Hepatocellular carcinoma (HCC) is the second leading cause of site-specific cancer-related death around the world¹. According to the National Institution of Health Surveillance, Epidemiology, and End Results (SEER) database, age-adjusted HCC incidence tripled between 1975 and 2005, from 1.6 per 100,000 to 4.8 per 100,000 in the United States (US)². In 2012 age-adjusted HCC incidence rates were 6.7/100,000³. In the latest annual report on the status of cancer in the US published in 2020, the cross-sectional incidence (2012–2016) and death (2013–2017) rates of primary liver cancer were increasing⁴, although the rate of increase was slowing⁵. HCC disproportionally affects racial/ethnic minorities in the US: during 2005–2007, the HCC incidence in the Black population was 1.5-fold higher than in the generalpopulation⁶. Hepatitis C virus (HCV) infection is the leading risk factor for liver cancer in the US^7,8 and also effects communities disproportionately: the estimated prevalence of HCV in the general population is 1.67% (95% CI 1.53–1.90)⁹, compared to 2.2% among Black individuals and 1.3% among non-Hispanic White individuals¹⁰.

The 5-year relative survival rate for liver cancer diagnosed between 2009 and 2015 was 18%, with large differences depending on the tumor status at the time of diagnosis; it was 33% for patients with localized tumors versus 3% for patients with extrahepatic metastases¹¹. Many patients are diagnosed with advanced HCC and receive only palliative treatment; however, early stage HCC can be cured surgically. The 5-year survival rate for patients who had surgery for early stage HCC was 50%, underscoring the importance of early detection at a potentially curative stage¹².

Black patients with HCC have the lowest overall survival of any racial/ethnic group^13,14. The reasons for this disparity are incompletely understood but are likely multifactorial and may include socioeconomic factors and differences in access to care^15,16, as well as possible differences in tumor biology. Black individuals are less likely to receive curative treatment than members of other racial groups ¹⁷. Screening for HCC occurs less frequently among Black patients than among other racial/ethnic groups¹⁸, which may increase the chances that diagnosis will be delayed until after HCC has reached an advanced stage, thereby increasing mortality.

In the Western world, up to 90% of HCCs arise in a cirrhotic liver¹⁹. Because cirrhosis is such a strong HCC risk factor, practice guidelines of the American Association for the Study of Liver Disease (AASLD)^20,21, the European Association for the Study of Liver Disease (EASL)²², and the Asian Pacific Association for the Study of Liver Disease (APASL)²³ recommend twice-annual HCC surveillance for patients with cirrhosis. Surveillance is considered to be cost-effective for groups of patients in whom the annual HCC incidence is ≥ 1.5% per year²⁴. Patients with biopsy-diagnosed bridging fibrosis (Metavir F3) are also at elevated risk for developing HCC²⁵. Accordingly, EASL recommends HCC surveillance for patients with bridging fibrosis in addition to patients with definite cirrhosis²². The FIB-4 score is a non-invasive alternative to biopsy: a value of FIB-4 >3.25 correlates with advanced fibrosis and cirrhosis²⁶ and has a positive predictive value of 82% with specificity of 98% for diagnosing cirrhosis²⁷.

Data suggest that Black patients at high risk for developing HCC may be less likely to meet commonly accepted criteria for HCC surveillance than members of other racial/ethnic groups. HCV-associated hepatic fibrosis progresses more²⁸ slowly in Black individuals than White patients. In the Veterans Administration HCV Clinical Case Registry, non-Hispanic Black patients were less likely to have cirrhosis than White or Hispanic patients (HR = 0.58, 95 % CI = 0.55 – 0.60)²⁸. Consistent with this, a small study from our group showed that Black patients have better liver function at diagnosis of HCC than other groups²⁹. Similar findings were published by Jones et al.,³⁰ who analyzed HCC in cirrhotic patients who had a variety of underlying liver diseases. They found that Black patients with HCC had better liver function, but worse tumor characteristics and the shortest survival of any group examined. Because HCC surveillance programs often focus on patients with cirrhosis, any group that tends to develop HCC without first developing cirrhosis may be less likely to receive HCC screening, increasing the likelihood of delayed HCC diagnosis.

To better understand the excess HCC-related mortality in the Black population, we aimed to compare liver function and presence of cirrhosis at the time of HCC diagnosis in Black versus non-Black patients with a history of HCV infection. Secondarily, we aimed to investigate whether HCC in Black patients with a history of HCV is associated with a more aggressive phenotype, as a potential biological contributor to excess mortality.

Approval for this retrospective study was obtained from the Institutional Review Board of the Icahn School of Medicine at Mount Sinai with a waiver of informed consent. All patients with a history of HCV infection who were diagnosed with HCC at the Mount Sinai Hospital from 2003 to August 2018 were included.

This study uncovered two striking features of HCC in Black patients with a history of HCV infection that exposure may contribute to the known higher HCC-related mortality in this demographic group. At the time of HCC diagnosis, liver fibrosis was significantly less advanced in Black patients, and yet their tumors were more advanced in stage and had worse pathologic prognostic features than those of non-Black patients. Black individuals had lower median survival and lower five-year survival, despite having better liver function at the time of HCC diagnosis. Our findings indicate that HCC in Black patients often has characteristics associated with a more aggressive disease course. Features of aggressive HCC include vascular invasion, greater tumor size and poor differentiation^33,34. Black patients in our study presented with larger tumors and a higher prevalence of multiple tumors, gross and microvascular invasion, and poorly differentiated tumors. More aggressive tumor biology is associated with poor outcomes in Black individuals with other types of cancer, including endometrial cancer³⁵, prostate cancer³⁶ and breast cancer; Black women have more aggressive breast cancer, and a higher prevalence of triple-negative tumors³⁷. Because HCC tumors in our Black cohort were larger, more likely to be multifocal, and with vascular invasion, Black patients were less likely to be within Milan criteria, limiting treatment options.

It is unclear to what extent these characteristics reflect a distinctive molecular profile that confers an inherently more aggressive phenotype and to what extent they reflect diagnosis at a more advanced stage of disease, due to delayed diagnosis. Black patients were less likely to have commercial insurance, as found in previous studies²¹, raising the possibility that barriers to accessing healthcare services may have contributed to delays in HCC diagnosis. However, they were also likely to meet screening criteria, and thus they and their providers may have thought that screening was not necessary.

In this study, Black patients developed HCC at earlier stages of liver fibrosis than other racial groups. According to AASLD guidelines, patients with cirrhosis should have life-long twice-annual HCC surveillance^20,21. As previously described, a value of FIB-4 greater than 3.25 correlates with advanced fibrosis and cirrhosis^26.27. Nearly one-third of the Black patients in our cohort had a FIB-4 score less than 3.25. Because of this, their need for HCC surveillance may have been underestimated by the patients and their healthcare providers. Moreover, half of the Black patients did not have any features of cirrhosis on imaging which could have been another trigger for HCC screening by the healthcare provider. Practice guidelines which recommend HCC surveillance for cirrhotic HCV patients may need to be expanded to serve the needs of Black patients.

AFP is a well-established HCC biomarker. A prospective randomized trial of HBV-positive patients conducted in China showed that a surveillance program using AFP and liver ultrasound performed every 6 months resulted in a 37% reduction in HCC mortality. As has been noted previously, Black patients with HCC have lower levels of AFP⁴⁰. Our findings corroborate this finding; one-third of the Black patients had AFP values below 10 ng/mL. Thus, surveillance guidelines that rely on AFP may not be optimal for Black patients and reliance on this test could contribute to delays in HCC diagnosis in the Black population.

The prevalence of co-infection with HIV and previous HBV infections was higher in Black individuals. The effect of HBV exposure on HCC risk in patients with a history of HCV infection has not been resolved^41–44. Kubo et al.⁴⁵ reported that HCC was more likely to develop in non-cirrhotic livers in patients with HCV RNA and anti-HBc antibody than in patients with HCV RNA and no evidence of HBV exposure. Matsuoka et al⁴² demonstrated that HCV-infected patients with anti-HBc antibodies and no other indication of HBV infection had greater fibrosis stage than patients with no HBV exposure. Other studies found no association between prior HBV infection and liver fibrosis stage⁴⁶. In our study, patients with HBV exposure have higher scores for fibrosis stage. Kubo et al.⁴⁵ reported that patients with HCV and anti-HBc antibodies had less well differentiated tumors, but tumors were similar in size. In our study, patients with prior HBV infection had larger tumors and a lower percentage were within Milan criteria. This finding suggests that Black patients with a history of HCV and HBV infection may require especially vigilant HCC surveillance.

In our study, HIV-positive patients had better liver function and more favorable tumor characteristics than HIV-negative patients, which differs from results in studies performed during the early years of antiretroviral therapy⁴⁷. Perhaps our findings of better liver function at HCC diagnosis reflect better screening in HIV-positive patients that occurred because these patients are more engaged with healthcare; unfortunately, the more favorable disease features were much more apparent in non-Black patients than in Black patients.

In a subset analysis of patients with neither HBV nor HIV exposure Black individuals had less advanced liver disease than non-Black individuals at the time of HCC diagnosis, but had their HCCs had worse prognostic features, indicating that the HCC profile identified in this study (i.e., relatively well-preserved liver function and more aggressive tumors) is characteristic of HCC in HCV-infected Black patients and is not due to the higher prevalence of HBV and/or HIV exposure in this group. Future research should investigate the molecular biology of this profile and seek to identify HCC risk factors in non-cirrhotic livers, specifically exploring germline and somatic mutations^46–50, toxic exposures (air pollution, alcohol ⁵¹ and cigarette smoke⁵²) and co-morbidities, such as type II diabetes^53,54.

Our single-site retrospective study has several limitations, including possible selection bias and an inability to establish causality; however, our findings are consistent with those reported previously³⁹. Cirrhosis was identified by FIB-4 scores and imaging data in most cases; however, the available biopsy data supported the conclusion that Black individuals had less advanced fibrosis. Additionally, our survival analysis included patients with coinfection of HIV and HBV and this could be a cofounder of the survival differences.

In conclusion, we describe a novel profile of HCC in Black patients with HCV where in patients present with less fibrosis progression, but with more advanced tumors that have more aggressive pathologic features. This profile was present in the study group as a whole and in the subgroup of Black patients who did not have any prior exposure to HIV or HBV. These findings provide a foundation for designing studies to define the molecular signature(s) of HCC in Black individuals and to identify any mutations/subtype that may guide targeted treatment. Our results also reveal the need to revise current HCC surveillance criteria to include non-cirrhotic Black patients with a history of HCV exposure, thereby ensuring that these guidelines serve the needs of the Black patient population.