Nasopharyngeal Carcinoma
        Treatment options under clinical evaluation
Esthesioneuroblastoma
Thyroid Tumors
Oral Cancers
Salivary Gland Tumors
Laryngeal Cancer and Papillomatosis
Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Head and neck cancers include nasopharyngeal carcinoma, esthesioneuroblastoma, thyroid tumors, mouth cancer, salivary gland cancer, laryngeal carcinoma, papillomatosis, and respiratory tract carcinoma involving the NUT gene on chromosome 15. The prognosis, diagnosis, classification, and treatment of these head and neck cancers are discussed below.

Nasopharyngeal cancer arises in the lining of the nasal cavity and pharynx.[1,2] This tumor accounts for about one-third of all cancers of the upper airways. The incidence of this tumor is approximately 1 in 100,000 persons younger than 20 years in the United States.[3] There is a higher frequency of this tumor in North Africa and Southeast Asia.

Nasopharyngeal carcinoma occurs in association with Epstein-Barr virus (EBV), the virus associated with infectious mononucleosis.[4] The virus can be detected in biopsy specimens of these cancers, and tumor cells can have EBV antigens on their cell surface. Three histologic subtypes are recognized by the World Health Organization. Type 1 is squamous cell carcinoma, type 2 is nonkeratinizing carcinoma, and type 3 is undifferentiated carcinoma.

This cancer most frequently spreads to lymph nodes in the neck, which may alert the patient, parent, or physician to the presence of this tumor. The tumor may also spread to the nose, mouth, and pharynx, causing snoring, epistaxis, obstruction of the eustachian tubes, or hearing loss; it may also invade the base of the skull, causing cranial nerve palsy or difficulty with movements of the jaw (trismus). Distant metastatic sites may include the bones, lungs, and liver. The location of the primary tumor can be made by direct inspection of the nasopharynx. A diagnosis can be made from a biopsy of the primary tumor or of enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, and Burkitt lymphoma must be considered, as should benign conditions such as nasal angiofibroma, which presents with epistaxis, and infections draining into the lymph nodes of the neck.

Diagnostic tests should determine the extent of the primary tumor and whether there are metastases. Visualization of the nasopharynx by an ear-nose-throat specialist using a mirror, examination by a neurologist, and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor. Evaluation of the chest and abdomen by computed tomography and bone scan should also be performed to determine whether there is metastatic disease. The levels of EBV and antibody to EBV should also be measured.[1,5]

Tumor staging is performed utilizing the tumor-node-metastasis classification system of the American Joint Committee on Cancer (AJCC).[6] The majority (>90%) of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[7] Metastatic disease at diagnosis is uncommon (stage IVC). Outcome is directly related to the stage of the disease, with overall survival ranging from 80% for stage I and stage II to 40% for stage III.[8] Other factors associated with an inferior outcome include node size larger than 6 cm, radiation dose less than 60 Gy, and poor response to chemotherapy.[8]

Surgery has a limited role in the management of nasopharyngeal carcinoma since the disease is usually considered unresectable because of extensive local spread. High-dose radiation therapy alone may have a role in the management of low-stage nasopharyngeal carcinoma; however, studies in both children and adults have shown that combined modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.[8-12] In a meta-analysis of studies adding chemotherapy to radiation therapy in adults with nasopharyngeal carcinoma, concomitant chemotherapy plus radiation therapy offered a significant benefit for survival, locoregional disease control, and reduction in distant metastases.[11] Neoadjuvant chemotherapy resulted in a significant reduction in locoregional recurrence only, while postradiation chemotherapy did not offer any benefit. In children, two studies utilizing preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without recombinant interferon-beta reported response rates of more than 90%.[13,14] Radiation therapy doses utilized in both studies were approximately 60 Gy. Additional drug combinations that have been used in children with nasopharyngeal carcinoma include bleomycin, epirubicin, and cisplatin, cisplatin and fluorouracil, and cisplatin, methotrexate, and bleomycin.[2] Incorporation of high-dose-rate brachytherapy into the chemoradiation therapy approach has been reported, but its role in the management of nasopharyngeal carcinoma in children is unknown.[15,16]

A preliminary report of the use of EBV-specific cytotoxic T-lymphocytes revealed minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.[17] (Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)

• ARAR0331: This Children's Oncology Group trial (COG-ARAR0331) is evaluating the efficacy of induction chemotherapy with cisplatin plus 5-FU followed by concomitant chemotherapy (cisplatin) plus radiation therapy with amifostine as a radioprotectant in patients with AJCC stages IIB to IV nasopharyngeal carcinoma. Patients with stages I to IIA disease will receive only radiation therapy with amifostine.

Esthesioneuroblastoma (olfactory neuroblastoma) is a very rare, small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[18-20] Most children present with a nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe, with associated symptoms. There appears to be a male predominance, and the average age of presentation is in adolescence. The youngest child reported with this diagnosis was aged 2 years. Metastatic disease is uncommon. The mainstay of treatment has been surgery and radiation. Newer techniques such as endoscopic sinus surgery, radiosurgery, and proton-beam therapy may play a role in the management of this tumor.[21] A retrospective analysis of data from the Surveillance, Epidemiology, and End Results program identified 311 patients with esthesioneuroblastoma.[22] Patients were staged by the extent of the tumor. Disease limited to the nasal cavity was considered the lowest stage and involvement of regional lymph nodes or metastasis was considered the highest stage. This staging system correlated well with outcome. A meta-analysis of 26 studies with a total of 390 patients, largely adults, with esthesioneuroblastoma indicates that higher histopathologic grade and metastases to the cervical lymph nodes may correlate with adverse prognostic factors.[23] Recent reports indicate increasing use of neoadjuvant chemotherapy.[18,19,24,25] Chemotherapy regimens that have been used with efficacy include etoposide (VP-16), ifosfamide, and cisplatin (Platinol),[26] vincristine, actinomycin D and cyclophosphamide without doxorubicin (Adriamycin), ifosfamide/etoposide, and cisplatin plus etoposide or doxorubicin.[24] The long-term survival rate appears to be approximately 60% to 80%. Local recurrences may occur later in life.

Tumors of the thyroid are classified as adenomas or carcinomas.[27-31] Adenomas are benign growths that may cause enlargement of all or part of the gland, which extends to both sides of the neck and can be quite large. Some of these tumors may secrete hormones. Transformation to a malignant carcinoma may occur in some cells, which then may grow and spread to lymph nodes in the neck or to the lungs.

Although rare, thyroid cancers represent about 1.5% of all tumors seen in the pediatric age group. Most thyroid carcinomas occur in girls.[32] Patients with thyroid cancer usually present with a thyroid mass with or without cervical adenopathy.[33-35] There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[36,37] When occurring in patients with the multiple endocrine neoplasia syndromes, thyroid cancer may be associated with the development of other types of malignant tumors. (Refer to the Multiple Endocrine Neoplasia Syndrome section of this summary for more information.) The American Thyroid Association Taskforce [38] has developed guidelines for management of thyroid nodules in older adolescents and adults, but it is not yet known how to apply these guidelines to thyroid nodules in children.[27]

Initial evaluation of a child or adolescent with a thyroid nodule should include an ultrasound of the thyroid. Tests of thyroid function are usually normal, but thyroglobulin can be elevated. Fine needle aspiration (FNA) is the initial diagnostic approach, though experience in FNA in pediatric hospitals may be limited, in which case open biopsy or lobe resection should be considered.[39,40] Open biopsy or resection may be preferable for young children as well.

Various histologies account for the general diagnostic category of carcinoma of the thyroid,[41] but the vast majority of tumors are differentiated. These tumors comprise papillary carcinoma (60%–75%),[37] follicular carcinoma (10%–20%), medullary carcinoma (5%–10%), and anaplastic carcinoma (<1%). Follicular carcinoma may be sporadic or familial and medullary carcinoma is usually familial.[42] Papillary carcinoma often has multicentric origins and a very high rate of lymph node metastasis (70%–90%).[41] Follicular carcinoma is usually encapsulated and has a higher incidence of bone and lung metastasis. Follicular carcinoma and papillary carcinoma generally have a benign course, with a 10-year survival rate of more than 95%.[43] Fifty percent of medullary thyroid carcinomas in adults and children have hematogenous metastases at diagnosis.[44] Patients with medullary carcinoma of the thyroid have a guarded prognosis, unless they have very small tumors (microcarcinoma, defined as <1.0 cm in diameter), which carry a good prognosis.[45]

Surgery by an experienced thyroid surgeon is the treatment required for all thyroid neoplasms.[43] Total or near-total thyroidectomy plus cervical lymph node dissection, when indicated, is the most common surgical approach.[33] For patients with obvious metastatic disease or heavy nodal invasion, total thyroidectomy and treatment with radioactive idodine is indicated. For patients with an isolated nodule in the thyroid, treatment may involve only a lobectomy.[33,46] During the 4- to 6-week period following surgery, patients who received a total thyroidectomy may develop hypothyroidism. A radioactive iodine (I-131) scan is then performed to search for residual, functionally active neoplasms. If there is no disease outside of the thyroid bed, an ablative dose of I-131 (approximately 29 mCi) is administered for total thyroid destruction. If there is evidence of nodal or disseminated disease, higher doses (100–200 mCi) of I-131 are required. In children, the I-131 dose may be adjusted for weight and other age-dependent safety factors.[47,48] After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress thyrotropin (TSH) production.[49]

Initial treatment (defined as surgery plus one radioactive iodine ablation plus thyroid replacement) is effective in inducing remission for 70% of patients. Extensive disease at diagnosis and larger tumor size predict failure to remit. With additional treatment, 89% of patients achieve remission.[50] Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary.[51] Thyroglobulin, T4, and TSH levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed.

Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[51-53] Recurrence is common (35%–45%), however, and is seen more often in children younger than 10 years and in those with palpable cervical lymph nodes at diagnosis.[29,54,55] Of note, the sodium-iodide symporter (a membrane-bound glycoprotein cotransporter) essential for uptake of iodide and thyroid hormone synthesis, is expressed in 35% to 45% of thyroid cancers in children and adolescents. Patients with expression of the sodium-iodide symporter have a lower risk of recurrence.[56] Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation.[57] Even patients with a tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment. (Refer to the PDQ summary on adult Thyroid Cancer Treatment for more information.)

Cancer of the oral cavity is extremely rare in children and adolescents.[3,58] The vast majority (>90%) of tumors and tumor-like lesions in the oral cavity are benign.[59-62] Benign odontogenic neoplasms include odontoma and ameloblastoma. The most common nonodontogenic neoplasms are fibromas, hemangiomas, and papillomas. Tumor-like lesions include lymphangiomas, granulomas, and eosinophilic granuloma (Langerhans cell histiocytoma [LCH]). Malignant tumors are found in 0.1% to 2% of a series of oral biopsies performed in children [59,60] and 3% to 13% of oral tumor biopsies.[61,62] Malignant tumor types include lymphomas (especially Burkitt) and sarcomas (including rhabdomyosarcoma and fibrosarcoma). The most common type of primary oral cancer in adults, squamous cell carcinoma (SCC), is extremely rare in children. Only occasional case reports are found in the literature.[63,64] Adolescents with an oral SCC should be screened for Fanconi anemia.[65,66]

Treatment of benign oral tumors is surgical. Management of malignant tumors is dependent on histology and may include surgery, chemotherapy, and radiation.[67] LCH may require other treatment besides surgery. (Refer to the PDQ summaries on adult Oropharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.)

Most salivary gland neoplasms arise in the parotid gland.[68-72] About 15% of these tumors may arise in the submandibular glands or in the minor salivary glands under the tongue and jaw. These tumors are most frequently benign but on very rare occasions may be malignant.[73] Sialoblastomas are usually benign tumors presenting in the neonatal period but can rarely metastasize.[74] A chemotherapy regimen of carboplatin, epirubicin, vincristine, etoposide, ifosfamide, and dactinomycin has been used in the treatment of metastatic sialoblastoma and has produced a response in one child.[75][Level of evidence: 3iiiDiv] The malignant lesions include mucoepidermoid carcinoma,[76] acinic cell carcinoma, rhabdomyosarcoma, adenocarcinoma, and undifferentiated carcinoma. These tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[77,78] Radical surgical removal is the treatment of choice, whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.[76,79,80] Prognosis for patients with these tumors is generally good.[71,81-83] (Refer to the PDQ summary on adult Salivary Gland Cancer Treatment for more information.)

Benign tumors of the larynx are rare. Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[84,85] These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck. Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group. SCC of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation.[86] Laser surgery may be the first type of treatment utilized for these lesions.

Papillomatosis of the larynx is a benign overgrowth of tissues lining the larynx and is associated with the human papillomavirus (HPV), most commonly HPV-6 and HPV-11.[87] The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6.[88] This condition is not cancerous, and primary treatment is surgical ablation with laser vaporization.[89] Frequent recurrences are common. If a patient requires more than four surgical procedures per year, treatment with interferon should be considered.[90] A pilot study of immunotherapy with HspE7, a recombinant fusion protein that has shown activity in other HPV-related diseases, has suggested a marked increase in the amount of time between surgeries.[91] These results, however, must be confirmed in a larger randomized trial. These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may rarely extend into the lung, producing significant morbidity. Malignant degeneration may occur with development of cancer in the larynx and squamous cell lung cancer. (Refer to the PDQ summary on adult Laryngeal Cancer Treatment for more information.)

Researchers have described a group of young patients with midline carcinomas with a very poor prognosis. The tumors arise in midline epithelial structures including the thymus, mediastinum, airway structures, and bladder. They exhibit squamous differentiation. Tumors from 8 of 11 patients exhibited a balanced chromosomal translocation t(15;19) involving the BRD4 and the NUT genes. These patients had no response to chemotherapy and died very quickly. Tumors from the remaining three patients had a chromosomal break in the NUT gene on chromosome 15 but had normal chromosome 19. These patients were older and had a slightly longer survival than the eight patients exhibiting t(15;19).[92]

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