Alva Weir, MD

Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.¹ Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.² HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.

Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.¹ HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.³

Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.⁴ First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.⁵ HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.⁶

There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.^7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.^1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.^10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.

Methods

A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.

The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.¹³ Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.

Data Analysis

Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ² analysis was used to investigate differences in treatment modalities.

Results

We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).

Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).

The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.

However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).

 

Discussion

In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.^{8,10,11,14,15} A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.¹⁶ One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.

This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.^1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.^12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.^17,18

Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).

Limitations

This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.

Conclusions

This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.

Acknowledgments

The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.

Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.¹ Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.² HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.

Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.¹ HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.³

Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.⁴ First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.⁵ HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.⁶

There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.^7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.^1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.^10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.

Methods

A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.

The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.¹³ Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.

Data Analysis

Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ² analysis was used to investigate differences in treatment modalities.

Results

We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).

Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).

The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.

However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).

 

Discussion

In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.^{8,10,11,14,15} A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.¹⁶ One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.

This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.^1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.^12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.^17,18

Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).

Limitations

This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.

Conclusions

This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.

Acknowledgments

The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.

Hepatocellular carcinoma (HCC) is the sixth most common and third most deadly malignancy worldwide, carrying a mean survival rate without treatment of 6 to 20 months depending on stage.¹ Fifty-seven percent of patients with liver cancer are diagnosed with regional or distant metastatic disease that carries 5-year relative survival rates of 10.7% and 3.1%, respectively.² HCC arises most commonly from liver cirrhosis due to chronic hepatocyte injury, which may be mediated by viral hepatitis, alcoholism, and metabolic disease. Other less common causes include autoimmune disease, exposure to environmental hazards, and certain genetic diseases, such as α-1 antitrypsin deficiency and Wilson disease.

Multiple staging systems for HCC exist that incorporate some variation of the following features: size and invasion of the tumor, distant metastases, and liver function. Stage-directed treatments for HCC include ablation, embolization, resection, transplant, and systemic therapy, such as tyrosine kinase inhibitors, immunotherapies, and monoclonal antibodies. In addition to tumor/node/metastasis (TNM) staging, α-fetoprotein (AFP) is a diagnostic marker with prognostic value in HCC with higher levels correlating to higher tumor burden and a worse prognosis. With treatment, the 5-year survival rate for early stage HCC ranges from 60% to 80% but decreases significantly with higher stages.¹ HCC screening in at-risk populations has accounted for > 40% of diagnoses since the practice became widely adopted, and earlier recognition has led to an improvement in survival even when adjusting for lead time bias.³

Systemic therapy for advanced disease continues to improve. Sorafenib remained the standard first-line systemic therapy since it was introduced in 2008.⁴ First-line therapy improved with immunotherapies. The phase 3 IMBrave150 trial comparing atezolizumab plus bevacizumab to sorafenib showed a median overall survival (OS) > 19 months with 7.7% of patients achieving a complete response.⁵ HIMALAYA, another phase 3 trial set for publication later this year, also reported promising results when a priming dose of the CTLA-4 inhibitor tremelimumab followed by durvalumab was compared with sorafenib.⁶

There has been a rise in incidence of HCC in the United States across all races and ethnicities, though Black, Hispanic, and Asian patients remain disproportionately affected. Subsequently, identifying causative biologic, socioeconomic, and cultural factors, as well as implicit bias in health care continues to be a topic of great interest.^7-9 Using Surveillance, Epidemiology, and End Results (SEER) data, a number of large studies have found that Black patients with HCC were more likely to present with an advanced stage, less likely to receive curative intent treatment, and had significantly reduced survival compared with that of White patients.^1,7-9 An analysis of 1117 patients by Rich and colleagues noted a 34% increased risk of death for Black patients with HCC compared with that of White patients, and other studies have shown about a 50% reduction in rate of liver transplantation for Black patients.^10-12 Our study aimed to investigate potential disparities in incidence, etiology, AFP level at diagnosis, and outcomes of HCC in Black and White veterans managed at the Memphis Veterans Affairs Medical Center (VAMC) in Tennessee.

Methods

A single center retrospective chart review was conducted at the Memphis VAMC using the Computerized Patient Record System (CPRS) and the International Statistical Classification of Diseases, Tenth Revision (ICD-10) code C22.0 for HCC. Initial results were manually refined by prespecified criteria. Patients were included if they were diagnosed with HCC and received HCC treatment at the Memphis VAMC. Patients were excluded if HCC was not diagnosed histologically or clinically by imaging characteristics and AFP level, if the patient’s primary treatment was not provided at the Memphis VAMC, if they were lost to follow-up, or if race was not specified as either Black or White.

The following patient variables were examined: age, sex, comorbidities (alcohol or substance use disorder, cirrhosis, HIV), tumor stage, AFP, method of diagnosis, first-line treatments, systemic treatment, surgical options offered, and mortality. Staging was based on the American Joint Committee on Cancer TNM staging for HCC.¹³ Surgical options were recorded as resection or transplant. Patients who were offered treatment but lost to follow-up were excluded from the analysis.

Data Analysis

Our primary endpoint was identifying differences in OS among Memphis VAMC patients with HCC related to race. Kaplan-Meier analysis was used to investigate differences in OS and cumulative hazard ratio (HR) for death. Cox regression multivariate analysis further evaluated discrepancies among investigated patient variables, including age, race, alcohol, tobacco, or illicit drug use, HIV coinfection, and cirrhosis. Treatment factors were further defined by first-line treatment, systemic therapy, surgical resection, and transplant. χ² analysis was used to investigate differences in treatment modalities.

Results

We identified 227 veterans, 95 Black and 132 White, between 2009 and 2021 meeting criteria for primary HCC treated at the Memphis VAMC. This study did not show a significant difference in OS between White and Black veterans (P = .24). Kaplan-Meier assessment showed OS was 1247 days (41 months) for Black veterans compared with 1032 days (34 months) for White veterans (Figure; Table 1).

Additionally, no significant difference was found between veterans for age or stage at diagnosis when stratified by race. The mean age of diagnosis for both groups was 65 years (P = .09). The mean TNM staging was 1.7 for White veterans vs 1.8 for Black veterans (P = .57). There was a significant increase in the AFP level at diagnosis for Black veterans (P = .001) (Table 2).

The most common initial treatment for both groups was transarterial chemoembolization and radiofrequency ablation with 68% of White and 64% of Black veterans receiving this therapy. There was no significant difference between who received systemic therapy.

However, we found significant differences by race for some forms of treatment. In our analysis, significant differences existed between those who did not receive any form of treatment as well as who received surgical resection and transplant. Among Black veterans, 11.6% received no treatment vs 6.1% for White veterans (P = .001). Only 2.1% of Black veterans underwent surgical resection vs 8.3% of White veterans (P = .046). Similarly, 13 (9.8%) White veterans vs 3 (3.2%) Black veterans received orthotopic liver transplantation (P = .052) in our cohort (eAppendix available at doi:10.12788/fp.0304). We found no differences in patient characteristics affecting OS, including alcohol use, tobacco use, illicit drug use, HIV coinfection, or liver cirrhosis (Table 3).

 

Discussion

In this retrospective analysis, Black veterans with HCC did not experience a statistically significant decrease in OS compared with that of White veterans despite some differences in therapy offered. Other studies have found that surgery was less frequently recommended to Black patients across multiple cancer types, and in most cases this carried a negative impact on OS.^{8,10,11,14,15} A number of other studies have demonstrated a greater percentage of Black patients receiving no treatment, although these studies are often based on SEER data, which captures only cancer-directed surgery and no other methods of treatment. Inequities in patient factors like insurance and socioeconomic status as well as willingness to receive certain treatments are often cited as major influences in health care disparities, but systemic and clinician factors like hospital volume, clinician expertise, specialist availability, and implicit racial bias all affect outcomes.¹⁶ One benefit of our study was that CPRS provided a centralized recording of all treatments received. Interestingly, the treatment discrepancy in our study was not attributable to a statistically significant difference in tumor stage at presentation. There should be no misconception that US Department of Veterans Affairs patients are less affected by socioeconomic inequities, though still this suggests clinician and systemic factors were significant drivers behind our findings.

This study did not intend to determine differences in incidence of HCC by race, although many studies have shown an age-adjusted incidence of HCC among Black and Hispanic patients up to twice that of White patients.^1,8-10 Notably, the rate of orthotopic liver transplantation in this study was low regardless of race compared with that of other larger studies of patients with HCC.^12,15 Discrepancies in HCC care among White and Black patients have been suggested to stem from a variety of influences, including access to early diagnosis and treatment of hepatitis C virus, comorbid conditions, as well as complex socioeconomic factors. It also has been shown that oncologists’ implicit racial bias has a negative impact on patients’ perceived quality of communication, their confidence in the recommended treatment, and the understood difficulty of the treatment by the patient and should be considered as a contributor to health disparities.^17,18

Studies evaluating survival in HCC using SEER data generally stratify disease by localized, regional, or distant metastasis. For our study, TNM staging provided a more accurate assessment of the disease and reduced the chances that broader staging definitions could obscure differences in treatment choices. Future studies could be improved by stratifying patients by variables impacting treatment choice, such as Child-Pugh score or Barcelona Clinic Liver Cancer staging. Our study demonstrated a statistically significant difference in AFP level between White and Black veterans. This has been observed in prior studies as well, and while no specific cause has been identified, it suggests differences in tumor biologic features across different races. In addition, we found that an elevated AFP level at the time of diagnosis (defined as > 400) correlates with a worsened OS (HR, 1.36; P = .01).

Limitations

This study has several limitations, notably the number of veterans eligible for analysis at a single institution. A larger cohort would be needed to evaluate for statistically significant differences in outcomes by race. Additionally, our study did not account for therapy that was offered to but not pursued by the patient, and this would be useful to determine whether patient or practitioner factors were the more significant influence on the type of therapy received.

Conclusions

This study demonstrated a statistically significant difference in the rate of resection and liver transplantation between White and Black veterans at a single institution, although no difference in OS was observed. This discrepancy was not explained by differences in tumor staging. Additional, larger studies will be useful in clarifying the biologic, cultural, and socioeconomic drivers in HCC treatment and mortality.

Acknowledgments

The authors thank Lorri Reaves, Memphis Veterans Affairs Medical Center, Department of Hepatology.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

HCC diagnosis was determined using International Classification of Diseases codes (9th revision: 155 and 155.2; 10th revision: CD 22 and 22.9). We also used records of multidisciplinary gastrointestinal malignancy tumor conferences to identify patient who had been diagnosed and treated for HCV infection. We identified patients who were treated with DAA vs IFN as well as patients who had achieved SVR (classified as having negative HCV RNA tests at the end of DAA treatment). We were unable to evaluate Barcelona Clinic Liver Cancer staging since this required documented performance status that was not available in many patient records. We selected cases consistent with both treatment for HCV infection and subsequent development of HCC. Patient data included age; OS time; HIV status HCV genotype; time and status of progression to HCC; type and duration of treatment; and alcohol, tobacco, and drug use. Disease status was measured using the Model for End-Stage Liver Disease (MELD) score (Table 2), Milan criteria (Table 3), and Child-Pugh score (Table 4).

 

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Multivariate Cox regression was used to determine factors with significant survival impact. Advanced age at diagnosis (aged ≥ 65 years) (HR, 0.53; 95% CI, 0.320-0.880; P = .01), SVR status (HR, 0.33; 95% CI, 0.190-0.587; P < .001), achieving SVR after HCC diagnosis (HR, 0.37; 95% CI, 0.20-0.71; P = .002), low MELD score (< 10) (HR, 0.49; 95% CI, 0.30-0.80; P = .004) and low Child-Pugh score (class A) (HR, 0.39; 95% CI, 0.24-0.64; P = .001) have a significant positive impact on OS. Survival was not significantly influenced by race, tobacco, drug use, HIV or cirrhosis status, or HCV treatment type. In addition, higher Child-Pugh class (B or C), higher MELD score (> 10), and younger age at diagnosis (< 65 years) have a negative impact on survival outcome (Table 5).

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

 

A higher MELD score (> 10) and a higher Child-Pugh class (B or C) score are associated with worse survival outcome regardless of SVR status. While patients with a low MELD score (≤ 10) have a better survival rate (HR 0.49), a higher MELD score has a significantly higher HR and therefore worse survival outcomes (HR, 2.20). Similarly, patients with Child-Pugh A (HR, 0.39) have a better survival outcome compared with those patients with Child-Pugh class B or C (HR, 2.57). This finding is consistent with results of multiple studies indicating that advanced liver disease, as measured by a high MELD score and Child-Pugh class score, can be used to predict the survival outcome in patients with HCV-related HCC.^20-22

Unlike other studies that look at a single prognostic variable, our study evaluated prognostic impacts of multiple variables (age, SVR status, the order of SVR in relation to HCC development, HCV treatment type, MELD score and Child-Pugh class) in patients with HCC. The study included patients treated for HCV after development of HCC along with other multiple variables leading to OS benefit. It is one of the only studies in the United States that compared 5-year OS and PFS among patients with HCC treated for HCV and achieved SVR. The studies by Nagaoki and colleagues and Sou and colleagues were conducted in Japan, and some of their subset analyses were univariate. Among our study population of veterans, 50% were African American patients, suggesting that they may have similar OS benefit when compared to White patients with HCC and HCV treatment.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

HCC diagnosis was determined using International Classification of Diseases codes (9th revision: 155 and 155.2; 10th revision: CD 22 and 22.9). We also used records of multidisciplinary gastrointestinal malignancy tumor conferences to identify patient who had been diagnosed and treated for HCV infection. We identified patients who were treated with DAA vs IFN as well as patients who had achieved SVR (classified as having negative HCV RNA tests at the end of DAA treatment). We were unable to evaluate Barcelona Clinic Liver Cancer staging since this required documented performance status that was not available in many patient records. We selected cases consistent with both treatment for HCV infection and subsequent development of HCC. Patient data included age; OS time; HIV status HCV genotype; time and status of progression to HCC; type and duration of treatment; and alcohol, tobacco, and drug use. Disease status was measured using the Model for End-Stage Liver Disease (MELD) score (Table 2), Milan criteria (Table 3), and Child-Pugh score (Table 4).

 

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Multivariate Cox regression was used to determine factors with significant survival impact. Advanced age at diagnosis (aged ≥ 65 years) (HR, 0.53; 95% CI, 0.320-0.880; P = .01), SVR status (HR, 0.33; 95% CI, 0.190-0.587; P < .001), achieving SVR after HCC diagnosis (HR, 0.37; 95% CI, 0.20-0.71; P = .002), low MELD score (< 10) (HR, 0.49; 95% CI, 0.30-0.80; P = .004) and low Child-Pugh score (class A) (HR, 0.39; 95% CI, 0.24-0.64; P = .001) have a significant positive impact on OS. Survival was not significantly influenced by race, tobacco, drug use, HIV or cirrhosis status, or HCV treatment type. In addition, higher Child-Pugh class (B or C), higher MELD score (> 10), and younger age at diagnosis (< 65 years) have a negative impact on survival outcome (Table 5).

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

 

A higher MELD score (> 10) and a higher Child-Pugh class (B or C) score are associated with worse survival outcome regardless of SVR status. While patients with a low MELD score (≤ 10) have a better survival rate (HR 0.49), a higher MELD score has a significantly higher HR and therefore worse survival outcomes (HR, 2.20). Similarly, patients with Child-Pugh A (HR, 0.39) have a better survival outcome compared with those patients with Child-Pugh class B or C (HR, 2.57). This finding is consistent with results of multiple studies indicating that advanced liver disease, as measured by a high MELD score and Child-Pugh class score, can be used to predict the survival outcome in patients with HCV-related HCC.^20-22

Unlike other studies that look at a single prognostic variable, our study evaluated prognostic impacts of multiple variables (age, SVR status, the order of SVR in relation to HCC development, HCV treatment type, MELD score and Child-Pugh class) in patients with HCC. The study included patients treated for HCV after development of HCC along with other multiple variables leading to OS benefit. It is one of the only studies in the United States that compared 5-year OS and PFS among patients with HCC treated for HCV and achieved SVR. The studies by Nagaoki and colleagues and Sou and colleagues were conducted in Japan, and some of their subset analyses were univariate. Among our study population of veterans, 50% were African American patients, suggesting that they may have similar OS benefit when compared to White patients with HCC and HCV treatment.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

HCC diagnosis was determined using International Classification of Diseases codes (9th revision: 155 and 155.2; 10th revision: CD 22 and 22.9). We also used records of multidisciplinary gastrointestinal malignancy tumor conferences to identify patient who had been diagnosed and treated for HCV infection. We identified patients who were treated with DAA vs IFN as well as patients who had achieved SVR (classified as having negative HCV RNA tests at the end of DAA treatment). We were unable to evaluate Barcelona Clinic Liver Cancer staging since this required documented performance status that was not available in many patient records. We selected cases consistent with both treatment for HCV infection and subsequent development of HCC. Patient data included age; OS time; HIV status HCV genotype; time and status of progression to HCC; type and duration of treatment; and alcohol, tobacco, and drug use. Disease status was measured using the Model for End-Stage Liver Disease (MELD) score (Table 2), Milan criteria (Table 3), and Child-Pugh score (Table 4).

 

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Multivariate Cox regression was used to determine factors with significant survival impact. Advanced age at diagnosis (aged ≥ 65 years) (HR, 0.53; 95% CI, 0.320-0.880; P = .01), SVR status (HR, 0.33; 95% CI, 0.190-0.587; P < .001), achieving SVR after HCC diagnosis (HR, 0.37; 95% CI, 0.20-0.71; P = .002), low MELD score (< 10) (HR, 0.49; 95% CI, 0.30-0.80; P = .004) and low Child-Pugh score (class A) (HR, 0.39; 95% CI, 0.24-0.64; P = .001) have a significant positive impact on OS. Survival was not significantly influenced by race, tobacco, drug use, HIV or cirrhosis status, or HCV treatment type. In addition, higher Child-Pugh class (B or C), higher MELD score (> 10), and younger age at diagnosis (< 65 years) have a negative impact on survival outcome (Table 5).

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

 

A higher MELD score (> 10) and a higher Child-Pugh class (B or C) score are associated with worse survival outcome regardless of SVR status. While patients with a low MELD score (≤ 10) have a better survival rate (HR 0.49), a higher MELD score has a significantly higher HR and therefore worse survival outcomes (HR, 2.20). Similarly, patients with Child-Pugh A (HR, 0.39) have a better survival outcome compared with those patients with Child-Pugh class B or C (HR, 2.57). This finding is consistent with results of multiple studies indicating that advanced liver disease, as measured by a high MELD score and Child-Pugh class score, can be used to predict the survival outcome in patients with HCV-related HCC.^20-22

Unlike other studies that look at a single prognostic variable, our study evaluated prognostic impacts of multiple variables (age, SVR status, the order of SVR in relation to HCC development, HCV treatment type, MELD score and Child-Pugh class) in patients with HCC. The study included patients treated for HCV after development of HCC along with other multiple variables leading to OS benefit. It is one of the only studies in the United States that compared 5-year OS and PFS among patients with HCC treated for HCV and achieved SVR. The studies by Nagaoki and colleagues and Sou and colleagues were conducted in Japan, and some of their subset analyses were univariate. Among our study population of veterans, 50% were African American patients, suggesting that they may have similar OS benefit when compared to White patients with HCC and HCV treatment.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

 

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologists 1 and 2 found 27 and 29 patients, respectively, that had HCC that might have been predicted in an earlier scan if LI-RADS had been utilized, while5 patients for radiologist 1 and 7 patients for radiologist 2 were determined to have benign disease that would have been incorrectly identified as likely HCC with LR4 or LR5 (Table 1).

 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Radiologist 3 scored the 12 samples that showed discrepancies. Radiologist 3 increased the false-negative rate as he incorrectly identified 5 malignancies as benign with a score ≤ LR3.   

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

The underscoring on CT often happened due to nonvisualization.²³ In both studies, imaging that was performed on patients at risk for HCC was retrospectively reviewed by multiple radiologists, and the CTs and MRIs occurred within 1 month.^22,23

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

 

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

 

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologists 1 and 2 found 27 and 29 patients, respectively, that had HCC that might have been predicted in an earlier scan if LI-RADS had been utilized, while5 patients for radiologist 1 and 7 patients for radiologist 2 were determined to have benign disease that would have been incorrectly identified as likely HCC with LR4 or LR5 (Table 1).

 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Radiologist 3 scored the 12 samples that showed discrepancies. Radiologist 3 increased the false-negative rate as he incorrectly identified 5 malignancies as benign with a score ≤ LR3.   

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

The underscoring on CT often happened due to nonvisualization.²³ In both studies, imaging that was performed on patients at risk for HCC was retrospectively reviewed by multiple radiologists, and the CTs and MRIs occurred within 1 month.^22,23

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

 

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

 

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologists 1 and 2 found 27 and 29 patients, respectively, that had HCC that might have been predicted in an earlier scan if LI-RADS had been utilized, while5 patients for radiologist 1 and 7 patients for radiologist 2 were determined to have benign disease that would have been incorrectly identified as likely HCC with LR4 or LR5 (Table 1).

 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Radiologist 3 scored the 12 samples that showed discrepancies. Radiologist 3 increased the false-negative rate as he incorrectly identified 5 malignancies as benign with a score ≤ LR3.   

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

The underscoring on CT often happened due to nonvisualization.²³ In both studies, imaging that was performed on patients at risk for HCC was retrospectively reviewed by multiple radiologists, and the CTs and MRIs occurred within 1 month.^22,23

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

 

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.