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Home > Be Healthy > Health Library > Unusual Cancers of Childhood Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgeons, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their 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. Therefore, all pediatric cancers are considered rare.
The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and are estimated to account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:
Most cancers within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.
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 (SEER) 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 (SEER) 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.
Some investigators have used large databases, such as the Surveillance, Epidemiology, and End Results (SEER) and the National Cancer Database, to gain more insight into these rare childhood cancers. However, these database studies are limited. Several initiatives to study rare pediatric cancers have been developed by the COG and other international groups, including 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 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 COG registries (Project Every Child) and tumor banking protocols, 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.[8,14]
The tumors discussed in this summary are very diverse; they are arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see less than a handful of some histologies in several years. The majority of the histologies described here occur more frequently in adults. Information about these tumors may also be found in sources relevant to adults with cancer.
Childhood sarcomas often occur in the head and neck area and they are described in other sections. Unusual pediatric head and neck cancers include the following:
It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from small case series or cohorts combining pediatric and adult patients.
Nasopharyngeal carcinoma arises in the lining of the nasal cavity and pharynx, and it accounts for about one-third of all cancers of the upper airways in children.[1,2]
Nasopharyngeal carcinoma is very uncommon in children younger than 10 years but increases in incidence to 0.8 cases per 1 million per year in children aged 10 to 14 years and 1.3 cases per million per year in children aged 15 to 19 years.[3,4,5]
The incidence of nasopharyngeal carcinoma is characterized by racial and geographic variations, with an endemic distribution among well-defined ethnic groups, such as inhabitants of some areas in North Africa and the Mediterranean basin, and, particularly, Southeast Asia. In the United States, the incidence of nasopharyngeal carcinoma is higher in black children and adolescents younger than 20 years.[4,5]
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.[4,5]
Signs and symptoms of nasopharyngeal carcinoma include the following:[2,8]
Given the rich lymphatic drainage of the nasopharynx, bilateral cervical lymphadenopathy is often the first sign of disease. The tumor spreads locally to adjacent areas of the oropharynx and may invade the skull base, resulting in cranial nerve palsy or difficulty with movements of the jaw (trismus).
Distant metastatic sites may include the bones, lungs, and liver.
Diagnostic and Staging Evaluation
Diagnostic tests will determine the extent of the primary tumor and the presence of metastases. Visualization of the nasopharynx by an otolaryngologist using nasal endoscopy and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor.
A diagnosis can be made from a biopsy of the primary tumor or enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin lymphoma including Burkitt lymphoma, and Hodgkin lymphoma must be considered, as well as benign conditions such as nasal angiofibroma, which usually presents with epistaxis in adolescent males, infectious lymphadenitis, and Rosai-Dorfman disease.
Evaluation of the chest and abdomen by computed tomography (CT) and bone scan is performed to determine whether there is metastatic disease. Fluorine F 18-fludeoxyglucose positron emission tomography (PET)–CT may also be helpful in the evaluation of potential metastatic lesions.
Stage Information for Childhood Nasopharyngeal Carcinoma
Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer.[10,11]
More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[12,13] Population-based studies have reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did adult patients.[4,5] However, less than 10% of children and adolescents with nasopharyngeal carcinoma presented with distant metastases at diagnosis.[12,13,14]
The overall survival of children and adolescents with nasopharyngeal carcinoma has improved over the last four decades; with state-of-the-art multimodal treatment, 5-year survival rates exceed 80%.[4,5,8,12,13,14,15,16] After controlling for stage, children with nasopharyngeal carcinoma have significantly better outcomes than do adults.[4,5] However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities, including subsequent neoplasms.[4,12,13,15]
Treatment of Newly Diagnosed Childhood Nasopharyngeal Carcinoma
Treatment of nasopharyngeal carcinoma is multimodal and includes the following:
The following two modifications of this approach have been investigated:
The combination of cisplatin-based chemotherapy and high doses of radiation therapy to the nasopharynx and neck are associated with a high probability of hearing loss, hypothyroidism and panhypopituitarism, trismus, xerostomia, dental problems, and chronic sinusitis or otitis.[12,13,15]; [Level of evidence: 3iiiA] (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Treatment of Refractory Childhood Nasopharyngeal Carcinoma
The outcome of patients with relapsed nasopharyngeal carcinoma is poor, and most patients present with distant metastases. However, long-term remissions can be achieved with conventional chemotherapy. In a retrospective review of 14 pediatric patients with relapsed nasopharyngeal carcinoma who were treated with varying chemotherapy regimens, the 3-year event-free survival was 34%, and the overall survival was 44%.
Given the unique pathogenesis of nasopharyngeal carcinoma, immunotherapy has been explored for patients with refractory disease, as follows:
Treatment Options Under Clinical Evaluation for Childhood Nasopharyngeal Carcinoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Esthesioneuroblastoma (also termed olfactory neuroblastoma) is a small round cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[35,36,37,38] In children, esthesioneuroblastoma is a very rare malignancy, with an estimated incidence of 0.1 cases per 100,000 per year in children younger than 15 years.
Despite its rarity, esthesioneuroblastoma is the most common cancer of the nasal cavity in pediatric patients, accounting for 28% of cases in a Surveillance, Epidemiology, and End Results (SEER) study. In a series of 511 patients from the SEER database, there was a slight male predominance, the mean age at presentation was 53 years, and only 8% of cases were younger than 25 years. Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%). In a retrospective, multi-institutional review of 24 pediatric patients with esthesioneuroblastoma, the median age at presentation was 14 years and 75% of patients were female.
Histology and Molecular Features
Esthesioneuroblastoma can be histologically confused with other small round cell tumors of the nasal cavity, including sinonasal undifferentiated carcinoma, small cell carcinoma, melanoma, and rhabdomyosarcoma. Esthesioneuroblastoma typically shows diffuse staining with neuron-specific enolase, synaptophysin, and chromogranins, with variable cytokeratin expression.
Sixty-six samples of olfactory neuroblastoma and tumor samples from other cancers, including alveolar rhabdomyosarcoma and sinonasal adenocarcinoma, were obtained from nine medical centers and analyzed by genome-wide DNA methylation profiling, copy number analysis, immunohistochemistry, and next-generation panel sequencing. Unsupervised hierarchal clustering analysis of DNA methylation data identified the following four distinct clusters:
Using this information, the authors developed an algorithm that incorporates methylation analysis to improve the diagnostic accuracy of this entity.
Most children present in the second decade of life with symptoms that include the following:
Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[45,46,47]
Stage Information for Childhood Esthesioneuroblastoma
Tumors are staged according to the Kadish system (refer to Table 1). Correlated with Kadish stage, survival ranges from 90% (stage A) to less than 40% (stage D). Most patients present with locally advanced–stage disease (Kadish stages B and C) and almost one-third of patients have tumors at distant sites (Kadish stage D).[39,40,42]
Recent reports suggest that positron emission tomography–computed tomography (PET-CT) may aid in staging the disease.
Treatment and Outcome of Childhood Esthesioneuroblastoma
The use of multimodal therapy optimizes the chances for survival, with more than 70% of children expected to survive 5 or more years after initial diagnosis.[39,49,50] A multi-institutional review of 24 patients younger than 21 years at diagnosis found a 5-year disease-free survival and overall survival of 73% to 74%.[Level of evidence: 3iiiA]
Treatment options according to Kadish stage include the following:
The mainstay of treatment is surgery and radiation. Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection.; [Level of evidence: 3iiiDii] Other techniques such as stereotactic radiosurgery and proton-beam therapy (charged-particle radiation therapy) may also play a role in the management of this tumor.[50,54]
Nodal metastases are seen in about 5% of patients. Routine neck dissection and nodal exploration are not indicated in the absence of clinical or radiological evidence of disease. Management of cervical lymph node metastases has been addressed in a review article.
Reports indicate promising results with the increased use of resection and neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease.[35,42,49,56,57]; [Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include cisplatin and etoposide with or without ifosfamide;[51,59] vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin; ifosfamide and etoposide; cisplatin plus etoposide or doxorubicin; vincristine, doxorubicin, and cyclophosphamide; and irinotecan plus docetaxel.[Level of evidence: 3iiA]
Treatment Options Under Clinical Evaluation for Childhood Esthesioneuroblastoma
The annual incidence of thyroid cancers is 4.8 to 5.9 cases per 1 million people aged 0 to 19 years, accounting for approximately 1.5% of all cancers in this age group.[62,63] Thyroid cancer incidence is higher in children aged 15 to 19 years (17.6 cases per 1 million people), and it accounts for approximately 8% of cancers arising in this older age group.[3,62] More thyroid carcinomas occur in females than in males. The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.
Two time-trend studies using the Surveillance, Epidemiology, and End Results (SEER) database have shown a 2% and 3.8% annual increase in the incidence of differentiated thyroid carcinoma in the United States among children, adolescents, and young adults in the 1973 to 2011 and 1984 to 2010 periods, respectively.[62,65] A similar trend towards an increase in the incidence of thyroid cancer among children, adolescents, and young adults over the last two decades has been documented in Canada. A Danish population-based study of thyroid cancer in patients younger than 24 years reported that the age-adjusted incidence rate (per 100,000) increased significantly from 0.36 in 1980 to 0.97 in 2014, with an average annual percent change of 2.9%. No change in overall survival was observed, but a significant increase was seen in the incidence of thyroid cancer among young adults (aged 18–24 years), mainly attributed to an increase among females and patients with papillary carcinoma.
The incidence of thyroid cancer is higher in whites (5.3 cases per 1 million vs. 1.5 cases per 1 million in blacks) and female adolescents (8.1 cases per 1 million vs. 1.7 cases per 1 million in male adolescents).
The papillary subtype is the most common, accounting for approximately 60% of the cases, followed by the papillary follicular variant subtype (20%–25%), the follicular subtype (10%), and the medullary subtype (<10%).The incidence of the papillary subtype and its follicular variant peaks between the ages of 15 and 19 years. The incidence of medullary thyroid cancer is the highest in the age group of 0 to 4 years and declines at older ages (refer to Figure 3).
Figure 3. Incidence of pediatric thyroid carcinoma based on most frequent subtype per 100,000 as a percent of total cohort. Reprinted from International Journal of Pediatric Otorhinolaryngology, Volume 89, Sarah Dermody, Andrew Walls, Earl H. Harley Jr., Pediatric thyroid cancer: An update from the SEER database 2007–2012, Pages 121–126, Copyright (2016), with permission from Elsevier.
Risk factors for pediatric thyroid cancer include the following:
Papillary thyroid carcinoma is the most frequent form of thyroid carcinoma diagnosed after radiation exposure. Molecular alterations, including intrachromosomal rearrangements, are frequently found; among them, RET/PTC rearrangements are the most common.
Tumors of the thyroid are classified as adenomas or carcinomas.[76,77,78] 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.[75,76]
The following histologies account for the general diagnostic category of carcinoma of the thyroid:
Thyroid Carcinoma of Follicular Cells
Thyroid tumorigenesis and progression of thyroid carcinomas of follicular cells (differentiated thyroid carcinoma, poorly-differentiated papillary thyroid carcinoma, and anaplastic thyroid carcinoma) are defined by a multistep process that results in aberrant activation of the MAPK and/or PI3K/PTEN/AKT signaling pathways. Comprehensive genomic studies performed over the last decade have defined the landscape of these tumors, as well as their genotype-phenotype correlations. Mutations in BRAF and RAS genes are the most common driver events, followed by gene fusions involving RET or NTRK:[73,74,80]
The presence of BRAF V600E has been associated with extrathyroidal tumor extension and an increased risk of recurrence; however, its prognostic significance is controversial. BRAF V600E tumors appear to show a broadly immunosuppressive profile with high expression of anti–programmed death-ligand 1 (PD-L1).[74,80]
A retrospective analysis of 80 Brazilian patients younger than 18 years with papillary thyroid carcinoma identified AGK-BRAF fusions and BRAF V600E point mutations.AGK-BRAF fusions, found in 19% of pediatric patients with papillary thyroid carcinoma, were associated with distant metastasis and younger age. BRAF V600E mutations, found in 15% of patients with pediatric papillary thyroid carcinoma, were correlated with older age and larger tumor size.
Other alterations include the following:[74,80]
The spectrum of somatic genetic alterations seems to be different between pediatric and adult patients when analyzing tumors with similar histologies, as follows:
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma is a neuroendocrine malignancy derived from the neural crest-originated parafollicular C cells of the thyroid gland. In children, medullary thyroid carcinoma is a monogenic disorder caused by a dominantly inherited or de novo gain-of-function mutation in the RET oncogene associated with multiple endocrine neoplasia type 2 (MEN2), either MEN2A or MEN2B, depending on the specific mutation. The highest medullary thyroid carcinoma risk is conferred by the RET M918T mutation, which is associated with MEN2B; the RET mutations associated with MEN2A confer a lower medullary thyroid carcinoma risk.
Clinical Presentation and Prognostic Factors
Differentiated Thyroid Carcinoma
Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy. On the basis of medical and family history and clinical constellation, the thyroid cancer may be part of a tumor predisposition syndrome such as multiple endocrine neoplasia, APC-associated polyposis, PTEN hamartoma tumor syndrome, Carney complex, Werner syndrome, and DICER1 syndrome.[74,75]
Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. The following observations have been reported:
In well-differentiated thyroid cancer, male sex, large tumor size, and distant metastases have been found to have prognostic significance for early mortality; however, even patients in the highest risk group who had distant metastases had a 90% survival rate. 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.
A review of the National Cancer Database found that patients aged 21 years and younger from lower-income families and those lacking insurance experienced a longer period from diagnosis to treatment of their well-differentiated thyroid cancer and presented with higher-stage disease.
Children with medullary thyroid carcinoma present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis. A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (NCT01660984). A review of 430 patients aged 0 to 21 years with medullary thyroid cancer reported that older age (16–21 years) at diagnosis, tumor diameter greater than 2 cm, positive margins after total thyroidectomy, and lymph node metastases were associated with a worse prognosis.
In children with hereditary multiple endocrine neoplasia (MEN) type 2B, medullary thyroid carcinoma may be detectable within the first year of life and nodal metastases may occur before age 5 years. The recognition of mucosal neuromas, a history of alacrima, constipation (secondary to intestinal ganglioneuromatosis), and marfanoid facial features and body habitus is critical to early recognition and diagnosis because the RET M918T mutation associated with MEN2B is often de novo. Approximately 50% of patients with MEN2B develop a pheochromocytoma, with a varying degree of risk of developing pheochromocytoma and hyperparathyroidism in MEN2A based on the specific RET mutation.[73,92] (Refer to the Multiple Endocrine Neoplasia [MEN] Syndromes and Carney Complex section of the PDQ summary on Unusual Cancers of Childhood Treatment for more information.)
For children 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.
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.
Treatment of Papillary and Follicular Thyroid Carcinoma
Treatment options for papillary and follicular (differentiated) thyroid carcinoma include the following:
In 2015, the American Thyroid Association (ATA) Task Force on Pediatric Thyroid Cancer published guidelines for the management of thyroid nodules and differentiated thyroid cancer in children and adolescents. These guidelines (summarized below) are based on scientific evidence and expert panel opinion, with a careful assessment of the level of evidence.
Pediatric thyroid surgery is ideally completed by a surgeon who has experience performing endocrine procedures in children and in a hospital with the full spectrum of pediatric specialty care.
For patients with papillary or follicular carcinoma, total thyroidectomy is the recommended treatment of choice. The ATA expert panel recommendation is based on data showing an increased incidence of bilateral (30%) and multifocal (65%) disease.
In patients with a small unilateral tumor confined to the gland, a near-total thyroidectomy—whereby a small amount of thyroid tissue (<1%–2%) is left in place at the entry point of the recurrent laryngeal nerve or superior parathyroid glands—might be considered to decrease permanent damage to those structures.
Total thyroidectomy also optimizes the use of radioactive iodine for imaging and treatment.
Despite the limited data in pediatrics, the ATA Task Force recommends the use of the tumor-node-metastasis (TNM) classification system to categorize patients into one of three risk groups. (Refer to the Stage Information for Thyroid Cancer section in the PDQ summary on Thyroid Cancer Treatment [Adult] for more information about the TNM system.) This categorization strategy is meant to define the risk of persistent cervical disease and help determine which patients should undergo postoperative staging for the presence of distant metastasis.
Initial staging should be performed within 12 weeks after surgery; the purpose is to assess for evidence of persistent locoregional disease and to identify patients who are likely to benefit from additional therapy with iodine I 131 (131I). The ATA Pediatric Risk Level (as defined above) helps determine the extent of postoperative testing.
For patients with antithyroglobulin antibodies, consideration can be given to deferred postoperative staging to allow time for antibody clearance, except in patients with T4 or M1 disease.
The goal of 131I therapy is to decrease the risks of recurrence and to decrease mortality by eliminating iodine-avid disease.
While rare, late effects of 131I treatment include salivary gland dysfunction, bone marrow suppression, pulmonary fibrosis, and second malignancies.
Larotrectinib (a targeted therapy) has been used to treat patients with TRK fusion–positive thyroid carcinoma. Five of five patients with TRK fusion–positive thyroid carcinomas who were treated with larotrectinib therapy achieved partial or complete responses.
Treatment of Recurrent Papillary and Follicular Thyroid Carcinoma
Despite the more advanced disease at presentation compared with adults, children with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[62,63,65]
Treatment options for recurrent papillary and follicular thyroid carcinoma include the following:
Radioactive iodine ablation with 131I is usually effective after recurrence. For patients with 131I-refractory disease, molecularly targeted therapies using kinase inhibitors may provide alternative therapies.
Tyrosine kinase inhibitors (TKIs) with documented efficacy for the treatment of adults include the following:
Pediatric-specific data are very limited; however, in one case report, sorafenib produced a radiographic response in a patient aged 8 years with metastatic papillary thyroid carcinoma.
(Refer to the PDQ summary on Thyroid Cancer Treatment [Adult] for more information.)
Treatment Options Under Clinical Evaluation for Recurrent Papillary and Follicular Thyroid Carcinoma
Treatment of Medullary Thyroid Carcinoma
Medullary thyroid carcinomas are commonly associated with the multiple endocrine neoplasia type 2 (MEN2) syndrome (refer to the Multiple Endocrine Neoplasia [MEN] Syndromes and Carney Complex section of the PDQ summary on Unusual Cancers of Childhood Treatment for more information).
Treatment options for medullary thyroid carcinoma include the following:
Most cases of medullary thyroid carcinoma in children occur in the context of the MEN2A and MEN2B 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.
A retrospective analysis identified 167 children with RET mutations who underwent prophylactic thyroidectomy; this group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Postoperative hypoparathyroidism was more frequent in older children (32% in the oldest age group vs. 3% in the youngest age group; P = .002), regardless of whether central node dissection was carried out. Three children developed recurrent laryngeal nerve palsy, all of whom had undergone central node dissection (P = .040). All complications resolved within 6 months. Postoperative normalization of calcitonin serum levels was achieved in 114 of 115 children (99.1%) with raised preoperative values. Children were classified into risk groups by their specific type of RET mutation (refer to Table 2).
The American Thyroid Association has proposed the following guidelines for prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (refer to Table 2).
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. A long-term outcome evaluation in a cohort of 17 children and adolescents with advanced medullary thyroid carcinoma who received vandetanib reported a median PFS of 6.7 years and a 5-year overall survival of 88.2%.
(Refer to the Multiple Endocrine Neoplasia [MEN] Syndromes and Carney Complex section of the PDQ summary on Unusual Cancers of Childhood Treatment and the Treatment for those with MTC section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
Treatment Options Under Clinical Evaluation for Medullary Thyroid Carcinoma
Oral Cavity Cancer
More than 90% of tumors and tumor-like lesions in the oral cavity are benign.[109,110,111,112] Oral cavity cancer is extremely rare in children and adolescents.[113,114] According to the Surveillance, Epidemiology, and End Results 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 increased by 4.4% per year in white men and 1.9% in white women.[116,117,118] Current practices to increase HPV immunization rates in both boys and girls may reduce the burden of HPV-related cancers.[119,120]
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.[109,110,111,112] (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 [109,110] and 3% to 13% of oral tumor biopsies.[111,112] 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 or intermediate grade and have a high cure rate with surgery alone.; [Level of evidence: 3iiiA]
Diseases that can be associated with the development of oral cavity and/or head and neck squamous cell carcinoma include the following:[123,124,125,126,127,128,129,130]
Review of the Surveillance, Epidemiology, and End Results (SEER) database identified 54 patients younger than 20 years with oral cavity squamous cell carcinoma (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] A retrospective study of the National Cancer Database identified 159 patients younger than 20 years with SCC of the head and neck. Of these tumors, 55% originated in the oral cavity, and patients with laryngeal tumors had a better survival rate than did those who presented with oral cavity primary tumors.
Treatment of Childhood Oral Cavity Cancer
Treatment of benign oral cavity tumors is surgical.
Treatment options for childhood oral cavity cancer include the following:
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 squamous cell carcinoma managed with surgery alone have done well without recurrence.[121,133] (Refer to the PDQ summary on Lip and Oral Cavity Cancer Treatment [Adult] for more information.)
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.)
Treatment Options Under Clinical Evaluation for Childhood Oral Cavity Cancer
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.[134,135] Salivary gland tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[136,137]
Overall 5-year survival in the pediatric age group is approximately 95%. A review of the Surveillance, Epidemiology, and End Results database identified 284 patients younger than 20 years with tumors of the parotid gland.[Level of evidence: 3iA] Overall survival was 96% at 5 years, 95% at 10 years, and 83% at 20 years. Adolescents had higher mortality rates (7.1%) than did children younger than 15 years (1.6%; P = .23).
Most salivary gland neoplasms arise in the parotid gland.[140,141,142,143,144,145] 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.[134,143,145,147,148,149] Mucoepidermoid carcinoma is usually low or intermediate grade, although high-grade tumors do occur. Mammary analog secretory carcinoma (MASC) of the salivary gland is a newly described pathologic entity that has been seen in children. In one review, it was estimated that 12% of MASC cases occurred in the pediatric population.[150,151]
Immunohistochemical and molecular profiling in a series of pediatric patients with salivary gland tumors showed similarities to those tumors observed in adults. 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. MASC is characterized by an ETV6-NTRK3 fusion.
Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[149,155,156]
Treatment of Childhood Salivary Gland Tumors
Treatment options for childhood salivary gland tumors include the following:
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, positive surgical margins, extracapsular extension, or perineural extension.[138,157,158]; [Level of evidence: 3iiiA] Parotid gland tumors are removed with the aid of neurological monitoring to prevent damage to the facial nerve.
One retrospective study compared proton therapy with conventional radiation therapy and found that proton therapy had a favorable acute toxicity and dosimetric profile. Also, in a retrospective study, brachytherapy with iodine I 125 seeds was used to treat 24 children with mucoepidermoid carcinoma who had high-risk factors. Seeds were implanted within 4 weeks of surgical resection. With a median follow-up of 7.2 years, the disease-free and overall survival rates were 100%; no severe radiation-associated complications were reported.[Level of evidence: 3iiDi]
Objective responses have been observed in all reported patients with recurrent NTRK fusion–positive mammary analog secretory carcinomas who were treated with entrectinib or larotrectinib.[96,161] Ten of 11 adolescent or adult patients with TRK fusion–positive salivary gland tumors who were treated with larotrectinib experienced partial or complete responses.
(Refer to the PDQ summary on Salivary Gland Cancer Treatment [Adult] for more information.)
Treatment Options Under Clinical Evaluation for Childhood Salivary Gland Tumors
Sialoblastoma is a usually benign tumor presenting in the neonatal period, but has been reported to present as late as age 15 years. Sialoblastoma rarely metastasizes to the lungs, lymph nodes, or bones.
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
Childhood Laryngeal Cancer
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.[166,167]
These tumors may present with the following:
Treatment of Childhood Laryngeal Cancer
Rhabdomyosarcoma is the most common pediatric malignant tumor of the larynx and is treated with chemotherapy and radiation therapy. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Squamous cell carcinoma of the larynx in children is managed in the same manner as it is in adults with carcinoma at this site, using surgery and radiation therapy. Laser surgery may be the initial treatment used for these lesions. (Refer to the PDQ summary on Laryngeal Cancer Treatment [Adult] for more information about treatment of laryngeal cancer in adults.)
Treatment Options Under Clinical Evaluation for Childhood Laryngeal Cancer
Childhood Laryngeal Papillomatosis
Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is associated with human papillomavirus (HPV) infection, most commonly HPV-6 and HPV-11.[170,171] The presence of HPV-11 appears to correlate with a more aggressive clinical course than does the presence of HPV-6. An Australian survey of pediatric otorhinolaryngologists documented a decline in the incidence of laryngeal papillomatosis after the introduction of HPV vaccinations for adolescent girls and young women aged 12 to 26 years.
These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords, and they 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.
Treatment of Childhood Laryngeal Papillomatosis
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.
The role of checkpoint inhibitors, such as PD-1 inhibitors, is currently being investigated. Reports with small numbers of patients have documented that in selected cases, the administration of a quadrivalent HPV vaccine can be associated with a complete remission and an increase in the intersurgical interval.[181,182] In contrast, other reports have not documented a therapeutic effect of the quadrivalent HPV vaccine.
Treatment Options Under Clinical Evaluation for Childhood Laryngeal Papillomatosis
Midline Tract Carcinoma Involving theNUTGene (NUTMidline Carcinoma)
NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the NUT gene. In most cases (75%), the NUT gene on chromosome 15q14 is fused with the BRD4 gene 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.
Clinical Presentation and Outcome
Childhood midline tract carcinomas (NUT midline carcinomas) arise in midline epithelial structures, typically mediastinum and upper aerodigestive tract, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation.[186,187] 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 a median survival of less than 1 year. Preliminary data suggest that NUT-variant tumors may have a more protracted course.[185,186]
Treatment of Childhood Midline Tract Carcinoma
Treatment options for childhood midline tract carcinoma include the following:
Treatment of childhood midline tract carcinoma involving the NUT gene (NUT midline carcinoma) has included 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, tumor progression occurs early in the course of the disease.; [Level of evidence: 3iiiB] In a report from the NUT Midline Carcinoma Registry, 40 patients with primary tumors in the head and neck were evaluable. Two-year overall survival was 30%. The three long-term survivors (35, 72, and 78 months) underwent primary gross-total resection and received adjuvant therapy.[Level of evidence: 3iiA]
Preclinical studies have shown that the NUT-BRD4 fusion 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, suggesting a potential role for this class of agents in the treatment of this malignancy.[190,191] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.
Treatment Options Under Clinical Evaluation for Childhood Midline Tract Carcinoma
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Unusual pediatric 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.
Fibroadenoma is the most frequent breast tumor seen in children.[2,3] Sudden rapid enlargement of a suspected fibroadenoma is an indication for needle biopsy or excision, as rare transformation leading to malignant phyllodes tumors has been reported.
Other benign lesions include tubular adenoma, benign phyllodes tumor, and benign fibroepithelial neoplasm.
Treatment of Fibroadenoma
Treatment options for fibroadenoma include the following:
Treatment options for phyllodes tumors include the following:
Breast cancer has been reported in both males and females younger than 21 years.[6,7,8,9,10,11,12] 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%.
A National Cancer Database report described 181 cases of breast malignancy in patients aged 21 years and younger; 65% of patients had invasive carcinoma and the remaining patients had sarcoma or malignant phyllodes. In this study, the authors compared the pediatric patients with the adult patients and found that pediatric patients were more likely to have an undifferentiated malignancy, more advanced disease at presentation, and more variable management. Outcomes between children and adults were similar.
A subsequent report from the SEER database (1973–2009) discovered 91 girls aged 10 to 20 years with breast cancer, predominantly carcinomas (57% invasive, 5.5% in situ) and sarcomas (37%, mostly phyllodes tumors). The mortality rate was 46.6% for patients with regional disease and 18.7% for patients with localized disease. The mortality rates for the patients in this study were higher than the rates for premenopausal and postmenopausal women, although the sample size was small.[Level of evidence: 3iiA]
While rare, breast cancer has also been described in males. In a review of the National Cancer Database, 677 male adolescents and young adults were diagnosed with breast cancer during the period of 1998 to 2010; most patients (82%) had invasive disease. Age younger than 25 years and absence of nodal evaluation at the time of surgery were associated with worse outcomes.
Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with HIV).
Risk factors for breast cancer in adolescents and young adults (AYA) 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
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.[16,22]
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.[23,24]
(Refer to the PDQ summary on adult Breast Cancer Treatment or the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Treatment Options Under Clinical Evaluation
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 following are the most common malignant primary tumors of the lung:
Tracheobronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of tracheobronchial tumors on occasion display malignant behavior. The following histologic types have been identified (refer to Figure 4):[29,30,31,32,33,34,35]
Figure 4. The most representative primary tracheobronchial tumors are described with their more frequent location. Reprinted from Seminars in Pediatric Surgery, Volume 25, Issue 3, Patricio Varela, Luca Pio, Michele Torre, Primary tracheobronchial tumors in children, Pages 150–155, Copyright (2016), with permission from Elsevier.
With the exception of rhabdomyosarcoma, tracheobronchial tumors of all histologic types are associated with an excellent prognosis after surgical resection in children, even in the presence of local invasion.[37,38]; [Level of evidence: 2A]
Clinical Presentation and Diagnostic Evaluation
The presenting symptoms of a tracheobronchial tumor are usually caused by an incomplete tracheobronchial 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.[25,41] 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 tracheobronchial tumors is somewhat controversial because tracheobronchial 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;[34,43] however, endoscopic resection is not recommended except in highly selected cases.[35,43,44] 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.
Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[46,47]; [Level of evidence: 2A] Chemotherapy and radiation therapy are not indicated for tracheobronchial tumors, unless evidence of metastasis is documented or the tumor is the rhabdomyosarcoma histologic type.
Treatment options for tracheobronchial tumors, according to histologic type, are as follows:
(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. In most cases, pleuropulmonary blastoma is associated with germline mutations of the DICER1 gene. The International Pleuropulmonary Blastoma Registry is a valuable resource for information on this rare malignancy.[56,57]
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.
In the Pleuropulmonary Blastoma Registry experience, most Type I and Ir cysts are unilateral (74%), half are unifocal, and 55% are larger than 5 cm. Pneumothorax may be present at diagnosis in up to 30% of Type I and Ir pleuropulmonary blastoma cases.
Anaplasia is present in up to 60% of the cases. In the Pleuropulmonary Blastoma Registry, the median age at diagnosis was 35 months, and distant metastases were present at the time of diagnosis in 7% of cases.
Median age at diagnosis in the Pleuropulmonary Blastoma Registry was 41 months, and distant metastases were present in 10% of patients at the time of diagnosis.
The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50-year period (refer to Table 3).
In a comprehensive analysis of 350 patients reported by the Pleuropulmonary Blastoma Registry, only two prognostic factors were identified: the type of pleuropulmonary blastoma and the presence of metastatic disease at diagnosis. (Refer to Table 3.) In three additional small cohort series, the ability to perform a complete surgical resection was also identified as a prognostic factor.[63,64,65]
The presence of a germline DICER1 mutation is not a prognostic factor.
Close to two-thirds of patients with pleuropulmonary blastoma have a germline DICER1 mutation. Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the DICER1 syndrome.[66,67,68] Most mutation carriers are unaffected, indicating that tumor risk is modest.
Germline DICER1 mutations have been associated with the following:[66,67,68,69,70]
The penetrance of DICER1 mutations associated with each pathologic condition is not well understood, but lung cysts, pleuropulmonary blastoma, and thyroid nodules are the most commonly reported manifestations in individuals who have loss-of-function mutations. 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.[68,70] Surveillance and screening recommendations have been proposed.
As with other cancer predisposition conditions, before individuals with DICER1 mutations are screened, factors that must be considered include typical age of onset of each disease, potential benefits of early detection, and risks and availability of screening modalities. A consensus panel convened by the International Pleuropulmonary Blastoma Registry has proposed guidelines for surveillance. In addition to imaging-based surveillance, individuals and families can be counseled at each visit regarding potential signs and symptoms of DICER1-associated conditions and undergo appropriate age-specific and gender-specific preventive screening studies.
Presenting symptoms are not specific, and commonly include the following:
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.[63,64] Tumor embolism is a known risk, and radiographic evaluation of the central circulation is performed to identify potentially fatal embolic complications.
There are no standard treatment options. Current treatment regimens for these rare tumors have been informed by consensus opinion.
Treatment options for pleuropulmonary blastoma include the following:
A complete surgical resection is required for cure.
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.[57,64,73]
Some general treatment considerations from the Pleuropulmonary Blastoma Registry include the following:[56,57]
Incidence and Histology
Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[74,75] Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma.
Risk Factors, Clinical Presentation, and Diagnostic Evaluation
Risk factors include caustic ingestion, gastroesophageal reflux, and Barrett esophagus. 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
Thymoma and thymic carcinoma originate within the epithelial cells of the thymus, resulting in an anterior mediastinal mass. The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component, whereas, a thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as thymic carcinoma or type C thymoma. Thymic carcinomas have a higher incidence of capsular invasion and metastases.[76,77,78] Other tumors that involve the thymus gland include lymphomas, germ cell tumors, carcinomas, and carcinoids. Hodgkin lymphoma and non-Hodgkin lymphoma may also involve the thymus and must be differentiated from true thymomas and thymic carcinomas.
Primary tumors of the thymus are exceptionally rare in children; very few pediatric series have been reported.[76,79,80,81]
The following studies have reported on outcomes associated with thymoma:
These neoplasms are usually located in the anterior mediastinum and discovered during a routine chest x-ray. Symptoms may include the following:
About 40% of adults with thymoma have one or more paraneoplastic disorders during their lifetime.[82,83] The most common associated disorder is myasthenia gravis, which occurs in approximately 30% of adult patients. This disorder has also been reported in children and is important to recognize it before a thoracotomy of a suspected thymoma. Various other paraneoplastic syndromes have been found to be associated with thymoma. These include pure red cell aplasia, hypogammaglobulinemia, nephrotic syndrome, and autoimmune or immune disorders such as scleroderma, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and thyroiditis. Endocrine disorders associated with thymoma include hyperthyroidism, Addison disease, and panhypopituitarism.[82,83,84]
Treatment options for thymoma include the following:
The European Cooperative Study Group for Pediatric Rare Tumors identified 20 patients with thymic carcinoma between 2000 and 2012. Complete resection was achieved in 1 of 20 patients with thymic carcinoma. Five patients with thymic carcinoma survived. Five-year OS for patients with thymic carcinoma was 21.0%.
Treatment options for thymic carcinoma include the following:
(Refer to the PDQ summary on adult Thymoma and Thymic Carcinoma Treatment 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:[96,97,98]
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[96,99,100,101,102]
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.[103,104,105] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[103,106]
Primary malignant pediatric heart tumors are rare and include the following:[96,107,108,109]
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, other sarcomas, melanoma, leukemia, thymoma, and carcinomas of various sites.[94,96]
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.[99,110] 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 some 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.[115,116,117]; [Level of evidence: 3iiA] In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.
Treatment options for cardiac tumors, according to tumor type or resectability, are as follows:
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.[128,129] The amount of exposure required to develop cancer is unknown. In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation. 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.[131,132,133] 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.
Treatment options for malignant mesothelioma include the following:
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.[133,137,138,139]
Hyperthermic chemotherapy has been used to treat adults with pleural mesothelioma.[140,141]
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.)
Unusual pediatric 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.)
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]
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.[8,9,10,11]
Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1.0.[3,5,6]
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 hemihyperplasia 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.[2,4] 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.[20,21,22]
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.[24,25] 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.[11,22,23,26]
A study performed on 71 pediatric adrenocortical tumors (37 in a discovery cohort and 34 in an independent cohort) provided a description of the genomic landscape of pediatric adrenocortical carcinoma.
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.[3,4]
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.
Overall, adverse prognostic factors for adrenocortical carcinoma include the following:
Stage I disease appears to be associated with a better prognosis.
The overall probability of 5-year survival for children with adrenocortical tumors depends on stage and ranges from greater than 80% for patients with resectable disease to less than 20% for patients with metastases.[3,4,5,26,30,31,32,33,37]
A portion of patients with adrenocortical carcinoma do not have a germline TP53 mutation. A retrospective review of children with adrenocortical carcinoma identified 60 patients without germline TP53 mutations. There was a strong female predominance (female to male ratio, 42:18) in this group of patients. Three-year progression-free survival (PFS) was 71.4%, and overall survival (OS) was 80.5%. Prognostic factors for this group were the same as the factors identified in previous analyses that did not segregate for TP53 germline status. Unfavorable prognostic features included older age, higher disease stage, heavier tumor weight, presence of somatic TP53 mutations, and higher Ki-67 labeling index. Ki-67 labeling index and age remained significantly associated with PFS after adjusting for stage and tumor weight.
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.[10,11,39,40]; [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.[11,46]
(Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)
Gastric (Stomach) Cancer
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. Rare cases of familial diffuse gastric cancer associated with CDH1 germline mutations have been reported in adolescents.
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 and Outcome
Treatment options for gastric carcinoma include the following:
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 Gastrointestinal Stromal Tumors [GIST] section of this summary for information about the treatment of GIST.)
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.[53,54,55,56]
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.[55,57] 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.[53,55,58] 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.
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.
Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[53,55,58] 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. A retrospective review of the National Cancer Database identified 21 pediatric patients (younger than 18 years) and 348 adult patients with solid pseudopapillary neoplasm of the pancreas. When compared with their adult counterparts, children with solid pseudopapillary neoplasms had similar disease severity at presentation, received similar treatments, and experienced equivalent postoperative outcomes.
The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates exceeding 95%.
Treatment options for solid pseudopapillary tumor of the pancreas include the following:
Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual. Whipple procedures (pancreaticoduodenectomy) are often necessary, but non-Whipple pancreatic-sparing resections may be possible utilizing a pancreatico-jejunostomy procedure. Surgery is usually curative, although local recurrences occur in 5% to 15% of the cases. A retrospective review of the Italian Pediatric Rare Tumor Registry identified 43 pediatric patients diagnosed with solid pseudopapillary tumor of the pancreas between 2000 and 2018.[Level of evidence: 3iiA] The median age at diagnosis was 13.2 years (range, 7–18 years). Only one patient presented with metastatic disease. At follow-up (median, 8.4 years; range, 0–17 years), one recurrence occurred in a patient who had intraoperative rupture, and all patients were alive.
Metastatic disease, usually in the liver, may occur in up to 15% of the cases.[53,55,58,59,60] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.
Incidence and Risk Factors
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.[53,65]
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 and IGF2 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.[68,69]
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 the 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.
Treatment options for pancreatoblastoma include the following:
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.[62,70]
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.[55,65,67,71]
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.
Response has been seen for patients with relapsed or persistent pancreatoblastoma treated with gemcitabine in one case  and vinorelbine and oral cyclophosphamide in two cases.
High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[55,74]
Islet Cell Tumors
Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[55,57,75] 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.
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 options for islet cell tumors include the following:
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 mTOR inhibitors are recommended.
The management of these tumors in children follows the consensus guidelines established for adult patients.[75,76] (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:[55,57]
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 (SEER) database recorded 174 cases of colorectal cancer in patients younger than 19 years. Colorectal carcinoma accounts for about 2% of all malignancies in patients aged 15 to 29 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.[83,84,85]
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.[80,86]
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:[87,88]
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,[79,80,86,90,91] 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.[91,92,93] Tumors with mucinous histology 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. In a genomic study that used exome and RNA sequencing to identify mutational differences in colorectal carcinomas of adults (n = 30), adolescents and young adults (n = 30), and children (n = 2), five genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR) were identified that were more frequently mutated in adolescents and young adult patients. These genes contained a damaging mutation and were identified through whole-exome sequencing and RNA sequencing. In addition, higher mutational rates in DNA mismatch and DNA repair pathways, such as MSH2, BRCA2, and RAD9B, were more prevalent in adolescent and young adult samples but the results were not validated by RNA sequencing.
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).[80,83,84,85,86,87,90,91,96,97,98,99,100,101,102]
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.[90,96] Of almost 160,000 patients with colorectal cancer included in the National Cancer Database, 918 pediatric patients were identified. Age younger than 21 years was a significant predictor of increased mortality.
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 PFS and OS in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[Level of evidence: 2A]
Ipilimumab and nivolumab demonstrated high response rates in pediatric patients aged 12 years and older with microsatellite instability–high or mismatch repair–deficient metastatic colorectal cancer who had disease progression after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[107,108,109,110]
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. Hereditary colorectal cancer has two well-described forms:[112,113]
Other colorectal cancer syndromes and their associated genes include oligopolyposis (POLE, POLD1),NTHL1, juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).
The incidence of these genetic syndromes in children has not been well defined, as follows:
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 in children 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.
Despite the increased risk of multiple malignancies in families with Lynch syndrome, the risk of malignant neoplasms during childhood in those families does not seem to be increased when compared with the risk in children from non-Lynch syndrome colorectal carcinoma families.
Neuroendocrine Tumors (Carcinoid Tumors)
These tumors, like tracheobronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[124,125,126,127,128,129] 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
A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[Level of evidence: 3iiDii] The most common primary site was the appendix (36 of 45 cases). No recurrences were observed among the patients with appendiceal primary tumors treated with appendectomy alone, which supports resection of the appendix without hemicolectomy as the procedure of choice.
Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, low-grade, localized tumors.[134,135,136]
Treatment options for neuroendocrine tumors of the appendix include the following:
In adults, it has been 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 lymph nodes.[137,138,139,140]
Study results suggest that appendectomy alone is sufficient treatment for childhood appendiceal carcinoids regardless of size, position, histology, or nodal or mesenteric involvement and that right hemicolectomy is unnecessary in children. Routine follow-up imaging and biologic studies were not beneficial.[137,140,141,142]
Evidence (appendectomy alone):
The study concluded that appendectomy alone should be considered curative for most cases of appendiceal neuroendocrine tumors. The procedure of choice is a resection of the appendix without hemicolectomy.
The investigator's recommendation was that appendectomy alone is sufficient treatment for neuroendocrine tumors of the appendix.
Nonappendiceal Neuroendocrine Tumors
A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[Level of evidence: 3iiDii] Extra-appendiceal primary tumors (n = 9) were associated with a higher risk of metastasis and recurrence.
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. Larger tumor size has been associated with a higher risk of recurrence.
Clinical experience with nonappendiceal neuroendocrine tumors is reported almost entirely in adults. Histopathology is graded by mitotic rate, Ki-67 labeling index, and presence of necrosis into well-differentiated (low grade, G1), moderately differentiated (intermediate grade, G2) and poorly differentiated (high grade, G3) tumors.
Treatment options for resectable nonappendiceal neuroendocrine tumors include the following:
Treatment options for unresectable or multifocal nonappendiceal neuroendocrine tumors include the following:
SSTR2 ligands include octreotide, long-acting repeatable octreotide, and lanreotide. Octreotide is not practical for therapy because of its short half-life, requiring frequent repeated administration. Long-acting repeatable octreotide and lanreotide have been evaluated in prospective, randomized, placebo-controlled trials.[147,148] Patient age was not specified in the first trial, and eligibility was restricted to age 18 years and older in the second trial. Neither agent produced significant objective responses in measurable tumors. Both agents were associated with statistically significant increases in PFS and time-to-progression, and both agents are recommended for the treatment of unresectable nonappendiceal neuroendocrine tumors in adults.
Conventional cytotoxic chemotherapy appears to be inactive.
In one retrospective, single-institution study, the 5-year relapse-free survival rate of nonappendiceal neuroendocrine tumors was 41%, and the OS rate was 66%.
(Refer to the Tracheobronchial Tumors section of this summary for information about tracheobronchial 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 Treatment 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.[154,155,156] 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.[156,158,159]
Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, the mitotic rate does not appear to accurately predict clinical behavior.[158,160] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[161,162] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[163,164]
Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[158,163,165] 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 categorized 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 GIST.
In an observational study carried out at the NCI, 116 patients with presumed wild-type GIST were evaluated, and 95 of these patients had an adequate tumor specimen available for molecular profiling. Among these 95 patients, the investigators identified the following three distinctive subgroups of patients:
Of the 95 patients that were evaluated at this clinic, 18 patients had syndromic GIST (i.e., Carney triad or Carney-Stratakis syndrome). Among the Carney triad patients, two patients had the complete triad, five patients had SDH mutations, and six patients had epimutant tumors. Seven patients with Carney-Stratakis syndrome had SDH-mutant GIST (n = 6) or SDH-epimutant GIST (n = 1).
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.[156,158,165] 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:[158,169]
Once the diagnosis of pediatric GIST is established, referral to medical centers with expertise in the treatment of GIST should be considered, with all samples evaluated for mutations in KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[172,173]
Treatment options for GIST depend 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.[158,175,176] 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 the phase III SWOG intergroup trial S0033 (NCT00009906), 20 tumors from patients who were presumed to be wild-type were resequenced. Twelve of these tumors were identified as being SDH mutant, and only one patient (8.3%) experienced a partial response to imatinib. 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.
Given the indolent course of the disease in pediatric patients, it is reasonable to avoid extensive initial surgeries and to withhold subsequent resections unless they are needed to address only symptoms such as obstruction or bleeding.[153,158]
Unusual pediatric 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; the most common presenting symptom is hematuria.
Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.[2,3,4] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.
Histologic classification of these neoplasms includes the following:
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.[4,5,6,7,8]
Treatment options for childhood bladder cancer include the following:
In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have an excellent prognosis after transurethral resection.[6,7,8,9] Squamous cell carcinoma and more aggressive carcinomas, however, have been reported and may require a more aggressive surgical approach.[7,10,11,12]
(Refer to the PDQ summary on adult Bladder Cancer Treatment for more information.)
Testicular Cancer (Non–Germ Cell)
Incidence and Clinical Presentation
Testicular tumors are very rare in young boys and account for an incidence of 1% to 2% of all childhood tumors.[13,14] 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 Treatment 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.[15,16] Most gonadal stromal tumors present as a painless testicular mass, while 10% to 20% of patients may have endocrine manifestations such as precocious puberty. 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). In older males, Leydig cell tumors are more common. In a report of 12 patients with Leydig cell tumors (aged 4.2–14.7 years), precocious puberty was the presenting symptom in 7 of 12 patients.[Level of evidence: 3iiA] Large cell calcifying Sertoli cell tumors may indicate an underlying genetic predisposition, such as Peutz-Jeghers syndrome or Carney complex. These tumors may occur in both testes, and some patients may have a slow and indolent course.
The prognosis for sex cord–stromal tumors is usually excellent after orchiectomy.[17,21,22]; [Level of evidence: 3iiiA] In a review of the literature, 79 patients younger than 12 years were identified. No patient had high-risk pathological findings after orchiectomy, and none had evidence of occult metastatic disease, suggesting a role for a limited surveillance strategy.[Level of evidence: 3iiiA]
Treatment options for testicular cancer (non-germ cell) include the following:
There are conflicting data about malignant potential in older males. Most case reports suggest that in 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)
Most 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.[31,32,33,34]
Most malignant ovarian tumors occur in girls aged 15 to 19 years.
Epithelial Ovarian Neoplasia
Histology, Clinical Presentation, and Prognosis
Ovarian tumors derived from malignant epithelial elements include the following:
Within each classification, subtypes include benign tumors, tumors with low malignant potential or borderline tumors, and adenocarcinomas. Most ovarian tumors in the pediatric age range are benign and borderline, with rare malignant lesions in adolescence. Studies have reported the following:
Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than do adults with similar histology, probably because girls usually present with low-stage disease.[39,40] The potential association with genetic predisposition (e.g., BRCA mutation) in pediatric patients has not yet been studied.
Treatment options for epithelial ovarian neoplasia include the following:
Treatment of epithelial ovarian neoplasia is based on stage and histology. Most pediatric and adolescent patients have stage I disease. In the TREP study, of the eight patients with benign tumors, seven patients were stage I and one patient was stage III. Of the eight patients with borderline tumors, three patients were stage I and five patients were stage III (on the basis of washings and omental implants). All 16 patients were treated with surgery alone. Fifteen patients are alive without disease; the one death was not from ovarian cancer.
Treatment options for malignant ovarian epithelial cancer include the following:
Treatment of malignant ovarian epithelial cancer is stage-related and follows adult protocols; it may include surgery, radiation therapy, and chemotherapy. (Refer to the PDQ summary on adult Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment for more information.)
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 (and, rarely, adult) granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. Other histological subtypes, such as steroid cell tumor, sex cord tumor with annular tubules, or thecoma, are exceedingly rare. 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 mostly occur in relapse situations. Some tumors may be associated with hormone secretion; for example, estrogen in granulosa cell tumors or androgens in Sertoli-Leydig cell tumors.
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.[44,45] The recommendations regarding diagnostic work-up, staging, and therapeutic strategy have been harmonized between these registries.
In a report from the German MAKEI study, 54 children and adolescents with prospectively registered sex cord–stromal tumors were analyzed. Forty-eight patients presented with stage I tumors and six patients had peritoneal metastases. While overall prognosis was favorable, patients at risk could be identified by stage (stage Ic, preoperative rupture, stages II and III) and histological criteria such as high mitotic count.
Treatment options for sex cord–stromal tumors include the following:
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 patients 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).[47,48] 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.[41,49,50,51]
Juvenile granulosa cell tumors have been reported in children with Ollier disease and Maffucci syndrome.[52,53]
Patients with juvenile granulosa cell tumors present with the following:[54,55]
Treatment options for juvenile granulosa cell tumors include the following:
Sertoli-Leydig Cell Tumors
Sertoli-Leydig cell tumors are rare in young girls and are more frequently seen in adolescents. They may secrete androgens and, thus, present with virilization, secondary amenorrhea, or precocious puberty. These tumors may also be associated with Peutz-Jeghers syndrome, but more frequently are a part of the DICER1-tumor spectrum.[42,61,62] Patients with Sertoli-Leydig cell tumors should be evaluated for germline DICER1 mutations. If a germline DICER1 mutation is found, regular follow-up for ovarian and other tumors such as thyroid disease (multinodular goiter, carcinoma) and genetic counseling should be considered.[62,63]
Treatment options for Sertoli-Leydig cell tumors include the following:
A study of 44 patients from the European Cooperative Study Group on Pediatric Rare Tumors showed that prognosis of Sertoli-Leydig cell tumors was determined by stage and histopathologic differentiation.
Small Cell Carcinoma of the Ovary, Hypercalcemia-Type
Incidence, Molecular Features, and Prognosis
Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia.
SMARCA4 mutations have been described in these tumors, putting these in the context of rhabdoid tumors.
The clinical course is usually aggressive and prognosis is poor.
Treatment options for small cell carcinoma of the ovary include the following:
Carcinoma of the Cervix and Vagina
Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence, with fewer than 50 reported cases.[34,74] 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.
Treatment options for carcinoma of the cervix and vagina include the following:
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 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 multiple endocrine neoplasia (MEN) syndromes are shown in Table 4.
A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients. Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.
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.
Clinical practice guidelines recommend 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 of the abdomen every 1 to 3 years.[7,8,9]
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.[10,11,12] Table 5 describes the clinical features of MEN2A and MEN2B syndromes.
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.[16,17]
A retrospective analysis identified 167 children with RET mutations who underwent prophylactic thyroidectomy; this group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Children were classified into risk groups by their specific type of RET mutation (refer to Table 2 in the PDQ summary on Childhood Thyroid Cancer Treatment for more information).
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.[17,19]
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.[17,20]
Treament options for MEN syndrome, according to type, are as follows:
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.[25,30,31,32]
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.[36,37,38] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. Patients with Hirschsprung disease are screened for mutations in RET exon 10; if such a mutation is discovered, a prophylactic thyroidectomy should be considered.[38,39,40]
(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.[43,44,45] 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.[46,47]
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:[48,49]
Genetic Factors and Syndromes Associated with Pheochromocytoma and Paraganglioma
It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (refer to Table 6). 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.[50,51,52,53]
Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:
(Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
These susceptibility genes can be divided into the following cluster groups on the basis of transcriptomic profiles:
The pseudohypoxia cluster group tumors are characterized by the absence of epinephrine production (noradrenergic phenotype), whereas tumors in the other two cluster groups produce epinephrine (adrenergic phenotype). These differences reflect the absence, versus the presence, of the enzyme phenylethanolamine N-methyltransferase, responsible for conversion of norepinephrine to epinephrine.
Studies of germline mutations in young patients with pheochromocytoma or paraganglioma have shown that these patients have a higher prevalence (70%–80%) of germline mutations and 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 6).
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.[61,62] 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. 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.
Given the higher prevalence of germline alterations in children and adolescents with pheochromocytoma and paraganglioma, genetic counseling and testing should be considered in this younger population.
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. Epinephrine production is also associated with cluster genotype. Cluster 1 tumors are characterized by absence of epinephrine production (noradrenergic phenotype), whereas cluster 2 tumors produce epinephrine (adrenergic phenotype).
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.[47,49,63] As previously discussed, children and adolescents with pheochromocytoma and paraganglioma have a higher prevalence of hereditary, extra-adrenal, multifocal, metastatic, and recurrent pheochromocytomas and paragangliomas; they also have a higher prevalence of cluster 1 mutations, which is paralleled by a higher prevalence of noradrenergic tumors than in adults.
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.[66,67]
For tumor localization, 18F-6F-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 18F-6F-FDA PET than by 123/131I-MIBG.[68,69] Other functional imaging alternatives include indium In 111-octreotide scintigraphy and fluorine F 18-fludeoxyglucose PET, both of which can be coupled with CT imaging for improved anatomic detail.
Treatment options for childhood paraganglioma and pheochromocytoma include the following:
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.[70,71,72] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival (OS) is less clear.
Responses have also been obtained to high-dose 131I-MIBG and sunitinib.[73,74]
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 and the Intraocular [Uveal] Melanoma section of this summary for information about uveal melanoma in children.)
Melanoma, although rare, is the most common skin cancer in children, followed by BCCs and SCCs.[75,76,77,78,79,80,81,82] 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 (2011–2015) increases with age, as follows:
Melanoma accounts for about 4% of all cancers in children aged 15 to 19 years.[85,86]
The incidence of pediatric melanoma increased by an average of 1.7% per year between 1975 and 1994, but then decreased by 0.6% per year from 1995 to 2014. 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:
Patients with central nervous system melanoma arising in the context of congenital melanocytic nevi syndrome have a very poor prognosis, with 100% mortality. Most of these patients will have NRAS mutations; therefore, there is potential rationale for treatment with mitogen-activated protein kinases (MAPK) pathway inhibitors. Transient symptomatic improvement was noted in four children receiving a MEK inhibitor, but all patients eventually died from disease progression.
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:[95,96,97,98,99,100,101]
Familial melanoma comprises 8% to 12% of melanoma cases. p16 germline mutations have been described in up to 7% of families with two first-degree relatives with melanoma and in up to 80% of families having one member with multiple primary melanomas.
In a prospective study of 60 families who had more than three members with melanoma, one-half of the 60 families studied had a germline CDKN2A mutation. Regardless of CDKN2A status, melanoma-prone families were found to have sixfold to 28-fold higher percentages of members with pediatric melanoma compared with the general population of patients with melanoma in the United States. Within CDKN2A-positive families, pediatric patients with melanoma were significantly more likely to have multiple melanomas compared with their relatives who were older than 20 years at diagnosis (71% vs. 38%, respectively; P = .004). CDKN2A-positive families had significantly higher percentages of pediatric patients with melanoma compared with CDKN2A-negative families (11.1% vs. 2.5%, respectively; P = .004).
Prognosis and Prognostic Factors
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.[87,98,105] More than 90% of children and adolescents with melanoma are expected to be alive 5 years after their initial diagnosis.[98,104,106,107]
The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[98,105,106] 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.[98,104,106,108]
The use of sentinel lymph 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. Studies addressing nodal involvement and the lack of effect on outcome include the following:
The association of thickness with clinical outcome is controversial in pediatric melanoma.[98,105,106,115,116,117,118,119] 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.[120,121]
The diagnostic evaluation of melanoma includes the following:
The role of completion lymph node dissection after a positive sentinel node and the value of adjuvant therapies in these patients is discussed in the Treatment section below.
Patients who present with conventional or adult-type melanoma should undergo laboratory and imaging evaluations on the basis of adult guidelines (refer to the Stage Information for Melanoma section in the PDQ summary on adult Melanoma Treatment for more information related to adult melanoma). In contrast, patients who are diagnosed with spitzoid melanomas have a low risk of recurrence and excellent clinical outcomes and do not require extensive radiographic evaluation either at diagnosis or follow-up.
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.[128,129] 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]
Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into the following three general groups:
The genomic characteristics of each tumor are summarized in Table 7.
The genomic landscape of conventional melanoma in children is represented by many of the genomic alterations that are found in adults with melanoma. A report from the Pediatric Cancer Genome Project observed that 15 cases of conventional melanoma had a high burden of somatic single-nucleotide variations, TERT promoter mutations (12 of 13), and activating BRAF V600 mutations (13 of 15), as well as a mutational spectrum signature consistent with ultraviolet (UV) light damage. In addition, two-thirds of the cases had MC1R variants associated with an increased susceptibility to melanoma. An Australian study compared the whole-genome sequencing of melanomas in adolescents and young adults (age range, 15–30 years) with the sequencing of melanomas in older adults. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the adolescent and young adult cohort were double the rates observed in the adult cohort. Adolescent and young adult melanomas contained a higher proportion of mutation signatures unrelated to UV radiation than did mature adult melanomas, as a proportion of total mutation burden.
The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes, including RET, ROS1, NTRK1, ALK, MET, and BRAF.[133,134,135] These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner.[131,134]TERT promoter mutations are uncommon in spitzoid melanocytic lesions and were observed in only 4 of 56 patients evaluated in one series. However, each of the four cases with TERT promoter mutations experienced hematogenous metastases and died of their disease. This finding supports the potential of TERT promoter mutations in predicting aggressive clinical behavior in children with spitzoid melanocytic neoplasms, but additional study is needed to define the role of wild-type TERT promoter status in predicting clinical behavior in patients with primary site spitzoid tumors.
Large congenital melanocytic nevi are reported to have activating NRAS Q61 mutations with no other recurring mutations noted. Somatic mosaicism for NRAS Q61 mutations has also been reported in patients with multiple congenital melanocytic nevi and neuromelanosis.
Treatment options for childhood melanoma include the following:
Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:
Sentinel lymph 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 larger than 1 mm with or without adverse features. Young patients have a higher incidence of sentinel lymph node positivity and this feature adversely affects clinical outcomes.[109,113]
If the sentinel lymph node is positive, the option to undergo a complete lymph node dissection should be discussed. An adult trial randomly assigned 1,934 patients with a positive sentinel node, identified by either immunohistochemistry or polymerase chain reaction, to either complete lymph node dissection or observation. The 3-year melanoma-specific survival was similar in both groups (86%), whereas the disease-free survival (DFS) was slightly higher in the dissection group (68% vs. 63%; P = .05). This advantage in DFS was related to a decrease in the rate of nodal recurrences because there was no difference in the distant metastases–free survival rates. It remains unknown how these results will affect the future surgical management of children and adolescents with melanoma.
Immune Checkpoint Inhibitors or BRAF/MEK Inhibitors
Patients with high-risk primary cutaneous melanoma, such as those with regional lymph node involvement, may be offered the opportunity to receive adjuvant treatment with immune checkpoint or BRAF inhibitors, as recently described in adults.[139,140,141] Specific trials evaluating these adjuvant therapies have not been conducted in pediatric patients.
Targeted therapies and immunotherapy that have been shown to be effective in adults with melanoma should be pursued in pediatric patients with conventional melanoma and metastatic, recurrent, or progressive disease.
Evidence (targeted therapy and immunotherapy):
The studies listed below are investigating the activity of targeted BRAF inhibitors, MEK inhibitors, and PDL-1 inhibitors in pediatric patients with melanoma.[148,149]
(Refer to the PDQ summary on adult Melanoma Treatment for more information.)
BCC and SCC
Nonmelanoma skin cancers are very rare in children and adolescents. In a report of 7,814 cases of primary skin cancers in individuals younger than 30 years who were recorded by the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2008, carcinomas accounted for 0.008% of all cases.
In one series of 28 patients, approximately one-half of patients had predisposing conditions such as nevoid BCC syndrome (Gorlin syndrome), and one-half of patients were exposed to iatrogenic conditions such as prolonged immunosuppression or radiation. Gorlin syndrome is a rare disorder with a predisposition to the development of early-onset neoplasms, including BCC, ovarian fibroma, and desmoplastic medulloblastoma.[152,153,154,155]
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. 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.
Treatment options for nonmelanoma skin cancer include the following:
Treatment for nonmelanoma skin cancer is predominantly surgical, either surgical excision or Mohs micrographic surgery.
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 metastatic or advanced BCC.[159,160,161] 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.)
Intraocular (Uveal) Melanoma
Uveal melanoma (iris, ciliary body, choroid) is the most common primary intraocular malignancy (about 2,000 cases are diagnosed each year in the United States) and accounts for 5% of all cases of melanoma. This tumor is most commonly diagnosed in older patients, and the incidence peaks at age 70 years.
Pediatric uveal melanoma is extremely rare and accounts for 0.8% to 1.1% of all cases of uveal melanoma. A retrospective, multicenter, observational study conducted by the European Ophthalmic Oncology Group from 1968 to 2014 identified 114 children (aged 1–17 years) and 185 young adults (aged 18–25 years) with ocular melanoma at 24 centers. The median age at the time of diagnosis for children was 15.1 years. The incidence of disease increased by 0.8% per year between the ages of 5 and 10 years and 8.8% per year between the ages of 17 and 24 years. Other series have also documented the higher incidence of the disease in adolescents.[166,167]
Risk factors include the following:[168,169,170]
In a European Oncology Group study, 57% of children were females and four had a preexisting condition that included oculodermal melanocytosis (n = 2) and neurofibromatosis (n = 2). In a review of 13 cases of uveal melanoma in the first 2 years of life, four patients had familial atypical melanoma mole syndrome, one patient had dysplastic nevus syndrome, and one patient had café au lait spots.
Uveal melanoma is characterized by activating mutations of GNAQ and GNA11, which lead to activation of the mitogen-activated protein kinases pathway (MAPK). In addition, mutations in BAP1 are seen in 84% of metastasizing tumors, whereas mutations in SF3B1 and EIF1AX are associated with a good prognosis.[172,173,174,175,176,177]
Treatment options for intraocular (uveal) melanoma include the following:
(Refer to the PDQ summary on Intraocular [Uveal] Melanoma Treatment for information on the treatment of uveal melanoma in adults.)
Survival of children appears to be more favorable than that of young adults and adults, suggesting that the biology of ocular melanoma might be different in children.[165,166]
Chordoma is a very rare tumor of bone that arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum; the most common site in children is the cranium. 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.[179,180] Most pediatric patients have the classical or chondroid variant of chordoma, while the dedifferentiated variant is rare in children.[179,181]
Younger children appear to have a worse outlook than do older patients.[179,182,183,184,185,186] The survival rate in children and adolescents ranges from about 50% to 80% for cranial chordomas.[179,183,185] A retrospective literature review and review of institutional patients identified 682 patients with chordomas of the spine, with a median age of 57 years.[Level of evidence: 3iiiA] Age younger than 18 years, location in sacral spine, dedifferentiated pathology, and chemotherapy were associated with a lower probability for progression-free survival (PFS). Young age (<18 years), old age (>65 years), bladder or bowel dysfunction at presentation, dedifferentiated pathology, recurrence or progression, and metastases were associated with a worse overall survival. Histopathology is also an important prognostic factor, with atypical or chondroid pathology having worse outcomes than classical pathology.[Level of evidence: 3iiiA]
A retrospective analysis identified seven children with poorly differentiated chordomas.[Level of evidence: 3iiA] The median survival of these patients was 9 months. All poorly differentiated chordomas showed loss of SMARCB1 expression by immunohistochemistry. Copy number profiles were derived from intensity measures of the methylation probes and indicated 22q losses affecting the SMARCB1 region in all poorly differentiated chordomas.
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.
Treatment options for chordoma include the following:
Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[185,191] 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. However, if gross-total resection can be achieved, outcome is improved.[Level of evidence: 3iiA]
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.[193,194]; [185,195][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.[197,198] 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.[199,200] 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 in adults.[201,202,203] One multicenter French retrospective study reported five patients who had partial responses to treatment with either imatinib, sorafenib, or erlotinib, with a median PFS of 36 months.
Recurrences are usually local but can include distant metastases to lungs or bone.
Patients with chordomas and SMARCB1 mutations may be offered treatment with tazemetostat on the APEC1621C (NCT03213665) treatment arm of this trial.
Cancer of Unknown Primary Site
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 fluorine F 18-fludeoxyglucose (18F-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 the ability to identify the putative tissue of origin and guide in the selection of targeted agents for specific mutations.[209,210,211,212,213] 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) are 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.
Head and Neck Cancers
Added text to state that a Danish population-based study of thyroid cancer in patients younger than 24 years reported that the age-adjusted incidence rate increased significantly from 0.36 in 1980 to 0.97 in 2014, with an average annual percent change of 2.9%. No change in overall survival was observed, but a significant increase was seen in the incidence of thyroid cancer among young adults, mainly attributed to an increase among females and patients with papillary carcinoma (cited Schmidt et al. as reference 67).
Added targeted therapy as a treatment option for papillary and follicular (differentiated) thyroid carcinoma.
Added text to state that larotrectinib has been used to treat patients with TRK fusion–positive thyroid carcinoma. Five of five patients with TRK fusion–positive thyroid carcinomas who were treated with lartotrectinib therapy achieved partial or complete responses (cited Drilon et al. as reference 96).
Added targeted therapy as a treatment option for childhood salivary gland tumors.
Added text to state that ten of 11 adolescent or adult patients with TRK fusion–positive salivary gland tumors who were treated with larotrectinib experienced partial or complete responses.
Added text to state that an Australian survey of pediatric otorhinolaryngologists documented a decline in the incidence of laryngeal papillomatosis after the introduction of human papillomavirus vaccinations for adolescent girls and young women aged 12 to 26 years (cited Novakovic et al. as reference 173).
Added text to state that other benign lesions include tubular adenoma, benign phyllodes tumor, and benign fibroepithelial neoplasm (cited McLaughlin et al. as reference 5).
Added Potter et al. as reference 36 and level of evidence 3iiA.
Added Surveillance as a new subsection in the Pleuropulmonary Blastoma section.
Added text to state that in a report of 12 patients with Leydig cell tumors, precocious puberty was the presenting symptom in 7 of 12 patients (cited Luckie et al. as reference 19 and level of evidence 3iiA).
Added text to state that in one series of patients with Leydig cell tumors, 3 of 12 patients were treated with enucleation alone, and 9 patients were treated with orchiectomy. All patients were alive at the last follow-up.
Other Rare Childhood Cancers
Added text about a retrospective analysis that identified 167 children with RET mutations who underwent prophylactic thyroidectomy and were classified into risk groups by their specific type of RET mutation (cited Machens et al. as reference 18).
Added text about three susceptibility gene cluster groups associated with an increased risk of pheochromocytoma and paraganglioma, including the pseudohypoxia group, the WNT signaling group, and the kinase signaling group (cited Crona et al. as reference 56).
Added text to state that the pseudohypoxia cluster group tumors are characterized by the absence of epinephrine production, whereas tumors in the other two cluster groups produce epinephrine. These differences reflect the absence, versus the presence, of the enzyme phenylethanolamine N-methyltransferase, responsible for conversion of norepinephrine to epinephrine.
Added text about the results of an Australian study that compared the whole-genome sequencing of melanomas in adolescents and young adults with the sequencing of melanomas in older adults (cited Wilmott et al. as reference 132).
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
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Levels of Evidence
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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: https://www.cancer.gov/types/childhood-cancers/hp/unusual-cancers-childhood-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389315]
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Last Revised: 2019-08-16
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