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    Liver Liver Presentation Transcript

    • LIVER CARCIN OMA (Prof. A. Riccardi)
    • PRIMARY TUMOR OF THE LIVER * hepatocellular carcinoma (HCC) =from hepatocytes; * cholangiocarcinoma = from bileducts
    • EPIDEMIOLOGYAND ETIOLOGY
    • 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
    • CIRRHOTIC LIVER
    • 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)
    • 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%
    • 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
    • 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)
    • FROM HBV INFECTION TO HCC staining for normal liver chronic hepatitis B cytoplasmic HbsAgstaining for nuclear cirrhotic liver HCC HbeAg
    • 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)
    • 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)
    • 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
    • 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)
    • 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)
    • 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)
    • 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)
    • 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
    • PATHOLOGY
    • PRIMARY HEPATOCELLULAR CARCINOMA
    • PRIMARY HCC massive nodular diffuse
    • PRIMARY HCC nodule at hilusmassive tumor, right lobe
    • PRIMARY HEPATOCELLULAR CARCINOMA HISTOLOGY
    • PRIMARY HEPATOCELLULAR CARCINOMA HISTOLOGY
    • CLINICAL FEATURES
    • 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
    • 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)
    • 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
    • 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
    • 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
    • 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
    • CT SCAN OF MULTIFOCALHEPATOCELLULAR CARCINOMA
    • 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
    • MANAGEMENT OF GASTROESOPHAGEAL HEMORRHAGE
    • DIAGNOSIS
    • 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
    • PRIMARY HEPATOCELLULAR CARCINOMA PERCUTANEOUS LIVER BIOPSY
    • _____________
    • PRIMARY HEPATOCELLULAR CARCINOMA LAPAROSCOPY OR MINILAPAROTOMY * occasionally, to permit liver biopsyunder direct vision (sometimes toidentifying and staging pts with alocalized resectable tumor)
    • ______
    • PRIMARY HEPATOCELLULAR CARCINOMA INTRAHEPATIC DISSEMINATION
    • PRIMARY HEPATOCELLULAR CARCINOMA LUNG METASTASES
    • 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
    • PREVENTION AND STAGING
    • 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)
    • 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)
    • 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
    • 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
    • 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
    • PRIMARY HEPATOCELLULAR CARCINOMA SURVIVAL BY STAGE Okuda TNM
    • TREATMENT
    • 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
    • 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
    • PRIMARY LIVER TUMORSLIVER TRANSPLANTATION
    • PRIMARY HEPATOCELLULAR CARCINOMA LIVER TRANSPLANTATION
    • PRIMARY LIVER TUMORSSURVIVAL BY LIVER TRANSPLANTATION
    • 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
    • PRIMARY HEPATOCELLULAR CARCINOMAHEPATIC ARTERY EMBOLIZATION ± CHEMOTHERAPY
    • PRIMARY HEPATOCELLULAR CARCINOMA THERMOABLATION. I.
    • PRIMARY HEPATOCELLULAR CARCINOMA THERMOABLATION. II.
    • PRIMARY HEPATOCELLULAR CARCINOMA TREATMENT. III. EXPERIMENTAL THERAPIES * immunotherapy with monoclonalantibodies tagged with cytotoxic agents,and * gene therapy with retroviral vectorscontaining genes expressing cytotoxicagents
    • SUMMARY TREATMENT OF PRIMARY HEPATOCELLULAR CARCINOMA
    • METASTATIC TUMORS OF THE LIVER
    • 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
    • METASTATIC TUMORS OF THE LIVER few small nodules large nodule from melanoma mutiple metastases
    • MELANOMAMETASTATICTO THE LIVER
    • INVOLVEMENT OF THE LIVERHodgkin’s diseaseacute leukemias
    • 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)
    • 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)
    • METASTATIC TUMORS IV. Clinical features* clinical signs of cancer and hepaticenlargement in pts with widespread liverinvolvement (localized induration ortenderness, a friction rub over tenderareas)
    • 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
    • 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
    • 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?