**2.1.4 Tumor invading the middle ear**

158 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

the middle ear, prevent the formation of excessively high negative middle-ear pressure from gaseous absorption through the middle-ear mucosa (Grontved *et al.,* 1990). This had been supported by animal studies where the prevention of middle ear ventilation by ligating the Eustachian tube led to maximum middle-ear pressures of only 116 mm water (Proud *et al.,*  1971). In humans, it had been observed that inadequate middle ear ventilation from organic obstruction by antro-choanal polyps and some other nasopharyngeal tumors seldom led to

However, for many years, the compliance of the Eustachian tube had been thought to be a factor causing MEE in children (Bluestone, 1985). More recently, the MEE's associated with cleft palate and Down's syndrome was believed to be the result of poorly developed

It is therefore reasonable to postulate that abnormal compliance of the Eustachian tube could also result from tumor erosion of the cartilaginous part of the tube and this may also play a role in the pathogenesis of NPC-associated MEE. Low et al. (1997) suggested that when tumour has affected the lamina and the hinge portion of the cartilage, it could lead to

NPC-induced Eustachian tube dysfunction could present as a sensation of ear blockage.

A 50-year-old Chinese man presented with the complaint of a sensation of blockage in his left ear lasting for two weeks. He had no preceding upper respiratory tract infection. Examination of the ears was normal. Examination of his nasopharynx with the flexible nasal-endoscope was unremarkable. Epstein-Barr viral serology (as an NPC screen) was positive for both viral capsid and early antigens. Random nasopharyngeal biopsies revealed undifferentiated carcinoma on the left side. Magnetic resonance scan showed a small T 1

Ear blockage is the result of negative middle ear pressures (MEPs) without actually developing MEE. Low (1995) carried out a prospective study to investigate MEPs in patients with NPC. Newly diagnosed patients with NPC were studied before and at three to 12 months (mean 7.5 months) after radiotherapy. MEPs were measured by tympanometry. The mean MEP before and after radiotherapy was -55.2 mm water (range -250 to 45 mm water) and -73.1 mm water (range -215 to 35 mm water) respectively. About two-thirds of assessable ears had an increase in negative MEPs after irradiation and the rest had less negative MEPs after irradiation. Those ears that developed post-irradiation middle ear effusions were found to have pre-irradiation negative middle ear pressures of at least -45 mm water. It was concluded that tympanometry before radiotherapy may prove to be useful

Sub-clinical Eustachian tube dysfunction caused by NPC might present clinically as barotrauma. Low & Goh (1999) illustrated this in a case report of a 40-year-old Chinese female complaining of right earache and blockage after descending from an air-flight. She

Eustachian cartilages with abnormal compliances (Shibahara and Sando, 1989).

a change of tubal compliance, resulting in MEE formation.

**2.1.2 Ear blockage and negative middle ear pressures** 

Low and Goh (1999) illustrated this with a case study:

submucosal lesion on the left side of the nasopharynx

**2.1.3 Barotrauma** 

in identifying ears with a high risk of developing post-irradiation MEE.

MEE formation (Sadé, 1994).

NPC may spread and occupy the middle ear space. It has been proposed that the routes of spread of NPC to the middle ear are via the eustachian tube, direct invasion from the parapharyngeal space and spread from the cavernous sinus through the carotid canal and into the middle ear (Low, 2002).

The incidence of middle ear invasion of NPC is probably higher than what has been reported, considering the anatomic communication and close proximity. Diagnosis may not necessarily be straightforward. Low (2002) reported a case where middle ear invasion by nasopharyngeal carcinoma was misdiagnosed as simple post-radiotherapy middle ear effusion for which myringotomy and ventilation tube insertion were performed. In a patient who had been previously irradiated, a recurrent tumour in the ear can be confused with other related conditions such as osteo-radionecrosis (Figure 1).

#### **2.2 Cerebello-pontine angle involvement**

In the work-up of a space occupying lesion cerebello-pontine angle (CPA), metastatic NPC is normally not considered. Although it is a rare complication, NPC should be kept in mind in a population where NPC is endemic (Yuh et al., 1993). It was observed in a study that when NPC involved the cerebello-pontine, it occurred in patients with advanced or recurrent disease (Low et al., 2000).

Involvement of the CPA can present a varied clinical picture. NPC manifesting as sensorineural hearing loss is rare (Bergstrom et al., 1977). It can be the result of the tumor affecting the cochlear nerve but it seldom affects the cochlea because of the tough otic capsule (Pringle et al., 1993). Although the resulting hearing loss is usually insidious in nature, it may occasionally present as sudden hearing loss (Low and Goh, 1999; Young, 2001**).** NPC involving the CPA can also affect the vestibular component of the 8th cranial nerve causing vestibular symptoms. This usually occurs insidiously and results in imbalance rather than true vertigo (Ramsden, 1987). NPC in the CPA can also affect the facial nerve resulting in facial palsy (Low, 2002).

Clinical diagnosis of NPC involvement at the CPA can be difficult. A patient who has received irradiation for NPC in the past may come to the Otologist with sensorineural deafness caused by recurrent NPC in the CPA. The attending physician may miss the diagnosis if he/she simply assumes the deafness to be radiation-induced (Low and Fong, 1998). Similarly, dizziness may be assumed to be the result of metabolic abnormalities and other post irradiation effects (Singh and Slevin 1991). Even facial palsy as the presenting symptom of NPC involvement of the CPA can be misleading because doctors are ever eager to attribute it to Bell's palsy, given that facial palsy as a consequence of NPC is rare (Skinner et al., 1991). The maxim, "All that palsies is not Bell's," is particularly relevant with respect to

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 161

sense of imbalance and light-headedness but not vertigo. The postnasal space was clinically free of tumor, and biopsy did not show malignancy. A CT scan showed a deep submucosal recurrent NPC with bony erosion of the left jugular foramen and extending to the left posterior cranial fossa. He was subsequently treated with gamma knife radio-surgery.

There are a few possible mechanisms by which NPC can involve the CPA. Isolated lesions in the CPA that did not have tumor involvement of the skull base can involve the CPA, suggesting spread from the hematogenous route (Gouliamos et al. 1996). Yuh et al. (1993) suggested that metastatic cancers to the CPA could also arise from direct leptomeningeal spread or from dissemination through cerebrospinal fluid. The jugular foramen also offers a route of communication between the region of the para-nasopharynx and the posterior cranial fossa (Low et al 2000). Goh and Lim et al. (2009) suggested it could be as a result of

According to Low et al. (2000), CPA manifestations of NPC can be as a result of inadequacies of standard radiotherapy techniques in the treatment of advanced NPC. The design of radiotherapy fields is based on the principle of maximal dose delivery to tumorbearing tissues and maximal sparing of normal structures. A normal tissue or organ is considered to be "dose limiting" if its tolerance to radiation is so poor that it affects the maximum dose deliverable to the adjacent tumor-bearing tissues. Such structures around the postnasal space include the contents of the orbits, the optic nerves and chiasm, the hypothalamic-pituitary axis, the inner ear, the spinal cord, the temporal lobes of the brain, and the brainstem. Encephalomyelopathy is a feared complication in NPC treatment. To minimize the dose to the brainstem, standard radiotherapy techniques to the postnasal space mandate a brainstem shield. Thus, even microscopic disease in this area is undertreated. Geographic under treatment of an initially advanced cancer may result in a patient's returning for treatment at a later stage with clinical manifestations of tumor involving the CPA. Low et al (2000) concluded that this might represent progression of persistent tumor

Treatment of NPC in the CPA is clinically challenging because when the standard radiotherapy techniques for NPC are applied to this region, the brainstem is at great risk. Gross disease extension into the CPA evident on CT scan is probably not radio-curable for this reason. In our center, such patients would be treated with initial chemotherapy in the hope that the tumor would shrink sufficiently to be encompassed by standard radiotherapy fields. Unfortunately, as illustrated by Low et al. (2000), NPC in the CPA may not respond

Where a tumor is localized in the CPA, focal means of delivering radiotherapy in the form of radiosurgery as delivered by the gamma knife or fractionated stereotactic Linac radiotherapy, may be considered. Such focal means of delivering radiotherapy have the advantage of depositing a high dose to a well-defined volume of tumor-bearing tissues, with rapid dose fall off to the surrounding structures. The disadvantage is that there is a 4 cm upper limit in diameter of tumor size beyond which the dose-sparing feature of this modality is rapidly lost. Where the tumor is larger than is feasible for stereotactic radiotherapy, a standard wedge pair technique may be feasible. The caveat, which cannot be overemphasized, is that the larger the tumor volume, the higher the likelihood of incurring

critical damage to surrounding structures (Low et. al., 2000)

perineural tumor spread.

than a true relapse.

well to chemotherapy.

Fig. 1. Axial CT Scan of the right temporal bone ear showing tumor recurrence of the middle ear and mastoid.

This 50 year old Chinese man who had radiotherapy for NPC 2 years ago presented with chronic right ear discharge. Examination of the right ear showed narrowed edematous external ear canal. The eardrum could not be seen from auroscopy. The CT scan showed bony involvement. The list of differential diagnoses included tumour recurrence, osteoradionecrosis and malignant otitis externa. He underwent surgical exploration and biopsy, which confirmed tumour recurrence. He was treated with palliative chemotherapy.

patients who have previously been treated for advanced NPC. In these patients, recurrent or persistent NPC involving the CPA, temporal bone, or parotid should be excluded (Low 2002**).** A factor that makes the diagnosis even more elusive is that postnasal space was often free of disease (Gouliamos et al, 1996).

Low et al (2000) reported the following case report, which illustrated the typical features of CPA involvement by NPC. A 53-year-old man was found to have NPC (stage T4N2, UICC 1997) when he experienced left vocal cord palsy (CN 10) and left CN 12 palsy. He was treated with radical radiotherapy. Two years later, he experienced left facial palsy (CN 7), giddiness, and left sensorineural hearing loss (CN 8). The giddiness was described as a

Fig. 1. Axial CT Scan of the right temporal bone ear showing tumor recurrence of the middle

patients who have previously been treated for advanced NPC. In these patients, recurrent or persistent NPC involving the CPA, temporal bone, or parotid should be excluded (Low 2002**).** A factor that makes the diagnosis even more elusive is that postnasal space was often

Low et al (2000) reported the following case report, which illustrated the typical features of CPA involvement by NPC. A 53-year-old man was found to have NPC (stage T4N2, UICC 1997) when he experienced left vocal cord palsy (CN 10) and left CN 12 palsy. He was treated with radical radiotherapy. Two years later, he experienced left facial palsy (CN 7), giddiness, and left sensorineural hearing loss (CN 8). The giddiness was described as a

This 50 year old Chinese man who had radiotherapy for NPC 2 years ago presented with chronic right ear discharge. Examination of the right ear showed narrowed edematous external ear canal. The eardrum could not be seen from auroscopy. The CT scan showed bony involvement. The list of differential diagnoses included tumour recurrence, osteoradionecrosis and malignant otitis externa. He underwent surgical exploration and biopsy, which confirmed tumour recurrence. He was treated with palliative chemotherapy.

ear and mastoid.

free of disease (Gouliamos et al, 1996).

sense of imbalance and light-headedness but not vertigo. The postnasal space was clinically free of tumor, and biopsy did not show malignancy. A CT scan showed a deep submucosal recurrent NPC with bony erosion of the left jugular foramen and extending to the left posterior cranial fossa. He was subsequently treated with gamma knife radio-surgery.

There are a few possible mechanisms by which NPC can involve the CPA. Isolated lesions in the CPA that did not have tumor involvement of the skull base can involve the CPA, suggesting spread from the hematogenous route (Gouliamos et al. 1996). Yuh et al. (1993) suggested that metastatic cancers to the CPA could also arise from direct leptomeningeal spread or from dissemination through cerebrospinal fluid. The jugular foramen also offers a route of communication between the region of the para-nasopharynx and the posterior cranial fossa (Low et al 2000). Goh and Lim et al. (2009) suggested it could be as a result of perineural tumor spread.

According to Low et al. (2000), CPA manifestations of NPC can be as a result of inadequacies of standard radiotherapy techniques in the treatment of advanced NPC. The design of radiotherapy fields is based on the principle of maximal dose delivery to tumorbearing tissues and maximal sparing of normal structures. A normal tissue or organ is considered to be "dose limiting" if its tolerance to radiation is so poor that it affects the maximum dose deliverable to the adjacent tumor-bearing tissues. Such structures around the postnasal space include the contents of the orbits, the optic nerves and chiasm, the hypothalamic-pituitary axis, the inner ear, the spinal cord, the temporal lobes of the brain, and the brainstem. Encephalomyelopathy is a feared complication in NPC treatment. To minimize the dose to the brainstem, standard radiotherapy techniques to the postnasal space mandate a brainstem shield. Thus, even microscopic disease in this area is undertreated. Geographic under treatment of an initially advanced cancer may result in a patient's returning for treatment at a later stage with clinical manifestations of tumor involving the CPA. Low et al (2000) concluded that this might represent progression of persistent tumor than a true relapse.

Treatment of NPC in the CPA is clinically challenging because when the standard radiotherapy techniques for NPC are applied to this region, the brainstem is at great risk. Gross disease extension into the CPA evident on CT scan is probably not radio-curable for this reason. In our center, such patients would be treated with initial chemotherapy in the hope that the tumor would shrink sufficiently to be encompassed by standard radiotherapy fields. Unfortunately, as illustrated by Low et al. (2000), NPC in the CPA may not respond well to chemotherapy.

Where a tumor is localized in the CPA, focal means of delivering radiotherapy in the form of radiosurgery as delivered by the gamma knife or fractionated stereotactic Linac radiotherapy, may be considered. Such focal means of delivering radiotherapy have the advantage of depositing a high dose to a well-defined volume of tumor-bearing tissues, with rapid dose fall off to the surrounding structures. The disadvantage is that there is a 4 cm upper limit in diameter of tumor size beyond which the dose-sparing feature of this modality is rapidly lost. Where the tumor is larger than is feasible for stereotactic radiotherapy, a standard wedge pair technique may be feasible. The caveat, which cannot be overemphasized, is that the larger the tumor volume, the higher the likelihood of incurring critical damage to surrounding structures (Low et. al., 2000)

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 163

Parotid metastasis is most commonly due to lymphatic spread (Wanamaker et al., 1994). The parotid is made up of a rich network of lymphatic vessels and interconnecting intraglandular and peri-glandular lymph nodes. NPC can affect the retropharyngeal lymph nodes, which can drain into the parotid nodes. From the parotid nodes, the tumor has access to the lymphatic plexus, parotid parenchyma, facial nerve, and even the parapharyngeal

As NPC is highly radiosensitive, radiation treatment stands as the primary modality of management. The aim of treatment is eradication of tumor through targeted delivery of radiation to the tumor bed, at tolerable doses to minimize acute and late complications. It is a challenge to balance cure on one hand, and prevention of complications from treatment on the other. The focus in this section is to highlight the impact of treatment of NPC on ear structures.

Megavoltage external beam radiotherapy is the primary treatment of choice. There are two lateral opposing and one anterior field beams. This is meant to cover the sides of the neck and entire nasopharynx. Radiotherapy is given prophylactically to the neck assuming there

A typical convention technique used by us involves patients treated with six megavolt (6MV) X-rays from linear accelerators. Chemotherapy was not part of the protocol for any patient. The primary volume covered the nasopharynx including the Eustachian tube, adjacent parapharynx to the level of the inferior border of C2, and posterior third to half of the nasal cavity and maxillary antra (Figures 2 and 3). As shown, the brainstem was shielded throughout on the lateral fields and the inner ear would be at the edge of this shield. A total dose of 66 – 70 Gys in 2 Gy daily increments was prescribed. The neck

MEE is a common finding among patients who have been irradiated for NPC patients and is generally attributed to Eustachian tube dysfunction. Post-irradiated ultra-structural findings of the Eustachian tubal mucosa showed ciliary loss, intercellular and intracellular vacuolation and ciliary dysmorphism (Lou et al., 1999). Most of these pathologic findings were observed to be persistent and did not resolve with time suggesting that radiation had caused long-term damage to the Eustachian tube epithelium. The Eustachian tube could grossly manifest in differing ways ranging from patulous Eustachian tube, adhesion,

MEE could be present in the early post-radiotherapy period and some persist in the longterm. Low & Fong (1998) studied the factors, which could possibly influence the development of long-term middle ear effusion in patients irradiated for NPC. Thirty-five patients (70 ears) were studied for 2-8 years (mean 5.5 years) post-radiotherapy. The factors studied were (a) sex (b) age (c) tumour size and (d) presence of pre-radiotherapy MEE. Only

**3. Otologic complications arising from treatment of NPC** 

received 60 Gy electively, with palpable nodes boosted to 70 Gy.

incomplete and complete obstruction (Zhou et al., 2003).

space (Batsakis & Bautina 1990).

**3.1 Radiation therapy** 

**3.1.1 Post-irradiation otitis media** 

**3.1.1.1 Middle ear effusion** 

is occult disease.

## **2.3 Referred otalgia**

Referred otalgia is pain felt in the ear but originating from a non-otologic source. Ear pain is a diagnostic dilemma when otoscopy reveals normal external ear and tympanic membrane. As the ear is innervated by sensory contributions of the the 5th, 7th, 9th and 10th cranial nerves as well as spinal nerves C2 and C3, lesions arising from areas supplied by these nerves may result in pain referred to the ear.

Theoretically, NPC can present as referred otalgia by involving the 9th cranial nerve. We concur with the observation by van Hasselt & Gibb (1991) that otalgia is less common than one might expect. We agree with the view that the most common description of pain is not "sharp" but "aching, dull or pressing" (Epstein and Jones, 1993). This is illustrated by a case report by Low & Goh (1999**):** 

A 48 year old man complained of a sensation of fullness in the left peri-auricular region, just antero-inferior to the tragus lasting for a month. Examination by manual palpation failed to reveal any mass in the region. CT scan of the parotid was normal. Nasal-endoscopy however, revealed a discrete mass in the left side of the post-nasal space. Biopsy of this nasopharyngeal mass showed undifferentiated nasopharyngeal carcinoma. His symptom resolved after radiation therapy.

## **2.4 Tinnitus**

It is common for patients to consult the Otologist for the complaint of tinnitus in the absence of other ear symptoms or signs. If unilateral, the Otologist often considers the possibility of an early acoustic neuroma and investigates as such. It is however, highly unlikely that NPC presents as tinnitus as an isolated symptom in the absence of other features relating to the ear, a view shared by van Hasselt & Gibb (1991). If present, it is normally a result of Eustachian tube, middle ear or auditory nerve involvement with the resulting associated aural manifestations as well.

## **2.5 Peri-auricular mass**

Although NPC metastasizing to the parotid is rare with only 14 cases reported in the literature (Wanamaker et al., 1994), this possibility should be considered in high-risk patients presenting with parotid masses. Batsakis and Bautina (1990) cautioned that some cases of 'primary undifferentiated carcinoma of nasopharyngeal type' in the major salivary glands might in fact be metastatic nasopharyngeal carcinoma. Low (2002) reported a case of metastatic NPC to the parotid and presenting with facial palsy as follows.

A 50-year-old man was treated for nasopharyngeal carcinoma overseas. Two years later, he exhibited complete left lower motor neuron facial nerve palsy. Examination revealed a hard mass in the left parotid over the region of the facial trunk in addition to multiple swollen cervical nodes (figure 3). The postnasal space was clinically free of tumor, and the appearance of the ears was unremarkable. Chest x-ray showed multiple metastases. Analysis of a fine-needle aspiration sample of the parotid mass identified an undifferentiated carcinoma consistent with metastatic nasopharyngeal carcinoma. The patient refused further treatment and died 3 months later.

Parotid metastasis is most commonly due to lymphatic spread (Wanamaker et al., 1994). The parotid is made up of a rich network of lymphatic vessels and interconnecting intraglandular and peri-glandular lymph nodes. NPC can affect the retropharyngeal lymph nodes, which can drain into the parotid nodes. From the parotid nodes, the tumor has access to the lymphatic plexus, parotid parenchyma, facial nerve, and even the parapharyngeal space (Batsakis & Bautina 1990).
