Primary Motility  Disorders of the  Esophagus
 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Screening and surveillance

Are methylene blue-directed biopsies a cost-effective method for surveillance of Barrett's patients?

M.I.F. Canto (Baltimore)

Methylene blue is a vital stain taken up by actively absorbing tissues such as small intestinal and colonic epithelium. It selectively and accurately stains the intestinal-type of metaplasia or specialized columnar epithelium [1, 2], which is considered pathognomonic of Barrett's esophagus. It is also the most clinically relevant type of epithelium due to its association with adenocarcinoma of the esophagus and esophagogastric junction

Interpretation of methylene blue staining

Methylene blue staining of nondysplastic Barrett's esophagus may be either focal or diffuse (i.e. > 75% of Barrett's mucosa stains blue) [3]. Nearly all patients with long-segment Barrett's esophagus (LSBE) have diffuse staining because specialized columnar epithelium comprises majority of the columnar mucosa [1]. In contrast, majority of short Barrett's esophagus exhibits focal staining due to the presence of gastric-type metaplasia.

Highly dysplastic specialized columnar epithelium in long Barrett's esophagus (> 3 cm) Barrett's esophagus appears to stain differently from non-dysplastic specialized columnar epithelium [2, 3]. Nearly all areas of high-grade dysplasia (HGD) or adenocarcinoma take up less methylene blue and therefore appear unstained or light blue. In contrast, nondysplastic Barrett's esophagus usually stains dark blue. Barrett's esophagus with lowgrade dysplasia stains variably [3]. The reason for this abnormal methylene blue staining is dysplastic Barrett's esophagus is possibly the decrease in goblet cells characteristic of dysplastic epithelium. The effect is similar to that seen with Lugol's iodine solution when used in early squamous cell esophageal carcinomas. Close attention should be paid to moderately or markedly heterogeneous staining or focal areas of nonstained (pink) mucosa within diffusely staining specialized columnar epithelium. This is usually observed in patients with more than 3 cm of Barrett's esophagus. This pattern has been highly associated with HGD or early adenocarcinoma [2, 3]. The endoscopist should meticulously biopsy both stained and unstained areas in the esophagus using large/"jumbo" biopsy forceps. Obtain biopsies from light blue or unstained areas first and place these in separate bottles. Increasing grade of dysplasia is significantly associated with focal areas of decreased stain intensity (from dark blue to light blue or absent stain/pink) and/or increased stain heterogeneity (i.e. increasing proportion of light blue or pink unstained mucosa compared to dark blue mucosa).

Methylene blue staining is cost-effective

In a prospective, controlled sequential trial [2], methylene blue staining led to a much larger proportion of specialized columnar epithelium in endoscopic biopsies compared to large particle 4-quadrant random biopsy (p = .0006), particularly in patients with limitedsegment (54% versus 94%) and LSBE (72% versus 92%). Moderate to marked heterogeneity of staining (i.e., decreased to absent staining within diffusely staining Barrett's esophagus) was highly associated with dysplasia or early cancer. Hence, despite fewer biopsies per patient, methylene blue directed biopsy diagnosed dysplasia or cancer in significantly more biopsies (9.2% versus 6.6%, p = 0.004) and more patients (46.5% versus 30%, p = 0.03) than random biopsy. The estimated average cost of diagnosing a cancer using methylene blue-directed biopsy was half that of 4-quadrant random biopsy.

In summary, methylene blue-directed biopsy is a more accurate and cost-effective technique than random biopsy for diagnosing specialized columnar epithelium and dysplasia/cancer, particularly in LSBE.


1. Canto MI, Setrakian S, Petras RE, Blades E, Chak A, Sivak MV. Methylene blue selectively stains intestinal metaplasia in Barrett's esophagus. Gastrointest Endosc 1996;44:1-7.

2. Canto M, Setrakian S, Willis J, Chak A, Petras RE, Powe NR, Sivak MV Jr. Methylene blue-directed biopsy for improved detection of intestinal metaplasia and dysplasia in Barrett's esophagus: a controlled sequential trial. Gastrointest Endosc 2000;51(5):560-568.

3. Canto M, Setrakian S, Willis J, Petras RE, Chak A, Sivak MV Jr. Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus:an in vivo and ex vivo study. Gastrointest Endosc 1996;43:164.

Publication date: August 2003 OESO©2015