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 DISEASE
Modified 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 DISEASE
Modified 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.
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