Pathology of HCC

Young Nyun Park  Department of Pathology and Institute of Gastroenterology, Center for Chronic Metabolic Disease, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Our research team (Park YN) have studied the multistep process of human hepatocarcinogenesis, focusing on the early stages such as dysplastic nodule (DN) and well differentiated early hepatocellular carcinoma (HCC). The first theme is on the pathological characteristics of early stage hepatocarcinogenesis. We reported that chromosomal instability, telomere shortening, telomerase re-activation, and increased expression of hTERT mRNA occur during the early stage of hepatocarcinogenesis with a significant change in the transition from high grade DN to HCC. Telomere-binding proteins, TRF1, TRF2, and TIN2 are related to telomere shortening. Inactivation of cell cycle checkpoints also occurs in DNs during early stage hepatocarcinogenesis. Before forming nodular lesions, there are numerous dysplastic foci in chronic liver disease including small liver cell change (SCC) and large liver cell change (LCC). We reported that the inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCCs and HCCs, suggesting that SCCs represent precancerous lesions. On the other hand, LCC seems to be a more heterogeneous lesion representing both reactive and precancerous changes. At least a fraction of LCCs, especially those associated with hepatitis B-viral cirrhosis, is suggested to be a precancerous lesion showing inactivation of cell cycle checkpoints and telomere shortening without senescent changes. The second theme is on the development of pathological markers for the diagnosis of well differentiated HCC. The differential diagnosis between DNs and well differentiated HCC constitutes a major task even for experienced pathologists, and recent guidelines for HCC management emphasize the need to identify features of malignancy in small nodules and to biopsy radiologically equivocal 1 to 2 cm-sized hepatocellular lesions. Thus, a distinction between regenerative, dysplastic, and malignant hepatocellular nodules is being increasingly requested by hepatologists on tiny biopsies, further complicating the diagnostic issue. We and prof. Roncalli M have worked on this issue and reported that the application of the following markers is helpful for the differential diagnosis between DNs and well differentiated HCCs. (i) The expression of CD34, detecting sinusoidal capillarization and unpaired arteries, significantly increases during the progression of hepatocarcinogenesis with the highest expression in HCCs. (ii) CK7/CK19 is helpful for detecting stromal invasion. The presence of tumor cell invasion into the intratumoral portal tracts is an important feature for the detection of well differentiated HCC, and the absence of CK7/CK19-positive ductular reactions is a useful marker for characterizing areas of stromal invasion. (iii) The panel application of glypican-3, HSP 70 and glutamine synthetase increases the sensitivity and specificity for the detection of well differentiated HCC, compared to single application of one of these markers. Using a 3-marker panel, when at least 2 of these markers - regardless of which - are positive, the sensitivity and specificity for the detection of well differentiated HCC/early HCC are reported to be 72% and 100%, respectively. The third theme is on cancer stem cell in hepatocarcinogenesis. We found that HCCs with progenitor cell markers have a worse prognosis and are reported as “intermediate carcinoma” expressing progenitor cell markers. We are currently working on the cancer stem cell population in human HCCs.