Abstract
IntroductionIt is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. Here we analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma.Materials and MethodsBrush cytology specimens from 119 patients with biliary strictures (malignant: n = 72; benign: n = 47) were analyzed in a retrospective cohort study. mRNA of IGF-II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), Forkhead box M1 (FOXM1), kinesin family member 2C (KIF2C) and serine/threonine kinase NEK2 was determined by semi-quantitative RT-PCR using the ΔCt method.ResultsIGF2BP3 (p<0.0001), HOXB7 (p<0.0001), and NEK2 (p<0.0001) mRNA expression levels were significantly increased in patients with cholangiocarcinoma or pancreatic cancer. Median ΔCt values differed by 3.5 cycles (IGF2BP3), 2.8 cycles (HOXB7) and 1.3 cycles (NEK2) corresponding to 11-fold, 7-fold and 2.5-fold increased mRNA levels in malignant versus benign samples. Sensitivity to detect biliary cancer was 76.4% for IGF2BP3 (80.9% specificity); 72.2% for HOXB7 (78.7% specificity) and 65.3% for NEK2 (72.3% specificity), whereas routine cytology reached only 43.1% sensitivity (85.4% specificity). Diagnostic precision was further improved, when all three molecular markers were assessed in combination (77.8% sensitivity, 87.2% specificity) and achieved 87.5% sensitivity and 87.2% specificity when molecular markers were combined with routine cytology.ConclusionsOur data suggest that measuring IGF2BP3, HOXB7 and NEK2 mRNA levels by RT-PCR in addition to cytology has the potential to improve detection of malignant biliary disorders from brush cytology specimens.
Highlights
It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures
Routine cytology failed to detect malignancy in 22 patients and remained indeterminate in further 19 patients, so that overall a correct diagnosis of malignancy was missed by cytology in 41 of 72 patients
Messenger-RNA Expression of Candidate Genes Sufficient mRNA could be extracted in each analyzed brush cytology specimen, and target gene mRNA expression levels of IGF2BP3, homeobox B7 (HOXB7), and NEK2 were significantly higher in the brush specimens from patients with malignant strictures than in those from patients with benign biliary strictures (DCt IGF2BP3: 9.5862.87 vs.13.0862.38, p,0.0001; DCt HOXB7: 8.3463.08 vs. 11.1362.51, p,0.0001; DCt NEK2: 8.6061.86 vs. 9.9161.81, p,0.0001)
Summary
It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. We analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma It is a challenging task for gastroenterologists to distinguish between benign and malignant lesions in patients with biliary strictures [1]. Current diagnostic imaging methods such as transabdominal ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) achieve a rather high sensitivity for detecting bile duct pathology, they cannot reliably differentiate between malignant and benign biliary strictures [2] Intraductal procedures, such as endoscopic retrograde cholangiography (ERC) with brushings for routine cytology (RC) and intraductal forceps biopsy are often applied to identify patients with biliary malignancy [3,4,5].
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