Model Of Development Of Nasopharyngeal Carcinoma

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Fig. 2.20 Nasopharyngeal carcinoma. Spectral karyotyping (SKY) analysis of a nasopharyngeal carcinoma cell line C66-1 exhibiting multiple structural rearrangements.

PIGR and TCR

The mechanism of the entry of EBV into the nasopharyngeal epithelium has not yet been conclusively elucidated, but a receptor on nasopharyngeal epithelial cells, namely polymeric immunoglobulin receptor (PIGR), has been proposed to be involved. It has been reported that one single nucleotide polymorphism (SNP) (1739C->T), located on exon 7 of the gene, is significantly associated with increased risk of NPC {1102}. The SNP is a missense mutation altering the amino acid alanine to valine, and it occurs adjacent to the endoproteolytic cleavage site of the PIGR extracellular domain. It is hypothesized that the homozygous 1739C state may result in the altered efficiency to release IgA-EBV complex and hence increase the possibility of nasopharyngeal epithelial cells to be infected by EBV.

Since T cell receptor (TCR) may mediate immunity against EBV infection, effort has been made to test the association between polymorphism of TCR and NPC. A study has shown NPC susceptibility to be associated dominantly with a 20-kb fragment (P=0.02, RR=8.2) {412}.

Chromosome 4p

With construction of a human genome genetic linkage map and development of methods and algorithms, linkage analysis has become the robust tool to connect phenotypes with genotypes. A whole genome scan for linkage with NPC has been performed on 32 high risk NPC Cantonese pedigrees {729}. The marker D4S405 on chromosome 4p12-p15 yielded a maximum multipoint lod score of 3.06, a heterogeneity adjusted lod score (HLOD) of 3.21, and a non-parametric linkage score of 2.75 (P=0.005),

Nasopharyngeal Carcinoma Test Algorithm
Fig. 2.20A Multistep evolution of nasopharyngeal cancer.

Fig. 2.22 A putative model for the development of the three forms of nasopharyngeal carcinoma.

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Fig. 2.22 A putative model for the development of the three forms of nasopharyngeal carcinoma.

suggesting that a disease susceptibility gene may be linked with D4S405. Fine mapping and haplotype analysis has localized the NPC predisposing gene to chromosome region 4p15.1-q12. In summary, NPC development may involve susceptibility gene mutations (major genes) and gene polymorphisms (minor-effect genes). In some familial cases, inherited genetic alterations (major gene transmission) could be the first "hit", and EBV infection may contribute to the second "hit". Therefore, familial cases usually have a much younger age of onset. However, some other familial cases and probably most sporadic cases may get the first "hit" from both inherited genetic alterations (minor-effect genes, such as HLA, CYP2E1) and somatic genetic changes. In the high prevalence areas like south China, most of the NPC cases belong to this type and they usually have older age of onset than the familial cases with a major gene transmission {2890}.

Prognosis and predictive factors

The mainstay of treatment for NPC is radiation therapy. Progressive improvement of treatment results for NPC has been reported both from endemic and non-endemic areas. The average 5-year survival steadily increased from around 35% for patients treated in the 1940-60 {1755,1785,2096}, to 55-60% in the 1970-90s {1061,1592,2096,2693}. A recent study of patients without distant metastases treated during 1996-2000 showed that a 5-year disease-specific survival (DSS) of 81% and overall sur-

Fig. 2.21 Nasopharyngeal carcinoma. Actuarial disease-specific survival for different stages of nasopharyngeal carcinoma (Source of data: Hong Kong Nasopharyngeal Cancer Study Group on 2687 patients staged with the UICC/AJCC 5th Edition at public centres in Hong Kong during 1996-2000).

vival 75% can now be achieved {1448}. The presenting stage is the most important prognostic factor. A recent study using the 2002 TNM staging System shows that the 5-year DSS for Stage I is 98%, Stage II A-B 95%, Stage III 86%, and Stage IVA-B 73%. In addition, tumour volume may prove to be useful for predicting local control {447,2520}. The importance of host factors varies among different series. In general, younger age (less than 40 years) and female gender are associated with better prognosis {2574}. Interestingly, the influence of age is mainly on local failure, while that of gender is on distant failure. The values of EBV antibodies for predicting prognosis and monitoring disease progression are rather limited {567, 2855}. High baseline titers often persist even in patients in remission. Although rising titers to VCA, EA and Zta are associated with disease relapse, the elevation is often not consistently high or early enough for disease monitoring. Circulating plasma/serum EBV DNA is a more promising prognostic factor. High plasma/serum EBV DNA titers are associated with advanced stages {1549}; both pre-treatment and post-treatment titers correlate significantly with survival {362,1547}. The titer is substantially elevated in patients with active disease (especially distant metastasis), and drops to very low titers upon remission

{362,1548,1882,2346}. Aneuploid status or high pre-treatment tumour proliferative fractions, as determined by DNA flow cytometry, correlate significantly with poor survival {2854}. Other biological factors that might have prognostic significance include tumour angiogenesis, c-erbB2 {2209}, p53 {1658}, nm23-HI {965}, interleukin-10 {828}, and vascular endothelial growth factor {2095}.

Treatment factors affect the ultimate survival. Significant improvements in treatment results have been attributed to refinement of radiotherapy technique {1454}, dose escalation {2561,2576}, accelerated fractionation {1447,2717}, addition of chemotherapy (concurrent + sequential) {29,1515,2180}, and combination of new strategies {2803}.

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