LIVER CARCIN�OMA(Prof. A. Riccardi)

PRIMARY TUMOR OF THE LIVER

* hepatocellular carcinoma (HCC) =from hepatocytes;* cholangiocarcinoma = from bile

ducts

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 CARCINOMAETIOLOGY. 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 CARCINOMAETIOLOGY. 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 with

chronic hepatitis B is 40%

* incidence of HCC in Taiwan, according to the presence orabsence of hepatitis B surface antigen (HBsAg) and hepatitisBe antigen (HBeAg) at diagnosis

HBV INFECTION AND HEPATOCELLULAR CARCINOMA

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. 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 the

process 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

normal liver chronic hepatitis B

staining for nuclearHbeAg

HCC

staining forcytoplasmic HbsAg

cirrhotic liver

* 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)

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. IV. �HCV

HCV (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)

THE HCV GENOME AND EXPRESSED POLYPROTEIN

A) specimen fromchronic HCV infection(dense portallymphocytic infiltrateand architecturalchanges); B)lymphocytes notlimited to portal tractbut also extend intothe lobules; C) normaliver architecture withscant fibrous tissue inportal tracts; D)fibrotic areas andbridging fibrosis; E)end stage cirrhosiswith marked fibrosisand regenerativenodules (RN); F) HCC

HISTOLOGIC STAGES OF HCV INFECTION

* 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)

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. V. �HBV vs HCV INFECTION

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)

* any factor leading to chronic, low-grade livercell damage and mitosis makes hepatocyteDNA more susceptible to genetic alterations: - chronic liver disease of any type (alcoholic

liver disease, αααα1-antitrypsin deficiency,hemochromatosis, and tyrosinemia);- mycotoxin aflatoxin B1 is a public health

hazard in Africa and southern China (inducing avery specific mutation at codon 249 in thetumor suppressor gene p53)

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. VI. OTHER FACTORS�

* 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 B1

enter the pathogenesis of HCC in regions ofAfrica and southern China (where both agentsare prevalent)

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. VI. �p53

* hormonal factors (male predominance ofHCC);* long-term androgenic steroid administration;* exposure to thorium dioxide or vinyl chloride,

and* ?exposure to estrogens as oral contraceptives

PRIMARY HEPATOCELLULAR CARCINOMAETIOLOGY. VII. OTHER FACTORS �

PATHOLOGY

PRIMARY HEPATOCELLULAR CARCINOMA

PRIMARY HCC

massive

nodular

diffuse

massive tumor, right lobe

PRIMARY HCC

nodule at hilus

PRIMARY HEPATOCELLULAR CARCINOMAHISTOLOGY

PRIMARY HEPATOCELLULAR CARCINOMAHISTOLOGY

CLINICAL FEATURES

* 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 right

upper quadrant

PRIMARY HEPATOCELLULAR CARCINOMACLINICAL FEATURES. I. �

* other signs:- friction rub or bruit over the liver;- blood - tinged ascites (hemoperitoneum, in

~ 20% of pts);- jaundice (rare, unless there is significant

deterioration of liver function or mechanicalobstruction of the bile ducts, as incholangiocarcinoma)

PRIMARY HEPATOCELLULAR CARCINOMACLINICAL FEATURES. II. �

* in a small % of pts:- erythrocytosis from erythropoietin-like

activity produced by HCC;- hypercalcemia (from secretion of a

parathyroid-like hormone): - hypercholesterolemia, hypoglycemia,

acquired porphyria, dysfibrinogenemia, andcryofibrinogenemia

PRIMARY HEPATOCELLULAR CARCINOMACLINICAL FEATURES

III. PARANEOPLASTIC SYNDROMES �

* commonly, serum elevations of alkalinephosphatase and αααα - fetoprotein (ΑΑΑΑFP);* presence of an abnormal prothrombin (des-

g-carboxy - prothrombin), correlating with ΑΑΑΑFPelevations

PRIMARY HEPATOCELLULAR CARCINOMALABORATORY FEATURES. I. �

* levels > 500 µg / L in 70 - 80% of pts;- lower levels in pts with large metastases from

gastric or colonic tumors and with acute orchronic hepatitis;- persistent presence of serum ΑΑΑΑFP > 500 - 1000

ug / L in an adult with liver disease and withoutan obvious GI tumor suggests HCC;- rising ΑΑΑΑFP levels suggest progression of tumor

or recurrence after therapy

PRIMARY HEPATOCELLULAR CARCINOMA LABORATORY FEATURES. II. �ΑΑΑΑ-FETOPROTEIN

* ultrasound, CT, MRI, hepatic arteryangiography, and radionuclide scans withtechnetium 99m;* ultrasound frequently used to screen high-

risk populations, and- first procedure (togheter with ΑΑΑΑFP

determination) if HCC is suspected (less costlythan TC, relatively sensitive, able at detectingmost tumors > 3 cm);* MRI used with increasing frequency

PRIMARY HEPATOCELLULAR CARCINOMAIMAGING PROCEDURES

CT SCANOF MULTIFOCAL

HEPATOCELLULARCARCINOMA

PRIMARY HEPATOCELLULAR CARCINOMAARTERIOGRAPHY (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

* diagnostic if sampletaken from an arealocalized by ultrasound orCT;- caution, because HCC

tends to be vascular;* cytologic examination of

ascitic fluid negative fortumor cells

PRIMARY HEPATOCELLULAR CARCINOMAPERCUTANEOUS LIVER BIOPSY

PRIMARY HEPATOCELLULAR CARCINOMAPERCUTANEOUS LIVER BIOPSY

_____________

* occasionally, to permit liver biopsyunder direct vision (sometimes toidentifying and staging pts with alocalized resectable tumor)

PRIMARY HEPATOCELLULAR CARCINOMA LAPAROSCOPY OR MINILAPAROTOMY

______

PRIMARY HEPATOCELLULAR CARCINOMAINTRAHEPATIC DISSEMINATION

PRIMARY HEPATOCELLULAR CARCINOMALUNG METASTASES

* 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 ofΑΑΑΑFP and ultrasound);

* in selected cases, therapies may prolonglife

PRIMARY HEPATOCELLULAR CARCINOMACLINICAL COURSE

PREVENTION AND STAGING

* preferred strategy:- hepatitis B vaccine prevents infection and its

sequelae (in Taiwan, reduction of HCC withuniversal vaccination of children); * interferon-αααα therapy lowers the risk of HCC

in pts with hepatitis C - related chronic activehepatitis and cirrhosis (additional studiesneeded)

PRIMARY HEPATOCELLULAR CARCINOMAPREVENTION

* 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 ΑΑΑΑFP determination;- serial ultrasonography (~ 20 - 30% of pts with

early HCC do not have elevated levels of ΑΑΑΑFP)

PRIMARY HEPATOCELLULAR CARCINOMA “SCREENING” PROGRAMS. I.

* 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“SCREENING” PROGRAMS. II.

Stage 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 CARCINOMATNM 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 than

American Joint Cancer Commission TNM system;- natural history without treatment: stage I = 8

mos; stage II = 2 mos and stage III < 1 mo

PRIMARY HEPATOCELLULAR CARCINOMAOKUDA STAGING

PRIMARY HEPATOCELLULAR CARCINOMASURVIVAL BY STAGE

Okuda TNM

TREATMENT

* only chance forcure;

- however, few ptswith resectabletumor at diagnosis(due to underlyingcirrhosis, bothhepatic lobesnvoved,metastases to lung,brain, bone, andadrenals)

PRIMARY HEPATOCELLULAR CARCINOMATREATMENT. I. SURGICAL RESECTION

- low 5-yr survival

* tumor recurrence or metastases limit itsusefulness;- but few pts who have a single lesion < 5

cm or ≤≤≤≤ 3 less than 3 cm lesions have thesame survival than liver transplantation fornonmalignant disease

PRIMARY HEPATOCELLULAR CARCINOMATREATMENT. II. LIVER TRANSPLANTATION

PRIMARY LIVER TUMORSLIVER TRANSPLANTATION

PRIMARY HEPATOCELLULAR CARCINOMALIVER TRANSPLANTATION

PRIMARY LIVER TUMORSSURVIVAL BY LIVER TRANSPLANTATION

* hepatic artery embolization (lipiodol) ±chemotherapy (chemoembolization);* ultrasound - guided cryoablation;* alcohol or radio-frequency ablation via

ultrasound - guided percutaneous injection

PRIMARY HEPATOCELLULAR CARCINOMATREATMENT. III. OTHER, MORE USUAL THERAPIES

PRIMARY HEPATOCELLULAR CARCINOMA HEPATIC ARTERY EMBOLIZATION ± CHEMOTHERAPY

PRIMARY HEPATOCELLULAR CARCINOMATHERMOABLATION. I.

PRIMARY HEPATOCELLULAR CARCINOMATHERMOABLATION. II.

* immunotherapy with monoclonalantibodies tagged with cytotoxic agents,and* gene therapy with retroviral vectors

containing genes expressing cytotoxicagents

PRIMARY HEPATOCELLULAR CARCINOMATREATMENT. III. EXPERIMENTAL THERAPIES

SUMMARY TREATMENT OF PRIMARY HEPATOCELLULAR CARCINOMA

METASTATIC TUMORSOF THE LIVER

METASTATIC TUMORS. I.

* common:- clinical incidence ≥≥≥≥ 20 times than that of

primary HCC;- at autopsy, in 30 - 50% of pts dying from

malignant disease;* second only to cirrhosis as a fatal liver

disease

mutiple metastases

METASTATIC TUMORSOF THE LIVER

large nodule

from melanoma

few small nodules

MELANOMAMETASTATICTO THE LIVER

Hodgkin’s disease

acute leukemias

INVOLVEMENTOF THE LIVER

* 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 TUMORSII. Pathogenesis

* usually, asymptomatic hepatic involvementdiscovered during clinical evaluation of pts onlyhaving symptoms referrable to primary tumor;- sometimes, paraneoplastic systemic

symptoms (weakness, weight loss, fever,sweating, and loss of appetite);- rarely, features indicating active hepatic

disease (abdominal pain, hepatomegaly, orascites)

METASTATIC TUMORSIII. Clinical features

* clinical signs of cancer and hepaticenlargement in pts with widespread liverinvolvement (localized induration ortenderness, a friction rub over tenderareas)

METASTATIC TUMORSIV. Clinical features

* 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 most

common and, frequently, the only abnormality);- hypoalbuminemia, anemia, and mild elevation of

aminotransferases with more widespread disease;- elevated serum levels of CEA when the

metastases are from primary malignancies fromgastrointestinal tract, breast, or lung

METASTATIC TUMORSV. Liver laboratory tests

* 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 levels

of alkaline phosphatase and / or a massapparent on ultrasound, CT, or MRI;- usually, definitive diagnosis from needle

biopsies directed by ultrasound or CT orobtained during laparoscopy

METASTATIC TUMORSVI. Diagnosis

* poor response to all therapies, usually palliative;- surgical removal of a single, large metastasis

(especially from GI tumors);- systemic CT slow growth and reduce symptoms

for a short time (it does not alter the prognosis);- thermoablation, chemoembolization,

intrahepatic chemotherapy, and alcohol ablation; - newer drugs or novel strategies (including

immunologic targeting) will be more effective?

METASTATIC TUMORSVII. Treatment