Liver cancer

Liver cancer is a malignant tumor that arises in the liver. Primary liver cancer, the form that starts in liver tissue itself, is mainly hepatocellular carcinoma (HCC), which accounts for roughly 80% of cases, while intrahepatic cholangiocarcinoma makes up most of the rest. It is one of the leading causes of cancer death worldwide, with about 870,000 new cases recorded in 2022. Liver cancer is usually the end point of long-standing liver injury, especially chronic viral hepatitis, cirrhosis, and metabolic fatty liver disease, so it sits at the intersection of oncology, hepatitis B, fatty liver disease, and public health. Survival has improved only slowly over recent decades, and most patients are still diagnosed at stages where cure is difficult.

Because the liver is both a metabolic organ and a site of constant regeneration, the disease has distinctive biology and clinical management. Most tumors develop in livers already damaged by inflammation and fibrosis, which shapes screening, staging, and treatment decisions. Major advances include the identification of hepatitis viruses as causes, the development of imaging-based diagnostic criteria, and the introduction of immune checkpoint inhibitors and combination therapies for advanced disease. At the same time, the rising share of cases linked to metabolic risk factors and the persistence of inequality between regions remain central concerns.

This entry describes primary liver cancer in its main forms and their definitions, then covers epidemiology and the global burden, causes and risk factors, pathogenesis and molecular changes, pathology and classification, clinical presentation, surveillance and diagnosis, staging and prognostic systems, surgical and transplant options, locoregional and systemic treatments, emerging therapies, prevention, survival and follow-up, the history of research, and unresolved questions.

Definition and classification

Primary liver cancer is a malignancy that begins within the liver itself. It must be distinguished from liver metastases, which are secondary tumours seeded from cancers that arose elsewhere. Secondary or metastatic liver cancer is more common than primary liver cancer. The usual sources include colorectal, pancreatic, melanoma, lung, and breast cancer. Because the origin and biology differ, metastases are generally managed under the framework of the original cancer rather than under the primary liver cancer pathways described in this article.

Primary tumours arise from the liver's resident cell populations. Sources commonly name hepatocytes, the cells lining the bile ducts, and vascular endothelial cells, sometimes in combination with mesenchymal components. Three adult entities account for nearly all cases:

• Hepatocellular carcinoma (HCC) is the dominant type. Estimates vary by source: one review puts it at roughly 70% of primary cases, while another gives approximately 80%. It is the form that arises from hepatocytes and is closely tied to cirrhosis.
• Intrahepatic cholangiocarcinoma (iCCA) arises from the biliary epithelium within the liver. Its share is reported differently across sources, from 5–10% of cases to 10% to 20% of newly diagnosed liver cancers. Macroscopically, it tends to be white and firm, because it contains more desmoplastic stroma than HCC.
• Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) contains unequivocal components of both HCC and iCCA. It is uncommon, accounting for 1.0% to 4.7% of primary liver cancer, and its histogenesis is debated: it is thought to derive from either transformed hepatocellular carcinoma cells or liver stem/progenitor cells.

Rarer entities include fibrolamellar carcinoma (FLC), a variant that comprises less than 1% of all primary liver tumors in the United States. It occurs mainly in people under 40 and affects men and women about equally. It usually develops without underlying cirrhosis or viral hepatitis, and its recognition as a distinct entity followed the identification of a DNAJB1::PRKACA fusion that is characteristic but not strictly exclusive to the tumour.

In children, the picture is different. Hepatoblastoma is the most common malignant liver tumor in children, and it accounts for roughly 67%–80% of pediatric liver cancers worldwide. It is typically seen in infants and young children, and it is usually associated with raised alpha-fetoprotein. Paediatric HCC, by contrast, is rare and occurs mostly in older children and adolescents.

The classification matters for several reasons. Prognosis and treatment differ substantially: HCC is currently the only one of these tumours that can be treated by liver transplantation. Treatment selection can also depend on histology, since small duct type iCCA harbors IDH1/2 mutations and FGFR2 fusions, which are targets for specific drugs. Eligibility for clinical trials is likewise defined by tumour type, so misclassification can distort trial populations and comparisons of outcomes. Because combined tumours and small-duct iCCA show similar clinical presentations, and their histological features are more complex than seen in HCC, pathological review is a necessary step in the classification itself.

Liver structure and the cirrhotic background

The liver receives blood from two sources. The portal vein carries most of the organ's blood flow, drawing nutrient-rich blood from the intestine, spleen and pancreas, while the hepatic artery supplies a smaller share of the flow but a substantial part of the oxygen. Hepatocytes, which make up roughly 70–80% of liver cells, process this blood. They store and release glucose, synthesize lipids and lipoproteins, produce albumin and most clotting factors, secrete bile, and metabolize drugs and toxins through cytochrome P450 enzymes and conjugation reactions. They also convert ammonia into urea. Because so many functions depend on hepatocytes, loss of liver tissue quickly affects the whole body.

The liver has an unusual capacity for regeneration. Hepatocytes are normally quiescent but can re-enter the cell-cycle after injury or partial removal, and the organ can regrow to near its original mass. This capacity is the basis for partial hepatectomy and living-donor transplantation. Repeated injury, however, changes the picture. Viral infection, alcohol, metabolic stress and autoimmune attack cause cycles of apoptosis and necrosis, followed by inflammation and repair. In the repair process, activated hepatic stellate cells deposit collagen and other extracellular matrix proteins. When injury is frequent enough, the fibrous septa link portal and central regions, and surviving hepatocytes form regenerative nodules that are separated by bands of scar. The normal lobular architecture is replaced, blood flow is redirected through abnormal shunts, and portal pressure rises. This nodular fibrotic state is cirrhosis, and a large majority of hepatocellular carcinomas develop on this background.

Progression from cirrhosis to cancer is thought to be multistep rather than abrupt. Regenerative nodules are the most common nodular lesions in cirrhosis and are generally benign. Some hepatocytes within these nodules accumulate changes in growth control, forming dysplastic nodules that are classified as low-grade or high-grade according to cytological and architectural features. Dysplastic nodules show increasing cell density, loss of normal structure and, in the high-grade group, a higher chance of containing malignant foci. The sequence is believed to involve the gradual accumulation of genetic and epigenetic alterations within clonal populations of hepatocytes, and it is not every nodule that progresses. Not all cirrhotic nodules become cancer, and the rate of transformation depends on the underlying cause, the degree of fibrosis and the persistence of injury.

Hepatocellular carcinoma can also arise in a liver without cirrhosis, and this occurs in a meaningful minority of cases. Chronic hepatitis B infection can drive tumor formation in patients with little or no fibrosis, partly through direct effects of viral proteins and viral DNA integration into host DNA. Non-cirrhotic HCC is also reported in metabolic dysfunction-associated steatotic liver disease, in which many tumors occur in livers with only mild fibrosis, and in some inherited metabolic conditions such as hemochromatosis. These tumors can be diagnosed later because they lack the surveillance setting that cirrhosis creates. Their biology may also differ from that of cirrhosis-associated tumors, which is an important consideration for prevention and treatment.

Epidemiology and global burden

Primary liver cancer is one of the most common and deadly malignancies. In 2022, approximately 866,136 new liver cancer cases and 758,725 related deaths were recorded worldwide. Ranked by rate, the disease sits sixth for new diagnoses among all cancers, yet third for cancer deaths, behind only lung and colorectal cancer (Liver cancer is now the sixth most common cancer globally and the third leading cause of cancer-related death). Its share of global cancer deaths has drifted down, from 9.1% in 2012 to 7.8% in 2022, though the absolute number remains large.

The burden is strongly skewed by sex and age. Men account for roughly seven in ten cases: the age-standardized incidence is 12.7 per 100,000 in men against 4.8 per 100,000 in women (GLOBOCAN 2022 figures, as analysed in the published study). Risk rises steeply with age, and the highest burden was observed in the elderly population. Because hepatocellular carcinoma usually develops after decades of chronic liver injury, most patients are diagnosed in middle or later life, and the sex gap largely mirrors differences in exposure to hepatitis infection, alcohol and metabolic risk factors.

Cases are heavily concentrated geographically. Eastern Asia recorded 432,684 new cases in 2022, about half of the global total, with an age-standardized incidence of 14.7 per 100,000 against a world figure of 8.6. Within this region, China dominates. Liver cancer is the fourth most common malignancy in China, and it is the second leading cause of cancer-related deaths, with an estimated 400,415 deaths in 2022. Northern Africa also has high rates, and the highest age-standardized hepatocellular carcinoma rates have been reported in Eastern Asia and Northern Africa. The concentration reflects the historical prevalence of chronic hepatitis B in these populations, a point developed in the causes section.

Projections point to substantial growth. Previous analyses have predicted that the number of new liver cancer cases will nearly double from 870,000 in 2022 to 1.52 million in 2050, primarily due to population growth and ageing populations, with the largest increases expected in Africa. Deaths are projected to rise from 760,000 in 2022 to 1.37 million in 2050. These figures assume that current trends continue unchecked; a sustained fall of 2–5% per year in age-standardized incidence would substantially change this trajectory, according to a Lancet Commission modelling exercise. Incidence and mortality diverge because they measure different things. Incidence counts new diagnoses, which track exposure to risk factors and screening intensity, while mortality also depends on how advanced tumours are when found and whether treatment is available. The global mortality-to-incidence ratio is 0.86 (with a global MIR of 0.86), meaning that most people diagnosed die of the disease. The ratio is highest in Eastern Africa, where it reaches 0.96, and lower in Northern America at 0.72, which signals the gap in access to early diagnosis and effective therapy between settings.

Survival has improved only modestly in many countries. Across regions, five-year survival rates range from approximately 5% to 30%. In the United Kingdom, one-year and five-year relative survival are estimated at about 40% and 10%, respectively, even in a high-income setting. Gains have occurred in some registries: in the United States, the 5-year OS rate almost doubled from 11.7% to 21.3% during 2000-2011, and mortality has started to decline since the mid-2010s. Yet the improvement is uneven, with persistent gaps by age, sex, race and tumour stage. Most cases are still detected at advanced stages, when resection or transplantation is no longer possible, and the underlying cirrhosis limits how much treatment patients can tolerate. Surveillance coverage is also uneven, so gains in individual registries have not translated into a broad shift in population-level survival.

Causes and risk factors

Chronic viral hepatitis

Chronic hepatitis B and hepatitis C remain the largest identified causes of primary liver cancer, although their relative weight differs sharply by region. In a worldwide population attributable analysis, 44% of hepatocellular carcinoma cases were attributed to chronic hepatitis B infection, with the majority of cases occurring in Asia, while hepatitis C was responsible for 21% of cases. The regional contrast is visible in the United States, where a separate estimate put the hepatitis B share at only 4.3%, against 20.5% for hepatitis C. Hepatitis B's dominance in East and Southeast Asia and sub-Saharan Africa reflects high rates of perinatal and childhood transmission, which lead to infection early in life and to cancer at younger ages.

Within populations where both infections are common, the attributable share depends on how the analysis is built. A 15-year cohort of 11,801 men in Taiwan used a causal-pie model and assigned a total causal-pie weight of 52.7% to four dose-response classes of hepatitis B, 14.4% to an independent effect of hepatitis C, 4.2% to a hepatitis B–alcohol interaction, 1.7% to a hepatitis B–hepatitis C interaction, and 27.0% to an all-unknown class. The same analysis estimated that eliminating hepatitis B-related risk could reduce HCC risk by around 60%, with a further reduction if hepatitis C control was added. Globally, the Lancet Commission projects that the hepatitis B share will fall from about 39% of cases in 2022 to 36.9% by 2050, and the hepatitis C share from 29.1% to 25.9% (Hepatitis B virus will remain the leading cause, although the proportion of HBV-related liver cancer will decrease from 39% to 36.9% among all liver cancers.)

Alcohol and metabolic dysfunction

Alcohol-related liver disease is the other major long-standing cause. In the worldwide analysis cited above, alcohol was the strongest lifestyle risk factor, contributing to 26% of HCC cases. In low-infection settings such as the United States and northern Europe, alcohol-related cirrhosis is most likely the main risk factor for HCC. Alcohol and hepatitis B also interact: the Taiwanese analysis assigned a separate causal class to their combined effect, which is consistent with the broader observation that heavy drinking raises HCC risk within hepatitis B–related cirrhosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease, has become the fastest-growing contributor in many high-income and transitioning economies. In a United States analysis, the population attributable fraction was greatest for metabolic disorders (32%), and between 2000 and 2011 the attributable fraction for metabolic disorders rose from 25.8% to 36%, while the alcohol and hepatitis C fractions stayed stable. The more inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), is projected to account for 10.8% of liver cancer cases by 2050, while alcohol's share rises to 21.1%. Within MASLD-related disease, the relationship with obesity and type 2 diabetes is strong: one review's combined estimate for diabetes and obesity was 36.6%, although such combined figures overlap with other categories and vary by method.

Other contributors

Dietary aflatoxin B1, a mycotoxin produced by fungi that contaminate stored maize, groundnuts and rice in hot, humid conditions, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Its burden is concentrated in parts of Asia and Africa. Estimates vary widely: one review suggested that 4.6–28.2% of all global HCC cases may be attributable to AFB1 exposure, and a Chinese estimate attributed about 25.0% of liver cancer deaths in both sexes to aflatoxin exposure in 2013. Aflatoxin leaves a characteristic signature: its activated form forms DNA adducts, and the resulting R249S mutation in TP53 is considered a molecular fingerprint of aflatoxin exposure. Hepatitis B's X protein, meanwhile, functionally inactivates wild-type p53 through direct binding and by promoting its degradation, so the two exposures converge on the same tumour-suppressor pathway.

Tobacco smoking contributed about 13% of HCC cases in the worldwide analysis, and 9% in the United States estimate. Obesity was linked to about 9% of cases worldwide, and the Lancet Commission expects its contribution to rise from 5 per cent to 11 per cent of cases over the period to 2050. Several rare inherited conditions also raise risk. The United States analysis listed porphyrias, hemochromatosis, Wilson disease, α-1 antitrypsin deficiency, and glycogen storage diseases among these, and assigned them a small attributable fraction of 1.5%. Iron overload acts mainly through its effect on hepatic fibrosis and oxidative injury, while autoimmune hepatitis and other immune-mediated liver diseases act principally through chronic liver damage that leads to cirrhosis.

Preventable fraction

Population attributable fractions estimate the share of cases that would not occur if a risk factor were removed, given current exposure levels. They are not additive, because the same case may be linked to more than one exposure. The Lancet Commission on liver cancer concluded that at least 60% of liver cancers are preventable via control of modifiable risk factors, including HBV, HCV, MASLD, and alcohol. A United States estimate that combined the factors it analysed gave a total fraction of 59.5%, which is close to the global figure despite the very different risk profiles. Because the attributable fractions depend on prevalence and risk estimates that differ between regions, the same numbers cannot be applied directly across countries.

Pathogenesis and molecular changes

Chronic injury, oxidative stress and clonal expansion

Most hepatocellular carcinomas (HCC) arise in a liver that has been damaged for years. Viral hepatitis, alcohol, metabolic stress and dietary toxins such as aflatoxin B1 repeatedly kill hepatocytes, which are then replaced by dividing cells. Infiltrating immune cells add cytokines and reactive oxygen species to this environment. Oxidative lesions in DNA, genomic instability and epigenetic shifts arise from persistent inflammatory activity, and together they gradually accumulate the key driver mutations. Each round of division then offers a chance for these lesions to be copied as permanent changes. Cells that acquire a growth or survival advantage expand into clonal populations, and in cirrhotic tissue these clones become the regenerative and dysplastic nodules described elsewhere in this entry. Immune control is weakened in parallel: T cell exhaustion and immune tolerance let altered cells escape clearance.

Recurrent driver genes

Telomerase reactivation is among the most common events. Mutations in the TERT promoter create new binding sites for ETS-family transcription factors, which increase TERT expression. Once telomerase is active, hepatocytes can evade replicative senescence and gain proliferative capacity. Reported frequencies vary by region and cause. In one Korean series, 41 of 109 patients (39.0%) harbored TERT mutations, and higher frequencies have been reported in Western HCC (54–60%) than in Eastern cohorts (29–31%). Hepatitis C-linked tumors carry these changes more often than hepatitis B-linked tumors. The timing of TERT mutation is debated: one study found them in dysplastic nodules, where they are described as a frequent alteration in dysplastic hepatocellular nodules arising in cirrhosis, whereas another reported that TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions.

CTNNB1 encodes β-catenin, and its exon 3 hotspot changes disrupt the protein's normal turnover. They predominantly occur at the phosphorylation sites, induce accumulation of nuclear β-catenin and lead to activation of the Wnt signaling pathway. Prevalence estimates are broad, from 10 to 30% of cases in some series to 20–40% in others. β-catenin also cooperates with telomerase: β-catenin interacts with TERT, enhancing its transcription. Tumors with these mutations tend to form a distinct subclass; the presence of CTNNB1 mutations has been associated with low genomic instability, well-differentiated histology, and persistent telomerase activity.

TP53 is the other central gene. Estimates for TP53 inactivating mutations span from roughly a fifth to four-fifths of tumors, shaped by geography and exposure history. Mutations at codon 249 are associated with aflatoxin exposure, a link that is especially prominent in parts of sub-Saharan Africa and East Asia. Beyond these three genes, the driver landscape includes SWI/SNF subunit mutations (ARID2, ARID1A, BRD7) that disrupt chromatin remodeling. NFE2L2 activation and KEAP1 mutations enhance oxidative stress resistance. Alterations in AXIN1 and RB1-related cell-cycle control are also recurrent.

Two routes and their limits

An early model proposed by Laurent-Puig and colleagues divided HCC into two routes. One route is marked by chromosome instability, TP53 mutations, Axin 1 mutations, HBV infection, poor differentiation, and poor prognosis, while the other is characterized by chromosomal stability, CTNNB1 mutations, absence of HBV, and tendency to form large tumors. The model was built on a modest sample, and it is not known whether this general model also applies to HCC from other geographic areas. The boundary is also not absolute. A mixed tumor case report described intratumor heterogeneity that challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC.

Epigenetic and chromosomal changes

Progression from cirrhosis to tumor involves more than point mutations. Promoter hypermethylation silences tumor suppressor genes, while global hypomethylation contributes to genomic instability; histone modification and microRNA dysregulation add further layers. Chromosomal abnormalities, including copy-number gains on chromosome 1q and losses on 8p, 16q and 17p, accumulate as nodules evolve. Telomere shortening during repeated regeneration can produce chromosomal fusions and crisis, creating selective pressure for telomerase reactivation.

Angiogenesis and the immunosuppressive niche

HCC is a highly vascular tumor, and hypoxia drives production of vascular endothelial growth factor (VEGF). As portal venous inflow declines in growing nodules, angiogenic signaling and arterial supply become increasingly important for tumor growth, which underpins the use of anti-VEGF agents and arterially directed treatments. The tumor microenvironment is also immunosuppressive, involving regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and TGF-β signaling, with PD-1 and PD-L1 expression on tumor and stromal cells. YAP/TAZ activity can be triggered by CTNNB1 mutation, epigenetic changes or NF2 loss, and drives TEAD-mediated transcription, leading to proliferation, metabolic reprogramming, and immune evasion. Through macrophage recruitment and cytokine secretion, this axis can promote CD8+ T cell exhaustion and PD-1/TOX-mediated immunotherapy resistance. These molecular differences are one reason why genotype and immune phenotype are studied as possible predictors of response to checkpoint inhibitors.

Pathology and molecular subclassification

Histological patterns and grading

Diagnosis of hepatocellular carcinoma (HCC) rests on recognizable architectural patterns. Four principal growth patterns are described, namely trabecular, pseudoglandular, solid and macrotrabecular, listed in decreasing order of frequency. The trabecular pattern consists of plates at least three cells thick. The pseudoglandular pattern forms acinus-like lumens, which often contain bile or protein precipitates. Pathologists rarely encounter one pattern in isolation: about half of cases have mixed patterns, and the macrotrabecular pattern is associated with a worse prognosis.

Cytological features support the architectural assessment. Tumor cells typically show a high nuclear-to-cytoplasmic ratio, irregular nuclear outlines and prominent nucleoli, and these features become more pronounced with rising grade. Differentiation is graded on a four-tier scale. Well-differentiated tumors have thin trabecular structures and minimal atypia, resembling mature hepatocytes. At the other end, grade IV tumors show a diffuse or medullary growth pattern, and typical hepatocyte trabeculae are not easily identified. Grading is not fully reproducible. In a central review of a European cohort, the 2019 WHO criteria changed the histological grade in 45% of HCCs, and TNM stage was modified from 1 to 2 in 22 of 100 HCCs.

Distinguishing HCC, cholangiocarcinoma and mixed tumors

Intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) require a different morphological and immunophenotypic approach. Hepatocytic differentiation is typically shown with HepPar-1 and arginase-1, while CK7 and CK19 indicate ductular or cholangiocytic differentiation. cHCC-CCA reportedly accounts for about 1–5% of all primary liver cancers, and it is diagnostically demanding because the tumor can mimic HCC or ICC on imaging or show overlapping features of both. Pathology practice holds that the diagnosis of cHCC-CCA is established on hematoxylin and eosin morphology, with immunohistochemistry as a supplement; expression of immunohistochemical markers alone is not sufficient for diagnosis.

Sampling is a central problem. If samples capture only one of the cHCC-CC components, the tumor may be misdiagnosed as HCC, ICC, or even metastatic adenocarcinoma. In one series, biopsy alone reached a sensitivity of 33% with 100% specificity for cHCC-CCA, and immunostaining raised this to 48%. For this reason, many tumors are only correctly diagnosed histologically following surgical resection or transplantation for presumptive HCC.

Biopsy is also not always required for HCC itself. In high-risk patients, typical imaging is accepted as diagnostic. When a hepatic lesion is categorized as LR-5, it can be diagnosed as HCC without a biopsy. Several authors have questioned how far this can be relied on. In one cohort, tumor biopsy allowed restoration of an accurate diagnosis in 11% of LR-5 cases, and when the lesion is categorized as LR-M, a biopsy is recommended for confirmative diagnosis.

Molecular subclasses

Molecular classifications of HCC are built from gene expression and mutation profiles, and they are not yet fully harmonized. Two transcriptomic schemes are widely discussed: one separates proliferative from non-proliferative tumors, and another defines six groups, G1 to G6, that correlate with clinical, morphological and genomic features. Both are associated with prognosis. The non-proliferative group is characterized by low AFP, good survival, differentiated tumors, chromosome stability, hypermethylation, CTNNB1 mutation and an immune suppression profile. By contrast, the intermediate subclass presents TP53 mutations and chromosomal losses. Tumors in the G1–G3 groups are associated with TP53 mutation, vascular invasion, poor differentiation, high AFP levels, HBV infection, clear cell or sarcomatoid features, and compact or macrotrabecular growth.

TP53 and CTNNB1, the two most frequently mutated driver genes, occur almost mutually exclusively, and their mutational status dictates significantly different gene expression signatures and chromatin states. Prognostic relevance follows this division. TP53-mutated HCCs are associated with a poor prognosis and the macrotrabecular-massive subtype. Subclass labels from different studies derive from separate cohorts and platforms, so they cannot be used interchangeably, and their links to response to specific systemic therapies remain under investigation.

Pathological review in rare subtypes

Rare variants depend heavily on expert review. Chromophobe HCC, for example, consists of round or polygonal, mostly clear cells, with some eosinophilic, granular cytoplasm, and its appearance can overlap with other tumors. Accurate classification of such variants, and of mixed or combined tumors, determines whether a patient receives a transplant, resection, or a non-HCC protocol. Pathological review therefore also serves to identify marker-based features that influence treatment choice.

Clinical presentation

Hepatocellular carcinoma (HCC) often declares itself late. In many programs, more than half of cases are found during scheduled surveillance, while the rest come to attention because of symptoms or abnormal tests. Around 80% of patients are diagnosed with advanced-stage disease. Patients with cirrhosis are a particular concern: early compensated cirrhosis is often asymptomatic and can be undiagnosed for years. Because the tumor is usually found in a liver that has already lost reserve, the silent interval before diagnosis is also the window in which curative options narrow. Some patients are entirely asymptomatic, others have nonspecific complaints, and others first present with features of liver decompensation.

Symptoms of advanced disease

When symptoms do appear, they tend to reflect either the growing mass or the failing liver. A triad of right upper quadrant pain, a palpable mass, and weight loss is described in most symptomatic patients. Abdominal discomfort in the right upper abdomen may result from an enlarging tumor that stretches the liver capsule, and signs of liver decompensation may accompany it. Other reported features include fatigue and weakness, nausea and vomiting, and obstructive jaundice, the latter being an initial symptom in a minority of patients. Progressive fatigue and weight loss are often the first clues for a clinician, but they are not specific to cancer. Accumulation of fluid in the peritoneal cavity (ascites) and the resulting abdominal swelling reflect both portal hypertension and tumor-related disease, and they usually signal that the disease has advanced.

Decompensated cirrhosis

In many patients, the cirrhotic liver rather than the tumor defines the clinical picture. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. Complications such as hepatic encephalopathy and intraperitoneal bleeding can therefore be the first events that bring a patient to care, and they may mask a coexisting tumor. Variceal bleeding from portal hypertension, confusion from encephalopathy, and ascites all complicate the work-up and limit the range of safe treatments, because a patient with poor hepatic reserve may not tolerate surgery, chemoembolization, or systemic drugs. Management therefore often proceeds in parallel: controlling the liver failure, then deciding whether any cancer-directed therapy is feasible.

Paraneoplastic syndromes

Some patients are diagnosed because of systemic effects of the tumor rather than local symptoms. Previous studies demonstrate that approximately 20% of HCC patients may display diverse clinical and biochemical abnormalities that are not explained by tumor size or spread. Hypoglycemia is among the most recognized. Non-islet cell tumor hypoglycemia occurs in 4–27% of patients with HCC, and the more common mechanism involves overproduction of incompletely processed insulin-like growth factor 2 by tumor cells. A less common type relates to the glucose demand of a rapidly growing tumor. In most cases, hypoglycaemia is severe and clinically evident with sweating, palpitations, confusion, and episodes of unconsciousness, and when it is the first sign it can lead to a diagnosis of a previously unsuspected liver mass.

Other frequent abnormalities include hypercalcemia, hypercholesterolemia, erythrocytosis, and thrombocytosis. Amongst various paraneoplastic phenomena, hypoglycemia, hypercalcemia, hypercholesterolemia, erythrocytosis and thrombocytosis are the more frequent abnormalities observed in HCC. Raised platelet counts can coexist with coagulation disturbances that arise from impaired synthetic function of the liver, which complicates bleeding risk assessment before procedures. Hypercalcemia is uncommon, and one review estimated its frequency at 4-8%. Proposed mechanisms include secretion of active molecules by tumor cells, and an immune-mediated cross-reactivity in which antibodies may damage normal tissue. Because these syndromes are often linked to more advanced disease, they are generally regarded as poor prognostic factors. Recognizing them early can prompt investigation of an otherwise silent tumor, but their absence does not rule out disease.

Surveillance, screening, and diagnosis

Surveillance of high-risk groups

Most liver cancers develop on a background of advanced fibrosis, and tumors detected while small are more often amenable to curative treatment. For this reason, people at high risk are enrolled in scheduled monitoring before any symptoms appear. The 2023 AASLD guidance recommends abdominal ultrasound combined with serum AFP at intervals of about six months for all adults with cirrhosis, a broadening from earlier versions that left AFP to clinician discretion. The 2023 AASLD HCC Guidance recommend HCC surveillance in all adults with cirrhosis, using abdominal ultrasound and serum AFP at a frequency of approximately every 6 months. This is a notable change from prior AASLD HCC guidelines, where the option of adding AFP was left to the provider's discretion. Hepatitis B guidance similarly calls for six-monthly ultrasound and AFP testing for people with cirrhosis regardless of age or other risk factors, while people with chronic hepatitis B without cirrhosis are selected by higher viral load, genotype, or Asian or African ancestry.

The six-month interval was itself set largely by empirical judgment. The current surveillance guidelines were determined empirically and were not validated through well-designed randomized trials. A randomized comparison of three- and six-monthly ultrasound is the main trial evidence; in it, the six-month schedule detected very early tumors and reduced advanced presentations relative to annual screening, while three-monthly intervals added little benefit.

Ultrasound, AFP, and their limits

Ultrasound is inexpensive and noninvasive, but its performance depends on the operator and on the patient's liver. One review reports a sensitivity of 58–89% and specificity above 90%, while a meta-analysis reported sensitivity up to 94%. Appropriate recall procedures should be in place in case a nodule is found in a screening US (new nodules that measure more than 1 cm, or nodules that enlarge over a time interval). Lesions under 1 cm are managed differently, because the majority of nodules smaller than 1 cm, which can be detected in a cirrhotic liver, are not HCCs. Current guidance advises repeat short-interval ultrasound and AFP for these small lesions, and returns patients to semiannual surveillance once stability has been shown on two or more examinations.

Serum AFP is the traditional companion marker, with a commonly used positive threshold of 20 ng/mL. Its main weakness is false positivity, since chronic hepatitis, cirrhosis, and other liver disorders also raise AFP. Among newer candidates, such as the fucosylated isoform AFP-L3, glypican-3, and des-gamma-carboxyprothrombin, many of these biomarkers are in clinical testing but other than AFP none has clinical approval. Furthermore, each of these biomarkers, including AFP, suffers from suboptimal sensitivity and specificity making its use as a standalone diagnostic unreliable. Professional bodies differ on AFP's role in surveillance; the Spanish SEOM guideline states that AFP and other tumor markers have no role in screening, whereas AASLD now includes it. Both agree that AASLD advises against use of biomarkers, including AFP alone or liquid biopsy, to make a diagnosis of HCC given insufficient accuracy.

Multiphase CT and MRI

Diagnostic imaging is the central step once a suspicious nodule is found. Multiphase contrast-enhanced CT or MRI characterizes a lesion by how it enhances over time. The defining features are non-rim arterial phase hyperenhancement, non-peripheral "washout," an enhancing capsule, and threshold growth. Washout is generally attributed to the lower extracellular volume of the tumor compared with the background liver, and it is assessed in the portal venous or delayed phase using an extracellular contrast agent. Late arterial timing is preferred, and the delayed phase is needed to evaluate washout and capsule appearance. MRI generally outperforms CT for the arterial feature: in one pooled analysis, sensitivity for arterial phase hyperenhancement was about 87% with MRI versus 50% with CT.

The LI-RADS system converts these findings into standardized categories. In the at-risk population, lesions 10–19 mm with arterial hyperenhancement and non-peripheral washout are classed as LR-5, regardless of prior ultrasound appearance, and LR-5 is considered "definitely HCC" and does not require further tissue biopsy for diagnosis. Categories LR-4 and LR-3 carry lower probabilities, while LR-M denotes malignant lesions that are not HCC-specific, such as cholangiocarcinoma. Rim enhancement alone cannot qualify a lesion for LR-5.

When biopsy is needed

Biopsy is not required to diagnose HCC in patients with cirrhosis or chronic hepatitis B when noninvasive criteria are met. Biopsy may be required in selected cases, but its routine use is not suggested. Biopsy is most useful for lesions that remain indeterminate, for patients without prior chronic liver disease, and for tumors that are not typical on imaging. In patients without previous chronic liver disease, a histopathological diagnosis is generally expected. Biopsy has risks, including bleeding and needle-tract seeding, and it carries a non-trivial false-negative rate. The PPV and NPV of the biopsies were 100% and 62%, respectively; 30 biopsies were non-contributive. In one study of LR-5 lesions, tumor biopsy corrected the diagnosis in about 11% of cases, indicating that radiology alone is not infallible. Where biopsy is performed, pathological diagnosis follows international consensus histological and immunohistochemical criteria. For indeterminate lesions that enlarge without clear HCC features, guidance generally recommends repeating the biopsy or continuing short-interval imaging.

Staging and prognostic systems

The Barcelona Clinic Liver Cancer (BCLC) system is the most widely used framework for staging hepatocellular carcinoma, and clinicians rely on it both to estimate prognosis and to choose treatment. It takes performance status and liver function into account, along with tumor size, number, vascular invasion and extrahepatic metastases, and it links each stage to treatment recommendations and expected outcomes. Very early and early disease (stages 0 and A) are considered for potentially curative options such as resection, ablation, and transplantation, while patients at end-stage should merely receive palliative care. Intermediate disease (stage B) is generally managed with locoregional therapy and advanced disease (stage C) with systemic treatment. The 2022 update subdivided patients with intermediate stage (stage B) disease and included transarterial radioembolization within the guidelines, and it also added new systemic agents for more advanced disease.

A key modification introduced in 2018 requires good baseline liver reserve: Child-Pugh A without any ascites is essential for all stages except stage D. The China Liver Cancer (CNLC) staging system, developed by Chinese investigators and widely applied in mainland China, follows a similar logic of tumor burden, vascular invasion, metastasis, performance status and hepatic function. It was built around a patient population in which hepatitis B-related disease and larger tumors at diagnosis are common, and it places relatively more weight on surgical resection for patients with preserved liver function.

Tumor and patient-level variables

Staging combines anatomic and clinical variables. Tumor size and number determine whether a lesion can be fully removed or ablated, and macrovascular invasion or extrahepatic spread generally moves a patient out of curative categories. Performance status, usually measured with the ECOG scale, captures whether the patient can tolerate active treatment, and a patient with poor performance status is typically placed in a more advanced group even when the tumor itself is limited. Because these variables interact, the same tumor burden can carry different prognoses depending on the patient's functional status and liver reserve.

Liver function scores

Liver function determines whether a patient can survive a procedure or a course of therapy. The Child-Pugh score combines bilirubin, albumin, prothrombin time, ascites and encephalopathy into classes A, B and C. Its clinical components are subjective, and subjectivity in its parameters limits reproducibility. The albumin-bilirubin (ALBI) score uses only serum albumin and bilirubin, with the log-transformed bilirubin weighted at 0.66 and albumin at −0.085:

The ALBI grade is stratified as grade 1 (−2.60 or less), grade 2 (−2.59 to −1.39), and grade 3 (greater than −1.39). Because it is entirely objective, it avoids the need for subjective assessment of clinical signs. Several studies report that ALBI discriminates survival better than Child-Pugh, particularly among patients with Child-Pugh class A liver function, where Child-Pugh offers little separation. Its performance is not uniform, however: one comparison found that Child-Pugh score was better in the advanced fibrosis group, so fibrosis and platelet count can change which score is more accurate. Portal hypertension is a further consideration, since clinically significant portal hypertension (defined by a hepatic venous pressure gradient above 10 mmHg) predicts a higher rate of postoperative complications and a lower long-term survival.

Transplant selection criteria

For patients with cirrhosis, transplant eligibility is determined mainly by tumor morphology. The Milan criteria, proposed in 1996, define eligibility as a single tumor of 5 cm or less, or up to three tumors each 3 cm or less, without macrovascular invasion or metastasis. The Up-to-Seven criteria, introduced in 2009, use the sum of the size of the largest tumor (in cm) and the number of tumors, with a cutoff of seven. In the original cohort, patients without microvascular invasion who met these criteria had a 5-year survival of 71.2%, compared with 73.3% for patients within the Milan criteria. Guidelines from EASL and AASLD recommend the Milan criteria for the indication of liver transplantation, and although the up-to-seven criteria have been analyzed all over the world, they have not been as widely accepted as the Milan criteria. A 2025 meta-analysis of resection and locoregional therapy cohorts found the Up-to-Seven criteria to have comparable and, in some cases, superior prognostic value compared to the Milan criteria.

Surgical resection and liver transplantation

Partial hepatectomy

Resection is the main curative option for many patients with primary liver cancer, but eligibility depends on more than tumor burden. Surgeons also assess liver function, the planned extent of the operation, the volume of liver expected to remain, and whether portal hypertension or comorbidities are present. A remnant liver volume of approximately 25–30% of the total liver volume in patients without cirrhosis, and 40% in case of cirrhosis, is required before a major hepatectomy to minimise the risk of postoperative liver failure. These thresholds are guidelines rather than fixed rules, and the future liver remnant (FLR) is usually measured on routine CT or MRI with semi-automatic software.

Underlying fibrosis narrows the margin of safety. In a background of liver fibrosis/cirrhosis, post-hepatectomy liver function can be compromised. In one series of 125 patients after hemihepatectomy, 13 (10.4%) developed liver failure, and a remnant percentage of about 42.7% separated patients who developed failure from those who did not with a sensitivity of 85.7% and specificity of 88.6%. After hepatectomy, 1 of 125 patients (0.8%) died within 3 months, 13 (10.4%) experienced liver failure, and 99 (79.2%) experienced complications. Remnant percentage was able to predict liver failure, with a cut-off value of 42.7%.

When the remnant is predicted to be too small, surgeons may use portal vein embolization, which occludes the branch supplying the part to be removed so that the remaining lobe hypertrophies. Portal vein embolisation (PVE) involves occluding the portal vein branch supplying the hemi-liver to be removed, which induces compensating hypertrophy of the future liver remnant. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a more aggressive alternative. It is an alternative to conventional two-stage hepatectomy and, comparing with portal vein embolization or portal vein ligation, can lead to a significant and quick growth of the future liver remnant. Its use in HCC carries higher mortality than in colorectal liver metastases, so its role remains under evaluation. ALPPS is indicated in selected patients with hepatocellular carcinoma and cholangiocarcinoma, but the procedure has higher mortality than for colorectal liver metastases.

Resection margins also influence outcomes. In a propensity-matched analysis of large solitary tumors (over 5 cm), a wider surgical margin was associated with better long-term survival.

Liver transplantation for early-stage disease

Transplantation removes both the tumor and the cirrhotic liver that produced it, which makes it attractive for patients whose tumors are small but whose liver function would not tolerate resection. Selection has historically relied on the Milan criteria. In the Milan cohort, the Milan criteria are established for liver transplant (LT) candidates with early-stage hepatocellular carcinoma (HCC), resulting in 5-year survival of 75% and recurrence rates < 10-15%. A single-centre cohort from 2006 to 2020 reported a similar pattern, with recurrence of 3.5% in patients within the criteria against 24% in those outside them.

Donor scarcity limits access. Living-donor transplantation has been used as a curative option for HCC because of a shortage of deceased donors. Several expanded criteria have been proposed to widen eligibility. The U7 criteria define eligibility when the sum of the largest tumor diameter (cm) and number of nodules is ≤7. The Kyoto criteria add a biomarker threshold, requiring ≤10 tumors each ≤5 cm in diameter, with a PIVKA-II level ≤400 mAU/mL.

Recurrence after resection and transplantation

Recurrence is the principal limitation of both approaches. After transplantation, recurrence occurs in approximately 8–20% of recipients and often leads to poor survival. In a study of recurrences at two centres, most recurrences (60 %) appeared within the first 18 months after transplantation, and more than half of the patients had been outside the Milan criteria at the time of transplant. Recurrence after resection is similarly high; the literature describes these rates as persisting despite improvements in surgical technique.

Neoadjuvant and downstaging strategies

Downstaging aims to shrink tumors into transplant criteria before surgery. Liver-directed treatments are the traditional tool, and 25%-70% of patients with HCC outside the Milan criteria achieve tumor downstaging after receiving neoadjuvant therapy; they received LT and achieved comparable prognosis to those who underwent initial LT. Success rates vary by criteria. The success rate of downstaging treatment was approximately 24%-58% according to UCSF criteria. Transarterial chemoembolization has been used for this purpose, with patients with downstaged tumors hav[ing] excellent survival after transplantation. These findings derive largely from small series, and selection is strict.

Neoadjuvant benefit is not uniform. A clinical study showed that neoadjuvant therapy was not beneficial for the prognosis of patients with Barcelona Clinic Liver Cancer (BCLC) stage 0/A HCC, increasing the recurrence risk after LT instead. Moreover, a meta-analysis demonstrated that neoadjuvant therapy had no efficacy for the overall survival and disease-free survival of patients with HCC within the Milan criteria. Immune checkpoint inhibitors add a further question, because immunosuppression after transplantation raises the risk of graft rejection. The use of pre-LT immunotherapy will be deemed 'high risk' unless robust data emerge demonstrating that HCC patients considered for LT achieve superior clinical outcomes with neoadjuvant immunotherapy compared to locoregional therapy and surveillance.

Ablation and locoregional therapies

Locoregional therapies act on tumours within the liver through image-guided needles or catheters. They are used when disease is confined to the liver but cannot be resected or transplanted, or as a bridge while a patient waits for transplantation. The choice among them depends mainly on tumour size, number and location, liver function, and vascular involvement.

Thermal ablation

Radiofrequency ablation (RFA) and microwave ablation (MWA) destroy tumour tissue by heating it, usually through a percutaneous probe guided by ultrasound or CT. Local ablation technologies, such as RFA, MWA and cryoablation, have become a standard treatment option for hepatocellular carcinoma less than 5 cm in size, particularly in individuals who are not candidates for hepatectomy. Most of the outcome data, however, come from lesions under 3 cm. Outcomes data are primarily reported in liver tumors less than 3 cm in diameter, while data for liver tumors greater than 3 cm are limited. Larger lesions make complete necrosis with a clear margin harder to achieve, which is why many centres have avoided ablation for tumours above 3–4 cm. Tumours near bile ducts or large vessels also carry a risk of thermal injury, and proximity to large vessels produces a heat-sink effect that carries heat away from the target.

Location predicts failure as much as size does. Predictive factors for local tumour progression include tumour size above 3 cm, subcapsular location, and proximity to major vessels. MWA has largely replaced RFA in many settings because it is less affected by the heat-sink effect and has lower rates of local progression, especially for tumours larger than 2.5 cm. Newer multipolar RF devices can cauterise up to about 6 cm in one session, and in one comparative series of tumours above 3 cm, local progression was far lower with multibipolar RFA than with single-needle MWA. Multipolar RFA, which can cause cauterization up to 6 cm in one session, and newer generation microwave ablation systems have been found to achieve treatment success for large HCC. A SAGES/AHPBA guideline panel concluded that there was insufficient evidence to recommend one modality over another in terms of oncologic outcomes. In a retrospective comparison of tumours of 3.1–5.0 cm, disease-free survival was significantly better for the RF ablation group than for the MW ablation group, although overall survival did not differ significantly. For tumours above 3 cm in patients unsuitable for surgery, ablation or TACE is commonly recommended, and combining RFA with TACE has been reported to be effective. Ablation treatment or TACE is recommended for patients with HCC with a diameter over 3.0 cm who are ineligible for surgery due to decreased cardiopulmonary function or tumor localization that is unsuitable for resection such as porta hepatis. Several studies have reported that RFA combined with TACE has a good treatment effect among patients with HCC with a diameter over 3.0 cm.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy

Because hepatocellular carcinoma draws most of its blood supply from the hepatic artery, catheters placed in those branches can concentrate treatment in the tumour. Transarterial chemoembolization (TACE) was first recommended for intermediate-stage (BCLC B) HCC but has lower necrosis rates. TACE combines an intra-arterial chemotherapy agent with an embolic material that blocks flow, so the drug is retained in the tumour for longer.

Hepatic arterial infusion chemotherapy (HAIC) instead delivers chemotherapy continuously or in pulses through a catheter connected to an implanted or external pump, usually with oxaliplatin-based regimens, and it does not block flow. A 2022 meta-analysis of unresectable HCC found that the objective response rate or partial response in the HAIC group was significantly more than that in the TACE group, and serious adverse events in the HAIC group were significantly fewer than in the TACE group. One-year survival did not differ, and the authors described HAIC as possibly better to some degree. The evidence is weak, since five of the six included studies were nonrandomized controlled trials. Combining the two approaches has also been studied. In a propensity-matched retrospective study of tumours over 10 cm, the TACE-HAIC group had significantly higher objective response (74.0% vs 58.4%) and disease control rates (93.5% vs 72.7%) than the TACE group.

Radioembolization and stereotactic body radiation therapy

Radioembolization uses yttrium-90 microspheres delivered through the hepatic arteries. It delivers high-dose yttrium-90 microspheres directly to hepatic tumors while sparing healthy parenchyma. It is especially beneficial for patients with portal vein tumor thrombosis or impaired liver function. The randomised SARAH and SIRveNIB trials compared it with sorafenib in advanced disease. On an intention-to-treat basis, there was no difference in overall survival between the groups, with median survival of 8 and 9.9 months in the radioembolization and sorafenib arms. In SIRveNIB, median overall survival in the intention-to-treat population was 11.3 and 10.4 months in the radioembolization and sorafenib arms. Radioembolization was generally better tolerated, and dosimetry has become central to its use. Recent analyses of the DOSISPHERE-01 trial and post-hoc analyses of SARAH demonstrated a direct correlation between tumor-absorbed dose and oncologic outcomes. A Cochrane review concluded that there is insufficient evidence to assess the beneficial and harmful effects of Y-90 SIRT for people with unresectable HCC.

Stereotactic body radiation therapy (SBRT) delivers a precisely shaped, high-dose external beam in a small number of fractions, with motion tracking to limit dose to adjacent normal liver. It is generally reserved for tumours that cannot be ablated or resected, such as those close to major vessels or bile ducts, and for selected patients with vascular invasion. Much of the published experience comes from retrospective and single-centre series.

Choosing and combining treatments

Selection depends on tumour number, size and location, vascular invasion, Child-Pugh liver reserve, performance status, BCLC stage, and whether transplantation is possible. In well-selected patients with small, properly located tumors, ablation should be considered a definitive treatment in the context of a multidisciplinary review. Many centres combine modalities. Combination of TACE with RFA or MWA is effective and promising in treating larger HCC lesions but needs more clinical data to confirm its long-term outcome. HAIC is also paired with systemic agents, and for high tumour burden, HAIC demonstrates comparable efficacy to TACE-HAIC both in combination with TKIs and ICIs. Because direct randomised comparisons between these options remain few, additional randomized controlled trials and studies involving Western cohorts are warranted.

Systemic therapy: targeted drugs and immunotherapy

The sorafenib era

Before 2007, cytotoxic drugs, hormonal agents, and their combinations were the main systemic options for advanced HCC, and some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. Doxorubicin, the most widely used cytotoxic agent, produced response rates of only about 11% to 15%.

Sorafenib, an oral multikinase inhibitor, changed this picture. It was first approved in 2007 by the U.S. FDA on the strength of two placebo-controlled phase 3 trials. In the SHARP trial, median overall survival was 10.7 versus 7.9 months for sorafenib and placebo. The benefit was modest: sorafenib prolongs the overall survival period by approximately 3 months compared with placebo. For roughly a decade it remained the only approved systemic treatment for advanced HCC patients. Later agents were tested against it, and none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo in that period. Lenvatinib was the first exception, showing non-inferiority to sorafenib in a phase 3 trial, and it became an alternative first-line option.

Immune checkpoint inhibitors and early trial failures

Checkpoint blockade entered HCC through single-agent studies. In the phase 1/2 CheckMate 040 trial, nivolumab produced an ORR by modified RECIST of 20% in the dose-expansion phase, and responses appeared regardless of PD-L1 expression or cause of liver disease. The FDA granted accelerated approval in September 2017 for patients with advanced HCC previously treated with sorafenib. Pembrolizumab showed a similar pattern in the phase 2 KEYNOTE-224 study, but its confirmatory phase 3 trial, KEYNOTE-240, did not meet its primary endpoints of OS and PFS, although the trend favored pembrolizumab over best supportive care. In the first-line setting, the CheckMate 459 trial found that first-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, although activity and a favourable safety profile were seen.

Single-agent trials thus showed durable responses in a minority of patients without a survival advantage that could satisfy confirmatory endpoints. Reliable predictive markers were lacking, which made it difficult to select patients for monotherapy. A combined nivolumab and ipilimumab regimen received accelerated approval on March 10, 2020 for sorafenib-pretreated patients, based on a 49-patient cohort of CheckMate 040.

Current first-line combinations

The shift to first-line immunotherapy came with combination regimens. The IMbrave150 trial evaluated atezolizumab (PD-L1 inhibitor) in combination with bevacizumab (vascular endothelial growth factor inhibitor) and showed better overall survival and progression-free survival than sorafenib. A second regimen pairs durvalumab, a PD-L1 inhibitor, with tremelimumab, a CTLA-4 antibody. Its STRIDE schedule, with a single tremelimumab dose followed by regular durvalumab, has recently been approved and made available for the treatment of unresectable advanced hepatocellular carcinoma as a new first-line treatment.

The choice between them is largely driven by patient factors. The anti-VEGF component of atezolizumab–bevacizumab raises bleeding and proteinuria concerns, so the PD-L1/CTLA-4 pairing without anti-VEGF therapy is generally considered for patients who cannot safely receive bevacizumab. Liver function is also central: in real-world cohorts, Child-Pugh scores were a key prognostic variable with both regimens. A 2025–2026 real-world comparison of 765 matched pairs found that atezo/bev and durva/treme demonstrated similar overall survival, while treatment-requiring immune-related adverse events occurred less often with atezolizumab–bevacizumab (adjusted HR 0.61). Because both A + B and D + T are valid treatment options and no head-to-head randomized trial exists, sequencing and selection remain judgments informed by these observational data. Sorafenib continues to be used in patients with contraindications to first-line immunotherapy combinations.

Second-line options and sequencing

Patients who progress on first-line therapy have several options. After sorafenib or lenvatinib, the RESORCE (regorafenib), CELESTIAL (cabozantinib), and REACH-2 (ramucirumab) trials showed survival benefit. Ramucirumab was studied in patients with high baseline alpha-fetoprotein, specifically at or above 400 ng/mL, a group in which AFP level is itself prognostic; in CheckMate 040 follow-up, baseline AFP ≥400 μg/l and extrahepatic spread were associated with shorter OS. Regulatory labels in some countries, such as Brazil, have reserved regorafenib, cabozantinib, ramucirumab, and nivolumab for patients previously treated with sorafenib.

The optimal sequence is unsettled. Although there is no randomized evidence supporting the use of second-line ICIs following sorafenib or lenvatinib despite the prolonged survival benefit observed in the KEYNOTE-240 study, clinicians increasingly use dual checkpoint blockade or switch to a different agent after first-line immunotherapy. Retrospective analyses have compared second-line durvalumab plus tremelimumab after first-line atezolizumab plus bevacizumab with lenvatinib, but no prospective evidence yet defines the preferred path.

Emerging therapies and ongoing trials

Adjuvant immunotherapy after resection or ablation

Recurrence is the main reason curative treatment fails in hepatocellular carcinoma, so several groups have tested whether immunotherapy given after surgery or ablation can prevent it. The most prominent example is IMbrave050, in which atezolizumab plus bevacizumab was shown to significantly improve recurrence-free survival compared with active surveillance in patients at high risk of recurrence. The benefit did not hold up over time. An updated analysis with extended follow-up failed to confirm sustained efficacy, and commentators questioned whether a recurrence-free survival gain without a demonstrated overall survival benefit justified the cost and toxicity of the regimen (the Lancet commentary). Other adjuvant studies with different eligibility criteria, dosing schedules and risk definitions are still running, and some authors argue that the disappointing results reflect imprecise selection of patients at highest risk rather than a failure of the principle (discrepancies between trials may partly reflect differences in baseline risk severity).

Observational data have been more encouraging but cannot settle the question. In one multicenter analysis of patients with intermediate or advanced disease, adjuvant immunotherapy was associated with improved recurrence-free and overall survival after curative resection, and the authors called for randomized trials to establish definitive evidence. Earlier randomized studies of autologous cytokine-induced killer cells had reported that this cell-based approach prolonged recurrence-free survival after curative treatment, although such trials were conducted mainly in settings with different treatment norms.

Cell-based and novel adoptive therapies

Chimeric antigen receptor (CAR) T cells directed at glypican-3 (GPC3) are among the most studied engineered cell therapies. The rationale rests on target selectivity: GPC3 is expressed in nearly all HCC yet is undetectable in normal adult hepatic tissues. Early phase I experience showed feasibility but modest benefit. In one dose-escalation study, pyrexia, decreased lymphocyte count, and cytokine release syndrome were the most frequent events, with cytokine release syndrome in nine of 13 patients. Systemically infused products produced a relatively low response rate, with a partial response rate below 20%. Current studies therefore test refinements such as locoregional delivery, which exploits the liver's dual blood supply through the hepatic artery and portal vein, and armored receptors that resist suppression by transforming growth factor beta. One such product is designed to decrease the inhibition of T cells by transforming growth factor beta, and patients receive lymphodepleting chemotherapy before infusion with cyclophosphamide and fludarabine.

Tumor-infiltrating lymphocytes (TILs) take a different route: they are harvested from resected tumor, expanded ex vivo, and returned to the patient. In an early phase I study from China, TIL were successfully expanded from 15 of 17 patients (88%), and after a median follow-up of 14 months, 12 patients (80%) showed no evidence of disease. The sample was tiny and uncontrolled, so these results only justify further study. Other TIL trials, including a randomized-design study in high-risk recurrent disease, remain ongoing with results not yet published.

Bispecific antibodies and therapeutic vaccines

Bispecific antibodies are engineered to bind two targets at once, most often a checkpoint receptor such as PD-1 together with a second immunoregulatory or angiogenic molecule, with the aim of combining effects that single agents achieve only partially. Several such molecules are in early or mid-stage clinical development for HCC, and their value will depend on whether they outperform the established combinations of checkpoint blockade with anti-VEGF or CTLA-4 therapy in randomized comparisons. Therapeutic vaccines have also been explored; GPC3-targeted approaches include vaccines, anti-GPC3 immunotoxins, combinations with immune checkpoint blockade, and CAR T or NK cells.

Next-generation checkpoint and co-stimulatory targets

Because PD-1 and PD-L1 blockade produces responses in only a minority of patients, researchers are testing additional inhibitory receptors expressed on exhausted T cells, including TIM-3, LAG-3 and TIGIT. LAG-3 blockade has an established place in combination with PD-1 inhibition in melanoma, but comparable benefit has not yet been shown in liver cancer. TIGIT-directed antibodies and TIM-3 inhibitors have had mixed or disappointing phase 3 results in several other tumor types, which has made investigators cautious about extrapolating to HCC. A parallel strategy uses co-stimulatory agonists, such as antibodies targeting OX40, 4-1BB or CD40, to strengthen T-cell activation rather than remove a brake. Their use in HCC is at an early stage, and combination designs with existing checkpoint inhibitors are the main focus.

Antiviral therapy and combined approaches

In chronic hepatitis B, nucleos(t)ide analogues suppress viral replication and reduce, but do not abolish, the risk of HCC, and direct-acting antivirals cure most hepatitis C infections. Combining antiviral therapy with immunotherapy is attractive because viral antigens may keep T cells in an exhausted state, and viral suppression could lessen the inflammatory background that promotes tumor growth. Evidence so far comes mainly from small retrospective series and subgroup analyses, which are vulnerable to selection bias because patients with better-preserved liver function are more likely to receive both treatments. Prospective trials that randomize or stratify by viral status and antiviral exposure are needed before these combinations can be recommended.

Prevention and public health strategies

Hepatitis B vaccination

Infant vaccination against hepatitis B is the clearest case in which removing a viral cause has lowered liver cancer rates. Taiwan introduced the first nationwide hepatitis B vaccination program in 1984, the first of its kind worldwide. Within 10 years, the program had reduced the HBV carrier rate among children from 10% to 1%. The cancer effect followed. In children aged 6 to 14, the average annual incidence of hepatocellular carcinoma declined from 0.70 per 100,000 between 1981 and 1986 to 0.36 between 1990 and 1994. A later cohort study of 1,509 patients found an incidence of 0.92 per 100,000 person-years in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The protection reached into adolescence and early adulthood, as immunization of infants against HBV reduces their risk of developing HCC as children and young adults.

The effect is much weaker in older adults, because most adult cancers reflect infections acquired decades earlier. In Taiwan, although the annual incidence of HCC slightly increased in adults, the annual incidence of primary liver cancer markedly decreased in children. For this reason, the Lancet Commission pairs vaccination with screening. It calls for vaccine mandates in high-prevalence countries and universal HBV screening for adults 18+, alongside targeted HCV screening in high-risk areas based on cost-effectiveness.

Hepatitis C treatment and case-finding

Modern hepatitis C therapy has changed the outlook. New direct-acting antivirals substantially improved the cure rate to above 90%. Cure is associated with a clear fall in cancer risk. Compared with patients without a sustained virological response, those with DAA-induced viral clearance had a decreased risk of HCC, with an adjusted hazard ratio of 0.28. The benefit, however, is not uniform across time. One review found that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. Cancer risk also persists in people with established fibrosis: cancer risk persists even after 10 years of viral cure, and thus a clinical strategy for its monitoring is urgently needed.

The main obstacle is not drug efficacy but reaching people who do not know they are infected. Access to therapies remains limited due to the high costs and under-diagnosis of infection in specific subpopulations, such as baby boomers, inmates, and people who inject drugs. Case-finding in these groups therefore determines how many cancers treatment can avert.

Alcohol, metabolic risk and environmental exposure

Policy measures against alcohol consumption include taxation, advertising limits, and minimum unit pricing. The Commission supports alcohol taxation, advertising restrictions, and minimum unit pricing as proven policy levers. Warning labels are also recommended. Policy makers should enact minimum alcohol unit pricing, warning labels, and advertisement restrictions for alcoholic beverages.

For metabolic dysfunction-associated steatotic liver disease, the proposed measures address the wider risk profile. Prevention here includes public health policies to combat obesity, improve diet, and promote physical activity. Some countries have built this into routine care. The Lancet Commission also suggests integrating liver screening into routine care for people with obesity, diabetes, and heart disease. Japan's approach, for example, included nutrition counseling, exercise promotion, and diabetes management to address MASLD/MASH.

Food safety is a further target. Dietary aflatoxin exposure, which comes from fungal contamination of stored crops such as maize, groundnuts, and tree nuts, is a recognized contributor, and its effect is strongest where hepatitis B is common. Prevention therefore relies on drying and storing crops properly, sorting out contaminated batches, and enforcing limits on food. The Commission also recommends controlling environmental risk factors, such as contaminated water.

Global targets

The Lancet Commission sets a quantitative goal. To reverse the trend of rising liver cancer burden, an annual reduction of at least 2% in the age-standardised incidence rate is necessary. For countries that have already had an annual reduction in the ASIR of 0·1–2·0% for liver cancer, a more ambitious target of an annual reduction in the ASIR of 5% is set. Without such action, the burden of new liver cancer cases is projected to increase to 1·52 million and liver cancer-related deaths to 1·37 million by 2050. The Commission estimates that a 2–5% annual reduction in age-standardized incidence rates could prevent 8.8 to 17.3 million new cases and save 7.7 to 15.1 million lives globally by 2050. Press materials give slightly different rounded ranges, with one citing nine to 17 million new cases and eight to 15 million lives. The Commission's basis for these figures is that at least 60% of liver cancers are preventable via control of modifiable risk factors, including hepatitis B virus (HBV), hepatitis C virus (HCV), MASLD, and alcohol.

Screening access, equity, and health systems

Surveillance gaps between settings

Surveillance works only when people with cirrhosis or chronic hepatitis B are identified and scanned on schedule. Semiannual ultrasound, with or without alpha-fetoprotein testing, is the standard surveillance approach for high-risk groups in guidelines (ultrasonography). In many low-income and middle-income countries, that infrastructure is thin. Because cirrhosis surveillance and treatment are substandard or unavailable, many tumors are found late. Ultrasound has been used with some success in Asian countries, but it is not feasible in African countries. A 2016 multinational cohort from sub-Saharan Africa illustrates the consequence: 72% of patients had Barcelona Clinic Liver Cancer stage D disease at diagnosis, and only 3% went on to receive any HCC-directed treatment.

Data gaps compound the problem. Many low-income countries do not have national cancer registries, and data on incidence and mortality are lacking in some countries, especially low-income and conflict-affected areas. Estimates for these settings are therefore uncertain, and low reported mortality may partly reflect weak death registration rather than a lower true burden.

Cost, specialists, and the location of services

Survival depends heavily on whether patients can reach specialist care and the few centers that offer transplantation, resection, and interventional therapy. Those services are unevenly distributed, and research on them is too. A systematic review of oncologic liver resections found only one study from a low-income country, and most African regions were not represented. Cost compounds the problem: the Lancet-linked burden analyses describe high medical costs driven by hospitalization and significant productivity loss from premature mortality.

Within high-income systems, access also varies by income. In a Swedish nationwide cohort, individuals with low household income had the highest incidence of HCC, were more likely to have underdiagnosed cirrhosis, and had higher ECOG performance status at diagnosis. The authors found these socioeconomic differences in surveillance, severity at diagnosis, treatment access, and survival persisted after adjustment for cirrhosis status.

Adapting guidelines and treatment pathways to local resources

Global frameworks increasingly emphasize prevention and feasible detection. The 2025 Lancet Commission provides ten recommendations for action across four thematic areas, with prevention as a central pillar, and it sets a goal of at least a 2% reduction in age-standardized incidence, with a more ambitious 5% target for some regions where declines are already visible. Some LMICs have shown that vaccination integrated into routine infant immunization can lower hepatitis-related liver cancer over time. Asian national surveillance programmes offer lessons on organizing surveillance at scale, and European uptake of surveillance has been described as suboptimal, with high rates of late-stage diagnosis and poor prognosis.

Pathways therefore need to be tailored. Where ultrasound is scarce, the realistic priorities may be hepatitis B vaccination, antiviral treatment, and referral systems rather than full surveillance programs. Where transplantation is unavailable, locoregional or systemic treatment choices must be made under different constraints, and stage-based prognosis tools carry different weight.

Disparities by ethnicity, sex, and socioeconomic status

In the United States, Black race and uninsured status are associated with decreased likelihood of receiving HCC screening. Treatment delays are also more common: Black patients and those living in high-poverty neighborhoods were more likely to experience treatment delays. Transplant access shows a similar pattern. Non-Hispanic White patients were more likely to undergo orthotopic liver transplantation than non-Hispanic Black patients in a National Cancer Database analysis, and rates of liver transplant among low-SES Black and Hispanic patients were lower than among low-SES White patients.

These patterns are not uniform. In one safety-net cohort, there were no racial/ethnic or socioeconomic disparities in receipt of treatment, and the authors concluded that poor liver function, no insurance, and advanced stage of presentation were the main determinants of not receiving treatment and of reduced survival. Sex differences are well documented in HCC, with men affected substantially more often than women, but the sources consulted here did not address sex-based disparities in access, so they are not described further in this section.

Prognosis, survival, and follow-up

Stage, liver function, and survival

Survival in hepatocellular carcinoma (HCC) depends on tumor burden, performance status, and the functional reserve of the cirrhotic liver, not on tumor size alone. The Barcelona Clinic Liver Cancer (BCLC) system was built on this principle, and its stages separate patients sharply. In an ESMO guideline summary of treated patients, median overall survival is more than five years for stages 0 and A, about 2.5 years for stage B, 2 years for stage C, and roughly 3 months for stage D. Five-year overall survival after curative hepatectomy in an international multicentre database was about 86% for stage 0, 69% for stage A, 57% for a single large tumor (A1), and 50% for stage B. Within stage B, tumor number matters: in a Hokkaido series of resected patients, five-year survival was 63.6% with a solitary tumor, 52.3% with two or three tumors, and 29.0% with four or more.

Five-year survival also varies widely for patients with advanced disease. Older registry-based estimates place it near 10.7% for locally advanced disease and 3.1% when distant metastases are present. Liver function can be as decisive as cancer stage: in the same Hokkaido series, most deaths after resection were due to recurrence, but a minority resulted from liver failure. A US integrated health system study found similar five-year survival for advanced and terminal stages in an earlier period but a widening gap later, suggesting that factors beyond stage at diagnosis now shape outcomes.

Recurrence after curative treatment

Recurrence, rather than the primary treatment failing, is the main obstacle after curative therapy. Cumulative five-year recurrence after anatomical resection is often quoted at 50–70%, reflecting both intrahepatic spread and de novo carcinogenesis in the remaining liver. After ablation, more than half of patients relapse within two years in one large cohort, with a 3-year recurrence-free survival of 37.4%. The hazard is highest in the first year, falls to its lowest point in the third year, and then rises again. The later phase is attributed to new lesions arising from the underlying chronic liver disease, whereas early recurrence is driven mainly by features of the primary tumor such as multifocality or vascular invasion.

Monitoring schedules

Contrast-enhanced CT or MRI is the recommended imaging after hepatectomy, but the ideal interval has not been established. Many centres use imaging every 3 months for the first two years and every 6 months thereafter. After ablation, an early scan within about one month is used to confirm complete treatment, and a Chinese cohort used dynamic CT at 4-month intervals combined with tumor markers, detecting most recurrences while still treatable by ablation. Follow-up visits every 3–6 months typically combine clinical examination, serum alpha-fetoprotein, and cross-sectional imaging. Irregular surveillance, defined as intervals beyond six months, has been linked to shorter median post-resection survival (21.2 vs 32.1 months) in one multicentre study. A post-ablation cohort found that longer intervals did not reduce survival in low-risk patients but did in high-risk patients. A randomized trial now under registration is testing risk-adapted scheduling, with next scans at 3, 4, or 6 months depending on estimated recurrence risk.

Advanced disease: palliative care and quality of life

For patients whose disease cannot be controlled or whose liver function has deteriorated, the goal shifts toward symptom relief and preserved function. Palliative care is usually delivered alongside systemic therapy rather than instead of it, addressing pain, abdominal distension from ascites, fatigue, pruritus, nausea, poor nutrition, and psychological distress. Decompensation, such as encephalopathy or variceal bleeding, often determines whether further anticancer treatment is feasible. Quality-of-life assessment helps clinicians judge the benefit of additional therapy, and it is commonly used alongside clinical measures when deciding whether to continue, change, or stop treatment.

Survivorship

Many people who have been treated for HCC continue to have cirrhosis or chronic viral or metabolic liver disease, so survivorship care includes ongoing management of the underlying liver condition, such as continued antiviral therapy for hepatitis B or C, alcohol abstinence, and surveillance for portal hypertension. Cardiometabolic risk is a substantial additional concern. In a cross-sectional study of 115 patients after HCC treatment (mean age 67.7 years, 73% male), central obesity was present in 72.2% and metabolic syndrome in 47%, with inadequate exercise and smoking common. The same study linked a healthier behavioural profile with better quality of life, and its authors called for outpatient education to reduce cardiometabolic risk. Broader cancer-survivorship guidance similarly recommends regular screening for hypertension, dyslipidaemia, and diabetes, and optimization of cardiovascular risk factors after treatment.

History of research

Early knowledge of liver tumors came from autopsy and anatomical observation. For much of the eighteenth and nineteenth centuries, pathologists described large hepatic masses without a reliable way to tell whether a growth had begun in the liver or had spread there from another organ. The separation of primary liver cancer from metastatic disease developed slowly. It depended on the cellular pathology that Rudolf Virchow promoted in the mid-nineteenth century, and later on the ability to identify tissue of origin under the microscope, which made it possible to say that a tumor was made of hepatocytes or bile duct cells rather than of cells from elsewhere.

The identification of hepatitis viruses in the twentieth century transformed the understanding of the disease's causes. In the 1960s, while analyzing blood samples from different populations across the world, Baruch Blumberg, MD, PhD, identified the surface antigen of HBV. The antigen had been named the Australia antigen, after an Australian donor's sample, and its meaning was unclear for a period. As early as 1969 Bruce Smith and I had postulated that HBV was a cause of primary cancer of the liver. Blumberg's team also developed a blood test that let blood banks screen out infected donations, and a vaccine made from the antigen in 1969. Blumberg and Gajdusek received the Nobel Prize for discovering "new mechanisms for the origin and dissemination of infectious diseases." The later discovery of hepatitis C, which was first cloned in 1989 and was recognized by the 2020 Nobel Prize in Physiology or Medicine, extended the viral link to a second major cause of liver cancer.

Serological markers came next. Alpha-fetoprotein was first identified in human fetal serum in 1956. Identified in human fetal sera by Bergstrand and Czar in 1956, AFP acts as a transporter for several ligands. In 1963 Garry Abelev and Yuri Tatarinov reported an immunochemical antigen in mouse hepatoma and in human primary liver cancer, respectively, and the protein was then designated alpha-fetoprotein, an early oncofetal biomarker. Afterwards, this oncofetal antigen was designated as alpha-fetoprotein and has become recognized as the first embryo-specific and cancer-associated biomarker. The introduction of radioimmunoassay in the early 1970s improved detection but reduced specificity, because low-level elevations were also found in hepatitis and cirrhosis. The diagnostic sensitivity of AFP became lower as a result of instituting an ultrasonographic screening system for early detection of hepatocellular carcinomas, a shift that reflected the growing role of imaging. Diagnostic and staging frameworks followed in the same period. Imaging-based criteria were gradually refined, with contrast-enhanced computed tomography and magnetic resonance imaging recognizing arterial enhancement and washout as hallmarks, and later guideline bodies accepted some lesions as diagnosable without biopsy. Staging systems were developed to link tumor burden and liver function to treatment, including the Okuda system in 1985 and the Barcelona Clinic Liver Cancer system in 1999.

Systemic treatment has changed more recently. For years, cytotoxic drugs offered little benefit: conventional chemotherapies, including doxorubicin and gemcitabine, failed to improve the overall survival (OS) of these patients. The multi-kinase inhibitor sorafenib changed this. Only in 2008, sorafenib, a VEGFR-inhibitor, demonstrated its efficacy in treating unresectable HCC in two randomized-controlled trials, and it then remained the principal option for advanced disease for about a decade. Every single one of the many drugs developed during the 10-year period from 2007 to 2016 was a failure. However, during the two-year period from 2017 through 2018, four drugs—regorafenib, lenvatinib, cabozantinib, and ramucirumab—emerged successfully from clinical trials in quick succession and became available for clinical use.

Immune checkpoint inhibitors followed a more difficult path. Targeting PD-1 and CTLA-4 produced measurable tumor responses, but monotherapies fell short of demonstrating evidence of significant survival extension in advanced disease. The turning point came with combinations. Atezolizumab and bevacizumab were the first immunotherapy regimen to demonstrate clear superiority in improving the survival of patients with unresectable HCC compared to sorafenib, and durvalumab (Durva) plus tremelimumab (Treme) later became another mainstay. Immunotherapy has since moved beyond advanced disease, and systemic therapy is now indicated for any stage of the disease.

Controversies and unresolved questions

Sequencing of systemic therapy

Since checkpoint-based combinations displaced sorafenib as the default first-line option, the main debate has been which regimen to use first, and for whom. Most pivotal trials compared a new regimen with sorafenib or lenvatinib rather than with each other, so direct randomized evidence for ranking atezolizumab plus bevacizumab, tremelimumab plus durvalumab, nivolumab plus ipilimumab, and immunotherapy-plus-TKI combinations is largely absent. Network meta-analyses have tried to fill the gap. One Bayesian analysis of 15 trials and 9,792 patients found that several combinations improved overall survival against sorafenib, but the leading regimen differed by endpoint in different syntheses. Those rankings are indirect comparisons, and they are sensitive to differences in trial populations, control arms and follow-up. Toxicity complicates the choice further: in network analyses, pairing a checkpoint inhibitor with a TKI carried a higher burden of severe treatment-related adverse events than checkpoint monotherapy.

The evidence is thinner after first-line failure. In one pooled analysis, active second-line agents compared with sorafenib showed no significant survival advantage, in contrast with the first-line setting, and the optimal order of later agents remains unsettled. Observational target-trial emulations comparing atezolizumab plus bevacizumab with tremelimumab plus durvalumab in real-world cohorts exist, but they cannot remove confounding by indication.

Alpha-fetoprotein surveillance and the search for better biomarkers

Alpha-fetoprotein (AFP) has been the classic serum marker for HCC for decades, yet its limitations are well documented. Reviews have estimated that about one-third of patients with HCC lack AFP elevation, while a separate analysis using a healthy-population cutoff classified about 15% of HCC patients as AFP-negative, so reported figures depend heavily on definitions. AFP is also raised in many non-malignant liver conditions, which lowers its specificity, and it is especially insensitive in hepatitis C-related tumors. Guidelines still recommend ultrasound with or without AFP at roughly six-month intervals, but fewer than one in five people at risk are reported to receive surveillance, so the weakness of the test has practical consequences.

The leading alternative is the GALAD score, which combines sex, age, AFP, AFP-L3 and des-gamma-carboxyprothrombin. In a phase 3 validation study in patients with cirrhosis, GALAD outperformed AFP for detection in the 12 months before diagnosis (AUC 0.78 versus 0.66); at 82% specificity, sensitivity was 62% versus 41%. Critics point out that this study did not compare GALAD with ultrasound plus AFP for early-stage tumors, that earlier phase 2 performance may have been overstated, and that the advantage over AFP was smaller for non-viral etiologies. External validations in Latin American and European cohorts have reported lower discrimination, which keeps the question of whether GALAD should replace AFP in guidelines open.

Metabolic-risk HCC

Metabolic dysfunction-associated steatotic liver disease (MASLD) is widely described as the fastest-growing contributor to liver cancer, with estimates of its share ranging up to about 35% of cases worldwide and varying by region. Regional estimates differ: one analysis places metabolic-risk HCC at 10–20% of cases in Western countries and 5–10% in Asia. A central unresolved issue is the non-cirrhotic case. Major series report that 35–55% of MASLD-related HCC arises without cirrhosis, yet the per-year incidence in non-cirrhotic MASLD is far lower than in steatohepatitis with cirrhosis. This creates a surveillance dilemma, because current US guidance generally limits surveillance to patients with cirrhosis or advanced fibrosis, while many tumors in this group are found at more advanced stages.

Whether metabolic-risk HCC differs biologically from viral HCC is also unsettled. Patients with MASLD-related HCC tend to be older, more often male, and less often have clinically significant portal hypertension, and a steatohepatitic histological variant has been described. Data on differential response to systemic therapy are mixed and mostly retrospective. Patients with non-viral liver disease are also poorly represented in many risk-prediction studies, which limits how confidently findings from viral-hepatitis cohorts can be applied.

Intrahepatic cholangiocarcinoma, cost and transplant access

Management of intrahepatic cholangiocarcinoma is less settled than that of HCC. Its evidence base is smaller, many systemic data come from trials that enrolled mixed biliary-tract tumors, and the role of adjuvant therapy after resection remains uncertain. Whether HCC-derived strategies transfer to cholangiocarcinoma is an open question.

Cost-effectiveness is a further dispute. Immunotherapy combinations are expensive, and their survival gains are typically measured in months, so the value assessments differ across health systems, price negotiations and reimbursement settings. Access to transplantation is limited by donor shortages and by eligibility rules that vary between centres and countries, and debates continue over whether selection criteria should be widened and how allocation should be weighed against the rising demand from metabolic-risk patients.

References

1. Recent Trends in Liver Cancer: Epidemiology, Risk Factors, and Diagnostic Techniquesncbi.nlm.nih.gov
2. Epidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma - PMCpmc.ncbi.nlm.nih.gov
3. A case report of primary intrahepatic adeno squamous cell cholangiocarcinomancbi.nlm.nih.gov
4. Synchronous Double Primary Combined Hepatocellular-cholangiocarcinoma and Cholangiolocarcinoma in a Cirrhotic Liver - PMCpmc.ncbi.nlm.nih.gov
5. Combined hepatocellular-cholangiocarcinoma: An analysis of clinicopathological characteristics after surgeryncbi.nlm.nih.gov
6. Fibrolamellar Variant of Hepatocellular Carcinoma in a Young Femalencbi.nlm.nih.gov
7. Pediatric epithelial liver tumorsatlasgeneticsoncology.org
8. Pediatric hepatocellular carcinoma - PMC - NIHpmc.ncbi.nlm.nih.gov
9. Histological Heterogeneity of Primary Liver Cancers: Clinical Relevance, Diagnostic Pitfalls and the Pathologist’s Rolencbi.nlm.nih.gov
10. Fibrolamellar Hepatocellular Carcinomaappliedradiology.com
11. Liver Cancer in Children and Teens - Together by St. Jude™together.stjude.org
12. Types of Liver Cancer: Cholangiocarcinoma, HCC and Morecancercenter.com
13. Global epidemiology of liver cancer 2022: An emphasis on geographic disparities - PMCpmc.ncbi.nlm.nih.gov
14. Lancet Commission 2025 Calls for Urgent Global Action: 60% of Liver Cancers Are Preventablekarger.com
15. Primary Liver Cancer Trends Worldwide and in China: Analysis of GLOBOCAN 2022 Data and Disease Management Implications - PMCpmc.ncbi.nlm.nih.gov
16. Global, regional, and national burden of hepatocellular carcinoma and contribution of nine modifiable risk factors across 185 countries/territories in 2022 - ScienceDirectsciencedirect.com
17. The Lancet: Three in five liver cancer cases due to preventable risk factors; obesity-linked cases on the rise, new analysis suggesteurekalert.org
18. Mortality and Overall Survival Trends of Primary Liver Cancer in the United Statesacademic.oup.com
19. Reversing the rise of liver cancer - The Lancetthelancet.com
20. Three in Five Liver Cancer Cases May Be Due to Preventable Risk Factors, <em>The Lancet</em> Commission Findsascopost.com
21. Trends of primary liver cancer incidence and mortality in the United States: A population-based study over the last four decadesncbi.nlm.nih.gov
22. Secular trends in the incidence, prevalence, and survival of primary liver cancer in the United Kingdom from 2000-2021: a population-based cohort studymedrxiv.org
23. Survival Trends of Liver Cancer in 1975-2019 and Projection for 2020-2024: A 50-Year Analysis Using SEER Database - PubMedpubmed.ncbi.nlm.nih.gov
24. Worldwide Incident Hepatocellular Carcinoma Cases Attributable to Major Risk Factors - PMCpmc.ncbi.nlm.nih.gov
25. Population attributable fractions of risk factors for hepatocellular carcinoma in the United States - Makarova‐Rusher - 2016 - Cancer - Wiley Online Libraryacsjournals.onlinelibrary.wiley.com
26. Fifteen-Year Population Attributable Fractions and Causal Pies of Risk Factors for Newly Developed Hepatocellular Carcinomas in 11,801 Men in Taiwanncbi.nlm.nih.gov
27. The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment - The Lancetthelancet.com
28. Alcohol and hepatocellular carcinoma: A review and a point of view - PMCpmc.ncbi.nlm.nih.gov
29. Challenging Role of Dietary Aflatoxin B1 Exposure and Hepatitis B Infection on Risk of Hepatocellular Carcinomancbi.nlm.nih.gov
30. Genome-wide association study of TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and hepatitis B virus infection in Guangxibiorxiv.org
31. Cooperation Between Aflatoxin-Induced p53 Aberrations and Hepatitis B Virus in Hepatocellular Carcinomancbi.nlm.nih.gov
32. The simple changes that could prevent three in five liver cancer casesaol.com
33. Chronic hepatitis B and metabolic dysfunction-associated steatotic liver disease: Metabolic risk factors are key drivers of hepatocellular carcinomancbi.nlm.nih.gov
34. Genetic variants underlying precancerous conditions of hepatocellular carcinomancbi.nlm.nih.gov
35. Geographic and Viral Etiology Patterns of TERT Promoter and CTNNB1 Exon 3 Mutations in Hepatocellular Carcinoma: A Comprehensive Review - PMCpmc.ncbi.nlm.nih.gov
36. CTNNB1 mutations, TERT polymorphism and CD8+ cell densities in resected hepatocellular carcinoma are associated with longer time to recurrencencbi.nlm.nih.gov
37. Frequent somatic TERT promoter mutations and CTNNB1 mutations in hepatocellular carcinomancbi.nlm.nih.gov
38. Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinomancbi.nlm.nih.gov
39. Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailandncbi.nlm.nih.gov
40. New understanding of the molecular pathogenesis and therapeutic progress of hepatocellular carcinoma - PubMedpubmed.ncbi.nlm.nih.gov
41. Liver cancer with concomitant TP53 and CTNNB1 mutations: a case reportncbi.nlm.nih.gov
42. TERT-TP53 mutations: a novel biomarker pair for hepatocellular carcinoma recurrence and prognosisnature.com
43. Pathology Outlines - Hepatocellular carcinoma overviewpathologyoutlines.com
44. The strengths and weaknesses of gross and histopathological evaluation in hepatocellular carcinoma: a brief reviewsurgexppathol.biomedcentral.com
45. Histopathology of hepatocellular carcinoma - when and whatoaepublish.com
46. Central histopathological review of a European hepatocellular carcinoma cohort: impact of the WHO 2019 classification on histological diagnosis and TNM staginglink.springer.com
47. Update on Pathologic and Radiologic Diagnosis of Combined Hepatocellular-Cholangiocarcinomae-jlc.org
48. An Updated Review of Combined Hepatocellular Cholangiocarcinoma: A Rare and Poorly Understood Neoplasmncbi.nlm.nih.gov
49. Pathology Outlines - Combined hepatocellular carcinoma-cholangiocarcinomapathologyoutlines.com
50. The Diagnostic Approach towards Combined Hepatocellular-Cholangiocarcinoma—State of the Art and Future Perspectivesdoi.org
51. Radiological diagnosis of hepatocellular carcinoma does not preclude biopsy before treatment - PMCpmc.ncbi.nlm.nih.gov
52. [Hepatocellular carcinoma: Histological and molecular classifications] - PubMedpubmed.ncbi.nlm.nih.gov
53. Specific features of ß-catenin-mutated hepatocellular carcinomasnature.com
54. Computational analysis of TP53 vs. CTNNB1 mutations in hepatocellular carcinoma suggests distinct cancer subtypes with differential gene expression profiles and chromatin states - ScienceDirectsciencedirect.com
55. CHROMOPHOBE HEPATOCELLULAR CARCINOMA: DIAGNOSTIC CHALLENGESncbi.nlm.nih.gov
56. Hepatocellular Carcinoma Signs and Symptoms - Rare Disease Advisorrarediseaseadvisor.com
57. Factors associated with unrecognized cirrhosis in patients with hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
58. Paraneoplastic Syndromes in Hepatocellular Carcinoma, Epidemiology, and Survival: A Retrospective Seven Years Studyncbi.nlm.nih.gov
59. Cirrhosis: Diagnosis and Managementaafp.org
60. Paraneoplastic Cutaneous Manifestations of Hepatocellular Carcinoma. A Systematic Review and Meta-analysisncbi.nlm.nih.gov
61. Intractable Fasting Hypoglycemia as a Manifestation of Hepatocellular Carcinomancbi.nlm.nih.gov
62. Hypoglycaemia in a patient with huge hepatocellular carcinoma responsive to chemoembolisation and tumour resection - PMCpmc.ncbi.nlm.nih.gov
63. A Case of Humoral Hypercalcemia of Malignancy Secondary to Hepatocellular Carcinoma with Fulminant Clinical Coursencbi.nlm.nih.gov
64. Search for Effective Serum Tumor Markers for Early Diagnosis of Hepatocellular Carcinoma Associated with Hepatitis Cncbi.nlm.nih.gov
65. Core Concepts - Surveillance for Hepatocellular Carcinoma - Evaluation, Staging, and Monitoring of Chronic Hepatitis C - Hepatitis C Onlinehepatitisc.uw.edu
66. Optimal surveillance intervals for hepatocellular carcinoma screening in cirrhotic patients with hepatitis C infection: a Taiwanese national cohort study - PMCpmc.ncbi.nlm.nih.gov
67. Clinical guideline SEOM: hepatocellular carcinomancbi.nlm.nih.gov
68. A Circulating Biomarker-based Framework for Diagnosis of Hepatocellular Carcinoma in a Clinically Relevant Model of Non-alcoholic Steatohepatitis; An OAD to NASHarxiv.org
69. AASLD Prevention, Diagnosis, and Treatment of Hepatocellular Carcinoma Guideline Summary - Guideline Centralguidelinecentral.com
70. AMPLIFAI: A Multiphase CT Dataset for Benchmarking Clinical Reasoning in LI-RADS Assessment of Liver Lesionsarxiv.org
71. 723 PRACTICE GUIDANCE|Hepatology, VOL. 68, NO. 2, 2018 VIRAL HEPATITISaasld.org
72. Surveillance for hepatocellular carcinoma (HCC) among people with CHB - Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection - NCBI Bookshelfncbi.nlm.nih.gov
73. Comparison between using hepatocellular carcinoma (HCC) risk scores and the HCC national guideline to identify high‐risk chronic hepatitis B patients for HCC surveillance in Thailandncbi.nlm.nih.gov
74. Hepatocellular Carcinoma (HCC) Guidelines: Guidelines Summaryemedicine.medscape.com
75. CT/MRI LI-RADS 2024 Update: Treatment Response Assessmentpubs.rsna.org
76. Full article: LI-RADS: a conceptual and historical review from its beginning to its recent integration into AASLD clinical practice guidancetandfonline.com
77. Liver Imaging Reporting and Data System (LI-RADS) Version 2018: Imaging of Hepatocellular Carcinoma in At-Risk Patientspubs.rsna.org
78. Comparison of Liver Biopsy and Noninvasive Methods for Diagnosis of Hepatocellular Carcinoma - Clinical Gastroenterology and Hepatologycghjournal.org
79. Non-invasive diagnosis strategy of hepatocellular carcinoma in low-risk population - PMCpmc.ncbi.nlm.nih.gov
80. Hepatocellular Carcinoma (HCC) Workup: Approach Considerations, Laboratory Studies, Ultrasonographyemedicine.medscape.com
81. Current Perspectives on the BCLC Staging System for Hepatocellular Carcinomadiagnosticimaging.com
82. Current strategy for staging and treatment: the BCLC update and future prospects - PubMedpubmed.ncbi.nlm.nih.gov
83. Adherence to the modified Barcelona Clinic Liver Cancer guidelines: Results from a high-volume liver surgery center in East Asiasncbi.nlm.nih.gov
84. Comparative Analysis of Albumin-Bilirubin (ALBI) Score and Child-Pugh Score for Prognostic Stratification in Hepatocellular Carcinoma Patients: A Single-Center Experience From North India - PMCpmc.ncbi.nlm.nih.gov
85. Alteration of prognostic efficacy of albumin‐bilirubin grade and Child‐Pugh score according to liver fibrosis in hepatocellular carcinoma patients with Child‐Pugh A following hepatectomyncbi.nlm.nih.gov
86. Breaking the Child-Pugh Dogma in Hepatocellular Carcinomaascopubs.org
87. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update - PMCpmc.ncbi.nlm.nih.gov
88. Milan Criteria - an overviewsciencedirect.com
89. Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteriamdpi.com
90. Comparison of Up-to-seven criteria with Milan Criteria for liver transplantation in patients with HCCoatext.com
91. Prognostic Significance of Up-to-Seven Criteria Versus Milan Criteria for Hepatocellular Carcinoma Patients Undergoing Resection or Locoregional Therapy: A Systematic Review and Meta-Analysis - PMCpmc.ncbi.nlm.nih.gov
92. Barcelona-Clinic Liver Cancer (BCLC) Staging Classification and Treatment Guidelines Calculatormdcalc.com
93. Comparative Analysis of Albumin-Bilirubin (ALBI) Score and Child-Pugh Score for Prognostic Stratification in Hepatocellular Carcinoma Patients: A Single-Center Experience From North India - PubMedpubmed.ncbi.nlm.nih.gov
94. The albumin-bilirubin score stratifies the outcomes of Child-Pugh class A patients after resection of hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
95. Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria: Multidisciplinary Approach to Improve Outcome - PMCpmc.ncbi.nlm.nih.gov
96. New frontiers in liver resection for hepatocellular carcinoma - ScienceDirectsciencedirect.com
97. One- versus two-stage partial hepatectomy for large resectable solitary hepatocellular carcinomas determined preoperatively to have a narrow resection margin: a propensity score matching analysis - Li - HepatoBiliary Surgery and Nutritionhbsn.amegroups.org
98. Evaluation of liver regeneration and post-hepatectomy liver failure after hemihepatectomy in patients with hepatocellular carcinomancbi.nlm.nih.gov
99. ALPPS: PAST, PRESENT AND FUTUREncbi.nlm.nih.gov
100. Survival in liver transplantation for hepatocellular carcinoma according to the milan criteria - HPBhpbonline.org
101. Survival Analysis after Living Donor Liver Transplantation for Hepatocellular Carcinoma: A Single Center Cohort Studyncbi.nlm.nih.gov
102. Hepatocellular Carcinoma Recurrence After Liver Transplantation: Current Insights and Future Directionsncbi.nlm.nih.gov
103. Factors predicting survival after post-transplant hepatocellular carcinoma recurrencencbi.nlm.nih.gov
104. Neoadjuvant treatment strategies for hepatocellular carcinomawjgnet.com
105. Selection of patients of hepatocellular carcinoma beyond the Milan criteria for liver transplantation - PMCpmc.ncbi.nlm.nih.gov
106. Emerging Trends in Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: A Focus on Liver Transplant Candidates - Yu - 2025 - Cancer Reports - Wiley Online Libraryonlinelibrary.wiley.com
107. Hepatocellular carcinoma and liver transplant: What about neo- and adjuvant immunotherapy - ScienceDirectsciencedirect.com
108. Neoadjuvant therapy for hepatocellular carcinoma—priming precision innovations to transform HCC treatmentncbi.nlm.nih.gov
109. Radiofrequency ablation of hepatocellular carcinoma: Current status, challenges, and prospects - ScienceDirectsciencedirect.com
110. SAGES/AHPBA Guidelines for the Use of Microwave and Radiofrequency Liver Ablation for the Surgical Treatment of Hepatocellular Carcinoma or Colorectal Liver Metastases less than 5 cm - A SAGES Publicationsages.org
111. Comparative Effectiveness of Radiofrequency or Microwave Ablation and Chemotherapy for the Treatment of Large (>5 cm) Hepatocellular Carcinoma Tumors - PMCpmc.ncbi.nlm.nih.gov
112. Multibipolar radiofrequency vs single needle microwave ablation for the treatment of newly diagnosed hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
113. Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameterncbi.nlm.nih.gov
114. Therapeutic Efficacy of Percutaneous Radiofrequency Ablation versus Microwave Ablation for Hepatocellular Carcinomancbi.nlm.nih.gov
115. Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameternature.com
116. The Combination Strategy of Transarterial Chemoembolization and Radiofrequency Ablation or Microwave Ablation against Hepatocellular Carcinomancbi.nlm.nih.gov
117. HAIC versus TACE for patients with unresectable hepatocellular carcinoma: A systematic review and meta-analysisncbi.nlm.nih.gov
118. HAIC versus TACE for patients with unresectable hepatocellular carcinoma: A systematic review and meta-analysisovid.com
119. TACE-HAIC versus TACE as Initial Regional Therapy for Unresectable Huge Hepatocellular Carcinoma (>10 cm): A Propensity Score-Matched Study - PMCpmc.ncbi.nlm.nih.gov
120. Overview of Yttrium-90 radioembolization for advanced hepatocellular carcinoma: Current status and future perspectives - PubMedpubmed.ncbi.nlm.nih.gov
121. Advances in Y-90 radioembolization for the treatment of hepatocellular carcinomaoaepublish.com
122. Yttrium-90 glass microsphere radioembolization as frontline treatment for hepatocellular carcinoma with localized portal vein invasionlink.springer.com
123. VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trialsncbi.nlm.nih.gov
124. Radiofrequency and Microwave Ablation of Liver Tumorsmcgs.bcbsfl.com
125. TACE-HAIC versus HAIC combined with TKIs and ICIs for hepatocellular carcinoma with a high tumor burden—a propensity-score matching comparative studyncbi.nlm.nih.gov
126. Transcatheter Arterial Chemoembolization Combined with Hepatic Arterial Infusion Chemotherapy Versus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Systematic Review and Meta-analysisncbi.nlm.nih.gov
127. Yttrium-90 radioembolization for unresectable hepatocellular carcinoma: predictive modeling strategies to anticipate tumor response and improve patient selectionlink.springer.com
128. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Futurencbi.nlm.nih.gov
129. A Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethistacdn.clinicaltrials.gov
130. Treating hepatocellular carcinoma progression following first-line sorafenib: therapeutic options and clinical observations - PMCpmc.ncbi.nlm.nih.gov
131. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinomancbi.nlm.nih.gov
132. Emerging therapies in advanced hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
133. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond - Cancer Treatment Reviewscancertreatmentreviews.com
134. Cabozantinib and Pembrolizumab for the First-Line Treatment of Advanced Liver Cancercdn.clinicaltrials.gov
135. Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancerscdn.clinicaltrials.gov
136. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial - The Lancet Oncologythelancet.com
137. Nivolumab/Ipilimumab in Patients With Sorafenib-Pretreated Hepatocellular Carcinoma - The ASCO Postascopost.com
138. First-line atezolizumab/bevacizumab or durvalumab/tremelimumab in advanced hepatocellular carcinoma: a real world, multicenter retrospective studyncbi.nlm.nih.gov
139. Two Cases of Advanced Hepatocellular Carcinoma Who Responded Well to the Combination of Durvalumab Plus Tremelimumab After Disease Progression During Atezolizumab Plus Bevacizumab Therapy Under Bevacizumab Withdrawalncbi.nlm.nih.gov
140. First-line atezolizumab/bevacizumab or durvalumab/tremelimumab in advanced hepatocellular carcinoma: a real world, multicenter retrospective studyacademic.oup.com
141. Comparative Effectiveness and Safety of Atezolizumab-Bevacizumab and Durvalumab-Tremelimumab as First-Line Systemic Therapy for Hepatocellular Carcinoma: A Real-World Study - PubMedpubmed.ncbi.nlm.nih.gov
142. Atezolizumab Plus Bevacizumab Versus Durvalumab Plus Tremelimumab for Advanced Hepatocellular Carcinoma: A Propensity-Score-Matched Analysis - PMCpmc.ncbi.nlm.nih.gov
143. Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040☆ - Annals of Oncologyannalsofoncology.org
144. Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma - PMCpmc.ncbi.nlm.nih.gov
145. Comparison of outcomes of second-line durvalumab plus tremelimumab and lenvatinib following first-line atezolizumab plus bevacizumab in unresectable hepatocellular carcinomamedrxiv.org
146. First-Line Targeted Therapy for Hepatocellular Carcinoma: Role of Atezolizumab/Bevacizumab Combinationdoi.org
147. Real-World, Observational, Retrospective Study to Evaluate the Effectiveness and Safety of Treatment with Sorafenib in Patients with Advanced Hepatocellular Carcinomancbi.nlm.nih.gov
148. Safety and Efficacy of Telatinib in Combination With Keytruda in Subjects With Advanced Stomach and Gastroesophageal Junction Cancers or Hepatocellular Carcinomacdn.clinicaltrials.gov
149. Phase III CheckMate 459 Trial in Unresectable HCC Misses Primary Endpointtargetedonc.com
150. Challenges in Adjuvant Immunotherapy after Resection or Ablation for Hepatocellular Carcinoma at High-Risk of Recurrence - PMCpmc.ncbi.nlm.nih.gov
151. Adjuvant therapy in hepatocellular carcinoma: the IMbrave050 trial - The Lancetthelancet.com
152. Adjuvant immunotherapy for hepatocellular carcinoma: Precision selection of the optimal target population as the core strategy - ScienceDirectsciencedirect.com
153. Adjuvant immunotherapy improves recurrence-free and overall survival following surgical resection for intermediate/advanced hepatocellular carcinoma a multicenter propensity matching analysis - PMCpmc.ncbi.nlm.nih.gov
154. Adjuvant cytokine-induced killer cell immunotherapy for hepatocellular carcinoma: a propensity score-matched analysis of real-world datancbi.nlm.nih.gov
155. GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Solid Tumor Malignanciesclinicaltrials.gov
156. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trialsclincancerres.aacrjournals.org
157. Enhanced Functionality of Anti‐GPC3 CAR‐T Cells Against Hepatocellular Carcinoma Through Locoregional Administrationncbi.nlm.nih.gov
158. Autologous CAR T Cells Targeting GPC3 (RPCAR01) for the Treatment of Advanced or Metastatic GPC3 Expressing Hepatocellular Carcinomaclinicaltrials.gov
159. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinomancbi.nlm.nih.gov
160. Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances - PMCpmc.ncbi.nlm.nih.gov
161. Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinomancbi.nlm.nih.gov
162. Novel GPC3 CAR-T Cell Therapy for Hepatocellular Carcinomaclinicaltrials.gov
163. Chronic hepatitis B infection and liver cancerncbi.nlm.nih.gov
164. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group - PubMedpubmed.ncbi.nlm.nih.gov
165. Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer - PubMedpubmed.ncbi.nlm.nih.gov
166. Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer - ScienceDirectsciencedirect.com
167. Letter: vaccination for global control of hepatitis B—from prevention to eliminationonlinelibrary.wiley.com
168. Hepatitis C-related hepatocellular carcinoma in the era of new generation antiviralsncbi.nlm.nih.gov
169. Risk of hepatocellular carcinoma for patients treated with direct-acting antivirals: steps after hepatitis C virus eradication to achieve elimination - PMCpmc.ncbi.nlm.nih.gov
170. Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigeneticsncbi.nlm.nih.gov
171. Lancet Commission 2025 Calls for Urgent Global Action: 60% of Liver Cancers Are Preventable - PMCpmc.ncbi.nlm.nih.gov
172. Newsletter Newsletters Events Events Podcasts Videos Africanewseuronews.com
173. Reducing the global burden of liver cancer: Recommendations from The Lancet commissioneurekalert.org
174. Risk of Hepatocellular Carcinoma After Direct-Acting Antiviral Treatment for Hepatitis C Virus Infection in People With Human Immunodeficiency Virus - PMCpmc.ncbi.nlm.nih.gov
175. Cancer Prevention in Low-Resource Countries: An Overview of the Opportunityascopubs.org
176. The current trends in the health burden of primary liver cancer across the globe - PMCpmc.ncbi.nlm.nih.gov
177. Global, regional and national burden of liver cancer 1990–2021: a systematic analysis of the global burden of disease study 2021bmcpublichealth.biomedcentral.com
178. A Systematic Review and Meta‐Analysis of Oncologic Liver Resections in Low‐ and Middle‐Income Countries: Opportunities to Improve Evidence and Outcomesncbi.nlm.nih.gov
179. Hepatocellular carcinoma surveillance: a health economic evaluation - PMCpmc.ncbi.nlm.nih.gov
180. Socioeconomic inequalities in diagnostics, care and survival outcomes for hepatocellular carcinoma in Sweden: a nationwide cohort study - ScienceDirectsciencedirect.com
181. Reversing the global burden of hepatocellular carcinoma - Journal of Hepatologyjournal-of-hepatology.eu
182. Most liver cancer preventable, Lancet Commission finds - Juta MedicalBriefmedicalbrief.co.za
183. Disparities in Diagnosis, Management, and Outcomes of Hepatocellular Carcinoma: A Review of Global and Sociodemographic Factorslink.springer.com
184. Racial, Ethnic, and Socioeconomic Disparities in Treatment Delay among Patients with Hepatocellular Carcinoma in the United States - PMCpmc.ncbi.nlm.nih.gov
185. Racial disparities in access to liver transplantation in patients with early-stage hepatocellular carcinoma - PubMedpubmed.ncbi.nlm.nih.gov
186. Dissecting disease, race, ethnicity, and socioeconomic factors for hepatocellular carcinoma: An analysis from the United States Safety Net Collaborative - PubMedpubmed.ncbi.nlm.nih.gov
187. Race/ethnicity and socioeconomic position in emergency department utilization in patients with hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
188. Medline ® Abstract for Reference 32 of 'Staging and prognostic factors in hepatocellular carcinoma' - UpToDateuptodate.com
189. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆ - Annals of Oncologyannalsofoncology.org
190. Survival outcomes of hepatectomy for stage B Hepatocellular carcinoma in the BCLC classificationwjso.biomedcentral.com
191. Survival Outcomes Among Patients With Hepatocellular Carcinoma in a Large Integrated US Health Systemjamanetwork.com
192. Conditional survival estimate in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy with/without concurrent radiotherapyncbi.nlm.nih.gov
193. Resection versus ablation for hepatocellular carcinoma: role of initial treatment - PMCpmc.ncbi.nlm.nih.gov
194. Impact of follow-up interval on patients with hepatocellular carcinoma after curative ablationncbi.nlm.nih.gov
195. Risk Factors for Recurrence in Patients with Hepatocellular Carcinoma After Curative Resection or Ablation - PMCpmc.ncbi.nlm.nih.gov
196. Pattern of disease recurrence and its implications for postoperative surveillance after curative hepatectomy for hepatocellular carcinoma: experience from a single center - Lee - HepatoBiliary Surgery and Nutritionhbsn.amegroups.org
197. Computed tomography follow-up for the detection of hepatocellular carcinoma recurrence after initial radiofrequency ablation: a single-center experience - PubMedpubmed.ncbi.nlm.nih.gov
198. Risk of early hepatocellular carcinoma recurrence following liver resection: arbitrary specification or possible target to improve outcome? - PMCpmc.ncbi.nlm.nih.gov
199. AI-Guided Surveillance and Curative Salvage of Recurrence After Hepatocellular Carcinoma Resection or Ablationclinicaltrials.gov
200. High Prevalence of Cardiometabolic Risks and Health Needs Among Patients With Hepatocellular Carcinoma After Treatment: A Cross-sectional Study - PubMedpubmed.ncbi.nlm.nih.gov
201. Cardiometabolic Comorbidities in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review - ScienceDirectsciencedirect.com
202. How Two Nobel Prize-winning Discoveries Help Shape Liver Cancer Prevention - American Association for Cancer Research (AACR)aacr.org
203. Nobel Prize in Physiology or Medicine 1976nobelprize.org
204. Baruch Samuel Blumbergen.wikipedia.org
205. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We?ijbs.com
206. (PDF) The history of alpha-fetoprotein discoveryresearchgate.net
207. Alpha-Fetoprotein in the 1990slink.springer.com
208. Systemic treatments for hepatocellular carcinoma: challenges and future perspectivesncbi.nlm.nih.gov
209. Systemic Therapy for Hepatocellular Carcinoma: Latest Advancesncbi.nlm.nih.gov
210. Immunotherapy in Hepatocellular Carcinomancbi.nlm.nih.gov
211. Systemic therapy for hepatocellular carcinoma, from the early to the advanced stage: a Japanese perspectivencbi.nlm.nih.gov
212. Human Alphafetoprotein 1956–1978link.springer.com
213. Baruch S. Blumberg, MD, PhD: Researchfoxchase.org
214. Baruch Blumberg, MD, DPhil » Hepatitis B Foundationhepb.org
215. A dual-level Bayesian network meta-analysis of first-line immunotherapy in advanced hepatocellular carcinoma: strategy-level and regimen-level evidence - PMCpmc.ncbi.nlm.nih.gov
216. Comprehensive Safety and Efficacy Evaluation of Immunotherapy Combination Approaches Versus Tyrosine Kinase Inhibitor Monotherapy as First-Line Treatment of Hepatocellular Carcinoma: A Network and Individual Patient Data (IPD) Meta-Analysis - PMCpmc.ncbi.nlm.nih.gov
217. Efficacy of immune-based combinations across treatment lines in advanced hepatocellular carcinoma: a systematic review and network meta-analysis - PMCpmc.ncbi.nlm.nih.gov
218. Frontiersfrontiersin.org
219. Efficacy and safety of immune-based combinations in metastatic hepatocellular carcinoma: a systematic review and network meta-analysis - PMCpmc.ncbi.nlm.nih.gov
220. Comparative effectiveness of two first-line, ICI-based regimens for advanced HCC: a target trial emulation using an electronic medical record networkncbi.nlm.nih.gov
221. Combined Immunotherapy in Treating Patients with Advanced Hepatocellular Carcinoma - PMCpmc.ncbi.nlm.nih.gov
222. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma - PMCpmc.ncbi.nlm.nih.gov
223. A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis - Gastroenterologygastrojournal.org
224. Surveillance for Hepatocellular Carcinoma in Cirrhosis: End of Monopoly for Serum Alpha Fetoprotein - Gastroenterologygastrojournal.org
225. Validation and optimization of AFP-based biomarker panels for early HCC detection in Latin America and Europencbi.nlm.nih.gov
226. Establishing alpha-fetoprotein reference ranges in patients with chronic liver disease and hepatocellular carcinoma - ScienceDirectsciencedirect.com
227. Biomarkers for the Early Detection of Hepatocellular Carcinomaaacrjournals.org
228. HCC in metabolic dysfunction-associated steatotic liver diseaseaasld.org
229. Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy responseoaepublish.com
230. Metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma: Challenges in clinical practice - PMCpmc.ncbi.nlm.nih.gov
231. Global trends and forecasts of nonalcoholic steatohepatitis causing liver cancer incidence and deathsncbi.nlm.nih.gov
232. Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumorsncbi.nlm.nih.gov
233. MASLD-related HCC: Multicenter study comparing patients with and without cirrhosisncbi.nlm.nih.gov