DEPARTMENT OF SURGICAL ONCOLOGY- GOVERNMANTROYAPETTAH HOSPITALPROF DR.R.RAJARAMAN ‘S UNIT
Hepatocellular Carcinoma Dr Sujay Susikar Post Graduate Student Department of Surgical Oncology Government Royapettah Hospital
Epidemiology 551000 cases per year worldwide Estimated new cases in India – 2011 – 14533 5th most common cancer 83 % of all HCC - seen in developing countries Male predominance > 2 times
EtiologyMajor Risk Factors Other risk factors Hepatitis B Male gender Age Cirrhosis Tobacco smoking HBV And HCV DM/ Insulin resistance Aflatoxin β 1 Radiation exposure Inorganic arsenic Hereditary Radioactive thorium hemochromatosis OC pills use > 8 years α 1 antitrypsin Glycogen storage diseases deficiency Membranous obstruction of IVC Hereditary tyrosinemia Saffrole oil Alcohol Non Alcoholic Steato Hepatitis
Global distribution of HCC < 8 / 100000 8 – 15/ 100000 > 15 / 100000
HCC surveillanceCirrhosis Without cirrhosis HBV and HCV Hepatitis B carriers Alcoholic Asian males > 40 yrs NASH Asian females > 50 yrs Family h/o HCC Genetic Africans > 20 years hemochromatosis Autoimmune hepatitis Primary biliary cirrhosis
Surveillance USG + α FP – every 6 monthsNodule < 1cm FU 3 – 4 months till 2 years No growth – 6 monthlyNodule 1 -2 cm Triphasic imaging on 2 modalities, Biopsy or FNACNodule > 2 cm Triphasic CT on single modality, FNAC or biopsy not be necessaryOnly increased α FP R/O GCT,. CT, MRI other markers
Clinical presentation Asymptomatic Non specific symptoms Tumor related – upper quadrant pain, hepatomegaly, acute abdomen, jaundice etc CLD related – UGI bleed, splenomegaly, ascites, encephalopathy Paraneoplastic syndromes- Hypoglycemia, Hypercalcemia, Polycythemia, PUO, Hypercholesterolemia, Gynaecomastia Metastasis related
Work up Imaging: UGG, CT, MRILabs:CBC, LFTs, Chemistries, Biopsy:Cioag panel, Hep B, C May not be requiredpanel, αFP
Criteria for Non Invasive DiagnosisLesions > 2 cm Arterial enhancement and venous washout on 1 imaging modality either on CT/MRI/USG or angiogram Only arterial enhancement on 2 contrast studiesLesions 1 – 2 cm Arterial enhancement and venous washout on 2 imaging modalities Arterial enhancement alone and αFP > 200 ng/ml
Clinical staging Numerous staging systems ( no consensus) TNM Okuda CLIP BCLC Incorporate 4 determinants of survival: 1. Severity of underlying liver disease 2. Size of the tumor 3. Extension of tumor into adjacent structures 4. Presence of metastasis Recent trials – BCLC and CLIP
TNM - AJCCT – primary tumor T1 - solitary tumor without vascular invasion T2 – solitary tumor with vascular invasion or multiple tumors, none more than 5 cm Stage I T1 N0 M0 T3 – multiple tumors T3a - any more than 5 cms or Stage II T2 N0 M0 T3b - involving a major branch of the portal or hepatic veins Stage IIIA T3a N0 M0 T4 – tumors with direct invasion of adjacent Stage IIIB T3b N0 M0 organs other than the gall bladder or with perforated visceral peritoneum Stage IIIC T4 N0 M0N – regional lymph nodes Stage IVA Any T N1 M0 Nx – regional nodes cannot be assessed Stage IVB Any T Any N M1 N0 – no regional nodal metastases N1 – regional nodal metastasesM – distant metastasis M0 – no distant metastases M1 – distant metastases
Okuda staging system Criteria Positive Negative Tumor size > 50% < 50% Ascites + _Albumin g/dl < 30 >30Bilirubin mg/dl >3 <3 Stage I All negative Stage II 1 or 2 positive Stage III 3 or 4 positive
CLIP scoreCriteria PointsChild – Pugh stageA 0B 1C 2Tumor morphologyUninodular and extension <50% 0Multinodular and extension < 50% 1Massive or extension > 50% 2Alpha feto protein level< 400 ng/ml 0> 400 ng/ml 1Portal vein thrombosisNo 0Yes 1
Barcelona Clinic Liver Cancer (BCLC) staging system BCLC STAGE PERFORMANCE TUMOR LIVER STATUS FEATURES FUNCTION0 0 Single < 2cm No portal HtnA1 0 Single < 5 cm No portal HtnA2 0 Single < 5 cm Portal Htn, normal bilirubinA3 0 Single < 5 cm Portal Htn, abnormal bilirubinA4 0 3 tumors, < 3cm Not applicableB 0 Large multinodular CP A-BC 1–2 Vascular invasion or CP A - B metastasesD 3–4 Any CP C
Resection Criteria : Medically fit for major surgery Single lesion < 3 – 5 cm , suitable location, no major vascular invasion Preserved liver function No portal hypertension, normal bilirubin 20% FLV in non cirrhotic liver and 30 – 40 % in child A cirrhotic liver Usually for non cirrhotics Recurrence 5 yrs – 70 % Pre resection portal vein embolization – doubtful benefits All resectable patients are eligible for liver transplantation
Functional liver reserveFor quantitative assessment of hepatic reserve Assessment of presence of portal hypertension – Clinically and Hepatic vein catheterization CT volumetric studies Most validated – Indocyanin green clearance test
Liver resection Liver resections (hepatectomies) can be separated into two groups. 1. Typical (anatomic) hepatectomies, the resection of hepatic parenchyma follows one or more anatomic scissurae. 2. Atypical (nonanatomic) hepatectomies, the resection is not limited by anatomic scissurae.
Typical hepatectomiesThe resection of hepatic parenchyma follows one or more anatomic scissurae.
Classification of Hepatectomies According to Anatomy Anatomic hepatectomies classified according to The Brisbane 2000 Terminology of Liver Anatomy and Resections. The classification based on the hepatic artery and bile duct and division of the portal vein.
Anatomic hepatectomiesRight Hemiliver Right anterior section Right Trisectionectomy Segments 1-8Left Hemiliver Right Posterior Section Left Trisectionectomy Contiguous
Classification According to Surgical Technique1. Hepatectomy with Preliminary Vascular Section2. Hepatectomy by Primary Parenchymal Transection3. Hepatectomy by Selective Clamping4. Hepatectomy with Total Vascular Exclusion5. Hepatectomy by Pedicular Clamping6. Hepatectomy by Suprahilar Clamping7. Hepatectomy by Intrahepatic Portal Control
Hepatectomy with Preliminary Vascular Section First step consists of ligating and dividing the glissonian pedicle (vein and artery), followed by ligation and section of the right hepatic vein before transecting the parenchyma.Advantages Darkening of the devascularized parenchyma permits demarcation of Decreased intraoperative bleeding from the portal and arterial branches.Disadvantages Risk of injury to the right hepatic vein Difficulty in controlling the middle and inferior branches of the right hepatic vein.
Hepatectomy by Primary Parenchymal Transection Begins with an incision of the parenchyma along the line of the scissura. The hilar elements are approached and ligated from Advantages within the liver during the •Excises an amount of liver parenchyma à parenchymal transection. la demande, according to the nature and the location of the lesion Section of the hepatic vein is •Ligation of the vessels is not hampered by performed at the end of the anatomic abnormalities procedure, also inside the Disadvantages liver. •Lack of preliminary vascular control can lead to considerable intraoperative bleeding,
Hepatectomy by Primary Parenchymal TransectionDissecting sealer Techniques and devices used to perform hepatic parenchymal dissection: Kelly clamp and bipolar forceps Water jet dissection Ultrasonic dissection Ultrasound cutting Dissecting sealer Kelly clamp and bipolar forceps Ultrasonic dissection Ultrasound Water jet cutting dissection
Hepatectomy by Selective Clamping Described by Morel - combines the advantages of both. Begin with a hilar dissection,gain separate control of the arterial and portal elements of the pedicle and clamp these without ligation. Right side of the retrohepatic inferior vena cava is freed without attempting to dissect the vena cava or the right hepatic vein Right hepatic vein is ligated from inside the liver. This technique provides control of the vessels before opening the parenchyma, and the vessels are ligated and divided inside the parenchyma, avoids the risks related to anatomic vascular variants.
Hepatectomy with Total Vascular Exclusion Completely preventing the inflow of blood to the liver. Total vascular exclusion is achieved by simultaneous clamping of the hepatic pedicle and the vena cava below and above the liver. At normal body temperature, normal liver parenchyma can tolerate 60 to 90 minutes of devascularization.
Hepatectomy by Pedicular ClampingInterrupts all inflow to the liver parenchyma from the portal vein and hepatic artery but leaves intact the outflow from the hepatic veins. It is useful in all types of hepatectomy, but the anatomic margins are not visible.
Hepatectomy by Suprahilar Clamping Allows superselective clamping at the suprahilar level after dissecting the hilar plate and exposing the sectorial branches of the glissonian pedicle . The anterior right sectorial portal branch is the easiest to control because the sectorial devascularization is apparent on the liver surface, which greatly facilitates right anterior and right posterior bisegmentectomies.
Hepatectomy by Intrahepatic Portal Control Useful for anatomic segmentectomy or subsegmentectomy Occlusion of the portal branch to the segment to be resected can be achieved by transhepatic balloon catheter placement. Segmental or subsegmental devascularization is accompanied by clear demarcation on the liver surface of the corresponding parenchymal distribution. An alternative method of demarcation involves injection of methylene blue dye into a tributary of the segmental portal branch near the lesion.
Atypical HepatectomiesThe resection is not limited by anatomic scissurae.
Atypical hepatectomies Wedge Resection (Limited Resection) Laparoscopic Liver Resection (also included in typical hepatectomies).
Wedge Resection Non-anatomical complete removal of the tumor with sufficient margin. Wide surgical margin (e.g., wider than 10mm) is not necessary, but care should be taken not to expose the tumor on the cut surface.
Laparoscopic Liver Resection• The first laparoscopic anatomical liver resection, a left lateral sectionectomy, was reported in 1996.More recently, larger hepatectomies and liver resections for malignant tumors have been described. Today, about 15–20% of liver resections might be considered for a laparoscopic approach.
Indications Non-pedunculated lesions less than 5cm in diameter Lesions located in the anterior segments of the liver (segments 2–6) Pedunculated lesions of any size
Contraindications Large non-pedunculated tumors (>5cm in dia.) Lesions of the hepatic dome (i.e.segments7&8) Lesions located in the vicinity of major hepatic veins, the inferior vena cava and the hepatic hilum Severe portal hypertension (portal p. >12mm Hg) Severe coagulopathy (e.g. platelet count <30000 ml)
Postoperative Tests (after liver resection) Postoperative surveillance in an intensive or intermediate care unit Coagulation parameters and hemoglobin for at least 48hrs Check daily for clinical signs of liver failure such as jaundice and encephalopathy
Postoperative Complications Short term Pleural effusion Ascites Liver failure Intra-abdominal bleeding Bile leak Subphrenic abscess Portal vein thrombosis Long term Biloma Biliary stricture Bronchobiliary fistula
Liver transplantation Milan’s criteria: Single lesion upto 5 cm Upto 3 lesions if each lesion <5 cm No extrahepatic disease UCSF criteria: Solitary lesion < 6.5 cm < 3 lesions each < 4.5 cm( total combined tumor diameter < 8 cm) No extrahepatic disease High cost Non availability of donors
Bridging or Downstaging approach In HCC exceeding transplantation criteria Treated with locoregional therapy – TACE and any ablation tharapy Disadvantage: Increasing pool of transplantation recipients Longer wait list times Higher drop out rates Greater wait list mortality
Adjuvant therapy Not recommended at present I 131 lipiodol – improved DFS but not OS Acyclic retinoid – improved OS – more followup required Sorafenib – in trial
Percutaneous injections Lesions > 3 cm Ethanol 95% Up to 3 lesions Acetic acid 15% No extrahepatic disease Multiple sessions ( 3-4) No portal vein USG guidance thrombosis Location suitable for Child Pugh class A/B injection Age > 75 yrs Volume needed V = 4/3п(r+0.5)3 for ethanol and 1/3 for acetic acid
Radiofrequency ablation Electrode insertion into the lesion High frequency alternating current at tip resulting in high frictional energy and cell death Less side effects than PEI and better outcomesCriteria Child Pugh A/B Solitary tumors < 4 cms 3 yr OS 78 – 87%
Trans arterial embolization TAE TACE TARE Dual blood supply Lipiodol concentrated by HCC Selective placement of a catheter Embolization with an emulsion of anticancer drug with lipiodol Sealing embolization with particulate material All sizes – provided arterial supply can be isolated without target embolization Contraindications – portal vein thrombosis, CP - C
Radiotherapy Radiosensitive tumor ( at high doses) but in a very radiosensitive organ, toxicity easily achieved Complications of liver failure can make treatment planning difficult Whole liver – palliative RT (21 Gy in 7 #) Partial liver – definitive RT Treatment free liver > 800 cc No extrahepatic disease No gross ascites Child Pugh A/B No variceal bleed No thrombocytopenia Lesion <6
Radio isotopes ( Selective Internal Radio Therapy) Most common used – yttrium-90 incoroporated into glass (TheraSphere) or resin (SIRTex) Delivered thro the hepatic artery segmentally, subsegmentally , regionally or to the whole liver Typical dose 150Gy Specific toxicities: Liver toxicity Pneumonitis GI Bleeding
Systemic chemotherapy for advanced HCC Relatively chemo refractory tumor Survival often determined by degree of hepatic dysfunction Systemic chemo not well tolerated No survival benefit Only SORAFENIB has shown survival benefit NCCN and FDA approved for systemic treatment Bevacizumab and Erlotinib – promising early phase II results
SHARP Trial h s 7.9 mt cebo s Pl a m ths V i b 11.7 rafen th So al w i urviv ian sMed
Summary HCC remains one of the leading causes of death Improved screening and surveillance have led to early detection and treatment with good outcomes Resection is feasible only in early tumors with well preserved liver function While liver transplantation remains a definitive therapy, scarcity of organs preclude this option Local ablation therapies and trans arterial treatment techniques have shown good results though not as a definitive treatment option Novel systemic agents – SORAFENIB- have shown encouraging results with possible role in adjuvant setting in the near future