Unusual Cancers of Childhood Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version

Head and Neck Cancers

Childhood sarcomas often occur in the head and neck area and they are described in other sections. Unusual pediatric head and neck cancers include 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

Incidence

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.[3-5]

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]

Risk Factors

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.[6] The circulating levels of EBV DNA and serologic documentation of EBV infection may aid in the diagnosis.[7] Specific HLA subtypes, such as the HLA A2Bsin2 haplotype, are associated with a higher risk of nasopharyngeal carcinoma.[1]

Histology

Three histologic subtypes of nasopharyngeal carcinoma are recognized by the World Health Organization (WHO):

Type I—keratinizing squamous cell carcinoma.
Type II—nonkeratinizing squamous cell carcinoma. Type II is distinguished by the presence of lymphoid infiltration as type IIa or IIb.
Type III—undifferentiated carcinoma. Type III is distinguished by the presence of lymphoid infiltration as type IIIa or IIIb.

Children with nasopharyngeal carcinoma are more likely to have WHO type II or type III disease.[4,5]

Clinical Presentation

Signs and symptoms of nasopharyngeal carcinoma include the following:[2,8]

Cervical lymphadenopathy.
Nosebleeds.
Nasal congestion and obstruction.
Headache.
Otalgia.
Otitis media.

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.[9]

Stage Information for Childhood Nasopharyngeal Carcinoma

Tumor staging is performed using the tumor-node-metastasis (TNM) classification systemof 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.[12-14]

Prognosis

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%.[4,5,8,12-16] 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:

Combined-modality therapy with chemotherapy and radiation. High-dose radiation therapy alone has a role in the management of nasopharyngeal carcinoma; however, studies in both children and adults show that combined-modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.
1. Several studies have investigated the role of chemotherapy in the treatment of adult nasopharyngeal carcinoma. The use of concomitant chemoradiation therapy has been consistently associated with a significant survival benefit, including improved locoregional disease control and reduction in distant metastases.[17-19] The addition of neoadjuvant chemotherapy to concomitant chemoradiation has further improved outcomes, whereas the impact of adjuvant chemotherapy is less defined.[18,19]
2. In children, most studies have used neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (5-FU) followed by concomitant chemoradiation with single-agent cisplatin.[13,14,20][Level of evidence: 2A] Using this approach, 5-year overall survival (OS) estimates are consistently above 80%.[14,20]
  The following two modifications of this approach have been investigated:
  - The NPC-2003-GPOH study included a 6-month maintenance therapy phase with interferon-beta, and reported a 30-month OS estimate of 97.1%.[14]
  - A randomized prospective trial compared cisplatin and 5-FU with cisplatin, 5-FU, and docetaxel.[20][Level of evidence: 1iiA] The addition of docetaxel was not associated with improved outcome.
3. While nasopharyngeal carcinoma is a very chemosensitive neoplasm, high radiation doses to the nasopharynx and neck (approximately 65–70 Gy) are required for optimal locoregional control.[17-19] However, in children, studies using neoadjuvant chemotherapy have shown that it is possible to reduce the radiation dose to 55 Gy to 60 Gy for good responders.[13,14]
Surgery. Surgery has a limited role in the management of nasopharyngeal carcinoma; the disease is usually considered unresectable because of extensive local spread.

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]; [8][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%.[21]

Given the unique pathogenesis of nasopharyngeal carcinoma, immunotherapy has been explored for patients with refractory disease, as follows:

The use of Epstein-Barr virus (EBV)–specific cytotoxic T-lymphocyte therapy has shown to be a very promising approach with minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.[22] In a phase I/II study of EBV-specific cytotoxic T-lymphocyte therapy in patients with refractory disease, response rates were observed in 33.3% of patients, and long-term remissions were obtained in 62% of patients treated in their second or subsequent remission.[23]
Anti–programmed death-ligand 1 (PD-L1) monoclonal antibodies have been studied in two phase II trials in adults with refractory nasopharyngeal carcinoma, with response rates of 20.5% to 25.9% (33% in patients with PD-L1–positive tumors) and evidence of long-term remissions.[24,25]

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:

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.

Esthesioneuroblastoma

Incidence

Esthesioneuroblastoma (also termed olfactory neuroblastoma) is a small round cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[35-38] 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.[39]

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.[40] 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.[41] Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%).[41] 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.[42]

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.[43]

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:[44]

The largest cluster, which comprised 64% of the samples, had classical histologic features of olfactory neuroblastoma and 10% had recurrent DNMT3A and TP53mutations.
A second cluster consisted of seven cases with a hypermethylator phenotype and IDH2mutations that clustered with the group of IDH2 sinonasal carcinomas.
A small third cluster was characterized by hypermethylation without IDH2 mutations, suggesting that this may represent a subgroup of olfactory neuroblastomas or an undefined sinonasal tumor entity.
The fourth cluster represented a heterogenous group of 13 tumors that clustered with other entities such as sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma.

Using this information, the authors developed an algorithm that incorporates methylation analysis to improve the diagnostic accuracy of this entity.[44]

Clinical Presentation

Most children present in the second decade of life with symptoms that include the following:

Nasal obstruction.
Epistaxis.
Hyposmia.
Exophthalmos.
Nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe.

Prognostic Factors

Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[45-47]

Higher histopathologic grade.
Positive surgical margin status.
Metastases to the cervical lymph nodes.

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.[48]

Table 1. Kadish Staging System

Stage	Description
A	Tumor confined to the nasal cavity.
B	Tumor extending to the nasal sinuses.
C	Tumor extending to the nasal sinuses and beyond.
D	Tumor metastases present.

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%.[42][Level of evidence: 3iiiA]

Treatment options according to Kadish stage include the following:[51]

Kadish stage A: Surgery alone with clear margins. Adjuvant radiation therapy is indicated in patients with close and positive margins or with residual disease.
Kadish stage B: Surgery followed by adjuvant radiation therapy. The role of adjuvant chemotherapy is controversial.
Kadish stage C: Neoadjuvant approach with chemotherapy, radiation therapy, or concurrent chemotherapy-radiation therapy followed by surgery.
Kadish stage D: Systemic chemotherapy and radiation therapy to local and metastatic sites.

The mainstay of treatment is surgery and radiation.[52] Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection.[41]; [53][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.[55] Management of cervical lymph node metastases has been addressed in a review article.[55]

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]; [58][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;[49] vincristine, doxorubicin, and cyclophosphamide;[60] and irinotecan plus docetaxel.[61][Level of evidence: 3iiA]

Treatment Options Under Clinical Evaluation for Childhood Esthesioneuroblastoma

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

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.

Thyroid Tumors

Incidence

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.[64] The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.[65]

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.[66]

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).[62]

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).[63]

Chart showing the incidence of pediatric thyroid carcinoma based on most frequent subtype per 100,000 as a percent of total cohort. — 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 Exit Disclaimer, 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

Risk factors for pediatric thyroid cancer include the following:

Radiation exposure. There is an excessive frequency of papillary thyroid adenoma and carcinoma after radiation exposure, either as result of environmental contamination or use of ionizing radiation for diagnosis or treatment.[67-70] (Refer to the Subsequent Neoplasms section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.) The risk increases after exposure to a mean dose of more than 0.05 Gy to 0.1 Gy (50–100 mGy), and follows a linear dose-response pattern up to 30 Gy and then declines, which is greater at younger age of exposure and persists more than 45 years after exposure.[70,71]
Papillary thyroid carcinoma is the most frequent form of thyroid carcinoma diagnosed after radiation exposure.[71] Molecular alterations, including intrachromosomal rearrangements, are frequently found; among them, RET/PTC rearrangements are the most common.[71]
Genetic inheritance. Genetic inheritance plays a role in a subset of thyroid carcinomas. In children, medullary thyroid carcinoma is caused by a dominantly inherited or de novo gain-of-function mutation in the RET proto-oncogene associated with multiple endocrine neoplasia (MEN) type 2, either MEN2A or MEN2B, depending on the specific mutation.[72] When occurring in patients with the MEN syndromes, thyroid cancer may be associated with the development of other types of malignant tumors. (Refer to the Multiple Endocrine Neoplasia [MEN] Syndromes and Carney Complex section of the PDQ summary on Unusual Cancers of Childhood Treatment for more information.)
Family history. For thyroid carcinomas of follicular cells, only 5% to 10% are familial cancers. Of those, most familial cases are nonsyndromic, while only a minority occur in the setting of well-defined cancer syndromes with known germline alterations, including the following:[73,74]
- APC-associated polyposis.
- Carney complex.
- PTEN hamartoma tumor syndrome.
- Werner syndrome.
- DICER1 syndrome.

Histology

Tumors of the thyroid are classified as adenomas or carcinomas.[75-77] 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.[74,75]

The following histologies account for the general diagnostic category of carcinoma of the thyroid:

Differentiated thyroid carcinoma: Papillary and follicular carcinoma are often referred to as differentiated thyroid carcinoma. The pathological classification of differentiated thyroid carcinomas in children is based on standard definitions set by the World Health Organization, and the criteria are the same for children and adults. Long-term outcomes for children and adolescents with differentiated thyroid carcinoma are excellent, with 10-year survival rates exceeding 95%.[62,63,74]
- Papillary thyroid carcinoma: Papillary thyroid carcinoma accounts for 90% or more of all cases of differentiated thyroid carcinoma occurring during childhood and adolescence. Pediatric papillary thyroid carcinoma may present with a variety of histological variants: classic, solid, follicular, and diffuse sclerosing. Papillary thyroid carcinoma is frequently multifocal and bilateral, and metastasizes to regional lymph nodes in most children. Hematogenous metastases to the lungs occur in up to 25% of cases.[74]
- Follicular thyroid cancer: Follicular thyroid cancer is uncommon. It is typically a unifocal tumor and more prone to initial hematogenous metastases to lungs and bones. Metastases to regional lymph nodes are uncommon. Histologic variants of follicular thyroid cancer include Hürthle cell (oncocytic), clear cell, and insular (poorly differentiated) carcinoma.[74]
Medullary thyroid carcinoma: Medullary thyroid carcinoma is a rare form of thyroid carcinoma that originates from the calcitonin-secreting parafollicular C cells and accounts for less than 10% of all cases of thyroid carcinoma in children.[63] In children, medullary thyroid carcinoma is usually associated with RET germline mutations in the context of multiple endocrine neoplasia type 2 syndrome.[78]
Anaplastic carcinoma: Less than 1% of pediatric thyroid carcinomas are anaplastic carcinoma.

Molecular Features

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:[72,73,79]

BRAF: Point mutations of the BRAF gene are the most common alteration found in thyroid carcinoma; the most common mutation is V600E (95% of BRAF-mutated cases). BRAF mutations are found in 40% to 80% of papillary thyroid carcinomas, and in a lower proportion of poorly-differentiated papillary thyroid carcinoma (5%–35%) and anaplastic thyroid carcinoma (10%–50%).[73,79]
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).[73,79]
A retrospective analysis of 80 Brazilian patients younger than 18 years with papillary thyroid carcinoma identified AGK-BRAF fusions and BRAF V600E point mutations.[80]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.
RAS: Oncogenic RAS activation can occur in any of the RAS family of genes (NRAS, HRAS, and KRAS) although the most frequent alterations are NRAS point mutations. RASmutations are markers of follicular-patterned thyroid lesions; they are present in 30% to 50% of follicular thyroid carcinoma and in 25% to 45% of follicular variants of papillary thyroid carcinoma, while they are seen in less than 10% of papillary thyroid carcinoma. They are also frequently found in poorly differentiated papillary thyroid carcinoma (20%–50%) and anaplastic thyroid carcinoma (10%–50%) and are believed to promote tumor progression. They have a higher prevalence in areas of iodine deficiency.[73,79]
RET-PTC rearrangements: Multiple RET-PTC rearrangements have been identified in approximately 5% to 25% of papillary thyroid carcinomas and in less than 10% of its follicular variant. They are strongly associated with environmental or therapeutic radiation exposure and are also common among young patients, many of whom present with nodal metastases and aggressive clinicopathological features. [73,79]
NTRK rearrangements: Rearrangements of NTRK1 and NTRK3 have been described in approximately 5% of papillary thyroid carcinomas; however, ETV6-NTRK3 has been reported in 15% of radiation-induced papillary thyroid carcinomas. In young patients and children, NTRK-rearranged papillary thyroid carcinomas may present with lymph node metastases and aggressive clinicopathological features, similar to the presentation of RET-rearranged tumors.[73,79]
DICER1 mutations: Conventional alterations were found in 12 of 30 (40%) papillary thyroid carcinomas (five cases with BRAF V600E, three cases with RET/PTC1, and four cases with RET/PTC3). Pathogenic mutations of DICER1 have been identified in approximately 10% of papillary thyroid carcinomas.[81]

Other alterations include the following:[73,79]

ALK rearrangements have been described in less than 10% of papillary thyroid carcinomas and are commonly associated with dedifferentiation.
Activating mutations of AKT1 have been described in 19% of recurrent or metastatic poorly differentiated papillary thyroid carcinoma.
PPARG rearrangements are present in 20% to 50% of follicular thyroid carcinoma and in a lower proportion of follicular variants of papillary thyroid carcinoma.
TERT-activating mutations are commonly seen in poorly differentiated papillary thyroid carcinoma (20%–50%) and anaplastic thyroid carcinoma (30%–75%), and have also been reported in 10% to 35% of follicular thyroid carcinomas and 5% to 15% of papillary thyroid carcinomas. TERT mutations are believed to promote tumor progression to poorly differentiated papillary thyroid carcinoma and anaplastic thyroid carcinoma and represent a negative prognostic marker.
TP53 is mutated in 40% to 80% of anaplastic thyroid carcinomas and 10% to 35% of poorly differentiated papillary thyroid carcinoma; it is considered to be a final step of tumor progression and a marker for poor prognosis.

The spectrum of somatic genetic alterations seems to be different between pediatric and adult patients when analyzing tumors with similar histologies, as follows:[72]

Gene fusions involving RET or, less frequently, NTRK account for approximately 50% of the molecular alterations in pediatric differentiated thyroid carcinoma, compared with approximately 15% in adults.
Point mutations involving BRAF or RAS, which are the defining alterations in approximately 70% of thyroid carcinomas diagnosed in adults, are noted in 30% to 40% of pediatric tumors; BRAF mutations have been described in approximately 30% of cases, while RAS mutations are much less frequently found in pediatrics (5%–10%).

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.[72]

Clinical Presentation and Prognostic Factors

Differentiated Thyroid Carcinoma

Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[82] 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.[73,74]

Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. The following observations have been reported:

In a cross-sectional study involving 20% of community hospitals in the United States, the clinical presentation of 644 pediatric cases was compared with that of more than 43,000 adult cases. Compared with adults, children had a higher proportion of nodal involvement (31.5% in children vs. 14.7% in adults) and lung metastases (5.7% in children vs. 2.2% in adults).[82]
Higher recurrence rates have been associated with younger age at presentation.[83]
Larger tumor size (>1 cm), extrathyroidal extension, and multifocal disease are associated with increased risk of nodal metastases.[84]
When compared with pubertal adolescents, prepubertal children have a more aggressive presentation with a greater degree of extrathyroid extension, lymph node involvement, and lung metastases. However, outcome is similar in the prepubertal and adolescent groups.[85]

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.[86] 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.[87]

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.[88]

Medullary Thyroid Carcinoma

Children with medullary thyroid carcinoma present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis.[89] 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.[90]

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 RETmutation.[72,91] (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.[91]

Diagnostic Evaluation

Initial evaluation of a child or adolescent with a thyroid nodule includes the following:

Ultrasound of the thyroid.
Serum thyroid-stimulating hormone (TSH) level.
Serum thyroglobulin level.

Tests of thyroid function are usually normal, but thyroglobulin can be elevated.

Fine-needle aspiration as an initial diagnostic approach is sensitive and useful. However, in doubtful cases, open biopsy or resection should be considered.[74]

Treatment of Papillary and Follicular Thyroid Carcinoma

Treatment options for papillary and follicular (differentiated) thyroid carcinoma include the following:

Surgery.
Radioactive iodine ablation.

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.[74]

Preoperative evaluation.[74]
1. A comprehensive ultrasound of all regions of the neck using a high-resolution probe and Doppler technique should be obtained by an experienced ultrasonographer. A complete ultrasound examination should be performed before surgery.
2. The addition of cross-sectional imaging (contrast-enhanced computed tomography [CT] or magnetic resonance imaging) should be considered when there is concern about invasion of the aerodigestive tract. Importantly, if iodinated contrast agents are used, further evaluation and treatment with radioactive iodine may need to be delayed for 2 to 3 months until total body iodine burden decreases.
3. Chest imaging (x-ray or CT) may be considered for patients with substantial cervical lymph node disease.
4. Thyroid nuclear scintigraphy should be pursued only if the patient presents with a suppressed thyroid-stimulating hormone (TSH).
5. The routine use of bone scan or fluorine F 18-fludeoxyglucose positron emission tomography (PET) is not recommended.
Surgery.[74]
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.
1. Thyroidectomy:
  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.[92]
  Total thyroidectomy also optimizes the use of radioactive iodine for imaging and treatment.
2. Central neck dissection:
  - A therapeutic central neck lymph node dissection should be done in the presence of clinical evidence of central or lateral neck metastases.[84]
  - For patients without clinical evidence of gross extrathyroidal invasion or locoregional metastasis, a prophylactic central neck dissection may be considered on the basis of tumor focality and size of the primary tumor. However, because of the increased morbidity associated with central lymph node dissection, it is important to carefully individualize each case on the basis of the risks and benefits of the extent of dissection.[93]
3. Lateral neck dissection:
  - Cytological confirmation of metastatic disease to lymph nodes in the lateral neck is recommended before surgery.
  - Routine prophylactic lateral neck dissection is not recommended.
Classification and risk assignment.[74]
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.
1. ATA Pediatric Low Risk: Disease confined to the thyroid with N0 or NX disease or patients with incidental N1a (microscopic metastasis to a small number of central neck nodes). These patients are at lowest risk of distant disease but may still be at risk of residual cervical disease, especially if the initial surgery did not include central neck dissection.
2. ATA Pediatric Intermediate Risk: Extensive N1a or minimal N1b disease. These patients are at low risk of distant metastasis but are at an increased risk of incomplete lymph node resection and persistent cervical disease.
3. ATA Pediatric High Risk: Regionally extensive disease (N1b) or locally invasive disease (T4), with or without distant metastasis. Patients in this group are at the highest risk of incomplete resection, persistent disease, and distant metastasis.
Postoperative staging and long-term surveillance.[74]
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.
1. ATA Pediatric Low Risk:
  - Initial postoperative staging includes a TSH-suppressed thyroglobulin. A diagnostic iodine I 123 (123I) scan is not required.
  - TSH suppression should be targeted to serum levels of 0.5 to 1.0 mIU/L.
  - In patients with no evidence of disease, surveillance should include ultrasound at 6 months postoperatively and then annually for 5 years; and thyroglobulin levels (on hormone replacement therapy) every 3 to 6 months for 2 years and then annually.
2. ATA Pediatric Intermediate Risk:
  - Initial postoperative staging includes a TSH-stimulated thyroglobulin and diagnostic 123I whole-body scan for further stratification and determination with 131I.
  - TSH suppression should be targeted to serum levels of 0.1 to 0.5 mIU/L.
  - In patients with no evidence of disease, surveillance should include ultrasound at 6 months postoperatively and then every 6 to 12 months for 5 years (and then less frequently); and thyroglobulin levels (on hormone replacement therapy) every 3 to 6 months for 3 years and then annually.
  - TSH-stimulated thyroglobulin and diagnostic 123I scan should be considered in 1 to 2 years for patients treated with 131I.
3. ATA Pediatric High Risk:
  - Initial postoperative staging includes a TSH-stimulated thyroglobulin and diagnostic 123I whole-body scan for further stratification and determination with 131I.
  - TSH suppression should be targeted to serum levels of less than 0.1 mIU/L.
  - In patients with no evidence of disease, surveillance should include ultrasound at 6 months postoperatively and then every 6 to 12 months for 5 years (and then less frequently); and thyroglobulin levels (on hormone replacement therapy) every 3 to 6 months for 3 years and then annually.
  - TSH-stimulated thyroglobulin and, possibly, a diagnostic 123I scan in 1 to 2 years in patients treated with 131I.
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.
Radioactive iodine ablation.[74]
The goal of 131I therapy is to decrease the risks of recurrence and to decrease mortality by eliminating iodine-avid disease.
1. The ATA Task Force recommends the use of 131I for the treatment of iodine-avid persistent locoregional or nodal disease that cannot be resected and known or presumed iodine-avid distant metastases. For patients with persistent disease after administration of 131I, the decision to pursue additional 131I therapy should be individualized on the basis of clinical data and previous response.
2. To facilitate 131I uptake by residual iodine-avid disease, the TSH level should be above 30 mIU/L. This level can be achieved by withdrawing levothyroxine for at least 14 days. In patients who cannot mount an adequate TSH response or cannot tolerate profound hypothyroidism, recombinant human TSH may be used.
3. Therapeutic 131I administration is commonly based on either empiric dosing or whole-body dosimetry. Based on the lack of data comparing empiric treatment and treatment informed by dosimetry, the ATA Task Force was unable to recommend one specific approach. However, because of the differences in body size and iodine clearance in children compared with adults, it is recommended that all activities of 131I should be calculated by experts with experience in dosing children.
4. A posttreatment whole-body scan is recommended for all children 4 to 7 days after 131I therapy. The addition of single-photon emission CT with integrated conventional CT (SPECT/CT) may help to distinguish the anatomic location of focal uptake.
  While rare, late effects of 131I treatment include salivary gland dysfunction, bone marrow suppression, pulmonary fibrosis, and second malignancies.[94]

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 iodine I 131 (131I).

Radioactive iodine ablation with 131I is usually effective after recurrence.[95] 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:

Sorafenib. Sorafenib is a vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAS kinase inhibitor. In a randomized phase III trial, sorafenib improved progression-free survival (PFS) when compared with placebo (10.8 months vs. 5.8 months) in adult patients with radioactive iodine–refractory locally advanced or metastatic differentiated thyroid cancer.[96] Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in November 2013 for the treatment of adults with late-stage metastatic differentiated thyroid carcinoma.
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.[97]
Lenvatinib. Lenvatinib is an oral VEGFR, fibroblast growth factor receptor, PDGFR, RET, and KIT inhibitor. In a phase III randomized study of adults with 131I-refractory differentiated thyroid cancer, lenvatinib was associated with a significant improvement in PFS and response rate when compared with a placebo.[98] Lenvatinib was approved by the FDA in February 2015 for the treatment of adults with progressive radioactive iodine–refractory differentiated thyroid carcinoma.
BRAF inhibitors. In an open-label, nonrandomized phase II study of vemurafenib in adult patients with 131I-refractory metastatic or unresectable BRAF-V600E positive papillary thyroid carcinoma who had not been previously treated with a TKI, a response rate of 38.5% was documented.[99] For patients with metastatic or advanced BRAFV600E–mutated anaplastic thyroid carcinoma, the combination of dabrafenib with the MEK inhibitor trametinib has shown a response rate of 69%.[100]

(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

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.

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:

Surgery: Treatment for children with medullary thyroid carcinoma is mainly surgical. Investigators have concluded that prophylactic central node dissection should not be performed on patients with hereditary medullary thyroid cancer if their basal calcitonin serum levels are lower than 40 pg/mL.[93]

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.[91]

A retrospective analysis identified 167 children with RET mutations who underwent prophylactic thyroidectomy, which 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).[101]

In the highest-risk category, medullary thyroid carcinoma was found in five of six children (83%) aged 3 years or younger.
In the high-risk category, medullary thyroid carcinoma was present in 6 of 20 children (30%) aged 3 years or younger, 16 of 36 children (44%) aged 4 to 6 years, and 11 of 16 children (69%) aged 7 to 12 years (P = .081).
In the moderate-risk category, medullary thyroid carcinoma was seen in one of nine children (11%) aged 3 years or younger, 1 of 26 children (4%) aged 4 to 6 years, 3 of 26 children (12%) aged 7 to 12 years, and 7 of 16 children (44%) aged 13 to 18 years (P = .006).

The American Thyroid Association has proposed the following guidelines for prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (refer to Table 2).[91]

Table 2. Risk Levels and Management Based on Common RETMutations Detected on Genetic Screeninga

	Medullary Thyroid Carcinoma Risk Level
	Highest (MEN2B)	High (MEN2A)	Moderate (MEN2A)
MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B.
aAdapted from Wells et al.[91]
RET Mutation	M918T	A883F, C634F/G/R/S/W/Y	G533C, C609F/G/R/S/Y, C611F/G/S/Y/W, C618F/R/S, C620F/R/S, C630R/Y, D631Y, K666E, E768D, L790F, V804L, V804M, S891A, R912P
Age for Prophylactic Thyroidectomy	Total thyroidectomy in the first year of life, ideally in the first months of life.	Total thyroidectomy at or before age 5 y based on serum calcitonin levels.	Total thyroidectomy to be performed when the serum calcitonin level is above the normal range or at convenience if the parents do not wish to embark on a lengthy period of surveillance.

Tyrosine kinase inhibitor (TKI) therapy: A number of TKIs have been evaluated and approved for patients with advanced thyroid carcinoma.
- Vandetanib. Vandetanib (an inhibitor of RET kinase, vascular endothelial growth factor receptor [VEGFR], and epidermal growth factor receptor signaling) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable, locally advanced, or metastatic disease. Approval was based on a randomized, placebo-controlled, phase III trial that showed a marked progression-free survival (PFS) improvement for patients randomly assigned to receive vandetanib (hazard ratio, 0.35); the trial also showed an objective response rate advantage for patients receiving vandetanib (44% vs. 1% for the placebo arm).[102,103]
  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.[104] 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%.[105]
- Cabozantinib. Cabozantinib (an inhibitor of the RET and MET kinases and VEGFR) has also shown activity against unresectable medullary thyroid cancer (10 of 35 adult patients [29%] had a partial response).[106] Cabozantinib was approved by the FDA in November 2012 for the treatment of adults with metastatic medullary thyroid cancer.

(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

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.

Oral Cavity Cancer

Incidence

More than 90% of tumors and tumor-like lesions in the oral cavity are benign.[107-110] Oral cavity cancer is extremely rare in children and adolescents.[111,112] 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.[113] 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.[114-116] Current practices to increase HPV immunization rates in both boys and girls may reduce the burden of HPV-related cancers.[117,118]

Histology

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.[107-110] (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 [107,108] and 3% to 13% of oral tumor biopsies.[109,110] 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.[119]; [120][Level of evidence: 3iiiA]

Risk Factors

Diseases that can be associated with the development of oral cavity and/or head and neck squamous cell carcinoma include the following:[121-128]

Fanconi anemia.
Dyskeratosis congenita.
Connexin mutations.
Chronic graft-versus-host disease.
Epidermolysis bullosa.
Xeroderma pigmentosum.
Human papillomavirus infection.

Outcome

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.[119][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.[129]

Treatment of Childhood Oral Cavity Cancer

Treatment of benign oral cavity tumors is surgical.

Treatment options for childhood oral cavity cancer include the following:

Surgery.
Chemotherapy.
Radiation therapy.

Management of malignant tumors of the oral cavity is dependent on histology and may include surgery, chemotherapy, and radiation.[130] Most reported cases of oral cavity squamous cell carcinoma managed with surgery alone have done well without recurrence.[119,131] (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

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.

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.[132,133] Salivary gland tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[134,135]

Overall 5-year survival in the pediatric age group is approximately 95%.[136] A review of the Surveillance, Epidemiology, and End Results database identified 284 patients younger than 20 years with tumors of the parotid gland.[137][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).

Clinical Presentation

Most salivary gland neoplasms arise in the parotid gland.[138-143] About 15% of these tumors arise in the submandibular glands or in the minor salivary glands under the tongue and jaw.[141] These tumors are most frequently benign but may be malignant, especially in young children.[144]

Histology and Molecular Features

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.[132,141,143,145-147] 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.[148,149]

Immunohistochemical and molecular profiling in a series of pediatric patients with salivary gland tumors showed similarities to those tumors observed in adults.[150] 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.[151] MASC is characterized by an ETV6-NTRK3 fusion.[152]

Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[147,153,154]

Treatment of Childhood Salivary Gland Tumors

Treatment options for childhood salivary gland tumors include the following:

Surgery.
Radiation therapy.

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.[136,155,156]; [142][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.[157] 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.[158][Level of evidence: 3iiDi]

Objective responses have been observed in all reported patients with recurrent NTRKfusion–positive mammary analog secretory carcinomas who were treated with entrectinib or larotrectinib.[159,160]

(Refer to the PDQ summary on Salivary Gland Cancer Treatment [Adult] for more information.)

Treatment Options Under Clinical Evaluation for Childhood Salivary Gland Tumors

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.

Sialoblastoma

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.[161]

Chemotherapy regimens with carboplatin, epirubicin, vincristine, etoposide, dactinomycin, doxorubicin, and ifosfamide have produced responses in two children with sialoblastoma.[162]; [163][Level of evidence: 3iiiDiv]

Laryngeal Cancer and Papillomatosis

Childhood Laryngeal Cancer

Histology

Tumors of the larynx are rare. The most common benign tumor is subglottic hemangioma.[164] Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[165,166]

Clinical Presentation

These tumors may present with the following:

Hoarseness.
Difficulty swallowing.
Enlargement of the lymph nodes of the neck.

Treatment of Childhood Laryngeal Cancer

Rhabdomyosarcoma is the most common pediatric malignant tumor of the larynx and is treated with chemotherapy and radiation therapy.[167] (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.[168] 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

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.

Childhood Laryngeal Papillomatosis

General Information

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.[169,170] The presence of HPV-11 appears to correlate with a more aggressive clinical course than does the presence of HPV-6.[171]

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.[172] 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.[173] Frequent recurrences are common. Lung involvement, although rare, can occur.[172]

If a patient requires more than four surgical procedures per year, other interventions may be necessary, including the following:

Interferon therapy.[174]
Immunotherapy with HspE7, a recombinant fusion protein that has shown activity in other HPV-related diseases. A pilot study suggested a marked increase in the amount of time between surgeries.[175]
Laser therapy combined with intralesional bevacizumab.[176]

The effectiveness of intralesional cidofovir has not been conclusively demonstrated.[177]

The role of checkpoint inhibitors, such as PD-1 inhibitors, is currently being investigated.[178] 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.[179,180] In contrast, other reports have not documented a therapeutic effect of the quadrivalent HPV vaccine.[181]

Treatment Options Under Clinical Evaluation for Childhood Laryngeal Papillomatosis

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

NCT02632344 (Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients With Laryngeal, Tracheal, and/or Pulmonary Involvement): In this research study, the investigators are determining whether pembrolizumab can restore the natural ability of the immune system to recognize and eliminate HPV-infected cells from the body. Pembrolizumab will be administered at a dose of 200 mg as a 30-minute intravenous infusion every 3 weeks. Treatment will be administered on day 1 of each cycle.

Midline Tract Carcinoma Involving the NUT Gene (NUT Midline Carcinoma)

Molecular Features

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;[182] these tumors are termed NUT-variant.[183]

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.[184,185] Although the original description of this neoplasm was made in children and young adults, individuals of all ages can be affected.[183] A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1–78 years).[186]

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.[183,184]

Treatment of Childhood Midline Tract Carcinoma

Treatment options for childhood midline tract carcinoma include the following:

Chemotherapy.
Surgery.
Radiation therapy.

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.[187]; [186][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.[185][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.[188,189] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.[182]

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:

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.
NCT01587703 (A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma and Other Cancers): This study is evaluating the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762, a BET bromodomain inhibitor, as well as the tolerability and clinical activity, in patients with NUT midline carcinoma and other solid tumors. Patients aged 16 years and older are eligible for this study.
NCT01987362 (A Two Part, Multicenter, Open-label Study of TEN-010 Given Subcutaneously): This is a phase I, nonrandomized, dose-escalating, open label, multicenter study of patients aged 18 years and older with histologically confirmed advanced solid tumors with progressive disease requiring therapy or NUT midline carcinoma. This study is evaluating the safety, tolerability, and pharmacokinetics of TEN-010, a small molecule bromodomain inhibitor.

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