Practice Essentials
A rare tumor, nasopharyngeal carcinoma (NPC) develops from the epithelium of the nasopharynx. [1]
Signs and symptoms of nasopharyngeal carcinoma
Clinically, NPC has few early warning signs, which often means late diagnosis. Early but nonspecific symptoms include the following:
-
Nasal obstruction
-
Blood-tinged sputum or nasal discharge
-
Headache
-
Ear fullness
-
Unilateral conductive hearing loss from serous otitis media or recurrent acute otitis media
Evidence of cranial nerve involvement (III-VI), including diplopia and numbness of the face, suggests cavernous sinus invasion.
Workup in nasopharyngeal carcinoma
Lab studies
Many studies have shown that NPC is closely associated with elevated titers of Epstein-Barr virus (EBV).
Seroepidemiologic studies have demonstrated that 80-90% of patients with World Health Organization (WHO) type 2 NPC and WHO type 3 NPC have elevated levels of immunoglobulin A (IgA) antibodies to viral capsid antigen (VCA) and early antigen (EA). However, only 10-20% of patients with WHO type 1 NPC have elevated levels of IgA to VCA.
Other serologic tests include the following:
-
IgA antibodies directed against EBV
-
EBV nuclear antigen (EBNA)–1 (found in about 90% of patients with NPC)
-
IgG antibodies to the EBV replication activator (ZEBRA) and BRLF1 transcription activator (Rta)
Imaging studies
Magnetic resonance imaging (MRI) with gadolinium and fat suppression is the radiologic modality of choice for assessing locoregional disease. [2]
In the detection of residual and/or recurrent NPC following radiation treatment, function-based modalities, such as 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning, are not affected by the anatomic distortion resulting from radiation-induced scarring, fibrosis, and edema of the nasopharyngeal tissue.
Diagnostic procedures
These include the following:
-
Transnasal biopsy of nasopharyngeal mass
-
Fine-needle aspiration of a neck mass
Management of nasopharyngeal carcinoma
External beam radiation therapy is the primary mode of management of nasopharyngeal carcinoma (NPC), both at the primary site and in the neck. This is mainly because of this tumor's high degree of sensitivity to radiation, as well as the anatomical constraints for surgical access to the highly complex nasopharyngeal region.
Recurrent or persistent disease remains a challenge to clinicians. Typically, re-irradiation is advocated. In some institutions, salvage nasopharyngectomy is used for the treatment of recurrent disease. [3] A high prevalence of distant metastases has been observed for patients with NPC.
History of the Procedure
In 1988, Fee and Tu published results of salvage nasopharyngectomy in a series of patients with recurrent NPC who failed previous treatment with radiation. [4, 5] The results were encouraging [4] and inspired other investigators to start using surgery in the treatment of patients with recurrent NPC. Since then, various surgical approaches to the nasopharynx have been proposed. These include the transpalatal-maxillary-cervical, maxillary swing, transmandibular, transcervico-mandibulo-palatal, infratemporal fossa, lateral temporal, endoscopic, and robotic approaches.
Problem
Despite recent advances in the management of NPC, locoregional failure is still significant, with reported rates of 15.6-58% (median, 34%). [6, 7, 8, 9] Salvage treatment for local failure continues to be challenging because of the proximity of tumors to vital structures.
Epidemiology
Frequency and mortality
Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia. [10] In areas such as southern China, Hong Kong, Singapore, Malaysia, and Taiwan, the reported incidence rate ranges from 10-53 cases per 100,000 persons per year. The incidence is also high among Eskimos in Alaska and Greenland and in Tunisians, ranging from 15-20 cases per 100,000 persons per year. Although NPC is a relatively uncommon disease in Western countries (< 1 case per 100,000 persons), it poses a significant health problem in regions of the United States with large Asian populations. The prevalence rate for people of Asian descent in the United States is 3.0-4.2 cases per 100,000 persons.
A study by Tang et al found that between 1970 and 2007, the age-standardized incidence rate of NPC saw significant reductions in southern and eastern Asia, North America, and the Nordic nations, with the average annual percent declines being 0.9-5.4% in males and 1.1-4.1% in females. Age-standardized mortality rates between 1970 and 2013 also fell, showing average annual percent reductions of 0.9-3.7% in males and 0.8-6.5% in females. The investigators suggested that the incidence reductions were associated with tobacco control, dietary changes, and economic development, while the drop in mortality rates stemmed not only from the reduced incidence but also from diagnostic advancements and improved radiotherapy techniques. [11]
Using 1992-2013 information from the Surveillance, Epidemiology, and End Results (SEER) Program database, Challapalli et al looked at the disease-specific survival rates in the United States for adult blacks, Hispanics, Asians/Pacific Islanders, and American Indians/Alaska natives, with NPC, finding the worst disease-specific survival rate to be among non-Hispanic American Indians/Alaska natives. The best disease-specific survival rate was found in non-Hispanic Asians/Pacific Islanders. [12]
Etiology
A clear etiology for nasopharyngeal carcinoma (NPC) is still lacking. In general, NPC is thought to be the result of both genetic susceptibility and environmental factors such as carcinogens and infection with Epstein-Barr virus (EBV). Evidence in support of genetic factors is the association of NPC with genotypes HLA-A2 and HLA-Bsin2, which are prevalent in individuals from southern China but rare in whites. Furthermore, abnormalities of multiple chromosomes, including 1, 2, 3, 4, 5, 6, 8, 9, 11, 13, 14, 15, 16, 17, 22, and X, have been identified.
Possible environmental or cultural factors that may be associated with NPC include the ingestion of Cantonese-style salted fish and preserved foods that contain carcinogenic nitrosamines, especially during childhood. Evidence of EBV-DNA in almost all NPC cells that were studied supports the association of NPC with EBV. Further, the detection of clonal EBV-DNA in NPC suggests that the malignancy is a clonal expansion of a single EBV-infected progenitor cell. This finding indicates that EBV is present within the cell at the time of malignant transformation and suggests a role for the virus in contributing to the early transformation event. The contribution of both genetic factors and environmental factors for this disease is reflected in the observation that the incidence of NPC for American-born, second-generation Chinese individuals is lower than that for Chinese-born individuals in China but remains higher than that for white individuals in the United States.
Presentation
Although reported in all age groups, a bimodal peak incidence appears to occur in individuals aged 30-40 years and 50-60 years. Nasopharyngeal carcinoma (NPC) is observed predominantly in males, with a male-to-female ratio of 3:1. Clinically, NPC has few early warning signs, which often means late diagnosis. Early but nonspecific symptoms include nasal obstruction, blood-tinged sputum or nasal discharge, tinnitus, headache, ear fullness, and unilateral conductive hearing loss from serous otitis media or recurrent acute otitis media. In advanced cases, the tumor can invade the skull base and spread intracranially through one of the many nearby foramina. Evidence of cranial nerve involvement (III-VI), including diplopia and numbness of the face, suggests cavernous sinus invasion.
The abundant supply of regional lymphatic vessels in the nasopharynx contributes to the high prevalence of cervical metastasis. Approximately 44-57% of patients initially seek medical attention because of a metastatic lymph node that manifests as a neck mass. At the time of diagnosis, 60-85% of patients already have cervical metastasis.
Systemic dissemination also occurs more readily in NPC than in other head and neck cancers. The most frequently involved sites are bone, lung, and liver. Distant metastases are present in 5-10% of patients at the initial presentation.
Indications
Salvage nasopharyngectomy and neck dissection may be indicated in patients with nasopharyngeal carcinoma (NPC) that persisted or recurred locoregionally following prior treatment with radiation with or without chemotherapy. The proper selection of patients and surgical approach are essential for a successful outcome.
Relevant Anatomy
Nasopharynx
The nasopharynx is defined anteriorly by the posterior choanae, posteriorly by the clivus and the first 2 cervical vertebrae, superiorly by the floor of the sphenoid, and inferiorly by the level of the free border of the soft palate. The nasopharynx is divided into 3 subsites: the posterosuperior wall, the lateral walls, and the posterosuperior surface of the soft palate. The torus tubarius is the opening of the eustachian tube into the lateral nasopharyngeal wall. The fossa of Rosenmüller is the groove or recess posterior to the torus at the junction between the lateral and posterior walls. Nasopharyngeal carcinoma (NPC) most commonly occurs in this location.
The posterior and lateral nasopharyngeal walls are composed of 3 layers of tissue. The mucosal epithelium of the nasopharynx is complex, consisting mainly of pseudostratified columnar ciliated epithelium near the choanae and the adjacent part of the roof of the nasopharynx, a transitional epithelium in the roof and the lateral walls, and stratified squamous epithelium along the posterior and inferior portions of the nasopharynx. The superior constrictor muscle and the buccopharyngeal fascia surround the mucosa. Superiorly, the buccopharyngeal fascia unites with the pharyngobasilar fascia, which is attached to the skull base.
The buccopharyngeal fascia extends posterolaterally from the free edge of the medial pterygoid plate to the lateral border of the carotid artery. This fascia separates the nasopharynx from the parapharyngeal (paranasopharyngeal) space. A line joining the free edge of the medial pterygoid plate posterolaterally to the styloid process divides the paranasopharyngeal space into the prestyloid space anteriorly and the retrostyloid space (containing the carotid sheath and the cranial nerves) posteriorly.
The paranasopharyngeal space is bound anteriorly by the pterygomandibular raphe, which joins the lateral pterygoid plate to the mandible. The retropharyngeal space contains the retropharyngeal lymph nodes and the node of Rouviere. This space is located posterior to the buccopharyngeal fascia and anterior to the prevertebral fascia; therefore, lesions that extend beyond the buccopharyngeal fascia posteriorly involve the retropharyngeal space, while lesions extending laterally beyond this fascia reach the parapharyngeal space.
The nasopharynx is an anatomically difficult area to expose surgically. This area is in close proximity to several foramina and associated vital neurovascular structures. These include the foramen ovale, the foramen spinosum, the foramen lacerum, the carotid canal, and the jugular foramen.
Neck
Ho originally described the supraclavicular fossa as a triangular region defined by 3 points: the sternal end of the clavicle, the lateral end of the clavicle, and the point where the neck meets the shoulder. [13] This area is clinically significant in that any nodal involvement within this triangle is, by definition, an N3 lesion and, therefore, stage IV cancer.
Contraindications
Salvage nasopharyngectomy is contraindicated in patients with locally unresectable recurrent nasopharyngeal cancer and patients with distant metastasis.
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Axial T2-weighted image shows a left-sided cervical nodal metastasis resulting from nasopharyngeal cancer.
Tables
- Table 1. Diagnostic profiles of IgA to EA and IgA to VCA [14]
- Table 2. Predictive Value of Epstein-Barr Virus Serology Combinations
- Table 3. Diagnostic Values of the 4 EBV Antibodies [15]
- Table 4. Diagnostic Accuracy based on Different Combination of the 4 EBV Antibodies
- Table 5. Prospective Randomized Clinical Trials of Chemoradiation Versus Radiation Alone in the Treatment of Locally Advanced NPC
- Table 6. Intergroup Study 0099. Subgroup Analysis of 5-Year Overall Survival Based on WHO Types [32]
Serology Status |
Sensitivity |
Specificity |
PPV |
NPV |
||
IgA to EA |
80.2% |
100% |
100% |
83.5% |
||
IgA to VCA |
97.3% |
46.8% |
64.7% |
94.5% |
||
IgA Antibody to EA |
IgA Antibody to VCA |
Probability of NPC |
+ |
+ |
100% |
+ |
— |
100% |
— |
— |
5.5% |
— |
+ |
37.8% |
Serology Status |
Sensitivity |
Specificity |
Area Under ROC Curve (95% CI) |
||
IgA to EA |
89.1% |
98.5% |
0.94 (0.92-0.96) |
|
|
IgA to VCA |
98.1% |
82.8% |
0.98 (0.96-0.99) |
|
|
IgG to Rta |
90.5% |
85.2% |
0.92 (0.89-0.95) |
|
|
IgA to EBNA1 |
87.2% |
84.2% |
0.92 (0.89-0.95) |
|
|
Combination |
Sensitivity |
Specificity |
Area Under ROC Curve (95% CI) |
||
IgG to Rta + IgA to EBNA1 |
93.4% |
90.6% |
0.97 (0.95-0.98) |
|
|
IgA to VCA + IgA to EA |
92.4% |
98.5% |
0.98 (0.96-0.99) |
|
|
IgA to VCA + IgA to EBNA1 |
94.3% |
98.0% |
0.98 (0.97-0.99) |
|
|
IgA to VCA + IgG to Rta |
94.8% |
98.0% |
0.99 (0.98-1.00) |
|
|
IgA to VCA + IgA to EA + IgA to EBNA1 |
97.2% |
95.6% |
0.98 (0.97-0.99) |
|
|
IgA to VCA + IgA to EA + IgG to Rta |
92.9% |
99.5% |
0.99 (0.98-1.00) |
|
|
IgA to VCA + IgG to Rta + IgA to EBNA1 |
94.8% |
98.5% |
0.99 (0.98-1.00) |
|
|
IgA to VCA + IgA to EA + IgG to Rta + IgA to EBNA1 |
96.7% |
97.0% |
0.99 (0.98-1.00) |
|
|
Author, Year |
Stage |
Number of Patients |
Treatment Arms |
Survival Rate |
P Value |
Neoadjuvant Chemotherapy Followed by Radiation |
|||||
VUMCA, 1996 [52] |
IV |
n=171 |
Bleomycin/epirubicin/cisplatin X 3 Radiation |
60% (3 yr OS) |
P > .05 |
n=168 |
Radiation alone |
54% (3 y OS) |
|||
Hareyama, 2002 [53] |
I-IV |
n=40 |
Cisplatin/5-FU X 2 Radiation |
60% (5 y OS) |
P > .05 |
n=40 |
Radiation alone |
45% (5 y OS) |
|||
Chua, 1998 [37] |
T3 N2-3 |
n=167 |
Cisplatin/epirubicin X 2-3 Radiation |
78% (3 y OS) |
P = .57 |
n=167 |
Radiation alone |
71% (3 y OS) |
|||
Ma, 2001 [38] |
III-IV |
n=224 |
Cisplatin/bleomycin/5-FU X 2-3 Radiation |
63% (5 y OS) |
P = .11 |
n=225 |
Radiation alone |
56% (5 y OS) |
|||
Concurrent Chemotherapy and Radiation |
|||||
Lin, 2003 [40] |
III-IV |
n=141 |
Cisplatin/5-FU X 2 + Radiation |
72.3% (5 y OS) |
P = .002 |
n=143 |
Radiation alone |
54.2% (5 y OS) |
|||
Chan, 2005 [39] |
II-IV |
n=174 |
Cisplatin weekly and Radiation |
70.3% (5 y OS) |
P = .048 |
n=176 |
Radiation alone |
58.6% (5 y OS) |
|||
Radiation Followed by Adjuvant Chemotherapy |
|||||
Rossi, 1988 [54] |
I-IV |
n=113 |
Radiation Vincristine/cyclophosphamide/Adriamycin X 6 |
59% (4 y OS) |
P > .05 |
n=116 |
Radiation alone |
67% (4 y OS) |
|||
Chi, 2002 [35] |
IV |
n=77 |
Radiation Cisplatin/5-FU/leucovorin X 9 |
61% (5 y OS) |
P = .5 |
n=77 |
Radiation alone |
55% (5 y OS) |
|||
Neoadjuvant Chemotherapy Followed by Radiation Followed by Adjuvant Chemotherapy |
|||||
Chan, 1995 [39] |
|
n=34 |
Cisplatin/5-FU X 2 Radiation Cisplatin/5-FU X 4 |
80% (5 y OS) |
P = .1 |
n=40 |
Radiation alone |
81% (5 y OS) |
|||
Concurrent Chemotherapy and Radiation Followed by Adjuvant Chemotherapy |
|||||
Al-Sarraf, 1998 [32] |
III-IV |
n=93 |
Cisplatin X 3 + Radiation Cisplatin/5-FU X 3 |
78% (3 y OS) |
P< 0.001 |
n=92 |
Radiation alone |
47% (3 y OS) |
|||
III-IV |
n=93 |
Cisplatin X 3 + Radiation Cisplatin/5-FU X 3 |
67% (5 y OS) |
P< 0.001 |
|
n=92 |
Radiation alone |
37% (5 y OS) |
|||
III-IV |
n=111 |
Cisplatin X 3 + Radiation Cisplatin/5-FU X 3 |
67% (5 y OS) |
P = 0.008 |
|
n=110 |
Radiation alone |
49% (5 y OS) |
|||
T1-4 N2-3 |
n=172 |
Cisplatin X 3 + Radiation Cisplatin/5-FU X 3 |
68% (5 y OS) |
P = 0.22 |
|
n=176 |
Radiation alone |
64% (5 y OS) |
|||
Chen, 2013 [46] |
III-IV |
n=158 |
1) Cisplatin weekly + radiation 2) Cisplatin/5-FU X 3 |
72% (5 y OS) |
P = 0.043 |
n=158 |
Radiation alone |
||||
62% (5 y OS) |
|||||
Treatment |
WHO I, II, III (n=147) OS, % |
WHO II and III (n=111, 75) OS, % |
WHO I (n=36, 25%) OS, % |
Radiation |
37 |
45 |
14 |
Chemoradiation |
67 |
70 |
59 |
