Page 242 - Textbook of Pathology, 6th Edition

226 However, like in case of Burkitt’s lymphoma, there may and is responsible for a carrier state, which can result in some
be some co-factors such as genetic susceptibility that account cases to chronic hepatitis progressing to hepatic cirrhosis,
for the unusual geographic distribution. and onto hepatocellular carcinoma. These lesions and the
structure of HBV are described in detail in Chapter 21. Suffice
EBV ONCOGENESIS IN HUMAN CANCER— this to say here that there is strong epidemiological evidence
Persistent EBV infection is implicated in the causation of
malignancies of B lymphocytes and epithelial cells. The linking HBV infection to development of hepatocellular
mechanism of oncogenesis is as under: carcinoma as evidenced by the following:
i) Latently infected epithelial cells or B lymphocytes express a) The geographic differences in the incidence of
viral oncogene LMP1 (latent membrane protein) which is hepatocellular carcinoma closely match the variation in
SECTION I
most crucial step in evolution of EBV-associated malig- prevalence of HBV infection e.g. high incidence in Far-East
nancies. Immunosuppressed individuals are unable to mount and Africa.
attack against EBV infection and thus are more affected. b) Epidemiological studies in high incidence regions
ii) LMP1 viral protein dysregulates normal cell proliferation indicate about 200 times higher risk of developing hepato-
and survival of infected cells and acts like CD40 receptor cellular carcinoma in HBV-infected cases as compared to
molecule on B cell surface. Thus, it stimulates B-cell uninfected population in the same area.
proliferation by activating growth signaling pathways via Posssible mechanism of hepatocellular carcinoma
nuclear factor κB (NF-κB) and JAK/STAT pathway. occurring in those harbouring long-standing infection with
iii) LMP1 viral oncoprotein also activates BCL2 and thereby HBV is chronic destruction of HBV-infected hepatocytes
prevents apoptosis. followed by continued hepatocyte proliferation. This process
iv) Persistent EBV infection elaborates another viral protein renders the hepatocytes vulnerable to the action of other risk
EBNA-2 which activates cyclin D in the host cells and thus factors such as to aflatoxin causing mutation and neoplastic
promotes cell proliferation. proliferation.
v) In immunocompetent individuals, LMP1 is kept under More recent evidence has linked an oncogenic role to
contro by the body’s immune system and in these persons another hepatotropic virus, hepatitis C virus (HCV) as well
therefore lymphoma cells appear only after another which is an RNA virus, while HBV is a DNA virus. HCV is
characteristic mutation t(8;14) activates growth promoting implicated in about half the cases of hepatocellular carcinoma
MYC oncogene. in much the same way as HBV.
HUMAN HERPESVIRUS 8 (HHV-8). It has been shown that HEPATITIS VIRUS ONCOGENESIS IN HUMAN CANCER—
infection with HHV-8 or Kaposi’s sarcoma-associated Epidemiologic data firmly support that two hepatotropic
General Pathology and Basic Techniques
herpesvirus (KSHV) is associated with Kaposi’s sarcoma, a viruses, HBV—a DNA virus, and HCV—an RNA virus, are
vascular neoplasm common in patients of AIDS. Compared currently involved in causation of 70-80% cases of
to sporadic Kaposi’s sarcoma, the AIDS-associated tumour hepatocellular carcinoma worldwide. Although HBV DNA
is multicentric and more aggressive. HHV-8 has lympho- has been found integrated in the genome of human
tropism and is also implicated in causation of pleural effusion hepatocytes in many cases of liver cancer which causes
lymphoma and multicentric variant of Castleman’s disease. mutational changes but a definite pattern is lacking. Thus,
exact molecular mechanism as to how HBV and HCV cause
HHV-8 (KSHV) ONCOGENESIS IN HUMAN CANCER—
i) Viral DNA is seen in nuclei of all tumour cells in Kaposi’s hepatocellular carcinoma is yet not quite clear. Probably,
sarcoma. multiple factors are involved:
ii) There is overexpression of several KSHV oncoproteins by i) Chronic and persistent viral infection with HBV or HCV
latently infected cells: v-cyclin, v-interferon regulatory factor incites repetitive cycles of inflammation, immune response,
(v-IRF) and LANA (latency-associated nuclear antigen). cell degeneration/cell death, and regeneration of the
iii) These viral proteins cause increased proliferation and hepatocytes which leads to DNA damage to liver cells of the
survival of host cells and thus induce malignancy. host.
ii) It is possible that immune response by the host to
3. ADENOVIRUSES. The human adenoviruses cause persistent unresolved infection with these hepatitis viruses
upper respiratory infections and pharyngitis. becomes defective which promotes tumour development.
In humans, they are not known to be involved in any iii) On regeneration, proliferation of hepatocytes is stimulated
tumour. by several growth factors and cytokines elaborated by
In hamsters, they may induce sarcomas.
activated immune cells which contribute to tumour
4. POXVIRUSES. This group of oncogenic viruses is development e.g. factors for angiogenesis, cell survival etc.
involved in the etiology of following lesions: iv) Activated immune cells produce nuclear factor κB
In rabbits—poxviruses cause myxomatosis. (NF-κB) that inhibits apoptosis, thus allowing cell survival
In humans—poxviruses cause molluscum contagiosum and growth.
and may induce squamous cell papilloma. v) HBV genome contains a gene HBx which activates growth
5. HEPADNAVIRUSES. Hepatitis B virus (HBV) is a signaling pathway.
member of hepadnavirus (hepa- from hepatitis, -dna from vi) HBV and HCV do not encode for any specific viral
DNA) family. HBV infection in man causes an acute hepatitis oncoproteins.