Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures

Abstract

Background and aims: Standard techniques for evaluating bile duct strictures have poor sensitivity for detection of malignancy. Newer imaging modalities, such as intraductal ultrasound (IDUS), and advanced cytologic techniques, such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH), identify chromosomal abnormalities, and may improve sensitivity while maintaining high specificity. Our aim was to prospectively evaluate the accuracy of these techniques in patients with indeterminate biliary strictures.

Methods: Cholangiography, routine cytology (RC), intraductal biopsy, DIA, FISH, and IDUS were performed in 86 patients with indeterminate biliary strictures. Patients were stratified based on the presence or absence of primary sclerosing cholangitis (PSC).

Results: RC provided low sensitivity (7-33%) but high specificity (95-100%) for PSC and non-PSC patients. The composite DIA/FISH results (when considering trisomy-7 [Tri-7] as a marker of benign disease) yielded a 100% specificity and increased sensitivity one- to fivefold in PSC patients versus RC, and two- to fivefold in patients without PSC, depending on how suspicious cytology results were interpreted. For the most difficult-to-manage patients with negative cytology and histology who were later proven to have malignancy (N = 21), DIA, FISH, composite DIA/FISH, and IDUS were able to predict malignant diagnoses in 14%, 62%, 67%, and 86%, respectively.

Conclusions: DIA, FISH, and IDUS enhance the accuracy of standard techniques in evaluation of indeterminate bile duct strictures, allowing diagnosis of malignancy in a substantial number of patients with false-negative cytology and histology. These findings support the routine use of these newer diagnostic modalities in patients with indeterminate biliary strictures.

Figure 1

(A) Feulgen staining during digital image analysis demonstrates a benign sample. (B) Feulgen staining during digital image analysis reveals a malignant specimen.

Figure 2

DNA histograms showing cell distributions based on nuclear DNA content. 2C represents cells in the diploid range, and 4C indicates tetraploid cells. Cells between 2C and 4C are considered aneuploid. (A) cells from a benign biliary stricture, and (B) cells from a malignant biliary tract stricture.

Figure 3

(A) Fluorescently labeled probes detect normal nuclear content (two signals per color), revealing a benign sample. (B) Fluorescently labeled probes detect abnormal nuclear content (>two signals per color), revealing a malignant sample.