Malignant Liver Tumours

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DEFINITION
ICC - intrahepatic cholangiocarcinoma
HCC - hepatoma aka hepatocellular carcinoma
mCRC - metastatic colorectal cancer (see elsewhere)
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EPIDEMIOLOGY

HCC

Incidence
Most common primary liver malignancy; 5th most common cancer worldwide.
Not common in West but is increasing rapidly including mortality.
- possibly due to maturation of the population infected with HCC in the 60s-70s.
Common in China and Africa.

Risk factors
Cirrhosis of any cause.
- most pts with HCC have cirrhosis; except fibrolamellar type
Typically:
- hep B and C; chronic Hep B = major risk in Asia and Africa; Hep C = major in Japan and West.
- alcoholism.
- haemochromatosis.
Iatrogenic OCP slightly, anabolic steroids.

ICC

Incidence
Second most common primary liver malignancies
Markedly increased incidence over recent decades; unclear why.

Risk Factors
Sclerosing cholangitis (~20% lifetime risk)
Choledochal cysts (~20% lifetime risk)
M1.5>F
Asians>Europeans
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AETIOLOGY

Primary malignancies
Secondaries discussed elsewhere.
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BIOLOGICAL BEHAVIOUR

Pathology

HCC
Frequently multicentric.
Often softer than surrounding liver.
- can be difficult to distinguish from regressive cirrhotic
Fibrolamellar type is mainly in young women,
- less cirrhosis; much better prognosis.

ICC
3 major types
- mass forming
- periductal infiltrating
- intraductal
Periductal infiltrating has the worse prognosis.

Natural history

HCC
Untreated 5-yr survival <5%
Treated, approaches 75%
- note this only applies to early or very early stage pts (who are suitable for surgery)
Negative prognostic factors include:
- larger tumours
 - positive margins
- major and minor vascular invasion
- increasing degrees of liver fibrosis
Spread is local; e.g. diaphragm
Then distant - often lung, bone.
Palliated pts tend to live 3-6m

ICC
Resectability rates for CC vary from 30-50%
- higher for ICC than external; maybe 2/3s of ICC
5-yr survival is about 50%
Negative prognostic factors:
- larger tumors
- positive margins
- less well differentiated
Palliated pts tend to die within 1 yr.

Complications
Rupture & bleeding
Portal hypertension
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MANIFESTATIONS

Symptoms
Pain, RUQ.
Jaundice due to biliary compression or replacement of liver tissue.
Consider rupture and bleeding.
Consider portal hypertension and its effects.
Consider features of distant spread.

Signs
Jaundice.
Abdo / liver exam

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INVESTIGATIONS

Biochemistry
Liver enzymes and function testing
AFP

Imaging
USS us. hypoechoic


Surveillance?
Controversial and suffers from a lack of controlled data.
Aims to identify patients at early stage when suitable for resection or liver transplant
American Association for the Study of Liver Diseases recommends surveillance in:
Hep B carriers with
- documented cirrhosis (2-5-5% develop HCC per year)
- Asians (all men, females >50y)
- Africans >20y
- fam hx of HCC
Hep C carriers with:
- cirrhosis (2-8% / yr)
- bridging fibrosis
Other cirrhosis
- alcohol induced
- haemochromatosis
- NASH
- other causes? = unclear

Surveillance Methods
AFP?
= best studied method
- 20 ng/mL is a common cutoff
- but sensitivity only 60% and sensitivity only 75%; inadequate for screening
- Other tests, eg prothrombin-induced-Vit K absence = not useful for screening
Radiology?
USS = sensitivity of 65-80% and specificity >90%
- operator dependent and unreliable if obese
CT & MRI
- cannot be recommended for screening due to expense and availability.
Bottom Line
No to AFP alone, use AFP and USS in combination.
Interval scan of 6-12mo
- based on tumour doubling times
One RCT has demonstrated survival benefit (Hpe B pts).
- reduced mortality one-third.
- early detection means better access to transplantation and enhanced survival.

HCC
Radiological diagnosis more difficult due to cirrhosis
- regenerative nodules, dysplastic nodules and HCC all appear similar
Nevertheless, CT and MRI can usually distinguish it.
- most small HCC enhance homogenously on arterial phase CT
- contrast classically washes out on portal venous phase
--> by contrast, regenerative nodules enhance most during the portal venous phase, and dysplastic nodules tend not to show wash-out of contrast
MRI better than CT
- areas of carcinoma show signal intensity changes distinct from cirrhotic parenchyma.
- T1 imaging is typically hypointense; T2 hyperintense.

ICC
CT shows a rim of peripheral enhancement
- upstream biliary dilation
Contrast enhancement persists on both CT and MRI in delayed phases.
- T2 MRI shows a hyperintense lesion, tends not to show capsule on MRI, which may help to distinguish ICCs

What is the role of biopsy?
Increasing focus on biopsy in view of expanding role for LT in early HCC management.
- accurate diagnosis essential given scarcity of livers.
- however(!) risk of seeding is very real and risks converting them from early to metastatic stage.
--> risk estimated at 0-5%, median 2.5% and is devastating

Hence AASLD (and European) guidelines as follows:
1. Utility of AFP is questionable.
- rely instead on radiologic and histologic features
2. Lesions >1cm:
- Characteristic features on 4-phase CT or contrast MRI = diagnostic of HCC.
- if one study inconclusive, second study performed.
- if both inconclusive, consider biopsy.
3. Lesions <1cm:
- most likely to be confused with cirrhotic nodules
- perform close follow-up at 3m intervals.
- biopsy of suspect lesions in the following circumstances:
--> to establish diagnosis, when lack diagnostic imaging features and are elegible for surgery
--> to optimize use of LT; higher threshold for biopsy proof.


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MANAGEMENT

Preoperative Preparation & Decision Making
Manage with an interdisciplinary team
- surgeons, hepatologists, radiologists, pathologists, oncologists
Remains risk of serious morbidity and mortality with liver procedures.
- management depends on stage, hepatic function and patient status.
Preoperative optimization and risk stratification is essential.
- nutritional status and cardiac / resp / renal problems.

To be resectable, you need:
1. Inflow (portal & arterial)
2. Outflow (hepatic venous)
3. Bile drainage.
4. Adequate functional liver remnant.
5. No extrahepatic disease
6. Can get -ve margins

Functional liver remnant
Volumetrics can be formally assessed via computer algorithms.
Depends on health of parenchyma.
- 20-30% for normal liver
- 30-40% for fatty liver
- 40-50% or more for cirrhosis.
If insufficient, may still be a candidate for 2-stage resection.
- allow remaining liver to hypertrophy to a resectable functional remnant.
- us. by preoperative portal vein embolization.
- (more frequently applied to bilobar mCRC)

Hepatic function assessment
Serum liver panel, PT, albumin.
ALP and GGT provides a measure of cholestasis
Bilirubin uptake, conjugation and excretion of bile.
Transaminases show degree of liver necrosis.
More sophisticated tests for specific clearances not usually performed.

Stratification of Cirrhosis
Child-Pugh Score:
- Class A has baseline morality of 10%
- B = 30%
- C = >80%
Portal hypertension is also a significant surrogate marker of perioperative complications.

MELD Score
Model for End-Stage Liver Disease; used for transplantation scoring.
Serum bilirubin, INR, creatinine, values from 6-40
- accurately measures prognosis of liver disease
Exception points given for HCC based on 3-m window for risk of progression

Resect or Transplant pts with HCC / cirrhosis?
Multiple trials comparing resection and liver transplant for HCC and cirrhosis
- Milan criteria 1996 = excellent 5 yr survival for LT in cirrhosis and stage I or II HCC (85%)
Hence, transplantation ideal if technically resectable HCC and severe cirrhosis
- both treated simultaneously.
--> BUT organ shortage and waiting time bad for tumours.
- the waiting time is ~7m average, which has caused greater support for resection.
--> want to intervent on these as early as possible
[- note also, may be an emerging role for serafinib while waiting]
 31-78% survival and 65% recurrence in resection (also new growths)
- ... but better rates for transplant come with a higher peri-op morbidity and mortality
- note also that resection in these patients complex due to poor regeneration and function of remnant
More controversial for smaller HCC
- can be amenable to resection, buying time away from transplant
- hence, some advocate transplantation as a 'salvage procedure' after failure / recurrence of initial resection. ,
- "bridge to transplant" option v. controversial as LT harder after r/v, and recurrence may prevent LT
--> case by case and service decision, e.g. based on portal hypertension, tumour stage, extent of resection, age and state of patient, organ usage and availability.
Bottom line:
There is no standardized guideline acceptable for all centers as to who should be operated and what option to take.
In young pts with HCC and cirrhosis, long-term outcline likely favours transplantation if expeditious; recurrence 10-15%/yr
Salvage transplantation may not be feasible if recurrence is aggressive or multifocal.

Transplantation for ICC?
Recent studies with adjuvant therapy have shown more promise, esp for perihilar disease
But in general, transplantation is disappointing for ICC and should currently only be considered in the context of clinical trials.

Staging

Child Pugh
Total Serum Bilirubin
Bilirubin <2 mg/dl: 1 point
Bilirubin 2-3 mg/dl: 2 points
Bilirubin >3 mg/dl: 3 points
Serum Albumin
Albumin >3.5 g/dl: 1 point
Albumin 2.8 to 3.5 g/dl: 2 point
Albumin <2.8 g/dl: 3 point
INR
INR <1.70: 1 point
INR 1.71 to 2.20: 2 point
INR >2.20: 3 point
Ascites
No Ascites: 1 point
Ascites controlled medically: 2 point
Ascites poorly controlled: 3 point
Encephalopathy
No Encephalopathy: 1 point
Encephalopathy controlled medically: 2 point
Encephalopathy poorly controlled: 3 point

Modified BCLC Staging System
Takes into account liver function and patient status so appears to have advantages.

0 = Very Early Stage
Very difficult to identify
And very difficult to diagnose
- imaging confuses vs nodules and biopsy is often challenging.
Single lesion <2cm, preserved
Normal portal pressure
Meet Childs-Pugh A criteria
Would not be eligible for a deceased donor organ.
--> resection is the treatment of choice

A = Early Stage
Preserved liver function
- Child Pugh A or B
Single tumour <5cm or up to 3 nodules, each <3cm
Adjuvant ablative techniques (TACE / RFA / Perc Ethanol Injection) considered when waiting times are long
- alternatively live donor transplantation if there is a suitable donor.

B = Intermediate Stage
Preserved liver function
 Large or multifocal disease without evidence of macrovascular invasion, extrahepatic spread or cancer-related symptoms
Usually candidates for TACE (transarterial chemoembolization).
- HCC notoriously resistant to standard chemo
Targeted therapies are emerging
- e.g. sorafenib tosylate; oral tyrosine kinase inhibitor
- blocks tumor cell proliferation by inhibition of Raf kinase
-> RCT evidence for improved survival (10.7 vs 7.9m) and reduced time to progression (5.5 vs 2.8m)

C = Advanced
Cancer related symptoms, macrovascular complications, distant mets.
Survival at 1 yr is 50%
TACE considered if no portal vein invasion or distant mets
Sorafenib (+/-TACE)
Prefarably in the context of clinical trials.

D = Terminal
Deterioration of physical capacity
Advanced tumor burden
Major impairment of liver function
Limited therapeutic options
Median survival 3m
Palliative care.



TACE Notes
Why Tace?
higher response rate (75% vs 25%)
Lower toxicity
- rate allows first pass metabolism from liver
Better survival
Disadvantages / risks
Operative procedure required to place catheter
Need day stay
Cost is higher
Specific complications eg dose-related cholangitis.
- 5FU may cause arterial thrombosis or rarely aneurysm and bleeding
Thrombosis of the catheter
Infection of catheter

Operative

Who?
As above, pts with early or very early stage HCC by the BCLC system
- (Barcelona Clinic Liver Cancer)
5- yr survival in these pts is good - 50-70%
But only 20% of pts are suitable for this line of therapy.
IF:
- adequate reserve (e.g. CP class AB)
- No portal hypertension (predictor of poor outcomes; will develop complications incl. ascites)
--> varices / ascites; or less obviously, splenomegaly and platelets <100,000/mm3, or hepatic vein testing can be performed.
--> normal BiliR in the absence of PH are bst indicators of surgical outcomes.
- Most groups say solitary tumours in a favourable location
- remaining residual liver should be 50% or more of total liver volume

Milan Criteria for Transplantation
Landmark NEJM study demonstrating very good outcomes and survival for transplantation
--> LT is the standard of care for HCC treatment in context of advanced cirrhosis and early tumours
--> unparalleled survival cf resection.
Consider LT if:
1. Tumour <=5cm, single HCC
2. OR, if multiple tumours, <3 nodules, each 3cm or less.
- expanded criteria have been proposed but this remains acceptable.
- an active area of interest is downstaging some tumours by ablation to meet these criteria; promising

Live Donor LT?
Complex procedure; donor mobility of 20-40% and mortality 0.3-0.5%
Prickly legal and ethical issues.
Disease free survival lower than for deceased LT
- preserving vena cava can compromise tumor margins

Curative - Principles
Broadly categorized into anatomical and non-anatomical
- small peripheral lesions are optimally positioned for non-anatomical or wedge resections.
- larger more central lesions require formal anatomic resection.
--> segmentectomy, sectionectomy, hemi-hepatectomy, or extended hemi-hepatectomy.

Approach
Best approached via a RUQ incision with an upper midline extension.
- Lap approaches continue to be developed
Search for mets
Mobilize appropriate portion of liver, dividing round, falciform and ipsilateral triangular ligaments.
Hepatic artery and portal inflow can be controlled at hilum.
- alternatively, intraparenchymally after starting the dissection.
Exposure of proximal hepatic ducts, especially left duct, may be facilitated by lowering the hilar plate (lesser omental attachments at hilum).
--> control inflow.
Then control hepatic venous outflow.- need to divide IVC ligament; Makuuchi's lig. with scissors or endostapler.
- hepatic veins can be suture ligated or stapled.
- alternatively can be done later through intraparenchymal access.
Then proceed with parenchymal transection
- a matter of surgeon preference; little firm evidence.
- old school finger clamp and Kelly clamp
- ultrasonic tissue sealing / CUSA and water jet dissection
- small vessels and ducts may be clipped
- larger ones require ligature and stapling.
Intermittent Pringle may help reduce bleeding but should be used sparingly.
Maintaining CVP at or below 5mmHg shows decreased blood loss and improved outcomes.

Palliation
Many patients present with unresectable disease.
Purely symptomatic therapy only option.
- aim to provide long term symptom relief
- typically via biliary drainage.
Stenting (ERCP) high rate of initial success
- but limited by frequent obstruction and need for replacement due to tumour ingrowth.
- self-expanding metal stents allow greater patency but can be difficult or impossible to move or change when get blocked.
- ptc stenting allows multiple isolated areas to be accessed, ease of revision, and possibility of transition to internal drainage.
Operative biliary-enteric bypass provides reliable and durable relief of obstructive jaundice.
- can be an option when found to be unresectable.
- but not the best option because of higher mortality and morbidity in these pts.

Other Liver-Directed Therapies
- Thermal ablation (microwave or radioablation)
--> RFA = radiofrequency ablation
- Embolization (chemoembolization or bland)
--> TACE = trans-arterial chemo-embolization
- Percutaneous ethanol injection
- Directed radioRx
Initial results have been promising but more RCTs needed to define their role in unresectable disease.
May prolong life and shd be considered.
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REFERENCES
Cameron 10th

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