Chapter 18: LIVER:MALIGNANT TUMORS

Question 1

Malignant tumors occurring in the liver can be what?

Answer 1

primary or metastatic.

Most of the discussion in
this section deals with primary hepatic tumors.

Question 2

Primary carcinomas of the liver are relatively
uncommon in North America and western Europe (0.5% to 2% of all cancers) but represent 20%
to 40% of cancers in many other countries.

Question 3

Most primary liver cancers arise from where?

Answer 3

hepatocytes
and are termed hepatocellular carcinoma (HCC).

Question 4

Much less common are carcinomas of bile
duct origin, cholangiocarcinomas.

The incidence of these two cancers is increasing in the
United States.

Question 5

Before embarking on a discussion of the major forms of malignancy affecting the liver, two rare
forms of primary liver cancer deserve brief mention:

Answer 5

hepatoblastomas and angiosarcomas.

Question 6

What is Angiosarcoma of the liver?

Answer 6

Angiosarcoma of the liver resembles those occurring elsewhere.

The primary liver form is of interest because of its association with exposure to vinyl chloride, arsenic, or Thorotrast ( Chapters 9 and 11 .

The latency period after exposure to the putative carcinogen may be several decades.

These highly aggressive neoplasms metastasize widely and generally kill
within a year.

Question 7

What is Hepatoblastoma?

Answer 7

Hepatoblastoma is the most common liver tumor of young childhood.

Its incidence, which is
increasing, is approximately 1 to 2 in 1 million births. [74] The tumor is usually fatal within a few
years if not treated.

Question 8

What are the two anatomic variants of Hepatoblastoma?

Answer 8

1. epithelial type
2. mixed epithelial and mesenchymal type

Question 9

What is the epithelial type of hepatoblastoma?

Answer 9

The epithelial type, composed of small polygonal fetal cells or smaller embryonal cells
forming acini, tubules, or papillary structures vaguely recapitulating liver development ( Fig. 18-46 )

Question 10

What is the mixed epithelial and mesenchymal type of hepatoblastoma?

Answer 10

The mixed epithelial and mesenchymal type , which contains foci of mesenchymal
differentiation that may consist of primitive mesenchyme, osteoid, cartilage, or striated
muscle

Question 11

Answer 11

FIGURE 18-46 Hepatoblastoma. The photograph shows proliferating hepatoblasts.

Question 12

What is the characteristic feature of hepatoblastomas?

Answer 12

A characteristic feature of hepatoblastomas is the frequent activation of the WNT/β-catenin
signaling pathway. [75]

Chromosomal abnormalities are common in hepatoblastomas, and FOXG1, a regulator of the TGF-β pathway, is highly expressed in some subsets of the
tumor. [76]

Question 13

Hepatoblastoma may be associated with what?

Answer 13

familial adenomatous polyposis syndrome and Beckwith-Wiedmann syndrome

Question 14

What is the treatment for hepatoblastoma?

Answer 14

The treatment is chemotherapy and complete surgical
resection.

The therapy has raised the 5-year survival to 80%.

Question 15

What is HCC?

Answer 15

On a global basis, there are more than 626,000 new cases per year of primary liver cancer,
almost all being HCC, and approximately 598,000 patients die from this cancer every year, [77]
the third most frequent cause of cancer deaths.

About 82% of HCC cases occur in developing
countries with high rates of chronic HBV infection, such as in southeast Asian and African
countries; 52% of all HCC cases occur in China.

In the United States the incidence of liver
cancer increased by 25% between 1993 and 1998, mainly due to HCV and HBV chronic infection.

There is a clear predominance of males with a ratio of 2.4 : 1.

Question 16

What are the Four major etiologic factors associated with HCC have been established?

Answer 16

• chronic viral infection (HBV, HCV),
• chronic alcoholism,
• non-alcoholic steatohepatitis (NASH), and
• food contaminants (primarily aflatoxins).

Other conditions include tyrosinemia, glycogen storage disease, hereditary hemochromatosis, non-alcoholic fatty liver disease, and α1-antitrypsin deficiency.

Question 17

What are the factors that interact in the development of HCC?

Answer 17

Many factors, including genetic factors, age, gender, chemicals, hormones, and nutrition,
interact in the development of HCC.

Question 18

What disease is most likely to give rise to HCC?

Answer 18

is the extremely rare hereditary tyrosinemia, in which almost 40% of patients develop the tumor
despite adequate dietary control.

Question 19

What is the pathogenesis of HCC?

Answer 19

The pathogenesis of HCC may be different in high-incidence, HBV-prevalent populations versus
low-incidence Western populations, in which other chronic liver diseases such as alcoholism,
non-alcoholic steatohepatitis, chronic HCV infection, and hemochromatosis are more common.

In high-prevalence regions the HBV infection begins in infancy by the vertical transmission of
virus from infected mothers, which confers a 200-fold increased risk for HCC development by
adulthood.

Cirrhosis may be absent in as many as half of these patients, and the cancer often occurs between 20 and 40 years of age.

In the Western world where HBV is not prevalent,
cirrhosis is present in 75% to 90% of cases of HCC, usually in the setting of other chronic liver
diseases.

Thus, cirrhosis seems to be a prerequisite contributor to the emergence of HCC in Western countries but may have a different role in HCC that develops in endemic areas.

In China and southern Africa, where HBV is endemic, there may also be exposure to aflatoxin, a
toxin produced by the fungus Aspergillus flavus, which contaminates peanuts and grains.
Aflatoxin can bind covalently with cellular DNA and cause a specific mutation in codon 249 of
p53 ( Chapter 9 ).

Question 20

What is the biochemical pathogenesis of HCC?

Answer 20

Although the precise mechanisms of carcinogenesis are unknown, several events have been
implicated.

Repeated cycles of cell death and regeneration, as occurs in chronic hepatitis from
any cause, are important in the pathogenesis of HCCs ( Chapter 7 ).

It is thought that the accumulation of mutations during continuous cycles of cell division may damage DNA repair mechanisms and eventually transform hepatocytes.

Preneoplastic changes can be recognized
morphologically by the occurrence of hepatocyte dysplasia.

Progression to HCC might result
from point mutations in selected cellular genes such as KRAS and p53, and constitutive
expression of c-MYC, c-MET (the receptor for hepatocyte growth factor), TGF-α, and insulinlike
growth factor 2.

Recent global gene expression studies revealed that approximately 50% of
HCC cases are associated with activation of WNT or AKT pathways.

A subgroup of tumors
expresses a high proportion of genes present in fetal liver and liver progenitor cells, suggesting
that at least some HCCs may be generated from liver stem cells ( Chapter 3 ).

Question 21

Molecular analysis of tumor cells in HBV-infected individuals showed that most nodules are
what?

Answer 21

.

clonal with respect to the HBV DNA integration pattern, suggesting that viral integration precedes or accompanies a transforming event

In HBV-induced carcinogenesis not only the
disruption of cell genome caused by virus integration but also the site of integration can be
important.

Depending on the integration site, HBV integration may activate proto-oncogenes
that contribute to tumorigenicity.

Alternatively, it has been proposed that the HBV X-protein, a transcriptional activator of multiple genes, might be the main cause of cell transformation.

The
situation is even more uncertain regarding the mechanisms of HCV carcinogenesis.

HCV is a
RNA virus that does not disrupt DNA, and it does not produce oncogenic proteins. However,
there are indications that the HCV core and NS5A proteins may participate in the development
of HCC.

Question 22

What can decrease the incidence of HCC?

Answer 22

Universal vaccination of children against HBV in endemic areas can dramatically decrease the incidence of HBV infection, and most likely, the incidence of HCC.

Such a program, started in
Taiwan in 1984, has reduced HBV infection rates from 10% to less than 1% in 20 years

Question 23

HCC may appear grossly as what?

Answer 23

• (1) a unifocal (usually large) mass ( Fig. 18-47A
• (2) multifocal, widely distributed nodules of variable size; or
• (3) a diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver.

All three patterns may cause liver enlargement, particularly the large unifocal and multinodular patterns. The diffusely infiltrative tumor may blend imperceptibly into a cirrhotic liver background.

Question 24

All patterns of HCCs have a strong propensity for invasion of vascular structures.

T or F

Answer 24

True

HCCs are usually paler than the surrounding liver, and sometimes take on a green hue when composed of well-differentiated hepatocytes capable of secreting bile.

All patterns of HCCs have a strong propensity for invasion of vascular structures.

Extensive intrahepatic metastases ensue, and occasionally, long, snakelike masses of tumor invade the portal vein (with occlusion of the portal circulation) or inferior vena cava, extending even into the right
side of the heart.

HCC spreads extensively within the liver by obvious contiguous growth and by the development of satellite nodules, which can be shown by molecular methods to be derived from the parent tumor.

Metastasis outside the liver is primarily via vascular invasion,
especially into the hepatic vein system, but hematogenous metastases, especially to the lung,
tend to occur late in the disease. Lymph node metastases to the perihilar, peripancreatic, and
para-aortic nodes above and below the diaphragm are found in fewer than half of HCCs that
spread beyond the liver.

If HCC with venous invasion is identified in explanted livers at the
time of liver transplantation, tumor recurrence is likely to occur in the transplanted donor liver.

Question 25

HCCs range from well-differentiated to highly anaplastic undifferentiated lesions.

Answer 25

In welldifferentiated
and moderately differentiated tumors, cells that are recognizable as hepatocytic in origin are disposed either in a trabecular pattern (recapitulating liver cell plates) ( Fig. 18- 7B ) or in an acinar, pseudoglandular pattern.

In poorly differentiated forms, tumor cells can
take on a pleomorphic appearance with numerous anaplastic giant cells, can be small and
completely undifferentiated, or may even resemble a spindle cell sarcoma.

Question 26

What is a distinctive variant of HCC?

Answer 26

A distinctive variant of HCC is the fibrolamellar carcinoma, which was first described in
1956.

This variant constitutes 5% of HCCs

. It occurs in young male and female adults (20 to
40 years of age) with equal incidence.

Patients usually do not have underlying chronic liver
diseases, and so the prognosis is better than the conventional HCC. [80]
The etiology of
fibrolamellar carcinoma is unknown.

It usually presents as single large, hard “scirrhous” tumor with fibrous bands coursing through it.

On microscopic examination it is composed of welldifferentiated polygonal cells growing in nests or cords, and separated by parallel lamellae of
dense collagen bundles.

The tumor cells have abundant eosinophilic cytoplasm and prominent nucleoli ( Fig. 18-48 ).

Question 27

Answer 27

FIGURE 18-47 Hepatocellular carcinoma. A, Liver removed at autopsy showing a unifocal,
massive neoplasm replacing most of the right hepatic lobe in a noncirrhotic liver; a satellite
tumor nodule is directly adjacent. B, Microscopic view of a well-differentiated lesion; tumor
cells are arranged in nests, sometimes with a central lumen.

Question 28

Answer 28

FIGURE 18-48 Fibrolamellar carcinoma.

A, Resected specimen showing a demarcated
nodule in an otherwise normal liver.

B, Microscopic view showing nests and cords of
malignant-appearing hepatocytes separated by dense bundles of collagen.

Question 29

What are the clinical manifestations of HCC?

Answer 29

The clinical manifestations of HCC are seldom characteristic and, in the Western population,
often are masked by those related to the underlying cirrhosis or chronic hepatitis.

In areas of
high incidence such as tropical Africa, patients usually have no clinical history of liver disease,
although cirrhosis may be detected at autopsy.

In both populations most patients have illdefined
upper abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an
abdominal mass or abdominal fullness

. In many cases the enlarged liver can be felt on
palpation, with sufficient irregularity or nodularity to permit differentiation from cirrhosis.

Jaundice, fever, and gastrointestinal or esophageal variceal bleeding are inconstant findings

Question 30

What are the lab findings in HCC?

Answer 30

Laboratory studies may be helpful but are rarely conclusive.

Elevated levels of serum α-
fetoprotein are found in 50% of persons with HCC.

However, false-positive results are
encountered with yolk-sac tumors and many non-neoplastic conditions, including cirrhosis,
massive liver necrosis (with compensatory liver cell regeneration), chronic hepatitis (especially
HCV infection), normal pregnancy, fetal distress or death, and fetal neural tube defects such as
anencephaly and spina bifida.

Laboratory testing for α-fetoprotein and other proteins (such as serum carcinoembryonic antigen levels) often fails to detect small HCC lesions.

Recently,
staining for Glypican-3 has been used to distinguish early HCC from dysplastic nodules. Most
valuable for detection of small tumors are imaging studies: ultrasonography, hepatic
angiography, computed tomography, and magnetic resonance imaging. Molecular analysis of
HCC is actively being pursued and will most likely lead to new HCC classifications that can help
determine treatment options. As already mentioned, some molecular signatures of HCC have
already been identified

Question 31

What is the clinical course of HCC?

Answer 31

The natural course of HCC involves the progressive enlargement of the primary mass until it
seriously disturbs hepatic function, ormetastasizes, generally first to the lungs and then to
other sites.

Question 32

In HCC Overall, death usually occurs from what?

Answer 32

• (1) cachexia,
• (2) gastrointestinal or esophageal
• variceal bleeding,
• (3) liver failure with hepatic coma, or, rarely,
• (4) rupture of the tumor with fatal hemorrhage.

Question 33

What is the prognosis of HCC?

Answer 33

The 5-year survival of large tumors is dismal, with the majority of patients dying within the first 2 years.

With implementation of screening procedures and advances in imaging, the detection of HCCs less than 2 cm in diameter has increased in countries where such facilities are available.

These small tumors can be removed surgically with good prognostic outcomes. Radiofrequency ablation is used for local control of large tumors, and chemoembolization can also be used, according to a clinical algorithm that has been widely
adopted. [82] Recent findings show that the kinase inhibitor sorafenib can prolong the life of
individuals with advanced-stage HCC chemoembolization can also be used, according to a clinical algorithm that has been widely
adopted. [82]

Recent findings show that the kinase inhibitor sorafenib can prolong the life of
individuals with advanced-stage HCC

Question 34

What is cholangiocarcinoma?

Answer 34

Cholangiocarcinoma, the second most common hepatic malignant tumor after HCC, is a
malignancy of the biliary tree, arising from bile ducts within and outside of the liver. [84]

It accounts for 7.6% of cancer deaths worldwide and 3% of cancer deaths in the United States.
The prevalence of the disease in the United States is variable, the highest being in Hispanics
(1.22 per 100,000 population), and the lowest in African-Americans (0.17–0.5 per 100,000).

Question 35

What are the risk factors for the development of CCA?

Answer 35

• primary sclerosing cholangitis (PSC),
• congenital fibropolycystic diseases of the biliary system (particularly Caroli disease and
• choledochal cysts that will be discussed later), HCV infection, and previous exposure to Thorotrast (formerly used in radiography of the biliary tract)

Question 36

.Most cholangiocarcinomas in the Western world, however, arise without evidence of such antecedent conditions.

T or F

Answer 36

True

Question 37

what is the major risk factor of Cholangiocarcinoma in Asia where the incidence rates are higher?

Answer 37

chronic infection of the biliary tract by the liver fluke Opisthorchis sinensis and its close relatives.

According to their
localization, CCAs are classified into intrahepatic and extrahepatic forms

. Eighty to 90% of the
tumors are extrahepatic.

However, the incidence of intrahepatic tumors has increased during the last two decades in the United States, western Europe, and Japan, while the incidence of extrahepatic CCA has remained constant.

The extrahepatic forms include perihilar tumors
known as Klatskin tumors, which are located at the junction of the right and left hepatic ducts
forming the common hepatic duct, and distal bile duct tumors.

A subgroup of distal tumors arise
in the immediate vicinity of the ampulla of Vater. Tumors of this region also include
adenocarcinoma of the duodenal mucosa and pancreatic carcinoma (discussed in Chapters 17
and 19 , respectively) and are collectively referred to as periampullary carcinomas.

Question 38

Fifty to 60% of all CCAs are where?

Answer 38

perihilar (Klatskin) tumors

, 20% to 30% are distal tumors,

and about 10% are intrahepatic.

Question 39

What is the prognosis of CCA?

Answer 39

In any case the prognosis is dismal, with survival rates of about 15% at 2 years after diagnosis.

The median time from diagnosis to death for intrahepatic CCAs is 6 months, even after surgery. Intrahepatic CCAs are not usually detected until late in their course, and come to the attention because of obstruction of bile flow, or as a symptomatic liver
mass.

In contrast, hilar and distal tumors present with symptoms of biliary obstruction, cholangitis, and right upper quadrant pain

Question 40

What is the morphology of extrahepatic CCAs?

Answer 40

Extrahepatic CCAs are generally small lesions at the time of diagnosis.

Most tumors appear as firm, gray nodules within the bile duct wall; some may be diffusely infiltrative
lesions; others are papillary, polypoid lesions.

Most are adenocarcinomas that may or may not
secrete mucin.

Uncommonly, squamous features are present.

For the most part, an abundant
fibrous stroma accompanies the epithelial proliferation. Klatskin tumors generally have slower
growth than other CCAs, show prominent fibrosis, and infrequently involve distal metastases

Question 41

What is the morphology if intrahepatic CCAs?

Answer 41

Intrahepatic CCAs occur in the noncirrhotic liver and may track along the intrahepatic portal
tract system to create a treelike tumorous mass within a portion of the liver.

Alternatively, a massive tumor nodule may develop. In either instance, vascular invasion and propagation
along portal lymphatics may be prominent features, giving rise to extensive intrahepatic
metastasis ( Fig. 18-49A ).

By microscopy, CCAs resemble adenocarcinomas arising in other parts of the body, and they may show the full range of morphologic variation.

Most are well- to
moderately differentiated sclerosing adenocarcinomas with clearly defined glandular and tubular structures lined by cuboidal to low columnar epithelial cells ( Fig. 18-49B ).

These
neoplasms are usually markedly desmoplastic, with dense collagenous stroma separating the glandular elements.

As a result, the tumor substance is extremely firm and gritty. Lymph node
metastasis and hematogenous metastases to the lungs, bones (mainly vertebrae), adrenals,
brain, or elsewhere are present at autopsy in about 50% of cases.

Question 42

Mixed variants occur, in
which elements of both HCC and CCA are present. Three forms are recognized:

Answer 42

• (1) separate tumor masses of HCC and CCA within the same liver;
• (2) “collision tumors,” in which tumorous masses of HCC and CCA commingle at an identifiable interface; and
• (3) tumors in which elements of HCC and CCA are intimately mixed at the microscopic level. These “mixed tumors” are infrequent, but careful microscopic examination of CCAs can often reveal small foci of hepatocellular differentiation.

The HCC-CCA may be generated from a common

bipotential precursor cell (oval cells, Chapter 3 ), capable of producing both hepatocytes and

bile duct epithelial cells (cholangiocytes).

Question 43

Answer 43

FIGURE 18-49 Cholangiocarcinoma.

A, Liver removed at autopsy showing a massive
neoplasm in the right hepatic lobe and innumerable metastases permeating the entire liver.
B, Microscopic view showing tubular glandular structures embedded in a dense sclerotic
stroma.

Question 44

What is the pathogenesis of CCA?

Answer 44

Several signaling pathways, some listed here, are involved in the pathogenesis of CCA.

Among
these is IL-6 overexpression that leads to activation of AKT and the anti-apoptotic protein MCL-1.

Also increased in CCAs is the expression of COX-2, ERB-2, and c-MET.

KRAS expression is
increased in 20% to 100% of cases in different studies, and p53 expression is decreased in
about 40% of cases.

Other alterations involve amplification of epidermal growth factor receptors, and decreases in the expression of the cell cycle regulator and tumor suppressor p16/ink4A.

In addition to cytologic diagnosis, fluorescence in situ hybridization using specific
probes for epidermal growth factor receptors and digital image analysis to determine ploidy are
now being used to improve diagnostic accuracy. Surgery, when possible, is the only treatment
that is potentially curative.

Question 45

What is more common than primary hepatic
neoplasia?

Answer 45

Involvement of the liver by metastatic malignancy is far more common than primary hepatic
neoplasia.

Question 46

What organs are being the visceral organs that are most often involved in the metastatic spread of cancers?

Answer 46

The liver and lungs share the dubious distinction of being the visceral organs that
are most often involved in the metastatic spread of cancers.

Although the most common primary
sources producing hepatic metastases are those of the colon, breast, lung, and pancreas, any cancer in any site of the body may spread to the liver, including leukemias, melanomas, and
lymphomas.

Typically, multiple nodular metastases are found that often cause striking hepatomegaly and may replace over 80% of existent hepatic parenchyma.

The liver weight can
exceed several kilograms. Metastasis may also appear as a single nodule, in which case it may
be resected surgically.

There is a tendency for metastatic nodules to outgrow their blood supply, producing central necrosis and umbilication when viewed from the surface of the liver.

Question 47

Always surprising is the amount of metastatic involvement that may be present in the absence
of clinical or laboratory evidence of hepatic functional insufficiency.

Often the only telltale clinical sign is what?

Answer 47

hepatomegaly, sometimes with nodularity of the free edge. However, with massive
destruction of liver substance or direct obstruction of major bile ducts, jaundice and abnormal
elevations of liver enzymes may appear.

Question 48

END

Chapter 18: LIVER:MALIGNANT TUMORS