Hepatocellular Carcinoma: Does the Background Liver With or Without Cirrhosis Matter?

Anisha Jain; Benjamin Mazer, MD; Yanhong Deng; Maria Ciarleglio, PhD; Dhanpat Jain, MD; Tamar Taddei, MD; Xuchen Zhang, MD, PhD


Am J Clin Pathol. 2022;157(2):305-313. 

In This Article

Abstract and Introduction


Objectives: The pathologic differences between hepatocellular carcinoma (HCC) arising in noncirrhotic and cirrhotic livers have not been well studied.

Methods: We performed a retrospective analysis of 378 HCC cases (95 in noncirrhotic, 283 in cirrhotic livers) from pathology archives (2010-2017).

Results: Patients without cirrhosis were more likely to have hepatitis B (13.68% vs 2.83%, P < .001) or no known liver disease (30.53% vs 4.24%, P < .001), while hepatitis C was more common in patients with cirrhosis (65.72% vs 30.53%, P < .001). HCCs in noncirrhotic livers were larger in size (P < .001); were more likely to have a macrotrabecular histologic pattern (13.68% vs 4.95%, P < .01); were more likely to have fibrolamellar (3.16% vs 0%, P = .02), macrotrabecular-massive (13.68% vs 6.01%, P = .03), and clear cell (16.84% vs 6.71%, P < .01) subtypes; have a higher histologic grade (P < .01); be anaplastic tumor cells (P < .001); have a higher rate of vascular invasion (P < .01); and have a higher tumor stage (P = .04).

Conclusions: The findings indicate that HCCs in noncirrhotic livers demonstrate a larger tumor size; have a more macrotrabecular histologic pattern; have fibrolamellar, macrotrabecular-massive, and clear cell subtypes; have a higher tumor grade and stage; have a higher rate of vascular invasion; and have more anaplastic tumor cells compared with cirrhotic livers. Further studies to explore different pathways that promote oncogenesis in noncirrhotic livers are needed to better understand the pathogenesis of HCC.


Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer mortality globally. The incidence of HCC in developed nations continues to rise. Liver cirrhosis is a major risk factor for HCC, and about 80% of HCCs arise in a cirrhotic liver worldwide.[1] In recent years, as the incidence of viral hepatitis has decreased worldwide, HCC has increasingly been found to arise in noncirrhotic livers.[2] It is speculated that this increase in HCC in noncirrhotic livers may be related to the rising epidemic of obesity and nonalcoholic fatty liver disease (NAFLD).[3] While the exact risk factors that underlie risk of HCC in noncirrhotic livers remain poorly understood, NAFLD, exposure to genotoxic substances, viral hepatitis, sex hormones, inherited/metabolic disease, and genetic predisposition/mutations have been speculated to play a role.

The HCCs arising in noncirrhotic livers show several differences from those arising in cirrhotic livers. Tumors in noncirrhotic livers typically present at more advanced tumor stages than HCC in cirrhotic livers, possibly because HCC in noncirrhotic livers is detected relatively later when the tumor becomes symptomatic rather than being detected during surveillance.[4,5] A comprehensive review has identified that HCC arising in the noncirrhotic liver is associated with a poor prognosis.[6] It is also known that certain subtypes of HCC (eg, fibrolamellar carcinoma) are seen more commonly in noncirrhotic livers.[7–11] Even in the category of noncirrhotic livers, the cases can be histologically subdivided into those with some background fibrosis or a known chronic liver disease and those without any underlying fibrosis or liver disorder.[12–14] We speculated that HCCs arising in patients without underlying cirrhosis are likely to be histologically and clinically different compared with those arising in livers with cirrhosis. The goal of the study was to compare the clinicopathologic features of HCCs in noncirrhotic livers with those in cirrhotic livers.