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Racial disparities in hepatocellular carcinoma, Hepatitis C‐positive Black patients develop hepatocellular carcinoma at earlier stages of liver disease and present with a more aggressive phenotype
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Download the PDF here
Download the PDF here
In February 2021 issue of Cancer is this study & Editorial in full below with pdfs reporting HCC risk higher for blacks with HCV exposure despite less fibrosis & other signs suggesting surveillance criteria be revised to screen all Black patients with HCV exposure regardless of cirrhosis. Jules
Black patients with HCV exposure develop HCC at earlier stages of liver disease than members of other racial groups. Nearly one‐third would not qualify for HCC screening using the common FIB‐4 cirrhosis threshold. Practice guidelines that stress HCC surveillance for cirrhotic patients with HCV may need to be revised to be more inclusive for Black patients. In addition, tumors in Black patients carry worse prognostic features, and molecular studies are needed to characterize their biologic properties.......Shaltiel et al have performed a thorough analysis that identifies a discrete racial disparity in HCC presentation......In light of these observed differences in disease presentation, the authors suggest that we revise the current surveillance criteria for HCC to account for this increased risk. They suggest screening all Black patients with a history of hepatitis C exposure, regardless of cirrhosis. Such a change could reduce disparities suffered by Black patients with HCC, with earlier diagnosis and more treatment options.
To better understand the excess HCC‐related mortality in the Black population, our objective was to compare liver function and the presence of cirrhosis at the time of HCC diagnosis between Black patients and non‐Black patients with a history of HCV infection. Our secondary objective was to investigate whether HCC in Black patients with a history of HCV is associated with a more aggressive phenotype, as a potential biologic contributor to excess mortality.
In conclusion, we describe a novel profile of HCC in Black patients with HCV in which 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 or subtype that may guide targeted treatment. Our results also reveal the need to revise current HCC surveillance criteria to include noncirrhotic Black patients with a history of HCV exposure, thereby ensuring that these guidelines serve the needs of the Black patient population.
This study uncovered 2 striking features of HCC in Black patients with a history of HCV infection, indicating 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 5‐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 cancer,35 prostate cancer,36 and breast cancer; and Black women have more aggressive breast cancer and a higher prevalence of triple‐negative tumors.37 Because HCC tumors in our Black cohort were larger, more likely to be multifocal, and had vascular invasion, Black patients were less likely to be within Milan criteria, limiting treatment options.38
It is unclear the extent to which these characteristics reflect a distinctive molecular profile that confers an inherently more aggressive phenotype and diagnosis at a more advanced stage of disease because of delayed diagnosis. Black patients were less likely to have commercial insurance, as observed in previous studies,21 raising the possibility that barriers to accessing health care services may have contributed to delays in HCC diagnosis. However, they were also likely to meet screening criteria; therefore, Black patients and their providers may have thought that screening was not necessary.
Black patients with HCC have the lowest overall survival of any racial or 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 care15, 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 patients of other racial or ethnic groups,18 which may increase the chances that diagnosis will be delayed until after HCC has reached an advanced stage, thereby increasing mortality.
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 patients than in 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 (hazard ratio, 0.58; 95 % CI, 0.55‐0.60).28 Consistent with this finding, a small study from our group demonstrated that Black patients had better liver function at diagnosis of HCC than other groups.29 Similar findings were published by Jones et al,30 who analyzed HCC in cirrhotic patients who had a variety of underlying liver diseases. Those authors observed 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.
HCC disproportionally affects racial/ethnic minorities in the United States: during 2005 through 2007, the HCC incidence in the Black population was 1.5‐fold higher than that in the general population.6 Hepatitis C virus (HCV) infection is the leading risk factor for liver cancer in the United States7, 8 and also affects communities disproportionately: the estimated prevalence of HCV in the general population is 1.67% (95% CI, 1.53%‐1.90%),9 compared with 2.2% among Black individuals and 1.3% among non‐Hispanic White individuals.10
The prevalence of coinfection 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.40-43 Kubo et al44 reported that HCC was more likely to develop in noncirrhotic livers among patients with HCV RNA and anti‐HBcAb than in patients with HCV RNA and no evidence of HBV exposure. Matsuoka et al41 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 stage.45 In our study, patients with HBV exposure had higher scores for fibrosis stage. Kubo et al44 reported that patients with HCV and anti‐HBc antibodies had less well differentiated tumors, but the tumors were similar in size. In our study, patients with prior HBV infection had larger tumors, and lower percentages were within Milan criteria. This finding suggests that Black patients with a history of HCV and HBV infection may require especially vigilant HCC surveillance.
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Editorial
Racial disparities in hepatocellular carcinoma
Cancer Feb 25 2021 - Richard S. Hoehn, MD
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Abstract
Racial inequities exist in the presentation, management, and survival of patients with hepatocellular carcinoma. Biologic factors may play a role, but complex social issues are likely to blame for these and other cancer disparities.
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide and represents a growing number of cancer deaths in the United States.1 Similar to other malignancies, disparities in management and survival exist for patients with HCC based on race and other socioeconomic characteristics. The incidence of HCC is higher for Black patients.2 After diagnosis, Black patients are less likely to receive surgery, wait longer for surgery, and have worse overall survival.3 Patients with low income who are underinsured or uninsured face similar disadvantages.
Some of these disparities are provider‐based. Patients with HCC who are treated at safety‐net hospitals are less likely to undergo surgery, and those who do receive fewer liver transplantations or resections and undergo more ablation procedures.4 Surgery is also less common at community versus academic cancer centers.4 However, hospital variation does not fully explain the observed survival inequities.
In this issue of Cancer, Shaltiel and colleagues deliver a thoughtful investigation of racial differences in HCC presentation.5 By using a modern series of patients from a high‐volume academic institution, the authors compared Black and non‐Black patients who had a history of hepatitis C and were diagnosed with HCC. Black patients had better liver function, lower α‐fetoprotein levels, and less fibrosis/cirrhosis according to several measures. Despite this advantage, they presented with more advanced HCC. Black patients were less likely to meet the Milan criteria and more likely to have bilateral, multifocal, poorly differentiated, and metastatic tumors.
Noting the increased rates of hepatitis B and human immunodeficiency virus (HIV) exposure and infection among Black patients, the authors performed subset analyses of HCC presentation for Black and non‐Black patients with and without these concurrent conditions. Regardless of hepatitis B and HIV status, Black patients still had less advanced liver disease but more advanced tumor characteristics.
Countless studies have correlated advanced cancer presentation with minority race, lack of health insurance, or low socioeconomic status. A common explanation for these findings is the barriers to health care experienced by vulnerable populations. Patients with limited resources are less likely to participate in cancer screening or even to present when they develop concerning symptoms. Other hypotheses include differences in diet, lifestyle, cultural factors, and medical comorbidities.6
Racial differences in tumor biology are often suggested but poorly understood. Triple‐negative breast cancer, which has fewer treatments and a worse prognosis than other tumors, is more common among Black women.7 Prostate cancers in Black men have increased inflammation and unique genetic mutations that correlate with inferior survival.8 The interesting and novel aspect of the current study is that advanced HCC presentation among Black patients was independent of known and measurable risk factors, such as fibrosis, cirrhosis, and coinfection with hepatitis B, hepatitis C, or HIV.
In light of these observed differences in disease presentation, the authors suggest that we revise the current surveillance criteria for HCC to account for this increased risk. They suggest screening all Black patients with a history of hepatitis C exposure, regardless of cirrhosis. Such a change could reduce disparities suffered by Black patients with HCC, with earlier diagnosis and more treatment options.
Still, we must dig deeper to understand the causes of these disparities. There is a growing body of evidence suggesting that unique genetic mutations increase cancer risk among patients of African ancestry.9 With regard to HCC, there appears to be a strong connection to epigenetic factors as well.10 Variations in cytochrome p450, glutathione‐S transferases, and other enzymes influence the ability to detoxify known hepatic carcinogens, many of which are chemical or industrial agents.11
Dietary and lifestyle factors also play a role. Diabetes, obesity, and hepatic steatosis are all correlated with an increased risk of HCC.12 Combined with hepatitis C, alcohol and tobacco use have a synergistic effect increasing HCC risk.13, 14Variation in N‐acetyltransferase 2 activity has been demonstrated among patients of certain African ancestries compared with European and Asian populations,15 and such polymorphisms are associated with differing HCC risks because of diet.16
Of course, race is more than genetics. It has been suggested that the drivers of racial disparities are more social than biologic.17 Indeed, racial inequity in exposure to the aforementioned HCC risk factors is well documented and has stemmed from years of racist laws and policies.
A combination of federal and local housing policies, combined with discriminatory lending and other racist practices in the private sector, have created a pattern of residential segregation and wealth inequality across the United States.18 Many Black communities were saddled with low property values and loose zoning policies that attracted industrial activity and subsequent pollution. This disproportionate exposure to hazardous waste, aromatic chemicals, lead poisoning, and other toxins contributes to worse health outcomes among Black patients.19
Residential segregation has also left many urban communities without access to healthy and affordable nutrition. Black families are twice as likely as white families to live in a food desert.20 and dietary risk factors for HCC are more prevalent in these malnourished communities. Government programs that reduce inequities in housing, pollution, and nutrition could improve outcomes for HCC and numerous other conditions.
Researchers investigating racial disparities in health care must no longer accept biologic differences as an explanation. This common conclusion is inaccurate and apathetic. When significant disparities exist, there is a reason. It is also increasingly important to take a translational approach to clinical and health services research. Shaltiel et al have performed a thorough analysis that identifies a discrete racial disparity in HCC presentation.5 Armed with this understanding, they suggest a targeted policy adjustment to improve outcomes. More studies should follow this example. We must start creating solutions rather than simply identifying problems.
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Hepatitis C‐positive Black patients develop hepatocellular carcinoma at earlier stages of liver disease and present with a more aggressive phenotype
Cancer Feb 25 2021 - Tali Shaltiel, MD 1; Serena Zheng, BA2; Cleo Siderides, BA2; Elizabeth M. Gleeson, MD1; Jacquelyn Carr, MD1; Eric R. Pletcher, MD1; Noah A. Cohen, MD1; Benjamin J. Golas, MD1; Deepa R. Magge, MD1; Daniel M. Labow, MD1; Andrea D. Branch, PhD3; and Umut Sarpel, MD1
Abstract
Background
In the United States, mortality after a diagnosis of hepatocellular carcinoma (HCC) is higher in patients who are Black than in patients of other racial groups. The objective of this study was to clarify factors contributing to this disparity by analyzing liver and tumor characteristics in patients with HCC who have a history of hepatitis C virus (HCV) infection.
Methods
Records of patients with HCV and HCC at the authors' institution from 2003 to 2018 were retrospectively reviewed. Race and ethnicity were self‐identified. Imaging, laboratory, and pathologic features were compared between Black and non‐Black cohorts.
Results
Among 1195 individuals with HCC, 390 identified as Black. At the time of HCC diagnosis, Black patients had better liver function, as measured by Child‐Pugh score, Model of End‐Stage Liver Disease score, histology of nontumor tissue, and fibrosis‐4 (FIB‐4) score (all P < .05). FIB‐4 scores were <3.25 in 31% of Black patients. In addition, Black patients had less early stage HCC (20.2% vs 32.3%; P < .05), larger tumors (median [interquartile range]: 3.5 cm [2.2‐6.2 cm] vs 3.1 cm [2.1‐5.1 cm]; P < .01), more multiple tumors (median, [interquartile range]: 1 tumor [1‐3 tumors] vs 1 tumor [1‐2 tumors]; P = .03), more poorly differentiated tumors (30.3% vs 20.5%; P < .05), and more microvascular invasion (67.2% vs 56.5%; P < .05).
Conclusions
Black patients with HCV exposure develop HCC at earlier stages of liver disease than members of other racial groups. Nearly one‐third would not qualify for HCC screening using the common FIB‐4 cirrhosis threshold. Practice guidelines that stress HCC surveillance for cirrhotic patients with HCV may need to be revised to be more inclusive for Black patients. In addition, tumors in Black patients carry worse prognostic features, and molecular studies are needed to characterize their biologic properties.
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