1. Liver Tumors
Karun Bhattarai (MBBS)
B.P. Koirala Institute of Health Sciences, Dharan, Nepal

2. Nodules
• Hepatic masses may come to attention for a variety of reasons. They may
generate epigastric fullness and discomfort or be detected by routine
physical examination or radiographic studies for other indications. Hepatic
masses include:
• nodular hyperplasia and true neoplasms

3. Nodular Hyperplasia
• Solitary or multiple hyperplastic hepatocellular nodules may develop in
the noncirrhotic liver.
Two such conditions are:
focal nodular hyperplasia and nodular regenerative hyperplasia.
The common factor in both types of nodules seems to be either focal or
diffuse alterations in hepatic blood supply, arising from obliteration of portal
vein radicles and compensatory augmentation of arterial blood supply.

8. Benign Neoplasm

9. Cavernous Hemangioma
• Cavernous hemangiomas, blood vessel tumors identical to those
occurring elsewhere, are the most common benign liver tumors.
• Benign tumor of the liver composed of a proliferation of widely dilated blood
vessels.
They appear as discrete red-blue, soft nodules, usually less than 2 cm in
diameter, generally located directly beneath the capsule.
Histologically, the tumor consists of
vascular channels in a bed of fibrous connective tissue (Fig. 18-52). Their
chief clinical significance is that they might be mistaken radiographically or
intraoperatively for metastatic tumors.

10. • Rare cause of intraperitoneal hemorrhage.
• Best diagnosed with an enhanced CT scan

12. Hepatocellular Adenomas
• Benign neoplasms developing from hepatocytes are called hepatocellular
adenomas (Fig. 18-53).
• Benign hormone-induced liver tumor that has a predilection to hemorrhage
into the peritoneal cavity

13. • They may be detected incidentally with abdominal imaging or when
they cause abdominal pain from their rapid growth, causing pressure
on the liver capsule, or following hemorrhagic necrosis as the lesion
outstrips its blood supply.

14. • Rupture of hepatocellular adenomas may lead to intraabdominal
bleeding that is a surgical emergency.

15. • Three large subtypes have been defined on the basis of molecular
analysis and associated clinical and pathologic findings, each with a
different relative risk of malignant transformation

16. • . Both oral contraceptives and anabolic steroids are associated with
the development of these adenomas.

17. • In fact before the advent of oral contraceptives, hepatocellular
adenomas were virtually unknown.

18. • The risk of developing these tumors is increased 30-40 fold in users of
oral contraceptives.

19. • The highest risk is from prolonged use of estrogen rich oral
contraceptives

20. • If surgery is not possible or is ill advised, cessation of exposure to sex
hormones often can lead to full regression.

21. • Epidemiology of liver cell adenoma
(1) More common in women than in men
(2) Causes include:
(a) OCPs (most common cause). Risk for adenoma correlates with duration of use and age
older than 30 years.
(b) anabolic steroids.
(c) Von Gierke glycogenosis.
(3) Highly vascular tumors that have a tendency to rupture during menstruation or pregnancy,
causing intraperitoneal hemorrhage (30%) and possible death of the patient
(4) Tend to regress if the patient stops taking OCPs or anabolic steroids
(5) May transform into HCC; risk is greatest if they are >4 to 5 cm.
Surgical removal is usually recommended because of their risk for hemorrhage

22. Pathogenesis
Three large subtypes have been defined on the basis of molecular analysis
and associated clinical and pathologic findings, each with a different relative
risk of malignant transformation:

25. HNF1-α Inactivated hepatocellular adenomas
Ninety percent of these tumors have inactivating mutations of HNF1-α that
are somatic, while 10% have germline mutations. HNF1-α encodes a
transcription factor. Heterozygous germline mutations are responsible for
autosomal dominant MODY-3 (maturity onset diabetes of the young, type
3). Patients with MODY-3 who develop hepatocellular adenomas have
acquired a second somatic mutation. These lesions are most commonly
found in women. Oral contraceptive pills are implicated in some.

27. β-Catenin Activated Hepatocellular Adenomas
Activating mutations of β-catenin are associated with neoplasia and
malignancy in many organs. In the liver they may give rise to hepatocellular
adenomas that are considered at very high risk for malignant
transformation and should be resected even when asymptomatic. They are
associated with oral contraceptive and anabolic steroid use. They are
found in men and women.

29. Inflammatory hepatocellular adenomas
These lesions are found in both men and women and are associated with non-
alcoholic fatty liver disease; thus, their incidence seems to be increasing. They
have a small but definite risk of malignant transformation and should probably
be resected even when asymptomatic. They are characterized by activating
mutations in gp130, a co-receptor for IL-6, that lead to constitutive JAK-STAT
signaling and overexpression of acute phase reactants, which you will recall are
normally upregulated in systemic inflammatory states. As will be discussed
later, IL-6 mediated JAK-STAT signaling has also been linked to the pathogenesis
of hepatocellular carcinoma, and undoubtedly explains the inflammatory
background that characterizes this subtype of hepatocellular adenoma. Ten
percent of inflammatory hepatocellular adenomas also have concomitant β-
catenin activating mutations and these tumors have a higher risk of malignant
transformation.

31. Malignant Tumors

32. • Malignant tumors occurring in the liver can be primary or metastatic.
Most of the discussion in this section deals with primary hepatic tumors.
Most primary liver cancers arise from hepatocytes and are termed
hepatocellular carcinoma (HCC). Much less common are carcinomas of
bile duct origin, cholangiocarcinomas.
• Before embarking on a discussion of the major forms of malignancy
affecting the liver, a rare form of primary liver cancer, hepatoblastoma
deserves a brief discussion.

33. Hepatoblastoma
• Hepatoblastoma is the most common liver tumor of early childhood. It is
rarely occurs over the age of 3 years. Its incidence, which is increasing, is
approximately 1 to 2 in 1 million births. Two primary anatomic variants are
recognized:
1. The epithelial type, composed of small polygonal fetal cells or smaller
embryonal cells forming acini, tubules, or papillary structures vaguely
recapitulating liver development (Fig. 18-55)
2. The mixed epithelial and mesenchymal type, which contains foci of
mesenchymal differentiation that may consist of primitive mesenchyme,
osteoid, cartilage, or striated muscle

35. • A characteristic feature of hepatoblastomas is the frequent activation of the
WNT signaling pathway. This occurs by a variety of mechanisms involving
mutations in molecules downstream of WNT signaling, including mutations in
APC gene. Patients with Familial adenomatous polyposis frequently develop
hepatoblastomas. Sporadic cases have activation of the beta-catenin signaling
through other mechanisms. Chromosomal abnormalities are common in
hepatoblastomas, and FOXG1, a regulator of the TGF-β pathway, is highly
expressed in some tumors. Hepatoblastoma may be associated Beckwith-
Wiedemann syndrome as well. The treatment is sugical resection and
chemotherapy. Untreated, the tumor is usually fatal within a few years, but
therapy has raised the 5-year survival to 80%.

36. Hepatocellular Carcinoma (HCC)
• Worldwide, HCC (also known erroneously as hepatoma) accounts for
approximately 5.4% of all cancers, but its incidence varies widely in
different parts of the world. More than 85% of cases occur in countries
with high rates of chronic HBV infection. The highest incidences of HCC are
found in Asian countries (southeast China, Korea, Taiwan) and sub-
Saharan African countries. In these locales, HBV is transmitted vertically
and, as already discussed, the carrier state starts in infancy. The peak
incidence of HCC in these areas is between 20 and 40 years of age, and in
almost 50% of cases, the tumor appears in the absence of cirrhosis. As
discussed later, many of these populations are exposed to aflatoxin, which
is also a carcinogen (Chapter 7). The risk of HCC is decreasing in China,
Singapore and Hong Kong, most likely due to institution of hepatitis B
vaccination.

39. Pathogenesis
• Chronic liver diseases are the most common setting for emergence of HCC. While
usually identified in a background of cirrhosis, cirrhosis per se is not a premalignant
lesion. Indeed, cirrhosis is not required for hepatocarcinogenesis (Fig. 18-56).
Rather, progression to cirrhosis and hepatocarcinogenesis take place in parallel over
years to decades.
The most important underlying factors in hepatocarcinogenesis are viral infections
(HBV, HCV) and toxic injuries (aflatoxin, alcohol). Thus where HBV and HCV are
endemic, there is a very high incidence of HCC. Co-infection further increases risk. In
Africa and Asia, aflatoxin, produced by Aspergillus species, is a mycotoxin that
contaminates staple food crops. Aflatoxin metabolites are present in the urine of
affected individuals as are aflatoxinalbumin adducts in serum. This helps to identify
the populations at risk and confirm the important influence of aflatoxin for
hepatocarcinogenesis. Aflatoxin also synergizes with HBV (perhaps also with HCV) to
increase risk further. Alcohol is another toxin which probably, by itself, is a risk factor
for HCC, but it also synergizes with HBV and HCV, and even, possibly, cigarette
smoking.

40. • Metabolic diseases such as hereditary hemochromatosis and α1AT deficiency markedly
increase the risk of HCC. Wilson disease probably does so with much less frequency. Of
probably greater import is the metabolic syndrome associated with obesity, diabetes
mellitus, and nonalcoholic fatty liver disease, all of which increase the risk of HCC.
• No single, universal sequence of molecular or genetic alterations leads to emergence of HCC.
Activation of β-catenin and inactivation of p53 are the two most common early mutational
events. Activating β-catenin mutations are identified in up to 40% of persons with HCC. These
tumors are more likely to be unrelated to HBV and to demonstrate genetic instability.
Inactivation of p53 is present in up to 60% of HCC cases. These tumors are strongly
associated with aflatoxin. Neither of these alterations, however, is found in premalignant
lesions.

41. • Recent evidence has provided some novel insights into the role of HBV, HCV,
alcoholic liver disease and other states of chronic inflammation in the
pathogenesis of HCC. Traditional thinking has been that cycles of cell death and
regeneration in chronic inflammatory states increases the risk of mutations in
regenerating hepatocytes. But the precise molecular mechanisms of such
changes have remained obscure. More recent studies implicate a role for
signaling through the IL-6/JAK/STAT pathway in the causation of HCC. IL-6 is an
inflammatory cytokine that is overproduced in many chronic hepatitides. Based
on some preliminary experiments, it has been proposed that IL-6 can suppress
hepatocyte differentiation and promote their proliferation by regulating the
function of the transcription factor HNF4-α. In keeping with this, hepatic
carcinogenesis can be suppressed by uncoupling HNF4-α from the control of IL-
6, in experimental animals. More studies are needed to determine the
significance of IL-6/HNF4-α signaling axis in human HCC

42. Precursor Lesions of HCC
• Several cellular and nodular precursor lesions to HCC have been identified
(Table 18-12). Hepatocellular adenoma has already been discussed, in
particular those with β-catenin activating mutations. In chronic liver disease
there are cellular dysplasias, called large cell change and small cell change (Fig.
18-57). These may be found at any stage of chronic liver disease, before or
after development of cirrhosis, and serve as markers in biopsy specimens to
indicate which patients need more aggressive cancer surveillance. Small cell
change is thought to be directly premalignant. Large cell change is at least a
marker of increased risk of HCC in the liver as a whole, but in hepatitis B they
may also be directly premalignant.

43. • Dysplastic nodules are usually detected in cirrhosis, either radiologically or in
resected specimens (including explants). These are nodules that have a
different appearance from the surrounding cirrhotic nodules (Fig. 18-58). The
differences are in size or vascular supply (increasingly arterial with increasingly
high grade, a defining feature in contrast radiologic studies) or other aspects
of appearance (color, texture). Low-grade dysplastic nodules, may or may not
undergo transformation to higher grade lesions, but they at least indicate a
higher risk for HCC in the liver as a whole. High-grade dysplastic nodules are
probably the most important primary pathway for emergence of HCC in viral
hepatitis and alcoholic liver disease. Subnodules of HCC are often found in
high-grade dysplastic nodules in biopsy or resection specimens.

54. Clinical Features
• masked by those related to the underlying cirrhosis or chronic hepatitis.
• In areas of high incidence of aflatoxin exposure, patients usually have no
clinical history of liver disease.
• most patients have ill-defined upper abdominal pain, malaise, fatigue,
weight loss, and sometimes awareness of hepatomegaly or an
abdominal mass or abdominal fullness. Jaundice, fever, and
gastrointestinal or esophageal variceal bleeding are inconstant findings.

55. Diagnosis
• Imaging studies: ultrasonography to identify distinctive nodules of all kinds,
and computed tomography and magnetic resonance imaging with
vascular/contrast studies.
• The increasing arterialization in the process of conversion from high grade
dysplastic nodule to early HCC and then to fully developed HCC, form the basis
of diagnostic imaging. HCC, even when small, has such characteristic vascular
changes that imaging can be diagnostic.

56. • The natural course of HCC involves the progressive enlargement of
the primary mass until it disturbs hepatic function or metastasizes to
the lungs or to other sites. Death usually occurs from (1) cachexia, (2)
gastrointestinal or esophageal variceal bleeding, (3) liver failure with
hepatic coma, or, rarely, (4) rupture of the tumor with fatal
hemorrhage. The 5-year survival of large tumors is dismal, the
majority of patients dying within the first 2 years.

57. Treatment:
• small tumors can be removed surgically or ablated (e.g., through
embolization or with microwave radiation or freezing) with good outcomes.
• Radiofrequency ablation is used for local control of large tumors, and
chemoembolization can also be used.

58. Cholangiocarcinoma
• Cholangiocarcinoma (CCA), the second most common primary malignant
tumor of the liver after HCC, is a malignancy of the biliary tree, arising
from bile ducts within and outside of the liver. It accounts for 7.6% of
cancer deaths worldwide and 3% of cancer deaths in the United States.
However, in some regions of Southeast Asia such as northeastern Thailand,
Laos, and Cambodia where infestation with liver flukes is endemic,
cholangiocarcinoma is more common than hepatocellular carcinoma.

59. Risk Factors:
• Infestation by liver flukes (particularly Opisthorchis and Clonorchis species),
• chronic inflammatory disease of the large bile ducts, such as primary
sclerosing cholangitis, hepatolithiasis, and fibropolycystic liver disease.
• It should be noted that patients with hepatitis B and C, and non alcoholic
fatty liver disease, not only have a higher risk of developing HCC, but also of
cholangiocarcinoma. Globally, cholangiocarcinomas are most often sporadic
and not associated with any preexisting condition.

60. Types:
• intrahepatic or
• extrahepatic.

61. • extrahepatic forms include perihilar tumors known as Klatskin tumors, which are
located at the junction of the right and left hepatic ducts. Fifty percent to 60% of
all cholangiocarcinomas are perihilar (Klatskin) tumors, 20% to 30% are distal
tumors, arising in the common bile duct where it lies posterior to the duodenum.
The remaining 10% are intrahepatic. Regardless of site, the prognosis is dismal,
with survival rates of about 15% at 2 years after diagnosis for extrahepatic tumors.
The median time from diagnosis to death for intrahepatic CCAs is 6 months, even
after surgery because intrahepatic CCAs are not usually detected until late in their
course. They 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.

62. • Premalignant lesions for cholangiocarcinoma are also known, the most
important of which are biliary intraepithelial neoplasias (low to high
grade, BilIN-1, -2, or -3). BilIN-3, the highest grade lesion, incurs the
highest risk of malignant transformation. More rare are mucinous cystic
neoplasms and intraductal papillary biliary neoplasia

66. Other Primary Hepatic Malignant Tumors
• combined hepatocellular and cholangiocarcinoma, suggesting an origin
from a multipotent stem cell. Mucinous cystic neoplasms and intraductal
papillary biliary neoplasia may occur as in situ lesions or as invasive
cholangiocarcinoma.

67. • Angiosarcoma of the liver resembles those occurring elsewhere and has
historical associations with vinyl chloride, arsenic, or Thorotrast, although
with reduced exposures to these compounds in recent decades, this
malignancy is becoming very rare. Epithelioid hemangioendothelioma,
another form of endothelial malignancy, has a much more variable prognosis
than the almost uniformly fatal angiosarcoma. Hepatic lymphomas are
primarily diseases of middle aged men and are seen, albeit rarely, in
association with hepatitis B and C, HIV, and PBC. Most are diffuse large B-cell
lymphomas, followed by MALT lymphomas. Hepatosplenic delta-gamma T cell
lymphoma, most common in young adult males, has a predilection for hepatic
and splenic sinusoids as well as the marrow.

68. Metastasis
• Involvement of the liver by metastatic malignancy is far more common than
primary hepatic neoplasia. Although the most common primary sources are the
colon, breast, lung, and pancreas, any cancer in any site of the body may spread
to the liver. Typically, multiple nodular metastases are found that often cause
striking hepatomegaly and replace much of the normal liver parenchyma. The
liver weight can exceed several kilograms. Metastasis may also appear as a single
nodule, in which case it may be resected surgically. 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 hepatomegaly. However, with massive destruction of liver
substance or direct obstruction of major bile ducts, jaundice and elevations of
liver enzymes may appear.