Nasopharyngeal carcinoma

Bernadette Brennan Correspondence: Bernadette Brennan bernadette.brennan@cmmc.nhs.uk Author Affiliations Royal Manchester Children's Hospital, Hospital Road, M27 4HA Manchester, UK Orphanet Journal of Rare Diseases 2006, 1:23 doi:10.1186/1750-1172-1-23 The electronic version of this article is the complete one and can be found online at: http://www.OJRD.com/content/1/1/23 Received: 12 May 2006 Accepted: 26 June 2006 Published:26 June 2006 2006 Brennan; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that cover the surface and line the nasopharynx. The annual incidence of NPC in the UK is 0.3 per million at age 014 years, and 1 to 2 per million at age 1519 years. Incidence is higher in the Chinese and Tunisian populations. Although rare, NPC accounts for about one third of childhood nasopharyngeal neoplasms. Three subtypes of NPC are recognized in the World Health Organization (WHO) classification: 1) squamous cell carcinoma, typically found in the older adult population; 2) non-keratinizing carcinoma; 3) undifferentiated carcinoma. The tumor can extend within or out of the nasopharynx to the other lateral wall and/or posterosuperiorly to the base of the skull or the palate, nasal cavity or oropharynx. It then typically metastases to cervical lymph nodes. Cervical lymphadenopathy is the initial presentation in many patients, and the diagnosis of NPC is often made by lymph node biopsy. Symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis of the soft palate, hearing loss and cranial nerve palsies. Larger growths may produce nasal obstruction or bleeding and a "nasal twang". Etiological factors include Epstein-Barr virus (EBV), genetic susceptibility and consumption of food with possible carcinogens volatile nitrosamines. The recommended treatment schedule consists of three courses of neoadjuvant chemotherapy, irradiation, and adjuvant interferon (IFN)-beta therapy.

Definition
Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that cover the surface and line the nasopharynx. NPC was first described as a separate entity by Regaud and

Schmincke in 1921 [1,2]. Approximately one third of nasopharyngeal carcinomas of the undifferentiated type are diagnosed in adolescents or young adults. Although rare, NPC accounts for one third of childhood nasopharyngeal neoplasms (data from USA) [3].

Epidemiology
The annual incidence of NPC in the UK is 0.25 per million (age standardized, age 0 14 years), 0.1 per million at age 09 years and 0.8 per million at age 1014 years. It seems reasonable to assume, on the basis of England and Wales cancer registry data, that at least 80% of nasopharyngeal cancers at age 1519 years are carcinomas. This suggests an incidence of 1 to 2 per million for NPC at age 1519 years. In comparison with other countries, the incidence in the UK is low. In particular, in Tunisia the incidence is relatively high [4]. In southern parts of China, Southeast Asia, the Mediterranean basin and Alaska the incidence of NPC is moderately elevated; an incidence of 2 per million of NPC in China has been reported [5]. In other countries, for example in India, the incidence is comparable to that in the UK at 0.9 per million. Furthermore, the younger age peak in the second decade found in India [6], is also found in the UK [7].

Etiology
NPC is the commonest epithelial cancer in adults. The detection of nuclear antigen associated with Epstein-Barr virus (EBNA) and viral DNA in NPC type 2 and 3, has revealed that EBV can infect epithelial cells and is associated with their transformation [8]. The etiology of NPC (particularly the endemic form) seems to follow a multi-step process, in which EBV, ethnic background, and environmental carcinogens all seem to play an important role. Lo et al. showed that EBV DNA was detectable in the plasma samples of 96% of patients with non-keratinizing NPC, compared with only 7% in controls [9]. More importantly, EBV DNA levels appear to correlate with treatment response [9-11] and they may predict disease recurrence [11], suggesting that they may be an independent indicator of prognosis [12]. In adults, other likely etiological factors include genetic susceptibility, consumption of food (in particular salted fish) containing carcinogenic volatile nitrosamines, and as in children, EBV [13,15-19].

Clinical presentation
NPC usually originates in the lateral wall of the nasopharynx, which includes the fossa of Rosenmuller. It can then extend within or out of the nasopharynx to the other lateral wall and/or posterosuperiorly to the base of the skull or the palate, nasal cavity or oropharynx. It then typically metastases to cervical lymph nodes. Distant metastases may occur in bone, lung, mediastinum and, more rarely, the liver. Cervical lymphadenopathy is the initial presentation in many patients, and the diagnosis of NPC is often made by lymph node biopsy. Symptoms related to the primary tumor include trismus,

pain, otitis media, nasal regurgitation due to paresis of the soft palate, hearing loss and cranial nerve palsies. Larger growths may produce nasal obstruction or bleeding and a "nasal twang". Metastatic spread may result in bone pain or organ dysfunction. Rarely, a paraneoplastic syndrome of osteoarthropathy may occur with widespread disease.

Histopathology
Three subtypes of NPC are recognized in the World Health Organisation (WHO) classification [20]: type 1: squamous cell carcinoma, typically found in the older adult population type 2: non-keratinizing carcinoma type 3: undifferentiated carcinoma Most cases in childhood and adolescence are type 3, with a few type 2 cases [21]. Type 2 and 3 are associated with elevated Epstein-Barr virus titers, but type 1 is not [22]. The Cologne modification of the WHO scheme by Krueger and Wustrow [23] includes the degree of lymphoid infiltration. Types 2 and 3 may be accompanied by an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils, which are abundant, giving rise to the term lymphoepithelioma. Two histological patterns may occur: Regaud type, with a well-defined collection of epithelial cells surrounded by lymphocytes and connective tissue, and Schmincke type, in which the tumor cells are distributed diffusely and intermingle with the inflammatory cells. Both patterns may be present in the same tumor.

Diagnostic methods
Diagnostic methods include: 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.

Staging
The tumor, node, metastasis (TNM) classification of the American Joint Committee on Cancer [24] sixth edition (Table 1) is usually used to determine the tumor staging (Table 2). This latest TNM classification takes into account Ho's [25] modifications for NPC, which utilizes the prognostic importance of affected nodes extending into the lower cervical and supraclavicular areas. Table 1. The tumor, node, metastasis (TNM) classification of the American Joint Committee on Cancer [24] Table 2. Stage grouping

Treatment
Surgery Due to the anatomical position of NPC and its tendency to present with cervical lymph node metastases, it is not amenable to surgery for local control. Biopsy of the involved lymph node is the usual surgical procedure. The nasopharyngeal primary tumor is rarely biopsied. Chemotherapy Several factors are taken into account in deciding the chemotherapy regimen. Firstly, efficacy: the figures for event-free survival are similar for most small chemotherapy series but therapy usually involves fairly high-dose radiotherapy to the nasopharynx 60 to 65 Gy. However, the most promising results with a recent update, are those obtained using the Mertens protocol NPC-91-GPOH (Society of Pediatric Oncology and Hematology). This protocol should therefore be considered as the best current treatment. Uniquely, the NPC-91GPOH protocol includes immunotherapy with interferon-beta after chemotherapy and radiotherapy, which may explain its superior results compared to regimens without interferon treatment [27]. Secondly, late effects: in terms of chemotherapy, the Manchester regimen doxorubicin, methotrexate and cyclophosphamide would produce infertility in boys (total dose of cyclophosphamide 12 gm/m2) and possible anthracycline toxicity (total dose of doxorubicin 360 mg/m2) [36]. The NPC-91-GPOH protocol might produce some infertility in older boys but the total dose of cisplatinum is only 300 mg/m2. Furthermore, the incidence of renal toxicity should be relatively low but auditory toxicity would be higher because of the additional effect of irradiation on the auditory apparatus. The degree of pituitary dysfunction obviously depends on the radiotherapy field and, potentially, on the dose of radiotherapy but some degree of

hypopituitarism is expected. Furthermore, irradiation to the neck would result in hypothyroidism for the majority of patients and irradiation to the oropharynx would result in xerostomia and resultant poor dentition. The later may be relieved by amifostine, as demonstrated in adult studies. Radiotherapy Although treatment with radiotherapy controls the primary tumor [28-30], it does not prevent the appearance of distant metastases [28,31]. Radiotherapy is given with megavoltage equipment after initial chemotherapy. A maximum dose of 45 Gy is given to the clinical target volume, which is a 1 cm margin around the MRI-detected primary site, and inferiorly down to the clavicles to include the lymph nodes. Treatment is given in two phases: Phase I parallel pair (mostly lateral unless the tumor extends anteriorly between the eyes). Eyes, brain and brain stem are shielded as much as possible. A mid-plane dose of 30 Gy in 15 fractions is given. Phase II a lateral parallel pair or three-fields technique is used for the primary site, delivering 15 Gy in seven fractions to the clinical target volume of the tumor with a 1 cm margin. Brain stem and eyes should be shielded. Any overlap with the neck field should be shielded. A matching anterior neck node field is used to deliver a prescribed maximum subcutaneous dose of 15 Gy in seven fractions. The spinal cord should be shielded in this field. This prescription for radiotherapy is used in Manchester, but it is recognized that higher doses may be used in some centers, possibly to a total of 60 Gy to the tumor volume. In an current GPOH study, patients in complete remission (CR) after three courses of chemotherapy, will have their radiotherapy dosage reduced to 54 Gy instead of 59 Gy. Recommendation In the current GPOH protocol NPC-2003-GPOH, low-risk patients with Stage I and II tumors receive radiotherapy only, followed by 105 g/Kg of adjuvant interferon beta (IFNbeta), intravenously (i.v.), three times a week for 6 months. High-risk patients receive cisplatinum (100 mg/m2 over 6 hours on day 1 with standard hydration), mannitol and electrolyte replacement, and folinic acid (25 mg/m2 every 6 hours for a total of six doses) as well as 5-fluorouracil (1000 mg/m2 per day from day 2 for 5 days) as a continuous infusion. They receive three courses of chemotherapy every 21 days or on full blood count recovery, followed by irradiation and IFNbeta as for low-risk patients. Methotrexate has been dropped because of severe mucositis. Patients not in CR after three courses of chemotherapy will receive concomitant cisplatinum (20 mg/m2/day for 3 days with radiotherapy for two courses).

Prognostic factors
Presentation with lymphadenomegalia implies that the disease has spread beyond the primary site. However, in childhood the presence of metastatic disease in cervical lymph nodes at

diagnosis does not adversely affect prognosis [30-33]. Factors associated with a poor prognosis are skull base involvement [33-35], extent of the primary tumor [31,32] and cranial nerve involvement [33,34].

Unresolved questions
1. What is the optimum radiotherapy dose? 2. Would exclusion of interferon from the treatment produce similar results? 3. The relationship between late effects and dose of radiotherapy should be investigated, as well as the exact nature and incidence of late effects.

References
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26. Mertens R, Granzen B, Lassay L, Bucsky P, Hundgen M, Stetter G, Heimann G, Weiss C, Hess CF, Gademann G: Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH). Cancer 2005, 104:1083-1089. PubMed Abstract | Publisher Full Text 27. Rodriguez-Galindo C, Wofford M, Castleberry RP, Swanson GP, London WB, Fontanesi J, Pappo AS, Douglass EC: Preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma. Cancer 2005, 103:850-857. PubMed Abstract | Publisher Full Text 28. Deutsch M, Mercado R Jr, Parsons JA: Cancer of the nasopharynx in children. Cancer 1978, 41:1128-1133. PubMed Abstract | Publisher Full Text 29. Pick T, Maurer HM, McWilliams NB: Lymphoepithelioma in childhood. J Pediatr 1974, 84:96-100. PubMed Abstract | Publisher Full Text 30. Jenkin RD, Anderson JR, Jereb B, Thompson JC, Pyesmany A, Wara WM, Hammond D: Nasopharyngeal carcinoma a retrospective review of patients less than thirty years of age: a report of Children's Cancer Study Group. Cancer 1981, 47:360-366. PubMed Abstract | Publisher Full Text 31. Jereb B, Huvos AG, Steinherz P, Unal A: Nasopharyngeal carcinoma in children review of 16 cases. Int J Radiat Oncol Biol Phys 1980, 6:487-491. PubMed Abstract 32. Lombardi F, Gasparini M, Gianni C, De Marie M, Molinari R, Pilotti S: Nasopharyngeal carcinoma in childhood. Med Pediatr Oncol 1982, 10:243-250. PubMed Abstract 33. Straka JA, Bluestone CD: Nasopharyngeal malignancies in children. Laryngoscope 1972, 82:807-816. PubMed Abstract 34. Nishiyama RH, Batsakis JG, Weaver DK: Nasopharyngeal carcinomas in children. Arch Surg 1967, 94:214-217. PubMed Abstract 35. Baker SR, Wolfe RA: Prognostic factors in nasopharyngeal malignancy. Cancer 1982, 49:163-169. PubMed Abstract | Publisher Full Text 36. Roper HP, Essex-Cater A, Marsden HB, Dixon PF, Campbell RH: Nasopharyngeal carcinoma in children. Pediatr Hematol Oncol 1986, 3:143-152. PubMed Abstract

TERJEMAHAN JURNAL THT 2 INGGRIS

Karsinoma nasofaring Bernadette Brennan Korespondensi: Bernadette Brennan bernadette.brennan @ cmmc.nhs.uk Penulis Afiliasi Manchester kerajaan Anak Rumah Sakit, Rumah Sakit Road, M27 4HA Manchester, Inggris Orphanet Jurnal Penyakit, Langka 2006 01:23 DOI: 10.1186/1750-1172-1-23

Abstrak Karsinoma nasofaring (NPC) adalah tumor yang timbul dari sel-sel epitel yang menutupi permukaan dan garis nasofaring. Kejadian tahunan NPC di Inggris adalah 0,3 per juta pada usia 0-14 tahun, dan 1 sampai 2 per juta pada usia 15-19 tahun. Insidensi lebih tinggi pada populasi Cina dan Tunisia. Meskipun jarang, NPC menyumbang sekitar sepertiga dari masa kanak-kanak neoplasma nasofaring. Tiga subtipe NPC diakui di Organisasi Kesehatan Dunia (WHO) klasifikasi: 1) karsinoma sel skuamosa, biasanya ditemukan pada populasi orang dewasa yang lebih tua; 2) non-keratinizing karsinoma; 3) karsinoma dibeda-bedakan. Tumor dapat memperpanjang dalam atau keluar dari nasofaring ke dinding lateral lain dan / atau posterosuperiorly ke dasar tengkorak atau langit-langit mulut, rongga hidung atau orofaring. Ini kemudian biasanya metastasis ke kelenjar getah bening leher. Limfadenopati serviks merupakan presentasi awal pada banyak pasien, dan diagnosis NPC sering dibuat oleh biopsi kelenjar getah bening. Gejala terkait dengan tumor primer meliputi trismus, nyeri, otitis media, regurgitasi hidung karena paresis dari langit-langit lunak, kehilangan pendengaran dan kelumpuhan saraf kranial. Pertumbuhan yang lebih besar dapat menghasilkan obstruksi hidung atau perdarahan dan "aksen hidung". Faktor etiologi termasuk virus Epstein-Barr (EBV), kerentanan genetik dan konsumsi makanan dengan kemungkinan karsinogen - nitrosamine volatile. Jadwal pengobatan yang dianjurkan terdiri dari tiga program dari neoadjuvant kemoterapi, radiasi, dan adjuvan interferon (IFN)-beta terapi. Definisi Karsinoma nasofaring (NPC) adalah tumor yang timbul dari sel-sel epitel yang menutupi permukaan dan garis nasofaring. NPC pertama kali dijelaskan sebagai entitas yang terpisah oleh Regaud dan Schmincke pada tahun 1921 [1,2]. Sekitar sepertiga dari karsinoma nasofaring tipe dibedakan didiagnosis pada remaja atau dewasa muda. Meskipun jarang, NPC account untuk satu sepertiga dari neoplasma anak nasofaring (data dari AS) [3]. Epidemiologi Kejadian tahunan NPC di Inggris adalah 0,25 per juta (umur standar, usia 0-14 tahun), 0,1 per juta pada usia 0-9 tahun dan 0,8 per juta pada usia 10-14 tahun. Tampaknya masuk akal untuk berasumsi, berdasarkan Inggris dan kanker Wales data registri, bahwa setidaknya 80% dari kanker nasofaring pada usia 15-19 tahun adalah karsinoma. Hal ini menunjukkan kejadian 1 sampai 2 per juta untuk NPC pada usia 15-19 tahun. Dibandingkan dengan negara lain, kejadian di Inggris rendah. Secara khusus, di Tunisia insiden ini relatif tinggi [4]. Di bagian selatan China, Asia Tenggara, cekungan Mediterania dan Alaska kejadian NPC adalah cukup tinggi, sebuah kejadian 2 per juta NPC di Cina telah dilaporkan [5].

Di negara-negara lain, misalnya di India, insiden sebanding dengan yang di Inggris pada 0,9 per juta. Selanjutnya, puncak usia muda pada dekade kedua ditemukan di India [6], juga ditemukan di Inggris [7]. Etiologi NPC merupakan kanker epitel yang paling umum pada orang dewasa. Deteksi antigen nuklir dikaitkan dengan virus Epstein-Barr (EBNA) dan DNA virus tipe 2 dan 3 NPC, telah mengungkapkan bahwa EBV dapat menginfeksi sel epitel dan berhubungan dengan transformasi mereka [8]. Etiologi NPC (terutama bentuk endemik) tampaknya mengikuti proses multilangkah, di mana EBV, latar belakang etnis, dan lingkungan karsinogen semua tampaknya memainkan peran penting. Lo dkk. menunjukkan bahwa DNA EBV terdeteksi pada sampel plasma 96% dari pasien dengan non-keratinizing NPC, dibandingkan dengan hanya 7% dalam kontrol [9]. Lebih penting lagi, EBV tingkat DNA tampaknya berkorelasi dengan respon pengobatan [9-11] dan mereka dapat memprediksi kekambuhan penyakit [11], menunjukkan bahwa mereka dapat menjadi indikator independen prognosis [12]. Pada orang dewasa, faktor lainnya kemungkinan etiologi termasuk kerentanan genetik, konsumsi makanan (dalam ikan asin khususnya) yang mengandung nitrosamin mudah menguap karsinogenik, dan seperti anak-anak, EBV [13,15-19]. Presentasi Klinis NPC biasanya berasal di dinding lateral nasofaring, yang meliputi fosa dari Rosenmuller. Hal ini kemudian dapat memperpanjang dalam atau keluar dari nasofaring ke dinding lateral lain dan / atau posterosuperiorly ke dasar tengkorak atau langit-langit mulut, rongga hidung atau orofaring. Ini kemudian biasanya metastasis ke kelenjar getah bening leher. Metastasis jauh dapat terjadi di tulang, mediastinum paru-paru, dan, lebih jarang, hati. Limfadenopati serviks merupakan presentasi awal pada banyak pasien, dan diagnosis NPC sering dibuat oleh biopsi kelenjar getah bening. Gejala terkait dengan tumor primer meliputi trismus, nyeri, otitis media, regurgitasi hidung karena paresis dari langit-langit lunak, kehilangan pendengaran dan kelumpuhan saraf kranial. Pertumbuhan yang lebih besar dapat menghasilkan obstruksi hidung atau perdarahan dan "aksen hidung". Penyebaran metastasis dapat menyebabkan sakit tulang atau disfungsi organ. Jarang, suatu sindrom paraneoplastic dari osteoarthropathy dapat terjadi dengan penyakit luas. Histopatologi Tiga subtipe NPC diakui di Organisasi Kesehatan Dunia (WHO) klasifikasi [20]: Tipe 1: karsinoma sel skuamosa, biasanya ditemukan pada populasi orang dewasa yang lebih tua tipe 2: non-keratinizing karsinoma tipe 3: karsinoma dibedakan Sebagian besar kasus di masa kecil dan masa remaja adalah tipe 3, dengan beberapa jenis 2 kasus [21]. Tipe 2 dan 3 terkait dengan peningkatan titer Epstein-Barr virus, tapi tipe 1 tidak [22]. Modifikasi Cologne dari skema WHO oleh Krueger dan Wustrow [23] termasuk tingkat infiltrasi limfoid. Jenis 2 dan 3 bisa disertai dengan peradangan menyusup limfosit, sel plasma, dan eosinofil, yang berlimpah, sehingga menimbulkan lymphoepithelioma panjang. Dua pola histologis dapat terjadi: jenis Regaud, dengan koleksi yang didefinisikan dengan baik sel epitel dikelilingi oleh limfosit dan jaringan ikat, dan jenis Schmincke, di mana sel-sel tumor

didistribusikan difus dan berbaur dengan sel-sel inflamasi. Kedua pola dapat hadir dalam tumor yang sama. Diagnostik metode Metode diagnostik mencakup: 1. Klinis evaluasi dari ukuran dan lokasi kelenjar getah bening leher. 2. Nasopharyngoscopy tidak langsung untuk menilai tumor primer. 3. Neurologis pemeriksaan saraf kranial. 4. Computed tomography (CT) / magnetic resonance imaging (MRI) scan kepala dan leher ke bawah klavikula untuk menilai dasar erosi tengkorak. 5. Dada radioterapi (anteroposterior dan lateral) untuk melihat apakah NPC telah menyebar ke paru-paru. 6. Skintigrafi tulang oleh Tc 99 diphosphonate untuk menunjukkan apakah kanker telah menyebar ke tulang. 7. Kendali hitung darah. 8. Urea, elektrolit, kreatinin, fungsi hati, Ca, PO4, fosfat alkali. 9. EBV antigen kapsid virus EBV dan DNA. 10. Biopsi baik kelenjar getah bening atau tumor primer untuk pemeriksaan histologis. Pementasan Tumor, node, metastasis (TNM) klasifikasi dari American Komite Bersama Kanker [24] - edisi keenam (Tabel 1) biasanya digunakan untuk menentukan staging tumor (Tabel 2). Klasifikasi TNM terbaru memperhitungkan Ho [25] modifikasi untuk NPC, yang memanfaatkan pentingnya prognostik node terkena memperluas ke daerah leher rahim dan supraklavikula rendah. Tabel 1. Tumor, node, metastasis (TNM) klasifikasi dari American Komite Bersama Kanker [24] Tabel 2. Tahap pengelompokkan Pengobatan Operasi Karena posisi anatomi NPC dan kecenderungan untuk hadir dengan metastasis kelenjar getah bening leher rahim, tidak setuju untuk operasi untuk kontrol lokal. Biopsi kelenjar getah bening yang terlibat adalah prosedur pembedahan biasa. Tumor primer nasofaring jarang dibiopsi. Kemoterapi Beberapa faktor yang diperhitungkan dalam menentukan rejimen kemoterapi. Pertama, keberhasilan: angka-angka untuk kelangsungan hidup acara bebas sama untuk seri kemoterapi yang paling kecil tapi terapi biasanya melibatkan cukup tinggi dosis radioterapi nasofaring - 60 sampai 65 Gy. Namun, hasil yang paling menjanjikan dengan update terbaru, adalah mereka diperoleh dengan menggunakan protokol Mertens NPC-91-GPOH (Masyarakat Pediatric Onkologi dan Hematologi). Protokol ini seharusnya dianggap sebagai pengobatan terbaik saat ini. Uniknya, NPC-91-GPOH protokol termasuk imunoterapi dengan interferon-beta setelah kemoterapi dan radioterapi, yang dapat menjelaskan hasil yang lebih unggul dibandingkan dengan rejimen tanpa pengobatan interferon [27]. Kedua, efek akhir: dalam hal kemoterapi, rejimen Manchester - doxorubicin, methotrexate dan cyclophosphamide - akan menghasilkan kemandulan pada laki-laki (total dosis siklofosfamid 12 gm/m2) dan toksisitas anthracycline mungkin (total dosis doxorubicin 360 mg/m2) [ 36]. NPC91-GPOH protokol mungkin menghasilkan beberapa infertilitas pada laki-laki yang lebih tua

tetapi dosis total cisplatinum hanya 300 mg/m2. Selanjutnya, kejadian toksisitas ginjal harus relatif rendah tetapi toksisitas pendengaran akan lebih tinggi karena efek tambahan iradiasi pada aparatus pendengaran. Tingkat disfungsi hipofisis jelas tergantung pada bidang radioterapi dan, berpotensi, pada dosis radioterapi tetapi beberapa derajat hipopituitarisme diharapkan. Selanjutnya, iradiasi untuk leher akan mengakibatkan hipotiroidisme bagi mayoritas pasien dan iradiasi untuk orofaring akan menghasilkan xerostomia dan gigi yang buruk dihasilkan. Kemudian dapat dihilangkan dengan amifostine, seperti yang ditunjukkan dalam penelitian orang dewasa. Radioterapi Walaupun pengobatan dengan radioterapi mengendalikan tumor primer [28-30], tidak mencegah munculnya metastasis jauh [28,31]. Radioterapi diberikan dengan peralatan megavoltage setelah kemoterapi awal. Dosis maksimum 45 Gy diberikan kepada target volume klinis, yang merupakan 1 cm marjin sekitar lokasi MRIterdeteksi utama, dan inferior ke klavikula untuk memasukkan kelenjar getah bening. Pengobatan diberikan dalam dua tahap: Tahap I - sepasang paralel (lateral yang sebagian besar kecuali tumor meluas anterior antara mata). Mata, otak dan batang otak yang terlindung sebanyak mungkin. Dosis pertengahan bidang 30 Gy dalam 15 fraksi diberikan. Tahap II - sepasang paralel lateral atau tiga bidang teknik yang digunakan untuk situs utama, memberikan 15 Gy dalam tujuh fraksi untuk target volume klinis tumor dengan margin 1 cm. Batang otak dan mata harus dilindungi. Setiap tumpang tindih dengan bidang leher harus terlindung. Bidang leher anterior pencocokan simpul digunakan untuk memberikan maksimum dosis subkutan diresepkan dari 15 Gy dalam tujuh pecahan. Sumsum tulang belakang harus terlindung dalam bidang ini. Ini resep untuk radioterapi digunakan di Manchester, tetapi diakui bahwa dosis tinggi dapat digunakan di beberapa pusat, mungkin untuk total 60 Gy dengan volume tumor. Dalam sebuah studi GPOH saat ini, pasien di remisi lengkap (CR) setelah tiga program kemoterapi, radioterapi dosis akan memiliki mereka dikurangi sampai 54 Gy, bukan dari 59 Gy. Rekomendasi Dalam protokol GPOH saat NPC-2003-GPOH, pasien berisiko rendah dengan Tahap I dan II tumor hanya menerima radioterapi, diikuti oleh 105 mg / Kg ajuvan interferon beta (IFNbeta), intravena (iv), tiga kali seminggu selama 6 bulan. Pasien berisiko tinggi menerima cisplatinum (100 mg/m2 lebih dari 6 jam pada hari 1 dengan hidrasi standar), manitol dan penggantian elektrolit, dan asam folinic (25 mg/m2 setiap 6 jam untuk total enam dosis) serta 5 - fluorouracil (1000 mg/m2 per hari dari hari 2 selama 5 hari) sebagai infus kontinyu. Mereka menerima tiga program kemoterapi setiap 21 hari atau pada pemulihan hitung darah lengkap, diikuti oleh iradiasi dan IFNbeta seperti untuk pasien berisiko rendah. Metotreksat telah menurun karena mucositis parah. Pasien tidak di CR setelah tiga program kemoterapi akan menerima cisplatinum bersamaan (20 mg/m2/day selama 3 hari dengan radioterapi untuk dua program). Faktor prognostik Presentasi dengan lymphadenomegalia menyiratkan bahwa penyakit telah menyebar di luar situs utama. Namun, di masa kecil adanya penyakit metastasis pada kelenjar getah bening leher rahim pada diagnosis tidak mempengaruhi prognosis [30-33]. Faktor yang terkait dengan prognosis yang miskin tengkorak keterlibatan dasar [33-35], luasnya tumor primer [31,32] dan keterlibatan saraf kranial [33,34]. Terselesaikan pertanyaan

1. Berapa dosis optimal radioterapi? 2. Apakah pengecualian dari pengobatan interferon menghasilkan hasil yang sama? 3. Hubungan antara efek akhir dan dosis radioterapi harus diselidiki, serta sifat yang tepat dan kejadian efek akhir.