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HCC & CRLM

HCC

Etiology:

  • M>F
  • Western countries :
    • Metabolic dysfunction associated fatty liver disease (MAFLD) - Cirrhosis/ Without Cirrhosis
  • Sub sahara Middle east-
    • HBV- Cirrhosis
    • Insertional mutagenesis -(De novo)
  • HCV - Sustained virologic response decreases risk of HCC by use of Antiviral agents but not zero risk
  • 2 factors are important:
    • HCC is a field defect in case of Cirrhosis; as we remove one tumor there is possibility of other lesions to develop in other areas of cirrhotic liver ⇒ No of lesions important
    • Propensity to vascular invasion increases as the size of tumor increases and when portal vein is involved it is treated as systemic disease ⇒ Size of tumor is important
  • There is no adjuvant therapy( systemic therapy) to prevent recurrence
  • Definitive treatment therefore is Liver Transplant

Molecular profile

  • Most frequent- telomerase maintenance (TERT promoter, CTNNB1 Wnt-Beta catenin, p53, MAP kinase )
    • Proliferating class- activation of RAS pathway, HBV infection, FGF amplification (Bad prognosis)
    • Non proliferating class- Wnt Beta catenin and HCV infection (Good prognosis)

Screening

  • Risk of HCC 1.5% per year
  • Cirrhosis, Chronic HBV, Chronic HCV = Premalignant Conditions
    • PAGE-B, Toronto THRI ( guidelines for screening)
  • Non cirrhosis HCV, MAFLD - No clear guidelines
  • USG-IOC, AFP is not included ( as AFP is not specific for HCC and also small size tumors dont secrete AFP)
  • Semiannual
  • If USG has a SOL ≥ 1cm ⇒ go for CT/MRI contrast ⇒ as diagnosis is radiological ⇒ no need for Biopsy
  • If SOL is ≤ 1cm ⇒ follow up USG after 3 months

DIAGNOSIS:

  • Arterial phase enhancement and venous phase washout (seen only if ≥2 cm nodule)
  • Markers:
    • AFP, PIVKA, AFP fractions (AFP-L3 more specific for HCC) , glypican-3
  • IHC: after liver biopsy:
    • Hsp-70, glypcan-3, glutamine synthetase

LIRADS:

Non rim APHE ⇒ central enhancement & Non rim washout also ⇒. HCC If tumor has all 5 features then it is for sure HCC

Non rim APHE ⇒ central enhancement & Non rim washout also ⇒. HCC If tumor has all 5 features then it is for sure HCC

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Key Points on LI-RADS Categories and HCC Imaging

LI-RADS (Liver Imaging Reporting and Data System)

  • Design:
    • LI-RADS categories are designed with high specificity to accurately diagnose hepatocellular carcinoma (HCC), often at the expense of sensitivity.

Major Features of HCC:

  • Non-Rim Arterial-Phase Hyperenhancement:
    • Mandatory for categorization as LR-5 (definitely HCC).
  • Non-Peripheral "Washout":
    • Indicates the reduction of enhancement in the venous or delayed phases.
  • Enhancing "Capsule":
    • A peripheral rim of enhancement seen in the portal or delayed phase, suggesting the presence of a fibrous capsule around the lesion.
  • Threshold Growth:
    • Defined as a significant increase in the size of a lesion by ≥ 50% within 6 months, supporting the diagnosis of HCC.

Ancillary Features Favoring HCC:

  • Nodule-in-Nodule or Mosaic Appearance:
    • Indicates a complex internal structure, often seen in HCC.
  • Intralesional Fat or Blood Products:
    • The presence of fat within the lesion or evidence of bleeding supports an HCC diagnosis.

Special Categories in LI-RADS:

  • LR-TIV (Tumor in Vein):
    • Assigned to observations with unequivocal enhancing soft tissue within a vein, indicating definite malignancy.
    • Macrovascular Invasion:
      • Most frequently associated with HCC but can also be seen in other liver tumors like intrahepatic cholangiocarcinoma.

Prognostic Scoring systems for HCC:

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BCLC Key points:

  • Tumor burden, liver function, cancer related symptoms
  • 0,A, B,C,D
  • Prognosis, clinical decision,staging
  • BCLC 0 (Very early), (Single tumor < 2cm)
  • BCLC A(Early- Single tumor (any size), Multiple (up to 3, <3 cm)
    • implies size is not a contraindication for resection if there is a single lesion
    • Resection is only done if Bilirubin is normal and NO Portal Hypertension
  • BCLC 0 & A:
    • Preserved liver function, No cancer related symptoms
    • 5 year survival- 50-70% if we follow milan criteria for LT
  • Intermediate Stage (BCLC B):
    • Multifocal tumors
    • Preserved liver function [PS 0]
    • TACE/TARE/RFA/systemic therapy
    • TACE preferred
      • Survival -50% at 3 years
    • Diffuse infiltrative, extensive bilobar --systemic treatment
  • BCLC C:
    • Preserved liver function [PS 1-2]
    • Extrahepatic spread
    • Vascular invasion
    • ECOG 1-2
    • Systemic therapy - OS of 2 year
  • BCLC D:
    • Terminal patients
    • Liver dysfunction
    • ECOG 3,4
    • Best Supportive Care

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Surgery:

  • Absence of cirrhosis
  • Child A cirrhosis
  • Normal Bilirubin
  • No clinically significant portal hypertension [HVPG< 10]
  • Number and size is not a contraindication if there is no Portal Hypertension
  • Vascular resection can be done
  • No benefit of adjuvant therapy

Liver Transplantation Criteria for Hepatocellular Carcinoma (HCC)

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  • Mazafaroo et I proposed Milan criteria
  • 5 year survival is 60-80%
  • Recurrence less than 15%
  • Bridging therapy may be needed if wait> 6 months

Milan Criteria

  • Eligibility:
    • Single lesion ≤ 5 cm
    • OR
    • Up to 3 nodules, each ≤ 3 cm
  • Exclusion:
    • No vascular invasion
    • No extrahepatic spread

UCSF (University of California, San Francisco) Expanded Criteria

  • Eligibility:
    • Single lesion ≤ 6.5 cm
    • OR
    • Up to 3 nodules with:
      • Largest tumor ≤ 4.5 cm
      • Total tumor diameter ≤ 8 cm
  • Exclusion:
    • No vascular invasion
    • No extrahepatic spread

Systemic Therapy for Hepatocellular Carcinoma (HCC)

1st Line Therapy:

  • Preferred Combination Therapies:
    • Atezolizumab + Bevacizumab
    • Durvalumab + Tremelimumab
  • Alternative Monotherapies (if combination not feasible):
    • Sorafenib
    • Lenvatinib
    • Durvalumab

2nd Line Therapy:

  • Post Sorafenib:
    • Regorafenib (for sorafenib-tolerant patients)
    • Cabozantinib
    • Ramucirumab (for patients with AFP ≥ 400 ng/mL)
  • Post Atezolizumab-Bevacizumab:
    • Cabozantinib
  • Post Durvalumab-Tremelimumab:
    • Cabozantinib
  • Post Lenvatinib or Durvalumab:
    • Cabozantinib

3rd Line Therapy:

  • Cabozantinib: Used if no other options are feasible or if other lines of therapy fail.

Clinical Trials:

  • Recommended as an option for patients where standard therapies are not feasible or available, providing access to new and potentially effective treatments.

Summary:

  • First-line therapy for HCC focuses on combination therapies, with monotherapy options available if combination treatments are not feasible.
  • Second-line options depend on the initial treatment, with Cabozantinib and Regorafenib commonly used.
  • Third-line therapy primarily involves Cabozantinib, especially when other treatments have been exhausted or are not suitable.
  • Clinical trials offer an alternative pathway for patients who may not be candidates for standard therapies.

TACE

  • Embolization + Chemotherapy
  • Bland embolization/ Chemoembolization
  • Most Commonly used- Doxorubicin ; others = Cisplatin, Epirubicin, Mitomycin C
  • Drug+ethiodized oil (preferentially taken up by tumor)
  • Embolization - Gelatin sponge (larger particle size)
  • PVA (polyvinyl alcohol)- More distal embolization

  • Preparation: ( small, expansile, Encapsulated, Hypervascular, Trabecular HCC = preferred)

    • Rule out significant arteriovenous and arterioportal shunts
    • Shunt reduction- large particle embolization + sorafenib
    • CBC, LFT, INR, tumor marker
    • CT angio- tumor size, location, growth pattern (expansile, replacing or infiltrating), vascular invasion, anatomy of artery
    • СEСТ
    • Antibiotics
    • Selective, or superselective embolization is done
    • Embolization of extrahepatic collaterals is done ( inferior phrenic and mammary )

  • Indications for TACE:

    • Unresectable HCC
    • Multifocal HCC (outside transplant criteria)
    • Survival benefit
    • Bridge therapy for HCC awaiting transplant
    • Downstaging of HCC
    • Child A, Early child B (CTP -7)
    • Intermediate stage HCC
    • Spontaneous rupture of tumor

  • Contraindications for TACE:

    • Decompensated cirrhosis
    • Main portal vein invasion
    • Active Gl bleed
    • Extrahepatic spread
    • Biliary obstruction
    • Hepatic encephalopathy
  • No evidence of neoadjuvant TACE before surgery = since no survival benefit
  • Complications for TACE:
    • Post embolization syndrome : 80% of patients -flu like illness, self limiting
    • Liver failure
    • Liver abscess - HJ, SOD dysfunction
    • Bile Duct injury
    • Non target embolization-
      • Gall bladder is MC
      • Skin complications
      • Gastroduodenal ischemia
      • Pulmonary complications

TARE:

  • Radioembolization
  • Non embolic, generation of free radicals
  • Can be used in PVT = because it doesnt hamper blood supply of liver by blocking hepatic artery
  • Selective internal radiation therapy (SIRT)
  • MC- yttrium -90 microsphere
  • Beta particle emitter decays into Zr 90
    • Thera sphere- 20-30 microns- Glass
    • SIR Spheres- 20-60 microns- Resin
  • Pretreatment planning:
    • Lung shunt fraction by doing 99TC-MAA scan and it should be <15%
    • Maximum dose 30 Gy per treatment
    • Cumulative 50 Gy
    • if more = radiation pneumonitis
  • Indications for TARE:
    • Similar indications to TACE
    • only used for Intrahepatic Cancers = cannot be used for Cholangiocarcinoma’s
    • Longer TTP (Time to Progression) for TARE- PREMIERE trial
    • No difference in survival
    • SARAH trial- SIRT vs sorafenib (No diff in OS)

Response assessment For Systemic therapy = TACE/TARE

  • m-RECIST criteria
  • Post radio embolization syndrome
  • Hepatic dysfunction
  • Radiation pneumonitis

Colorectal Liver Metastasis

  • 15% to 25% of patients with CRC with synchronous liver metastases
  • 20-30% have metachronous liver metastases
  • Median survival - 10 months if left untreated
  • Liver resection - Survival rate of 60% (5 years)

Chemotherapy

  • FOLFOX
  • FOLFIRI
  • FOLFOXIRI
  • Biologics: (combined with above regimes)
    • Bevacizumab (anti VEGF)
    • Cetuximab (KRAS wild type)

BEACON trial : BRAF V600E (worst) mutation -Triplet therapy ( FOLFOX or FOLFIRI wont work here)

  • Encorafenib (BRAF Inhibitor), binimetinib (MAK kinase inhibitor) and cetuximab (anti EGFR)
  • Detrimental effect of cetuximab with KRAS exon 2 wild type resectable CRLM
  • Perioperative chemotherapy >> Surgery alone
  • Conversion to resectable after preoperative chemotherapy
  • Chemotherapy toxicity:
    • Oxaliplatin - Blue liver syndrome-(Sinusoidal injury = SOS), peripheral neuropathy
    • Irinotecan- Steatohepatitis [CASH}
    • Preoperative chemotherapy upto 6 cycles only
    • Use of bevacizumab and oxaliplatin [ incidence of blue liver syndrome comes down]
    • Interval of 5 weeks is recommended for surgery [ in Liver regeneration chapter it was given 3 weeks]

Criteria for resectability

  • B/L liver metastases is not a contraindication = do parenchyma preserving resection as recurrence occurs and we can resect recurrent lesions
  • Staged liver resection can be done = if B/L mets are present.
  • Extrahepatic disease (limited lung and peritoneal deposists & limited Portal and retroperitoneal node is not a contraindication)
  • RAS / TP 53 mutation
  • Liver remnant should have adequate FLR - 20% - normal liver, 30% for chemotherapy, 40% for cirrhosis
  • R1 microscopic (but not R1 macroscopic resection) is acceptable

Imaging

  • Triphasic CT - Portal venous phase to see for metastases
  • MRI- Better than CT in steatotic liver
  • PET- poor sensitivity for lesions less than 1 cm
  • Fudicial markers for disappearing liver metastases (5-24%)

Synchronous metastases

  • Depends on extent of resection
  • Two major procedures are contraindicated ⇒ donot combine Major Hepatectomy with Colectomy
  • One procedure is minor
  • Short course chemotherapy is given
  • Staged Resection:
    • Conventional = Primary ⇒ Chemo ⇒ Liver mets
    • Liver First (reverse) = Adj Chemo ⇒ Liver mets ⇒ Chemo ⇒ Primary

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Key points:

  • Right sided tumors have worse prognosis than left sided
  • BRAF mutation - worse prognosis
  • Anti EGFR therapy is not beneficial in right sided
  • Tumor location did not affect efficacy of bevacizumab

Molecular determinants of outcome

  • RAS- MAP kinase pathway, K ras, N Ras, Hras
  • Ras mutation - resistance to therapies with EGFR inhibitor
  • Wild RAS- Cetuximab can be given
  • BRAF- MAPK signalling cascade, aggressive disease, poor survival
  • BRAF V6000E- worse prognosis
  • SMAD 4 (tumor suppressor gene) TGF Beta- Poor prognosis

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MCQ: Identify the Condition with the Lowest Risk of Developing Hepatocellular Carcinoma (HCC)

Options:

  • A) HCV (Hepatitis C Virus)
  • B) HBV (Hepatitis B Virus)
  • C) Alcoholic cirrhosis
  • D) Alpha-1 antitrypsin deficiency

Correct Answer: C) Alcoholic cirrhosis

Explanation:

  • A) HCV (Hepatitis C Virus):
    • High risk of developing HCC, especially in patients with chronic infection and cirrhosis.
  • B) HBV (Hepatitis B Virus):
    • High risk of HCC, even without cirrhosis, due to the virus’s direct oncogenic effects.
  • C) Alcoholic cirrhosis:
    • Lower risk compared to viral hepatitis (HCV and HBV) and certain genetic conditions like alpha-1 antitrypsin deficiency. Although alcohol abuse significantly increases the risk of HCC, the risk is generally lower than that associated with chronic HBV or HCV infections.
  • D) Alpha-1 antitrypsin deficiency:
    • Moderate risk of HCC, especially in those with cirrhosis caused by this genetic disorder.

Relationship Between Cirrhosis and Hepatocellular Carcinoma (HCC)

Cirrhosis and HCC:

  • Complex Relationship:
    • The true relationship between cirrhosis and HCC is difficult to ascertain.
    • Causation remains speculative: Not all cases of cirrhosis lead to HCC, and cirrhosis is not required for HCC development.
    • Both conditions share common associations (e.g., HBV, HCV, hemochromatosis).
  • Variable Risk of HCC:
    • Higher Risk:
      • HBV infection
      • Hemochromatosis
    • Lower Risk:
      • Alcohol abuse
      • Primary biliary cirrhosis
    • Research suggests that cirrhotic livers with higher DNA replication rates are more prone to developing HCC.

Risk Factors for HCC:

  • Alcohol Abuse:
    • Increases risk of HCC, particularly when combined with HBV or HCV infection (synergistic effect).
    • Alcohol is not directly carcinogenic but likely acts as a cocarcinogen in hepatocarcinogenesis.
  • Cigarette Smoking:
    • Linked to HCC, but the evidence is inconsistent.
    • The risk independent of viral hepatitis is likely small.
  • Aflatoxin:
    • Produced by Aspergillus spp., a powerful hepatotoxin and carcinogen.
    • Chronic exposure increases the risk of HCC.
    • Found in contaminated grains, peanuts, and other food products, particularly in tropical and subtropical regions.

Summary:

  • Cirrhosis is a significant risk factor for HCC, but not all cirrhotic patients develop HCC, and not all HCC cases arise from cirrhosis.
  • HCC risk varies based on the underlying etiology of cirrhosis, with factors like HBV, hemochromatosis, alcohol abuse, and aflatoxin exposure playing critical roles.
  • Alcohol and smoking contribute to HCC risk but are less directly associated with hepatocarcinogenesis compared to viral infections and aflatoxin exposure.

MCQ: Identify the False Statement Regarding the Epidemiology of Hepatocellular Carcinoma (HCC)

Options:

  • A) NASH is the most common cause in Western countries
  • B) HCC can arise in the background of a non-cirrhotic liver in NASH
  • C) HCV treatment eliminates the risk of further HCC development
  • D) USG is the screening modality of choice in high-risk populations

Correct Answer: C) HCV treatment eliminates the risk of further HCC development

Explanation:

  • A) NASH is the most common cause in Western countries:
    • True—Non-Alcoholic Steatohepatitis (NASH) is increasingly recognized as a leading cause of HCC in Western countries, particularly with the rising prevalence of metabolic syndrome and obesity.
  • B) HCC can arise in the background of a non-cirrhotic liver in NASH:
    • True—While cirrhosis is a significant risk factor, HCC can also develop in patients with NASH without cirrhosis.
  • C) HCV treatment eliminates the risk of further HCC development:
    • False—Achieving a Sustained Virologic Response (SVR) with HCV treatment significantly reduces the risk of developing HCC, but it does not completely eliminate the risk, especially in patients who already have advanced fibrosis or cirrhosis.
  • D) USG is the screening modality of choice in high-risk populations:
    • True—Ultrasound (USG) is widely used as the screening tool of choice for HCC in high-risk populations, often in combination with alpha-fetoprotein (AFP) testing.

Molecular Alterations in Hepatocellular Carcinoma (HCC)

Frequent Genetic Alterations:

  • Telomerase Maintenance:
    • TERT (Telomerase Reverse Transcriptase) Promoter Mutations: These mutations are commonly seen in HCC and contribute to the maintenance of telomerase activity, allowing cancer cells to avoid senescence.
  • Wnt/Beta-Catenin Pathway:
    • CTNNB1 Mutations: Activation of the Wnt/Beta-catenin pathway is a frequent event in HCC, particularly in the non-proliferative class of the disease.
  • p53 Mutations:
    • TP53 Mutations: The p53 tumor suppressor gene is frequently mutated in HCC, particularly in more aggressive forms of the disease.
  • MAP Kinase Signaling:
    • MAPK Pathway Activation: This signaling pathway is involved in cell proliferation and survival and is often dysregulated in HCC.

Targetable Pathways Under Research:

  • c-MET Activation: This pathway is involved in cellular growth and metastasis.
  • Fibroblast Growth Factor Receptor (FGFR): Aberrations in this pathway can lead to uncontrolled cell growth.
  • Vascular Endothelial Growth Factor Receptor (VEGFR): Targeting this pathway can inhibit angiogenesis in tumors.
  • Transforming Growth Factor Beta (TGF-B): This pathway plays a role in tumor progression and immune evasion.

Molecular Classification of HCC:

  • Proliferative Class:
    • RAS Pathway Activation
    • FGF Amplification
    • HBV Infection
    • Associated with poor prognosis.
  • Non-Proliferative Class:
    • Characterized by Wnt/Beta-catenin alterations.
    • Frequently associated with HCV infection.

Whole-Genome Sequencing Approach:

  • Cluster 1:
    • Low CTNNB1 mutation frequency
    • Low TERT expression
    • Associated with early-stage disease and Asian origin.
  • Clusters 2 and 3:
    • Higher prevalence of TERT promoter and CTNNB1 mutations.
    • Cluster 3 also presents with a high occurrence of p53 mutations.

Crash Course HCC

  • Risk Factors for HCC:

    • MC risk factor for HCC is HBV > HCV
    • Upcoming risk factors for HCC = NASH will surpass HBV in future
    • Alcohol
    • male sex [ FEMALES = Protective]
    • Hemochromatosis
    • Cirrhosis of any etiology
    • aflatoxin
    • Metabolic syndromes; obesity; NASH ; haemochromatosis
    • Primary biliary cirrhosis

  • Protective:

    • Coffee intake = decreases incidence = PROTECTIVE
    • Female Sex

CRLM

A comparison table between the Fong and Nordlinger prognostic scoring systems for colorectal liver metastasis (CRLM):

Criteria Fong Prognostic System Nordlinger Prognostic System
Risk Factors - Node-positive primary CRC
- Time interval from primary CRC to CRLM < 1 year
- Number of CRLM > 1
- Size of largest CRLM > 5 cm
- CEA > 200 ng/mL - Age > 60 years
- Extension of primary CRC into serosa
- Node-positive primary CRC
- Time interval from primary CRC to CRLM < 2 years
- Size of largest CRLM ≥ 5 cm
- Number of CRLM ≥ 4
- Margin less than 1 cm
Risk Categories Based on the number of risk factors from 0 to 5 Categorized as low (0-2 risk factors), intermediate (3-4), high (5-7)
Survival Predictions - 5-year survival ranges from 60% (0 risk factors) to 14% (5 risk factors)
- Median survival ranges from 74 months (0 risk factors) to 22 months (5 risk factors) 2-year survival rates:
- Low: 79%
- Intermediate: 60%
- High: 43%
Primary Usage Used to predict overall survival and recurrence post-resection of liver metastases Predicts 2-year survival based on the number of risk factors

Both systems use factors related to primary colorectal cancer and liver metastases characteristics, but they differ in their specific risk factors and survival predictions. The Fong system is widely used for long-term survival prediction, while Nordlinger focuses more on 2-year survival.

  • Components of Clinical Risk Score in CRLM:

    • CEA >200
    • largest liver mets > 5cm
    • More than one Liver lesion
    • disease free interval < 1 yr

  • presence of extrahepatic disease

  • positive resection margin

  • Node positive primary

    previously these were considered okey but now omitted from CRS score

  • LIVER Resection:

    • Positive margin = R1
      • early recurrence
      • but still pt has good prognosis therefore avoid major liver resections and go for parenchyma preserving liver surgeries.
    • Portal lymph nodes = can be resected
    • Recurrence in 75% of cases: in 50% cases re- resection can be done
      • FLR with inflow and outflow = ONLY prerequisite

  • Contraindications for resection in CRLM:

    • Unresectable Colorectal primary

  • NOT a Contraindication:

    • Extrahepatic Disease
      • Solitary lung or limited peritoneal disease
    • Bilobar Liver mets = only for CRLM but not for other primaries like Stomach/ Pancreas Ca

  • CHEMOTHERAPY:

    • FOLFOX and FOLFIRI for metastatic colorectal cancer
    • FOLFOX = adjuvant chemotherapy = can also be used in locally advanced cancer
    • S/E :
      • FOLFOX = neurotoxicity and neutropenia
      • FOLFIRI = nausea, vomitting, MUCOSITIS & ALOPECIA
      • BLUE LIVER Sx = OXALIPLATIN
      • FATTY LIVER = IRINOTECAN
    • XELOX = Capecitabine ( 5 FU oral) and Oxaliplatin
    • Bevacizumab = increase PFS
    • Cetuximab - Chimeric EGFR monoclonal antibody; KRAS wild type ( donot have KRAS Mutation)
    • Panitumumab - fully humanized monoclonal antibody
    • Median survival after chemotherapy alone is 24 months
    • FUDR = Fluorodeoxyuridine is used in hepatic artery infusional therapy (MCQ)
      • Artery of choice = Gastroduodenal Artery

  • Approach to CRLM + Primary tumor:

    • Classical approach:
      1. Address primary tumor
      2. 3-6 cycles of chemo
      3. resection of liver mets
    • Liver first approach:
      1. Upfront chemo
      2. resection of colorectal mets
      3. chemotherapy +/- radiotherapy
      4. Sx for primary colorectal
    • Combined approach
      • Principle is to never combine a major liver resection with colectomy.

Neuroendocrine Metastasis

  • MC NET which causes Liver mets = GASTRINOMA > Carcinoid tumor
  • Insulinoma and carcinoid tumor metastasize to liver less frequently
  • Carcinoid tumor gives rise to two third of NET liver mets
  • Rectal carcinoid have the highest risk of mets
  • 10% of patients develop carcinoid syndrome
  • Debulking : more than 90% of tumor should be resected ( only place in oncology where debulking is possible)
  • Ga DOTA PET/CT = for imaging
  • 5 yr survival = 50-75%
  • Formal resection with wide margin is NOT MANDATORY
  • RFA/ Cryoablation can be done
  • Peptide receptor Radionuclide therapy used in mx of Metastatic NET’s

Portal Vein Embolisation:

  • one of the ways of Liver Augmentation
  • Generally we do it for right sided resections as the left lobe needs augmentation
  • different approaches:
    • Percutaneous approach
      • Ipsilateral - Directly puncture the liver to be resected = difficult because of short extrahepatic course - but preferred approach
      • Contralateral - we puncture the FLR
    • Laparotomy - trans iliocolic approach
  • Absolute Contraindications:
    • Established PHTN
    • Portal Vein Thrombosis
  • Degree of Hypertrophy > 5% + sFLR >20% ⇒ good response
  • Kinetic Growth rate > 2% per week
  • Segment IV vein is also embolised for better hypertrophy

Treatment options for HCC

  • BCLC staging

    • First line =
      • Resection = Only for pt’s with single lesion without cirrhosis / Child A cirrhosis
      • Transplant =
        • Child B pt’s with increased portal pressures or bilirubin & Child C pt’s
        • Considered in some cases of Intermediate stage( Multinodular) with extended liver tx criteria ( size and AFP)
      • RFA / PEI =

    • Second line =

      • TACE =
        • Indications:
          • Intermediate stage BCLC
          • Neoadjuvant therapy for downstaging for Transplant ( NOT indicated in Resectable tumor)
          • Bridge therapy for transplant
          • Multifocal HCC
          • Survival benefit
          • TACE + PVE ( in case of HCC requiring right hepatectomy) requiring volume augmentation
        • cannot be done in:
          • If Portal vein thrombosis is present
          • Child C pt
          • Extrahepatic spread
          • LN involvement
          • Poor performance status
          • Ascites
          • Encephalopathy, HRS
        • Agents used in TACE :
          • Doxorubicin, Cisplatin, Epirubicin, Mitomycin C + Lipoidal = PVA, Microspheres ,Absolute ethanol, Cyanoacrylate
        • Bland Embolization with microspheres
        • TACE with Drug eluting beads
        • Preoperative = Embolize Arteriovenous shunts
        • Post Embolisation Syndrome = MC (60%)
        • Non Target Embolisation - MC is Gall Bladder

      • TARE =

        • Y90 is MC used
        • beta emitter
        • can be done in PVT
        • both TACE / TARE can be done only if disease limited to liver, Good performance status, Child A/B

        • Preop workup before TARE:

          • Angiography
          • Coil embolisation of non target vessels
          • Tc MAA scan = to calculate lung shunt fraction
            • Dose >30 Gy to lung in single treatment and 50 Gy in cumulative dose = Contraindication

          No need of Biopsy of tumor for TARE

        • Complications:

          • Radiation Pneumonitis
          • RILD ( radiation induced Liver damage) = 4-8 weeks
          • Veno Occlusive disease

    • 3rd Line = Chemotherapy

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  • Milan criteria for transplant:
    • Single tumor, not > 5cms
    • Upto 3 tumor, not > 3cms each
    • Absence of macroscopic vascular invasion
    • Absence of Extrahepatic spread\
    • 5 yr survival with transplantation = 70%
    • 5 yr recurrent rates < 15%
  • UCSF criteria = Outside Milan
    • Single lesion < 6.5 cm
    • Upto 3 lesions
      • largest <4.5cm
      • Total sum < 8cm
    • No gross vascular invasion

FIBROLAMELLAR HCC

  • Young pt’s
  • Centra scar mimic FNH
  • Presence of Calcification differentiates from FNH
  • AFP is normal
  • Neurotensin is elevated
  • Recurrence is common and occurs in 80% of patients

AFP levels

  • Normal AFP without HCC:
    • Small tumors
    • HCC in background of adenoma
    • Sarcomatoid cell variant
  • Elevated AFP without HCC
    • Active viral hepatitis
    • Cholangiocarcinoma
    • Colorectal Liver Metastasis

Volume Assessment:

  • Safe FLR for resection in
    • Normal liver = 20-25%
    • Damaged ( steatotic, Post Chemo) = 30-40%
    • cirrhosis = >40%
  • TLV = calculated by CT /MR volumetry
  • TELV = calculated by using URATA formula based on BSA
  • TELV is a better easure of postoperative hepatic insufficiency
  • sFLR = FLR/TELV =
  • FLR = FLR/TLV

Liver Fibrogenesis:

  • Collagen IV is replaced by I and III
  • Induced by TGF B
  • Hepatic stellate cells modulate fibrogenesis
  • MMP 1,8 and 13 expression decreases and MMP 2 increases
  • Fenestration is reduced
  • HSC —> myofibroblast —> TGF b —> fibrogenesis
  • (MCQ) CAP score in fibroscan measures? a)Liver Fibrosis b)Liver Regeneration c)Liver Steatosis d)Liver vascularity
  • Assessment of FIBROSIS by histological / or after Biopsy :
    • KLEINER score = NAFLD
    • LUDWIG score = PBC; PSC
    • METAVIR score = Fibrosis & Activity ; Viral Infections ; Auto immune
    • Knodell Histology activity index = 3 stages
    • Ishak score = 6 stages
    • Fibrosis in NAFLD and ALD is centrilobular whereas in viral infection it is periportal.

  • Biochemical assessment of fibrosis:

    • The most studied combination serum tests are the:
    • AST- to-platelet ratio index,
    • the Fibrosis-4 (FIB-4) index,
    • the enhanced liver fibrosis (ELF) test,
    • the FibroTest (FT; Biopredictiv, Paris
    • Newer biomarker scores include the HepaScore and measurement of collagen propeptides.

  • FIBROSCAN:

    • Measures Fibrosis ( Kpa) and STEATOSIS ( CAP SCORE)
    • Kpa = 2-6 ( Normal) highest 75 Kpa
    • Limitation:
      • Active hepatitis
      • Tumors in Liver
      • CHF
      • Obesity
      • Ascites, Jaundice

  • Liver Attenuation Index:

    • Average attenuation of Liver on NONcontrast CT = 50-65 HU
    • 8-10 HU greater than spleen
    • LAI = Difference between Liver and Splenic attenuation
    • LAI >5 = absence of significant steatosis
    • LAI = -10 to 5 = moderate steatosis
    • LAI = < -10 ⇒ 30% steatosis
  • Functional assessment of FLR is done by : MRI Gd EOB DTPA

  • ICG =

    • gives global functional assessment cannot do it for FLR
    • ICG is water soluble compound that binds to albumin
    • Filtered and excreted unchanged in BILE
    • Limited usefulness in pt’s with jaundice and intrahepatic shunting

  • Liver Regeneration in LDLT:

    • Complete regeneration occurs at 3 months post transplant
    • Collagen content is predominantly Type IV and Type I
    • Proliferation starts in periportal area
    • Hepatocytes are primary mediators of regeneration after surgical trauma BUT NOT Hepatic Progenitor Cells (HPC =STEM CELLS).

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Liver Atrophy

  • Portal Vein ligation : Necrosis and apoptosis
  • Bile duct ligation = apoptosis
  • Hepatic artery ligation = Necrosis ; however it can cause atrophy if adequate collateral flow is present

ALPPS ( Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy)

  • Dr Hans Schlitt,
  • Hilar CCA
  • Maximum volume gain, tumor in FLR, Rescue ALPPS
  • Stage 1
    • Tumor bearing lobe = portal vein is divided
    • Parenchymal transection is performed
    • Bile Duct, HA, HV is not divided
  • Stage 2
    • Complete resection (7-14days) vs 3-4 weeks PVE
    • shorter duration with more hypertrophy in ALPPS
    • but increased morbidity and poorer survival compared to 2 stage hepatectomy
  • Most common Morbidity = Bile Leak

Post Hepatectomy Complications:

  • Post Hepatectomy Liver cell failure:

    Definition: on or after POD 5 if there is increased Bilirubin or INR. Other obvious causes of biochemical and clinical alterations such as biliary obstruction should be ruled out.

    Grades:

    • A = PHLF resulting in abnormal laboratory parametres but requiring no change in the clinical management of the patient.
    • B = deviation from regular clinical management but manageable without invasive treatment
    • C = requiring invasive treatment
    • Strategies to Prevent Post op Liver cell failure:
      • Surgical methods: ( ensure adequate FLR)
        • Portal vein embolization
        • 2 staged hepatectomy
        • ALPPS
        • Intra op Hepatic venous reconstruction
        • Ishcemic pre conditioning
        • Portocaval shunt
        • Splenectomy
        • Insitu hypothermic liver perfusion ( not ex situ)
      • Pharmacological:
        • Role of Somatostatin
      • Preventive strategies:
        • Adequate preoperative preparation
        • Meticulous surgical techniques : Low CVP during liver transection, minimising blood transfusion, avoid extensive skeletonising of HD ligament.
        • Early recognition of Post op complications ( hemorrhage, Bile leaks)