Background Nasopharyngeal carcinoma is a rare tumor arising from the epithelium of the nasopharynx.

It accounts for approximately 1% of all childhood malignancies. Whereas almost all adult nasopharyngeal cancers are carcinomas, only 35-50% of nasopharyngeal malignancies are carcinomas in children. In the pediatric population, additional nasopharyngeal malignancies includerhabdomyosarcomas or lymphomas. Pathophysiology The detection of the Epstein-Barr virus (EBV) nuclear antigen and viral DNA in nasopharyngeal carcinoma has revealed that EBV can infect epithelial cells and is associated with their malignant transformation.[1] EBV genome has been found in cells of preinvasive lesions, suggesting that it is directly related to the process of transformation.

Frequency
United States Incidence varies according to geographic location. Incidence is approximately 1 in every 100,000 children annually among white children in North America and Europe. International The disease is far more common in children of Southeast Asian and Northern African descent, with an incidence of 8-25 in every 100,000 children annually.

Mortality/Morbidity
When radiotherapy is used alone, survival rates range from 40-50%. Use of combination radiation therapy and chemotherapy allows long-term survival rates of 55-80%.

Race
In the United States, the incidence of nasopharyngeal carcinoma is increased among black teenagers.[2] Children of Asian, Middle Eastern, and Northern African descent are also more commonly affected.

Sex
A male preponderance is observed. The male-to-female ratio is approximately 2:1.

Age
Nasopharyngeal carcinoma has a bimodal age distribution. A small peak is observed in late childhood, and a second peak occurs in people aged 50-60 years. Childhood nasopharyngeal carcinoma is usually a disease of adolescence.[3]

History
Nasopharyngeal carcinoma rarely comes to medical attention before it has spread to regional lymph nodes. Enlargement and extension of the tumor in the nasopharynx may result in symptoms of nasal obstruction (eg, congestion, nasal discharge, bleeding), changes in hearing (usually associated with blockage of the eustachian tube, but direct extension into the ear is possible), and cranial nerve palsies (usually associated with extension of the tumor into the base of the skull). One study indicated the following symptoms:[4] Nasal symptoms, including bleeding, obstruction, and discharge (78%) Ear symptoms, including infection, deafness, and tinnitus (73%) Headaches (61%) Neck swelling (63%)

Physical
The most common physical finding is a neck mass consisting of painless firm lymph node enlargement (80%). Neck involvement is often bilateral; the most common nodes involved are the jugulodigastric, and upper and middle jugular nodes in the anterior cervical chain. Cranial nerve palsy at initial presentation is observed in 25% of patients. On nasopharyngoscopy, a mass arising in the nasopharynx is often visible. The most frequent site is the fossa of Rosenmller. A paraneoplastic osteoarthropathy has been described in patients with widespread metastatic or recurrent disease.

Causes
Viral DNA in nasopharyngeal carcinoma has revealed that Epstein-Barr virus (EBV) can infect epithelial cells and is associated with their transformation to cancer. [1] Genetic and environmental factors have been implicated in the development of this disease. A genetic etiology has been considered due to the higher rates of disease within specific ethnic groups, patients with first-degree relatives with the disease, patients with A2 HLA haplotypes, and cytogenetic abnormalities identified within tumor samples. [5, 6] Environmental causes must be considered due to the geographical distribution of the disease and association seen in patients who consume a large amount of preserved foods and/or salted fish.[7]
differential

Nasal Polyps Non-Hodgkin Lymphoma Rhabdomyosarcoma

Laboratory Studies
Perform routine blood work, including a CBC count and chemistry profile. Liver function test results may be abnormal in those rare cases with hepatic metastases. Uric acid levels may be elevated in patients with rapidly growing tumors. Epstein-Barr virus (EBV) titers, including immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to the viral capsid antigen, early antigen, and nuclear antigen should be performed. These titers may correlate with tumor burden and decrease with treatment.[8, 9] New data have emerged that plasma EBVDNA levels may be a helpful marker for pretreatment risk categorization, for initial treatment response, and at the time of relapse.[10]

Imaging Studies
CT scanning CT scanning of the head and neck is used to determine tumor extent, base of skull erosion, and cervical lymphadenopathy. CT scanning of the chest is used to search for distant metastases. When intracranial extension is suspected, MRI may reveal the extent of the tumor.

MRI of the head and neck in patient with nasopharyngeal carcinoma showing the primary tumor and cervical lymph node metastases

Bone scans are used to search for distant bony metastatic disease.

Positron emission tomography (PET) imaging has been used to assess questionable neck nodes and

evaluate for other sites of distant disease.

images for patient with nasopharyngeal carcinoma

Intensity modulated radiotherapy

Other Tests
A baseline audiogram is helpful prior to radiotherapy, especially in children who receive cisplatin. Creatinine clearance rates (24-hour collection or nuclear GFR testing) should be obtained at baseline and during treatment for those patients being treated with platinum-based chemotherapy because decreases in renal function, requiring dose modifications, have been reported.

Procedures
A biopsy of the primary lesion or neck node is obtained for diagnosis. Because of severe oropharyngeal mucositis that can be seen with radiation therapy, strong consideration of gastrostomy tube placement should happen at diagnosis and/or prior to initiation of radiation therapy in order to sustain proper hydration and nutrition.

Histologic Findings
The World Health Organization (WHO) has classified nasopharyngeal carcinoma into 3 categories. WHO-1 is defined as welltomoderately differentiated squamous or transitional cell carcinoma with keratin production. WHO-2 is nonkeratinizing carcinoma. WHO-3 is undifferentiated carcinoma, including lymphoepithelioma. This entity consists of malignant epithelial cells with lymphocytic infiltration. The vast majority of children are found to have WHO-3 disease.[11, 12]

Staging
Various staging schema have been proposed for nasopharyngeal carcinoma in children. [13] No single system has proven satisfactory in correlating disease extent to prognosis. The TNM system, widely used in adult head and neck cancers, places most childhood disease in the advanced-stage category and does not recognize the relatively good prognosis of many children in these stages. Modification of the TNM system that further divides patients into various groups based on prognosis has been proposed. The T stage alone has been shown to have limited predictive value.

Medical Care
Radiation therapy is the mainstay of treatment, with chemotherapy used in advanced cases. Concurrent cisplatin, 5-fluorouracil, and radiotherapy have been shown to improve survival. [14, 15, 16] Many pediatric studies have used neoadjuvant chemotherapy followed by radiation therapy with improvement in local control or progression-free survival rates over radiotherapy alone.[17, 18, 19] Radiotherapy is administered to the primary tumor and level II-V neck nodes. Care should be taken to include the skull base in the initial field because nasopharyngeal cancer can travel via the foramen lacerum. Traditionally, the initial radiotherapy fields are often treated with 2 parallel opposed lateral fields that encompass the nasopharynx and upper cervical nodes. The lower cervical nodes are treated with an anterior field, which abuts the upper lateral fields superiorly. These patients are now commonly treated with 3-dimensional treatment, conformal radiotherapy, or intensity modulated radiation therapy (IMRT). Avoid overdose to the spinal cord at this junction by using a spinal cord block at the upper lateral fields or lower anterior supraclavicular field. Treatments are administered at 1.8-2 Gy/d for 5 days a week until

a dose of 40-44 Gy has been administered. Thereafter, additional radiation is administered to the posterior neck nodes using electron beam to avoid radiation myelitis. A dose of 50 Gy to the neck is desirable; bulky neck masses may need higher doses of 66-70 Gy. Nasopharyngeal tumors and anterior neck tumors continue to be treated with parallel opposed fields to a dose of at least 50 Gy. The primary site then receives a boost, delivering a dose of 50-70 Gy. Threedimensional (conformal) radiotherapy may be used to spare more critical structures next to the nasopharynx, such as the brain, pituitary gland, optic chiasm, optic nerve, and spinal cord. Data show that lower doses of radiotherapy may suffice when the response to neoadjuvant chemotherapy is excellent.[20] However, a multi-institutional study showed that doses of at least 66 Gy are needed for optimal local control.[21] Others have used a radiotherapy dose adaptation strategy where children responding well to chemotherapy receive less radiotherapy dose. In one study, cervical nodal irradiation was reduced to < 50 Gy with good response to chemotherapy (>90% shrinkage of original tumor) with a 5-year, event-free survival rate of 75%.[22] Parotid sparing techniques are also available in some centers with 3-dimensional treatment capability or IMRT.[23] Data using IMRT reveal equivalent or better locoregional control compared with conventional radiotherapy and sparing of the parotid glands from high doses of radiation therapy. [24] During the course of radiotherapy, several immediate effects may occur, usually after the first 2 weeks of treatment. Confluent mucositis usually occurs, especially in children receiving both radiotherapy and 5-fluorouracil. Dry mouth and thick saliva are also likely secondary to irradiation of the salivary glands. Redness, itching, and peeling of the treated skin can occur towards the end of radiotherapy and may need to be treated with topical antibiotics and Silvadene. Because of this oropharyngeal mucositis, consideration of placement of a gastrostomy tube prior to initiation of radiotherapy. If a gastrostomy tube is not placed, poor nutrition and dehydration are quite common, and intravenous fluids may need to be administered. A study of children treated with IMRT showed less acute toxicity (skin, mucous membrane, pharynx) compared with conventional radiotherapy.[25] Some centers use amifostine, a radioprotective agent, to help reduce radiation-related xerostomia. Possible side effects of amifostine such as flulike symptoms, nausea, and hypotension have limited its widespread use in the oncologic community.

Surgical Care
Surgical therapy for these patients is often limited to a biopsy for tissue diagnosis. Nearly all tumors are unresectable at diagnosis because of tumor location.

Consultations
Consultation with an otolaryngologist is often required in the initial management to obtain tissue diagnosis and in follow-up endoscopic examinations to rule out recurrence. An otolaryngologist may also be involved if the child develops sensorineural hearing loss from cisplatin and radiotherapy. Consultation with an endocrinologist may be required in the future if the child shows signs of growth retardation or hypothyroidism secondary to radiotherapy. [23] Occasionally, children develop panhypopituitarism. Consultation with a dentist familiar with radiation effects should be performed prior to initiation of radiotherapy to minimize risk of osteoradionecrosis. Patients also need to be followed after treatment as xerostomia and change in salivary consistency may predispose the patient to dental caries.

Diet
Many patients experience severe mucositis during radiotherapy. Certain foods may irritate irradiated mucosa, causing pain or difficulty swallowing or chewing. Soft foods such as milkshakes, mashed potatoes, and pureed meats are advisable during the course of radiotherapy. Citrus fruits, spicy foods, salty foods, and coarse foods can make the irritated mucosa worse. Gastrostomy tube placement allows adequate hydration and calorie intake during radiotherapy.

Activity

Activity depends on the child's condition. During periods of chemotherapy-induced thrombocytopenia, some limitation of strenuous activity and avoidance of contact sports is necessary. Infectious contacts should be avoided where possible, especially during periods of neutropenia.

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