Unfortunately, the onset of symptoms is insidious and symptoms are seen when the tumor has reached advanced stages. Nasal or eustachian tube obstruction that causes hearing loss is often the first symptoms, followed by bloody rhinorrhea, epistaxis, and palsies of the 3rd, 4th and 6th cranial nerves [6], suggesting that the tumor has reached stage IV. Headache and cervical lymphadenopathy that is often bilateral may also be present [1]. Anterior rhinoscopy may reveal the presence of a mass, after which appropriate diagnostic procedures should be conducted.

• Infectious Mononucleosis

  The Epstein-Barr virus, which causes infectious mononucleosis, plays a role in the development of nasopharyngeal cancer. There is also a hereditary predisposition. [msdmanuals.com]

• Nasal Congestion

  Palpable lymph nodes in the neck are the most common presenting finding in nasopharyngeal cancer; other symptoms include nasal congestion with epistaxis, blood in the saliva, and hearing loss. [msdmanuals.com]

• Rhinorrhea

  Other symptoms include ear pain, purulent bloody rhinorrhea, frank epistaxis, cranial nerve palsies, and cervical lymphadenopathy. [msdmanuals.com]

• Epistaxis

  Other symptoms include ear pain, purulent bloody rhinorrhea, frank epistaxis, cranial nerve palsies, and cervical lymphadenopathy. [msdmanuals.com]

Initial workup should include either CT or gadolinium-enhanced MRI to assess the scope of tumor extension into tissues, after which a biopsy is necessary. Guided by either endoscopy or nasopharyngeal mirror procedure, a sample must be obtained for histopathological identification [6]. Detection of EBV antibodies in serum has shown to be a marker of disease severity and increased titers further support the diagnosis [12]. Once these modalities are performed, tumor staging can be determined and treatment may be initiated accordingly.

Because nasopharyngeal carcinomas cannot be treated by surgery due to its location and proximity to numerous anatomical structures, chemotherapy and radiotherapy are used in different combinations against this tumor. Earlier reports suggested the use of chemotherapy as first-line for treatment of NPCs [13], but advances in radiotherapy have replaced chemotherapy and is recommended for less severe stages, since NPC is quite radiosensitive and very good results are seen with this form of therapy [3]. Concomitant administration of chemotherapy is becoming increasingly more common [8], especially in intermediate (T2) and advanced stages (T3,4) of the disease. Although simultaneous therapy somewhat increases the risk for severe toxicity, mainly of the hematopoietic system, chemotherapy-radiotherapy combination showed marked improvements in survival rates for many patients [3]. Platinum analogs such as cisplatin and oxaliplatin, together with 5-fluorouracil are agents that are most effective. The use of adjuvant chemotherapy after radiation-chemotherapy treatment has shown promising results and its use is becoming more frequent [3].

The prognosis significantly depends on staging at the time of diagnosis. NPC, according to TNM classification, is divided into [7]:

• Stage 1 (T1) - Tumor is localized in the nasopharynx.
• Stage 2 (T2) - Extension of the tumor to soft tissues of the oropharynx and/or nasal fossa is observed and can be accompanied with parapharyngeal extension (T2b) or without (T2a).
• Stage 3 (T3) - Invasion of paranasal sinuses and/or bony structures are seen.
• Stage 4 (T4) - Intracranial spreading of the tumor, together with involvement of the cranial nerves, infratemporal fossa, hypopharynx and the orbit.

Effective treatment for stages I and IIa range result in 5-year survival rates between 80-90%, but advanced stages of the disease carry a poor prognosis, with median survival rates around 12-20 months, which illustrates the importance of an early diagnosis [3].

The pathogenesis model of NPC is composed of several factors [1] [5]:

• EBV infection - More than 95% of NPCs are associated with EBV, since viral DNA/RNA is almost universally found in tumor tissues, coupled by the fact that substantially higher IgG/IgA antibody titers were observed in patients suffering from this type of malignancy. EBV is known for its oncogenic properties, as it induces expression of various latent pro-oncogenic genes, including Epstein-Barr nuclear antigens (EBNA1 and EBNA2) and latent membrane protein-1 (LMP1), which is expressed in 80-90% of patients and is responsible for evasion of both the immune system and apoptosis [1].
• Alterations of various signaling pathways - Extensive research into the process of malignant transformation of NPC has been made. The Wnt pathway, that involves genes such as adenomatous polyposis coli (APC) and β-catenin, is shown to be upregulated, leading to abnormal cellular proliferation. Additionally, expression of several tumor suppressor genes, including p53, p27 and p16 is altered. Finally, evasion of apoptosis, through increased expression of Bcl-2 and Survivin is achieved, together with increased activity of telomerases, a phenomonenon thought to be EBV-induced [1].
• Familial components - Though still unexplained, various studies have shown that hereditary factors may also play a role in the development of this malignancy [9].

NPC is quite rare in Europe and the United States. Incidence rates show a 0.5-2 per 100,000 person years incidence [3], but substantially higher rates have been observed in other parts of the world. Namely, certain provinces of China and Southeast Asia show an incidence rate of up to 30 per 100 000 person years, making these regions endemic for NPC [11]. In addition, a significant gender predilection of 2-3:1 toward males has been established [4]. Several risk factors have been established, including:

• Dietary habits - Consumption of salted fish and other preserved foods is shown to be one of the most important factors in the development of NPC, as geographical areas where these foods are consumed more commonly exhibit substantially higher incidence rates.
• Cigarette smoking and alcohol consumption have shown a 2-6 fold increased risk for NPC, especially type I [5].
• Occupational exposure - Numerous compounds have been associated wit an increased risk, including dust, fumes and certain chemicals such as formaldehyde and nitrites [5], but further studies have to be conducted in order to solidify these findings.
• Family history - First-degree relatives that have NPC are also an important risk factor, as 5-19% of patients with NPC have a positive family history [9].

Pathogenesis of NPC starts with EBV infection and viral-induced mutations of various host factors. Firstly, LMP1 and EBNA1 and 2 proteins are expressed [10], leading to induction of several signaling pathways, including NF-κB and mitogen-activating protein (MAP) kinases that cause pro-oncogenic changes [6]. Additionally, LMP1 aids in evasion of apoptosis and the immune response [1]. The Wnt pathway that involves APC and β-catenin is upregulated in many cancer forms, including NPC, while apoptotic signaling is impaired as well through overexpression of Bcl-2 and Survivin genes (in addition to LMP1 effects), together with increased activity of telomerases [1]. Finally, the activity of p53, p26 and p17, some of the most important tumor suppressor genes, are also shown to be altered.

Prevention strategies can be aimed at reducing exposure to risk factors that are known to be associated with NPC and screening of patients at risk. Substantially higher rates of NPC detection in early stages have been observed through screening techniques, which potentiates its widespread use [9] [14]. Reduction of cigarette smoking and alcohol consumption, but also reduction of salted and preserved foods, while butyric acid, a substance found in butter and some other foods, has shown to be a substance of interest as well [15]. Occupational exposure can be reduced through use of appropriate protective equipment. Vaccination against EBV is currently not possible.

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells of the nasopharynx and according to the World Health Organization (WHO) classification system, there are three distinct types [1]: Type I (known as keratinizing squamous cell carcinoma), type II (non-keratinizing squamous cell carcinoma) and type III (undifferentiated carcinoma). This malignancy is strongly associated with Epstein-Barr virus (EBV) and it is thought that more than 95% of nasopharyngeal carcinomas are on the grounds of EBV infection [1]. Moreover, the severity of infection is shown to directly influence the course of tumor progression, as EBV induces both mutagenic and oncogenic changes in the human host. In addition to EBV, numerous genetic alterations have been documented, including dysregulation of apoptosis, stimulation of transcription factor nuclear factor kappa B (NF-κB), increased expression of β-catenin and many other [1]. Environmental factors such as dietary habits have also shown to be vital in the pathogenesis of NPC, as several studies have confirmed a strong association with consumption of salted fish and other preserved products in certain geographical regions [2]. Conversely, incidence rates significantly vary across various parts of the globe. In the Western world, NPC is rarely encountered and incidence rates are estimated to be 0.5–2 per 100 000 person years across Europe and the United States [3]. On the other hand, certain parts of China and Hong Kong have established a rate of 25-30 per 100,000 person years [4], the reason presumably being dietary habits. Across all studies, a significant predilection toward males has been observed, with a 2-3:1 ratio [3]. Other risk factors include alcohol consumption, cigarette smoking, occupational exposure to certain chemicals, while human leukocytic antigen (HLA) mutations and hereditary components have also been reported [5]. Progression of the tumor is slow and symptoms appear when the tumor has reached advanced stages. The clinical presentation initially involves nasal or eustachian tube obstruction that may lead to hearing impairment, while bloody rhinorrhea, epistaxis and cranial nerve palsies may also be reported [6]. To make the diagnosis, imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI) are recommended to asses the extent of tumor involvement, but it is necessary to obtain a biopsy of the lesion, guided either by nasopharyngeal examination or endoscopy. Treatment principles depend on tumor staging. According to TNM classification, stages range from 1, where the tumor is confined to the nasopharynx, whereas stage 4 implies that the tumor has spread intracranially and/or involves the cranial nerves, infratemporal fossa or the orbit [7]. Although surgery is often not an option due to the anatomical location of the tumor, chemotherapy and radiation are usually used in combination to achieve higher success rates. Despite the fact that NPC is highly sensitive to radiotherapy, 5-year survival rates for stages I and II range between 80-90%, but a median survival time of 11 months was established in patients with recurrent and metastatic disease [8]. Having in mind the very low survival rates of patients when the tumor is diagnosed in later stages, early recognition of NPC can significantly prolong the patient's life, which can be achieved by screening of patients at risk.

Nasopharyngeal carcinoma is a rare form of malignancy but it has an insidious progress and causes symptoms when advanced stages of the disease are reached. The cause seems to be multifactorial, but the single most important culprit is Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis. Although more than 90% of the population had some form of EBV infection throughout their lifetime (including asymptomatic forms), EBV infection is known to trigger numerous genetic changes that alter normal cellular proliferation and differentiation, eventually leading to formation of malignant cells. In addition to EBV infection, several other risk factors have been established. Cigarette smoking, alcohol consumption, dietary habits that include salted fish and other preserved foods and positive family history. This tumor is rarely encountered in Europe and the United States, but significantly high rates are seen in certain parts of Southeast Asia and several provinces of China, which can be attributed to very high consumption of salted fish and occupational exposure to various compounds, which is also a risk factor. In most cases, patients present with nasal obstruction and hearing loss, as the tumor extends to obstruct the eustachian tube, while rhinorrhea, nose bleeding, enlarged lymph nodes of the neck and various neurological symptoms primarily related to eye movement may be observed. The presumptive diagnosis can be made during physical examination, when inspection of the nose can reveal the presence of a mass. Imaging studies such as computed tomography (CT scan) or magnetic resonance imaging (MRI) can determine the exact location of the tumor as well as its spread into local tissues. To confirm nasopharyngeal carcinoma, it is necessary to perform a biopsy. Once the diagnosis is confirmed, tumor staging based on involvement of various tissues is made: stage I implying the presence of the tumor in the nasopharynx without involvement of other tissues and stage IV demarcating extensive progression of the tumor with possible metastases. Treatment includes radiation in early stages, whereas concomitant use of chemotherapy and radiotherapy is recommended for advanced stages of the disease. Surgery cannot be performed due to the delicate location of the tumor. Survival rates exclusively depend on stage of the tumor at the diagnosis. 5-year survival rates for stages I and II are between 80-90% if treatment is successful, while a median survival time of 12-20 months is observed for patients in stages III and IV. For these reasons, it is imperative to make the diagnosis early on, but recognizing nasopharyngeal carcinoma may be difficult as it rarely produces symptoms in early stages. Screening of patients at risk, such as individuals having a positive family history, have shown markedly increased rates of tumor detection in early stages, which could be one of the main strategies in reducing the burden of this malignant tumor.

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