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Nasopharyngeal Carcinoma

Fuad Ridha Mahabot

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History of the Procedure

• external beam radiation therapy - primary mode of therapy for previously untreated NPC

• recurrent or persistent disease remains a challenge to clinicians• in some institutions, salvage nasopharyngectomy is used for the

treatment of recurrent disease• 1998 - Fee and Tu published results of salvage nasopha-

ryngectomy in a series of patients with recurrent NPC that failed previous treatment with radiation inspired other investigators to start using surgery in the treatment of

patients with recurrent NPC since then, various surgical approaches to the nasopharynx have been

proposed

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these include the transpalatal-maxillary-cervical, maxillary swing, transmandibular, transcervico-mandibulo-palatal, infratemporal fossa, lateral temporal, and endoscopic approaches

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Anatomy of Nasopharynx• 4cm high, 4cm wide and 3cm in

length• anterior -choanal orifice and

posterior margin of nasal septum• floor - upper surface of the soft

palate• roof and posterior wall

Body of the sphenoid, Basiocciput

First two cervical vertebrae• lateral wall

Eustachian Tube orifice Fossa of ROSSENMULLER

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Anatomical relation of FOR• anteriorly

eustachian tube and levator palatini

• posteriorly pharyngeal wall mucosa

overlying pharyngobasilar fascia & retropharyngeal space

• medially nasopharyngeal cavity

• superiorly foramen lacerum & floor of

carotid canal• posterolateral

carotid canal & petrous apex, foramen ovale and spinosum

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Histology

3 types of epithelium

• pseudostratified columnar ciliated epithelium - near the choanae and the adjacent part of the roof of the nasopharynx

• transitional epithelium - roof and the lateral walls• stratified squamous epithelium - along the posterior and

inferior portions of the nasopharynx

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Epidemiology & Frequency

Geographical and race

• is a prevalent malignancy in Southeast Asia• southern China, Hong Kong, Singapore, Malaysia, and Taiwan -

10-53 cases per 100,000 persons per year• eskimos in Alaska and Greenland and in Tunisians - 15-20 cases

per 100,000 persons per year• relatively uncommon in Western countries (<1 case per 100,000

persons) however, prevalence rate for people of Asian descent in the United

States is 3.0-4.2 cases per 100,000 persons.

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Aetiology

Environmental factors

• geographical clustering in Southern China• time trend - High risks among Chinese in Southern China

incidence in Hong Kong, Singapore virtually remained unchanged 50 yrs 2nd and 3rd generation born in USA shows decline

• NPC constitute 16% of all malignant tumors among the chinese

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Smoking and Alcohol consumptionOccupational• exposure to nickel, chromium• radioactive metal• inhalation of chemical fumes

Ingestions• salted fish - Nitrosamine• smoked food

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Drugs• chinese herbal medicine

Cooking habits• household smoke and fumes

Religious practice• incense and joss stick smoke

Socioeconomic status• nutritional deficiencies eg. Vitamin A & C

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Aetiological role of Epstein-Barr virus in NPC

• more than 90% of patients having elevated antibody titres to Epstein-Barr virus are those who have NPC of the undifferentiated / poorly differentiated forms

• moderate to well differentiated NPC are devoid of Epstein-Barr virus antigen

• thus the role of virus in NPC is still controversial

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Immunogenetics of NPC

prominent genetic susceptibilityhigh risk among southern Chinese populationdifferential high risk in emigrant Chinese compared to

indigenous population family clustering of NPC in Chineseelevated risk in people having genetic admixture with

Chinese low risk in other racial groups despite living in high-risk

countries eg. Indians in Malaysia / Singapore

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Classification

• WHO classes based on light microscopy findings

• 3 histological types type I – Keratinizing SCC type II – Nonkeratinizing Differentiated Carcinoma type III – Nonkeratinizing Undifferentiated Carcinoma

Type I • 25 % of NPC• moderate to well differentiated cells similar to other keratinizing SCC

(keratin, intercellular bridges)

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Type II• 12 % of NPC• variable differentiation of cells ( mature to anaplastic)• minimal if any keratin production• may resemble transitional cell carcinoma of the bladder

Type III• 60 % of NPC, majority of NPC in young patients• difficult to differentiate from lymphoma by light microscopy requiring

special stains & markers

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• Differences between type I and types II & III 5 year survival

• Type I - 10% • Types II, III - 50%

Long-term risk of recurrence for types II & III Viral associations

• Type I - HPV• Types II, III – EBV - full EBV genome present in all NPC epithelial cells

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Pathology

• Grossly the tumour presents in 3 formsProliferative growth causing nasal obstructionUlcerative causing epistaxis Infiltrative which causes cranial nerve involvement

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Clinical Features

• bimodal peak incidence - 30-40 years and 50-60 years• male:female – 3:1• early symptoms - nasal obstruction, blood-tinged sputum or

nasal discharge, tinnitus, headache, ear fullness, and unilateral conductive hearing loss from serous otitis media or recurrent acute otitis media

• advanced cases - cranial nerve involvement (III-VI), including diplopia and numbness of the face

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• neck lump - 60%• block sensation of ear - 41%• hearing loss - 37%• nasal bleeding - 30%• nasal obstruction - 29%• headache - 16%• ear pain - 14%• neck pain -13%• weight loss 10%• diplopia - 10%

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Cervical Lymphadenopathy (60%)

• tendency for early lymphatic spread• commonest palpable node - jugulodiagastric, L2/L3/L5 level• contralateral lymph nodes metastasis (nasopharynx is midline

structure)

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Aural Symptoms

• NPC leads to eustachian tube occlusion sensation of a blocked ear impaired hearing tinnitus serous otitis media

“Adult Chinese patients with unresolving unilateral serous otitis media have to be presumed to have nasopharyngeal carcinoma until proven otherwise”

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Epistaxis and Nasorespiratory Symptoms

• blood stained nasal discharge• blood stained saliva on hawking• profuse epistaxis• nasal obstruction• ozanea due to tumor necrosis

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Neurological Palsies

• Most frequently involved are: VI - Lateral rectus palsy - Diplopia & squint III, IV, VI - are commonly affected together (opthalmoplegia) V - High neck & pacial pain & paraesthesia IX, X & XI - Jugular Foramen Syndrome (involvement of the IX, X, and

XI CN)

• Isolated single C.N. palsy common with nerves V & VI• Horner’s syndrome – due to involvement to cervical sympathetic chain

ptosis, miosis, dilation lag, enophthalmos (the impression that the eye is sunk in), anhydrosis (decreased sweating), loss of ciliospinal reflex and blood shot conjunctiva

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Pain and Headache

• Hallmark of terminal disease Erosion of skull base (intracranial extension) Sepsis - sphenoidal sinusitis

• Trismus Inviltration of pterygoid muscles

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Diagnostic Evaluation• Anterior Rhinoscopy Examination

blood stain nasal discharged tumour extending into nasal cavity

• Post-Nasal Examination post nasal mirror - can assess NP space and tumour difficult to perform in sensitive patients

• Head and Neck Examination Lymph node

• Level 2/3/5• Progressively enlarging, hard, fixed, painless swelling

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• Aural Examination Otoscopy Examination under microscope

• retracted tympanic membrane• fluid in the middle ear

• Cranial Nerve Examination

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• Rigid Nasal Endoscope Inspection of the nasopharynx space Localisation and extent of tumour Biopsy under vision

• Shanmugaratnam et al - found that 26.4% of NPCs had features of more than 1 histologic type

• Fee et al - encountered similar findings in 35% of recurrent NPC cases

• Diagnostic Nasal Endoscopy Flexible Nasal Endoscope

• Fine Needle Aspiration Cytology of the neck lymph node

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Imaging

• CT Scan Extent of tumor Neck node involvement

• Bone Scan Skeletal metastasis- thoracolumbar region

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• MRI – radiologic modality of choice

to determine if any intracranial extension of the tumor involves the brain parenchyma or the cavernous sinus

intracranial spread can occur through foramen ovale, the foramen spinosum, the foramen lacerum, the carotid canal, and the jugular foramen that are in close proximity to the nasopharynx

to detect any tumor extension into the retropharyngeal, parapharyngeal, and pterygomaxillary spaces, as well as the infratemporal fossa and the sinuses

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Seroepidemiologic Studies

• demonstrated that 80-90% of patients with WHO type 2 NPC and WHO type 3 NPC have elevated levels of immunoglobulin A (IgA) antibodies to viral capsid antigen (VCA) and early antigen (EA)

• however, only 10-20% of patients with WHO type 1 NPC have elevated levels of IgA antibodies to VCA

• elevated EBV titers may also be associated with other disease entities, such as sinonasal undifferentiated carcinoma (SNUC), sinonasal lymphoma, and tongue cancer

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Distant Metastasis

• Incidence rate is about 30%• Sites commonly involved:

skeletal - thoracolumbar spine > 50% lung metastasis liver metastasis

• 90% of patients die within the 1st year of diagnosis of the first metastasis

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Staging of NPC - TNM Classification

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Treatment

• External Beam Radiotherapy primary mode of management of NPC at the primary site and in the neck mainly because of tumor's high degree of sensitivity to radiation as well

as the anatomical constraints for surgical access recent advances in imaging capabilities and improved radiotherapy

techniques have helped to improve the locoregional control rate

• Chemotherapy can be delivered before (neoadjuvant), during (concurrent), or following

(adjuvant) radiation therapy active chemotherapeutic - cisplatin, 5-fluorouracil (5-FU), doxorubicin,

epirubicin, bleomycin, mitoxantrone, methotrexate, and vinca alkaloids

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Chan et al - demonstrated that for patients with stage II and III NPC, the 5-year overall survival rate is better in patients treated with concurrent chemoradiotherapy (70.3%) than for patients treated with radiation alone (58.6%)

also for distant metastases

complications of radiotherapy• brain - Pituitary dysfunction, brainstem encephalopathy, temporal

lobe necrosis, cranial nerve palsy• ear - Sensorineural hearing loss, otitis media with effusion,

eustachian tube dysfunction• eye - Dry eye syndrome, ischemic retinopathy• thyroid - Hypothyroidism

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• gastrointestinal system - Severe mucositis, xerostomia, nausea, vomiting, dysphagia, dehydration, esophageal stricture

• musculoskeletal system - Excessive fibrosis, trismus, radiation myelitis, osteoradionecrosis, soft tissue necrosis, osteomyelitis

• vascular system - Stenosis of common carotid artery or internal carotid artery

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• Surgery only for treatment of recurrent NPC with limited disease contraindicated in involvement of the cavernous sinus clear appreciation of the tumor in relation to the internal carotid artery is

essential approaches

• Fee - transpalatal, transmaxillary, and transcervical approach– provides excellent exposure to both sides of the nasopharynx with

minimal morbidity to the patient– minimal risk to the internal carotid artery and the cranial nerves

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• Fisch - infratemporal fossa approach; Gross and Panje - lateral temporal approach

– both provide excellent exposure of tumors that extend into the infratemporal fossa and the parapharyngeal space

– disadvantage - difficult if the tumor extends to the contralateral nasopharynx

– morbidity - sensorineural hearing loss, CSF leak, unilateral laryngeal paralysis, and facial nerve deficit

• Biller and Krespi - transcervico-mandibulo-palatal approach– a wide-field exposure of the nasopharynx and excellent protection of

internal carotid artery– Morton et al - 67% local control rate at 2 years with this approach

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Follow Up• 1st year: once a month• 2nd year: every 2nd month• 3rd year: every 3 months• 4th year: every 6 months• >5years: Once a year

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Prognosis• prognostic factors

extent of the primary tumor (ie, skull base invasion, cranial nerve involvement, parapharyngeal infiltration)

level of the disease in the neckhistologic subtypeage and the sex of the patienttype and technique of radiotherapy

• 5-year overall survival (OS) rate (radiotherapy alone)• 85-95% in stage I• 70-80% in stage II • 24-80% in stage III and IV

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• 5-year overall survival (OS) rate60-80% in WHO type III NPC - high degree of radiosensitivity20-40% in WHO type I NPC - low degree of radiosensitivity

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