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Nasopharyngeal carcinoma (NPC)

Nasopharyngeal carcinoma (NPC)Identitas PasienNama: Ibu THUmur: 48 tahunPekerjaan: -Pendidikan: -Tanggal Periksa: Poli THT RSUDSH Purworejo, 5 Desember 2013

AnamnesisKeluhan Utama:Pasien kontrol ke Poli RSUDSH tanggal 5 desember 2013 karena post biopsy 2 minggu sebelum periksa.Saat ini terdapat benjolan pada leher sebelah kanan ukuran 4x3x3 cm pada leher, keras, tidak mobile.Riwayat Penyakit SekarangPasien dilakukan biopsy 2 minggu sebelum periksaSaat ini hanya terdapat keluhan benjolan pada leher. Sesak (-), dysphagia (-). Sebelum biopsi OS merasakan sering pilek, cairan jernih, terkadang berdarah, terutama pada hidung kanan. Bersin (-), nasolalia (+), rhinalgia (-), foetor (+), hyposmia (+) Os juga terkadang merasakan berdenging pada telinga. Otorrhea (-/-), deafness (-/-), otalgia (-/-), itching (-/-)

Tidak ada keluhan penurunan berat badan, pengelihatan ganda, nyeri kepala, sulit menelan, kelumpuhan bahu, sulit bicara, serak, sesak, batuk darah. RPD: Riwayat penyakit serupa (-), riwayat pengobatan (+: obat warung), RPK: Riwayat keganasan keluarga (-), keluhan serupa (-)Riwayat Alergi: (-)Pemeriksaan FisikKeadaan Umum: Compos MentisVital Sign:Tensi: 100/70RR: 20x/mNadi: 74x/mSuhu: 36.7 CKepala: Conjunctiva anemis (-/-), Ikterik (-/-)Leher: Terdapat benjolan 4x3x3 cm pada Lnn Coli Dextra, keras, tidak mobile, batas tidak tegasParu: Tidak dilakukanJantung: Tidak dilakukanAnggota gerak: Tidak dilakukan

NoPemeriksaan TelingaTelinga KananTelinga Kiri1TragusNyeri Tekan (-), Edema (-)Nyeri Tekan (-), Edema (-)2Daun TelingaBentuk dan ukuran dbn, hematoma (-), nyeri tarik (-)Bentuk dan ukuran dbn, hematoma (-), nyeri tarik (-)3Liang TelingaSerumen (-), Hiperemis (-), furunkel (-), Edema (-), otorrhea (-)Serumen (-), Hiperemis (-), furunkel (-), Edema (-), otorrhea (-)4Membran TimpaniRetraksi (-), Bulging (-), hiperemis (-), edema (-), perforasi (-), cone of light (+)Retraksi (-), Bulging (-), hiperemis (-), edema (-), perforasi (-), cone of light (+)No.PemeriksaanTelingaTelingakananTelingakiri1.TragusNyeritekan(-),edema(-)Nyeritekan(-),edema(-)2.DauntelingaBentukdanukurandalambatasnormal, hematoma (-), nyeritarik aurikula (-)Bentuk dan ukuran dalam batasnormal, hematoma (-), nyeritarik aurikula (-)3.LiangtelingaSerumen(-),hiperemis(-),furunkel (-), edema (-), otorhea(-)Serumen (-), hiperemis (-),furunkel (-), edema (-), otorhea(-) Pemeriksaan hidungPemeriksaan hidungHidung KananHidung KiriHidung LuarBentuk normal, hiperemis (-). Nyeri tekan (-), deformitas (-)Bentuk normal, hiperemis (-). Nyeri tekan (-), deformitas (-)Rhinoskopi anteriorVestibulum nasiNormal, ulkus (-)Normal, ulkus (-)Cavum nasiBentuk normal, mukosa pucat (-), hiperemis (-)Bentuk normal, mukosa pucat (-), hiperemis (-)Meatus nasi mediaMukosa hiperemis, sekret (+), bening, massa (-)Mukosa hiperemis, sekret (+), bening, massa (-)Konka nasi inferiorEdema (-), mukosa hiperemis (-)Edema (-), mukosa hiperemis (-)Septum nasiDeviasi (-), perdarahan (-), ulkus (-)Deviasi (-), perdarahan (-), ulkus (-)

Pemeriksaan TenggorokanBibirMukosa bibir basah, pucatMulutMukosa mulut basah berwarna merah mudaLidahPermukaan lidah pink, saat dijulurkan simetrisGigiKaries (+), tambalan (-)UvulaSimetrisPalatum MoleSimetris, massa (-), bercak putih (-)FaringHiperemis (-)Tonsila PalatinaHipertrofi (-)NasopharynxDinding BelakangChoanaeMuara Tuba eustachiiTidak diperiksaAdenoidTumor

LaryngopharynxDinding BelakangParapharynxTidak diperiksaLarynxEpiglotisAritenoidPlica VocalisGerakan Plica vocalis Tidak diperiksaTumorSubglotisTracheaPemeriksaan PenunjangPemeriksaan Pathology AnatomyMakroskopik: Kiri: Jaringan pecah belah sebanyak 0.5 cc berwarna coklat kehitaman, semua cetak (A)Kanan: Jaringan pecah belah sebanyak 0.5 cc berwarna coklat kehitaman, semua cetak (B)MikroskopikA dan B kedua sediaan menunjukkan jaringan nasofaring dengan diantara haringan limfoid ditemukan sarang kecil karsinoma sel skuamosa tanpa keratinisasiKesimpulanNasofaring: Non Keratinizing Carcinoma (WHO tipe II)

DiagnosisNon Keratinizing Carcinoma of NasopharynxPlanRujuk RSUP dr Sardjito

Anatomy Anatomy

16The nasopharynx is a roughly cuboidal space, opening into the nasal cavity through the posterior choane anteriorly, and the oropharynx, inferiorly. The lateral and the posterior wall are bounded by the pharyngobasilar fascia, descending from the base of the skull. The roof contains abundant lymphomatous tissue special in children and the aggregate of lymphomatous tissue forms the pharyngeal tonsil in this age group. The Eustachian tube opens into the lateral wall of the nasopharynx, and the posterior cartilaginous edge of the same makes the bulge, which is known as the torus tubaris. Just posterior to this torus lies the fossa of Rosenmuller which is considered as the most common site for origin of nasopharyngeal carcinomas. This is the place where the nasopharynx is at its widest.Anatomy

Foramen lacerum

Foramen spinosumForamen ovaleForamen rotundum17This diagram shows the base of the skull from below, and the close relationship of the foramen lacerum to the nasopharynx is immediately apparent. Since the foramen lacerum opens directly into the middle cranial fossa, It forms an important route by which nasopharyngeal cancers can spread into this area. In addition to this important foramen, other foramina in close relationship, include the foramen rotundum, which transmits the maxillary division of the trigeminal nerve, foramen ovale which transmits the mandible division of the trigeminal nerve, foramen spinosum, which transmits the middle meningeal vessels and the recurrent branch of the mandibular nerve. In addition to this the hypoglossal canal and jugular foramen are in close relationship posteriorly and serve as potential pathways of spread to the cranial nerves, particularly 9th, 10th, 11th and 12th .CT anatomy

18Anasopharyngeal carcinoma (NPC)isthe most commonprimary malignancy of the nasopharynx. It is of squamous cell origin andsome types of which are strongly associated withEpstein Barr virus (EBV).EpidemiologyNasopharyngeal carcinomas account for approximately 70% of all primary malignancies of the nasopharynx.Although it is rare in western populations, it is one of the most common malignancies encountered in Asia, especially China.Department of Radiotherapy, PGIMER, ChandigarhIncidence

Incidence: Sex

EtiologyNormal EpitheliumLow Grade DysplasiaHigh Grade DysplasiaInvasive CarcinomaMetastatic CarcinomaP53 MutationGain Chromosome 12Deletion 11 and 13Deletion of Chromosomes 3p and 9pInactivation of Chromosome p14, 15 and 16EBV infection23Inactivation of the tumor suppressor genes namely the Chromosomes 14, 15 and 16 are considered central steps in the pathogenesis of high grade dysplasia.RiskEnvironmentalVirusesEBV- well documented viral fingerprints in tumor cells and also anti-EBV serologies with WHO type II and III NPCHPV - possible factor in WHO type I lesionsNitrosamines - salted fishOthers - polycyclic hydrocarbons, chronic nasal infection, poor hygiene, poor ventilation

Clinical ManifestationClinical presentation, and often only when the tumor has grown significantly in size and has invaded adjacent structures.Actual presentation is often delayed until more sinister signs are evident including nodal masses in the neck (most common), cranial nerve palsies, tinnitus, headache or even diplopia and proptosis.Cervical adenopathy 60%Epistaxis & Nasorespiratory symptomsAudiological symptoms 30%Neurological symptoms 20%Cervical adenopathyNPC has a tendency for early lymphatic spread.Retropharyngeal node of Rouviere is the first echelon node.Commonest first palpable node is the J.D. node and the apical node under sternomastoid muscle.27Contralateral node involvement is also common. The parotid gland and lymph nodes can be involved if the parapharyngeal space is breached.Epistaxis & Nasal symptomsCommonly seen in advanced NPCs.Complete nasal obstruction is a late presentation.Ozaena occurs as a result of tumour necrosis.

28If complete nasal obstruction occur at an early stage of the disease, it is often due to superimposed infection.Tinnitus & Aural symptomsSerous otitis media is commonAcute otitis media Aural blockTinnitus29Adult Chinese patients with unresolving serous otitis media have to be presumed to have NPC until proven otherwise.Nerve palsiesAll cranial nerves can be affectedFrequently involved are iv, v, vi, ix, & x.Nerves ix & x are invariably involved together.Nerves of the ocular muscles are the next commonly affected.Pain & HeadacheThis is an ominous symptomSevere pain is hallmark of terminal disease.Signifies tumour erosion into skull base.If accompanied by trismus,the disease is very advanced and has extended into pterygopalatine fossa.31Sepsis, particularly sphenoidal sinusitis produces intense headache. Atypical facial pain or unexplained headache in the absence of obvious clinical findings in the nasopharynx may be a presenting symptom of NPC.MetastasisTumors arising from fossa of Rosenmuller frequently extend to paranasopharyngeal space, then along trigeminal nerveOften metastasizes to regional nodes; common presentation is unilateral cervical lymphadenopathy; 25% have bilateral nodal metastasesMay have distant metastases to bonesAfter radiation therapy, risk of 0.4% of subsequent carcinoma in nasal cavity of nasopharynx; differentiate from recurrence based on > 5 year delay, different histology, EBV negativeLocal SpreadNasal cavity & PNSOrbital invasionBase of Skull, ClivusSphenoid sinusCavernous Sinus Lateral Parapharyngeal spaceMiddle ear cavityOropharynx (tonsillar pillars)C1 vertebraeNodal Spread

34Lymph nodes are involved at presentation in 89%. There is unilateral involvement in 39% and bilateral involvement in 51%. Low-grade squamous cell carcinomas produce fewer metastases (73%) than high-grade carcinomas (92%). Metastases to submental and occipital nodes may appear when there is blockage of the common lymphatic pathways either by massive neck disease or by an untimely neck dissection. Cranial Nerve involvement

35The exact incidence of cranial nerve involvement varies from series to series being higher in Asian series and those using CT scans. 12% patients have clinically detected cranial nerve palsy while 29% have radiologically detected cranial nerve involvement.DiagnosisDiagnosis is usually achieved with endoscopic guided biopsy. A minority of patients have submucosal disease, with normal appearing overlying mucosa. MRI is then essential in guiding biopsy.blind biopsies, particularly in fossa of Rosenmuller, can also be done(70% sensitive)

Nasopharyngeal biopsyMethods:Transnasal a. Blind b. Post. Mirror rhinoscopy c. Endoscopy rigid and flexibleTransoral a. Yankauer speculum b. Rigid endoscopy37The forceps used to take biopsy is known as Hildyard biopsy forceps.Laboratory:IgG against early EBV antigen is suggestive, but has 30% false positives; IgA against viral capsid antigen has 9-18% false positives

ImmunologyEB virus antigens a. Viral capsid antigen (VCA) b. Early antigen (EA) c. Nuclear antigen 39Of the many types of NPC only the undifferentiated / poorly differentiated forms consistently express E.B. virus nuclear antigen.Serological markersIgA and IgG to viral capsid antigenIgA and IgG to early antigenAntibody to nuclear antigenAntibody dependent cellular cytotoxic antibodies.40Estimation of these markers help in determining the stage of the disease, effect of treatment, clinical course and survival.Radiographic featuresImaging is crucial in delineating the extent of local tumor extension, as well as detecting nodal metastases which are present in the vast majority of patients at the time of diagnosis (75-90%). Unfortunately imaging in isolation is not only unable to distinguish between the various types of nasopharyngeal carcinoma, but also unable to distinguish NPCs from otherprimary malignancies of the nasopharynx.CT Findings

Mildly enhancing off-midline nasopharyngeal massMetastatic nodes often large, necrosisRetropharyngeal nodes often subtle on imaging as appears isodense to muscleBone CT: May show destruction of clival cortex or pterygoid plates

MR FindingsT1WIAsymmetric mass, hypo- to isointense to muscleSensitive for infiltration of parapharyngeal fatMarrow involvement results in low T1 signalT2WIModerate hyperintensity of NPC compared to muscleObstructed middle ear secretions markedly hyperintenseT1WI C+ FSBest illustrates infiltration of deep face, intracranial, and cavernous sinus diseaseCoronal images aid in this evaluationMild homogeneous tumor enhancement

(Left) Axial T7WI MR shows isointense right lateral pharyngeal recess NPCa (arrow). Note low signal in pterygoid plates (open arrow) & right clivus (curved arrow) due to bony tumor invasion.

(Right) Axial T2WI MR reveals low signal intensity mass in lateral pharyngeal recess, invading prevertebral muscles (arrow), right pterygoid plates & parapharyngeal space (open arrow). CurVE'd arrow: RPS node.

(Left) Axial T7 C+ MR shows a large, invasive right NPCa. Tumor has invaded prevertebral muscles (arrow), nasopharyngeal carotid space (open arrow) and parapharyngeal space (curved arrow).

(Right) Coronal T7 C+ MR in same patient reveals NPCa has destroyed large area of skull base bone (arrows) surrounding the foramen ovale. Opposite normal foramen ovale has V3 traversing it (open arrow).

(Left) Axial T2WI MR demonstrates a small, minimally invasive NPCa (arrow). Despite its small size, nodal metastatic tumor is already visible in the contralateral lateral retropharyngeal node (open arrow).

(Right) Coronal T7 C+ MR in a patient with NPCa reveals bulky bilateral cervical adenopathy(arrows). Notice that a smaller, right lateral retropharyngeal node can also be seen near skull base (open arrow).Nuclear Medicine FindingsPET/CTMarkedly FDG-avid tumor, nodes, and metastasesIf small primary, can miss with thick slices due to brain FDG uptakeNeed thin collimation, review in coronal planeMR still necessary for skull base & intracranial disease

Imaging RecommendationsBest imaging toolMR is recommended by AJCC for stagingMost sensitive for skull base and intracranial tumor spreadMore sensitive than clinical exam/US/CT for detection of retropharyngeal nodesCECT is alternative choicePET/CT often obtained if N2/3 disease at staging or recurrent tumor

StagingSeveral staging systems are in use:Complex anatomy and spread patternsLack of international consensus:Separate Chinese, Hong Kong and American staging systemsSystems available:Fletcher (1967)Hos staging (1978)IUAC (1988)Huaqing staging (1994)AJCC (revised in 2010)AJCC Nasopharynx Staging (2010)Tumor Stage (T)Nodal Stage (N)T1: Confined to nasopharynx or extension to oropharynx or nasal cavityN1: 1 unilateral metastasis 6 cm &/or unilateral/bilateral retropharyngeal nodes 6 cmT2: Extension to parapharyngeal fatN2: Bilateral nodal metastases 6 cmT3: Clivus or paranasal sinus invasionN3a: Nodal metastases > 6 cmT4: Intracranial spread, cranial nerve, orbit, hypopharynx, masticator spaceN3b: Nodal metastasis to supraclavicular fossaDistant Metastasis (M)NOTE: This nodal staging is unique to NPCM0: No distant metastasis,M1: Distant metastasis

AJCCSome authors consider carcinomas to be of two types:Keratinizing Non keratinizingOthers consider carcinomas to be of 4 types:Keratinizing SquamousNon Keratinizing SquamousLymphoepitheliomaUndifferentiated carcinomas55The Lymphoepitheliomas subtype consists of undifferentiated cells forming syncitial mass is along with which large number of small lymphocytes are interspersed. Some authors believe that this histology confers a higher local control rate, as well as better prognosis than squamous cell carcinoma. Overall, it has been found that patients with undifferentiated histology have a higher proportion of advanced stage at presentation.PathologyNasopharyngeal carcinomas are divided into three types (WHO)type I- keratinizing squamous cell carcinomatype II- non-keratinizing squamous cell carcinoma (aka lymphoepithelioma)type III- undifferentiated carcinomaAll three types express cytokeratin, and types II and III have incorporation of the EBV into their genome, and circulating IgA antibodies to EBV in peripheral blood.

Keratinizing squamous cell carcinoma of nasopharynxAlso called WHO type 1Minority of nasopharyngeal carcinomasOften EBV negative, older age group5 year survival is close to 0%Treatment:dont respond to radiotherapy, but tend to remain localizedMicro:squamous differentiation with intercellular bridges or keratinization in most of tumor; rarely adenoid or acantholytic forms that mimic adenocarcinoma

Nonkeratinizing nasopharyngeal carcinoma-differentiatedAlso called WHO type 2Rare in childhood5 year survival 35-50%Treatment:variably radiosensitive, may metastasize to regional lymph nodesMicro:cells lack squamous differentiation but have variable levels of maturation; cells are stratified with well defined cell margins that interdigitate in a pavement stone pattern; no mucin or glandular differentiation; variable chronic inflammatory cellsPositive stains:CK5/CK6, CK8, CK13, CK14, CK19Negative stains:CK4, CK7Nonkeratinizing nasopharyngeal carcinoma-undifferentiatedAlso called WHO type 3Very rare in US, common in Taiwan and China (EBV endemic areas)Often called lymphoepithelioma, although lymphocytes are not neoplastic and some cases lack lymphocytesBimodal age distribution (teens, 50+); in Taiwan, median age is 58 years (range 36-75 years); 2/3 male5 year survival after radiation therapy alone is based on stage--confined to nasopharynx (stage I): 50-60%; cervical node involvement (stage II): 20-30%; invasion of surrounding structures (stage III): 5-30%Survival does not vary based on Regaud or Schminke patterns belowTends to metastasize to regional lymph nodesTreatment:supervoltage radiotherapy and cis-platinum based chemotherapy (70-90% 5 year survival overall)Micro:syncytial arrangement of relatively uniform cells with indistinct cell margins; cells have vesicular nuclei and prominent nucleoli; may have spindle cells and scattered effete (worn out) cells with shrunken, hyperchromatic nuclei that are more variable than sinonasal undifferentiated carcinoma; usually (but not always) non-neoplastic lymphocytic infiltrate (often T cells) with plasma cells, eosinophils and macrophages; patterns below may be mixed; no necrosis

Nasopharyngeal nonkeratinizing carcinoma, differentiated type. This carcinoma is characterized by the presence of interconnecting cords of neoplastic cells.B,at higher magnification the cellular infiltrate of the nasopharyngeal nonkeratinizing carcinoma, differentiated type shows the absence of keratinization

Most cases in childhood and adolescence are type 3, with a few type 2 cases. Type 2 and 3 are associated with elevated Epstein-Barr virus titers, but type 1 is not 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.Endemic NPCKnown to occur in China, Hong Kong, South Eastern Asia, GreenlandAssociated with EBV virus infectionPresent a decade younger.Associated with undifferentiated carcinoma ( WHO II and III)Associated with more advanced disease at presentationNodal stage also more advanced and more frequently involved.Both chemo and radio sensitiveHistologically more vascularized (Better Rx response)Greater % of cell in the growth fraction.Better loco regional control and survival than sporadic variants.Several markers for predicting biological behavior

64The biological markers include IgA , IgE , anti-VCA often are predictors of relapse. Similiarly high ADCC levels are correlated with a better prognsis.D/DAdenoidal Benign Lymphoid HyperplasiaChildren and teens typically have large adenoidsReactive hypertrophy seen in HIV patientsSymmetric enlargement without infiltration of adjacent tissuesNasopharyngeal Non-Hodgkin LymphomaMidline symmetric mass, deep infiltration to prevertebral musclesIn clivus, tends to expand rather than infiltrate

Nasopharyngeal Minor Salivary Gland MalignancyUncommon primary tumorMay be small primary with extensive infiltrationAssociated nodal metastases uncommonPituitary MacroadenomaLarge sella mass extending through sphenoid to nasopharynxExpansion of sella is key imaging findingPharyngeal Mucosal Space SarcomaRare; more common differential in childrenSubmucosal, aggressive mass

TreatmentTreatment for stage I NPCPatients with stage I disease should be treated with RT alone.IMRT alone is effective at treating over 90% of patients with stage I NPCTreatment for stage II NPCthe outcomes in patients with stage II disease have been reported to be less favorableThe Society of Clinical Oncology terminology, the European Head and Neck SocietyEuropean Society for Medical OncologyEuropean Society for Radiotherapy and Oncology Clinical Practice Guidelines also considered CCRT for stage II NPC as level I evidence with a grade B recommendationTreatment for stages IIIIVb NPCRole of exclusive concurrent chemoradiotherapyThe current standard of care for locoregionally advanced (AJCC stages IIIIVb) NPC is cisplatin-based CCRT31% improvement in 3-year OS compared to RT alone using concurrent RT and high-dose cisplatin followed by adjuvant cisplatin and fluorouracilthey were accompanied by severe toxicity, including mucositis and bone marrow suppression.the dose of cisplatin during the concurrent phase of CCRT had a significant impact on locoregional control, while additional adjuvant chemotherapy with a fluorouracil-containing combination contributed to improved distant controlNo other regimens have been reported to be as effective as cisplatin and fluorouracil for treating NPC in an adjuvant settingThe NCCN guidelines currently include induction + CCRT as an option (category 3). Adjuvant chemotherapy is poorly tolerated, and compliance is limited because patients suffer substantial toxicities from CCRTCompared with adjuvant chemotherapy, induction chemotherapy appears to be better tolerated, even with more aggressive regimens.Treatment for stage IVc NPCPatients who present with distant metastasis (stage IVc disease) might account for approximately 10% of all NPC cases in the endemic area of NPCin a study of 125 patients with stage IVc NPC, Yeh et alfound improved 1-year OS in patients receiving RT alone versus chemotherapy alone or versus no treatment (48% vs 36% vs 25%, respectively), despite using conventional RTIn light of the poor prognosis in stage IVc NPC, treatment has conventionally been palliative in nature.It is reasonable to assume that a combination of chemotherapy and RT might have potential survival benefits for selected patients with stage IVc NPCTreatment for reccurent NPCabout 10% of patients still develop recurrent disease either in the neck or at the primary siteThe options include brachytherapy,external RT,stereotactic radiosurgery,nasopharyngectomy,and microwave coagulation therapy,either alone or in different combinationsSalvage nasopharyngectomy carried out for 246 selected patients showed a 5-year local control of disease of 74% and the 5-year disease-free survival was 56%Endoscopic nasopharyngectomy is a choice for recurrent NPC with central roof or floor lesions with minimal lateral extension.Hua et al reported the long-term treatment outcome of 151 recurrent NPC patients treated with salvage IMRT. The 5-year local control rate and OS for restage I, II, III, and IV were 80.0%, 85.0%, 80.0%, 78.7% and 71.4%, 62.9%, 35.5%, 30.2%When the recurrent disease is only in the neck lymph nodes, salvage surgery is the optimal treatment method. Radical neck dissection is currently an accepted surgical management for recurrent nodal disease in patients with NPC, with well-proven efficacy and safetyNovel systemic therapyEpidermal growth-factor receptor (EGFR) and vascular endothelial growth-factor receptor (VEGFR) targeted therapies have been clinically studied in NPC patients.Cetuximab is a chimeric anti-EGFR immunoglobulin G1monoclonal antibody, the first EGFR inhibitor that is clinically tested to treat NPCA phase II study by Ma et al recently evaluated the feasibility of adding cetuximab to current cisplatin and IMRT in locoregionally advanced NPCSeveral phase I and II studies that have generated EBV-Specific Cytotoxic T Cells for posttransplant lymphoproliferative disorders have shown potential efficacies against NPCAutologous EBV-transformed B-lymphoblastoid cell line (LCL) reactivated T cells were generated in vitro and used to treat advanced cases of NPC.Smith et al recently reported the effectiveness of a phase I study involvingadenoviral-based EBV vaccine (referred to as AdE1-LMPpoly)-stimulated T-cell immunotherapy for EBV-associated recurrent and metastatic NPC.Irradiation with protons instead of the currently used photons generally results in a significantly lower physical dose in the coirradiated healthy tissues, due to its superior beam propertiesDose responseSignificant dose response relationship exists.Several series demonstrate that an increased-dose leads to better survivalDoses of 90 Gy delivered by boost increase the local control and the distant metastasis free rate significantly over doses > 70 GyPrice however paid in increased morbidityLocal recurrence rate reduced with the use of larger fields (Field size more than 250 cm2 associated with a doubling of local control as compared to field size of 100 cm2)Dose-response

Doses usedRadical radiotherapy:60 66 Gy in 2 Gy per fraction over 6 6 weeksHigher dose can be given with more conformal techniques:ICBTIMRT3 DCRTIn our patients with poor nutrition, advanced disease and absence of individualized care split course radiotherapy is an alternative35 Gy in 15 # 25 30 Gy in 10 15 # after 2-3 weeksPalliative radiotherapy:30 Gy / 10#20 Gy / 5#800 -1000 cGy single fractionTreatment Surgical managementMainly diagnostic - Biopsyconsider clinic bx if cooperative patientmust obtain large biopsyclinically normal NP - OR for panendo and bxSurgical treatmentprimary lesion regional failure with local controlETD Treatment Surgical managementPrimary lesion consider for residual or recurrent diseaseapproachesinfratemporal fossa transparotid temporal bone approachtransmaxillarytransmandibulartranspalatalPrognostic factorsMost important stage.Parapharyngeal extension is associated with a poorer prognosis.A Chinese series found that 4th cranial nerve involvement poor prognosis.Nodal disease status:Bilateral cervical lymphadenopathy Supraclavicular lymphadenopathy Lymph node fixityLymphoepithelioma histology: better prognosisUndifferentiated histology: better prognosisMolecular markers:Ki -67 over expressionP 53E cadherin expression

JCO 2006 Dec.1EBV and NPC prognosisKey factsTerminologyNasopharyngeal carcinoma (NPC)Mucosal tumor of lateral pharyngeal recess (fossa of Rosenmller), strongly associated with EBV infectionImagingMR best demonstrates parapharyngeal fat, skull base infiltration, & intracranial tumorNodal disease in 90% at presentation: Retropharyngeal, levels II & V most commonMetastatic nodes often large necrosis

Clinical IssuesPeak incidence: 40-60 yearsPediatric NPC rare; most often undifferentiated NKBloody nasal discharge or epistaxis50-70% present with mass from metastatic nodesNitrosamines - salted fishSerous otitis from eustachian tube obstructionNonkeratinizing NPC has 5-year survival ~ 75%Keratinizing NPC has 5-year survival 20-40%BSCC generally poor prognosis

Top Differential DiagnosesAdenoidal benign lymphoid hyperplasiaNasopharyngeal non-Hodgkin lymphomaNasopharyngeal minor salivary gland malignancyPituitary macroadenomaPathology25% keratinizing NPC(previously type I)Nonkeratinizing NPC(NK NPC)Strongly associated with EBV15% differentiated(previously type II)60% undifferentiated(previously type III)Rarely basaloid squamous cell carcinoma