Transcript CanceroftheLiver.pptx

 Viral
Hepatitis and Hepatocellular Carcinoma
chronic hepatitis BHCV
 Alcohol-Induced Hepatocarcinogenesis
 Other Etiologic Considerations
 Chemical Carcinogens
 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
 benign
 the
or malignant
tissue of origin (mesenchymal tumorsepithelial 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.
T1
Solitary tumor without vascular invasion
T2
Solitary tumor with vascular invasion, or Multiple tumors
no more than 5 cm
T3
Multiple tumors more than 5 cm or Tumor involving a
major branch of the portal or hepatic vein(s)
T4
Tumor(s) with direct invasion of adjacent organs other
than the gallbladder or with perforation of visceral
peritoneum
 N1
 M1
Regional lymph node metastasis
Distant metastasis
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
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 (wellcompensated disease);
 7-9 is grade B (significant functional
compromise);
 10-15 is grade C (decompensated disease).
 These grades correlate with one- and twoyear patient survival: grade A - 100 and 85
percent; grade B - 80 and 60 percent; and
grade C - 45 and 35 percent.
 Morphology
and hepatic replacement
 Child-Pugh Score
 AFP (ng/mL)
 Portal vein thrombosis
1.
2.
3.
4.
Tumor size
Ascites
Serum albumin
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
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.

 Common
symptoms
abdominal pain,weight loss, weakness, fullness
and anorexia, abdominal swelling, jaundice,
and vomiting.
 Uncommon
Hemoperitoneum, Weakness, malaise,
anorexia, and weight loss , Jaundice,
Hematemesis, Bone pain , Respiratory
symptoms , Pleural effusions ,










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
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.

 History
and Physical Examination
 Serologic Assays
 Radiology
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.

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.
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
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
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 acidgalactosyl 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.
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.

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: Contrastenhanced 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.
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 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.

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. Triplephase 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 (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 multirow 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.

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.
 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
 core
biopsies are most preferred
 laparoscopic
 Surgery
 biopsy or necropsy
 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, imageguided 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.
 AASLD
Practice Guideline provided evidencebased 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.


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.
1.
2.
chronic hepatitis B viral infection
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.

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 HCC
Nonhepatitis B cirrhosis
Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Insufficient 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.

 Patients
presenting with advanced tumors
(vascular invasion, symptoms, extrahepatic
spread) have a median survival of about 5
months with no treatment


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
 Surgical
Excision
 Laparoscopic Resection
 Local Ablation Strategies
 Local Injection Therapy
 Transplantation
 Adjuvant Therapy
 1-cm



margin
Deep tumors and tumors greater than 5 cm
Centrally located tumors
Pringle maneuver
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.
 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.
 less
morbidity and quicker recovery
 able to assess margins pathologically
 bleeding,
hepatic failure, and ascites
 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%
 absolute
ethanol
 15% risk of recurrence
 Acetic acid
 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.
5-year survival =70% to 75%.
 strict criteria

 waiting
list
 Neoadjuvant
approaches such as
chemoembolization have been successful as
a bridge to transplantation, and have
decreased tumor burden in resection
candidates to improve resectability.
a
major hepatectomy
 Child-Pugh A cirrhosis ‫مورتالیتی و موربیتی باال )با‬
)‫لوبکتومی‬
 Preoperative
portal vein occlusion
no transplantation
 neoadjuvant treatment such as embolization.
 Successful regional therapy strategies may
make the patient eligible for transplantation.

 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.
 Palliative
Liver Radiation Therapy
 Conformal Radiation TherapyCharged Particle
Therapy
 Brachytherapy
 Radioisotopes
 Radioisotopes
 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
 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%.
 Whole-liver
irradiation
 HCC metastases to bone, brain, lymph nodes,
and other sites.

Hyperfractionated radiation therapy+fluorodeoxyuridine [FUdR] ‫یا‬
‫تالیدومید‬
 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
 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.
 less
experience in HCC
radioisotopes by hepatic arterial delivery
 yttrium-90 (Y90)
 iodine-131 (I131)
 150 Gy

 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.
 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.
 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
 encouraging
 cisplatin,
reports
doxorubicin, mitomycin C, and
others
 bolus administrationan
 Add embolizing agent
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.
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.
 resection
is the first line of therapy
 unresectable, liver transplantation
 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.

 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.