Nasopharyngeal carcinoma

doi:10.1016/S0140-6736(05)66698-6

The Lancet

Volume 365, Issue 9476, 11–17 June 2005, Pages 2041-2054

https://doi.org/10.1016/S0140-6736(05)66698-6 Get rights and content

Summary

Incidence of nasopharyngeal carcinoma has remained high in endemic regions. Diagnosing the disease in the early stages requires a high index of clinical acumen and, although most cross-sectional imaging investigations show the tumour with precision, confirmation is dependent on histology. Epstein-Barr virus (EBV)-encoded RNA signal is present in all nasopharyngeal carcinoma cells, and early diagnosis of the disease is possible through the detection of raised antibodies against EBV. The quantity of EBV DNA detected in blood indicates the stage and prognosis of the disease. Radiotherapy with concomitant chemotherapy has increased survival, and improved techniques (such as intensity-modulated radiotherapy), early detection of recurrence, and application of appropriate surgical salvage procedures have contributed to improved therapeutic results. Screening of high-risk individuals in endemic regions together with developments in gene therapy and immunotherapy might further improve outcome.

Introduction

Nasopharyngeal carcinoma is a non-lymphomatous, squamous-cell carcinoma that occurs in the epithelial lining of the nasopharynx. This neoplasm shows varying degrees of differentiation and is frequently seen at the pharyngeal recess (Rosenmüller's fossa) posteromedial to the medial crura of the eustachian tube opening in the nasopharynx.¹

The first report on a group of 14 patients who had this type of tumour was published in 1901.² A further clinical study of 79 patients was published in 1922.³ The first comprehensive study of nasopharyngeal carcinoma was done in 1941, and described clinicopathological features in 114 patients.⁴ This neoplasm is an uncommon disease in most countries, and its age-adjusted incidence for both sexes is less than one per 100 000 population.⁵ However, the disease occurs with much greater frequency in southern China, northern Africa, and Alaska. The Inuits of Alaska⁶ and ethnic Chinese people living in the province of Guangdong are especially prone to the disease. The reported incidence of nasopharyngeal carcinoma among men and women in Hong Kong (geographically adjacent to Guangdong province) is 20–30 per 100 000 and 15–20 per 100 000, respectively.⁵ That the incidence of nasopharyngeal carcinoma remains high among Chinese people who have immigrated to southeast Asia or North America, but is lower among Chinese people born in North America than in those born in southern China, is noteworthy.7, 8 This finding suggests that genetic, ethnic, and environmental factors could have a role in the cause of the disease.

Section snippets

Pathology

The malignant epithelial cells of the nasopharynx are large polygonal cells with a syncytial composition. Their nuclei are round or oval with scanty chromatin and distinct nucleoli. The cells show no parakeratosis or cornification and are frequently intermingled with lymphoid cells in the nasopharynx, giving rise to the introduction of the term lymphoepithelioma.⁹ Electronmicroscopy studies have established that these tumour cells are of squamous origin and that the undifferentiated carcinoma

Symptoms and serological diagnosis

Patients with nasopharyngeal carcinoma can present with symptoms from one or more of four categories. The categories consist of (1) presence of tumour mass in the nasopharynx (epistaxis, nasal obstruction, and discharge); (2) dysfunction of the eustachian tube, associated with the lateroposterior extension of the tumour to the paranasopharyngeal space (tinnitus and deafness); (3) skull-base erosion and palsy of the fifth and sixth cranial nerves, associated with the superior extension of the

Population screening

In southern China, where nasopharyngeal carcinoma is endemic, EBV serology has been used for population screening. In a study undertaken in Wuzhou (Guangxi province, China)²⁴ in the early 1980s, 1136 individuals identified as positive for immunoglobulin A against viral capsid antigen received regular clinical examinations of the nasopharynx and neck for 4 years. During this follow-up period, 35 cases of nasopharyngeal carcinoma were detected, most of which (92%) were diagnosed early at either

Imaging studies

Before the introduction of cross-sectional imaging, little was known about the natural behaviour and routes of extension of nasopharyngeal carcinomas in the early stages of development. Surgery was not a primary treatment, and post-mortem examinations of patients who died from nasopharyngeal carcinoma were of little importance since the tumours were usually very advanced by the time of death and had undergone significant secondary changes as a result of treatment. The best that could be done

Staging system

There are various ways of classifying nasopharyngeal carcinomas. At present the American Joint Committee on Cancer Staging and End Result Reporting/ International Union Against Cancer (AJC/UICC) system is preferred in Europe and America,⁴⁷ whereas Ho's system is frequently used in Asia.48, 49 The nodal classification in Ho's system has incorporated prognostic significance, but the stratification of the T stages into five sectors differs from most staging systems.

The development of a revised

Prognosis

As with most other tumours, the extent of a nasopharyngeal carcinoma as embodied in the TMN staging system (table 1) is the most important prognostic factor. Indeed, most other known prognostic factors are directly or indirectly related to the extent or bulk of the tumour. The changes in prognostic factors identified and reported at different times in the past probably represented adoption of these known adverse factors in the new staging systems, or the use of treatment strategies to address

Radiotherapy

Radiotherapy is the standard treatment for nasopharyngeal carcinoma. Unfortunately, it can produce undesirable complications after treatment because of the location of the tumour at the base of skull, closely surrounded by and in close proximity to radiation dose-limiting organs, including the brain stem, spinal cord, pituitary-hypothalamic axis, temporal lobes, eyes, middle and inner ears, and parotid glands. Since nasopharyngeal carcinomas tend to infiltrate and spread towards these

Clinical

Documentation of complete remission in the nasopharynx and neck lymphatics, with the application of clinical examination, endoscopic examination with or without biopsy, and imaging studies, is important. For assessment of complete remission in the nasopharynx, the decision about where to draw the line between a slow regressing tumour and a residual tumour remains problematic, but in most cases salvage treatment should not be delayed for longer than about 10 weeks.¹¹⁰ Residual tumours in the

Management of residual or recurrent disease

Despite the effectiveness of radiation and chemotherapy in the management of nasopharyngeal carcinoma, local failure or regional failure presenting as persistent or recurrent tumour still occurs. To attain a high salvage rate, early detection and treatment is essential.¹⁸ FDG PET is better than CT in detecting residual or recurrent disease in the nasopharynx,¹³⁹ and its results can usually be confirmed with biopsy through endoscopic examination. Residual or recurrent tumour in the neck after

Recent developments

In addition to the novel treatment approaches that are generally applicable to cancers at other sites, the close association between EBV and nasopharyngeal carcinoma gives further opportunities for novel treatment. Strategies targeted at EBV include gene therapy and immune therapy, and the proof-of-principles studies have been done in laboratories. Gene therapy with a novel replication-deficient adenovirus vector in which transgene expression is under the transcriptional regulation of oriP of

Search strategy and selection criteria

We did an extensive search of published work about nasopharyngeal carcinoma through the Pubmed/MEDLINE database from 2004 back to the mid-60's, and this search included the OLDMEDLINE. We also searched The Cochrane Library for review articles published between 1990 and 2003. Search terms included: “nasopharyngeal carcinoma”, “nasopharynx cancer”, “radiotherapy”, “chemotherapy”, “salvage therapy”, “nasopharyngectomy”, “combined treatment modality”, “clinical trials”, “randomized controlled

References (177)

JS Sham et al.
Detection of subclinical nasopharyngeal carcinoma by fibreoptic endoscopy and multiple biopsy
Lancet
(1990)
D Svoboda et al.
Ultrastructure of nasopharyngeal carcinoma in American and Chinese patients: an application of electron microscopy to geographic pathology
Exp Mol Pathol
(1965)
ML Gulley
Molecular diagnosis of Epstein-Barr virus-related diseases
J Mol Diagn
(2001)
N Raab-Traub
Epstein-Barr virus in the pathogenesis of NPC
Semin Cancer Biol
(2002)
SP Reddy et al.
Prognostic significance of keratinization in nasopharygeal carcinoma
Am J Otolaryngol
(1995)
P Olmi et al.
Staging and follow-up of nasopharyngeal carcinoma: magnetic resonance imaging versus computerized tomography
Int J Radiat Oncol Biol Phys
(1995)
SH Cheng et al.
Prognostic features and treatment outcome in locoregionally advanced nasopharyngeal carcinoma following concurrent chemotherapy and radiotherapy
Int J Radiat Oncol Biol Phys
(1998)
MB Kumar et al.
Tailoring distant metastatic imaging for patients with clinically localized undifferentiated nasopharyngeal carcinoma
Int J Radiat Oncol Biol Phys
(2004)
E Cellai et al.
Computed tomography in nasopharyngeal carcinoma—part II: impact on survival
Int J Radiat Oncol Biol Phys
(1990)
B Emami et al.
Influence of MRI on target volume delineation and IMRT planning in nasopharyngeal carcinoma
Int J Radiat Oncol Biol Phys
(2003)

FM Fang et al.

Computed tomography findings of bony regeneration after radiotherapy for nasopharyngeal carcinoma with skull base destruction: implications for local control

Int J Radiat Oncol Biol Phys

(1999)

TX Lu et al.

Important prognostic factors in patients with skull base erosion from nasopharyngeal carcinoma after radiotherapy

Int J Radiat Oncol Biol Phys

(2001)

P Teo et al.

Significant prognosticator after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography

Int J Radiat Oncol Biol Phys

(1996)

E Özyar et al.

Comparison of AJCC 1988 and 1997 classifications for nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(1999)

CA Perez et al.

Carcinoma of the nasopharynx: factors affecting prognosis

Int J Radiat Oncol Biol Phys

(1992)

SH Cheng et al.

Examining prognostic factors and patterns of failure in nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy: impact on future clinical trials

Int J Radiat Oncol Biol Phys

(2001)

DT Chua et al.

Volumetric analysis of tumor extent in nasopharyngeal carcinoma and correlation with treatment outcome

Int J Radiat Oncol Biol Phys

(1997)

WM Sze et al.

Primary tumor volume of nasopharyngeal carcinoma: prognostic significance for local control

Int J Radiat Oncol Biol Phys

(2004)

JB Mesic et al.

Megavoltage irradiation of epithelial tumors of the nasopharynx

Int J Radiat Oncol Biol Phys

(1981)

AW Lee et al.

Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure

Int J Radiat Oncol Biol Phys

(1992)

DL Kwong et al.

The effect of interruptions and prolonged treatment time in radiotherapy for nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(1997)

AW Lee et al.

Treatment of stage I nasopharyngeal carcinoma: analysis of the patterns of relapse and the results of withholding elective neck irradiation

Int J Radiat Oncol Biol Phys

(1989)

D Kwong et al.

The effect of loco-regional control on distant metastatic dissemination in carcinoma of the nasopharynx: an analysis of 1301 patients

Int J Radiat Oncol Biol Phys

(1994)

PC Levendag et al.

High-dose, high-precision treatment options for boosting cancer of the nasopharynx

Radiother Oncol

(2002)

QT Le et al.

Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(2003)

DT Chua et al.

Linear accelerator-based stereotactic radiosurgery for limited, locally persistent, and recurrent nasopharyngeal carcinoma: efficacy and complications

Int J Radiat Oncol Biol Phys

(2003)

J Waldron et al.

Limitation of conventional two dimensional radiation therapy planning in nasopharyngeal carcinoma

Radiother Oncol

(2003)

SL Wolden et al.

Failure of a 3D conformal boost to improve radiotherapy for nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(2001)

VW Wu et al.

Target dose conformity in 3 dimensional conformal radiotherapy and intensity modulated radiotherapy

Radiother Oncol

(2004)

CY Hsiung et al.

Intensity-modulated radiotherapy versus conventional three-dimensional conformal radiotherapy for boost or salvage treatment of nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(2002)

N Lee et al.

Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience

Int J Radiat Oncol Biol Phys

(2002)

TX Lu et al.

Initial experience using intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma

Int J Radiat Oncol Biol Phys

(2004)

AW Lee et al.

Retrospective analysis on treating nasopharyngeal carcinoma with accelerated fractionation (6 fractions per week) in comparison with conventional fractionation (5 fractions per week): report on 3-year tumor control and normal tissue toxicity

Radiother Oncol

(2001)

G Franchin et al.

Nasopharyngeal cancer WHO type II-III: monoinstitutional retrospective analysis with standard and accelerated hyperfractionated radiation therapy

Oral Oncol

(2002)

JJ Jian et al.

Improvement of local control of T3 and T4 nasopharyngeal carcinoma by hyperfractionated radiotherapy and concomitant chemotherapy

Int J Radiat Oncol Biol Phys

(2002)

PM Teo et al.

Final report of a randomized trial on altered-fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by significant increase in neurologic complications

Int J Radiat Oncol Biol Phys

(2000)

KH Chi et al.

A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients

Int J Radiat Oncol Biol Phys

(2002)

C Jackson

Primary carcinoma of the nasopharynx: a table of cases

JAMA

(1901)

GB New

Syndrome of malignant tumors of the nasopharynx, a report of seventy-nine cases

JAMA

(1992)

KH Digby et al.