What is the value of methylene blue stained biopsies in endoscopic surveillance of patients with Barrett's esophagus?
M.I.F. Canto (Baltimore)
Barrett's esophagus (BE) is the metaplastic replacement of squamous epithelium in the esophagus by cells resembling the small intestine or the gastric cardia or fundus. The presence of BE increases a patient's risk for the development of cancer 30-125 times that in the average person [1, 2]. Since dysplasia generally preceeds cancer , endoscopic biopsy can detect early treatable malignant tumors [3-5]. Although regular endoscopic surveillance is generally recommended, the optimum method for performing endoscopic surveillance has not yet been determined. Dysplastic cells may occupy variably-sized areas of normal appearing mucosa adjacent to a cancer . Hence, the chance of missing dysplasia or cancer is significant unless a rigorous program involving repeated, 4-quadrant random biopsy (RB) is followed . Levine et al. obtained up to 84 biopsy specimens during each surveillance endoscopy and examined 27-331 biopsy samples preoperatively before high-grade dysplasia or cancer was diagnosed . Unfortunately, this type of surveillance program is time-consuming, costly, and not feasible in the clinical setting .
Methylene blue reversibly stains actively absorbing cells (i.e. intestinal-type mucosa) . In a prospective pilot study, we showed that methylene blue selectively and reversibly stains specialized columnar epithelium (SCE) in BE with an accuracy of 95% . Since SCE is the precursor lesion for adenocarcinoma of the esophagus and esophagogastric junction [1, 11, 12], methylene blue staining can potentially improve endoscopic surveillance in three ways.
First of all, methylene blue staining can help the endoscopist more accurately detect SCE in asymptomatic patients with hiatal hernias, irregular Z lines, or islands/ tongues of columnar-type mucosa. The diagnosis of SCE by endoscopic biopsy has been shown to be problematic, particularly in patients with short-segment (i.e. < 3 cm) BE . Methylene blue staining can be used to screen for BE in patients with gastroesophageal reflux disease, usually after active inflammation has subsided in order to minimize falsely positive staining . Hence, surveillance can be performed in these patients at risk for adenocarcinoma who might otherwise not be diagnosed prior to the onset of symptoms.
Secondly, methylene blue can also help the endoscopist direct biopsies towards SCE in patients with limited- (i.e. > 3 to 6 cm) and long (> 6 cm)-segment BE. Since the majority of patients with limited-segment BE have nondiffuse or focal staining , methylene blue can increase the probability of sampling SCE using fewer biopsies. In a recent prospective controlled sequential trial comparing methylene blue-directed biopsy (MBDB) and
4-quadrant "jumbo" random biopsy (RB) techniques , we showed that MBDB led to a much larger proportion of SCE in each biopsy than RB (p = .0006). MBDB also led to a significantly lower total and average number of biopsies obtained per patient at each upper endoscopy compared to RB (p = .001).
Methylene blue staining can also highlight subtle differences in dye uptake among dysplastic and nondysplastic SCE. Ulcerated or depressed lesions would be appreciable at endoscopy and readily diagnosed by biopsy. However, endoscopically "normal" or flat mucosa with high grade dysplasia or CA could be appreciable as differential MB staining, which could be targeted for biopsy. Our preliminary data from ex vivo and in vivo MB staining suggest that dysplastic SCE stains differently from nondysplastic SCE . Correlation of methylene blue staining intensity with the results of blinded examination of 265 endoscopic biopsies (246 stained and 19 unstained) obtained at 31 upper endoscopies and 40 sections (29 stained and 11 unstained) from 4 surgical specimens showed that there was a significant association between decreasing stain intensity and increasing severity of dysplasia (p = .009). Moderate to marked stain heterogeneity (p = .01) and light or no MB staining (p = .01) were associated with high grade dysplasia/cancer in a multivariate model including ulceration. Marked stain heterogeneity was the single best predictor of high grade dysplasia and/or cancer. Focal non- or light blue staining and moderate to marked heterogeneity predicted the presence of high grade dysplasia and/or cancer in all 3 patients diagnosed endoscopically.
When we compared MBDB and RB for the detection of dyplasia/cancer in BE, the former biopsy technique proved to be superior. In 15 of 63 patients with dysplasia or cancer on any biopsy, MBDB diagnosed dysplasia in more patients with long-segment BE than RB
(18.7% vs. 11%. p = 0.03) despite fewer biopsies per patient . MBDB detected low grade dysplasia (n = 6) and high grade dysplasia (n = 3) in all patients diagnosed by RB. MBDB missed focal low grade dysplasia in 1 patient. On the other hand, RB missed 7 of the
15 patients with dysplasia or cancer: 5 of 11 patients with low grade dysplasia as their worst lesion, 1 of 2 patients with high grade dysplasia, and 1 of 3 patients with cancer.
Lastly, MBDB could lower the cost of performing endoscopic surveillance in patients with BE. In our study , the cost of endoscopic surveillance using MBDB was significantly lower compared to RB. Using 1995 Medicare dollars, the average direct cost for diagnosing a patient with cancer using MBDB under $15,000, signicantly lower and almost half that for RB. The mean difference in the cost of MBDB and RB for each patient was $7179 (using charges, p = .0001) and $2993 (using Medicare reimbursement,
p = .0001), with cost savings of $17,645/dysplastic biopsy. Overall, MBDB led to significantly lower cost but higher diagnostic yield for SCE and dysplasia than RB. This advantage is most prominent in patients with longer lengths of BE. In future studies, MBDB may prove to be a more cost-effective method of performing endoscopic surveillance in patients with BE.
3. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology 1988;94(1):81-90.
7. Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus. Gastroenterology 1993;105(1):40-50.
14. Canto M, Setrakian S, Petras R, Chak A, MV Sivak J. Methylene blue-directed biopsy for improved detection of intestinal metaplasia and dysplasia in Barrett's esophagus: a controlled sequential trial. Gastrointest Endosc 1996;43:165.
15. Canto M, Setrakian S, Willis J, Petras R, Chak A, MV Sivak J. Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study. Gastrointest Endosc 1996;43:164.