Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It is the fifth most common cancer worldwide and the third leading cause of cancer death. The main risk factors are hepatitis B, hepatitis C, alcoholism, and cirrhosis. HCC often develops from chronic liver inflammation and regeneration caused by these conditions. Patients may present with non-specific symptoms like abdominal pain, weight loss, and fatigue. Diagnosis involves blood tests, imaging studies, and biopsy. Prognosis is generally poor, with most patients dying within 2 years from cancer progression or liver failure.

1. Hepatocellular Carcinoma
Lecture 27
HCC
Hepatoma
HCC,,,.2,28,28

2. Epidemiology
• The fifth most common cancer worldwide and the
third most common cause of cancer mortality.
• Because of its high fatality rates, the
incidence and mortality rates are almost equal..
HCC

3. About 82% of HCC cases occur in developing
countries with high rates of chronic HBV infection
(& HCV), such as in southeast Asian and
African countries;
52% of all HCC cases occur in
China.
• There is a clear predominance of males with a
ratio of 2.4 : 1.
HCC

4. Risk factors
The main risk factors for hepatocellular carcinoma
are;
• Alcoholism
• Hepatitis B
• Hepatitis C (25% of causes globally)
• Aflatoxin (Mycotoxin) B1 produced by Aspergillus
flavus
• Cirrhosis of the liver
• Hemochromatosis
• Wilson's disease
• Type 2 Diabetes (probably aided by obesity)HCC

5. • Alpha 1 antitrypsin deficiency
• Chemical carcinogens: butter yellow,
nitrosamines
• Prolonged immunosuppressive therapy
• Other types of viral hepatitis
• Tobacco smoking
• Parasitic infestations: clonorchiasis,
schistosomiasis
HCC

6. HCC

7. Pathogenesis
• Hepatocellular carcinoma develops when
there is a mutation to the
cellular machinery that causes the cell to
replicate at a higher rate and/or results in
the cell avoiding apoptosis.
HCC
UNCERTAIN

8. Pathogenesis
Four major etiologic factors associated with
HCC have been established:
1. Chronic viral infection (HBV, HCV),
2.Chronic alcoholism,
3.Food contaminants (primarily
aflatoxins).
4.Non-alcoholic Steatohepatitis (NASH),
HCC

9. Other conditions include:
• Tyrosinemia, 40%
• Glycogen storage disease,
• Hereditary hemochromatosis,
• Non-alcoholic fatty liver disease, and
• α1-antitrypsin deficiency.
HCC

10. Many factors interact in the development
of HCC, including:
• Genetic factors,
• Age,
• Gender,
• Chemicals,
• Hormones, and
• Nutrition,
HCC

11. Cirrhosis seems to be a prerequisite
contributor to the emergence of HCC in
Western countries.
HCC

12. Pathogenesis
• Repeated cycles of cell death
and regeneration, in chronic
hepatitis damage DNA repair
mechanisms and eventually transform
hepatocytes &
HCC develops.
HCC
Developing countries (endemic areas)

13. •Aflatoxincan bind covalently with
cellular DNA and cause a specific mutation in
p53.
HCC

14. HCC

15. HCC may appear grossly as
(1) unifocal
(2) multifocal,
(3) diffusely
infiltrative/spreading cancer,
HCC

16. 1.Unifocal tumor
AKA Expanding type, most frequently, it forms a
single, yellow-brown, large mass, most often in the
right lobe of the liver with central necrosis,
hemorrhage and occasional bile-staining. It may be
deceptively encapsulated.
HCC

17. 2.Multifocal type
• Less often, multifocal, multiple masses, 3-5 cm in
diameter, scattered throughout the liver are seen.
HCC

18. 3. Infiltrating (Spreading) type
• Rarely, the HCC forms diffusely infiltrating
tumor mass.
HCC

19. • 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.
HCC

20. HCC

21. HCC

22. Liver removed at autopsy showing a unifocal, massive
neoplasm replacing most of the right hepatic lobe in a
noncirrhotic liver;
HCC

23. •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.
HCC

24. • HCC spreads extensively withinthe
liver by obvious contiguous
growth and by the development of
satellite (outpost) nodules, which can be
shown by molecular methods to be
derived from the parent tumor.
HCC

25. •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.
HCC

26. • 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.
HCC

27. HCC

28. • All patterns of HCCs have a strong propensity for
invasion of vascular structures.
Extensive intrahepatic metastases ensue
(develop), 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

29. • 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.
HCC

30. • HCCs range from well-differentiated to highly
anaplastic undifferentiated lesions.
I. In well-differentiated and moderately
differentiated tumors, cells that are
recognizable as hepatocytic in origin are
disposed either in a trabecular
pattern or in an acinar, pseudoglandular
pattern.
HCC

31. Microscopy
• In the better differentiated variants,
globules of bile may be found
within the cytoplasm of cells and in
pseudocanliculi between cells.
HCC

32. Microscopy
• Acidophilic hyaline inclusions
within the cytoplasm may be present,
resembling Mallory bodies. There is
surprisingly scant stroma in most HCCs,
explaining the soft consistency of
these tumors.
HCC

33. II. 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.
HCC

34. Important diagnostic features are:
1.Histologic patterns
2.Cytologic features
HCC

35. Histologic patterns
i) Trabecular or sinusoidal patterns- is the
most common.
The trabecullae are made up of 2-8 cell wide
layers of tumors cells separated by vascular
spaces or sinusoids which are endothelium-
lined.
HCC

36. Histologic Patterns
• ii) Pseudo glandular or acinar
patterns is seen sometimes. The tumor
cells are disposed around central cystic
space formed by degeneration and
breakdown in the trabeculae.
HCC

37. Histologic Patterns
• iii) Compact pattern resembles
trabecular pattern but the tumor cells form
large solid masses with
conspicuous sinusoids.
HCC

38. • iv) Scirrhous pattern is characterised by
more abundant fibrous stroma.
HCC

39. 2. Cytologic features:
• The typical cytologic features in the HCC
consist of
cells resembling hepatocytes having
vesicular nuclei with prominent
nucleoli.
HCC

40. • The cytoplasm is granular and
eosinophilic
but becomes increasingly basophilic
with increasing malignancy.
HCC

41. Aside from these features, a few others
cytologic variants are:
• Pleomorphism,
• Bizarre giant cell formation,
• Spindle-shaped cells,
• Tumor cells with clear cytoplasm,
• Presence of bile within dilated canaliculi, and
• Inracytoplasmic mallory’s hyline.
HCC

42. HCC

43. Microscopic view of a well-differentiated lesion; tumor
cells are arranged in nests, sometimes with a central
HCC

44. HCC

45. HCC

46. HCC

47. Fibrolamellar Carcinoma
• This variant constitutes 5% of HCCs. It
occurs in young male and female adults
(20 to 40 years of age) with equal
incidence.
HCC

48. • Patients usually do not have underlying
chronic liver diseases, and so the
prognosis is better than the
conventional HCC.
HCC

49. • The etiology of fibrolamellar carcinoma is
unknown.
• It usually presents as
• single large, hard “scirrhous” tumor with
fibrous bands coursing through it.
HCC

50. On microscopic examination it is composed of
well-differentiated 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 .
HCC

51. Fibrolamellar carcinoma. A, Resected specimen
showing a demarcated nodule in an otherwise normal liver
HCC

52. HCC

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

54. •Part II,• Lecture 28
HCC

55. Recap
• The main primary tumor is HCC
• More common (82%) in Asia & Africa.
• The main etiologic agents for HCC are
hepatitis B, C, alcoholic cirrhosis,
hemochromatosis, and more rarely,
tyrosinemia.
HCC

56. • In the western population about 90% of HCC
develop in cirrhotic livers;
• In Asia almost 50% of cases develop in
noncirrhotic livers.
HCC

57. • The chronic inflammation and cellular
regeneration associated with viral hepatitis
may be predisposing factors for development
of carcinomas.
HCC

58. • Hepatocellular carcinomas may be unifocal or
multifocal, tend to invade blood vessels, and
recapitulate normal liver architecture to
varying degrees.
HCC

59. Clinical Features
• 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.
HCC

60. • 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.
HCC

61. • In both populations most patients have
• ill-defined upper abdominal pain,
• malaise,
• fatigue,
• weight loss, and
• sometimes awareness of an abdominal mass
or abdominal fullness.
HCC

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

63. • Jaundice,
• fever, and
• gastrointestinal or esophageal variceal
bleeding
are inconstant findings.
HCC

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

65. • Recently, staining for Glypican-3 has
been used to distinguish early HCC
from dysplastic nodules.
HCC

66. Imaging studies
• Most valuable for detection of small tumors
are imaging studies:
• Ultrasonography,
• Hepatic angiography,
• Computed tomography, and
• Magnetic resonance imaging.
HCC

67. Prognosis
Overall, 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.
HCC

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

69. • 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.
HCC

70. Treatment
• 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.
HCC

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

72. Primary billiary cirrhosis
Secondary billiary cirrhosis
HCC

73. Primary Billiary Cirrhosis
• PBC is an inflammatory autoimmune disease
mainly affecting the intrahepatic bile ducts.
The primary feature of this disease is a
nonsuppurative, inflammatory destruction of
medium-sized intrahepatic bile ducts. It is
accompanied by portal inflammation,
scarring, and eventual development of
cirrhosis and liver failure
HCC

74. Secondary billiary cirrhosis
• Secondary biliary cirrhosis is a condition
resulting most often from uncorrected
obstruction of the extrahepatic biliary tree.
HCC

75. HCC

76. HCC