Liver

LIVER CARCIN OMA
(Prof. A. Riccardi)

PRIMARY TUMOR OF THE LIVER
* hepatocellular carcinoma (HCC) =
from hepatocytes;
* cholangiocarcinoma = from bile
ducts

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 / 100,000
people / yr, usually in 4th - 5th decade);
- much less common in USA and Western Europe
[1 - 2% of tumors; increased incidence (from 1.4 in
76’ - 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

PRIMARY HEPATOCELLULAR CARCINOMA
ETIOLOGY. I.

* the high incidence in Asia and Africa
accounted by frequency of chronic infection
with hepatitis B virus (HBV) and hepatitis C
virus (HCV), frequently leading to cirrhosis (in
itself a risk factor for HCC: ~3% / yr, with 60 -
90% in macronodular cirrhosis)

ETIOLOGY. II. HBV

* in regions of Asia where HCC and HBV
infection 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%

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

ETIOLOGY. III. HBV
* in pts with HBV infection and HCC, HBV DNA is
integrated into host genomic DNA (both in tumor
cells and adjacent, uninvolved hepatocytes);
* beside, modifications (probably during the
process of liver cell injury and repair) of cellular
gene expression (by insertional mutagenesis,
chromosomal rearrangements, or transcriptional
transactivating activity of the X and pre-S2
regions of the HBV genome)

FROM HBV INFECTION TO HCC

staining for
normal liver chronic hepatitis B cytoplasmic HbsAg

staining for nuclear cirrhotic liver HCC
HbeAg

ETIOLOGY. IV. HCV
* responsible for most cases of non-A, non-B
hepatitis and implicated in HCC;
- in Europe and Japan, HCV greatly prevalent
over HBV;
* unclear mechanism of HCV carcinogenesis
(HCV genetic material does not integrate into
host genomic DNA);
* both HBV and HCV in some pts (the clinical
course of HCC does not differ from when only
one virus is implicated)

THE HCV GENOME AND EXPRESSED POLYPROTEIN

HCV (single-stranded RNA virus) consists of a single open reading frame and two untranslated
regions (UTRs). It encodes a polyprotein of about 3000 amino acids, which is cleaved into single
proteins by a host signal peptidase in structural region and HCV-encoded proteases in the
nonstructural (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 extreme
sequence variability, as the result of selective pressure by virus-specific Abs. E2 also contains the
binding site for CD81, the putative HCV receptor or coreceptor. The nonstructural proteins have
been assigned functions as proteases (NS2, NS3, NS4A), helicase (NS3), and RNA-dependent RNA
polymerase (NS5B). The crystal structure of NS3 and NS5 is known. The function and properties of
other proteins (such as p7) are less characterized. A region in NS5A has been linked to the response
to 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

ETIOLOGY. V. HBV HCV INFECTION
vs
* different timing of onset of HCC in HBV- or
HCV-infection;
- in Asia, HBV acquired at birth via perinatal
transmission, while HCV acquired primarily
during adulthood from transfused blood;
- correspondingly, HCC occurs ~ 1 - 2 decades
earlier in lifelong hepatitis B pts than in adult-
acquired hepatitis C pts (HCC occurs ~ 30 yrs
after HCV infection and almost exclusively in pts
with 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 other
virus coinfection;

* pts with a favorable risk may not have progressive liver disease
until > 30 yrs; in contrast, 20% of pts with chronic hepatitis C,
especially with alcohol abuse or coinfection with HIV type 1 or
HBV, have cirrhosis in ≤ 20 yrs (with a risk of HCC of 1-4% / yr)

ETIOLOGY. VI. OTHER FACTORS
* any factor leading to chronic, low-grade liver
cell damage and mitosis makes hepatocyte
DNA more susceptible to genetic alterations:
- chronic liver disease of any type (alcoholic
liver disease, α1-antitrypsin deficiency,
hemochromatosis, and tyrosinemia);
- mycotoxin aflatoxin B1 is a public health
hazard in Africa and southern China (inducing a
very specific mutation at codon 249 in the
tumor suppressor gene p53)

ETIOLOGY. VI. p53

* loss, inactivation, or mutation of the p53
gene implicated in tumorigenesis and is the
most common genetic derangement present
in human cancers;
- by altering p53, both HBV and aflatoxin B1
enter the pathogenesis of HCC in regions of
Africa and southern China (where both agents
are prevalent)

ETIOLOGY. VII. OTHER FACTORS

* hormonal factors (male predominance of
HCC);
* long-term androgenic steroid administration;
* exposure to thorium dioxide or vinyl chloride,
and
* ?exposure to estrogens as oral contraceptives

PRIMARY HCC

massive

nodular

diffuse

PRIMARY HCC

nodule at hilus

massive tumor, right lobe

HISTOLOGY

CLINICAL FEATURES. I.

* may escape early clinical recognition
because often occurs in pts with underlying
cirrhosis, and symptoms and signs may
suggest progression of cirrhotic disease;
* most common presenting features:
- abdominal pain and / or
- detection of an abdominal mass in right
upper quadrant

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 significant
deterioration of liver function or mechanical
obstruction of the bile ducts, as in
cholangiocarcinoma)

CLINICAL FEATURES
III. PARANEOPLASTIC SYNDROMES
* 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, and
cryofibrinogenemia

LABORATORY FEATURES. I.

* commonly, serum elevations of alkaline
Α
phosphatase and α - fetoprotein (ΑFP);
* presence of an abnormal prothrombin (des-
g-carboxy - prothrombin), correlating with ΑFP
elevations

LABORATORY FEATURES. II. Α-FETOPROTEIN
* levels > 500 µg / L in 70 - 80% of pts;
- lower levels in pts with large metastases from
gastric or colonic tumors and with acute or
chronic hepatitis;
- persistent presence of serum ΑFP > 500 - 1000
ug / L in an adult with liver disease and without
an obvious GI tumor suggests HCC;
- rising ΑFP levels suggest progression of tumor
or recurrence after therapy

IMAGING PROCEDURES
* ultrasound, CT, MRI, hepatic artery
angiography, and radionuclide scans with
technetium 99m;
* ultrasound frequently used to screen high-
risk populations, and
- first procedure (togheter with ΑFP
determination) if HCC is suspected (less costly
than TC, relatively sensitive, able at detecting
most tumors > 3 cm);
* MRI used with increasing frequency

CT SCAN
OF MULTIFOCAL
HEPATOCELLULAR
CARCINOMA

ARTERIOGRAPHY (VARICEAL BLEEDING)

left: 1) hypervascular mass in the liver; 2) massive shunting from
hepativ artery to 3) main portal vein; right: filling of portal vein,
causing variceal bleeding

MANAGEMENT OF GASTROESOPHAGEAL HEMORRHAGE

PERCUTANEOUS LIVER BIOPSY

* diagnostic if sample
taken from an area
localized by ultrasound or
CT;
- caution, because HCC
tends to be vascular;
* cytologic examination of
ascitic fluid negative for
tumor cells

PERCUTANEOUS LIVER BIOPSY

LAPAROSCOPY OR MINILAPAROTOMY

* occasionally, to permit liver biopsy
under direct vision (sometimes to
identifying and staging pts with a
localized resectable tumor)

INTRAHEPATIC DISSEMINATION

LUNG METASTASES

CLINICAL COURSE

* the course of clinically apparent disease is
rapid;
- if untreated, most pts die within 3 - 6 mos of
diagnosis;
- survival of 1 - 2 yrs possible when HCC is
detected very early (by serial screening of
ΑFP and ultrasound);
* in selected cases, therapies may prolong
life

PREVENTION

* preferred strategy:
- hepatitis B vaccine prevents infection and its
sequelae (in Taiwan, reduction of HCC with
universal vaccination of children);
α
* interferon-α therapy lowers the risk of HCC
in pts with hepatitis C - related chronic active
hepatitis and cirrhosis (additional studies
needed)

“SCREENING” PROGRAMS. I.

* to identify small, resectable tumors in pts at
high risk for HCC [hepatitis B surface antigen
(HBsAg) pts+, HCV+ pts and pts with cirrhosis of
any type];
- serial ΑFP determination;
- serial ultrasonography (~ 20 - 30% of pts with
early HCC do not have elevated levels of ΑFP)

“SCREENING” PROGRAMS. II.
* in Far East, screening HBsAg+ persons (with or
without liver disease) identifies pts with small,
subclinical tumors (minimal or no liver disease, tumors
unifocal 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 survival
benefit for screening pts at high risk for HCC

TNM STAGING
Stage I: solitary tumor ≤ 2 cm, with no blood vessel invasion;
Stage II: solitary tumor ≤ 2 cm with vascular invasion, or multiple
tumors in a single lobe none > 2 cm, without vascular invasion, or a
solitary tumor of any size limited to one lobe of liver, without
vascular invasion;
Stage IIIA: solitary tumor > 2 cm with vascular invasion or multiple
tumors limited to one lobe of the liver of any size, with or without
vascular invasion;
Stage IIIB: tumor invades a nearby organ (other than the
gallbladder) or penetrates the lining of the liver;
Stage IVA: multiple tumors in > 1 lobe of the liver or tumors
involving a major branch of portal or hepatic vein (s);
Stage IVB: tumors involving distant metastasis in organs beyond
the liver

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 than
American Joint Cancer Commission TNM system;
- natural history without treatment: stage I = 8
mos; stage II = 2 mos and stage III < 1 mo

SURVIVAL BY STAGE

Okuda TNM

TREATMENT. I. SURGICAL RESECTION
* only chance for
cure;
- however, few pts
with resectable
tumor at diagnosis
(due to underlying
cirrhosis, both
hepatic lobes
nvoved,
metastases to lung,
brain, bone, and
adrenals) - low 5-yr survival

TREATMENT. II. LIVER TRANSPLANTATION
* tumor recurrence or metastases limit its
usefulness;
- but few pts who have a single lesion < 5
cm or ≤ 3 less than 3 cm lesions have the
same survival than liver transplantation for
nonmalignant disease

PRIMARY LIVER TUMORS
LIVER TRANSPLANTATION

LIVER TRANSPLANTATION

PRIMARY LIVER TUMORS
SURVIVAL BY LIVER TRANSPLANTATION

TREATMENT. III. OTHER, MORE USUAL THERAPIES
* hepatic artery embolization (lipiodol) ±
chemotherapy (chemoembolization);
* ultrasound - guided cryoablation;
* alcohol or radio-frequency ablation via
ultrasound - guided percutaneous injection

HEPATIC ARTERY EMBOLIZATION ± CHEMOTHERAPY

THERMOABLATION. I.

THERMOABLATION. II.

TREATMENT. III. EXPERIMENTAL THERAPIES
* immunotherapy with monoclonal
antibodies tagged with cytotoxic agents,
and
* gene therapy with retroviral vectors
containing genes expressing cytotoxic
agents

SUMMARY TREATMENT OF PRIMARY HEPATOCELLULAR CARCINOMA

METASTATIC TUMORS
OF 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

METASTATIC TUMORS
OF THE LIVER

few small nodules

large nodule

from melanoma

mutiple metastases

MELANOMA
METASTATIC
TO THE LIVER

INVOLVEMENT
OF THE LIVER

Hodgkin’s disease

acute leukemias

METASTATIC TUMORS
II. Pathogenesis
* the liver is highly vulnerable to invasion by tumor
cells (the 2nd most common site of metastases after
lymph nodes), due to combination of:
- its size, high rate of blood flow, double perfusion
by hepatic artery and portal vein, Kupffer cell
filtration function and local tissue factors or
endothelial membrane characteristics (enhancing
metastatic implants);
- all neoplasms metastasize to liver (especially
from gastrointestinal tract, lung, breast and
melanoma)

METASTATIC TUMORS
III. Clinical features
* usually, asymptomatic hepatic involvement
discovered during clinical evaluation of pts only
having 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, or
ascites)

METASTATIC TUMORS
IV. Clinical features
* clinical signs of cancer and hepatic
enlargement in pts with widespread liver
involvement (localized induration or
tenderness, a friction rub over tender
areas)

METASTATIC TUMORS
V. Liver laboratory tests
* often abnormal, but usually mild and nonspecific
(reflecting effects of fever and wasting as well as
those 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 from
gastrointestinal tract, breast, or lung

METASTATIC TUMORS
VI. Diagnosis
* liver metastases to be sought actively before
surgery 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 mass
apparent on ultrasound, CT, or MRI;
- usually, definitive diagnosis from needle
biopsies directed by ultrasound or CT or
obtained 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 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?

Liver

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Liver

Similar to Liver (20)

Recently uploaded

Recently uploaded (20)

Liver