Email updates

Keep up to date with the latest news and content from Orphanet Journal of Rare Diseases and BioMed Central.

Open Access Highly Accessed Review

Nasopharyngeal carcinoma

Bernadette Brennan

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 0–14 years, and 1 to 2 per million at age 15–19 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 0–9 years and 0.8 per million at age 10–14 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 15–19 years are carcinomas. This suggests an incidence of 1 to 2 per million for NPC at age 15–19 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-91-GPOH 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 μg/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

  1. Regaud C: Lympho-épitheliome de l'hypopharynx traité par la roentgenthérapie.

    Bull Soc Franc Otorhinolaryngol 1921, 34:209-214. OpenURL

  2. Schmincke A: Über lymphoepitheliale Geschwülste.

    Beitr Pathol Anat 1921, 68:161-170. OpenURL

  3. Young JL Jr, Miller RW: Incidence of malignant tumors in U. S. children.

    J Pediatr 1975, 86:254-258. PubMed Abstract | Publisher Full Text OpenURL

  4. Ellouz R, Cammoun M, Attia RB, Bahi J: Nasopharyngeal carcinoma in children and adolescents in Tunisia: clinical aspects and the paraneoplastic syndrome.

    IARC Sci Publ 1978, 20:115-129. PubMed Abstract OpenURL

  5. Stiller CA: International variations in the incidence of childhood carcinomas.

    Cancer Epidemiol Biomarkers Prev 1994, 3:305-310. PubMed Abstract OpenURL

  6. Balakrishnan U: An additional younger-age peak for cancer of the nasopharynx.

    Int J Cancer 1975, 15:651-657. PubMed Abstract OpenURL

  7. Singh W: Nasopharyngeal carcinoma in Caucasian children. A 25-year study.

    J Laryngol Otol 1987, 101:1248-1253. PubMed Abstract OpenURL

  8. Wolf H, zur Hausen H, Becker V: EB viral genomes in epithelial nasopharyngeal carcinoma cells.

    Nat New Biol 1973, 244:245-247. PubMed Abstract OpenURL

  9. Lo YM, Chay LYS, Lo K-W, Zhang J, Lee JC, Hjelm NM, Johnson PJ, Huang DP: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma.

    Cancer Res 1999, 59:1188-1191. PubMed Abstract | Publisher Full Text OpenURL

  10. Lo YM, Leung SF, Chan LY, Chan AT, Lo KW, Johnson PJ, Huang DP: Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma.

    Cancer Res 2000, 60:2351-2355. PubMed Abstract | Publisher Full Text OpenURL

  11. Lo YM, Chan LY, Chan AT, Leung SF, Lo KW, Zhang J, Lee JC, Hjelm NM, Johnson PJ, Huang DP: Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma.

    Cancer Res 1999, 59:5452-5455. PubMed Abstract | Publisher Full Text OpenURL

  12. Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS: Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma.

    N Engl J Med 2004, 350:2461-2470. PubMed Abstract | Publisher Full Text OpenURL

  13. Yu MC, Ho JH, Lai SH, Henderson BE: Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: report of a case-control study in Hong Kong.

    Cancer Res 1986, 46:956-961. PubMed Abstract OpenURL

  14. zur Hausen H, Schulte-Holthausen H, Klein G, Henle W, Henle G, Clifford P, Santesson L: EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx.

    Nature 1970, 228:1056-1058. PubMed Abstract | Publisher Full Text OpenURL

  15. de-Vathaire F, Sancho-Garnier H, de-The H, Pieddeloup C, Schwaab G, Ho JH, Ellouz R, Micheau C, Cammoun M, Cachin Y, et al.: Prognostic value of EBV markers in the clinical management of nasopharyngeal carcinoma (NPC): a multicenter follow-up study.

    Int J Cancer 1988, 42:176-181. PubMed Abstract OpenURL

  16. Chan SH, Day NE, Kunaratnam N, Chia KB, Simons MJ: HLA and nasopharyngeal carcinoma in Chinese – a further study.

    Int J Cancer 1983, 32:171-176. PubMed Abstract OpenURL

  17. Porter MJ, Field JK, Lee JC, Leung SF, Lo D, Van Hasselt CA: Detection of the tumour suppressor gene p53 in nasopharyngeal carcinoma in Hong Kong Chinese.

    Cancer Res 1994, 14:1357-1360. OpenURL

  18. Lo KW, Tsao SW, Leung SF, Choi PHK, Lee JCK, Huang DP: Detailed deletion mapping on the short arm of chromosome 3 in nasopharyngeal carcinomas.

    Int J Oncol 1994, 4:1359-1364. OpenURL

  19. Huang DP, Lo KW, van Hasselt CA, Woo JK, Choi PH, Leung SF, Cheung ST, Cairns P, Sidransky D, Lee JC: A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma.

    Cancer Res 1994, 54:4003-4006. PubMed Abstract OpenURL

  20. Shanmugaratnam KS, Sobin LH: Histological typing of upper respiratory tract tumors. Geneva: World Health Organization; 1978. OpenURL

  21. Pizzo PA, Poplack DG: Principle and practice of pediatric oncology. Philadelphia: Lippencott-Raven; 1997. OpenURL

  22. Neel HB 3rd, Pearson GR, Taylor WF: Antibodies to Epstein-Barr virus in patients with nasopharyngeal carcinoma and in comparison groups.

    Ann Otol Rhinol Laryngol 1984, 93:477-482. PubMed Abstract OpenURL

  23. Krueger GRF, Wustrow J: Current classification of nasopharyngeal carcinoma at Cologne University. In Nasopharyngeal carcinoma. Volume 5. Edited by Grundmann E, Krueger GRF, Ablashi DV. Stuttgart: Gustay Fisher; 1981::11-5. OpenURL

  24. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M: AJCC Cancer Staging Manual. 6th edition. New York: Springer – Verlag; 2002. OpenURL

  25. Ho JHC: Clinical staging recommendations. In Nasopharyngeal Carcinoma: Etiology and Control. Edited by de The G, Ito Y. Lyon: International Agency for Research on Cancer; 1978. OpenURL

  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 OpenURL

  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 OpenURL

  28. Deutsch M, Mercado R Jr, Parsons JA: Cancer of the nasopharynx in children.

    Cancer 1978, 41:1128-1133. PubMed Abstract | Publisher Full Text OpenURL

  29. Pick T, Maurer HM, McWilliams NB: Lymphoepithelioma in childhood.

    J Pediatr 1974, 84:96-100. PubMed Abstract | Publisher Full Text OpenURL

  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 OpenURL

  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 OpenURL

  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 OpenURL

  33. Straka JA, Bluestone CD: Nasopharyngeal malignancies in children.

    Laryngoscope 1972, 82:807-816. PubMed Abstract OpenURL

  34. Nishiyama RH, Batsakis JG, Weaver DK: Nasopharyngeal carcinomas in children.

    Arch Surg 1967, 94:214-217. PubMed Abstract OpenURL

  35. Baker SR, Wolfe RA: Prognostic factors in nasopharyngeal malignancy.

    Cancer 1982, 49:163-169. PubMed Abstract | Publisher Full Text OpenURL

  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 OpenURL