Extrahepatic Distal Cholangiocarcinoma vs. Pancreatic Ductal Adenocarcinoma: Histology and Molecular Profiling for Differential Diagnosis and Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are very aggressive tumors with a high mortality rate. Pancreas and distal bile ducts share a common embryonic development. Hence, PDAC and dCCA exhibit similar histological features that make a differential diagnosis during routine diagnostic practice challenging. However, there are also significant differences, with potential clinical implications. Even if PDAC and dCCA are generally associated with poor survival, patients with dCCA seem to present a better prognosis. Moreover, although precision oncology-based approaches are still limited in both entities, their most important targets are different and include alterations affecting BRCA1/2 and related genes in PDAC, as well as HER2 amplification in dCCA. Along this line, microsatellite instability represents a potential contact point in terms of tailored treatments, but its prevalence is very low in both tumor types. This review aims at defining the most important similarities and differences in terms of clinicopathological and molecular features between these two entities, also discussing the main theranostic implications derived from this challenging differential diagnosis.

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

“…Extrahepatic cholangiocytes derive from endoderm and are closely related to the pancreas and duodenum, whereas intrahepatic cholangiocytes arise from hepatoblasts, closely resembling hepatocytes [13]. Distal CCA can often be difficult to distinguish from ampullary and pancreatic ductal adenocarcinoma (PDAC) given their similar embryological development and overlapping mutational profile [14].…”

“…KRAS G12D variant is most common in dCCA and GBC, followed by G12V in pCCA. Though not quite approaching the >90% incidence of KRAS mutations seen in PDAC, dCCA has the most similar mutation profile to PDAC [14,24]. Most notably, two of the most common actionable genomic alterations with FDA-approved targeted therapies, IDH1 and FGFR2 alterations, occurring approximately 18% and 15% of iCCA, respectively, are rarely found in eCCA [15, 25•, 26, 27].…”

The Italian Rare Biliary tract Cancer initiative (IRaBiCa): A multicentric observational study of Gruppo Oncologico dell’Italia Meridionale (GOIM) in collaboration with Gruppo Italiano Colangiocarcinoma (GICO)

“…ERBB2/3 amplifications (10%) and KRAS mutations (8-45%) are more represented in the extrahepatic forms. [6][7][8] The first-line use of durvalumab in combination with chemotherapy is now clinical practice. 9 Recently, several molecularly targeted drugs have been approved by FDA such as pemigatinib 10 and futibatinib 11 in patients with fusion and/or rearrangement of FGFR2 and ivosidenib in patients with IDH1 mutations.…”

“…ERBB2/3 amplifications (10%) and KRAS mutations (8-45%) are more represented in the extrahepatic forms. 6 -8…”

The coexistence of myosteatosis and the creatinine/cystatin C ratio are determinants of outcomes in cholangiocarcinoma patients undergoing curative surgery

“…extrahepatic cholangiocarcinoma includes hilar cholangiocarcinoma and distal cholangiocarcinoma(32). The preoperative diagnosis of distal cholangiocarcinoma and pancreatic ductal adenocarcinoma has been a focus of research(33). Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are two types of highly aggressive cancers that are associated with an inferior prognosis (34).…”