nasopharyngeal carcinoma ( npc ) is a nonlymphomatous squamous cell carcinoma that occurs in the epithelial lining of the nasopharynx .
this neoplasm shows varying degrees of differentiation and is frequently seen in the pharyngeal recess ( rosenmller 's fossa ) , posteromedial to the medial crura of the eustachian tube opening in the nasopharynx .
npc is a distinct form of head and neck cancer that differs from other malignancies of the upper aerodigestive tract in terms of its etiology , epidemiology , pathology , clinical presentation , and response to treatment . outside of endemic areas in southeast asia
, npc is rare , occurring in less than 1/1,000,000 people . in north america , npc accounts for approximately 0.2% of all malignancies , with approximately 0.52 cases per 100,000 males and about one - third of that in females [ 46 ] .
the incidence of npc reportedly remains high among chinese people who have emigrated to southeast asia or north america , but is lower among chinese people born in north america than in those born in southern china [ 7 , 8 ] .
this finding suggests that genetic as well as environmental factors play a role in the cause of the disease .  
the mainstay of npc treatment is radiotherapy , but treatment results for advanced npc is not satisfactory .
the focus of this review is to provide an overview of npc , especially the recent insights regarding early detection of npc .
it accounts for 2% of all head and neck squamous cell carcinomas , with an incidence of 0.5 to 2 per 100,000 in the united states .
however , it is endemic in many geographical regions , including southern china , southeast asia , japan , and the middle east / north africa [ 10 , 11 ] .
ho   reported that npc is the third most common malignancy among men , with an incidence of between 50 per 100,000 in the guangdong province of southern china .
emigration from high- to low - incidence areas such as the united states and canada reduces the incidence of npc in first - generation chinese , but it still remains at seven - times the rate in caucasians .  
npc presents as a complex disease caused by an interaction between chronic infection with oncogenic gamma herpesvirus epstein - barr virus ( ebv ) and environmental and genetic factors , involving a multistep carcinogenic process .
ebv exists worldwide , infecting over 95% of the global adult population . in hong kong ,
80% of children are infected by 6 years of age , and almost 100% have seroconverted by 10 years of age .
although primary ebv infection is typically subclinical , the virus is associated with the later development of several malignancies , including npc .
it is transmitted by saliva , and its primary infection occurs during childhood with replication of the virus in the oropharyngeal lining cells , followed by a latent infection of b lymphocytes ( primary target of ebv ) . elevated titers of ebv - associated antigens ( especially of iga class ) , a latent ebv infection indentified in neoplastic cells of virtually all cases of npc , and the clonal ebv genome consistently detected in invasive carcinomas and high - grade dysplastic lesions suggest a critical role of ebv in the pathogenesis of npc in endemic areas .    nonviral exposure associated with the risk of npc involves the consumption of salt - preserved fish , a traditional staple food in several npc - endemic areas . in studies of chinese populations , the relative risk of npc associated with weekly consumption , compared with no or rare consumption , generally ranged from 1.4 to 3.2 per 100,000 whereas that for daily consumption ranged from 1.8 to 7.5 [ 1522 ] .
thus , this dietary staple pattern may explain part of the international distribution of npc incidence .
the carcinogenic potential of salt - preserved fish is supported by experiments in rats , which develop malignant nasal and nasopharyngeal tumors after salted fish consumption [ 18 , 24 , 25 ] .
the process of salt preservation is inefficient , allowing fish and other foods to become partially putrefied . as a result
, these foods accumulate significant levels of nitrosamines , which are known carcinogens in animals [ 23 , 26 , 27 ] .
salt - preserved fish also contain bacterial mutagens , direct genotoxins , and ebv - reacting substances [ 2830 ] , any or all of which could also contribute to the observed association .
however , there have been no prospective studies of npc risk associations with salt - preserved fish consumption , or virtually any other environmental exposure , in endemic areas .      
several associations have been described between the frequency of human leukocyte antigen ( hla ) class i genes in certain populations and the risk of developing npc .
for example , increased risk of npc was observed in individuals with the hla - a2 allele , particularly hla - a0207 .
recent genome - wide association studies confirmed involvement of hla molecules in npc generation [ 32 , 33 ] .   cellular gene alterations also contribute to development of npc , especially inactivation of tumor suppressor genes , splunc1 , ubap1 , brd7 , nor1 , ngx6 , and ltf .
in 1978 , the histological classification guideline proposed by the world health organization ( who ) categorized npc into three groups : type 1 ( keratinizing squamous cell carcinoma ) , type 2 ( nonkeratinizing carcinoma ) , and type 3 ( undifferentiated carcinoma ) . the 1991 who classification of nasopharyngeal carcinoma divided them into two groups : squamous cell carcinoma ( keratinizing squamous cell carcinoma , type 1 of the former classification ) , and nonkeratinizing carcinoma ( types 2 and 3 of the former classification combined into a single category ) .
this classification is more applicable for epidemiological research and has also been shown to have a prognostic significance .
undifferentiated carcinomas have a higher local tumor control rate with treatment and a higher incidence of distant metastasis than do differentiated carcinomas [ 36 , 37 ] .       published data indicate a higher proportion of keratinizing squamous cell carcinoma among all npc in nonendemic compared with endemic areas .
some studies reported that squamous cell carcinoma accounts for approximately 25% of all npc in north america , but only 1% in endemic areas ; whereas undifferentiated carcinoma accounts for 95% of all cases in high - incidence areas , but 60% of cases in north america [ 9 , 10 , 38 ] .
the control rate on conventional radiotherapy is 75 to 90% in t1 and t2 tumors , and 50 to 75% in t3 and t4 tumors . because of the high incidence of occult cervical node metastasis ,
the control of cervical nodal regions is achieved in 90% of n0 and n1 cases , and about 70% of n2 and n3 cases .
it is mandatory to keep the treatment schedule because interrupted or prolonged treatment reduces the benefits of radiotherapy .      
recent studies have suggested that addition of chemotherapy to radiotherapy improves the treatment results in patients with nasopharyngeal carcinoma .
phase iii randomized intergroup study 0099 showed that patients treated with radiation alone had a significantly lower 3-year survival rate than those receiving radiation with cisplatin and 5-fluorouracil chemotherapy . a meta - analysis of chemotherapy for npc conducted by baujat et al .  
they reported a definite improvement of the 5-year survival rate due to the addition of chemotherapy ( 56% with radiotherapy alone versus 62% with chemoradiotherapy ) .
in addition to these findings , other phase iii or meta - analysis studies also reported the superiority of concurrent chemoradiotherapy versus radiotherapy alone [ 4446 ] .
the above - described reports suggest the benefits of the addition of chemotherapy , especially in advanced npc cases
. however , there is still debate on the effectiveness of the addition of chemotherapy , and issues regarding the addition of adjuvant chemotherapy are even more controversial .
      wei and sham   divided symptoms presented by npc patients into four categories : ( 1 ) symptoms caused by the presence of a tumor mass in the nasopharynx ( epistaxis , nasal obstruction , and discharge ) , ( 2 ) symptoms associated with dysfunction of the eustachian tube ( hearing loss ) , ( 3 ) symptoms associated with the superior extension of the tumor ( headache , diplopia , facial pain , and numbness ) , and ( 4 ) neck masses . because symptoms related to npc in the early stage are usually nonspecific ,
most npc patients are diagnosed in the advanced stage . as treatment results for npc are not satisfactory in the advanced stage , early diagnosis and appropriate management are important to achieve favorable treatment results .
the development of a good primary npc screening protocol may thus contribute to the early detection and improve the treatment outcome .      
the endemic form of npc is associated with ebv , although the exact role of ebv in the pathogenesis of npc remains unclear .
iga antibody titers to ebv viral capsid antigen ( ebv - iga - vca ) and ebv early antigen ( ebv - ea ) in immunofluorescent assays may be used for the serologic screening of npc [ 47 , 48 ] . in recent years , enzyme - linked immunosorbent assays ( elisa ) employing purified recombinant ebv antigens
these tests frequently precede the appearance of npc and serve as tumor markers of remission and relapse [ 50 , 51 ] .
they confirmed that elevation of the ebv antibody levels preceded the clinical onset of npc .
they also reported that there is a window of about 3 years preceding the clinical onset , when the antibody level is elevated and maintained at high levels .
however , none of these serologic screening tests appear satisfactory to date because of low - level sensitivity or specificity .
detection of the ebv gene in nasopharyngeal swabs from symptomatic patients has been shown to be highly predictive of symptomatic npc [ 54 , 55 ] .  
proteomic approaches have been applied for the analysis of malignant neoplasms . for practical usage in tumor screening
recently , wei et al .   analyzed serum samples from patients with npc employing proteomic analysis . in their report , four protein peaks at 4,097 , 4,180 , 5,912 , and 8,295 daltons ( da ) discriminated npc patients with a sensitivity of 94.5% and specificity of 92.9% .
furthermore , chang et al .   reported that the use of a three - marker panel ( cystatin a , mnsod , and mmp2 ) could contribute to improved npc detection .
other potential markers for the diagnosis of npc include galectin-1 , fibronectin , mac-2 binding protein , and plasminogen activator inhibitor 1 [ 57 , 58 ] .
there is a possibility that the incorporation of these tests in the routine screening of npc may enhance its early detection .  
the importance of clinical syndromes , history , and clinical examination for helping the early diagnosis of npc could not be ignored .
any adult presenting with unexplained unilateral serous otitis media should be carefully examined to rule out npc .
endoscopy plays a key role in detecting the early npc lesions , and endoscopic biopsy enables their definitive diagnosis .
reported an objective endoscopic score of abnormality of nasopharynx to predict the likelihood of npc .
however , clinicians should keep in mind the fact that detection of npc is sometimes difficult with endoscopy .
endoscopic findings may be subtle in early npc lesions : only slight fullness in the rosenmller 's fossa , or a small bulge or asymmetry in the roof . when npc is strongly suspected , considering early diagnosis of npc , appropriate imaging examinations and/or biopsy of the nasopharyngeal mucosa
careful attention should be paid when mri is conducted for a patient with unilateral serous otitis media ( stasis of secretions in unilateral middle ear ) or cervical lymph node adenopathy .
60 to 96% of npc patients exhibited cervical lymph node adenopathy at the time of presentation [ 6163 ] .
t1 tumors , confined to the nasopharynx , may be clinically occult , and also may be difficult to differentiate from the normal mucosa on a ct scan and mri .
however , such small tumors are usually readily evident by their less intense enhancement by gadolinium than the normal nasopharyngeal mucosa .
it has been suggested that mri is superior to 18-fluoro-2-deoxyglucose ( fdg ) positron emission tomography ( pet ) for the assessment of locoregional invasion and retropharyngeal nodal metastasis .
pet is not suitable for detecting small retropharngeal nodes or for distinguishing retropharyngeal nodes from adjacent primary tumors .
      to date , the modalities commonly used in the followup of patients with npc include clinical examinations and imaging studies .
inspection with a flexible fiberscope plays a primary role in followup examinations . however , mucosal reactions to radiotherapy make it difficult to find early recurrent lesions . secretions and
in addition , the detection of submucosal or deep - seated recurrent lesions is difficult with fiberscopic examinations .
if recurrent npc lesions can be diagnosed properly and in a timely manner , these lesions may be treated by chemotherapy , reirradiation , such as further conventional external beam radiotherapy , brachytherapy , and stereotactic radiotherapy , or surgery . regarding surgery , conventional nasopharyngectomy for recurrent npc lesions can still result in serious complications .
however , early recurrent lesions ( such as rt1 lesions ) may be effectively treated with laser nasopharyngectomy .
diagnostic uncertainty may result in delayed treatment , which reduces the life expectancy of patients with recurrent npc lesions .      
narrow - band imaging ( nbi ) is a novel technique that enhances the diagnostic sensitivity of endoscopes for characterizing tissues using narrow - bandwidth filters in a sequential red - green - blue illumination system .
superficial mucosal carcinoma lesions , which are rarely detected using conventional endoscopy , can be observed with nbi by viewing the nonangiogenetic , microvascular proliferation pattern [ 68 , 69 ] .
recently , lin and wang   applied this technique to the detection of early recurrent mucosal lesions of npc .
they reported that early recurrent lesions of npc after radiotherapy were successfully detected by nbi coupled with conventional endoscopy .      
regarding imaging studies after initial treatment , ct and mri are widely used for the detection of recurrent lesions . generally , mri is superior to ct in the detection of soft tissue abnormalities .
the baseline mri study is often conducted 2 to 3 months after termination of the initial treatment .
after the baseline evaluation , close evaluation is recommended with further imaging followup every 3 to 6 months for the first 2 years posttreatment .
however , any signal abnormalities in the nasopharynx on mri should be stable or reduced in this followup period .
after 2-year followup without evidence of recurrence , the imaging interval is extended to be every 6 to 12 months .
recently , the effectiveness of fdg - pet in the detection of residual or recurrent npc lesions has been reported from several institutes .
fdg - pet is increasingly being used for detection of recurrent lesions in many types of tumor .
pet is reportedly useful to distinguish recurrent npc tumors from postirradiation changes , such as tissue necrosis , fibrosis , and edema [ 7073 ] .
liu et al .   reported that sensitivities of ct , mri , and pet for the detection of residual or recurrent npc lesions were 76 , 78 , and 95% , respectively .
these findings suggest that pet can be a useful tool for the detection of recurrent npc lesions . however , there are also some limitations regarding the use of pet for the detection of early recurrent npc lesions
furthermore , a recent cost - based analysis suggested that it is most cost - effective to perform pet if mri results are unclear .
      npc detection in the early stage is often difficult because the symptoms are not specific .
ebv - related serologic tests are used as screening tools in high - risk populations , although the screening tests available in daily clinics are not satisfactory .
molecular biomarkers are under examination as a new tool for the detection of early npc lesions .
regarding imaging modalities , mri seems suitable for the detection of early lesions , and the routine use of pet for the initial diagnosis of npc does not seem to be justified .
in addition to the new diagnostic modalities , improvement in the awareness of physicians and the general population regarding this carcinoma undoubtedly contributes to the earlier detection of the disease .
 nasopharyngeal carcinoma ( npc ) is a unique disease with a clinical presentation , epidemiology , and histopathology differing from other squamous cell carcinomas of the head and neck . 
 npc is an epstein - barr virus - associated malignancy with a marked racial and geographic distribution . 
 specifically , it is highly prevalent in southern china , southeast asia , and the middle east . to date 
 , most npc patients have been diagnosed in the advanced stage , but the treatment results for advanced npc are not satisfactory . 
 this paper provides a brief overview regarding npc , with the focus on the early detection of initial and recurrent npc lesions . 