hepatocellular%20carcinoma
HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma is malignancy that originates from the liver.

Physical signs are hepatomegaly and ascites. It is usually asymptomatic for much of its natural history.

Liver cancer is the second most common cause of cancer-related mortality worldwide & hepatocellular carcinoma accounts for >90% of liver cancers.

 

Hepatocellular%20carcinoma Diagnosis

Diagnosis

Diagnostic Criteria

  • Diagnosis of hepatocellular carcinoma is established by fulfilling the criteria of the 2018 American Association for the Study of Liver Diseases (AASLD) guidelines based on the Liver Imaging Reporting and Data System (LI-RADS)
  • Criteria for LI-RADS 5, which confirm the diagnosis of HCC, include the following:
    • ≥20 mm lesions: Arterial phase hyperenhancement (APHE) and ≥1 of the following:
      • Nonperipheral "washout"
      • Enhancing capsule
      • Threshold growth (increase in lesion's size by ≥50% in ≤6 months)
    • 10-19 mm lesions: APHE and nonperipheral "washout", enhancing capsule and threshold growth, or APHE and"washout" or APHE and threshold growth 
    • Lesions must be nodules >1 cm in diameter with imaging studies findings typical of hepatocellular carcinoma (ie hypervascular in the arterial phase with hypodensity in the portal venous or delayed phase) on a 4-phase (unenhanced, arterial, portal venous and delayed phases) multidetector computed tomography (MDCT) scan, or a 4-phase dynamic contrast-enhanced magnetic resonance imaging (MRI) in a liver that has cirrhosis
  • Biological imaging with gadoxetic acid may be utilized for the diagnosis of hepatocellular carcinoma for suspicious lesions that do not fulfill the AASLD requirements for diagnosis by imaging
    • There is a high likelihood of having high-grade dysplastic nodules or well-differentiated hepatocellular carcinoma in lesions without arterial phase hyperenhancement, but with both venous phase hypoenhancement and hepatobiliary phase hypointensity by gadoxetic acid-enhanced MRI; these lesions should be considered as "high-risk" lesions
  • In patients with risk factors for hepatocellular carcinoma such as chronic viral hepatitis, liver cirrhosis, etc, an alternative diagnostic criterion can be met if space occupying lesions of the liver demonstrated by CT scan (non-dynamic) or MRI (non-dynamic) are present, together with either:
    • Serum AFP level of ≥400 mcg/L or
    • Dense homogenous lipiodol retention shown after hepatic lipiodol angiography with follow-up post-lipiodol CT scan

Staging

  • There are several staging systems that have been devised for patients with hepatocellular carcinoma that each includes variables to evaluate any of the following factors that affect the prognosis of hepatocellular carcinoma patients:
    • Clinical stage
    • Aggressiveness and growth rate of the tumor
    • General health of the patient
    • Liver function of the patient
    • Treatments administered 

Barcelona Clinic Liver Cancer (BCLC) Staging System

  • Widely accepted in clinical practice and trials as a basis for appropriate treatment modalities depending on the disease's Okuda system stage and other tumor characteristics, measurements of liver function, and patient 's Eastern Cooperative Oncology Group (ECOG) performance status (PS)
    • Stage 0 (very early HCC): <2 cm single nodule, ECOG PS 0, Child-Pugh A; may benefit from curative therapies
    • Stage A (early HCC): Single nodule of any size or ≤3 cm x 2-3 nodules, ECOG PS 0-1, Child-Pugh A; may benefit from curative therapies
    • Stage B (intermediate HCC): Multiple nodules, ECOG PS 0, Child-Pugh A-B; may benefit from palliative treatments
    • Stage C (advanced HCC): With microvascular invasion and/or extrahepatic metastases, ECOG PS 1 or 2, Child-Pugh A/B, N1 or M1; may benefit from palliative treatments
    • Stage D (terminal HCC): ECOG PS 3 or 4, Child-Pugh C, any T, N or M; patients with very poor life expectancy

American Joint Commission on Cancer (AJCC) Staging System

  • Gives information about the pathologic characteristics of the resected specimens only while the Okuda staging system incorporates aspects of liver function and tumor characteristics

Primary Tumor

Tx - Primary tumor cannot be assessed

T0 - Absence of evidence of primary tumor

T1 - Single tumor ≤2 cm or >2 cm with no vascular invasion

T1a - Single tumor ≤2 cm

T1b - Single tumor >2 cm with no vascular invasion

T2 - Single tumor >2 cm with vascular invasion, or multiple tumors but none measuring >5 cm

T3 - Several tumors with at least one of which is measuring >5 cm

T4 - Single or multiple tumors of any size that involve any branch of the portal vein or hepatic vein, or tumor(s) with direct invasions of adjacent organs other than the gallbladder or with perforation of visceral peritoneum

Regional Lymph Node (LN)

Nx - Regional LN cannot be assessed

N0 - Absence of regional LN metastasis

N1 - Presence of regional LN metastasis

Distant Metastasis

M0 - No distant metastasis

M1 - Distant metastasis present

Histologic Grade (G)

Gx - Grade cannot be assessed

G1 - Well differentiated

G2 - Moderately differentiated

G3 - Poorly differentiated

G4 - Undifferentiated

Anatomic Staging

Stage IA - T1a N0 M0

Stage IB - T1b N0 M0

Stage II - T2 N0 M0

Stage IIIA - T3 N0 M0

Stage IIIB - T4 N0 M0

Stage IVA - Any T N1 M0

Stage IVB - Any T Any N M1

Fibrosis Score

F0 - None to moderate fibrosis

F1 - Severe fibrosis or cirrhosis

Assessment

  • Once diagnosis of hepatocellular carcinoma is established, the following factors influence the workup, treatment staging and treatment options:
    • Tumor burden
    • Liver function and general health of the patient 
  • Workup, as may be appropriate, will be based on:
    • Hepatitis panel for detection of HBV and/or HCV infection
    • Renal panel by measuring blood urea nitrogen (BUN) and creatinine
    • Liver function tests by measuring serum levels of bilirubin, aspartate aminotransferase, alanine transaminase and alkaline phosphatase; measuring prothrombin time, albumin and platelet count
    • Complete blood count
    • Measurement of serum AFP
    • Chest CT scan for assessing the presence of any comorbidity or metastatic disease in the lung
    • Indocyanine green (ICG) retention test performed to assess liver function if resection is being considered for the patient

Pre-operative Imaging

  • Essential for surgical planning
  • CT/MRI are used to:
    • Facilitate characterization of the number and size of the hepatocellular carcinoma lesions in order to detect the presence of satellite nodules, extrahepatic metastasis, and tumor invasion of the portal vein or the hepatic veins/inferior vena cava
    • Aid in establishing the location of the tumors with respect to vascular and biliary structures

Child-Pugh Score

Chemical and Biochemical Parameters Scores (Points) for Increasing Abnormality
1 2 3
Encephalopathy (grade) None 1-2 3-4
Ascites Absent Slight Moderate
Albumin (g/dL) >3.5 2.8-3.5 <2.8
Prothrombin time
Seconds over control
INR

<4
<1.7

4-6
1.7-2.3

>6
>2.3
Bilirubin (mg/dL)
For primary biliary cirrhosis
<2
<4
2-3
4-10
>3
>10

Class A: 5-6 points; good operative risk
Class B: 7-9 points; moderate operative risk
Class C: 10-15 points; poor operative risk

  • Child-Pugh scoring is used to estimate liver function or as a tool to rule out patients for liver resection
  • The finding of esophageal varices and/or splenomegaly with blood platelet counts of <100,000/µL suggest clinically important portal hypertension, which can also be measured by transjugular route

UNOS Criteria

  • UNOS criteria specify that patients eligible for liver transplantation should not be candidates for liver resection:
    • Radiologic evidence of a single tumor 2-5 cm in diameter or
    • 2-3 tumors ≤3 cm in diameter
    • No evidence of macrovascular involvement or extrahepatic disease 

Milan Staging Criteria

  • Early stage hepatocellular carcinoma
    • Solitary tumors ≤5 cm in diameter or ≤3 multiple tumors, each measuring ≤3 cm in diameter
    • No macrovascular invasion
    • No distant metastases shown during preoperative imaging
  • Locally advanced hepatocellular carcinoma are tumors outside of the Milan criteria without any distant metastases and with or without macrovascular invasion
  • Metastatic hepatocellular carcinoma

Pre-operative Assessments

  • Careful patient selection should be done before liver resection with considerations on patient characteristics as well as the characteristics of the liver and the tumor
    • Patient performance status assessments should also be considered before resection
    • Estimates of the overall liver function and the size and function of the putative future liver remnant (FLR) together with technical considerations related to tumor and liver anatomy should be taken into account before a patient can be considered to have resectable disease 
  • Presence of significant portal hypertension should also be a part of surgical assessment
  • In general, liver resection is possible in patients with optimal liver function characterized by a Child-Pugh class A score with no evidence of portal hypertension
    • However, in highly selected cases, patients with a Child-Pugh score B may be considered for limited liver resection when liver function tests are normal and clinical signs of portal hypertension are absent
    • Also, limited resection can be feasible in cases where portal hypertension is mild 
  • Optimal tumor characteristics for liver resection are single tumors with no major vascular invasion
    • Although there is no limitation on the size of tumor that is considered for liver resection, the risk of vascular invasion and dissemination increases with size
    • A strong predictor of hepatocellular carcinoma recurrence is the presence of macro- or microscopic vascular invasion 
  • Evaluation of the postoperative FLR volume is also an essential preoperative assessment to be done
    • CT is utilized to measure FLR directly and estimates of total liver volume can be calculated
    • The ratio of future remnant/total liver volume (subtracting tumor volume) is then determined
    • It is recommended that the ratio be at least 25% in patients without cirrhosis and at least 30-40% in patients with chronic liver disease and a Child-Pugh A score
    • Preoperative portal vein embolization (PVE) should be considered in patients with an estimated FLR/total liver volume ratio below recommended values who are otherwise suitable candidates for liver resection
    • PVE is a procedure that redirects blood flow toward the portion of the liver that will remain following surgery; it is safe and effective
      • Hypertrophy is induced in these segments of the liver while the embolized portion of the liver undergoes atrophy 
  • Presence of extrahepatic metastasis is contraindicated for resection

Pre-Arterial Directed Therapies Assessments

  • Prior to the initiation of arterially directed therapy, an evaluation of the arterial anatomy of the liver, patient's performance status, and liver function is essential
    • General patient selection criteria for arterially directed therapy include tumors that are unresectable or inoperable and not amenable to ablation therapy only, and large volume extrahepatic disease is not present
    • Arterially directed therapies are relatively contraindicated in patients with >3 mg/dL bilirubin levels unless segmental treatment can be performed and in patients with main PVT
    • It is not recommended in patients with Child-Pugh class C

Laboratory Tests

Serum Alpha Fetoprotein (AFP)

  • Commonly used tumor marker for hepatocellular carcinoma and widely used method of screening
  • AFP cut-off value of 100 ng/mL was associated with high specificity but low sensitivity
  • Normal level in up to 35% of patients with small hepatocellular carcinoma and can be nonspecifically raised in patients with active hepatitis or active hepatocyte regeneration
  • Recent studies have shown that it lacks adequate sensitivity and specificity for effective surveillance and diagnosis thus this screening method can be optional

Biopsy

  • Indicated in patients with conditions associated with formation of nonmalignant nodules that may be confused with hepatocellular carcinoma during imaging
  • Considered if there is suspicion of malignancy in the lesion but multiphasic CT or MRI results do not meet imaging criteria for hepatocellular carcinoma
  • Considered in patients with elevated CA 19-9 or carcinoembryonic antigen (CEA) in order to rule out intrahepatic cholangiocarcinoma
  • May be done in patients who are not considered high risk for developing hepatocellular carcinoma

Serum Biomarkers

  • Des-gamma-carboxy prothrombin (DCP) or protein induced by vitamin K absence or antagonist-II (PIVKA-II))
  • Lens culinaris agglutinin-reactive AFP (AFP-L3) which is an isoform of AFP

Imaging

Ultrasonography

  • Radiographic choice for surveillance
  • A screening test and not a test to confirm diagnosis 
  • Sensitivity of 94% in detecting lesions and specificity >90%
  • Recommended screening interval is 6 months in patients who are at-risk
  • For patients with <10 mm nodules in ultrasound, repeat ultrasound and AFP testing in 3-6 months is recommended
  • Patients with positive AFP or nodules ≥10 mm in ultrasound should undergo additional tests to confirm the diagnosis of hepatocellular carcinoma

4-Phase Multidetector Computed Tomography (MDCT)/Contrast-Enhanced Dynamic Magnetic Resonance Imaging (MRI)

  • Primary diagnostic examination of hepatocellular carcinoma using extracellular contrast agents
  • Diagnostic imaging characteristic is the presence of arterial phase hypervascularity, nonperipheral venous or delayed venous phase wash-out, enhanced capsule appearance and threshold growth

Screening

  • Ultrasonography and/or alpha fetoprotein (AFP) testing are used for screening patients at risk for HCC
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