NASOPHARYNGEAL CARCINOMA

M. IVAN DJAJALAGA

SCHOOL OF MEDICINE PADJADJARAN UNIVERSITY DEPARTMENT OF OTOLARYNGOLOGY HEAD NECK SURGERY HASAN SADIKIN GENERAL HOSPITAL
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INTRODUCTION

A tumor arising from the epithelium of the nasopharynx. The poor prognoses : Proximity to multiple vital structures. The difficulty of recognize early symptoms. The difficulty of nasopharyngeal examination. Complex interplay : Genetic : chromosomal abnormalities, HLA genotypes. Epstein-Barr virus. Environmental factors, preserved food, smooking.

Malignant tumors of nasopharynx

Tumor type

No. 120 31 18 6 3 2 2 2 1 1 1 169

% 71 18 11

Squamous cell carcinomaa Lymphoma Miscellaneous Adenocarcinoma Plasma cell myeloma Cylindroma Rhabdomyosarcoma Melanoma Fibrosarcoma Carcinosarcoma Unclassified malignant Total

EPIDEMIOLOGY

85% 95% of nasopharyngeal malignancies. Frequency: North America and Europe : 1 / 100,000 annually. Southeast Asian and Northern African : 8 / 100,000 annually.

Mortality/Morbidity: Radiotherapy : survival rates 40-50%. Radiotherapy and chemotherapy : survival rates 55-70%.

EPIDEMIOLOGY

Race: United States : increase among black teenagers. Asian and Northern African : more commonly affected. Sex: The male-to-female ratio is approximately 2:1. Age: Bimodal age distribution : A small peak is observed in late childhood. A second peak in people aged 50-60 years.

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PATHOPHYSIOLOGY

EBV : EBV infect epithelial cells transformation epithelial cells to cancer detection EBV (EBV VCA and EBV viral DNA in nasopharyngeal carcinoma . Genetic analysis : HLA-A2, HLA-B17, and HLA-Bw46 ~ two-fold risk for NPC. Abnormalities on chromosome 65.

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HISTOPATOLOGY

At birth : the pseudostratified columnar epithelium. One ages : stratified squamous epithelium. Beyond age 10 years : stratified squamous epithelium.

Lateral : pseudostratified columnar epithelium intermixed with stratified squamous mucosa.

This change ~ metaplastic reaction to environmental.

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HISTOPATOLOGY

1979, WHO : squamous cell :

Type I (keratinizing squamous cell carcinoma) : Prominent keratin formation, 1%-2%. Type II (nonkeratinizing squamous cell carcinoma) : Definite maturation but no keratin formation. Type III (undifferentiated carcinoma of the nasopharyngeal type) : prominent nucleoli, and multinucleated giant cells, > 95%.

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Diagnosis Nasopharyngeal cancer

Symptoms/signs Neck mass Ear fullness Hearing loss Nasal obstruction Head/neck pain Ear pain Diplopia/cranial neuropathy Radiology/nuclear scanning Computed tomography (CT)contrast enhanced Magnetic resonance imaging (MRI) Laboratory tests Viral capsid antigen (VCA)IgG and IgA antibodies Early antigen (EA)IgG antibodies Antibody-dependent cellular cytotoxicity (ADCC)

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CLINICAL EVALUATION

History: Medical attention : spread to regional lymph nodes. Asymptomatic neck mass 70% The complaints location of the primary tumor and the degree and direction of spread : Nasal obstruction (congestion, nasal discharge, bleeding). Changes in hearing (blockage of the eustachian tube). Cranial nerve palsies (extension to the base of the skull) : Cranial nerves III, IV, V, VI, IX, X, XI,

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CLINICAL EVALUATION

Physical examination :

Nasopharyngoscopy : friable exophytic mass. Otoscopic examination ~ serous otitis media.

Neck mass : painless, firm, often bilateral, upper and middle jugular nodes.
Maxillofacial : cranial nerve palsy.

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CLINICAL EVALUATION

Lab Studies:

Blood test : Routine blood work, CBC. Chemistry profile (liver function test).
Serologic test : EBV titers : IgA and IgG antibodies to VCA, and EA.. Cerebrospinal fluid examination.

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Antibody responses by group studied and type of antibody IgA antibody to VCA Group studied

IgG antibody to EA % positivea 76 86 35

No. 182 145 37

% positivea 69 82 16

NPC WHO type II and IIIb WHO type Ib Patient comparison groups SC cancer, head and neck Other cancer, head and neck Benign disease, head and neck Healthy donors

147 71 407 278

18 13 14 9

31 38 37 29

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CLINICAL EVALUATION

Imaging studies:

Computed tomography imaging : Determination tumor extention, base of skull erosion, and cervical lymphadenopathy. Searching for distant metastases.
Magnetic resonance imaging (MRI): Define tumor margins within soft tissue. Define extention of the tumor. Positron emission tomography (PET) :

Assessment questionable neck nodes.

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CLINICAL EVALUATION

Other Tests:

A audiogram : prior to radiotherapy.

A biopsy of the primary lesion or neck node : Confirmation of the diagnosis Removing multiple deep specimens from mucosal abnormalities. Preoperative head and neck CT as a guidence the biopsy process.

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STAGING

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Working formulation for staging by score: 1988 approach

Scorea
Characteristic Seven or more symptoms Nodes in lower neck or supraclavicular region WHO type 1 tumor Extensive tumor in nasopharynx Symptoms for <2 mo WHO, World Health Organization. Stage A, total score, <0 B, 0 to 0.99 C, 1.00 to 1.99 D, >2.00. If yes +1 +1 +1 +0.5 -0.5 If no 0 0 0 0 0

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Components of prognostic score in nasopharyngeal carcinoma

Scorea If yes If no

Risk factor Score to death Seven or more symptoms +1.14 0 Positive nodes in lower neck or supraclavicular regionb +1.10 0 WHO type 1 tumor +1.04 0 Extensive tumor in nasopharynx +0.53 0 Symptoms for <2 mo -0.63 0 Score to death including ADCC ADCC titer <1:960 +1.36 0 Seven or more symptoms +1.28 0 Positive nodes in lower neck or supraclavicular regionc +1.19 0 WHO type 1 tumor +1.14 0 Extensive tumor in nasopharynx +0.56 0 ADCC titer >1:15,360 -0.86 0 Symptoms for <2 mo -1.05 0 a. Prognostic score is equal to sum of scores. b. Regression weights. Negative value reflects better survival (lower score).

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Treatment Nasopharyngeal cancer

Radiation therapy External-beam supervoltage radiation Intracavitary brachytherapy

Surgical treatment Plays limited role in management Infratemporal fossa approach Transparotid temporal bone approach Transpalatal approach Chemotherapy No proven efficacy regarding survival Immunotherapy Impact on long-term survival obscure

Vaccines Future potential development

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MANAGEMENT
Radiotherapy

Use megavoltage radiation 60Co, 4 to 6 MeV photons . Dose : 1.8-2.0 Gy/d, 5 days/week until 40-44 Gy 50 Gy. Port : 2 parallel opposed lateral fields that encompass the nasopharynx and upper cervical nodes. The lower cervical nodes are treated with an anterior field. Three-dimensional radiotherapy : spare critical structures. Parotid sparing techniques + 3-dimensional treatment capability.

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MANAGEMENT

Boost : 10 to 20 MeV photon energies 60 to 70 Gy. Recurrent disease : total dose 10,000 cGy. Advance cases : + chemotherapy.

Brachytherapy :

Permanently implants high-activity 125I into the tumor bed. Endotracheal tube + high activity 198Au or 192Ir.

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MANAGEMENT

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MANAGEMENT
Medical Therapy Period of growth DNA synthesis premitotic phase mitotic cell division. Antineoplastic : the bulk of disease, the risk of recurrence. Antineoplastic agents interfere cell reproduction. Cell cycle specific (eg, alkylating agents, anthracyclines, cisplatin). Scheme : concurrent treatment with cisplatin, 5-fluorouracil, neoadjuvant. Result : Significant decrease in distant metastasis. Little or no improvement in local control or disease-free survival.

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MANAGEMENT
Surgical Treatment

Surgical treatment of the primary tumor has been limited : Location limits tumor resectability. Approaches to this region substantial risks of morbidity or death. Indication : Neck dissection to remove clinically positive cervical disease. Node has not eradicated by full-course radiation therapy. Patients with recurrent or residual nasopharyngeal disease.

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MANAGEMENT

Approaches to the nasopharynx :

Panje - Gross : transparotid temporal bone approach 8 = 5 died. Fisch : infratemporal fossa approach 6 = 6 died (2 years). Wei et al, Fee et al : maxillary swing procedure Fee et. al : 7 = 4 died, 3 alive and free of disease more than 5 years postoperatively.

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PROGNOSIS

5-year survival rate : 30% - 48%. Mesic et al. :5-year survival rate 52% Neel and Taylor : 5-year survival rate 50% 10-year disease-free survival rate : 34%. Danish : 10-year survival rate 37%. Chen et. Al : 10-year survival rate of 30.5%. Recurrent disease : About half of the patients. A median of 1.4 years 40%. Improved 5-year survival of 57%.

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COMPLICATION

Radiation : Insufficient shielding or miscalculation of doses to surrounding tissues complication :

The salivary glands : xerostomia loss of salivary flow protecting the teeth dental caries, dehydration. Eustachian tube : fibrosis dysfunction serous otitis media. Trismus, discomfort, and induration of the neck.

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Complications Radiation therapy

Complication

No.

Dryness of mouth Fluctuating hearing lossotitis media Dental caries Trismus Pituitary dysfunction Myelitis Massive neck fibrosis Pharyngeal wall necrosis Base of skull necrosis

62 18 10 14 15 8 2 2 1

24.7 7.2 4.0 5.6 6.0 3.2 1.6 0.8 0.4

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ONGOING RESEARCH

Genetic : Tumor-cell DNA. Deletion of alleles at loci on chromosome 3 (3p) tumor suppressor genes. Epstein Barr Virus : Whether and how EBV may facilitate oncogenesis. EBV fragmentation of cellular DNA. EBV DNA tumor growth and division. EBV latent membrane protein LMP-1.

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ONGOING RESEARCH

LMP-1 :

Arrest cellular differentiation. Alter cell morphology.

Protect cells from apoptosis.

Stimulation of cell growth and division. Interact with EGF receptor upregulating its anabolic activity.

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THE FUTURE

Advance in the diagnosis :

Development of clinically identifiable tumor : EBV VCA and EA Presence of EBV DNA : PCR.

Risks of relapse and death from NPC : CD23.

Selecting patients for aggressive initial treatment : CD23, ADCC.

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THE FUTURE

Advance in treatment :

Computer technology Analyze radiation dose improvement of radiation treatment. Analyze deliver maximal energy to tumor improve local control. Dosage & combination of chemotherapeutic distant metastasis.
T cells could be directed against tumor cells Immunotherapy ?

IgA anti-EBV antibodies vaccines against EBV development ?

vaccine

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HIGHLIGHTS

WHO divides NPC into three histologic categories [squamous cell carcinomas (type I), nonkeratinizing carcinomas (type II), and undifferentiated carcinomas (type III)]. Most NPC arises in the fossa of Rosenmller, a small recess located behind the torus tubarius at the junction of the lateral and posterosuperior walls of the nasopharynx. The patient with NPC usually presents with a neck mass and serous otitis media; however, because of the proximity of the fossa of Rosenmller to multiple vital structures, various local, regional, and distant manifestations are possible.

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HIGHLIGHTS

NPC is a relatively rare tumor in most parts of the world, with an incidence of 1 per 100,000 in the North American white population; this incidence increases as much as 30-fold in endemic populations such as the Hong Kong Chinese. Genetic, environmental, and viral factors all play a role in the genesis of certain histologic types of NPC. Numerous pieces of biologic and immunologic data support an association between EBV and certain forms of NPC. External-beam megavoltage irradiation, brachytherapy in selected cases, is the standard first-line therapy for most patients with NPC.

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HIGHLIGHTS

Surgery has a limited role in the management of NPC patients. Chemotherapy adjunctive to radiation therapy improves control of local disease and may soon improve survival rates. The prognosis of patients with NPC is strongly related to several factors, including tumor extent within the nasopharynx, duration and number of symptoms at presentation, histologic type of NPC, parapharyngeal spread of tumor, lymph node involvement in the lower neck or supraclavicular region, and ADCC titer. The most common complication from radiation therapy is xerostomia; however, one must be aware of rare hypothalamic dysfunction, hypopituitarism, and hypothyroidism associated with radiation therapy for NPC.

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THANK YOU
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Bcl-2

The B-cell lymphoma/leukemia-2 gene (bcl-2) is a tumor-suppressor gene and primary regulator of apoptosis. Normal bcl-2 expression inhibits apoptosis, counteracting the effects of p53. The bcl-2 proteins are found predominantly in the mitochondrial membrane and have been demonstrated in a variety of tissues, including lymphoid tissue, bronchial epithelium, skin, intestine, breast, prostate, thyroid, and nasopharynx1.

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p53

The p53 tumor suppressor gene is responsible for arrest in the cell cycle following genetic injury, thus allowing the cell to repair the DNA defect before the next cell division. The gene also induces apoptosis. Alteration in the p53 gene locus is the most commonly identified genetic mutation in head and neck SCC and in human cancers overall.

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Chemotherapy agents
Class of drugs Alkylating agents Examples Nitrogen mustard, cyclophosphoamide, chlorambucil, melphalan, nitrosourea, cisplatin Methotrexate, 5-fluorouracil, cytosine arabinoside, hydroxyurea, gemcitabine Vincristine, vinblastine, vinorelbine Doxorubicin, bleomycin, dactinomycin, mitomycin C, etoposide Paclitaxel, docetaxel Irinotecan, topotecan inhibitors Tamoxifen, leuprolide

Antimetabolites

Natural products Vinca alkaloids Antibiotics

Taxanes Topoisomerase I
Hormones

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Benefits of chemoradiotherapy

Drugs and irradiation may be active against different tumor cell subpopulations based on cell cycle specificity, pH, and oxygen supply. Cells resistant to one modality of treatment may be eradicated by the other. Tumor shrinkage may decrease interstitial pressure and therefore increase drug and oxygen delivery. Cell-cycle synchronization increases the effectiveness of both therapies.

Chemotherapy inhibits repair of sublethal radiation damage and inhibits recovery from potentially lethal radiation damage.

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Advantages and disadvantages of induction chemotherapy

Advantages Drug delivery to cancer cells is unimpaired. Tumor may be downsized, allowing for more successful surgery or radiation therapy with less radical treatment. Patient performance status at surgery may be improved. Disadvantages Original extent of tumor may be obscured. Performance status may decline. Tumor may increase during chemotherapy. Duration, toxicity, and cost of treatment are increased.

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Emergencies Chemotherapy related Signs and Symptoms Fever, chills, infections symptoms plus absolute neutrophil count <500 Platelet count <20, petechiae, overt bleeding

Emergency Neutropenic fever

Treatment Hospitalization antibiotics, granulocyte stimulating factor

Thrombocyclopenia/ bleeding

Allergic Reaction
Extravasation

Overdose

Transfuse, find source of bleeding, avoid aspirin and nonsteroidal antiinflammatory drugs Rash, hives Antihistamine, stridor, hypotension steroids, epinephrine or Redness, Subcutaneous swelling, pain epinephrine hyaluronidase Drug dependent Supportive, antidote if available

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Possible mechanisms of immunosuppression in head and neck cancer

IgA blocking antibody Circulating immune complexes Antigenic modulation of the tumor cells Suppressor T cells Prostaglandin secretion by tumor, inhibiting interleukin-1 Transforming growth factor-b inhibition of lymphokines Low levels of exogenous interferon Exogenous administration of immunosuppressive agents (chemotherapy, radiation) Histamine activation of suppressor lymphocytes and inhibition of cytokine production Tumor cell production of p15e

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Select leukocyte subsets and CD classifications

CD antigen Cellular subsets CD1 CD2 CD3 CD4 CD8 CD11a CD11b CD16 CD19 CD25 CD32 CD45R CD54 CD56 Thymocytes T lymphocytes, NK cells, thymocytes T lymphocyte antigen receptor Helper T lymphocytes Cytotoxic/suppressor T lymphocytes, NK cells Leukocyte adhesion antigen Complement receptor, T cells, monocytes, granulocytes IgG Fc receptor, NK cells B lymphocytes T and B lymphocytes, large granular lymphocytes (IL-2 receptor) IgG Fc receptor T and B lymphocytes, NK cells, granulocytes Activated lymphocytes, macrophages (intercellular adhesion molecule NK cells

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Cytokines involved in the immune response to head and neck cancer Cytokine Cell sources Immunologic effects

IL-1
IL-2 IL-4 TNF-a, TNF-b TGF-b IFN-a IFN-b IFN-g

Macrophages, dendritic cells,

epithelial cells Activated T lymphocytes Activated T lymphocytes

Lymphocyte activation/proliferation, increase NK activity, increase lymphokine production, bone resorption Increase T-cell activity, LAK induction, NK activity, lymphokine production, macrophage activation B-cell proliferation, immunoglobulin production, MHC-II/Fc receptor expression, macrophage activation
Tumor necrosis/cytotoxicity, neutrophilia, increase lymphokine production Inhibit lymphocyte proliferation, suppress NK/LAK activity Antiviral, augment lymphokines, antiproliferative Cytotoxic, antiproliferative, increase NK activity, MHC expression, cytotoxic T lymphocyte activation, increase lymphokine production

Lymphocytes, macrophages, endothelium, keratinocytes Lymphocytes, macrophages, platelets Leukocytes Fibroblasts T lymphocytes, large granular lymphocytes

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TABLE 109-1. Nodal size and presence of histologic metastases Histologic status (%) Negative Positive

Node size (cm) 1 2 3 4 5

67 38 19 12 0

33 62 81 88 100

Positive with extranodal extension 14 26 49 71 76

From ref. 16, with permission.

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TABLE 109-2. Classification of neck dissections

Radical Modified radical (I, II, and III) Selective

Lateral Anterolateral (supramyohyoid or supraomohyoid) Posterolateral Anterior

Extended

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