Hepatocellular carcinoma

UPDATE

1. HEPATOCELLULAR CARCINOMA ARKAPROVO ROY MS, GENERAL SURGERY ASSISTANT PROFESSOR MALDA MEDICAL COLLEGE WEST BENGAL INDIA

2. EPIDEMIOLOGY Most common primary malignancy of the liver. Geographical distribution is clearly related to the incidence of Hepatitis B infection. The highest incidence in - Southeast Asia and Tropical Africa . The lowest incidence in - Australia , North America and Europe . Epidemiologic evidence strongly suggests that HCC is largely related to environmental factors.

3. A significant rise in the incidence of HCC in the United States and other Western countries over the last 35 years. The explanation for this rising incidence is not understood. The emergence of hepatitis C ( HCV) infection and immigration patterns have been suggested.

4. HCC is two to eight times more common in males compared with females in low- and high-incidence areas . The higher incidence in males is probably related to higher rates of associated risk factors. HBV infection, Cirrhosis, Smoking, Alcohol abuse, and Higher hepatic DNA synthesis in cirrhosis.

5. Agents Known to Be Associated with the development of HCC Infections     Hepatitis B virus   Hepatitis C virus Cirrhosis     Alcohol induced   Autoimmune hepatitis   Primary biliary cirrhosis Environmental     Aflatoxins   Pyrrolizidine alkaloids Thorotrast   N- nitrosylated compounds Metabolic diseases     Hemochromatosis   Alpha 1 -antitrypsin deficiency  Wilson's disease   Porphyria cutanea tarda   Type 1 and 3 glycogen storage disease   Galactosemia   Citrullinemia   Hereditary tyrosinemia   Familial cholestatic cirrhosis

6. Causative factors INFECTION : 75% - 80 % of HCC cases are related to HBV (50% to 55%) or HBC (25 % to 30%) infections . Studies have estimated relative risks of 5 to 100 for the development of HCC in HBV-infected individuals compared with non-infected individuals.

7. Other evidence includes the following observations : ( 1) Geographic areas high in HBV infection have high rates of HCC ; ( 2) HBV infection precedes the development of HCC. ( 3) the sequence of HBV infection to cirrhosis to HCC is well documented; and ( 4) the HBV genome is found in the HCC genome. The HBV has no known oncogenes , but insertional mutagenesis into hepatocytes may be a contributing factor to the development of HCC.

8. The risk of HCC is not simply related to HBV exposure, but requires chronic infection (i.e., chronically positive HBV surface antigen ). There is a higher risk of persistent infection ( carrier state ) when the infection is acquired at birth or during early childhood .

9. Hepatitis C has been discovered to be a major cause of chronic liver disease in Japan, Europe, and the United States, where there is a relatively low rate of HBV infection . HBV and HCV infection are both independent risk factors for the development of HCC but probably act synergistically when an individual is infected with both viruses.

10. Factors associated with a more rapid progression include male gender, chronic alcohol use, and older age at the time of infection. HCV is an RNA virus that does not integrate into the host genome and therefore the pathogenesis of HCV-related HCC may be related to more chronic inflammation and cirrhosis than to direct carcinogenesis .

11. The true relationship of cirrhosis and HCC is difficult to ascertain , and suggestions of causation remain speculative. Cirrhosis is not required for the development of HCC and hepato -carcinogenesis is not an inevitable result of cirrhosis. The relationship of cirrhosis and HCC is further complicated by the fact that they share common associations.

12. Furthermore, some associations (e.g., HBV infection, hemochromatosis ) are associated with higher risk of HCC, whereas others (e.g., alcohol, primary biliary cirrhosis ) are associated with a lower risk of HCC. Research has demonstrated that cirrhotic livers with higher DNA replication rates are associated with the development of HCC.

13. Chronic alcohol abuse has been associated with an increased risk of HCC and there may be a synergistic effect with HBV and HCV infection. Alcohol causes cirrhosis , but has never been shown to be directly be carcinogenic in hepatocytes.Thus , alcohol likely acts as a cocarcinogen . Cigarette smoking has been linked to the development of HCC, but the evidence is not consistent and the contributing risk independent of viral hepatitis is likely small.

14. Clinical presentation Most commonly, patients presenting with HCC are men 50 to 60 years of age who complain of right upper quadrant abdominal pain and weight loss, and have a palpable mass. In countries endemic for HBV, presentation at a younger age is common and probably related to childhood infection .

15. Unfortunately, in unscreened populations, HCC tends to present at a later stage because of the lack of symptoms in early stages. Presentation at an advanced stage is often with vague right upper quadrant abdominal pain that sometimes radiates to the right shoulder. Nonspecific symptoms of advanced malignancy such as anorexia, nausea, lethargy, and weight loss are also common.

16. Another common presentation of HCC is hepatic decompensation in a patient with known mild cirrhosis or even in patients with unrecognized cirrhosis. HCC can rarely present as a rupture, with the sudden onset of abdominal pain followed by hypovolemic shock secondary to intraperitoneal bleeding.

17. Other rare presentations include hepatic vein occlusion (Budd- Chiari syndrome), Obstructive jaundice, hemobilia , and fever of unknown origin. Less than 1% of cases of HCC present with a paraneoplastic syndrome, usually hypercalcemia , hypoglycemia, and erythrocytosis . Small incidentally noted tumors have become a more common presentation because of the knowledge of specific risk factors, Screening programs for diagnosed HBV or HCV infection, Increasing use of high-quality abdominal imaging.

18. DIAGNOSIS For patients suspected of suffering from HCC, the aims of diagnostic investigations are (1) verification of diagnosis, (2) determine extent of disease, (3) determine functional liver reserve, and (4) assess biologic determinants that are predictors of long-term prognosis.

19. How is Hepatocellular Carcinoma Diagnosed? Diagnosis is often confirmed with a biopsy Diagnosis can sometimes be confirmed with blood or imaging tests Physical examination Blood test for alpha-fetoprotein (AFP); 50%-70% of people with primary liver cancer have elevated levels Ultrasound of the abdomen Computed tomography (CT or CAT) scan Magnetic resonance imaging (MRI) Angiogram Laparoscopy

20. Radiologic investigation is a critical part of the diagnosis of HCC. Ultrasound plays a significant role in screening and early detection of HCC, but definitive diagnosis and treatment planning rely on CT and/or MRI. Contrast-enhanced CT and MRI protocols aimed at diagnosing HCC take advantage of the hypervascularity of these tumors, and arterial phase images are critical to assess the extent of disease adequately.

21. CT and MRI also evaluate the extent of disease in terms of peritoneal metastases, nodal metastases, and extent of vascular and biliary involvement. Detection of bland or tumor thrombus in the portal or hepatic venous system is also important and can be diagnosed with any of these modalities.

22. AFP measurements can be helpful in the diagnosis of HCC. An AFP level higher than 20 ng / mL is noted in approximately 75% of documented cases of HCC. False-positive elevations of serum AFP levels can be seen in inflammatory disorders of the liver, such as chronic active viral hepatitis. The specificity and positive predictive values of AFP improve with higher cutofflevels (e.g., 400 ng / mL ), but at the cost of sensitivity. With improvements in imaging technology and the ability to detect smaller tumors, AFP is largely used as an adjunctive test in patients with liver masses. AFP levels are particularly useful in monitoring treated patients for recurrence after normalization of levels.

23. If atypical features appear on imaging, a biopsy should be obtained for histologic diagnosis. For hepatic nodules larger than 2 cm, a triple-phase CT or MRI scan is required if typical features of HCC are identified in combination with an AFP level higher than 200 ng / mL. If typical features appear on imaging, the diagnosis of HCC is confirmed. If atypical features are seen, then biopsy is required to confirm the histologic diagnosis.

24. At present, the diagnosis of HCC can be made according to the guidelines of the Barcelona-2000 European Association for the Study of the Liver (EASL) Conference and to successive modifications of guidelines from the American Association for the Study of Liver Disease (AASLD). Pathologic diagnoses of HCC are made according to the International Working Party criteria. For hepatic nodules from 1 to 2 cm in size, a triplephase CT and MRI scan must show typical features of HCC— arterially enhancing mass with washout of contrast in delayed phases—to confirm the diagnosis.

25. Pathology Histologically , HCC is graded as well, moderately, or poorly differentiated. The grade of HCC, however, has neverbeen shown to predict outcome accurately. Grossly, the growth patterns of HCC have been classified in a number of ways. The most useful scheme divides HCC into three distinct growth patterns that have distinct relationships to outcome. The hanging type of HCC is 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. This type can grow to substantial size without involving much normal liver tissue. The pushing type of HCC is well demarcated and often contains a fibrous capsule. It is characterized by growth that displaces vascular structures rather than invading them. This type is usually resectable . The last type is called the infiltrative type of HCC , which tends to invade vascular structures, even at a small size. Resecting the infiltrative type is often possible, but positive histologic margins are common.

26. Small tumors (<5 cm) usually do not fall into any of these groups and are often discussed as a separate entity. Finally, HCC can present in a multifocal manner. Most HCC probably starts as a single tumor, but ultimately multiple satellite lesions can develop secondary to portal vein invasion and metastases. Multifocal tumors throughout the liver probably represent the end stage of HCC, with multiple metastases and multiple primary tumors.

27. Treatment There are a large number of treatment options for patients with HCC, reflecting the heterogeneity of this disease and the lack of a proven superior treatment, except complete resection. Selection of the appropriate patient for resection is critical and must take into account the condition of the liver and extent of disease. Patients with Child-Pugh class B or C cirrhosis or portal hypertension do not tolerate resection.

28. Treatment Options for Hepatocellular Carcinoma Surgica l Resection Orthotopic liver transplantation Ablative Ethanol ( EtOH ) injection Acetic acid injection Thermal ablation ( cryotherapy , radiofrequency ablation, microwave) Transarterial Embolization Chemoembolization Radiotherapy Combination Transarterial and Ablative: External Beam Radiation Systemic Chemotherapy Hormonal Immunotherapy

29. Liver transplantation

30. Pugh's Modification of Child's Grading of Cirrhosis Measurements 1 point 2 points 3 points Bilirubin (mg/ dL ) 1–1.9 2–2.9 >2.9 Prothrombin time prolongation ( secs ) 1–3 4–6 >6 Albumin (g/dL)  >3.5 2.8–3.4 <2.8 Ascites none mild moderate to severe Child's A: 5–6 points; B: 7–9 points; C: 10–15 points.

31. Cancer of the Liver Italian Group Score CLINICAL PARAMETERS CUT OFF VALUES POINTS Child-Pugh class A B 1 C 2 Tumor morphology Uninodular , <50% extension Multinodular , <50% extension 1 Massive or extension >50% 2 AFP ( ng / dL ) < 400 > 400 1 Portal vein thrombosis No Yes 1 Score ranges from 0 to 6; a score of 4 to 6 is generally considered advanced disease, whereas a score of 0 to 3 has the potential for long-term survival.

32. Cancer Treatment: Surgery Most successful in patients with small tumors (smaller than 5 cm) and with good liver function Hepatectomy: portion of the liver is removed when the cancer is limited to one part of the liver Liver transplantation: used to treat cancer confined to the liver if a suitable donor is found. Must fulfill strict criteria

33. A variety of prognostic factors predictive of survival after resection have been identified, but none are universally agreed on . The most commonly cited negative prognostic factors are tumor size, cirrhosis, infiltrative growth pattern, vascular invasion, intrahepatic metastases, multifocal tumors, lymph node metastases, margin less than 1 cm, and lack of a capsule. The best outcomes are found in patients with single small tumors, but size alone should not contraindicate resection. Multifocal tumors and major vascular invasion are generally associated with a poor outcome but some groups advocate resection in highly select patients.

34. ABLATION OF LIVER TUMOR

35. ROUTES Percutaneous Laparoscopy Open method Percutaneous technique is best choice for early stage liver tumor who are not surgical candidates.

36. SELECTION CRITERIA Single tumor < 5cm Multiple tumors< 3 nodule and < 3cm No evidence of vascular invasion No extrahepatic spread Performance status test– 0 Cirrhosis with Child Pugh class A or B

37. PERCUTANEOUS METHODS A-Chemical ablation :- 1- ethanol injection 2- acetic acid injection B- Thermal ablation :- 1- RFA 2- Microwave 3- Laser ablation 4- Cryoablation

38. PERCUTANEOUS ETHANOL INJECTION Mechanism:- coagulative necrosis, protein denaturation chemical occlusion of small tumor vessels . Well established technique for cirrhotic liver with tumor nodule results in 70% tumor necrosis but ineffective in metastatic nodule. Performed under USG guidence . 4-6 session is required

39. RADIOFREQUENCY ABLATION Radiofrequency ablation uses electrical current, passed through a small needle placed directly into a liver tumor, to destroy cancer cells with heat As the temperature within the tissue becomes elevated beyond 60°C, necrosis happens. RFA can be performed by percutaneous , surgical, or laparoscopic approaches

40. The electrical current is actually passed across an array of hook electrodes that are deployed from the tip of the needle after the needle is placed into the tumor. The hook electrodes look like the ribs of an umbrella, with a diameter of 3.5 cm when fully deployed. Early RFA electrode were unipolar and they produce only 1.5-2 cm cylindrical zone of necrosis, but current were multiarray electrode ,created larger more spherical zone of ablation .

41. RFA AND EARLY STAGE HCC RFA has been most widely assesed alternate to PEI for local ablation. Compele tumor necrosis was shown by pathology in 83% of tumor <3 cm and 88% of tumor in nonperivascular location. In two comparative studies , the rate of complete tumor response shown by post treatment CT were higher in patient who underwent RFA compared with patient who underwent PEI. In a comparative study of RFA versus surgical resection in patients with Child-Pugh score of 5 and a single HCC of <4 cm , no difference in over all survival and cumulative recurrence free survival rate were observed, despite a higher rate of local recurrence in RFA group.

42. COMPLICATION OF RFA Three separate multicenter survey reported acceptable morbidity and mortality rate. The mortality range from 0.1-0.5%, major complication 2.2 – 3.1% and minor complications 5-9%. Most common cause of death were sepsis, hepatic failure, colonic perforation and portal vein thrombosis . The most common of intraperitonial bleeding, hepatic abscess, bile duct injury, hepatic decompensation and ground pad burn.

43. COMPLICATION OF RFA Abscess, one of the most frequent complication of RFA , typically occurs 1 week after ablation and require percutaneous or surgical drainage . Patients with bilio -enteric anastomosis or biliary stenting seem to have a higher rate of abscess formation. Tumor seeding vary from 0.5 to 12% , possibly reflecting difference in follow-up. Injury to bile duct during RFA can result in stenosis and proximal biliary dilatation. Most physician agree that tumors within 15 to 20 mm of a major bile duct should not be treated by RFA.

44. Conclusion RFA can treat primary or metastatic liver tumors with success rate of 90% and little morbidity or mortality . Best for early stage liver tumor who are not candidate for surgery . A randomized prospective study is necessary to determine survival and recurrence rate after RFA versus resection . For now, resection remains the initial choice for patients whose disease is confined to liver. RFA may be alternate for patients unable to undergo resection.

45. RFA can treat primary or metastatic liver tumors with success rate of 90% and little morbidity or mortality. Best for early stage liver tumor who are not candidate for surgery. A randomized prospective study is necessary to determine survival and recurrence rate after RFA versus resection. For now, resection remains the initial choice for patients whose disease is confined to liver. RFA may be alternate for patients unable to undergo resection.

46. Chemoembolization Image courtesy of www.hopkinscoloncancercenter.org.

47. Cancer Treatment: Radiation Therapy The use of high-energy x-rays to destroy cancer cells The use of high energy x-rays or other particles to destroy cancer cells Internal beam: use of implants inside the body. Radioactive beads may be inserted into the artery that supplies the tumor with blood External beam: outside the body – rarely used for HCC Side effects can include fatigue, mild skin reactions, upset stomach and loose bowel movements

48. Cancer Treatment: Chemotherapy Use of drugs to kill cancer cells One or a combination of drugs may be used Side effects may include nausea and vomiting, loss of appetite, diarrhea, fatigue, and risk of infection Side effects often go away after treatment is finished

49. Cancer Treatment: Targeted Therapy Targets faulty genes or proteins that contribute to cancer growth and development Sorafenib (Nexavar), an anti-angiogenic and anti-proliferative drug (starves the tumor by disrupting its blood supply), may be used to treat tumors that cannot be removed with surgery

50. Comparison of Standard HCC with Fibrolamellar Variant Characteristic HCC Fibrolamellar HCC Male: Female 4:1–8:1 1:1 Median age 55 25 Tumor Invasive Well circumscribed Resectability <25% 50–75% Cirrhosis 90% 5% AFP + 80% 5% HepB+ 65% 5%

51. Targeting Signaling Pathways in HCC: Novel Molecular Targeted Therapies on the Horizon

52. HCC context Investigational strategies Staging Sorafenib Sunitinib Brivanib Linifanib Sorafenib ± erlotinib Doxorubicin ± sorafenib Ramucirumab Everolimus ± sorafenib Tivantinib

53. Investigational Strategies for Improving Outcomes in Advanced HCC New targeted agents Sorafenib combination therapy Sorafenib + chemotherapy Sorafenib + another targeted agent Brivanib Erlotinib Linifanib Sunitinib Bevacizumab Ramucirumab Everolimus

54. Ramucirumab VEGFR-2 and its ligands (including VEGF-A, -C, and -D) are important mediators of angiogenesis and angiogenesis is integral to HCC carcinogenesis and pathogenesis Ramucirumab is a recombinant human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2 with high specificity and affinity Ramucirumab was well tolerated in 2 phase I studies involving patients with advanced, refractory solid tumors; 2 HCC patients (receiving doses of 10 mg/kg q2w) achieved disease stabilization on-study for 9 and 14 months, respectively