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Published in final edited form as: Lasers Surg Med. 2012 Apr 25;44(5):390–396. doi: 10.1002/lsm.22033

The Effect of Reactive atypia/Inflammation on the Laser-Induced Fluorescence Diagnosis of Non-dysplastic Barrett’s Esophagus

Masoud Panjehpour 1, Bergein F Overholt 2, Tuan Vo-Dinh 3, Domenico Coppola 4
PMCID: PMC3371107  NIHMSID: NIHMS370746  PMID: 22535652

Abstract

Background and Objectives

Differential Normalized Fluorescence (DNF) technique has been used to distinguish high-grade dysplasia from non-dysplastic Barrett’s esophagus. This technology may assist gastroenterologists in targeting biopsies, reducing the number of biopsies using the standard protocol. In the presence of reactive atypia/inflammation, it becomes difficult for the pathologist to differentiate non-dysplastic Barrett’s esophagus from Barrett’s esophagus with low grade dysplasia. Before DNF technique may be used to guide target biopsies, it is critical to know whether reactive atypia/inflammation in non-dysplastic Barrett’s may result in false positives.

This study was conducted to determine whether DNF technique is adversely affected by the presence of reactive atypia/inflammation in non-dysplastic Barrett’s esophagus resulting in false positives.

Study Design/Materials and Methods

410-nm laser light was used to induce autofluorescence of Barrett's mucosa in 49 patients. The clinical study included 37 males and 12 females. This was a blinded retrospective data analysis study. A total of 303 spectra were collected and matched to non-dysplastic Barrett’s biopsy results. 175 spectra were collected from areas with a pathology of non-dysplastic Barrett’s esophagus with reactive atypia/inflammation. 128 spectra were collected from areas with non-dysplastic Barrett’s esophagus without reactive changes/ inflammation. The spectra were analyzed using the DNF Index at 480 nm and classified as positive or negative using the threshold of −0.75 × 10−03 .

Results

Using DNF technique, 92.6% of non-dysplastic samples with reactive atypia/inflammation were classified correctly (162/175). 92.2 % of non-dysplastic samples without reactive atypia/inflammation were classified correctly (118/128). Comparing the ratios of false positives among the two sample groups, there was not a statistically significant difference between the two groups.

Conclusion

Using Differential Normalized Fluorescence technique for classification of non-dysplastic Barrett’s mucosa doesn’t result in false positive readings due to reactive atypia/inflammation. Target biopsies guided by DNF technique may drastically reduce the number of pinch biopsies using the standard biopsy protocol.

Keywords: Laser-Induced fluorescence spectroscopy, non-dysplastic Barrett’s esophagus, Intestinal Metaplasia (IM), inflammation, acid reflux, Reactive atypia, Differential Normalized Fluorescence Index, optical biopsy

INTRODUCTION

Laser-induced fluorescence (LIF) spectroscopy has been used to distinguish normal from malignant tissue in different organs such as breast, lung, colon, and esophagus (1–6). These studies clearly show the potential application of LIF spectroscopy as a non-invasive diagnostic technique for detecting cancer.

Barrett's esophagus is a condition in which the squamous lining of the esophagus is replaced by specialized columnar epithelium (7–8). The prevalence of adenocarcinoma in Barrett's esophagus is approximately 10% (9, 10). The estimated incidence of adenocarcinoma in Barrett's esophagus ranges from one in 52 to one in 441 patient years, reflecting an increased risk of 30 to 125-folds (9, 11–14). Development of cancer is preceded by dysplastic transformation of Barrett's mucosa (15), thereby providing a clinical setting that allows identification of patients at high risk for developing esophageal adenocarcinoma.

Our previous studies indicate that Differential Normalized Fluorescence (DNF) may be used to detect esophageal cancer (16) and distinguish non-dysplastic Barrett’s (also called Intestinal Metaplasia or IM) from high-grade dysplasia in Barrett’s esophagus (17).

In Barrett’s esophagus, this technique has the potential to assist the physician in only targeting the pinch biopsies to areas that show positive DNF readings. This may result in drastically reducing the number of tissue sampling needed using the standard technique of four-quadrant every 1–2 centimeter of Barrett’s mucosa.

Presence of chronic acid reflux creates difficulty for the pathologist in differentiating Barrett’s esophagus with reactive atypia from Barrett’s esophagus with low grade dysplasia. The features used to differentiate among these two entities are surface maturation, glandular architecture, cytologic features, and the presence of inflammation. In order to have the highest degree of accuracy in evaluating Barrett’s pathology, the national guidelines recommend using a minimum of two pathologists who are experts in esophageal histopathology.

Before DNF technique is used to guide target biopsy of the Barrett’s mucosa, it is important to determine whether reflux-induced reactive changes and inflammation in non-dysplastic Barrett’s may cause a false positive reading of high-grade dysplasia.

This study was designed to determine whether Differential Normalized Fluorescence index at 480 nm is affected by reactive atypia/inflammation in non-dysplastic Barrett’s esophagus resulting in false positive readings as high-grade dysplasia.

MATERIALS AND METHODS

Patient Population

Data were collected in 49 patients, including 37 males and 12 females. This was a blinded retrospective data analysis study. There were 303 fluorescence measurements that were matched with pathology. 175 spectra were collected from non-dysplastic areas with reactive atypia/inflammatory features. 128 spectra were collected from non-dysplastic Barrett’s without any reactive atypia/inflammation features. This study was approved by the Institutional Review Board of the Thompson Cancer Survival Center. All patients signed an informed consent prior to being included in the study.

Laser-Induced Fluorescence Measurement System

Figure 1 shows a schematic diagram of the Laser Induced Fluorescence (LIF) system. A detailed technical description of the system is provided in previous publication (6, 16, 17) and will not be discussed here. To summarize, a nitrogen-pumped dye-laser was used to deliver pulses of 410 nm excitation light. The laser light was delivered to the tissue using a fiber optic bundle passed through the working channel of the endoscope. The same bundle was used to collect the fluorescence from tissue and deliver to the entrance slit of a spectrograph.

Figure 1.

Figure 1

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Schematic of laser-Induced fluorescence system.

The spectrally dispersed emission spectrum was imaged on a gated intensified 1024-diode array detector controlled by an Optical Multichannel Analyzer, OMA III. A personal computer was used to control the entire system. OMA-Vision-PDA spectroscopy software was utilized to conduct the measurements.

Endoscopic Fluorescence Measurement

Fluorescence measurements were performed during routine upper endoscopy procedures. The endoscopist passed the flexible fiber optic fluorescence probe through the biopsy channel of the endoscope and touched it lightly to the tissue. Measurements were initiated by pressing the foot-switch. The collected spectra were automatically saved in separate coded data files.

The probe was gently pressed against the tissue to distort the surface superficially and imbed the tip of the probe onto the tissue fold. Due to the small diameter of the probe tip, good contact was easily made with the tissue. The proper placement of the probe against the tissue was verified on the endoscopy monitor by an independent observer and noted during each measurement. If accurate verification was not possible, the measured fluorescence was discarded. It must be noted that while fluorescence intensity is strongly affected by probe placement against tissue, the lineshape (normalized fluorescence spectrum) is not affected. Multiple measurements were obtained, typically in four quadrants every 2 cm of the columnar lined mucosa (occasionally every 1.0 cm). The location of each fluorescence measurement was determined by centimeter markings on the endoscope using dental margin. Each measurement was analyzed as a separate biopsy, and the data collected from the same distance were not averaged. Four quadrant pinch biopsies were then obtained from the same locations where fluorescence measurements were taken. The majority of the biopsies were performed using jumbo forceps. The pathology results were used for tabulation of the fluorescence spectra.

Differential Normalized Fluorescence (DNF) Spectral Analysis

A mathematical model based on Differential Normalized Fluorescence (DNF) Index has been developed and described previously for the endoscopic fluorescence diagnosis of esophageal cancer (16) and high-grade dysplasia in Barrett’s esophagus (17). To summarize the mathematical model, each tissue spectrum was normalized with respect to the total photon count for that spectrum to obtain a normalized fluorescence spectrum. Normalized fluorescence spectrum is basically the lines-shape for the spectrum. Using a previously obtained line-shape spectrum for normal esophageal mucosa, Differential Normalized Fluorescence (DNF) spectrum was calculated by subtracting the line-shape of normal tissue from the line-shape of the unknown tissue. The DNF Index at a given wavelength is simply the intensity of the DNF spectrum at that wavelength. In this study (and previously), we used DNF at 480 nm to classify each spectrum as positive (false positive for this study) or negative (true negative for this study), noting that all spectra in this report were taken from Barrett's mucosa without dysplasia (which should read as negative). As in previous studies, the DNF Index value of −0.75 × 10−3 was the threshold used to classify each spectrum as either positive or negative. The spectra with DNF index values of less than the threshold value were classified as positive. The spectra with DNF index of greater than −0.75 × 10−3 was classified as negative. All the pathologies were subdivided into two groups, those with inflammation and those without inflammation. All data being from non-dysplastic Barrett’s mucosa, the ideal result would be 100 % classifying as true negatives. The DNF classifications results were then compared with histological results as the gold standard.

Pathology Evaluation of Samples

In the presence of chronic acid reflux, it is difficult to differentiate Barrett’s esophagus with reactive atypia from Barrett’s esophagus with low grade dysplasia. The features that were used in differentiating these two entities were surface maturation, glandular architecture, cytologic features, and presence of inflammation.

In the non-dysplastic mucosa, the surface of the intestinalized mucosa appeared more mature than the underlying basal glands. There was some loss of surface mucin. The surface epithelium showed cells with a normal nuclear-to-cytoplasmic ratio (1:4) and the glandular architecture was normal as defined by the presence of abundant lamina propria between the glands.

Cytologically, in a Barrett’s mucosa without dysplasia the cells exhibited some degree of nuclear enlargement and atypia but these findings were mainly in the basal zone. The surface epithelial cells were cytologically normal. Mitoses and nuclear stratification if present were also located in the basal zone only. At high power the nuclei of the cells without dysplasia showed smooth nuclear membranes and only inconspicuous nucleoli. Importantly, nuclear polarity was not lost in any portion of the mucosa.

Acute and chronic inflammation when present had infiltrated the Barrett’s cells, a process called emperipolesis. These cells were reactive showing enlargement of both nuclei and cytoplasm, but the N:C ratio remained normal. Some nucleoli became prominent. A high percentage of non-dysplastic samples with acute and chronic inflammation showed presence of neutrophils (acute) or lymphocytes and plasma cells (chronic ). As recommended by national guidelines, all slides were evaluated by at least two expert esophageal histopathologists.

RESULTS

Figures 2, 3 and 4 are the normalized fluorescence spectra of three non-dysplastic Barrett’s (also referred to as IM= Intestinal Metaplasia) sites with and without reactive atypia/inflammation. Figure 2 is from a site without reactive atypia/inflammation that classified correctly as a true negative. Figure 3 is the spectrum of a site with reactive atypia/inflammation that classified correctly as a true negative. Figure 4 show a spectrum of a typical site with reactive atypia/inflammation that classified incorrectly as a false positive. The difference between spectrum in Figure 4 (false positive) and those in Figures 2 and 3 (both true negatives) is not very obvious when looking at the normalized fluorescence spectra alone.

Figure 2.

Figure 2

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Normalized fluorescence spectrum for a sample without reactive atypia/inflammation that classified correctly as a true negative.

Figure 3.

Figure 3

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Normalized fluorescence spectrum of a sample with reactive atypia/inflammation that classified correctly as a true negative.

Figure 4.

Figure 4

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Normalized fluorescence spectrum of a sample with reactive atypia/inflammation that classified incorrectly as a false positive.

However, the difference is easily seen when looking at the corresponding Differential Normalized Fluorescence spectra for the above spectra. Figure 5 shows the corresponding Differential Normalized Fluorescence for the spectrum seen in Figure 2 for the site without reactive atypia/inflammation that classified correctly as a true negative. The DNF index threshold, the intensity of −0.75 × 10−3 at 480 nm, is indicated by the cross hair and a small circle in Figures 5–7. In Figure 5 it can be seen that the intensity of the signal at 480 nm is higher than the threshold value. Figure 6 shows the Differential Normalized Fluorescence for the spectrum in Figure 3 for the site with reactive atypia/inflammation that classified correctly as a true negative. Again, the intensity of signal at 480 nm is higher than the threshold value. Similarly, Figure 7 shows the Differential Normalized Fluorescence spectrum corresponding to the spectrum in Figure 4 for the site with reactive atypia/inflammation that classified incorrectly as a false positive. The signal intensity at 480 nm is lower than the threshold value. The difference between false positive and true negative spectra is clearly seen at the wavelength of 480 nm (DNF Index). The true negative sites have a flat featureless spectra, while the false positive spectrum has a negative dip around the wavelength of 480 nm with the intensity less than the threshold value.

Figure 5.

Figure 5

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Differential Normalized Fluorescence spectrum for the same data in Figure 2 for a sample without reactive atypia/inflammation that classified correctly as a true negative. The DNF index threshold (intensity of −0.75 × 10−3 at 480 nm) is indicated by the cross hair and small circle. The intensity of signal at 480 nm is more than the threshold value.

Figure 7.

Figure 7

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Differential Normalized Fluorescence spectrum corresponding to the data in Figure 4 for a sample with reactive atypia/inflammation that classified incorrectly as a false positive The DNF index threshold (intensity of −0.75 × 10−3 at 480 nm) is indicated by the cross hair and small circle. The intensity of signal at 480 nm is lower than the threshold value.

Figure 6.

Figure 6

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Differential Normalized Fluorescence for the spectrum in Figure 3 for a sample with reactive atypia/inflammation that classified correctly as a true negative The DNF index threshold (intensity of −0.75 × 10−3 at 480 nm) is indicated by the cross hair and small circle. The intensity of signal at 480 nm is more than the threshold value.

Each DNF spectrum was classified as negative or positive by comparing the intensity of the signal at the wavelength of 480 nm to the threshold value of −0.75 × 10−3. Those with an intensity higher than −0.75 × 10−3 were classified as negative (true negative) and those with intensity less than −0.75 × 10−3 were classified as positive (false positive).

Figures 8 and 9 are microscopic views (H&E, magnification of 200) of typical non-dysplastic Barrett’s esophagus without reactive atypia/inflammation and with reactive atypia/ inflammation, respectively.

Figure 8.

Figure 8

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Non-dysplastic Barrett’s esophagus with negligible inflammation (H&E, Magnification of 200).

Figure 9.

Figure 9

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Non-Dysplastic Barrett’s esophagus with inflammation and maturation of the epithelium. See stratification, hyperchromasia and elongation of nuclei at the base of the gland but not on the surface (H&E, Magnification of 200).

Using the DNF technique at 480 nm, 92.6% of non-dysplastic samples with reactive atypia/inflammatory features were classified correctly (162/175). 92.2 % of non-dysplastic samples without reactive atypia/inflammation were classified correctly (118/128). In other words, there were 7.4% (13/175) false positives in the group with reactive atypia/inflammation and 7.8% (10/128) false positives in the group without reactive atypia/inflammation. Comparing the ratios of false positive classifications among the two groups, there was not a statistically significant difference between the two groups (p value =0.90).

DISCUSSION

In Barrett's patients, chronic acid reflux is responsible for development of Barrett’s mucosa where the squamous lining is replaced by specialized columnar mucosa (7–8). Adenocarcinoma is preceded by dysplastic transformation of Barrett's mucosa (15) which is not detectable through white light endoscopy. Dysplasia can only be detected histologically from biopsy specimens.

Barrett's esophagus is found in 10% to 12% of patients with symptomatic gastroesophageal reflux disease who undergo endoscopy (18,19), but its frequency may be 20 times higher in general population (20). In Barrett's patients with no apparent adenocarcinoma, the prevalence of positive dysplasia is 5 to 10 percent (21–25). Dysplasia may be found in different levels of severity including lowgrade (LG) or high grade (HG). Altorki, et al. (26) reported detecting carcinoma in 45% of the surgically resected specimens from symptomatic Barrett's patients who underwent surgery for high grade dysplasia.

Due to the focal nature of dysplasia, extensive biopsies are required for reliable diagnosis. A commonly used protocol for sampling of Barrett’s esophagus is four quadrant biopsies at 2 cm (or 1 cm) intervals within the Barrett's mucosa (27). However, this method is far from ideal for effectively detecting dysplasia. First, the focal nature of dysplasia creates the possibility of sampling error even when conducting four quadrant biopsies at 1- cm intervals. Second, performing endoscopic biopsies in patients with long segments of Barrett's mucosa results in a prolonged procedure. Third, bleeding during and following endoscopic biopsies interferes with the accuracy of determining the precise location of biopsies. In addition, bleeding may limit the number of biopsies that may be taken. Furthermore, there is always potential risk of greater bleeding following biopsy in patients with a coagulation disorder. Fourth, interobserver variability exists in the pathological interpretation of pinch biopsy samples (28) creating concerns and problems for clinicians. In fact, the national guidelines recommend evaluation of Barrett’s samples by a minimum of two pathologists who are considered experts in esophageal histopathology.

Laser-induced fluorescence spectroscopy (sometimes called optical biopsy) offers the potential to diagnose flat dysplasia in Barrett’s esophagus prior to development of visible lesions. When compared to standard pinch biopsies, optical biopsy offers many advantages. First, due to the rapidity of the fluorescence measurement, the LIF technique allows examination of a practically unlimited number of sites thereby reducing the sampling error while at the same time reducing the length of the procedure significantly. Typically, 6 to 7 optical biopsies can be performed in the time taken for one pinch biopsy. In addition, the non-invasive nature of the measurements allows for multiple optical biopsies to be taken without any bleeding.

Furthermore, this technique may potentially reduce the human variability in histological interpretation of biopsy samples by establishing a standard mathematical/statistical technique for interpretation of the data. Last, the results of the optical biopsy can be available to the endoscopist within minutes, perhaps seconds, rather than days. This may allow the endoscopist to decide on further diagnostic studies or on a choice of treatment, with possible implementation during the same procedure.

Panjehpour, et al (17) used Differential Normalized Fluorescence technique for detecting high grade dysplasia in Barrett’s esophagus. Using DNF at 480 nm, 96% of non-dysplastic Barrett's and all low-grade dysplasia samples were classified as Benign. Ninety percent of tissues with high grade dysplasia were classified as Premalignant. They also used DNF technique at 660nm for detecting high-grade dysplasia. Using the two DNF indices at 480 nm and 660 nm concurrently, all patients with high-grade dysplasia classified as having Premalignant lesions indicating that optical biopsy may be used as a reliable screening technique for detecting high-grade dysplasia in Barrett's esophagus patients. This study showed that the fluorescence line-shape of high-grade dysplasia has similar characteristics as that of esophageal cancer. Therefore, this model could not differentiate between high grade-dysplasia and carcinoma, similar to results reported by Lam, et al. (29) in lung tissue. In the study by Panjehpour, et al. (17), all non-dysplastic samples were grouped together regardless of presence or absence of reactive atypia/inflammatory features.

Pathologist often have difficulty diagnosing dysplasia in the presence of reactive atypia/inflammation from chronic acid reflux (30). Specifically, it is difficult to differentiate Barrett’s esophagus with reactive atypia from Barrett’s esophagus with low grade dysplasia. Pathologists examine surface maturation, glandular architecture, cytologic features, and presence of inflammation for proper diagnosis of dysplasia. Similarly, if optical biopsy using the DNF technique is to be used to help clinicians in targeting biopsies in Barrett’s patients, it important to determine whether reactive atypia/inflammation in the non-dysplastic Barrett’s mucosa causes a false positive reading as high grade dysplasia. This study investigated the effect of acid reflux-induced reactive atypia and inflammation on DNF Index diagnosis of non-dysplastic Barrett’s mucosa. The study divided all the non-dysplastic Barrett’s pathologies into two subcategories, those with reactive atypia/inflammatory features and those without any such features. The results indicated that the classification of non-dysplastic Barrett’s esophagus was not affected by the presence of reactive changes and inflammation in the tissue. The specificity in correctly classifying non-dysplastic Barrett’s mucosa was 92.6% for samples with reactive atypia/inflammation compared to 92.2% for those without atypia/inflammation. We caution against DNF analysis of areas with endoscopically visible esophageal erosions and ulcerations.

Additional microscopic fluorescence studies are required to determine whether or not specific histologic features are responsible for the small number of false positive classifications. This study did not include any dysplastic samples. Therefore, it is not possible to discuss the effect of reactive atypia and inflammation on DNF diagnosis of dysplastic tissue. However, since inflammation did not appear to affect the DNF diagnosis of non-dysplastic tissue, one may anticipate that it would also not affect the diagnosis of dysplastic samples.

In summary, laser-induced fluorescence spectroscopy using DNF Index at 480 nm can classify non-dysplastic Barrett’s esophagus accurately regardless of reactive atypia/ inflammatory features that are often seen in such samples due to chronic acid reflux. Differential Normalized fluorescence spectroscopy may be used as a tool for screening Barrett’s patients for high-grade dysplasia. Performing target biopsies guided by laser-induced fluorescence technology may drastically reduce the number of pinch biopsies needed using the standard four-quadrant biopsies protocol. While the rate of false diagnosis was less than 10% in this study, additional studies are needed to properly investigate how many less pinch biopsies are needed if DNF technique is used to guide the gastroenterologist in targeting biopsies.

Acknowledgments

The authors acknowledge partial support from the National Institutes of Health (R01 CA088787).Tuan Vo-Dinh, Ph.D. acknowledges the support of Oak Ridge National Laboratory for initial studies of this work.

Contributor Information

Masoud Panjehpour, Laser Center, Thompson Cancer Survival Center, Knoxville, TN 37916

Bergein F. Overholt, Laser Center, Thompson Cancer Survival Center, Knoxville, TN 37916

Tuan Vo-Dinh, Fitzpatrick Institute for Photonics, Departments of Biomedical Engineering and Chemistry, Duke University, Durham, NC 27708-0281

Domenico Coppola, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612

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