Nasopharyngeal Carcinoma: Diagnostic Strategies
Clinical Features
Compared with other malignancies in the head and neck region, nasopharyngeal carcinoma (NPC) affects a relatively younger age group of patients1 and this has remained much the same over the years.2,3 In most countries it is 2 to 3 times more common in males than females.4 The symptoms of NPC are related to the location of the tumor in the nasopharynx, the degree of its infiltration and effect on surrounding structures, and its metastases both regionally and distantly.
Commonly, NPC patients present with one or more of the four groups of symptoms.
Nasal symptoms related to the presence of tumor mass in the nasopharynx. This could be unilateral nasal obstruction when the tumor reaches a significant size or, when the tumor ulcerates, blood-stained nasal discharge frequently seen in the early-morning postnasal discharge. Severe epistaxis is rarely seen and only presents in advanced-stage disease when the tumor erodes a vessel.
Aural symptoms include hearing loss, tinnitus and, less frequently, otalgia and otorrhea. This is related to the location of the tumor at the fossa of Rosenmüller or its posterolateral extension to the paranasopharyngeal space, leading to eustachian tube dysfunction.5 This might cause the collection of fluid in the middle ear, which is responsible for the conductive hearing loss. Serous otitis media was reported to be present in ~30% of patients at diagnosis.6 In an ethnic Chinese patient, the presentation of serous otitis media after childhood should alert the attending clinician to the possible diagnosis of NPC.7,8
Cranial nerve palsies, which are associated with the superior extension of the tumor. The incidence of cranial nerve involvement on presentation is ~20% and is related to skull base erosion and direct tumor infiltration.9 The patient might experience headache, diplopia, facial pain, and numbness. Cranial nerves III, IV, and VI are involved when a tumor extends upward and affects the cavernous sinus (Fig. 24.1). The trigeminal nerve will be affected when the tumor involves the foramen ovale region.10 Cranial nerves IX to XII are frequently affected when the tumor extends to the paranasopharyngeal space below the base of the skull.
Metastatic cervical lymph node presenting as neck masses. This is the commonest mode of presentation of NPC, a painless unilateral mass in the upper neck.11 Bilateral cervical nodal involvement is not uncommon as the nasopharynx is a central structure with a rich lymphatic supply and the tumor frequently crosses the midline (Fig. 24.2). The lymph nodes around the posterior belly of the digastric muscle and upper jugular groups are frequently affected before those in the middle and lower neck.12 This orderly involvement of lymph nodes, from upper neck to lower neck has been shown to be of prognostic significance.13
A larger retrospective analysis of 4,768 patients suffering from nasopharyngeal carcinoma showed that the median duration between the onset of symptoms and establishing diagnosis was 8 months. The symptoms at presentation were neck mass (75.8%), nasal-related symptoms (73.4%), aural-related symptoms (62.4%), headache (34.8%), diplopia (10.7%), facial numbness (7.6%), weight loss (6.9%), and trismus (3.0%).14 The physical signs elicited at diagnosis were enlarged neck node (74.5%), and cranial nerve palsy (20.0%). The cranial nerves most commonly involved were the fifth, sixth, third, and twelfth.15 The presenting symptoms in young patients, those below 20 years of age, were in general similar to those in adults. Nasal and aural symptoms were more frequently seen than neck masses.16
Trismus and headache are less frequently seen as the presenting symptom, as they are related to extensive tumor involvement and usually accompany other symptoms. Trismus is caused by tumor extension laterally to involve the pterygoid muscles, while headache is due to involvement of the skull base. The incidence of distant metastasis on presentation in general is less than 5%. The frequent sites of metastasis are the vertebrae and femoral heads. Radiologically, 66% of the lesions are lytic, although mixed lytic and sclerotic lesions are seen in 13% of patients.17 The main symptom associated with bone metastasis is localized bone pain. Less frequent sites of metastasis are the lungs and liver and these patients could have chest symptoms and deranged liver function. General symptoms of malignancy such as anorexia and weight loss are uncommon in NPCs, and disseminated disease should be suspected when these symptoms are present.
Unfortunately, symptoms of early-stage disease—those related to nasal and aural symptoms—are usually trivial and nonspecific, and thus are often ignored by the patient or misinterpreted by the physician. A full clinical examination of the nasopharynx is also not easy; thus the majority of NPC patients are only diagnosed when the tumor has reached advanced stages.
Diagnosis
Clinical
Symptoms of nasopharyngeal carcinoma vary greatly between different patients, even when they have in the same stage of disease. Some of the symptoms may be trivial and patients may not be aware of them, thus it is difficult to arrive at the diagnosis by taking history alone. A full clinical examination of the head and neck region is essential, and particular effort should be exercised to detect the presence of serous otitis media, cervical lymphadenopathy, and any cranial nerve involvement.
When a patient is suspected to be suffering from nasopharyngeal carcinoma, a thorough examination of the nasopharynx is mandatory. The posterior nasal space in some patients can be adequately examined indirectly with a mirror, while in other patients the examination is limited by anatomical variation of the nasopharynx such as the approximation of the soft palate toward the posterior wall of the nasopharynx. Other patients may have an exaggerated gag reflex, making the examination difficult.
The nasopharynx can be examined directly under local anesthesia with either a rigid or a flexible endoscope. When a suspicious lesion is seen, a biopsy can be taken at the same time. The rigid 0° and 30° Hopkin rod endoscopes provide an excellent view of the nasopharynx on the side of the insertion (Fig. 24.3) and the superficial extent of the tumor can be determined (Fig. 24.4). The 30° endoscope can be used to view the opposite side of the nasopharynx when an anatomical variation, such as a deviated nasal septum, does not allow the introduction of the endoscope through the nasal passage (Fig. 24.5). Alternatively, the 70° endoscope introduced through the mouth beyond the soft palate can provide a centered view of the whole nasopharynx, including the extent of the tumor (Fig. 24.6). These rigid endoscopes with an outer diameter of 3 or 4 mm do not have a suction or biopsy channel. Therefore, a separate suction catheter has to be inserted alongside the endoscope to remove blood or mucus before an unobstructed view of the nasopharynx can be obtained. A pair of forceps also has to be inserted separately along the endoscope in the same nasal passage, or through the other nasal cavity to obtain a biopsy.
A flexible fiberoptic endoscope, with or without a suction and biopsy channel, allows a more thorough examination of the nasopharynx compared with a rigid endoscope. This is because the tip of the endoscope can be manipulated to turn round angles to reach the tumor. The image obtained from the flexible fiberoptic endoscope is inferior to that from the rigid endoscope, although with the flexible videoendoscopes the quality of images are much better (Fig. 24.7). The flexible endoscope can be inserted through one nasal cavity and then turned behind the nasal septum to examine the opposite nasopharynx. Thus, the entire nasopharynx can be adequately examined with the endoscope inserted once. When there is difficulty in passing the endoscope through the nasal cavity owing to the presence of a large tumor or other anatomical variation, the flexible endoscope can be inserted through the mouth and manipulated to above the soft palate to examine the entire nasopharynx (Fig. 24.8).
After adequate examination of the tumor following removal of mucus by suction, a biopsy is taken of any suspicious lesion in the nasopharynx as seen through the endoscope (Fig. 24.9). When a separate forceps (Fig. 24.10) is used for taking the biopsy, a large piece of tissue can be obtained for histological examination (Fig. 24.11). When a flexible endoscope is used, only a small biopsy forceps can be inserted through the narrow flexible endoscopic channel and the amount of tissue obtained may not be sufficient for diagnosis. However, the small biopsy forceps are useful for taking biopsies from the narrow confines of the pharyngeal recess. The mucosa overlying the lesion should be broken with the forceps and then one jaw of the forceps is inserted through the mucosal wound into the submucosa to obtain more tissue for histological examination.18
Serology
The ubiquitous Epstein-Barr Virus (EBV) has a strong association with NPC. EBV-specific antigens can be grouped into latent-phase antigens, early replicative antigens, and late antigens. Latent-phase antigens include the EBV-associated nuclear antigen (EBNA) and the latent membrane proteins (LMPs).19 The early antigens are the early membrane antigen (EMA) and early intracellular antigen (EA).20 The late antigens are the viral capsid antigen (VCA) and late membrane antigen (LMA).21
The immunological response of a patient infected with EBV varies between individuals and depends on the manifestation of the associated disease. Patients suffering from NPC have a high level of immunoglobulin (IgA) response to VCA and EA. This has been used for decades as a diagnostic indicator for nasopharyngeal carcinoma.22,23 The antibodies for viral capsid antigen (IgA anti-VCA) and early antigen (IgA anti-EA) have been used widely to screen for early nasopharyngeal carcinoma.24,25 Determination of levels of these antibodies has been used in the screening of NPC in endemic areas.26 The IgA anti-VCA is a more sensitive but less specific test than IgA anti-EA. Endoscopic examination and biopsy of the nasopharynx, aiming at early detection of NPC, were performed in patients with high IgA levels.27
A prospective study was performed in Guangdong, southeast China, to evaluate the efficacy of serology in detecting early nasopharyngeal carcinoma.28 IgA levels against the VCA and EA of the Epstein-Barr virus were tested in 67,891 healthy persons. A total of 6,102 subjects (9%) were found to have an elevated serum antibody titer. On endoscopic examination and biopsy 48 (0.8%) of the seropositive subjects had NPC although they were asymptomatic. Of the remaining 6,054 seropositive patients, 130 were randomly recruited for endoscopic examination and biopsy of the nasopharynx. There were 71 men and 59 women, ages ranging from 30 to 61 years (median, 44 years). Positive biopsy was obtained from seven patients, confirming NPC.
From this prospective study, subclinical NPC was diagnosed in 5.4% of patients (7/130) with elevated IgA titer against EBV. Thus in high-risk regions, patients with elevated antibody levels should undergo an endoscopic examination of the nasopharynx.
The level of the IgA anti-EBV has also been shown to be related to the stage of the tumor, which is proportional to the tumor burden.29 Most of the studies on the EBV serology for early diagnosis of NPC were performed in the 1980s. When IgA anti-VCA was compared with antibodies against other EBV antigens such as EBNA in the diagnosis of nasopharyngeal carcinoma, IgA anti-VCA has the lowest false-negative value.30 A recent meta-analysis of 20 of these types of studies showed that IgA anti-VCA when elevated has a sensitivity of 91% and specificity of 92% in the diagnosis of nasopharyngeal carcinoma.31 Although the level of IgA anti-VCA has been shown to decrease in NPC patients whose tumors have been eradicated,32 its value in the monitoring of recurrence is not established.33
As EBV is frequently detected in nasopharyngeal undifferentiated carcinoma cells and on the lysis of these malignant cells, EBV DNA is released into the blood. This DNA has a short half-life but, with a high turnover rate of malignant cells, increasingly numerous copies of EBV DNA are released and this circulating free EBV DNA can now be detected by PCR in patients with NPC.34 In 96% of patients suffering from NPC, EBV DNA can be detected in plasma.35 This is further supported by the fact that increased copies of EBV DNA were found in the blood during the initial phase of radiotherapy, suggesting that the viral DNA was released into the circulation after cell death.36 The quantity of free plasma EBV DNA as measured by real-time quantitative PCR has been shown to be related to the stage of the disease.37 The detection of EBV DNA has increasingly been used for the diagnosis of NPC and this has been shown to be more accurate than measuring the antibody titers against the various EBV antigens.38
The use of serum EBV DNA has been shown to be sensitive and reliable for the detection of distant metastases.39 The numbers of EBV DNA copies before and after treatment are significantly related to the rates of overall and disease-free survival.40,41 There were reports stating that the levels of posttreatment EBV DNA, when compared with pretreatment EBV DNA, had a better prediction for progression-free survival,42 and they have also been used to monitor any recurrent disease after treatment.43 Elevated levels of EBV DNA were, however, detected in only 67% of patients with locoregional recurrence when the recurrence volume was small.44 When EBV DNA was employed together with IgA against viral capsid antigen of EBV, the sensitivity of early diagnosis of nasopharyngeal carcinoma increased.45
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