Nasopharyngeal Carcinoma

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Nasopharyngeal Carcinoma

Head and Neck Surgery
Author Credentials 

Rusha Patel, MD
1 Medical Center Drive
Morgantown, WV

Module Summary

Nasopharyngeal carcinoma is a distinct epidemiological, pathological, and clinical entity. Progress in defining its carcinogenetic evolution and understanding its association with the Epstein-Barr virus has been made. Therapeutically, radiation therapy has constituted the major therapeutic modality for many years. Recent evidence suggests that the concurrent administration of chemotherapy during radiation therapy significantly improves survival rates, at least in nonendemic areas. In contrast, the use of induction chemotherapy might require further studies since a significant survival advantage has not yet been found. Patients with recurrent disease should be carefully assessed for possible second-line curative-intent radiation therapy or surgical salvage. In addition, many of these patients will benefit from the use of combination chemotherapy.

Module Learning Objectives 
  1. Review the anatomy of the nasopharynx (NP).
  2. Explain the histopathology of NPC and its clinical implications.
  3. Describe the epidemiology and pathogenesis of NPC.
  4. Recognize the signs and symptoms of NPC to make an early diagnosis.
  5. Explain the usefulness of serology and imaging studies for NPC.
  6. Review the principles of staging of NPC.
  7. Review the principles of treatment of NPC.
  8. Explain the management of locoregionally advanced, recurrent, or metastatic disease.

Anatomy

Learning Objectives 
  1. Understand the anatomic boundries of the nasopharnx.
    1. Anteriorly: Posterior choanae.
    2. Superiorly: by the declivity of the sphenoid.
    3. Posteriorly: Clivus, C1/C2 vertebrae
    4. Inferiorly: Soft palate.
  2. Be familiar with the arterial and venous supply to the nasopharynx.
  3. Understand the lymphatic drainage pattern of the nasopharynx and relationship to nodal metastasis.
References 
  1. Altun M, Fandi A, Dupuis O, et al. Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects. Int J Radiat Biol Phys. 1995;32:859-77.
  2. Vokes EE, Weichselbaum RR, Lippman SM, et al. Medical progress in head and neck cancer. New Engl J Med. 1993;383:184-94.
  3. Joiner M C, van der Koegel A. Basic Clinical Radiobiology, Fifth Edition. CRC Press. ISBN:1444179632.

Pathogenesis

Learning Objectives 
  1. Understand the multifactorial etiology of nasopharyngeal carcinoma (NPC). etiological factors of NPC include the Epstein-Barr virus (EBV), environmental risk factors, and genetic susceptibility.
  2. Describe the role of Epstein-Barr virus in the pathogenesis of NPC.
  3. Be familiar with genetic association of NPC.
    1. HLA-class
  4. Be familiar with environmental factors that cause NPC.
    1. Alcohol
    2. Environmental carcinogens
References 
  1. Henderson BE, Louie E, Jing JSH, et al. Risk factors associated with nasopharyngeal carcinoma. New Engl J Med. 1976;295:1101-106.
  2. Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med. 1995;333:693-98.
  3. Raab Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986;47:883-89.
  4. Rickinson AB, Kieff E. Epstein-Barr virus. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology. 3rd ed. Philadelphia: Lippincott-Raven; 1996:2397-446.
  5. Yu MC, Mo C-C, Chong W-X, et al. Preserved foods and nasopharyngeal carcinoma: a case-control study in Guangxi, China. Cancer Res. 1988;48:1954-959.
  6. Zeng Y, Zhang LG, Wu YC, et al. Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive in Wuzhou City, China. Int J Cancer. 1985;36:545-47.

Basic Science

Learning Objectives 
  1. Be familiar with the structure of EBV and methods of carcinogenesis.
  2. Describe the structure of the EBV virus.
  3. Understand the effect of EBV nuclear proteins (EBNAs) and membrane progeins (LMPs) on cell proliferation.
    1. EBNA-1 is expressed in nearly all cases and LMP1 in about two-thirds of cases of EBV-positive NPC.
References 
  1. Dawson CW, Rickinson AB, Young LS. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature. 1990;344:777-80.
  2. Fahraeus R, Rymo L, Rhim JS, et al. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus. Nature. 1990;345:447-49.
  3. Kieff E. Epstein-Barr virus and its replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology. 3rd ed. Philadelphia: Lippincott-Raven; 1996:2343-396.

Incidence

Learning Objectives 
  1. Be familiar with regional differences in NPC incidence.
  2. Understand that in the United States and Western world, NPC occurs sporadically and has an low incidence overall (1/100,000).
  3. Know that the highest incidence is among the Southern Chinese population of Guangdong, Unuits of Alaska, and native Greenlanders.
References 
  1. Vokes EE, Weichselbaum RR, Lippman SM, et al. Medical progress in head and neck cancer. New Engl J Med. 1993;383:184-94.
  2. Parkin DM, Muir CS. Cancer incidence in five continents. Comparability and quality of data. IARC Sci Publ. 1992;(120):45-173.

Genetics

Learning Objectives 
  1. Understand the role of genetics in predisposing to NPC.
  2. Early evidence for a genetic determinant among Chinese was an HLA-associated higher risk for NPC.
  3. Know that familial forms of NPC occur at younger ages.
References 
  1. Huang DP, Lo K-W, van Hasselt CA, et al. A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma. Cancer Res. 1994;54:4003-4006.
  2. Simons MJ, Wee GB, Goh EH, et al. Immunogenetic aspects of nasopharyngeal carcinoma. IV. Increased risk in Chinese of nasopharyngeal carcinoma associated with a Chinese-related HLA profile (A2, Singapore2). J Natl Cancer Inst. 1976;57:977-80.
  3. Zeng YX, Jia WH. Familial nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12(6):443-450.

Patient Evaluation

Learning Objectives 
  1. Understand that NPC has a few early warning symptoms and signs.
    1. Ears: sensation of ear blockage, serous otitis media, and conductive hearing loss, especially unilateral.
    2. Neck: a lump in the neck.
    3. Nose: nasal obstruction, blood-tinged anterior or postnasal drainage.
    4. Cranial nerves: diplopia, pain high in the neck, facial paresthesia.
  2. Be familiar with thorough clinical evaluation of NPC.
    1. Fiberoptic examination.
    2. Neck examination.
    3. Evaluation of cranial nerves (I, II, III, IV, V, VI, VIII, IX, XII), including audiometry.
    4. Biopsy under local anesthesia.
  3. Understand methods to determine a diagnosis.
    1.  
    2. Fine needle aspiration of neck lymph nodes if primary not accessible for biopsy.
  4. Be familiar with the role of laboratory tests for NPC.
    1. Serum measurement of EBV DNA correlates to disease treatment outcomes.
References 
  1. Altun M, Fandi A, Dupuis O, et al. Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects. Int J Radiat Biol Phys. 1995;32:859-77.
  2. Vokes EE, Weichselbaum RR, Lippman SM, et al. Medical progress in head and neck cancer. New Engl J Med. 1993;383:184-94.

Measurement of Functional Status

Learning Objectives 
  1. Understand the functional deficits that occur with NPC and pre-treatment considerations.
  2. Hearing loss can occur from serous effusion due to eustachian tube obstruction. Audiogram should be considered to assess hearing loss prior to therapy.  
  3. Be familiar with cranial nerve deficits in advanced NPC can involve cranial nerves, resulting in changes with vision and swallowing.
  4. Dental hygiene should be evaluated by a dentist prior to radiation therapy to prevent oral complications.
References 
  1. Kuo CL, Wang MC, Chu CH et al. New therapeutic strategy for treating otitis media with effusion in postirradiated nasopharyngeal carcinoma patients. J Chin Med Assoc. 2012 July;75(7):329-34.
  2. Epsteinabac, JB, Emertonb S, Lunna R et al. Pretreatment assessment and dental management of patients with nasopharyngeal carcinoma. Oral Oncology. 1999 Jan;53(1):33-39.
  3. Li JC, Mayr NA, Yuh WT wt al. Cranial nerve involvement in nasopharyngea carcinoma: response to radiotherapy and its clinical impact. Ann Otol Rhinol Laryngol. 2006 May;115(5):340-5.

Imaging

Learning Objectives 
  1. Recognize that imaging studies for NPC are done to assess the extent of disease, to determine the clinical staging of the disease, and to delineate the field for radiation treatment.
  2. Local: magnetic resonance imaging (MRI) ± computed tomography (CT) scan.
  3. Metastatic workup: thoracic and abdominal CT scan, bone scintigraphy, positron emission tomography (PET) scan.
References 

1.    Altun M, Fandi A, Dupuis O, et al. Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects. Int J Radiat Oncol Biol Phys. 1995;32:859-77.

Pathology

Learning Objectives 
  1. Understand the importance of establishing EBV status of the primary tumor.
  2. Tumor biopsy specimen should be tested for EBV expression to provide prognostic as well as potential therapeutic information.
    1. In-situ hybridization (ISH) for EBV-encoded RNA (EBER) is a sensitive method for testing tumor specimen for EBV.
    2. Immunohistochemistry for LMP1, a latent protein, is only seen in 50% of EBV-positive tumors.
References 

1. Straatof KC, Bollard CM, Popat UM, et al. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T-lymphocytes. Blood. 2005 March;105(5):1898-1904.

Treatment

Learning Objectives 

Understand the primary treatment modalities for NPC and the role of surgery.

  1. Chemotherapy and radiation are main methods for treating NPC.
    1. T1N0M0 disease may be treated with radiation alone.
    2. T1-T4N+ disease is treated with concurrent chemoradiation.
      1. Recognize the importance of the Intergroup trial 0099 in treatment recommendation of chemoradiation for NPC.
      2. Understand the role of multimodality clinical trials are encouraged for N+ disease.
  2. Understand advantage of Intensity-modulated radiotherapy (IMRT) radiation technique, as compared to 3D conformal techniques, in sparing critical anatomic structures when treating NPC.
  3. Metastatic disease can be treated on trial or with systemic chemotherapy.
  4. Be familiar with role of EBV DNA in monitoring treatment results and recurrence.
References 
  1. Al-Sarraf M, LeBlanc M, Fu K, et al. Superiority of chemo-radiotherapy (CT-RT) vs. radiotherapy in patients with locally advanced nasopharyngeal cancer (abstr). Am Soc Clin Oncol. 1996;15(882):313.
  2. Boussen H, Cvitkovic E, Wendling JL, et al. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol. 1991;9:1675-681.
  3. Chan ATC, Teo PML, Leung TWT, et al. A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1995;33:569-77.
  4. Garden AS, Lippman SM, Morrison WH, et al. Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma? Results of treatment in the era of computerized tomography. Int J Radiat Oncol Biol Phys. 1996;36:1005-1012.
  5. International Nasopharynx Cancer Study Group. VUMCA I trial. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV (> or = t0N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. Int J Radiat Oncol Biol Phys. 1996;35:463-69.
  6. Lee AWM, Foo W, Law SCK, et al. Reirradiation for recurrent nasopharyngeal carcinoma: factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys.1997;38:43-52.
  7. Sanguineti G, Geara FB, Garden AS, et al. Carcinoma of the nasopharynx treated by radiotherapy alone: detriments of local and regional control. Int J Radiat Oncol Biol Phys. 1997;37:985-96.
  8. Tannock I, Payne D, Cummings B, et al. Sequential chemotherapy and radiation for nasopharyngeal cancer: absence of long-term benefit despite a high rate of tumor response to chemotherapy. J Clin Oncol. 1987;5:629-34.
  9. Wang CC. Improved local control of nasopharyngeal carcinoma after intracavitary brachytherapy boost. Am J Clin Oncol. 1991;14:5-8.
  10. Wang CC. Re-irradiation of recurrent nasopharyngeal carcinoma: treatment techniques and results. Int J Radiat Oncol Biol Phys. 1987;13:953-56.

Pharmacology

Learning Objectives 

Be familiar with the chemotherapeutics used for NPC in conjunction with radiation therapy, well as in the adjuvant therapy. 

  1. Know that cisplatin is recommended for chemoradiation therapy for NPC.
  2. Be familiar with alternative agents:
    1. Carboplatin
    2. Docetaxel
    3. Epirubicin
    4. Paclitaxel

Surgical Therapies

Learning Objectives 

Understand the surgical management of NPC.

  1. Know that surgery usually performed in salvage setting for residual disease at neck or primary site.
  2. Pre-operative evaluation should include detailed exam and imaging to determine resectability.
  3. Be familiar with approach to the nasopharynx, including:
    1. Intratemporal fossa approach (lateral approach)
    2. Transcervico-mandibulo-palatal approach (inferolateral approach)
    3. Maxillary swing and facial translocation (anterolateral approach)
    4. Midface degloving
    5. Endoscopic approach
References 

1. Tsang RK, William WI. Salvage surgery for nasopharyngeal cancer. World Journal of Otorhinolaryngology-Head and Neck Surgery. 2015;1(1):34-43.

Rehabilitation

Learning Objectives 

Appreciate the need for multifactorial rehabilitation in NPC patients.

  1. Recognize the most common functional losses after treatment for NPC
    1. Dysphagia
    2. Hearing loss
    3. Xerostomia

Staging

Learning Objectives 

Understand staging of NPC and nodal disease.

  1. Recognize the difference in N-staging as compared to head and neck cancers of other sites.
References 
  1. Greene FL, Page DL, Fleming ID, et al.,eds. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2002:33-42.

Case Studies

A 54-year-old Hispanic male presented with a 6-week history of left-sided ear pressure, some decrease in hearing, and a complaint that sounds were “muffled.” He was placed on antibiotics 2 weeks ago by his family physician. His symptoms did not improve. On physical examination, the left tympanic membrane was retracted. Nasal endoscopy revealed a lesion in the posterior nasal cavity. A 4 X 4 cm mobile, nontender lymph node was palpated at the left level III in the neck. MRI scan of the head and neck showed a mass in the NP extending to the left nasal cavity and metastatic cervical lymph node. PET scan revealed no distant metastasis. A biopsy obtained from the mass in the nose under local anesthesia confirmed undifferentiated carcinoma.

T2N1M0 undifferentiated carcinoma of the NP.

The patient underwent external radiation therapy and adjuvant chemotherapy. At 1-year followup he had no evidence of disease.

Complications

Learning Objectives 

Understand that both radiation and chemotherapy can produce immediate and late complications.

  1. Evolution of late toxicity (EORTC/RTOG) scale.
  2. Cranial neuropathies.
References 
  1. Lee AWM, Foo W, Law SCK, et al. Reirradiation for recurrent nasopharyngeal carcinoma: factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys. 1997;38:43-52.

Review

Review Questions 
  1. What are the risk factors for NPC?
  2. Describe EBV genome.
  3. Between EBNA-1 and LMP1, which protein is more commonly expressed in NPC?
  4. What are the two most common clinical presentations in NPC?
  5. How does the N staging of NPC differ from N staging of other head and neck mucosal squamous cell carcinomas?
  6. Describe the boundary of supraclavicular fossa.
  7. What are the adverse prognostic factors for NPC?
  8. What can be monitored in serum plasma for disease recurrence?
  9. Which treatment modalities are most effective for NPC without distant metastasis.
Resources 

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  1. Annual Meeting Webcast (AMW):