Need for normalization: the non-standard reference standard for microvascular invasion diagnosis in hepatocellular carcinoma

Background: Preoperative microvascular invasion (MVI) assessment in hepatocellular carcinoma (HCC) is one of the current research focuses, with studies reporting controversial results regarding MVI-associated risk factors. As a possible source of bias, reported MVI rate (percentage of MVI-positive patients) varies a lot among studies. Pathological examination should have been the golden criteria of MVI diagnosis, but no standard and generally adopted pathological examination protocol exists. Methods and results: It is highly possible that underestimated pathological diagnosis of MVI exists. We present two likely examples to stress the problem and indicate the root of the problem partially being an unreliable pathological examination. Results of studies basing on unreliable reference standard can be less convincing and even misleading, which is the most basic and fundamental problem in this research field. Conclusion: There is an urgent need to settle the disputes regarding pathological sampling, microscopy, and reporting, in order to promote future academic exchange and consensus development on MVI assessment. Several concerns about pathological MVI assessment should be focused on in the future research as we put up in the review.