Hepatocellular carcinoma

HCC

Epidemiology

• Most common in Asia/sub-Saharan Africa (where HBV is rampant)
• Primarily men 50-60yo

Risk factors:

• Essentially, chronic inflammation, mostly in the setting of cirrhosis
  • Cirrhosis of any cause (present in 80% of patients with FCC, but not required)
  • Chronic HBV in the absence of cirrhosis (most common individual cause worldwide)
  • HCV in Western countries
  • Obesity and NASH/NAFLD (becoming more important)
  • Aflatoxins a/w Aspergillus
  • Azo dyes
  • Aromatic amines
  • Smoking
  • Anabolic steroid use
  • Alpha-1 antitrypsin deficiency
  • Haemochromatosis
  • Alcoholic liver disease
  • Chronic Wilson's disease
• Fibrolamellar HCC occurs in patients with no underlying liver disease

Pathophysiology

• Grade - well, moderately, or poorly differentiated
  • Never been shown to predict outcome
• Growth
  • Hanging - connected to the liver by a small vascular stalk, and is easily resected without sacrifice of a significant amount of adjacent non-neoplastic liver tissue. Can grow large without involving much normal liver tissue.
  • Pushing - well-demarcated and often contains a fibrous capsule. Characterised by growth that displaces vascular structures rather than invading them. Usually resectable.
  • Infiltrative - tends to invade vascular structures, even at a small size. Resection is possible, must positive margins are common.
  • Small tumours <5cm usually don't fall into any of the above groups
• Fibrolamellar HCC
  • Distinct variant with different clinical features
  • Typically younger patients without a history of cirrhosis
  • Usually well-demarcated with a central fibrotic area (can be hard to distinguish from FNH)
  • Composed of large polygonal tumour cells embedded in a fibrous stroma, forming lamellar structures
  • Does not produce AFP, but is a/w high neurotensin levels
  • Has a better prognosis than HCC - high resectability rates, lack of chronic liver disease, and more indolent course
  • Long-term survival in 50-75% of patients after complete resection, but recurrence eventually occurs in 80%

• Mixed hepatocellular-cholangiocellular tumour (rare)
  • Both types of cellular differentiation present
  • Either two cancers growing into one another or a mixed differentiation
  • Prognosis as per intra-hepatic cholangiocarcinoma
• Clear cell HCC
• Childhood HCC
  • Associated with viral hepatitis and other inherited metabolic liver diseases
  • Long-term survival 10-20%

Presentation

• RUQ pain (sometimes radiates to right shoulder)
• Weight loss
• Palpable mass
• Anorexia, nausea, lethargy
• Can present with hepatic decompensation in recognised or unrecognised cirrhosis
• Complications
  • Rupture (sudden-onset pain, followed by hypovolaemic shock)
  • Budd-Chiari syndrome
  • Obstructive jaundice
  • Haemobilia
  • Paraneoplastic syndromes
    • Hypercalcaemia
    • Hypoglycaemia
    • Erythrocytosis

Screening

• Note that there is a lot of controversy regarding screening.
• High-risk/cirrhosis of any cause: USS and AFP every six months
  • Also includes chronic HBV without cirrhosis in certain high-risk populations

Tumour markers

• AFP can be elevated, but overall sensitivity and specificity are low
  • False positives with inflammatory disorders of the liver, intra-hepatic cholangiocarcinoma, colorectal mets, germ cell tumours elsewhere e.g. testes
  • Better for surveillance than diagnosis
  • AFP > 400 is associated with an 'almost definite' diagnosis of HCC, once differentials are excluded, according to Eunice

Imaging (see 'liver lesions' under 'Radiology' for more)

• Either CT or MRI can be specific individually, but both scans may be required to increase sensitivity in difficult cases
• LI-RADS can be assessed on either contrast CT or MRI
  • LI-RADS 5 (Definitely HCC) - MDT discussion for management consensus
    • Arterial phase enhancement, washout, capsule appearance
  • 4 (High probability - 31%-79% chance of HCC) - MDT discussion for further workup
  • 3 (intermediate - 6-9%) - repeat imaging 3-6 months
  • 2 (probably benign - 0%) - repeat diagnostic imaging in 6 months
  • 1 - return to surveillance in 6 months
  • LR-M (other malignancy)
  • LR-TIV (Tumour in vein)
• Features assessed:
  • Arterial enhancement, size, washout, enhancing 'capsule', and growth
• Inclusion criteria for LI-RADS (must be high pre-test probability): chronic HBV or cirrhosis or current/prior hx HCC or transplant recipient
• Exclusion criteria: vascular aetiology of liver disease, congenital hepatic fibrosis, nodular regenerative hyperplasia, paediatric patients

LI-RADS categorization of liver lesions in patients at risk for hepatocellular carcinoma
Category	Assessment	Diagnostic considerations	Action
LR-1	Definitely benign	Includes hemangiomas with characteristic features or cysts.	Continue routine surveillance imaging for HCC Δ
LR-2	Probably benign	Includes hemangioma without characteristic features and wedge-shaped arterioportal shunts.	For most patients, continue routine surveillance imaging for HCCΔ For some patients, image with a different modality or MRI contrast agent◊
LR-3	Intermediate probability of malignancy	Includes dysplastic nodules, benign lesions without characteristic features, and rounded arterioportal shunts.	Repeat contrast-enhanced CT, MRI, or ultrasound for liver lesion evaluation in 3 to 6 months¶ Continue serial imaging every 3 to 6 months while the lesion remains LR-3 for ≥2 years or until the lesion has a conclusive diagnosis§ If the lesion remains LR-3 for ≥2 years on imaging follow-up, return to routine surveillance imaging for HCCΔ
LR-4	Probably HCC	Includes HCC with some characteristic features.¥	Multidisciplinary consultation to tailor further management. Options include: Alternative or follow-up imaging Biopsy the lesion Presumptive treatment without conclusive diagnosis
LR-5	Definitely HCC†	HCC with characteristic features.**	Treatment for HCC No biopsy needed
LR-M	Probably or definitely malignant, not specific for HCC	Most LR-M lesions are malignant. Includes HCC without characteristic features¶¶ and other malignancies (eg, cholangiocarcinoma, combined hepatocellular carcinoma and cholangiocarcinoma, lymphoma, or metastasis).	Multidisciplinary consultation to tailor further management. Options include: Evaluate for underlying malignancyΔΔ Perform biopsy if it will alter management◊◊
LR-NC	Not categorizable	Images are insufficient for assessment. Common reasons include imaging protocol not tailored for liver lesion or images degraded from patient motion.	Repeat imaging for liver lesion evaluation with same or alternate modality in ≤3 months
LR-TIV	Tumor in vein	Unequivocal enhancing soft tissue in vein indicating tumor, either from HCC or another malignancy.	Multidisciplinary consultation to tailor further management. Options include: Alternative or follow-up imaging Biopsy the tumor in vein Presumptive treatment without histologic confirmation

Biopsy

• Unnecessary in most cases
• Risk of seeding/spillage and bleeding, especially in cirrhotic livers and subcapsular tumours
• Indications
  • Imaging inconclusive for HCC
  • Other potential diagnoses for liver lesion - cholangiocarcinoma, liver metastases

Staging

• Harder to stage than most cancers, due to complexity and multiplicity of factors involved
• Need to do an extent of disease and an extent of cirrhosis workup
• Barcelona Liver Clinic staging system is most commonly used in Australia (see below)
• AJCC/UICC TNM classification of HCC can be used (see below)
  • Doesn't accurately predict survival, because it doesn't take liver function into account
  • Not commonly used
• Cancer of liver Italian program score (see below)
• Okuda staging system - older but simple and effective
• Commonly metastasises to lung, bone and peritoneum
  • Only need to do a bone scan if suggestive symptoms
• Staging laparoscopy can provide information about the extent of disease in the liver, extra-hepatic disease, and cirrhosis
• FDG PET is not routine

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Solitary tumor ≤2 cm, or >2 cm without vascular invasion
T1a	Solitary tumor ≤2 cm
T1b	Solitary tumor >2 cm without vascular invasion
T2	Solitary tumor >2 cm with vascular invasion, or multiple tumors, none >5 cm
T3	Multiple tumors, at least one of which is >5 cm
T4	Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
T1a	N0	M0	IA
T1b	N0	M0	IB
T2	N0	M0	II
T3	N0	M0	IIIA
T4	N0	M0	IIIB
Any T	N1	M0	IVA
Any T	Any N	M1	IVB

Treatment options

• Locoregional
• Resection
• Transplant
• Chemotherapy
• Other
  • Radiotherapy - not commonly used
  • Immunotherapy - developing

Situations:

• Resectable disease with maintained liver reserve and absence of portal hypertension: resection
• Resectable disease with underlying advanced liver disease or portal hypertension: resection and transplantation
• Potentially resectable disease with contra-indication to simple resection, but doesn't meet Milan criteria: consider resection or TACE
• Very small tumours and comorbid patient: percutaneous ablative techniques
• Advanced disease but ECOG <=2: sorafenib
• Extensive disease and ECOG 3 or 4: supportive only

Locoregional therapy

• Considerations
  • Generally should be ECOG 2 or less to qualify
  • Doesn't confer a survival benefit if extrahepatic spread
  • Unacceptable morbidity risk if more than half liver parenchyma involved
• Other factors to consider:
  • Proximity to vessels/bile duct/liver capsule
  • Vascular invasion
  • Tumour size
• Indications:
  • Curative (only RFA is curative)
  • Bridging (prevent increase in tumour burden and therefore patient dropping off transplant list)
  • Downstaging (if transplant candidate apart from tumour burden, can attempt to downstage to bring back within Milan criteria)
  • Palliative - ineligible for transplant either due to comorbidities or stage. Survival benefit and symptom control.
• Types
  • Trans-arterial (takes advantage of fact that HCC gets most blood supply from HA)
    • Select asymptomatic multi-nodular tumours without vascular invasion for best results
    • TAE (trans-arterial embolization)
      • Good for haemostasis in presentation of acute haemorrhage from HCC rupture
      • Shown to be as effective as DEB-TACE in survival
    • HAIC
    • TACE (trans-arterial chemo-embolization)
      • Injected directly into feeding hepatic artery
      • Can be paired with ablation for down-staging then curative treatment
      • Overall response rate around 50%, but disease control 75-80%
      • Not considered curative alone
      • Uses chemicals such as ethiodol
      • Complications
        • Post-embolisation syndrome
          • 2-7% of patients
          • Abdo pain, nausea, vomiting, mild fever
          • Supportive care only
        • Hepatic insufficiency - 20%
        • Cerebral lipiodil embolism
        • PE
    • DEB-TACE
    • TARE (trans-arterial radio-embolization)
    • SIRT
      • Intra-tumoural brachytherapy
      • No survival benefit over systemic therapy
      • Only used for very select patients
  • Percutaneous ablative - appropriate for tumours <3cm, equivalent outcomes to surgery for tumours <2cm
    • Contraindications
      • Tumour >3cm
      • Close to large bile duct - can cause strictures
      • Exophytic tumour - risk of rupture, or ablating other adjacent organs
      • Vascular invasion
      • Close to GB/stomach/large vessels
    • Complications
      • Post-ablation syndrome - occurs 2 days to 3 weeks afterwards - flu-like syndrome including fever. Self-resolving.
      • Liver failure
      • Abscess
      • Bleeding
      • Bile duct injury
      • Hollow viscus perforation
    • Ethanol - recurrence 40% and 67.5% at one and two years respectively
      • Good for tumours <2cm, mostly works with one treatment
      • Good for patients with technical contraindications for RFA/MFA
    • Acetic acid
      • Stronger necrotizing abilities than ethanol - good for septated tumours
    • RFA - five-year survival rates of 55-82%
      • Best in small tumours up to 3cm
      • Does not ablate well near blood vessels due to heat-sink effect
    • Microwave ablation - five-year survival 59.8%
      • Less heat-sink effect than RFA
      • More frequently used than RFA now for this reason
    • Cryoablation - not in widespread use
    • Irreversible electroporation - limited data, novel, expensive
  • Portal vein embolisation can be performed pre-op to induce hypertrophy of future liver remnant in patients with borderline future liver volume

Resection for HCC

• Indications
  • The treatment of choice in patients with solitary HCC confined to liver and early stage cirrhosis without portal hypertension.
• Contraindications
  • Portal hypertension
  • C-P B or C cirrhosis
  • Unable to achieve adequate FLR for liver function (keep in mind this can be optimised with PV embolisation)
    • See 'liver resection' page for discussion of FLR in general
• Factors predictive of poor outcome after resection:
  • Tumour size
  • Cirrhosis
  • Infiltrative growth
  • Vascular invasion
  • Intra-hepatic metastases
  • Multifocal tumours
  • Lymph node metastases
  • Margin <1cm
  • Lack of a capsule

Transplant for HCC

• Theoretically the perfect treatment because it fixes the HCC and the underlying cirrhosis
• Gold standard for patients with CP-B/C cirrhosis and limited hepatic reserve
• Downsides - limited donor organ availability, long wait times can lead to progression or drop-out
• Indications:
  • Consider in:
    • CP B or C cirrhosis, or portal hypertension
    • Early-stage HCC
    • No extrahepatic disease or macrovascular invasion
  • Previously Milan criteria for transplant eligibility - eligible if:
    • Single tumours <=5cm OR
    • up to 3 tumours, largest of which is <=3cm
  • Now Metroticket 2.0 additional criteria
    • General AFP cut-off <1000
    • No macrovascular invasion, no extrahepatic spread
    • Can be down-staged to meet criteria
• While awaiting transplant, can control progression with ablation/trans-arterial therapy
• Histological information is actually very useful in prognosticating, but is not often available, due to risk of seeding from biopsy.
• 5-year overall survival 84%, 9% HCC recurrence
• If patients present beyond Milan criteria, they can be down-staged with RFA/TACE/TARE and then transplanted with similar outcomes to those that present within criteria
• MELD score - originally developed to predict mortality of patients undergoing TIPS, but can be used to generalise how sick a patient is and is also used to allocate livers on transplant list.

Systemic therapy for metastatic/inoperable disease

• Overall rationale
  • Traditional systemic chemotherapy has a poor outcome and doesn't help much, only a few months over best supportive care
• First-line:
  • Atezolizumab (PD-L1 inhibitor) + bevacizumab (VEGF inhibitor)
  • Contraindicated in CP-B or C cirrhosis
• Second-line:
  • Sorafenib - tyrosine kinase inhibitor
  • Immunotherapy - now a valid alternative to sorafenib, improved OS and QoL
• Third-line:
  • Regorafenib (multi-kinase inhibitor) - CP-A only
  • Nivolumab (anti-PD-1 immune checkpoint inhibitor) - can be given in CP-B
• No benefit to adjuvant chemotherapy to date although MAY be a role for sorafenib in high-risk patients after resection - phase II trial ongoing
• Also no clear benefit to sorafenib along with regional therapy, although this decision is complex and patient-specific
• IMBrave150 trial currently under way - sorafenib vs atezolizumab + bevacizumab, strong benefit to the latter, also better tolerated, will likely alter the treatment paradigm
• Any disease progression is an indication to cease
• Adjuvant therapy:
  • Currently not recommended
• Indications
  • Advanced unresectable HCC
  • Unable to deliver locoregional therapy
  • Contraindicated in CP-B/C or ECOG 2/3/4

Best supportive care

• 1 year survival 11%
• Patients presenting with advanced disease have median survival 3-4 months
• Most common symptom is pain

Surveillance

• Follow-up scan 4-12 months after treatment (CT quad phase or MRI + AFP), then imaging 3-monthly for two years
• Assessment of tumour response - mRECIST score

Recurrence

• Recurrence after resection
  • Five-year recurrence is about 50%
  • Increased mortality in:
    • Tumour >7cm
    • Multifocal HCC
    • Albumin <3.5g/mL
    • Major vascular invasion
    • Ruptured HCC
    • Age >65
    • Zheng et al proposed a score to stratify recurrence/mortality in these patients
  • Treatment after recurrence after hepatectomy?
    • Re-resection
    • Loco-regional treatment
    • Salvage transplantation