SCIENTIFIC PAPER COMPILATION

1st NATIONAL CONFERENCE OF

NASOPHARYNGEAL CARCINOMA
“Prevention is Better than Cure”

Editor:
Farhat

Toba Beach Hotel, Samosir

October 18-20, 2018
 SCIENTIFIC PAPER COMPILATION
1st NATIONAL CONFERENCE OF
NASOPHARYNGEAL CARCINOMA
“Prevention is Better than Cure”

Editor:
Farhat

Reviewer:
Marlinda Adham
Bambang Hermani
Widodo Ario Kentjono
Yussy Afriani Dewi

Toba Beach Hotel, Samosir

October 18-20, 2018
 PREFACE

First of all, thanks to The Almighty God for all of His blessings and guidance in
finishing this Scientific Paper Compilation: 1st National Conference of
Nasopharyngeal Carcinoma, which has published at 18th of October.

This book consists of articles and ideas regarding the nasopharyngeal carcinoma by
many Head and Neck Oncologist from various study center in Indonesia. We do
hope that this book will benefit everyone to develop further study especially about
nasopharyngeal carcinoma.

Lastly, we sincerely apologize for any mistakes. We are looking forward for your
critics and suggestions for the sake of the better future.

Chairman,
Center of Excellence Nasopharyngeal Carcinoma
Universitas Sumatera Utara

Dr. dr. Farhat, M.Ked(ORL-HNS), Sp.T.H.T.K.L.(K).

iv
 TABLE OF CONTENTS

The Development of Nasopharyngeal Carcinoma in Indonesia

Farhat and A.Yudhistira ..................................................................................

Nasopharyngeal Carcinoma Understanding the Anatomy, Ebv Marker, and

Clinical Presentation
M. Adham .........................................................................................................

Nasopharyngeal Carcinoma Book Writing in Indonesia

Y. A. Dewi ........................................................................................................

Methods of Nasopharyngeal Carcinoma Early Detection and Screening

in Indonesia
S. R. Indrasari and C. Herdini ........................................................................

The Demography of NPC in Sanglah Denpasar General Hospital during

January-September 2018
I. G. A. Nuaba .................................................................................................

Anatomy and Physiology of Nasopharynx

D. S. Utama ......................................................................................................

Clinical Presentation and Diagnosis of Nasopharyngeal Carcinoma

Yulvina ............................................................................................................

Surgery for Nasopharyngeal Carcinoma

I. D. Mayangsari .............................................................................................

Rigid Nasopharyngoscopy and Flexible Endoscopy Evaluation for Diagnosis

and Recurrent Nasopharyngeal Carcinoma
C. Herdini ........................................................................................................

FNAB’S and Incisional Biopsy on Nasopharyngeal Cancer

H. Kadriyan .....................................................................................................

Risk Factor of Nasopharyngeal Carcinoma in Dr. Hasan Sadikin General

Hospital Bandung
R. A. Hardianti, Y. A. Dewi ..............................................................................

v
The Importance of Early Detection of Nasopharyngeal Carcinoma: A Case Report
M. Adham, A. S. Zhafira, A. C. Paramitha, B. Adhyatmoko, G. Hanafi, R.Hiksas,
K. Culham ........................................................................................................

Symptom Improvement in the Stage IV Nasopharyngeal Cancer after

Chemoradiation
Y. K. Inardi, W. Yusmawan dan D. Antono .....................................................

Management of Nasopharyngeal Carcinoma

Muhtarum Yusuf ...............................................................................................

vi
 THE DEVELOPMENT OF NASOPHARYNGEAL CARCINOMA
IN INDONESIA

Farhat, Ashri Yudhistira

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Sumatera Utara

In International Agency for Research on Cancer World Health Organization

(WHO) in year 2018 there are roughly 129.079 new cases of nasopharyngeal
carcinoma and 72.987 death in year 2018. Based on the data, it is stated that
nasopharyngeal carcinoma became a rare case in the world. Around 92% new cases
of nasopharyngeal cancer occured in develpoing country. Guangdong Province
(Kwangtung) has the highest prevalence of nasopharyngeal cancer in the world,
around 20-40 cases per 100.000 lifes. One of the highest incidence occured among
Kanton “pesisir race” with the incidence 54,7/100.000 lifes. (Jemal, 2011) (Adham,
2012).
Several countries in South East Asian has a several to high incidence of
nasopharyngeal cancer. Data from Guangdong found that the native Bidayu race in
Serawak, Malaysia also had a high incidence of nasopharyngeal carciona
(23,1/100.000). Other South East countries such as Singapore (15/100.000),
Malaysia (9,7/100.000), Vietnam (7,5/100.000) and Philipines (6,4/100.000).
Epidemiologically, nasopharygneal carcinoma has became an interesting cancer
due to geographical effect, racial distribution, genetic, social and environment.
(Adham, 2012).
Based on International Agency for Research on Cancer World Health
Organization (WHO) in 2018 there are 348.809 new cancer cases. Prevelance of
nasopharyngeal carcinoma in Indonesia is quite high, which is on the 5th place after
breast cancer, cervix, lungs and liver, with 17.992 new cases. Incidence of patients
suffering from nasopharyngeal carcinoma more often found in male than female
with ratio 3:1 (Adham, 2012).
Nasopharyngeal carcinoma frequency prevale in almost every Indonesia
regions. There are more than 100 cases per year was found in Cipto Mangunkusumo
Hospital Jakarta. In Hasan Sadikin Bandung around 60 cases per year, Makassar 25
cases per year, Palembang 25 cases per year, Denpasar 15 cases per year and in
Padang 11 cases per year. The frequencies found in Medan, Semarang, Surabaya
and other cities in Indonesia are not much different. This shows that malignancy
incidence prevail in whole Indonesia. (Soepardi, 2007)
In the last one and a half century, nasopharyngeal carcinoma has caused
many death. (Clifford, 1970). The oldest pathological specimen from
nasopharyngeal carcinoma originated from Northeast and Middle East Africa

1
population around 3500-3000 B.C (Wells, 1963), (Krogman, 1940), (Smith dan
Dawson, 1924), dan (Derry, 1909). Wells (1964) stated that only 3 or 4 definite
cases of carcinoma which was found from tens of thousands ancient Egypt
mummies has been researched. These specimens shows defect of posterior
alalveolus left maxilla near hard palate and lamina pterygoid. (Picture 1)
Based on Smith and Dawson (1924) research, Wells (1964) concluded that
the found specimen was not a pictured condition of nasopharyngeal carcinoma.
Smith and Dawson (1924) found in Rome-Egypt population case, male pre-
Christian Nubian specimen had a wide defect in basis cranii from cribiform plate to
occipital base, almost reached the foramen magnum. The location and presence of
destruction showed a case of sphenoidal sinus carcinoma case or nasopharyngeal
carcinoma. These case is difficult to be differentiated even with physical
examination. Evidence which was found untill now is still far from assurance that
nasopharyngeal carcinoma had been experienced by the Northeast and Middle East
African population around 5000 years ago.

Picture 1. Photograph of skull specimen No. 236. Dotted line indicates the
nasopharyngeal boundaries on the right side (R). Destruction of bone is limited to
the floor of the left maxillary sinus and adincent hard palate and pterygoid
laminae.

Since the majority of nasopharyngeal carcinoma was found in Kwangtung,

China, thus nasopharyngeal carcinoma was aptly named Kwangtung Carcinoma.
This can be found in an Ancient Chinese medical literature. In a book titled “Dalam
sebuah buku volume 50, “Aetiology and Symptomatology of Various Disease”,
written by Chou Uen Fung also known as Chou Yuan Fang, an emperor physician
from the Sui Dynasty (A.D 589-617), contain some description about the types of

2
superficial tumor swellings. Jung and Yu (1963) found an impossibility to
differentiate the “lo li” case (enlargement of neck glandular in chinese writtings) is
a malignancy or tubercolosis disease or other disease. In a Chinese Medical
encyclopedia that was edited by Wu (1921), there is a disease called “shih ying” or
“shih jung” which defines a lack of nutritions that was described as one of four fatal
disease with clinical symptom such as:
A mass was found in front or behind the ear part of the neck. Hard
consistency, immobile, hot or cold when touched and painless in the beginning, and
getting bigger and more painful progressively. Sero-sanguineous discharge but no
pus. At the end phase, necrotic fiber was formed and great pain is suffered during
this phase. Bleed easily from ulcer and can cause massive hemorrage even death.
There’s no more debate that this clinical presentation is a form of metastasis, not
tuberculosis, lymph node and high possibility of primer nasopharyngeal carcinoma.
No report was found in the encyclopedia when was this disease first reported in
Chinese medical writing.
First Medical Journal about nasopharyngeal carcinoma was described in
Durand Fardel (1837), Michaux (1845) and Bosworth (1889). Jackson (1901)
reported primer nasopharyngeal case and reviewed 13 cases which was collected
from England, France, Italy and German, including six cases belonged to Bosworth.
Jackson concluded in his report that irritation is not the cause of nasopharyngeal
carcinoma development significantly, because even though the nasopharynx was
exposed to smoke and dust, larynx carcinoma is exposed even more. (Clifford,
1970).
Most of South East Asia Countries had contact with Chinese people, it’s
because of war or trading. In other side, Chinese people marries the locals.
Nasopharyngeal carcinoma has a high incidence rate among the Chinese
immigrants in Thailand, Singapore, Malaysia, Indonesia, Phillipines and Vietnam.
These incidence is much lower compared to Chinese people that was born and
raised in south China. (Clifford, 1970) (Asroel, 2002).
Nasopharyngeal carcinoma is affected by EBV virus, enviroments and
genetic as its etiology. Migration from high risk country to low risk country cause
the incidence in said country to rise. Implication of an area and or genetics and the
possibility of EBV virus infection can be an important causage of nasopharyngeal
carcinoma. EBV was first identified by Sir Epstein and colleagues in 1964 by
lymphoma Burkitt tumor. This virus became the first virus to be linked with
oncogenesis because it’s linked to the appearance of Burkitt lymphoma and some
other causage of lymphoma and epitelial malignancy. (Adham, 2012) (Jemal,
2011).
In Indonesia, 100% of 5 year old children which is infected by EBV
virusand became latent infection for the rest of their lives.Primary infection often
found in children and is assymptomatical or a upper respiratory tract infection. After
being infected, EBV infiltrate the submucos and transforms B cell lymphocytes

3
until it becomes latent infection which is persintent in nasopharynx mucosa
(Adham, 2012).
Nasopharyngeal carcinoma is not too easy to associate with EBV infection.
More than 95% adult in the whole ethnic group all over the world also has been
infected by EBV. Other research reported that the rising risk of nasopharyngeal
carcinoma is related to the food that is being eaten such as spices that contains
nitroso and nitrosamines compound. Yu’s research (1981) stated that salted fish
consumption that contains nistrosamine in kanton people becomes the main risk
factor of nasopharyngeal carcinoma compared to smoking. Malaysian Chinese
comunnity consumes cow’s liver, with salted fish and salted egg shows a significant
relation with the appearance of nasopharyngeal carcinoma (Jemal, 2011) (Adham,
2012).
Until now, radiotherapy is still the main therapy for nasopharyngeal
carcinoma since 1982. Radiotherapy is a main therapy for cancer which haven’t
reach far metastases. The radiation that was given is hoped to improve the quality
and prolonged the live of the patient. (Kentjono, 2003).
Epidemiological research shows that the consumption of fresh fruits and
vegetables can prevent the occurance of nasopharyngeal carcinoma. Vitamin C can
prevents nitroso metabolism and reactivate of EBV. The daily consumption of dried
salted fish of Indonesian community, foods that cointains formaline compounds and
poliaromatic coloring compounds in local food can become carcinogenic and must
be avoided. Smoking tobacco and other inhaler which is common in Indonesia, can
also become a co-carcinogenic compund from enviroments. Repetitive exposure to
those compunds can increase the risk of EBV latent infection and the risk of
nasopharyngeal carcinoma occurance. (Adham, 2012).

4
 NASOPHARYNGEAL CARCINOMA
UNDERSTANDING THE ANATOMY, EBV MARKER , AND CLINICAL
PRESENTATION

Marlinda Adham

Oncology subdivision Faculty of Medicine Universitas Indonesia

Dr. Cipto Mangunkusumo Hospital Jakarta Indonesia

1. NASOPHARYNGEAL CARCINOMA
1.1. Anatomy of the nasopharynx and the lymphogenic spread of
nasopharyngeal carcinoma
Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the
world and it is one of the most confusing, commonly misdiagnosed and poorly
understood diseases.
The nasopharynx (NP) is defined as the part of the pharynx, which lies
behind the nasal fossa and extends inferiorly as far as the level of the soft palate
(Fig.1). The NP is a hollow, air-containing passageway. The posterior wall occupies
the angle between the base of skull above and the vertebral column. Anterior, the
NP communicates with the nasal cavity through the posterior nares or choanae. The
lower part of the anterior wall is formed by the soft palate. The lateral wall is formed
by the superior constrictor muscles. The Eustachian tube ostium is situated in the
lateral wall of the NP and the lateral pharyngeal recess or fossa of Rossenmuller1,2.
In this area stratified squamous and ciliated epithelia meet. This is called the
transitional zone and is liable to metaplastic and neoplastic changes.
It has been shown that opening of the Eustachian tube is dependent on the
action of the musculus tensor veli palatini. Interference with its action by tumor
infiltration is associated with tubal dysfunction and middle ear problems with
hearing loss, which is an early sign of NPC. Its inaccessible location underlines the
problem of the otolaryngologist in performing a thorough examination of the area.
The NP is the side of marked aggregation of lymphoid tissue and forms part
of a lymphoid ring i.e the Waldeyer’s ring. The lymphatic drainage system is
correspondingly extensive. A dense capillary network in the mucosa exists
throughout the pharynx and gives origin to three main groups of sub-mucosal
collecting trunks. The retropharyngeal space needs some more attention in that it
contains the median and lateral groups of retropharyngeal lymph nodes including
the node of Rouviere. A good understanding of this extensive lymphatic system is
of great importance in tumor staging and management of tumor spread and it should
be noted that lymphatic channels do cross the midline.3,4

5
 Picture 1. The Anatomy of nasopharynx and connection with other structures in
the back of the nasal cavity4.

1.2. Epidemiology of the tumor

NPC has a remarkable racial and geographical distribution with complex
interactions of genetic, viral, environmental and dietary factors.
There was an estimated incidence of 84,400 cases of NPC and 51,600 deaths
in 2008, representing about 0.7% of the global cancer burden. This disease may be
considered as one of the rarer cancer forms globally, ranking as the 24th most
frequently diagnosed cancers worldwide and 22nd within the developing world5.
NPC is a relatively rare malignancy in most parts of the world. It is more
frequent in males than females in both the developing and developed world, with
incidence rates commonly 2 to 3 times higher in males in higher resource countries.
It accounts for 2% of all head and neck squamous cell carcinomas, with and
incidence of 0.5 to 2 per 100,000 in the United States6. However, it is endemic in
many geographical regions, including Southern China, Southeast Asia, Indonesia,
Japan, the Middle East/North Africa and Eskimos in arctic regions3,6–8. Some
North-East parts of India have a high incidence of NPC as well. Ho et al. reported
that NPC is the third most common malignancy among men, with an incidence of
50 per 100,000 in the Guangdong province of Southern China9.Some references
report much higher incidences of 50-150 cases per 100,000 in Southern China,
particularly in Hong Kong and Guangzhou (formerly known as Canton, and the
capital of the province of Guangdong). Indeed, this malignancy is often referred to
as “Cantonese cancer” or “Kwangtung tumor”10–12. Emigration from high to low
incidence areas such as the United States and Canada reduces the incidence of NPC
in first generation Chinese, but it still remains at seven times the rate compared to
Caucasians13,14. Chinese of southern origin have a uniquely high risk up to 10-20
/100,000 for males resulting in around 20.000 new cases yearly in China. The
highest recorded NPC incidence is found in the Bidayu people of Borneo Island
(Kalimantan), with an age-adjusted incidence of 35/100,00015. In Indonesia it is the

6
most frequent cancer in the head and neck and ranks as number 4 in males with an
incidence of 6.2/100,000 and has been added to the Globocan overview of WHO-
IARC only recently, because of prior lack of specific diagnostic facilities and data16.
The epidemiology and etiology specifically for Indonesia will be discussed in detail
in chapter 217.

1.3. Etiology and risk factors

NPC presents as a complex disease caused by an interaction between
chronic infection with an oncogenic gamma herpes virus, the Epstein-Barr virus
(EBV) and environmental and genetic factors, involving a multistep carcinogenic
process6. EBV exists worldwide, infecting over 95% of the global adult
population18. In Hong Kong, 80% of the children are infected by 6 years of age, and
almost 100% have seroconverted by 10 years of age19. Although primary EBV
infection is typically subclinical, the virus is associated with the later development
of several malignancies including NPC7. It is transmitted by saliva, and its primary
infection occurs during childhood with replication of the virus in the oro-pharyngeal
lining cells, followed by a latent infection of B lymphocytes (primary target of
EBV). Epstein-Barr virus initiates an early active (or lytic) infection; the virus then
persists in a latent state until it is reactivated under certain conditions of
immunosuppression or illness. Elevated titers of EBV-associated antigens
(especially of IgA class), a latent EBV infection identified in neoplastic cells of
virtually all cases of NPC, the clonal EBV genome consistently detected in invasive
carcinoma and high-grade dysplastic lesions suggest a critical role of EBV in the
pathogenesis of NPC in endemic areas6.
Environmental factors and dietary habits are also reported to be related to
NPC. Salted fish consumption in early childhood has been correlated with an
unusually high incidence of nasopharyngeal cancer in the boat communities of
Hong Kong’s harbors12,20. N-nitrosodimethylamine in salted fish, perhaps in
combination with vitamin deficiency, has been considered a likely
carcinogen10,12,21. The process of salt preservation is inefficient, allowing fish and
other foods to become partially putrefied. As a result, these foods accumulate
significant levels of nitrosamines, which are known to be carcinogenic in animals22.
Salt preserved fish also contain bacterial mutagens, direct genotoxins, and EBV-
reactivating substances23,24, any or all of which could also contribute to the observed
association.
Occupational hazards, including exposures to formaldehyde, dust and
smoke particles and certain aromatic hydrocarbons, have been investigated as risk
factors for nasopharyngeal cancer25–27. Formaldehyde is a recognized nasal cavity
carcinogen in rodents. Smoke particles from incomplete combustion of coal, wood,
and other materials are also of the size and weight to be deposited mostly in the
nasopharynx28. Several studies conducted in high-and low-risk populations during
the past decade have obviously indicated the nasopharynx as a tobacco susceptible

7
cancer site20,29, and that exposure to parental smoking during childhood plays a role.
Ever smokers exhibit a roughly 30%-100% excess risk compared with life-long
non-smokers30. In low risk populations, data on risk factors are scarce. Also, a
proportion of cases of NPC are of the differentiated type (WHO type I) and the
etiology of these tumors is different from that of the UCNT. A case-control study
conducted in the USA on 231 cases and 246 controls revealed that only
differentiated NPCs (118 cases) were clearly related to heavy drinking and tobacco.
A strong dose response relationship between cigarette smoking and the risk of
differentiated squamous cell carcinoma was observed31,32. The use of certain
Chinese medical herbs has been suggested to increase the risk for NPC by
reactivating EBV infection in the host33.
A genetic predisposition is suggested by a high incidence of NPC in patients
with specific histocompatibility complex profiles, including HLA-A2, HLA-B46
and HLA B58. AW19, BW46 and B17 have also been reported to be associated
with an increased risk, whereas HLA-A11 is associated with a decreased risk34–36.
In rare familial cases, inherited genetic alterations could be the first “hit” and EBV
infection may contribute to the second “hit”. Therefore these familial cases usually
occur with a younger age of onset37. The finding of translocation, amplification and
deletion of 3p, 5p and 3q indicates that genetic abberations are possibly contributing
to NPC development38,39.
Viral infection by EBV together with environmental co-carcinogens rather
than genetic predominance is believed to be the strongest etiological forces for the
development of NPC.

1.4. Histopathology
According to WHO classification, NPC is histopathologically divided into
3 categories i.e. keratinizing squamous cell carcinoma (type 1), non-keratinizing
carcinoma (type 2), and undifferentiated carcinoma (type 3). The pathology of the
different NPC types is presented in figure 2. EBV is more deeply related to the
undifferentiated type of carcinoma. This type has a better prognosis than the
differentiated non-keratinizing and keratinizing types of carcinoma1,20. This is
related to the higher (chemo-) radiosensitivity of undifferentiated carcinomas.
Undifferentiated NPC has a higher local tumor control rate, despite a higher
incidence of distant metastasis compared to differentiated carcinomas1,40.
A “Working Formulation Classification” based on the degree of anaplasia
and pleomorphism of different cell types was suggested by Yeh41. Tumors with
cells with marked nuclear hyperchromatism and or evident variation in nuclear size
were designated as Type A, whereas those with little to moderate pleomorphism
and hyperchromatism were designated as Type B42.
Both cell types and the degree of anaplasia reflect important prognostic
significance and further impact on the patient’s outcome. Tumors with evident
anaplasia and or pleomorphism (Types A) have a significantly less favorable

8
outcome with a 5 year survival of 30-40% than their counterparts with mild
anaplasia (Types B) with a 5 year survival of 60-72%42.
Published data indicate a higher proportion of keratinizing squamous cell
carcinoma among all NPC cases in non-endemic compared with endemic areas.
Some studies reported that WHO type 1 accounts for approximately 25% of all NPC
in North America, but only 1% in endemic areas; whereas undifferentiated
carcinoma, WHO type 3, accounts for 95% of all cases in high incidence areas and
60% of cases in North America1,22,43.

2A. Nasopharyngeal keratinizing squamous cell carcinoma (WHO-1). The island

of tumor shows invasion into the stroma. The tumors cells show obvious
squamous differentiation and keratinization and round prominent nucleoli and
eosinophilic cytoplasms

2B. Nasopharyngeal non-keratinizing, differentiated carcinoma (WHO-2). The

tumor cells show differentiation with some cytokeratin expression, but in which
squamous differentiation is not evident by light microscopy.

2C. Nasopharyngeal non-keratinizing, undifferentiated carcinoma (WHO-3). The

tumor cells in syncytial arrangements show round nuclei, pleomorphic, vesicular
with prominent nucleoli and spindle cell with dark staining nuclei and
inconspicious nucleoli.

9
2D. EBER-RISH showing positive expression in nuclei of NPC tumor cells in the
routine paraffin-embedded histopathology specimen

Picture 2. A,B,C, and D Histopathology pictures of different Types of WHO

classification (Courtesy of Lisnawati Rachmadi. MD Path, her own work in
Histopathology UI Jakarta )

1.5. Clinical Presentations

Wei and Sham1 divided symptoms presented by NPC patients into four
categories (1) symptoms caused by the presence of a tumor mass in the nasopharynx
(epistaxis, nasal obstruction, and discharge), (2) symptoms associated with
dysfunction of the Eustachian tube (hearing loss), (3) symptoms associated with the
superior extension of the tumor (headache, diplopia, facial pain, and numbness),
and (4) neck masses. The clinical appearance of NPC is depicted in figure 3. Since
the nasopharynx has an abundant supply of regional lymphatic vessels, metastases
are frequently found. Cervical lymphadenopathy is often the only clinical
manifestation of NPC in patients. Because symptoms, related to NPC in the early
stage, are usually nonspecific, most NPC patients are diagnosed in advanced stage.
Spread to the neck nodes occurs in a predictable manner; upper levels first, mid
jugular and supraclavicular chains later1,4,44. Paulino et al. found that a unilateral
neck mass was the most common presenting sign, occurring in 80%45 of the
patients.
Cranial nerve involvement, subsequent to invasion of the skull base is seen
in 25% of cases46. The two principle cranial nerve syndromes associated with
nasopharyngeal carcinoma are the retroparotid syndrome (involving cranial nerves
IX, X, XI and XII) and the petrosphenoid syndrome (involving cranial nerves III,
IV, V, and VI). Occasionally, cranial nerve II becomes involved through the
foramen lacerum43. Isolated cranial nerves most commonly affected was the III, V,
VI and XIIth nerves, with symptoms of diplopia, trigeminal neuralgia and or
deviation of the tongue1,44. Headache can be explained by extension into sphenoid,
middle cranial fossa and intracranial extension.
NPC produces its clinical features by invading adjacent structures locally
and spreading to neck nodes regionally. Extension of local spread is associated with
adverse prognosis. The presence of bulky cervical lymphadenopathy is predictive
for distant metastasis. Lung, followed by bone, are the most common sites for
metastasis11.

10
 Picture 3. Clinical appearance of NPC: Enlargement of lymph nodes, and
involvement of cranial nerve 3,4,6 that caused diplopia , ptosis and lagophtalmus.

1.6. Diagnosis and staging

Diagnosis of nasopharyngeal carcinoma is primarily based on the history,
physical examination and imaging. For definitive diagnosis a biopsy of the lesion
is required. Biopsy can be performed in the office or in the operating room by rigid
or flexible endoscope and has a high specificity (99.6%)2. Endoscopy gives
adequate information of the local status of the disease. Endoscopic evaluation gives
the possibility to take a direct biopsy of the lesion for histopathological
examination. As long as the tumor involves the mucosa it will be visible by direct
endoscopy. Sub-mucosal tumor extension is more difficult to evaluate by
endoscopy (Picture 4.) due to the fact that the extension of the lesion is hardly
visible. Imaging is indispensable for this reason.1,47
The primary tumor extent should be evaluated by CT scan and/or MRI. MRI
is the preferred modality of choice for the imaging of NPC48,49. MRI is more
sensitive than CT scan for the detection of the extension of the primary tumor. It
can reveal soft tissue extent, regional nodal metastasis and perineural growth and
may help to depict subclinical NPC missed at endoscopy. MRI is better than CT in
displaying both superficial and deep nasopharyngeal soft tissue and for
differentiating tumor from soft tissue. MRI is also more sensitive for assessment of
retropharyngeal and deep cervical nodal metastases and it can detect bone marrow
infiltration11,50–52. Bone marrow infiltration is associated with an increased risk of
distant metastases53. CT scan is considered as a better tool for defining bone
erosion1. CT has been used for long in staging NPC (Fig.5), especially for the
detection of skull base tumor involvement with lytic or sclerotic lesions54,55, but
now it has been largely replaced by MRI for primary tumor and nodal staging.
However, CT scan is still used for radiotherapy planning and, in some centers, it is
used together with PET using 18F-FDG. PET/CT scan has been shown to be of
great value in NPC staging, where the main advantage is for the detection of distant
metastasis56. It is also used for monitoring patients post-treatment and detecting
NPC recurrence. In case a PET scan is not available, chest radiography, hepatic

11
ultrasonography and bone scanning can be used in the assessment of metastatic
disease and, ultimately, the staging of this malignancy57.

Picture 4. Endoscopic appearance shows tumor involvement of the fossa of

Rosenmuller, obstruction of the Eustachian tube and extension into the nasal
cavity through the choanae (first picture), and tumor from the left side of
nasopharynx involved the roof of nasopharynx with extension to the right side of
nasopharynx4.

Picture 5. T1 (former T2a) Nasopharyngeal Carcinoma: tumor from the Left

Fossa of Rosenmuller spreading to the nasal cavity

Clinical staging of the tumor represents 4 stages (Table.1) According to the

AJCC 2010 7th edition, stage I is T1N0, local disease in soft tissue only. Stage II
represents stage I with N1 disease, which is uni or bilateral- retropharyngeal nodes,
or unilateral upper neck nodes not greater than 6 cm, or primary tumor extension
(T2) into the parapharyngeal region. Stage III is stage II plus N2 disease, which is
bilateral upper neck nodes <6 cm, or local tumor invasion (T3) with minimal bone
invasion or into the paranasal sinus. Stage IV is stage III with N3 disease, which is
nodal involvement in the supraclavicular fossa, or lymph nodes greater than 6 cm,
or local disease (T4) with cranial nerve involvement, extension to intracranial, or to
the hypopharynx, infratemporal fossa, orbit or oropharynx 58,59. In comparison to
the 6th edition a few changes have been made60. First, patients with nasal cavity or
oropharynx involvement who were classified as T2a in the 6th edition are now
classified as T1 and T2b, which in case of parapharyngeal extension has become
T2. Second, the role of retropharyngeal lymph node is clarified in the staging

12
system, and (uni- or bilateral) retropharyngeal lymph node invasion is staged as N1.
Third, the addition of the term ‘‘masticator space’’ (as a synonym for infratemporal
fossa), which was introduced in the 6th edition, has been abandoned, and anatomic
masticator space involvement is staged as T4.

Table 1. Classification criteria and stage grouping by different systems. Changes

in the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer61.

Narrow-band imaging (NBI) endoscopy is a promising tool to differentiate

non-malignant from malignant nasopharyngeal lesions on the basis of the
morphologic findings of mucosal capillary vessels in vivo. In addition, NBI may
increase the diagnostic value of endoscopy in populations at high risk for NPC62.
For diagnosis and typing, EBER in situ hybridization is the most reliable
method for determining if a lesion is EBV associated and considered as the gold
standard for detecting and localizing latent EBV in tissue samples63.

1.7. Treatment of NPC

NPC is more sensitive to radiotherapy and or chemotherapy than other head
and neck cancers. The 5 years overall survival rates for stage I, II, III and IV disease
is 90%, 80%, 70% and 50% respectively. Since NPC is highly radiosensitive,
radiotherapy (RT) has always been the main treatment of choice for this cancer. The
major limitations of 2D planning for nasopharyngeal carcinoma can now be
overcome with 3D conformal radiotherapy and intensity-modulated radiotherapy
(IMRT)64,65. The main aim of using 3D-CRT (Conformal Radiation therapy) and
IMRT is to produce isodose curves with high conformity for the target volume,
while decreasing the dose into surrounding tissues. Consequently, acute and late
morbidity will decrease, while increasing the dose to the target volume.
Prophylactic neck treatment is recommended for NPC without clinical neck nodes,

13
because 30% - 40% of these patients will develop regional disease if the neck is not
treated.
For early stage disease (T1N0M0), radiotherapy is given to the nasopharynx
and the neck1,6. For advanced stage (T1N1-3M0 and T2-4N0-3M0), chemoradiation
is the treatment of choice. Chemotherapy can be administered as neoadjuvant or
concurrent to radiation. The standard agent used in concurrent chemoradiotherapy
is cisplatin. This provides a benefit in terms of overall survival and on both loco-
regional and distant control66–72. While three cycles of adjuvant cisplatin-5FU has
been a standard part of many concurrent chemoradiotherapy regimens, the actual
benefit of the adjuvant cycles are uncertain and toxic effect is substantial73.
Cisplatinum based induction chemotherapy has been shown by some studies to
improve disease-free survival and may be considered in locally advanced disease
although it is not seen as a standard treatment.74
Radiotherapy is applied with a dose of 65-75 Gy to the primary tumor and
65-70 Gy to the involved neck nodes, whereas the dose for prophylactic treatment
for the node-negative neck is 50-60 Gy. This treatment has successfully controlled
T1 and T2 tumors in 75-90% of cases and T3 and T4 tumors in 50-75% of cases61,75–
78
. For T1 and T2 tumors, a booster dose by use of intracavitary brachytherapy can
improve tumor control by 16%79.
Nodal control is achieved in 90% of N0 and N1 cases, but the control rate
drops to 70% for N2 and N3 cases74. Evaluation is performed with CT scan or MRI,
ultrasound of the neck and endoscopy of the nasopharynx 8-12 weeks post
treatment to assess the tumor response. For patients with distant metastasis,
platinum based combination of chemotherapy or radiotherapy for brain metastasis
and weight bearing bones can be considered.
To minimize the risk of late toxicity (particularly, to adjacent neurological
structures), fractional dose >2 Gy per day and excessive acceleration with multiple
fractions >1.9 Gy/fraction should be avoided. IMRT may offer improvement in
local tumor control, and reduction in radiation xerostomia in early-stage disease.
It is well demonstrated that once radiotherapy has started the full course of
radiation should be given in 45-47 days, due to the fact that the number of
clonogenic cells in cycle will increase once radiotherapy is started. Interruptions
have been shown to be hazardous for the expected outcome of radiotherapy, due to
a phenomenon known as accelerated repopulation which occurs in the tumor
tissue.80
Complications of treatment are hearing deficits due to chemotherapy,
reduced smell and vision due to decreased function of olfactory and optical nerve,
vascular stenosis and or induced malignancy by the radiotherapy it self.
Radiotherapy also effects dental hygiene, due to a reduction of the function of the
salivary glands.

14
1.8. Follow-up after primary treatment.
The modalities commonly used in the follow up of patients with NPC
include clinical examination, endoscopy and imaging. Inspection with a flexible or
rigid endoscope plays a primary role in follow up examination. However, mucosal
reactions after radiotherapy make it difficult to find early recurrent lesions.
Secretions and crust covering the nasopharyngeal mucosa also hamper the early
detection of local recurrence. Detection of sub-mucosal or deep-seated recurrent
lesions is difficult with endoscopic examinations only.
For the imaging after initial treatment, CT and MRI are widely used for the
detection of recurrent or residual lesions. MRI is superior to CT in the detection of
soft tissue abnormalities. The baseline MRI or CT study is conducted 2 to 3 months
after termination of the initial treatment. After the baseline evaluation, close follow
up is recommended every 3 to 6 months for the first 2 years post-treatment81. FDG-
PET in the detection of residual or recurrent NPC lesions has been reported from
several institutes. FDG-PET is increasingly being used for detection of recurrent
lesions and may distinct tumor from post irradiation changes, such as tissue
necrosis, fibrosis, and edema82–84. Liu reported that sensitivities for CT, MRI, PET
for the detection of residual or recurrent NPC lesions were 76, 78, and 95%
respectively85. This suggests that PET can be a useful tool for the detection of
recurrent or residual NPC lesions, but there are also limitations with the use of PET
for the detection of early recurrent NPC lesions. FDG uptake can be increased by
inflammatory reactions in the early period after radiotherapy85. For the detection of
distant metastases, the use of serum EBV DNA has been shown to be more sensitive
and reliable than other options86.
Narrow Band Imaging (NBI) is a novel technique that enhances the
diagnostic sensitivity of endoscopes for characterizing tissues using narrow-band
width filters in a sequential red-green-blue illumination system. Superficial
mucosal carcinoma lesions, which are rarely detected using conventional
endoscopy, can be observed with NBI by viewing the non-angiogenic,
microvascular proliferation pattern87,88 (Adham ongoing study). Lin and Wang88
reported that early recurrent lesions of NPC after radiotherapy were successfully
detected by NBI coupled with conventional endoscopy.

1.9. Treatment of locoregional recurrent and persistent NPC.

Based on retrospective analysis on diagnosis of recurrent regional disease,
the recommended procedure after curative intent chemo-radiotherapy is a FNAC
and CT scan. When positive nodes are detected, radical neck dissection is the
preferred treatment. When the FNAC is negative or inconclusive, excision biopsy
of the affected node should be done, preferably with frozen sections in combination
with neck dissection if malignant cells are found.89 Radical neck dissection offers
better results than re-irradiation. The overall 5 years survival rate for treatment with
radiation is around 20%46. Radical neck dissection as salvage procedure has

15
achieved a 5 years tumor control rate of 66% in the neck and a 5 year actuarial
survival of 38%90. When tumor in the neck node extends beyond the confines of the
lymph node, brachytherapy should be applied to the tumor bed in addition to radical
neck dissection1.
Locally persistent and recurrent tumors after radiotherapy or chemo-
radiation can be addressed by re-irradiation, brachytherapy, stereotactic
radiotherapy, photodynamic therapy or surgically. Surgery can be performed either
through a minimal invasive (endoscopic) approach, or with open surgery by a
mandibular or maxillary swing procedure or infratemporal approach from the
lateral aspect,91,92, transpalatal, transmaxillary, and transcervical approaches from
the inferior aspect93,94. Surgery remains a challenge due to the hidden position of
the nasopharynx95. The 5 year actuarial control of tumors in the nasopharynx is
about 65% and the 5 year disease free survival rate is around 54%96,97.
Nasopharyngectomy is usually offered when there is only evidence of local
recurrence or persistent disease. 91,92,98,99.
Re-irradiation can also be used as therapy for local recurrent NPC, although
its use is limited by the cumulative dose toxicity. Re-irradiation can be given by
external beam RT, stereotactic radiotherapy or brachytherapy. The use of
brachytherapy and surgery has generally resulted in better outcomes compared to
external re-irradiation for the small recurrent leasions92,93. Stereotactic
radiotherapy, when used for the management of limited residual or recurrent tumor,
is associated with a 2 year local tumor control rate of 72%100.
Photodynamic therapy is a relatively new modality for treating NPC, with
good results for local failures of NPC. PDT is an established non-invasive treatment
modality for incurable head and neck cancer101,102. A photosensitizer is
administered to the patient followed by illumination of the tumor with a specific
wavelength. This causes tumor destruction. Several clinical trials with first
generation haematoporphorin-derived photosensitizers (HpD or Photofrin) have
shown that PDT is effective in destroying NPC, with good local tumor control and
complete responses in the majority of patients with limited recurrent or persistent
disease, while achieving long-term palliation in cases with extensive recurrence103–
105
. Although these results were encouraging, PDT for NPC has not yet been
considered as a breakthrough in this field. The two major drawbacks of these studies
were (1) the light delivery and (2) the selection of photosensitizer. First, light
delivery in the nasopharynx is extremely difficult106. It is almost impossible to
illuminate the whole tumor area with a lens fiber, guided with endoscopes or trans-
orally with a mirror system. The problem of proper illumination of the
nasopharyngeal cavity has now been solved by the development of a special
applicator, which allows one-stage illumination of the entire nasopharynx. The
second drawback is the use of HpD/Photophrin (the first generation
photosensitizer). This photosensitizer has a limited depth penetration of <5 mm and
a prolonged light hypersensitivity of several months. Temoporfin (Foscan®), a

16
second-generation photosensitizer and approved in Europe for treatment of
incurable head and neck cancer, has a depth penetration of 1 cm and light
hypersensitivity of only a few weeks. Research in NPC cell lines by Yow et al
confirmed that Temoporfin showed much better PDT efficiency as compared with
HpD. These authors also observed significant photo destruction of the
mitochondria, especially in Foscan® mediated PDT. Mitochondria are an important
sub-cellular target and may play a role in cell death. Temoporfin, in combination
with the special designed nasopharyngeal applicator for proper illumination, has the
potential to effectively treat recurrent and or residual NPC also in the current
Indonesian medical system.

1.10. Distant metastases

The frequency of distant metastasis is 4,4% to 7% at diagnosis and 20% to
27% during follow up50,107,108.. In case of metastatic NPC (stage IVC) only palliative
treatment remains. In chemo-naïve patients, platinum-based regimens are the first
choice and give the best results109. Chen et al showed the benefit of a combination
chemotherapy with radiation for loco-regional disease in case of distant metastases
at diagnoses110. When the above mentioned strategies have failed, limited options
are left. Best response rates for palliative chemotherapy only were found with
gemcitabine, capecitabine or docetaxel, with a median survival of 9.5-15 months111.
Apart from the poor outcome, combination chemotherapy in metastatic
NPC in general results in increased toxicity112.

1.11. Targeted therapy

Epidermal growth factor receptor (EGFR) is highly expressed in NPC. A
strong expression is associated with poor survival outcome113. Combination of the
monoclonal antibody against EGFR, cetuximab, with carboplatin in patients with
metastatic NPC who have failed prior platinum-based therapies achieved a response
rate of 12% and a clinical benefit rate of 60%69. Cetuximab has been combined with
cisplatin and IMRT in locoregionally advance NPC, demonstrating good
tolerability despite a significant incidence of radiation dermatitis, mucositis and
dysphagia114. The approach of adding EGFR-targeted therapy to conventional
treatment approaches is being actively studied in locoregionally advanced NPC.
Overexpression of the markers associated with hypoxia, including hypoxia-
inducible factor 1 Alpha (HIF-1A), carbonic anhydrase 9 (CA-9) and vascular
endothelial growth factor (VEGF), is associated with poorer survival outcome in
NPC115. VEGF and VEGF Receptor targeted therapies, including use of
Bevacizumab (Avastin) and small molecule or DNAzyme inhibitors116, are
underway to limit neovascularization in NPC.
In undifferentiated NPC, EGFR overexpression was up to 83% and was
found to correlate with primary tumor stages of disease and locally aggressive
diseases117.

17
 Overexpression of epidermal growth factor receptor (EGFR) has been
correlated with alterations in cell cycle progression, increased invasive capacity,
enhanced angiogenesis, and decreased apoptosis of tumor cells. Overexpression
also associated with larger and advanced stage tumor and poor prognosis, while
EGFR activation associated with resistance to radiation118,119. Study in five NPC
cases, has found the effectiveness of EGFR blockade in tumors without deleterious
skin toxicity (skin rash) commonly found in treatment with other EGFR
inhibitors120.
The viral antigens expressed by the tumor cells are attractive targets for
immunotherapy and may be a potential avenue for the development of new
therapies for the treatment of NPC121,122.
When cytotoxic T-lymphocytes (CTL) are added, the EGFR concentration
in the tumor cell membranes (EGFRs) is suppressed and the activity of EGFR
declines during CTL immunotherapy, which is consistent with the finding of Yuan
et al123,124.
The combination of nimotuzumab (anti-EGFR) and radiotherapy in head
and neck cancer is well tolerated and can enhance tumor radiocurability. The
addition of nimotuzumab to standard modalities might increase the response and
survival rates without significantly potentiating toxicity. A recent study showed
combination of nimotuzumab and radiation achieved a highest tumor volume
reduction of 98%, and drastic reduction of more than 90% in nodal volume114.

2. EPSTEIN-BARR VIRUS AND NPC

2.1. Introduction to EBV
EBV is the first discovered human tumor virus and is associated with variety
lymphomas and carcinomas. In these tumors EBV is actively present in all tumor
cells resulting in an increased proliferation and decreased apoptosis. More than 95%
of adult population throughout the world is EBV positive as defined by serology.
However presence and active role of EBV in NPC pathogenesis can be detected by
a rise of IgA titers to EBV antigens. The aberrant serology correlates with tumor
development, remission and recurrences125–127. Viral DNA load in plasma has been
shown as promising alternative marker128–132, although EBV DNA in whole blood
samples does not appear to have similar diagnostic value133. Furthermore, viral
DNA load in nasopharyngeal (NP) brushings is a direct reflection of aberrant local
viral NPC activity in the nasopharynx134–136. Besides EBV DNA load in NP-
brushings, altered methylation of tumor suppressor gene promoter regions is
indicative of tumor presence in situ 137–139. Therefore, the presence of aberrant
antibody responses to EBV and viral presence and activity in all tumor cells may
enable us to use the virus and virus-induced changes as biomarker(s) for early
detection of NPC, monitoring of therapy outcome/efficacy and prediction of
recurrences or distant metastases. The studies presented in this thesis were planned

18
in part to evaluate viral biomarkers contributing to the clinical decision making for
patients with NPC.

2.2. Epstein-Barr virus

The Epstein-Barr virus (EBV) was discovered 50 years ago by electron
microscopy examination of cells cultured from Burkitt’s lymphoma tissue by
Epstein, Achong and Barr140. Four years later, EBV was shown to be the etiologic
agent of heterophile-positive infectious mononucleosis141. Aberrant anti-EBV
antibody responses in NPC patients were a first hint for EBV involvement in
NPC142,143 and EBV DNA was detected in the tumor cells in tissues from patients
with NPC in 1970144. In the 1980s and 1990s, EBV was shown to be associated
with B-cell non-Hodgkin’s lymphoma and so-called lymphoproliferative disease
(PTLD) in transplant recipients receiving immunosuppressive medication as well
as with brain lymphomas and oral hairy leukoplakia in patients with the acquired
immunodeficiency syndrome (AIDS)145–147. Since then, EBV DNA, RNA and
proteins have been detected in tissues from other cancers, including T-/NK-cell
lymphomas and Hodgkin’s disease and B-cell lymphomas arising in other immune
compromised patients148–151.
EBV is a human herpesvirus (HHV) with a 172 kb long, double-stranded
DNA genome that encodes >80 genes152. As for other herpesviruses, EBV
represents an enveloped virus that consists of a protein core wrapped with DNA
surrounded by an icosahedral nucleocapsid and a tegument layer enclosed by a lipid
envelope containing glycoprotein spikes for cell attachment. There are 3 main
subclasses within the HHV family; alpha-herpesviruses including herpes simplex I
and II and Varicella-Zoster virus, beta-herpesviruses including cytomegalovirus
(CMV) and HHV6, HHV7 and gamma-herpesviruses including EBV and Kaposi
sarcoma herpesvirus (KSHV) or HHV8. EBV is also known as HHV4 and has
unique DNA structure and coding sequences separating it from the other HHVs.
The gamma herpesviruses can be subdivided into gamma-1 (lymphocryptoviruses,
EBV) and gamma-2 (Rhadinoviruses, HHV8). These are the only HHVs directly
associated with human tumor formation. Human tumors have been attributed to
both human herpesvirus 8 (Kaposi’s sarcoma, primary effusion lymphoma and
Castleman’s disease) and to EBV (Burkitt’s lymphoma, various types of classic
Hodgkin lymphoma, as well as extranodal NK- and T-cell non-Hodgkin
Lymphoma, nasopharyngeal carcinoma, gastric adenocarcinoma,
immunodeficiency associated B cell Lymphoma and most recently B cell non-
Hodgkin’s lymphomas in elderly153,154. Humans serve as the only natural host for
EBV with target cells predominantly being B cells and epithelial cells155.

19
2.3. Biology of EBV
EBV infects nearly all humans (>90%) by the time they reach adulthood,
but infection occurs mostly at early age142,156. EBV can infect a number of different
cell types, including B cells and epithelial cells. Under certain condition, it may
infect T cells, natural killer cells, monocytes, and smooth muscle cells as well. The
mechanisms for entering these cells are different.
EBV enters B lymphocytes by binding with its envelope gp350/220 protein
to the CD21 receptor (also known as CR2), which is located at the surface of B
cells, whereas viral gp42 interacts with cellular MHC class II molecules as co-
receptor. This triggers fusion of the viral envelope with the cell membrane, allowing
EBV to enter the B cell155,157–159. Entry into epithelial cells is considered to involve
cell contact from EBV producing plasma B cells and epithelia, or binding of virions
to integrin beta-1 via the envelope BMRF2 protein containing RDG motif and
subsequent membrane fusion via gH/gL and gB glycoprotein interaction with other
integrins155,160,161. Indirect transfer of the virion via monocytes has been described
as well as transfer of IgA coated virions via IgA receptors on polarized epithelial
cells as alternative routes162,163.
During acute infection, EBV primarily infects B lymphocytes in the
sinonasal lymphoid tissue and replicates in the stratified squamous epithelium of
the oropharynx155,164,165. The infected individual remains a lifelong carrier of the
virus and EBV establishes persistent infection in the host, residing in a small
fraction of memory B lymphocytes166.
Primary infection with EBV typically occurs within the first few years of
life, usually asymptomatic and ranges from a mild self-limiting disease in children
to infectious mononucleosis (IM) in adolescents and adults in more developed
areas. EBV is transmitted by salivary exchange (e.g. pre-chewing food, kissing,
etc.), but not every person will get IM symptoms after contact with an EBV carrying
individual. EBV infection will result in transient viremia followed by a rapid
immune response that will control EBV for life in a permanent well balanced
dynamic equilibrium between virus reactivation and immunological control167,168.
EBV will remain in a dormant state in most humans for long time without serious
consequences.
This persistent infection with EBV is reflecting the virus lifelong balance
with its human host and where it hides from the immune system via latent infection
of B lymphocytes. The latency state allows the virus to be maintained in cells with
a highly restricted viral gene expression, which is needed for survival without being
recognized and eliminated. The expressed essential viral latency proteins are low
immunogenic and have properties to evade the immune system 169–171.
Although EBV exists in 95% of the world population without symptoms
and EBV has a strong capacity to immortalize infected host cells, strong host
immune responses prevent outgrowth of such potentially dangerous cells. However,
in a minority of infected individuals EBV is linked to the development of a variety

20
of lymphoid and epithelial malignancies. EBV is biologically active in the
malignant cells of these tumors and each type of tumor has a distinct pattern of EBV
gene expression. The EBV genome within the tumor cells shows different patterns
(latent) gene expression characteristics for each tumor and reflecting defined
episodes (stages) of normal viral activity, as will be described here below.

2.4. The life cycle of Epstein-Barr virus.

2.4.1. General features
EBV infection of lymphocytes leads to two alternate outcomes. Firstly,
EBV can infect naive B cells and let them grow out into memory B cells, which
persist with the virus in long-term latency expressing only few of its genes. On the
other hand, these B cells can differentiate upon antigen stimulation toward plasma
cells that then can produce new infectious virions and will die. Thus, the EBV
infection has two different phases, a latent persistent and lytic reproductive
phase167. Lifelong infection of the human host relies on this dual phase of infection.
Viral replication is naturally enriched in the oral mucosa where memory B cells are
routinely stimulated to differentiate after exposure to foreign antigens. The role of
mucosal epithelial cells in viral persistence and reactivation is still under
debate172,173.

2.4.2 EBV infection (primary infection and persistence)

Picture 6. A Schematic presentation of EBV infection in healthy carriers

(adopted from Udumade et al.142).

21
 Primary EBV infection begins in the oral cavity and affects epithelial cells
and naïve B cells. The Waldeyer ring’s lympho-epithelial region in nasopharynx
and oropharynx, is considered as the location for primary EBV infection, viral
replication and EBV persistence. EBV genome will transport into naïve B-cell
nuclei followed by B cell immortalization and creation of a B cell memory niche
through epigenetic modulation of the host cell. Activation of B cell growth program
by EBV gene products will drive proliferation of blasting B cells, at the same time
countered and controlled/eliminated by T cells primed by EBV antigens on B cells,
acting themselves as the antigen-presenting cells. In the blood, memory B cells with
largely quiescent viral genomes will circulate and occasionally enter lymphoid
tissues in the head & neck region, to be triggered into activation as plasma cells and
switching-on lytic replication. This results in transfer of virus to susceptible
epithelial cells further amplify virus production and shed virus into the saliva.
The oropharynx is rich in aggregates of lymphoid tissue, such as the lingual,
palatine and pharyngeal tonsils (Waldeyer’s Ring). During primary infection, the
virus can infect B cells within the tonsillar crypts (squamous epithelium covering
tonsils which dips into the connective tissue beneath), thereby entering the “growth
program”, expanding the number of virus infected cells before entering the latency
program156,165 (Fig. 6). EBV may also persist and replicate in oropharyngeal
epithelial cells172,174. EBV latent infection of B lymphocytes is necessary for virus
persistence, subsequent infectious replication in epithelial cells, and release of
infectious virus into saliva. EBV replication in latently infected B cells needs
additional triggering by chemical agents or immunoglobulins receptors175,176.

2.4.3. Replicative cycle

The virus is periodically replicated in most asymptomatic carriers of EBV
and infectious virions can be recovered in oral secretions173. EBV lytic replication
will produce infectious virus in mucosal epithelia, after being activated in
circulating memory B cells that have re-entered the oropharyngeal lymphoid tissue
and upon triggering by antigen or other (chemical or hormonal) triggers that drive
B cells to differentiate into plasma cells. This triggering ultimately results in
expression of more than 80 viral proteins175.
Lytic EBV replication is rarely associated with disease except in oral hairy
leukoplakia and chronic active EBV syndrome177,178 and more recently in chronic
periodontitis179.
While EBV latency is dominated by few genes driving cell growth and
survival while maintaining the viral genome as a mini-chomosome, the lytic cycle,
or productive phase of EBV infection, involves the expression of up to 80 genes
and results in the production of new infectious virions. EBV can undergo lytic
replication in both B cells and epithelial cells. In B cells, lytic replication normally
only takes place after reactivation from latency. In epithelial cells, lytic replication
often directly follows viral entry175. Virus-encoded DNA polymerase and accessory

22
proteins are required for linear viral DNA replication during the lytic phase of the
viral life cycle. This contrasts with latency, when host DNA polymerase copies the
viral genome175.

Picture 7. Life cycle of the Epstein-Barr virus (Adapted from Tsurumi180).

Lytic gene products are produced in three consecutive stages: immediate-

early, early, and late. Immediate-early lytic gene products act as transactivators,
enhancing the expression of lytic viral genes as well as host genes. Immediate-early
(IE) lytic gene products include BZLF1 (also known as EB1, Zta or ZEBRA) and
BRLF1 (Rta or EB2) are part of the IE products that act as transcriptional activators
of multiple (methylated) virus and host genes in an auto-stimulatory fashion180–
182
.Early lytic gene products have many more functions, preparing the cell for viral
DNA replication, enhancing nucleotide metabolism, and blockade of antigen
processing. Early lytic gene products include BMRF1, BALF2 and BALF5 that
have functions for replication, BGLF5, BNLF2a, and BILF1 that, function in RNA
metabolism and blockage of antigen processing. Late lytic gene products tend to
code for structural proteins, like viral capsid antigens (VCA p18, p40, p160,
encoded in BFRF3, BDRF1 and BcLF1, respectively), which form the viral capsid,
membrane antigens (MA gp350/220, gp125/110 encoded in BLLF1 and BALF4)
that form the viral envelope and gene products for apoptosis resistance, like BHRF1
and BALF1, and immune evasion like BCRF1, the viral IL-10 homologue142.
The gp350/220 envelope protein binds to CD21, to mediate EBV attachment
to B cells183,184. Besides the VCA capsid proteins, the gp125/110 (BALF4), or gB
homologue, is believed to be the major immunogen of the VCA complex185.
Gp350/220 is a target for neutralizing antibodies, but also a prominent constituent
of the plasma membrane of the EBV-producing cell and can serve as a target antigen
for EBV specific ADCC186.

23
 Unlike lytic replication for many other viruses, EBV lytic replication does
not inevitably lead to lysis of the host cell because EBV virions are produced by
budding from the infected cell.

2.5. Latency phase of EBV

Three different programs of latent viral gene expressions are defined (Table
2) and can be observed in defined EBV-linked disease entities, as well as certain
cell lines in vitro.
Type I latency is characterized by a limited spectrum of latent viral gene
expression, namely non-coding EBER and BART transcripts along with EBNA1
protein. This pattern is found in circulating memory B lymphocytes of healthy viral
carriers. Burkitt’s lymphoma is an EBV-related tumor characterized by latency type
I gene expression.
Type II latency is mostly seen in tumors arising in immunocompetent hosts
characterized by EBNA1, LMP1 and LMP2 protein expression in addition to the
presence of non-coding EBER and BART transcripts, as seen in Hodgkin’s disease,
T cell Lymphoma, and NPC, with the later also expressing the BARF1 protein.
EBV associated gastric carcinoma (GC) shows similar type-II latent gene
expression with BARF1 but without LMP1.
Type III latency is mostly seen in B cell lymphoproliferative diseases and
lymphoma immunocompromised hosts and refers to the full spectrum of latent
viral gene expression as found transiently in acute infectious mononucleosis187.
The higher EBNA proteins (EBNA2, 3a, 3b, 3c, 5) are highly immunogenic and
therefore this latency pattern is only observed in the absence of an adequate T cell
response as in immunocompromised hosts168. In immunocompromised individuals,
EBV is related to post-transplant (PTLD) and AIDS-related lymphoproliferative
disorders, autoimmune lymphomas and lymphomas in the elderly, but not
particularly with NPC154,187,188. In HIV carriers Hodgkin’s disease is virtually
always EBV positive as it is in most developing countries189.

24
 Table 2. Expression of EBV latent genes in disease (adopted from Cohen190).
Pattern EBNA EBNA EBNA LPM1 LPM2 EBERs BARTs DISEA
of 2 3 SE
1
Latency

Burkitt’
s
-Type 1 + - - - + +
lympho
ma

NPC,
GC,
Hodgki
n’s
disease,
Type 2 + - - + + + +
periphe
ral T-
cell
lympho
ma

PTLD,

X-
linked
LPD ,
Type 3 + + + + + + +
infectio
us
mononu
cleosis

Healty
Other +/_ - - - +/- + +
carrier

2.5.1. Function(s) of EBV latent genes.

Latent infection in benign and malignant cells is characterized by limited
expression of viral proteins to avoid immune recognition and destruction. Most
latent protein functions have been defined in the background of EBV-infected and
immortalized B-cells as cultured in vitro. The resulting lymphoblastoid cell lines
(LCLs) express most latent EBV gene products, like six nuclear proteins (EBNA-
1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C and EBNA-LP), three membrane
proteins (LMP-1, LMP-2A, LMP-2B), EBV-encoded small RNAs (EBER1 and
EBER2) and rightward transcripts from the BamHI A region (BARTs).

25
 Table 3. Function of EBV latent genes
Gene products Function
EBNA1 Maintenance of EBV episome in dividing cells through
sequence-specific binding at OriP and linking EBV genome to
chromosomes.
Inhibits proteosomal degradation and presentation to MHC
class I via gly-ala repeat.
Destabilises p53 via interaction with cellullar ubiquitin-
specific protease (USP7) and interferes with PML-bodies
affecting DNA damage repair.
Enhances cellular gene transcription and induces surviving
expression.
EBNA2 EBV transcriptional enhancer and oncogene required for B
cell transformation together with EBNA-LP (and LMP1).
Interact with RBP-Jκ to transcriptionally activate cMyc,
Runx-5, CD23 and other cellular genes as well as viral LMP1
and LMP2 early after infection.
EBNA-LP Upregulation of transcription factors needed for B cell
transformation and growth.
EBNA-3A Essential for EBV-mediated transformation of primary B
lymphocytes and interacts with RBP-Jκ, balancing EBNA2
binding to RBP-Jκ transcription factor.
Together with EBNA3C prevents pro-apoptotic Bim
expression in Burkitt cells with enhanced c-Myc expression,
stimulating survival.
EBNA-3B Transcriptional regulator, not essential for initial
transformation
EBNA-3C Essential for EBV-mediated transformation of primary B
lymphocytes and interacts with RBP-Jκ.
Promotes LMP1 expression in the presence of EBNA2.
LMP1 Essential for EBV transformation of B cell in vitro and drives
proliferation through NF-κB, AP-1 and JAK/STAT pathway
activation.
Mimics CD40 activity by providing growth and
differentiation signals to B cell.
Up-regulation of anti-apoptotic proteins (Bcl-2, A20).
Induces malignant transformation in human cells and
transgenic mice.
Activates transcription of epidermal growth factor receptor
(EGFR) in epithelial cells.
LMP2A Inhibits signaling through BCR and promotes the proliferation
and survival of B cells.

26
 Promotes migration and stem-cell characteristics in epithelial
cells.
LMP2B Modulator of LMP2A
EBER1,2 Counteracts the anti-viral effects of interferon and PKR
activation in infected B cells. Induces TLR3 signaling in
external recipient cells, stimulating innate immunity.
BARF1 Induce tumorigenicity and malignant transformation in
primary epithelial cells.
Induces apoptosis-resistance via up-regulating Bcl-2.
Share homology with c-Kit, binds CSF1 and modulates
monocytes activation.
BARTs Encode >40 miRNAs that regulate EBV latent infection and
modulate host immune responses by targeting a variety of
viral and cellular messenger RNAs.

Epstein-Barr nuclear antigen 1 (EBNA1)

EBNA1 is a DNA-binding nuclear phosphoprotein which is required for the
replication and maintenance of the episomal EBV genome in dividing cells through
binding to the origin of plasmid replication (Ori-P) on the viral genome191. The
tethering of the viral genome to the host chromosome is mediated via so-called AT-
hook domains within GR-repeats of EBNA1, allows the replication of EBV during
cell division by the replication machinery of the host192. EBNA1 also functions as
a transcriptional enhancer, driving defined host promoters into altered activity193–
195
and induces Survivin expression leading to apoptosis resistance196. EBNA1 is
the only EBV protein that is expressed in all latently EBV-infected cells. Although
EBNA1 is a foreign protein to the host, EBV-infected cells expressing EBNA1 are
not killed by CTLs. This is due to a inhibitory effect of the protein’s Gly-Ala repeat
on proteasomal processing thereby preventing endogenous MHC class I-restricted
presentation197,198. EBNA1 is capable of inducing genomic instability and interferes
with p53 stability and DNA repair mechanisms, enhancing the risk for genomic
alterations in the host cell, thus increasing the potential for cancer development199–
201
.

Latent membrane protein 1 (LMP1)

LMP1 is considered the major EBV oncogene and functions as a viral mimic
of the TNFR family member CD40. LMP1 signals constitutively without the need
for a ligand and thereby exhibits properties of a classical oncoprotein, inducing
promotion of cell growth and inhibition of apoptosis in a variety of cell types in
vitro152. The regulation of LMP1 expression occurs both at the transcriptional and
post-translational level and LMP1 is secreted into exosomes202. LMP1 is often
present in NPC and can be detected in pre-invasive lesions of nasopharynx203.
LMP1 is considered to, have an important role in the pathogenesis NPC and its

27
detectable expression showed to correlate with poor prognosis204. LMP1 induces
expression of the epidermal growth factor receptor (EGFR) in epithelial cells and
EGFR is expressed at high level in NPC205. The induction of EGFR expression may
be an important contributing factor to the deregulated cellular growth in this
epithelial tum
LMP1 induces secretion of IL-6 in epithelial cells and decreases expression
of cytokeratins and E-cadherin206. LMP1 inhibits apoptosis in B-lymphocytes
triggering expression of the Bcl-2207. LMP1 achieves its wide-ranging phenotypic
effects through the activation of multiple signaling cascades. Its activates the NF-
κB, JNK and JAK/STAT pathways through direct interaction with pathway
intermediary proteins208,209. LMP1 induces expression and secretion of MMPs
thereby promoting metastatic behaviour, and induces cytokine secretion thereby
providing growth stimuli (IL-6), neo-angiogenesis (IL-8) and immunosuppression
(IL-10). Secreted in exosomes, LMP1 may have modulatory functions in recipient
cells in the tumor cell microenvironment and mediate immune evasion171,210–212.

Latent membrane protein 2a and 2b (LMP2a and -2b)

EBV LMP2A prevents reactivation of EBV from latently infected cells by
blocking B-cell receptor tyrosine kinase phosphorylation205. LMP2 is not required
for B cell transformation, but essential for long term persistence for the viral
episome by providing B cell survival signals in the lymphoid organs 150,213. LMP2b
modulates the function of LMP2a in regulating BCR signaling, driving the latently
infected B cells to lytic reactivation150. In epithelial cells LMP2a is considered to
contribute to migration and invasion and induce stem-cell like characteristics214–216.
LMP2a is considered to cooperate with LMP1 in epithelial transformation and
carcinogenesis217,218.

BamHI rightward frame 1 (BARF1) protein

The EBV-encoded BARF1 gene is located in the BamHI-A fragment of the
EBV genome and has oncogenic activity, encodes 221 amino acids219. BARF1
functions as a viral oncogene, immortalizing and transforming epithelial cells of
different origin by acting as a mitogenic growth factor, inducing Cyclin-D1
expression, and up-regulating anti-apoptotic Bcl-2, stimulating host cell growth and
survival220. Since BARF1 is expressed in tissues of various EBV-associated
epitheloid malignancies, the possibility cannot be excluded that BARF1 expression
in EBV-associated epitheloid malignancies reflects spontaneous induction of the
lytic cycle in carcinoma cells. Because expression of the BARF1 gene is induced
on the induction of the lytic cycle in EBV-positive cell lines221,222 and in Burkitt’s
lymphoma cell lines, expression of BARF1 in NPC tissues is thought to reflect
spontaneous induction of the lytic cycle in carcinoma cells. Quantitative real-time
RT-PCR assay revealed that BARF1 was highly expressed in nasopharyngeal
carcinoma (NPC) and EBV-positive gastric carcinoma tissues in the absence of

28
expression of lytic gene BARF1 is expressed in NPC and EBV-positive gastric
carcinoma tissues as a latent gene and suggest that BARF1 plays a role in the
pathogenesis of these malignancies135,223,224. BARF1, an intracellular and secreted
protein, has multiple pathogenic functions and also can function as a target for
immune responses220.

EBV-encoded small RNAs (EBERs)

The EBV encoded small RNAs (EBERs) comprise the highly abundant
EBER1 and EBER2 molecules of 162-176 nucleotides in size. EBER transcripts
are expressed in all latency states and represent a reliable target for detecting and
localizing EBV in tissue sections by RNA in situ hybridization225. The EBERs are
expressed in many of the malignancies linked to EBV, including NPC and
presumably contribute in some way to the maintenance of latency in vivo226.
The high level of sequence conservation, suggests that EBERs are important
in EBV biology, even though EBERs do not play a role in establishment of latent
viral infection and replication227. EBERs were found to interact with cellular
proteins that play a key role in antiviral innate immunity. EBERs can be secreted
from EBV-infected cells in exosomes and protein-RNA complexes and are
recognized by toll-like receptor (TLR) 3, leading to induction of type-I IFNs and
inflammatory cytokines, and subsequent immune activation228. Furthermore,
EBER1 was detected in sera of patients with active EBV disease, suggesting that
activation of TLR3 signaling by EBER1 can account for some pathogenic
characteristics of reactive EBV diseases229.
EBER in situ hybridization is the gold standard for detecting and localizing
latent EBV infected cells in tissue samples in every benign and malignant lesion63.
EBER in situ hybridization is often helpful in making the correct diagnosis230,231.
In cases of metastatic cancer of unknown origin, it is reasonable to consider NPC if
EBV is present in the tumor cells232.

Rightward transcripts of the BamHI-A region of the viral genome (BARTs)

BARTs are abundant transcripts derived from the BamHI-A fragment of the
viral genome and expressed in all EBV infected cells and have elevated levels in
NPC and GC. Structural analysis of the BARTs revealed the presence of several
open reading frames. These are RPMI-1 and -2, A73 and BARF0 or depending on
the splicing of the transcript RK-BARF0233,234. However the protein products of
these putative genes remain undefined235. The function of most of the BARTs is
still under investigation, but their detection in infected B cells and in many EBV-
associated malignancies suggests that they might have an important role in viral
persistence and pathogenesis150. Recently BARTs were found to encode for about
40 individual microRNA species, that are abundantly expressed in NPC and other
EBV-driven cancers236–238. MicroRNAs (miRNAs) are small non-coding RNAs
that play important roles in post-transcriptional gene regulation. In animal cells,

29
miRNAs regulate their targets by translational inhibition and mRNA
destabilization239. Recent findings show that miRNAs can also modulate the cell
microenvironment, enabling immune escape and metastasis240,241.

2.6. EBV is linked to NPC carcinogenesis

EBV related malignancies primarily arise from infected lymphocytes and
epithelial cells, leading to lymphomas and carcinomas, respectively. The tumors are
latently infected with EBV yet express distinct subsets of viral proteins that are
contributing to growth, survival and immune evasion. In some of the viral cancers,
viral proteins are barely expressed, but the viral small and miRNAs can alter growth
by decreasing expression of negative regulators of cell growth such as tumor
suppressors and cellular proteins that induce apoptosis242 (Picture 8).
In Southern China NPC is the third most common malignancy among men,
where the incidence is approximately of 30–80/100,000 in the Cantonese region
around Guangzhou, Province of Southern China9,243. Genetic as well as
environmental factors play a role in the cause of the disease1. The disease is
classified by World Health Organization (WHO) into three histological types: I,
squamous; II, non-keratinizing; III, undifferentiated244. Circular EBV is present in
NPCs with a latency type II. High titers of serum IgA to EBV viral VCA and EA
antigens have diagnostic value. Rise in IgA titers may be evident several years
before the development of an undifferentiated NPC126. The link between EBV and
NPC was initially based on serological findings143,245, and later confirmed by
detection of viral DNA, RNA and protein in the tumor cells in situ using nucleotide
probes and specific antibody reagents144,246,247. High titer antibodies to VCA and
early antigen especially of IgA class, or high titers that persist after therapy, where
found to be associated with a poorer prognosis248. Detection of EBV DNA in
peripheral blood plasma is an important risk factor that indicates a significantly high
likelihood of developing distant metastasis as well as poor survival249,250.

30
 Picture 8. Role of EBV in the pathogenesis of NPC ( Adopted from Young LS
and Rickinson AB251, Lo KW et al.252).

The pathogenesis of NPC involves 3 factors. First, early and repeated EBV
infection and chronic triggering of aberrant viral replication by exposure to
environmental factors like dietary components such as nitrosamines in salty fish;
Secondly, loss of heterozygosity (LOH), usually occurring early in the NPC
pathogenesis and possible induced by EBNA1 expression as outlined above, will
produce low-grade pre-invasive lesions. Thirdly, accumulation of epigenetic and
genetic lesions in key regulatory genes leading to loss of cell cycle control and
enhanced survival138.
In EBV positive NPC and GC, the tumor cells carry monoclonal viral
genomes, which indicates that EBV infection must have occurred prior to expansion
of the malignant cell clone253. EBV infection has been detected both by EBER RNA
in situ hybridization and by the presence of monoclonal EBV genomes in high-
grade pre-invasive lesions (severe dysplasia and carcinoma in situ) in the
nasopharynx, but not in low-grade disease203. Multiple genetic changes have been
found in NPC, with frequent deletion of regions on chromosomes 3p, 9p, 11q and
14q and promoter hypermethylation of specific genes on chromosomes 3p
(RASSFIA and retinoic-acid receptor B2) and 9p. Deletions of some chromosomal
regions of low-grade dysplastic lesions from high-risk persons in the absence of
EBV infection in those lesions, indicate that genetic defects may occur earlier than
EBV infection. Therefore in the pathogenesis the genetic events caused by exposure

31
to chemical carcinogens might cause predisposition to subsequent EBV infection
leading to NPC254. Interestingly, recent data indicate that the EBV genome is more
stably maintained in epithelial cells aberrantly expressing Cyclin D1, which may be
an initiating event in the pathogenesis of NPC255.

2.7. Immune response to EBV and evasion of the immune system by the virus
Infection of humans with EBV results in both lifelong humoral and cellular
immunity to the virus. Although the finding of antibodies directed against virus
structural proteins and the EBNAs is important for the diagnosis of infection, the
cellular immune response is more important for the control of EBV infection.
Natural killer cells and CD4+ and CD8+ cytotoxic T cells control proliferating
EBV-infected B cells during primary infection168. After recovery from acute
infection, HLA-restricted cytotoxic T cells are important in controlling EBV, and
CD8+ T cells are targeted both replicative and latent antigens. Many of the
cytotoxic T cell responses directed against latent proteins are targeted to the EBNA3
proteins controlling the potentially dangerous latency-III stage of infection168,256 .
The ability of EBV to persist, despite potent immune effector responses
against it, indicates that the virus has evolved strategies to elude the immune
system. EBV encodes a cytokine and a cytokine receptor that may be important for
modulating the immune system to allow persistent infection. The BCRF1 protein
mimics the activity of interleukin-10 by inhibiting interferon- synthesis by human
peripheral-blood mononuclear cells in vitro257. The EBV BARF1 protein functions
as a soluble receptor for Colony-Stimulating Factor 1. Since Colony-Stimulating
Factor 1 normally enhances the expression of Interferon- by monocytes, BARF1
protein may function as a decoy receptor or scavenger to block the action of the
cytokine220,258. Since interferon-γ and Interferon-α inhibit the outgrowth of EBV-
infected cells in vitro, the BCRF1 and BARF1 proteins may help the virus to evade
the host’s immune system during acute EBV infection or reactivation of virus from
latently infected cells.
EBNA1 has been shown to block its own degradation by proteasomes in the
197
cell . Since viral proteins are normally broken down by proteasomes to peptides
for presentation to cytotoxic T cells, the ability of EBNA-1 to inhibit its degradation
may allow the protein to avoid triggering the activation of cytotoxic T cells. In
addition, lytic phase proteins encoded in BGLF5, BILF1 and BNLF2a genes
interfere with antigen processing and presentation in MHC-I avoiding elimination
of cells that switch to virus production259–261.
EBV encodes at least two proteins that inhibit apoptosis. The EBV BHFR1
protein, expressed early during lytic reactivation and some stages of viral latency is
a homologue of the human Bcl-2 protein, which also blocks apoptosis262, whereas
EBV LMP1 up regulates the expression of several cellular proteins that inhibit
apoptosis, including Bcl-2 and A20263. In addition, LMP1 contains an
immunosuppressive domain, which –upon LMP1 secretion-, can interfere with T-

32
cell activation171,210. In vivo evidence for local evasion of cellular immune
responses by NPC tumor cells is illustrated by induction of silencing Treg cells in
the tumor, not present in the circulation264. Together these data indicate that,
although NPC tumor cells express potentially immunogenic viral proteins, the
tumor cells exhibit several ways of evading these responses, resulting in extended
survival and continued growth. However, raising the level and activity of anti-EBV
immunity by vaccination or immunotherapy, may provide future options for
intervention265.
Humoral responses to EBV antigens are broad and strongly elevated, in both
IgG and IgA classes. Predominant antigens recognized by these antibodies include
the latent EBNA1 protein as well as EA, VCA antigens266. High level neutralizing
antibodies exist in NPC patients267. It is considered that the humoral immune
response to EBV antigens in NPC is reflecting antigen expression during tumor
development, rather than being protective. However, these aberrant anti-EBV
antibody responses are very useful in diagnosis of NPC, as outlined below.

2.8. EBV related laboratory tests

The fact that EBV is present and active in almost all NPC cases makes EBV
an ideal tumour marker for NPC. Quantitative analyses of EBV antibodies and EBV
DNA have been shown to be clinically useful for the early detection, monitoring
and prognostication of NPC129,268,269. Early detection is essential since patients with
NPC usually enter the clinic with an advanced stage of disease decreasing therapy
success rate. Population screening for high-risk individuals would allow the
recognition of early-stage NPC. To aid the clinical diagnosis, early detection can be
achieved by new EBV-based serodiagnostic tests and parallel molecular diagnostic
tests. The viral markers could also be used for the prediction of recurrence in
addition to monitoring therapy responses to guide the clinicians in decision making.
A wide variety of diagnostic approaches for prediction, diagnosis and prognosis of
EBV-associated diseases have been described

2.8.1. Serodiagnostic approaches

The initial link between EBV and NPC was based on identification of EBV-
specific serological abnormalities in NPC patients to viral antigens present in newly
discovered Burkitt Lymphoma cells143. In particular the presence of IgA antibodies
to several EBV antigen complexes defines NPC patients, as confirmed in larger
studies by the Henles245. For diagnosis of acute versus past EBV infection and
definition of EBV carriership in immunocompetent hosts EBV-specific serological
testing is the gold standard. EBV-specific serology involves the analysis of
antibody responses to distinct viral antigens, originally defined by patterns of
immunofluorescent staining on Burkitt-lymphoma cells, comprising the viral
capsid antigen complex (VCA), the EBV nuclear antigen complexes (EBNA) and
the early antigen complex (EA), the latter divided into diffuse (EAd) and restricted

33
(EAr) complexes, with different serological implication245. In recent years the
molecular basis of EBV serology has been defined, gradually leading to
replacement of the laborious and poorly reproducible immunofluorescence tests to
more defined and reliable assays270–272. Early serological studies in South-East Asia
and Indonesia have shown that at age 5 nearly 100% of Indonesians are infected by
EBV273. Serological test consists of agglutination tests, immunofluorescence,
immunoblot or enzyme immunoassays (EIA) and more recently automated and
multiplex tests which allow accurate definition of acute or convalescent EBV
infection274,275.
At the time of acute infection IgM anti-VCA will arise first, followed by
IgG anti-VCA and IgG anti-EA, with symptoms of primary infection and a positive
heterophile test. After symptoms resolve around 2 months post infection, remote
infection is characterized by persistent IgG anti-EBNA and VCA without IgG-EA,
reflecting lifelong EBV carriership. IgG-EA may reappear without symptoms upon
viral reactivation or EBV related neoplasia few years late272 (Figure 9).
For EBV related malignancies serology alone appeared not to be adequate
for diagnosis. Although patients with EBV associated tumor shave often higher
titers of IgG antibodies against EBV proteins, this is not always related to tumor
presence and is not specific for malignancy as it can also be found in autoimmune
disease, chronic EBV infections and other immune disfunctions276–278. In contrast,
NPC often associates with elevated levels of IgG-VCA antibodies, particularly
against the lytic VCA-p18 protein and the EBNA1 protein, and IgA antibodies
against early antigen (EA)129,266,279–282.
IgA antibodies against EBV antigens in serum of patients with NPC, reflect
the tumor’s origin in the mucosa of the nasopharynx. The anti-viral capsid antigen
IgA antibody (IgA-VCA), measured by indirect immunofluorescence or ELISA, is
the most widely used antibody marker for diagnosis and screening. The preferred
assay is based on ELISA, since the interpretation of the immunofluorescence assay
is subjective and the technique needs expert skills283. EBV-IgA testing, combining
VCA with EBNA1 or VCA with EA antigens successfully used for defining high
risk population of NPC and to evaluate prognosis and detection of recurrences after
completion of therapy266,284–286. The first mass-screening studies were performed in
complete city populations in Southern China by Zeng Yi 280,287, followed by
multiple large-scale studies confirming the use of IgA-VCA (and –EA) for NPC
diagnosis The sensitivity of EBV-IgA in the diagnosis of WHO type II and II NPC
in areas both endemic and non-endemic for the disease has been reported to be 85-
90% 266,288–291. The EBV-IgA markers frequently precede the appearance of NPC
and may serve for early-stage NPC detection and possibly also serve as markers of
remission and relapse 126,248,284,292.
Ji et al confirmed that elevation of the EBV antibody levels preceded the
clinical onset of NPC by as much as prior to the clinical onset, and that the antibody
level is subsequently elevated and maintained at high levels126. Most IgG of healthy

34
EBV carriers recognize a restricted pattern of EBV proteins in immunoblot, which
includes strong IgG reactivity against VCA-p18 and EBNA1270,293. In many NPC
patients IgA antibodies against EBV proteins are detectable, even before the
carcinoma becomes clinically evident. These antibodies are reflecting the abnormal
activity of EBV within the nasopharynx. Both IgA-VCA and IgA-EAd have been
proposed for NPC follow-up monitoring post treatment.

Picture 9. with permission Cyto-Barr BV, Netherlands

2.8.2. Molecular diagnostic approaches

Next to the indirect serological assays for NPC detection, a direct
measurement of NPC presence could be obtained by detecting and quantification
of the viral genome within the tumor cells. EBV DNA levels in nasopharyngeal
brushings from NPC patients are significantly higher than in brushing from healthy
controls. NPC may be more directly reflected by elevated viral DNA levels plus
carcinoma-specific viral transcriptional activity at the site of the primary tumor, this
hypothesis is analyzed in recent reports, showing elevated EBV DNA loads in NP
brush samples in NPC patients using non-standardized PCR techniques135,136,294.
Patients with active infection or EBV-related cancer tend to have high levels
of EBV DNA in the cell-free fraction of blood (plasma or serum), whereas in
healthy carriers the virus is restricted to the intracellular compartment of the blood.
Quantitative EBV DNA measurement is essential for differentiating the low-level
infection of healthy carriers from the high levels characteristic of EBV-related
disease272.
EBV DNA levels began to rise within 2 weeks after primary infection after
which the viral load declines to nearly undetectable levels. In most EBV infected
healthy individuals EBV DNA is undetectable in plasma or serum or remains low
positive for life. The viral DNA load will increase according to the development of

35
EBV related malignancy, decreases after treatment rapidly, and showed elevated
levels again if the tumor relapsed. Most clearly this is seen in transplant recipients
developing EBV-driven PTLD, where DNA viral load in whole blood showed,
rising levels prior to diagnosis and clinical relapse, and declining levels indicate
success of treatment295–297.
EBV viral load and circulating free EBV DNA is a marker of tumor burden
in NPC patients where it is useful for diagnosis, prognostication and monitoring of
the disease in response to therapy249,269,298–300. Plasma EBV DNA appears more
sensitive and reliable than whole blood cell EBV DNA for diagnosis staging and
therapeutic effect evaluation at a molecular level in NPC clinical practice133,269.
Levels of plasma EBV DNA may rise before clinical diagnosis, implying that
screening in high-risk groups, might be beneficial for early-stage NPC
detection132,193,301–304.
The detection of plasma EBV DNA might directly reflect tumor growth and
130,305,306
decline , and has proven to be an important and sensitive index in
diagnosing the residual and relapse of NPC129,301,302. Successful therapy is marked
by a decline to baseline, and rising levels may serve as a relapse305. The increased
number of EBV DNA copies in blood during the initial phase of radiotherapy
suggests that viral DNA was released into the circulation after cell death193,300. The
plasma EBV DNA load may improve the accuracy of diagnosing NPC in high-risk
individuals, but it appears to have limited value in screening patients who have early
stage NPC and predicting NPC development307.

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58
 NASOPHARYNGEAL CARCINOMA BOOK WRITING IN INDONESIA

Yussy Afriani Dewi

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Padjajaran

INTRODUCTION
Nasopharyngeal Carcinoma Book (KNF) Head Surgery Study Oncology Group
The security neck of all Kodi members and multidisciplinary other sciences such as
radiotherapy, radiology, anatomical pathology, clinical nutrition, and hemato-oncology.
The KNF book here is complete by the end of 2018 and startmultiplied in 2019 and
will be translated in 2019.

KNF BOOK WRITING GUIDE:

1. Title
- Made in Indonesian.
- The use of abbreviations or formulas should be avoided.
- The term foreign language is written in italics (italic).
- Title is written in Times New Roman with a size of 14 single spaces and
bold.
- Each initial letter of the word in the title is written in capital letters except
conjunctions and prepositions.
- If there are subtitles written in plain letters (plain) measuring 12 pts.

2. Author's name
- Name of all authors without mentioning titles, no abbreviations.
- The author's name is written in Times New Roman 12 pts and bold.
- Authors and addresses are written using 10 pts of Times New Roman and
italicized.

3. Heading
- The title for each section written using Times New Roman 12 pts and
printed in bold with the left position.
- If there are subtitles from headings then they are numbered and arranged in
the following order: 1, 2, 3, etc.

4. Bibliography
Written according to Vancouver's writing method. Bibliography is identified in
a script with Arabic numerals and given a serial number in accordance with the
order of appearance in the text. All authors' names are included, if there are more

59
than 6 authors, the names of the first 6 authors are followed by et al. Bibliography
is limited to a maximum of 30.
Example of writing a bibliography:
a. From the journal: Sivam A, Jeswani S, Reder L, Wang J, Detineo M, Taxy
J, et al. Olfactory cleft inflammation is present in seasonal allergic rhinitis
and is reduced with intranasal steroids. Am J Rhinol Allergy 2010; 24 (2):
286-90.
b. From the chapter in the book: Tos M, Larsen PL. Nasal polyps: origin,
etiology, pathogenesis and stucture. In: Kennedy DW, Bolger W, Zinreich
SJ, editors. Disease of sinuses. Ontario: BC Decker Inc; 2001. p. 57-68
c. From Book: Halliwel B, Gutteridge JM. Free radicals in biology and
medicine. 3th ed. New York: Oxford University Press, 1999. p.604-9
d. From the seminar: Rizayani, Madiadipoera T, Sudiro M, Generous A.
Effectiveness of immunotherapy for 3 years in patients with allergic rhinitis.
Presented at the 7th Jakarta International FESS Course Workshop, Jakarta,
11-13 March 2011.
e. From the dissertation/thesis/thesis: Wardani RS. Profile of gene
expression of nasal polyp sufferers related to therapeutic response to
protocols of endoscopic simple polypectomy treatment protocols and
intranasal glucocorticoids. Dissertation. Jakarta: Postgraduate University of
Indonesia; 2011. p. 99-10.Dari media elektronik: Center for voice and
swallowing UC Davis health system. Laryngopharyngeal reflux disease.
Available from: http://www/ucdmc.ucdavis.edu. Accessed Juli, 2010.
f. From electronic media: Abood S. Quality improvement initiative in
nursing homes: the ANA acts in an advisory role. Am J Nurs [serial on the
internet]. 2002 [cited 2002 Aug 12]; 102(6): [about 3 p.]. Available from:
http://www.nursingworlds.org/AJN/2002/june/Wawatch.htm.
g. From electronic media: Cancer-Pain.org [homepage on the internet]. New
York: Association of Cancer Online Resources, Inc.; c2000-01 [updated
2002 May 16; cited 2002 Jul 9]. Available from: http://www.cancer-
pain.org.
h. From electronic media: Who’s certified [database on the internet].
Evanston (IL): The American Board of Medical Spesialists. c2000 - [cited
2001 Mar 8]. Available from: http://www.abms.org/newsearch.asp.
i. From electronic media: Greet Barrier Reef Marine Park Authority [image
on the internet]. C2002 [updated 2006 Jan 28; cited 2006 Feb 15]. Available
from:http://www.gbrmpa.gov.au/corp_site/info_service/science/bleaching.

60
5. The manuscript
Submitted in CD form and typed using the Microsoft Word program with Times
New Roman font size 12 with a space of 1.5 or via email to
oncologyhnsstudygroup@yahoo.co.id.

6. Paper size
Paper size is A4 (20.99 x 29.69 cm)
- Pitch (margin) above: 4 cm from the edge of the paper
- Left margin (margin): 4 cm from the edge of the paper
- Bottom margin: 3 cm from the edge of the paper
- Right margin (margin): 3 cm from the edge of the paper

7. Space
- The distance between lines is 1.5 spaces.
- The distance between the headings of the chapter and the first text of the
text or between the headings of the chapter and the headings of the sub-
chapter are 3 spaces.
- The distance between the headings of the subchapter (chapter title) and the
first line of text in the text content is 1.5 spaces.
- Each paragraph text the contents of the manuscript is typed in (right) as far
as 1 tab.
- The distance between the end line of the text and the next sub text is 3
spaces.
- The distance between text and tables, pictures, graphs, or diagrams is 2
spaces.
- Instructions for chapter chapters and headings are always typed on new
pages.

8. Numbering of chapters, chapters and paragraphs

- Chapter numbering uses Roman numerals in the middle of the page (for
example (CHAPTER I).
- Numbering of sub-chapters using Arabic numbers typed on the edge of the
left (for example 2.1, 2.2, etc.).
- Numbering of children subchapters adapted to chapter numbers (eg 2.1.1,
2.1.2, etc.).
- Numbering is not a sub-chapter done with Arabic numerals and parentheses,
for example 1), 2) etc. For children, sub-chapters are not (1), (2), etc.

61
 TABLE OF CONTENTS
- Foreword to the Chair of Kodi Oncology of Neck Head Surgery
- Foreword to the Chair of the Indonesian College of Health Sciences T.H.T.K.L
- Foreword to Chairperson of PP Perhati-KL Indonesia
CHAPTER I Introduction
CHAPTER II Epidemiology
CHAPTER III Anatomy
CHAPTER IV Histopathology
CHAPTER V Etiology and Pathogenesis
CHAPTER VI Risk Factors
a. Gender
b. Race
c. Diet
d. Genetics
e. Epstein Barr virus
f. Others (family history, smoking, alcohol, pollution)
CHAPTER VII Early Detection
CHAPTER VIII Clinical Presentation
CHAPTER IX Diagnosis
CHAPTER X Supporting Examination
CHAPTER XI Laboratory
CHAPTER XII Prognosis Factors
CHAPTER XIII Stadium
CHAPTER XIV Therapy
a. Radiotherapy
b. Chemotherapy
- The basic principle of chemotherapy
- NPC chemotherapy
c. Surgery (including recurrence)
d. Target therapy
e. Other therapeutic options:
- Photodynamic Therapy (PDT)
- Immunotherapy
f. Palliative
CHAPTER XV Follow Up
CHAPTER XVI KNF therapy algorithm in Indonesia

62
PAPER RECEIVED
CHAPTER II Epidemiology
(Nani Iriani Djufri, Nova Audrey Pieter)
CHAPTER VI Risk Factors
a. Gender
(Imam Prabowo)
b. Race
(Imam Prabowo)
c. Diet
(Imam Prabowo)
d. Genetics
(Farhat, Rizalina Asnir, Ashri Yudistira)
e. Epstein Barr virus
(Yussy Afriani Dewi)
f. Others (family history, smoking, alcohol, pollution)
(Yussy Afriani Dewi)
CHAPTER VIII Clinical Presentation
(Yussy Afriani Dewi)
CHAPTER IX Diagnosis
(Yussy Afriani Dewi)
CHAPTER XII Prognosis Factors
(I Gde Ardika Nuaba, Ketut Suanda)
CHAPTER XIII Stadium
(I Gde Ardika Nuaba, Ketut Suanda)
CHAPTER XIV Therapy
a. Chemotherapy
- The basic principle of chemotherapy
- NPC chemotherapy
b. Target therapy
c. Other therapeutic options
- Photodynamic Therapy (PDT)
- Immunotherapy
d. Palliative

UNACCEPTED PAPER
CHAPTER I Introduction
(Marlinda Adham)
CHAPTER III Anatomy
(Willy Yusmawan)
CHAPTER IV Histopathology
(Soehartono)
CHAPTER V Etiology and Pathogenesis
(Soehartono)

63
CHAPTER VII Early Detection
(Camelia Herdini)
CHAPTER X Supporting Examination
(Sukri Rahman)
CHAPTER XI Laboratory
(Marlinda Adham)
CHAPTER XIV Therapy
a. Radiotherapy
b. Surgery (including recurrence)
CHAPTER XV Follow Up
(Marlinda Adham)
CHAPTER XVI KNF therapy algorithm in Indonesia

64
 METHODS OF NPC EARLY DETECTION AND SCREENING
IN INDONESIA

Sagung Rai Indrasari, Camelia Herdini

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Gadjah Mada

Nasopharyngeal carcinoma has a unique and striking geographical

distribution throughout the world.1 Although rare in most regions, it is very
common in Southern China and South East Asia.2 In Indonesia, the estimated
incidence of nasopharyngeal carcinoma is 6.2 per 100,000 population.3
Undifferentiated carcinoma (WHO type III) is the most common type of NPC and
among the five most prevalent cancers overall. Due to unspecific symptoms and the
hidden localization of the primary tumor at the early stage, more than 80% of the
patients come to the hospital at a late stage (III or IV), when they already have
metastasis in the cervical lymph node. Whereas late-stage disease has a poor
prognosis and requires combined chemo-radiotherapy, early stage NPC may reach
complete remission by radiotherapy.4 Therefore, treatment results tend to be poor.
For this reason, a screening program to detect nasopharyngeal carcinoma at an early
stage will be crucial for decreasing disease burden and increasing treatment
efficacy. The success of screening depends on the availability of specific tests and
the existence of a well-defined population at high risk for developing the disease.5
Epstein Barr Virus (EBV) has long been implicated in the pathogenesis of
NPC. Old et al.6 first made the association of EBV with NPC using
3

immunodiffusion when patients with undifferentiated NPC showed elevated

immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody titers against EA-
D (early antigen-diffuse) and VCA (viral capsid antigen). Using in situ
hybridization techniques, EBV DNA has also been confirmed in NPC tumor cells.7
The close relationship between EBV and nasopharyngeal carcinoma is
highlighted by the presence of viral DNA, RNA, and protein in all tumor cells, viral
reactivation and the aberrant antibodies against EBV antigens in patient sera.8
Aberrant antibodies against EBV antigens such as viral capsid antigen (VCA),
DNase, early antigen (EA), and EBV nuclear antigen 1 (EBNA1) have benefit in
clinical diagnosis.9,10 Aberrant seroreactivity in nasopharyngeal carcinoma is
detectable prior to onset of clinical manifestation of the disease. Studies in China
and Taiwan have shown the feasibility of using EBV serology as a predictive
marker for disease development.11,12
Although EBV is the strongest risk factor for NPC, there are additional
exogenous factors, which are also closely linked with the malignancy. Food such
as salted fish13, other preserved foods14, and herbal medicine15 have been linked to
nasopharyngeal carcinoma but not consistently. Several compounds in food have

65
been demonstrated to induce in vitro EBV reactivation suggesting their capability
of initiating enhanced in vivo virus replication.16 Furthermore, tobacco smoke17,
passive smoke18, alcohol consumption19, occupational dust20, and other inhalants21
are among environmental factors related to nasopharyngeal carcinoma.
A family history of nasopharyngeal carcinoma has also been associated with
increased risk of the disease. First-degree relatives of patients have 6- to 19- fold
excess risk of developing the disease compared to those without a family linkage.22
This effect observed among cases is the strongest compared to other cancers. 23 An
increased risk for EBV-associated nasopharyngeal carcinoma and other infectious
agent-related cancers were recorded among families with a history of
nasopharyngeal carcinoma especially among the multiplex cases. This suggests an
increased frequency for viral reactivation among family members of EBV-
associated cases. Aberrant EBV reactivation among family members was also
indicated by studies on EBV immunoglobulin A (IgA) detection in the sera among
core family members of cases.24 These studies indicate that both genetic and
environmental factors responsible for the aberrant EBV IgA are shared in the
family.
Because involvement of both genetic and environmental factors in
carcinogenesis has been proposed, it is reasoned that healthy individuals from
families with members affected by nasopharyngeal carcinoma might have an EBV
antibody profile that is distinct from that seen in healthy individuals from the com-
munity at large. A peptide-based ELISA has been developed for measuring EBV
IgA in (dried) blood samples, allowing finger prick sampling on paper filters, that
may serve as tool for early screening.9 The first step to define the usefulness of this
assay in a screening approach is to validate it in families with nasopharyngeal
carcinoma cases versus controls without a family history.
Recently, an EBV IgA ELISA is developed based on a combination of VCA
p18- and EBNA1-derived synthetic peptides which is routinely used as an NPC
diagnostic test in Sardjito Hospital, Yogyakarta, Indonesia. This EBV IgA ELISA
combines the separate features of IgA VCA and IgA EBNA1, each of which has its
value in NPC diagnosis. The combination of these markers in a single assay
provided sensitivity and specificity of 85.4% and 90.1%, respectively.9 The
presence of NPC-related serological abnormalities can be confirmed by
immunoblotting to reveal the spectrum of antibody responses, which has diagnostic
value by itself.25, 26, 27 The combined EBV IgA ELISA and immunoblot assay
showed increased sensitivity and specificity and positive predictive value (PPV)
and negative predictive value (NPV) of more than 95%.25 Because immunoblot
studies revealed a diagnostic value of multiple EBV proteins, in particular certain
EBV-EA markers, a separate IgA EA ELISA using native EA proteins28 is
developed. In addition to their role in primary diagnosis, anti-EBV IgA responses,
in particular the IgA EA response, also have a distinct role for posttreatment follow-
up monitoring, as declining responses correlate with a good prognosis and

66
increasing responses are related to persistence of relapsing tumor.26,29 The
availability of two distinct and biochemically well-defined EBV IgA ELISA
systems addressing responses to different EBV antigens for NPC specific serology
may add to further standardization.
Universitas Gadjah Mada now is developing a rapid test tool for NPC
screening, namely NPC G Strip. This tool works by detecting immunoglobulin G
(IgG) antibodies in the blood or serum or plasma of patients who then react with
the protein Epstein Barr Virus (EBV), especially the early antigen (EA) that has
been attached to the strip. The method used in this examination is known as the
immunochromatography method. Antibodies to EBV protein are used as markers
for several malignancies, one of which is NPC. The use of EA in the manufacture
of NPC Strip G because the molecular size of this protein complex is quite large,
so that it can be mobilized in the pores of the membrane strip. NPC Strip G requires
only 10ml of blood from a fingertip prick or using 2ml of blood serum or plasma
which is then placed on the strip using a loop, then the strip is dipped into the buffer
and waited for 3 minutes for the value of the result. If two lines are formed, it
indicates that the EBV IgG titer in the patient is above normal. This is not
necessarily that the patient is suffering from NPC, but the patient can be referred to
ENT Specialist for further examination such as nasoendoscopy and CT scan. If
there is a suspected tumor in the nasopharynx followed by nasopharyngeal biopsy
to get the right histopathology. But if there is no clinical abnormality, then the NPC
Strip G examination can be repeated every 6 months for 2 years.
For a screening program to be successful, not only must it be applied to a
disease with characteristics appropriate for screening, but also a suitable screening
test must be available. This NPC Strip G appears to fulfill some of the criteria as a
screening tool. It is relatively inexpensive, easy to administer and imposes minimal
discomfort on the screening. A screening test must also be valid, reliable and
reproducible.
In conclusion, screening should be focused on populations at high risk of
developing NPC. These high-risk groups include individuals with; (1) There are
one or more cases of NPC in the family, (2) Specific chronic complaints in the head
and neck area, and (3). Environmental related risks (diet and non-diet).
Treatment outcome of nasopharyngeal carcinoma is stage-dependent. Up to
85% cure can be achieved for early stage of disease whereas the cure rate is 30%
for advanced disease. There is no good evidence currently supporting or against
NPC screening but we hope to detect the disease at an early stage and improve the
cure rate.

67
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Cancer J Clin 2005; 55:74-108.
2. Ho JH. Nasopharyngeal carcinoma (NPC). Adv Cancer Res 1972; 15:57-92.
3. Soeripto. Epidemiology of nasopharyngeal carcinoma. Berita Kedokteran
Masyarakat (Ina) XIII1998:207-211.
4. Lin, JC, Jan JS, Hsu CY, Liang WM, Jiang RS, and Wang WY. Phase III study
of concurrent chemoradiotherapy versus radiotherapy alone for advanced
nasopharyngeal carcinoma: positive effect on overall and progression-free
survival. J. Clin. Oncol 2003; 21:631-637.
5. Hutajulu SH, Ng N, Jati BR, Fachiroh J, Herdini C, Hariwiyanto B, et al.
Seroreactivity against Epstein- Barr virus (EBV) among first-degree relatives
of sporadic EBV-associated nasopharyngeal carcinoma in Indonesia. J Med
Virol 2012; 84(5): 768-76.
6. Old LJ, Boyes EA, Oettgen HF, De Harven E, Geering G, Williamson B,
Clifford P. Precipitating antibody in human serum to an antigen present in
cultured Burkitt’s lymphoma cells. Proc Natl Acad Sci USA 1966; 56:1699-
704.
7. Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N. Clonal
proliferations of cells infected with Epstein-Barr virus in preinvasive lesions
related to nasopharyngeal carcinoma. N Engl J Med 1995; 333: 693-8.
8. Middeldorp JM, Brink AA, van den Brule AJ, Meijer CJ. Pathogenic roles for
Epstein-Barr virus (EBV) gene products in EBV- associated proliferative
disorders. Crit Rev Oncol Hematol 2003; 45: 1-36.
9. Fachiroh J, Paramita DK, Hariwiyanto B, Harijadi A, Dahlia HL, Indrasari SR,
Kusumo H, Zeng YS, Schouten T, Mubarika S, Middeldorp JM. Single-assay
combination of Epstein-Barr Virus (EBV) EBNA1- and viral capsid antigen-
p18-derived synthetic peptides for measuring anti-EBV immunoglobulin G
(IgG) and IgA antibody levels in sera from nasopharyngeal carcinoma patients:
Options for field screening. J Clin Microbiol 2006; 44:1459-1467.
10. Paramita DK, Fachiroh J, Haryana SM, Middeldorp JM. Two-step Epstein-
Barr virus immunoglobulin A enzyme-linked immunosorbent assay system for
serological screening and confirmation of nasopharyngeal carcinoma. Clin
Vaccine Immunol 2009; 16:706-711.
11. Ji MF, Wang DK, Yu YL, Guo YQ, Liang JS, Cheng WM, Zong YS, Chan
KH, Ng SP, Wei WI, Chua DT, Sham JS, Ng MH. Sustained elevation of
Epstein-Barr virus antibody levels pre-ceding clinical onset of nasopharyngeal
carcinoma. Br J Cancer 2007; 96:623-630.
12. Li S, Deng Y, Li X, Chen QP, Liao XC, Qin X. Diagnostic value of Epstein-
Barr virus capsid antigen-IgA in nasopharyngeal carcinoma: A meta-analysis.
Chin Med J (Engl) 2010; 123:1201-1205.

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13. Jia WH, Luo XY, Feng BJ, Ruan HL, Bei JX, Liu WS, Qin HD, Feng QS, Chen
LZ, Yao SY, Zeng YX. Traditional Cantonese diet and nasopharyngeal
carcinoma risk: A large-scale case-control study in Guangdong, China. BMC
Cancer 2010; 10: 446.
14. Gallicchio L, Matanoski G, Tao XG, Chen L, Lam TK, Boyd K, Rob-inson
KA, Balick L, Mickelson S, Caulfield LE, Herman JG, Guallar E, Alberg AJ.
Adulthood consumption of preserved and nonpreserved vegetables and the risk
of nasopharyngeal carcinoma: A systematic review. Int J Cancer 2006; 119:
1125-1135.
15. Zheng YM, Tuppin P, Hubert A, Jeannel D, Pan YJ, Zeng Y, de The G.
Environmental and dietary risk factors for nasopharyngeal carcinoma: A case-
control study in Zangwu County, Guangxi, China. Br J Cancer 1994; 69: 508-
514.
16. Chen CJ, Liang KY, Chang YS, Wang YF, Hsieh T, Hsu MM, Chen JY, Liu
MY. Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus,
malarial infection, cigarette smoking and familial tendency. Anticancer Res
1992; 10: 547-553.
17. Feng BJ, Khyatti M, Ben-Ayoub W, Dahmoul S, Ayad M, Maachi F, Bedadra
W, Abdoun M, Mesli S, Bakkali H, Jalbout M, Hamdi-Cherif M, Boualga K,
Bouaouina N, Chouchane L, Benider A, Ben-Ayed F, Goldgar DE, Corbex M.
Cannabis, tobacco and domestic fumes intake are associated with
nasopharyngeal carcinoma in North Africa. Br J Cancer 2009; 101: 1207-1212.
18. Lee YC, Boffetta P, Sturgis EM, Wei Q, Zhang ZF, Muscat J, Lazarus P, Matos
E, Hayes RB, Winn DM, Zaridze D, Wunsch-Filho V, Eluf-Neto J, Koifman
S, Mates D, Curado MP, Menezes A, Fernandez L, Daudt AW, Szeszenia-
Dabrowska N, Fabianova E, Rudnai P, Ferro G, Berthiller J, Brennan P,
Hashibe M. 2008. Involuntary smoking and head and neck cancer risk: Pooled
analysis in the International Head and Neck Cancer Epidemiology Consortium.
Cancer Epidemiol Biomarkers Prev 2008; 17: 1974-1981.
19. Nam JM, McLaughlin JK, Blot WJ. Cigarette smoking, alcohol, and
nasopharyngeal carcinoma: A case-control study among U.S. whites. J Natl
Cancer Inst 1992; 84: 619-622.
20. Hildesheim A, Dosemeci M, Chan CC, Chen CJ, Cheng YJ, Hsu MM, Chen
IH, Mittl BF, Sun B, Levine PH, Chen JY, Brinton LA, Yang CS. Occupational
exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal
carcinoma. Cancer Epidemiol Biomarkers Prev 2001; 10: 1145–1153.
21. Feng BJ, Khyatti M, Ben-Ayoub W, Dahmoul S, Ayad M, Maachi F, Bedadra
W, Abdoun M, Mesli S, Bakkali H, Jalbout M, Hamdi- Cherif M, Boualga K,
Bouaouina N, Chouchane L, Benider A, Ben-Ayed F, Goldgar DE, Corbex M.
Cannabis, tobacco and domestic fumes intake are associated with
nasopharyngeal carcinoma in North Africa. Br J Cancer 2009; 101: 1207-1212.

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22. Zou J, Sun Q, Akiba S, Yuan Y, Zha Y, Tao Z, et al. A case-control study of
nasopharyngeal carcinoma in the high background radiation areas of
Yangjiang, China. J Radiat Res 2000; 41 Suppl: 53-62.
23. Chang ET, Adami HO. 2006. The enigmatic epidemiology of naso- pharyngeal
carcinoma. Cancer Epidemiol Biomarkers Prev2006; 15: 1765-1777.
24. Pickard A, Chen CJ, Diehl SR, Liu MY, Cheng YJ, Hsu WL, Sun B, Hsu MM,
Chen IH, Chen JY, Yang CS, Mittl BL, Chou SP, Rug- gles DD, Goldstein
AM, Hildesheim A. Epstein–Barr virus seroreactivity among unaffected
individuals within high-risk nasopharyngeal carcinoma families in Taiwan. Int
J Cancer 2004; 111: 117-123.
25. Fachiroh, J., T. Schouten, B. Hariwiyanto, D. K. Paramita, A. Harijadi, S. M.
Haryana, M. H. Ng, and J. M. Middeldorp. Molecular diversity of Epstein-Barr
virus IgG and IgA antibody responses in nasopharyngeal carcinoma: a
comparison of Indonesian, Chinese, and European subjects. J. Infect. Dis 2004;
190:53-62.
26. Karray, H., W. Ayadi, L. Fki, A. Hammami, J. Daoud, M. M. Drira, M. Frikha,
R. Jlidi, and J. M. Middeldorp. Comparison of three different serological
techniques for primary diagnosis and monitoring of nasopharyn-geal
carcinoma in two age groups from Tunisia. J. Med. Virol 2005; 75:593-602.
27. Van Grunsven, W. M. J., A. Nabbe, and J. M. Middeldorp. Identification and
molecular characterization of two diagnostically relevant marker proteins of
the Epstein-Barr virus capsid antigen complex. J. Med. Virol. 1993; 40:161-
169.
28. Paramita, D. K., J. Fachiroh, W. T. Artama, E. van Benthem, S. M. Haryana,
and J. M. Middeldorp. Native early antigen of Epstein-Barr virus, a promising
antigen for diagnosis of nasopharyngeal carcinoma. J. Med. Virol 2007;
79:1710-1721.
29. Stevens, S. J. C., S. A. W. M. Verkuijlen, M. C. Zwaan, and J. M. Middel-
dorp. Epstein-Barr virus (EBV) serology, but not EBV DNA load, for
predicting distant metastases in a juvenile Caucasian nasopharyngeal carci-
noma (NPC) patient without clinical response upon EBV lytic induction
therapy. Head Neck 2006; 28:1040-1045.

70
71
 THE DEMOGRAPHY OF NPC IN SANGLAH DENPASAR GENERAL
HOSPITAL DURING JANUARY-SEPTEMBER 2018

I Gde Ardika Nuaba

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Udayana

INTRODUCTION
Nasopharyngeal carcinoma (NPC) is the most common head and neck
cancer. NPC is a cancer that grows on the posterior nasal cavity and pallatum of
mouth. The area with a high risk of developing the NPC is mainly Southern China,
Southeast Asia, the Southwest of India, North Africa, Eskimo, and Alaska.1
NPC is considered one the most common cancer in Indonesia, placing 4th
after cervical cancer, breast cancer, and skin cancer, also the most common cancer
of the head and neck region. NPC derived from the fossa Rosenmuller where the
transitional zone of the cuboidal to squamous epithelium exist.1
Statistical data showed that the Chinese ethnics has the highest incidence
rate. The prevalence rate in Singapore is 15/100,000 populations, 9.7/100,000
populations in Malaysia, 7.5/100,000 populations in Vietnam, and 6.4/100,000
populations in The Philippines. NPC ranked 4th in Indonesia.2

METHOD
This is a descriptive study to map the demography and epidemiology of
NPC patients in Sanglah Denpasar Genereal Hospital dated 1st January up to 30th
September 2018. The population and sample of this study is all the NPC patients
who came to ENT clinic within 1st January - 30th September 2018. The data will
then be presented descriptively with table and narration.

RESULTS
Within 1st January to 30th September 2018, 53 cases were reported which
suited the inclusion criteria. The statistical data showed that range of the NPC
patients is 18-72 years old, majority are the patients age 51-60 (33.96%), while the
lowest are 11-20 years old (3.77%). The youngest patient is 18 years old and the
oldest is 72 years old. Men consists of 36 people (67.92%) and women 17 people
(32.08%).

72
 Table 1. Age and Gender
VARIABEL FREQUENCY PERCENTAGE (%)
Range of Age
11-20 2 3.77
21-30 2 3.77
31-40 6 11.32
41-50 15 28.33
51-60 18 33.96
61-70 7 13.20
>70 3 5.65
Gender
Male 36 67.92
Female 17 32.08

Graph 1. Range of Age

18
16
14
12
10
8 Frequency
6
4
2
0
11-20 21-30 31-40 41-50 51-60 61-70 >70
years years years years years years
old old old old old old

73
 Graph 2. Gender

Gender

32,08 %
Male

67,92% Female

Bali province consists of 8 districts which are Badung, Tabanan, Gianyar,

Buleleng, Karangasem, Jembrana, Klungkung, Bangli, and Denpasar. This study
categorized the data based on the districts in Bali and outside of Bali. Majority of
patients were from Bali, 14 people (21.41%) and the lowest rate is from Bangli
District and Klungkung District both only 2 cases (3.77%).

Table 2. Demography
VARIABLE FREQUENCY PERCENTAGE (%)
Demography
Denpasar 14 21.41
Badung 3 5.66
Tabanan 6 11.32
Gianyar 4 7.54
Buleleng 8 11.89
Karangasem 4 7.51
Jembrana 3 5.66
Klungkung 2 3.77
Bangli 2 3.77
NTB 3 5.66
NTT 2 3.77

74
 Graph 3. Demography

16

14

12

10

11.89%
5.66 % 3.77%
7.51%
11.32%

3.77%
7.54%
%%%

21.41%

5.66%

Picture 1. Demography Mapping

75
DISCUSSION
NPC is a cancer that grows on the posterior nasal cavity and pallatum of
mouth. The area with a high risk of developing the NPC is mainly Southern China,
Southeast Asia, the Southwest of India, North Africa, Eskimo, and Alaska.1
The statistical data showed that range of the NPC patients is 18-72 years
old, majority are the patients age 51-60 (33.96%), while the lowest are 11-20 years
old (3.77%). The youngest patient is 18 years old and the oldest is 72 years old.
Men consists of 36 people (67.92%) and women 17 people (32.08%). Statistical
data showed that the Chinese ethnics has the highest incidence rate. The prevalence
rate in Singapore is 15/100,000 populations, 9.7/100,000 populations in Malaysia,
7.5/100,000 populations in Vietnam, and 6.4/100,000 populations in The
Philippines. NPC ranked 4th in Indonesia.2
According to the data in Cipto Mangunkusumo Hospital, there were 6,000
cases of malignancies of Head and Neck recorded within 1995-2005. Among them
there were 1,121 cases of NPC, consisting of 789 men and 332 women.2
NPC patients in several countries have the range of 4-91 years old with the
peak incidence 50-60 years old. Loh et., al., showed that the highest prevalence rate
of NPC in China is those who were 50-60 years old.3

CONCLUSION
This study consists of 53 people, 36 men (67.92%) and 17 women (32.08%),
majority age groups is 51-60 years old (33.96%), while the lowest rate are 11-20
years old group. (3.77%). The clinical signs that mostly manifested is the swelling
of neck (30.18%). Patients mostly are from Denpasar (21.41%).
Demography pattern of the NPC is important to understand the
epidemiology and spreading of NPC in Bali Province and can be use as the early
detection of NPC.

REFFERENCE
1. Hutajulu SH, Indrasari SR, Indrawati LP, et al. epigenetic markers for early
detection of nasopharyngeal carcinoma in a high risk population. Mol cancer,
2011, 10:48
2. Adham Marlinda, dkk. Nasopharyngeal carcinoma in Indonesia:
Epidemiology, incidence, signs, and symptoms at presentation. Chin J Cancer;
2012. Vol 31 issue 4.
3. Loh KS, Goh BC, Lu J, dkk. Familial Nasopharyngeal Carcinoma in a cohort
200 patients. Arch Otolarngology Head Neck Surgery, 2006, 132:82-85.

76
 ANATOMY AND PHYSIOLOGY OF NASOPHARYNX

Denny Satria Utama

Otorhinolaryngology Head and Neck Surgery

Faculty of Medicine Universitas Sriwijaya

ANATOMY
Pharynx is an irregulary tubular structure, extending from base of the skull
base to the esophageal inlet, pharynx has anterior opening into the nasal and oral
cavities, inferiorly it open into the larynx and esophagus. Pharynx consist of three
segments; Nasopharynx, Oropharynx, and Hypopharynx. There is a three Pharygeal
muscles begin from Superior constrictor is suspended from base of the skull, medial
pterygoid plate, Pterygomandibular raphe, Mylohyoid line of the mandible, and the
lateral of tongue, Middle constrictor muscle anterior attaches to hyoid bone and
stylohyoid ligament, also Inferior constrictor attaches to the thyroid & cricoid
cartilages.1
Nasopharynx is an nasal part of the pharynx that continuous anteriorly
through the choanae with the nasal cavities, is an open cuboidal chamber that lies
beneath the base of the skull at the posterior aspect of the nasal fossa. It measures
4.0 to 5,5 cm transversely and 2,5 to 3,5 cm in the anteroposterior dimension andi
s roughly 4.0 cm in height. The close proximity to the nose and pharynx plus its
connection with the middle ear via eustachian tube, identify the nasopharynx as the
central hub around which the specialty of otorhinolaryngology revolves. Region of
the nasopharynx according to UICC in 1963 Anteriorly, it borders the posterior
nares,within which lie the posterior ends of the middle and inferior turbinates. The
roof is a sloping concave surface formed by the posterior body of the sphenoid,
basilar component of the occipital bone, and anterior arch of the atlas. The
nasopharyngeal tonsil lies in the midline in the roof and posterior wall. The superior
pharyngeal constrictor and fascia complete the posterior wall. The floor of the
nasopharynx is composed of the soft palate. The lateral walls contain important
structures such as the pharyngotympanic tube, situated 10 mm behind and slightly
below the level of the posterior part of the inferior turbinate. The lateral walls
consist of only two layers: the mucous membrane and the pharyngeal aponeurosis.
The cartilaginous eustachian tube passes through this aponeurosis, opening into the
fossa of Rosenmüller. Lateral to the lateral wall, the mandibular nerve exits the
foramen ovale into the infratemporal fossa. Posterior to the eustachian tube is the
retroparotid space, which contains the pharyngeal lymph nodes, internal carotid
artery, internal jugular vein, and glossopharyngeal, vagus, spinal accessory, and
hypoglossal nerves as well as the cervical sympathetic nerve.1,2

77
 Picture 1. Nasopharynx Anatomy2

Understanding the relative contents and locations of the foramina

surrounding the nasopharynx allows the clinician to predict the extent of tumor
spread based on cranial nerve examination. Six foramina are adjacent to the wall of
the nasopharynx: (1) foramen lacerum, (2) foramen ovale, (3) foramen spongiosum,
(4) carotid canal, (5) jugular foramen, and (6) hypoglossal canal. The foramen
lacerum and the foramen ovale offer little resistance to tumor spread into the
cranium, and their close proximity to the cavernous sinus and cranial nerves II, III,
IV, and VI explains the frequency of cranial nerve palsies at diagnosis. The
lymphatics of the nasopharynx drain either through direct efferent channels to the
deep lymph nodes of the posterior triangle or first through the lateral pharyngeal
wall to the retroparotid or lateral pharyngeal lymph nodes and then on to the upper
jugular chain. Some channels may pass directly to the jugulodigastric chain.
Lymphatic channels often cross the midline and offer ready access to both sides of
the neck.1,2

PHYSIOLOGY
The nasopharynx is not, as is commonly supposed an immobile entity, is
only a small area anterior to the Eustachian tube orifices which has rigid bony walls.
Vigorous contractions even in the areas of the tubal eminence and the fossa of
rosenmuller, below this level the nasopharynx is a muscular tube, constantly
participating in active contraction during swallowing and speech especially in the
region of the isthmus.1,2

78
NASOPHARYGEAL WALL
The wall of nasopharynx are composed of the muscular, Fibrous, mucosal
layer. The Muscular layer comprises outer oblique and inner longitudinal
component derived from the superior constrictor mucle. Between the upper edge of
the muscle and the base of the skull, the muscular layer is absent, the deficiency
being strengthened by a thickening of the fibrous layer. The Fibrous Layers
comprises two layers which provide an outer and inner lining for the constrictor
muscles. Both layer are continuous with the general fascia of the neck. Outer layer
or buccopharyngeal fascia covers the superficial aspect of the superior constrictor
muscle. The inner component or pharyngeal aponeurosis, which lies between the
mucosal layer and the contrictor muscle is part of the pharyngobasilar fascia. Both
fascial layers unite at the upper edge of the superior constrictor muscle and ascend
towards the base of skull as a single entity.1,2,3
The mucosal layer, in adult nasopharynx is lined mainly by pseudostratified
columnar ciliated mucosa near the choanae and adjacent part of the roof. While the
lower and posterior regions of the nasopharynx, the lining assumes a stratified
squamous character. Areas of transitional epithelium are encountered at the
junctional zone located on the roof and lateral walls. The lamina propria is
frequently infiltrated by lymphoid tissue, while the submucosal layers contains
serous and mucous glands.1,2,3

Picture 2. Nasopharynx Histology3

SPECIAL FEATURES
Pharyngeal Tonsil is detectable beneath the mucous membrane at the
junction of the roof and posterior wall of the nasopharynx. Rapid hypertrophy takes
place in early childhood followed by gradual regression after the age of 8-10 years.
The lymphoid mass is triangular in shape with the apex pointing towards the
posterior free margin of the nasal septum, the surface is irregular with several
prominent ridges interrupted by deep furrows lined with epithelium. The lymphoid
follicles embedded beneath the surface epithelium contains T and B lymphocytes,

79
reticular cells and fibroblasts. Large adenoid masses may extend laterally into the
fossa rosenmuler.2,3,4
Torus Tubarius, the pharyngeal orifice of the Eustachian tube lies 1 - 1,25
cm behind and below the posterior end of the inferior turbinate. The orifice is
partially shielded especially on its posterior and superior aspects, by prominent
comma shaped elevation termed the Eustachian cushion which is formed by the
medial extremity of the cartilaginous part of tube. The Eustachian tube 3 to 4 cm in
length runs laterally and backwards from the nasopharygeal orifice to the tympanic
cavity. The anteromedial two third are composed of cartilage and connective tissue
whereas the posterolateral one third is bony. The cartilaginous segment occuoues a
groove between the greater wing of sphenoid and the petrous temporal bone. The
cartilage of the tube is elactic in type and has the shape of an inverted U , the inferior
deficiency being closed by connective tissue. The cartilaginous portion of the tube
is lined by pseudostratified columnar ciliated epithelium while the bony segment
has non ciliated cuboidal epithelium. 2,3,4
Fossa rosenmuller, immediately above and behind the tubal elevation lies
the pharyngeal recess or fossa rosenmuller. It extends laterally into the sinus of
Morgagni immediately above the upper limit of the superior constrictor muscle of
the pharynx. The fossa is variable in size and depth and is conical or slit-like in
shape. Usualy occur bilaterally, one such diverticulum measured in 2.5-3 cm in
vertical height and 2.5 cm in depth. In large diverticula the lining may appears
smooth or granular and varying degrees of epithelial metaplasia may be evident on
histological examination. The fossa rosenmuller is great importance since it
represents by far the commonest site of origin of the nasopharygeal carcinoma.
More over its inaccesable location underlines the problems of the otolayngologist
in performing a thorough examination of the area. Relations of the fossa as tumour
spread generally radiates from the fossa of rosemuller the anatomical relations are
the great clinical significance, anteriorly is Eustachian tube, anterolateral levator
veli palatini muscle, posterior is retropharygeal space, superior is foramen lacerum,
medialy the petrous apex and carotid canal, posteriorly the foramina ovale and
spinosum anterolateraly, Lateral is tensor veli palatine muscle, pharyngeal space,
inferior is superior constrictor muscle. The close proximity of the fossa to the
foramen laserum and other important structures at the skull base readily accounts
for the ease and rapidity with which tumour can spread and cause serious
neurological complications.2,3,4

80
 Picture 3. Lateral Relations of Fossa Rosenmuller4

IMPORTANCE COMPARTMENT
The Formation of a number of compartments which are great importance to
the clinician. The Retropharyngeal space lies behind the nasopharynx separating it
from prevertebral (alar) fascia. The firm midline attachment between the
buccopharyngeal fascia and the prevertebral (alar) fascia divides the space into two
segments. Laterally the space is sealed by the attachment of both these fascial layers
to the carotid sheath. The space is of special impotance in as much as it contains the
median and lateral groups of retropharyngeal lymph nodes, including the node of
Rouviere. The Parapharyngeal space is triangular on cross section and lies
immediately lateral to the pharynx, extending from the base of skull above, to the
superior mediastinum below. In its upper part, it is related laterally to the ascending
ramus of the mandible and medial pterygoid muscle in front and to the parotid gland
further back. The space is sub divided into two compartments by the styloid process
and attached muscles together with the fascial connection between the carotid sheat
and prevertebral (alar) fascia. The Prestyloid compartment is related in its upper
part to the lateral wall of the nasopharynx and fossa rosenmuller and contains the
maxilarry artery and inferior dental, lingual and auriculo temporal nerves. The
retrostyloid compartment is more deeply placed and contains the carotid sheath and
its contents, the upper deep cervical lymph nodes, the cervical sympathetic chain
and the last four cranial nerves. 1

81
 Picture 4. Horizontal Section Nasopharynx4

BLOOD VESSELS, NERVES AND LYMPHATICS

The mayor arteries supplying the nasopharynx ascending pharyngeal,
ascending palatine, descending palatine, and pharyngeal branch of the
sphenopalatine. All originate from external carotid artery and its various branches.
A venous plexus situated beneath the mucous membrane communicates with the
pterygoid plexus superiorly and the posterior facial or internal jugular veins below.
The sensory nerves supply of the nasopharynx including the posterior part of soft
palate, is derived from cranial nerves IX excepting an ill defined area of the
nasopharygeal roof adjacent to the tubal orifices which is supplied by cranial nerve
V through its maxillary division. The glossopharyngeal component is mainly
derived through several small branches, including a communicating twig from the
tympanic branch of the nerve which follows the course of the greater superior
petrosal nerve. The supply to the upper surface of the soft palate and adjacent
nasopharynx comes directly from the glossopharyngeal nerve as it descents in close
proximity to the tonsillar fossa.1
The trigimenal component leaves the maxillary division of the nerve in the
pterygopalatine fossa and after traversing the pterygopalatine ganglion, it enters the
tiny palatinovaginal canal to reac the roof of the nasopharynx. The motor
innervation is supplied by way of the pharyngeal plexus, comprising cranial nerves
IX and X together with branches of the cervical sympathetic. The main innervation
to the pharyngeal musculature is derived from the cranial root of the XI nerve
passing via cranial nerve X. The nasopharynx is site of a marked aggression of
lymphoid tissue, concentrated mainly in the pharyngeal tonsil, which form part of
the lymphoid ring of waldayer. The drainage area of the middle collecting trunks
includes the soft palate and palatine tonsils but it may extend upwards as far as the
Eustachian tube orifice. The lymphatic channels run outwards traversing the lateral
wall of pharynx to terminate in the lateral retropharygeal node. The retropharygeal
nodes are located in the retrophayrgeal space between the posterior wall of the

82
nasopharynx and the prevertebral fascia. They are prominent in the neworn and in
early childhood but tend to atrophy with age and some nodes may disappear by
adult life. They comprise two group, median and lateral, the medial retropharygeal
nodes are of limited importance being inconstant and often absent in adulthood.
They consist of one or two small applied directly to the posterior surface of the
nasopharynx lying in the course of the median group of collecting trunks. The
lateral groups of nodes is larger and more constant than the median group usualy
consist of a single node on either side often referres to as the node of rouviere.1

ROUTES OF TUMOUR SPREAD

The direction of spread is partly dependent on the site of origin of the
neoplasm but in large tumours this mauy be difficult to determine. Tumours arising
near the midline may spread to one or other side but more often spread bilateraly.
Tumours of the lateral wall however also occasionaly transgress the midline so that
bilateral or even contralateral spread may occur.
Intralumenary expansion is common and as the growth enlarges it may spread from
the nasopharynx into the pharynx into the pharynx and nose. Causing resorption of
adjacent tissue with occasional destruction of the palate, maxillary sinus or orbit.
Retropharyngeal space is frequently the first route spread. Lymphatic spread
to the node of rouviere is commonest but direct invasion also occurs. Further
extension of the tumour may result in compression or infiltration of the retrostyloid
space and its contents or destruction of the lateral mass of the atlas vertebra.
Paraphargeal space is compose of prestyloid compartment, normaly taken place by
direct extension of the tumour. Disturbances of the sensory root of the trigeminal
nerve followed later by motor root may become evident. Trismus is also
encountered due to invasion of the ptergoid muscles while asymmetry of palate in
the resting position due to infiltration of the levator muscle is frequently
encountered. Facial paralysis due to damage to cranial nerve VII is rare. Further
spread of the tumour may take place to the palate, sinuses, parotid gland, the
pterygomaxillary fissure and the infratemporal fossa while very large tumours may
invade the maxilarry or frontal sinuses.2,3,4
Retrostyloid Compartment, invasion of the retrostyloid space by direct or
lymphatic spread may result in paralysis of the last four cranial nerves and the
cervical symphatetic chain. The internal carotid artery and jugular vein may also be
compressed or infiltrated. Upward spread from the parapharygeal space may lead
to erosion of the base of skull, including sphenoid body and sinus, foramina ovale,
spinosum and roundum also the greater wing of the sphenoid. In extensive growths
tumour deposits may penetrate the pterygoid muscle and gain acces to the
infratemporal fossa. Further migration by this route into the orbit and maxillary
sinus is possible. Downward extension of the tumour result in invasion of the palate
causing associated ear problems, and the parotid and submandibular salivary glands
may also be infiltrated.2,3,4

83
REFERENCE
1. Snow JB, Ballenger JJ. Ballenger’s: Otorhinolaryngology Head and Neck
Surgery. Edisi 18. Ontario: BC Decker Inc. 2016. 1042-1043.
2. Woodson GE. Upper airway anatomy. In: Bailey BJ, Johnson JT ed. Head and
neck surgery otolaryngology. Fifth edition. Lippincott Williams and Wikins.
Philadelphia. 2014: 868-890.
3. Gibb AG. Anatomy and Development. In: Nasopharyngeal Carcinoma. Second
edition. Hongkong: Chinese university press. 1999. 13-20
4. Ali MY. Histology of the human nasopharyngeal mucosa. J Anal. 1965. Jul; 99
(Pt 3):675-672.

84
 CLINICAL PRESENTATION AND DIAGNOSIS OF
NASOPHARYNGEAL CARCINOMA

Yulvina

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Indonesia

ABSTRACT
Nasopharyngeal carcinoma (NPC) is unique in its epidemiologic pattern. It
is common in certain ethnic groups. The risk factor for NPC are genetic,
environment and EBV infection. Eighty percent patient come in a late stage. The
symptoms depend on tumor expansion. Symptoms can be nasal obstruction,
epistaxis and bloody saliva. Superior expansion reveals neurologic complain such
as diplopia, ptosis and dysphagia. Otitis Media with effusion caused by lateral
expansion of nasopharyngeal carcinoma. The most common symptoms is palpable
neck lump caused by metastasis of the cancer to neck lymph node. The gold
standard for NPC diagnosis is nasopharyngeal biopsy.

INTRODUCTION
Nasopharynx is posterior to the nose and the upper part of the pharynx. The
superior part borders are the base of the brain and the posterior is the cervical
vertebra. Because of the Capacity for tumor growth in nasopharynx, the space also
difficult to see without endoscopic, patients generally come in an advanced stages.
These tumors usually reach a certain size before causing symptoms in the patient.
Almost all patients with nasopharyngeal carcinoma have symptoms at the time of
diagnosis, only 1 percent of the cases detected are accidentally when the patient
checks for periodic check ups or during imaging examinations that show the
presence of masses in the nasopharynx.1

PREVALENCE
Nasopharyngeal carcinoma are found in certain ethnic groups. This cancer
often occurs in China and Hong Kong. The highest incidence of nasopharyngeal
cancers found in Guang Zhou China with prevalence rates is 30/100,000 population,
in Hong Kong 20.2/100,000 in men and 7.8 / 100,000 in women. In China, most are
from Cantonese and Fujians ethnic, while in Hong Kong the most are Cantonese.
In Singapore the prevalence of NPC patients is 10.8/100,000 population. In the past
10 years, the incidence of nasopharyngeal cancer began to decline, this is associated
with changes in diet.1, 2
Nasopharyngeal cancer is rare in white people. Seventy-five percent of NPC
patients are male. More than 80% of cases are between 30-60 years old.1 In

85
Indonesia Nasopharyngeal carcinoma is the highest malignancy of the head and
neck cancer.

ETIOLOGY
The main factors related to nasopharyngeal cancer are genetic factors,
environment and Epstein Barr Virus infections.1, 2

Genetic and nasopharyngeal carcinoma

Many studies revealed a link between genetic factors and nasopharyngeal
cancer (NPC). Ung et al, confirmed that NPC patients who have a family history is
15.5%, have a probability 8 times higher than the normal population without a
history of NPC. Sibling have a 70% higher risk compared to 30 % for parents and
children. The presence of NPC patients in the family group is said to have the same
genes, but some argue because they are also affected by the same environment. 1
The Incidence of NPC in the Chinese population in the United States shows
influential environmental factors. These factors are related to modified diet,
especially in children's, ventilation, occupational exposure to dust and smoke.
Dymethylnitrosamine in salted fish causes upper respiratory tract cancer in studies
with mice.2

Human Leucocyte Antigen (HLA) and nasopharyngeal cancer

The relationship between HLA and nasopharyngeal cancer has been
presented since 1975. The human leucocyte antigen is HLA class I, including HLA
A, B and D groups on chromosome 6. HLA A2, Bw46, B17, Bw58, DR3 and DR
9 are obtained by a significant amount of nasopharyngeal carcinoma with the
highest risk was found in people who had high HLA A2 and Bw46. Most patients
with Chinese races with NPC have predominantly HLA A0207, which is different
from the dominant white people who have HLA A0201.1

Genetic Changes and Chromosome

Studies shows that Chromosome changes are loss of chromosomes 3, 9 and
11. The loss of chromosomes causes loss of certain functions such as chromosome
9p21 which functions as a regulator for cell cycle development such as p15 and
p16. P 16 itself is not active in NPC patients.1, 2

Environment Factor and NPC

The most influential environmental factor is the high diet of preservatives
like salted fish. Carcinogens in salted fish are nitrosamines. Other environmental
factors are wood dust and chemical substances. Some literature reveals the link
between smoking and NPC and is associated with higher cancers of squamous cell
carcinoma and not with differentiated carcinomas.2

86
Nasopharyngeal Carcinoma and EBV infections
EBV is an encapsulated herpesvirus. Infection occurs in children or
adolescents. Infection in children can be asymptomatic, but infection at adolescence
will have symptoms. The symptoms are like mononucleosis. Once the man is
infected with EBV, he will be immune to this infection, but EBV is present in B
lymphocytes for life and is transmitted through saliva. Immunoglobulins M and G
will increase in the acute phase. The antigen in this virus is the Early Antigen (EA)
and Viral Capsid Antigen (VCA). In patients with NPC, IgA VCA and EA increase
and are used as tumor markers. EBV antigen is also found in nasopharyngeal cancer
cells both lytic and nuclear antigen. Lytic antigens include LMP1, 2 and 3. Nuclear
antigen is Epstein Barr Nuclear Antigen (EBNA) 1 to 6. Both EBNA 1 and LMP1
are always expressed in significant amounts. EBNA functions to maintain viral
episomes in tumors and LMP 1 plays a role in increasing cell growth. NPC patients
also always express Epstein Barr Encoded Ribonucleosid Acid (EBER) in the
cytoplasm. These antigens and EBERs are not obtained in normal nasopharyngeal
cells.1, 3

CLINICAL PRESENTATION AND NASOPHARYNGEAL CARCINOMA

Symptoms of nasopharyngeal cancer are neck lumps, blood in the saliva,
epistaxis, nasal obstruction, hearing loss and cranial nerve disorders.
The most common symptom in nasopharyngeal carcinoma is a neck lump.
Sixty percent of patients come to the doctor with this complaint. This neck lump is
a metastasis or spread of this tumor in the neck lymph nodes. Lymph node
metastasis usually has the upper part of the neck and posterior neck (at level II and
level V), it also can be seen on level III and rarely at level IV. Some literature
mention NPC with the spread of lumps in the parotid lymph nodes. Sometimes there
is central necrosis of the lymph nodes and is followed by the formation of abscesses
in the gland. NPC patients who come on treatment usually have 80% have
metastasis in the lymph nodes, because there are 20 percent of the glandular
metastases that are not palpable but detected on imaging such as CT scans.1

87
 Picture 1. Lymph node pathway of nasopharyngeal carcinoma

The second most common symptom is blood saliva. Epistaxis was also
reported in 23% of patients. Another symptom is feeling full in the ear and hearing
loss. This is due to impaired tubal function due to the closure of the fallopian tubes
by the tumor and will form fluid in the ear and up as conductive hearing loss. With
the tuning fork examination, it is found that there is a weber lateralization to the
affected ear and the negative rhinne on the affected side. On otoscopic examination,
there is an air bubbles in the tympanic membrane. Tympanometry examination
shows type B.1
Persistent headache complaints were also found in patients with intracranial
extension or clivus erosion. Cranial nerve paralysis is found in 10 percent of cases.
The nerves that are often affected are nerves to 5, 6, 9, 10 and 12. In endemic areas
such as in China, if there is a strabismus cause by nerve VI disorders, nasopharynx
should be evaluated with an endoscope and CT scan to evaluate the presence of
NPC.1
Endoscopic examination shows an exophytic mass in the nasopharynx area.
But in 10 percent of cases, NPC is submucosal and nasopharyngeal appearance can
be within normal limits or only slightly irregular. In endemic areas, patients with
neck lumps, blood-mixed saliva, unilateral deafness should be considered the
possibility of NPC and will be evaluated to look for the presence of NPC until it is
proven not NPC.1
Pain in NPC is obtained due to compression of trigeminal nerve because the
tumor erodes the bones and base of the brain. Pain is usually in the face, occipital
and temporal areas. Pain when lifting the head is felt by the patient if the tumor has
infiltrated the prevertebral muscles.2

88
CLINICAL INVESTIGATION
Computer tomography Scan (CT-Scan) can show the nasopharynx, clivus
and basic erosion of the brain. Magnetic resonance imaging (MRI) is superior
compare with CT scan because it can better to see soft tissue changes and see
intracranial involvement. When looking at the MRI, radiologist should be able to
look to extension nasopharyngeal cancer to superior border: to the cavernous sinus,
meninges, the foramen laserum, rotundum and ovale. Posteriorly, they should
assess the clivus and sphenoid. To the Anterior part, they should investigate
Involvement in the sinuses, To the lateral expansion, investigate the pterygopalatine
fossa, and the infratemporal fossa involvement. The retropharyngeal gland is
assessed and assessed as a central neck gland that is classified as N1 and also
assesses the supraclavicular and mediastinal glands and axilla.1
Chest X ray, liver ultrasound, and bone scan should be performed to see
distant metastases. The most common metastasis is bone. Positron emission therapy
(PET) has been widely used to assess local, regional and metastatic tumors, but PET
cannot replace the superiority of MRI which can see the meninges, foramen in skull
base. Positron emission therapy will be very useful when combined with MRI.
Audiogram and tympanometry examination is performed as a basic
examination, this is important because the patient can experience hearing
deterioration due to chemotherapy and xerostomia post radiation. IgA EA
examination that is specific for NPC and IgA VCA that are sensitive to NPC. This
examination does not replace a biopsy but can be used as a follow-up to assess
recurrence, assess the therapeutic response and or can be for tumor markers.1

NASOPHARYNGEAL CARCINOMA DIAGNOSIS

Gold standard for NPC diagnosis is histopathology through nasopharyngeal
biopsy. Biopsy can be performed with local anesthesia. The tumor is biopsied
through the nose with the rigid endoscope guidance. In some cases, general
anesthesia should be done for nasopharyngeal exploration. This procedure is
perform if the result of Fine needle aspiration biopsy (FNAB) is metastasis/spread
from carcinoma and the previous biopsy show no cancer in nasopharynx. This
procedure is repeated by taking deeper biopsy. Imunohistochemical examinations
such as cytokeratin, EBER can help differentiate NPC from sinonasal tumors that
are undifferentiated carcinoma types.1

HISTOLOGICAL CLASSIFICATION OF NPC

According to WHO, the classification of nasopharyngeal cancer is
squamous cell carcinoma, non-keratinized squamous cell carcinoma and non-
keratinized carcinoma.2

89
STAGING OF NASOPHARYNGEAL CARCINOMA

Table 1. Union International Centre Cancer Tumor of NPC1:

T Classifictaion Manifestation
Tx Primary tumor unable to be assed
T0 No evidence of tumor
T1 Confined to nasopharynx or extend to oropharynx and/or
nasal cavity
T2 Tumor extend to parapharyngeal space
T3 Tumor involved sinus or skull based
T4 Intracranial, infratemporal/masticator space involvement,
cranial nerve involvement orbit or hypopharynx.

Table 2. Union International Centre Cancer Nodes of NPC1:

N Classifictaion Manifestation
N0 No nodal involvement
N1 Unilateral cervical lymph nodes ≤ 6cm, or unilateral or
bilateral retropharyngeal nodes ≤ 6cm above fossa
supraclavicular
N2 Bilateral lymph nodes ≤ 6cm above supraclavicular fossa
N3A Lymph node > 6cm
N3B Supraclavicular lymph node

Table 3. Union International Centre Cancer Metastases of NPC1:

M Classifictaion Manifestation
M0 No distant metastasis
M1 Distant including mediastinum node

Table 4. Union International Centre Cancer Staging of NPC1:

Stadium Classification
I T1N0M0
II T1N1M0, T2N0M0, T2N1M0
III T3N0M0, T3N1M0, T3N2M0
IVA T4, any N, M0
IVB Any T, N3M0
IVC Any T, Any N, M1

After the stadium is determined, the NPC will be treated according to the
guidelines made by NCCN.

90
REFERENCE
1. Tan L, Loh T. Benign and Malignant Tumors of nasopharynx. In: Cummings
otolaryngology. Second ed. 2015. p.1420-5
2. Lee N, Colevas D, Fu K. Cancer of Nasopharynx in: Head and Neck tumors.
1st ed. p 523-528
3. Lee N, Riaz N, Ove R, reyngold ML, Foote RL, Bonner J.Nasopharyngeal
Carcinoma in: Clinical Radiation Oncology. Fourth ed. Section 34:p. 629-648.

91
 SURGERY FOR NASOPHARYNGEAL CARCINOMA

Ika Dewi Mayangsari

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Indonesia

INTRODUCTION
Nasopharyngeal carcinoma (NPC), one of the most common cancer in the
head and neck area, is a cancer arising from the epithelium and usually develops at
the fossa of Rosenmuller and invades adjacent spaces or organs. Nasopharyngeal
cancer worldwide prevalence is less than 1/100,000. However, it is a malignant
disease and a leading cause of death in several regions, such as Asia and Africa.
There were 86,691 cases of nasopharyngeal carcinoma worldwide with Southeast
Asian countries contributed large number of those cases in 2012. Indonesia has the
second highest number (13,084 cases) of nasopharyngeal carcinoma in the world
after China (42,100 cases) with at least 5.7 per 100,000 in males and 1.9 per 100,000
in women. Men are two to three times at risk of nasopharyngeal carcinoma than
women.1
Beside its relatively high incidence, nasopharyngeal carcinoma is one of the
leading cause of death in five countries worldwide, respectively. In 2012, Indonesia
had the highest standardized mortality rate (3.3 per 100,000 people) followed by
Vietnam (3.3 per 100,000 people), Singapore (2.8 per 100,000 people), Malaysia
(2.5 per 100,000 people), and Brunei (2.1 per 100,000 people). One of the main
causes of the high mortality rate in Indonesia, as a developing countries, is the delay
in diagnosis and most of the patients come with an advanced stage of the disease.
The prognosis for advanced stage is very weak and it has higher risk for relapse,
especially in elderly.2
Treatment of choice for nasopharyngeal carcinoma is radiotherapy, with
chemotherapy combination or not. However, local failure occurs in 10 to 30% of
the patients.1 It is a challenging situation for treating the local failure of
nasopharyngeal carcinoma. The difficulties arise from the anatomy of the residual
or recurrent carcinoma, involvement of surrounding structures, and the therapy-
related complications. The treatment for recurrent nasopharyngeal carcinoma
follows the guidelines of the 2016 National Comprehensive Cancer Network. The
treatment options varies from surgery, re-irradiation by external beam, stereotactic
radiotherapy or brachytherapy, and chemotherapy. However in Indonesia, there are
still minimal data on the outcome of recurrent nasopharyngeal carcinoma after the
treatment. This review will explore more on the outcomes of salvage surgery and
re-irradiation in recurrent nasopharyngeal carcinoma.

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 Diagram 1. Guidelines National Comprehensive Cancer Network 2016 for
Recurrent Nasopharyngeal Carcinoma3

RECURRENT NASOPHARYNGEAL CARCINOMA

The management of recurrent NPC is still challenging in the medical field.
Some of the things that cause difficulty in treating recurrent NPC are the location
of the cancer adjacent to the vital structures i.e. brainstem, temporal lobe, and optic
apparatus.4 On the other hand, long-term complications due to re-irradiation can
also occur and damage the surrounding organs, therefore the selection for managing
the recurrent NPC should be carefully thought out and weigh all possible risks.5
Management for recurrent NPC is currently following the guidelines of the 2016
National Comprehensive Cancer Network but the selection of treatment depends on
the condition of each patient. Some things that need to be considered in choosing a
treatment for recurrent NPC are the size, stage, connection with the surrounding
tissue, whether it can be resected or not, and the availability of experts and surgical
instruments.
All patients must be fully evaluated before deciding which treatment to
choose. Re-staging must be done and discussed in a multidisciplinary team. The
doctor must also make plans regarding the handling of teeth, nutrition, and
evaluation of health behavior and intervention. For patients who will undergo
surgery, surgical procedures, operating margins, and reconstruction plans must be
discussed carefully with the ultimate goal is tumor-free margin.6,7

RE-IRRADIATION
There are various types of radiotherapy modalities to treat NPC, including
brachytherapy, stereotactic radiation, and radiation of external beams.8 The choice
of treatment of re-irradiation in patients with recurrent or persistent NPCs needs to
be done very carefully. Every benefit and complication that may occur must be

93
thought through carefully because each patient is in different conditions. For
example, re-irradiation does improve control of the tumor, but if the interval time
of re-irradiation is too close from the last one, it can cause high levels of toxicity to
the surrounding organs. Some things that need to be considered in re-radiation are
the interval between initial radiation and re-irradiation, tumor volume, and the
general condition. The choice of re-irradiation is thought only for groups of patients
who have no other curative treatment options or just as an addition to surgery. Short
time intervals, greater tumor volume, and poor general patient conditions associated
with a poor prognosis.9,10
Brachytherapy was first used for the treatment of NPC in the 1920s and is
one type of radiotherapy that gives high doses of radiation to the target area with
very high doses to avoid high-dose toxic effects on the surrounding tissue. For
residual KNF, it can be used with intersisial gold implants or by using an applicator
(intracavitary brachytherapy).4
Stereotactic radiation is used for NPC management with local failure. The
use of stereotactic radiation is different for each patient and is generally used if
brachytherapy or nasopharyngectomy cannot be performed in these patients. There
are two types of stereotactic radiation, namely single doses and multiple fractions.4
The use of intensity-modulated radiation therapy (IMRT) generally varies
depending on the patient's condition, if the patient has a severe disease condition, it
can be used around 66 to 74 Gy, while for subclinical diseases can be given as much
as 50 to 60 Gy. The radiation field for radiotherapy in NPC covers the superior limit
of cranial base, including the sphenoid sinus, the vocal cords in the inferior border,
the spinous process for the posterior boundary, and 2 to 3 cm from the tumor border
for the anterior border, including the pterygoid and 1/3 posterior maxillary sinus.9
One of the requirements for doing re-irradiation is the 6 months interval
from the last radiotherapy. Re-irradiation can cause complications in the form of
organ poisoning due to the level of radiation received. The study from Barnett et al
(2009) states that there are two types of toxicity, which are early and late toxicity.
Early toxicity occurs within a few weeks from the first radiotherapy, while late
toxicity occurs after 6 months to several years after radiotherapy begins.10
Side effects related to radiotherapy can occur in all organs of the body.
There are 6 toxicity levels from 0 to 5. Level 0 means there are no side effects or
within normal limits, level 1 means mild side effects, level 2 means moderate side
effects, level 3 means severe side effects, level 4 means life threatening, and level
5 can cause death. The side effects of acute toxicity to the skin are in the form of
hyperemia, dry and wet desquamation, ulceration; in hair is in the form of alopecia;
on the mucosa are in the form of erythema, edema, patchy and confluent mucositis;
in the esophagus is in the form of retrosternal pain due to esophagitis; on the
salivary glands is in the form of reduced amount and viscosity of saliva, and the pH
becoming so acidic. While the side effects of chronic toxicity to the skin and
mucosa are telangiectasia, fibrosis, tissue necrosis; in the esophagus is fibrosis,

94
necrosis or perforation of the fistula; in the salivary gland is fibrosis and does not
respond to stimulation; in the brain are in the form of mild to severe headaches,
convulsions, or paralysis and coma; in the eye are in the form of cataracts, keratitis,
panophthalmitis, blindness; in the larynx are in the form of edema, condritis,
necrosis. From Tian YM's study (2017), the incidence of severe acute toxicity
(grade III acute mucositis) reached 12.7%, while the side effects of late toxicity in
the form of grade III mucosal necrosis reached 26.9%. The high toxicity that occurs
due to re-irradiation has led experts to look for other alternatives in the form of
surgery for the management of recurrent NPC.11

NASOPHARYNGECTOMY FOR LOCALLY RECURRENT

Nasopharyngectomy plays an important role in patients with recurrent or
persistent NPC. Nasopharyngectomy is surgery on the nasopharynx and
surrounding tissue. Surgery can reduce the long-term toxic effects that occur as a
result of re-irradiation, such as multiple cranial nerve palsies, osteoradionecrosis,
cervical subcutaneous fibrosis, hearing loss, temporal lobe damage; therefore
surgery is chosen as an alternative treatment for recurrent NPC with an early stage
(rT1-2). There are various ways and various access routes for nasopharyngeal
surgery, starting with open surgery to a minimally invasive approach. Various
options for surgery will be discussed below.12

MAXILLARY SWING APPROACH

The maxillary swing approach was first introduced by Wei et al in 1991 and
is a very good surgical method for looking at the entire nasopharynx and the area
of the ipsilateral parapharynx. This approach performs surgery through the
anterolateral side and can be used for tumors with retropharyngeal lymph node
metastases.5
This surgical procedure begins with the Weber-Ferguson incision then the
incision is extended to reach the anterior zygoma area and is carried along the
midline of the hard palate to reach the connection of the hard and soft palate. Then
an incision is made on the lips until it reaches the gingivobuccal sulcus laterally
then turns medially to the maxillary tuberosity until it meets the hard palate incision.
After the zygoma anterior and maxilla separation incisions have been performed,
the maxilla remains left attached to the anterior cheek skin and then it can be pulled
laterally to provide a clear field of view of the nasopharynx and parapharynx area.
There are several additional procedures to expand the contralateral nasopharyngeal
field, one of which is posterior septectomy. After resection is performed, the
maxilla will be repositioned using a titanium plate. Some complications that may
occur from this procedure are middle ear effusion (37.8%), trismus (9.2%), facial
numbness (7.4%), epiphora (6.5%), palate fistula (4,3%), nasal blockade, and
ectropion (1.8%).5, 13

95
 Data from Wei et al (2011) study of a total of 246 patients with 229 patients
with undifferentiated carcinoma, 8 patients with squamous cell carcinoma (KSS),
and 9 differentiated SSC patients, found that 5-year local control after surgery with
maxillary swing technique is 74% with 5-year overall survival reaching 56%. Data
from Hao et al (2015) study found that 5-year total control of 53.6% with 5-year
overall survival reaching 48.7%. Study of Chan et al (2013) stated that the rate of
local recurrence was higher in patients with a positive surgical margin on previous
nasopharynectomy.13, 14

MIDFACIAL DEGLOVING
The midfacial degloving procedure is a safe approach for midface lesions
with low complication rate and excellent cosmetic outcomes. It lacks of facial
incision and no disruption of palatal function. It was first suggested by Portmann in
1927 but it was first done by Casson and colleagues in 1974. This technique was
reported to be useful in allowing adequate bilateral maxillary and lower nasal cavity
exposure, therefore midfacial degloving is widely used to expose and treat lesions
of the facial cavities, orbits, central compartment of the anterior and middle cranial
fossae, paranasal sinuses, and nasopharynx.5
The degloving approach is performed with an incision in the maxillary
vestibular mucosa and bilateral intercartilaginous incision, complete transfixion,
and bilateral piriform apperture to elevate the entire midface skin and expose the
skeleton. The incision in intercartilaginous will divides the cartilages to upper and
lower part. The upper lateral cartilage will remain attached to the skeleton, whereas
the lower cartilage will be displaced during the procedure. The operator then made
an incision along the inferior border of the upper lateral cartilage and meet the
transfixion incision of the nasal columellar and this incisions would allow the
separation of soft tissue of the nasal alar, nasal tip and the nasal bone. After the
separation, the whole midface, soft tissue could be elevated to the infraorbital
foramen and exposed all of the bony anterior midface and midfacial osteotomies
can be performed. This procedure has narrow view of nasopharynx, therefore
bilateral medial maxillectomies (Denker’s procedure) could be performed to
improve the exposure of the nasopharynx.13
Temporary infraorbital anesthesia or hypesthesia are common
complications to the midfacial degloving procedure. The other complications that
may arise are nasal obstruction and epiphora. However, the infraorbital anesthesia
for most patients are fully recover within 5 months and the rate of permanent
infraorbital anesthesia is less than 3%.13 The study of To et al in 7 rT1 patients, 5
rT2 patients, and 3 rT4 patients showed that 80% of the results of surgery using this
procedure had a negative surgical margins.13

96
INFRATEMPORAL FOSSA APPROACH
This technique was first performed by Ugo Fisch in 1979 in 7 rT4 patients,
4 persistent T1 patients, and 2 T2 patients. This technique uses a neuro-otology
approach. This procedure starts with a retroauricular skin incision, transection of
the external canal and the facial nerve will appear in the parotid area. Then the skull
bone in the part of the cranial fossa of the media is removed so that the structure of
the infratemporal fossa which consist of the eustasia tube, external pterigoid muscle
and media, and palatine tensor muscle are seen. Hen the branch of the trigeminal
nerve must be separated and the pterygoid muscle must be removed from the lateral
pterygoid plate so that the internal carotid artery can be identified and can be
protected when the resection is performed and this is one of the advantages of this
procedure. However, the operator cannot see the contralateral part of the
nasopharynx and this is one of the disadvantages of using this procedure.5, 15
Possible complications are cranial nerve palsies, including the mandibular
branch trigeminal nerve, facial nerve, glossopharyngeal and vagus nerves. From a
study conducted by Fisch in 1983 on a total of 13 patients who experienced local
failure, 6 patients with an early stage T1-2 did not experience recurrence within two
to five years after surgery, but all patients with early stages of T4 experienced local
recurrence and died within three years.15

TRANSPALATAL APPROACH
Tu et al first introduced this technique in 1988 to 9 patients who experienced
recurrence in stage rT1 to 2. This procedure uses an inferior approach by making a
‘U’ flap on the palate mucosa. Then separation between the hard and soft palate and
posterior retraction is performed. After that the nasopharynx can be seen and
resection can be done. After resection is performed, the palate flap is then sutured
back to the anterior portion of the hard palate and the wound is closed.5, 12
Study conducted by Fee in 37 patients in 2002 showed that the 5-year
survival rate was 52% and the 5-year local control was 67%. Fee also compared the
results between treatment using transpalatal surgery with re-irradiation, it was
found that the results were comparable or even better using surgery than re-
irradiation for local control.5

TRANSCERVICO-MANDIBULO-PALATAL APPROACH
This procedure was first performed by Morton et al in 1996 in 7 patients
with rT1-2. This procedure uses an inferolateral approach. Initially begins with the
separation of the lips with mandibulotomy, then the incision is extended to the upper
ipsilateral neck. The incision is then carried out at the floor of the mouth and the
soft palate is separated from the hard palate to obtain an adequate nasopharyngeal
field. This procedure has the advantage of being able to easily search for the internal
carotid artery from the neck to the base of the skull, therefore the internal carotid
artery can be protected during the resection. However, this procedure causes

97
extensive tissue damage compared to other procedures and endoscopic
techniques.5, 16
Morton's study in 1966 stated that of the 7 patients who underwent surgery
using this technique, one patient had an early recurrence within one year after
surgery and one patient had a late recurrence within 10 years after
nasopharyngectomy.16

ENDOSOPIC APPROACH
Endoscopic technique, as one of the approach for recurrent NPC, was first
introduced by Yoshizaki et al in 2004. Endoscopic approach surgery has several
advantages compared to open approach surgery, that are minimal bleeding, no
scarring, minimal surrounding tissue damage, and recovery period faster.17
There are 3 types of nasopharyngeal resection using endoscopy. Type 1
begins with a resection of the posterior part of the nasal septum until it reaches the
base of the sphenoid and pharyngobasilar sinus bones or inferior prevertebral fascia.
While type 2 is carried superiorly until it reaches the anterior wall and the base of
the sphenoid sinus. Type 3 incision is carried out laterally to reach the lateral
nasopharyngeal wall and Eustasia tubal cartilage. Then a medial maxillectomy is
performed with removal of the inferior conca, the media maxillary wall, and the
naso-lacrimal duct, and then the incision is extended along the piriform apperture.
After the sphenopalatine artery, the major palatine artery, and the palato-vaginal
artery are clearly visible, cauterization can be performed, leaving the septal branch
of the sphenopalatine artery for the nasopharyngeal flap. Doppler ultrasound
guidance can be used to identify the internal carotid artery. Then the frozen section
analysis is carried out and nasoseptal flap is returned to cover the defect.18
The choice of endoscopic treatment depends on the location and stage of the
NPC. For recurrent NPC, endoscopic surgery is generally performed if the tumor is
located on the nasopharyngeal palate with minimal lateral invasion. Thus,
endoscopic surgery is generally performed on NPC rT1-2 and in recurrent tumors
that are not too close to the base of the skull and internal carotid artery. The study
of MY Chen in 72 patients consisting of 32 rT1 patients, 27 rT2 patients, and 13
rT3 patients showed a 5-year overall survival of 77.1% and a 5-year loco-regional
relapse free survival of 67.4%. In this study no serious complications were found,
but 22% of patients experienced otitis media. Study from Hao et al (2008)
performed endoscopic surgery on a total of 53 patients with details of 27 rT1
patients, 9 rT2 patients, 9 rT3 patients, and 8 rT4 patients showing a 5-year overall
survival of 48.7% and 5-year local control of 53.6%. Contraindications to surgery
using endoscopy are massive intracranial involvement, invasion of orbital contents,
and location of the tumor covering the internal carotid artery. It is necessary to
conduct pre-operation examination and planning before selecting a treatment so that
the selection of management can be done appropriately.19

98
 Tabel 1. Comparison of nasopharyngectomy and radiotherapy therapy results in
recurrent nasopharyngeal carcinoma.
Reference Pasient T Stage Management Local Survival Complications
(n) (%) Control (%)
(%)
King et al, 31 rT1: 65 Transpalatal, LRFS: 44,9 at 5 Hemorrhage:
200013 maxillary 85,8 at 5 years 47/132
swing, years
transmandibular
Fee et al, 37 rT1: 59 Transpalatal 67 at 5 52 at 5 5% experienced
200213 years years death and
permanent
dysphagia
Hao et al, 53 rT1-2: 66 Endoscopic 53,6 at 5 48,7 at 5 2 patients died
200814 years years from massive
bleeding
Chen MY 37 rT1: 17 Endoscopic LRFS: 84,2 at 2 1 patient died
et al, rT2: 18 86,3 at 2 years from distant
200917 rT3: 2 years metastasis and 1
patient had
intracranial
infection
Roeder et 17 rT3-4: 36 IMRT, FSRT 69 at 2 37 at 3 Grade 3 late
al, 201113 years years toxicity: 29%
Qiu et al, 70 rT3-4: 57 IMRT 65,8 at 2 67,4 at 2 Cranial nrve
201213 years years palsies: 24,3%
Trismus: 17,1%;
Deafness:
17,1%
IMRT: intensity-modulated radiation therapy
FSRT: fractionated stereotactic radiotherapy
LRFS: local relapse-free survival

SURGERY FOR NODAL RECURRENCES IN NPC

Management of patients with NPC recurrence and lymph node involvement
has a poor prognosis with re-irradiation. Obtained data for 5-year overall survival
only reached 19.7%. In addition re-irradiation is associated with an increased risk
of toxicity due to excessive radiation doses. Therefore, experts are looking for
alternative ways to manage NPC with lymph node recurrence. The study of Wei et
al (2001) stated that 70% lymph node recurrence has extra capsular spread so Wei
proposes an alternative way of radical neck dissection. While the study of Khafiff
et al proposed the use of imaging to increase accuracy in performing modified or
selective neck dissection. Chen et al used selective neck dissection for NPC with
lymph node recurrence and found 5-year overall survival of 66.81% and 5-year
regional free survival of 78.67%.5

99
CONCLUSION
Currently surgery for nasopharyngeal carcinoma is still a challenge in the
medical field. Advances in technology today make surgical techniques more
developed and the use ofconventional surgical techniques are abandoned.
Nasopharyngectomy with a transpalatal procedure is a simple surgery, but the field
of view of the nasopharynx is very limited and the complication rate of oronasal
fistula is high. The transmandibular approach also has a narrow visual field of the
superior nasopharynx because of the inferior approach. However, the internal
carotid artery can be clearly seen with this approach. The maxillary swing
procedure and midface degloving are anterior approaches, these types of procedure
is best for tumors located in the nasopharynx with minimal parapharyngeal
involvement. While endoscopic use is indeed limited to the location and size of
certain tumors. It can be combined with a neurosurgical approach to obtain a good
visual field in NPC surgery, as an example of the subfrontal approach to provide a
superior visual field.
Surgery plays an important role in the management of recurrent NPC
without metastasis. Compared with re-irradiation, surgery for early stage recurrent
NPC is preferred as the main treatment because it can reduce the effects of toxicity
that can occur due to re-irradiation. However, the management of patients with
recurrent NPC varies depending on the patient's condition and tumor extension. It
should be noted that positive post resection margins are associated with a poor
prognosis and administration of radiotherapy to patients with a positive post
resection margin does not improve survival rates in patients with recurrent NPC.

100
REFERENCES
1. Salehiniya H, Mohammadian M, Hafshejani AM, Mahdavifar N.
Nasopharyngeal cancer in the world: epidemiology, incidence, mortality and
risk factors. WCRJ. 2018; 5(1):e1046.
2. Mahdaviar N, Ghoncheh M, Hafshejani AM, Khosravi B, Salehiniya H.
Epidemiology and inequality in the incidence and mortality of nasopharynx
cancer in asia. Osang Public Health Res Perspect. 2016; 7(6): 360-72.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines
in Oncology: Head and Neck Cancers. 2016.
4. Stoker DS, Diessen JNA, Boer JP, Karakullukcu B, Leemans CR, Tan IB.
Current treatment options for local residual nasopharyngeal carcinoma. Current
Treatment Options in Oncology. 2013; 14: 475-91.
5. Tsang RK, Wei WI. Salvage surgery for nasopharyngeal cancer. World Journal
of Otorhinolaryngology-Head and Neck Surgery. 2015; 1: 34-43.
6. Chan JYW. Surgical management of recurrent nasopharyngeal carcinoma. Oral
Oncol. 2013; 1-4.
7. Brown JJ, Fee WE. Surgical resection of the nasopharynx. Operative
Techniques in Otolaryngology. 2010; 21: 26-34.
8. Suarez C, Rodrigo JP, Rinaldo A, Langendijk JA, Shaha AR, Ferlito A. Current
treatment options for recurrent nasopharyngeal cancer. Eur Arch
Otorhinolaryngology. 2010; 267: 1811-24.
9. Beyzadeoglu M, Ozyigit G, Ebruli C. Basic radiation oncology. Springer; New
York: 2010. p. 213-7.
10. Barnett GC, West CML, Dunning AM, Elliottt RM, Coles CE, Pharoah PDP,
et al. Normal tissue reactions to radiotherapy. Nat Rev Cancer. 2009; 9(2): 134-
42.
11. Leong YH, Soon YY, Lee KM, Wong LC, Tham IWK, Ho FCH. Long-term
outcomes after reirradiation in nasopharyngeal carcinoma with intensity-
modulated radiotherapy: a meta-analysis. Head & neck. 2017; 1-10.
12. Choi JY, Lee WS. Curative surgery for recurrent nasopharyngeal carcinoma
via the infratemporal fossa approach. Arch Otolaryngol Head Neck Surg. 2005;
131: 213-6.
13. Tao X, Tang J, Gu M, Liu L, Wei W, Yang H. Recurrent nasopharyngeal
carcinoma: a clinical challenge. Curr Oncol. 2013; 20: e406-19.
14. Hao SP, Tsang NM, Chang KP, Hsu YS, Chen CK, Fang KH.
Nasopharyngectomy for recurrent nasopharyngeal carcinoma: a review of 53
patients and prognostic factors. Acta Oto-Laryngologica. 2008; 128: 473-81.
15. Fisch U. The infratemporal fossa approach for nasopharyngeal tumors.
Laryngoscope. 1983; 93.
16. Morton RP, Liavaag PG, McLean M, Freeman JL. Transcervico-mandibulo-
palatal approach for surgical salvage of recurrent nasophrayngeal cancer. Head
& Neck. 1996; 18: 352-8.

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17. Chen MY, Wen WP, Guo X, Yang AK, Qian CN, Hua YJ, et al. Endoscopic
nasopharyngectomy for locally recurrent nasopharyngeal carcinoma. The
Laryngoscope. 2009; 516-22.
18. Castelnuovo P, Nicolai P, Zanoni MT, Battaglia P, Villaret AB, Gallo S.
Endoscopic endonasal nasopharyngectomy in selected cancers.
Otolaryngology-Head and Neck Surgery. 2013; 149 (3): 424-30.
19. Zou X, Han F, Ma WJ, Deng MQ, Jiang R, Guo L. Salvage endoscopic
nasopharyngectomy and intensity-modulated radiotherapy versus conventional
radiotherapy in treating locally recurrent nasopharyngeal carcinoma. Head &
Neck. 2014; 1-8.

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 RIGID NASOPHARYNGOSCOPY AND FLEXIBLE ENDOSCOPY
EVALUATION FOR DIAGNOSIS AND RECURRENT
NASOPHARYNGEAL CARCINOMA

Camelia Herdini

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Gadjah Mada

Nasoendoscopy involves evaluation of the nasal and sinus passages with

direct vision using a magnified high-quality view. It is a commonly performed
procedure in the otolaryngologist’s office and serves as an objective diagnostic tool
in the evaluation of nasal mucosa, sinonasal anatomy, and nasal pathology.
Nasoendoscopy may be accomplished with either a flexible fiberoptic endoscope
or a rigid endoscope. When performed by experienced practitioners, both flexible
endoscopy and rigid endoscopy are usually well tolerated.
The fiberoptic telescope has the advantage of being flexible and generally
smaller in diameter, which means that it is readily manipulated in multiple
directions to permit visualization of tight areas. However, flexible endoscopy
requires 2 hands for manipulation of the instrument and is thus a more difficult
procedure. Traditionally, flexible endoscopy has provided inferior visualization, but
this drawback has been overcome with the development of digital flexible
endoscopes.
The rigid endoscope provides superior image clarity, facilitates culture and
tissue sampling, control epistaxis better, and affords the doctor to be able to perform
surgery.1, 2 Rigid endoscopes for the nose come in diameters of 2.7-4 mm and have
tips of different angles (generally 0-70º), allowing the physician to visualize various
sinuses and areas within the nasal cavity and sinuses.
Indications for nasoendoscopy are; (1) Initial identification of disease in
patients experiencing sinonasal symptoms (eg, mucopurulent drainage, facial pain
or pressure, nasal obstruction or congestion, or decreased sense of smell), (2)
Evaluation of patients' response to medical treatment (eg, resolution of polyps,
inflammation after treatment with topical nasal steroids, post chemo-radiation), (3)
Evaluation and biopsy of nasal massed or lesion, (4) Evaluation of nasopharynx,
eustachian tube problems and nasal obstruction, (5) Evaluation of CSF leak, and
(6) Evaluation and treatment of epistaxis and nasal foreign bodies.
No absolute contraindications to nasoendoscopy exist; however, some
patient populations are at increased risk for complications. In patients who have a
history of a bleeding disorder or are receiving anticoagulants, nasal endoscopy
should be performed carefully so as not to provoke bleeding. Additionally, in an
anxious patient or a patient with cardiovascular disease, there is a risk of a
vasovagal episode.

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 Rigid endoscopes are made in various angles (0º, 30º, 45º, and 70º). The
angled telescopes are used to see around corners and to evaluate areas not easily
examined under direct vision. The 4 mm 30º scope has been shown to provide
sufficient illumination and an adequate field of vision and may therefore be the
most useful telescope in an average patient. Nasal endoscopes also come in
pediatric sizes (2.7 mm), which are also available in various angles and which may
be used for increased comfort in adults.
In addition to affording superior visualization, nasal endoscopy provides
improved illumination, greater magnification, and the ability to navigate directly to
pathologic areas. As a result, examiners obtain a more accurate and thorough
diagnostic evaluation. In one study, rigid nasal endoscopy identified nasal
pathology in almost 40% of patients who had normal examinations on anterior
rhinoscopy.3 Endoscopy plays an important role in the preoperative, postoperative,
and medical management of patients with sinonasal complaints.
Steps of nasoendoscopy preparation are; (1). Equipment preparation, 0º
scope is needed for evaluating nasopharynx, light source, and light cable, (2)
appropriate positioning, (3) Before nasoendoscopy, nasal cavities are often sprayed
with a nasal decongestant, such as oxymetazoline and xylocaine 4% spray.
Anesthetics are typically applied either with a spray atomizer or directly on a cotton
pledget.4 Before application, patients should be questioned about medication
allergies. The topical anesthetic should be applied to the inferolateral surface of the
middle turbinate, to the surface of the inferior turbinate, and to any other sites where
pressure may be exerted by insertion of the scope. (4) Ask the patient to breath
through his/her mouth to avoid blurred vision, (5) Gently insert the endoscope into
the nose along the base of the nose to the nasopharynx, (6) Evaluate the
Rossenmuller fossa, torus tubarius, and eustachian tube, (7) If masses are seen in
the nasopharynx, do biopsy.
Overall, nasoendoscopy is a safe and low-risk procedure. Potential
complications associated with the procedure include an adverse reaction to the
topical decongestant or anesthetic, pain or discomfort, epistaxis, and vasovagal
episodes. Before the topical medications are administered, the patient’s allergies
should be verified.
Narrow-band imaging (NBI) is a novel optical technique that enhances the
diagnostic sensitivity of endoscopes for characterizing tissues by using narrow-
bandwidth filters in a sequential red–green–blue illumination system. The central
wavelengths of each band are 415 and 540 nm.5 The narrowband blue light, which
has a short wavelength (415 nm), penetrates the mucosa and highlights the
superficial vasculature. Furthermore, the blue filter is designed to correspond to the
peak absorption spectrum of hemoglobin, and thus enhances the image of the
capillary vessels on the surface mucosa. Thus, superficial mucosal lesions that
usually cannot be detected by regular white-light endoscopy can be identified on
the basis of their neoangiogenetic vasculature pattern by using blue light in NBI.6

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 The literature review showed that the effectiveness of NBI in the early
detection of head and neck squamous cell carcinoma (SCC) over the mouth floor7,
larynx8, oropharynx, and hypopharynx 9, 10, have been documented through the
years. It is now generally accepted that NBI is of great benefit in detecting
superficial mucosal lesions over the pharyngeal mucosa.11 Except for one case that
we reported previously of irradiated NPC with early recurrence successfully
detected by NBI coupled with conventional endoscopy12, there has been still no
documentation of its application to primary NPC and the screening performance of
NBI for high-risk populations.
There are five distinctly different findings that need to be examined by NBI:
Type I: brownish spots, Type II: irregular microvascular pattern (IMVP), Type III:
light crests, Type IV: side-difference, Type V: presence of either IMVP or side-
difference, of which last three (Type III–V) were a new concept. Previous studies
showed that Type I pattern is ordinarily observed in superficial cancers of the
oropharynx and hypopharynx.9, 10 Even Type II pattern is encountered in carcinoma
of the oropharynx, hypopharynx, esophagus and stomach.13, 14, 15
NBI can identify the microvascular architecture and mucosal microsurface
structure, including detecting tortuous microvessels, a fine white line on the crests
of the surface, and easily compare the both side difference of nasopharynx.
Therefore, NBI reduced the number of false-negative cases except for one with
mainly downward invasive NPC.16
The utility of NBI as an adjunctive technique to perform NPC screening in
a high-risk population is recommended. Even though large-scale screening program
should be established to verify the accuracy of this technique in the daily practice,
nonetheless its low cost, easy of use, and non-invasiveness seem quite encouraging.

REFERENCES
1. Stammberger H. Functional endoscopic sinus surgery. Philadelphia: BC
Decker; 1991.
2. Kennedy DW, Zinreich SJ, Rosenbaum AE, Johns ME. Functional endoscopic
sinus surgery. Theory and diagnostic evaluation. Arch Otolaryngol. 1985;
111(9): 576-82.
3. Levine HL. The office diagnosis of nasal and sinus disorders using rigid nasal
endoscopy. Otolaryngol Head Neck Surg 1990; 102(4): 370-3.
4. Mishra P, Kaushik M, Dehadaray A, Qadri H, Raichurkar A, Seth T.
Preparation of nose for nasal endoscopy: cotton pledget packing versus topical
spray. A prospective randomized blinded study. Eur Arch Otorhinolaryngol
2013; 270 (1): 117-21.
5. Gono K, Yamazaki K, Doguchi N, et al. Endoscopic observation of tissue by
narrowband illumination. Opt Rev 2003; 10(4): 211-215.
6. Piazza C, Dessouky O, Peretti G, Cocco D, De Benedetto L, Nicolai P. Narrow-
band imaging: a new tool for evaluation of head and neck squamous cell

105
 carcinomas. Review of the literature. Acta Otorhinoparyngol Ital 2008; 28(2):
49-54.
7. Katada C, Nakayama M, Tanabe S, et al. Narrow-band imaging for detecting
superficial oral squamous cell carcinoma: a report of two cases. Laryngoscope
2007; 117: 1596-1599.
8. Watanabe A, Taniguchi M, Tsujie H, Hosokawa M, Fujita M, Sasaki S. The
value of narrow-band imaging for early detection of laryngeal cancer. Eur Arch
Otorhinolaryngol 2009; 266: 1017-1023.
9. Muto M, Nakane M, Katada C, et al. Squamous cell carcinoma in situ at
oropharyngeal and hypopharyngeal mucosal sites Cancer 2004; 101: 1375-
1381.
10. Watanabe A, Tsujie H, Taniguchi M, Hosokawa M, Fujita M, Sasaki S.
Laryngoscopic detection of pharyngeal carcinoma in situ with narrowband
imaging. Laryngoscope 2006; 116: 650-654.
11. Nonaka S, and Saito Y. Endoscopic diagnosis of pharyngeal carcinoma by
NBI. Endoscopy 2008: 40: 347-351.
12. Lin YC, Wang WH. Narrow band imaging for detecting early recurrent
nasopharyngeal carcinoma. Head Neck 2009.
13. Ugumori T, Muto M, Hayashi R, Hayashi T, Kishimoto S. Prospective study
of early detection of pharyngeal superficial carcinoma with the narrowband
imaging laryngoscope. Head Neck 2009; 31(2): 189-194.
14. Anagnostopoulos GK, Yao K, Kaye P, Hawkey CJ, Ragunath K. Novel
endoscopic observation in Barrett’s oesophagus using high resolution
magnification endoscopy and narrow band imaging. Aliment Pharmacol Ther
2007: 26(3): 501-507.
15. Yao K, Oishi T, Matsui T, Yao T, Iwashita A. Novel magnified endoscopic
findings of microvascular architecture in intramucosal gastric cancer
Gastrointest Endosc 2002: 56(2): 279-284.
16. Wang WH, Lin YC, Lee KF, Weng HH. Nasopharyngeal carcinoma detected
by narrow-band imaging endoscopy. Oral Oncol 2011; 47(8): 736-741.

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FNAB’S AND INCISIONAL BIOPSY ON NASOPHARYNGEAL CANCER

Hamsu Kadriyan

Otorhinolaryngology Head and Neck Surgery Department,

Faculty of Medicine, Universitas Mataram

INTRODUCTION
The cases of nasopharyngeal cancer (NPC) frequently found in advanced
stage. This happened due to location of nasopharynx is isolated in the posterior part
of nasal cavity, under the skull bases and above oropharynx. According to American
Joint Committee on Cancer (AJCC), the stages of NPC divided into stage 1 to 4.
Stage 1 define as a tumor localized on nasopharynx without any enlargement of
lymph node on the neck. On the other hand, stage 2 or higher, the neck node must
be appear at least on one side with the diameter less than 3 cm or bigger.1
The management of neck lymph node is one of the important things on the
management of nasopharyngeal cancer. There is some question appear related to
management of neck lymph node on the case of its enlargement. Is it necessary to
manipulate the neck node or are there any benefit of fine needle aspiration biopsy
(FNAB) or incisional biopsy on the presentation of neck lymph node? This paper
will describe about the benefit and disadvantages as well as indication to perform
FNAB and incisional biopsy of the neck lymph node and its relation to
nasopharyngeal cancer management.

EPIDEMIOLOGY OF NASOPHARYNGEAL CANCER

The incidence of nasopharyngeal cancer is found difference between one
country to the others. The high incidence is found in South China and Southeast
Asia, including Indonesia. In Indonesia, the incidence is 6.2/100,000 or almost
15,000 cases will be find annually2, furthermore, in West Nusa Tenggara Province
with 4.8 million population3, the number of cases predicted about 300 per year.
According to epidemiologic data in West Nusa Tenggara Hospital, from
January to December 2015 found 48 patients. The cases became from all district in
West Nusa Tenggara with the highest incidence in west Lombok (27%). The most
cases found in male with the male to female ratio 3:1. Based on age category, the
most cases found under 50 years old (69%) with the peak incidence in 40 years old.
The detailed data as showed on table 1.4
Recent study found that most cases found on the advance stage, Xing Li et
al (2018) found on their research about 61% were found on stage 3 and 4. According
to AJCC, on stage 3 and 4, the neck node must be appear.5 Pelealu et al (2015)
found the cervical node enlargement on 26 patients (50%) nasopharyngeal cancer.6

107
 Although not all of enlargement of lymph node on the cervical are cancer,
the fact showed that most of them are the spreading of others disease from the other
site of body. Zbaren et al (1993) found that 80% metastasis lymph node on the neck
is originated from ear, nose and throat region. Ten percent of them is originated
from bronchus and esophagus.7 In advance, Adoga et al (2009) found almost 80%
of patients with cervical lymph node enlargement are originated from
nasopharyngeal cancer.8

Table 1. Distribution of nasopharyngeal cancer in West Nusa Tenggara Province

(January-December 2015)
District Frequency Gender Age category
N (%) Male Female <50 >50
N (%) N (%) N (%) N (%)
Mataram 6 (13) 5 (11) 1 (2) 5(11) 1(2)
West Lombok 13 (27) 8 (17) 5 (11) 8(17) 5(11)
Central Lombok 12 (25) 8 (17) 4 (9) 9 (19) 3 (7)
East Lombok 8 (17) 5 (11) 3(7) 5(11) 3(7)
North Lombok 2 (4) 2 (5) 0 (0) 1(2) 1(2)
Sumbawa 1 (2) 0 (0) 1(2) 1(2) 0 (0)
West Sumbawa 1 (2) 1(2) 0 (0) 1(2) 0 (0)
Dompu 1 (2) 1(2) 0 (0) 1(2) 0 (0)
Bima 3 (6) 2(5) 1(2) 2(5) 1(2)
Bima city 1 (2) 0 (0) 1(2) 0 (0) 1(2)
Province 48 (100) 32 (67) 16 (33) 33 (69) 15 (31)

Based on the fact above, all physician should be aware to looking for the
primary site of cervical lymph node enlargement. A complete work up should be
done to explore the primary site, including history taking, physical examination
especially ear nose and throat as well as surrounding organ such as eyes and nerve
disorder, additional examination such as imaging with CT scan or MRI with
contrast, endoscopic view and serologic for Epstein Barr virus (EBV). On the
history taking, the questions should be arrange to explore several symptoms that
may appear, such as epistaxis, nasal blocking, eye problem, headache, etc.
A detailed physical examination such as rhinoscopy anterior and posterior as well
as otoscopy are needed to view the nasal cavity, oral cavity, nasopharynx and the
eardrum in order to directly find the primary site (Balm et al, 2010; NCCN, 2018).9,
10

Imaging on nasopharynx and surrounding structures are very important to

decides the primary site and also for the staging of the malignancy in enlargement
of cervical lymph node. However, the gold standard for diagnosis of
nasopharyngeal carcinoma is the biopsy nasopharynx itself.9

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FINE NEEDLE ASPIRATION BIOPSY
The cytology examination from the cervical lymph node aspiration can be
done to make an early diagnosis and to eliminate such differential diagnosis of
cervical lymph node. FNAB is an easy, simple and quick as well as low price
procedure which can be done on outpatient setting. This procedure is frequently use
to diagnose the thyroid mass. The equipment including the 10 ml spuit, alcohol
swab, object glass, hematoxylin eosin staining and microscope. The result can be
obtained in 1-2 days.11 The pain may occur after FNAB, however, visual analog
scale (VAS) is relatively low with the mean 3616.12
The sensitivity, specificity and diagnostic accuracy of FNAB in head and
neck lesion (excluding thyroid) is excellent. Goret et al (2013) found in his research,
the sensitivity 94.6%, specificity 97.9% and accuracy 96.7%.13 This result similar
with research by Alam et al (2009), consecutively the found 93.3%, 94% and
95.65%.14
On the National comprehensive cancer network (NCCN) guideline version
2.2018, FNAB is one of the recommendation in nasopharyngeal carcinoma
workup.10 However, the most important thing is a biopsy on the primary site with
the endoscopic guided biopsy in nasopharynx.

INCISIONAL BIOPSY ON CERVICAL LYMPH NODE

Neck node biopsy should be avoided although a direct effect on tumor
recurrence has not been demonstrated (Balm et al, 2010).9 Pastor M, et al (2018),
emphasized that Incisional cervical biopsy should be avoided as this procedure will
negatively impact the subsequent treatment. Incisional cervical lymph node biopsy
is only indicated to those who repetitive negative or non-diagnostic FNAC as well
as repetitive negative imaged guided true cut biopsy on the primary tumor.15
Incisional biopsy can be done under local or general anesthesia, it depends
on patient conditions including the renal and hepatic function, age and
psychological status. Incisional biopsy is started with making an incision in the
bigger palpable node, then goes deeper until the node is free from others tissue, so
the node sample will easily to carry out. Finally, the tissue sample send to pathology
laboratory to be proceeds for histopathologic examination. In Indonesia the result
usually will be find in 5-7 days.11
There are several effects of incisional biopsy on cervical lymph node,
including scar formation which is occur in 100% cases, skin metastasis and distance
metastasis are occur in 57% cases. (Adoga et al, 2009).8 In Indonesia, pathologic
workup need about 5-7 days to be finished, furthermore, if cervical node biopsy
was done and then followed by biopsy in the primary tumor, this will take at least
2 weeks to make a definitive diagnosis. A late start of radiotherapy and or
chemotherapy will reduce the survival rate. Cai et al (1983) found that 5 years
survival rate of patient with nasopharyngeal cancer who received the radiotherapy
and or chemotherapy within 2 weeks after diagnosis will have a better survival rate

109
(65%) than those who start the radiotherapy and or chemotherapy more than 2
weeks (45%).16
Another research found there is no significant different between patient with
and without incisional neck biopsy on the overall survival rate, loco-regional
recurrence, or distance metastasis with intensity modulated radiotherapy (IMRT).
They found the 4 years survival rate 88.4% and 92.3% consecutively in group with
and without incisional biopsy with the p value 0.195. Loco-regional recurrence in
both group consecutively 93.9% and 97.3% (p value 0.56). Distance metastasis
85.8% and 86.5% consecutively in both group with p value 0.58. IMRT is
Relatively New Modality to Treat Nasopharyngeal Cancer.5
In Indonesia, only a few hospitals using this modality, furthermore, not all
province in Indonesia have the radiotherapy unit. Hiswara (2017) report in 2017
there are 33 radiotherapy center in Indonesia. Another obstacles in Indonesia are a
period to waiting time for starting the radiotherapy was more than 3 month, and
also pausing time when the equipment need a repair or maintenance.17 This make
the prognosis of nasopharyngeal cancer will lower than others who use IMRT and
starting the treatment within 2 week as well as there is no any pausing time.

DISCUSSION
According to several literatures above, FNAB is superior in early detection
of type of lymph node on the neck. So, it can differentiate the node as an infection,
benign or malignant mass with less invasive, economist and well tolerated
procedure. On the other hand, incisional biopsy is superior in case of negative
repetitive true cut biopsy. So, it can be as a final decision to make diagnosis in
unknown origin head and neck cancer. According to the complication, FNAB has
a minimal effect as a result of their simple procedure compared to incisional biopsy.
The detailed comparison of these procedure as showed on table 2.

110
 Table 2. Comparison of FNAB vs incisional biopsy
Category FNAB Incisional Biopsy
Procedure Simple, unneeded the Complex, should use the
anesthesia anesthesia, sometime
need a general anesthesia
Procedure impact Minimal Could be severe
Days to obtained the result 1-2 days 5-7 days
Indication Early diagnosis Repetitive negative result
from true cut primary
biopsy
Complication Mild pain Scar formation in the
incision line,
micrometastis, bleeding
Price Low Higher

Although both procedures have its superiority on head and neck cancer
management, physician have a duty to find out the primary site of the tumor.
According to NCCN guideline, the treatment should be focused on the primary
tumor, the different primary tumor has their own management guideline. Finally,
the definitive primary tumor and primary histopathologic finding is the most
important things on management of head and neck cancer, including
nasopharyngeal cancer.

REFERENCES
1. Edge SB eds. 7th ed American Joint Committee on Cancer, Springer 2015:21-
100.
2. Adham M, KurniawanAN, Muhtadi AI, Roezin A, et al. (2012).
Nasopharyngeal cancer in Indonesia: Epidemiology, incidence symptom at
presentation. Chinese Journal of Cancer 31(4): 185-196
3. BPS NTB 2017. http//www.bpsntb.go.id
4. Kadriyan H, Djannah F, Rambu M, et al. (2018). Profile of nasopharyngeal
cancer in West Nusa Tenggara, Indonesia (The opportunity to explore
characteristics). Challenges and opportunities on public health and biomedical
research; Asian Perspective 2018.http://www.Googlescholar.com/Kadriyan
5. Xing-Li Y, Yan W, Yong B, Shao-Bo L, Sha-Sha H, Dan-Ming C, Hai-Yang
C, Li-Xia L, Yong C. Additional Cervical Lymph Node Biopsy is Not a
Significant Prognostic Factor for Nasopharyngeal Carcinoma in the Intensity-
Modulated Radiation Therapy Era: A Propensity Score-matched Analysis from
an Epidemic Area. J Cancer 2018; 9(16): 2844-2851.
6. Pelealu O, Palandeng O, Adithia IPA, Rahardjo SP. Nasopharyngeal
carcinoma at otolaryngology department Prof. RD Kandou hospital Manado

111
 Indonesia. American Journal of Medical Sciences and Medicine. 2015, 3(1), 1-
3.
7. Zbaren P, Speiser M: Cervical lymph node metastases. Schweiz Rundsch Med
Prax 1993, 82(50):1452-6.)
8. Adoga AA, Silas OA, Nimkur TL. Open cervical lymph node biopsy for head
and neck cancer: any benefit? Head and neck oncology. Head and oncology
2009;1(9):1-4
9. Balm AJM, van Velthuysen MLE, Hoebers FJP, Vogel WV, van den Brekel
MWM. Diagnosis and Treatment of a Neck Node Swelling Suspicious for a
Malignancy: An Algorithmic Approach. Int J Surg Oncol. 2010; 2010:1-8.
10. Cancer of the nasopharyngs. National collaboration on cancer network
(NCCN) Guideline ed. 2.2018.
11. Perhimpunan dokter spesialis patologi anatomi Indonesia. Buku pedoman
pelayanan patologi anatomi Indonesia. Depkes RI 2017.
12. Toman H, Ozkul F, Erbag G, Simesk T, Adam G, et al. Effects of fine-needle
aspiration biopsy (FNAB) nodule depth on pain score. Irish journal of medical
science 2015, 185(3):673-676
13. Goret CC, Goret NE, Ozdemir ZT, Ozkan EA, et al. Diagnostic value of fine
needle aspiration biopsy in no-thyroidal neck lesions: a retrospective study of
866 aspiration materials. Int J Clin exp pathol 2015; 8(8):8709-8716
14. Alam K, Khan R, Jain A, Maheshwari V, Agrawal S, Chana RS, Harris SH.
The value of fine-needle aspiration cytology in the evaluation of pediatric head
and neck tumors. Int J Pediatr Otorhinolaryngol. 2009; 73: 923-927.
15. Pastor M, Pousa LA, Barco ED, Segura PP, Astorga BG, et al. SEOM clinical
guideline in nasopharynx cancer (2017). Clin Transl Oncol (2018) 20:84-88
16. Cai WM, Zhang HX, Hu YH, Gu XZ. Influence of biopsy on the prognosis of
nasopharyngeal carcinoma--a critical study of biopsy from the nasopharynx
and cervical lymph node of 649 patients. Int J Radiat Oncol Biol Phys. 1983
Oct; 9(10):1439-44.
17. Hiswara E. Status terkini dan perspektif masa depan radioterapi di Indonesia.
http://www.digilib.batan.go.id/e-prosiding 2017

112
 RISK FACTOR OF NASOPHARYNGEAL CARCINOMA IN
DR. HASAN SADIKIN GENERAL HOSPITAL BANDUNG

R. Ayu Hardianti, Yussy Arifani Dewi

Otorhinolaringology Head and Neck Surgery Department

Faculty of Medicine Universitas Padjadjaran

ABSTRACT
Introduction: Nasopharyngeal carcinoma (NPC) is malignancy of squamous cells
on nasopharyngeal epithelial layer and the most common otorhinolaryngology malignancy
found in Indonesia. Etiology of NPC is multifactorial including, food, environment,
genetics, and Epstein-Barr virus infection. The study aimed to determine the highest risk
factors on the incidence of nasopharyngeal carcinoma in Otorhinolaringology-Head and
Neck Surgery Department dr. Hasan Sadikin General Hospital Bandung.
Methods: The study design was descriptive retrospective from medical record of
NPC patients at Otorhinolaringology-Head and Neck Surgery Department, dr. Hasan
Sadikin General Hospital Bandung in 2010–2015.
Result: There were 462 nasopharyngeal carcinoma patients in this research (265
men and 161 women) with three most common risk factors history of smoking (50,7%),
mosquito coils use (43,2%), and consumption of salty fish (39,7%).
Conclusion: Smoking, mosquito coils, and consumption of salty fish affect the
incidence of nasopharyngeal carcinoma.
Keywords: Risk factor, nasopharyngeal carcinoma, smoking, mosquito coils use,
consumption of salty fish.

INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a malignancy of squamous cells on
nasopharyngeal epithelial layer with Rosenmuller fossa is the most common
predilection site. Nasopharyngeal carcinoma belongs to the top five malignancies
after cervical cancer, breast cancer, lymph nodes, and skin.1
The highest incidence of NPC is found in Asia and rarely found in American
and Europe. 2 Nasopharyngeal carcinoma can be found in all countries from five
continents, but the highest incidence is in southern China, especially in Guangdong
province, which is 17.8 per 100,000 population per year with a frequency 100 times
higher than Caucasians.3
The prevealence of NPC in Indonesia is 4.7 new cases per 100,000
population per year or around 12,000 cases per year and is the most commonly
found otolaryngology malignancy in Indonesia. Comparison between men and
women is 2–3: 1.4 There are 692 (43,7%) NPC patients in Hasan Sadikin General
Hospital, Bandung within 2010-2014 with more male patients (65.7%) and occur
most in the 46-55 age group (29.6%).

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 Etiology of NPC is multifactorial including genetic factors, Epstein Barr
virus infection (EBV), environmental factors such as exposure to carcinogens
(formaldehyde), wood dust and firewood fumes, smoking, and food (consume
salted fish that contain nitrosamine).6,7
Research on the risk factors for NPC in Indonesia has never been done. On
this basic researchers want to conduct research. The purpose of this study was to
determine the risk factors for NPC at RSHS as a referral center Hospital in West
Java.

RESEARCH METHODS
This research method is a retrospective descriptive based on medical
record data of NPC patients that including the inclusion and exclusion criteria. The
inclusion criteria were all patients diagnosed with NPC seeking treatment at the
ORL-HNS outpatient ward subdivision of Head Neck Surgery, RSHS, Bandung
within 2010 to 2015. Exclusion criteria are incomplete medical records.

RESEARCH RESULT
There were 482 patients with head and neck malignancy in ORL-HNS
RSHS, 426 data for NPC and 56 data for non-NPC pastients, with the results :

Table 1. Characteristics of Research Subjects

Group
Variable NPC Non-NPC
N = 426 N = 56
Age
Mean ± STD 43.34 ± 14,351 53,553 ± 13,962
Median 45 53,50
Range (min-max) From 10.00 to 86,00 20,00-81,00
Sex
Male 265 (62.2%) 28 (50%)
Female 161 (37.8%) 28 (50%)

Based on these results, obtained a comparison of risk factors

between NPC and non- NPC. Average for the NPC group, it was 43,34 ± 14,351
while in the non-NPC group it was 53.553 ± 13, 962. Male (62.2%) in the NPC
group was more than female (37.8%) while in the non-NPC group there was no
difference between the gender.

114
 Table 2. Risk Factors for NPC and Non-NPC
Group
Variable NPC Non-NPC
N = 426 N = 56
Use of ONB
Yes 184 (43.2%) 15 (26.7%)
No 242 (56.8%) 41 (73.3%)
Number of ONB
<1 24 (5.6%) 5 (33.4%)
2-4 160 (37.6%) 10 (66.7%)
Time of smoking
<10 years 77 (18.1%) 10 (17.8%)
> 10 years 139 (32.6%) 23 (41%)
Do not smoke 153 (35.9 %) 19 (39.9%)
Passive 57 (13.4%) 4 (7.3%)
Alcohol consumption
Yes 60 (14.1%) 20 (35.7%)
No 366 (85.9%) 36 (64.3%)
Family history of cancer
Yes 30 (7,0%) 2 (3,6%)
No 396 (93,0%) 54 (96,4%)
Salted Fish
Yes 169 (39,7%) 3 (5,4%)
No 257 (60,3%) 53 ( 94,6%)
Description: ONB = Mosquito coils

The risk factors that increase the incidence of NPC consists of a history of
smoking (50.7%), use of mosquito coils (43.2%), history of consuming salted fish
(39.7%), alcohol consumption (14.1%), and a family history of cancer (7%).

Table 3. Most Risk Factors in NPC

Research Group
Variable Year 2010-2015
(n = 426 )
Cigarettes 216 (50.7%)
Mosquito coils 184 (43.2%)
Consumption of salted fish 169 (39.7%)

The most risk factors for NPC group consisted of smoking history (50.7%)
with smoking duration more than 10 years (32.6%), use of mosquito coils (43.2%),
and consuming salted fish (39.7%)

115
 Table 4. Most Risk Factors for non- NPC
Year 2010-2015
Variable
(n = 56 )
Cigarettes 33 (58.8%)
Alcohol consumption 20 (35.7%)
Mosquito coils 15 (26.7%)

In the non-NPC group the most risk factors consisted of smoking history
(58.8%) with smoking durationmore than 10 years (41%), alcohol consumption
(35.7%), and use of mosquito coils (26.7%).

DISCUSSION
In this study showed male more than women with a ratio of 1-2 : 1 and the
non-NPC group there is no difference based on gender. Based on the research that
is not mentioned why men are more than women. The NPC occurred at age of 29-
57 years of age and non-NPC groups at the age of 40-68 years. Based on the results
of Septiani's (2016), NPC patients have the range age between 50-59 years, men
more than women.8 In the United States, age and sex are very important
to determine the risk of carcinoma of the head neck. The average age of patients at
diagnosis is 55-65 years, so it can be concluded that parents and older adults have
a greater risk than children and young adults. Age and sex in NPC are associated
with other factor etiology of NPC such as genetic, environmental, and EBV
infection.9
Risk factors for smoking in cases of NPC (50.7%) were lower than non-
NPC cases (58.8%). Smoking and alcohol consumption are thought to be the
dominant risk factors. Research conducted according to Stevens, smoking can
increase the risk of NPC by 5.8 times, alcohol can increase the risk by 3.6 times, so
both can increase the risk up to 19 times.10 Research conducted by Wen-Qiong Xue
shows that smoking can increase the occurrence of NPC compared to non-
NPC. Cigarettes contain carcinogenic substances such as nicotine and polycyclic
aromatic hydrocarbons that cause gene mutations, and methylation so that there is
a change in nasopharyngeal epithelial cells that are in direct contact with the
mucosa during inhalation.11
The use of mosquito coils in NPC patients was (43.2%) and non-NPC
(26.7 %). Based on Septiani's research (2016), mosquito coils have a 2.58 times risk
of NPC.8 According to the 2013 Basic Health Research Basis, Indonesia is a country
of use of mosquito coils at 48.8%.12 According to Moore MA, mosquito coils are the
most common risk factor for NPC in Indonesia and Malaysia. The mosquito coils
contain carcinogenic ingredients in the form of formaldehyde and acetaldehyde
which can irritate the upper respiratory tract.13 According to the International
Agency for Research on Cancer (IARC), formaldehyde and acetaldehyde are at risk

116
of developing NPC. Formaldehyde and acetaldehyde from mosquito coils bind
to intracellular proteins that interfere with DNA replication and cause mutations
in oncogenic, resulting in changes in morphology, cell function, and
immunological reaction abnormalities in nasopharyngeal epithelial cells.14
Other risk factors that influence its high incidence of NPC is regularly
consume salted fish. According to Tabuchi's research in Japan, the consumption of
salted fish food regularly increases the incidence of NPC 3.15 times. Salted fish
contains nitrosamine which appears in the process of salting and drying of salted
fish under the heat of the sun. In the process, sunlight will react with nitrates in the
salted fish meat and form nitrosamine compounds that increase carcinogenesis in
nasopharyngeal epithelial cells.15
Nasopharyngeal risk factors are not only affected by one risk factor. In this
study, not all NPC patients based on medical record data accompanied by data
regarding NPC risk factors, this was one of the weaknesses of this study.

CONCLUSION
The most risk factors that influence the occurrence of NPC at ORL-HNS
RSHS Bandung outpatient ward in 2010-2015 consist of the use of mosquito coils,
smoking and consumption of salted fish.

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treatment modalities. Cancer Treat Rev. 2009; 35: 237 - 45.
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Hua Jia. Systematic Reviews and Meta- and Pooled Analyzes: Quantitative
Association of Tobacco Smoking with the Risk of Nasopharyngeal Carcinoma:
A Comprehensive Meta-Analysis of Studies Conducted Between 1979 and
2011. American Journal of Epidemiology Oxford Journal. 2013: 1-14.
12. Health D, RI KK. Basic Health Research. Jakarta: Republic of Indonesia's
Ministry of Health's Health Research and Development Agency. 2013.
13. Moore MA, Manan A, Chow KY, Cornain SF, Devi C, Triningsih F, et
al. Cancer epidemiology and control in peninsular and island South-East Asia-
past, present and future. Asian Pac J Cancer Prev. 2010; 11 (Suppl 2): 81-98.
14. Sharma TD, Singh TT, Laishram RS, Sharma L, Sunita A, Imchen
LT. Nasopharyngeal carcinoma in a regional cancer center of northeastern
India. Asian Pac J Cancer Prev. 2011; 12 (6): 1583-7.
15. Tabuchi K, Nakayama M, Nishimura B, Hayashi K, Hara A. Early detection of
nasopharyngeal carcinoma. International journ al of otolaryngology. 2011. 1-6

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 THE IMPORTANCE OF EARLY DETECTION
OF NASOPHARYNGEAL CARCINOMA: A CASE REPORT

Marlinda Adham1, Aqila Sakina Zhafira2, Antonia Christa Paramitha2, Bhanu

Adhyatmoko2, Gryselda Hanafi2, Rabbania Hiksas2, Kevin Culham2

1. Otorhinolaryngology-Head and Neck Surgery Department,

Faculty of Medicine Universitas Indonesia
2. Otorhinolaryngology-Head and Neck Surgery Department,
Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

ABSTRACT
Introduction: Nasopharyngeal carcinoma (NPC) is the fourth most
common cancer found in Indonesia. It is a malignant tumor arising from the
epithelium of the nasopharynx. NPC may cause serious complications; therefore,
an early detection and management is crucial. Physicians must be observant to
detect NPC due to its tricky anatomical predilection site.
Case report: A 37-year-old man was admitted to ORL-HN outpatient’s
clinic in Dr. Cipto Mangunkusumo Hospital with NPC. He had complained feeling
of fullness in the left ear, spontaneous nosebleeding from left nostril, severe
headache in his left side, numbness on his cheek, and double vision when looking
to the left. In a series of approximately 2 years, the patient had underwent a
septoplasty, an installation of tympanostomy tube, and a conchotomy to relieve the
symptoms he experienced. Only 6 months ago, the patient was finally diagnosed
with NPC.
Conclusion: It is very important for a physician to be more observant when
meeting a patient with numerous chief complaints. They should not treat every
symptoms the patient had, but to find out whether those symptoms are actually
related to each other and treat the patient accordingly.
Keyword: nasopharyngeal carcinoma, early diagnosis

INTRODUCTION
The Nasopharynx is the highest part of the pharynx. It is connected to the
nasal cavity via the choanae and to the middle ear by the eustachian tube orifice.
The concavity behind the nasopharynx is termed the pharyngeal recess
(Rosenmüller fossa). 1 This is the most common site of nasopharyngeal carcinoma
(NPC) lesion.2 The anatomical region is a very important clue to determine the
extend of NPC size as the clinical manifestation is largely affected by the anatomy
of nasopharynx. NPC is a malignant tumor arising from the epithelium of the
nasopharynx.3

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 Southeast Asia has the highest number of NPC cases with the prevalence
rate of 15-50 cases per 100,000 inhabitants.4 In Indonesia, NPC is the fourth most
common cancer after cervical cancer, breast cancer, and skin cancer with the
prevalence of 6 cases per 100 000 inhabitants.5 NPC is strongly related to Epstein
Barr Virus (EBV) infection and its development is influenced by geographical
distribution, rac e, genetic, sex, occupation, environment, culture, lifestyle,
and socioeconomic status.3,6
NPC may cause serious complications; therefore, an early detection and
management is crucial. The gold standard for diagnosing NPC is biopsy whereas
CT scan is important for detection of metastases.3 In this case report, we will discuss
an unfortunate case of a patient with NPC that came to the tertiary hospital in
Indonesia.

CASE REPORT
A 37-year-old man with NPC was admitted to ORL-HNS in Dr.Cipto
Mangunkusumo Hospital. In 2015 (approximately two-and-a-half years ago) he
experienced the feeling of fullness in his left ear. He denied any hearing
disturbances, tinnitus, fluid oozing from the ear canal or pain in the ear. The patient
also complained of frequent spontaneous nose bleeding from the left nostril.
Usually, the bleeding stopped in one to two minutes. The blood sometimes omitted
a foul odor. In addition, he experienced a severe headache, especially in the left
region of his head. The headache could not be localized. The pain felt like the head
was being stabbed, throbbed, and pressed by a heavy load at the same time. The
patient denied history of hypertension, vision impairment, frequently carrying
heavy weights, psychological problems, nausea, vomiting, trauma, and history of
unilateral body weakness or facial asymmetry.
Two-years ago, patient finally went to an ENT surgeon and was suggested
to undergo a head CT-Scan. The result revealed that he had a septal deviation. He
underwent septoplasty procedure. After the surgery, the nosebleeds stopped.
However, other symptoms persisted.

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 Picture 1. Head CT-Scan taken in March 2016

Four months later, during the patient’s control to the outpatient’s clinic, he
mentioned that the feeling of fullness in his left ear persisted. The clinician then
diagnosed the patient with glue ear. Thus, the patient underwent installation of
tympanostomy tube (grommet tube) scheduled 5 months after the visit. However,
his symptoms did not go away after the intervention.
Ten months ago, he went to a neurologist for his persistent cephalgia. He
was diagnosed with trigeminal neuralgia and was recommended to do head MRI.
The result revealed that patient suffered from sinusitis and suggested to undergo
conchotomy.

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 Picture 2. Head MRI taken in March 2017

Sixth months ago, conchotomy using CWL was conducted. After the
surgery, his complained of cephalgia and feeling of fullness in his left ear still
persisted, also felt an additional symptoms of numbness on his cheek and double
vision when looking to the left.
He was then referred to another ENT surgeon. There, he was suggested a
mastoid CT-scan. From the CT-scan, he was informed that he had an asymmetrical
nasopharynx which suggested that he had a nasopharyngeal carcinoma (NPC).
Then, he underwent biopsy of the nasopharyngeal mass. The result showed that he
suffered from non-keratinizing squamous cell carcinoma, undifferentiated type. He
went to Dr. Cipto Mangunkusumo Hospital for further treatments ever since.

Discussions
Our patient has been experienced the symptoms since approximately 2 years
ago. In this case, he suffered from of fullness sensation in his left ear, spontaneous
bloody discharge from left nostril, and severe cephalgia in the left region. Fullness
sensation on his left ear suggested that there was a middle ear effusion of the
blocked Eustachian tube which might be the result of compression from the
enlarging tumor. Bloody discharge from the nostril suggested that the NPC grows
anteriorly. In addition, this discharge was coming out only from the left nostril, and
there was no history of epistaxis or trauma at the nostril before.

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This increases the possibility that NPC was the cause of this bleeding. The cephalgia
suggested that there was a skull base involvement as the tumor also grow superior-
inferiorly. Therefore, it is common that the patient may also suffered from facial
pain from unilateral trigeminal neuralgia. The five most common symptoms that
appear in the first time in NPC patients in Indonesia are ear problem, nasal
congestion, bloody discharge, cephalgia and bilateral lymph node enlargement.
Since this patient was suffered from 3 out of 5 symptoms at the first time, therefore
physicians must suspected NPC until proven otherwise.
Physical examination must involve not only the ear, nose, throat, head, and
neck, but also other examinations such as ophthalmologic, neurologic, and
complete general physical examination to find the metastasis. For instance,
posterior rhinoscopy should be done in this patient earlier. Ear examination using
otoscope and tuning fork examination are also needed to evaluate ear problem.
Cranial nerve examination should also be done to examine the level of neurologic
damage and find the extent of intracranial defect.
In this patient, the tuning fork examination revealed that the patient had a
mixed of conductive and sensorineural hearing loss, indicated by a positive Rinne
test, lateralization to the healthy ear (right ear), and Schwabach test similar to the
examiner’s ear. The cranial nerves examination also showed that there is
abnormality in the sensoric function of cranial nerve V, which means that there
might be intracranial involvement in this patient.
It is very unfortunate for this patient that he was diagnosed with NPC only after
numerous doctor’s appointments and even ENT specialist . He had underwent
septoplasty, installation of typanostomy tube, and conchotomy before the physician
found the NPC. If the physician were aware with the characteristic of the disease,
he might not need to have those procedure done. Due to the fact that the patient’s
diagnosis was formed late, currently, the patient had to suffer from complications
of NPC.
Presentation of the nasopharyngeal carcinoma is variable. Patient’s can
present with ontological, neck mass, nasal, or neurological features. Majority of the
cases presented with unilateral or bilateral neck masses and /or deafness.
The importance of doing full ENT examination in cases of persistent middle
ear disease, recurrent or persistent nasal symptoms, headache or neck swelling. A
high index of suspicion with awareness of the disease is required to detect early
tumors. Flexible endoscopic examination with documentation of the nasopharynx
is the valuable procedure. This facility should be provided to the physicians and
surgeons involved in the management of nasopharyngeal carcinoma, especially in
areas where the disease is thought to be more prevalent.7
Health education and training for primary care physicians can also be of great help
in early diagnosis of these cases, and it’s also important to give more hours to teach
the Medical students since beginning how to understand the clinical presentation,

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early sign about Head and neck cancer especially Nasopharyngeal carcinoma,
because they are in the first basis patient’s search for treatment .
However the early diagnosis of nasopharyngeal carcinoma can be a difficult
task because the post nasal space is relatively inaccessible to examination. The fact
that the presentation of nasopharyngeal carcinoma is variable (headache, cranial
nerve involvement, nasal obstruction or a neck mass due to nodal metastases).
Patients may remain asymptomatic for a long time, given the often clinically occult
site of presentation and patients consult doctors of different specialties who have
little experience in managing NPC. It is not surprising that the diagnosis of NPC is
delayed.8 While Van Hasselt stated only 10% of patients are diagnosed early at
stage I.9

CONFLICT OF INTERESTS
The authors declare no conflicts of interest.

REFERENCES
1. Sobotta J, Putz R, Pabst R, Putz R. Sobotta atlas anatomy. 1st ed. Munchen:
Elsevier/Urban & Fischer; 2008.
2. Kamio Y, Sakai N, Takahasi G, Baba S, Namba H. Nasopharyngeal
carcinoma presenting with rapidly progressive severe visual disturbance: a
case report. J Med Case Rep. 2014; 8: 361. Published online 2014 Nov 6. doi:
10.1186/1752-1947-8-361
3. Soepardi EA, Iskandar N, Bashiruddin J, Restuti RD. Buku Ajar Ilmu
Kesehatan: Telinga Hidung Tenggorok Kepala & Leher. 7th ed. Jakarta: Badan
Penerbit Fakultas Kedokteran Universitas Indonesia; 2017.
4. Mahdavifar N, Ghoncheh M, Mohammadian-Hafshejani A, Khosravi B,
Salehiniya H. Epidemiology and inequality in the incidence and mortality of
nasopharynx cancer in Asia. Osong Public Health Res Perspect. 2016 Nov 7;
7(6):360-72.
5. Adham M, Kurniawan AN, Muhtadi AI, Roezin A, Hermani B, Gondhowiardjo
S, et al. Nasopharyngeal carcinoma in Indonesia: epidemiology, incidence,
signs, and symptoms at presentation. Chin J Cancer. 2012 Apr; 31(4):185-96.
doi: 10.5732/cjc.011.10328. Epub 2012 Feb 7.
6. Lu JJ, Cooper JS, Lee AWM. Nasopharyngeal cancer: multidisciplinary
management. 1sted. Springer: New York; 2010.
7. Ali HAM, Shubber MRH. Modes of Nasopharyngeal carcinoma Presentation.
Int. J.Curr.Microbiol.app.Sci (2016_):401-6
8. Indudharam R, Dip NB, Valuyectharn KA. Nasopharyngeal carcinoma:
Clinical trends. J Laryngol Otol.1997;111:724-9
Van Hasselt A, Woo JKS. Nasopharyngeal carcinoma. Scott Brown’s
Otorhinolaryngology and head and neck surgery, 7ed Ed.2008;2;ch188:2445-
74

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 SYMPTOM IMPROVEMENT IN THE STAGE IV NASOPHARYNGEAL
CANCER AFTER CHEMORADIATION
Yoke Kurniawan Inardi,Willy Yusmawan dan Dwi Antono

Otorhinolaringology Head and Neck Surgery Department

Faculty of Medicine Universitas Diponegoro

ABSTRACT
Background: Nasopharyngeal cancer (NPC) is the most common cancer
found in head and neck and most prevalently found in men. The prognosis of this
cancer depends on tumor aggressiveness, and therapeutic intervention. The extent
of local invasion, regional lymphatic spread, and distant metastases are reflected in
the TNM stage. Due to the limitations of NPC anatomy and its high radio
sensitivity, NPC is treated with chemoradiation therapy. Objective: To report the
symptom improvement after chemoradiation for patients with stage IV
nasopharyngeal carcinoma at dr. Kariadi Hospital. Cases: Male and female patients
with stage IV nasopharyngeal cancer having ptosis and disorder movement eye
symptoms. Treatment: chemoradiation is performed. Summary: Chemoradiation
provides improvement in stage IV nasopharyngeal cancer patients.
Keywords: Nasopharyngeal Cancer, Chemoradiation
INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma of the
nasopharyngeal epithelial layer. These neoplasms can appear from various sides of
the nasopharynx and are more commonly seen in the fossa of Rosenmüller. One of
the symptoms that can be caused is a disturbance in nerve III causing palpebral
ptosis, and disorders in the nerve IV and VI causing ophthalmoplegia.
Mixed chemoradiotherapy has been accepted by most oncologists as a
standard treatment for advanced NPC. There, however, is still controversy in the
optimal medicine, time, dose and duration of chemotherapy. In general, there are
three different ways to incorporate chemotherapy into curative therapy of the
radiation therapy: before (neoadjuvant), while (concurrent), and after (adjuvant)
radiation therapy.
So far, there is a few reports of symptom improvement in the stage IV
nasopharyngeal cancer after chemoradiation at dr. Kariadi Hospital. Hence, this
report is made to elevate the knowledge about stage IV nasopharyngeal cancer after
chemoradiation.

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CASE REPORT
The first case was a 44-year-old man coming to the ENT-HN clinic with a
complaint of left and right stuffy nose. In the beginning, 8 months before, it was
only left stuffy nose and it felt heavier time after time. It was weighing on the right
nose and kept continuing. Nosebleeds were experienced and followed by the noisy
on the left ear. Then, 4 months before, the patient experienced a headache and
leisure, dual visions on the right and left eyes, and the right and left eyelids could
not open. The results of examining the eyes showed that both eyes were ptosis and
the movements of the eyes were limited. The examination of MSCT
nasopharyngeal scan with facial contrast resulted the mass in the left and right side
of nasopharynx spread to the left and right space of parapharyngeal,
retropharyngeal space, right and left cavum nasi posterior, right and left ethmoidal
sinus, right and left sphenoid sinus, right and left parasellar, oropharynx as high as
the corpus vertebrae cervical 2 with destruction on the medial wall of the left
maxillary sinus, os clivus, dorsum sella, processus of anterior-posterior clinoid,
minor sphenoid wing, multiple lymphadenopathy level 2,3 of the right regio colli
(size of ±1.91x0.89 cm at level 2) and lymphadenopathy level 2 of the left regio
colli (size of ±2.35 x 1.18cm). The results of PA provide non-keratinizing
carcinoma and undifferentiated subtypes

1A 1B 1C 1D
Picture 1. 1A Patient profile before chemoradiation, while 1B, 1C, 1D after
chemoradiation

2A 2B

Picture 2. 2A MSCT before chemoradiation, while 2B after chemoradiation

Patient was treated in neoadjuvant chemoradiation with 6 series of
paclitaxel-cisplatin chemotherapy and rays. After 3 times of chemotherapy, the

126
patient’s complaints began to improve. The patient’s eyelids were able to open and
the eyeballs were able to move in all directions. Afterward, evaluation was
conducted. The evaluation showed that the patient was no longer complaining the
stuffy nose, noisy ears, double vision, nosebleeds, headaches. The physical
examination showed there was no ptosis, the movement of the right and left eye
balls could move in any direction, and there was no lump in the neck. MSCT
Nasopharyngeal scan with contrast found nasopharyngeal mass spreading to the
right-left parapharyngeal space, with a reduced size compared to the previous one,
lymphadenopathy multiple 2.3 levels of the right regio colli (largest size of ±23
1.23 x 0.57 cm) and level 2 of the left regio colli left (size of ±1.54 x 0.86 cm).
The second case was 41-year-old woman coming with a complaint of double
vision of the left eye. In the beginning, 1 year before, the patient experienced noisy
on the left ear getting more severe time after time. Then, the patient has experienced
stuffy nose on the left nose for 2 months as well as dual vision of the left eye view
for 4 days with headache which got heavier and the left eyelid could not open. The
results of examining the eyes showed that the left eye was ptosis and left eye
movement was limited. MSCT scan showed a solid mass in the left nasopharyngeal
region spreading to the mucosal pharyngeal space, parapharyngeal space, carotid
space, masticator space, left paracella, multiple lymphadenopathy in the regio colli
level 2.3 of the right and left largest size of ±AP 1.16 x LL 1.43 x CC 1.78 cm. PA
results provide non-keratinizing carcinoma and undifferentiated subtype.

3A 3B 3C 3D
Picture 3. 3A Patient profile before chemoradiation, 3B, 3C, 3D after
chemoradiation

4A 4B
Picture 4. 4A MSCT before chemoradiation, 4B after chemoradiation
The patient was treated with neoadjuvant chemoradiation with 6 series
paclitaxel-cisplatin chemotherapy and rays. After 3 times of chemotherapy, the
patient began to get better. The patient’s eyelids were able to open, and the eyeball

127
was able to move in all directions. Afterwards, the evaluation was conducted. The
results of evaluation showed that the patient was no longer complaining stuffy nose,
noisy ears, double vision, nosebleeds, headaches, and there was no lump in the neck.
Nasopharyngeal scan MSCT with contrast was found to decrease the size of the
rigio nasopharyngeal tumor mass appeared to be smaller, malignant
lymphadenopathy in the right and left regio colli was not seen anymore.

DISCUSSION
Nasopharyngeal cancer has typical symptoms and signs such as epistaxis,
nasal congestion, noisy ears, swelling of neck lymph gland, and in stage IV tumors
spreading to intra-cranial headaches, ptosis due to N III disorders, and eye
movement disorders due to disturbances N III, IV, VI. The most common
histopathology is keratinizing squamous cell carcinoma, Non-keratinizing
Carcinoma, and undifferentiated carcinoma which has the most and has a better
prognosis than these three histopathologies, i.e. undifferentiated carcinoma.
Mixed chemoradiotherapy has been accepted by most oncologists as a
standard treatment for advanced NPC. There, however, is still controversy in the
optimal medicine, time, dose and duration of chemotherapy. In general, there are
three different ways to incorporate chemotherapy into curative therapy of the
radiation therapy: before (neoadjuvant), while (concurrent), and after (adjuvant)
radiation therapy.
One of nasopharyngeal cancer complications is petrosphenoidal jacob
syndrome i.e. the tumor grows upward to the base of the skull through the foramen
lacerum until the cavernous sinus suppresses N.III, N.IV, N.VI, and N.II which
leads to trigeminal neuralgia (N.V) abnormalities. Trigeminal neuralgia is a pain on
the side of the face that is characterized by a feeling like being exposed to electricity
which is limited to the distribution area and trigeminal nerve, palpebral Ptosis
(N.III), Ophthalmoplegia (N.III, N.IV, N.VI).
The malignancy stage is usually measured by clinical or pathological stage.
However, because NPC is usually treated conservatively, it is usually done
clinically based on the results of physical examination and radiology. It is important
to recognize that the clinical stage is not only important in knowing the extent of
the disease and predicting patient outcomes, but it is also important in determining
the right management strategy.

SUMMARY
Neoadjuvant chemoradiation is one of the treatments for nasopharyngeal
cancer that can improve symptoms in patients.

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 MANAGEMENT OF NASOPHARYNGEAL CARCINOMA

Muhtarum Yusuf

Otorhinolaringology Head and Neck Surgery Department

Faculty of Medicine Universitas Airlangga

INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a carcinoma type of malignancy
derived from epithelial and lymphoid gland kriptae of the nasopharynx mucosal.
Nasopharyngeal carcinoma frequently found in North Africa, Alaska, Southeast
Asia including Indonesia, and South China specifically Guangdong province. The
highest incident found in Guangdong South China reported 20-30/100.000/year, the
lowest incident found in Western country reported 1/200.000/year.1 Incident of
NPC in Indonesia reported 6,2/100.000/year, it was in rank four after cervical
cancer, breast cancer and skin cancer.2 In head and neck malignancy, NPC is in the
first place. According to previous study conducted in RSUD Dr. Soetomo Surabaya,
based on electronic medical record (EMR) data of out patient departement from
2010 – 2012 NPC case was 61,10% of total head and neck malignancy, meanwhile
in RS. Cipto Mangunkusumo Jakarta from 1996–2005 NPC case was 28,40% of
total head and neck malignancy.2
The exact cause of NPC is still unknown, but already known that NPC has
multifactorial etiologies. There are 3 factors that have important role in causing
NPC, Epstein-Barr virus (EBV), environmental factor, and genetic factor. Overall
the prognosis of NPC is getting better because of radiotherapy and chemotherapy
technology development, local control can be achieved by both modalities
especially in early stage. The problem that remains a challenge in managing NPC
is cancer cell resistance to chemotherapy, radiotherapy, or both chemotherapy and
radiotherapy. Cancer cell resistance is a cause for recurrence, residual tumour, or
distant metastasis. Cancer cell resistance is the main cause of morbidity and
mortality in NPC.1
The better understanding of NPC management need to be improved in order
to reach better therapy result, hence in this article is elaborated several topics which
include the risk factors, clinical symptoms, diagnosis, histopatology, staging,
therapy, and follow-up.

1. ETIOLOGY
The etiology factor of NPC is multifactorial. There are 3 factors EBV,
environmental factor, and genetic factor. These 3 factors interacting with each other
in synergy that can cause NPC (Figure 1).3

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 Figure 1. Etiology factors of nasopharyngeal carcinoma .3
NPC : Nasopharyngeal carcinoma, EBV : Epstein Barr virus, HLA TCR : human
leucocyte antigen, T cell receptor

1.1 Epstein-Barr Virus

Previous study proved that there is a close relation between EBV and NPC.
Epstein-Barr virus mainly transmitted by saliva and also through blood transfusion.
The transmission through saliva occurred because intimate oral contact and also
saliva that left at glasses, plates, toys and other objects. The viral entrance is through
oropharynx, in this area EBV replicates in many elements of parotid gland
epithelial, pharynx, tongue, and B cell lymphocyte. After EBV replicates in B cell
lymphocyte and human nasopharynx epithelial, turns out to be dormant for long
periods of time without any symptom. The EBV must be activated in the first place
before interfere the host become malignant and conduct replication without
control.2,3
Activation happens because of several factors, such as consuming salted
fish, plant extracts that used in many traditional medications and low socio-
economic level. Salted fish contains of nitrosamin, it is a carcinogenic that can
activate the EBV. Nitrosamin also found in preserved food, fermented vegetable,
smoked salmon that consumed by people in China. The habit of consuming salted
fish is the main factor that can activated EBV. Plant extracts contain N-Butyric acid
known as EBV promotor and activator.3
Most of NPC patients are from low social-economy level, it relates with
environmental factors and life style. Unhealthy environment such as a house with
less ventilation can cause smoke trapped inside the house. Smoke can be derived
from incense burning, insect repellent and certain kind of woods. Unhealthy life
style such as cooking with certain ingredients, eating hot foods, lack of fruits and

130
vegetables. These conditions cause iritation and chornic inflamation at nasopharynx
that makes mucosa more vunerable to carcinogenic agent.3

1.2 Environmental Carcinogenic

Carcinogenic is a term that used to describe the substance that increase
cancer insident. Carcinogenic not only activates EBV but also causes mutation. The
carcinogenic substances are nitrosamine, benzopyrenem, benzoanthracene,
chemical gas, and industrial smoke. Other environmental factors are smoking and
alcohol. Many studies stated that smoking can increase the possibility 2-6 times
higher than non smoking, and also stated about increase possibility in alcohol.4,5

1.3 Genetic Factor

The genetic susceptibility associated with NPC based on the fact that NPC
found frequently in South China. Many studies conducted in Singapore chinese,
Malaysia, Hongkong and China proved that HLA Bw 46 Bw 58 correlate with
increasing risk. Genetic susceptibility relates with NPC based on the facts that many
NPC cases in South China. A Study conducted in Jakarta found HLA-A24 and B63
as a suspicious cause of NPC in Indonesians. Someone with HLA-A24 has 5,96
times more susceptible of NPC. This is different with Malaysian, HLA-B17 and
B18 are found. People with HLA-B17 3,4 times more susceptible of NPC and B18
4,4 times more susceptible of NPC. 6

2. CLINICAL SYMPTOM
Clinical symptom of NPC devided in to 4 groups: first, local symptom cause
by primary tumour. The nasal symptoms such as flu, blocking nose, and bloody
discharge or smelly pus. Tumour could expand to nose, throat, skull base, spread
downward to soft palate and causing bombans. (figure 2A). Second, the ear
symptoms are tinnitus, hearing loss, or repeating otitis media. (figure 2B). Third,
tumour growth that infiltrated upward through foramen lacerum until duramater
that cause severe headache. Upward infiltration also damage cranial nerves, when
N.VI damage can cause diplopia, N.V can cause trigeminal neuralgia, N.III and IV
can cause ptosis and opthalmoplegy. (figure 3). Tumour can grow further through
foramen jugulare and damage N. IX, X, XI and XII. Tumour that damage N.IX and
X can cause soft palate paralysis, pharynx and larynx. The nerve damages cause
eating disturbance, drinking disturbance and dysphonia. 1

131
A. B.

Picture 1. A. Primary tumour block the choana B. Primary tumour block

Eustachian tube.1

Picture 3. Paralysis of trochlear nerve.1

Four, lymph node metastasis can cause lymph node enlargement and usually
bilateral/unilateral. The most frequent area is one-third upper jugular, seldomly at
submandible or submental area. (figure 4). Common symptoms of malignancy are,
anorexia, thin body, subfebrile, trismus, and swallowing disturbance. The
symptoms of distant metastasis mostly found in liver, lungs, and bone. 1

Picture 4. Nasopharyngeal carcinoma through lymph node.1

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 Nasopharyngeal carcinoma patients usually come to medical services in the
late stage. Lymph node enlargement is the most common symptom found, followed
by nasal blocking, epitaxis, hearing loss, proptosis, flu, vision disturbance, weight
loss, ear pain, and cranial nerves paralysis.

3. DIAGNOSIS
Diagnosis based on history taking, physical examination,
nasopharyngoscopy, and endoscopy. Additional examination including head and
neck CT scan, magnetic resonance imaging (MRI) if there is any intracranial
infiltration. Nasopharynx biopsy specifically at Rosenmuller fossa, continued with
histopatology examination. Immunology test including indirect
immunofluorescence for IgA anti viral capsid antigen (VCA) and early antigen
(EA). The combination between these two examinations is sensitive and specific
for screening, early detection and to evaluate the progressiveness, but comercially
not available. 7

4. HISTOPATOLOGY
World Health Organization (WHO) in 1978 devided NPC in to 3 type based
on histopatology findings.1

Table 1. Nasopharyngeal carcinoma classification based on WHO in 1978.

Classification Histopatology
Type 1 Keratinizing squamous cell carcinoma
Type 2 Non keratinizing squamous cell carcinoma
Type 3 Undifferentiated carcinoma

5. STAGING
Staging needs to be done to define therapy and prognosis. Staging
classification based on American Joint Committee on Cancer Staging and End
Result Reporting/International Union Againt Cancer (AJCC/IUAC) 2011(table 2-
5).8

Table 2. Primary tumour

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 Table 3. Lymph node

Table 4. Distant metastasis

Table 5. Staging group

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6. THERAPY
Nasopharyngeal carcinoma therapy modality consist of radiotherapy,
chemotherapy and surgery, single radiotherapy or combination with chemotherapy.

6.1 Radiotherapy
Radiotherapy is a method using ion light to eradicate carcinoma and
preservate healthy tissue around. Until now radiotherapy is still a primary therapy
for NPC, and even single therapy for early stage of NPC. The consideration to
choose radiotherapy as treatment choice because histopatology findings of NPC
(75-95%) undifferentiated type (WHO 3) and non-keratinizing type (WHO 2)
which is more radio-sensitive in early stage. The other consideration is anatomy of
nasopharynx that difficult to perform radical surgery. 9,10
Radiotherapy dose that used depends on therapy purpose. Curative
radiotherapy given in all stages, except in distant metastasis. Radiotherapy target is
primary tumour, neck and supraclavicle lymph nodes. Total dose given for T1-T2
is 65 Gy, can be raise to 70-76 Gy for T3-T4. The fraction is 1,8-2Gy per day given
5 times per week. Spinal cord dose can not be more than 45 Gy. Paliative
radiotherapy given for tumour metastasis in bones and local recurrency.
Radiotherapy dose in recurrency is 20-30 Gy. 10
There are 2 methods of radiotherapy transmissions, convensional 2
dimensional (2D) and conformal 3 dimensional (3D). The 2D technique is
frequently use in developing country. In early stage, T1 and T2 give local control
success for 75-90% of all cases, and for T3 and T4 give local control success for
50-75% of all cases. The weakness of this technique is low level of protection to
the important organs near nasopharynx such as brain, spinal cord, fiber optic, and
parotid. The side effects that might happen stomatitis, teeth caries, otitis media,
external otitis, and trismus. The weakness of 2D technique could be take over by
3D and intensity modulation radiotherapy (IMRT). Intensity modulation
radiotherapy is the development of 3D technique, which given high dose in tumour
and low dose in normal tissue. Therapy result is better, higher local control, normal
tissue preservation, and less complications. 1

6.2 Chemotherapy
Nasopharyngeal carcinoma relatively sensitive to radiotherapy, in early stage
single radiotherapy is quite effective. In fact mostly NPC patients come in late
stage, so that single radiotherapy won’t give satisfying result. The 5 years survival
rate of late stage NPC is 34-52% with poor prognosis. Late stage NPC
chemotherapy is very important because NPC not only radiosensitive but also
chemosensitive and shows good response to chemotherapy agents. The
chemotherapy combination with radiotherapy for patient with stage III/IV without
metastasis based on consideration, first minimized distant metastasis risk by
eradicating micrometastasis. Second, strengthen synergetic effect of radiotherapy

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with chemotherapy as radio-sensitizer agents. Third, fascilitate radiotherapy plan
and increase local control with decrease tumour volume before radiotherapy. 11

6.2.1 Route of transmission and regiment

According to priority there are 2 types of regiments, primary therapy and
adjuvant therapy. Primary therapy means there is no additional therapy needed,
whereas adjuvant therapy means accompanying primary therapy, which is surgery
or radiotherapy. According to route of transmissions there are 3 types routes,
induction, concurrent, and adjuvant. The choice depend on the purpose by
considering the risks and benefits.
a. Neoadjuvant
Neoadjuvant chemotherapy is a chemotherapy given before the definitive
radiotherapy. There are 3 important considerations in chemotherapy, the benefit
for patient, duration, and survival. Survival based on staging, tumour size,
physical status, and any other things relate to main disease. Some clinical trials
recommend that only patients who give complete response get the clinical
beneficial.12
This type of chemotherapy has many benefits, reduce metastasis risk by
eradicating micrometastasis dan locoregional microscopy. The better tissue
preservation, easier surgery, less radical, reduce tumour size, strenghten
radiotherapy, better vascularization, and become the success indicator of other
therapy. There are many disadvantages including decrease of clinical status,
tumour size getting bigger, need more time, toxicity, higher cost, and delay the
definitive therapy. 12,13
The standard regiment for neoadjuvant chemotherapy are cisplatin and 5
fluorouracyl (FU). Regiment, dose and shcedule of neoadjuvant chemotherapy
can be seen at table 6.

Table 6. Regiment, dose, route of transmission neoadjuvant chemotherapy.14

General treatment notes: Squamous Cell Cancers of the head and neck include
lip, oral cavity, hypopharynx, glottis larynx, supraglottic larynx, ethmoid sinus,
maxillary sinus, occult primary.14

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b. Concurrent
Concurrent chemotherapy is a chemotherapy that given combine with
radiotherapy (chemoradiotherapy). Theoretically this type of chemotherapy is
very useful, radiotherapy anti tumour strengthen simultaneously by
radiosensitizer effect of chemotherapy. Systemic activity of chemotherapy could
eradicate the micrometastasis at the area outside radiotherapy. Strengthen cell
distribution that sensitive to chemoradiotherapy. Decrease tumour size and
increase drug transmission.
Cell that resistant to any modality could be eradicate by other modality. The
advantages of this treatment are, inrease survival rate, increase local control,
organ preservation, and shorter time. The disadvantages are, increase toxicity
and side effects. 13 Regiment, dose and chemotherapy schedule can be seen at
table 7.

Table 7. Regiment, dose, route of transmission concurrent chemotherapy.14

REGIMEN DOSING
Squamous Cell Cancers
Primary Systemic Therapy + Concurrent Radiotherapy
Cisplatin (CDDP; Days 1, 22 and 43: Cisplatin 100mg/m2 IV +
Platinol) + radiotherapy concurrent radiotherapy 2Gy/day to a total of
1-3
70Gy.
Cisplatin + paclitaxel Day 1: Paclitaxel 30mg/m2 IV (begin on
(Taxol)1,5 Monday), plus
Day 2: Cisplatin 20mg/m2 IV (every Tuesday).
Repeat cycle every week for 7 cycles, plus
Radiotherapy: 70Gy, delivered in 35 fractions;
1 fraction delivered daily Monday-Friday.
Carboplatin (Paraplatin) Days 1-4: 5-FU 600mg/m2/day as continuous IV
+ infusional 5-FU1,6 infusion + carboplatin 70mg/m2/day IV bolus.
Repeat cycle every 3 weeks for 3 cycles given
concurrently with radiotherapy

c. Adjuvant
Adjuvant chemotherapy is a chemotherapy given after definitive
radiotherapy. This type of therapy needed to prevent recurrency. Adjuvant
chemotherapy has many advantages, such as increase locoregional control,
eradicate residual tumour, and eradicat distant metastasis. Whereas there are also
disadvantages such as poor vascular bed, increase toxicity, longer time.13
Regiment, dose, and chemotherapy dose can be seen at table 8.

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 Table 8. Regiment, dose, Route of transmission of adjuvant chemotherapy.14

d. Sequential
Sequential therapy is a combination of neoadjuvant chemotherapy followed
with concurrent chemoradiotherapy. These combination has advantages and
disadvantages. As an example the use of classic neoadjuvant chemotherapy in
locoregional and distant metastasis. For distant metastasis the purpose is to
eradicate micrometastasis, whereas locoregional the purpose is to decrease
tumour size before radiotherapy. The toxicity is less, but need more time for
therapy. On the other hand, chemoradiotherapy increase the locoregional dose
intensity to control the locoregional control. This is not effective because can
increase the local toxicity and systemic significsntly. 13

e. Targeted Therapy
There are many targeted molecules identified in NPC and tested in order to
increase therapy effect. A molecule that already known and recommended is
anti-epidermal growth factor receptor (EGFR), although in clinical practice still
need further evaluation. In head and neck malignancy include NPC 80-90%
cases found excessive expression of EGFR molecules, that is why anti-EGFR
therapy is needed. The use of anti-EGFR in NPC has already been tested. The
use of anti-EGFR as single treatment is disappointed, therefore it must combine
with other modality, including radiotherapy or chemotheapy. An example of
anti-EGFR drug that already in market is cetuximab. Cetuximab recommended
for head and neck malignancy squamous cell carcinoma type with metastasis,
recurrent, or allergic to chemotherapy drugs. Cetuximab transmission with initial
dose 400mg/m2 continue 250mg/m2 every week, given before chemotherapy or
radiotherapy for 6 weeks. 11

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7. FOLLOW-UP
After therapy given it should be evaluate with follow-up 3-4 weeks after
therapy. The assessment of response can be seen from two aspects, survival rate
and response rate. Response rate, the aspect regarded as covering diminution neck
lymph node and decrease of primary tumour size in nasipharynx. The assessment
of therapy response was done based on the WHO criteria, complete response is
when primary tumour disappeared 100%, partial response is when parimary tumour
narrowed 50-100%, no response is when primary tumour narrowed less than 50%
or remain the same, and progressive is when primary tumour is getting bigger than
before or arising new lesion. Complete response including high response,
meanwhile partial reponse, no response and progressive response including low
response.15 The follow-up schedules are every 1-2 months in the first year, every 2-
3 months in the second year, every 3-5 months in the third until fifth year, every 6
months in the fourth until seventh year, every 6 months – 1 year in the seventh year
and beyond. Each follow-up schedule consist of history taking, physical
examination, CT scan, and biopsy when needed.9

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SUMMARY

Picture 5. Management algorithm of NPC.16

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