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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgeons, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years. The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons and, by definition, all pediatric cancers are considered rare. The designation of a pediatric rare tumor is not uniform among international groups:
These rare cancers are extremely challenging to study because of the low incidence of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers such as melanoma.
Figure 1. Age-adjusted and age-specific (0-14 years) Surveillance, Epidemiology, and End Results cancer incidence rates from 2009 to 2012 by International Classification of Childhood Cancer group and subgroup and age at diagnosis, including myelodysplastic syndrome and group III benign brain/central nervous system tumors for all races, males, and females.
Figure 2. Age-adjusted and age-specific (15-19 years) Surveillance, Epidemiology, and End Results cancer incidence rates from 2009 to 2012 by International Classification of Childhood Cancer group and subgroup and age at diagnosis, including myelodysplastic syndrome and group III benign brain/central nervous system tumors for all races, males, and females.
Several initiatives to study rare pediatric cancers have been developed by the COG and other international groups, such as the International Society of Paediatric Oncology (Société Internationale D'Oncologie Pédiatrique [SIOP]). The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) rare tumor project was founded in Germany in 2006. The Italian cooperative project on rare pediatric tumors (TREP) was launched in 2000, and the Polish Pediatric Rare Tumor Study Group was launched in 2002. In Europe, the rare tumor studies groups from France, Germany, Italy, Poland, and the United Kingdom have joined in the European Cooperative study Group on Pediatric Rare Tumors (EXPeRT), focusing on international collaboration and analyses of specific rare tumor entities. Within the COG, efforts have concentrated on increasing accrual to the COG registry (now known as the Childhood Cancer Research Network/Project Every Child) and the rare tumor bank, developing single-arm clinical trials, and increasing cooperation with adult cooperative group trials. The accomplishments and challenges of this initiative have been described in detail.[6,12]
The tumors discussed in this summary are very diverse; they are arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see less than a handful of some histologies in several years. The majority of the histologies described here occur more frequently in adults. Information about these tumors may also be found in sources relevant to adults with cancer.
Childhood sarcomas often occur in the head and neck area and they are described in other sections. Unusual pediatric head and neck cancers include the following:
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 small case series or cohorts combining pediatric and adult patients.
Nasopharyngeal carcinoma arises in the lining of the nasal cavity and pharynx, and it accounts for about one-third of all cancers of the upper airways in children.[1,2] Nasopharyngeal carcinoma is very uncommon in children younger than 10 years but increases in incidence to 0.8 cases per 1 million per year in children aged 10 to 14 years and 1.3 cases per million per year in children aged 15 to 19 years.[3,4,5]
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 the Mediterranean basin, and, particularly, Southeast Asia. In the United States, the incidence of nasopharyngeal carcinoma is higher in black children and adolescents younger than 20 years.
Nasopharyngeal carcinoma is strongly associated with Epstein-Barr virus (EBV) infection. In addition to the serological evidence of infection in more than 98% of patients, 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. Specific HLA subtypes, such as the HLA A2Bsin2 haplotype, are associated with a higher risk of nasopharyngeal carcinoma.
Three histologic subtypes of nasopharyngeal carcinoma are recognized by the World Health Organization (WHO):
Children with nasopharyngeal carcinoma are more likely to have WHO type II or type III disease.
Signs and symptoms of nasopharyngeal carcinoma include the following:[2,8]
Given the rich lymphatic drainage of the nasopharynx, bilateral cervical lymphadenopathy is 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 and Staging Evaluation
Diagnostic tests will determine the extent of the primary tumor and the presence of metastases. Visualization of the nasopharynx by an ear-nose-throat specialist using nasal endoscopy 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 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 including Burkitt lymphoma, and Hodgkin lymphoma must be considered, as well as benign conditions such as nasal angiofibroma, which usually presents with epistaxis in adolescent males, infectious lymphadenitis, and Rosai-Dorfman disease.
Evaluation of the chest and abdomen by computed tomography (CT) and bone scan is performed to determine whether there is metastatic disease. Fluorine F 18-fludeoxyglucose positron emission tomography (PET)-CT may also be helpful in the evaluation of potential metastatic lesions.
Stage Information for Childhood Nasopharyngeal Carcinoma
Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC, 8th edition).[10,11]
More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[12,13,14] Metastatic disease (stage IVC) at diagnosis is uncommon. A retrospective analysis of data from the Surveillance, Epidemiology, and End Results program reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did older patients.
The overall survival (OS) 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 exceed 80%.[4,5,8,13,14,15,16,17] After controlling for stage, children with nasopharyngeal carcinoma have significantly better outcomes than do adults.[4,5] However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities, including subsequent neoplasms.[4,13,14,16]
Treatment of Childhood Nasopharyngeal Carcinoma
Treatment of nasopharyngeal carcinoma is multimodal and includes the following:
The use of Epstein-Barr virus-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 [Adult] for more information.)
Treatment Options Under Clinical Evaluation for Childhood Nasopharyngeal Carcinoma
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
Esthesioneuroblastoma (olfactory neuroblastoma) is a small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[37,38,39,40] In children, esthesioneuroblastoma is a very rare malignancy, with an estimated incidence of 0.1 cases per 100,000 per year in 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 cases in a Surveillance, Epidemiology, and End Results (SEER) study. 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 the following:
Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[44,45,46]
Stage Information for Childhood Esthesioneuroblastoma
Tumors are staged according to the Kadish system (refer to Table 1). Correlated with Kadish stage, survival ranges from 90% (stage A) to less than 40% (stage D). Most patients present with locally advanced-stage disease (Kadish stages B and C) and almost one-third of patients have tumors at distant sites (Kadish stage D).[41,42] Recent reports suggest that positron emission tomography-computed tomography (PET-CT) may aid in staging the disease.
Treatment and Outcome of Childhood Esthesioneuroblastoma
The use of multimodal therapy optimizes the chances for survival, with more than 70% of children expected to survive 5 or more years after initial diagnosis.[41,48,49] A multi-institutional review of 24 patients younger than 21 years at diagnosis found a 5-year disease-free survival and overall survival of 73% to 74%.[Level of evidence: 3iiiA]
Treatment options according to Kadish stage include the following:
The mainstay of treatment is 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.[49,54]
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 promising results with the increased use of resection and neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease.[37,48,50,56,57]; [Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include cisplatin and etoposide with or without ifosfamide;[51,59] vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin; ifosfamide and etoposide; cisplatin plus etoposide or doxorubicin; vincristine, doxorubicin, and cyclophosphamide; and irinotecan plus docetaxel.[Level of evidence: 3iiA]
Treatment Options Under Clinical Evaluation for Childhood Esthesioneuroblastoma
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
The annual incidence of thyroid cancers is 2.0 cases per 1 million people per year in children younger than 15 years, 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 cases per 1 million people), and it accounts for approximately 8% of cancers arising in this older age group.[3,62] More thyroid carcinomas occur in females than in males.
A retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2011 identified 2,504 cases of papillary thyroid carcinoma in patients aged 20 years and younger. The incidence of papillary thyroid carcinoma increased over this interval by roughly 2% each year. The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.
An update from the SEER database for the period of 2007 to 2012 identified 1,723 pediatric patients with thyroid cancer. The average age-adjusted incidence of pediatric thyroid cancer was 0.59 cases per 100,000 patients. When the incidence in females was compared with the incidence in males, the ratio of pediatric thyroid cancer was 4.4:1. The incidences of papillary, follicular variant, follicular, and medullary subtypes differ over the pediatric age range (refer to Figure 3).
Figure 3. Incidence of pediatric thyroid carcinoma based on most frequent subtype per 100,000 as a percent of total cohort. Reprinted from International Journal of Pediatric Otorhinolaryngology, Volume 89, Sarah Dermody, Andrew Walls, Earl H. Harley Jr., Pediatric thyroid cancer: An update from the SEER database 2007-2012, Pages 121-126, Copyright (2016), with permission from Elsevier.
There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[66,67] 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 chromosome band 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 the PDQ summary on Unusual Cancers of Childhood Treatment for more information.)
Tumors of the thyroid are classified as adenomas or carcinomas.[70,71,72] Adenomas are benign, well circumscribed and encapsulated nodules 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 may grow and spread to lymph nodes in the neck or to the lungs. Approximately 20% of thyroid nodules in children are malignant.[70,73]
Various histologies account for the general diagnostic category of carcinoma of the thyroid; papillary and follicular carcinoma are often referred to as differentiated thyroid carcinoma:
Molecular Features and Tumor Characteristics
Studies have shown subtle differences between the genetic profiling of childhood differentiated thyroid carcinomas and that of adult tumors (refer to Table 2). In one study, a higher prevalence of RET/PTC rearrangements was reported in pediatric papillary thyroid carcinoma (45%-65% in children vs. 3%-34% in adults).BRAF V600E mutations are seen in more than 50% of adults with papillary thyroid carcinoma; although it likely occurs in a similar frequency in pediatric patients, studies have revealed a wide variation in frequency of this mutation.[78,79,80,81] In children, the correlation between the genomic alteration and stage or prognosis has not been well defined. While two studies failed to show a correlation,[80,81] one study that included 55 pediatric thyroid carcinoma cases demonstrated a significant correlation between the presence of a BRAF V600E mutation and an increased risk of recurrence. Differentiated thyroid carcinoma has been associated with germline DICER1 mutations and it is considered part of the DICER1 syndrome.
Clinical Presentation and Outcome
Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[85,86,87] On the basis of medical and family history and clinical constellation, the thyroid cancer may be part of a tumor predisposition syndrome such as multiple endocrine neoplasia or DICER1 syndrome.
Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. Children have a higher proportion of nodal involvement (40%-90% in children vs. 20%-50% in adults) and lung metastases (20%-30% in children vs. 2% in adults) than do adults.[79,89] Larger tumor size (>1 cm), extrathyroidal extension, and multifocal disease are associated with increased risk of nodal metastases. 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 sex, 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 have distant metastases had excellent survival at 90%. A French registry analysis found similar outcomes in children and young adults who developed papillary thyroid carcinoma after previous radiation therapy compared with children and young adults who developed spontaneous papillary thyroid carcinoma; patients with previous thyroid irradiation for benign disease, however, presented with more invasive tumors and lymph node involvement.
Initial evaluation of a child or adolescent with a thyroid nodule includes the following:
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.[94,95,96,97] Open biopsy or resection may also be preferable for young children (refer to Table 3).
Treatment of Papillary and Follicular Thyroid Carcinoma
Treatment options for papillary and follicular (differentiated) thyroid carcinoma may include the following:
The management of differentiated thyroid cancer in children has been reviewed in detail.[73,98] In 2015, the American Thyroid Association (ATA) Task Force on Pediatric Thyroid Cancer published guidelines for the management of thyroid nodules and differentiated thyroid cancer in children and adolescents. These guidelines (summarized below) are based on scientific evidence and expert panel opinion, with a careful assessment of the level of evidence.