**2. Otological manifestations of NPC**

Middle ear effusion resulting from NPC is a well-known presenting feature. However, there are other less common otological presentations including otalgia, giddiness, heamotympanum, barotrauma and periauricular mass which one should be mindful of (Low and Goh 1999).

#### **2.1 Middle ear involvement**

The link between the middle ear and nasopharynx by the Eustachian tube is one of the important reasons why the middle ear is frequently involved in patients with NPC.

A small tumor in the Fossa of Rosenmüller of the nasopharynx does not necessarily impair the Eustachian tubal function, but involvement of the Fossa by NPC seems necessary for Eustachian tube dysfunction to occur (Su et al., 1993). Tumour may spread outward via the mucosa and submucosa, or along the muscle bundles within the fibro-fatty tissue planes that surround the muscles or along the neuro-vascular planes (Miura et al., 1990).

#### **2.1.1 Middle ear effusion**

Middle ear effusion (MEE) is a common otological manifestation of NPC and may be the only presenting symptom of the disease. The resulting conductive hearing loss is usually unilateral and is due to the tumour causing Eustachian tube dysfunction.

Sham et al. (1992) evaluated the relationship between the paranasopharyngeal extension of tumor and the presence of MEE using CT scans (1992). The Eustachian tube traverses the paranasopharyngeal space and the presence of tumor in this region was likely to have an impact on tubal function, either mechanical or functional. The degree of paranasopharyngeal extension of tumor, erosion of petrous temporal bone and the obliteration of pharyngeal recess were found to be significantly related to the development of MEE, but not sex and age. Erosion of the petrous temporal bone was not as strong a risk factor for MEE as paranasopharyngeal involvement. The functional derangement of the cartilaginous part of the Eustachian tube was more important than its bony part in the development of MEE.

Despite numerous studies, uncertainty exists with regards to the exact patho-physiological process culminating in MEE. Although Eustachian tube dysfunction can be caused by inflammation within the lumen and invasion of the tubal orifice, there is mounting evidence pointing towards functional pathology rather than true mechanical obstruction of the tubal lumen (Bluestone 1983; Choa, 1981). More recent studies showed that in patients with NPCassociated MEE; the Eustachian tube was actually patent (Young & Hsieh, 1992). This led to the evolution of various theories to explain the observed functional rather than mechanical obstruction.

## **2.1.1.1 Muscle infiltration theory**

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

NPC namely, radiotherapy with and without chemotherapy. There is a relative paucity of world literature focusing on the impact of NPC on the Otologist. A major part of this review is from the principal author's previous work spanning 2 decades and review of other

Middle ear effusion resulting from NPC is a well-known presenting feature. However, there are other less common otological presentations including otalgia, giddiness, heamotympanum, barotrauma and periauricular mass which one should be mindful of

The link between the middle ear and nasopharynx by the Eustachian tube is one of the

A small tumor in the Fossa of Rosenmüller of the nasopharynx does not necessarily impair the Eustachian tubal function, but involvement of the Fossa by NPC seems necessary for Eustachian tube dysfunction to occur (Su et al., 1993). Tumour may spread outward via the mucosa and submucosa, or along the muscle bundles within the fibro-fatty tissue planes

Middle ear effusion (MEE) is a common otological manifestation of NPC and may be the only presenting symptom of the disease. The resulting conductive hearing loss is usually

Sham et al. (1992) evaluated the relationship between the paranasopharyngeal extension of tumor and the presence of MEE using CT scans (1992). The Eustachian tube traverses the paranasopharyngeal space and the presence of tumor in this region was likely to have an impact on tubal function, either mechanical or functional. The degree of paranasopharyngeal extension of tumor, erosion of petrous temporal bone and the obliteration of pharyngeal recess were found to be significantly related to the development of MEE, but not sex and age. Erosion of the petrous temporal bone was not as strong a risk factor for MEE as paranasopharyngeal involvement. The functional derangement of the cartilaginous part of the Eustachian tube was more important than its bony part in the

Despite numerous studies, uncertainty exists with regards to the exact patho-physiological process culminating in MEE. Although Eustachian tube dysfunction can be caused by inflammation within the lumen and invasion of the tubal orifice, there is mounting evidence pointing towards functional pathology rather than true mechanical obstruction of the tubal lumen (Bluestone 1983; Choa, 1981). More recent studies showed that in patients with NPCassociated MEE; the Eustachian tube was actually patent (Young & Hsieh, 1992). This led to the evolution of various theories to explain the observed functional rather than mechanical

important reasons why the middle ear is frequently involved in patients with NPC.

that surround the muscles or along the neuro-vascular planes (Miura et al., 1990).

unilateral and is due to the tumour causing Eustachian tube dysfunction.

relevant literature.

(Low and Goh 1999).

**2.1 Middle ear involvement** 

**2.1.1 Middle ear effusion** 

development of MEE.

obstruction.

**2. Otological manifestations of NPC** 

Sadé (1994) argued that MEE in NPC was usually the consequence of faulty middle ear aeration, due to the inability to introduce air through the Eustachian tube. This was because of its muscles being affected and not because of it's opening in the nasopharynx being blocked by a tumor. He observed that in animal studies, MEE could be produced experimentally by damaging the tensor veli palatini muscles in monkeys (Casselbrandt *et al,*  1988 as cited in Sadé 1994). In post-mortem studies, histological examination of the Eustachian tube in patients with NPC revealed that while sometimes the tumour infiltrated the Eustachian tube submucosa and cause obstruction **(**Cundy *et al.,* 1973 as cited in Sadé 1994); it usually infiltrated the Eustachian tube muscles and did not involve the Eustachian tube opening or its lumen at all (Cundy *et al.,* 1973**;** Takahara *et al.,* 1986 as cited in Sadé 1994). In various clinical studies, **(**Honjo, 1988 as cited in Sadé 1994; Sham *et al.,* 1992) demonstrated a direct relationship between the frequency of MEE in NPC and the extent of its infiltration to the parapharyngeal region where the Eustachian tube muscles were probably infiltrated. Myers *et al.,* (1984) also pointed to the presence of MEE in cases of other head or neck tumours such as maxillary sinus carcinoma and its surgery. They showed that in these cases, damage to the Eustachian tube muscles rather than obstruction of the Eustachian opening or lumen led to the effusion.

#### **2.1.1.2 Neurogenic theory**

Su et al., (1993) conducted an electromyogenic (EMG) study of the tensor veli palatini (TVP) and levator veli palatini (LVP) muscles in NPC patients. An abnormal TVP wave pattern coincided with a symptomatic ear whereas the non-symptomatic ear had a normal wave pattern. A paralyzed LVP with intact TVP did not result in effusion. NPC invasion generally did not demonstrate a myopathic EMG finding in both muscles. This led to the conclusion that neurogenic paralysis of TVP muscle on the lesion side played an important role in the pathogenesis of functional obstruction of the Eustachian tube leading to MEE. The tough pharyngobasilar fascia not only separated the TVP and LP, but also kept the tensor lateral to it. Anatomically the nerve to TVP was placed in a more vulnerable position and hence, a neurogenic cause of TVP paralysis was more likely (Su et al., 1993; Miura et al 1990).

#### **2.1.1.3 Cartilage erosion theory**

Low et al. (1997) found in a MRI study that NPC patients who had associated MEE had a tendency for the Eustachian tube cartilage to be eroded by tumour. Based on these findings and other observations relating to MEE, the authors postulated that the effect of tumour on Eustachian tube cartilage played an important role in the genesis of MEE in NPC.

The authors argued that MEE could not be explained by simple mechanical obstruction of the Eustachian tube alone. The 'hydrops-ex-vacuo' theory of MEE based on the concept that continuous gaseous absorption occurs in a closed biological air pocket until very high negative pressures capable of inducing MEEs develop, had largely been discredited (Grontved *et al.,* 1990). More recent studies had shown that in an unventilated middle-ear cavity, bidirectional gaseous exchange took place between the middle ear and the circulatory system of the local tissues until an equilibrium was reached, resulting in middleear pressures which were only slightly negative or even positive (Hergils and Magnuson, 1990**;** Sadé and Luntz**,** 1991). It had been postulated that pressure-regulatory mechanisms in

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 159

did not have history of rhinitis prior to nor during the flight. She was diagnosed by her general practitioner to have sustained barotrauma and was treated medically with partial improvement of symptoms. The blockage in her right ear however, deteriorated a month later and was diagnosed by an Otolaryngologist as due to middle-ear effusion. Post-nasal space examination revealed a tumor on the right side, which was histologically proven to be

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

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

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

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

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

other related conditions such as osteo-radionecrosis (Figure 1).

NPC.

**2.1.4 Tumor invading the middle ear** 

**2.2 Cerebello-pontine angle involvement** 

recurrent disease (Low et al., 2000).

resulting in facial palsy (Low, 2002).

into the middle ear (Low, 2002).

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 MEE formation (Sadé, 1994).

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

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 a change of tubal compliance, resulting in MEE formation.

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

NPC-induced Eustachian tube dysfunction could present as a sensation of ear blockage. Low and Goh (1999) illustrated this with a case study:

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 submucosal lesion on the left side of the nasopharynx

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

#### **2.1.3 Barotrauma**

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 did not have history of rhinitis prior to nor during the flight. She was diagnosed by her general practitioner to have sustained barotrauma and was treated medically with partial improvement of symptoms. The blockage in her right ear however, deteriorated a month later and was diagnosed by an Otolaryngologist as due to middle-ear effusion. Post-nasal space examination revealed a tumor on the right side, which was histologically proven to be NPC.
