HCC is the fifth most common cancer in the world. The incidence of HCC has doubled in the United States over the past 25 years and the incidence and mortality rates of HCC seem likely to double again over the next 10–20 years.
Epidemiology
Primary Liver Cancer, or Hepatocellular Carcinoma (HCC) is the fifth most common neoplasm in the world, and the third most common cause of cancer-related death.
It is estimated that every year more than 500,000 new cases are diagnosed worldwide, amounting to approximately 5.6 percent of all human cancers.
Most HCCs arise in liver cirrhosis through progressive malignant transformation of cirrhotic nodules. Among them, large parenchymal nodules, also called macronodules, represent an early step in the carcinogenesis pathways of HCC.
According to histopathology, cirrhotic macronodules are categorized as benign, dysplastic (low or high grade), and malignant. Although grading of macronodules has been described in detail, classification of borderline macronodules is sometimes challenging for pathologists.
Macroscopy
Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, grey or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).
Microscopy
In well differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords and nests, and may contain bile pigment in cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.
Growth pattern
- trabecular (Typical trabecular pattern of growth of liver cell carcinoma)
- solid (or compact)
- tubular
- These should not be interpreted as evidence of a bile duct carcinoma component.
- also referred to as pseudoglandular or acinar and may result in papillary-like formations.
A network of sinusoidal vessels surrounds tumor cells.
- important diagnostic feature
- some sinusoids seem to be lined by tumor cells.
- The widely dilated sinusoids of this liver cell carcinoma result in sharply outlined tumor islands which are very typical of the entity.
Thickness of the trabeculae
- great diagnostic significance as estimated in H&E sections, but better evaluated in reticulin stains
- the thicker the hepatocytic plates, the more likely the diagnosis of carcinoma
Stroma
- usually scanty
Wide range of differentiation
- less well differentiated:
- considerable pleomorphism
- bizarre mitotic figures
- tumor giant cells
- prominent nuclei and nucleoli
- scanty and basophilic cytoplasm
- may be difficult or impossible to identify as liver cell carcinoma
- better differentiated:
- easily recognizable hepatocytes
- may be difficult to categorize as malignant, particularly at the interphase between tumor and normal liver, in which the former may show a well-developed normotrabecular pattern
- the only clue to the malignant nature of the lesion may be an occasional cluster of enlarged hyperchromatic nuclei, an atypical mitotic figure, a blood vessel with a thrombus
Tumor cells
- often exhibit intranuclear pseudoinclusions caused by cytoplasmic invaginations
- cytoplasm may contain:
- Mallory’s hyaline (similar to that in alcoholic liver disease)
- round hyaline globules (some containing α-fetoprotein and others α1-antitrypsin) which the major constituent is p62, a phosphotyrosine-independent ligand of p561 ck kinase
- copper
- ‘pale bodies’ (seen ultrastructurally as a membrane-bound mass of granular or fibrillary material immunoreactive for fibrinogen)
- bile pigment - an important diagnostic feature
- copper and copper-binding proteins
- Rarely, the tumor can be black due to accumulation of a Dubin-Johnson-like pigment.
Bile canalicular structures (Canalicular formations in liver cell carcinoma) between tumor cells
- important diagnostic feature
- demonstrated in cytologic or histologic preparations with stains for alkaline phosphatase, biliary glycoprotein (using a polyclonal antibody for CEA, which cross reacts with this marker), CD10 (neprilysin), low-molecular-weight keratin
- Canalicular formations in liver cell carcinoma can be demonstrated immunohistochemically with polyclonal CEA.
Commonly invasion of veins in the portal tract
Rarely, focal neuroendocrine differentiation:
- analogous to that in most glandular epithelial tumors of other organs
- not to be equated with carcinoid tumor/neuroendocrine carcinoma
Kuppfer cells
- may be present
- usually scanty and irregularly distributed
Ultrastructure
recapitulates the normal adult hepatocyte
Malignant hepatocyte with numerous mitochondria, microbodies, and abundant glycogen. Cells also contain intracytoplasmic bile products.
Bile canaliculus with stubby microvilli and cell junctions of the tight and intermediate types.
Clusters of electron-dense glycogen particles are also evident.
vessels have features of true capillaries (unlike the sinusoids of normal liver)
Types
Microscopically, there are four architectural and cytological subtypes of hepatocellular carcinoma:
fibrolamellar
pseudoglandular (adenoid)
pleomorphic (giant cell)
clear cell.
childhood hepatocellular carcinoma
fibrolamellar hepatocellular carcinoma
spindle cell hepatocellular carcinoma
clear cell hepatocellular carcinoma
giant cell hepatocellular carcinoma
combined hepatocellular carcinoma
hormonally active hepatocellular carcinoma
carcinosarcoma
sclerosing hepatocellular carcinoma
Predisposing lesions
cirrhosis
multilobular hepatic adenoma (8385884)
Loci involved
1p34 LOH
3p22-p21
7q31
8p22-p21.3
9p21.3-p21.2
15q21.1-q22.2
16p13.3
16q23 LOH (11526514)
17p13.1
somatic mutations of TP53 (MIM.191170)
somatic mutations of MET (MIM.164860) (juvenile type hepatocellular carcinoma)
anomalies of the WNT signaling pathway
- somatic mutations of CTNNB1 (MIM.116806)
- somatic mutations of AXIN1 (MIM.603816)
- somatic mutations of APC (16897741)
Allelotyping (LOH) (16102588, 15918185)
| LOH | % | Inactivated Gene |
| 1p34 LOH | 70% | - |
| 4q | 71% | - |
| 7 | ||
| 8p | 66% | - |
| 13q | ||
| 16q23 | 66% | - |
| 17p13 LOH | 64% | TP53 |
| 19q | ||
| X |
CGH
| Losses | -1p | -4q | -7 | -8p | -13q | -16q | -17p | -19q | -X |
| Gains | +1q | +8q | +9q | +10 | +19p |
MSI
MSI: 32.1% (15918185)
MSI-H: 17.9%
Variants
sarcomatoid hepatocellular carcinoma
Predisposition
macroregenerative and dysplastic nodules (MDNs) are hepatocellular carcinoma (HCC) precursor lesions
Allelotyping (11391792)
allelic loss (11391792)
- 17p13 LOH (65%),
- 9p21-p23 LOH (55%)
- 4q LOH (35-51%)
- 16q21-q23.3 LOH (52%)
- 13q LOH (39-46%),
- 8p21-p23 LOH (41-45%),
- 6q24-q27 LOH
allelic gain (11391792)
- 1q32 gain (40%).
- 17q gain
- 8q24 gain (41%)
alleic imbalance (11391792)
- 19p13.3 AI
- 16p13.3 AI -* 13q33-q34 AI
- 9q13-31 AI
- 7q AI
Expression profiling
Ju-Seog Lee, et al. Nature Medicine - 12, 410 - 416 (2006)
Pathogenesis
Hepatocellular carcinoma, like any other cancer, 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.
In particular, chronic infections of Hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body’s own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders.
While this constant cycle of damage followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to Hepatitis C.
Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic Hepatitis B, however, the integration of the viral genome into infected cells can directly induce a non-cirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. Besides, cirrhosis is commonly caused by alcoholism, chronic hepatitis B and chronic hepatitis C.
The toxin aflatoxin from certain Aspergillus species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in countries like China and western Africa has led to relatively high rates of heptatocellular carcinoma in these regions.
Other viral hepatitides such as hepatitis A have no potential to become a chronic infection and thus are not related to hepatocellular carcinoma.
Prognosis
Individuals with HCC have a highly variable clinical course. The prognostic variability of individuals with HCC supports the notion that HCC comprises several biologically distinct subgroups.
This variability probably reflects a molecular heterogeneity that has not been appreciated from methods traditionally used to characterize HCC.
Improving the classification of individuals with HCC would at minimum improve the application of currently available treatment modalities and at most offer new treatment strategies.
The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin.
Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells.
Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development. (Ju-Seog Lee et al.)
Links
Videos
Hepatocellular carcinoma in cirrhosis
See also
hepatocellular carcinogenesis
Reviews
Molecular Classification and Novel Targets in Hepatocellular Carcinoma: Recent Advancements. Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Semin Liver Dis. 2010 Feb;30(1):35-51. PMID: 20175032
Coleman WB. Mechanisms of human hepatocarcinogenesis. Curr Mol Med. 2003 Sep;3(6):573-88. PMID: 4527088
Suriawinata A, Xu R. An update on the molecular genetics of hepatocellular carcinoma. Semin Liver Dis. 2004 Feb;24(1):77-88. Review. PMID: 15085488
Tannapfel A, Wittekind C. Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis. Virchows Arch. 2002 Apr;440(4):345-52. PMID: 11956813
References (Prognosis)
Iguchi T, Aishima S, Taketomi A, Nishihara Y, Fujita N, Sanefuji K, Maehara Y, Tsuneyoshi M. Extracapsular Penetration is a New Prognostic Factor in Human Hepatocellular Carcinoma. Am J Surg Pathol. 2008 Aug 30. PMID: 18769333
References (Genetics)
Wang G, Zhao Y, Liu X, Wang L, Wu C, Zhang W, Liu W, Zhang P, Cong W, Zhu Y, Zhang L, Chen S, Wan D, Zhao X, Huang W, Gu J. Allelic loss and gain, but not genomic instability, as the major somatic mutation in primary hepatocellular carcinoma. Genes Chromosomes Cancer. 2001 Jul;31(3):221-7. PMID: 11391792
Wong N, Lai P, Pang E, Fung LF, Sheng Z, Wong V, Wang W, Hayashi Y, Perlman E, Yuna S, Lau JW, Johnson PJ. Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin Cancer Res. 2000 Oct;6(10):4000-9. PMID: 11051249
References (Molecular pathology)
H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1. Magerl C, Ellinger J, Braunschweig T, Kremmer E, Koch LK, Höller T, Büttner R, Lüscher B, Gütgemann I. Hum Pathol. 2009 Nov 5. PMID: 19896696