Pre-Operative Differentiation Between Pancreatic Cancer (PC) and Distal Bile Duct Cancer (DBDC) Based on Endoscopic Brushing/FNA Mutational Analysis

Abstract

Background: Malignant distal CBD strictures may be related to PC or DBDC. Accurate diagnosis is of prognostic value given better survival with resected DBDC (∼50% 5 yr survival) vs. resected PC (∼25% 5 yr survival). Currently employed pre-operative diagnostic modalities cannot accurately differentiate between DBDC and PC in malignant CBD strictures. The role of molecular markers in this context remains unknown. Methods: Twenty-eight patients with surgically confirmed PC (16) or DBDC (12) were studied. Biliary brushings (17) or EUS guided FNA (11) had been performed on all. Representative malignant cells from stained cytology slides and corresponding resection specimen (malignant and benign tissue) from all cases were micro-dissected and subjected to direct PCR amplification. The PCR products were analyzed for (1) k-ras codon 12/13 mutations and (2) microsatellite losses targeting 1p36, 3p26, 5q23, 9p21, 10q23 and 17p13, utilizing fluorescent capillary electrophoresis. The pattern of mutation acquisition and microsatellite loss was compared to the surgical pathology. Results: All malignant cytology and surgical specimens carried multiple mutations whereas the benign (control) samples carried none. Multiple microsatellite losses were seen in both PC and DBDC but K-ras codon 12 mutation was seen in 14/16 PC cases and only 1/12 DBDC cases (p < 0.001). This mutational pattern differentiated between PC and CBDC with a sensitivity of 88% and specificity of 92%. Conclusions: Although patients with resected DBDC can expect better survival than those with resected PC, this information is only available post-resection. A detailed molecular analysis applied to endoscopically acquired cytologic samples can help in reaching an accurate diagnosis of PC or DBDC. Multiple microsatellite losses are seen in both PC and DBDC but the presence of k-ras mutation is an accurate predictor of malignancy of pancreatic ductal origin.