**1. Introduction**

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

Shalet, S. M., Rosenstock, J. D., Beardwell, C. G., Pearson, D. & Jones, P. H. (1977). Thyroid

Shalet, S. M., Toogood, A. A., Rahim, A. & Brennan, B. M. D. (1998). The diagnosis of growth

Sham, J., Choy, D., Kwong, P. W., Cheng, A. C., Kwong, D. L., Yau, C. C., Wan, K. Y. & Au,

Sklar, C., Whitton, J., Mertens, A., Stovall, M., Green, D., Marina, N., Greffe, B., Wolden, S. &

Sklar, C. A. (2004). Growth hormone treatment: cancer risk*. Hormone Research*, Vol. 62, Suppl

Sulmont, V., Brauner, R., Fontoura, M. & Rappaport, R. (1990). Response to growth hormone

Thames, H. D. & Hendry, J. H. (1987). Response of tissues to fractionated irradiation: effect of repair, In: *Fractionation in Radiotherapy*. pp (53-99) Taylor & Francis: London. Tillmann, V., Shalet, S. M., Price, D. A., Wales, J. K., Pennells, L., Soden, J., Gill, M. S.,

Wei, W. I. (2001). Nasopharyngeal cancer: current status of management: a New York Head

Wilton, P. (1994). on behalf of the International Board of the Kabi Pharmacia International

Withers, H. R. (1994). Biology of radiation oncology, In: *Current radiation oncology*, J.S. Tobias

Wu, Y. H., Wang, H. M., Chen, H. H., Lin, C. Y., Chen, E. Y., Fan, K. H., Huang, S. F., Chen,

Yoshimoto, Y., Moridera, K. & Imura, H. (1975). Restoration of normal pituitary

Zubizarreta, P. A., D'Antonio, G., Raslawski, E., Gallo, G., Preciado, M. V., Casak, S. J.,

and P.R.M. Thomas, Editors, pp. (5-23), Edward Arnold: London.

*Oncology. Biology. Physics,* Vol. 76, No. 4, March 2010. pp: 1133-9.

combined therapy*. Cancer*, Vol. 89, No. 3, August 2000. pp: 690-5.

childhood*. Clinical Radiology*, Vol. 28, No. 5, 1977. pp: 511-5.

*Physics,* Vol. 29, No. 4, July 1994. pp: 699-704.

*Scandinavica*, Vol. 79, No. 5, May1990. pp: 542-9.

*Research*, Vol. 50, No. 2, 1998. pp: 71-7.

Vol. 292, No. 5, January 1975. pp: 242-5.

No. 7, July 2001. pp: 766-9.

*Metabolism,* Vol. 85, No. 9, September 2000. pp: 3227-32.

*Pediatric Endocrinology*, Vol. 3, Suppl 5, 1994. pp: 61-71.

pp: 203-23.

3, 2004. pp: 30-4.

dysfunction following external irradiation to the neck for Hodgkin's disease in

hormone deficiency in children and adults*. Endocrine Reviews*, Vol. 19, No. 2, 1998.

G. K. (1994). Radiotherapy for nasopharyngeal carcinoma: shielding the pituitary may improve therapeutic ratio*. International Journal of Radiation Oncology. Biology.* 

Robison, L. (2000). Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study*. Journal of Clinical Endocrinology &* 

treatment and final height after cranial or craniospinal irradiation*. Acta Paediatrica* 

Whatmore, A. J. & Clayton, P. E. (1998). Serum insulin-like growth factor-I, IGF binding protein-3 and IGFBP-3 protease activity after cranial irradiation*. Hormone* 

and Neck Society lecture*. Archives of Otolaryngology-Head & Neck Surgery*, Vol. 127,

Growth Study. Safety of growth hormone (GH) - Value of a large data base. *Clinical* 

I. H., Liao, C. T., Cheng, A. J. & Chang, J. T. (2010). Hypothyroidism after radiotherapy for nasopharyngeal cancer patients*. International Journal of Radiation* 

gonadotropin reserve by administration of luteinizing-hormone-releasing hormone in patients with hypogonadotropic hypogonadism*. New England Journal of Medicine*,

Scopinaro, M., Morales, G. & Sackmann-Muriel, F. (2000). Nasopharyngeal carcinoma in childhood and adolescence: a single-institution experience with Nasopharyngeal carcinoma (NPC) is the sixth most common cancer in Singapore amongst males. Each year, there are 300-400 new cases diagnosed **(**Singapore cancer registry 2005- 2009). NPC is endemic in Southeast Asia, North Africa, and parts of the Mediterranean basin, with the highest prevalence in Southern China where an average of 80 cases per 100,000 populations is reported each year **(**Loong et al., 2008).

The nasopharynx is at a point where the ear, nose and upper pharynx converge. NPC is relevant to the Otologist although the nasopharynx is located outside the precincts of the anatomical confines of the ear, since it frequently manifests itself in the form of ear-related symptoms. The ear deserves special attention not only during diagnosis, but also in treatment and follow-up of patients with NPC. NPC is extremely radiosensitive and potentially curable provided the diagnosis is made early. As ear structures are often included in the radiation fields, ear-related complications of radiotherapy are common as well.

Early diagnosis is important as it has better treatment outcomes. Patients with early stages of the disease may present with ear-related complaints. In advanced disease, adjuvant chemotherapy may become necessary. Chemotherapy usually involves using Cisplatin (CDDP), which is potentially ototoxic. It is of concern that only 10% of patients are diagnosed early at stage I (van Hasselt and Woo, 2008). According to Leong et al.(1999), patient factors identified which contributed to delayed diagnosis included deferment in seeking medical help, defaulting follow up visits and refusing investigations. Other factors contributing to further delay in diagnosis were Clinicians not considering a diagnosis of NPC and Clinicians suspecting NPC but misled by the results of investigations. These factors contributed to nearly a fifth of patients with NPC having delayed diagnosis. Many of the factors responsible for the delays appear to be preventable by better patient education and counseling, doctors having sharper clinical acumen and skills in NPC diagnosis and the hospital administration having a system of tracking down high risk patients who default. Therefore, Clinicians should be familiar with the ear-related manifestations of NPC, which may help in its early diagnosis

This review aims to highlight ear-related issues in NPC patients from 2 perspectives: 1) as a manifestation of the disease itself and 2) ear-related complications arising from treatment of

Ear-Related Issues in Patients with Nasopharyngeal Carcinoma 157

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

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).

Eustachian tube cartilage played an important role in the genesis of MEE in NPC.

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

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

**2.1.1.1 Muscle infiltration theory** 

Eustachian opening or lumen led to the effusion.

**2.1.1.2 Neurogenic theory** 

**2.1.1.3 Cartilage erosion theory** 

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 relevant literature.
