Abstract

Nasopharyngeal carcinoma is the most common malignant tumour of the nasopharynx with lymphoepithelioma being a more common subtype. It presents often in younger age groups and shows a definite association with Epstein-Barr virus. In our case report, the patient presented with nasal obstruction and left cervical lymphnode mass. There was involvement of the skull base, with extension to cavernous sinus, epidural and intraspinal space. The patient was given radiotherapy following which the neck mass subsided completely. The primary treatment of nasopharyngeal carcinoma is high dose radiation therapy, both for the primary tumour site and the neck. Surgery is indicated in case of nodes that do not regress after radiation or that reappear following complete clinical response. Neoadjuvant chemotherapy is used to shrink the tumours to make them more definitely treatable with radiation . An effective immunologically based approach in future, with certain antiEBV antibodies associated with improved prognosis, offers good hope.

Introduction

Nasopharyngeal carcinoma is the most common malignant tumour of the nasopharynx with Lymphoepithelioma being a more common sub-type. This term implies a carcinoma containing lots of immune system cells especially “Lymphocytes” among the cancer cells, the presence of which does not affect the choice of treatment options.It tends to spread widely, is not often treated by surgery and has different risk factors from most oral cancers.

The nasopharynx contains several layers of tissue with many cell types, each kind of cell can give rise to different cancers, and these differences determine the seriousness of cancer and the type of treatment needed. The nasopharynx is lined by stratified squamous epithelium or pseudostratified columnar epithelium which can give rise to nasopharyngeal carcinoma. All sub-types develop from the epithelial cells that cover the surface lining of the nasopharynx. It is worth mentioning here, that the stage is often more important than its type, in predicting the outlook for survival.

Nasopharyngeal carcinoma is more commonly found in Asian countries, especially the Chinese population. It presents more often in younger age groups as compared to other head and neck cancers.

There is a definite association with Epstein-Barr virus with many patients having antiEBV antibodies. It has both genetic and environmental aetiologies. HLA-A2 and HLA-B-sin2 histocompatibility loci have been identified as possible markers for genetic susceptibility.1 Though nasopharyngeal carcinoma has good treatment modalities, it is often missed or misdiagnosed early, due to vague presenting symptoms, and difficulty in examining the nasopharynx.

Case Report

A 13 year old male patient from Raipur who came with complaints of nasal obstruction and mouth breathing since 3 months. He also had swelling in the left cervical region associated with pain since 3 months, reduced vision in the right eye and reduced hearing in both ears since 3 months. The patient complained of occasional breathlessness, chest pain, loss of weight and appetite since 1 year. He also had 2 episodes of projectile vomiting and headache in 1 year. He was admitted in a hospital at Raipur 3 months ago. FNAC was done there and report showed TB lymphadenitis and was given anti-tuberculous treatment (AKT4) for 3 months. CT scan neck was done, which showed a mass in the nasopharynx and oropharynx, extending intracranially around the right cavernous sinus. The patient was treated conservatively and sent to our hospital. On examination, he was thin built, emaciated (20 kg), with apparent dislocation of atlanto-axial joint. (He had to lift his head with support of his hands). Examination of the ears was normal. Secretions were present in the nose, and the throat showed a mass in the oral cavity coming from nasopharynx. This was smooth and pinkish in colour and occupied more than half the oropharynx on the left side. On local examination, a mass was present in the left cervical region about 3 cm x 4 cm, firm in consistency, tender and fixed (Fig. 1).

Eye movements were normal with reduced vision on right side; sensations on the left side of face were reduced. The patient was investigated and blood parameters were normal. He was Hepatitis B positive. X-ray of cervical spine showed destruction of dens and arch. CT scan neck was done which showed large homogeneously enhancing nasopharyngeal mass extending to involve the skull base and the right cavernous sinus, right orbital apex, right half of sphenoid and post nasal cavity (Figs. 2,3).

There was bony destruction of the right medial pterygoid plate, floor of sphenoid and anterior arch of atlas with epidural and intraspinal extension (Fig. 4).

Right cavernous mass was 3.2 x 2.8 cm. The patient underwent nasal endoscopy with biopsy of the mass and FNAC of cervical lymph node under local anaesthesia. Histopathology showed undifferentiated carcinoma of nasopharynx of lymphoepithelioma type. FNAC report showed suspicion of malignancy. Patient was given radiotherapy for 42 days which included a total of 36 fractions and 59.90 grey units. After radiation cervical swelling subsided completely and nasopharyngeal mass greatly reduced in size (Fig. 5).

Fig. 1 :Clinical photo showing swelling on left side of neck.	Fig. 2 :Coronal CT scan showing mass in nasopharynx and right cavernous sinus.	Fig. 3 :Axial CT scan showing intracranial involvement of right cavernous sinus
Fig. 4 :Axial CT scan showing intra-spinal extension with destruction of dens and arch of atlas.	Fig. 5 :Clinical photo post-radiotherapy showing regression of neck nodes.

The patient was then discharged and consequently was scheduled for chemotherapy.

Discussion

Nasopharyngeal carcinoma has 3 subtypes:

1. Keratinising squamous cell carcinoma
2. Non-keratinising carcinoma
3. Undifferentiated carcinoma

Type 1 : The prevalence is 25% with survival rates of 10%. It contains moderate to well differentiated cells producing keratin and intercellular bridges. Human papilloma viruses (types 11 and 16) have been identified.

Type 2 : It comprises 12% cases. The cells vary from mature to anaplastic with survival rates being 50%.

Type 3 : It is the most common variety with 60% cases with diverse cells including lymphoepithelioma, anaplastic, clear cells and spindle cells.

It is sometimes difficult to differentiate them from lymphomas and special stains and markers are required for the same.

Here we use the term lymphoepithelioma when tumour cells are located in a lymphoid stroma with density of the stroma being greater than the tumour cells themselves. Survival rates of this type are 50%. The lesions of type 2 and 3 tend to be more chronic with recurrences occurring several years later after the initial treatment. There is a common association seen with anti-EBV serologies and EBV DNA in tumour cells.

To diagnose nasopharyngeal carcinoma early, a high index of suspicion is required as the initial symptoms are often subtle and vague.

The most common presenting symptom is a neck mass (due to adenopathies). The commonest finding is unilateral hearing loss from middle ear effusion and this should be considered an indication for nasopharyngeal examination. Other symptoms are nasal obstruction, epistaxis and at a later stage, with skull base invasion, cranial nerves may become involved. Orbital invasion can also occur. With the involvement of greater superficial petrosal nerve at the foramen lacerum, xerophthalmia may result and trigeminal involvement may lead to facial pain. The patient may have diplopia due to isolated involvement of abducens nerve and ophthalmoplegia with involvement of cranial nerves 3, 4, 6 in the cavernous sinus or the superior orbital fissure. Horner’s syndrome may occur due to injury to cervical sympathetic.2 Due to a rich lymphatic network, in the nasopharynx, which crosses the midline, bilateral regional spread is quite common. Distant spread to lungs, bone or liver is rare.1

The most common site of origin of these tumours is fossa of Rosenmuller and it can spread laterally through an anatomical opening in the pharyngo-basilar fascia, reaching the parapharyngeal space, and from here the mass may spread to skullbase or masticator space.

In about 25% of patients, direct superior extension in, or through the skullbase is seen, commonly occurring at the level of foramen lacerum, or petro-clinoid fissure. From the masticator space, the lesion can spread superiorly along the mandibular nerve (through foramen ovale), inferiorly along the pharyngeal walls, and anteriorly to the nasal cavity. Most of the patients have lymphatic spread at the time of presentation, and the first ones to be involved are the retro-pharyngeal lymph nodes.

The nasopharyngeal carcinoma can be staged as below:

Cellular Classification

This includes lymphoepithelioma (schminke tumour), transitional cell tumours, well to poorly differentiated grade, and keratinizing or non keratinizing variety.3

The presence of “keratin” has been associated with reduced local control and survival. The American Joint Committee on cancer (AJCC) has designated staging by TNM classification to define nasopharyngeal carcinoma.

Tnm Definitions

Management

The primary tumour is assessed by inspection and palpation when possible and by both indirect mirror examination and direct endoscopy.

It is confirmed by histology and biopsy. The cranial nerves functions should be evaluated and appropriate nodal drainage areas are examined by careful palpation. For staging diagnostic imaging studies may be used. While contrast CT is the imaging tool of choice, MRI offers an advantage over the CT scanning in detection and localization of head and neck tumours, and distinction of lymph nodes from blood vessels. CT is needed for evaluation of early bone invasion. MRI is helpful in evaluation of soft tissue involvement especially with recurrent cancer. In case of a relapse, a complete reassessment must be done to select the appropriate additional therapy.

Immunofluorescence for IgA antibodies to the viral capsid antigen and IgG antibodies to the early antigen can help identify occult or early disease in many cases.

Three types of treatments are used.

A) Radiation therapy

This treatment uses high energy X-rays or other types of radiation to kill cancer cells. It is of two types.

1. External radiation – uses machine outside the body to send radiation towards the cancer. The radiation therapy to thyroid or the pituitary may change the way the thyroid gland works, so it has to be tested before and after the therapy. It is also important to evaluate dental health before beginning the therapy.
2. Internal radiation – This uses a radioactive substance sealed in needles, seeds, wires or catheters that are placed directly into or near the cancer. The radiation therapy depends on type and stage of cancer being treated.

B) Chemotherapy

It is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. It is divided into

1. Systemic – when drug is taken by mouth or given intravenous/intramuscular in the bloodstream.
2. Regional - when drugs are directly placed into spinal column an organ or a body cavity like abdomen. This also depends on the type and stage of cancer.
3. Surgery - It can be used for nasopharyngeal carcinoma that does not respond to radiation. The lymph node extension can also be resected by surgery.

Biologic therapy

It is a treatment that uses patient’s immune system to fight cancer. The substances made by the body or made in a laboratory boost, direct or restore the body’s natural defences against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

The treatment is usually radiation therapy to the tumour and lymph nodes in the neck.

Chemotherapy is combined with radiation therapy.

Radiation therapy to the tumour and lymph nodes in the neck.

Chemotherapy combined with radiation therapy.

Radiation therapy to the tumour and lymph nodes in the neck.

The radiation therapy is given followed by surgery to remove cancer containing lymph nodes in the neck that persist or come after radiation therapy. A clinical trial of chemotherapy before, combined with, or after radiation therapy is given.

Chemotherapy combined with radiation therapy.

High dose or super fractionated radiation therapy to the primary tumour site and bilateral lymph nodes that are clinically positive is given.4 The neck dissection should be reserved for persistent or recurrent nodes.4 Chemotherapy is for the patients with stage 4c disease.5

Treatment Options Under Clinical Evaluation

Neoadjuvant Chemotherapy as given in clinical trials has been used to shrink tumours, thereby rendering them more definitely treatable with radiation.

For the advanced tumours, clinical trials to evaluate the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant therapy after radiation therapy should be considered.

Treatment Option Overview

The primary treatment of nasopharyngeal cancer is high dose radiation therapy, both for the primary tumour site and the neck. Surgery is used for nodes that fail to regress after radiation or that reappear following complete clinical response.

Those patients undergoing external radiation to thyroid or pituitary show high incidence (> 30% - 40%) of hypothyroidism.6 Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumours, thereby making them more definitely treatable with radiation. Here the chemotherapy is given prior to other modalities hence it is called neoadjuvant as compared to standard adjuvant which is given after or during definitive with radiation or after surgery.

In case of advanced tumours, the clinical trials to evaluate the use of chemotherapy before radiation therapy, concomitant with radiation therapy, or as adjuvant after radiation should be considered.

Conclusion

It is found that adjuvant chemotherapy, race or sex has no prognostic value. It is also difficult to analyse the prognostic significance of histology and nodal status due to disparities in the distribution of patients with lymphoepithelioma and squamous histologies.

The fundamental obstacles to effective management and enhanced survival for the patients with nasopharyngeal carcinoma are high doses of radiation and a high systemic failure rate. An improved prognosis associated with certain anti-EBV antibodies offers the hope of effective immunologically based approach in future.

References

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2. Gustafson RO, Neel HB. Cysts and Tumors of the Nasopharynx. In: Paparella MM et al. eds. Otolaryngology. Philadelphia: W.B. Saunders, 1991: 2189-98.
3. Ensley J, Crissman J, Kish J, et al.The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 1986; 57 (4) : 711-7.
4. Schantz SP, Harrison LB, Forastiere AA. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2001, pp 797-860.
5. Ma BB, Tannock IF, Pond GR, et al. Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer 2002; 95 (12) : 2516-23.
6. Turner SL, Tiver KW, Boyages SC. Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 1995; 31 (2) : 279-83.

*Senior Resident; **Associate Consultant, Department of E.N.T, Bombay Hospital and Medical Research Centre, Mumbai - 400 020, India.