that molecular and lifestyle risk factors interact to modulate individual susceptibility to malignant progression [18–20] . The incorporation of clinically relevant molecular markers into future screening and endoscopic surveillance programs [21–24] may well identify individuals with BE who are at increased risk for progression to invasive EADC, thereby providing a unique opportunity for early intervention, and potentially improved outcomes for this disease [25] .
“…molecular and lifestyle risk factors interact to modulate individual susceptibility to malignant progression.” The potential of Fourier transform infrared (FTIR) spectroscopy as a diagnostic technique has been recognized for decades. Absorption of radiation in the mid-infrared spectral region provides rich information on the molecular properties of a sample, in particular the molecular structure and chemical composition of biologic tissues. As many pathological conditions are associated with perturbations of metabolism, which are reflected in homeostatic changes of molecular components in cells and tissues [26] , the clinical potential of FTIR spectroscopy to detect such changes, and its use as a diagnostic tool for ‘molecular fingerprinting’ has, therefore, received increasing attention [27] .
© 2009 Expert Reviews Ltd
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One particular advantage of this approach is that FTIR measurements do not affect the sample in any significant way, as photons in the mid-infrared spectral region are nonionizing. The high sensitivity of this approach allows the use of a power density that is too low to cause heat-induced tissue damage. Staining of tissue samples is also not required for recording an FTIR absorption spectrum, which may even be applied to microgram quantities of tissues, for example as obtained from fine-needle aspiration biopsies. These considerations make FTIR spectro scopy an attractive, nondestructive and rapid technique, allowing for the recovery and storage of samples for repeated studies and multitechnique analyses.
“…Fourier transform infrared spectroscopy [is] an attractive, nondestructive and rapid technique, allowing for the recovery and storage of samples for repeated studies and multitechnique analyses.” Currently, the principal limitation of this technique results from the high absorption of mid-infrared radiation by liquid or solid samples, in particular aqueous samples. This requires working with samples as thin as a few micrometers whenever measurements of transmitted light are performed. Sectioning is necessary for solid samples and enclosure within a thin, sealed sample holder is required for liquid samples and cell suspensions. The attenuated total reflection (ATR) optical configur ation, in which an infrared beam is internally reflected within a crystal on the surface in contact with a sample, is often used to overcome this limitation. ATR allows selective measurement of infrared absorption spectra from the surface of bulky samples, and is generally easy to implement with minimal sample preparation. As a consequence, ATR is particularly valuable for the measurement of thick tissue samples without the need for sectioning, and under conditions that retain tissue integrity and viability [28,29] . Recent work by Wang et al. has shown that FTIR-ATR measurements can be used to identify dysplastic and nondysplastic (metaplastic) changes in BE biopsies, with greater diagnostic accuracy than conventional histopathologic interpretation [30] . However in this study, measurements were performed with limited spatial resolution in the horizontal plane, using biopsy samples of approximately 1-mm diameter. This approach introduces the possibility that the observed spectral properties may be dominated by the response of various cellular and tissue types that typically exist within human premalignant and malignant tissues. Under such conditions, the response from minority components, which display distinct histopathologic characteristics, may go undetected [31,32] . We have recently shown that the diagnostic viability of FTIR measurements used to identify BE can be validated and further enhanced by using FTIR spectroscopy in the microscopy optical configuration [33] . Focusing the infrared beam to the scale of a few micrometers allowed us to evaluate and compare high spatial resolution with samples of histologically normal esophageal squamous epithelium and BE, and to match these 578
features to specific cellular areas in corresponding histologic tissue sections. We initially used FTIR mapping with a conventional infrared light source, followed by hierarchical clustering analysis of resulting infrared spectra [34] to classify microscopic regions of the sample with specific infrared spectral features. These measurements allowed us to identify the crypt region as displaying an infrared spectral pattern characteristic of BE, and were indicative of an accumulation of glycoprotein, most likely mucin [33] . Furthermore, we used a synchrotron light source to expand the imaging capability of FTIR mapping. The use of synchrotron light sources provides a significant advantage in brightness that may be utilized to improve spatial resolution for confocal microscopy and spectromicroscopy applications [35] . The synchrotron light source allowed us to obtain maps with diffraction-limited resolution, corresponding to approximately 3–10 µm for the mid-infrared spectral range, showing the accumulation of mucin on the luminal side of individual goblet cells, the characteristic histologic feature of BE [33] . Such recent exploratory studies have demonstrated the feasibility of FTIR to identify and validate infrared absorption signatures (metabolic and structural) associated with a defined esophageal premalignant lesion (e.g., BE). Although it is unlikely that such an approach alone will replace current histopathologic and molecular diagnoses, FTIR spectroscopy and spectromicroscopy may well see future clinical application in diagnostic protocols designed to identify individuals with BE at increased risk for progression to invasive EADC, particularly when used in conjunction with infrared-based endoscopic instruments (e.g., fiberoptic evanescent wave spectroscopy) [36] . The sensitivity of the measurement, the reliability, and the potential for single-cell and subcellular resolution all suggest the future evolution of this technique into a high-throughput screening method for the identification and sorting of cell populations.
“Of particular interest in human tumor biology is the potential for synchrotron radiation-Fourier transform infrared spectroscopy to define the molecular fingerprint of individual cells.” Of particular interest in human tumor biology is the potential for synchrotron radiation-FTIR to define the molecular fingerprint of individual cells. Utilizing this approach, ongoing studies in our laboratory are focused on the use of synchrotronbased FTIR to identify esophageal cancer stem cell-like cell populations [37] . Financial & competing interests disclosure
Alan G Casson is currently supported by the Saskatchewan Health Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Expert Rev. Gastroenterol. Hepatol. 3(6), (2009)
Shining light on Barrett’s esophagus
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Potential molecular basis underlying the association between GERD and the risk for BE and esophageal adenocarcinoma.
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Rabinovitch PS, Longton G, Blount PL, Levine DS, Reid BJ. Predictors of progression in Barrett’s esophagus III: baseline flow cytometric variables. Am. J. Gastroenterol. 96(11), 3071–3083 (2001).
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Flow cytometric criteria used to identify patients with BE at increased risk for progression to invasive esophageal adenocarcinoma.
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Reid BJ, Prevo LJ, Galipeau PC et al. Predictors of progression in Barrett’s esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am. J. Gastroenterol. 96(10), 2839–2848 (2001).
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Fernando HC, Murthy SC, Hofstetter W et al. The Society of Thoracic Surgeons Practice Guideline Series: guidelines for the management of Barrett’s esophagus with high-grade dysplasia. Ann. Thorac. Surg. 87(6), 1993–2002 (2009).
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Comprehensive study utilizing Fourier transform infrared spectroscopy (FTIR) to characterize BE.
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Quaroni L, Casson AG. Characterization of Barrett esophagus and esophageal adenocarcinoma by Fourier-transform infrared microscopy. Analyst (Cambridge, UK) 134(6), 1240–1246 (2009).
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Report of the use of FTIR spectromicroscopy to characterize esophageal tissues.
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Preliminary report of the potential for synchrotron FTIR to characterize esophageal stem cell-like cell populations.
Expert Rev. Gastroenterol. Hepatol. 3(6), (2009)
