Conceptual Model for the Hepatocellular Carcinoma Screening Continuum: Current Status and Research Agenda

Abstract

Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide.¹ HCC incidence has historically been highest in Asian countries due to endemic chronic hepatitis B virus (HBV) infection; however, HCC incidence has been increasing in many Western countries, including the United States, due to an aging hepatitis C virus (HCV)–infected cohort and the emergence of metabolic-associated fatty liver disease (MAFLD) as the most common cause of chronic liver disease.² Over 90% of HCC cases arise in the setting of cirrhosis, and HCC is one of the leading causes of death in this population.³ Over the past 40 years, the 5-year survival for HCC has minimally improved and remains below 20% globally. The poor prognosis of HCC has been attributed to failures along the HCC screening continuum including underrecognition of at-risk individuals, underuse of HCC screening, and suboptimal screening test performance resulting in a high proportion of patients being diagnosed at advanced stages, delays in diagnosis and treatment delivery, and underuse of curative therapies in clinical practice.⁴ Better understanding these process failures, and how they compare with those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality.

Conceptual Model For HCC Screening Continuum

We adapted a trans–organ cancer screening conceptual model⁵ to illustrate the required steps and successful interfaces required for effective implementation of the HCC screening process in practice (Figure 1). The HCC screening process includes several discrete steps including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. While all patients should undergo risk assessment, subsequent steps are applicable to a subset of patients (eg, screening initiation only in patients with sufficient risk and diagnostic evaluation only in those with abnormal screening results). Some steps in the screening process are conducted by a single provider; however, most require interfaces (ie, communication and shared responsibility with other providers such as between hepatology and radiology). Each step and interface in the screening continuum are prone to delays or failure, resulting in worse outcomes, such as late-stage diagnosis or poor survival.

Figure 1.

Conceptual model for hepatocellular carcinoma screening continuum.

Risk assessment is the first step in the screening process, in which providers must determine a person’s risk of HCC and their potential for benefit from screening. Decision analyses demonstrate screening is cost effective if annual HCC risk exceeds 0.2% in patients without cirrhosis and approximately 0.4% for those with cirrhosis.^6–8 Therefore, professional societies, including the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver, recommend screening in subgroups of patients with chronic hepatitis B (eg, Asian men >40 years of age and women >50 years of age, Africans at younger age, or those with family history of HCC) and those with cirrhosis from any etiology.^7,8 Although risk models may further stratify these patients into higher-risk vs lower-risk groups, they have not been sufficiently validated for routine use in clinical practice, and a risk-stratified approach is not currently recommended.^9,10 In addition to determining if a patient has sufficient risk, providers must determine if they have significant comorbid conditions that would preclude HCC screening from being of benefit.

HCC screening should be initiated in patients of sufficient risk and who are likely to benefit from early HCC detection. HCC screening is typically performed in clinic when patients are seen by primary care providers or gastroenterologists/hepatologists, although there may be some cases in which this is prompted by patient request. While studies have suggested a benefit of in-reach (eg, electronic medical record reminders) and outreach (eg, mailed invitations) strategies, most health systems have not adopted either strategy in routine practice.^11–14 HCC screening is typically performed using semi-annual abdominal ultrasound with or without, α-fetoprotein (AFP).^8,15 Some providers use contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) for HCC screening in practice, although concerns about cost, patient acceptability, access for large populations, and potential harms have precluded these tests from being incorporated into professional society guidelines.

Follow-up evaluation is dictated by results of screening tests. If ultrasound and AFP are both normal, patients should repeat screening in 6 months. Patients with an abnormal screening result (solid lesion ≥1 cm on ultrasound, AFP ≥20 ng/mL, or rising AFP) should undergo diagnostic evaluation with multiphase CT or dynamic contrast-enhanced MRI.⁸ Patients with indeterminate results (solid lesion <1 cm on ultrasound) are recommended to undergo short-interval screening in 3 months, given low risk of HCC in lesions of this size and poor accuracy of cross-sectional imaging to characterize subcentimeter lesions. Patients who undergo CT- or MRI-based HCC screening bypass this step as these modalities serve as both screening and diagnostic tests.

Diagnostic evaluation for HCC differs from most cancers, in that a diagnosis can often be made by radiologic imaging (multiphase CT or dynamic contrast-enhanced MRI), without a need for histologic confirmation. A standardized reporting nomenclature, Liver Imaging Reporting and Data System, classifies liver lesions into 5 main categories ranging from definite benign (LR-1) to definitive HCC (LR-5) based on criteria including size, arterial phase hyperenhancement, delayed phase washout, and enhancing capsule.¹⁶ A systematic review found the sensitivity of LR-3, LR-4, and LR-5 for HCC are 38%, 74%, and 94%, respectively.¹⁷ Patients with indeterminate results on diagnostic evaluation can undergo repeat cross-sectional imaging in 3–6 months or biopsy.⁸ The decision to perform repeat cross-sectional imaging vs biopsy is based on several factors, including level of suspicion for malignancy (eg, LR-3 vs LR-4), impact on treatment decisions (eg, exception points for liver transplantation), and patient preference. Patients with an incidental liver lesion on cross-sectional imaging performed for other reasons or symptoms suspicious for HCC may bypass prior steps in the screening continuum and enter at follow-up or diagnostic evaluation.

Treatment evaluation is indicated for patients with definitive HCC. There is a wide range of treatment options depending on tumor burden and degree of liver dysfunction, each delivered by different subspecialists: surgical resection (hepatobiliary or transplant surgeons), liver transplantation (transplant hepatologists and surgeons), locoregional therapy (interventional radiology or radiation oncology), and systemic therapy (medical oncology).⁸ Assessment and management of liver dysfunction is required regardless of tumor stage, necessitating continued involvement of the hepatologist.

While most evident in the setting of HCC treatment, multidisciplinary care is needed across the HCC screening spectrum. Risk assessment and screening initiation is completed by primary care providers or gastroenterologists and hepatologists, although most patients with cirrhosis in the United States are followed by the former.¹⁸ Further, patients are transferred to specialty teams at various points along the screening process. For example, HCC screening and diagnosis are image based, requiring appointments and communication with radiology.

Finally, the conceptual model highlights that factors at the patient, provider, and health care system levels can contribute to failures across the cancer screening process. For example, patient or provider attitudes and knowledge may impact likelihood of provider recommendation or patient adherence to HCC screening, diagnostic evaluation, or treatment.^19–21 Taplin et al²² presented a conceptual model illustrating multilevel factors that influence cancer care delivery. This model can serve as a framework to guide understanding of factors that may serve as barriers or facilitators of HCC screening (Figure 2). Although most studies focus on factors at the patient level (eg, risk factors, attitudes) or provider level (eg, knowledge, attitudes), the influence of social-level (eg, caregiver support), organization-level (eg, decision support systems), community-level (eg, neighborhood socioeconomic status), and policy-level (eg, guidelines and reimbursement) factors must also be considered when evaluating cancer care delivery and developing interventions to improve cancer-related outcomes.²³

Figure 2.

Multilevel factors affecting the hepatocellular carcinoma screening process. GI, gastrointestinal.

HCC Screening Processes Failures And Lessons From Other Cancer Screening Programs

Failures have been described at each step in the HCC screening continuum, which contribute to poor long-term survival. Comparing cancer screening processes for HCC with those employed with well-established processes in other cancers, such as breast cancer and colorectal cancer (CRC), can identify opportunities for improvement and inform intervention strategies. Similar to HCC in at-risk patients, breast cancer and CRC are common, have known asymptomatic stages that can be identified with screening tests, and can be more effectively treated in early stages than when presenting symptomatically. Comparisons across cancer types can help understand the reasons behind differences in screening process completion. For example, breast and CRC screening is performed in over 70% of eligible persons whereas regular HCC screening occurs in only 20%–30% of at-risk patients.¹¹ We use our conceptual framework to discuss some reasons subsequently.

Risk Assessment

Differential rates of screening for breast cancer, CRC, and HCC are at least in part related to the differences in the complexity of risk assessment.

Risk assessment for breast cancer and CRC is relatively simple, with high-risk groups defined using patient age and sex. Specifically, the U.S. Preventive Services Task Force recommends breast cancer screening for all women 50–74 years of age and CRC screening for both genders 45–75 years of age.^24,25 Although most clinicians would remember to discuss screening with patients older than 45–50 years of age, this can also be easily reinforced by electronic health record (EHR) reminders that are easy to implement given age and sex are both discrete, readily available data fields in the EHR. Additionally, stopping rules for breast cancer and CRC screening have been proposed to prevent overscreening, and there are recommended upper limits of age beyond which routine screening is no longer recommended.^24,25

In contrast, risk assessment for HCC screening requires a tiered and more nuanced approach, including purposeful and repeated assessment of underlying liver disease and disease severity to allow timely recognition of cirrhosis diagnosis. Furthermore, compensated cirrhosis is often associated with no or subtle signs or symptoms and can be easily overlooked in clinical practice. Accordingly, prior studies suggest 25%–50% of patients with HCC present with previously unrecognized cirrhosis.^26,27 Therefore, improvement in cirrhosis recognition is the first step to promote cirrhosis-related preventive care including HCC screening. It is plausible that noninvasive laboratory-based algorithms can help identify patients with advanced fibrosis or cirrhosis; however, the performance characteristics of these measures may be less accurate in patients with MAFLD than in those with viral hepatitis.²⁸ Additionally, these measures have yet to be widely assessed for population-based screening. Potential future interventions for risk assessment could include novel laboratory-based algorithms for chronic liver disease and advanced fibrosis detection, particularly among high-risk populations (eg, diabetes, obesity), and alerts nested within the EHR to flag those identified as having cirrhosis.

While suboptimal completion of screening for HCC is of primary concern, there is also the potential for over-use of screening in some patient populations. For example, screening is not recommended for patients with Child-Pugh C cirrhosis who are not transplant candidates because of a significant competing risk of cirrhosis-related mortality²⁹; however, other stopping rules based on patient age and comorbidities have not been established. Studies are needed to define age and co-morbidity thresholds at which HCC screening is no longer cost-effective.

Increasingly, there are patients who present with HCC that are not included in the recommended screening populations, most notably patients with noncirrhotic MAFLD.³⁰ Although the incidence of HCC in noncirrhotic MAFLD is low, the prevalence of MAFLD in the general population is high; thus, the burden of noncirrhotic MAFLD-related HCC will continue to increase.³¹ Similarly, HCC risk and screening recommendations in other groups, such as HCV-infected patients with F3 fibrosis, are controversial. Screening has not been deemed cost-effective in these low-risk groups at this time,³² and current efforts should focus on increasing screening among established at-risk populations such as those with cirrhosis; however, improved risk stratification using demographic and clinical data such as measures of portal hypertension or more than 1 liver disease etiology (eg, nonalcoholic steatohepatitis and HCV) may identify certain subgroups who could benefit from routine screening.

Cancer Screening

Evidence-based guidelines endorse screening for breast cancer, CRC, and HCC; however, the levels of evidence demonstrating decreased disease-specific mortality differs across the 3 cancer types.

For breast cancer screening, large randomized control trials have demonstrated a 20%–35% risk reduction in breast cancer mortality with screening; others have shown a significant reduction in CRC incidence and disease-specific mortality with CRC screening.^33,34

In contrast, the effectiveness of HCC screening remains a subject of debate given the lack of level I evidence. Cohort studies showing an association between HCC screening and mortality reduction have known limitations including lead time bias, length time bias, and risk of residual confounding.³⁵ Given the lack of high-quality evidence, the U.S. Preventive Services Task Force does not recommend HCC screening, potentially contributing to underuse of HCC screening in practice. Professional society guidelines such as AASLD recommend HCC screening, and HCC screening measure is part of the AASLD cirrhosis quality metrics. However, in the absence of widely acceptable benchmarks and methods of attribution, it may be premature to tie performance on this metric with physician reimbursement. Efficacy data from high-quality studies are needed to strengthen the evidence supporting use of HCC screening.

Test effectiveness is a key driver of screening efficacy for early detection and mortality reduction.³⁶ In breast cancer screening, mammography has a sensitivity of over 80% and specificity of 98%, although accuracy is lower in women with dense breasts.³⁷

Currently available HCC screening tests, abdominal ultrasound and AFP, have lower accuracy for early detection than do tests used for breast cancer and CRC screening. Even when implemented, abdominal ultrasound and AFP have limited sensitivity (63%) for early HCC detection and some concerns about inadequate specificity (84%) that can lead to screening-related harms.^15,38,39 Ultrasound sensitivity can also vary significantly based on the experience of the ultrasonographer and patient-related factors, such as obesity or presence of abdominal ascites.⁴⁰ Multiphasic cross-sectional imaging (ie, CT or MRI) has improved sensitivity for early HCC detection compared with ultrasound; however, routine screening using these imaging methods has not been shown to be cost-effective, and this strategy may be plagued by low utilization if required on a semi-annual basis.⁴¹ Concerns about capacity and patient tolerance, as seen with colonoscopy-based CRC screening, may also apply to MRI-based screening if applied in larger populations.

We believe the promise of HCC screening in reducing HCC-related mortality cannot be fulfilled with currently available tests. An accurate blood-based screening test could improve on both utilization of screening and performance characteristics. Similar to work evaluating biomarkers in colon cancer, such as SEPTIN-9 and stool-based DNA, there is enthusiasm for potential of biomarkers to improve effectiveness of HCC screening.⁴³ There are several candidate biomarker panels for early HCC detection, although they still require phase III and IV validation in large cohort studies prior to routine use.⁴²

All 3 cancer screening programs require repeated application of screening tests (eg, every other year for mammography, annual for fecal immunohistochemical test [FIT], and semi-annual for ultrasound for HCC). These intervals are based on expected tumor doubling times for each cancer, with HCC typically having shorter tumor doubling times than breast cancer and CRC. The few available data show a steady decline in adherence to screening over subsequent rounds of screening in breast cancer and CRC.⁴³ For example, adherence to initial fecal occult blood test was 57% in the UK National Health Service Bowel Cancer Screening Program, but only 44% completed all 3 screening rounds. One study of adherence to stool testing within an integrated U.S. health system, Kaiser Permanente, showed that the initial adherence to FIT was 47%, but only 24% adhered to annual testing over 4 rounds.

HCC screening suffers from worse adherence when compared with breast cancer and CRC. Some patients at risk for HCC undergo intermittent screening; however, only a small minority undergo consistent semi-annual screening over extended periods of time. A meta-analysis demonstrated screening receipt among patients with cirrhosis remains disappointingly low at ~24%, albeit higher in the subset of patients followed by gastroenterology or hepatology subspecialty providers.^11,45 Up to half of patients undergoing HCC screening express barriers to screening including difficulty with scheduling, costs of testing, and difficulty with transportation.¹⁹ These barriers are partly related to the dependence on imaging-based screening, which often requires a separate appointment in a separate location than the related clinic visit. Health care providers also endorse several barriers to HCC screening, including lack of knowledge about professional society recommendations and competing clinical concerns with limited time in clinic.²¹ While patient-level barriers appear more specific to imaging-based screening, provider-level barriers would need to be addressed for imaging and biomarker-based screening strategies. Several multifaceted interventions such as patient and provider education, best practice advisories for providers, and mailed outreach for patients have been shown to increase screening adherence in other cancers and have now been evaluated in single-center trials for HCC screening; however, the effectiveness and sustainability of such approaches in large, diverse patient populations have yet to be evaluated.¹¹

Mammogram reporting is standardized (Breast Imaging Reporting and Database System), which includes reporting on the presence or absence of dense breasts and if this impacts quality. There have also been innovations to address this limitation, including digital breast tomosynthesis (3-dimensional mammography) and breast ultrasound. For CRC screening, sensitivity and specificity of screening tests vary based on the modality used—colonoscopy, FIT, or stool DNA–based test—although the sensitivity for each exceeds 70%, with a specificity of at least 90%.⁴⁴ Colonoscopy is used as a diagnostic test to follow up on abnormal screening test using stool samples, but it is also used as a primary screening modality, given a higher sensitivity for advanced neoplasia than FIT and stool-based DNA testing as well as added benefit of removing precancerous neoplasia.

Similarly, the recent adoption of ultrasound Liver Imaging Reporting and Data System for HCC screening provides a visualization score, although there are few studies evaluating the impact of poor visualization on ultrasound performance and if these patients may benefit from alternative screening modalities. Patients with poor visualization may benefit from using contrast-enhanced MRI or CT imaging instead of ultrasound; however, few data support this practice.

Follow-Up and Diagnosis

Studies show shortfalls in timely follow-up after an abnormal screening test for CRC; these gaps are less evident for breast cancer. For example, in a large population-based cohort enrolled at 7 research centers comprising the National Cancer Institute–sponsored PROSPR (Population-based Research Optimizing Screening through Personalized Regimens) consortium, the percentage with timely follow-up after an abnormal screen was 93.2%–96.7% for breast cancer but dropped to 46.8%–68.7% for colorectal cancer.⁴⁶ These shortfalls are not clinically inconsequential. A large-scale analysis of patients with positive FIT tests found that a delay in the receipt of follow-up colonoscopy was associated with higher rates of CRC diagnosis as well as with more advanced stage CRC than when colonoscopy was completed without delay (ie, within 8–30 days of the FIT).⁴⁷ This and other studies provided the basis for using time to colonoscopy following a positive FIT as one of the quality metrics focused on improving the effectiveness of overall screening process. The delays in follow-up testing for CRC screening underscore the complexity of coordinating the next steps in clinical care following an abnormal screening test for CRC and how they may impact the success of overall screening process. For example, higher follow-up for breast abnormalities may be because follow-up for breast cancer screening abnormalities are often disclosed the same day and entails additional imaging, which may be completed in the same setting on the same day. In contrast, the lower follow-up rates for CRC screening abnormalities may be due to inconvenience and invasive nature of colonoscopy, including the need for bowel preparation. Patients undergoing colonoscopy typically need to take time off work for themselves and their driver, which may pose a barrier especially for lower-income individuals. Patients with a positive FIT must transition from the primary care setting to gastrointestinal specialty care with a transfer of role and responsibility between primary care and specialist.

Similar to CRC screening, follow-up for HCC screening abnormalities is complex, necessitating cross-sectional imaging (sometimes more than 1) and evaluations by several physicians, often from different specialties—introducing numerous opportunities for missed care. The interface between radiology and clinic provider and communication of results is particularly prone to failure if imaging is not performed within the same health system. Given these similarities, interventions such as internal alert structures or EHR natural language processing systems developed for CRC screening follow-up may serve as the basis for similar clinical decision support tools for mitigating the risk of diagnostic delays in HCC.⁴⁸ There have not been any large-scale studies to define a metric for time to diagnostic evaluation in HCC screening; however, diagnostic evaluation should likely occur within 3–4 months to reduce risk of interval tumor growth based on a tumor doubling time of approximately 4–6 months.^49,50 Accordingly, the literature evaluating diagnostic delays is sparse, with 1 study from a safety-net health system suggesting diagnostic delays in up to one-third of patients; however, it is unclear if this is generalizable to other health care systems.⁵¹

Indeterminate nodules on cross-sectional imaging (LR-3 and LR4) is an area that commonly leads to diagnostic uncertainty, as it is unclear which nodules will progress to HCC during follow-up. Optimal diagnostic algorithms have yet to be defined, and follow-up testing for these lesions appears to be a common source of screening-related harms. Risk stratification of indeterminate lesions may potentially be achieved through use of blood-based biomarkers or automated imaging analysis (ie, radiomics), although further research is needed in this area.

Treatment Evaluation

Success of screening programs is contingent upon access to curative treatments for early-stage disease. Current treatment for breast cancer and CRC in the U.S. involves a combination of therapies—most patients with screen-detected early cancer undergo curative surgery, with excellent short- and long-term outcomes.

Several treatment options exist for treating patients with early-stage HCC, including liver resection, radio-frequency ablation, and liver transplantation. However, treatment decisions for HCC are typically more complex than for many other cancers, with staging systems and treatment decisions needing to account for the degree of liver dysfunction in addition to tumor burden. Accordingly, fewer than 50% of screen-detected early HCC cases receive curative treatments. For example, in a systematic review of 14 studies, only a small proportion of patients had hepatic resection (range, 2.8%–23.9%) or liver transplantation (range, 1%–15% in 5 studies; 23% and 30% in 2 other studies), likely because of underlying liver dysfunction or limited access to curative treatments.⁵² Even among those who undergo HCC treatment, a single-center study suggested that time to therapy may exceed 3 months in up to 30% of patients with HCC; however, generalizability of these results is unclear.⁵³

Improvement in care navigation and treatment algorithms are necessary to address deficiencies in this aspect of the HCC screening continuum. The complexity of cancer treatment decisions has motivated the development of multidisciplinary tumor boards and clinics to promote increased communication between providers. Multidisciplinary tumor boards have been used for years in other cancers, including breast cancer, and are now increasingly being applied in HCC. Several studies have highlighted the importance of multidisciplinary care in HCC management given associations with increased curative treatment receipt and improved overall survival.^54,55 In an analysis of data from the Veterans Health Administration, only 34% of patients with HCC were presented at multidisciplinary tumor board; presentation at tumor board was associated with reduced mortality (hazard ratio, 0.83; 95% confidence interval, 0.77–0.90).⁵⁵ This is likely mediated by increased guideline-concordant treatment decisions, suggesting that multidisciplinary tumor board review should be standard of care for all patients with HCC.

Role of Community Awareness, Public Reporting, and Research Consortia

We discussed the roles that patient, provider, and health care system factors play at each of the steps in the previous screening process. As posited in our conceptual model, factors at the community and public health levels also play a significant role in improving the effectiveness of cancer screening programs. There are major deficits in public awareness about the need for HCC screening; this is in stark contrast to widespread public awareness about breast cancer and CRC screening. Over the years, notable public figures endorsed breast cancer or CRC screening or shared their experiences with these cancers. This has not been the case for HCC screening. Many individuals who develop HCC are from marginalized or stigmatized populations, and this demographic likely explains why there have not been any public campaigns on the risk and importance of screening for HCC, contributing to general lack of knowledge about screening.

Health system and provider quality assessment and reporting based on receipt of appropriate treatment, and patient outcomes could also be effective methods to improve receipt of appropriate therapy. While performance of screening in at-risk populations has been the most commonly proposed quality metric in patients undergoing HCC surveillance, breast cancer and CRC screening have comprehensive established quality metrics. The Mammography Quality Standards Guidelines Act, first passed in 1992, has established quality metrics for mammogram including receipt of testing, minimum standards for equipment and staff, timely communication of results, reporting on the follow-up of abnormal mammography results, and evaluation of the correlation between radiographic and pathologic findings.⁵⁶ In CRC screening, receipt of testing, adenoma detection rate, and adequate follow-up testing intervals are established metrics for endoscopic examination quality. Notably, national accreditation and professional groups use quality benchmarks for both breast cancer and CRC to assure consistency of care (Table 1).

Table 1.

Examples of Quality Metrics for Breast Cancer, Colorectal Cancer, and Hepatocellular Cancer Screening

Metric	Source
Percentage of women age 51–74 y who had a mammogram to screen for breast cancer	CMS MIPS
Benchmark of 60 d or less from screening to diagnosis of breast lesiona	BCCEDP
Percentage of patients age 50–75 y who had appropriate screening for colorectal cancer	CMS MIPS
Percentage of patients age 50–75 y who received a screening colonoscopy without biopsy or polypectomy who had a recommended follow-up interval of at least 10 years for repeat colonoscopy documented in their colonoscopy report	CMS MIPS
Adenoma detection rate	CMS MIPS
Benchmark 60-d target for completion of diagnostic colonoscopy from the date of the positive fecal test result*	Veterans’ Health Administration
Patients with cirrhosis should undergo HCC screening using abdominal imaging with or without serum α-fetoprotein every 6 mo.	AASLD

AASLD, American Association for the Study of Liver Diseases; BCCEDP, Breast and Cervical Cancer Early Detection Program; CMS, Centers for Medicare and Medicaid; HCC, hepatocellular carcinoma; MIPS, Merit-Based Incentive Payments System.

^aThere was limited evidence for a specific optimal time to diagnostic testing after a positive screening test.

Recently, the AASLD defined practice standards for receipt of HCC screening and proportion of early-stage HCC detected in patients with cirrhosis.⁵⁷ Other metrics in HCC beyond receipt of surveillance could include time from a positive screening result to subsequent diagnostic evaluation and proportion of false positive screening exams. Wider adoption, measurement, and reporting of these quality metrics has the potential to improve HCC screening adherence. There are opportunities to further develop these metrics to ensure the quality of surveillance also meets minimum standards.

In order to improve HCC early detection, the National Cancer Institute established the Translational Liver Cancer (TLC) consortium in 2018 with the goal of improving early detection of HCC. The specific goals of the consortium are to better risk-stratify patients for developing HCC, improve HCC screening in high-risk populations, and increase the proportion of HCC detected at an early stage. The TLC consortium is composed of 5 sites (Baylor College of Medicine; George Washington University; University of Michigan, University of California, Los Angeles; and University of Texas Southwestern Medical Center) and a data coordinating center (Fred Hutchinson Cancer Research Center).

The TLC consortium sites have several studies evaluating the first 3 steps of the screening process continuum including risk stratification, screening, and follow-up. Specifically, the TLC consortium is deriving clinical risk models, blood-based biomarkers, and analytic morphomic signatures for risk stratification; characterizing barriers to screening completion and evaluating interventions to increase HCC screening completion; validating novel blood- (eg, methylated DNA markers) and imaging-based (eg, abbreviated MRI) strategies for HCC early detection in patients with cirrhosis; comparing the cost-effectiveness of screening strategies in patients with cirrhosis; and enumerating the frequency and natural history of indeterminate nodules identified during screening (Table 2).

Table 2.

Translational Liver Cancer Consortium Research Agenda

Screening Process Step	Project
Risk stratification	Identification of clinical and genetic risk factors for HCC in patients with NASH Derivation and validation of blood-based risk stratification biomarkers in patients with cirrhosis Identification of morphomic signatures from CT scans associated with HCC in patients with cirrhosis
Screening utilization	Characterization of screening process failures and patient barriers contributing to screening underuse Evaluation of electronic medical record prompts to increase HCC screening use
Screening test effectiveness	Validation of novel biomarker test performance in large cohorts, including methylated DNA markers and serum protein biomarkers Evaluation of novel imaging screening strategies such as abbreviated MRI Establish large cohorts of patients for biomarker and imaging validation Cost-effectiveness of screening strategies in patients with cirrhosis
Follow-up	Characterization of screening-related harms in patients with cirrhosis Frequency and natural history of indeterminate nodules in patients with cirrhosis

CT, computed tomography; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; NASH, nonalcoholic steatohepatitis.

Conclusion

Our HCC screening conceptual model, adapted from a well-accepted model applied in other cancers, illustrates sequential steps and interfaces required for effective implementation of HCC screening process in clinical practice. This framework can be used to guide a research agenda as well as quality improvement programs focused on improving the overall effectiveness of HCC screening. Specifically, each step and interface can serve as targets in interventions designed to improve effectiveness of HCC screening. We identified lessons from breast cancer and CRC screening programs that can be used to improve HCC screening process. For example, lessons from breast cancer screening can enhance appropriate use of imaging-based HCC screening tests, whereas lessons from CRC screening may help improve timely follow-up and diagnosis following an abnormal screening test. We also highlight aspects of cancer screening that are either unique to or disproportionately problematic for HCC, including complexity in risk assessment, suboptimal accuracy of available biomarkers, and limited options for curative treatment. These gaps are high-priority areas for translational, clinical, and implementation research.

Abbreviations used in this paper:

AASLD

American Association for the Study of Liver Diseases

AFP

α-fetoprotein

CRC

colorectal cancer

CT

computed tomography

EHR

electronic health record

FIT

fecal immunohistochemical test

HBV

hepatitis B virus

HCV

hepatitis C virus

HCC

hepatocellular carcinoma

MAFLD

metabolic-associated fatty liver disease

MRI

magnetic resonance imaging

TLC

Translational Liver Cancer