Integrative Analysis of Intrahepatic Cholangiocarcinoma Subtypes for Improved Patient Stratification: Clinical, Pathological, and Radiological Considerations

SIMPLE SUMMARY: Liver cancer subtypes differ in prognosis and genetic alterations. An accurate diagnosis made on time is the key aspect of clinical decision-making. Hence, a correct diagnosis is of pivotal importance for individual patients. In this study, we identified the most relevant clinical, radiological, and histological parameters for an improved subtype diagnosis of intrahepatic cholangiocarcinoma. As a result of our study, the radiologist should consider factors such as growth pattern, location, and contrast agent behavior. For the pathologist, precursor lesions, mucin secretion, and a periductal-infiltrating growth are of utmost importance, while immunohistochemical analyses are essential for exclusion of extrahepatic malignancies, but have so far only value for iCCA subtype analysis in the context with other parameters. ABSTRACT: Intrahepatic cholangiocarcinomas (iCCAs) may be subdivided into large and small duct types that differ in etiology, molecular alterations, therapy, and prognosis. Therefore, the optimal iCCA subtyping is crucial for the best possible patient outcome. In our study, we analyzed 148 small and 84 large duct iCCAs regarding their clinical, radiological, histological, and immunohistochemical features. Only 8% of small duct iCCAs, but 27% of large duct iCCAs, presented with initial jaundice. Ductal tumor growth pattern and biliary obstruction were significant radiological findings in 33% and 48% of large duct iCCAs, respectively. Biliary epithelial neoplasia and intraductal papillary neoplasms of the bile duct were detected exclusively in large duct type iCCAs. Other distinctive histological features were mucin formation and periductal-infiltrating growth pattern. Immunohistochemical staining against CK20, CA19-9, EMA, CD56, N-cadherin, and CRP could help distinguish between the subtypes. To summarize, correct subtyping of iCCA requires an interplay of several factors. While the diagnosis of a precursor lesion, evidence of mucin, or a periductal-infiltrating growth pattern indicates the diagnosis of a large duct type, in their absence, several other criteria of diagnosis need to be combined.