Familial Nasopharyngeal Carcinoma 6

68 K. S. LohTable 6.2. Causal associations in familial NPCStudy Region Cohort(families)LinkageFeng et al. (2002) Guangdong 20 4p15.1-q12Xiong et al. (2004) Hunan 18 3p21.31-21.2Hu et al. (2008) Guangdong 15 5p13.1needed to detect small but significant risk factors insuch setting may require a vast number of cases ofpatients fulfilling the criteria of familial NPC. Inaddition, a good proportion of affected family membersmay not be alive, the parents of the proband maybe deceased, or the affected first-degree memberscould have succumbed owing to the progression oftheir disease. Furthermore, reliability of data recallof specific dietary habits and/or occupational exposuresmay not be accurate. Controlling for the multiplevariables is a mammoth task in case controlstudies like these. Determining causal relationship ofnongenetic factors for familial NPC seems to be aninsurmountable task.Current evidence suggests that genetic factors playa more significant role in the development of NPC inmultiple first-degree relatives of a family than environmentalfactors. The genetic associations in familialNPC are summarized Table 6.2. It is important toremember that no consistent linkage between familialNPC and a single chromosome has been confirmed inthe reported literature. The fact that chromosomes 3, 4,5, and 6 have been reported as possible associations infamilial NPC suggests that substantial heterogeneitymay exist among familial clusters with NPC. Based onthese findings, a number of tumor susceptibility genesmay be responsible for NPC. Furthermore, it is alsopossible that NPC patients from different geographicalregions may possess different susceptibility genes. Andeven different families from the same region may havediffering susceptibility locus. However, prediction forthe likelihood of NPC among first-degree relatives of apatient is not currently possible using genetic markersdue to such heterogeneity.6.4Clinical Manifestation of Familial NPCThe available data in the current literature confirmsthat the clinical characteristics of familial NPC doesnot present any differently from sporadic NPC (Lohet al. 2006). Hence, it is expected that patients who fitthe definition of familial NPC will most likely presentwith typical NPC presenting symptoms like nodalmetastasis, blood stained saliva, and/or otitis mediawith effusion. In addition, no specific features arepresent on imaging studies of the primary tumor andnodal disease. There is also no significant differencein the levels of IgA viral capsid antigen (VCA) andIgA early antigen (Ea) titers between familial andsporadic NPC patients. The rate of distant metastasisis not higher than in patients with sporadic NPC, andthe stage of disease is expected to be similar in bothgroups of patients, with patients predominantlydiagnosed with stage III or stage IV NPC. Interestingly,some authors believe that patients with familial NPCtend to be diagnosed at an earlier age (Ng et al. 2009;Zeng et al. 2002). The pattern of earlier onset of disease,if it is confirmed, will lend weight to the beliefthat familial NPC is strongly associated with geneticpredisposition. However, other authors do not reportany differences in the age at diagnosis of familialNPC patients (Loh et al. 2006; Chen et al. 1990). It isalso thought that first-degree relatives have a higherrisk if the proband was diagnosed at age 40 years orless (Zeng et al. 2002). None of the reported seriesconclude any gender difference between familialNPC and the sporadic form, and the majority of NPCpatients are male, like in its sporadic form.Clinically, familial NPC does not seem to be a distinctdisease entity, as clinical behavior does not differfrom the more commonly diagnosed sporadicNPC. The significance of this lack of a clear clinicalpattern of familial NPC is that one is unable to useobjective clinical criteria to define familial NPC. Infact, it suggests that the factors that cause both sporadicand familial forms of NPC produce the samephenotypic results. The more obvious features offamilial NPC are in Table 6.3.Although all first-degree family members are atrisk of NPC once a new diagnosis is made, the availabledata suggest a clear predominance of the diseasein siblings over other first-degree relatives of thefamily. It is estimated that 30% of the affected firstdegreefamily members are parents and 70% are siblingsin the affected families. The period from anaffected parent to a child being diagnosed with NPCis reported to be about 25 years; however, the periodbetween affected siblings is about 5 years (Loh et al.2006). These findings provided significant implicationsfor screening protocols for first-degree relatives,which suggested that siblings might need to be