Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version
Other Rare Childhood Cancers
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.[1] Changes may include hyperplasia, benign adenomas, and carcinomas.
There are two main types of MEN syndrome:
- Type 1.
- Type 2.
- Type 2A.
- Type 2B.
- Familial medullary thyroid carcinoma.
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)
Clinical Presentation and Diagnostic Evaluation
The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 4.
- Multiple endocrine neoplasia type 1 (MEN1) syndrome (Werner syndrome): MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 4 are present.A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients.[3] Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.
- Primary hyperparathyroidism. Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[3,4]
- Pituitary adenomas. Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[3]
- Pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[3]
- Malignant tumors. Four patients had malignant tumors (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years from rapidly progressive disease.
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.[5] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[6]It is recommended that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[7-9] - Multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B) syndromes: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.[10-12] Table 5 describes the clinical features of MEN2A and MEN2B syndromes.
- MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 4) in an individual or in close relatives.[13] RET mutations in these patients are usually confined to exons 10 and 11.
- MEN2B: MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[13-15] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[16] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus.
- Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases.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.[17,19]
Treatment
Treament options for MEN syndrome, according to type, are as follows:
- MEN1 syndrome: Treatment of patients with MEN1 syndrome is based on the type of tumor. The outcome of patients with MEN1 syndrome is generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors.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.[4]
- MEN2 syndromes: The management of medullary thyroid cancer in children from families having MEN2 syndromes relies on presymptomatic detection of the RETproto-oncogene mutation responsible for the disease.
- MEN2A syndrome: For children with MEN2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a mutation is identified.[12,20-24] The outcome for patients with MEN2A syndrome is also generally good, yet the possibility exists for recurrence of medullary thyroid carcinoma and pheochromocytoma.[25-27] A retrospective analysis identified 262 patients with MEN2A syndrome.[28] Median age of the cohort was 42 years and ranged from age 6 to 86 years. There was no correlation between the specific RET mutation identified and the risk of distant metastasis. Younger age at diagnosis did increase the risk of distant metastasis.
- MEN2B syndrome: Because of the increased virulence of medullary thyroid carcinoma in children with MEN2B and in those with mutations in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[16,21,32]; [33][Level of evidence: 3iiiDii] Patients who have MEN2B syndrome have a worse outcome primarily because of more aggressive medullary thyroid carcinoma. Prophylactic thyroidectomy has the potential to improve the outcome in MEN2B.[34]
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. RETgermline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[35-37] 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.[37-39](Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasiasfor 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.[40] 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.[41]
Treatment Options Under Clinical Evaluation
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:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
Carney Complex
Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1Agene, located in chromosome 17.[42] 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.[42-44] There are published surveillance guidelinesfor 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
Incidence
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.[45,46]
Anatomy
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:[47,48]
- Sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines.
- Parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.
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.[49-52]
Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:
- von Hippel-Lindau (VHL) syndrome: Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL.
- Multiple Endocrine Neoplasia (MEN) Syndrome Type 2: Codon-specific mutations of the RET gene are associated with a 50% risk of development of pheochromocytoma in MEN2A and MEN2B. Somatic RET mutations are also found in sporadic pheochromocytoma and paraganglioma.
- Neurofibromatosis type 1 (NF1): Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1, and typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.
- Familial pheochromocytoma/paraganglioma syndromes, associated with germline mutations of mitochondrial succinate dehydrogenase (SDH) complex genes (refer to Table 6). They are all inherited in an autosomal dominant manner but with varying penetrance.
- PGL1: Associated with SDHD mutations, manifests more commonly with head and neck paragangliomas, and has a very high penetrance, with more than 80% of carriers developing disease by age 50 years.
- PGL2: Associated with SDHAF2 mutations, is very rare, and generally manifests as parasympathetic paraganglioma.
- PGL3: Associated with SDHC mutations, is very rare, and usually presents with parasympathetic paraganglioma, often unifocal, benign, and in the head and neck.
- PGL4: Associated with SDHB mutations and usually manifests with intra-abdominal sympathetic paraganglioma. The neoplasms associated with this mutation have a much higher risk of malignant behavior, with more than 50% of patients developing metastatic disease. There is also an increased risk of renal cell carcinoma and gastrointestinal stromal tumor (GIST).
(Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.) - Other syndromes:
- Carney triad syndrome. Carney triad syndrome is a condition that includes three tumors: paraganglioma, GIST, and pulmonary chondromas. Pheochromocytomas and other lesions such as esophageal leiomyomas and adrenocortical adenomas have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of the patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately 20% of the cases. About 20% of the patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn’t appear to run in families; however, approximately 10% of the patients have germline variants in the SDHA, SDHB or SDHC genes.[53,54]
- Carney-Stratakis syndrome. Carney-Stratakis syndrome (Carney dyad syndrome) is a condition that includes paraganglioma and GIST, but not pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. Most patients with this syndrome have been found to carry germline mutations in the SDHB, SDHC, or SDHDgenes.[54]
- Other susceptibility genes recently discovered include KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX.[52]
These susceptibility genes can be divided into the following cluster groups on the basis of transcriptomic profiles:[55,56]
- Cluster 1: Resulting from mutations in genes encoding the VHL suppressor, the four subunits of SDH complex (SDHA, SDHB, SDHC, and SDHD), SDHAF2, and other less frequent enzymes.
- Cluster 2: Resulting from mutations in NF1, RET, TMEM127, and MAX.
Molecular Features
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:
- In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline mutation that involved the SDHB (n = 27; 55%), SDHD (n = 4; 8%), VHL (n = 6; 12%), or NF1 (n = 2; 4%) gene.[46] The incidence and type of mutation correlated with the site and extent of disease.
- The germline mutation rates for patients with nonmetastatic disease were lower than those observed in patients who had evidence of metastases (64% vs. 87.5%).
- Among patients with metastatic disease, the incidence of SDHB mutations was very high (72%) and most presented with disease in the retroperitoneum; five died of their disease.
- All patients with SDHD mutations had head and neck primary tumors.
- In another study, the incidence of germline mutations involving RET, VHL, SDHD and SDHB in patients with nonsyndromic paraganglioma was 70% for patients younger than 10 years and 51% among those aged 10 to 20 years.[57] In contrast, only 16% of patients older than 20 years had an identifiable mutation.[57]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).
- In a retrospective review of 55 patients younger than 21 years referred to the National Cancer Institute, 80% of patients had a germline mutation.[58]
- Most patients were found to have either the VHL (38%) or the SDHB (25%) mutation. Pheochromocytoma was present in 67% of the patients (37 of 55) and was bilateral in 51% of patients (19 of 37).
- Most patients with bilateral pheochromocytomas had VHL mutations (79%).
- A retrospective analysis from the European-American-Pheochromocytoma-Paraganglioma-Registry identified 177 patients with paraganglial tumors who were diagnosed before age 18 years.[59][Level of evidence: 3iiA]
- Eighty percent of registrants had germline mutations (49% with VHL, 15% with SDHB, 10% with SDHD, 4% with NF1, and one patient each with RET, SDHA, and SDHC).
- A second primary paraganglial tumor developed in 38% of patients, with increasing frequency over time, reaching 50% at 30 years from initial presentation.
- Prevalence of second tumors was higher in patients with hereditary disease. Sixteen patients (9%) with hereditary disease had malignant tumors, ten at initial presentation and another six during follow-up. Malignancy was associated with SDHB mutations. Eight patients (5%) died, all of whom had a germline mutation. Mean life expectancy was 62 years for patients with hereditary disease.
- A large retrospective review from tertiary medical centers identified 95 of 748 patients whose tumor first presented in childhood.[60]
- Children showed higher prevalence of hereditary (80.4% vs. 52.6%), extra-adrenal (66.3% vs. 35.1%), multifocal (32.6% vs. 13.5%), metastatic (49.5% vs. 29.1%), and recurrent (29.5% vs. 14.2%) pheochromocytoma or paraganglioma than did adults.
- Tumors caused by cluster 1 mutations, which are associated with the absence of epinephrine production, were more prevalent among children than adults (76% vs. 39%; P < .0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs. 57.3%).
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.
Clinical Presentation
Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production:
- Hypertension.
- Headache.
- Perspiration.
- Palpitations.
- Tremor.
- Facial pallor.
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).[47]
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.[47] 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).[60]
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.[63] 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.[46,48,63] 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.[60]
Diagnostic Evaluation
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging:
- Biochemical testing: Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when the diagnosis of a secreting paraganglioma or pheochromocytoma is suspected. A 24-hour urine collection for catecholamines (epinephrine, norepinephrine, and dopamine) and fractionated metanephrines can also be performed for confirmation.[64,65]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]
- Imaging: Imaging modalities available for the localization of paraganglioma and pheochromocytoma include the following:
- Computed tomography (CT).
- Magnetic resonance imaging.
- Iodine I 123 or iodine I 131-labeled metaiodobenzylguanidine (123/131I-MIBG) scintigraphy.
- Fluorine F 18-6-fluorodopamine (18F-6F-FDA) positron emission tomography (PET).
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
Treatment options for childhood paraganglioma and pheochromocytoma include the following:
- Surgery.
- Chemotherapy, for patients with metastatic disease.
- High-dose 131I-MIBG.
- Tyrosine kinase inhibitor therapy (sunitinib).
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.[70-72] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival (OS) is less clear.
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
- NCT02961491 (Expanded Access Program of Ultratrace Iobenguane I 131 for Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma): The purpose of this study is to provide expanded access to iobenguane I 131 for newly enrolled subjects with iobenguane-avid metastatic and/or recurrent pheochromocytoma/paraganglioma and to collect additional safety data.
- NCT01163383 (131I-MIBG Therapy for Refractory Neuroblastoma and Metastatic Paraganglioma/Pheochromocytoma): MIBG is a substance that is taken up by neuroblastoma or pheochromocytoma/paraganglioma tumor cells. MIBG is combined with radioactive iodine (131I) in the laboratory to form a radioactive compound, 131I-MIBG. This radioactive compound delivers radiation specifically to the cancer cells, causing them to die. The purpose of this research protocol is to provide a mechanism to deliver MIBG therapy when clinically indicated, but also to provide a mechanism to continue to collect efficacy and toxicity data that will be provided.
- NCT03165721 (A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine [SGI-110], in Children and Adults With Wild-Type GIST, Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer): Most people with GIST are treated with imatinib; however, it may not work in many children with GIST. Researchers hypothesize that the drug SGI-110 may help treat people with GIST, pheochromocytoma and paraganglioma, or kidney cancer related to hereditary leiomyomatosis and renal cell carcinoma. The objective of this trial is to determine whether SGI-110 shrinks tumors or slows tumor growth and to test how it acts in the body.
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] Melanomasection of this summary for information about uveal melanoma in children.)
Melanoma
Incidence
Melanoma, although rare, is the most common skin cancer in children, followed by BCCs and SCCs.[75-82] 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.[83]
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.[84] Melanoma annual incidence in the United States (2011–2015) increases with age, as follows:[85]
- Children younger than 10 years: <1.8 cases per 1 million.
- Children aged 10 to 14 years: 3.2 cases per 1 million.
- Children aged 15 to 19 years: 10.4 cases per 1 million.
The incidence of pediatric melanoma increased by an average of 1.7% per year between 1975 and 1994,[85] but then decreased by 0.6% per year from 1995 to 2014.[87] 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.[88]
Risk Factors
Conditions associated with an increased risk of developing melanoma in children and adolescents include the following:
- Giant melanocytic nevi.[78]
- Xeroderma pigmentosum (a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations).[78]
- Immunodeficiency or immunosuppression.[80]
- Hereditary retinoblastoma.[89]
- Werner syndrome.[90,91]
- Neurocutaneous melanosis. Neurocutaneous melanosis is an unusual condition that arises in the context of congenital melanocytic nevi and is associated with large or multiple congenital nevi of the skin in association with meningeal melanosis or melanoma; approximately 2.5% of patients with large congenital nevi develop this condition, and those with increased numbers of satellite nevi are at greatest risk.[92,93]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.[94]
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:[95-101]
- Exposure to UV sunlight.
- Red hair.
- Blue eyes.
- Poor tanning ability.
- Freckling.
- Dysplastic nevi.
- Increased number of melanocytic nevi.
- Family history of melanoma.
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.[102]
In a prospective study of 60 families who had more than three members with melanoma,[103] 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.[104] 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,[98] but this result was not duplicated in another study from the National Cancer Database.[106]
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.[109] Studies addressing nodal involvement and the lack of effect on outcome include the following:
- Younger patients appear to have a higher incidence of nodal involvement; this finding does not appear to significantly impact clinical outcome in this population.[108,110]
- In other series of pediatric melanoma, a higher incidence of nodal involvement did not appear to impact survival.[111-113]
- In a retrospective cohort study from the National Cancer Database, all records of patients with an index diagnosis of melanoma from 1998 to 2011 were reviewed. The data were abstracted from medical records, operative reports, and pathology reports and did not undergo central review. A total of 350,928 patients with adequate information were identified; 306 patients were aged 1 to 10 years (pediatric), and 3,659 patients were aged 11 to 20 years (adolescent).[114] Pediatric patients had longer OS than did adolescent patients (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.25–0.98) and patients older than 20 years (HR, 0.11; 95% CI, 0.06–0.21). Adolescents had longer OS than did adults. No difference in OS was found between pediatric node-positive patients and node-negative patients. In pediatric patients, sentinel lymph node biopsy and completion of lymph node dissection were not associated with increased OS. In adolescents, nodal positivity was a significant negative prognostic indicator (HR, 4.82; 95% CI, 3.38–6.87).[114]
The association of thickness with clinical outcome is controversial in pediatric melanoma.[98,105,106,115-119] 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]
Diagnostic Evaluation
The diagnostic evaluation of melanoma includes the following:
- Biopsy or excision. Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Although BCCs and SCCs are generally curable with surgery alone, the treatment of melanoma requires greater consideration because of its potential for metastasis. The width of surgical margins in melanoma is dictated by the site, size, and thickness of the lesion and ranges from 0.5 cm for in situ lesions to 2 cm or more for thicker lesions.[78] To achieve negative margins in children, wide excision with skin grafting may become necessary in selected cases.
- Lymph node evaluation. Examination of regional lymph nodes using sentinel lymph node biopsy has become routine in many centers [122,123] and is recommended in patients with lesions measuring more than 1 mm in thickness or in those whose lesions are 1 mm or less in thickness and have unfavorable features such as ulceration or mitotic rate of 1 per mm2 or higher.[122,124,125] However, the indications for this procedure in patients with spitzoid melanomas has not been clearly defined. In a systematic review of 541 patients with atypical Spitz tumors, 303 (56%) underwent sentinel lymph node biopsy and 119 (39%) had a positive sentinel node; additional lymph node dissection in 97 of these patients revealed additional positive nodes in 18 patients (19%).[126] Despite the high incidence of nodal metastases, only six patients developed disseminated disease, questioning the prognostic and therapeutic benefit of this procedure in children with these lesions. In the future, molecular markers may help identify which patients might benefit from this procedure.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 Treatmentfor 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.[127]
The diagnosis of pediatric melanoma may be difficult and many of these lesions may be confused with the so-called MELTUMP.[128] 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).[130][Level of evidence: 3iiA]
Molecular Features
Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into the following three general groups:[131]
- Large/giant congenital melanocytic nevus.
- Spitzoid melanocytic tumors ranging from atypical Spitz tumors to spitzoid melanomas.
- Melanoma arising in older adolescents that shares characteristics with adult melanoma (i.e., conventional melanoma).
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.[131] 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 light damage. In addition, two-thirds of the cases had MC1Rvariants associated with an increased susceptibility to melanoma.
The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes, including RET, ROS1, NTRK1, ALK, MET, and BRAF.[132-134] These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner.[131,133] 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 TERTpromoter status in predicting clinical behavior in patients with primary site spitzoid tumors.
Treatment
Treatment options for childhood melanoma include the following:
- Surgery and, in certain cases, sentinel lymph node biopsy and lymph node dissection.
- Immune checkpoint inhibitors or BRAF/MEK inhibitors.
Surgery
Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:
- 0.5 cm for melanoma in situ.
- 1 cm for melanoma thickness less than 1 mm.
- 1 cm to 2 cm for melanoma thickness of 1.01 mm to 2 mm.
- 2 cm for tumor thickness greater than 2 mm.
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.[137]
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.[138-140] 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):
- A phase I trial of ipilimumab in children and adolescents, which used a dose of 5 mg/kg or 10 mg/kg every 3 weeks for four cycles, enrolled 12 patients with melanoma.[141]
- This treatment demonstrated a similar toxicity profile as that seen in adults.
- A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed; however, there was reported activity in patients with melanoma who were aged 12 years to younger than 18 years, with a similar safety profile as that seen in adults.[142][Level of evidence: 2Div]
- At 1 year, three of four patients who received 3 mg/kg and five of eight patients who received 10 mg/kg were alive.
- Two patients who received 10 mg/kg had partial responses, and one patient who received 3 mg/kg had stable disease.
- In adults, ipilimumab administered at a dose of 10 mg/kg every 3 weeks for four doses followed by one dose every 3 months for up to 3 years has been shown to prolong DFS and OS in patients with completely resected, stage III cutaneous melanoma, with little impairment in health-related quality of life.
- Ipilimumab and nivolumab or nivolumab alone, as well as combinations of BRAF and MEK inhibitors for BRAF-mutant melanoma, have now become the standard of care for adult patients with advanced-stage melanoma.[137,143-146]
The studies listed below are investigating the activity of targeted BRAF inhibitors, MEK inhibitors, and PDL-1 inhibitors in pediatric patients with melanoma.[147,148]
(Refer to the PDQ summary on adult Melanoma Treatment for more information.)
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
- NCT02332668 (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1 (PDL1)-positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.
- NCT02304458 (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): This trial is evaluating the side effects and best dose of nivolumab when given with or without ipilimumab to see how well they work in treating younger patients with solid tumors.
- NCT01677741 (A Study to Determine Safety, Tolerability, and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects): This is a two-part study to determine the safety, tolerability, and pharmacokinetics of oral dabrafenib in children and adolescent patients with advanced BRAF V600 mutation–positive solid tumors. Part 1 will identify the recommended dose and regimen using a dose-escalation procedure. Part 2 will treat four disease-specific cohorts of patients with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis, and other tumors such as melanoma and papillary thyroid carcinoma) using the dose and regimen determined in part 1.
BCC and SCC
Incidence and Risk Factors
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.[149]
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.[150] Gorlin syndrome is a rare disorder with a predisposition to the development of early-onset neoplasms, including BCC, ovarian fibroma, and desmoplastic medulloblastoma.[151-154]
Clinical Presentation
BCCs generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure.[155] These tumors may be multiple and exacerbated by radiation therapy.[156] SCCs are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.
Diagnostic Evaluation
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
Treatment options for nonmelanoma skin cancer include the following:
- Surgery.
Treatment for nonmelanoma skin cancer is predominantly surgical, either surgical excision or Mohs micrographic surgery.[150]
Most BCCs have activation of the hedgehog pathway, generally resulting from mutations in PTCH1.[157] Vismodegib (GDC-0449), a hedgehog pathway inhibitor, has been approved for the treatment of adult patients with metastatic or advanced BCC.[158-160] This drug also reduces the tumor burden in patients with basal cell nevus syndrome.[161]
(Refer to the PDQ summary on adult Skin Cancer Treatment for more information.)
Treatment Options Under Clinical Evaluation
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:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
Intraocular (Uveal) Melanoma
Incidence and Risk Factors
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.[162] This tumor is most commonly diagnosed in older patients, and the incidence peaks at age 70 years.[163]
Pediatric uveal melanoma is extremely rare and accounts for 0.8% to 1.1% of all cases of uveal melanoma.[164] 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.[164] 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.[165,166]
- Light eye color.
- Fair skin color.
- Inability to tan.
- Oculodermal melanocytosis.
- Presence of cutaneous nevi.
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).[164] 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.[170]
Molecular Features
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 SF3B1and EIF1AX are associated with a good prognosis.[171-176]
Treatment and Outcome
Treatment options for intraocular (uveal) melanoma include the following:
- Surgery.
- Radiation therapy.
- Laser surgery.
(Refer to the PDQ summary on Intraocular [Uveal] Melanoma Treatment for information on the treatment of uveal melanoma in adults.)
Treatment Options Under Clinical Evaluation
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:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
Chordoma
Incidence
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.[177] 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.[178,179] Most pediatric patients have the classical or chondroid variant of chordoma, while the dedifferentiated variant is rare in children.[178,180]
Prognosis
Younger children appear to have a worse outlook than do older patients.[178,181-185] The survival rate in children and adolescents ranges from about 50% to 80% for cranial chordomas.[178,182,184] A retrospective literature review and review of institutional patients identified 682 patients with chordomas of the spine, with a median age of 57 years.[186][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.[187][Level of evidence: 3iiiA]
A retrospective analysis identified seven children with poorly differentiated chordomas.[188][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.
Clinical Presentation
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.[189]
Treatment
Treatment options for chordoma include the following:
- Surgery.
- Radiation therapy.
Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[184,190] 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.[191][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.[192,193]; [184,194][Level of evidence: 3iiA]; [195][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.[196,197] 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.[198,199] 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.[199] 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.[199] Other tyrosine kinase inhibitors and combinations involving kinase inhibitors have been studied in adults.[200-202] 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.[203]
Recurrences are usually local but can include distant metastases to lungs or bone.
Treatment Options Under Clinical Evaluation
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:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.Patients with chordomas and SMARCB1 mutations may be offered treatment with tazemetostat on the APEC1621C (NCT03213665) treatment arm of this trial.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.
Cancer of Unknown Primary Site
Incidence and Clinical Presentation
Children represent less than 1% of all solid cancers of unknown primary site and because of the age-related incidence of tumor types, embryonal histologies are more common in this age group.[204]
Cancers of unknown primary site present as a metastatic cancer for which a precise primary tumor site cannot be determined.[205] 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.
Diagnostic Evaluation
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.[205]
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.[206] 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.[207]
Treatment
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.[213]
(Refer to the PDQ summary on adult Carcinoma of Unknown Primary Treatment for more information.)
Treatment Options Under Clinical Evaluation
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:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.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.
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- Singh AD, De Potter P, Fijal BA, et al.: Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology 105 (1): 195-8, 1998. [PUBMED Abstract]
- Yousef YA, Alkilany M: Characterization, treatment, and outcome of uveal melanoma in the first two years of life. Hematol Oncol Stem Cell Ther 8 (1): 1-5, 2015. [PUBMED Abstract]
- Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010. [PUBMED Abstract]
- Harbour JW, Onken MD, Roberson ED, et al.: Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330 (6009): 1410-3, 2010. [PUBMED Abstract]
- Gupta MP, Lane AM, DeAngelis MM, et al.: Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. JAMA Ophthalmol 133 (8): 881-7, 2015. [PUBMED Abstract]
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- Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009. [PUBMED Abstract]
- Sebro R, DeLaney T, Hornicek F, et al.: Differences in sex distribution, anatomic location and MR imaging appearance of pediatric compared to adult chordomas. BMC Med Imaging 16 (1): 53, 2016. [PUBMED Abstract]
- Hoch BL, Nielsen GP, Liebsch NJ, et al.: Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases. Am J Surg Pathol 30 (7): 811-8, 2006. [PUBMED Abstract]
- Lau CS, Mahendraraj K, Ward A, et al.: Pediatric Chordomas: A Population-Based Clinical Outcome Study Involving 86 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (1973-2011). Pediatr Neurosurg 51 (3): 127-36, 2016. [PUBMED Abstract]
- McMaster ML, Goldstein AM, Bromley CM, et al.: Chordoma: incidence and survival patterns in the United States, 1973-1995. Cancer Causes Control 12 (1): 1-11, 2001. [PUBMED Abstract]
- Coffin CM, Swanson PE, Wick MR, et al.: Chordoma in childhood and adolescence. A clinicopathologic analysis of 12 cases. Arch Pathol Lab Med 117 (9): 927-33, 1993. [PUBMED Abstract]
- Borba LA, Al-Mefty O, Mrak RE, et al.: Cranial chordomas in children and adolescents. J Neurosurg 84 (4): 584-91, 1996. [PUBMED Abstract]
- Jian BJ, Bloch OG, Yang I, et al.: A comprehensive analysis of intracranial chordoma and survival: a systematic review. Br J Neurosurg 25 (4): 446-53, 2011. [PUBMED Abstract]
- Yasuda M, Bresson D, Chibbaro S, et al.: Chordomas of the skull base and cervical spine: clinical outcomes associated with a multimodal surgical resection combined with proton-beam radiation in 40 patients. Neurosurg Rev 35 (2): 171-82; discussion 182-3, 2012. [PUBMED Abstract]
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- Tsitouras V, Wang S, Dirks P, et al.: Management and outcome of chordomas in the pediatric population: The Hospital for Sick Children experience and review of the literature. J Clin Neurosci 34: 169-176, 2016. [PUBMED Abstract]
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- McMaster ML, Goldstein AM, Parry DM: Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet 48 (7): 444-9, 2011. [PUBMED Abstract]
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- Stacchiotti S, Longhi A, Ferraresi V, et al.: Phase II study of imatinib in advanced chordoma. J Clin Oncol 30 (9): 914-20, 2012. [PUBMED Abstract]
- Lindén O, Stenberg L, Kjellén E: Regression of cervical spinal cord compression in a patient with chordoma following treatment with cetuximab and gefitinib. Acta Oncol 48 (1): 158-9, 2009. [PUBMED Abstract]
- Singhal N, Kotasek D, Parnis FX: Response to erlotinib in a patient with treatment refractory chordoma. Anticancer Drugs 20 (10): 953-5, 2009. [PUBMED Abstract]
- Stacchiotti S, Marrari A, Tamborini E, et al.: Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 20 (11): 1886-94, 2009. [PUBMED Abstract]
- Lebellec L, Chauffert B, Blay JY, et al.: Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF). Eur J Cancer 79: 119-128, 2017. [PUBMED Abstract]
- Pavlidis N, Pentheroudakis G: Cancer of unknown primary site. Lancet 379 (9824): 1428-35, 2012. [PUBMED Abstract]
- Kuttesch JF Jr, Parham DM, Kaste SC, et al.: Embryonal malignancies of unknown primary origin in children. Cancer 75 (1): 115-21, 1995. [PUBMED Abstract]
- Bohuslavizki KH, Klutmann S, Kröger S, et al.: FDG PET detection of unknown primary tumors. J Nucl Med 41 (5): 816-22, 2000. [PUBMED Abstract]
- Han A, Xue J, Hu M, et al.: Clinical value of 18F-FDG PET-CT in detecting primary tumor for patients with carcinoma of unknown primary. Cancer Epidemiol 36 (5): 470-5, 2012. [PUBMED Abstract]
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Changes to This Summary (06/04/2019)
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.
Added text to state that 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 (cited Sisdelli et al. as reference 80).
Added text about DICER1 mutations to state that conventional alterations were found in 12 of 30 papillary thyroid carcinomas. Pathogenic mutations of DICER1 have been identified in approximately 10% of papillary thyroid carcinomas (cited Wasserman et al. as reference 81).
Added text about the results of a retrospective analysis that identified 167 children with RETmutations who underwent prophylactic thyroidectomy (cited Machens et al. as reference 101).
Added text to state that a subsequent report from the Surveillance, Epidemiology, and End Results (SEER) database discovered 91 girls aged 10 to 20 years with breast cancer, predominantly carcinomas and sarcomas. 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 (cited Murthy et al. as reference 14 and level of evidence 3iiA).
Revised text to state that 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.
Revised text to state that primary malignant pediatric heart tumors include various sarcomas, such as rhabdomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, and infantile fibrosarcoma (cited Ostrowski et al. as reference 107).
Added text to state that radiation therapy is a rare treatment option for patients with unresectable disease. Radiation therapy is used with the intent of preventing progression because it is unlikely to produce full disease resolution (cited Movsas et al., Simpson et al, Mery et al., and Zerkowski et al. as references 120, 121, 122, and 123, respectively).
Added Gupta et al. as reference 26.
Added text to state that a retrospective review of the National Cancer Database identified 21 pediatric patients 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 (cited Leraas et al. as reference 61).
Added text to state that 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 (cited Overman et al. as reference 106).
Added Hampel and Briggs et al. as references 112 and 113, respectively.
Added Broderick et al. as reference 114.
Added text to state that 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 and genetic counseling should be considered (cited Schultz et al. as reference 62).
Added Baykara et al. as reference 75.
Added Vannucci et al. and Thakker et al. as references 8 and 9, respectively.
Added text to state that familial melanoma comprises 8% to 12% of melanoma cases. p16germline 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 (cited Soufir et al. as reference 102).
Added text to state that patients who present with conventional or adult-type melanoma should undergo laboratory and imaging evaluations on the basis of adult guidelines. 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 (cited Halalsheh et al. as reference 127).
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.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of unusual cancers of childhood. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Unusual Cancers of Childhood Treatment are:
- Denise Adams, MD (Children's Hospital Boston)
- Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
- Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
- Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
- Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
- Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
- Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Unusual Cancers of Childhood Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/hp/unusual-cancers-childhood-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389315]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
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