Liver cancer by Dr. Basil Tumaini

A presentation on primary and secondary liver cancers by Dr. basil Tumaini, done during the residency in Internal Medicine at Muhimbili University

1. Primary and Secondary Liver Cancers Basil Tumaini , MD MMED (Int. Med.) Resident Muhimbili University of Health and Allied Sciences June 2017 1

2. Headings Introduction Epidemiology Clinical features Diagnosis ± staging Treatment Prognosis ± Prevention Introduction Primary liver cancers HCC Cholangiocarcinoma Angiosarcoma Secondary liver cancers 2 Sub headings

3. Introduction A primary liver cancer arises from cells and/or structures of the liver itself whereas a secondary liver cancer spreads from other organ to the liver When diagnosis is made late , as is often the case, prognosis is poor 3

4. Primary liver cancers Hepatocellular carcinoma ( hepatoma ) Cholangiocarcinoma Angiosarcoma Others: embronal sarcoma, fibrosarcoma , rhabdomyosarcoma 4

5. Primary liver cancers Globally The 6 th most frequent cancer The 2 nd leading cause of cancer death In 2012, diagnosed in 782,000 people, caused 746,000 deaths In US Five-year survival rates are 17% 5

6. http://www.wcrf.org/int/cancer-facts-figures/worldwide-data 6

7. Hepatocellular carcinoma (HCC) Arises from parenchymal cells ( hepatocytes ) Heterogeneous geographical distribution Prevalence is much higher in developing countries (high prevalence of HBV infection, aflatoxin B1 contamination of foods, hepatotoxic drugs) 7

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10. Hepatocellular carcinoma (HCC) 10

11. Hepatocellular carcinoma (HCC) Four times commoner in blacks More in rural areas Sex distribution, M :F ~ 2-6:1 (androgenic trophic effect, hepatitis/exposure variation) 11

12. PROVEN PROBABLE POSSIBLE Cirrhosis Alcohol Schistosomiasis Hepatitis B , C Tobacco Hormonal factor Aflatoxins Diabetes Porphyria disease Obesity Haemachromatosis Non alcoholic steatohepatitis (NASH) Deficit of alfa-1 antitrypsin Risk factors 12

13. Cirrhosis of almost any cause, appearing 20-30 years after the initial insult 85% of Pts with HCC in the West have cirrhosis 3% with cirrhosis develop HCC annually The cause is hepatitis B in 39% of cases, hepatitis C in 27% and alcoholism in 37% 25% of afflicted individuals have no risk factors for the development of cirrhosis 13

14. Epidemiological Study of Carcinoma of Liver in Dodoma Region In Dodoma Region, the populace consumes large numbers of ground nuts which are believed to predispose to liver cancer Of 939 clinically diagnosed malignancies in the Region during 1972-1976, 256 (27 percent) were hepatocellular carcinomas [P.R. Hiza ] 14

15. In retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013 Seventy-four (52.1%) patients stated a history of ingestion of foods stored in humid conditions (a likely suspected source of aflatoxin B1 exposure) Eighty-five (59.9%) patients had a past history of jaundice 32 (22.5%) had scarification marks 15 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

16. In retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013 The use of traditional herbal concoctions was documented in 82 (57.7%) patients A history of heavy alcohol consumption was reported in 86 (60.6%) patients A past blood transfusion was documented in 28 (19.7%) patients 16 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

17. 17 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

18. 18 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

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21. 21 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

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23. Treatment modalities All of the patients (100%) received supportive therapy only because of the advanced nature of the disease No patients received any curative treatment such as liver transplantation , percutaneous ethanol ablation , or radio frequency ablation due to the lack of these treatment modalities in our setting and due the advanced nature of the disease at presentation 23 Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

24. Diagnosis 24

25. Investigations USS/Helical CT scan/MRI Hepatic arteriography Tumor markers: AFP, other markers Histopathology LFTs + liver enzymes: serum albumin, bilirubin T+D, AST, ALT, ALP CBC: HBsAg , HCV Ab Ascitic fluid analysis 25

26. Ultrasound Used to assess tumor size , vascular invasion and the existence of hilar adenopathies Sensitivity for tumors ˂ 1 cm is about 42% reaching 95% for tumors of larger size . The combination of Doppler with US can be useful for the identification of portal thrombosis in patients with HCC, with 89 to 92% sensitivity and 100% specificity in the identification of tumor thrombosis 26

27. Helicoidal /Spiral CT Suspicion of HCC by US in a patient with cirrhosis. The sensitivity of CT for the diagnosis of HCC is similar to that of US Diagnostic efficacy depends on technical factors, mainly the injection of contrast, and on factors inherent to the tumor, the most tumor size and vascularity 27

28. Helicoidal /Spiral CT CT should be performed by the spiral (or helicoidal ) technique with intravenous injection of contrast and images should be obtained in the basal, arterial, portal, and equilibrium phases Early arterial enhancement and delayed washout (less enhancement than the rest of the liver) in the venous or delayed phase of tri- phasic multidetectorCT (the three phases are arterial, venous, and delayed) 28

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34. MRI MR has been used to obtain a better characterization of hepatic lesions suggestive of HCC and also for their differentiation from benign lesions Sensitivity depends on tumor size ( eg for tumor ˂ 2cm =30% and tumors ˃2cm is about 95%) 34

35. Hepatic arteriography The diagnostic efficacy of hepatic arteriography depends on tumor size and on the extent of tumor vascularization Small tumors tend to be well differentiated and consequently present low vascularization , thus being difficult to detect by this technique. For tumors smaller than 5 cm, HA has 82 to 93% diagnostic sensitivity, 73% specificity and 89% diagnostic accuracy 35

36. Tumor Markers: Alpha-1 fetoprotein Progressively increasing AFP concentrations during screening are suggestive of HCC Considered to be diagnostic ( 400-500 ng /ml) 29% of patients with HCC may present serum AFP levels within normal limits At the time of tumor diagnosis, AFP seems to be of prognostic value Increase in pregnancy, chronic and other regenerative liver disease 36

37. Cytology and/or histology Histopathological examination is the main method for a sure diagnosis of HCC. FNAB is a safe technique with minimal risks of complications and provides adequate material when performed by trained personnel Diagnostic accuracy may vary from 60 to 90% The specificity and positive predictive value of this technique are higher than 90%, 37

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39. Indications of Image-guided biopsy: Focal hepatic masses with atypical imaging features Discrepant findings on CT and MRI Lesions detected in the absence of cirrhosis The risk of tumor seeding along the needle track after biopsy in patients with suspected hepatocellular carcinoma is low (2.7%) 39

40. Diagnosis of HCC according to the Barcelona-2000 Conference of the European Association for the Study of the Liver (EASL) 40

41. Treatment Stage-guided treatment The choice of treatment Cancer stage Resources available The level of practitioner expertise 41

42. Staging To determine the prognosis of the disease and best therapeutic method Okuda TNM Barcelona Clinic of Liver Cancer (BCLC) French Classification Cancer of the Liver Italian Program BCLC is the only classification which correlates prognostic data with treatment possibilities 42

43. Okuda 1= 11.5 months, Okuda 2 = 3 months, Okuda 3= 0.9 month 43

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45. 45 BCLC Performance Status Tumor Features Liver Fn Treatment option A1 Single <5cm No PH Surgery/RFA A2 Single <5cm PH, Bil Normal Surgery/RFA/ Transplant A3 Single <5cm PH, Abnormal Bilirubin RFA/Transplant A4 3 tumors <3cm N/A Transplant/TACE B Large multinodular CP A-B TACE C 1-2 Vascular Invasion/Mets CP A-B Sorafenib D 3-4 Any CP C Supportive

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47. 7 stages (0-6) Stage 0=35 months, 2 =8months and 4-6 =3 months 47

48. Treatment 48

49. HCC – Treatment: Surgical Resection Surgical resection is the treatment of choice in patients without cirrhosis who are in the very early stage For patients with cirrhosis, resection produces the best results when the tumor is small (<5 cm in diameter), portal hypertension (a hepatic venous pressure gradient >10 mm Hg) is absent, and the total bilirubin level is normal (≤1 mg per deciliter [≤17.1 μmol per liter])* The 5-year risk of recurrence of hepatocellular carcinoma after resection is as high as 70%* In the United States, less than 5% of patients are candidates for hepatic resection, associated with an overall survival rate of 90% Llovet JM, Schwartz M,  Mazzaferro V.  49

50. Surgical Resection Surgical resection should be considered for patients with solitary tumors and no portal hypertension However, the most appropriate treatment for patients with early-stage hepatocellular carcinoma is liver transplantation Patients with HCC who meet the Milan criteria for orthotopic liver transplantation have an expected 4-year overall survival rate of 85% and a recurrence-free survival rate of 92%* If transplantation is not possible, local ablation is the next best option MazzaferroV, Regalia E, Doci R, et al. 50

51. Local Ablation RFA, best treatment alternative for patients with early-stage HCC who are not eligible for surgical resection or transplantation Several recent randomized trials have shown radiofrequency ablation to be more effective than ethanol injection in treating patients with small hepatocellular tumors (2 to 3 cm in diameter), with lower rates of local recurrence and higher rates of overall and disease-free survival* Short-term outcomes are excellent, with overall survival rates of 100% and 98% at 1 and 2 years, respectively* Cho YK, Kim JK, Kim MY,  Rhim H, Han JK.  51

52. Local Ablation 5-year recurrence rates as high as 70% The results of two randomized, controlled trials comparing radiofrequency ablation and surgical resection showed no significant differences in overall or recurrence-free survival; as expected, radiofrequency ablation was associated with lower rates of complications and hospitalization* Chen MS, Li JQ,  Zheng Y, et al.  Livraghi T, Meloni F, Di Stasi M, et al.  52

53. Transarterial chemoembolization (TACE) and Radioembolization Patients with compensated cirrhosis, but with large or multifocal lesions but no vascular invasion are considered to have intermediate-stage hepatocellular carcinoma Improve survival among patients with preserved liver function, who do not have extrahepatic metastases, vascular invasion or prominent cancer-related symptoms 53

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56. Transarterial chemoembolization (TACE) and Radioembolization  A meta-analysis of randomized, controlled trials assessing the use of arterial embolization , chemoembolization , or both as primary palliative treatment for hepatocellular carcinoma showed that these procedures were associated with an improved 2-year survival rate by 20 – 25% as compared with conservative treatment* 56 Bruix J,  Sala M,  Llovet JM.

57. Transarterial Chemoembolization and Radioembolization Neoadjuvant therapy or as a means of downstaging a patient’s condition before liver transplantation Modalities include: Selective TACE Drug - eluting Beads (DB)-TACE, Radioembolization or combination approaches e.g., TACE and radiofrequency ablation gave promising results 57

58. Transarterial Chemoembolization and Radioembolization Embolization should not be performed without the use of a chemotherapeutic agent, there are few data to guide the choice of the chemotherapeutic agent In recent randomized, controlled trials, the use of a drug-eluting bead that releases the drug in a controlled fashion during TACE has been shown to be associated with a reduction in both hepatic and systemic side effects and with an increase in local tumor response* Lammer J,  Malagari K,  Vogl T, et al. Lencioni R.  58

59. Radioembolization with yttrium-90 microspheres has recently been used as palliative treatment for patients with Child–Pugh class A cirrhosis and intermediate-stage hepatocellular carcinoma However, there have been no controlled trials comparing yttrium-90 radioembolization with TACE or with other types of treatment 59 Transarterial Chemoembolization and Radioembolization

60. Contraindications to TACE 60 Absolute contraindications • Decompensated cirrhosis (Child-Pugh B ≥8) including: – Jaundice – Clinical encephalopathy – Refractory ascites – Hepatorenal syndrome • Extensive tumor with massive replacement of both entire lobes • Severely reduced portal vein flow

61. Technical contraindications to hepatic intra-arterial treatment Untreatable arteriovenous fistula Renal insufficiency ( creatinine ≥2 mg/dl or creatinine clearance <30 ml/min) 61

62. Relative contraindications to TACE Tumor size ≥10 cm Co-morbidities involving compromised organ function: Active cardiovascular disease Active Lung disease Untreated varices at high risk of bleeding Bile-duct occlusion or incompetent papilla due to stent or surgery 62

63. Sorafenib Patients with mild cancer-related symptoms, vascular invasion , or extrahepatic spread are considered to have advanced-stage disease and are not suitable candidates for radical therapies TACE has increased the survival rate among well-selected candidates, but the primary treatment option for patients with this stage of disease is the oral chemotherapeutic agent sorafenib 63 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M. Sorafenib in advanced hepatocellular carcinoma. New England journal of medicine. 2008 Jul 24;359(4):378-90.

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65. An oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor Antiproliferative and antiangiogenic properties The only approved drug for Rx HCC BCLC –C stage 37% increase in overall survival as compared to placebo, in patients with advanced HCC and compensated cirrhosis* Llovet JM, Ricci S, Mazzaferro V, et al.  65 Sorafenib

66. Indications Pts unsuitable to TACE Pts in whom TACE resulted in unacceptable toxicity * Combination studies underway 66 Sorafenib

67. Rash on the hands and feet Diarrhea Fatigue Other small molecules, brivanid , and erlotinib , and monoclonal antibodies, bevacizumab and cetuximab , are being studied 67 Sorafenib SEs

68. Rash on the hands and feet Diarrhea Fatigue Other small molecules, brivanid , and erlotinib , and monoclonal antibodies, bevacizumab and cetuximab , are being studied 68 Sorafenib SEs

69. Supportive treatment Patients with terminal-stage disease present with cancer symptoms related to liver failure, vascular involvement, or extrahepatic spread The 1-year survival rate for such patients is less than 10%, and they do not benefit from the treatments mentioned above 69

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71. Recurrence Cancer recurrence, generally in the hepatic remnant, occurs in 70% to 100% of cases after resection Accounts for the cause of death in 82.5% of the patients while only 9% of deaths were due to hepatic failure. 71

72. Recommendations: AASLD USS of the liver combined with measurement of serum AFP levels every 6 to 12 months as surveillance for HCC in patients with cirrhosis or advanced hepatic fibrosis , irrespective of the cause Both are also useful in surveillance of HBV carriers with or without cirrhosis if they are Africans older than 20 years of age or Asians older than 40 years of age or if they have a family history of HCC HCC is rare in HCV-infected patients with mild or no hepatic fibrosis, surveillance is not recommended for this group 72

73. Prevention In 2002, Tanzania introduced mandatory immunization of Hepatitis B to all children under EPI Tanzania is an endemic area for viral hepatitis Immunization against Hepatitis B is very important to health workers who are at higher risk and community at large 73

74. Cholangiocarcinoma Malignancies of the biliary duct system May originate in the intrahepatic bile ducts extrahepatic bile ducts distal extrahepatic bile ducts which terminate at the ampulla of Vater 74

75. Perihilar tumors ( Klatskin tumors) are the commonest cholangiocarcinomas and intrahepatic cholangiocarcinomas are the least common Klatskin tumors occur at the bifurcation of the common hepatic duct (into right and left hepatic ducts) 75

76. Epidemiology <2% of all human malignancies, 2 nd most common primary liver cancer Accounts for 6-10% of all primary liver cancer Highest incidence in S.E. Asia, associated with liver fluke infection – Clonorchis sinensis and Opisthorchis viverrini 2500 cases of cholangiocarcinoma each year, avg incidence ranges from 2 - 6 cases per 100,000 people/year 76

77. Epidemiology Not associated with cirrhosis . Aggressive disease , median survival rate is low (6 months) 90% are not eligible for curative resection M: F = 1:2.5 in patients (60 – 70s) 77

78. Risk factors Sclerosing cholangitis (7-42%) Congenital fibropolycystic diseases of the biliarysystem-10% (particularly Caroli disease and choledochal cysts ) Previous exposure to Thorotrast (formerly used in radiography of the biliarytract ) In the Orient, the incidence rates are higher, and it is due to chronic infection of the biliary tract by liver flukes e.g., Clonorchis sinensis . 78

79. Risk factors I BD ( UC>CD)* Chemical exposures ( workers in aircraft, rubber, and wood-finishing industries) Others: congenital diseases, bile duct adenomas, α -1 antitrypsin deficiency, obesity Gallstones ,viral hepatitis and cirrhosis do not appear to be risk factors 79

80. Pathophysiology Long-standing inflammation, as with PSC or chronic parasitic infection Hyperplasia, cellular proliferation and malignant transformation > 90% are adenocarcinoma , remainder are squamous cell tumors 80

81. Clinical presentation Intrahepatic cholangiocarcinomais usually detected late in its course as the result of obstruction to bile flow through the hilum of the liver as a symptomatic liver mass 50 -75% metastasize to regional lymph nodes, lungs, vertebrae, adrenals, brain, elsewhere at autopsy 81

82. Clinical features P ruritus - 66% Abdominal pain - 30-50% Wt loss - 30-50% Fever - 20% J aundice - 90% Hepatomegaly - 25-40% Palpable gallbladder ( Courvoisier sign ) 82

83. Diagnosis Pre operatively, dx is often difficult 1/3 of pts with symptoms and cholangiogram suggestive of cholangiocarcinoma will have a benign fibrosing disease or other metastasis 83

84. Diagnosis Elevated conjugated bilirubin, ALP, GGT Aminotransferases : normal or minimally elevated LFT: normal in early disease Tumor markers, CA 19-9 > 180 ng /dl, CEA x 20 ( Dx , Rx, and monitoring of HC with 89% sensitivity and 86% specificity) Cholangiocarcinoma does not produce AFP 84

85. Imaging USS CT scan: benign vs. malignancy, resectability MRCP: 3-dimensional view of the biliary tree ERCP and PTC: assess local ductal extent of the tumor while allowing for therapeutic biliary drainage PET scan: detect lymph node and distant metastases EUS: bile duct visualization and nodal evaluation, aspirate for cytological studies 85

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87. Staging 87

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89. Treatment Standard therapy consists of extrahepatic bile duct resection, hepatectomy and en bloc lymphadenectomy Surgical resection Absence of retropancreatic and paraceliac nodal metastases or distant liver metastases Absence of invasion of the portal vein or main hepatic artery (although some centers support en bloc resection with vascular reconstruction) Absence of extrahepatic adjacent organ invasion Absence of disseminated disease 89

90. Treatment Among patients undergoing complete resection, 5-year overall survival rates are btn 15 and 40% Other treatment modalities include: Stenting , Photodynamic therapy, Radiation therapy and Chemotherapy 90

91. Postop adjuvant therapy for + ve resection margin ( Fluoropyrimidine -based chemotherapy) Radiochemotherapy if nodal positive In general, no single drug or combination has consistently increased median survival beyond the expected six to eight months The most active agents are 5-FU, gemcitabine , cisplatin , and oxaliplatin 91

92. Prognosis Prognosis is poor The median time from diagnosis to death is 6 months Aggressive surgery remains the only treatment offering hope for long-term survival 92

93. Hepatic angiosarcoma Hepatic angiosarcoma is a very rare disease, accounting for only 2% of primary liver malignancy Ranks in the third place in the list of most common primary liver malignancies It originates from endothelial cells of the blood vessels Difficult to diagnose in the early stage due to unspecific symptoms 93

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95. Difficult to differentiate liver angiosarcoma radiologically from other vascular tumors in liver, such as hepatoma due hypervascularity No therapeutic guideline for liver angiosarcoma has been set up partial liver resection to remove the tumor radically still remains to be the cornerstone of treatment options 95

96. Prognosis of hepatic angiosarcoma is very poor : rapid progression high recurrence rate resistant to traditional chemotherapy and radiotherapy Even liver transplantation could not benefit patients with liver angiosarcoma 96

97. Secondary liver cancers Metastatic involvement of the liver is commoner (×20) than primary neoplasia In 50% of all cases the primary tumor is of the GIT Other common primaries producing hepatic metastases breast lung Any cancer in any site of the body may spread to the liver including leukemias and lymphomas 97

98. Secondary liver cancers Typically, multiple nodular metastases are found that often cause striking hepatomegaly and may replace over 80% of existent hepatic parenchyma The liver weight can exceed several kilograms 98

99. Liver provides a fertile soil in which metastasis may become established rich, dual blood supply humoral factors that promote cell growth The fenestrations in the sinusoidal endothelium allow a foothold into the space of Disse ( perisinusoidal space) for tumor emboli arriving via the blood stream 99

100. 77% of pts both lobes are involved Growing metastases compress adjacent liver parenchyma, causing atrophy and forming a connective tissue rim Large metastases often outgrow their blood supply, causing hypoxia and necrosis at the centre of the lesion 100

101. Metastases to the Liver Factors influencing the incidence and pattern of liver metastasis: Patients age and sex The primary site The histologic type Duration of the tumor The median survival time after the diagnosis of hepatic metastasis was 75 days in one series, and only 6.6% of pts survived longer than one year 101

102. Symptoms & Signs Hepatomegaly Ascites 50% of pts have clinical signs of hepatomegaly or ascites Tenderness Cachexia Jaundice Pyrexia 102

103. Investigations Level of serum ALP, AST, ALT is elevated or normal In 10% of patients ALP and GGT are elevated US/CT/MRI IOUS of the liver has the highest sensitivity 96% Duplex and color-flow imaging CT permits better evaluation of the involvement of extrahepatic tissues including: bones, bowel, LN and mesentery MRI allows effective localization of hepatic and vascular invasion Ultrasound scan and CT scan can demonstrate multiple filling defects 103

104. Fluorodeoxyglucose (FDG) PET is the most sensitive noninvasive imaging modality for the diagnosis of liver metastasis Liver biopsy, US/CT guided Angiography – for planning vascular intervention 104

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108. Diagnosis Limitations of imaging techniques Seldom enable a tissue diagnosis The differentiation of granulomatous lesions of the liver from primary benign or malignant liver lesions may be difficult Diagnostic difficulties may be encountered in the characterization of atypical hemangiomas and FNH Hydatid liver disease may be a great mimic of liver metastasis Focal fatty infiltration may also mimic liver metastasis 108

109. Treatment Hepatic Resection Currently the most effective form of therapy for metastases confined to the liver Resectability is defined as complete gross resection while retaining a sufficient liver remnant with intact biliary drainage and vasculature Anatomic or segmental resections are currently favored over large wedge resections Accepted contraindications to metastasectomy include: Poor overall health Inadequate liver reserve Inability to achieve margin-negative resection Presence of extrahepatic disease 109

110. Treatment Ablative therapies (e.g. RFA) are also available for patients with unresectable disease who do not have apparent extrahepatic metastases Hepatic arterial infusion pump (HAIP) placement and administration of chemotherapy (TACE) Fluorodeoxyuridine is the most common agent administered by the intra-arterial route Other includes: IR and OX 110

111. For most patients no effective treatment exists because both lobes usually involved making surgical resection impossible. Younger patients with metastases from CRC confined to 1 lobe of liver and up to 4 in number, may be treated by partial hepatectomy 111

112. 112 THANKS