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.

 

Diagnosis

Diagnostic Criteria

  • Diagnosis of hepatocellular carcinoma is established by fulfilling the criteria of the 2011 American Association for the Study of Liver Diseases (AASLD) guidelines
    • Lesions must be nodules >1 cm in diameter w/ imaging studies findings typical of hepatocellular carcinoma  (ie hypervascular in the arterial phase w/ hypodensity in the portal venous or delayed phase) on a 4-phase (unenhanced, arterial, portal venous & 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 w/ 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 w/ both venous phase hypoenhancement & hepatobiliary phase hypointensity by gadoxetic acid-enhanced MRI; these lesions should be considered as "high-risk" lesions
  • In patients w/ 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 w/ either:
    • Serum AFP level of ≥400 mcg/L or
    • Dense homogenous lipiodol retention shown after hepatic lipiodol angiography w/ follow-up post-lipiodol CT scan

Staging

  • There are several staging systems that have been devised for patients w/ hepatocellular carcinoma that each includes variables to evaluate any of the following factors that affect the prognosis of hepatocellular carcinoma patients:
    • Clinical stage
    • Aggressiveness & growth rate of the tumor
    • General health of the patient
    • Liver function of the patient
    • Treatments administered 
  • The Barcelona Clinic Liver Cancer (BCLC) staging system is the widely accepted in clinical practice & trials
    • It incorporates the Okuda system together w/ other tumor characteristics, measurements of liver function, & patient performance status
    • Links staging of hepatocellular carcinoma in cirrhosis w/ treatment modalities
    • The system identifies those patients w/ early hepatocellular carcinoma who may benefit from curative therapies (stage 0 & A), those at intermediate (stage B) or advanced stage (stage C) who may benefit from palliative treatments & those w/ a very poor life expectancy (stage D)
  • 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 & 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 w/ no vascular invasion

T1a - Single tumor ≤2 cm

T1b - Single tumor >2 cm w/ no vascular invasion

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

T3 - Several tumors w/ 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) w/ direct invasions of adjacent organs other than the gallbladder or w/ 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 & treatment options:
    • Tumor burden
    • Liver function & general health of the patient 
  • Workup, as may be appropriate, will be based on:
    • Hepatitis panel for detection of HBV &/or HCV infection
    • Renal panel by measuring blood urea nitrogen (BUN) & creatinine
    • Liver function tests by measuring serum levels of bilirubin, aspartate transaminase, alanine transaminase, & alkaline phosphatase; measuring prothrombin time, albumin & platelet count
    • Complete blood count
    • Measuremet of serum AFP
    • Chest CT scan for asssessing the presence of any comorbidity or metastatic disease in the lung
    • Indocyanine greeen (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 & size of the hepatocellular carcinoma lesions in order to detect the presence of satellite nodules, extrahepatic metastasis, & tumor invasion of the portal vein or the hepatic veins/inferior vena cava
    • Aid in establishing the location of the tumors w/ respect to vascular & biliary structures

Child-Pugh Score

Chemical & 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 &/or splenomegaly w/ 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 & w/ or without macrovascular invasion
  • Metastatic hepatocellular carcinoma

Pre-operative Assessments

  • Careful patient selection should be done before liver resection w/ considerations on patient characteristics as well as the characteristics of the liver & the tumor
    • Patient performance status assessments should also be considered before resection
    • Estimates of the overall liver function & the size & function of the putative future liver remnant (FLR) together w/ technical considerations related to tumor & 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 w/ optimal liver function characterized by a Child-Pugh class A score w/ no evidence of portal hypertension
    • However, in highly selected cases, patients w/ a Child-Pugh score B may be considered for limited liver resection when liver function tests are normal & 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 w/ 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 & dissemination increases w/ 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 & 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 & at least 30-40% in patients w/ chronic liver disease & a Child-Pugh A score
    • Preoperative portal vein embolization (PVE) should be considered in patients w/ 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 & 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, & liver function is essential
    • General patient selection criteria for arterially directed therapy include tumors that are unresectable or inoperable & not amenable to ablation therapy only, & large volume extrahepatic disease is not present
    • Arterially directed therapies are relatively contraindicted in patients w/ >3 mg/dL bilirubin levels unless segmental treatment can be performed & in patients w/ main PVT
    • It is not recommended in patients w/ Child-Pugh class C

Laboratory Tests

Blood Tests

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

Biopsy

  • Indicated in patients w/ conditions associated w/ formation of nonmalignant nodules that may be confused w/ 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 w/ elevated CA 19-9 or 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
  • Sensitivity of 94% in detecting lesions & specificity >90%
  • Recommended screening interval is 6 months in patients who are at-risk
  • A screening test & not a test to confirm diagnosis

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

  • Primary diagnostic examination of hepatocellular carcinoma using extracellular contrast agents
  • Diagnostic imaging characteristic is the presence of arterial phase hypervascularity & venous or delayed venous phase wash-out

Screening

Pathology

Types of Hepatocellular Carcinoma by Morphology

  • Nodular - characterized by nodules that are well-circumscribed & often associated w/ cirrhosis
  • Massive - occupies a large area that may or may not have satellite nodules in the surrounding liver; usually associated w/ noncirrhotic liver
  • Diffuse - less common type; characterized by diffuse involvement of many small indistinct tumor nodules throughout the liver
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