HCC Malignant Tumor Derived From Hepatocytes or Their Precursors

HCC
Malignant tumor derived from hepatocytes or their precursors.

INCIDENCE- highest incidences of HCC are found in Asian countries (southeast China,
Korea, Taiwan) and sub-Saharan African countries due to prevalence of Vertical
transmission of HBV and exposure to alfatoxin.
PEAK INCIDENCE- b/w 20 and 40 yrs of age, and in almost 50% of cases, the tumor
appears in the absence of cirrhosis in Asian endemic countries.
Western countries- 60 yrs/after cirrhosis/hep c pandemic.
SEX FACTOR- M>F
3:1 in low incidence areas and 8:1 in high incidence areas.
PATHOGENESIS-
Chronic liver diseases are the most
common setting for emergence of HCC in a background of cirrhosis, progression to
cirrhosis and hepatocarcinogenesis take place in parallel over years to decades.
Factors in hepatocarcinogenesis:
● viral infections (HBV, HCV)
● toxic injuries (aflatoxin, alcohol). 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
aflatoxin albumin adducts in serum. This helps to identify the populations at
risk and confirm the important influence of aflatoxin for hepatocarcinogenesis.
Aflatoxin and alcohol also synergizes with HBV/HCV to increase risk further.
● Cigarette smoking.
● Metabolic diseases such as hereditary hemochromatosis
and α1AT deficiency markedly increase the risk of HCC.
● Wilson disease, metabolic syndrome associated with obesity, diabetes
mellitus, and nonalcoholic fatty liver disease, increase the risk
of HCC.
● Activation of β-catenin and inactivation of p53 are the two most common early
mutational events. β-catenin mutations in up to 40% of persons with
HCC,unrelated to HBV and to demonstrate genetic instability. Inactivation of
p53 is present in up to 60% of HCC strongly associated
with aflatoxin. Neither of these alterations, however, is
found in premalignant lesions.
● Role of inflammation- IL-6 is an inflammatory cytokine that is overproduced in
many chronic hepatitides which can suppress hepatocyte differentiation and
promote their proliferation by regulating the function of the transcription factor
HNF-4α.
PREMALIGNANT LESIONS OF HCC

1.Hepatocellular adenoma particularly those with Beta-catenin activating mutations.
2. Cellular dysplasias in chronic liver disease: seen in chronic liver disease, before or
after development of cirrhosis.
● Small-cell change: is probably premalignant. These liver cells have high
nuclear–cytoplasmic ratio and mild nuclear hyperchromasia and/or
pleomorphism.Hepatocytes exhibiting small cell change often form tiny expansile
nodules within a single parenchymal lobule.In Hepatocytes exhibiting small cell
change often form tiny expansile nodules within a single parenchymal lobule.
● Large-cell change: is a marker of increased risk of HCC in the liver and in hepatitis
B. They may also
be directly premalignant. These cells larger than normal liver cells having large, multiple,
moderately pleomorphic nuclei with normal nuclear–cytoplasmic ratio.Large cell change
shows scattered hepatocytes, usually near
portal tracts or septa.
3. Dysplastic nodules: These are nodules having different appearance than cirrhotic
nodules, that are usually detected radiologically or in resected specimens of
cirrhosis.
● Low-grade dysplastic nodules: They may or may not transform to higher grade
lesions, but they are indicator of higher risk for HCC. They don’t have cytological or
architectural atypia but have been shown to be clonal and are
probably neoplastic, rather than simply large cirrhotic nodules.Portal tracts are still
present within these nodules, often in near cancer, permeating widely and sometimes
involving the entire
liver.
● High-grade dysplastic nodules: Important precursors of HCC in viral hepatitis and
alcoholic liver disease.
The cells of these nodules have cytological (e.g., small cell change) or architectural features
suggestive of, but not sufficient for diagnosis of frank HCC.
MORPHOLOGY OF HCC:
GROSS
Three patterns. All patterns may cause enlargement of the liver.
1. Small cell change.
2. Large cell change.
3. Low dysplastic nodules.
HCCs may be pale compared to surrounding liver or they may have a variegated
appearance reflecting different differentiation states:
● white - abundant stroma,
● yellow -fatty change predominates,
● green-well-differentiated malignant hepatocytes make abundant bile).
MICROSCOPY
HCC graded as well-differentiated,moderately differentiated, and undifferentiated
(pleomorphic) forms.
1. Well-differentiated HCC: Tumor cells can be recognizable as hepatocytic in origin. Bile
production by tumor cells is the hallmark of HCC. Tumor cells are arranged in trabecular and
acinar (pseudoglandular) patterns.
2. Moderately differentiated HCC: This grade may show solid, scirrhous, and clear-cell
pattern with rare bile production.
3. Poorly or undifferentiated HCC: It consist of pleomorphic cells with great variation in size
and shape. The nuclei also are extremely variable in size and shape. Many bizarre-looking
anaplastic giant cells can be seen.
METASTASIS:
1. Local spread: HCC may first spread within the liver itself and develop satellite
nodules. Intrahepatic metastases (by vascular invasion/direct extension) more likely
to occur when the size of tumors reach 3 cm. Local invasion of the diaphragm is
common.
2. Lymphatic spread: HCC may spread to portal lymph nodes, perihilar, peripancreatic,
and para-aortic nodes.
3. Blood spread: All patterns of HCCs have a strong tendency for invasion of vessels
and may result in extensive intrahepatic metastases.The portal vein and its branches
are infiltrated by tumors.Occasionally, long, snake-like tumor masses may invade the
portal vein and occlude portal circulation.Rarely, tumor may invade IVC and extend
into the right side of the heart through the hepatic veins.It may metastasize to the
lungs.If venous invasion is identified in HCC-bearing explanted livers at the time of
transplantation, tumor recurrence is likely to occur in the transplanted liver due to
seeding of circulating tumor cells in the transplant recipient. Such lesions may appear
months after the operation.
FIBROLAMELLAR VARIANT OF HCC

A distinctive variant of HCC constituting less than 5% of HCCs.
OCCURRENCE- under the age
of 35 years and M=F.
Etiology- unknown. It usually presents as single large, hard“scirrhous” tumor with fibrous
bands coursing through it.
Microscopy- they are composed of well-differentiated cells rich in mitochondria (oncocytes)
growing in nests or cords
separated by parallel lamellae of dense collagen bundles.
BETTER PROGNOSIS THAN HCC and have normal AFP levels.Neurotensin is the
marker.
CLINICAL FEATURES- Most patients present with ill-defined upper abdominal pain,
malaise, fatigue and weight loss.On examination,hepatomegaly,irregular/
nodular liver.
DIAGNOSTIC MARKERS
1.ALPHA FETO PROTEIN LEVELS INCREASED( non specific)
2. ARGINASE INCREASED (specific)
3.HEP-PAR-1
4.GLYPICAN 3
5.Biopsy is not investigation of choice IOC due to 3% risk of spread.
6.IOC - Radiological investigation
USG
Multidetector 4 phase CT scan - shows arterial hypervascularity and venous washout.
Cause of Death
Cachexia,Gastrointestinal or esophageal variceal bleeding,Liver failure with hepatic coma,
Rupture of the tumor with fatal hemorrhage (rare).

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HCC

Malignant tumor derived from hepatocytes or their precursors.

PREMALIGNANT LESIONS OF HCC

FIBROLAMELLAR VARIANT OF HCC

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