Unusual Cancers of Childhood Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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General Information About Unusual Cancers of Childhood

Introduction

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgeons, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons and, by definition, all pediatric cancers are considered rare. The designation of a pediatric rare tumor is not uniform among international groups:

  • The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP]) defines a pediatric rare tumor as one with an incidence of less than two cases per 1 million population per year and is not included in other clinical trials.[5]
  • The Children's Oncology Group (COG) has opted to define rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[6] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years (refer to Figures 1 and 2).[7] Most cancers within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low incidence of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers such as melanoma.


Pie chart showing age-adjusted and age-specific cancer incidence rates for patients aged 0-14 years (SEER 2009-2012).
Figure 1. Age-adjusted and age-specific (0-14 years) Surveillance, Epidemiology, and End Results cancer incidence rates from 2009 to 2012 by International Classification of Childhood Cancer group and subgroup and age at diagnosis, including myelodysplastic syndrome and group III benign brain/central nervous system tumors for all races, males, and females.
Pie chart showing age-adjusted and age-specific cancer incidence rates for patients aged 15-19 years (SEER 2009-2012).
Figure 2. Age-adjusted and age-specific (15-19 years) Surveillance, Epidemiology, and End Results cancer incidence rates from 2009 to 2012 by International Classification of Childhood Cancer group and subgroup and age at diagnosis, including myelodysplastic syndrome and group III benign brain/central nervous system tumors for all races, males, and females.

Several initiatives to study rare pediatric cancers have been developed by the COG and other international groups, such as the International Society of Paediatric Oncology (Société Internationale D'Oncologie Pédiatrique [SIOP]). The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) rare tumor project was founded in Germany in 2006.[8] The Italian cooperative project on rare pediatric tumors (TREP) was launched in 2000,[5] and the Polish Pediatric Rare Tumor Study Group was launched in 2002.[9] In Europe, the rare tumor studies groups from France, Germany, Italy, Poland, and the United Kingdom have joined in the European Cooperative study Group on Pediatric Rare Tumors (EXPeRT), focusing on international collaboration and analyses of specific rare tumor entities.[10] Within the COG, efforts have concentrated on increasing accrual to the COG registry (now known as the Childhood Cancer Research Network/Project Every Child) and the rare tumor bank, developing single-arm clinical trials, and increasing cooperation with adult cooperative group trials.[11] The accomplishments and challenges of this initiative have been described in detail.[6,12]

The tumors discussed in this summary are very diverse; they are arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see less than a handful of some histologies in several years. The majority of the histologies described here occur more frequently in adults. Information about these tumors may also be found in sources relevant to adults with cancer.

References:

  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
  4. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
  5. Ferrari A, Bisogno G, De Salvo GL, et al.: The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer 43 (4): 654-9, 2007.
  6. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.
  7. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed February 15, 2017.
  8. Brecht IB, Graf N, Schweinitz D, et al.: Networking for children and adolescents with very rare tumors: foundation of the GPOH Pediatric Rare Tumor Group. Klin Padiatr 221 (3): 181-5, 2009 May-Jun.
  9. Balcerska A, Godzinski J, Bien E, et al.: [Rare tumours--are they really rare in the Polish children population?]. Przegl Lek 61 (Suppl 2): 57-61, 2004.
  10. Bisogno G, Ferrari A, Bien E, et al.: Rare cancers in children - The EXPeRT Initiative: a report from the European Cooperative Study Group on Pediatric Rare Tumors. Klin Padiatr 224 (6): 416-20, 2012.
  11. Musselman JR, Spector LG, Krailo MD, et al.: The Children's Oncology Group Childhood Cancer Research Network (CCRN): case catchment in the United States. Cancer 120 (19): 3007-15, 2014.
  12. Pappo AS, Furman WL, Schultz KA, et al.: Rare Tumors in Children: Progress Through Collaboration. J Clin Oncol 33 (27): 3047-54, 2015.

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:

  • Nasopharyngeal carcinoma.
  • Esthesioneuroblastoma.
  • Thyroid tumors.
  • Oral cavity cancer.
  • Salivary gland tumors.
  • Laryngeal carcinoma and papillomatosis.
  • Midline tract carcinoma involving the NUT gene.

The prognosis, diagnosis, classification, and treatment of these head and neck cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from small case series or cohorts combining pediatric and adult patients.

Nasopharyngeal Carcinoma

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.[3,4,5]

The incidence of nasopharyngeal carcinoma is characterized by racial and geographic variations, with an endemic distribution among well-defined ethnic groups, such as inhabitants of some areas in North Africa and the Mediterranean basin, and, particularly, Southeast Asia. In the United States, the incidence of nasopharyngeal carcinoma is higher in black children and adolescents younger than 20 years.[4]

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 is keratinizing squamous cell carcinoma.
  • Type II is nonkeratinizing squamous cell carcinoma. Type II is distinguished into type IIa and IIb depending on the presence of lymphoid infiltration.
  • Type III is undifferentiated carcinoma. Type III is distinguished into type IIIa and IIIb depending on the presence of lymphoid infiltration.

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

Clinical Presentation

Signs and symptoms of nasopharyngeal carcinoma are as follows:[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 ear-nose-throat specialist using nasal endoscopy and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor.

A diagnosis can be made from a biopsy of the primary tumor or enlarged lymph nodes of the neck. Nasopharyngeal carcinomas must be distinguished from all other cancers that can present with enlarged lymph nodes and from other types of cancer in the head and neck area. Thus, diseases such as thyroid cancer, rhabdomyosarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, and Burkitt lymphoma must be considered, as well as benign conditions such as nasal angiofibroma, which usually presents with epistaxis in adolescent males, infectious lymphadenitis, and Rosai-Dorfman disease.

Evaluation of the chest and abdomen by computed tomography (CT) and bone scan is performed to determine whether there is metastatic disease. Fludeoxyglucose positron emission tomography (PET)-CT may also be helpful in the evaluation of potential metastatic lesions.[9]

Staging

Tumor staging is performed using the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC, 7th edition).[10]

More than 90% of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[11,12,13] Metastatic disease (stage IVC) at diagnosis is uncommon. A retrospective analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program reported that patients younger than 20 years had a higher incidence of advanced-stage disease than did older patients.[4]

Prognosis

The overall survival (OS) of children and adolescents with nasopharyngeal carcinoma has improved over the last four decades; with state-of-the-art multimodal treatment, 5-year survival rates are in excess of 80%.[4,5,8,12,13,14,15] 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

Treatment of nasopharyngeal carcinoma is multimodal and includes the following:

  1. 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.[12,13,14,16,17,18,19][Level of evidence: 2A]
    1. Randomized studies have investigated the role of chemotherapy in the treatment of adult nasopharyngeal carcinoma. The use of concomitant chemoradiation therapy was associated with a significant survival benefit, including improved locoregional disease control and reduction in distant metastases.[18,20] The use of neoadjuvant chemotherapy has also resulted in better local and distant control rates, whereas postradiation chemotherapy does not seem to offer any benefit.[20]
    2. In children, four studies used preradiation chemotherapy with different combinations of methotrexate, cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without recombinant interferon-beta.[13,14,21,22][Level of evidence: 2A]
      • These four studies reported response rates of more than 90% and excellent outcomes.
      • Neoadjuvant chemotherapy with cisplatin and 5-FU (with or without leucovorin), followed by chemoradiation with single-agent cisplatin has yielded 5-year OS rates consistently above 80%.[13,14]
      • A preliminary analysis of the NPC-2003-GPOH study, which included a 6-month maintenance therapy phase with interferon-beta, reported a 30-month OS estimate of 97.1%.[14]
    3. While nasopharyngeal carcinoma is a very chemosensitive neoplasm, high radiation doses to the nasopharynx and neck (approximately 60 Gy) are required for optimal locoregional control.[12,13,14,15] 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]
    4. A randomized prospective trial compared cisplatin and fluorouracil with cisplatin, fluorouracil, and docetaxel for the treatment of nasopharyngeal carcinoma in children and adolescents.[23][Level of evidence: 1iiA] The addition of docetaxel was not associated with improved outcome.
    5. Additional drug combinations that have been used in children with nasopharyngeal carcinoma include bleomycin with epirubicin and cisplatin, and cisplatin with methotrexate and bleomycin.[1]
    6. Other approaches to the management of nasopharyngeal carcinoma in children have been evaluated and include the following:
      • Incorporation of high-dose-rate brachytherapy into the chemoradiation therapy approach.[24,25]
      • Following adult studies and data, taxanes have been incorporated into the treatment of childhood nasopharyngeal carcinoma; studies have shown good objective response rates and favorable outcomes with the use of docetaxel in combination with cisplatin.[26][Level of evidence: 3iiiDiv]
  2. Surgery: Surgery has a limited role in the management of nasopharyngeal carcinoma because the disease is usually considered unresectable due to extensive local spread.

The use of EBV-specific cytotoxic T-lymphocytes has shown to be a very promising approach with minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.[27]

(Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)

Treatment Options Under Clinical Evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

  • H-25145 (NCT00953420) (Carboplatin, Docetaxel, and Laboratory-Treated T Cells in Treating Patients With Refractory or Relapsed EBV-Positive Nasopharyngeal Cancer): The objective of this trial is to determine the overall response rate in patients with relapsed/refractory, advanced-stage, EBV-positive nasopharyngeal carcinoma after treatment with docetaxel and carboplatin followed by immunotherapy with EBV-specific cytotoxic T lymphocytes. Individuals aged 10 years and older are eligible for this trial.

Esthesioneuroblastoma

Incidence

Esthesioneuroblastoma (olfactory neuroblastoma) is a small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[28,29,30,31] In children, esthesioneuroblastoma is a very rare malignancy, with an estimated incidence of 0.1 cases per 100,000 children younger than 15 years.[32]

Despite its rarity, esthesioneuroblastoma is the most common cancer of the nasal cavity in pediatric patients, accounting for 28% of cases in a SEER study.[33] 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.[34] Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%).[34]

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.

Staging

Tumors are staged according to the Kadish system (refer to Table 1). Correlated with Kadish stage, prognosis ranges from 90% (stage A) to less than 40% (stage D). Most patients present with locally advanced-stage disease (Kadish stages B and C) and almost one-third of patients show tumor at distant sites (Kadish stage D).[32,33] Recent reports suggest that PET-CT may aid in staging the disease.[35]

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.

Review of multiple case series of mainly adult patients indicate that the following may correlate with adverse prognosis:[36,37,38]

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

Treatment and Outcome

The use of multimodal therapy optimizes the chances for survival, with over 70% of children expected to survive 5 or more years after initial diagnosis.[32,39,40] A multi-institutional review of 24 patients younger than 21 years at diagnosis found a 5-year disease-free survival and OS of 73% to 74%.[41][Level of evidence: 3iiiA]

Treatment options according to Kadish stage include the following:[42]

  1. Kadish stage A: Surgery alone with clear margins. Adjuvant radiation therapy is indicated in patients with close and positive margins or with residual disease.
  2. Kadish stage B: Surgery followed by adjuvant radiation therapy. The role of adjuvant chemotherapy is controversial.
  3. Kadish stage C: Neoadjuvant approach with chemotherapy, radiation therapy, or concurrent chemotherapy-radiation therapy followed by surgery.
  4. Kadish stage D: Systemic chemotherapy and palliative radiation therapy to local and metastatic sites. Palliative care is incorporated into the treatment plan to improve quality of life.

The mainstay of treatment is surgery and radiation.[43] Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection.[34]; [44][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.[40,45]

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.[46] Management of cervical lymph node metastases has been addressed in a review article.[46]

Reports indicate promising results with the increased use of resection and neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease.[28,39,41,47,48]; [49][Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include cisplatin with etoposide with or without ifosfamide;[42,50] vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin; ifosfamide/etoposide; cisplatin plus etoposide or doxorubicin; [39] vincristine, doxorubicin, and cyclophosphamide;[51] and irinotecan plus docetaxel.[52][Level of evidence: 3iiA]

Thyroid Tumors

Incidence

The annual incidence of thyroid cancers is 2.0 cases per 1 million people per year in children younger than 15 years, accounting for approximately 1.5% of all cancers in this age group.[3] 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.[3,53] More thyroid carcinomas occur in females than in males.[54]

A retrospective review of the SEER database from 1973 to 2011 identified 2,504 cases of papillary thyroid carcinoma in patients aged 20 years and younger.[53] The incidence of papillary thyroid carcinoma increased over this interval by roughly 2% each year. The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.[55]

Risk Factors

There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[56,57] In the decade following the Chernobyl nuclear incident, there was a tenfold increase in the incidence of thyroid cancer compared with the previous and following decades.[58] In this group of patients with exposure to low-dose radiation, tumors commonly show a gain of 7q11.[59]

When occurring in patients with the multiple endocrine neoplasia syndromes, thyroid cancer may be associated with the development of other types of malignant tumors. (Refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information.)

Histology

Tumors of the thyroid are classified as adenomas or carcinomas.[60,61,62] 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.[60,63]

Various histologies account for the general diagnostic category of carcinoma of the thyroid; papillary and follicular carcinoma are often referred to as differentiated thyroid carcinoma:[57]

  • Papillary carcinoma (60%-75%): Papillary carcinoma often has a multicentric origin and a very high rate of lymph node metastasis (70%-90%).[64] Metastases to the lungs occur in about 25% of cases. Papillary carcinoma generally has a benign course, with a 10-year survival rate of more than 95%.[65,66] Overall, long-term outcomes for children and adolescents with papillary thyroid cancer are excellent, with 2% cause-specific mortality at 40 years.[66]
  • Follicular carcinoma (10%-20%): Follicular carcinoma is usually encapsulated and has a higher incidence of bone and lung metastases.[64] It may be sporadic or familial.[67] Follicular carcinoma also has a generally benign course, with a 10-year survival rate of more than 95%.[65]
  • Medullary carcinoma (5%-10%): Medullary carcinoma is a form of thyroid carcinoma that originates from the calcitonin-secreting parafollicular C cells. It is usually familial.[67]
  • Anaplastic carcinoma (<1%).

Molecular Features and Tumor Characteristics

Studies have shown subtle differences between the genetic profiling of childhood differentiated thyroid carcinomas and that of adult tumors. In one study, a higher prevalence of RET/PTC rearrangements was reported in pediatric papillary carcinoma (45%-65% in children vs. 3%-34% in adults).[68]BRAF V600E mutations are seen in more than 50% of adults with papillary thyroid carcinoma;[69] although it likely occurs in a similar frequency in pediatric patients, studies have revealed a wide variation in frequency of this mutation.[68,69,70,71] In children, the correlation between the genomic alteration and stage or prognosis has not been well defined. While two studies failed to show a correlation,[70,71] one study that included 55 pediatric thyroid carcinoma cases demonstrated a significant correlation between the presence of a BRAF V600E mutation and an increased risk of recurrence.[72] Differentiated thyroid carcinoma has been associated with germline DICER1 mutations and it is considered part of the DICER1 syndrome.[73]

Table 2. Comparison of Thyroid Carcinoma Characteristics in Children and Adolescents and Adultsa
Characteristic Children and Adolescents (%) Adults (%)
a Yamashita et al.,[74]Nikita et al.,[71]and Alzahrani et al.[72]
Histologic subtype:    
Papillary 67-98 85-90
Follicular 4-23 <10
Medullary 2-8 3
Poorly differentiated <0.1 2-7
 
Gene rearrangements:    
RET/PTC 21-87 0-35
NTRK 1 5-11 5-13
AKAP9-BRAF 11 1
PAX8-PPARG Unknown 0-50
 
Point mutations:    
BRAF 0-63 0-43
RASfamily 0-16 25-69
GNAS 0 11
TP53 0-23 0-20
TERT 0 16
 
Other:    
Multicentric 30-50 40-56
Lymph node involvement 30-90 5-55
Extrathyroid extension 24-51 16-46
Vascular invasion <31 14-37
Distant metastases 10-20 5-10

Clinical Presentation and Outcome

Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[75,76,77] On the basis of medical and family history and clinical constellation, the thyroid cancer may be part of a tumor predisposition syndrome such as MEN or DICER-1 syndrome.[78]

Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. Children have a higher proportion of nodal involvement (40%-90% in children vs. 20%-50% in adults) and lung metastases (20%-30% in children vs. 2% in adults) than do adults.[69] Likewise, when compared with pubertal adolescents, prepubertal children have a more aggressive presentation with a greater degree of extrathyroid extension, lymph node involvement, and lung metastases. However, outcome is similar in the prepubertal and adolescent groups.[79]

In well-differentiated thyroid cancer, male gender, large tumor size, and distant metastases have been found to have prognostic significance for early mortality; however, even patients in the highest risk group who have distant metastases had excellent survival at 90%.[80] 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.[81]

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.[82,83,84,85] Open biopsy or resection may also be preferable for young children.

Table 3. Thyroid Carcinomas in Children
Histology Associated Chromosomal Abnormality Presentation Diagnosis Treatment
EGF = epidermal growth factor; MEN2 = multiple endocrine neoplasia type 2; TSH = thyroid-stimulating hormone.
Differentiated thyroid carcinoma RET/PTCmore common in children.BRAFV600E mutations occur with similar frequency in children and adults. Association with rare hereditary tumor syndromes:APC-associated polyposis,DICER1syndrome, Carney complex,PTENhamartoma tumor syndrome, Werner syndrome. Thyroid mass. Prepubertal children more often with nodal and lung metastases. Ultrasound, TSH, thyroglobulin. Fine needle or open biopsy. Total or near-total thyroidectomy; I-131; thyroid hormone. In metastatic or recurrent disease, tyrosine kinase or EGF receptor inhibitors may be of benefit.
Medullary thyroid carcinoma MEN2 Aggressive. 50% with metastases at presentation. In familial MEN2,RETtesting. Aggressive surgical intervention. Prophylactic thyroidectomy is indicated in familial cases.

Treatment of Papillary and Follicular (Differentiated) Thyroid Carcinoma

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

  1. Surgery.
  2. Radioactive iodine ablation.

The management of differentiated thyroid cancer in children has been reviewed in detail.[63,86] 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.[63]

  1. Preoperative evaluation.
    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 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 TSH.
    5. The routine use of bone scan or 2-deoxy-2-[18F]-fluoro-deoxyglucose (18 F-FDG) PET is not recommended.
  2. Surgery.

    Pediatric thyroid surgery should ideally be performed by a surgeon who performs at least 30 or more cervical endocrine procedures annually 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. 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.
      • For patients with no clinical evidence of gross extrathyroidal invasion or locoregional metastasis, a prophylactic central neck dissection should be considered on the basis of tumor focality and size of the primary tumor. For patients with unifocal disease, ipsilateral central neck dissection, with contralateral central neck dissection based on intraoperative findings, may also be considered.
    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.
  3. Classification and risk assignment.

    Despite the limited data in pediatrics, the ATA Task Force recommends the use of the 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 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.
  4. Postoperative staging.

    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 131 I. 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
    2. ATA Pediatric Intermediate and High Risk: TSH-stimulated thyroglobulin and diagnostic 123 I whole-body scan are recommended for further stratification and determination with 131 I.

    For patients with anti-thyroglobulin antibodies, consideration can be given to deferred postoperative staging to allow time for antibody clearance, except in patients with T4 or M1 disease.

  5. Radioactive iodine ablation.

    The goal of 131 I 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 131 I 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 131 I, the decision to pursue additional 131 I therapy should be individualized on the basis of clinical data and previous response.
    2. To facilitate 131 I 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 131 I 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 131 I 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 131 I therapy. The addition of single-photon emission CT with integrated conventional CT (SPECT/CT) may help to distinguish the anatomic location of focal uptake.
  6. Surveillance and follow-up.

    The ATA Task Force recommends the following risk-adapted approach to follow-up:

    1. ATA Pediatric Low Risk:
      • TSH goal of 0.5 to 1.0 mIU/L.
      • Ultrasound at 6 months and then annually for 5 years.
      • Thyroglobulin levels on levothyroxine treatment every 3 to 6 months for 2 years and then annually.
    2. ATA Pediatric Intermediate Risk:
      • TSH goal of 0.1 to 0.5 mIU/L. In patients who have no evidence of disease after 3 to 5 years of follow-up, the TSH can be allowed to rise to the low-normal range.
      • Ultrasound at 6 months postoperatively, every 6 to 12 months for 5 years, and then less frequently.
      • Thyroglobulin levels on levothyroxine treatment every 3 to 6 months for 3 years and then annually.
      • Consider TSH-stimulated thyroglobulin and diagnostic 123 I scan in 1 to 2 years in patients treated with 131 I.
    3. ATA Pediatric High Risk:
      • TSH goal of less than 0.1 mIU/L. In patients who have no evidence of disease after 3 to 5 years of follow-up, the TSH can be allowed to rise to the low-normal range.
      • Ultrasound at 6 months postoperatively, every 6 to 12 months for 5 years, and then less frequently.
      • Thyroglobulin levels on levothyroxine treatment every 3 to 6 months for 3 years and then annually.
      • Consider TSH-stimulated thyroglobulin and diagnostic 123 I scan in 1 to 2 years in patients treated with 131 I.

Treatment of Recurrent Papillary and Follicular (Differentiated) Thyroid Carcinoma

Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[87,88,89] However, recurrence is common (35%-45%) and is seen more often in children younger than 10 years and in those with palpable cervical lymph nodes at diagnosis.[90,91] Even patients with a tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment.[92] Of note, the sodium-iodide symporter (a membrane-bound glycoprotein cotransporter), essential for uptake of iodide and thyroid hormone synthesis, is expressed in 35% to 45% of thyroid cancers in children and adolescents. Patients with expression of the sodium-iodide symporter have a lower risk of recurrence.[93]

Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation.[94]

TKIs such as sorafenib have been shown to induce responses in up to 15% of adult patients with metastatic disease.[95] Response to sorafenib has also been documented in a pediatric case.[96]

TKIs approved 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 in adult patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer.[97] In one case report, sorafenib produced a radiographic response in a patient aged 8 years with metastatic papillary thyroid carcinoma.[98] 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.
  • Lenvatinib. Lenvatinib is an oral VEGFR, fibroblast growth factor receptor, PDGFR, RET, and KIT inhibitor. In a phase III randomized study of adults with I-131 refractory differentiated thyroid cancer, lenvatinib was associated with a significant improvement in PFS and response rate when compared with a placebo.[99] Lenvatinib was approved by the FDA in February 2015 for the treatment of adults with progressive radioactive iodine-refractory differentiated thyroid carcinoma.

Given the high incidence of BRAF mutations in patients with papillary thyroid carcinoma, the use of selective RAF/MEK inhibitors is being investigated.[95,100,101]

(Refer to the PDQ summary on adult Thyroid Cancer Treatment for more information.)

Treatment of Medullary Thyroid Carcinoma

Medullary thyroid carcinomas are commonly associated with the MEN2 syndrome (refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information). They present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis.[102] Patients with medullary carcinoma of the thyroid have a guarded prognosis, unless they have very small tumors (microcarcinoma, defined as <1.0 cm in diameter), which carry a good prognosis.[103] A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (NCT01660984). For patients with de novo RET mutations and no familial history, nonendocrine manifestations such as intestinal ganglioneuromatosis or skeletal or ocular stigmata, may facilitate early diagnosis and result in better outcomes.[104]

Treatment options for medullary thyroid carcinoma include the following:

  1. Surgery: Treatment for children with medullary thyroid carcinoma is mainly surgical. 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.[105] This suggests that central neck node dissection and dissection of nearby positive nodes should improve the 10-year survival for these patients.

    Most cases of medullary thyroid carcinoma occur in the context of the MEN 2A and MEN 2B syndromes. In those familial cases, early genetic testing and counseling is indicated, and prophylactic surgery is recommended for children with the RET germline mutation. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur.[102]

  2. TKI therapy: A number of TKIs have been evaluated and approved for patients with advanced thyroid carcinoma.
    • Vandetanib. Vandetanib (an inhibitor of RET kinase, VEGFR, and epidermal growth factor receptor signaling) is approved by the U.S. 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 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).[106,107]

      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.[108]

    • 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).[109] 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 this summary and the Treatment for those with MTC section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)

Oral Cavity Cancer

Incidence

More than 90% of tumors and tumor-like lesions in the oral cavity are benign.[110,111,112,113] Cancer of the oral cavity is extremely rare in children and adolescents.[114,115] According to the SEER Stat Fact Sheets, only 0.6% of all cases are diagnosed in patients younger than 20 years, and in 2008, the age-adjusted incidence for this population was 0.24 cases per 100,000.

The incidence of cancer of the oral cavity and pharynx has increased in adolescent and young adult females, and this pattern is consistent with the national increase in orogenital sexual intercourse in younger females and human papillomavirus (HPV) infection.[116] It is currently estimated that the prevalence of oral HPV infection in the United States is 6.9% in people aged 14 to 69 years and that HPV causes about 30,000 oropharyngeal cancers. Furthermore, from 1999 to 2008, the incidence rates for HPV-related oropharyngeal cancer have increased by 4.4% per year in white men and 1.9% in white women.[117,118,119] Current practices to increase HPV immunization rates in both boys and girls may reduce the burden of HPV-related cancers.[120]

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.[110,111,112,113] (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 [110,111] and 3% to 13% of oral tumor biopsies.[112,113] Malignant tumor types include lymphomas (especially Burkitt) and sarcomas (including rhabdomyosarcoma and fibrosarcoma). Mucoepidermoid carcinomas of the oral cavity have rarely been reported in the pediatric and adolescent age group. Most are low grade and have a high cure rate with surgery alone.[121]; [122][Level of evidence: 3iiiA]

The most common type of primary oral cavity cancer in adults, squamous cell carcinoma (SCC), is extremely rare in children. Review of the SEER database identified 54 patients younger than 20 years with oral cavity SCC between 1973 and 2006. Pediatric patients with oral cavity SCC were more often female and had better survival than adult patients. When differences in patient, tumor, and treatment-related characteristics are adjusted for, the two groups experienced equivalent survival.[121][Level of evidence: 3iA]

Diseases that can be associated with the development of oral cavity and/or head and neck SCC include Fanconi anemia, dyskeratosis congenita, connexin mutations, chronic graft-versus-host disease, epidermolysis bullosa, xeroderma pigmentosum, and HPV infection.[123,124,125,126,127,128,129,130]

Treatment

Treatment of benign oral cavity tumors is surgical.

Management of malignant tumors of the oral cavity is dependent on histology and may include surgery, chemotherapy, and radiation.[131] Most reported cases of oral cavity SCC managed with surgery alone have done well without recurrence.[121,132] (Refer to the PDQ summary on adult Lip and Oral Cavity Cancer Treatment 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.)

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.[133,134] Salivary gland tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[135,136,137]

Overall 5-year survival in the pediatric age group is approximately 95%.[138] A review of the SEER database identified 284 patients younger than 20 years with tumors of the parotid gland.[139][Level of evidence: 3iA] OS was 96% at 5 years, 95% at 10 years, and 83% at 20 years. Adolescents had higher mortality rates (7.1% vs. 1.6% for children aged <15 years, P = .23).

Clinical Presentation

Most salivary gland neoplasms arise in the parotid gland.[140,141,142,143,144,145,146] About 15% of these tumors arise in the submandibular glands or in the minor salivary glands under the tongue and jaw.[144] These tumors are most frequently benign but may be malignant, especially in young children.[147]

Histology

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.[133,144,146,148,149,150] Mucoepidermoid carcinoma is usually low or intermediate grade, although high-grade tumors occur. In one study, 12 of 12 tumors were positive for MECT1/MAML2 fusion transcripts. This reflects the common chromosome translocation t(11;19)(q21;p13) that is seen in adults with salivary gland tumors.[151] Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[146,150,152,153]

Treatment

Radical surgical removal is the treatment of choice for salivary gland tumors whenever possible, with additional use of radiation therapy for high-grade tumors or tumors that have invasive characteristics, such as lymph node metastasis, lymphovascular invasion, or perineural extension.[138,149,154]; [145][Level of evidence: 3iiiA] One retrospective study compared proton and conventional radiation therapy and found proton therapy to have a favorable acute toxicity and dosimetric profile.[155]

There are inadequate data regarding the efficacy of adjuvant chemotherapy in children.

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

Sialoblastoma

Sialoblastoma is a usually benign tumor presenting in the neonatal period and rarely metastasizes.[156] Chemotherapy regimens with carboplatin, epirubicin, vincristine, etoposide, dactinomycin, doxorubicin, and ifosfamide have produced responses in two children with sialoblastoma.[157]; [158][Level of evidence: 3iiiDiv]

Laryngeal Cancer and Papillomatosis

Tumors of the larynx are rare. The most common benign tumor is subglottic hemangioma.[159] Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[160,161] These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck.

Treatment of Laryngeal Cancer

Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group and is treated with chemotherapy and radiation therapy.[162] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) SCC of the larynx is managed in the same manner as in adults with carcinoma at this site, with surgery and radiation.[163] Laser surgery may be the initial treatment utilized for these lesions. (Refer to the PDQ summary on Laryngeal Cancer Treatment for more information about treatment of laryngeal cancer in adults.)

Treatment of Papillomatosis

Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is associated with HPV infection, most commonly HPV-6 and HPV-11.[164] The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6.[165] These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may rarely extend into the lung, producing significant morbidity.[166] Malignant degeneration may occur with development of cancer in the larynx and squamous cell lung cancer.

Papillomatosis is not cancerous, and primary treatment is surgical ablation with laser vaporization.[167] Frequent recurrences are common. Lung involvement, although rare, can occur.[166] If a patient requires more than four surgical procedures per year, other interventions may be necessary, including the following:

  • Interferon.[168]
  • 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.[169]
  • Laser therapy combined with intralesional bevacizumab.[170]

The effectiveness of intralesional cidofovir has not been conclusively demonstrated.[171]

Midline Tract Carcinoma Involving theNUTGene (NUTMidline Carcinoma)

NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the gene NUT. In the majority (75%) of cases, the NUT gene on chromosome 15q14 is fused with BRD4 on chromosome 19p13, creating chimeric genes that encode the BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 on chromosome 9q34 or to NSD3 on chromosome 8p11;[172] these tumors are termed NUT-variant.[173]

The tumors arise in midline epithelial structures, typically mediastinum and upper aerodigestive tract, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation.[174] Although the original description of this neoplasm was made in children and young adults, individuals of all ages can be affected.[173] A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1-78 years).[175]

The outcome is very poor, with an average survival of less than 1 year. Preliminary data seem to indicate that NUT-variant tumors may have a more protracted course.[173,174]

Treatment

Treatment includes a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success; however, while early response is common, tumors progress early in the course of the disease.[175][Level of evidence: 3iiiB]

Preclinical studies have shown that NUT-BRD4 is associated with globally decreased histone acetylation and transcriptional repression; studies have also shown that this acetylation can be restored with histone deacetylase inhibitors, resulting in squamous differentiation and arrested growth in vitro and growth inhibition in xenograft models. Response to vorinostat has been reported in two separate cases of children with refractory disease, thus suggesting a potential role for this class of agents in the treatment of this malignancy.[176,177] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.[172]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.

  • 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 or 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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Thoracic Cancers

Thoracic cancers include the following:

  • Breast cancer.
  • Lung cancer.
    • Bronchial tumors.
    • Pleuropulmonary blastoma.
  • Esophageal tumors.
  • Thymoma and thymic carcinoma.
  • Cardiac tumors.
  • Mesothelioma.

The prognosis, diagnosis, classification, and treatment of these thoracic cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.[1]

Breast Cancer

Fibroadenoma

The most frequent breast tumor seen in children is a fibroadenoma.[2,3] These tumors can be observed and many will regress without a need for surgical resection. However, rare malignant transformation leading to phyllodes tumors has been reported.[4] Sudden rapid enlargement of a suspected fibroadenoma is an indication for needle biopsy or excision.

Treatment of Fibroadenoma

Phyllodes tumors can be managed by wide local excision without mastectomy.[4]

Breast Cancer

Incidence and Outcome

Breast cancer has been reported in both males and females younger than 21 years.[5,6,7,8,9,10] A review of the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute shows that 75 cases of malignant breast tumors in females aged 19 years or younger were identified from 1973 to 2004.[11] Fifteen percent of these patients had in situ disease, 85% had invasive disease, 55% of the tumors were carcinomas, and 45% of the tumors were sarcomas-most of which were phyllodes tumors. Only three patients in the carcinoma group presented with metastatic disease, while 11 patients (27%) had regionally advanced disease. All patients with sarcomas presented with localized disease. Of the carcinoma patients, 85% underwent surgical resection, and 10% received adjuvant radiation therapy. Of the sarcoma patients, 97% had surgical resection, and 9% received radiation. The 5- and 10-year survival rates for patients with sarcomatous tumors were both 90%; for patients with carcinomas, the 5-year survival rate was 63% and the 10-year survival rate was 54%.

Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with the human immunodeficiency virus).

Risk Factors

Risk factors for breast cancer in adolescents and young adults include the following:

  1. Previous malignancy. A retrospective review of the American College of Surgeons National Cancer Database from 1998 to 2010 identified 106,771 patients aged 15 to 39 years with breast cancer.[12] Of these patients, 6,241 (5.8%) had experienced a previous histologically distinct malignancy. Patients with breast cancer as a subsequent neoplasm had a significantly decreased 3-year overall survival (OS) (79% vs. 88.5%, P <.001), with subsequent neoplasm status identified as an independent risk factor for increased mortality (hazard ratio, 1.58; 95% confidence interval, 1.41-1.77).
  2. Chest irradiation. There is an increased lifetime risk of breast cancer in female survivors of Hodgkin lymphoma who were treated with radiation to the chest area; however, breast cancer is also seen in patients who were treated for any cancer that was treated with chest irradiation.[9,13,14,15,16][Level of evidence: 1A] Carcinomas are more frequent than sarcomas.

    Mammograms with adjunctive breast magnetic resonance imaging (MRI) start at age 25 years or 10 years postexposure to radiation therapy (whichever came last). (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.)

Treatment of Breast Cancer in Adolescents and Young Adults (AYA)

Breast cancer is the most frequently diagnosed cancer among AYA women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses.[17] Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different from that in older women and correlates with a worse prognosis.[12,18]

Treatment of the AYA group is similar to that of older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.[19,20]

(Refer to the PDQ summary on adult Breast Cancer Treatment or the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Lung Cancer

Primary lung tumors are rare in children and histologically quite diverse.[1] When epithelial cancers of the lung occur, they tend to be of advanced stage, with prognosis dependent on both histology and stage.[21] Most primary lung tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign.[22] A review of primary malignant epithelial lung tumors using the National Cancer Data Base found that the most common primary malignant pediatric lung neoplasms were carcinoid tumors (63%) followed by mucoepidermoid carcinoma of the lung (18%).[23]

Most pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5.[24]

The most common malignant primary tumors of the lung are bronchial tumors and pleuropulmonary blastoma.

Bronchial Tumors

Histology

Bronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of bronchial tumors on occasion display malignant behavior. The following three histologic types have been identified:[25,26,27,28,29,30]

  • Carcinoid tumor (neuroendocrine tumor of the bronchus). Carcinoid tumors account for 80% to 85% of all bronchial tumors in children.[25,26,27,28,29] It is the most common bronchial tumor.
  • Mucoepidermoid carcinoma.
  • Adenoid cystic carcinoma. It is the least common bronchial tumor.

Prognosis

Bronchial tumors of all histologic types are associated with an excellent prognosis after surgical resection in children, even in the presence of local invasion.[31,32]; [33][Level of evidence: 2A]

Clinical Presentation and Diagnostic Evaluation

The presenting symptoms of a bronchial tumor are usually caused by an incomplete bronchial obstruction and include the following:

  • Cough.
  • Recurrent pneumonitis.
  • Hemoptysis.

Because of difficulties in diagnosis, symptoms are frequently present for months, and, occasionally, children with wheezing have been treated for asthma, with delays in diagnosis for as long as 4 to 5 years.[34]

Metastatic lesions are reported in approximately 6% of carcinoid tumors, and recurrences are reported in 2% of cases. Atypical carcinoid tumors are rare but more aggressive, with 50% of patients presenting with metastatic disease at diagnosis.[21,35] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[36] Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread.

The management of bronchial tumors is somewhat controversial because bronchial tumors are usually visible endoscopically. Biopsy of these lesions may be hazardous because of the risk of hemorrhage. New endoscopic techniques have allowed biopsy to be performed safely;[30,37] however, endoscopic resection is not recommended except in highly selected cases.[37,38] Bronchography or computed tomography scan may be helpful to determine the degree of bronchiectasis distal to the obstruction since the degree of pulmonary destruction may influence surgical therapy.[39]

Treatment

Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[40,41]; [33][Level of evidence: 2A] Adenoid cystic carcinomas (cylindroma) have a tendency to spread submucosally, and late local recurrence or dissemination has been reported. In addition to en bloc resection with hilar lymphadenectomy, a frozen section examination of the bronchial margins is performed in children with this lesion.

Neither chemotherapy nor radiation therapy is indicated for bronchial tumors, unless evidence of metastasis is documented.

(Refer to the Neuroendocrine Tumors (Carcinoid Tumors) section of this summary for information about neuroendocrine carcinoid tumors.)

Pleuropulmonary Blastoma

Types of Pleuropulmonary Blastoma

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy that can present as a pulmonary or pleural mass. The International Pleuropulmonary Blastoma Registry is a valuable resource for information on this rare malignancy.[42]

The following three subtypes of pleuropulmonary blastoma have been identified:

  • Type I: A purely lung cystic neoplasm with subtle malignant changes that typically occurs in the first 2 years of life and has a good prognosis. Transition from Type I to Type III occurs;[43,44] however, a significant proportion of type I lesions may not progress to types II and III.[44]

    Histologically, these tumors appear as a multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface, with skeletal differentiation in one-half of the cases.[44] This form of disease can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts.

  • Type Ir: A purely cystic tumor that lacks a primitive cell component. The r designation signifies regression or nonprogression. Type Ir was originally recognized in older siblings of pleuropulmonary blastoma patients, but can be seen in very young children. A lung cyst in an older individual with a DICER1 mutation or in a relative of a pleuropulmonary blastoma patient is most likely to be type Ir.[45]
  • Type II: Type II exhibits both cystic and solid components. The solid areas have mixed blastomatous and sarcomatous features; most of the cases exhibit rhabdomyoblasts, and nodules with cartilaginous differentiation are common.[46] Cerebral metastasis may occur in 11% of patients.[47]
  • Type III: A purely solid neoplasm, with the blastomatous and sarcomatous elements described above.[48,49] Cerebral metastasis occurs in up to 50% of patients with Type III tumors.[47]

The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50 year period.[45]

Table 4. Relative Proportions and Features of Pleuropulmonary Blastomaa
Type I Type Ir Type II Type II/III or III
a Adapted from Messinger et al.[45]
Relative proportion of pleuropulmonary blastoma cases 33% 35% 32%
Median age at diagnosis (months) 8 47 35 41
5-year overall survival 89% 100% 71% 53%

Prognostic Factors

Prognostic factors for pleuropulmonary blastoma include the following:[45]

  • Type of pleuropulmonary blastoma. The pleuropulmonary blastoma type was the strongest predictor of outcome. (Refer to Table 4.)
  • Presence of metastatic disease. The presence of metastatic disease at diagnosis was also an independent unfavorable prognostic factor. There is an increased risk of developing brain metastases, with a 5-year cumulative probability of 11% for Type II disease and 54% for Type III disease.[47]
  • Complete surgical resection.[50]

Of the 97 patients who were tested, 66% had a heterozygous germline DICER1 mutation, confirming that this is a familial cancer syndrome.[45] In this subset, DICER1 mutation status was not related to outcome.

Risk Factors

Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the pleuropulmonary blastoma family tumor and dysplasia syndrome. Germline mutations in the DICER1 gene are considered the major genetic determinant of the complex.[51,52,53] Importantly, while DICER1 mutations cause a wide range of phenotypes, pleuropulmonary blastoma does not occur in all families with DICER1 mutations; therefore, the term DICER1 syndrome is generally used for these families. Also, most mutation carriers are unaffected, indicating that tumor risk is modest.[52] Conversely, approximately 40% of patients with pleuropulmonary blastoma tumors do not have DICER1 germline mutations.[45]

The most relevant association is with cystic nephroma; up to 10% of pleuropulmonary blastoma cases have been reported to develop cystic nephroma or Wilms tumor, malignancies that are also more prevalent among family members.[54] Germline DICER1 mutations have also been associated with ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor), multinodular goiter, uterine cervix embryonal rhabdomyosarcoma, cervical primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration, juvenile intestinal polyps, ciliary body medulloepithelioma, medulloblastoma, and seminoma.[46,53,54,55,56,57,58,59]

DICER1 mutations appear to have a low penetrance, with pleuropulmonary blastoma, cystic nephroma, and multinodular goiter being the most frequently reported manifestations; not all families include pleuropulmonary blastoma, and m