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A. Characteristics navigator

  1. Fifth most common neoplasm worldwide
    1. Annually, >500,000 new cases worldwide
    2. Incidence ~10 per 100,000
    3. Extremely high rates in some areas of Asia
  2. Overall incidence in USA is ~6000 cases per year [2]
    1. >90% are typical HCC associated with typical risk factors
    2. <2% are fibrolamellar variants not associated with typical risk factors
    3. Incidence of HCC in USA has increased ~2.5 fold from 1981 to 1998 (~3 per 100,000) [12]
  3. Major Risk Factors: Cirrhosis and Chronic Hepatitis
    1. Cirrhosis: 12.5% develop liver cancer over 3 years
    2. Chronic hepatitis: 3.8% develop liver Ca over 3 years
  4. Male : Female ~3:1
  5. Generally poor prognosis if >1-2 nodules is present
  6. Micrometastases detected in 88% of patients with clinically localized disease

B. Oncogenesis [1,2]navigator

  1. Hepatitis B Virus (HBV)
    1. HBV integration is usually found in HBV-associated tumors
    2. HBV integration promotes genomic instability
    3. HBV integration into host genome causes deregulation of certain host genes
    4. Chronic HBV carries risk of 1.3%-15% over ~10 years, dependent on HBV DNA levels [11]
  2. Hepatitis C Virus (HCV)
    1. HCV appears to have a direct oncogenic effect
    2. HCV NS3 protein may cause cell transformation
    3. HCV with HBV coinfection has additive increase in liver cancer risk
  3. Non-Viral Hepatitis
    1. Liver damage
    2. Liver regeneration often follows
    3. Nodular regeneration occurs between fibrotic tissue
    4. Fibrosis with regeneration is called cirrhosis
    5. Nodules may progress to adenomatous hyperplasia
    6. Appears that adenomatous hyperplasia progresses to hepatocellular Ca
  4. Blockade of Apoptosis [15]
    1. Insufficient apoptosis of DNA-damaged and malignant cells is found
    2. Normally, proapoptotic Fas protein is highly expressed in liver
    3. In liver cancers, Fas levels are reduced or absent
    4. Poorly differentiated HCC do not express Fas
    5. TGFß1 receptors are also down regulated in HCC and TGFß1 cannot induce apoptosis
    6. Dysfunctional or absent p53 regulatory protein is also found in HCC
  5. Fibrolamellar Variant [17]
    1. Relatively rare variant, typically occurs in persons <35 years of age
    2. Not associated with usual hepatitis viruses or alcohol intake
    3. Typically this is a solitary nodule; may be associated with spider angiomata
    4. Not associated with increase in serum alphafetoprotein levels
    5. Slower growth and better prognosis than typical HCC
    6. Pathology shows large hepatic cells within dense dcollagenous stroma
    7. Eosinophilic hyaline globules composed of alpha1-antitrypsin are found
    8. Associated with elevated serum levels of vitamin B12 and neurotensin
    9. Surgery is curative in >50% of patients

C. Risk Factors [12]navigator

  1. Overall, cirrhosis of any cause is the major risk factor
    1. Epidermal growth factor (EGF) gene polymorphisms affect EGF transcript levels and proteins by ~2 fold
    2. Cirrhotic patients with EGF polymorphisms associated with increased EGF levels have
  2. 5-4 fold increased risk of hepatocellular carcinoma [9]
  3. Viral Hepatitis
    1. Hepatitis B sAg (chronic HBV) have ~100X increased incidence, 75% over 15 years [1]
    2. Highest risk in patients with persistent HBV envelope antigen (HBeAg) [24]
    3. HBsAg+ and HBeAg+ has overall 60X risk of HCC compared with negative persons [4]
    4. HBV DNA levels are independently correlated with HCC risk [11]
    5. Hepatitis C virus (HCV) - 4X increased incidence, 27% over 15 years [2]
    6. Increasing age, male sex, and portal hypertension increase risk of liver cancer [3]
    7. Coinfection with HCV and HBV increase risk
    8. Hepatitis A or hepatitis G viruses carry no increased risk
    9. Interferon alpha (IFNa) treatment leading to prolonged responses reduces risk of developing HCC in patients with chronic HCV infection or cirrhosis [6]
    10. INFa reduces risk of HCC in HBV and/or HCV infected patients with frank cirrhosis [6,14]
  4. Alcoholic Hepatitis and Cirrhosis
  5. Metabolic Disorders
    1. Hemochromatosis
    2. Hereditary Tyrosinemia
    3. alpha-1 antitrypsin deficiency
    4. Type 1 Glycogen Storage Disease
  6. Various toxins including mushroom toxins, aflatoxin B1 in particular
  7. Prevention
    1. Reduce alcohol intake
    2. IFNa treatment of HCV+ or HCV+ / HBV+ patients reduces risk of liver cancer >50% [3]
    3. IFNa likely reduces risk of liver cancer in HBV and/or HCV positive patients with frank cirrhosis [14]
    4. High dose IFNa following HCC ablation in the liver improves outcomes [25]
    5. Likely that eradication of HBV or HCV also reduces risk of developing liver cancer
    6. Screening cirrhotic patients for HCC with ultrasound + alphafetoprotein semiannually [1]

D. Diagnosis navigator

  1. Ultrasound (US), computerized tomography (CT), or magnetic resonance imaging (MRI) [5]
    1. Ultrasound: sensitivity 60%, specificity ~97%
    2. CT with IV Contrast: sensitivity ~70%, specificity 93%
    3. MRI: sensitivity ~80%, specificity ~85%
    4. US with AFP is usually used in screenin, but no good data support this as best policy
  2. CT with IV Contrast
    1. CT is currently preferred modality
    2. Shows necrotic center in most tumors
    3. Angiogram shows high vascularity oif tumor
  3. Serum alpha-fetoprotein (AFP) subtype levels may be a useful screening method
    1. Elevated AFP ~60% sensitivity for detection of HCC in patients with cirrhosis
    2. Elevated AFP >90% specificity in screening for HCC in cirrhosis
  4. Serum AFP (alpha-fetoprotein) Correlates with HCC Risk [5]
    1. Level 10-11 ng/mL: sensitivity ~85%, specificity 75%
    2. Level 17-21 ng/mL ng/mL: sensitivity 65%, specificity 85%
    3. Level 50 ng/mL ng/mL: sensitivity 60%, specificity 85%
    4. Level >100ng/mL ng/mL: sensitivity ~45%, specificity 98%
    5. Differential includes some teratomas
    6. Specific isozymes of AFP are found more often in hepatocellular CA versus hepatitis
  5. Screening Class A cirrhotics semiannually with ultrasound + AFP is not cost effective
  6. Screening HCV Infected Patients [26]
    1. AFP screening at 6 month intervals has been advocated to detect HCC
    2. Sensitivitive of AFP for detecting HCV induced HCC is likely only ~50%
    3. AFP coupled with liver ultrasound should be used to detect screen for HCC in chronic HCV
  7. Cirrhotic patients should be screened twice annually with ultrasound and AFP
  8. TNM Staging
    1. Tumor (T): T0=no evidence of primary
    2. T1=single tumor without blood vessel invasion
    3. T2: single tumor with invasion into blood vessels or multiple tumors all <5cm
    4. T3: multiple tumors >5cm or tumor involving major portal or hepatic vein branch
    5. T4: tumor invading nearby organ or invading visceral peritoneum
    6. N0: no lymph node (LN) involvement; N1: spread to regional LN
    7. M0: no spread to distant LN or ot other organs; M1: spread to regional LN
  9. Overall Staging
    1. Stage I: N1, N0, M0
    2. Stage II: T2, N0, M0 (usually multiple tumors all <5cm)
    3. Stage IIIA: T3, N0, M0
    4. Stage IIIB: T4, N0, M0
    5. Stage IIIC: Any T, N1, M0 (LN invasion)
    6. Stage IV: anyt T, any N, M1

E. Treatment [1,2,7,8]navigator

  1. Overview
    1. Stage I: optimal candidates for surgical resection
    2. Stage II: chemoembolization and/or radiofrequency ablation
    3. Stage III: treatment with new experimental agents
    4. Stage IV: symptomatic treatment only
  2. Surgical Resection of Local Disease
    1. Surgical resection mainstay of therapy for local HCC with reasonable liver function
    2. Amount of resected liver is reduced in cirrhotics who have reduced functional reserve
    3. 30% of patients undergo exploratory laparotomy
    4. Must leave ~30% of liver (may regenerate)
    5. Functional reserve is critical: severe cirrhosis has >15% associated mortality
    6. Goal is at least 1cm disease free margins, though this is controversial [7]
    7. Complete encapsulation of tumor is not a significant prognostic indicator
    8. Overall tumor recurrence is ~70% at 5 years
    9. Five year survival: cirrhotic patients 25%; non-cirrhotic patients ~40%
  3. Chemoembolization [1,19,20]
    1. Transcatheter arterial chemoembolization (TACE) slows tumor progression
    2. Chemotherapy targeted to lesion and arterial supply embolized causing ischemia
    3. Embolization promotes retention of cytotoxic drug within tumor, induces tumor necrosis
    4. Ischemic necrosis of area distal to arterial supply kills tumor also
    5. Embolization with doxorubicin + mitomycin C shrinks >75% of tumors
    6. Lipiodol chemoembolization carries high risk for acute liver failure, with mortality benefit in some studies [13,19] but not in others [23]
    7. Chemoembolization with doxorubicin + cisplatin + mitomycin provides a survival benefit in focal but not diffuse HCC [23]
    8. May also be used as adjuvant therapy after surgical resection of tumor
    9. Thus, tumor characteristics and hepatic reserve are essential criteria for successful chemoembolization
    10. Chemoembolization with doxorubicin in gelatin sponge improves survival in patients with Child Class A or B and Okuda Stage I or II [22]
    11. Treatment of choice for Stage II HCC
  4. Radiofrequency Thermal Ablation (RFA)
    1. Thermal radiofrequency ablation with juxtaposition of catheter RF tip to lesions
    2. Often used as alterative to, or adjuvant to, chemoembolization for Stage II
  5. Combined RFA+TACE superior to either alone for Stage II HCC with tumors >3cm [13]
  6. Liver Transplantation
    1. May be viable treatment for small, unresectable hepatocellular carcinomas
    2. Size <5-7cm with one nodule, <3-5cm each for 2-3 nodules
    3. No vessel and no metastatic involvement
    4. Transplants can be carried out in patients with HBV or HCV associated HCC
    5. Benefit to transplant only if waiting time <6 months for transplant
    6. Overall mortality was 17% (about 13% in first year)
    7. Prognosis: ~80% recurrence free survival >4 years
    8. Recurrent viral infections can occur; newer drugs may reduce the risk
    9. A small liver Ca found during transplant evaluation does not rule out transplant
    10. Adjuvant chemotherapy may be given after transplantation with promising early results; randomized trials are being conducted
    11. Transplantation superior to resection for relapse free survival with tumors <5cm
    12. Cadavaric and living donor transplants have been performed
  7. Systemic Chemotherapy [8]
    1. High risk of second and recurrent tumors (~50% over 3-4 years)
    2. Preliminary data indicate that sorafenib improves overall survival (see below)
    3. Chemotherapy with 5-Fluorouracil (5FU) + adriamycin has response rates <20%
    4. Many tumors express estrogen receptors, but tamoxifen has no benefit on survival [10]
    5. Adjuvant chemotherapy after surgery or transplant may be used
    6. Cisplatin + IFNa + doxorubicin + 5FU (PIAF) provides a 16% response rate, median survival ~31 weeks [21]
    7. PIAF responders had less cirrhosis, lower bilirubin, and HCV positive versus nonresponders [21]
    8. Interferon alpha (IFNa) reduces risk of recurrent tumor following resection in patients with HCV+ HCC [18]
  8. Sorafenib (Nexavar®)
    1. Multikinase inhibitor (oral), blocks VEGF, PGDF, and other tyrosine kinase receptors
    2. Blocks both tumor cell and vasculature targets
    3. Improved survival in renal cell carcinoma (approved) and in HCC
    4. Dose is 200mg po qd up to 400mg po bid
    5. Rash, hypertension, fatigue, nausea, weight loss, neuropathy (pain)
  9. Percutaneous Ethanol Injection (PEI)
    1. May be beneficial especially in Child B cirrhosis
    2. 40% 3 year surival with PEI versus 10-15% with surgery or no therapy in Child B
  10. Palliative Measures
    1. Surgical debulking
    2. Stent placement as needed for bile duct obstruction
    3. Percutaneous ethanol injection - only for leasions <4cm in diameter
    4. Transcatheter arterial chemotherapy (methotrexate+5FU+cisplatin+IFNa)
    5. Embolization with chemotherapy superior to embolization alone [1]
    6. Cryoablation (percutaneous or open) for tumors <5 cm
    7. Radiofrequency ablation (heating) for tumors <5 cm
  11. Adoptive Immunotherapy [16]
    1. Objective response rates to adoptive immunotherapy in HCC documented
    2. Adoptive immunotherpay analyzed in post-surgical patients (Stages I, II, IIIa, IVa)
    3. Autologous mononuclear cells from 50mL of peripheral blood expanded in interleukin 2 (IL2) and CD3 Ab
    4. Cells cultured for 2 weeks and shown to have anti-tumor activity
    5. Immunotherapy group had longer disease free survival and reduced recurrence 18%
    6. Adoptive immunotherapy should be studied further in liver cancer
  12. Interferon alpha (IFNa) 6 million units 3X weekly intramuscular improved outcomes in patients with HCV-associated HCC who received PEI [25]
  13. Radiation Therapy [7]
    1. Liver is a radiosensitive organ
    2. Normal liver can tolerate 30 Gy radiation
    3. Selective internal radiation therapy with radioactive resin or glass microspheres
    4. These radioactive microspheres can be infused into hepatic artery
    5. Target dose up to 100 Gy to tumor
    6. Response rate of 27% for this experimental therapy

F. Prognosis [1,2]navigator

  1. Tumor size is most important predictor
    1. Tumors <5cm has ~80% 2 year survival rates
    2. Tumors >5cm has ~40% 2 year survival rates
  2. Post-Surgical Tumor Properties [7]
    1. Histology Grade 1 (good prognosis), grade 2 (moderate), grades 3 and 4 (poor prognosis)
    2. Nuclear atypia also graded (good-moderate-poor)
    3. Presence of microvascular invasion is a poor prognostic factor
    4. Complete encapsulation is not a prognostic marker
  3. Post-Surgical Tumor staging (pTNM) is also highly correlated with outcomes
    1. For pTNM Stage I 5 year survival 38%
    2. Stage II 5 year survival 34%
    3. Stage III 5 year survival 17%'
    4. Prognostic calculation based on histologic data
  4. Small Tumors treated with surgery or transplantation can be cured
  5. Multimodal therapies may lead to >50% survival at 5 years
  6. Most patients die from complications of local tumor growth
    1. Portal vein invasion and decompensated cirrhosis
    2. Metastatic disease is an uncommon cause of death

References navigator

  1. Liovet JM, Burroughs A, Bruix J. 2003. Lancet. 362(9399):1907 abstract
  2. Mor E, Kaspa RT, Sheiner P, Schwartz M. 1998. Ann Intern Med. 129(8):643 abstract
  3. International IFNa Hepatocellular Carcinoma Study Group. 1998. Lancet. 351(9115):1535 abstract
  4. McMahon BJ, Holck P, Bulkow L, Snowball M. 2001. Ann Intern Med. 135(9):759 abstract
  5. Colli A, Fraquelli M, Casazza G, et al. 2006. Am J Gastroenterol. 101(3):513 abstract
  6. Shiratori Y, Ito Y, Yokosuka O, et al. 2005. Ann Intern Med. 142(2):105 abstract
  7. Tanabe K, Blaszkowsky LS, Chung RT, et al. 2005. NEJM. 353(4):401 (Case Record) abstract
  8. Zhu AX, D'Andrea AD, Sahani DV,hasserjian RP. 2006. NEJM. 354(17):1828 abstract
  9. Tanabe KK, Lemoine A, Finkelstein DM, et al. 2008. JAMA. 299(1):53 abstract
  10. CLIP Group. 1998. Lancet. 352(9121):17 abstract
  11. Chen CJ, Yang HI, Su J, et al. 2006. JAMA. 295(1):65 abstract
  12. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. 2003. Ann Intern Med. 139(10):817 abstract
  13. Cheng BQ, Jia CQ, Liu CT, et al. 2008. JAMA. 299(14):1669 abstract
  14. Baffis V, Shrier I, Sherker AH, Szilagyi A. 1999. Ann Intern Med. 131(9):696 abstract
  15. Rust C and Gores GJ. 2000. Am J Med. 108(7):567 abstract
  16. Takayama T, Sekine T, Makuuchi M, et al. 2000. Lancet. 356(9232):802 abstract
  17. Reinus JF and Yantiss RK. 2000. NEJM. 343(21):1553 (Case Record)
  18. Kubo S, Nishiguchi S, Hirohashi K, et al. 2001. Ann Intern Med. 134(10):963 abstract
  19. Pelletier G, Ducreux M, Gay F, et al. 1998. J Hepatol. 29:129 abstract
  20. Lopez RR Jr, Pan SH, Hoffman AL, et al. 2002. Arch Surg. 1376):653
  21. Leung TW, Tang AM, Zee B, et al. 2002. Cancer. 94(2):421 abstract
  22. Llovet JM, Real MI, Montana X, et al. 2002. Lancet. 359(9319):1734 abstract
  23. Lo CM, Ngan H, Tso WK, et al. 2002. Hepatology. 35(5):1164 abstract
  24. Yang HI, Lu SN, Liaw YF, et al. 2002. NEJM. 347(3):168 abstract
  25. Shiratori Y, Shiina S, Teratani T, et al. 2003. Ann Intern Med. 138(4):299 abstract
  26. Gupta S, Bent S, Kohlwes J. 2003. Ann Intern Med. 139(1):46 abstract