Home > Health Library > Unusual Cancers of Childhood Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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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:
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 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]
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 are as follows:[2,7]
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, Hodgkin lymphoma, and Burkitt 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. Fludeoxyglucose positron emission tomography (PET)–CT may also be helpful in the evaluation of potential metastatic lesions.
Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC, 7th edition).
More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[10,11,12] Metastatic disease (stage IVC) at diagnosis is uncommon. 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.
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 are in excess of 80%.[4,7,11,12,13] After controlling for stage, children with nasopharyngeal carcinoma have significantly better outcomes than do adults. However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities, including subsequent neoplasms.[4,11,12]
Treatment of nasopharyngeal carcinoma is multimodal and includes the following:
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.)
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Esthesioneuroblastoma (olfactory neuroblastoma) is a small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[25,26,27,28] In children, esthesioneuroblastoma is a very rare malignancy, with an estimated incidence of 0.1 cases 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 cases in a 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:
Tumors are staged according to the Kadish system (refer to Table 1). Correlated with Kadish stage, prognosis 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 show tumor at distant sites (Kadish stage D).[29,30] Recent reports suggest that PET-CT may aid in staging the disease.
Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[33,34,35]
Treatment and outcome
The use of multimodal therapy optimizes the chances for survival, with over 70% of children expected to survive 5 or more years after initial diagnosis.[29,36,37] A multi-institutional review of 24 patients younger than 21 years at diagnosis found a 5-year disease-free survival and OS 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.[37,42]
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 neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease.[25,36,38,44,45]; [Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include cisplatin with etoposide with or without ifosfamide;[39,47] vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin; ifosfamide/etoposide; cisplatin plus etoposide or doxorubicin;  vincristine, doxorubicin, and cyclophosphamide; and irinotecan plus docetaxel.[Level of evidence: 3iiA]
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. 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. More thyroid carcinomas occur in females than in males.
There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[52,53] 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.[56,57,58] 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.[56,59]
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. A higher prevalence of RET/PTC rearrangements is seen in pediatric papillary 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.[64,65,66] In children, there does not appear to be a correlation between presence of the BRAF V600E mutation and stage or prognosis. 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.[69,70,71] On the basis of medical and family history and clinical constellation, the thyroid cancer may be part of a tumor predisposition syndrome such as MEN or DICER-1 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. 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 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.[76,77,78,79] Open biopsy or resection may also be preferable for young children.
Treatment of papillary and follicular (differentiated) 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.
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 achieve remission. With additional treatment, 89% of patients achieve remission.
Treatment options for papillary and follicular (differentiated) thyroid carcinoma may include the following:
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).[56,86,87]
After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress TSH production.
Periodic evaluation is required to determine whether there is metastatic disease involving the lungs. Lifelong monitoring is necessary. T4 and TSH levels are evaluated periodically to determine whether replacement hormone is appropriately dosed. The general aim is to suppress TSH secretion to levels less than 0.1 mIU/L.[Level of evidence: 1A]
The use of various tyrosine kinase inhibitors (TKIs) or vascular endothelial growth factor receptor inhibitors has been approved for the treatment of metastatic or recurrent thyroid cancer in adults.[91,92,93,94,95,96,97]
The American Thyroid Association has defined three levels for assessing risk of recurrent disease in children aged 18 years and younger with disseminated thyroid cancer, based on findings at initial workup and status after surgery, while receiving levothyroxine replacement. These levels apply only to patients with no evident disease within 12 weeks after thyroidectomy and no anti-thyroglobulin antibodies. Extent of disease is classified using the AJCC TNM system.
If thyroglobulin levels exceed the postthyroidectomy baseline levels at any time, disease recurrence is likely, and a thorough physical examination and imaging studies should be considered.
Treatment of recurrent papillary and follicular (differentiated) thyroid carcinoma
Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[89,98,99] However, recurrence is common (35%–45%) and is seen more often in children younger than 10 years and in those with palpable cervical lymph nodes at diagnosis.[100,101] 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.
TKIs such as sorafenib have been shown to induce responses in up to 15% of adult patients with metastatic disease. Response to sorafenib has also been documented in a pediatric case.
TKIs approved for the treatment of adults include the following:
Given the high incidence of BRAF mutations in patients with papillary thyroid carcinoma, the use of selective RAF/MEK inhibitors is being investigated.[91,108,109]
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. A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (NCT01660984). For patients with de novo RET mutations and no familial history, nonendocrine manifestations such as intestinal ganglioneuromatosis or skeletal or ocular stigmata, may facilitate early diagnosis and result in better outcomes.
Treatment options for medullary thyroid carcinoma include the following:
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 for 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.
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, for an objective response rate of 44%. 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. The median duration of therapy for the entire cohort was 27 months, with a range of 2 to 52 months.
(Refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information.)
Oral Cavity Cancer
More than 90% of tumors and tumor-like lesions in the oral cavity are benign.[117,118,119,120] Cancer of the oral cavity is extremely rare in children and adolescents.[121,122] 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 cases per 100,000.
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 papillomavirus (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, from 1999 to 2008, the incidence rates for HPV-related oropharyngeal cancer have increased by 4.4% per year in white men and 1.9% in white women.[124,125,126] 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 Langerhans cell histiocytosis.[117,118,119,120] (Refer to the Oral cavity subsection in the PDQ summary on Langerhans Cell Histiocytosis Treatment for more information about Langerhans cell histiocytosis of the oral cavity.)
Malignant lesions of the oral cavity were found in 0.1% to 2% of a series of oral biopsies performed in children [117,118] and 3% to 13% of oral tumor biopsies.[119,120] 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: 3iiiA]
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.[130,131,132,133,134,135,136,137]
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.[128,139] 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
Incidence and outcome
Salivary gland tumors are rare and account for 0.5% of all malignancies in children and adolescents. After rhabdomyosarcoma, they are the most common tumor in the head and neck.[140,141] Salivary gland tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[142,143,144]
Overall 5-year survival in the pediatric age group is approximately 95%. A review of the SEER database identified 284 patients younger than 20 years with tumors of the parotid gland.[Level of evidence: 3iA] OS was 96% at 5 years, 95% at 10 years, and 83% at 20 years. Adolescents had higher mortality rates (7.1% vs. 1.6% for children aged <15 years, P = .23).
Most salivary gland neoplasms arise in the parotid gland.[147,148,149,150,151,152,153] About 15% of these tumors 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.
The most common malignant salivary gland tumor in children is mucoepidermoid carcinoma, followed by acinic cell carcinoma, and adenoid cystic carcinoma; less common malignancies include rhabdomyosarcoma, adenocarcinoma, and undifferentiated carcinoma.[140,151,153,155,156,157] Mucoepidermoid carcinoma is usually low or intermediate grade, although high-grade tumors occur. In one study, 12 of 12 tumors were positive for MECT1/MAML2 fusion transcripts. This reflects the common chromosome translocation t(11;19)(q21;p13) that is seen in adults with salivary gland tumors. Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[153,157,159,160]
Radical surgical removal is the treatment of choice for salivary gland tumors whenever possible, with additional use of radiation therapy for high-grade tumors or tumors that have invasive characteristics, such as lymph node metastasis, lymphovascular invasion, or perineural extension.[145,156,161]; [Level of evidence: 3iiiA] One retrospective study compared proton and conventional radiation therapy and found proton therapy to have a favorable acute toxicity and dosimetric profile.
There are inadequate data regarding the efficacy of adjuvant chemotherapy in children.
(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.[167,168] These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck.
Treatment of laryngeal cancer
Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group and is treated with chemotherapy and radiation therapy. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) SCC of the larynx is managed in the same manner as in adults with carcinoma at this site, with surgery and radiation. Laser surgery may be the initial treatment utilized for these lesions. (Refer to the PDQ summary on Laryngeal Cancer Treatment for more information about treatment of laryngeal cancer in adults.)
Treatment of papillomatosis
Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is associated with HPV infection, 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, other interventions may be necessary, including the following:
The effectiveness of intralesional cidofovir has not been conclusively demonstrated.
Midline Tract Carcinoma Involving theNUTGene (NUTMidline 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 to NSD3 on chromosome 8p11; 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, individuals 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.[180,181]
Treatment includes a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success; however, while early response is common, tumors progress early in the course of the disease.[Level of evidence: 3iiiB]
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 two separate cases of children with refractory disease, thus suggesting a potential role for this class of agents in the treatment of this malignancy.[183,184] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Thoracic cancers include the following:
The prognosis, diagnosis, classification, and treatment of these thoracic 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.
The most frequent breast tumor seen in children is a fibroadenoma.[2,3] These tumors can be observed and many will regress without a need for surgical resection. However, rare malignant transformation leading to phyllodes tumors has been reported. Sudden rapid enlargement of a suspected fibroadenoma is an indication for needle biopsy or excision.
Treatment of fibroadenoma
Phyllodes tumors can be managed by wide local excision without mastectomy.
Breast cancer has been reported in both males and females younger than 21 years.[5,6,7,8,9,10] A review of the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute shows that 75 cases of malignant breast tumors in females aged 19 years or younger were identified from 1973 to 2004. Fifteen percent of these patients had in situ disease, 85% had invasive disease, 55% of the tumors were carcinomas, and 45% of the tumors were sarcomas—most of which were phyllodes tumors. Only three patients in the carcinoma group presented with metastatic disease, while 11 patients (27%) had regionally advanced disease. All patients with sarcomas presented with localized disease. Of the carcinoma patients, 85% underwent surgical resection, and 10% received adjuvant radiation therapy. Of the sarcoma patients, 97% had surgical resection, and 9% received radiation. The 5- and 10-year survival rates for patients with sarcomatous tumors were both 90%; for patients with carcinomas, the 5-year survival rate was 63% and the 10-year survival rate was 54%.
Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with the human immunodeficiency virus).
Risk factors for breast cancer in adolescents and young adults include the following:
Mammograms with adjunctive breast magnetic resonance imaging (MRI) start at age 25 years or 10 years postexposure to radiation therapy (whichever came last). (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.)
Treatment of breast cancer in adolescents and young adults (AYA)
Breast cancer is the most frequently diagnosed cancer among AYA women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses. Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different from that in older women and correlates with a worse prognosis.[12,18]
Treatment of the AYA group is similar to that of older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.[19,20]
(Refer to the PDQ summary on adult Breast Cancer Treatment for more information.)
Primary lung tumors are rare in children and histologically quite diverse. When epithelial cancers of the lung occur, they tend to be of advanced stage, with prognosis dependent on both histology and stage. Most primary lung tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign. A review of primary malignant epithelial lung tumors using the National Cancer Data Base found that the most common primary malignant pediatric lung neoplasms were carcinoid tumors (63%) followed by mucoepidermoid carcinoma of the lung (18%).
Most pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5.
The most common malignant primary tumors of the lung are bronchial tumors and pleuropulmonary blastoma.
Bronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of bronchial tumors on occasion display malignant behavior. The following three histologic types have been identified:[25,26,27,28,29,30]
Bronchial tumors of all histologic types are associated with an excellent prognosis after surgical resection in children, even in the presence of local invasion.[31,32]; [Level of evidence: 2A]
Clinical presentation and diagnostic evaluation
The presenting symptoms of a bronchial tumor are usually caused by an incomplete bronchial obstruction and include the following:
Because of difficulties in diagnosis, symptoms are frequently present for months, and, occasionally, children with wheezing have been treated for asthma, with delays in diagnosis for as long as 4 to 5 years.
Metastatic lesions are reported in approximately 6% of carcinoid tumors, and recurrences are reported in 2% of cases. Atypical carcinoid tumors are rare but more aggressive, with 50% of patients presenting with metastatic disease at diagnosis.[21,35] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome. Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread.
The management of bronchial tumors is somewhat controversial because bronchial tumors are usually visible endoscopically. Biopsy of these lesions may be hazardous because of the risk of hemorrhage. New endoscopic techniques have allowed biopsy to be performed safely;[30,37] however, endoscopic resection is not recommended except in highly selected cases.[37,38] Bronchography or computed tomography scan may be helpful to determine the degree of bronchiectasis distal to the obstruction since the degree of pulmonary destruction may influence surgical therapy.
Treatment of bronchial tumors
Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[40,41]; [Level of evidence: 2A] Adenoid cystic carcinomas (cylindroma) have a tendency to spread submucosally, and late local recurrence or dissemination has been reported. In addition to en bloc resection with hilar lymphadenectomy, a frozen section examination of the bronchial margins is performed in children with this lesion.
Neither chemotherapy nor radiation therapy is indicated for bronchial tumors, unless evidence of metastasis is documented.
(Refer to the Neuroendocrine Tumors (Carcinoid Tumors) section of this summary for information about neuroendocrine carcinoid tumors.)
Types of pleuropulmonary blastoma
Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy that can present as a pulmonary or pleural mass. The International Pleuropulmonary Blastoma Registry is a valuable resource for information on this rare malignancy.
The following three subtypes of pleuropulmonary blastoma have been identified:
Histologically, these tumors appear as a multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface, with skeletal differentiation in one-half of the cases. This form of disease can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts.
The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50 year period.
Prognostic factors for pleuropulmonary blastoma include the following:
Of the 97 patients who were tested, 66% had a heterozygous germline DICER1 mutation, confirming that this is a familial cancer syndrome. In this subset, DICER1 mutation status was not related to outcome.
Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the pleuropulmonary blastoma family tumor and dysplasia syndrome. Germline mutations in the DICER1 gene are considered the major genetic determinant of the complex.[51,52,53] Importantly, while DICER1 mutations cause a wide range of phenotypes, pleuropulmonary blastoma does not occur in all families with DICER1 mutations; therefore, the term DICER1 syndrome is generally used for these families. Also, most mutation carriers are unaffected, indicating that tumor risk is modest. Conversely, approximately 40% of patients with pleuropulmonary blastoma tumors do not have DICER1 germline mutations.
The most relevant association is with cystic nephroma; up to 10% of pleuropulmonary blastoma cases have been reported to develop cystic nephroma or Wilms tumor, malignancies that are also more prevalent among family members. Germline DICER1 mutations have also been associated with ovarian sex cord–stromal tumors (especially Sertoli-Leydig cell tumor), multinodular goiter, uterine cervix embryonal rhabdomyosarcoma, cervical primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration, juvenile intestinal polyps, ciliary body medulloepithelioma, medulloblastoma, and seminoma.[46,53,54,55,56,57,58,59]
DICER1 mutations appear to have a low penetrance, with pleuropulmonary blastoma, cystic nephroma, and multinodular goiter being the most frequently reported manifestations; not all families include pleuropulmonary blastoma, and most mutation carriers do not develop tumors. Most associated conditions occur in children younger than 10 years, although ovarian tumors and multinodular goiters are described in children and adults aged up to 30 years.
Presenting symptoms are not specific, and commonly include the following:
Up to 50% of patients with type I disease have multiple lesions, and in 33% of the cases lesions are bilateral.
The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the heart/great vessels, mediastinum, diaphragm, and/or pleura.[50,60] The International Pleuropulmonary Blastoma Registry identified 11 cases of Type II and Type III pleuropulmonary blastoma with tumor extension into the thoracic great vessels or the heart. Radiographic evaluation of the central circulation is performed in children with suspected or diagnosed pleuropulmonary blastoma to identify potentially fatal embolic complications.
Treatment of pleuropulmonary blastoma
There are no standard treatment options. Current treatment regimens for these rare tumors have been informed by consensus opinion.
A complete surgical resection is the most important prognostic factor; however, surgery alone results in high relapse rates.[44,49]
Data from the International Pleuropulmonary Blastoma Registry and from the European Cooperative Study Group in Pediatric Rare Tumors (EXPeRT) suggest that adjuvant chemotherapy may reduce the risk of recurrence.; [Level of evidence: 3iiiA] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.[45,48,62,63]
High-dose chemotherapy with stem cell rescue has been used without success.
Some general treatment considerations from the Pleuropulmonary Blastoma Registry include the following:
Radiation therapy may be used in patients with type III pleuropulmonary blastoma, although this has no impact on survival.
Incidence and histology
Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[67,68] Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma.
Symptoms are related to difficulty in swallowing and associated weight loss. Diagnosis is made by histologic examination of biopsy tissue.
Treatment options for esophageal carcinoma include the following:
Prognosis is generally poor for this cancer, which rarely can be completely resected.
(Refer to the PDQ summary on adult Esophageal Cancer Treatment for more information.)
Thymoma and Thymic Carcinoma
A cancer of the thymus is not considered a thymoma or a thymic carcinoma unless there are neoplastic changes of the epithelial cells that cover the organ.[69,70,71] The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component. Thymic carcinomas have a higher incidence of capsular invasion and metastases. A thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as thymic carcinoma, also known as type C thymoma. Other tumors that involve the thymus gland include lymphomas, germ cell tumors, carcinomas, carcinoids, and thymomas. Hodgkin lymphoma and non-Hodgkin lymphoma may also involve the thymus and must be differentiated from true thymomas and thymic carcinomas.
Thymoma and thymic carcinomas are very rare in children.[72,73,74] In the Tumori Rari in Età Pediatrica registry, only eight cases were identified over a 9-year period. A review of 73 cases of anterior mediastinal tumors using the SEER registry identified thymic epithelial tumors as having the worst survival rate at 10 years from diagnosis; better survival rates occurred in patients with lymphomas and germ cell tumors. A review of 48 published cases of thymoma in patients younger than 18 years, excluding thymic carcinoma, found an association between stage of disease and survival; it also suggested guidelines for treatment. The overall 2-year survival in this series was 71%.
Various diseases and syndromes are associated with thymoma, including the following:[75,76,77]
These neoplasms are usually located in the anterior mediastinum and are usually discovered during a routine chest x-ray. Symptoms can include the following:
Nonspecific symptoms may also occur.
These tumors generally are slow growing but are potentially invasive, with metastases to distant organs or lymph nodes. Staging is related to invasiveness. Most children present with low-stage disease.
Treatment options for thymoma and thymic carcinoma include the following:
Sunitinib has yielded clinical responses in four adult patients with thymic carcinoma.
(Refer to the adult Thymoma and Thymic Carcinoma Treatment summary for more information on the treatment of thymoma and thymic carcinoma.)
Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%; in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%. The most common primary tumors of the heart are benign and include the following:[87,88,89]
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[87,90,91,92,93]
Myxomas are the most common noncutaneous finding in Carney complex, a rare syndrome characterized by lentigines, cardiac myxomas or other myxoid fibromas, and endocrine abnormalities.[94,95,96] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[94,97]
Primary malignant pediatric heart tumors are rare but may include the following:[87,98,99]
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, other sarcomas, melanoma, leukemia, thymoma, and carcinomas of various sites.[85,87]
The distribution of cardiac tumors in the fetal and neonatal period is different from that in older patients, with two-thirds of teratomas occurring during this period of life. Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[90,100] A retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography showed that 68% of the patients exhibited features of tuberous sclerosis. In another study, 79% of patients (15 of 19) with rhabdomyomas discovered prenatally had tuberous sclerosis, while 96% of those diagnosed postnatally had tuberous sclerosis. Most rhabdomyomas, whether diagnosed prenatally or postnatally, will spontaneously regress.
Patients may be asymptomatic and present with sudden death,[Level of evidence: 3iiiA] but about two-thirds of patients have symptoms that may include the following:
The utilization of new cardiac MRI techniques can identify the likely tumor type in most children. However, histologic diagnosis remains the standard for diagnosing cardiac tumors.
Successful treatment may require surgery, debulking for progressive symptoms, cardiac transplantation, and chemotherapy that is appropriate for the type of cancer that is present:[105,106,107]; [Level of evidence: 3iiA]
In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.
Incidence, risk factors, and clinical presentation
Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life. Fewer than 300 cases in children have been reported.
Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.[112,113] In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation. The amount of exposure required to develop cancer is unknown, and there is no information about the risk for children exposed to asbestos.
This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[115,116,117] These tumors can spread over the surface of organs, without invading far into the underlying tissue, and may spread to regional or distant lymph nodes.
Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive and with those that recur. In general, the course of the disease is slow, and long-term survival is common.
Diagnostic thoracoscopy should be considered in suspicious cases to confirm diagnosis.
Radical surgical resection has been attempted with mixed results. In adults, a multimodal therapy including extrapleural pneumonectomy and radiation therapy after combination chemotherapy with pemetrexed-cisplatin may achieve durable responses.[Level of evidence: 2A] However, this approach remains highly controversial. In children, treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[117,121,122,123]
Pain is an infrequent symptom; however, if pain occurs, radiation therapy may be used for palliation.
Papillary serous carcinoma of the peritoneum may be mistaken for mesothelioma. This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel.
(Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)
Abdominal cancers include the following:
The prognosis, diagnosis, classification, and treatment of these abdominal 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. (Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors for information about kidney tumors.)
Carcinoma of the Adrenal Cortex
Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior.
The incidence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers). Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[2,3] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[4,5,6,7,8]
In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million individuals. Internationally, however, the incidence of adrenocortical tumors appears to vary substantially. It is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[10,11,12,13]
Female gender is consistently predominant in most studies, with a female to male ratio of 1.6 to 1.0.[8,14]
Germline TP53 mutations are almost always the predisposing factor. The likelihood of a TP53 germline mutation is highest in the first years of life and diminishes with age. Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe and in 95% of the Brazilian cases. 
Patients with Beckwith-Wiedemann and hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors. Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome. However, less than 1% of children with adrenocortical tumors have these syndromes.
The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.
Unlike adult adrenocortical tumors, histologic differentiation of pediatric adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,5] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.
Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[23,24]
Morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[26,27] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from tumor characteristics, such as tumor necrosis, mitotic rate, the presence of atypical mitoses, and venous, capsular, or adjacent organ invasion.[13,25]
Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[3,5]
Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.
Nonfunctional tumors are rare (<10%) and tend to occur in older children.
In patients with localized disease, younger age (<4 years), virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight no greater than 200 grams are associated with a greater probability of survival. In a Cox regression model analysis, only stage I, virilization alone, and age 0 to 3 years were independently associated with a better outcome. Available data suggest that tumor size is especially important in children; patients with small tumors have an excellent outcome with surgery alone, regardless of histologic features.
A low expression of the HLA class II antigens HLA-DRA, HLA-DPA1, and HLA-DPB1 has been associated with older age, larger tumor size, presence of metastatic disease, and worse outcome.
The overall probability of 5-year survival for children with adrenocortical tumors is reported to be 54% to 74%.[3,5,6,8,30,31,32]
At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.
Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used. Surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[12,13,34,35]; [Level of evidence: 3iiiA]
Treatment options for childhood adrenocortical tumors include the following:
The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. One study reported that three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.[13,41]
Carcinoma of the Stomach
Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual. In one series, gastric cancer in children younger than 18 years accounted for 0.11% of all gastric cancer cases seen over an 18-year period. The frequency and death rate from stomach cancer has declined worldwide for the past 50 years with the introduction of food preservation practices such as refrigeration.
The tumor must be distinguished from other conditions such as non-Hodgkin lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach. Symptoms of carcinoma of the stomach include the following:
Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to confirm the diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.
Treatment includes surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as fluorouracil (5-FU) and irinotecan. Other agents that may be of value are the nitrosoureas with or without cisplatin, etoposide, doxorubicin, or mitomycin C.
Prognosis depends on the extent of the disease at the time of diagnosis and the success of treatment that is appropriate for the clinical situation. Because of the rarity of stomach cancer in the pediatric age group, little information exists regarding the treatment outcomes of children.
(Refer to the PDQ summary on adult Gastric Cancer Treatment for more information.)
Cancer of the Pancreas
Malignant pancreatic tumors are rare in children and adolescents, with an incidence of 0.46 cases per 1 million individuals younger than 30 years.[47,48,49,50]
The primary pancreatic tumors of childhood can be classified into the following four categories:
Solid pseudopapillary tumor of the pancreas
Solid pseudopapillary tumor of the pancreas, also known as Frantz tumor, is the most common pediatric pancreatic tumor, accounting for up to 70% of cases in most institutional series.[49,51] This tumor has low malignant potential and most commonly affects females of reproductive age (median age, 21 years), with a predilection for blacks and East Asians.[47,49,52] There is no known genetic or hormonal factor to explain the strong female predilection, although it has been noted that all tumors express progesterone receptors.
Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[47,49,52] Tumors can occur throughout the pancreas and are often exophytic. On imaging, the mass shows typical cystic and solid components, with intratumoral hemorrhage and a fibrous capsule. Histologically, the tumors are characterized by a combination of solid, pseudopapillary, and cystic changes. The fragility of the vascular supply leads to secondary degenerative changes and cystic areas of hemorrhage and necrosis. The cells surrounding the hyalinized fibrovascular stalks form the pseudopapillae. A highly specific paranuclear dot-like immunoreactivity pattern for CD99 has been described.
The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates in excess of 95%.
Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual. Surgery is usually curative, although local recurrences occur in 5% to 15% of the cases.
Metastatic disease, usually in the liver, may occur in up to 15% of the cases.[47,49,52,53,54] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.
Pancreatoblastoma accounts for 10% to 20% of all pancreatic tumors during childhood. It is the most common pancreatic tumor of young children and typically presents in the first decade of life, with a median age at diagnosis of 5 years.[47,56]
Patients with Beckwith-Wiedemann syndrome have an increased risk of developing pancreatoblastoma; this syndrome is identified in up to 60% of cases of pancreatoblastoma developing during early infancy and in 5% of children developing pancreatoblastoma later in life. Pancreatoblastoma has also been associated with familial adenomatous polyposis syndromes.
This tumor is thought to arise from the persistence of the fetal analog of pancreatic acinar cells. Pathology shows an epithelial neoplasm with an arrangement of acinar, trabecular, or solid formations separated by dense stromal bands.CTNNB1 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.
Although approximately one-half of the cases originate in the head of the pancreas, jaundice is uncommon. Close to 80% of the tumors secrete alpha-fetoprotein, which can be used to measure response to therapy and monitor for recurrence. In some cases, the tumor may secrete adrenocorticotropic hormone (ACTH) or antidiuretic hormone, and patients may present with Cushing syndrome and syndrome of inappropriate antidiuretic hormone secretion. Metastases are present in 30% to 40% of the patients, usually involving liver, lungs, and lymph nodes.
Using a multimodality approach, close to 80% of patients can be cured.
Surgery is the mainstay in the treatment of pancreatoblastoma, and a complete surgical resection is required for cure. Because of the common origin in the head of the pancreas, a Whipple procedure is usually required.
For large, unresectable, or metastatic tumors, preoperative chemotherapy is indicated; pancreatoblastoma commonly responds to chemotherapy, and a cisplatin-based regimen is usually recommended. The PLADO regimen, which includes cisplatin and doxorubicin, is the most commonly used regimen, and treatment is modeled after the management of hepatoblastoma, with two to three cycles of preoperative therapy, followed by resection and adjuvant chemotherapy.[49,56,58,60]
Although radiation therapy has been used in unresectable or relapsed cases, its role in the treatment of microscopic disease after surgery has not been defined.
High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[49,61]
Islet cell tumors
Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[49,51,62] These tumors usually present in middle age and may be associated with multiple endocrine neoplasia type 1 (MEN1) syndrome; less than 5% of islet cell tumors occur in children.
The most common type of functioning islet cell tumor is insulinoma, followed by gastrinoma. Patients with insulinoma present with fasting hyperinsulinic hypoglycemia; in young children, presentation may include behavioral problems, seizures, or coma. Gastrinoma presents with Zollinger-Ellison syndrome, with recurrent peptic ulcers in uncommon locations, and diarrhea due to gastric hypersecretion. While most insulinomas are benign, a significant proportion of gastrinomas are malignant. Other less common tumors seldom seen in children are the ACTHoma, which presents as Cushing syndrome, and the VIPoma, which presents as Verner-Morrison syndrome. Nonfunctioning tumors are extremely rare in pediatrics, except when associated with MEN1. Islet cell tumors are typically solitary; when multiple tumors are present, the diagnosis of MEN1 syndrome should be considered.
On imaging, these tumors are usually small and well defined. Somatostatin receptor scintigraphy is useful for the location of islet cell tumors; however, only 60% to 70% express somatostatin receptor.
Treatment of islet cell tumors includes medical therapy for control of the syndrome and complete surgical resection. For patients with malignant tumors and unresectable or metastatic disease, chemotherapy and mammalian target of rapamycin (mTOR) inhibitors are recommended. The management of these tumors in children follows the consensus guidelines established for adult patients.[62,63]
(Refer to the PDQ summary on adult Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment for more information.)
Pancreatic carcinomas (acinar cell carcinoma and ductal adenocarcinoma) are extremely rare in children. These malignancies represent less than 5% of pediatric pancreatic tumors and include the following:[49,51]
Presenting symptoms are nonspecific and are related to local tumor growth. However, 4% to 15% of adult patients with acinar cell carcinoma may present with a lipase hypersecretion syndrome, manifesting as peripheral polyarthropathy and painful subcutaneous nodules.
(Refer to the PDQ summary on adult Pancreatic Cancer Treatment for information about the treatment of pancreatic carcinoma.)
Carcinoma of the large bowel is rare in the pediatric age group. It is seen in one case per 1 million persons younger than 20 years in the United States annually; fewer than 100 cases are diagnosed in children each year in the United States. From 1973 to 2006, the Surveillance, Epidemiology, and End Results database recorded 174 cases of colorectal cancer in patients younger than 19 years.
Colorectal tumors can occur in any location in the large bowel. Larger series and reviews suggest that ascending and descending colon tumors are each seen in approximately 30% of cases, with rectal tumors occurring in approximately 25% of cases.[68,69,70]
Signs and symptoms in children with descending colon tumors include the following:
The median duration of symptoms before diagnosis was about 3 months in one series.[66,71]
Changes in bowel habits may be associated with tumors of the rectum or lower colon.
Tumors of the right colon may cause more subtle symptoms but are often associated with the following:
Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.
Diagnostic studies include the following:[72,73]
There is a higher incidence of mucinous adenocarcinoma in the pediatric and adolescent age group (40%–50%), with many lesions being the signet ring cell type,[66,71,75] whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. In the adolescent and young adult population with the mucinous histology, there is a higher incidence of signet ring cells, microsatellite instability, and mutations in the mismatch repair genes. These tumors arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.
Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRAS mutations and other cytogenetic anomalies seen in older patients.
Most reports also suggest that children present with more advanced disease than do adults, with 80% to 90% of patients presenting with Dukes stage C/D or TNM stage III/IV disease (refer to the Stage Information for Colon Cancer section of the PDQ summary on adult Colon Cancer Treatment for more information about staging).[66,68,69,70,71,72,75,78,79,80,81,82,83,84]
Most patients present with evidence of metastatic disease, either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[75,78]
Treatment options for childhood colorectal cancer include the following:
A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved progression-free survival and overall survival (OS) in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[Level of evidence: 2A]
Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[88,89,90,91]
Survival is consistent with the advanced stage of disease observed in most children with colorectal cancer, with an overall mortality rate of approximately 70%. For patients with a complete surgical resection or for those with low-stage/localized disease, survival is significantly prolonged, with the potential for cure.
Genetic syndromes associated with colorectal cancer
About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome. The incidence of these genetic syndromes in children has not been well defined, as follows:
The most common genetic syndromes associated with the development of colorectal cancer are shown in Tables 5 and 6.
Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminates the risk of developing carcinomas of the large bowel. Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma. Familial adenomatous polyposis (FAP) syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps. A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with FAP reported that celecoxib at a dose of 16 mg/kg per day is safe for administration for up to 3 months. At this dose, there was a significant decrease in the number of polyps detected on colonoscopy.[Level of evidence: 1iiDiv] The role of celecoxib in the management of FAP is not clear.
Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I and several other rare syndromes.
(Refer to the PDQ summary on Genetics of Colorectal Cancer for more information about the genetic syndromes associated with childhood colorectal cancer.)
Neuroendocrine Tumors (Carcinoid Tumors)
These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[101,102,103,104,105,106] Most lung lesions are benign; however, some metastasize.
The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver. Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms. Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.
Neuroendocrine tumors of the appendix
Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, low-grade, localized tumors; simple appendectomy is the therapy of choice.[110,111,112]
For larger (>2 cm) tumors or tumors that have spread to local nodes, cecectomy or rarely, right hemicolectomy, is the usual treatment. It has become accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (>2 cm in diameter) or with tumors that have spread to the nodes; however, this practice remains controversial.
There are no reported cases of recurrence of appendiceal carcinoid tumors in children and adolescents after surgical resection without right hemicolectomy.
Overall, the prognosis for patients with appendiceal carcinoids is excellent. The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP] enrolled 113 children younger than 18 years with appendiceal neuroendocrine tumors between 2000 and 2013.[Level of evidence: 3iiiA] They found no relapses or deaths in this cohort after appendectomy for incompletely resected tumors. These data support the conclusion that observation alone is adequate follow-up after resection of appendiceal carcinoid tumors. A MEDLINE search did not find any documented cases of childhood localized appendiceal carcinoid in children younger than 18 years with complete resection who relapsed.
Nonappendiceal neuroendocrine tumors
Nonappendiceal neuroendocrine tumors in the abdomen can occur in the pancreas, stomach, and liver. The most common clinical presentation is an unknown primary site. Nonappendiceal neuroendocrine tumors are more likely to be larger, higher grade, or present with metastases.
In one retrospective, single-institution study, the 5-year relapse-free survival rate of nonappendiceal neuroendocrine tumors was 41% and the overall survival rate was 66%. Chemotherapy for these tumors was largely ineffective.
(Refer to the Bronchial tumors section of this summary for information about bronchial carcinoid tumors.)
Metastatic neuroendocrine tumors
Treatment of metastatic carcinoid tumors of the large bowel, pancreas, or stomach becomes more complicated and requires treatment similar to that given for adult high-grade neuroendocrine tumors. (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors for treatment options in patients with malignant carcinoid tumors.)
Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults. These tumors are rare in children. Approximately 2% of all GIST occur in children and young adults.[120,121,122] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas. Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas.
In pediatric patients, GIST are most commonly located in the stomach and almost exclusively affect adolescent females.[122,124,125]
Histology and molecular features
Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, their mitotic rate does not appear to accurately predict clinical behavior.[124,126] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[127,128] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[129,130]
Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[124,129,131] The lack of SDHB expression in most pediatric GIST implicates cellular respiration defects in the pathogenesis of this disease and supports the notion that this disease is better classified as SDH-deficient GIST. Furthermore, about 50% of patients with SDH-deficient GIST have germline mutations of the SDH complex, most commonly involving SDHA, supporting the notion that SDH-deficient GIST is a cancer predisposition syndrome and testing of affected patients for constitutional mutations for the SDH complex should be considered. A small percentage of SDH-deficient GIST lack somatic or germline mutations of the SDH complex and are characterized by SDHC promoter hypermethylation and gene silencing and are categorized as SDH epimutant tumors.
Most pediatric patients with GIST are diagnosed during the second decade of life with anemia-related gastrointestinal bleeding. In addition, pediatric GIST have a high propensity for multifocality (23%) and nodal metastases.[122,124,131] These features may account for the high incidence of local recurrence seen in this patient population. Despite these features, patients have an indolent course characterized by multiple recurrences and long survival.
SDH-deficient GIST can arise within the context of the following two syndromes:[124,134]
Once the diagnosis of pediatric GIST is established, referral to medical centers with expertise in the treatment of GIST should be considered, and that all samples be evaluated for mutations of KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[137,138]
Treatment of GIST depends on whether a mutation is detected, as follows:
Responses to imatinib and sunitinib in pediatric patients with SDH-deficient GIST are uncommon and consist mainly of disease stabilization.[124,139,140] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease. In another study, sunitinib appeared to show more activity, with one partial response and five cases of stable disease in six children with imatinib-resistant GIST. Unlike the adult recommendations, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.
Genital/urinary tumors include the following:
The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below. It must be emphasized that these tumors are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.
Carcinoma of the Bladder
Urothelial bladder neoplasms are extremely rare in children.
Histologic classification of these neoplasms includes urothelial papillomas, papillary neoplasms of low malignant potential, low-grade urothelial carcinoma, and high-grade urothelial carcinoma. An alternative designation is transitional cell carcinoma of the bladder. The most common histology is papillary urothelial neoplasm of low malignant potential, while high-grade, invasive urothelial carcinomas are extremely rare in young patients.[1,2,3,4,5]
Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.[4,6,7] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.
In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have an excellent prognosis after transurethral resection.[2,3,5,8] Squamous cell carcinoma and more aggressive carcinomas, however, have been reported and may require a more aggressive surgical approach.[3,9,10,11]
(Refer to the PDQ summary on adult Bladder Cancer Treatment for more information.)
Testicular Cancer (Non–Germ Cell)
Testicular tumors are very rare in young boys and account for an incidence of 1% to 2% of all childhood tumors.[12,13] The most common testicular tumors are benign teratomas followed by malignant nonseminomatous germ cell tumors. (Refer to the PDQ summary on Childhood Extracranial Germ Cell Tumors for more information.)
Non–germ cell tumors such as sex cord–stromal tumors are exceedingly rare in prepubertal boys. In a small series, gonadal stromal tumors accounted for 8% to 13% of pediatric testicular tumors.[14,15] In newborns and infants, juvenile granulosa cell and Sertoli cell tumors are the most common stromal cell tumor. Juvenile granulosa cell tumors usually present in infancy (median age, 6 days) and Sertoli cell tumors present later in infancy (median age, 7 months). The prognosis for sex cord–stromal tumors is usually excellent after orchiectomy.[Level of evidence: 3iiiA] In older males, Leydig cell tumors are more common. Stromal cell tumors have been described as benign in young boys.[18,19,20]
There are conflicting data about malignant potential in older males. Most case reports suggest that in the pediatric patients, these tumors can be treated with surgery alone.[Level of evidence: 3iii]; [Level of evidence: 3iiiA]; [Level of evidence: 3iiiDii] It is prudent to check alpha-fetoprotein (AFP) levels before surgery. Elevated AFP levels are usually indicative of a malignant germ cell tumor. However, AFP levels and decay in levels are often difficult to interpret in infants younger than 1 year.
However, given the rarity of this tumor, the surgical approach in pediatrics has not been well defined.
Ovarian Cancer (Non–Germ Cell)
The majority of ovarian masses in children are not malignant.
The most common neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then other tumors such as Burkitt lymphoma.[26,27,28,29] The majority of malignant ovarian tumors occur in girls aged 15 to 19 years.
Epithelial ovarian neoplasia
Ovarian tumors derived from malignant epithelial elements include adenocarcinomas, cystadenocarcinomas, (mucinous) borderline tumors, endometrioid tumors, clear cell tumors, and undifferentiated carcinomas. In one series of 19 patients younger than 21 years with epithelial ovarian neoplasms, the average age at diagnosis was 19.7 years. Dysmenorrhea and abdominal pain were the most common presenting symptoms; 79% of the patients had stage I disease with a 100% survival rate, and only those who had small cell anaplastic carcinoma died.
Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than do adults with similar histology, probably because girls usually present with low-stage disease.
Treatment is stage-related and may include surgery, radiation, and chemotherapy with cisplatin, carboplatin, etoposide, topotecan, paclitaxel, and other agents.
Ovarian surface epithelial neoplasms comprise a small subset of ovarian epithelial neoplasms; in children, most of the cases are of serous or mucinous histology and have a low malignant potential. Surgery and chemotherapy have been used to treat ovarian surface epithelial neoplasms.
Sex cord–stromal tumors
Ovarian sex cord–stromal tumors are a heterogeneous group of rare tumors that derive from the gonadal non–germ cell component. Histologic subtypes display some areas of gonadal differentiation and include juvenile granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. Ovarian Sertoli-Leydig cell tumors in children and adolescents are commonly associated with the presence of germline DICER1 mutations and may be a manifestation of the familial pleuropulmonary blastoma syndrome.
The clinical presentation and prognosis of sex cord–stromal tumors varies by histology. In all entities, metastatic spread occurs rarely and if present, is usually limited to the peritoneal cavity. Distant metastases may rarely occur, mostly in relapse situations.
In the United States, these tumors may be registered in the Testicular and Ovarian Stromal Tumor registry. In Europe, patients are prospectively registered in the national rare tumor groups.[37,38] The recommendations regarding diagnostic work-up, staging, and therapeutic strategy have been harmonized between these registries.
A French registry identified 38 girls younger than 18 years with ovarian sex cord tumors. Complete surgical resection was achieved in 23 of 38 girls who did not receive adjuvant treatment. Two patients recurred, one patient's tumor responded to chemotherapy, and the other patient died. Fifteen girls had tumor rupture and/or ascites. Eleven of the 15 patients received chemotherapy and did not recur; of the four who did not receive chemotherapy, all recurred and two died.
Juvenile granulosa cell tumors
The most common histologic subtype in girls younger than 18 years is juvenile granulosa cell tumors (median age, 7.6 years; range, birth to 17.5 years).[39,40] Juvenile granulosa cell tumors represent about 5% of ovarian tumors in children and adolescents and are distinct from the granulosa cell tumors seen in adults.[34,41,42,43]
Patients with juvenile granulosa cell tumors present with the following:[44,45]
Juvenile granulosa cell tumors have been reported in children with Ollier disease and Maffucci syndrome.
As many as 90% of children with juvenile granulosa cell tumors will have low-stage disease (stage I) by International Federation of Gynecology and Obstetrics (FIGO) criteria and are usually curable with unilateral salpingo-oophorectomy alone.
Patients with spontaneous tumor rupture or malignant ascites (FIGO stage Ic), advanced disease (FIGO stage II–IV), and those with high mitotic activity tumors have a poorer prognosis and require chemotherapy.[23,38] Use of a cisplatin-based chemotherapy regimen has been reported in both the adjuvant and recurrent disease settings with some success.[38,39,43,46,47]
Sertoli-Leydig cell tumors
Sertoli-Leydig cell tumors are rare in young girls and are more frequently seen in adolescents. They may present with virilization  or precocious puberty. These tumors may also be associated with Peutz-Jeghers syndrome, but more frequently are a part of the DICER-1 tumor spectrum.[35,50]
A study of 44 patients from the European Cooperative Study Group on Pediatric Rare Tumors showed that prognosis of Sertoli-Leydig tumors was determined by stage and histopathologic differentiation.
Surgery is the primary treatment for Sertoli-Leydig cell tumors and is the only treatment for low-stage disease (FIGO stage Ia), with essentially 100% event-free survival.
Patients with Sertoli-Leydig tumors with abdominal spillage during surgery, spontaneous tumor rupture, or metastatic disease (FIGO stages IC, II, III, and IV) are treated with cisplatin-based combination chemotherapy, although the impact of chemotherapy has not been studied in clinical trials.[23,51] An additional study reported on 40 women with FIGO stage I or Ic Sertoli-Leydig cell tumors of the ovary, with an average age of 28 years.[Level of evidence: 3iiA] Of 34 patients with intermediate or poor differentiation, 23 patients received postoperative chemotherapy (most regimens included cisplatin); none recurred. Of the 11 patients who did not receive postoperative chemotherapy, two recurred; both had tumors that were salvaged with chemotherapy.
Small cell carcinoma of the ovary
Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia. Successful treatment with aggressive therapy has been reported in a few cases.[53,54][Level of evidence: 3iiB]; [55,56][Level of evidence: 3iiiA]
Carcinoma of the Cervix and Vagina
Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence, with fewer than 50 reported cases.[29,57] Two-thirds of the cases are related to exposure to diethylstilbestrol in utero.
The median age at presentation is 15 years, with a range of 7 months to 18 years, and most patients present with vaginal bleeding. Adults with adenocarcinoma of the cervix or vagina will present with stage I or stage II disease 90% of the time. In children and adolescents, there is a high incidence of stage III and stage IV disease (24%). This difference may be explained by the practice of routine pelvic examinations in adults and the hesitancy to perform pelvic exams in children.
The treatment of choice is surgical resection, followed by radiation therapy for residual microscopic disease or lymphatic metastases. The role of chemotherapy in management is unknown, although drugs commonly used in the treatment of gynecologic malignancies, carboplatin and paclitaxel, have been used.
The 3-year event-free survival (EFS) for all stages is 71% ± 11%; for stage I and stage II, the EFS is 82% ± 11%, and for stage III and stage IV, the EFS is 57% ± 22%.
Other rare childhood cancers include the following:
The prognosis, diagnosis, classification, and treatment of these other rare childhood 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.
Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex
MEN syndromes are familial disorders characterized by neoplastic changes that affect multiple endocrine organs. Changes may include hyperplasia, benign adenomas, and carcinomas.
There are two main types of MEN syndrome:
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)
The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 7.
The first manifestation of disease in 90% of patients is hypercalcemia; the most common cause of morbidity and mortality in these patients is the development of gastrinomas that lead to Zollinger-Ellison syndrome.[2,3]
Primary hyperparathyroidism is very rare in children and, unlike adults, has an equal sex distribution. Nephrolithiasis is the leading cause of objective symptoms. In a review of 38 cases, 28 children were found to have familial disease; of those children, 26 patients were diagnosed with MEN1 syndrome. Modern genetic testing can detect approximately 70% to 95% of patients with hyperparathyroidism that is secondary to MEN1 syndrome. A series of 160 patients with MEN1 syndrome was the first large study of patients diagnosed before age 21 years. Four patients had a malignant tumor, and one of these patients died.
Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors. Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.
It is recommended that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography (CT) of the abdomen every 1 to 3 years.
A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[9,10,11]
A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in these patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[15,16]
Guidelines for genetic testing of suspected patients with MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[16,17]
The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less than ten, patients with RET germline mutations; small families in which two or fewer members in a single generation have germline RET mutations; and single individuals with a RET germline mutation.[16,18]
The standard approach to patients who present with hyperparathyroidism and MEN1 syndrome is genetic testing and treatment with a cervical resection of at least three parathyroid glands and transcervical thymectomy.
Relatives of patients with MEN2A undergo genetic testing in early childhood, before the age of 5 years. Carriers undergo total thyroidectomy as described above with autotransplantation of one parathyroid gland by a certain age.[23,27,28,29]
Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children because there is a high incidence of bilateral disease.
Hirschsprung disease has been associated in a small percentage of cases with the development of neuroendocrine tumors such as medullary thyroid carcinoma. RET germline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[33,34,35] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. It has been recommended that patients with Hirschsprung disease be screened for mutations in RET exon 10 and consideration be given to prophylactic thyroidectomy if such a mutation is discovered.[35,36,37]
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN2A and MEN2B.)
In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with either vandetanib (a selective inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor) or placebo, vandetanib administration was associated with significant improvements in progression-free survival, response rate, disease control rates, and biochemical response. Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only one had no response and seven 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.
Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17. The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[40,41,42] There are published surveillance guidelines for patients with Carney complex that include cardiac, testicular, and thyroid ultrasound.
For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.
Pheochromocytoma and Paraganglioma
Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. Paraganglioma and pheochromocytoma are exceedingly rare in the pediatric and adolescent population, accounting for approximately 20% of all cases.[43,44]
Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into the following subtypes:[45,46]
It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (refer to Table 9). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of subjects have disease by age 26 years.[47,48,49,50]
Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:
Immunohistochemical SDHB staining may help triage genetic testing; tumors of patients with SDHB, SDHC, and SDHD mutations have absent or very weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[53,54] Therefore, immunohistochemical SDHB staining can help identify potential carriers of a SDH mutation early, obviating the need for extensive and costly testing of other genes.
Younger patients have a higher incidence of bilateral adrenal pheochromocytoma and extra-adrenal paraganglioma, and a germline mutation can be identified in close to 60% of patients. Therefore, genetic counseling and testing is always recommended in young patients.
Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production:
These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half of patients. These symptoms can also be induced by exertion, trauma, induction of anesthesia, resection of the tumor, consumption of foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder).
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression, but also may be asymptomatic and diagnosed incidentally.
The pediatric and adolescent patient appears to present with symptoms similar to those of the adult patient, although with a more frequent occurrence of sustained hypertension. The clinical behavior of paraganglioma and pheochromocytoma appears to be more aggressive in children and adolescents and metastatic rates of up to 50% have been reported.[44,46,55]
Studies of germline mutations in young patients with pheochromocytoma or paraganglioma have further characterized this group of neoplasms, as follows:
It is important to note that these two studies did not include systematic screening for other genes that have been recently described in paraganglioma and pheochromocytoma syndromes, such as KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX (refer to Table 9).
These findings suggest that younger patients with extra-adrenal nonsyndromic pheochromocytoma and paraganglioma are at high risk for harboring SDHB mutations and that this phenotype is associated with an earlier age of onset and a high rate of metastatic disease. Early identification of young patients with SDHB mutations using radiographic, serologic, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB mutation.
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging:
Catecholamine metabolic and secretory profiles are impacted by hereditary background; both hereditary and sporadic paraganglioma and pheochromocytoma differ markedly in tumor contents of catecholamines and corresponding plasma and urinary hormonal profiles. About 50% of secreting tumors produce and contain a mixture of norepinephrine and epinephrine, while most of the rest produce norepinephrine almost exclusively, with occasional rare tumors producing mainly dopamine. Patients with epinephrine-producing tumors are diagnosed later (median age, 50 years) than those with tumors lacking appreciable epinephrine production (median age, 40 years). Patients with MEN2 and NF1 syndromes, all with epinephrine-producing tumors, are typically diagnosed at a later age (median age, 40 years) than are patients with tumors that lack appreciable epinephrine production secondary to mutations of VHL and SDH (median age, 30 years). These variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of paraganglioma and pheochromocytoma for different progenitor cells with variable susceptibility to disease-causing mutations.[60,61]
For tumor localization, 6-[18 F]FDA PET and 123/131 I-mIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 6-[18 F]FDA PET than by 123/131 I-mIBG. Other functional imaging alternatives include indium In-111 octreotide scintigraphy and fluorodeoxyglucose F-18 PET, both of which can be coupled with CT imaging for improved anatomic detail.
Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha- and beta-adrenergic blockade must be optimized before surgery.
For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or different combinations of vincristine, cyclophosphamide, doxorubicin, and dacarbazine.[63,64,65] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival is less clear.
Responses have also been obtained to high-dose 131 I-mIBG and sunitinib.[66,67]
Skin Cancer (Melanoma, Basal Cell Carcinoma [BCC], and Squamous Cell Carcinoma [SCC])
(Refer to the PDQ summary on Genetics of Skin Cancer for more information about specific gene mutations and related cancer syndromes.)
Melanoma, although rare, is the most common skin cancer in children, followed by BCCs and SCCs.[68,69,70,71,72,73,74,75] In a retrospective study of 22,524 skin pathology reports in patients younger than 20 years, investigators identified 38 melanomas, 33 of which occurred in patients aged 15 to 19 years. Study investigators reported that the number of lesions that needed to be excised to identify one melanoma was 479.8, which is 20 times higher than in the adult population.
It is estimated that approximately 400 cases of melanoma are diagnosed each year in patients younger than 20 years in the United States, accounting for less than 1% of all new cases of melanoma. Melanoma annual incidence in the United States (2002–2006) increases with age, as follows:[78,79]
Melanoma accounts for about 6% of all cancers in children aged 15 to 19 years.
The incidence of pediatric melanoma increased by an average of 2% per year between 1973 and 2009. The increased incidence was especially notable in females between the ages of 15 and 19 years. Increased exposure to ambient ultraviolet (UV) radiation increases the risk of the disease. However, a review of United States Surveillance, Epidemiology, and End Results data from 2000 to 2010 suggested that the incidence of melanoma in children and adolescents decreased over that interval.
Conditions associated with an increased risk of developing melanoma in children and adolescents include the following:
Phenotypic traits that are associated with an increased risk of melanoma in adults have been documented in children and adolescents with melanoma and include the following:[87,88,89,90,91,92,93]
Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is dependent on stage. As in adults, most pediatric cases (about 75%) are localized and have an excellent outcome.[79,90,95] More than 90% of children and adolescents with melanoma are expected to be alive 5 years after their initial diagnosis.[90,94,96,97]
The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[90,95,96] In one study, the outcome for patients with metastatic disease was favorable, but this result was not duplicated in another study from the National Cancer Database.
Children younger than 10 years who have melanoma often present with poor prognostic features, are more often non-white, have head and neck primary tumors, thicker primary lesions, a higher incidence of spitzoid morphology vascular invasion and nodal metastases, and more often have syndromes that predispose them to melanoma.[90,94,96,98]
The use of sentinel node biopsy for staging pediatric melanoma has become widespread, and the thickness of the primary tumor, as well as ulceration, have been correlated with a higher incidence of nodal involvement. Younger patients appear to have a higher incidence of nodal involvement; this finding does not appear to significantly impact clinical outcome in this population.[98,100] In other series of pediatric melanoma, a higher incidence of nodal involvement did not appear to impact survival.[101,102,103]
The association of thickness with clinical outcome is controversial in pediatric melanoma.[90,95,96,104,105,106,107,108] In addition, it is unclear why some variables that correlate with survival in adults are not replicated in children. One possible explanation for this difference might be the inclusion of patients who have lesions that are not true melanomas in the adult series, considering the problematic histological distinction between true melanoma and melanocytic lesions with unknown malignant potential (MELTUMP); these patients are not included in pediatric trials.[109,110]
The diagnostic evaluation of melanoma includes the following:
Lymph node dissection is recommended if sentinel nodes are involved with tumor, and adjuvant therapy with high-dose interferon alfa-2b for a period of 1 year should be considered in these patients.[71,111,116,117,118] Clinically benign melanocytic lesions can sometimes pose a significant diagnostic challenge, especially when they involve regional lymph nodes.[119,120,121]
The diagnosis of pediatric melanoma may be difficult and many of these lesions may be confused with the so-called MELTUMP. These lesions are biologically different from melanoma and benign nevi.[122,123] The terms Spitz nevus and Spitzoid melanoma are also commonly used, creating additional confusion. One retrospective study found that children aged 10 years or older were more likely to present with amelanotic lesions, bleeding, uniform color, variable diameter, and elevation (such as a de novo bump).[Level of evidence: 3iiA]
Novel diagnostic techniques are actively being used by various centers in an attempt to differentiate melanoma from these challenging melanocytic lesions. For example, the absence of BRAF mutations or the presence of a normal chromosomal complement with or without 11p gains strongly argues against the diagnosis of melanoma.[125,126] In contrast, the use of fluorescence in situ hybridization (FISH) probes that target four specific regions in chromosomes 6 and 11 can help distinguish melanoma from common nevi; however, atypical Spitzoid lesions will also have chromosomal alterations on FISH analysis and some will also have BRAF V600E mutations and BAP1 loss.[127,128,129,130]
Patients with atypical Spitzoid neoplasm tumors that harbored a 9p21 homozygous deletion had the highest risk for developing locoregional and distant disease. However, in another study, 9p21 deletion was not associated with an unfavorable clinical outcome.HRAS mutations have been described in some cases of Spitz nevi but they have not been described in Spitzoid melanoma. The presence of an HRAS mutation may aid in the differential diagnosis of Spitz nevus and Spitzoid melanoma. Some of the characteristic genetic alterations seen in various melanocytic lesions are summarized in Table 10 below.[134,135]
A study demonstrated that there are three distinct genomic subtypes of childhood melanocytic lesions. Conventional melanomas had a high burden of somatic single nucleotide variations, TERT promoter mutations, and activating BRAF V600 mutation, as well as a signature consistent with UV damage; two-thirds had MC1R variants associated with an increased susceptibility to melanoma. In contrast, melanomas that developed in a congenital melanocytic nevus contained activating NRAS Q61 mutations. About 40% of Spitzoid melanomas had kinase fusions involving various genes including RET, ROS1, NTRK1, ALK, and BRAF and were absent TERT mutations, except in cases of Spitzoid melanomas with fatal outcome.MET fusions have also been recently described in atypical Spitzoid tumors and Spitzoid melanoma. These studies emphasize the need to promote sun protection practices in early life, to individualize therapy based on the type of melanocytic lesion, and to improve access to therapeutic agents being explored in adults in young patients.[132,137]
Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:
Sentinel node biopsy should be considered in patients with thin lesions (≤1 mm) and ulceration, mitotic rate greater than 1 mm2, young age, and in patients with lesions greater than 1 mm with or without adverse features. Young patients have a higher incidence of sentinel node positivity and this feature adversely affects clinical outcomes.[99,103] If the sentinel node is positive, the option to undergo a complete lymph node dissection should be considered. Patients with high-risk primary cutaneous melanoma, such as those with regional lymph node involvement, can be offered the option to receive adjuvant interferon alfa-2b, a therapy that is well tolerated in children.[116,117,138] Trials of other adjuvant therapies, such as BRAF and MEK inhibitors and checkpoint inhibitors, are currently not available for pediatric patients.
For patients with metastatic, recurrent, or progressive disease, prognosis is poor. Various agents such as interferon, dacarbazine, temozolomide, sorafenib, or interleukin-2, and biochemotherapy can be used.[139,140,141] The results of pediatric trials that incorporate newer therapies such as vemurafenib and checkpoint inhibitors including ipilimumab and PD-1 inhibitors are not yet available.[142,143]
(Refer to the PDQ summary on adult Melanoma Treatment for more information.)
BCC and SCC
BCCs generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure. These tumors may be multiple and exacerbated by radiation therapy. Nevoid BCC syndrome (Gorlin syndrome) is a rare disorder with a predisposition to the development of early-onset neoplasms, including BCC, ovarian fibroma, and desmoplastic medulloblastoma.[146,147,148,149] SCCs are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.
Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. BCCs and SCCs are generally curable with surgery alone and further diagnostic workup is not indicated.
Most BCCs have activation of the hedgehog pathway, generally resulting from mutations in PTCH1. Vismodegib (GDC-0449), a hedgehog pathway inhibitor, has been approved for the treatment of adult patients with BCC.[151,152] It was approved by the U.S. Food and Drug Administration for the treatment of adults with metastatic BCC or with locally advanced BCC that has recurred after surgery or who are not candidates for surgery, and who are not candidates for radiation. This drug also reduces the tumor burden in patients with basal cell nevus syndrome.
(Refer to the PDQ summary on adult Skin Cancer Treatment for more information.)
Chordoma is a very rare tumor of bone that arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum. The incidence in the United States is approximately one case per one million people per year, and only 5% of all chordomas occur in patients younger than 20 years. Most pediatric patients have the classical or chondroid variant of chordoma, while the dedifferentiated variant is rare in children.[154,155]
Younger children appear to have a worse outlook than do older patients.[154,156,157,158,159,160] The survival rate in children and adolescents ranges from about 50% to 80%.[154,157,159]
Patients usually present with pain, with or without neurologic deficits such as cranial or other nerve impairment. Diagnosis is straightforward when the typical physaliferous (soap-bubble-bearing) cells are present. Differential diagnosis is sometimes difficult and includes dedifferentiated chordoma and chondrosarcoma. Childhood chordoma has been associated with tuberous sclerosis complex.
Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[159,162] Surgery is not commonly curative in children and adolescents because of difficulty obtaining clear margins and the likelihood of the chordoma arising in the skull base, rather than in the sacrum, making them relatively inaccessible to complete surgical excision. The best results have been obtained using proton-beam therapy (charged-particle radiation therapy) because these tumors are relatively radiation resistant, and radiation-dose conformality with protons allows for higher tumor doses while sparing adjacent critical normal tissues.[163,164]; [159,165][Level of evidence: 3iiA]; [Level of evidence: 3iiiDiii]
There are only a few anecdotal reports of the use of cytotoxic chemotherapy after surgery alone or surgery plus radiation therapy. Treatment with ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide has been reported with some success.[167,168] The role for chemotherapy in the treatment of this disease is uncertain.
Imatinib mesylate has been studied in adults with chordoma on the basis of the overexpression of PDGFR alpha, beta, and KIT in this disease.[169,170] Among 50 adults with chordoma treated with imatinib and evaluable by Response Evaluation Criteria In Solid Tumors (RECIST) guidelines, there was one partial response and 28 additional patients had stable disease at 6 months. The low rate of RECIST responses and the potentially slow natural course of the disease complicate the assessment of the efficacy of imatinib for chordoma. Other tyrosine kinase inhibitors and combinations involving kinase inhibitors have been studied.[171,172,173]
Recurrences are usually local but can include distant metastases to lungs or bone.
Cancer of Unknown Primary Site
Incidence and clinical presentation
Children represent less than 1% of all solid cancers of unknown primary site and because of the age-related incidence of tumor types, embryonal histologies are more common in this age group.
Cancers of unknown primary site present as a metastatic cancer for which a precise primary tumor site cannot be determined. As an example, lymph nodes at the base of the skull may enlarge in relationship to a tumor that may be on the face or the scalp but is not evident by physical examination or by radiographic imaging. Thus, modern imaging techniques may indicate the extent of the disease but not a primary site. Tumors such as adenocarcinomas, melanomas, and embryonal tumors such as rhabdomyosarcomas and neuroblastomas may present in this way.
For all patients who present with tumors from an unknown primary site, treatment is directed toward the specific histopathology of the tumor and is age-appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.
Studies in adults suggest that PET imaging can be helpful in identifying cancers of unknown primary site, particularly in patients whose tumors arise in the head and neck area. A report in adults using 2-deoxy-2-[18F]-fluoro-D-glucose (18 F-FDG ) PET-CT identified 42.5% of primary tumors in a group of cancers of unknown primary site.
The use of gene expression profiling and next-generation sequencing can enhance our ability to identify the putative tissue of origin and guide in the selection of targeted agents for specific mutations.[178,179,180,181,182] No pediatric studies have been conducted to date.
Chemotherapy, targeted therapy, and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending on the histologic findings, symptoms, and extent of tumor) is initiated as early as possible.
(Refer to the PDQ summary on adult Carcinoma of Unknown Primary Treatment for more information.)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of unusual cancers of childhood. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Unusual Cancers of Childhood Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Unusual Cancers of Childhood Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/childhood-cancers/hp/unusual-cancers-childhood-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389315]
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Last Revised: 2016-04-29
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