Identitas Pasien
Nama: Ibu TH Umur: 48 tahun Pekerjaan: Pendidikan: Tanggal Periksa: Poli THT RSUDSH Purworejo, 5 Desember 2013
Anamnesis
Keluhan 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 Sekarang Pasien dilakukan biopsy 2 minggu sebelum periksa Saat 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 Fisik
Keadaan Umum: Compos Mentis Vital Sign: Tensi: 100/70 RR: 20x/m Nadi: 74x/m Suhu: 36.7 C Kepala: Conjunctiva anemis (-/-), Ikterik (-/-) Leher: Terdapat benjolan 4x3x3 cm pada Lnn Coli Dextra, keras, tidak mobile, batas tidak tegas Paru: Tidak dilakukan Jantung: Tidak dilakukan Anggota gerak: Tidak dilakukan
No Pemeriksaa Telinga Kanan n Telinga 1 Tragus Nyeri Tekan (-), Edema (-)
Daun Telinga
Liang Telinga
Serumen (-), Serumen (-), Hiperemis (-), Hiperemis (-), furunkel furunkel (-), Edema (-), otorrhea (-) (-), Edema (-), otorrhea (-)
Membran Timpani
Retraksi (-), Bulging (- Retraksi (-), Bulging (-), hiperemis ), hiperemis (-), (-), edema (-), perforasi (-), cone edema (-), perforasi (- of light (+) ), cone of light (+)
Pemeriksaan hidung
Pemeriksaan hidung Hidung Luar Hidung Kanan Bentuk normal, hiperemis (-). Nyeri tekan (-), deformitas (-) Normal, ulkus (-) Hidung Kiri Bentuk normal, hiperemis (-). Nyeri tekan (-), deformitas (-) Normal, ulkus (-)
Rhinoskopi anterior Vestibulum nasi Cavum nasi Meatus nasi media Bentuk normal, mukosa Bentuk normal, mukosa pucat (-), hiperemis (-) pucat (-), hiperemis (-) Mukosa hiperemis, sekret (+), bening, massa (-) Edema (-), mukosa hiperemis (-) Deviasi (-), perdarahan (-), ulkus (-) Mukosa hiperemis, sekret (+), bening, massa (-) Edema (-), mukosa hiperemis (-) Deviasi (-), perdarahan (-), ulkus (-)
Pemeriksaan Tenggorokan Bibir Mulut Mukosa bibir basah, pucat Mukosa mulut basah berwarna merah muda
Lidah
Gigi Uvula Palatum Mole Faring Tonsila Palatina
Nasopharynx
Dinding
Tidak diperiksa
Laryngopharynx
Dinding Belakang Parapharynx
Tidak diperiksa
Larynx
Epiglotis Aritenoid Plica Vocalis Gerakan Plica vocalis Tumor Subglotis Trachea
Tidak diperiksa
Pemeriksaan Penunjang
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)
Mikroskopik
A dan
B kedua sediaan menunjukkan jaringan nasofaring dengan diantara haringan limfoid ditemukan sarang kecil karsinoma sel skuamosa tanpa keratinisasi Non Keratinizing Carcinoma (WHO tipe II)
Kesimpulan
Nasofaring:
Diagnosis
Plan
Anatomy
Anatomy
Anatomy
CT anatomy
A nasopharyngeal carcinoma (NPC) is the most common primary malignancy of the nasopharynx. It is of squamous cell origin and some types of which are strongly associated with Epstein Barr virus (EBV).
Epidemiology
Nasopharyngeal 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.
Incidence
Incidence: Sex
Etiology
Normal Epithelium
Deletion of Chromosomes 3p and 9p
Deletion 11 and 13
Invasive Carcinoma
P53 Mutation
Metastatic Carcinoma
Risk
Environmental
Viruses
well documented viral fingerprints in tumor cells and also anti-EBV serologies with WHO type II and III NPC HPV - possible factor in WHO type I lesions
EBV-
Nitrosamines
- salted fish Others - polycyclic hydrocarbons, chronic nasal infection, poor hygiene, poor ventilation
Clinical Manifestation
Clinical 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 symptoms Audiological symptoms 30% Neurological symptoms 20%
Cervical adenopathy
NPC 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.
Commonly seen in advanced NPCs. Complete nasal obstruction is a late presentation. Ozaena occurs as a result of tumour necrosis.
Serous otitis media is common Acute otitis media Aural block Tinnitus
Nerve palsies
All cranial nerves can be affected Frequently involved are iv, v, vi, ix, & x. Nerves ix & x are invariably involved together. Nerves of the ocular muscles are the next commonly affected.
This is an ominous symptom Severe 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.
Metastasis
Tumors arising from fossa of Rosenmuller frequently extend to paranasopharyngeal space, then along trigeminal nerve Often metastasizes to regional nodes; common presentation is unilateral cervical lymphadenopathy; 25% have bilateral nodal metastases May have distant metastases to bones After 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 negative
Local Spread
Sphenoid sinus Cavernous Sinus
Lateral Parapharyngeal space Middle ear cavity Oropharynx (tonsillar pillars) C1 vertebrae
Nodal Spread
Diagnosis
Diagnosis 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 biopsy
Methods: 1. Transnasal a. Blind b. Post. Mirror rhinoscopy c. Endoscopy rigid and flexible 2. Transoral a. Yankauer speculum b. Rigid endoscopy
Laboratory: IgG against early EBV antigen is suggestive, but has 30% false positives; IgA against viral capsid antigen has 9-18% false positives
Immunology
EB virus antigens a. Viral capsid antigen (VCA) b. Early antigen (EA) c. Nuclear antigen
Serological markers
IgA and IgG to viral capsid antigen IgA and IgG to early antigen Antibody to nuclear antigen Antibody dependent cellular cytotoxic antibodies.
Radiographic features
Imaging 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 other primary malignancies of the nasopharynx.
CT Findings
Mildly
mass Metastatic nodes often large, necrosis Retropharyngeal nodes often subtle on imaging as appears isodense to muscle
MR Findings T1WI
Asymmetric mass, hypo- to isointense to muscle Sensitive for infiltration of parapharyngeal fat Marrow involvement results in low T1 signal Moderate hyperintensity of NPC compared to muscle Obstructed middle ear secretions markedly hyperintense Best illustrates infiltration of deep face, intracranial, and cavernous sinus disease
T2WI
T1WI C+ FS
(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
(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
(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
FDG-avid tumor, nodes, and metastases If small primary, can miss with thick slices due to brain FDG uptake
Need
MR
Most
sensitive for skull base and intracranial tumor spread More sensitive than clinical exam/US/CT for detection of retropharyngeal nodes CECT is alternative choice
PET/CT
Staging
systems
Systems available:
Fletcher
(1967) Hos staging (1978) IUAC (1988) Huaqing staging (1994) AJCC (revised in 2010)
T4: Intracranial spread, cranial N3b: Nodal metastasis to nerve, orbit, hypopharynx, masticator supraclavicular fossa space Distant Metastasis (M) M0: No distant metastasis, M1: Distant metastasis NOTE: This nodal staging is unique to NPC
AJCC
Pathology
I - keratinizing squamous cell carcinoma type II - non-keratinizing squamous cell carcinoma (aka lymphoepithelioma) type III - undifferentiated carcinoma
All 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 nasopharynx Also called WHO type 1 Minority of nasopharyngeal carcinomas Often EBV negative, older age group 5 year survival is close to 0% Treatment: dont respond to radiotherapy, but tend to remain localized Micro: squamous differentiation with intercellular bridges or keratinization in most of tumor; rarely adenoid or acantholytic forms that mimic adenocarcinoma
Nonkeratinizing nasopharyngeal carcinomadifferentiated Also called WHO type 2 Rare in childhood 5 year survival 35-50% Treatment: variably radiosensitive, may metastasize to regional lymph nodes Micro: 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 cells Positive stains: CK5/CK6, CK8, CK13, CK14, CK19 Negative stains: CK4, CK7
Nonkeratinizing nasopharyngeal carcinoma-undifferentiated Also called WHO type 3 Very rare in US, common in Taiwan and China (EBV endemic areas) Often called lymphoepithelioma, although lymphocytes are not neoplastic and some cases lack lymphocytes Bimodal age distribution (teens, 50+); in Taiwan, median age is 58 years (range 36-75 years); 2/3 male 5 year survival after radiation therapy alone is based on stage--confined to nasopharynx (stage I): 50-60%; cervical node involvement (stage II): 2030%; invasion of surrounding structures (stage III): 5-30% Survival does not vary based on Regaud or Schminke patterns below Tends to metastasize to regional lymph nodes Treatment: 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
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 NPC
Known to occur in China, Hong Kong, South Eastern Asia, Greenland Associated with EBV virus infection Present a decade younger. Associated with undifferentiated carcinoma ( WHO II and III) Associated with more advanced disease at presentation Nodal stage also more advanced and more frequently involved. Both chemo and radio sensitive
Histologically 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
D/D
and teens typically have large adenoids Reactive hypertrophy seen in HIV patients Symmetric enlargement without infiltration of adjacent tissues
Pituitary Macroadenoma
Large sella mass extending through sphenoid to nasopharynx Expansion of sella is key imaging finding
Treatment
Treatment for stage I NPC Patients with stage I disease should be treated with RT alone. IMRT alone is effective at treating over 90% of patients with stage I NPC
Treatment for stage II NPC the outcomes in patients with stage II disease have been reported to be less favorable The Society of Clinical Oncology terminology, the European Head and Neck Society European Society for Medical Oncology European Society for Radiotherapy and Oncology Clinical Practice Guidelines also considered CCRT for stage II NPC as level I evidence with a grade B recommendation
Treatment for stages IIIIVb NPC Role of exclusive concurrent chemoradiotherapy The current standard of care for locoregionally advanced (AJCC stages IIIIVb) NPC is cisplatin-based CCRT 31% improvement in 3-year OS compared to RT alone using concurrent RT and high-dose cisplatin followed by adjuvant cisplatin and fluorouracil they were accompanied by severe toxicity,
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 control No other regimens have been reported to be as effective as cisplatin and fluorouracil for treating NPC in an adjuvant setting
The 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 CCRT Compared with adjuvant chemotherapy, induction chemotherapy appears to be better tolerated, even with more aggressive regimens.
Treatment for stage IVc NPC Patients who present with distant metastasis (stage IVc disease) might account for approximately 10% of all NPC cases in the endemic area of NPC in a study of 125 patients with stage IVc NPC, Yeh et al found 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 RT
In 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 NPC
about 10% of patients still develop recurrent disease either in the neck or at the primary site The options include brachytherapy, external RT, stereotactic radiosurgery, nasopharyngectomy, and microwave coagulation therapy, either alone or in different combinations Salvage 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 safety
Epidermal 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 G1 monoclonal antibody, the first EGFR inhibitor that is clinically tested to treat NPC A phase II study by Ma et al recently evaluated the feasibility of adding cetuximab to current cisplatin and IMRT in locoregionally advanced NPC
Several phase I and II studies that have generated EBV-Specific Cytotoxic T Cells for posttransplant lymphoproliferative disorders have shown potential efficacies against NPC Autologous 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 properties
Dose response
Significant dose response relationship exists. Several series demonstrate that an increaseddose leads to better survival
Doses
of 90 Gy delivered by boost increase the local control and the distant metastasis free rate significantly over doses > 70 Gy Price however paid in increased morbidity
Local 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
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 50 - 60 Gy 60 - 67.5 Gy > 67.5 Gy T1 T2 T3 T4
Doses used
Radical radiotherapy:
60 66 Gy in 2 Gy per fraction over 6 6 weeks Higher dose can be given with more conformal techniques: ICBT IMRT 3 DCRT In our patients with poor nutrition, advanced disease and absence of individualized care split course radiotherapy is an alternative 35 Gy in 15 # 25 30 Gy in 10 15 # after 2-3 weeks 30 Gy / 10# 20 Gy / 5# 800 -1000 cGy single fraction
Palliative radiotherapy:
Treatment
Surgical management
clinic bx if cooperative patient must obtain large biopsy clinically normal NP - OR for panendo and bx
Surgical treatment
primary
Treatment
Surgical management
Primary lesion
consider
Prognostic factors
Most important stage. Parapharyngeal extension is associated with a poorer prognosis. A Chinese series found that 4th cranial nerve involvement poor prognosis. Nodal disease status:
Lymphoepithelioma histology: better prognosis Undifferentiated histology: better prognosis Molecular markers:
Key facts
Terminology
Nasopharyngeal
carcinoma (NPC) Mucosal tumor of lateral pharyngeal recess (fossa of Rosenmller), strongly associated with EBV infection
Imaging
MR
best demonstrates parapharyngeal fat, skull base infiltration, & intracranial tumor Nodal disease in 90% at presentation: Retropharyngeal, levels II & V most common Metastatic nodes often large necrosis
Clinical Issues
Peak
incidence: 40-60 years Pediatric NPC rare; most often undifferentiated NK Bloody nasal discharge or epistaxis 50-70% present with mass from metastatic nodes Nitrosamines - salted fish Serous otitis from eustachian tube obstruction Nonkeratinizing NPC has 5-year survival ~ 75% Keratinizing NPC has 5-year survival 20-40% BSCC generally poor prognosis
Pathology
(previously type I) Nonkeratinizing NPC (NK NPC)
Strongly associated with EBV 15% differentiated (previously type II) 60% undifferentiated (previously type III)