Clinical Practice Guidelines Management of Nasopharyngeal Carcinoma 2016 PDF

CPG Management of Nasopharyngeal Carcinoma 2016 CLINICAL PRACTICE GUIDELINES 2016 MOH/P/PAK/326.16(GU) MANAGEMENT OF NASOPHARYNGEAL CARCINOMA The Nasophary...

CPG Management of Nasopharyngeal Carcinoma 2016 CLINICAL PRACTICE GUIDELINES 2016 MOH/P/PAK/326.16(GU) MANAGEMENT OF NASOPHARYNGEAL CARCINOMA The Nasopharyngeal Carcinoma Society of Malaysia Ministry of Health Malaysian Society of Academy of Malaysia Otorhinolaryngologists Medicine Malaysia Head & Neck Surgeons (MSO-HNS) i  CPG Management of Nasopharyngeal Carcinoma 2016 Published by: Malaysia Health Technology Assessment Section (MaHTAS) Medical Development Division, Ministry of Health Malaysia Level 4, Block E1, Precinct 1 Federal Government Administrative Centre 62590, Putrajaya, Malaysia Copyright The copyright owner of this publication is MaHTAS. Content may be reproduced in any number of copies and in any format or medium provided that a copyright acknowledgement to MaHTAS is included and the content is not changed, not sold, nor used to promote or endorse any product or service, and not used in an inappropriate or misleading context. ISBN: Available on the following websites: http://www.moh.gov.my http://www.acadmed.org.my http://www.msohns.com http://www.npcresearch.org Also available as an app for Android and IOS platform: MyMaHTAS STATEMENT OF INTENT These clinical practice guidelines (CPG) are meant to be guides for clinical practice, based on the best available evidence at the time of development. Adherence to these guidelines may not necessarily guarantee the best outcome in every case. Every healthcare provider is responsible for the management of his/her unique patient based on the clinical picture presented by the patient and the management options available locally. Review o These guidelines were issued in 2016 and will be reviewed in 2020 or sooner if new evidence becomes available. When it is due for updating, the Chairman of the CPG or National Advisor of the related specialty will be informed about it. A discussion will be done on the need for a revision including the scope of the revised CPG. A multidisciplinary team will be formed and the latest systematic review methodology used by MaHTAS will be employed. Every care is taken to ensure that this publication is correct in every detail at the time of publication. However, in the event of errors or omissions, corrections will be published in the web version of this document, which is the definitive version at all times. This version can be found on the websites mentioned above. ii  CPG Management of Nasopharyngeal Carcinoma 2016 KEY RECOMMENDATIONS The following recommendations were highlighted by the guidelines Development Group as the key clinical recommendations that should be prioritise for implementation.  Clinical Presentations and Referral Recommendation 1  Patients presenting with any of the following symptoms should be referred to Otorhinolaryngologists as soon as possible to rule out nasopharyngeal carcinoma : o painless neck lump o blood-stained nasal discharge/saliva o unilateral ear block or hearing loss o unilateral headache o facial numbness o diplopia  Investigations Recommendation 2  Nasopharyngeal carcinoma should be diagnosed by histopathological examination of the nasopharynx.  In patients presenting with cervical lymphadenopathy, full head and neck assessment and fine needle aspiration cytological examination of the nodes should be done.  Staging Recommendation 3  All nasopharyngeal carcinoma patients should be staged using the tumour node metastasis (TNM) system.  Treatment Recommendation 4  Radiotherapy alone is the main treatment in Stage I nasopharyngeal carcinoma (NPC).  Concurrent chemoradiotherapy should be offered in Stage II, III, IVA and IVB NPC.  Intensity modulated radiotherapy is the preferred radiation technique in NPC. Recommendation 5  In recurrent nasopharyngeal carcinoma, nasopharyngectomy or re-irradiation may be offered. Recommendation 7  All nasopharyngeal carcinoma patients should have dental assessment prior to radiotherapy and treated accordingly. iii  CPG Management of Nasopharyngeal Carcinoma 2016 No. Title Page Levels of Evidence & Formulation of Recommendation v Guidelines Development and Objectives vi Guidelines Development Group viii Review Committee ix External Reviewers x ALGORITHM A : Management of Nasopharyngeal Carcinoma xi ALGORITHM B : Management of Persistent Disease or Recurrent NPC xii 1. INTRODUCTION 1 2. EPIDEMIOLOGY AND RISK FACTORS 1 2.1 Epidemiology 1 2.2 Risk Factors 1 2.3 Screening 2 3. CLINICAL PRESENTATION AND REFERRAL 2 4. INVESTIGATIONS 3 5. STAGING 4 6. TREATMENT 7 6.1 Primary Cancer 7 6.2 Recurrent Disease 8 6.3 Advanced Disease 9 7. SUPPORTIVE CARE 10 7.1 Dental Care 7.2 Otitis Media with Effusion 7.3 Contraception 7.4 Nutrition 8. MANAGEMENT OF COMPLICATIONS 11 8.1 Oral Complications 8.2 Cranial Nerve Palsy 8.3 Osteoradionecrosis 8.4 Otitis Media with Effusion 9. PROGNOSIS AND FOLLOW - UP 12 10. IMPLEMENTING THE GUIDELINES 14 REFERENCES 15 Appendix 1 Examples of Search Strategy 19 Appendix 2 Clinical Questions 20 Appendix 3 Clinical Presentations 21 Appendix 4 TNM Staging Diagram 24 Appendix 5 Radiological Staging 28 Appendix 6 Chemotherapy Drugs and Side Effects 30 Appendix 7 Eastern Cooperative Oncology Group Performance Status 31 Appendix 8 Toxicities of Radiotherapy on Head and Neck 32 List of Abbreviations 33 Acknowledgement 34 Disclosure Statement 34 Source of Funding 34 iv  CPG Management of Nasopharyngeal Carcinoma 2016 LEVELS OF EVIDENCE Level Study design I Evidence from at least one properly randomised controlled trial II -1 Evidence obtained from well-designed controlled trials without randomisation II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or group II-3 Evidence from multiple time series with or without intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence III Opinions of respected authorities based on clinical experience; descriptive studies and case reports; or reports of expert committees SOURCE: US / CANADIAN PREVENTIVE SERVICES TASK FORCE 2001 In line with new development in CPG methodology, the CPG Unit of MaHTAS is in the process of adapting Grading Recommendations, Assessment, Development and Evaluation (GRADE) in its work process. The quality of each retrieved evidence and its effect size are carefully assessed/reviewed by the CPG Development Group. In formulating the recommendations, overall balances of the following aspects are considered in determining the strength of the recommendations:-  overall quality of evidence  balance of benefits versus harms  values and preferences  resource implications  equity, feasibility and acceptability v  CPG Management of Nasopharyngeal Carcinoma 2016 GUIDELINES DEVELOPMENT AND OBJECTIVES GUIDELINES DEVELOPMENT The members of the Development Group (DG) for these CPG were from the Ministry of Health (MoH) and Ministry of Education (MoE). There was active involvement of a multidisciplinary Review Committee (RC) during the process of the CPG development. A systematic literature search was carried out using the following electronic databases/platform: Guidelines International Network (G-I-N), Medline via Ovid, Cochrane Database of Systemic Reviews (CDSR) and Pubmed. Refer to Appendix 1 for Example of Search Strategy). The inclusion criteria are all patients with nasopharyngeal carcinoma (NPC) regardless of study design. The search was limited to literature published in the last 20 years and on humans and in English. In addition, the reference lists of all retrieved literature and guidelines were searched and experts in the field contacted to identify relevant studies. All searches were conducted from 22 January 2015 to 24 February 2016. Literature search was repeated for all clinical questions at the end of the CPG development process allowing any relevant papers published before 31 July 2016 to be included. Future CPG updates will consider evidence published after this cut-off date. The details of the search strategy can be obtained upon request from the CPG Secretariat. Reference was also made to other CPGs namely Nasopharyngeal Cancer Treatment by Alberta Health Services published in 2013 and Diagnosis and Management of Head and Neck Cancer by Scottish Intercollegiate Guidelines Network published in 2006. The CPGs were evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II prior to it being used as reference. A total of 10 clinical questions were developed under different sections. Members of the DG were assigned individual questions within these sections. Refer to Appendix 2 for Clinical Questions. The DG members met 23 times throughout the development of these guidelines. All literatures retrieved were appraised by at least two DG members using Critical Appraisal Skill Programme checklist, presented in evidence tables and further discussed in each DG meetings. All statements and recommendations formulated after that were agreed upon by both the DG and RC. Where evidence was insufficient, the recommendations were made by consensus of the DG and RC. Any differences in opinion are resolved consensually. The CPG was based largely on the findings of systematic reviews, meta-analyses and clinical trials, with local practices taken into consideration. The literatures used in these guidelines were graded using the US/Canadian Preventive Services Task Force Level of Evidence (2001) while the grading of recommendation was done using the principles of GRADE (refer to the preceding page). On completion, the draft CPG was reviewed by external reviewers. It was also posted on the MoH Malaysia official website for feedback from any interested parties. The draft was finally presented to the Technical Advisory Committee for CPG, and the HTA and CPG Council MoH Malaysia for review and approval. vi  CPG Management of Nasopharyngeal Carcinoma 2016 OBJECTIVES The objectives of the Clinical Practice Guideline (CPG) are to provide evidence-based recommendations on the following: i. diagnosis and staging of NPC ii. treatment and follow-up of NPC CLINICAL QUESTIONS Refer to Appendix 2 TARGET POPULATION All patients with NPC TARGET GROUP/USER This CPG is intended to guide those involved in the management of NPC either in primary or secondary/tertiary care namely: i. Medical officers and specialists in government and private practice ii. Allied health professionals iii. Trainees and medical students iv. Patients and their advocates v. Professional societies HEALTHCARE SETTINGS Outpatient, inpatient and community settings vii  CPG Management of Nasopharyngeal Carcinoma 2016 GUIDELINES DEVELOPMENT GROUP Chairperson Dato' Dr. Pua Kin Choo Consultant Otorhinolaryngologist Hospital Pulau Pinang Members (alphabetical order) Dr. Amali Ahmad Dr. Mohd. Khairi Mohd. Noor Radiologist Family Medicine Specialist Hospital Kuala Lumpur Klinik Kesihatan Sekinchan Dr. Faridah Hassan Dr. Noraida Khalid Consultant Otorhinolaryngologist Pathologist (Anatomic Pathology) Head of Othorhinolaryngology Department Hospital Sultanah Aminah Hospital Selayang Dr. Fazlina Mohamed Yusoff Dr. Sha’ariyah Mohd. Mokhtar Family Medicine Specialist Otorhinolaryngologist Klinik Kesihatan Seksyen 7 Shah Alam Hospital Tengku Ampuan Rahimah Dr. Hanin Farhana Kamaruzaman Dr. Wong Yoke Fui CPG Unit Clinical Oncologist Health Technology Assessment Section National Cancer Institute, Putrajaya Ministry of Health Malaysia Miss Kamarun Neasa Begam Mohd Kassim Dr. Yogendren Letchumanasamy Pharmacist Nuclear Medicine Specialist National Cancer Institute, Putrajaya National Cancer Institute, Putrajaya Dr. Kong Min Han Dr. Zakinah Yahaya Otorhinolaryngologist & Lecturer Consultant Otorhinolaryngologist Universiti Kebangsaan Malaysia Medical Centre Hospital Kuala Lumpur Kuala Lumpur Dr. Mohd. Aminuddin Mohd. Yusof Head of CPG Unit Health Technology Assessment Section Ministry of Health Malaysia viii  CPG Management of Nasopharyngeal Carcinoma 2016 REVIEW COMMITTEE The draft CPG was reviewed by a panel of experts from both public and private sectors. They were asked to comment primarily on the comprehensiveness and accuracy of the interpretation of evidence supporting the recommendations in the CPG. Chairperson Datin Dr. Siti Sabzah Mohd. Hashim Senior Consultant Otorhinolaryngologist Hospital Sultanah Bahiyah, Alor Setar, Kedah Members (alphabetical order) Dr. Alan Khoo Head of Molecular Pathology Unit, Cancer Research Centre Institute for Medical Research (representative from Nasopharyngeal Carcinoma Society of Malaysia) Dr. Fadzilah Hamzah Nuclear Medicine Specialist Hospital Pulau Pinang Dr. Junainah Sabirin Deputy Director Health Technology Assessment Section Ministry of Health Malaysia Dr. Lau Fen Nee Consultant Clinical Oncologist National Cancer Institute, Putrajaya Professor Dr. Primuharsa Putra Sabir Husin Athar Consultant Otorhinolaryngologist & Clinical Professor KPJ Seremban Specialist Hospital KPJ Healthcare University College Negeri Sembilan Dr. Norzaini Rose Mohd Zain Consultant Radiologist Hospital Kuala Lumpur Dr. Patimah Amin Head of Surgical & Emergency Medicine Services Unit Medical Development Division Ministry of Health Malaysia Puan Rozita Mohamad Senior Pharmacist & Head of Pharmacy Department National Cancer Institute, Putrajaya Datin Dr. Zil Falillah Hj. Mohd. Said Consultant Family Medicine Klinik Kesihatan Paka ix  CPG Management of Nasopharyngeal Carcinoma 2016 EXTERNAL REVIEWERS (in alphabetical order) The following external reviewers provided feedback on the draft: (pending review) Professor Anne Wing-Mui Lee Dr. Noraini Ab Rahim Clinical Professor Consultant Radiologist Head, Department of Clinical Oncology Head of Radiology Department The University of Hong Kong National Cancer Institute Dr. Arni Talib Dr. Richard Lim Boon Leong Consultant Pathologist Consultant Palliative Medicine Head of Pathology Department Head of Palliative Medicine Department Hospital Kuala Lumpur Hospital Selayang Dr. Fauzia Abdul Majid Dr. Wee Tien Seng Joseph Consultant Family Medicine Senior Consultant/Chairman Klinik Kesihatan Kempas, Johor Division of Radiation Oncology National Cancer Centre Singapore Dr. Gerard Lim Chin Chye Emeritus Professor William Ignace Wei Consultant Oncologist Head of Surgery Department Head of Radiotherapy & Oncology Department Director, Li Shu Pui ENT Head & Neck National Cancer Institute Surgery Centre Hong Kong Sanatorium & Hospital Dr. Lee Boon Nang Dr. Yap Yoke Yeow Consultant Nuclear Medicine Consultant Otorhinolaryngologist Head of Nuclear Medicine Department KPJ Johor Specialist Hospital National Cancer Institute Johor Bahru Associate Prof. Dr. Mohd Zulkiflee Abu Bakar Dr. Zulkifli Yusof Consultant Otorhinolaryngologist & Lecturer Consultant Otorhinolaryngologist Faculty of Medicine Head of Othorhinolaryngology Department University Malaya Hospital Sultanah Bahiyah Dr. Nor Saleha Ibrahim Tamin Dr. Norjehan Dato’ Haji Yahaya Head of Cancer Unit Special Needs Dental Specialist Disease Control Division Head of Special Needs Dental Unit Ministry of Health Malaysia Department of Oral Surgery Hospital Kuala Lumpur Miss Tajunisah Mohamed Eusoff Pharmacist Hospital Pulau Pinang x  CPG Management of Nasopharyngeal Carcinoma 2016 ALGORITHM A : MANAGEMENT OF NASOPHARYNGEAL CARCINOMA  History taking  Complete physical examination  Nasopharyngeal examination & biopsy  +/- FNAC of regional lymph nodes  Baseline investigations (FBC, renal profile, random blood sugar, liver function test, chest X- ray and electrocardiogram)  MRI of nasopharynx & neck (from base of skull to thoracic inlet) or CT with contrast  PET-CT or CT thorax/abdomen or ultrasound and bone scan, as indicated  Dental evaluation  Nutritional evaluation Determine disease stage Stage I (T1N0M0) Stage II, III, IVA and IVB Stage IVC (distant metastasis) Treatment with definitive Concurrent chemoradiotherapy Palliative treatment radiotherapy (RT) to nasopharynx & elective RT to neck  Cisplatin + RT  Consider clinical trial if  Conventional fractionation: available  Definitive RT:- o Primary site: total of 66-70 Gy for o Primary site: total of 66-70 Gy 33-35 fractions, treated one  Palliative chemotherapy to for 33-35 fractions, treated one fraction/day for 6-7 weeks (1.8-2.0 be considered in patients fraction/day for 6-7 weeks Gy/fraction) with good ECOG (1.8-2.0 Gy/fraction) performance status (0-2) o Prophylactic neck: 54-60 Gy o Neck: 54-70 Gy for 30-35 for 30 fractions , treated one fractions, treated one fraction/day  RT to palliate symptoms fraction/day for 6 weeks (1.8- for 6-7 weeks (1.8-2.0 Gy/fraction) 2.0 Gy/fraction)  Referral to palliative care/  IMRT recommended to minimise palliative home care dose to critical structures  IMRT recommended to minimise dose to critical structure Follow-up and Surveillance  Head & neck and systemic examination: Year Intervals First year Every 1 to 2 months Second year Every 2 to 3 months Third year Every 3 to 5 months Fourth to fifth year Every 6 months After fifth year Every 6 to 12 months  Cross-sectional imaging in the initial 5 years  Speech/swallowing assessment as clinically indicated  Hearing evaluation & rehabilitation as clinically indicated  Weight assessment on follow-up  Annual thyroid function test (TFT) screening xi  CPG Management of Nasopharyngeal Carcinoma 2016 ALGORITHM B : MANAGEMENT OF PERSISTENT DISEASE OR RECURRENT NPC  Restage to assess recurrent or persistent disease – MRI or CT scan and PET/CT scan  Biopsy of recurrent lesion(s), as clinically indicated  Treatment should be individualised based on patient performance status and extent of disease Local disease Regional disease Distant disease Options include: Options include:  Consider clinical trial if available Nasopharyngectomy  Neck dissection  Palliative chemotherapy to OR be considered in patients  Re-irradiation with good ECOG Re-irradiation with external performance status (0-2) beam RT or brachytherapy  Chemotherapy  RT to palliate symptoms  Referral to palliative care/ palliative home care Follow-up and Surveillance  Head & neck and systemic examination: Year Intervals First year Every 1 to 2 months Second year Every 2 to 3 months Third year Every 3 to 5 months Fourth to fifth year Every 6 months After fifth year Every 6 to 12 months  Cross-sectional imaging in the initial 5 years  Speech/swallowing assessment as clinically indicated  Hearing evaluation & rehabilitation as clinically indicated  Weight assessment on follow-up  Annual TFT screening xii  CPG Management of Nasopharyngeal Carcinoma 2016 1. INTRODUCTION Nasopharyngeal carcinoma (NPC) is an epithelial malignant tumour of nasopharynx. It is most common among Chinese but constitutes only 0.7% of cancers worldwide.1, level I According to Global Cancer Statistic 2008, the incidence rate of NPC is 1 per 100,000 people and it was estimated that men are two to three times more likely to develop NPC than women.2, level III Geographically, Southeast Asia, Southern China, and North African countries have the highest prevalence of NPC compared with other parts of the world. NPC is the fourth most common cancer among Malaysians (5.2% of all cancers).3, level III There are several risk factors associated with the disease. NPC is usually diagnosed late due to trivial presentation of painless neck lump, blood stained saliva or nasal secretion and unilateral mild ear block.4-6, level III In view of late presentation, its survival outcome is poor. The optimal management of NPC involves a multidisciplinary team. The main challenge for the team is for early diagnosis to prompt access to treatment such as radiation therapy. For those with intermediate or advanced disease, the aim is to minimise treatment side effects without compromising the outcome. In view of high disease burden of NPC in Malaysia, variation in practice, resource implications as well as lack of local guidelines, the development of an evidence-based CPG for NPC is timely and essential to assist the healthcare providers in managing the disease locally. 2. EPIDEMIOLOGY AND RISK FACTORS 2.1 Epidemiology The number of new cancer cases is increasing worldwide. In 2012, there was an estimated of 86,700 new NPC cases with 50,800 deaths. Although NPC may be considered one of the rarer forms of cancer globally, the incidence is notably high in selected geographic and ethnic populations, such as in South-East Asia and Southern China.7, level III In Malaysia, NPC is the fourth (5.2%) most common cancer among Malaysians and the third (8.4%) most common cancer among males.3, level III The male to female ratio is 3:1 for both newly diagnosed and recurrent cases.4-6, level III Most common age group at presentation is 40 to 60 years old.4-6, level III However, NPC may also occur in younger age group and the youngest case of NPC detected was in a 6 year old.8, level III NPC is predominant among Chinese (49%), followed by the natives of Sabah and Sarawak (28%) and Malay (22%).4, level III In Sarawak, high incidence of NPC is reported among Bidayuh (48.4%).8, level III 2.2 Risk Factors Other risk factors for NPC are:  Infection – increased risk of NPC in those tested positive for Epstein-Barr virus antibodies (RR of 3.5 to 32.8)9, level II-2  Family – the risk of NPC among the first-degree relatives was 3.1 to 8.0 compared to those without family history 10-11, level II-2  Lifestyle and environment o Tobacco smoking is one of the important risk factors for NPC (OR=2.41, 95% CI 1.61 to 3.60).12, level II-2 The risk rise by 1 - 2% with each pack-year of smoking.13, level II-2 o Consumption of salted fish has higher risk of getting NPC in people who consume it since childhood (OR=2.45, 95% CI 2.03 to 2.94)10, level II-2 and those who have it for three times or more in 1 month (OR=1.9, 95% CI 1.1 to 3.5). 14, level II-2Exposure to 1  CPG Management of Nasopharyngeal Carcinoma 2016 domestic wood cooking fires for more than 10 years (OR=5.8; 95%CI 2.5 to 13.6).10, level II-2 o Exposure to occupational solvents for 10 or less years (OR=2.6; 95%CI 1.4 to 4.8).10, level II-2 o Occupational exposure to wood dust (OR=1.63, 95%CI 1.02 to 2.61).12, level II-2. 2.3 Screening Screening of NPC for general population in endemic area has been extensively studied. The methods used are Epstein-Barr virus (EBV) serology test and nasopharyngoscopy. The Health Technology Assessment (HTA) report by Ministry of Health (MOH) Malaysia published in 2011 concluded that there was insufficient evidence to recommend a population-based NPC screening programme as a public health policy.15, level II-2 The findings of a recent Cochrane systematic review on NPC screening published in 2015 were consistent with the HTA report.16, level I  Screening of NPC in general population could not be recommended due to insufficient evidence for its effectiveness and safety. 3. CLINICAL PRESENTATION AND REFERRAL 3.1 Clinical Presentation Healthcare providers need to be aware that NPC patients often present with nonspecific symptoms and signs in the head and neck region. A proper clinical workup which begins with a detailed history of the presenting complaints is pertinent in diagnosing NPC. The most common presenting symptoms of NPC are:4-6, level III; 8, level III  neck lump/mass (42 - 80.8%) - always painless, can be unilateral or bilateral  nasal symptoms (26 - 49.8%) - blood-stained nasal discharge or saliva, unilateral nose block, epistaxis or bad breath  ear symptoms (11 - 48.4%) - ear block, deafness, tinnitus or pain; the symptoms are usually unilateral but can be bilateral as the disease progresses  ophthalmo-neurologic symptoms (11 - 14.6%) - unilateral headache, facial numbness, diplopia, ptosis, trismus, dysphagia or hoarseness of voice. The most common cranial nerve involvement is 5th followed by 6th, 3rd, 4th and others. The images of these symptoms can be viewed in Appendix 3. Majority of NPC patients in Malaysia present with advanced stage (Stages III/IV) at the time of diagnosis (75 - 85%). This is due to lack of awareness of NPC symptoms and signs among patients and doctors.4, level III; 6, level III; 8, level III 3.2 Referral There is no evidence retrieved on referral criteria for patients with NPC. In view of delayed in diagnosis of NPC, the CPG DG uses consensus method to address the importance of referral to Otorhinolaryngology services as soon as possible. Early referral is crucial in establishing diagnosis of NPC so that the patients could receive definitive treatment. 2  CPG Management of Nasopharyngeal Carcinoma 2016 Recommendation 1  Patients presenting with any of the following symptoms should be referred to Otorhinolaryngologists as soon as possible to rule out nasopharyngeal carcinoma : o painless neck lump o blood-stained nasal discharge/saliva o unilateral ear block or hearing loss o unilateral headache o facial numbness o diplopia 4. INVESTIGATION 4.1 Baseline Investigations There is no retrievable evidence on baseline investigations for NPC patients. The established baseline investigations which include full blood count, renal profile, random blood sugar, liver function test, chest X-ray and electrocardiogram (ECG) are required to assess patient’s general health. 4.2 Histopathology and Cytology Biopsy of nasopharynx is mandatory in diagnosis of NPC. It is the preferred method for obtaining a definitive histological diagnosis as diagnostic sensitivity of nasopharyngeal cytology is limited (70 - 90%). Biopsies are taken from the gross lesions. In the absence of a gross lesion, multiple biopsies should be taken from nasopharynx for patients with high suspicion of NPC.17 Fine needle aspiration cytological (FNAC) examination of enlarged cervical lymph nodes is useful in reaching a diagnosis of metastatic NPC, either for initial diagnosis or staging. Histological grading of NPC is based on World Health Organization (WHO) Classification of Tumours, Pathology and Genetics of Head and Neck Tumours as outlined in Table 1.17 Table 1 : Histopathological Classification of Nasopharyngeal Carcinoma WHO Classification 2005 WHO Classification 1991 WHO Classification 1978 Keratinizing squamous cell Squamous cell carcinoma WHO Type I carcinoma (SCC) (well-differentiated keratinized SCC Non-keratinizing carcinoma Non-keratinizing carcinoma WHO Type II  Differentiated  Differentiated (differentiated keratinized  Undifferentiated  Undifferentiated non-SCC) Basaloid squamous cell No synonym exists (recently WHO Type III carcinoma described) (undifferentiated carcinoma)  In doubtful situation where the histological finding is unclear, ancillary tests such as immunohistochemical staining and EBV encoded early RNAs (EBER) in-situ hybridization will be performed. 3  CPG Management of Nasopharyngeal Carcinoma 2016 Non-keratinizing carcinoma is the commonest histological subtype (75 - 99%) while the basaloid squamous cell carcinoma (SCC) is the least common (6 cm and/or to supraclavicular fossa* N3a >6 cm in dimension N3b Extension to the supraclavicular fossa** *Note: Midline nodes are considered ipsilateral nodes. **Note: Supraclavicular zone or fossa is defined by three points: (1) the superior margin of the sternal end of the clavicle, (2) the superior margin of the lateral end of the clavicle, (3) the point where the neck meets the shoulder. All cases with lymph nodes (whole or part) in the fossa are considered N3b. Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T1 N1 M0 T2 N0 M0 T2 N1 M0 Stage III T1 N2 M0 T2 N2 M0 T3 N0 M0 T3 N1 M0 T3 N2 M0 Stage IVA T4 N0 M0 T4 N1 M0 T4 N2 M0 Stage IVB Any T N3 M0 Stage IVC Any T Any N M1 5  CPG Management of Nasopharyngeal Carcinoma 2016 Radiological Staging Imaging studies are essential in clinical staging of the NPC as it identifies the deep tumour infiltration and locoregional cervical lymph nodes involvement. It is mandatory to complete the staging process for further management of the disease.20 Magnetic resonance imaging (MRI) is superior to computed tomography (CT) scan in demonstrating soft tissue involvement. It is more sensitive than CT scan for skull base and intracranial tumour infiltration as well as identification of retropharyngeal lymph node metastasis (69.0% vs 52.1%, p