Liver

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Liver

  1. 1. LIVER CARCIN OMA (Prof. A. Riccardi)
  2. 2. PRIMARY TUMOR OF THE LIVER * hepatocellular carcinoma (HCC) =from hepatocytes; * cholangiocarcinoma = from bileducts
  3. 3. EPIDEMIOLOGYAND ETIOLOGY
  4. 4. PRIMARY HEPATOCELLULAR CARCINOMA (HCC) EPIDEMIOLOGY * one of the most common tumors in the world: - especially prevalent in regions of Asia and sub- Saharan Africa (up to 500 cases / 100,000people / yr, usually in 4th - 5th decade); - much less common in USA and Western Europe[1 - 2% of tumors; increased incidence (from 1.4 in76’ - 80’ to 2.4 cases / 100,000 people / yr in 91’ -95’; usually in 5th-7th decade ]; * ~ 4 times > common in men than in women; * usually arises in a cirrhotic liver
  5. 5. CIRRHOTIC LIVER
  6. 6. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. I. * the high incidence in Asia and Africaaccounted by frequency of chronic infectionwith hepatitis B virus (HBV) and hepatitis Cvirus (HCV), frequently leading to cirrhosis (initself a risk factor for HCC: ~3% / yr, with 60 -90% in macronodular cirrhosis)
  7. 7. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. II. HBV * in regions of Asia where HCC and HBVinfection are prevalent, incidence is until 100 -fold higher in HBV+ individuals than in HBV-controls; - in China, the lifetime risk of HCC in pts withchronic hepatitis B is 40%
  8. 8. HBV INFECTION AND HEPATOCELLULAR CARCINOMA * incidence of HCC in Taiwan, according to the presence or absence of hepatitis B surface antigen (HBsAg) and hepatitis Be antigen (HBeAg) at diagnosis
  9. 9. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. III. HBV * in pts with HBV infection and HCC, HBV DNA isintegrated into host genomic DNA (both in tumorcells and adjacent, uninvolved hepatocytes); * beside, modifications (probably during theprocess of liver cell injury and repair) of cellulargene expression (by insertional mutagenesis,chromosomal rearrangements, or transcriptionaltransactivating activity of the X and pre-S2regions of the HBV genome)
  10. 10. FROM HBV INFECTION TO HCC staining for normal liver chronic hepatitis B cytoplasmic HbsAgstaining for nuclear cirrhotic liver HCC HbeAg
  11. 11. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. IV. HCV * responsible for most cases of non-A, non-Bhepatitis and implicated in HCC; - in Europe and Japan, HCV greatly prevalentover HBV; * unclear mechanism of HCV carcinogenesis(HCV genetic material does not integrate intohost genomic DNA); * both HBV and HCV in some pts (the clinicalcourse of HCC does not differ from when onlyone virus is implicated)
  12. 12. THE HCV GENOME AND EXPRESSED POLYPROTEINHCV (single-stranded RNA virus) consists of a single open reading frame and two untranslatedregions (UTRs). It encodes a polyprotein of about 3000 amino acids, which is cleaved into singleproteins by a host signal peptidase in structural region and HCV-encoded proteases in thenonstructural (NS) region. The structural region contains the core protein and two envelope proteins(E1 and E2). Two regions in E2 (hypervariable regions 1 and 2, HVR 1 and HVR 2), show extremesequence variability, as the result of selective pressure by virus-specific Abs. E2 also contains thebinding site for CD81, the putative HCV receptor or coreceptor. The nonstructural proteins havebeen assigned functions as proteases (NS2, NS3, NS4A), helicase (NS3), and RNA-dependent RNApolymerase (NS5B). The crystal structure of NS3 and NS5 is known. The function and properties ofother proteins (such as p7) are less characterized. A region in NS5A has been linked to the responseto interferon alfa therapy and is therefore called the interferon-sensitivity–determining region (ISDR)
  13. 13. HISTOLOGIC STAGES OF HCV INFECTION A) specimen from chronic HCV infection (dense portal lymphocytic infiltrate and architectural changes); B) lymphocytes not limited to portal tract but also extend into the lobules; C) norma liver architecture with scant fibrous tissue in portal tracts; D) fibrotic areas and bridging fibrosis; E) end stage cirrhosis with marked fibrosis and regenerative nodules (RN); F) HCC
  14. 14. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. V. HBV HCV INFECTION vs * different timing of onset of HCC in HBV- orHCV-infection; - in Asia, HBV acquired at birth via perinataltransmission, while HCV acquired primarilyduring adulthood from transfused blood; - correspondingly, HCC occurs ~ 1 - 2 decadesearlier in lifelong hepatitis B pts than in adult-acquired hepatitis C pts (HCC occurs ~ 30 yrsafter HCV infection and almost exclusively in ptswith cirrhosis)
  15. 15. VARIABILITY OF NATURAL HISTORY OF HCV INFECTION* factors < the risk of progression: female sex and young age;* factors > the risk: male sex, older age, alcohol intake, and othervirus coinfection;* pts with a favorable risk may not have progressive liver diseaseuntil > 30 yrs; in contrast, 20% of pts with chronic hepatitis C,especially with alcohol abuse or coinfection with HIV type 1 orHBV, have cirrhosis in ≤ 20 yrs (with a risk of HCC of 1-4% / yr)
  16. 16. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. VI. OTHER FACTORS * any factor leading to chronic, low-grade livercell damage and mitosis makes hepatocyteDNA more susceptible to genetic alterations: - chronic liver disease of any type (alcoholicliver disease, α1-antitrypsin deficiency,hemochromatosis, and tyrosinemia); - mycotoxin aflatoxin B1 is a public healthhazard in Africa and southern China (inducing avery specific mutation at codon 249 in thetumor suppressor gene p53)
  17. 17. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. VI. p53 * loss, inactivation, or mutation of the p53gene implicated in tumorigenesis and is themost common genetic derangement presentin human cancers; - by altering p53, both HBV and aflatoxin B1enter the pathogenesis of HCC in regions ofAfrica and southern China (where both agentsare prevalent)
  18. 18. PRIMARY HEPATOCELLULAR CARCINOMA ETIOLOGY. VII. OTHER FACTORS * hormonal factors (male predominance ofHCC); * long-term androgenic steroid administration; * exposure to thorium dioxide or vinyl chloride,and * ?exposure to estrogens as oral contraceptives
  19. 19. PATHOLOGY
  20. 20. PRIMARY HEPATOCELLULAR CARCINOMA
  21. 21. PRIMARY HCC massive nodular diffuse
  22. 22. PRIMARY HCC nodule at hilusmassive tumor, right lobe
  23. 23. PRIMARY HEPATOCELLULAR CARCINOMA HISTOLOGY
  24. 24. PRIMARY HEPATOCELLULAR CARCINOMA HISTOLOGY
  25. 25. CLINICAL FEATURES
  26. 26. PRIMARY HEPATOCELLULAR CARCINOMA CLINICAL FEATURES. I. * may escape early clinical recognitionbecause often occurs in pts with underlyingcirrhosis, and symptoms and signs maysuggest progression of cirrhotic disease; * most common presenting features: - abdominal pain and / or - detection of an abdominal mass in rightupper quadrant
  27. 27. PRIMARY HEPATOCELLULAR CARCINOMA CLINICAL FEATURES. II. * other signs: - friction rub or bruit over the liver; - blood - tinged ascites (hemoperitoneum, in~ 20% of pts); - jaundice (rare, unless there is significantdeterioration of liver function or mechanicalobstruction of the bile ducts, as incholangiocarcinoma)
  28. 28. PRIMARY HEPATOCELLULAR CARCINOMA CLINICAL FEATURES III. PARANEOPLASTIC SYNDROMES * in a small % of pts: - erythrocytosis from erythropoietin-likeactivity produced by HCC; - hypercalcemia (from secretion of aparathyroid-like hormone): - hypercholesterolemia, hypoglycemia,acquired porphyria, dysfibrinogenemia, andcryofibrinogenemia
  29. 29. PRIMARY HEPATOCELLULAR CARCINOMA LABORATORY FEATURES. I. * commonly, serum elevations of alkaline Αphosphatase and α - fetoprotein (ΑFP); * presence of an abnormal prothrombin (des-g-carboxy - prothrombin), correlating with ΑFPelevations
  30. 30. PRIMARY HEPATOCELLULAR CARCINOMA LABORATORY FEATURES. II. Α-FETOPROTEIN * levels > 500 µg / L in 70 - 80% of pts; - lower levels in pts with large metastases fromgastric or colonic tumors and with acute orchronic hepatitis; - persistent presence of serum ΑFP > 500 - 1000ug / L in an adult with liver disease and withoutan obvious GI tumor suggests HCC; - rising ΑFP levels suggest progression of tumoror recurrence after therapy
  31. 31. PRIMARY HEPATOCELLULAR CARCINOMA IMAGING PROCEDURES * ultrasound, CT, MRI, hepatic arteryangiography, and radionuclide scans withtechnetium 99m; * ultrasound frequently used to screen high-risk populations, and - first procedure (togheter with ΑFPdetermination) if HCC is suspected (less costlythan TC, relatively sensitive, able at detectingmost tumors > 3 cm); * MRI used with increasing frequency
  32. 32. CT SCAN OF MULTIFOCALHEPATOCELLULAR CARCINOMA
  33. 33. PRIMARY HEPATOCELLULAR CARCINOMA ARTERIOGRAPHY (VARICEAL BLEEDING)left: 1) hypervascular mass in the liver; 2) massive shunting fromhepativ artery to 3) main portal vein; right: filling of portal vein,causing variceal bleeding
  34. 34. MANAGEMENT OF GASTROESOPHAGEAL HEMORRHAGE
  35. 35. DIAGNOSIS
  36. 36. PRIMARY HEPATOCELLULAR CARCINOMA PERCUTANEOUS LIVER BIOPSY * diagnostic if sampletaken from an arealocalized by ultrasound orCT; - caution, because HCCtends to be vascular; * cytologic examination ofascitic fluid negative fortumor cells
  37. 37. PRIMARY HEPATOCELLULAR CARCINOMA PERCUTANEOUS LIVER BIOPSY
  38. 38. _____________
  39. 39. PRIMARY HEPATOCELLULAR CARCINOMA LAPAROSCOPY OR MINILAPAROTOMY * occasionally, to permit liver biopsyunder direct vision (sometimes toidentifying and staging pts with alocalized resectable tumor)
  40. 40. ______
  41. 41. PRIMARY HEPATOCELLULAR CARCINOMA INTRAHEPATIC DISSEMINATION
  42. 42. PRIMARY HEPATOCELLULAR CARCINOMA LUNG METASTASES
  43. 43. PRIMARY HEPATOCELLULAR CARCINOMA CLINICAL COURSE * the course of clinically apparent disease israpid; - if untreated, most pts die within 3 - 6 mos ofdiagnosis; - survival of 1 - 2 yrs possible when HCC isdetected very early (by serial screening ofΑFP and ultrasound); * in selected cases, therapies may prolonglife
  44. 44. PREVENTION AND STAGING
  45. 45. PRIMARY HEPATOCELLULAR CARCINOMA PREVENTION * preferred strategy: - hepatitis B vaccine prevents infection and itssequelae (in Taiwan, reduction of HCC withuniversal vaccination of children); α * interferon-α therapy lowers the risk of HCCin pts with hepatitis C - related chronic activehepatitis and cirrhosis (additional studiesneeded)
  46. 46. PRIMARY HEPATOCELLULAR CARCINOMA “SCREENING” PROGRAMS. I. * to identify small, resectable tumors in pts athigh risk for HCC [hepatitis B surface antigen(HBsAg) pts+, HCV+ pts and pts with cirrhosis ofany type]; - serial ΑFP determination; - serial ultrasonography (~ 20 - 30% of pts withearly HCC do not have elevated levels of ΑFP)
  47. 47. PRIMARY HEPATOCELLULAR CARCINOMA “SCREENING” PROGRAMS. II. * in Far East, screening HBsAg+ persons (with orwithout liver disease) identifies pts with small,subclinical tumors (minimal or no liver disease, tumorsunifocal or encapsulated): - surgical resection → 5 - & 10 - yr survival = 70 & 50%; * by constrast, in Italy, screening pts with cirrhosis(mostly associated with HBV and / or HCV infections)every 3 - 12 mos detects a 3% yearly incidence of HCC,surgically incurable; - however, no randomized study has shown survivalbenefit for screening pts at high risk for HCC
  48. 48. PRIMARY HEPATOCELLULAR CARCINOMA TNM STAGINGStage I: solitary tumor ≤ 2 cm, with no blood vessel invasion;Stage II: solitary tumor ≤ 2 cm with vascular invasion, or multipletumors in a single lobe none > 2 cm, without vascular invasion, or asolitary tumor of any size limited to one lobe of liver, withoutvascular invasion;Stage IIIA: solitary tumor > 2 cm with vascular invasion or multipletumors limited to one lobe of the liver of any size, with or withoutvascular invasion;Stage IIIB: tumor invades a nearby organ (other than thegallbladder) or penetrates the lining of the liver;Stage IVA: multiple tumors in > 1 lobe of the liver or tumorsinvolving a major branch of portal or hepatic vein (s);Stage IVB: tumors involving distant metastasis in organs beyondthe liver
  49. 49. PRIMARY HEPATOCELLULAR CARCINOMA OKUDA STAGING * based on: - tumor size (< or > 50% of liver); - ascites (absent or present); - bilirubin (< or > 3 mg / dl), and - albumin (< or > 3 g / dl); * Okuda system predicts prognosis better thanAmerican Joint Cancer Commission TNM system; - natural history without treatment: stage I = 8mos; stage II = 2 mos and stage III < 1 mo
  50. 50. PRIMARY HEPATOCELLULAR CARCINOMA SURVIVAL BY STAGE Okuda TNM
  51. 51. TREATMENT
  52. 52. PRIMARY HEPATOCELLULAR CARCINOMA TREATMENT. I. SURGICAL RESECTION * only chance forcure; - however, few ptswith resectabletumor at diagnosis(due to underlyingcirrhosis, bothhepatic lobes nvoved,metastases to lung,brain, bone, andadrenals) - low 5-yr survival
  53. 53. PRIMARY HEPATOCELLULAR CARCINOMA TREATMENT. II. LIVER TRANSPLANTATION * tumor recurrence or metastases limit itsusefulness; - but few pts who have a single lesion < 5cm or ≤ 3 less than 3 cm lesions have thesame survival than liver transplantation fornonmalignant disease
  54. 54. PRIMARY LIVER TUMORSLIVER TRANSPLANTATION
  55. 55. PRIMARY HEPATOCELLULAR CARCINOMA LIVER TRANSPLANTATION
  56. 56. PRIMARY LIVER TUMORSSURVIVAL BY LIVER TRANSPLANTATION
  57. 57. PRIMARY HEPATOCELLULAR CARCINOMATREATMENT. III. OTHER, MORE USUAL THERAPIES * hepatic artery embolization (lipiodol) ±chemotherapy (chemoembolization); * ultrasound - guided cryoablation; * alcohol or radio-frequency ablation viaultrasound - guided percutaneous injection
  58. 58. PRIMARY HEPATOCELLULAR CARCINOMAHEPATIC ARTERY EMBOLIZATION ± CHEMOTHERAPY
  59. 59. PRIMARY HEPATOCELLULAR CARCINOMA THERMOABLATION. I.
  60. 60. PRIMARY HEPATOCELLULAR CARCINOMA THERMOABLATION. II.
  61. 61. PRIMARY HEPATOCELLULAR CARCINOMA TREATMENT. III. EXPERIMENTAL THERAPIES * immunotherapy with monoclonalantibodies tagged with cytotoxic agents,and * gene therapy with retroviral vectorscontaining genes expressing cytotoxicagents
  62. 62. SUMMARY TREATMENT OF PRIMARY HEPATOCELLULAR CARCINOMA
  63. 63. METASTATIC TUMORS OF THE LIVER
  64. 64. METASTATIC TUMORS. I. * common: - clinical incidence ≥ 20 times than that ofprimary HCC; - at autopsy, in 30 - 50% of pts dying frommalignant disease; * second only to cirrhosis as a fatal liverdisease
  65. 65. METASTATIC TUMORS OF THE LIVER few small nodules large nodule from melanoma mutiple metastases
  66. 66. MELANOMAMETASTATICTO THE LIVER
  67. 67. INVOLVEMENT OF THE LIVERHodgkin’s diseaseacute leukemias
  68. 68. METASTATIC TUMORS II. Pathogenesis * the liver is highly vulnerable to invasion by tumorcells (the 2nd most common site of metastases afterlymph nodes), due to combination of: - its size, high rate of blood flow, double perfusionby hepatic artery and portal vein, Kupffer cellfiltration function and local tissue factors orendothelial membrane characteristics (enhancingmetastatic implants); - all neoplasms metastasize to liver (especiallyfrom gastrointestinal tract, lung, breast andmelanoma)
  69. 69. METASTATIC TUMORS III. Clinical features * usually, asymptomatic hepatic involvementdiscovered during clinical evaluation of pts onlyhaving symptoms referrable to primary tumor; - sometimes, paraneoplastic systemicsymptoms (weakness, weight loss, fever,sweating, and loss of appetite); - rarely, features indicating active hepaticdisease (abdominal pain, hepatomegaly, orascites)
  70. 70. METASTATIC TUMORS IV. Clinical features* clinical signs of cancer and hepaticenlargement in pts with widespread liverinvolvement (localized induration ortenderness, a friction rub over tenderareas)
  71. 71. METASTATIC TUMORS V. Liver laboratory tests * often abnormal, but usually mild and nonspecific(reflecting effects of fever and wasting as well asthose of infiltrating neoplastic process); - ↑ in serum alkaline phosphatase (the mostcommon and, frequently, the only abnormality); - hypoalbuminemia, anemia, and mild elevation ofaminotransferases with more widespread disease; - elevated serum levels of CEA when themetastases are from primary malignancies fromgastrointestinal tract, breast, or lung
  72. 72. METASTATIC TUMORS VI. Diagnosis * liver metastases to be sought actively beforesurgery in any pt with a technically resectable,primary malignancy (especially from lung,gastrointestinal tract, and breast); - presumptive diagnosis from elevated levelsof alkaline phosphatase and / or a massapparent on ultrasound, CT, or MRI; - usually, definitive diagnosis from needlebiopsies directed by ultrasound or CT orobtained during laparoscopy
  73. 73. METASTATIC TUMORS VII. Treatment * poor response to all therapies, usually palliative; - surgical removal of a single, large metastasis(especially from GI tumors); - systemic CT slow growth and reduce symptomsfor a short time (it does not alter the prognosis); - thermoablation, chemoembolization,intrahepatic chemotherapy, and alcohol ablation; - newer drugs or novel strategies (includingimmunologic targeting) will be more effective?

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