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Hepatocellular Carcinoma

Hepatocellular Carcinoma. Incidence. One of the most common malignancies worldwide More common in Asia and Africa than in the United States Highest incidence of HCC is in Japan (4-5%) Other high-incidence regions (sub-Saharan Africa)

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Hepatocellular Carcinoma

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  1. Hepatocellular Carcinoma

  2. Incidence One of the most common malignancies worldwide More common in Asia and Africa than in the United States Highest incidence of HCC is in Japan (4-5%) Other high-incidence regions (sub-Saharan Africa) Internationally, the common causes of HCC are hepatitis B, hepatitis C, and aflatoxin exposure Annual global incidence of 1 Million cases Male: Female = 4:1 Incidence rate = death rate http://emedicine.medscape.com/article/369226-overview Harrison’s Principles of Internal Medicine 17th ed

  3. Incidence • Most patients die within 1 year after diagnosis • Survival dependent on : • tumor size • associated diseases at the time of diagnosis Patients with cirrhosis have a shorter survival. Surgical cure is possible in less than 5% of patients. Annual Death Rates in Males • Low-incidence countries (US) • 1.9 per 100,000 • Intermediate-incidence (Austria and South Africa) • 5.1-20.0 per 100,000 • High-incidence (Asia, China, Korea) • 23.1-150 per 100,000 http://emedicine.medscape.com/article/369226-overview Harrison’s Principles of Internal Medicine 17th ed

  4. Incidence Age: Patients with cirrhosis may present earlier. • In high-incidence regions of the world (ie, Asia, Africa), patients present at age 30-50 years • In low-incidence regions (ie, Western Hemisphere), patients present at age 70-80 years United States • 4 Million chronic HCV carriers • 400,000 will likely develop cirrhosis • 20,000 may develop HCC annually http://emedicine.medscape.com/article/369226-overview Harrison’s Principles of Internal Medicine 17th ed

  5. Epidemiology • Endemic hot spots: • in areas of China and sub-Saharan Africa • associated with both high endemic hepatitis B carrier rates and mycotoxin contamination of foodstuffs, stored grains, drinking water, and soil • Environmental factors are important: • Japanese in Japan have a higher incidence than those living in Hawaii, who in turn have a higher incidence than those living in California. Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed.

  6. Etiologic Factors Chemical carcinogens Hepatitis Others

  7. Chemical Carcinogens Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed. Goldman, Ausiello. 2007. Cecil Medicine, 23rd ed. http://www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.htm • Aflatoxin B1 • Product of Aspergillus flavus and parasiticus • Most potent ubiquitous natural chemical carcinogen • Found in stored grains in hot, humid places where peanut and rice are stored in unrefrigerated conditions • Pyrrollizidine alkaloids • Plant sources such as comfrey; used in herbal food supplements • Tannic acid and safrole

  8. Etiologic Factors of HCC Chemical carcinogens Hepatitis Others

  9. Hepatitis • Hepatitis B • HBsAg positive = 98-fold greater risk for HCC (a study on Taiwanese male postal carriers) • HCC may arise from rounds of hepatic destruction with subsequent proliferation • Only half of patients have cirrhosis; other half, chronic active hepatitis • Vaccine against hepatitis B – reduced the incidence of HBV-associated HCC high-prevalence regions (Alaska, Africa) Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed. Goldman, Ausiello. 2007. Cecil Medicine, 23rd ed.

  10. Hepatitis • Hepatitis C • Patients tend to have more frequent advanced cirrhosis • Approximately 80% will develop chronic hepatitis C, and of this 20-30% will develop cirrhosis • HCC then develops in up to 20% of individuals with cirrhosis from chronic HCV, at a rate of 2 to 6% per year. • A typical interval between HCV-associated transfusion and subsequent HCC is ~30 years. Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed. Goldman, Ausiello. 2007. Cecil Medicine, 23rd ed.

  11. Cirrhosis • It is still not clear whether • Cirrhosis itself is a predisposing factor to the development of HCC, or • Underlying causes of the cirrhosis are the carcinogenic factors • ~20% of patients with HCC do not have underlying cirrhosis • Etiology is unclear Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed. Goldman, Ausiello. 2007. Cecil Medicine, 23rd ed.

  12. Cirrhosis in the Patient Physical stigmata of cirrhosis: Spider angiomata Palmar erythema Ascites Edema Clubbing Enlarged parotid glands Gynecomastia Prominent venous collaterals on the abdomen Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed.

  13. Cirrhosis in the Patient Physical stigmata of cirrhosis: • Spider angiomata • Palmarerythema • Ascites • Edema • Clubbing • Enlarged parotid glands • Gynecomastia • Prominent venous collaterals on the abdomen Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed.

  14. Etiologic Factors of HCC Chemical carcinogens Hepatitis Others

  15. Others • More common risk factors • Hepatitis • Alcohol abuse • Autoimmune chronic active hepatitis • Cryptogenic cirrhosis • Nonalcoholic steatohepatitis (NASH) • Less common risk factors • Primary biliary cirrhosis • Metabolic diseases • Hemochromatosis, Wilson’s dse, α1-antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, glycogenesis types 1 & 3, citrullinemia, orotic aciduria Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed.

  16. HCC Risk Factors Present in the Patient Common Cirrhosis from any cause Hepatitis B or C chronic infection Ethanol chronic consumption Nonalcoholic steatohepatitis (NASH) Aflatoxin B1 or other mycotoxins Unusual • Primary biliary cirrhosis • Hemochromatosis • Wilson’s dse • α1-antitrypsin deficiency • Tyrosinemia • Porphyria cutanea tarda • Glycogen storage diseases • Citrullinemia Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed.

  17. Clinical Features Patients who develop HCC usually have no symptoms other than those related to their chronic liver disease Mild to moderate abdominal pain with fullness and swelling Weight loss or early satiety Jaundice due to invasion of biliary tree, compression of the intrahepatic duct or as a result of hemobilia Bone pain or dyspnea due to metastases Intraperitoneal bleeding

  18. Physical signs Hepatomegaly is the most common physical sign occurring in 50-90% of patients Splenomegaly due to portal hypertension Muscle wasting and weight loss Ascites Signs of chronic liver disease: jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy and peripheral edema

  19. Paraneoplastic syndromes Disorders that are triggered by an altered immune system response to a neoplasm defined as clinical syndromes involving nonmetastatic systemic effects that accompany malignant disease. may result from production and release of antibodies and physiologically active substances or it may be idiopathic

  20. Diagnosis History & PE Serologic Assays Radiology Pathologic Diagnosis

  21. History & PE • History • Evaluating positive predisposing factors • History of hepatitis or jaundice • Blood transfusion • Use of intravenous drugs • Family history of HCC or hepatitis • Social history • Job descriptions/ industrial exposure to carcinogenic drugs • Contraceptive hormones Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

  22. History & PE • Physical Examination • Assessing stigmata of underlying liver disease • Jaundice • Ascites • Peripheral edema • Spider nevi • Palmar erythema • Weight loss • Evaluation of abdomen • Hepatic size • Masses or ascites • Hepatic nodularity • Tenderness • Splenomegaly Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

  23. Serologic Assays • AFP (α- fetoprotein) • DCP (des-γ-carboxy prothrombin) • CEA, Vitamin B12, AFP, Ferritin, PIVKA-2 antimitochondrial Ab • Standard liver function tests (PT, PTT, albumin,transaminases, γ-glutamyl transpeptidase, alkaline phosphatase) • Hepatitis A, B, C serology Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

  24. Radiology • Ultrasound • Excellent screening tool • Findings: • Hypervascularity of the tumor mass • Thrombosis by tumor invasion of normal portal veins • Echogenic masses Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA Novelline, R. Squire’s Fundamentals of Radiology 6th edition.Harvard University Press

  25. Radiology • CT (Helical/ Triphasic) • To determine tumor size and extent and presence of portal vein invasion • Accurately localizes the tumor and determine whether resection is possible • Findings: • Portal vein invasion is detected as an obstruction and expansion of the vessel • Liver tumors tend to have ill-defined margins and sometimes necrotic centers and calcification Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA Novelline, R. Squire’s Fundamentals of Radiology 6th edition.Harvard University Press

  26. Radiology • MRI - indicated if CT is inconclusive - can provide detailed information of the mass - Findings: - mass will typically be hypo-intense or iso- intense on a T1 weighted image - brighten markedly with T2 weighting Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA Novelline, R. Squire’s Fundamentals of Radiology 6th edition.Harvard University Press

  27. Pathologic Diagnosis • Histologic proof of the presence of HCC • Core liver biopsy of the mass under ultrasound guidance • Bleeding risk is increased compared to other cancers because: • Tumors are hypervascular • Px often have thrombocytopenia & decreased clotting factors * For patients suspected of having portal vein involvement, a core biopsy of the portal vein may also be indicated Fauci et.al. Harrison’s principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

  28. Staging CLIP Classification Clip stages(= sum of points): CLIP 0, )points; CLIP1, 1 point; CLIP2, 2 points; CLIP 3, 3 points Harrison’s Principle of Internal Medicine 17th edition 2008

  29. Staging Okuda Classification Okuda stages: stage 1, all (-); stage 2, 1 or 2(+); stage 3, 3 or 4(+) Harrison’s Principle of Internal Medicine 17th edition 2008

  30. Staging Harrison’s Principle of Internal Medicine 17th edition 2008 • The best prognosis is Stage I, solitary tumor ,2cm in diameter without vascular invasion. • Adverse prognostic features include: • Ascites, vascular invasion, and lymph node spread • Most large tumors have microscopic vascular invasion, so full staging can only be made after surgical resection. • Stage III – contains a mixture of lymph node- positive and –negative tumors • Patients with lymph node positive have a poor prognosis and few patients survive one year

  31. Staging • Stage IV • Poor after either resection or transplantation, and 1-year survival is rare. • A working staging system based entirely on clinical grounds that incorporates the contribution of the underlying liver disease was developed by Okuda et al. • Patients with Okuda stage III have a dire prognosis, because they usually cannot be curatively resected and the condition of their liver typically precludes chemotherapy Harrison’s Principle of Internal Medicine 17th edition 2008

  32. Treatment

  33. Stage I and II HCC • Important principle is to use liver-sparing treatments and to focus on treatment of both tumor and cirrhosis • Surgical resection • Local ablation (thermal or radiofrequency) • Local injection therapies (ethanol or acetic acid)

  34. Surgical Excision • Only Child A patients should be considered for surgical resection • Child B and C stage I and II including patients with ascitis and history of variceal bleeding should be referred for OLTX • Open surgical incision is most reliable • Laparoscopic resection: RFA or PEI ***No adequate comparison of techniques and choice of treatment depends on physician skill

  35. Local Ablation Strategies RFA – uses heat to ablate tumor which can be performed percutaneously with CT, US guidance or by laparoscopy with US Maximum probe size allows 7 cm zone of necrosis adequate for 3-4 cm of tumor Heat kills cells within zone of necrosis Limitation: treatment of tumors close to main portal pedicles are can lead to bile duct injury and obstruction

  36. Local Injection Therapy • Percutaneous Ethanol Injection – most common agent used - causes direct destruction of cancer cells but is not selective and will destroy normal cells in the vicinity - requires multiple injection (average -3) - maximum size of tumor reliably treated – 3cm

  37. Liver Transplantation • UNOS for Organ sharing point system for priority scoring of OLTX recipients • OLTX for patients with a single </=5 or 3 or fewer nodules with each </=3 (Milan criteria ) resulted in excellent tumor-free survival ( >/= 70% at 5 years) • Therapies as “bridge” to OLTX • RFA • PEI • TACE ***These pretransplant treatments allow patients to remain in the waiting list longer, giving them greater opportunities to be transplanted

  38. Adjuvant Therapy The role of adjuvant chemotherapy for patients after resection or OLTX remains unclear. No clear advantage in disease-free or overall survival

  39. Stages III and IV HCC Stage III tumors • without cirrhosis • major hepatectomy is feasible • prognosis is poor • Child's A cirrhosis • may be resected • long-term prognosis is poor. • even successful resection can be followed by rapid recurrence. • not considered candidates for transplantation because of the high tumor recurrence rates Stage IV tumors • prognosis is poor • no surgical treatment is recommended

  40. Systemic Chemotherapy No single agent or combination of agents given systemically reproducibly leads to even a 25% response rate or has any effect on survival

  41. Regional Chemotherapy • The legitimate goal of regional therapies: improving patient quality of life • Given via the hepatic artery have activity in HCC confined to the liver • Only 2 randomized controlled trials that showed a survival advantage for TACE • One that used Doxorubicin and the other Cisplatin • Uses also an embolizing agent • Eg. ethiodol, gelatin sponge particles (Gelfoam), starch (Spherex), or microspheres • Advantage: showed higher objective response rates for arterial administration of drugs together with some form of hepatic artery occlusion compared with any form of systemic chemotherapy to date • Disadvantage: Increased toxicities

  42. Regional Chemotherapy • Toxicities seen with addition of embolizing agents: • transient fever, abdominal pain, anorexia, • increased ascites or transient elevation of transaminases • cystic artery spasm and cholecystitis • The hepatic toxicities associated with embolization may be ameliorated by the use of degradable starch microspheres, with 50–60% response rates. • “A major problem in showing a survival advantage in patients responding to TACE is that many patients die of their underlying cirrhosis, not the tumor. “

  43. Experimental Therapies

  44. Experimental Therapies • Therapies that show encouraging survival effects: • pure beta emitter 90yttrium attached to either glass or resin microspheres (in Phase II trials of HCC) • Oral sorafenib - increases median survival from 6 to 9 months in advanced, unresectable HCC. • Therapy that show decreased tumor occurrence • Vitamin K (high dosage) (in clinical trials) • Therapy that show no effects on survival • Epidermal growth factor (EGF) receptor antibodies and EGF receptor kinase inhibitors (in clinical trials) • anti-angiogenesis therapies (in clinical trials) • Other forms of radiation therapy used in HCC • external beam • conformal radiation therapy • significant dose-limiting problem: Radiation hepatitis

  45. Summary of Therapy HCC < 2 cm: RFA ablation, PEI, or resection HCC > 2 cm, no vascular invasion: liver resection, RFA, or OLTX Multiple unilobar tumors or tumor with vascular invasion: TACE Bilobar tumors, no vascular invasion: TACE with OLTX for patients whose tumors have a response Extrahepatic HCC or elevated bilirubin: Phase I and II studies.

  46. References Fauci, et al. 2008. Harrison’s Principles of Internal Medicine, 17th ed. Goldman, Ausiello. 2007. Cecil Medicine, 23rd ed. Novelline, R. Squire’s Fundamentals of Radiology 6th edition.Harvard University Press http://www.fda.gov/Food/DietarySupplements/Alerts/ucm111219.htm http://emedicine.medscape.com/article/369226-overview

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