CHAPTER I

REVIEW

1.1 Anatomy

Nasopharynx is a space or a cube-shaped cavity that lies behind the nose. This

cavity is very difficult to see, so in the past so-called "dead-end cavity or hidden

cavity". The boundaries of nasopharyngeal cavity at the front is koana (posterior

nares). Upper, which is also the roof is cranii base. The back is the mucosal tissue

in front of the cervical vertebrae. The lower is the isthmus of the pharynx and soft

palate.1

Figure 1.1. Nasal and Nasopharynx Side Anatomy

Figure 1.2. Nasopharyx Anatomy from the back

Important parts located in the nasopharynx are: 1

1. Adenoid or tonsil Lushka

The building is only found in children aged less than 14 years. In adults

this structure has undergone regression.

2. Nasopharyngeal Fossa

This structure is a small indentation which is predilection of nasopharynx

angiofibroma

3. Torus Tubarius

It is a bulge where the estuary of the Eustachian tube (tubal ostia) .

4. Fossa Rosenmuller

It is a small dent in the rear of tubarius torus. This small dent passed down

behind as a small groove called the sulcus salfingo-pharynx. Rosenmulleri

fossa is the place where the replacement of columnar epithelium/cuboidal

epithelium becomes squamous epitel. This interchange place is considered

a predilection for the occurrence of nasopharyngeal malignancy.

1.2 Definition

Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that

cover the surface and line the nasopharynx.2 It involves squamous cell carcinoma,

non-keratinizing carcinoma (differentiated or undifferentiated) and basaloid

squamous cell carcinoma. Adenocarcinoma and salivary gland-type carcinoma are

excluded.3

1.3 Epidemiology

Nasopharyngeal carcinoma is a malignant tumor of the head - neck which most

are found in Indonesia. Nearly 60% of malignant tumors of the head and neck is a

nasopharyngeal carcinoma, followed by malignant tumors of the nose and

paranasal sinuses (18%), larynx (16%), and malignant tumors of the oral cavity,

tonsils, hypopharynx in low percentage.4

Cancer registration data in Indonesia based on histopathology of 2003

showed that the NPC ranks first of all primary malignant tumors in male and the

8th in female. Nasopharyngeal carcinoma can affect all ages, the incidence

increases after age 30 years old and reached the peak at age 40-60 years old.

During 2006-2008 found as many as 45 cases of nasopharyngeal

carcinoma in West Sumatra. Most patients were men, that is 32 cases (71.1%).

WHO subtype-2 and WHO-3 have the same lot number of cases, each 17 cases

(37.8%). 5

1.4 Etiology and Risk Factor

Epstein-Barr virus

The near constant association of EBV with NPC, irrespective of ethnic

background, indicates a probable oncogenic role of the virus in the genesis of this

tumour. The evidence is there is higher levels of antibodies, especially IgA,

against EBV (most commonly viral capsid antigen and early antigen) in most

patients with NPC compared with normal controls and patients with other cancer

types.3

Environmental factors

Diet

In high incidence regions, high levels of volatile nitrosamines in preserved food

have been implicated as the putative carcinogen for NPC development. In the

1960s, it was proposed that the increased incidence of NPC among Hong Kong

boat dwellers compared to house dwellers may have been due to their staple diet

of salted fish.

Several studies found that only the consumption of salted fish during

childhood and weaning is significantly associated with NPC, while consumption

during adulthood is not. Besides the age of consumption the manner of cooking

and the type of fish may also be important, sea salted fish carried a higher risk

than fresh-water fish, as well as steamed fish than fried, grilled or boiled salted

fish.6

Other environmental risk factors

Other purported risk factors include cigarette smoking, occupational exposure to

smoke, chemical fumes and dusts, formaldehyde exposure, and prior radiation

exposure.Busson Matched case-control study reported in Semarang vaporous

formaldehyde exposure and inhalation of smoke that the most likely towards the

NPC. Heavy smokers who smoke 2-4 times a day has more risk than non-

smokers. High alcohol consumption showed no risk in Chinese society, although

in the United States suggest a correlation.

Genetic Factors

Based on the facts that there are significant differences in the frequency among

some ethnic groups, namely the existence of an increased risk in families NPC

patients. In ethnic Chinese, NPC connected with the discovery of HLA type A2

and Bw46. Research in Medan find that the potential gene as the cause of the

onset of NPC susceptibility in Batak is HLA-DRB1.7

1.5 Pathogenesis

EBV plays a role in the pathogenesis of nasopharyngeal carcinoma, which was

originally of infection from this virus causes changes in low-grade dysplasia cells

in the nasopharynx. cell low-grade dysplasia has been caused by predisposing

factors such as diet, genetic sueptibilitas and others. With the infection of EBV

and the influence of chromosomal disorders develop into cancer invasif.

Metastastasis of these tumors is influenced by the presence of p53 mutation and

over-expression of kaderin.8

Figure 1.3. Pathogenesis of Nasopharyngeal Carcinoma9

Figure 1.4. The Microbiologic Changing in Nasopharyngeal Carcinoma9

1.6 Clinical Manifestation

Symptoms or clinical manifestations of nasopharyngeal carcinoma can be divided

into several groups, namely4:

1. Nasal / Nasopharyngeal Symptoms

Nasopharyngeal carcinoma should be suspected when any of these symptoms:

If the patient has a cold a long time, more than 1 month, especially patients

aged over 40 years, currently there are abnormalities in the nasal examination.

If the patient is cold and has thick discharge, foul-smelling, especially if there

is a point or a line of bleeding without abnormalities in the nose or paranasal

sinuses.

In patients over the age of 40 years, frequent bleeding from the nose

(epistaxis), while normal blood pressure and from nasal examination, there is

no abnormalities.

2. Ear Symptoms

Symptoms in the ear are reduced hearing, the ear feels full as filled with water, or

buzzing (tinnitus) and pain (otalgia). Hearing loss that occurs usually in the form

of conductive deafness and occurs when there is an extension to the

nasopharyngeal carcinoma tumor or around the tube, resulting in blockage.

3. Neck Tumor Symptoms

Enlarged neck or neck tumors is the nearest limphogenic spread of

nasopharyngeal carcinoma. This deployment can be unilateral or bilateral. The

specificity of tumor as metastasis of nasopharyngeal carcinoma neck is the

location of the tumor which is at the end of the mastoid process, behind the angle

of the mandible, in the sternocleidomastoid muscle, hard and not easily move.

Suspicions grew when the examination of the oral cavity, tongue, pharynx,

tonsils, hypopharynx and larynx found no abnormality.

4. Eye Symptoms

Patients will complain of reduced vision, but when asked carefully, people will

explain that he saw something in half or double. Clear what is meant is diplopia.

This occurs due to paralysis N.VI located above the foramen laserum lesions due

to tumor expansion. Other circumstances that could give eye symptoms are due to

paralysis N.III and N.IV, causing paralysis of the eye called the ophthalmoplegia.

When the expansion of the tumor on the optic chiasm and N.II then the patient

may experience blindness

.

5. Nerve Symptoms

Prior to the cranial nerve paralysis is usually preceded by some subjective

symptoms are perceived by patients as very disturbing headache or head was

spinning, hipoestesia on the cheek and nose, and often complain of difficulty in

swallowing (dysphagia). Are not uncommon symptoms of trigeminal neuralgia by

a neurologist when there has been no significant complaints. Process of further

carcinoma will make lesion of N.IX, X, XI, and XII when expand through the

jugular foramen. This disorder is called the Jackson syndrome. When the entire

cranial nerve have lesions, it called the unilateral syndrome. Can also be

accompanied by the destruction of the skull and it becomes a worse prognosis.

1.7 Classification

Based on histopathologic pattern, nasopharyngeal carcinoma can be divided into

three types according to the WHO. This division is based on examination by

electron microscopy which nasopharyngeal carcinoma is one variant of

epidermoid carcinoma. This division has supported by more than 70% pathologist

and retained to this day3:

a. WHO Type 1

These include squamous cell carcinoma (SCC). WHO Type 1 has a clear

growth type on the surface of the nasopharyngeal mucosa, differentiated

cancer cells well to moderate and produce quite a lot of keratin both inside and

outside the cell.

b. WHO Type 2

These include non-keratinizing carcinoma (NKC). WHO Type 2 is the most

various type, some tumor has moderately differentiated and the other half has

well differentiated, microscopic finding of this type is similar to transitional

cell carcinoma.

c. WHO Type 3

This type is a Undifferentiation Carcinoma (UDC). The picture of cancer cells

most heterogeneous. The WHO Type 3 includes the formerly called

limfoepitelioma, anaplastic carcinoma, clear cell carcinoma, and spindle

variations.

Type without differentiation and without keratinization in the same nature,

which are radiosensitive, while this type with keratinization not so

radiosensitive.

Figure 1.5. Squamous cell carcinoma, polymorphic nuclei, khromatin rugged,

clear cell boundaries, cytoplasmic bluish (Barnes, 2005)

Figure 1.6. Classify undifferentiated epithelial cells, with a background of

lymphocytes. Appearance of eosinophilic cytoplasm and prominent nuclei child

(Barnes, 2005).

Figure 1.7. Keratinizing Squamous Cell Carcinoma (Barnes, 2005).

Figure 1.8. Non-keratinizing Squamous Cell Carcinoma. (Barnes, 2005)

Figure 1.9. Undifferentiated Carcinoma. (Barnes, 2005).

1.8 Diagnostic Methods

Clinicians need to be aware that NPC patients often present with nonspecific

symptoms and signs in the head and neck region. A proper clinical workup begins

with a detailed history of the presenting complaints. The next step is through

physical examination including endoscopic examination of the head and neck

region. This should be followed by investigations to confirm the diagnosis and

assess teh extent of the disease prior to treatment.6

Among cases of newly diagnosed NPC (totalling over 1200 cases),

reported from the year 2007 to 2010 to the Malaysian Nasopharyngeal Carcinoma

Database, the most common presenting symptoms were neck lumps (40%), nasal

symptoms (blood stained nasal discharge, blood stained saliva, or nasal blockage)

(26%), aural symptoms (unilateral blocked ear, pressure sensation in the ears,

mild hearing loss or tinnitus) (14%) and ophthalmo-neurologic symptoms

(unilateral facial numbness, diplopia or unilateral headache) (10%). Similar

spectrum of presenting symptoms are reported elsewhere in the world across

time.6

Figure 1.10 . Nasopharyngx as viewed through a fiberoptic endoscope. i) Normal

nasopharyngx showing the fossa of Rossenmuller (arrow). (ii) Nasopharyngeal carcinoma

(arrow).

Diagnostic methods include2:

1. Clinical evaluation of the size and location of cervical lymph nodes.

2. Indirect nasopharyngoscopy to assess the primary tumor.

3. Neurological examination of cranial nerves.

4. Computed tomography (CT)/magnetic resonance imaging (MRI) scan of

the head and neck to below clavicles to assess base of skull erosion.

5. Chest radiotherapy (anteroposterior and lateral) to see if NPC has spread

to the lungs.

6. Bone scintigraphy by Tc 99 diphosphonate to show whether cancer has

spread to the bones.

7. Full blood count.

8. Urea, electrolyte, creatinine, liver function, Ca, PO4, alkaline phosphate.

9. EBV viral capsid antigen and EBV DNA.

10. Biopsy of either the lymph nodes or primary tumor for histological

examination.

Table 1.1 . WHO histopathological classification of NPC6

Figure 1.11. Patient with nasopharyngeal carcinoma (NPC) with skull base invasion and pterygoid

sclerosis (T3). Axial CT bone window shows large NPC filling nasopharynx and nasal cavity with

bony destruction of sphenoid bone, including right pterygoid base, which also shows sclerosis

(arrow). Right middle ear effusion is present.10

Figure 1.12. 49-year-old woman with nasopharyngeal carcinoma (NPC) localized to nasopharynx

(T1). Axial contrast-enhanced T1-weighted image shows small NPC (short arrows) centered in left

Rosenmüller fossa (long arrow), which is the most common site for this cancer, and involving

posterior wall. Tumor is confined to nasopharynx, and there is small metastatic left

retropharyngeal node (curved arrow).10

Staging of NPC according to the seventh edition of the American Joint

Committee on Cancer’s (AJCC)/UICC TNM staging system relies on evaluation

of the primary tumor (T category), the draining nodal groups (N category), and

evidence or absence of metastatic disease (M category).10

Table 1.2. Nasopharyngeal Carcinoma TNM Staging3

1.9 Differential Diagnoses

Crush artifacts are common, mandating careful evaluation of better preserved

areas. Keratin staining will help in uncertain cases. Keratinizing squamous cell

carcinoma is not difficult to separate from other lesions. However, what percent of

the tumor is squamous versus “undifferentiated” before it is placed in a different

category is still open to discussion. In radiation cases, the stromal atypia and

cytologic atypia within the epithelium may make reactive versus neoplastic

separation more difficult. 11

A non-keratinizing carcinoma has a much broader differential diagnosis

and includes melanoma, rhabdomyosarcoma, lymphoma, olfactory

neuroblastoma, Ewing sarcoma and primitive neuroectodermal tumors. In fact,

even floridly reactive germinal centers can sometimes contain large vesicular

nuclei and lack a well-defined mantle zone. Plump endothelial cells in reactive

lymphoid aggregates can also have vesicular nuclei which can be confused with

NPC. These cells usually do not contain nucleoli and are negative for keratin.

Sinonasal undifferentiated carcinoma (SNUC) is a completely separate tumor

based on location and pattern of growth. The differential considerations can often

be confirmed with a pertinent immunohistochemistry panel.11

Table 1.3. Non-keratinizing carcinoma versus sinonasal undifferentiated carcinoma11

1.10 Management

1. Radiotherapy

Radiotherapy (RT) is the mainstay for the radical treatment for NPC. The

anatomical location, ropensity for loco-regional spread, and proximity of

critical structures makes wide field surgical treatment unacceptably morbid as

a first line option. The therapeutic ratio of RT is improved greatly by the

synchronous use of chemotherapy (CT) and advances in radiation delivery

techniques, both of which result in better disease control and survival along

with lower rates of long term toxicity. Intensity modulated radiotherapy

(IMRT) allows concavities to be created in the RT dose distribution, which is

particularly useful for the treatment of head and neck cancer. It facilitates

improved coverage of the primary tumour volume, particularly in the

pharyngeal recesses, and reduction of parotid gland dose, substantially

reducing long term xerostomia, thereby improving quality of life.

Radiotherapy is also useful in the palliative setting. It can be used to

treat symptomatic metastases and local disease in the presence of widespread

metastases when aggressive local therapy is clinically inappropriate.12

2. Chemotherapy

Concurrent chemo-radiotherapy offers as significant improvement in over-all

survival in stage III and IV disease. There is evidence confirming significant

improvement in overall survival (OS) in the patients treated concurrently with

chemo-radiotherapy for NPC as compared to RT alone. The roles of neo-

adjuvant and adjuvant chemotherapy are more controversial with no proven

survival advantage but confirmed event free survival (EFS) benefit with neo-

adjuvant chemotherapy. Adjuvant chemotherapy after RT is less well tol-

erated and benefits are still unproven.

Cisplatin based chemotherapy is commonly used concurrently with

radiation and combination of cisplatin and fluorouracil may be used in the

neo-adjuvant setting, in selected cases. Platinum based chemotherapy has

been effective in palliation of recurrent and metastatic NPC. Single centre

(Level 2) studies have reported activity with the use of capecitabine,

gemcitabine and taxanes as single agent or in combination with platinum for

second and third line treatment for metastatic disease.12

3. Primary Surgery

Surgery should only be used to obtain tissue for diagnosis and to deal

with otitis media with effusion. Surgery is only used in the following

scenarios12:

To obtain tissue for diagnosis. Contact endoscopic diagnosis of NPC

remains experimental.

To obtain tissue from clinically involved neck nodes using FNAC or core

biopsy. If these techniques are non-diagnostic open biopsy can be used. In

cases with obvious fungation open biopsy is the method of choice.

To deal with otitis media with effusion.

Treatment Recommendations

Stages I and II

Patients with early disease can be treated with RT alone, resulting in disease free

survival rates of 90% and 84%. The dose to the primary tumour should be equiva-

lent to 70 Gy in 2Gy factions and at least 50Gy in 2Gy fractions to the bilateral

neck and other sites of potential microscopic spread. IMRT should be used where

possible. Evidence of benefit from the addition of chemotherapy to radiotherapy

in early disease is lacking.Intermediate stage II disease is treated with

combination chemo-radiotherapy (CRT). IMRT should be used where possible. A

dose of 70 Gy is recommended to the primary, 66 to 70Gy to gross disease in

lymph nodes and 50Gy to the bilateral neck and other sites of potential

microscopic spread. Radiobiological equivalents are given if a fraction size other

than 2Gy is employed, for example with intensity modulation.12

The most commonly used chemotherapy schedule is Cisplatin 100 mg/m2

on days 1,22 and 43 of radiotherapy based on the United States Intergroup Study

Nasopharyngeal Cancer 0099. Weekly cisplatin at a dose of 40 mg/m2 is effective

but has not been com-pared to the standard regimen in a randomised study. It can

be considered for older patients and/or those with significant comorbidities. 12

Stages III and IV

Concurrent CRT is the standard of care for advanced nasopharyngeal cancers.

This improves overall survival by up to 6% at 5 yrs compared to radical RT. A

dose of 70 Gy (2Gy per fraction) with concurrent cisplatin chemotherapy is

recommended. Several trials have explored the role of neo-adjuvant

chemotherapy, with a recent meta-analysis confirming an improvement in disease

free survival (DFS) whilst having no effect on overall survival (OS). Radiotherapy

target volume definition must include gross tumour (clinical, endoscopic and

radiological), the nasopharynx, and the pterygopalatine fossa, the base of skull

and clivus, posterior part of sphe-noid sinus, posterior third of the nasal cavity and

the maxillary sinus, retropharyngeal lymph nodes, and parapharyngeal space.

Prophylactic irradiation must include uninvolved level I to V nodal areas.12

IMRT is increasingly being used with either fixed gantry linear accelerator

based techniques or with helical tomotherapy techniques with confirmed benefits

in pre-serving parotid gland function. Studies are currently exploring the role of

further dose escalation with IMRT to improve local control.Surgical treatment is

reserved for salvage following CRT failure. 12

Recommendations 12:

• RT is the treatment of choice for stage I and II disease

• IMRT techniques should be employed whenever possible

• CRT is the treatment of choice for stage III and IV disease

1.11 Prognosis

The current TNM is a better staging system than past models, with an overall 5-

year survival in the United States of about 40–80% (dependent on endemic versus

sporadic tumor). Squamous cell carcinoma has a lower survival (20–40%) than

undifferentiated (65%), although basaloid squamous has the lowest survival

(<10%). A better prognosis is seen in young patients (<40 years) and women.11

Poor prognostic indicators include advanced clinical stage, cranial nerve

involvement, keratinizing histology and an absence of EBV. EBV titers have been

correlated with survival when EBV is present, with serum EBV DNA showing

promise in monitoring disease status. Keratinizing squamous cell carcinoma has

the greatest propensity for locally advanced tumor growth, but a lower chance of

metastasis than other types.11