Head and Neck Cancers
Childhood sarcomas often occur in the head and neck area and they are described in other sections. Unusual pediatric head and neck cancers include nasopharyngeal carcinoma, esthesioneuroblastoma, thyroid tumors, oral 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. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.
Nasopharyngeal carcinoma arises in the lining of the nasal cavity and pharynx.[2-4] This tumor accounts for about one-third of all cancers of the upper airways. Nasopharyngeal carcinoma is very uncommon in children younger than 10 years but increases in incidence to 0.8 and 1.3 per 1 million per year in children aged 10 to 14 years and in children aged 15 to 19 years, respectively.[5,6] The incidence of nasopharyngeal carcinoma is characterized by racial and geographic variations, with an endemic distribution among well-defined ethnic groups, such as inhabitants of some areas in North Africa and Southeast Asia. In the United States, nasopharyngeal carcinoma is overrepresented in black children when compared with other malignancies.
Nasopharyngeal carcinoma is strongly associated with Epstein-Barr virus (EBV) infection. In addition to the serological evidence of infection, EBV DNA is present as a monoclonal episome in the nasopharyngeal carcinoma cells, and tumor cells can have EBV antigens on their cell surface. The circulating levels of EBV DNA, and serologic documentation of EBV infection, may aid in the diagnosis.
Three histologic subtypes of nasopharyngeal carcinoma are recognized by the World Health Organization (WHO). Type 1 is squamous cell carcinoma; type 2 is nonkeratinizing squamous cell carcinoma; and type 3 is undifferentiated carcinoma. Children with nasopharyngeal carcinoma are more likely to have WHO type 2 or type 3 disease.
Nasopharyngeal carcinoma commonly presents as nosebleeds, nasal congestion and obstruction, or otitis media. Given the rich lymphatic drainage of the nasopharynx, bilateral cervical lymphadenopathies are often the first sign of disease. The tumor spreads locally to adjacent areas of the oropharynx and may invade the skull base, resulting in cranial nerve palsy or difficulty with movements of the jaw (trismus). Distant metastatic sites may include the bones, lungs, and liver.
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 nasal endoscopy, examination by a neurologist, and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor. 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 usually presents with epistaxis in adolescent males, and infectious lymphadenitis. Evaluation of the chest and abdomen by computed tomography and bone scan should also be performed to determine whether there is metastatic disease.
Tumor staging is performed utilizing the tumor-node-metastasis classification system of the American Joint Committee on Cancer (AJCC). The majority (>90%) of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[7,11,12] Metastatic disease at diagnosis is uncommon (stage IVC). A retrospective analysis of data from the Surveillance Epidemiology and End Results (SEER) program reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did older patients, higher risk of developing a second malignancy, and a superior outcome after controlling for stage.
The overall survival of children and adolescents with nasopharyngeal carcinoma has improved over the last four decades; with state-of-the-art multimodal treatment, 5-year survival rates are in excess of 80%.[6,7,12,13] However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities.[7,12]
Treatment of nasopharyngeal carcinoma is multimodal:
- Combined-modality therapy with chemotherapy and radiation: High-dose radiation therapy alone has had a role in the management of low-stage nasopharyngeal carcinoma, but studies in both children and adults show that combined modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.[7,12-17]
- Many randomized studies have investigated the role of chemotherapy in the treatment of adult nasopharyngeal carcinoma. In a meta-analysis of ten randomized studies and 2,450 patients, the use of concomitant chemoradiation therapy was associated with a significant survival benefit, including improved locoregional disease control and reduction in distant metastases. Neoadjuvant chemotherapy resulted in a significant reduction in locoregional recurrence only, while postradiation chemotherapy did not offer any benefit.
- In children, four studies utilizing preradiation chemotherapy with different combinations of methotrexate, cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without recombinant interferon-beta have reported response rates of more than 90%.[12,13,18,19]
- Neoadjuvant chemotherapy with cisplatin and 5-FU (with or without leucovorin), followed by chemoradiation with single-agent cisplatin yield 5-year overall survival (OS) rates consistently above 80%.[12,13]
- A preliminary analysis of the NPC-2003-GPOH study, which included a 6-month maintenance therapy phase with interferon-beta, reported a 30-month OS estimate of 97.1%.
- While nasopharyngeal carcinoma is a very chemosensitive neoplasm, high radiation doses to the nasopharynx and neck (approximately 60 Gy) are required for optimal locoregional control.[7,12,13] The combination of cisplatin-based chemotherapy and high doses of radiation therapy to the nasopharynx and neck are associated with a high probability of hearing loss, hypothyroidism and panhypopituitarism, trismus, xerostomia, dental problems, and chronic sinusitis or otitis.[7,12]; [Level of evidence: 3iiiA]
- Additional drug combinations that have been used in children with nasopharyngeal carcinoma include bleomycin with epirubicin and cisplatin and cisplatin with methotrexate and bleomycin.
- Other approaches to the management of nasopharyngeal carcinoma in children have been evaluated and include the following:
- Incorporation of high-dose-rate brachytherapy into the chemoradiation therapy approach.[21,22]
- Following adult data, taxanes have been incorporated into the treatment of childhood nasopharyngeal carcinoma; studies have shown good objective response rates and favorable outcomes with the use of docetaxel in combination with cisplatin.[Level of evidence: 3iiiDiv]
- Surgery: Surgery has a limited role in the management of nasopharyngeal carcinoma because the disease is usually considered unresectable due to extensive local spread.
- EBV-specific cytotoxic T-lymphocytes: The use of EBV-specific cytotoxic T-lymphocytes has shown to be a very promising approach with minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.
(Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)
Esthesioneuroblastoma (olfactory neuroblastoma) is a small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[25-28] In children, esthesioneuroblastoma is a very rare malignancy with an estimated incidence of 0.1 per 100,000 children younger than 15 years. Despite its rarity, esthesioneuroblastoma is the most common cancer of the nasal cavity in pediatric patients, accounting for 28% of all cases.[29,30] In a series of 511 patients from the SEER database, there was a slight male predominance, the mean age at presentation was 53 years, and only 8% of cases were younger than 25 years. Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%).
Most children present in the second decade of life with symptoms that include nasal obstruction, epistaxis, hyposmia, exophthalmos, or a nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe. Most patients present with advanced-stage disease (Kadish stages B and C).[29,30] Recent reports suggest that positron emission tomography–computed tomography may aid in staging the disease.
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.
The mainstay of treatment has been surgery and radiation. Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection.; [Level of evidence: 3iiiDii] Other techniques such as stereotactic radiosurgery and proton-beam therapy (charged-particle radiation therapy) may also play a role in the management of this tumor. Nodal metastases are seen in about 5% of patients. Routine neck dissection and nodal exploration are not indicated in the absence of clinical or radiological evidence of disease. Management of cervical lymph node metastases has been addressed in a review article.
Reports indicate the increasing use of neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease with promising results.[25,26,38-40]; [Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include etoposide with ifosfamide and cisplatin; vincristine, actinomycin D, and cyclophosphamide with and without doxorubicin; ifosfamide/etoposide; cisplatin plus etoposide or doxorubicin;  and irinotecan plus docetaxel.[Level of evidence: 3iiA]
The annual incidence of thyroid cancers is low in children younger than 15 years (2.0 per 1 million people), accounting for approximately 1.5% of all cancers in this age group. Thyroid cancer incidence is higher in children aged 15 to 19 years (17.6 per 1 million people), and it accounts for approximately 8% of cancers arising in this older age group. Most thyroid carcinomas occur in girls. From 1990 to 2009, incidence rates for differentiated thyroid carcinomas increased in children, adolescents, and young adults in the United States. The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.
There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[46,47] In the decade following the Chernobyl nuclear incident, there was a tenfold increase in the incidence of thyroid cancer compared with the previous and following decades. In this group of patients with exposure to low-dose radiation, tumors commonly show a gain of 7q11. 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 (MEN) Syndromes and Carney Complex section of this summary for more information.)
Tumors of the thyroid are classified as adenomas or carcinomas.[50-54] 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 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. Approximately 20% of thyroid nodules in children are malignant.[50,55]
- Papillary carcinoma (60%–75%): Papillary carcinoma often has multicentric origin and a very high rate of lymph node metastasis (70%–90%). Papillary carcinoma (often referred to as differentiated thyroid cancer) generally has a benign course, with a 10-year survival rate of more than 95%.[57,58] Overall, long-term outcomes for children and adolescents with papillary thyroid cancer are excellent, with 2% cause-specific mortality at 40 years.
- Follicular carcinoma (10%–20%): Follicular carcinoma is usually encapsulated and has a higher incidence of bone and lung metastases. It may be sporadic or familial. Follicular carcinoma (often referred to as differentiated thyroid cancer) generally has a benign course, with a 10-year survival rate of more than 95%.
- Medullary carcinoma (5%–10%): Medullary carcinoma is usually familial.
- Anaplastic carcinoma (<1%).
Studies have shown subtle differences in the genetic profiling of childhood differentiated thyroid carcinomas compared with adult tumors. A higher prevalence of RET/PTC rearrangements is seen in pediatric papillary carcinoma (45%–65% vs. 3%–34% in adults). Conversely, BRAF V600E mutations, which are seen in more than 50% of adults with papillary thyroid carcinoma, are extremely rare in children.
|Characteristic||Children and Adolescents (%)||Adults (%)|
|aAdapted from Yamashita et al.|
|Lymph node involvement||30–90||5–55|
Patients with thyroid cancer usually present with a thyroid mass with or without cervical adenopathy.[62-65] Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. Compared with adults, children have a higher proportion of nodal involvement (40%–90% vs. 20%–50%) and lung metastases (20%–30% vs. 2%). Likewise, when compared with pubertal adolescents, prepubertal children have a more aggressive presentation with a greater degree of extrathyroid extension, lymph node involvement, and lung metastases. However, outcome is similar in the prepubertal and adolescent groups. In well-differentiated thyroid cancer, male gender, large tumor size, and distant metastases have been found to have prognostic significance for early mortality; however, even patients in the highest risk group who had distant metastases had excellent survival at 90%.
Initial evaluation of a child or adolescent with a thyroid nodule should include the following:
- Ultrasound of the thyroid.
- Serum thyroid-stimulating hormone (TSH) level.
- Serum thyroglobulin level.
Tests of thyroid function are usually normal, but thyroglobulin can be elevated.
Fine-needle aspiration as an initial diagnostic approach is sensitive and useful. However, in doubtful cases, open biopsy or resection should be considered.[68-72] Open biopsy or resection may be preferable for young children as well.
|Histology||Associated Chromosomal Abnormality||Presentation||Diagnosis||Treatment|
|EGF = epidermal growth factor; MEN2 = multiple endocrine neoplasia type 2; TSH = thyroid-stimulating hormone.|
|Papillary thyroid carcinoma (differentiated with generally a benign course)||RET/PTC more common in children. BRAF V600E mutations seen in adults are rare in children.||Thyroid mass. Prepubertal children more often with nodal and lung metastases.||Ultrasound, TSH, thyroglobulin. Fine needle or open biopsy.||Total or near-total thyroidectomy; I-131; thyroid hormone. In metastatic or recurrent disease, tyrosine kinase or EGF receptor inhibitors may be of benefit.|
|Follicular thyroid carcinoma (differentiated with generally benign course)||Sporadic or familial||Thyroid mass. Prepubertal children more often with nodal and lung metastases.||Ultrasound, TSH, thyroglobulin. Fine needle or open biopsy.||Total or near-total thyroidectomy; I-131; thyroid hormone. In metastatic or recurrent disease, tyrosine kinase or EGF receptor inhibitors may be of benefit.|
|Medullary thyroid carcinoma||MEN2||Aggressive. 50% with metastases at presentation.||In familial MEN2, RET testing.||Aggressive surgical intervention. Prophylactic thyroidectomy is indicated in familial cases.|
Treatment of papillary and follicular thyroid carcinoma
The management of differentiated thyroid cancer in children has been reviewed in detail. Also, the American Thyroid Association Taskforce  has developed guidelines for management of thyroid nodules and differentiated thyroid cancer in older adolescents and adults; however, it is not yet known how to apply these guidelines to thyroid nodules in children.
Surgery performed by an experienced thyroid surgeon is the treatment required for all thyroid neoplasms.[57,60] For patients with papillary or follicular carcinoma, total or near-total thyroidectomy plus cervical lymph node dissection is the recommended surgical approach.[57,62,74] This aggressive approach is indicated for several reasons:
- Up to 40% of children with differentiated thyroid carcinoma have multifocal disease and a higher recurrence risk if less than a total thyroidectomy is performed.
- Many children have disseminated disease and require radioactive iodine therapy.
- Sensitive assays for serum thyroglobulin are used as a marker for active disease and are most useful after total thyroidectomy.[50,55,57]
The use of radioactive iodine ablation for the treatment of children with differentiated thyroid carcinoma has increased over the years. Despite surgery, most children have a significant radioactive iodine uptake in the thyroid bed, and studies have shown increased local recurrence rates for patients who did not receive radioactive iodine after total thyroidectomy compared with those who did receive radioactive iodine. Thus, it is currently recommended that children receive an ablative dose after initial surgery.[50,55,60] For successful remnant ablation, serum TSH levels must be elevated to allow for maximal radioactive iodine uptake; this can usually be achieved with thyroid hormone withdrawal for 3 to 4 weeks after thyroidectomy. A radioactive iodine (I-131) scan is then performed to search for residual, functionally active neoplasm. If there is no disease outside of the thyroid bed, an ablative dose of I-131 (approximately 30 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.[Level of evidence: 3iDiv] In younger children, the I-131 dose may be adjusted for weight (1–1.5 mCi/kg).[50,78,79] After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress TSH production.
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.
Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary. T4 and TSH levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed. If thyroglobulin levels rise above postthyroidectomy baseline levels, recurrence of the disease is possible, and physical examination and imaging studies should be repeated. The use of various tyrosine kinase inhibitors or vascular endothelial growth factor receptor inhibitors has shown promising results in patients with metastatic or recurrent thyroid cancer in adults.[83-86]
Treatment of recurrent papillary and follicular thyroid carcinoma
Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[82,87,88] 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.[52,89,90] Even patients with a tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment. 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.
Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation. Tyrosine kinase inhibitors such as sorafenib have shown to induce responses in up to 15% of adult patients with metastatic disease. Responses to sorafenib have also been documented in pediatric cases. Given the high incidence of BRAF mutations in older patients with papillary thyroid carcinoma, the use of selective RAF/MEK inhibitors is being investigated.[83,95,96]
Treatment of medullary thyroid carcinoma
Medullary thyroid carcinomas are commonly associated with the MEN2 syndrome (refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information). They present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis. 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.
Treatment for children with medullary thyroid carcinoma is mainly surgical. A recent review of 430 patients aged 0 to 21 years with medullary thyroid cancer reported older age (16–21 years) at diagnosis, tumor diameter greater than 2 cm, positive margins after total thyroidectomy, and lymph node metastases were associated with a worse prognosis. This suggests that central neck node dissection and dissection of nearby positive nodes should improve the 10-year survival for these patients. Most cases of medullary thyroid carcinoma occur in the context of the MEN 2A and MEN 2B syndromes. In those familial cases, early genetic testing and counseling is indicated, and prophylactic surgery is recommended in children with the RET germline mutation. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur. A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (NCT01660984).
A number of tyrosine kinase inhibitors have been evaluated for patients with unresectable medullary thyroid cancer. Vandetanib (an inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling) is approved by the U.S. Food and Drug Administration for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable, locally advanced, or metastatic disease. Approval was based on a randomized, placebo-controlled, phase III trial that showed a marked progression-free survival improvement for patients randomly assigned to receive vandetanib (hazard ratio, 0.35); the trial also showed an objective response rate advantage for patients receiving vandetanib (44% vs. 1% for the placebo arm).[100,101] Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only 1 had no response, and 7 had a partial response. Disease in three of those patients subsequently recurred, but 11 of 16 patients treated with vandetanib remained on therapy at the time of the report. Cabozantinib (an inhibitor of the RET and MET kinases and vascular endothelial growth factor receptor) has also been active against unresectable medullary thyroid cancer (10 of 35 patients [29%] had a partial response).
(Refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information.)
Oral Cavity Cancer
The vast majority (>90%) of tumors and tumor-like lesions in the oral cavity are benign.[104-107] Cancer of the oral cavity is extremely rare in children and adolescents. According to the SEER Stat Fact Sheets, only 0.6% of all cases are diagnosed in patients younger than 20 years, and in 2008, the age-adjusted incidence for this population was 0.24 per 100,000.[108,109]
The incidence of cancer of the oral cavity and pharynx has increased in adolescent and young adult females, and this pattern is consistent with the national increase in orogenital sexual intercourse in younger females and human papilloma virus (HPV) infection. It is currently estimated that the prevalence of oral HPV infection in the United States is 6.9% in people aged 14 to 69 years and that HPV causes about 30,000 oropharyngeal cancers. Furthermore, the incidence rates for HPV-related oropharyngeal cancer from 1999 to 2008 have increased by 4.4% per year in white men and 1.9% in white women.[111-113] Current practices to increase HPV immunization rates in both boys and girls may reduce the burden of HPV-related noncervical cancers.
Benign odontogenic neoplasms of the oral cavity include odontoma and ameloblastoma. The most common nonodontogenic neoplasms of the oral cavity are fibromas, hemangiomas, and papillomas. Tumor-like lesions of the oral cavity include lymphangiomas, granulomas, and eosinophilic granuloma (Langerhans cell histiocytosis).[104-107] (Refer to the Oral cavity subsection in the PDQ summary on Langerhans Cell Histiocytosis Treatment for more information about Langerhans cell histiocytosis.)
Malignant lesions of the oral cavity were found in 0.1% to 2% of a series of oral biopsies performed in children [104,105] and 3% to 13% of oral tumor biopsies.[106,107] Malignant tumor types include lymphomas (especially Burkitt) and sarcomas (including rhabdomyosarcoma and fibrosarcoma). Mucoepidermoid carcinomas of the oral cavity have rarely been reported in the pediatric and adolescent age group. Most are low grade and have a high cure rate with surgery alone.; [Level of evidence: 3iiA]
The most common type of primary oral cavity cancer in adults, squamous cell carcinoma (SCC), is extremely rare in children. Review of the SEER database identified 54 patients younger than 20 years with oral cavity SCC between 1973 and 2006. Pediatric patients with oral cavity SCC were more often female and had better survival than adult patients. When differences in patient, tumor, and treatment-related characteristics are adjusted for, the two groups experienced equivalent survival.[Level of evidence: 3iA] Diseases that can be associated with the development of oral cavity and/or head and neck SCC include Fanconi anemia, dyskeratosis congenita, connexin mutations, chronic graft-versus-host disease, epidermolysis bullosa, xeroderma pigmentosum, and HPV infection.[117-124]
Treatment of benign oral cavity tumors is surgical.
Management of malignant tumors of the oral cavity is dependent on histology and may include surgery, chemotherapy, and radiation. Most reported cases of oral cavity SCC managed with surgery alone have done well without recurrence.[115,126] Langerhans cell histiocytosis of the oral cavity may require treatment in addition to surgery. (Refer to the PDQ summary on Langerhans Cell Histiocytosis Treatment for more information.)
Salivary Gland Tumors
Salivary gland tumors are rare and account for 0.5% of all malignancies in children and adolescents. Most salivary gland neoplasms arise in the parotid gland.[128-135] 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 may be malignant, especially in young children. Overall 5-year survival in the pediatric age group is approximately 95%.
The most common malignant lesion is mucoepidermoid carcinoma.[127,134,138,139] Less common malignancies include acinic cell carcinoma, rhabdomyosarcoma, adenocarcinoma, adenoid cystic carcinoma, and undifferentiated carcinoma. These tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[140,141] Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[142,143]
Radical surgical removal is the treatment of choice for salivary gland tumors whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.[137,139,144,145]; [Level of evidence: 3iiiA]
(Refer to the PDQ summary on adult Salivary Gland Cancer Treatment for more information.)
Sialoblastoma is a usually benign tumor presenting in the neonatal period and rarely metastasizes. Chemotherapy regimens with carboplatin, epirubicin, vincristine, etoposide, dactinomycin, doxorubicin, and ifosfamide have produced responses in two children with sialoblastoma.; [Level of evidence: 3iiiDiv]
Laryngeal Cancer and Papillomatosis
Tumors of the larynx are rare. The most common benign tumor is subglottic hemangioma. Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[150,151] 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 and is usually managed with chemotherapy and radiation therapy following biopsy, rather than laryngectomy. SCC of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation. 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 HPV, most commonly HPV-6 and HPV-11. The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6. 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.
Papillomatosis is not cancerous, and primary treatment is surgical ablation with laser vaporization. Frequent recurrences are common. Lung involvement, although rare, can occur. If a patient requires more than four surgical procedures per year, treatment with interferon may be considered. 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. These results, however, must be confirmed in a larger randomized trial.
(Refer to the PDQ summary on adult Laryngeal Cancer Treatment for more information.)
Midline Tract Carcinoma Involving the NUT Gene (NUT Midline Carcinoma)
NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the gene NUT. In the majority (75%) of cases, the NUT gene on chromosome 15q14 is fused with BRD4 on chromosome 19p13, creating chimeric genes that encode the BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 on chromosome 9q34 or an unknown partner gene; these tumors are termed NUT-variant.
The tumors arise in midline epithelial structures, typically mediastinum and upper aerodigestive track, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation. Although the original description of this neoplasm was made in children and young adults, patients of all ages can be affected. A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1–78 years). The outcome is very poor, with an average survival of less than 1 year. Preliminary data seem to indicate that NUT-variant tumors may have a more protracted course.[160,161]
Preclinical studies have shown that NUT-BRD4 is associated with globally decreased histone acetylation and transcriptional repression; studies have also shown that this acetylation can be restored with histone deacetylase inhibitors, resulting in squamous differentiation and arrested growth in vitro and growth inhibition in xenograft models. Response to vorinostat has been reported in a case of a child with refractory disease, thus suggesting a potential role for this class of agents in the treatment of this malignancy.
- Gil Z, Patel SG, Cantu G, et al.: Outcome of craniofacial surgery in children and adolescents with malignant tumors involving the skull base: an international collaborative study. Head Neck 31 (3): 308-17, 2009. [PUBMED Abstract]
- Vasef MA, Ferlito A, Weiss LM: Nasopharyngeal carcinoma, with emphasis on its relationship to Epstein-Barr virus. Ann Otol Rhinol Laryngol 106 (4): 348-56, 1997. [PUBMED Abstract]
- Ayan I, Kaytan E, Ayan N: Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol 4 (1): 13-21, 2003. [PUBMED Abstract]
- Yan Z, Xia L, Huang Y, et al.: Nasopharyngeal carcinoma in children and adolescents in an endemic area: a report of 185 cases. Int J Pediatr Otorhinolaryngol 77 (9): 1454-60, 2013. [PUBMED Abstract]
- Horner MJ, Ries LA, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2006. Bethesda, Md: National Cancer Institute, 2009. Also available online. Last accessed December 15, 2014.
- Sultan I, Casanova M, Ferrari A, et al.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 55 (2): 279-84, 2010. [PUBMED Abstract]
- Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011. [PUBMED Abstract]
- Dawson CW, Port RJ, Young LS: The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol 22 (2): 144-53, 2012. [PUBMED Abstract]
- Lo YM, Chan LY, Lo KW, et al.: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59 (6): 1188-91, 1999. [PUBMED Abstract]
- Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.
- Casanova M, Ferrari A, Gandola L, et al.: Undifferentiated nasopharyngeal carcinoma in children and adolescents: comparison between staging systems. Ann Oncol 12 (8): 1157-62, 2001. [PUBMED Abstract]
- Casanova M, Bisogno G, Gandola L, et al.: A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer 118 (10): 2718-25, 2012. [PUBMED Abstract]
- Buehrlen M, Zwaan CM, Granzen B, et al.: Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer 118 (19): 4892-900, 2012. [PUBMED Abstract]
- Al-Sarraf M, LeBlanc M, Giri PG, et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16 (4): 1310-7, 1998. [PUBMED Abstract]
- Wolden SL, Steinherz PG, Kraus DH, et al.: Improved long-term survival with combined modality therapy for pediatric nasopharynx cancer. Int J Radiat Oncol Biol Phys 46 (4): 859-64, 2000. [PUBMED Abstract]
- Langendijk JA, Leemans ChR, Buter J, et al.: The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol 22 (22): 4604-12, 2004. [PUBMED Abstract]
- Venkitaraman R, Ramanan SG, Sagar TG: Nasopharyngeal cancer of childhood and adolescence: a single institution experience. Pediatr Hematol Oncol 24 (7): 493-502, 2007 Oct-Nov. [PUBMED Abstract]
- Mertens R, Granzen B, Lassay L, et al.: Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH). Cancer 104 (5): 1083-9, 2005. [PUBMED Abstract]
- Rodriguez-Galindo C, Wofford M, Castleberry RP, et al.: Preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil, and leucovorin for pediatric nasopharyngeal carcinoma. Cancer 103 (4): 850-7, 2005. [PUBMED Abstract]
- Hu S, Xu X, Xu J, et al.: Prognostic factors and long-term outcomes of nasopharyngeal carcinoma in children and adolescents. Pediatr Blood Cancer 60 (7): 1122-7, 2013. [PUBMED Abstract]
- Nakamura RA, Novaes PE, Antoneli CB, et al.: High-dose-rate brachytherapy as part of a multidisciplinary treatment of nasopharyngeal lymphoepithelioma in childhood. Cancer 104 (3): 525-31, 2005. [PUBMED Abstract]
- Louis CU, Paulino AC, Gottschalk S, et al.: A single institution experience with pediatric nasopharyngeal carcinoma: high incidence of toxicity associated with platinum-based chemotherapy plus IMRT. J Pediatr Hematol Oncol 29 (7): 500-5, 2007. [PUBMED Abstract]
- Varan A, Ozyar E, Corapçioğlu F, et al.: Pediatric and young adult nasopharyngeal carcinoma patients treated with preradiation Cisplatin and docetaxel chemotherapy. Int J Radiat Oncol Biol Phys 73 (4): 1116-20, 2009. [PUBMED Abstract]
- Straathof KC, Bollard CM, Popat U, et al.: Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. Blood 105 (5): 1898-904, 2005. [PUBMED Abstract]
- Kumar M, Fallon RJ, Hill JS, et al.: Esthesioneuroblastoma in children. J Pediatr Hematol Oncol 24 (6): 482-7, 2002 Aug-Sep. [PUBMED Abstract]
- Theilgaard SA, Buchwald C, Ingeholm P, et al.: Esthesioneuroblastoma: a Danish demographic study of 40 patients registered between 1978 and 2000. Acta Otolaryngol 123 (3): 433-9, 2003. [PUBMED Abstract]
- Dias FL, Sa GM, Lima RA, et al.: Patterns of failure and outcome in esthesioneuroblastoma. Arch Otolaryngol Head Neck Surg 129 (11): 1186-92, 2003. [PUBMED Abstract]
- Nakao K, Watanabe K, Fujishiro Y, et al.: Olfactory neuroblastoma: long-term clinical outcome at a single institute between 1979 and 2003. Acta Otolaryngol Suppl (559): 113-7, 2007. [PUBMED Abstract]
- Bisogno G, Soloni P, Conte M, et al.: Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. BMC Cancer 12: 117, 2012. [PUBMED Abstract]
- Benoit MM, Bhattacharyya N, Faquin W, et al.: Cancer of the nasal cavity in the pediatric population. Pediatrics 121 (1): e141-5, 2008. [PUBMED Abstract]
- Soler ZM, Smith TL: Endoscopic versus open craniofacial resection of esthesioneuroblastoma: what is the evidence? Laryngoscope 122 (2): 244-5, 2012. [PUBMED Abstract]
- Broski SM, Hunt CH, Johnson GB, et al.: The added value of 18F-FDG PET/CT for evaluation of patients with esthesioneuroblastoma. J Nucl Med 53 (8): 1200-6, 2012. [PUBMED Abstract]
- Dulguerov P, Allal AS, Calcaterra TC: Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol 2 (11): 683-90, 2001. [PUBMED Abstract]
- Ozsahin M, Gruber G, Olszyk O, et al.: Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study. Int J Radiat Oncol Biol Phys 78 (4): 992-7, 2010. [PUBMED Abstract]
- Gallia GL, Reh DD, Lane AP, et al.: Endoscopic resection of esthesioneuroblastoma. J Clin Neurosci 19 (11): 1478-82, 2012. [PUBMED Abstract]
- Unger F, Haselsberger K, Walch C, et al.: Combined endoscopic surgery and radiosurgery as treatment modality for olfactory neuroblastoma (esthesioneuroblastoma). Acta Neurochir (Wien) 147 (6): 595-601; discussion 601-2, 2005. [PUBMED Abstract]
- Zanation AM, Ferlito A, Rinaldo A, et al.: When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. Eur Arch Otorhinolaryngol 267 (11): 1667-71, 2010. [PUBMED Abstract]
- Eich HT, Müller RP, Micke O, et al.: Esthesioneuroblastoma in childhood and adolescence. Better prognosis with multimodal treatment? Strahlenther Onkol 181 (6): 378-84, 2005. [PUBMED Abstract]
- Loy AH, Reibel JF, Read PW, et al.: Esthesioneuroblastoma: continued follow-up of a single institution's experience. Arch Otolaryngol Head Neck Surg 132 (2): 134-8, 2006. [PUBMED Abstract]
- Porter AB, Bernold DM, Giannini C, et al.: Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol 90 (2): 201-4, 2008. [PUBMED Abstract]
- Benfari G, Fusconi M, Ciofalo A, et al.: Radiotherapy alone for local tumour control in esthesioneuroblastoma. Acta Otorhinolaryngol Ital 28 (6): 292-7, 2008. [PUBMED Abstract]
- Kim DW, Jo YH, Kim JH, et al.: Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer 101 (10): 2257-60, 2004. [PUBMED Abstract]
- Kiyota N, Tahara M, Fujii S, et al.: Nonplatinum-based chemotherapy with irinotecan plus docetaxel for advanced or metastatic olfactory neuroblastoma: a retrospective analysis of 12 cases. Cancer 112 (4): 885-91, 2008. [PUBMED Abstract]
- Shapiro NL, Bhattacharyya N: Population-based outcomes for pediatric thyroid carcinoma. Laryngoscope 115 (2): 337-40, 2005. [PUBMED Abstract]
- Vergamini LB, Frazier AL, Abrantes FL, et al.: Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. J Pediatr 164 (6): 1481-5, 2014. [PUBMED Abstract]
- Cotterill SJ, Pearce MS, Parker L: Thyroid cancer in children and young adults in the North of England. Is increasing incidence related to the Chernobyl accident? Eur J Cancer 37 (8): 1020-6, 2001. [PUBMED Abstract]
- Kaplan MM, Garnick MB, Gelber R, et al.: Risk factors for thyroid abnormalities after neck irradiation for childhood cancer. Am J Med 74 (2): 272-80, 1983. [PUBMED Abstract]
- Demidchik YE, Saenko VA, Yamashita S: Childhood thyroid cancer in Belarus, Russia, and Ukraine after Chernobyl and at present. Arq Bras Endocrinol Metabol 51 (5): 748-62, 2007. [PUBMED Abstract]
- Hess J, Thomas G, Braselmann H, et al.: Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation. Proc Natl Acad Sci U S A 108 (23): 9595-600, 2011. [PUBMED Abstract]
- Dinauer C, Francis GL: Thyroid cancer in children. Endocrinol Metab Clin North Am 36 (3): 779-806, vii, 2007. [PUBMED Abstract]
- Vasko V, Bauer AJ, Tuttle RM, et al.: Papillary and follicular thyroid cancers in children. Endocr Dev 10: 140-72, 2007. [PUBMED Abstract]
- Grigsby PW, Gal-or A, Michalski JM, et al.: Childhood and adolescent thyroid carcinoma. Cancer 95 (4): 724-9, 2002. [PUBMED Abstract]
- Skinner MA: Cancer of the thyroid gland in infants and children. Semin Pediatr Surg 10 (3): 119-26, 2001. [PUBMED Abstract]
- Halac I, Zimmerman D: Thyroid nodules and cancers in children. Endocrinol Metab Clin North Am 34 (3): 725-44, x, 2005. [PUBMED Abstract]
- Waguespack SG, Francis G: Initial management and follow-up of differentiated thyroid cancer in children. J Natl Compr Canc Netw 8 (11): 1289-300, 2010. [PUBMED Abstract]
- Feinmesser R, Lubin E, Segal K, et al.: Carcinoma of the thyroid in children--a review. J Pediatr Endocrinol Metab 10 (6): 561-8, 1997 Nov-Dec. [PUBMED Abstract]
- Hung W, Sarlis NJ: Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review. Thyroid 12 (8): 683-702, 2002. [PUBMED Abstract]
- Hay ID, Gonzalez-Losada T, Reinalda MS, et al.: Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg 34 (6): 1192-202, 2010. [PUBMED Abstract]
- Skinner MA: Management of hereditary thyroid cancer in children. Surg Oncol 12 (2): 101-4, 2003. [PUBMED Abstract]
- Rivkees SA, Mazzaferri EL, Verburg FA, et al.: The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy. Endocr Rev 32 (6): 798-826, 2011. [PUBMED Abstract]
- Yamashita S, Saenko V: Mechanisms of Disease: molecular genetics of childhood thyroid cancers. Nat Clin Pract Endocrinol Metab 3 (5): 422-9, 2007. [PUBMED Abstract]
- Thompson GB, Hay ID: Current strategies for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma. World J Surg 28 (12): 1187-98, 2004. [PUBMED Abstract]
- Harness JK, Sahar DE, et al.: Childhood thyroid carcinoma. In: Clark O, Duh Q-Y, Kebebew E, eds.: Textbook of Endocrine Surgery. 2nd ed. Philadelphia, PA: Elsevier Saunders Company, 2005., pp 93-101.
- Rachmiel M, Charron M, Gupta A, et al.: Evidence-based review of treatment and follow up of pediatric patients with differentiated thyroid carcinoma. J Pediatr Endocrinol Metab 19 (12): 1377-93, 2006. [PUBMED Abstract]
- Wada N, Sugino K, Mimura T, et al.: Treatment strategy of papillary thyroid carcinoma in children and adolescents: clinical significance of the initial nodal manifestation. Ann Surg Oncol 16 (12): 3442-9, 2009. [PUBMED Abstract]
- Lazar L, Lebenthal Y, Steinmetz A, et al.: Differentiated thyroid carcinoma in pediatric patients: comparison of presentation and course between pre-pubertal children and adolescents. J Pediatr 154 (5): 708-14, 2009. [PUBMED Abstract]
- Shayota BJ, Pawar SC, Chamberlain RS: MeSS: A novel prognostic scale specific for pediatric well-differentiated thyroid cancer: a population-based, SEER outcomes study. Surgery 154 (3): 429-35, 2013. [PUBMED Abstract]
- Flannery TK, Kirkland JL, Copeland KC, et al.: Papillary thyroid cancer: a pediatric perspective. Pediatrics 98 (3 Pt 1): 464-6, 1996. [PUBMED Abstract]
- Willgerodt H, Keller E, Bennek J, et al.: Diagnostic value of fine-needle aspiration biopsy of thyroid nodules in children and adolescents. J Pediatr Endocrinol Metab 19 (4): 507-15, 2006. [PUBMED Abstract]
- Stevens C, Lee JK, Sadatsafavi M, et al.: Pediatric thyroid fine-needle aspiration cytology: a meta-analysis. J Pediatr Surg 44 (11): 2184-91, 2009. [PUBMED Abstract]
- Bargren AE, Meyer-Rochow GY, Sywak MS, et al.: Diagnostic utility of fine-needle aspiration cytology in pediatric differentiated thyroid cancer. World J Surg 34 (6): 1254-60, 2010. [PUBMED Abstract]
- Redlich A, Boxberger N, Kurt Werner S, et al.: Sensitivity of fine-needle biopsy in detecting pediatric differentiated thyroid carcinoma. Pediatr Blood Cancer 59 (2): 233-7, 2012. [PUBMED Abstract]
- Cooper DS, Doherty GM, Haugen BR, et al.: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19 (11): 1167-214, 2009. [PUBMED Abstract]
- Raval MV, Bentrem DJ, Stewart AK, et al.: Utilization of total thyroidectomy for differentiated thyroid cancer in children. Ann Surg Oncol 17 (10): 2545-53, 2010. [PUBMED Abstract]
- Newman KD, Black T, Heller G, et al.: Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children's Cancer Group. Ann Surg 227 (4): 533-41, 1998. [PUBMED Abstract]
- Chow SM, Law SC, Mendenhall WM, et al.: Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer 42 (2): 176-83, 2004. [PUBMED Abstract]
- Verburg FA, Biko J, Diessl S, et al.: I-131 activities as high as safely administrable (AHASA) for the treatment of children and adolescents with advanced differentiated thyroid cancer. J Clin Endocrinol Metab 96 (8): E1268-71, 2011. [PUBMED Abstract]
- Luster M, Lassmann M, Freudenberg LS, et al.: Thyroid cancer in childhood: management strategy, including dosimetry and long-term results. Hormones (Athens) 6 (4): 269-78, 2007 Oct-Dec. [PUBMED Abstract]
- Parisi MT, Mankoff D: Differentiated pediatric thyroid cancer: correlates with adult disease, controversies in treatment. Semin Nucl Med 37 (5): 340-56, 2007. [PUBMED Abstract]
- Yeh SD, La Quaglia MP: 131I therapy for pediatric thyroid cancer. Semin Pediatr Surg 6 (3): 128-33, 1997. [PUBMED Abstract]
- Powers PA, Dinauer CA, Tuttle RM, et al.: Tumor size and extent of disease at diagnosis predict the response to initial therapy for papillary thyroid carcinoma in children and adolescents. J Pediatr Endocrinol Metab 16 (5): 693-702, 2003. [PUBMED Abstract]
- Vassilopoulou-Sellin R, Goepfert H, Raney B, et al.: Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up. Head Neck 20 (6): 549-55, 1998. [PUBMED Abstract]
- Kloos RT, Ringel MD, Knopp MV, et al.: Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 27 (10): 1675-84, 2009. [PUBMED Abstract]
- Cohen EE, Rosen LS, Vokes EE, et al.: Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26 (29): 4708-13, 2008. [PUBMED Abstract]
- Schlumberger MJ, Elisei R, Bastholt L, et al.: Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 27 (23): 3794-801, 2009. [PUBMED Abstract]
- Cabanillas ME, Waguespack SG, Bronstein Y, et al.: Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab 95 (6): 2588-95, 2010. [PUBMED Abstract]
- Wiersinga WM: Thyroid cancer in children and adolescents--consequences in later life. J Pediatr Endocrinol Metab 14 (Suppl 5): 1289-96; discussion 1297-8, 2001. [PUBMED Abstract]
- Jarzab B, Handkiewicz-Junak D, Wloch J: Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer 12 (4): 773-803, 2005. [PUBMED Abstract]
- Alessandri AJ, Goddard KJ, Blair GK, et al.: Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma. Med Pediatr Oncol 35 (1): 41-6, 2000. [PUBMED Abstract]
- Borson-Chazot F, Causeret S, Lifante JC, et al.: Predictive factors for recurrence from a series of 74 children and adolescents with differentiated thyroid cancer. World J Surg 28 (11): 1088-92, 2004. [PUBMED Abstract]
- Biko J, Reiners C, Kreissl MC, et al.: Favourable course of disease after incomplete remission on (131)I therapy in children with pulmonary metastases of papillary thyroid carcinoma: 10 years follow-up. Eur J Nucl Med Mol Imaging 38 (4): 651-5, 2011. [PUBMED Abstract]
- Patel A, Jhiang S, Dogra S, et al.: Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents. Pediatr Res 52 (5): 737-44, 2002. [PUBMED Abstract]
- Powers PA, Dinauer CA, Tuttle RM, et al.: Treatment of recurrent papillary thyroid carcinoma in children and adolescents. J Pediatr Endocrinol Metab 16 (7): 1033-40, 2003. [PUBMED Abstract]
- Waguespack SG, Sherman SI, Williams MD, et al.: The successful use of sorafenib to treat pediatric papillary thyroid carcinoma. Thyroid 19 (4): 407-12, 2009. [PUBMED Abstract]
- Falchook GS, Long GV, Kurzrock R, et al.: Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379 (9829): 1893-901, 2012. [PUBMED Abstract]
- Hayes DN, Lucas AS, Tanvetyanon T, et al.: Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res 18 (7): 2056-65, 2012. [PUBMED Abstract]
- Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011. [PUBMED Abstract]
- Krueger JE, Maitra A, Albores-Saavedra J: Inherited medullary microcarcinoma of the thyroid: a study of 11 cases. Am J Surg Pathol 24 (6): 853-8, 2000. [PUBMED Abstract]
- Raval MV, Sturgeon C, Bentrem DJ, et al.: Influence of lymph node metastases on survival in pediatric medullary thyroid cancer. J Pediatr Surg 45 (10): 1947-54, 2010. [PUBMED Abstract]
- Wells SA Jr, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [PUBMED Abstract]
- Thornton K, Kim G, Maher VE, et al.: Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res 18 (14): 3722-30, 2012. [PUBMED Abstract]
- Fox E, Widemann BC, Chuk MK, et al.: Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 19 (15): 4239-48, 2013. [PUBMED Abstract]
- Kurzrock R, Sherman SI, Ball DW, et al.: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29 (19): 2660-6, 2011. [PUBMED Abstract]
- Das S, Das AK: A review of pediatric oral biopsies from a surgical pathology service in a dental school. Pediatr Dent 15 (3): 208-11, 1993 May-Jun. [PUBMED Abstract]
- Ulmansky M, Lustmann J, Balkin N: Tumors and tumor-like lesions of the oral cavity and related structures in Israeli children. Int J Oral Maxillofac Surg 28 (4): 291-4, 1999. [PUBMED Abstract]
- Tröbs RB, Mader E, Friedrich T, et al.: Oral tumors and tumor-like lesions in infants and children. Pediatr Surg Int 19 (9-10): 639-45, 2003. [PUBMED Abstract]
- Tanaka N, Murata A, Yamaguchi A, et al.: Clinical features and management of oral and maxillofacial tumors in children. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88 (1): 11-5, 1999. [PUBMED Abstract]
- Young JL Jr, Miller RW: Incidence of malignant tumors in U. S. children. J Pediatr 86 (2): 254-8, 1975. [PUBMED Abstract]
- Berstein L, Gurney JG: Carcinomas and other malignant epithelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., Chapter 11, pp 139-148. Also available online. Last accessed October 29, 2014.
- Bleyer A: Cancer of the oral cavity and pharynx in young females: increasing incidence, role of human papilloma virus, and lack of survival improvement. Semin Oncol 36 (5): 451-9, 2009. [PUBMED Abstract]
- D'Souza G, Dempsey A: The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med 53 (Suppl 1): S5-S11, 2011. [PUBMED Abstract]
- Gillison ML, Broutian T, Pickard RK, et al.: Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 307 (7): 693-703, 2012. [PUBMED Abstract]
- Simard EP, Ward EM, Siegel R, et al.: Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 62 (2): 118-28, 2012 Mar-Apr. [PUBMED Abstract]
- Gillison ML, Chaturvedi AK, Lowy DR: HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 113 (10 Suppl): 3036-46, 2008. [PUBMED Abstract]
- Morris LG, Ganly I: Outcomes of oral cavity squamous cell carcinoma in pediatric patients. Oral Oncol 46 (4): 292-6, 2010. [PUBMED Abstract]
- Perez DE, Pires FR, Alves Fde A, et al.: Juvenile intraoral mucoepidermoid carcinoma. J Oral Maxillofac Surg 66 (2): 308-11, 2008. [PUBMED Abstract]
- Oksüzoğlu B, Yalçin S: Squamous cell carcinoma of the tongue in a patient with Fanconi's anemia: a case report and review of the literature. Ann Hematol 81 (5): 294-8, 2002. [PUBMED Abstract]
- Reinhard H, Peters I, Gottschling S, et al.: Squamous cell carcinoma of the tongue in a 13-year-old girl with Fanconi anemia. J Pediatr Hematol Oncol 29 (7): 488-91, 2007. [PUBMED Abstract]
- Ragin CC, Modugno F, Gollin SM: The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res 86 (2): 104-14, 2007. [PUBMED Abstract]
- Fine JD, Johnson LB, Weiner M, et al.: Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol 60 (2): 203-11, 2009. [PUBMED Abstract]
- Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123 (2): 241-50, 1987. [PUBMED Abstract]
- Alter BP: Cancer in Fanconi anemia, 1927-2001. Cancer 97 (2): 425-40, 2003. [PUBMED Abstract]
- Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, et al.: Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol 156 (5): 1015-9, 2007. [PUBMED Abstract]
- Alter BP, Giri N, Savage SA, et al.: Cancer in dyskeratosis congenita. Blood 113 (26): 6549-57, 2009. [PUBMED Abstract]
- Sturgis EM, Moore BA, Glisson BS, et al.: Neoadjuvant chemotherapy for squamous cell carcinoma of the oral tongue in young adults: a case series. Head Neck 27 (9): 748-56, 2005. [PUBMED Abstract]
- Woo VL, Kelsch RD, Su L, et al.: Gingival squamous cell carcinoma in adolescence. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107 (1): 92-9, 2009. [PUBMED Abstract]
- Sultan I, Rodriguez-Galindo C, Al-Sharabati S, et al.: Salivary gland carcinomas in children and adolescents: a population-based study, with comparison to adult cases. Head Neck 33 (10): 1476-81, 2011. [PUBMED Abstract]
- Ethunandan M, Ethunandan A, Macpherson D, et al.: Parotid neoplasms in children: experience of diagnosis and management in a district general hospital. Int J Oral Maxillofac Surg 32 (4): 373-7, 2003. [PUBMED Abstract]
- da Cruz Perez DE, Pires FR, Alves FA, et al.: Salivary gland tumors in children and adolescents: a clinicopathologic and immunohistochemical study of fifty-three cases. Int J Pediatr Otorhinolaryngol 68 (7): 895-902, 2004. [PUBMED Abstract]
- Shapiro NL, Bhattacharyya N: Clinical characteristics and survival for major salivary gland malignancies in children. Otolaryngol Head Neck Surg 134 (4): 631-4, 2006. [PUBMED Abstract]
- Ellies M, Schaffranietz F, Arglebe C, et al.: Tumors of the salivary glands in childhood and adolescence. J Oral Maxillofac Surg 64 (7): 1049-58, 2006. [PUBMED Abstract]
- Muenscher A, Diegel T, Jaehne M, et al.: Benign and malignant salivary gland diseases in children A retrospective study of 549 cases from the Salivary Gland Registry, Hamburg. Auris Nasus Larynx 36 (3): 326-31, 2009. [PUBMED Abstract]
- Fu H, Wang J, Wang L, et al.: Pleomorphic adenoma of the salivary glands in children and adolescents. J Pediatr Surg 47 (4): 715-9, 2012. [PUBMED Abstract]
- Galer C, Santillan AA, Chelius D, et al.: Minor salivary gland malignancies in the pediatric population. Head Neck 34 (11): 1648-51, 2012. [PUBMED Abstract]
- Thariat J, Vedrine PO, Temam S, et al.: The role of radiation therapy in pediatric mucoepidermoid carcinomas of the salivary glands. J Pediatr 162 (4): 839-43, 2013. [PUBMED Abstract]
- Laikui L, Hongwei L, Hongbing J, et al.: Epithelial salivary gland tumors of children and adolescents in west China population: a clinicopathologic study of 79 cases. J Oral Pathol Med 37 (4): 201-5, 2008. [PUBMED Abstract]
- Rutt AL, Hawkshaw MJ, Lurie D, et al.: Salivary gland cancer in patients younger than 30 years. Ear Nose Throat J 90 (4): 174-84, 2011. [PUBMED Abstract]
- Rahbar R, Grimmer JF, Vargas SO, et al.: Mucoepidermoid carcinoma of the parotid gland in children: A 10-year experience. Arch Otolaryngol Head Neck Surg 132 (4): 375-80, 2006. [PUBMED Abstract]
- Kupferman ME, de la Garza GO, Santillan AA, et al.: Outcomes of pediatric patients with malignancies of the major salivary glands. Ann Surg Oncol 17 (12): 3301-7, 2010. [PUBMED Abstract]
- Kaste SC, Hedlund G, Pratt CB: Malignant parotid tumors in patients previously treated for childhood cancer: clinical and imaging findings in eight cases. AJR Am J Roentgenol 162 (3): 655-9, 1994. [PUBMED Abstract]
- Whatley WS, Thompson JW, Rao B: Salivary gland tumors in survivors of childhood cancer. Otolaryngol Head Neck Surg 134 (3): 385-8, 2006. [PUBMED Abstract]
- Verma J, Teh BS, Paulino AC: Characteristics and outcome of radiation and chemotherapy-related mucoepidermoid carcinoma of the salivary glands. Pediatr Blood Cancer 57 (7): 1137-41, 2011. [PUBMED Abstract]
- Védrine PO, Coffinet L, Temam S, et al.: Mucoepidermoid carcinoma of salivary glands in the pediatric age group: 18 clinical cases, including 11 second malignant neoplasms. Head Neck 28 (9): 827-33, 2006. [PUBMED Abstract]
- Kamal SA, Othman EO: Diagnosis and treatment of parotid tumours. J Laryngol Otol 111 (4): 316-21, 1997. [PUBMED Abstract]
- Ryan JT, El-Naggar AK, Huh W, et al.: Primacy of surgery in the management of mucoepidermoid carcinoma in children. Head Neck 33 (12): 1769-73, 2011. [PUBMED Abstract]
- Williams SB, Ellis GL, Warnock GR: Sialoblastoma: a clinicopathologic and immunohistochemical study of 7 cases. Ann Diagn Pathol 10 (6): 320-6, 2006. [PUBMED Abstract]
- Prigent M, Teissier N, Peuchmaur M, et al.: Sialoblastoma of salivary glands in children: chemotherapy should be discussed as an alternative to mutilating surgery. Int J Pediatr Otorhinolaryngol 74 (8): 942-5, 2010. [PUBMED Abstract]
- Scott JX, Krishnan S, Bourne AJ, et al.: Treatment of metastatic sialoblastoma with chemotherapy and surgery. Pediatr Blood Cancer 50 (1): 134-7, 2008. [PUBMED Abstract]
- Bitar MA, Moukarbel RV, Zalzal GH: Management of congenital subglottic hemangioma: trends and success over the past 17 years. Otolaryngol Head Neck Surg 132 (2): 226-31, 2005. [PUBMED Abstract]
- McGuirt WF Jr, Little JP: Laryngeal cancer in children and adolescents. Otolaryngol Clin North Am 30 (2): 207-14, 1997. [PUBMED Abstract]
- Bauman NM, Smith RJ: Recurrent respiratory papillomatosis. Pediatr Clin North Am 43 (6): 1385-401, 1996. [PUBMED Abstract]
- Wharam MD Jr, Foulkes MA, Lawrence W Jr, et al.: Soft tissue sarcoma of the head and neck in childhood: nonorbital and nonparameningeal sites. A report of the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer 53 (4): 1016-9, 1984. [PUBMED Abstract]
- Siddiqui F, Sarin R, Agarwal JP, et al.: Squamous carcinoma of the larynx and hypopharynx in children: a distinct clinical entity? Med Pediatr Oncol 40 (5): 322-4, 2003. [PUBMED Abstract]
- Kashima HK, Mounts P, Shah K: Recurrent respiratory papillomatosis. Obstet Gynecol Clin North Am 23 (3): 699-706, 1996. [PUBMED Abstract]
- Maloney EM, Unger ER, Tucker RA, et al.: Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 132 (7): 711-5, 2006. [PUBMED Abstract]
- Gélinas JF, Manoukian J, Côté A: Lung involvement in juvenile onset recurrent respiratory papillomatosis: a systematic review of the literature. Int J Pediatr Otorhinolaryngol 72 (4): 433-52, 2008. [PUBMED Abstract]
- Andrus JG, Shapshay SM: Contemporary management of laryngeal papilloma in adults and children. Otolaryngol Clin North Am 39 (1): 135-58, 2006. [PUBMED Abstract]
- Avidano MA, Singleton GT: Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 112 (2): 197-202, 1995. [PUBMED Abstract]
- Derkay CS, Smith RJ, McClay J, et al.: HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial. Ann Otol Rhinol Laryngol 114 (9): 730-7, 2005. [PUBMED Abstract]
- French CA: NUT midline carcinoma. Cancer Genet Cytogenet 203 (1): 16-20, 2010. [PUBMED Abstract]
- French CA, Kutok JL, Faquin WC, et al.: Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol 22 (20): 4135-9, 2004. [PUBMED Abstract]
- Bauer DE, Mitchell CM, Strait KM, et al.: Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 18 (20): 5773-9, 2012. [PUBMED Abstract]
- Schwartz BE, Hofer MD, Lemieux ME, et al.: Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 71 (7): 2686-96, 2011. [PUBMED Abstract]