Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, typically arising in the setting of chronic liver disease and cirrhosis. Major risk factors include chronic hepatitis B or C infection, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD/NAFLD). HCC pathogenesis involves multiple molecular pathways including WNT/beta-catenin, TP53, telomere maintenance, and chromatin remodeling. The combination of atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) has established immunotherapy as first-line treatment for advanced HCC, based on the IMbrave150 trial.
graph LR
Accumulation_of_Driver_Mutations["Accumulation of Driver Mutations"]
WNT_Beta_Catenin_Pathway_Activation["WNT/Beta-Catenin Pathway Activation"]
Chronic_Liver_Injury_and_Cirrhosis["Chronic Liver Injury and Cirrhosis"]
Telomere_Dysfunction_and_Genomic_Instability["Telomere Dysfunction and Genomic Instability"]
Enhanced_Hepatocyte_Proliferation["Enhanced Hepatocyte Proliferation"]
Chronic_Liver_Injury_and_Cirrhosis --> Telomere_Dysfunction_and_Genomic_Instability
Chronic_Liver_Injury_and_Cirrhosis --> Accumulation_of_Driver_Mutations
Telomere_Dysfunction_and_Genomic_Instability --> WNT_Beta_Catenin_Pathway_Activation
WNT_Beta_Catenin_Pathway_Activation --> Enhanced_Hepatocyte_Proliferation
style Accumulation_of_Driver_Mutations fill:#dbeafe
style WNT_Beta_Catenin_Pathway_Activation fill:#dbeafe
style Chronic_Liver_Injury_and_Cirrhosis fill:#dbeafe
style Telomere_Dysfunction_and_Genomic_Instability fill:#dbeafe
style Enhanced_Hepatocyte_Proliferation fill:#dbeafe
name: Hepatocellular Carcinoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-02-27T22:30:28Z'
description: >-
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, typically arising
in the setting of chronic liver disease and cirrhosis. Major risk factors include chronic
hepatitis B or C infection, alcohol-related liver disease, and metabolic dysfunction-associated
steatotic liver disease (MASLD/NAFLD). HCC pathogenesis involves multiple molecular pathways
including WNT/beta-catenin, TP53, telomere maintenance, and chromatin remodeling. The
combination of atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) has established
immunotherapy as first-line treatment for advanced HCC, based on the IMbrave150 trial.
categories:
- Gastrointestinal Cancer
- Hepatobiliary Cancer
- Liver Cancer
parents:
- liver carcinoma
has_subtypes:
- name: Viral Hepatitis-Associated HCC
description: >-
HCC arising in the context of chronic hepatitis B or C infection. HBV can be directly
oncogenic through viral integration, while HCV promotes HCC primarily through cirrhosis
and chronic inflammation.
- name: Alcohol-Related HCC
description: >-
HCC arising in alcohol-related liver disease and cirrhosis. Associated with specific
molecular features and generally presents at more advanced stage.
- name: MASLD-Associated HCC
description: >-
HCC arising in metabolic dysfunction-associated steatotic liver disease (formerly NAFLD/NASH).
Increasingly common subtype that can occur even without cirrhosis. May have distinct
immune microenvironment features affecting immunotherapy response.
- name: Fibrolamellar HCC
description: >-
Rare variant occurring in younger patients without cirrhosis. Characterized by DNAJB1-PRKACA
fusion. Distinct clinical behavior and treatment considerations.
pathophysiology:
- name: Chronic Liver Injury and Cirrhosis
description: >-
Most HCC arises in the context of chronic liver disease and cirrhosis. Persistent
hepatocyte death and regeneration in an inflammatory environment promotes accumulation
of genetic alterations. Cirrhosis itself is a premalignant condition with ongoing
oxidative stress and genomic instability.
evidence:
- reference: PMID:41567639
supports: PARTIAL
snippet: HCC typically arises in patients with chronic liver disease, including hepatitis, cirrhosis, and non-alcoholic fatty liver diseases.
explanation: This abstract states that HCC commonly arises in chronic liver disease and cirrhosis, supporting the mechanism described.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
downstream:
- target: Telomere Dysfunction and Genomic Instability
description: Repeated hepatocyte division leads to telomere shortening
- target: Accumulation of Driver Mutations
description: Chronic regeneration promotes mutation accumulation
- name: Telomere Dysfunction and Genomic Instability
description: >-
Chronic hepatocyte proliferation leads to telomere shortening, causing genomic instability.
TERT promoter mutations, which are the most common HCC mutations, reactivate telomerase
to enable unlimited replication. This creates a checkpoint bypass allowing survival
of genetically unstable cells.
biological_processes:
- preferred_term: telomere maintenance
modifier: ABNORMAL
term:
id: GO:0000723
label: telomere maintenance
downstream:
- target: WNT/Beta-Catenin Pathway Activation
description: Genomic instability promotes acquisition of pathway-activating mutations
- name: Accumulation of Driver Mutations
description: >-
Multiple driver genes are recurrently mutated in HCC, including TERT promoter (60%),
TP53 (30%), CTNNB1 (30%), AXIN1 (10%), and ARID1A (10%). These mutations affect
telomere maintenance, cell cycle control, WNT signaling, and chromatin remodeling.
biological_processes:
- preferred_term: DNA repair
modifier: DECREASED
term:
id: GO:0006281
label: DNA repair
- name: WNT/Beta-Catenin Pathway Activation
description: >-
Activating mutations in CTNNB1 (beta-catenin) or inactivating mutations in AXIN1
lead to constitutive WNT pathway activation. This drives cell proliferation and is
associated with a distinct molecular subclass of HCC with specific clinical features
including cholestasis and immune exclusion.
biological_processes:
- preferred_term: Wnt signaling pathway
modifier: INCREASED
term:
id: GO:0016055
label: Wnt signaling pathway
downstream:
- target: Enhanced Hepatocyte Proliferation
description: WNT signaling drives cell proliferation and stemness
- name: TP53 Pathway Inactivation
description: >-
TP53 mutations are common in HCC, particularly in HBV-associated and aflatoxin-associated
tumors. Loss of p53 function removes a critical checkpoint, allowing survival of cells
with DNA damage and promoting genomic instability.
biological_processes:
- preferred_term: apoptotic process
modifier: DECREASED
term:
id: GO:0006915
label: apoptotic process
- name: Enhanced Hepatocyte Proliferation
description: >-
Combined effects of telomerase reactivation, cell cycle checkpoint loss, and
mitogenic signaling drive uncontrolled hepatocyte proliferation and tumor growth.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
- name: Angiogenesis and VEGF Signaling
description: >-
HCC is a highly vascular tumor dependent on angiogenesis. VEGF signaling promotes
new blood vessel formation supplying the tumor. VEGF also has immunosuppressive
effects, contributing to the immune-excluded microenvironment. This provides the
rationale for anti-VEGF therapy in combination with immunotherapy.
evidence:
- reference: PMID:19637355
supports: SUPPORT
snippet: "Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression."
explanation: "Abstract notes HCC is highly vascular and angiogenesis plays a major role, supporting this mechanism."
biological_processes:
- preferred_term: angiogenesis
modifier: INCREASED
term:
id: GO:0001525
label: angiogenesis
histopathology:
- name: Hepatocellular Carcinoma
finding_term:
preferred_term: Hepatocellular Carcinoma
term:
id: NCIT:C3099
label: Hepatocellular Carcinoma
frequency: VERY_FREQUENT
description: Hepatocellular carcinoma is the most common primary liver malignancy.
evidence:
- reference: PMID:27785449
supports: SUPPORT
snippet: "Hepatocellular carcinoma (HCC) is the most common primary liver malignancy"
explanation: Abstract states that HCC is the most common primary liver malignancy.
phenotypes:
- category: Hepatic
name: Hepatomegaly
frequency: FREQUENT
description: >-
Liver enlargement from tumor mass. May be palpable as a hard, irregular mass in the
right upper quadrant.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
- category: Hepatic
name: Ascites
frequency: FREQUENT
description: >-
Abdominal fluid accumulation from portal hypertension (cirrhosis) and/or tumor-related
factors. Presence indicates advanced disease and decompensated liver function.
phenotype_term:
preferred_term: Ascites
term:
id: HP:0001541
label: Ascites
- category: Hepatic
name: Jaundice
frequency: OCCASIONAL
description: >-
Yellowing of skin and sclera from elevated bilirubin. May result from biliary obstruction
by tumor, hepatic failure, or diffuse tumor infiltration.
phenotype_term:
preferred_term: Jaundice
term:
id: HP:0000952
label: Jaundice
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Right upper quadrant pain or discomfort from liver capsule distension or tumor growth.
Sudden severe pain may indicate tumor rupture.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Constitutional
name: Weight Loss
frequency: VERY_FREQUENT
description: >-
Unintentional weight loss is common in HCC due to cancer cachexia, reduced oral intake,
and altered metabolism.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Constitutional
name: Fatigue
frequency: VERY_FREQUENT
description: >-
Fatigue from liver dysfunction, anemia, and cancer-related factors.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Gastrointestinal
name: Nausea
frequency: FREQUENT
description: >-
Nausea and anorexia from liver dysfunction and advanced disease.
phenotype_term:
preferred_term: Nausea
term:
id: HP:0002018
label: Nausea
biochemical:
- name: Alpha-Fetoprotein (AFP)
notes: >-
Serum AFP is elevated in approximately 60% of HCC cases. Levels greater than 400 ng/mL
are highly specific for HCC in the setting of cirrhosis. Used for diagnosis (with
imaging) and monitoring treatment response. AFP-L3 fraction improves specificity.
- name: Liver Function Tests
notes: >-
Elevated transaminases, alkaline phosphatase, and bilirubin may occur. Pattern depends
on underlying liver disease and tumor burden. Child-Pugh score assesses hepatic reserve
and guides treatment decisions.
- name: PIVKA-II (DCP)
notes: >-
Des-gamma-carboxy prothrombin is an alternative biomarker to AFP. May be elevated
when AFP is normal. Useful in combination with AFP for surveillance and diagnosis.
genetic:
- name: TERT Promoter
association: Somatic Activating Mutation
notes: >-
TERT promoter mutations (C228T, C250T) are the most common genetic alterations in HCC,
present in approximately 60% of cases. These mutations create binding sites for ETS
transcription factors, reactivating telomerase expression and enabling unlimited
cell division.
- name: TP53
association: Somatic Loss of Function
notes: >-
TP53 mutations occur in approximately 30% of HCC, enriched in HBV-associated and
aflatoxin-associated tumors. The R249S hotspot mutation is specifically associated
with aflatoxin B1 exposure.
- name: CTNNB1
association: Somatic Activating Mutation
notes: >-
CTNNB1 (beta-catenin) mutations occur in approximately 30% of HCC, causing constitutive
WNT pathway activation. Associated with distinct clinical features including
cholestasis and immune exclusion, potentially affecting immunotherapy response.
- name: AXIN1
association: Somatic Loss of Function
notes: >-
AXIN1 inactivating mutations occur in approximately 10% of HCC, also activating
WNT signaling. AXIN1 and CTNNB1 mutations are typically mutually exclusive.
- name: ARID1A
association: Somatic Loss of Function
notes: >-
ARID1A mutations affect chromatin remodeling and occur in approximately 10% of HCC.
Part of the SWI/SNF complex alterations seen across multiple cancer types.
treatments:
- name: Atezolizumab plus Bevacizumab
description: >-
First-line standard of care for unresectable HCC based on IMbrave150 trial. Anti-PD-L1
(atezolizumab) combined with anti-VEGF (bevacizumab) demonstrated superior overall
survival compared to sorafenib. Requires adequate liver function (Child-Pugh A) and
no high-risk varices.
evidence:
- reference: PMID:39687036
supports: SUPPORT
snippet: "Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib"
explanation: "IMbrave150 abstract reports improved overall and progression-free survival with atezolizumab plus bevacizumab versus sorafenib."
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: atezolizumab
term:
id: NCIT:C106250
label: Atezolizumab
- preferred_term: bevacizumab
term:
id: NCIT:C2039
label: Bevacizumab
- name: Durvalumab plus Tremelimumab
description: >-
Alternative first-line immunotherapy option. HIMALAYA trial demonstrated durvalumab
(anti-PD-L1) with single priming dose of tremelimumab (anti-CTLA-4) improves survival
compared to sorafenib. Option for patients who cannot receive bevacizumab.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: durvalumab
term:
id: NCIT:C103194
label: Durvalumab
- preferred_term: tremelimumab
term:
id: NCIT:C49085
label: Tremelimumab
- name: Sorafenib
description: >-
Multi-kinase inhibitor targeting RAF, VEGFR, and PDGFR. Was first systemic therapy
to improve survival in HCC. Now used in second line or when immunotherapy is
contraindicated.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: sorafenib
term:
id: CHEBI:50924
label: sorafenib
- name: Lenvatinib
description: >-
Multi-kinase inhibitor with activity against VEGFR, FGFR, PDGFR, RET, and KIT.
Non-inferior to sorafenib in first line. Alternative when immunotherapy not appropriate.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: lenvatinib
term:
id: CHEBI:85994
label: lenvatinib
- name: Surgical Resection
description: >-
Potentially curative for early-stage HCC in patients with preserved liver function
(Child-Pugh A). Limited by underlying cirrhosis in many patients. Requires adequate
future liver remnant.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Liver Transplantation
description: >-
Potentially curative treatment that addresses both tumor and underlying cirrhosis.
Milan criteria (single tumor 5 cm or less or up to 3 tumors each 3 cm or less, no
vascular invasion, no metastases) guide patient selection. Limited by organ availability.
treatment_term:
preferred_term: organ transplantation
term:
id: MAXO:0010039
label: organ transplantation
- name: Transarterial Chemoembolization (TACE)
description: >-
Locoregional therapy delivering chemotherapy directly to tumor via hepatic artery
followed by embolization. Standard for intermediate-stage HCC (BCLC-B). Can be used
as bridge to transplant or with systemic therapy.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Radiofrequency/Microwave Ablation
description: >-
Thermal ablation for small tumors (typically less than 3 cm). Effective alternative
to resection for early-stage HCC, particularly in patients with limited liver function.
treatment_term:
preferred_term: ablation therapy
term:
id: MAXO:0000452
label: ablation therapy
disease_term:
preferred_term: hepatocellular carcinoma
term:
id: MONDO:0007256
label: hepatocellular carcinoma
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor