Nasopharyngeal carcinoma is uncommon in the United States, with only 0.2 to 0.5 cases per 100,00 people; this is in contrast to southern China and Hong Kong, where the incidence is 25 to 50 per 100,000 people. There is a potential link between Epstein-Barr virus and the development of nasopharyngeal carcinoma. Radiotherapy alone as a single modality leads to similar 10-year survival rates in United States, Denmark, and Hong Kong (34%, 37%, and 43%, respectively). Multiple studies have shown an advantage to concurrent chemoradiation in the treatment of advanced disease. Radiation therapy remains the mainstay of salvage therapy, and modern techniques have allowed clinicians to achieve adequate local control without excessive toxicity.
Key points
- •
Nasopharyngeal carcinoma (NPC) is uncommon in the United States, with only 0.2 to 0.5 cases per 100,000 people; this is in contrast to southern China and Hong Kong, where the incidence is 25 to 50 per 100,000 people.
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There is a potential link between Epstein-Barr virus (EBV) and the development of NPC.
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Radiotherapy alone as a single modality leads to similar 10-year survival rates in the United States, Denmark, and Hong Kong (34%, 37%, and 43%, respectively). Multiple studies have shown an advantage to concurrent chemoradiation in the treatment of advanced disease.
- •
Radiation therapy remains the mainstay of salvage therapy, and modern techniques have allowed clinicians to achieve adequate local control without excessive toxicity.
Introduction
Epidemiology
Nasopharyngeal is an uncommon disease in the United States. The incidence is approximately 0.2 to 0.5 cases per 100,000 people. In Southeast Asia, North Africa, and parts of the Mediterranean basin, however, approximately 80 cases per 100,000 of the population are reported. Among the Inuit who reside in Alaska and Greenland, the incidence is also high (15 to 20 cases per 100,000 people). Several etiologic factors have been implicated. Dr John Ho’s observations in the 1970s on boat people in southern China with a high incidence of NPC led him in the search and identification of salted fish as a carcinogen. Cantonese salted fish is now identified as a group 1 human carcinogen according to the International Agency for Research on Cancer ( http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E-12.pdf ). Other etiologic risk factors include alcohol consumption, cigarette smoking, and exposure to dust, fumes, and formaldehyde. The role of alcohol and cigarette smoking has been controversial, because prior studies have suggested no association. A case-control study conducted in 1992, however, showed that both cigarette smoking and alcohol consumption were risk factors for NPC. NPC risk was increased 3-fold with heavy smoking (adjusted for alcohol consumption), and an excess risk of 80% was demonstrated for heavy alcohol consumption (adjusted for cigarette usage). The possibility that environmental factors are important in the pathogenesis of NPC is supported by the finding that incidence rates decrease for successive generations of people who emigrated from southern China to California. Socioeconomic development in Hong Kong, along with dramatic lifestyle changes (including the marked decrease in consumption of salted fish and tobacco), as well as increased consumption of fresh vegetables, has led to a to a decrease in the age-standardized incidence rate of NPC in Hong Kong by more than 50% over 30 years.
In endemic areas, EBV has been tightly associated with the development of NPC. EBV infection is found in 90% to 100% of NPC cases in endemic regions. EBV is typically associated with mononucleosis or malignancies, such as Burkitt lymphoma and Hodgkin disease, in Western countries whereas in Asia it is closely linked to NPC. This association was described more than 30 years ago. Molecular biology advances have furthered understanding of the association. EBV infection is ubiquitous; this and other evidence suggests that that NPC has a multifactorial etiology.
Pathology
The tumor arises from epithelial cells on the surface of the nasopharynx. There are 3 different histologic subtypes according to the World Health Organization (WHO): keratinizing squamous cell carcinoma (WHO type I), nonkeratinizing differentiated carcinoma (WHO type II), and nonkeratinizing undifferentiated carcinoma (WHO type III). Nonkeratinized undifferentiated carcinoma comprise 90% to 95% of cases in endemic regions, such as southern China. EBV is more tightly associated with NPC in endemic regions. In contrast, keratinizing squamous cell carcinomas are most commonly found in Western countries. EBV DNA is detected less frequently in patients with keratinizing squamous cell carcinomas. The prognosis for keratinizing squamous cell carcinomas has been poorer as compared to nonkeratinizing histologic subtypes. However, a recent study of 2436 new cases in the United States demonstrated that Chinese keratinizing squamous cell carcinoma NPC patients had statistically improved survival as compared to keratinizing squamous cell carcinoma NPC patients from other ethnicities, suggesting that ethnicity plays a role in NPC pathogenesis.
Molecular Biology
The causal link between EBV and the development of NPC remains to be elucidated, despite advances in molecular biology confirming the association. EBV-encoded proteins are expressed from the EBV genome on entry into host cells, such as latent membrane proteins (LMPs) 1, 2A, and 2B; 6 EBV nuclear antigens (EBNAs) 1, 2, 3A to C, and LP; and 2 small noncoding nuclear RNAs (EBERs). EBV has been shown to immortalize and transform B cells into lymphoblastoid cells. Infection of epithelial cells by EBV is inefficient, however, and how EBV infects epithelium and transforms the cells is unknown. Perhaps EBV infection of the nasopharyngeal epithelium is an early event, with further processes leading to malignant transformation. Recent studies have suggested that a transcription factor, signal transducer and activator of transcription 3 (STAT3), may be the mechanism for NPC pathogenesis. STAT3 overexpression has been demonstrated in greater than 75% of NPCs in endemic regions. EBV infection can induce the activation of STAT3, a well-characterized oncogenic transcription factor.
EBV DNA levels in pretreatment and postradiotherapy plasma samples from patients in Hong Kong correlated with outcome, which could be useful in risk stratification and therapeutic interventions.
High levels of EBNA-1 DNA after treatment of NPC in plasma predicted a high risk of distant metastases and low risk of survival. The DNA was measured by real-time polymerase chain reaction (qPCR) techniques. The median follow-up time during this study was 30 months, suggesting a promising biomarker to predict those patients at risk for metastasis or even relapse and potentially allowing high-risk patients to receive more intensive treatment.
Recently, mutational analysis of NPC using single nucleotide polymorphism arrays revealed 9 significantly mutated genes, many of which were novel. Several cellular processes and pathways were involved, including chromatin modifications, autophagy, and ERBB-PI3K signaling. This study identified new pathways and genes that are novel and potential targets for drug treatment (druggable). The work affords new insights into the pathogenesis of NPC.
Introduction
Epidemiology
Nasopharyngeal is an uncommon disease in the United States. The incidence is approximately 0.2 to 0.5 cases per 100,000 people. In Southeast Asia, North Africa, and parts of the Mediterranean basin, however, approximately 80 cases per 100,000 of the population are reported. Among the Inuit who reside in Alaska and Greenland, the incidence is also high (15 to 20 cases per 100,000 people). Several etiologic factors have been implicated. Dr John Ho’s observations in the 1970s on boat people in southern China with a high incidence of NPC led him in the search and identification of salted fish as a carcinogen. Cantonese salted fish is now identified as a group 1 human carcinogen according to the International Agency for Research on Cancer ( http://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E-12.pdf ). Other etiologic risk factors include alcohol consumption, cigarette smoking, and exposure to dust, fumes, and formaldehyde. The role of alcohol and cigarette smoking has been controversial, because prior studies have suggested no association. A case-control study conducted in 1992, however, showed that both cigarette smoking and alcohol consumption were risk factors for NPC. NPC risk was increased 3-fold with heavy smoking (adjusted for alcohol consumption), and an excess risk of 80% was demonstrated for heavy alcohol consumption (adjusted for cigarette usage). The possibility that environmental factors are important in the pathogenesis of NPC is supported by the finding that incidence rates decrease for successive generations of people who emigrated from southern China to California. Socioeconomic development in Hong Kong, along with dramatic lifestyle changes (including the marked decrease in consumption of salted fish and tobacco), as well as increased consumption of fresh vegetables, has led to a to a decrease in the age-standardized incidence rate of NPC in Hong Kong by more than 50% over 30 years.
In endemic areas, EBV has been tightly associated with the development of NPC. EBV infection is found in 90% to 100% of NPC cases in endemic regions. EBV is typically associated with mononucleosis or malignancies, such as Burkitt lymphoma and Hodgkin disease, in Western countries whereas in Asia it is closely linked to NPC. This association was described more than 30 years ago. Molecular biology advances have furthered understanding of the association. EBV infection is ubiquitous; this and other evidence suggests that that NPC has a multifactorial etiology.
Pathology
The tumor arises from epithelial cells on the surface of the nasopharynx. There are 3 different histologic subtypes according to the World Health Organization (WHO): keratinizing squamous cell carcinoma (WHO type I), nonkeratinizing differentiated carcinoma (WHO type II), and nonkeratinizing undifferentiated carcinoma (WHO type III). Nonkeratinized undifferentiated carcinoma comprise 90% to 95% of cases in endemic regions, such as southern China. EBV is more tightly associated with NPC in endemic regions. In contrast, keratinizing squamous cell carcinomas are most commonly found in Western countries. EBV DNA is detected less frequently in patients with keratinizing squamous cell carcinomas. The prognosis for keratinizing squamous cell carcinomas has been poorer as compared to nonkeratinizing histologic subtypes. However, a recent study of 2436 new cases in the United States demonstrated that Chinese keratinizing squamous cell carcinoma NPC patients had statistically improved survival as compared to keratinizing squamous cell carcinoma NPC patients from other ethnicities, suggesting that ethnicity plays a role in NPC pathogenesis.
Molecular Biology
The causal link between EBV and the development of NPC remains to be elucidated, despite advances in molecular biology confirming the association. EBV-encoded proteins are expressed from the EBV genome on entry into host cells, such as latent membrane proteins (LMPs) 1, 2A, and 2B; 6 EBV nuclear antigens (EBNAs) 1, 2, 3A to C, and LP; and 2 small noncoding nuclear RNAs (EBERs). EBV has been shown to immortalize and transform B cells into lymphoblastoid cells. Infection of epithelial cells by EBV is inefficient, however, and how EBV infects epithelium and transforms the cells is unknown. Perhaps EBV infection of the nasopharyngeal epithelium is an early event, with further processes leading to malignant transformation. Recent studies have suggested that a transcription factor, signal transducer and activator of transcription 3 (STAT3), may be the mechanism for NPC pathogenesis. STAT3 overexpression has been demonstrated in greater than 75% of NPCs in endemic regions. EBV infection can induce the activation of STAT3, a well-characterized oncogenic transcription factor.
EBV DNA levels in pretreatment and postradiotherapy plasma samples from patients in Hong Kong correlated with outcome, which could be useful in risk stratification and therapeutic interventions.
High levels of EBNA-1 DNA after treatment of NPC in plasma predicted a high risk of distant metastases and low risk of survival. The DNA was measured by real-time polymerase chain reaction (qPCR) techniques. The median follow-up time during this study was 30 months, suggesting a promising biomarker to predict those patients at risk for metastasis or even relapse and potentially allowing high-risk patients to receive more intensive treatment.
Recently, mutational analysis of NPC using single nucleotide polymorphism arrays revealed 9 significantly mutated genes, many of which were novel. Several cellular processes and pathways were involved, including chromatin modifications, autophagy, and ERBB-PI3K signaling. This study identified new pathways and genes that are novel and potential targets for drug treatment (druggable). The work affords new insights into the pathogenesis of NPC.
Patient evaluation overview
Prevention and Detection
Nasopharynx cancer often is not detected until a tumor has grown large enough to invade a critical structure. The association of EBV and NPC might play a role in screening for tumors. A study from China of 338,868 patients who underwent serologic screening for EBV titer revealed that of nearly 10,000 patients who had antibodies to EBV, NPC was detected in 113 (approximately 1.2%). Most (>85%) were early-stage cancers.
qPCR techniques may be helpful in detecting early nasopharyngeal cancer. Screening for LMP1 in nasopharyngeal swabs was shown to be a promising screening tool in high-risk populations, with a sensitivity of 87% and a specificity of 98%. Technological advances and other genetic or environmental markers proving useful in the detection of early NPC may lead to the identification of populations benefitting from rigorous screening or chemoprevention.
Clinical Manifestations
Nasopharyngeal cancer is rare in the Western countries and therefore seldom suspected when patients present with early symptoms. In a Texas series analyzing 378 patients, presenting symptoms included a neck mass in 41%; ear complaints (including hearing loss and drainage) in 27%; nasal bleeding/obstruction in 21%; cranial nerve deficits in 8%; and other nonspecific symptoms in 8%. Level VA lymph nodes were most commonly enlarged (54% of patients), followed by the level II nodes (49% of patients). The level III and lower-level VA/upper-level VB groups were involved in 24% and 22% of patients, respectively. Level IV, lower-level VB, and supraclavicular lymph nodes were less commonly involved (approximately 10%–13%). Cranial nerve VI was the nerve most frequently affected.
Detection/Patient Evaluation
All patients who have a diagnosis of NPC must undergo a history and physical examination. Documentation of the clinically involved lymph nodes in the neck is helpful, especially when a radiotherapy boost is considered. All patients should have nasopharyngoscopy to determine involvement of mucosal surfaces. This is also useful for a biopsy of the primary lesion.
CT and MRI of the head and neck are valuable in the evaluation of the tumor and associated lymphadenopathy. MRI may be more useful in delineating soft tissue invasion outside the nasopharynx, which is required for T staging, and extent of retropharyngeal lymph node involvement ; hence, MRI is necessary for evaluating nasopharyngeal tumors. MRI is also superior to CT for assessing clival involvement and perineural invasion. Positron emission tomography (PET)/CT evaluation for distant metastases completes the staging/work-up. It may be useful after treatment, when persistent anatomic changes limits the ability of other modalities to detect local recurrence.
Blood tests as well as a preradiation therapy dental assessment and audiology evaluation should be undertaken.
Staging
Clinical staging has been a matter of controversy. The most common staging systems used in North America and Europe include those of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (Union Internationale Contre le Cancer [UICC]). In Asia, the Ho classification system, developed in Hong Kong, is widely used. In China, specifically, physicians adopted an independent classification, similar to the Ho system ( Table 1 ). The AJCC/UICC staging is most commonly used in the English literature.
| Classification | American Joint Committee on Cancer | 2002/1997 American Joint Committee on Cancer | Ho | 2008 Chinese |
|---|---|---|---|---|
| T1 | Confined to nasopharynx, or extends to oropharynx and/or nasal cavity | Confined to nasopharynx | Confined to nasopharynx | Confined to nasopharynx |
| T2 | With parapharyngeal extension |
| Nasal fossa, oropharynx, muscle, or nerves below base of skull | Nasal cavity, oropharynx, parapharyngeal extension |
| T3 | Bony or paranasal sinus extension | Bony or paranasal sinus extension |
| Skull base or medial pterygoid extension |
| T4 | Intracranial extension, or cranial nerve or infratemporal fossa, a hypopharynx, or orbital involvement | Intracranial extension, or cranial nerve or infratemporal fossa, a hypopharynx, or orbital involvement | — | Cranial nerves, paranasal sinuses, masticator space a (excluding medial pterygoid muscles), intracranial (cavernous sinus, dural meninges) extension |
| N1 | Unilateral, ≤6 cm and/or unilateral or bilateral retropharyngeal ≤6 cm | Unilateral, ≤6 cm | Upper neck above thyroid notch |
|
| N2 | Bilateral, ≤6 cm | Bilateral, ≤6 cm | Below thyroid notch above line joining end of clavicle and superior margin of trapezius muscle | Bilateral level Ib, II, III, and Va or >3 cm or with extranodal spread |
| N3 |
|
| Supraclavicular fossa b or skin involvement | Level IV or Vb involvement |
| M1 | — | Metastases | Metastases | Metastases |
| Stage I | T1N0M0 | T1N0M0 | T1N0 | T1N0M0 |
| Stage II | T1N1 T2N0 T2N1 |
| T2 and/or N1 | T1N1a-1bM0 or T2N0-1bM0 |
| Stage III | T1N2M0 T2N2M0 T3N0-2M0 | T1-2bN2M0 T3N0-2M0 | T3 and/or N2 | T1-2N2M0 or T3N0-2M0 |
| Stage IV |
|
| N3 (any T) |
|
| Stage V | — | — | M1 | — |
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