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Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 1-6

Pediatric nasopharyngeal carcinoma

1 Department of Otorhinolaryngology, IMS and SUM Hospital, Siksha “O” Anusandhan University (Deemed to be), Bhubaneswar, Odisha, India
2 Medical Research Laboratory, IMS and SUM Hospital, Siksha “O” Anusandhan University (Deemed to be), Bhubaneswar, Odisha, India

Date of Submission03-Sep-2019
Date of Decision03-Sep-2019
Date of Acceptance14-Oct-2019
Date of Web Publication13-Jan-2020

Correspondence Address:
Prof. Santosh Kumar Swain
Department of Otorhinolaryngology, IMS and SUM Hospital,Siksha "O" Anusandhan University (Deemed to be), K8, Kalinga Nagar, Bhubaneswar - 751 003, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijhas.IJHAS_6_19

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Nasopharyngeal carcinoma (NPC) is an extremely rare malignancy among pediatric age group. The relative rarity of pediatric NPC makes the diagnosis difficult and associated with late diagnosis and advanced locoregional disease. The clinical presentations of pediatric NPC are usually nonspecific. The children with NPC have excellent survival except those with metastatic disease. The tumor, nodes, metastases (TNM) staging has the most relevant prognostic factor. Unfortunately, NPC tends to be locally advanced at the time of diagnosis in pediatric age group and sometimes associated with distant metastasis. NPC in pediatric age is usually not suspected clinically until the patient in the late stage. The diagnosis of pediatric NPC should prompt and require early treatment. Delayed diagnosis of NPC affects the management and prognosis. The purpose of this review article is to discuss the etiopathology, epidemiology, clinical presentations, diagnosis, current treatment, complications of treatment, and prognosis of pediatric NPC.

Keywords: Chemoradiation, nasopharyngeal carcinoma, pediatric age, radiotherapy

How to cite this article:
Swain SK, Samal S, Anand N, Mohanty JN. Pediatric nasopharyngeal carcinoma. Int J Health Allied Sci 2020;9:1-6

How to cite this URL:
Swain SK, Samal S, Anand N, Mohanty JN. Pediatric nasopharyngeal carcinoma. Int J Health Allied Sci [serial online] 2020 [cited 2020 Aug 8];9:1-6. Available from: http://www.ijhas.in/text.asp?2020/9/1/1/275649

  Introduction Top

Nasopharyngeal carcinoma (NPC) is a malignant neoplasm arising from the epithelial cells lining the nasopharynx. NPC is a head-and-neck malignancy with remarkable ethnic and geographical variations in incidence. It is a rare malignancy with an incidence in high-risk areas as 20/100,000 persons in a year and lower rates seen in pediatric age.[1] NPC is a rare tumor in children younger than 10 years of age, and the incidence rises gradually with age of the patient. It is a common head-and-neck tumor seen in adults, and its incidence varies in the different parts of the world. The high-risk regions for NPC are South China, Taiwan, and Hong Kong.[2] NPC is extremely rare among children regardless of the different regions in the world. Approximately 5% of the primary malignant neoplasm in children arise from the head-and-neck area,[3] whereas NPC represents around 2% of the head-and-neck malignant neoplasm in pediatric age group.[1] As this is rare in pediatric age group and its nonspecific clinical presentations such as nasal congestion, lymphadenopathy, and ear symptoms, the diagnosis often delayed because of initial thinking of benign etiologies. The standard treatment of NPC is radiotherapy. In pediatric population, early diagnosis of NPC prior to locoregional spread will avoid the extent of radiation and associated comorbidities of the treatment. Here, we attempt to discuss the epidemiology, etiopathology, clinical presentations, investigations, current treatment, complications of treatment, and prognosis of pediatric NPC.

  Method Of Literature Search Top

For searching the published article, we conducted an electronic search of the MEDLINE, PubMed, and Scopus. Articles regarding NPC in pediatric age group were identified through a multistage systematic approach. The search term in the database included NPC, pediatric age, radiotherapy, and chemoradiation. The abstracts of the published article are identified by this search method, and other articles were identified manually from citations. Then, we systematically analyzed and reviewed all the literature. This review article presents baseline from where further prospective trials can be designed and help as a spur for further research in this clinical entity where not many studies are done.

  Epidemiology Top

NPC among pediatric age group constitutes 1%–5% of all pediatric cancers and 20%–50% of all primary nasopharyngeal malignant neoplasms of children.[4] NPC is a head-and-neck malignancy commonly seen in South China, Southeast Asia, and North Africa.[2] NPC is an endemic disease in Southeast Asian countries where the incidence is 30–50 in 100,000 population and often strongly associated with Chinese ethnic origin.[5]

Pediatric NPC is a rare neoplasm, and the incidence varies from endemic to nonendemic areas. The annual incidence of NPC is around 0.5/million children (aged 10–14 years ) and 1.08 million adolescents (aged 15–17 years).[6] The incidence of childhood NPC is <1% of all pediatric malignant neoplasms.[7] In the present study, the incidence of NPC among boys and girls is in the ratio of 2.2:1, consistent with previous studies,[8],[9] and in the general population (2–3:1).[10] The incidence of NPC is more among black teenagers in the United States. Children of Asian and North Africa descent are often affected.

  Etiopathology Top

NPC is a common malignant tumor seen in the nasopharynx. The causes of NPC are multifactorial and include viral, environmental, and genetic.[2] NPC is usually caused due to genetic susceptibility, environmental factors such as exposure to chemical carcinogens, and infections with Epstein–Barr virus (EBV). Raised antibody titers to EBV antigens are diagnostic markers.[11] NPC in children differs from the elderly in that the former is closely associated with EBV infection. The younger patients often consist of undifferentiated or poorly differentiated carcinoma in contrast to ordinary squamous cell carcinoma in elderly person.[12] The detection of EBV nuclear antigen and viral DNA in NPC has shown that EBV can infect intact epithelial cells and is often associated with their transformation to carcinoma. Clonal EBV DNA is seen in cells at the preinvasive lesions, and it suggests that it is directly associated with the process of transformation.[13] NPC is pathologically classified (WHO classification) into three categories: keratinizing squamous cell carcinoma (WHO Type I), nonkeratinizing squamous cell carcinoma (WHO Type II), and undifferentiated carcinoma (WHO Type III). The majority of the cases are undifferentiated carcinoma (WHO Type III) in advanced stage.[14] In comparison to adults, NPC in pediatric age group have certain characteristics such as undifferentiated carcinoma being the most common histological type; advanced locoregional disease is seen at the first diagnosis in majority of the cases, advanced locoregional disease is seen at the first diagnosis, higher prevalence of distant metastasis; it is closely associated with EPV etiology and higher prevalence of treatment/therapy-related complications.[15],[16]

  Clinical Presentations Top

Historically, NPC has been thought as a disease of elderly people as the incidence of NPC increases with an increase of age and attends peak at the age of 50–59 years with a small peak in late childhood.[7] The incidence of NPC is higher among males than females across the world, particularly in endemic areas. Pediatric NPC is usually not suspected until late into the disease process. The common clinical symptoms are epistaxis, nasal obstruction, and ear symptoms such as deafness and tinnitus, headache, and neck swelling. The clinical features of neck mass [Figure 1], epistaxis, nasal obstruction, and serous otitis media are less common in comparison to adults. Bone erosion at the skull base region with or without affecting cranial nerves is common at the time of diagnosis. Cranial nerves of III–VI are commonly involved in NPC. In contrast to other cancers of the head and neck, NPC has a greater tendency for early metastasis.[17] NPC rarely comes to medical attention before it has spread to the regional lymph nodes at the neck. The most common site of origin for NPC is the fossa of Rosenmuller. This is an occult location where patients are usually asymptomatic for a prolonged period. As there is rich lymphatic drainage of the nasopharynx, bilateral neck node metastasis is often the first clinical sign. The rarity of NPC in children often leads to delayed diagnosis, so childhood NPC is associated with advanced locoregional spread and higher chance of distant metastasis.[18] In many cases, the diagnosis is delayed as the cervical lymphadenopathy suspected to be of infectious cause. The neck mass in the pediatric age may confuse with some common differential diagnosis of childhood neck swelling as in infectious mononucleosis, deep neck abscess, mycobacterial cervical lymphadenopathy, or malignant conditions such as sinonasal carcinoma, lymphoma, parameningeal rhabdomyosarcoma, and cervical neuroblastoma.[19] Unilateral serous otitis media is a common presentation in adult patients with NPC, whereas in children, this is not an atypical presentation. Otalgia and cervical lymphadenopathy are in favor of infectious etiology in pediatric age group. Absence of improvement with course of antibiotic treatment require further workup of the patient. Persistent unilateral otological findings need flexible nasopharyngolaryngoscopic examination to rule out nasopharyngeal pathology. The peak incidence of NPC in children of nonendemic region is in the age of 15–19 years with a male-to-female ratio of >2:1.[20] As there is no exact time frame for initiating a malignancy workup in pediatric age group with one-sided otological symptoms, a higher degree of suspicion may be needed in childhood.
Figure 1: A 9-year-old female child with nasopharyngeal carcinoma presenting with right-sided neck mass

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Skull base erosion by NPC with or without involvement of cranial nerves at the time of diagnosis is commonly seen. Skull base invasion is seen in 63% of cases seen in a study where 150 patients studied.[21] Cranial nerves III–VI are often affected. In contrast to other epidermoid cancers of the head-and-neck region, NPC has a higher chance for early metastatic spread.[17]

  Staging Top

The staging of NPC as per the 8th Edition of the American Joint Committee on Cancer and International Union Against Cancer[22] is T-classification: T0 – no tumor identified but EBV-positive neck node involvement, T1 – nasopharynx, oropharynx, and nasal cavity without parapharyngeal involvement, T2 – parapharyngeal space and/or adjacent soft-tissue involvement (medial pterygoid, lateral pterygoid, and prevertebral muscles), T3 – bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses, and T4 – intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft-tissue infiltration beyond the lateral surface of the lateral pterygoid; N-classification: N0 –none, N1 – unilateral, cervical, and/or unilateral or bilateral retropharyngeal node(s), ≤6 cm in greatest dimension, above the caudal border of the cricoid cartilage, N2 – bilateral cervical node(s), ≤6 cm in greatest dimension, above the caudal border of the cricoid cartilage, N3 – unilateral or bilateral cervical node(s), >6 cm in greatest dimension, below the caudal border of the cricoid cartilage; and M-classification: M0 – no distant metastasis and M1 – distant metastasis.

  Investigations Top

Fiber-optic or rigid nasopharyngoscopy often shows a mass originating from the nasopharynx [Figure 2]. The most common site for NPC is the fossa of Rosenmuller. The radiological picture of NPC in adults is commonly addressed in several studies, yet to our knowledge, the radiological features of NPC in the children were only a few studies.[23] Computed tomography (CT) scan of the head and neck is done to assess the tumor extent, base of skull erosion, and cervical lymphadenopathy. CT scan of the chest and bone is done to search distant metastasis. Magnetic resonance imaging (MRI) is usually more accurate for detecting the perineural spread and intracranial extension of the tumor and also more accurate for the detection of marrow infiltration, whereas cortical destruction by NPC is better assessed by CT scan. Both types of imaging have almost similar accuracy in assessing the lymph nodes of the neck.
Figure 2: Endoscopic picture shows an irregular mass at the nasopharynx

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Positron emission tomography imaging is done to assess the questionable neck nodes. Both types of imaging are almost of the same accuracy for assessing the lymph nodes. Diagnostic nasal endoscopy with biopsy is a must for confirmation of the diagnosis. The most confirmative investigation is a biopsy of the primary lesion. In comparison to adult patients with NPC, pediatric age group has certain characteristics such as undifferentiated carcinoma being the most common histological type [Figure 3]. Combined MRI and CT scans are needed to stages of NPC. EBV DNA can be used for screening and monitoring of the treatment of NPC in the endemic region, which has higher positive rate of plasma EBV DNA(>95%).[24] High titers of the antibody to EBV antigens are often useful for diagnosis and so many tests to detect immunoglobulin G (IgG) and IgA titers.[11]
Figure 3: Histopathology picture of nasopharyngeal carcinoma shows invasive cords and nests of oval-to-cuboidal cells with large hyperchromatic and mitotically active nuclei

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  Treatment Top

The treatment of pediatric NPC usually follows the protocol for adult NPC along with a trend toward upfront chemotherapy in neoadjuvant form. The quality of life enhancement by reducing long-term morbidities in pediatric patients provides a favorable outcome, and the potential for longevity is often a challenge. Radiotherapy is the treatment of choice, whereas neoadjuvant chemotherapy is given in advanced cases. Radiation of 1.8 Gy/day for 5 days a week and total dose of 40–44 Gy given to the primary site and neck nodes and usually a dose of 50 Gy is desirable. The chemotherapy included methotrexate, bleomycin, and cisplatin. NPCs are more radiosensitive. The majority of the patients show a significant improvement after radiotherapy and chemotherapy. NPC is usually inoperable due to complex anatomical location of disease, and surgery of this primary neoplasm is confined to biopsy only. The radical neck dissection is considered if the primary tumor seems to be controlled or there are persistent neck nodes after chemoradiation or isolated recurrence in the neck after radiation.[4] Pediatric patients with NPC respond better than adult patients to treatment and so outcome tends to be better. In children, early diagnosis of NPC before locoregional spread will hopefully avoid the extent of radiation-associated comorbidities. Radiation dose should be reduced for patients of NPC with positive outcome to neoadjuvant chemotherapy.

The standard treatment for NPC is concurrent chemoradiation with surgery, particularly reserved for salvage treatment. Induction chemotherapy is often well tolerated than adjuvant chemotherapy and nowadays implemented and studied in case of locally advanced disease. In some Phase III trials have demonstrated induction chemotherapy provides reduced recurrence and disease-free survival rates.[20] There is some conflicting evidence regarding to its benefits when comparing with chemoradiation therapy alone.[25] Hence, the benefit and use of induction chemotherapy in NPC remains under investigations. Intensity-modulated radiotherapy is a breakthrough in the treatment for NPC which provides highly conformal dose distributions to the targeted site with simultaneously avoiding radiation to normal tissue which helps to improve survival and decrease the late toxicity. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy has event-free survival rates of around 70%–80% for pediatric age groups with NPC.[26] However, outcomes for pediatric patients with relapsed NPC remain poor.[3] Most of the patients with relapsed NPC present with distant metastatic disease.[27] Alone radiotherapy is often inadequate for treating relapsed NPC as most of the relapses occur at the distant sites. Furthermore, the radiotherapy doses required to treat distant metastatic NPC may lead to severe organ toxicity. Hence, chemotherapy is usually needed to treat the majority of pediatric patients with NPC. Early diagnosis and treatment of pediatric NPC help to prevent morbidity and mortality.

  Complications Of The Treatment Top

In NPC, the side effects of radiotherapy to the head-and-neck region vary, and it includes some degree of xerostomia. The chemotherapeutic agent such as cisplatin is commonly prescribed and leads to ototoxicity, typically bilateral and irreversible.[28] Loss of hearing in childhood can affect speech, cognitive, and social development. In future the treatment option need avoidance such drugs due to its side effects. Cisplatin often gives rise to ototoxicity and typically bilateral and irreversible. The risk of ototoxicity is more in case of concomitant use of high dose of radiation.[28] In pediatric age group, ototoxicity or hearing loss has an impact on speech, cognitive, and social development. A baseline audiogram is helpful prior to radiotherapy, especially those receive cisplatin. Hence, future treatment needs less ototoxic chemotherapy. In addition to this, myringotomy and grommet placement also help to prevent effusion in the middle ear and contribute to the hearing and speech problems.

  Prognosis Top

NPC at presentation is at more advanced stage than adults. However, the tumors are associated with a higher cure rate as these are more radiosensitive. If radiotherapy is used for treatment alone, the survival rate varies from 40% to 50%, whereas it is 55%–70% in case of combination of radiotherapy and chemotherapy which allows longer survival. Systemic or distance metastasis is the main obstacle for cure of NPC and is seen in 30%–50% of the patients at the time of diagnosis or local relapse.[29] The 5-year survival of pediatric patients under the age of 18 years is 77% ± 7.3%, whereas NPC-specific 5-year survival is 83% ± 3.9%.[30] The risk of developing second cancer after treatment is significantly more in case of pediatric NPC.[9]

The overall outcome is almost similar between adult and pediatric NPCs with a 5-year disease-specific survival of between 38% and 51%.[31] NPC patients aged between 20 and 45 years have an almost double risk for mortality in comparison to children or adolescents. However, children or adolescents have a higher risk for getting second cancer compared to adults with NPC, which may be due to treatment-related complications.[18]

  Conclusion Top

NPC in pediatric age group is very rare, whereas it presents with advanced locoregional disease if diagnosed in late. Early administration of treatment is required for childhood NPC. The treatment of pediatric NPC is essentially multimodal and includes radiotherapy and chemotherapy. High dose of radiation has an excellent control of NPC at the cost of the toxicity with serious consequences in the pediatric age group. Reduction of radiation dose to the nasopharynx with the help of neoadjuvant or concomitant chemotherapy helps to reduce late toxicity with hampering local control of the tumor. It should be considered as a differential diagnosis when a child presented with neck swelling, nasal obstruction, nasal bleeding, and growth in the nasopharynx. Awareness of pediatric NPC among clinicians will prompt careful evaluation and treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]


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