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Fig. 2.3 Nasopharyngeal carcinoma in Hong Kong, 5-year trends in age-standardized incidence, 19762000.

Migration

In general, populations that migrate from high to low risk areas retain much of the elevated risk {304} seen in their country of origin, although this, and the extent to which the risk diminishes in successive generations, varies according to ethnicity. Such heterogeneity may be associated with several factors, possibly acting in combination - the degree of genetic predisposition, and the prevalence of certain risk factors related to lifestyle upon migration.

Time trends

Recent trends in NPC incidence in high-risk countries reveal convincing evidence of a decline in rates since the mid-1970s in Hong Kong {1446}. The speed of the decline points to the role of changing environmental risk factors. Rates in low-risk areas are, in view of the rarity of the disease, subject to a great deal of random variation, and trends are often difficult to interpret. In U.S. Whites and in England, rates are low and in slow decline. The evolution of trends in U.S. Blacks is unclear.

Etiology

The specific geographical and demographic distribution of nasopharyngeal carcinoma (NPC), the time trends, and patterns observed in migrants reflect the interplay of genetic susceptibility, infection by Epstein-Barr virus (EBV) and environmental factors (dietary and non-dietary) in disease causation.

Table 2.01 Reported EBV association in nasopharyngeal squamous cell carcinoma

Report

Technique of EBV

EBV positivity rate

demonstration

Niedobitek e al 1991 {1892}

ISH for EBV DNA

Germany 0/7

China 0/1

Dickens et al 1992 {599}

DNA slot-blot hybridization

Hong Kong 5/8

Chen et al 1993 {405}

ISH for EBV DNA

Taiwan 9/9

Hording et al 1993 {1124,1125}

PCR for EBV DNA

Denmark 2/15

Della Torre et al 1994 {580}

PCR for EBV DNA

Italy 2/9

Pathmanathan et al 1995 {1988}

ISH for EBER, immunohisto-chemistry for LMP-1

Malaysia (Chinese patients) 31/31

Gulley et al 1995 {961}

ISH for EBER

USA 0/3

Kanavaros et al 1995 {1262}

ISH for EBER

Greece 0/13

Nicholls et al 1997 {1885}

ISH for EBER

Hong Kong 22/22 Chengdu, China 7/10 Birmingham, UK 3/7

Hwang et al 1998 {1157}

ISH for EBER

Taiwan 1/1

Zhang et al 1998 {2894}

ISH for EBER, IHC*

Southern China 10/10

Inoue et al 2002 {1176}

ISH for EBER

Japan 4/4

ISH = in-situ hybridization; PCR = polymerase chain reaction; EBV = Epstein-Barr virus EBER = EBV-encoded early RNA, LMP-1 = latent membrane protein-1

*Immunohistochemistry (IHC) for early antigen-diffuse and 350/220 kd membrane glycoprotein of EBV

Epstein-Barr virus

The near constant association of EBV with NPC, irrespective of ethnic background, indicates a probable oncogenic role of the virus in the genesis of this tumour {1166,2107}. The evidence includes: (1) raised levels of antibodies, especially IgA, against EBV (most commonly viral capsid antigen and early antigen) in most patients with NPC compared with normal controls and patients with other cancer types; (2) higher titers of IgA antibodies against EBV in patients with large tumour bulk; (3) presence of EBV DNA or RNA in practically all tumour cells; (4) presence of EBV in a clonal epi-somal form, indicating that the virus has entered the tumour cell before clonal expansion; (5) presence of EBV in the precursor lesion of NPC, but not in the normal nasopharyngeal epithelium. The evidence was considered sufficient to classify EBV as carcinogenic by the International Agency for Research on Cancer (IARC) in 1997 {1166}. Nevertheless, it is likely that EBV infection takes place relatively late in the oncogenic process {1893}. The EBV infection in NPC exhibits the type II latency pattern, that is, expression of EBV nuclear antigen-1 (EBNA-1) and latent membrane protein-1 (LMP-1), but not the immunogenic EBNA2-6. EBV encoded early RNAs (EBERs) are expressed in abundance. BZLF (Zebra) protein, which is expressed in lytic infec-

tion by EBV, is not detected. LMP-1, a viral protein with transforming properties, can induce epidermal hyperplasia, inhibit squamous differentiation, upregulate the adhesion molecule ICAM-1 and CD40, activate nuclear factor-kB (NF-k-B), and induce expression of epidermal growth factor receptor.

Table 2.02 Common presenting symptoms and signs of nasopharyngeal carcinoma. Data from 722 consecutive patients treated at the Pamela Youde Nethersole Eastern Hospital, Hong Kong, during 1994 to 2001.

Presenting features Frequency (%)

Symptoms

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