Continuing Education Activity

Nasopharyngeal carcinoma (NPC), previously known as lymphoepithelioma, is a malignancy arising from the epithelium of the nasopharynx. Endemic to China, the malignancy shows a variable rate of occurrence ranging from high incidence in the Southern part of China to a low rate in the white population and Northern China, with an incidence ranging from 15 to 50 per 100000. A complex interplay of genetic susceptibility and Epstein-Barr virus (EBV) infection is responsible for the disease. This activity describes in detail the incidence, epidemiology, clinical manifestations, evaluation, and treatment of nasopharyngeal carcinoma and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology and epidemiology of nasopharyngeal carcinoma.
• Outline the appropriate history, physical, and staging evaluation of nasopharyngeal carcinoma.
• Review the treatment and management options available for nasopharyngeal carcinoma.
• Describe interprofessional team strategies for improving care coordination and communication to advance care and allow early detection of nasopharyngeal carcinoma and improve outcomes.

Introduction

Nasopharyngeal carcinoma (NPC), previously known as lymphoepithelioma, is an undifferentiated form of squamous cell carcinoma arising from the epithelium of the nasopharynx. It is the most common malignancy of the nasopharynx. Endemic to parts of Asia and Africa but found worldwide, the malignancy shows a variable rate of occurrence ranging from high incidence in the southern part of China (25 to 50 cases per 100,000) to a low rate in European populations (1 case per 100,000).[1] A complex interplay of genetic susceptibility and Epstein-Barr virus (EBV) infection is responsible for these epidemiological patterns. There is a male predominance.[2]

Etiology

An interplay of environmental factors, genetic structure, and EBV infection is involved in the etiology of the disease. Environmental factors, including smoking (2 to 6 fold increased risk), heavy alcohol consumption, and nitrosamine-containing food agents, have been considered to have an involvement.[3] Secondly, the genetic structure of the demographics involved also plays a vital role, as explained by the overwhelming incidence in the Chinese population (representing up to 18% of all cancers in parts of southern China and Taiwan).[1] Lastly, EBV infection, coupled with genetic susceptibility, has shown a substantial relevance to the disease.[4][5]

Epidemiology

Nasopharyngeal carcinoma (NPC) is endemic to southern China, other parts of Southeast Asia, and parts of Africa. The rate varies from a minuscule value of less than 1 per 100,000 individuals in non-endemic areas to a high of 25 to 50 cases per 100,000 males and 15 to 20 cases per 100,000 individuals in females in endemic regions.[6]

Histopathology

Histopathological evaluation can elucidate in which category the tumor falls.[7] On histopathological grounds, NPC can fall into three main sub-groups as per WHO classification:

1. Keratinizing type (20% to 25%)
2. Non-keratinizing differentiated type (10% to 15%)
3. Non-keratinizing undifferentiated (60% to 65%)

History and Physical

Patients can have variable presentations depending on the area of involvement of the disease. The most common site of origin is the lateral aspect of the nasopharynx and the fossa of Rosenmuller.

• Nasal symptoms: A subset of patients present with nasal symptoms, including nasal obstruction, epistaxis, post-nasal drip, hyponasal speech, or cacosmia. Symptomatology is proportionate to the size of growth and the extent of local involvement—around 80% of the individuals suffering from the disease present with nasal symptoms.
• Otological symptoms: Patients may present with symptoms secondary to Eustachian tube obstruction by the tumor, such as conductive hearing loss, middle ear effusion, or aural fullness. An adult with unilateral middle ear effusion requires visualization of the nasopharynx to exclude neoplasm. Half of the patients with NPC have some form of otological complaint during the disease caused because of the growing mass obstructing the outflow of the Eustachian tube.
• Neurological symptoms: Intracranial extension is prevalent among 8% to 12% of patients — various forms of cranial nerve involvement present with the associated symptom. Cranial nerve palsy is found in 20% of nasopharyngeal carcinoma patients and may be the presenting symptom[8]. The most commonly involved nerve is the abducens nerve.[9]
• Nodal involvement: One of the most common presenting features is an enlarged cervical lymph node. Lymph nodes of the apex of the posterior triangle and the upper jugular are initially most commonly involved, together with retropharyngeal nodes. Supraclavicular nodes are the last to be involved and are a sign of advanced disease.[10]

Distant metastasis and paraneoplastic syndrome: Symptoms associated with distant spread rarely present to the primary caregiver. The most significant spread includes the liver and lungs. It is sometimes difficult to assess the primary site of malignancy when metastatic pulmonary lesions occur. PET scan aids in the differentiation of the two. Secondly, a handful of cases present with symptoms of dermatomyositis. The progression of the disease might initiate with the malignant lesion or can present after the initial diagnosis of NPC.[11]

Evaluation

Lab Investigations

• Baseline investigations may include complete blood count, and renal and liver function tests can be obtained if there is a concern for metastasis or paraneoplastic syndrome.
• Epstein Barr virus serum IgA levels may carry diagnostic and prognostic significance, particularly in endemic populations.[11]

Imaging Studies

• Computed tomography: CT scan with IV contrast is the modality of choice for bone invasion and extent of some soft tissues, as well as in assessing cervical nodal basins.
• Magnetic resonance imaging: MRI is the superior modality for assessing intracranial extension, cranial nerve involvement, and defining paranasal sinus involvement. MRI also provides excellent soft-tissue detail when assessing muscle involvement. There is also no radiation exposure with MRI as compared to CT.
• PET scan: It is the modality of choice for assessing remission and investigating recurrence. It is also routinely employed at initial staging to identify distant metastases.

Endoscopic Evaluation and Histopathological Analysis

• The nasopharynx is readily accessible for biopsy via endoscopic, trans-nasal routes. Cervical metastases can also be biopsied via fine-needle aspiration if they are easily palpable or visualized under ultrasound or CT guidance.

Treatment / Management

The mainstay of treatment for NPC is radiotherapy, with the addition of chemotherapy for advanced-stage disease. Surgical intervention is limited to extremely small primary lesions or small recurrences, as the morbidity of large-scale surgical resection is often significantly more than the morbidity associated with radiotherapy to the region.

Radiotherapy

Radiation therapy is the management of choice for primary lesions and cervical metastases. NPC often metastasizes early to the cervical lymph nodes, and this is frequently a presenting complaint. The tumor also grows locally, involving the paranasopharyngeal spaces and musculature, and may do so with little to no symptoms present. Consequently, a dose of approximately 65 Gy for primary tumors with 50 to 55 Gy is also necessary for node-negative necks.

A recent innovation in the delivery system employed for radiation is intensity modulation or intensity-modulated radiotherapy (IMRT). The system comes equipped with a CT taking slices of the area involved. The physician specifies the targeted area of the beam and modulates the intensity of the beam employed.[12]

Brachytherapy is another innovative technique for targeted radiotherapy. The technique used is the implantation of gold grains or iridium implants, jacketed for localized radiotherapy, via a split incision of the soft palate. In the modern era of IMRT, this technique is very infrequently used.

Radiotherapy is also employed for recurrent nasopharyngeal carcinoma, though repeat radiation to the same area with curative intent will depend on the time elapsed since initial treatment and may fall into the realm of clinical trials. Radiation therapy can be used for palliative intent as well.[5][13] 

Chemotherapy

In locally advanced regional disease, concomitant chemoradiotherapy is the mainstay of management, either via induction or concurrent therapy protocols. The most frequently used initial agent is cisplatin. The standard of care is a dose of 100 mg every third week.

Chemotherapy is also the option of choice when distant metastasis is involved. NPC with distant poly-metastasis is offered palliative chemotherapy. The agents of choice are cisplatin and 5-fluorouracil. With recent advances, several chemotherapeutic agents are available for the continuation of therapy. However, the median survival rate is not more than a year.[5][13]  

Surgical Intervention

Surgical intervention is employed primarily as a salvage option. The nasopharynx is a small and deep area that is hard to access, thus making the surgical approach to it sometimes difficult and inappropriate. However, when encountering locally recurring disease, patients should be given the option of surgical intervention.[14][15]

Nasopharyngectomies are carried out by several approaches, and the approach decided should be tailored in accordance with the expertise of the surgeon and the general condition of the patient. The following are some of the popular approaches to the cavity.

• Inferior approach- via transpalatal incision
• Lateral approach- via the lateral skull base
• Inferolateral approach
• Midfacial degloving
• Endoscopic approach

Neck dissections often accompany the procedures mentioned above, where extensive neck involvement is present. Neck dissection is frequently a component of surgical salvage, particularly in the case of regional recurrence.

Differential Diagnosis

Benign Conditions

• Nasopharyngeal polyposis
• Angiofibromas
• Antro-choanal polyp
• Inverting papilloma
• Adenoid hypertrophy
• Thornwaldt cyst
• Encephalocele

Malignant Lesions

• Lymphoma
• Sarcoma
• Mucosal melanomas

Staging

The nuances in imaging techniques and the improved outcomes associated with optimum therapy have caused the American Joint Committee on Cancer (AJCC) to reevaluate the staging process in 2018.[16] As per the recent guidelines, the TNM staging has been defined as:

Primary Tumor (T)

• T0: No primary tumor identified (but with EBV-positive cervical node)
• Tis: Carcinoma in situ, no invasive tumor present
• T1: Tumor involves nasopharynx, oropharynx, and/or nasal cavity without parapharyngeal involvement
• T2: Tumor extension into the parapharyngeal spaces or adjacent soft tissue (pterygoids, prevertebral muscles)
• T3: Tumor involves bony skull base, pterygoid bones, paranasal sinuses, cervical vertebrae
• T4:Tumor involves intracranial extension, deficits of cranial nerves, hypopharynx, orbit, parotid gland, and/or soft tissue infiltration beyond the lateral surface of the lateral pterygoid

Nodal metastasis (N)

• N0: No involvement
• N1: Unilateral cervical or unilateral or bilateral retropharyngeal node(s), ≤ 6 cm in greatest dimension, all located above the caudal border of the cricoid cartilage
• N2: Bilateral cervical node(s), ≤ 6 cm in greatest dimension, all located above the caudal border of the cricoid cartilage
• N3: Unilateral or bilateral cervical node(s) > 6 cm in greatest dimension or located below the caudal border of the cricoid cartilage

Distant Metastasis (M)

• M0: No distant metastases
• M1: Distant metastases present

Stage Grouping

• Stage 0: T1s-N0-M0
• Stage I: T1-N0-M0
• Stage II: T1-N1-M0 and T2-N0, N1-M0 
• Stage III: T1, T2, T3-N2-M0 and T3-N0, N1, N2-M0
• Stage IVA: T4-any N-M0 and Any T, N3-M0
• Stage IVB: Any T-any N, M1

Prognosis

The overall prognosis and the 5-year survival rate have improved with the advent of improved radiotherapy techniques. This has resulted in reported 5-year survival rates increasing from 25% to 40% historically to approximately 70% in the modern treatment era.[17]

Complications

Obstruction of Eustachian tubes causing otitis media with effusion (OME) is the most common complication, but persistent nasal obstruction and obstruction of the oropharyngeal airway are also possible. Intracranial extension and involvement of cranial nerves are debilitating and can have a lifelong disability even after management, as the return of cranial nerve function is not always possible even after the malignancy has been treated. More than one cranial nerve deficit is a poor prognostic sign.[18]

Consultations

• Otolaryngology - nasopharyngeal biopsy and placement of tympanostomy tube
• Pathology or radiology - FNA of cervical lymph node
• Radiation oncology - definitive treatment
• Hematology/Oncology - concurrent chemotherapy
• Psychiatry - mental health in the setting of a new cancer diagnosis

Deterrence and Patient Education

Patients endemic to prevalent areas should be more vigilant regarding the symptoms of the disease. Moreover, the demographics of the western population having environmental factors (smoking, etc.) associated with NPC should also receive education regarding their hazardous effects. Also, the subset of people having genetic susceptibility along with recurrent EBV infection should have a higher index of suspicion for the disease.

Pearls and Other Issues

• NPC is a malignancy having a variable incidence depending on the region.
• Endoscopic biopsy should be the first and foremost step in evaluating the lesion.
• NPC has a high index of susceptibility to radiotherapy, and this forms the mainstay of treatment at nearly every stage
• In advanced cases, chemotherapy is given concomitantly to produce optimum results. The drug of choice is cisplatin.

Enhancing Healthcare Team Outcomes

After diagnosis, a radiotherapist and oncologist should educate the patient regarding the favorable outcome associated with strict adherence to the program. Otolaryngology and otolaryngology nurses provide care and education to these patients after nasopharyngeal biopsy and regarding hearing optimization if Eustachian tube dysfunction is present. Board-certified oncologic pharmacists review prescriptions and check for drug-drug interactions. Oncology specialty nursing staff can administer chemotherapy, assist in post-procedural care and monitoring, and report any concerns to the treating clinicians.

All these interprofessional team members are tasked with keeping meticulous patient records so that everyone involved in the patient's care has the most accurate and updated information, and everyone must maintain open communication lines so interventions can be promptly initiated when needed. Also, patients having the psychological burden of a malignant diagnosis benefit from structured support groups and psychologist sessions, so mental health practitioners should also be part of the interprofessional team. [Level 5]