CANCER OF THE LIVER

ETIOLOGIC FACTORS Viral Hepatitis and Hepatocellular

Carcinoma chronic hepatitis B- HCV Alcohol-Induced Hepatocarcinogenesis Other Etiologic Considerations Chemical Carcinogens

VIRAL HEPATITIS AND HEPATOCELLULAR CARCINOMA

chronic hepatitis B HBV sequences are not regularly

associated with specific human genes rounds of hepatic destruction following

replicative repair lead to the accumulation of mutations associated with cancer development

a series of somatic genetic alterations Nodules evolve from cirrhosis to low-

grade dysplastic nodules, then high-grade dysplastic nodules, then to cancer.

The most frequently mutated genes in HCC include p53, PIK3CA, and b-catenin

PATHOLOGY benign or malignant

the tissue of origin (mesenchymal tumors- epithelial neoplasms)

Malignant epithelial (85% to 95% of all tumors of the liver)

Benign(6-21%) 1% to 3% of liver tumors are malignant

mesenchymal tumors.

AMERICAN JOINT COMMISSION ON CANCER STAGING

Solitary tumor without vascular invasion T1

Solitary tumor with vascular invasion, or Multiple tumors no more than 5 cm

T2

Multiple tumors more than 5 cm or Tumor involving a major branch of the portal or hepatic

vein(s)

T3

Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of

visceral peritoneum

T4

N1 Regional lymph node metastasis M1 Distant metastasis

STAGE GROUPING I T1 N0 M0 II T2 N0 M0 III A T3 N0 M0 III B T4 N0 M0 III C Any T N1 M0 IV Any T Any N M1

CHILD-PUGH CLASSIFICATION OF SEVERITY OF LIVER DISEASEModified Child-Pugh classification of the severity of

liver disease according to the degree of ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and the degree of encephalopathy.

A total score of 5-6 =grade A (well-compensated disease);

7-9 is grade B (significant functional compromise);

10-15 is grade C (decompensated disease). These grades correlate with one- and two-year

patient survival: grade A - 100 and 85 percent; grade B - 80 and 60 percent; and grade C - 45 and 35 percent.

CANCER OF THE LIVER ITALIAN PROGRAM (CLIP) STAGING SYSTEM Morphology and hepatic replacement Child-Pugh Score AFP (ng/mL) Portal vein thrombosis

THE OKUDA STAGING SYSTEM

1. Tumor size2. Ascites3. Serum albumin4. Serum bilirubin

The American Association for the Study of Liver Diseases (AASLD) has endorsed the use of the Barcelona Clinic (BCLC) system for staging of HCC. This has now been validated both internally and externally in several studies. This system combines assessment of tumor stage, liver function, and patient symptoms with a treatment algorithm and has been shown to correlate well with patient outcomes

MOLECULAR CHARACTERISTICS By comparing the genotyping of multiple lesions

in the liver, one can define whether these are multiple primary tumors or intrahepatic metastases, which have a much worse prognosis.33 They found that among multiple de novo tumors, 94.4% are bilobar and multiple intrahepatic metastases are bilobar 62.9% of the time.

The measure of allelic loss of heterozygosity combined with tumor number, tumor size, vascular invasion, lobar distribution, and patient gender provided a highly discriminatory model for predicting cancer recurrence after liver transplantation.

CLINICAL FEATURES Common symptoms abdominal pain,weight loss, weakness,

fullness and anorexia, abdominal swelling, jaundice, and vomiting.

UncommonHemoperitoneum, Weakness, malaise,

anorexia, and weight loss , Jaundice, Hematemesis, Bone pain , Respiratory symptoms , Pleural effusions ,

PHYSICAL SIGNS Hepatomegaly Abdominal bruits Ascites (hemoperitoneum ) Splenomegaly Weight loss and muscle wasting Fever (10% to 50% ) signs of chronic liver disease (jaundice, dilated abdominal

veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema)

The Budd-Chiari syndrome (invasion of the hepatic veins) Virchow-Trosier nodes may occur in the supraclavicular

region

Cutaneous metastases have also been reported as red-blue nodules

PARANEOPLASTIC SYNDROMES Most of these are biochemical abnormalities

without associated clinical consequences hypoglycemia (also caused by end-stage liver

failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenaemia, carcinoid syndrome, increased thyroxin-binding globulin, sexual changes (gynecomastia, testicular

atrophy, and precocious puberty), and porphyria cutanea tarda.

CLINICAL EVALUATION History and Physical Examination Serologic Assays Radiology

HISTORY AND PHYSICAL EXAMINATION a history of viral hepatitis or other liver disease,

blood transfusion, or use of intravenous drugs. It should include a family history of HCC or hepatitis and detailed social history to include job descriptions for industrial exposure to possible carcinogenic drugs as well as sex hormones.

PhE (underlying liver disease such as jaundice, ascites, peripheral edema, spider nevi, palmar erythema, and weight loss) Evaluation of the abdomen for hepatic size, presence of masses, hepatic nodularity, and tenderness, and presence of splenomegaly should be carried out. Assessment of overall performance status is essential for management decisions.

SEROLOGIC ASSAYS

AFP(high-risk patients and patients being treated either with surgical resection or chemotherapy)

Des-gamma-carboxy prothrombin (also known as "prothrombin produced by vitamin K absence or antagonism II" [PIVKA II]) has also shown promise in the diagnosis of HCC

It may even have prognostic value.44 The elevations of both AFP and PIVKA-2 observed in chronic hepatitis and cirrhosis in the absence of HCC sometimes make it difficult to interpret these assays. Although many other assays have been developed, none have greater aggregate sensitivity and specificity.

Assessment of liver function Hepatic synthetic function ( serum albumin,

bilirubin, and prothrombin time ) Other tests such as isocyanine green retention and

99m-Tc GSA (diethylenetriamine-penta-acetic acid-galactosyl human serum albumin) scintigraphy have been described as more specific indicators of hepatic reserve in preparation for resection, but have not surpassed the Child-Pugh classification as a predictor of postoperative complications and liver failure.52 Platelet count and white blood cell count decreases may reflect portal hypertension and associated hypersplenism.

HBsAg and anti-HCV; if either test is positive, further confirmatory testing should be done including HBV DNA or HCV RNA.

SEROLOGIC ASSAYS

RADIOLOGY

Ultrasound(an excellent screening tool) a good-quality multiphasic computed

tomography (CT) or MRI(local extent of tumor and accurately determine its size and extent)

A characteristic feature of HCC is rapid enhancement during the arterial phase of contrast administration and washout during the later venous phases. Hepatic tumors are usually hypervascular, show tortuosity of the vessels, vascular pooling, and hepatic staining, and often demonstrate rapid entry of contrast into the associated hepatic veins. Arterial portal shunting in the presence of portal hypertension can also be observed.

TRIPLE PHASE CT SCANNING OF HEPATOCELLULAR CARCINOMA

a 74-year-old man with cirrhosis and a history of alcohol exposure. Panel A: Unenhanced scan of liver shows exophytic mass (arrow) in segment VII; panel B: Contrast-enhanced scan of the liver during late arterial phase shows the lesion more clearly and multiple additional enhancing masses suspicious for multifocal disease (arrows); panel C: contrast-enhanced scan during venous delayed phase of enhancement shows decrease in the contrast between lesion and adjacent liver.

MAGNETIC RESONANCE IMAGING (MRI) OF HEPATOCELLULAR CANCER

MRI of the liver performed in a 73-year-old man with hepatitis C and cirrhosis, and a newly diagnosed hepatocellular cancer. Panel A: axial fast spin-echo T2-weighted MR image shows tumor to be slightly hyperintense, with a thin low-signal intensity capsule (arrow); panel B: delayed fat-saturated gadolinium-enhanced axial spin-echo T1-weighted MR image shows the low signal intensity of the tumor relative to adjacent liver, and the capsule is enhancing (arrow).

ULTRASONOGRAPHY Ultrasonography screening in prospective

studies has been shown to be more sensitive than repetitive AFP testing, especially for small tumors in high-risk patients.

particularly in surveillance programs for patients with chronic liver disease who are at risk for the development of HCC.

Ultrasonography is particularly useful for the diagnosis of portal venous thrombosis.

Ultrasound is also helpful in distinguishing HCC from metastatic tumors because HCC has a typical ring sign when smaller than 2 cm.

CT SCAN display tumor extent better than sonography

but both imaging modalities can miss lesions smaller than 1 cm to 2 cm, especially in the presence of the nodular, cirrhotic liver.

Angioportography, . CT portography has a high sensitivity, but

drawbacks include the detection of small abnormalities that represent flow voids or benign lesions. False-negative findings have also been identified, especially in instances in which there is fatty infiltration of the liver. Triple-phase helical CT ) appears to be a current standard, especially with a fast bolus of contrast injection to detect small vascular HCCs

CT ARTERIAL PORTOGRAPHY CT ARTERIAL PORTOGRAPHY — CT arterial

portography (CTAP) was used for the detection of intrahepatic tumors and portal vein obstruction, but because of its invasive nature and the improved resolution of the newest multi-row CT scanners, it is seldom used any longer in practice. CTAP involves portal enhancement of the liver by infusion of contrast material via an angiographically placed catheter in the superior mesenteric artery, providing good delineation of intrahepatic vessels and the hepatic parenchyma. Since most liver tumors receive an arterial blood supply, this technique enhances differences between the normal parenchyma and most liver lesions.

PET

A prospective comparison of triphasic CT, gadolinium-enhanced MRI, ultrasound, and FDG-PET was reported and verified by explanted liver specimens after transplant. This study revealed similar results for CT, MRI, and ultrasound, while none of the lesions were detected by PET imaging.

OBTAINING A DIAGNOSIS

its hazards Not only are bleeding studies often

abnormal because of thrombocytopenia and decrease in liver-dependent clotting factors, but these tumors tend to be hypervascular. Spillage of tumor has also been suggested as a problem following percutaneous biopsy, but is relatively rare

OBTAINING A DIAGNOSIS core biopsies are most preferred laparoscopic Surgery biopsy or necropsy The AASLD Practice Guideline on

Management of Hepatocellular Carcinoma

THE AASLD PRACTICE GUIDELINE ON MANAGEMENT OF HEPATOCELLULAR CARCINOMA

criteria for diagnosis of HCC: Detection of a hepatic mass within a cirrhotic liver is

highly suspicious of HCC. If a mass more than 2 cm is detected and the serum

AFP level is more than 200 ng/mL with a radiologic appearance of the mass suggestive of HCC (arterial vascularization with washout on one study or arterial vascularization on two separate dynamic studies), biopsy is not essential

For lesions between 1 and 2 cm in diameter, image-guided biopsy is recommended.

Lesions less than 1 cm ,it is recommended that these nodules be followed up every few months in order to detect growth suggestive of malignant transformation.

SCREENING POPULATIONS AT HIGH RISK OF HEPATOCELLULAR CARCINOMA AASLD Practice Guideline provided

evidence-based recommendations for identification of patients at risk, and recommended screening with periodic ultrasound examination with standardized recall policies and an algorithm for diagnosis of HCC.

HCC is potentially curable when treated at an early stage. Thus, results of liver transplantation for well-selected patients with stage I or II HCC show patient survival of 70% to 75% at 5 years.

hepatic resection and local ablative therapies have been associated with good survival rates. Early diagnosis is therefore the key to successful management of HCC. Because HCC is very often associated with underlying liver disease, it is the hepatologist who is providing care for these patients and who shoulders the burden of screening for HCC.

AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES Surveillance, on the other hand, refers to the

repeated application of screening tests, as might be done as part of a systematic program in combination with standardized recall procedures and quality-control measures. The subject of screening for HCC has been somewhat controversial. On the one hand there was wide recognition that patients with chronic liver disease were at risk of HCC and that screening with ultrasound and serum AFP allowed the detection of early tumors. On the other hand, there was not high level evidence that such screening improved patient outcomes or survival of those with HCC. The AASLD has recently published a practice guideline on management of HCC.75 This guideline includes a detailed, evidence-based recommendation for screening.

POPULATIONS AT RISK OF HCC

1. chronic hepatitis B viral infection 2. cirrhosis of any other cause

Surveillance of patients waiting for liver transplantation is recognized as being in a special category because, at least in the United States, the development of HCC gives increased priority for orthotopic liver transplantation and because failure to screen means that patients may develop HCC that progresses beyond listing criteria while the patient is waiting.

GROUPS RECOMMENDED TO BE UNDER SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA (HCC) Hepatitis B carriers

   Asian men >40 y   Asian women >50 y   All cirrhotic hepatitis B carriers   Family history of HCC   Africans >20 y   Patients with high HBV DNA and ongoing hepatic injury remainat risk of HCCNonhepatitis B cirrhosis   Hepatitis C   Alcoholic cirrhosis   Genetic hemochromatosis   Primary biliary cirrhosisInsufficient data to make recommendations   Cirrhosis due to Alpha-1 antitrypsin (AAT) deficiency    Cirrhosis due to nonalcoholic steatohepatitis   Cirrhosis due to autoimmune hepatitis

a surveillance interval of 6 to 12 months has been

Tumor volume doubling times have ranged between 29 and 398 days (median, 117 days).

Thus, although there is considerable variability, in general HCC is a slow-growing tumor. Thus, a screening interval of 6 to 12 months should be adequate to detect all but the fastest growing tumors before they exceed 5 cm in diameter. It is important to emphasize that the surveillance interval is determined by the growth rate of the tumor in question, not by the degree of risk of the individual.

CLINICAL MANAGEMENT Patients presenting with advanced

tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of about 5 months with no treatment

TREATMENT OPTIONS FOR HEPATOCELLULAR CARCINOMA Surgery

   Partial hepatectomy   Liver transplantation

Local ablative therapies   Cryosurgery   Microwave ablation   Ethanol injection   Acetic acid injection   Radiofrequency ablation

Regional therapies: hepatic artery transcatheter treatments   Transarterial chemotherapy   Transarterial embolization   Transarterial chemoembolization   Transarterial radiotherapy   90Y microspheres   131I lipiodol

Conformal external-beam radiation therapy

Systemic therapies   Chemotherapy   Immunotherapy   Hormonal therapy + growth control

Supportive care

STAGE I AND II HEPATOCELLULAR CARCINOMA Surgical Excision Laparoscopic Resection Local Ablation Strategies Local Injection Therapy Transplantation Adjuvant Therapy

SURGICAL EXCISION(STAGE I AND II )

1-cm margin

Deep tumors and tumors greater than 5 cm

Centrally located tumors Pringle maneuver

CHILD-PUGH CLASSIFICATION OF SEVERITY OF LIVER DISEASEModified Child-Pugh classification of the severity of

liver disease according to the degree of ascites(Absent Slight Moderate ), the plasma concentrations of bilirubin(2-3mg/d) and albumin(2.8-3.5 g/Dl), the prothrombin time, and the degree of encephalopathy.

A total score of 5-6 =grade A (well-compensated disease);

7-9 is grade B (significant functional compromise); 10-15 is grade C (decompensated disease). These grades correlate with one- and two-year

patient survival: grade A - 100 and 85 percent; grade B - 80 and 60 percent; and grade C - 45 and 35 percent.

STAGE I AND II The Child-Pugh classification of liver

failure is still the most reliable prognosticator for tolerance of hepatic surgery

Child-Pugh A =surgical resection Child-Pugh B and C patients , stage I

HCC =transplant ascites or a recent history of variceal

bleeding =transplantation.

LAPAROSCOPIC RESECTION less morbidity and quicker recovery able to assess margins pathologically

bleeding, hepatic failure, and ascites

LOCAL ABLATION STRATEGIES Radiofrequency ablation excellent response, with a local recurrence

rate (at the site of ablation) of between 5% and 20%

CT or ultrasound guidance(at the time of laparoscopy with ultrasound guidance)

best suited overall to small tumors (less than 3 cm) deep within the hepatic parenchyma and away from the hepatic hilum.

local recurrence rate (at the site of ablation) of between 5% and 20%

LOCAL INJECTION THERAPY

absolute ethanol 15% risk of recurrence Acetic acid

( STAGE I AND II) TRANSPLANTATION indications for transplantation (i) the patient was not a liver resection

candidate, (ii) the tumor(s) was 5 cm or less in

diameter, (iii) there was no macrovascular

involvement (iv) there was no identifiable

extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal organs, or bone.

TRANSPLANTATIONSTAGE I AND II

5-year survival =70% to 75%. strict criteria

waiting list

ADJUVANT THERAPY Neoadjuvant approaches such as

chemoembolization have been successful as a bridge to transplantation, and have decreased tumor burden in resection candidates to improve resectability.

STAGE III TUMORS a major hepatectomy Child-Pugh A cirrhosis ) باال موربیتی و با مورتالیتی

(لوبکتومی Preoperative portal vein occlusion

no transplantation neoadjuvant treatment such as

embolization. Successful regional therapy strategies

may make the patient eligible for transplantation.

STAGE IV TUMORS The prognosis is poor and no surgical

treatment is recommended. Care must be taken to differentiate multifocal disease from intrahepatic metastases, as the latter has a much worse prognosis. Molecular genotyping may be the best way to make this differentiation.

RADIATION THERAPY Palliative Liver Radiation Therapy Conformal Radiation TherapyCharged

Particle Therapy Brachytherapy Radioisotopes

Radioisotopes

LIVER TOLERANCE TO RADIATION radiation-induced liver disease (RILD seen within 3 months clinical syndrome mimicking veno-

occlusive disease following bone marrow transplantation

presenting with anicteric ascites, hepatosplenomegaly, and elevated alkaline phosphatase

TX:supportive measures

LIVER TOLERANCE TO RADIATION non-RILD hepatic toxicities, including

elevation of transaminases, thrombocytopenia, variceal bleeding, and general decompensation of liver function, have also been observed.

Reactivation of hepatitis B has been suggested to be precipitated by interleukin-6 released by irradiated endothelial cells.

Changes in CT and MRI contrast enhancement and perfusion have been seen within regions of the liver irradiated to high doses. Ultimately, the high-dose liver volume becomes fibrotic while the spared liver hypertrophies.

whole-liver irradiation above 32 Gy in 1.5 Gy per fraction twice daily, 25 Gy in 10 fractions, or 21 Gy in 7 fractions are estimated to have a risk of RILD of more than 5%.

PALLIATIVE LIVER RADIATION THERAPY Whole-liver irradiation HCC metastases to bone, brain, lymph

nodes, and other sites.

(IV ,III) CONFORMAL RADIATION THERAPY

Hyperfractionated radiation therapy+fluorodeoxyuridine [FUdR] تالیدومید یا

Hypofractionation(referred to as stereotactic body radiation therapy)

conventional fractionated conformal irradiation

Radiation therapy combined with transhepatic arterial chemoembolization (TACE). prior to or following TACE

CHARGED PARTICLE THERAPY protons or heavy ions large tumors and/or Child-Pugh B or C

cirrhosis Proton and photon radiation therapy

have been used to treat portal venous thrombosis,

Proton and photon therapy have also been used as a bridge to liver transplantation, with pathologic complete responses observed.

BRACHYTHERAPY

less experience in HCC

RADIOISOTOPES

radioisotopes by hepatic arterial delivery

yttrium-90 (Y90) iodine-131 (I131) 150 Gy

Y90

liver toxicity ,pneumonitis, and gastrointestinal bleeding , ascites, elevated bilirubin, and elevated transaminases

Y90 microsphere therapy should be used with caution in patients with poor underlying liver function.

CHALLENGES difficulty describing partial liver

dosimetry, lost radioisotopes No eradicated Safety of this treatment has been

established and outcomes following various hepatic arterial radioisotope therapies are excellent, providing rationale for confirmatory randomized studies.

SYSTEMIC CHEMOTHERAPY The consensus is that no single agent or

combination of agents given systemically reproducibly leads to more than 25% response rates or has any effect on survival

? systemic interferon therapy antiandrogen Anandron thalidomide, megesterol, and vitamin K

REGIONAL CHEMOTHERAPY encouraging reports

cisplatin, doxorubicin, mitomycin C, and others

bolus administrationan Add embolizing agent

A RECENT SYSTEMATIC REVIEW AND META-ANALYSIS concluding that (i) no chemotherapeutic agent appears

better than any other, (ii) there is no benefit with lipiodol (iii) TAE appears as effective as TACE.

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA a rare histologic variant of HCC younger age group (peak incidence third

decade), without associated with cirrhosis or viral

hepatitis, affects males and females equally. more positive lymph nodes than normal

variant HCC. more favorable outcome after surgical

treatment remains controversial.

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA TX resection is the first line of therapy unresectable, liver transplantation

HEPATOBLASTOMA

childhood. a peak incidence occurring within the

first 2 years of life highly sensitive to chemotherapy Surgical resection is considered first line

of therapy liver transplantation Survival rates for these children after

livr transplantation is excellent, with 1-, 3-, and 5-year survivals reported at 92%, 92%, and 83%, respectively.

EPITHELIOD HEMANGIOENDOTHELIOMA predominantly in females survival ranged from 4 months to 28

years Surgical resection is choice multifocal(transplantation the only

surgical option) The presence of metastatic disease

does not seem to influence survival and should not be considered an absolute contraindication to either surgical resection or transplantation.