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Nasopharyngeal Carcinoma was first documented in 1901 and described clinically in 1921. (We I* et al.2007). The malignancy continued to evolve reaching a global death rate of 50,800 deaths in 2012. The epidemiology is still perplexing. Worldwide it is an uncommon tumour. Nevertheless, in certain regions such as China, NPC occur with a drastically high incidence. The age-adjusted incidence rate for men per 100 000 people per year is 0.6 in the United States in contrast to 26.9 in Guangdong province, China. More than 20 cases per 100 people are reported. This represents a considerable major health burden. Therefore, the tumour has also been termed as “Guangdong tumour” or even “Canton tumour” due to its high prevalence among Cantonese also. South China including Cantonese people and Hong Kong are those areas reported to harbour the malignancy preferentially and are considered regions of high risk. South Asia, Arctic, Middle East represent regions of average risk. Moving from north to south China, an increase in incidence has been observed. In a low-risk individual, the NPC has a bimodal age of distribution with the first peak at 15-25 years and the second peak at 50-59 years. However, in high-risk individuals, the tumour most frequently present in a fourth or fifth decade of life. Nasopharyngeal cancer strikes men more often with a male to female ratio ranging from 2:1 to 3:1. As such, NPC is well known to have a characteristic ethnic and geographic distribution.

According to WHO, NPC is classified histologically based on the degree of differentiation. The main classes identified are as follows: keratinizing and non-keratinizing variants. The keratinizing form the Type 1 also called as squamous cell carcinoma. They account for about 5 -10 % of cases. Type I tumours are well differentiated with the production of keratin. Under the electron microscope, intracellular bridges can be identified. The non- keratinizing class are further subdivided into Type II differentiated and Type III non-differentiated. In type III, the cells vary from mature to anaplastic. Variable kinds of cells: spindle, clear cells, anaplastic cells are identified in type III. Type II and type III are more commonly associated with EBV infection. In China, 97% of cases are type III.

Histopathology of Nasopharyngeal carcinoma
The origin of NPC roots from genetic, environmental and viral factors which interact to promote carcinogenesis. The environmental factors include high salt consumption as a prime environmental influence in endemic regions such as China. The salted food contains nitrosamines which are accumulated upon preservation. The latter is also rich in lignin which has been proposed to be an EBV virus activator and promoter. Other environmental factors are smoking, alcohol, dust, fumes, formaldehyde. Smoking and alcohol play a synergistic role.

The classical regional and racial distribution of NPC suggests a clear genetic aetiology. NPC has been classically linked to HLA haplotype. HLA A2 B46 B17 are more susceptible to develop nasopharyngeal carcinoma. Furthermore, alteration of oncogenes on chromosome 8 and 12 also have been implicated. Genetic pleomorphism in the gene that metabolises nitrosamines such as cytochrome P4502E1, cytochrome P4502A6 also account for the oncogenic process.

EBV forms part of the herpesvirus family, also called as Herpes virus 4-HH4. Discovered in 1964, it is identified as the first tumour virus (Young and Rickman 2004). It forms the main etiological factor in several malignancies including; Burkitt lymphoma, NPC, Hodgkin lymphoma, NKT lymphoma and leiomyosarcoma in immunocompromised individuals.

Worldwide EBV affects 90% adult population. The site of infection is oral via saliva. The virus exhibit tropism for oropharyngeal epithelial cells and B cells in lymphoid organs given their close proximity to the epithelial cells in the oropharynx. In cases of NPC, the virus targets the epithelial cells in fossa of rosenmuller in waldeyer ring.
EBV infection occurs primarily in childhood. It may be asymptomatic or may lead to infectious mononucleosis which is usually self-limiting. This is followed by a period of latency. B cells and epithelial cells are affected differently. The initial step is the attachment of CD 21 molecule on the surface of B cells via gp350/220.In the case of B cells, the virus triggers a proliferating process resulting in a clone of cells and paving the pathway for malignancy. EBV virus may also persist in circulating memory B cells and shredding from the oropharyngeal epithelial cells occurs for years. In contrast to B cells, the virus does not transform the epithelial cells directly. Instead, it has a lytic effect on the epithelial cells. Active replication with the production of the virus and lysis of the epithelial cells result. This is termed as lytic replication.

Figure : Adapted from
This Herpesvirus 4 has a size of approximately 122-180nm.Its DNA is double helix and contains 172 000 base pairs and 85 genes. The genetic materials are protected by the capsid which is in turn surrounded by a tegument made of protein. Beyond the tegument is the envelope which contains lipids(fats) and the surface projection of glycoproteins. Below is the structure of EBV:

Figure : Adapted from
Almost all NPC cells contain EBV episomes. The role of EBV is still enigmatic as not all infected individual develop a malignant process. This suggests that EBV infection is not the prime factor but instead co-factors such inflammation and genetic changes act as complementary enhancers in the pathogenesis.

Following attachment of CD 21 to gp 350/220, a series of interactions are activated. Several molecular pathways are involved. Tyrosine kinases are activated promoting the mobilization of calcium. This is then followed by m RNA expression, the formation of blasts cells, homotopic cell adhesion, expression of surface CD 23, IL-6. A cascade of events is launched leading to expression of EBNA proteins {EBNA 1,2, 3A 3B 3C} and latent membrane proteins {LMP1 2A 2B}. They interact with a range of signalling molecules such as apoptotic molecules and cytokines to enhance the infection and oncogenic process.

Figure : Adapted from

The nuclear antigen is present in all EBV linked malignancies. It plays a key role in maintaining the latency of EBV.EBNA-1 is also of immense value for EBV genome replication and maintenance. EBNA-1 binds to plasmid origin of replication, Orip (Kiff and Rickinoun-2001). This launches a sequence of events for replication. EBNA-1 binding sites are also situated at +10 and +34 nucleosides downstream of Qp allowing it to negatively regulates its own expression by binding these two downstream sites. (Nankwelo et al.).EBNA-1 has also been shown to upregulate Cp and LMP-1 promoter ( Kiff and Rickinoun 2001).

It has a central role in the transformation of B cells. It upregulates CD 21, CD 23, LMP-1 LMP-3. In early B cell infection, it causes a switch from Wp to Gp by transactivating viral promoter Cp.

It is a family of EBNA 3A, 3B, 3C. It collaborates with other EBNA to regulate the expression of cellular genes.

It is among the first viral products produced during the infection. It is also called as EBNA-5. It interacts with both pRb, p55 (Jieng et al. 1991, Szekely et al. 1993). It works with EBNA-2 to drive resting B lymphocytes in the G1 phase of the cell cycle.

Its role in oncogenesis is of high importance. It has the virtue to mimic normal growth signals by attaching to CD 40 ligand and inhibit apoptosis by increasing BCL-2 level. It activates a cascade of reaction leading to B cell proliferation.

This protein block tyrosine kinase phosphorylation. It helps to maintain EBV latency and prevent reactivation of EBV.
They do not encode proteins but may be important for viral persistence.

The main function is still unclear but is also believed to be associated with persistence of EBV virus.

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