This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up 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 less than 13,000 cases diagnosed before the age of 20 years each year in the United States. The Rare Disease Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons in the United States and thus, by definition, all pediatric cancers would be considered rare. The designation of a pediatric rare tumor is not uniform; for example, 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 per 1 million population per year and is not the subject of specific clinical trials. Yet, this definition excludes common histologic subtypes such as melanoma and thyroid carcinoma, both of which have an incidence rate in excess of five per 1 million per year.
Most diagnoses included in this summary of rare cancers are in the subset of malignancies listed in the International Classification of Childhood Cancer (ICCC) subgroup XI, including thyroid cancer, melanoma and nonmelanoma skin cancers, as well as multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.). These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed for adolescents aged 15 to 19 years (see Figure 1). The majority of 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 within adolescents aged 15 to 19 years. The very low incidence of patients with any individual diagnosis, as well as their age distribution, makes these rare cancers extremely challenging to study.
Figure 1. Cancer incidence rates for patients aged 0 to 14 years and 15 to 19 years in the Surveillance Epidemiology and End Results (SEER) program from 2005 to 2009. Incidence rates are age-adjusted and age-specific and are shown for leukemia, lymphoma, central nervous system (CNS) tumors, neuroblastoma, retinoblastoma, renal tumors, hepatic tumors, bone tumors, soft tissue tumors, germ cell tumors, carcinomas and melanomas, and other cancers. Retinoblastoma occurs infrequently in adolescents aged 15 to 19 years.
Several initiatives to study rare pediatric cancers have been developed by the Children's Oncology Group (COG) as well as international groups. The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) rare tumor project was founded in Germany in 2006. The TREP project was launched in Italy in 2000, and the Polish Pediatric Rare Tumor Study Group was launched in 2002. Within the COG, efforts have concentrated on increasing accrual to the COG registry and the rare tumor bank, as well as developing single-arm clinical trials and increasing cooperation with adult cooperative group trials. The accomplishments and challenges of this initiative are described in detail.
The tumors discussed in this summary are very diverse; they are arranged in descending anatomic order, from infrequent tumors of the head and neck to rare tumors of the urogenital tract and skin. All of these cancers are rare enough that most pediatric hospitals might see less than a handful of some histologies in several years. The majority of the histologies described here occur more frequently in adults. Information about these tumors may also be found in sources relevant to adults with cancer.
Childhood sarcomas often occur in the head and neck area and they are described in other sections. Unusual pediatric head and neck cancers include nasopharyngeal carcinoma, esthesioneuroblastoma, thyroid tumors, oral cancer, salivary gland cancer, laryngeal carcinoma, papillomatosis, and respiratory tract carcinoma involving the NUT gene on chromosome 15. 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 case series.
Nasopharyngeal carcinoma arises in the lining of the nasal cavity and pharynx.[2,3] This tumor accounts for about one-third of all cancers of the upper airways. Nasopharyngeal carcinoma is very uncommon in children younger than 10 years but increases in incidence to 0.8 and 1.3 per 1 million per year in children aged 10 to 14 years and in children aged 15 to 19 years, respectively.[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 Southeast Asia. In the United States, nasopharyngeal carcinoma is overrepresented in black children when compared with other malignancies.
Nasopharyngeal carcinoma is strongly associated with Epstein-Barr virus (EBV) infection. In addition to the serological evidence of infection, EBV DNA is present as a monoclonal episome in the nasopharyngeal carcinoma cells, and tumor cells can have EBV antigens on their cell surface. The circulating levels of EBV DNA, as well as serologic documentation of EBV infection, may aid in the diagnosis.
Three histologic subtypes of nasopharyngeal carcinoma are recognized by the World Health Organization (WHO). Type 1 is squamous cell carcinoma; type 2 is nonkeratinizing squamous cell carcinoma; and type 3 is undifferentiated carcinoma. Children with nasopharyngeal carcinoma are more likely to have WHO type 2 or type 3 disease.
Nasopharyngeal carcinoma commonly presents as nosebleeds, nasal congestion and obstruction, or otitis media. Given the rich lymphatic drainage of the nasopharynx, bilateral cervical lymphadenopathies are 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 tests should determine the extent of the primary tumor and whether there are metastases. Visualization of the nasopharynx by an ear-nose-throat specialist using nasal endoscopy, examination by a neurologist, 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 of 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 should benign conditions such as nasal angiofibroma, which usually presents with epistaxis in adolescent males, and infectious lymphadenitis. Evaluation of the chest and abdomen by computed tomography and bone scan should also be performed to determine whether there is metastatic disease.
Tumor staging is performed utilizing the tumor-node-metastasis classification system of the American Joint Committee on Cancer (AJCC). The majority (>90%) of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).[6,10,11] Metastatic disease at diagnosis is uncommon (stage IVC). 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, higher risk of developing a second malignancy, and a superior outcome after controlling for stage.
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 are in excess of 80%.[5,6,11,12] However, the intensive use of chemotherapy and radiation therapy results in significant acute and long-term morbidities.[6,11]
Treatment of nasopharyngeal carcinoma is multimodal:
(Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)
Esthesioneuroblastoma (olfactory neuroblastoma) is a small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[23,24,25,26] In children, esthesioneuroblastoma is a very rare malignancy with an estimated incidence of 0.1 per 100,000 children younger than 15 years. Despite its rarity, esthesioneuroblastoma is the most common cancer of the nasal cavity in pediatric patients, accounting for 28% of all cases.[27,28] In a series of 511 patients from the SEER database, there was a slight male predominance, the mean age at presentation was 53 years, and only 8% of cases were younger than 25 years. Most patients were white (81%) and the most common tumor sites were the nasal cavity (72%) and ethmoid sinus (13%).
Most children present in the second decade of life with symptoms that include nasal obstruction, epistaxis, hyposmia, exophthalmos, or a nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe. Most patients present with advanced-stage disease (Kadish stages B and C).[27,28]
A meta-analysis of 26 studies with a total of 390 patients, largely adults with esthesioneuroblastoma, indicates that higher histopathologic grade and metastases to the cervical lymph nodes may correlate with adverse prognostic factors.
The mainstay of treatment has been surgery and radiation. Newer techniques such as endoscopic sinus surgery may offer similar short-term outcomes to open craniofacial resection. 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. Nodal metastases are seen in about 5% of patients. Routine neck dissection and nodal exploration are not indicated in the absence of clinical or radiological evidence of disease. Management of cervical lymph node metastases has been addressed in a review article.
Reports indicate the increasing use of neoadjuvant or adjuvant chemotherapy in patients with advanced-stage disease with promising results.[23,24,34,35,36]; [Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include etoposide with ifosfamide and cisplatin; vincristine, actinomycin D, and cyclophosphamide with and without doxorubicin; ifosfamide/etoposide; cisplatin plus etoposide or doxorubicin;  and irinotecan plus docetaxel.[Level of evidence: 3iiA]
The use of multimodal therapy optimizes the chances for survival with over 70% of children expected to survive 5 or more years following initial diagnosis.[27,34]
The annual incidence of thyroid cancers is low in children younger than 15 years (2.0 per 1 million people), accounting for approximately 1.5% of all cancers in this age group. Thyroid cancer incidence is higher in children aged 15 to 19 years (17.6 per 1 million people), and it accounts for approximately 8% of cancers arising in this older age group. Most thyroid carcinomas occur in girls.
There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[41,42] In the decade following the Chernobyl nuclear incident, there was a tenfold increase in the incidence of thyroid cancer compared to the previous and following decades. In this group of patients with exposure to low-dose radiation, tumors commonly show a gain of 7q11. When occurring in patients with the multiple endocrine neoplasia syndromes, thyroid cancer may be associated with the development of other types of malignant tumors. (Refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information.)
Tumors of the thyroid are classified as adenomas or carcinomas.[45,46,47,48,49] Adenomas are benign growths 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 then may grow and spread to lymph nodes in the neck or to the lungs. Approximately 20% of thyroid nodules in children are malignant.[45,50]
Various histologies account for the general diagnostic category of carcinoma of the thyroid:[42,51]
Studies have shown subtle differences in the genetic profiling of childhood differentiated thyroid carcinomas compared with adult tumors. A higher prevalence of RET/PTC rearrangements is seen in pediatric papillary carcinoma (45%–65% vs. 3%–34% in adults). Conversely, BRAF V600E mutations, which are seen in more than 50% of adults with papillary thyroid carcinoma, are extremely rare in children.
Patients with thyroid cancer usually present with a thyroid mass with or without cervical adenopathy.[57,58,59,60] Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. Compared with adults, children have a higher proportion of nodal involvement (40%–90% vs. 20%–50%) and lung metastases (20%–30% vs. 2%). Likewise, when compared to 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.
Initial evaluation of a child or adolescent with a thyroid nodule should include the following:
Tests of thyroid function are usually normal, but thyroglobulin can be elevated.
Fine-needle aspiration as an initial diagnostic approach is sensitive and useful. However, in doubtful cases, open biopsy or resection should be considered.[62,63,64,65] Open biopsy or resection may be preferable for young children as well.
Treatment of papillary and follicular thyroid carcinoma
The management of differentiated thyroid cancer in children has been reviewed in detail. Also, the American Thyroid Association Taskforce  has developed guidelines for management of thyroid nodules and differentiated thyroid cancer in older adolescents and adults; however, it is not yet known how to apply these guidelines to thyroid nodules in children.
Surgery performed by an experienced thyroid surgeon is the treatment required for all thyroid neoplasms.[52,55] For patients with papillary or follicular carcinoma, total or near-total thyroidectomy plus cervical lymph node dissection is the recommended surgical approach.[52,57,67] This aggressive approach is indicated for several reasons:
However, for patients with a small (<1 cm) unifocal nodule, treatment may involve only a lobectomy.[50,57,68]
The use of radioactive iodine ablation for the treatment of children with differentiated thyroid carcinoma has increased over the years. Despite surgery, most children have a significant radioactive iodine uptake in the thyroid bed, and studies have shown increased local recurrence rates for patients who did not receive radioactive iodine after total thyroidectomy compared with those who did receive radioactive iodine. Thus, it is currently recommended that children receive an ablative dose after initial surgery.[45,50,55] For successful remnant ablation, serum TSH levels must be elevated to allow for maximal radioactive iodine uptake; this can usually be achieved with thyroid hormone withdrawal for 3 to 4 weeks after thyroidectomy. A radioactive iodine (I-131) scan is then performed to search for residual, functionally active neoplasm. If there is no disease outside of the thyroid bed, an ablative dose of I-131 (approximately 30 mCi) is administered for total thyroid destruction. If there is evidence of nodal or disseminated disease, higher doses (100–200 mCi) of I-131 are required.[Level of evidence: 3iDiv] In younger children, the I-131 dose may be adjusted for weight (1–1.5 mCi/kg).[45,71,72] After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress TSH production.
Initial treatment (defined as surgery plus one radioactive iodine ablation plus thyroid replacement) is effective in inducing remission for 70% of patients. Extensive disease at diagnosis and larger tumor size predict failure to remit. With additional treatment, 89% of patients achieve remission.
Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary. T4 and TSH levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed. If thyroglobulin levels rise above postthyroidectomy baseline levels, recurrence of the disease is possible, and physical examination and imaging studies should be repeated. The use of various tyrosine kinase inhibitors or vascular endothelial growth factor receptor inhibitors has shown promising results in patients with metastatic or recurrent thyroid cancer in adults.[76,77,78,79]
Treatment of recurrent papillary and follicular thyroid carcinoma
Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[75,80,81] Recurrence is common (35%–45%), however, and is seen more often in children younger than 10 years and in those with palpable cervical lymph nodes at diagnosis.[47,82,83] Even patients with a tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment. Of note, the sodium-iodide symporter (a membrane-bound glycoprotein cotransporter), essential for uptake of iodide and thyroid hormone synthesis, is expressed in 35% to 45% of thyroid cancers in children and adolescents. Patients with expression of the sodium-iodide symporter have a lower risk of recurrence.
Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation. Tyrosine kinase inhibitors such as sorafenib have shown to induce responses in up to 15% of adult patients with metastatic disease. Responses to sorafenib have also been documented in pediatric cases. Given the high incidence of BRAF mutations in older patients with papillary thyroid carcinoma, the use of selective RAF/MEK inhibitors is being investigated.[76,88,89]
Treatment of medullary thyroid carcinoma
Medullary thyroid carcinomas are commonly associated with the MEN2 syndrome (refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary for more information). They present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis. Patients with medullary carcinoma of the thyroid have a guarded prognosis, unless they have very small tumors (microcarcinoma, defined as <1.0 cm in diameter), which carry a good prognosis.
Treatment for children with medullary thyroid carcinoma is mainly surgical. A recent review of 430 patients aged 0 to 21 years with medullary thyroid cancer reported 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. 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 in children with the RET germline mutation. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur. A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (NCT01660984).
A number of tyrosine kinase inhibitors have been evaluated for patients with unresectable medullary thyroid cancer. Vandetanib (an inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling) is FDA-approved 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 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).[93,94] A phase I trial of vandetanib for children has been completed. Cabozantinib (an inhibitor of the RET and MET kinases and vascular endothelial growth factor receptor) has also shown activity against unresectable medullary thyroid cancer (10 of 35 patients [29%] had a partial response).
(Refer to the Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex section of this summary 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 Web site.
The vast majority (>90%) of tumors and tumor-like lesions in the oral cavity are benign.[97,98,99,100] Cancer of the oral cavity is extremely rare in children and adolescents. 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 per 100,000.[101,102]
The incidence of cancer of the oral cavity 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 papilloma virus (HPV) infection. It is currently estimated that the prevalence of oral HPV infection in the United States is 6.9% in people aged 14 to 69 years and that HPV causes about 30,000 oropharyngeal cancers. Furthermore, the incidence rates for HPV-related oropharyngeal cancer from 1999 to 2008 have increased by 4.4% per year in white men and 1.9% in white women.[104,105,106] Current practices to increase HPV immunization rates in both boys and girls may reduce the burden of HPV-related noncervical cancers.
Benign odontogenic neoplasms include odontoma and ameloblastoma. The most common nonodontogenic neoplasms are fibromas, hemangiomas, and papillomas. Tumor-like lesions include lymphangiomas, granulomas, and eosinophilic granuloma (Langerhans cell histiocytosis; refer to the Oral mucosa subsection in the PDQ summary on Langerhans Cell Histiocytosis Treatment for more information).
Malignant lesions were found in 0.1% to 2% of a series of oral biopsies performed in children [97,98] and 3% to 13% of oral tumor biopsies.[99,100] Malignant tumor types include lymphomas (especially Burkitt) and sarcomas (including rhabdomyosarcoma and fibrosarcoma). Mucoepidermoid carcinomas have rarely been reported in the pediatric and adolescent age group. Most are low grade and have a high cure rate with surgery alone.; [Level of evidence: 3iiA]
The most common type of primary oral cancer in adults, squamous cell carcinoma (SCC), is extremely rare in children. Review of the SEER database identified 54 patients younger than 20 years with oral cavity SCC between 1973 and 2006. Pediatric patients with oral cavity SCC were more often female and had better survival than adult patients. When differences in patient, tumor, and treatment-related characteristics are adjusted for, the two groups experienced equivalent survival.[Level of evidence: 3iA] Diseases that can be associated with the development of oral SCC include Fanconi anemia, dyskeratosis congenita, connexin mutations, chronic graft-versus-host disease, epidermolysis bullosae, xeroderma pigmentosum, and HPV infection.[110,111,112,113,114,115,116,117]
Treatment of benign oral tumors is surgical. Management of malignant tumors is dependent on histology and may include surgery, chemotherapy, and radiation. Langerhans cell histiocytosis may require other treatment besides surgery. (Refer to the PDQ summaries on adult Oropharyngeal Cancer Treatment; Lip and Oral Cavity Cancer Treatment; and Langerhans Cell Histiocytosis Treatment for more information.)
Most reported cases of SCC managed with surgery alone have done well without recurrence.[108,119]
Salivary Gland Tumors
Salivary gland tumors are rare and account for 0.5% of all malignancies in children and adolescents. Most salivary gland neoplasms arise in the parotid gland.[121,122,123,124,125] About 15% of these tumors may arise in the submandibular glands or in the minor salivary glands under the tongue and jaw. These tumors are most frequently benign but may be malignant, especially in young children. Overall 5-year survival in the pediatric age group is approximately 95%.
The most common malignant lesion is mucoepidermoid carcinoma.[120,128,129] Less common malignancies include acinic cell carcinoma, rhabdomyosarcoma, adenocarcinoma, adenoid cystic carcinoma, and undifferentiated carcinoma. These tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[130,131] Mucoepidermoid carcinoma is the most common type of treatment-related salivary gland tumor, and with standard therapy, the 5-year survival is about 95%.[132,133]
Radical surgical removal is the treatment of choice for salivary gland tumors whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.[127,129,134,135]
(Refer to the PDQ summary on adult Salivary Gland Cancer Treatment for more information.)
Sialoblastomas are usually benign tumors presenting in the neonatal period and rarely metastasize. Chemotherapy regimens with carboplatin, epirubicin, vincristine, etoposide, dactinomycin, doxorubicin, and ifosfamide have produced responses in two children with sialoblastoma.; [Level of evidence: 3iiiDiv]
Laryngeal Cancer and Papillomatosis
Tumors of the larynx are rare. The most common benign tumor is subglottic hemangioma. Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[140,141] These tumors may cause hoarseness, difficulty swallowing, and enlargement of the lymph nodes of the neck.
Rhabdomyosarcoma is the most common malignant tumor of the larynx in the pediatric age group and is usually managed with chemotherapy and radiation therapy following biopsy, rather than laryngectomy. SCC of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation. Laser surgery may be the first type of treatment utilized for these lesions.
Papillomatosis of the larynx is a benign overgrowth of tissues lining the larynx and is associated with the HPV, most commonly HPV-6 and HPV-11. The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6. These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may rarely extend into the lung, producing significant morbidity. Malignant degeneration may occur with development of cancer in the larynx and squamous cell lung cancer.
Papillomatosis is not cancerous, and primary treatment is surgical ablation with laser vaporization. Frequent recurrences are common. Lung involvement, though rare, can occur. If a patient requires more than four surgical procedures per year, treatment with interferon may be considered. A pilot study of immunotherapy with HspE7, a recombinant fusion protein that has shown activity in other HPV-related diseases, has suggested a marked increase in the amount of time between surgeries. These results, however, must be confirmed in a larger randomized trial.
(Refer to the PDQ summary on adult Laryngeal Cancer Treatment for more information.)
Midline Tract Carcinoma Involving theNUTGene (NUT Midline 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 an unknown partner gene; these tumors are termed NUT-variant.
The tumors arise in midline epithelial structures, typically mediastinum and upper aerodigestive track, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation. Although the original description of this neoplasm was made in children and young adults, patients of all ages can be affected. 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.[150,151]
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 a case of a child with refractory disease, thus suggesting a potential role for this class of agents in the treatment of this malignancy.
Thoracic cancers include breast cancer, bronchial adenomas, bronchial carcinoid tumors, pleuropulmonary blastoma, esophageal tumors, thymomas, thymic carcinomas, cardiac tumors, and 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.
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 biopsy. However, rare malignant transformation leading to phyllodes tumors has been reported. Sudden rapid enlargement of a suspected fibroadenoma is an indication for needle biopsy or excision. Phyllodes tumors can be managed by wide local excision without mastectomy.
Malignant breast tumors
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 shows that 75 cases of malignant breast tumors in females 19 years or younger were identified from 1973 to 2004. Fifteen percent of these patients had in situ disease, 85% had invasive disease, 55% of the tumors were carcinomas, and 45% of the tumors were sarcomas—most of which were phyllodes tumors. Only three patients in the carcinoma group presented with metastatic disease, while 11 patients (27%) had regionally advanced disease. All patients with sarcomas presented with localized disease. Of the carcinoma patients, 85% underwent surgical resection, and 10% received adjuvant radiation therapy. Of the sarcoma patients, 97% had surgical resection, and 9% received radiation. The 5- and 10-year survival rates for patients with sarcomatous tumors were both 90%; for patients with carcinomas, the 5-year survival rate was 63% and the 10-year survival rate was 54%.
Breast cancer is the most frequently diagnosed cancer among adolescent and young adult (AYA) women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses. Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different than in older women and correlates with a worse prognosis. Treatment in the AYA group is similar to that in older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.
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.[9,15,16,17,18] Carcinomas are more frequent than sarcomas. Mammograms with adjunctive breast magnetic resonance imaging (MRI) should 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.) 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).
(Refer to the PDQ summary on adult Breast Cancer Treatment for more information.)
Primary lung tumors are rare in children and histologically quite diverse. When epithelial cancers of the lung occur, they tend to be of advanced stage with prognosis dependent on both histology and stage. The majority of pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5. While primary pulmonary tumors are rare in children, the majority of these tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign. These tumors may respond to the ALK inhibitor crizotinib in the presence of ALK translocations.[Level of evidence: 3iiiDiv]
The most common malignant primary tumors of the lung, bronchial tumors and pleuropulmonary blastoma, are discussed below.
Bronchial tumors are a heterogeneous group of primary endobronchial lesions, and though adenoma implies a benign process, all varieties of bronchial tumors on occasion display a malignant behavior. There are three histologic types:[23,24,25,26,27,28]
Bronchial tumors of all histologic types are associated with an excellent prognosis in children, even in the presence of local invasion.[29,30]
The presenting symptoms of a cough, recurrent pneumonitis, and hemoptysis are usually due to an incomplete bronchial obstruction. 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 as long as 4 to 5 years.
Metastatic lesions are reported in approximately 6% of carcinoid tumors and recurrences are reported in 2% of cases. Atypical carcinoid tumors are rare but more aggressive with 50% of patients presenting with metastatic disease at diagnosis.[19,32] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome. Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread.
The management of bronchial tumors is somewhat controversial because bronchial tumors are usually visible endoscopically. Biopsy in these lesions may be hazardous because of hemorrhage, and endoscopic resection is not recommended. Bronchography or computed tomography scan may be helpful to determine the degree of bronchiectasis distal to the obstruction since the degree of pulmonary destruction may influence surgical therapy.
Conservative pulmonary resection, including sleeve segmental resection when feasible, with the removal of the involved lymphatics, is the treatment of choice.[35,36] 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 should be carried out in children with this lesion. Neither chemotherapy nor radiation therapy is indicated for bronchial tumors, unless evidence of metastasis is documented.
Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. Pleuropulmonary blastoma appears to progress through the following stages:
The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the heart/great vessels, mediastinum, diaphragm, and/or pleura.[42,43] The International Pleuropulmonary Blastoma Registry identified 11 cases of Type II and Type III pleuropulmonary blastoma with tumor extension into the thoracic great vessels or the heart. Radiographic evaluation of the central circulation should be performed in children with suspected or diagnosed pleuropulmonary blastoma to identify potentially fatal embolic complications.
Approximately one-third of families affected by 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.[45,46] A family history of cancer in close relatives has been noted for many young patients affected by this tumor.[47,48] In addition, pleuropulmonary blastoma has been reported in siblings. There has been a reported association between pleuropulmonary blastoma and cystic nephroma, ciliary body medulloepithelioma of the eye, and primary ovarian neoplasms, particularly ovarian sex cord–stromal tumors.[46,50,51,52,53] 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.
Achieving total resection of the tumor at any time during treatment is associated with improved prognosis. The tumors may recur or metastasize, in spite of primary resection.[38,41] The cerebral parenchyma is the most common metastatic site. Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma, and adjuvant chemotherapy may benefit patients with Type I pleuropulmonary blastoma by reducing the risk of recurrence.[40,54] Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, doxorubicin, and irinotecan. High-dose chemotherapy with stem cell rescue has been used without success. Radiation, either external beam or P-32, may be used when the tumor cannot be surgically removed. Data from the International Pleuropulmonary Blastoma Registry suggest that adjuvant chemotherapy may reduce the risk of recurrence.
There are no standard treatment options. Current treatment regimens have been informed by consensus conferences. The rare occurrence of these tumors makes recommending treatment difficult. Some general treatment considerations from the Pleuropulmonary Blastoma Registry include:
An independent group of researchers has established a registry and resource Web site for this rare tumor.
Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[60,61] Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma.
Symptoms are related to difficulty in swallowing and associated weight loss. Diagnosis is made by histologic examination of biopsy tissue.
Treatment options for esophageal carcinoma include either external-beam intracavitary radiation therapy or chemotherapy agents commonly used to treat carcinomas: platinum derivatives, paclitaxel, and etoposide. Prognosis is generally poor for this cancer, which rarely can be completely resected.
(Refer to the PDQ summary on adult Esophageal Cancer Treatment for more information.)
Thymoma and Thymic Carcinoma
A cancer of the thymus is not considered a thymoma or a thymic carcinoma unless there are neoplastic changes of the epithelial cells that cover the organ.[62,63,64] The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component. Thymic carcinomas have a higher incidence of capsular invasion and metastases. A thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as thymic carcinoma, also known as type C thymoma. Other tumors that involve the thymus gland include lymphomas, germ cell tumors, carcinomas, carcinoids, and thymomas. Hodgkin lymphoma and non-Hodgkin lymphoma may also involve the thymus and must be differentiated from true thymomas and thymic carcinomas.
Thymoma and thymic carcinomas are very rare in children.[65,66] In the Tumori Rari in Età Pediatrica (TREP) registry, only eight cases were identified over a 9-year period. Various diseases and syndromes are associated with thymoma, including myasthenia gravis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, Isaacs syndrome or neuromyotonia (continuous muscle stiffness resulting from persistent muscle activity as a consequence of antibodies against voltage-gated potassium channels), and pure red-cell aplasia.[68,69] Endocrine (hormonal) disorders including hyperthyroidism, Addison disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.
These neoplasms are usually located in the anterior mediastinum and are usually discovered during a routine chest x-ray. Symptoms can include cough, difficulty with swallowing, tightness of the chest, chest pain, and shortness of breath, although nonspecific symptoms may occur. These tumors generally are slow growing but are potentially invasive, with metastases to distant organs or lymph nodes. Staging is related to invasiveness.
Surgery is performed with the goal of a complete resection and is the mainstay of therapy. Radiation therapy is used in patients with invasive thymoma or thymic carcinoma, and chemotherapy is usually reserved for patients with advanced-stage disease who have not responded to radiation therapy or corticosteroids. Agents that have been effective include doxorubicin, cyclophosphamide, etoposide, cisplatin, ifosfamide, and vincristine.[64,67,70,71,72,73] Responses to regimens containing combinations of some of these agents have ranged from 26% to 100% and survival rates have been as high as 50%.[73,74] Response rates are lower for patients with thymic carcinoma, but 2-year survival rates have been reported to be as high as 50%. Sunitinib has yielded clinical responses in four patients with adult thymic carcinoma.
The most common primary tumors of the heart are benign. In adults, myxoma is the most common tumor; however, these tumors are rare in children. The most common primary heart tumors in children are rhabdomyomas and fibromas.[78,79,80,81] Other benign tumors include myxomas (as noted above), histiocytoid cardiomyopathy tumors, teratomas, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[78,80,82,83,84] Myxomas are the most common noncutaneous finding in Carney complex, a rare syndrome characterized by lentigines, cardiac myxomas or other myxoid fibromas, and endocrine abnormalities.[85,86,87] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[85,88] Primary malignant pediatric heart tumors are rare but may include malignant teratomas, rhabdomyosarcomas, chondrosarcomas, infantile fibrosarcoma, and other sarcomas.[78,89]
The utilization of new cardiac MRI techniques can identify the likely tumor type in the majority of children. However, histologic diagnosis remains the standard for diagnosing cardiac tumors.
The distribution of cardiac tumors in the fetal and neonatal period is different, with more benign teratomas occurring. Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis. A retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography shows that 68% of the patients exhibited features of tuberous sclerosis. In another study, 79% (15 out of 19) of patients with rhabdomyomas discovered prenatally had tuberous sclerosis, while 96% of those diagnosed postnatally had tuberous sclerosis. Most rhabdomyomas, whether diagnosed prenatally or postnatally, will spontaneously regress.
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, and carcinoma of other sites. Patients may be asymptomatic for long periods. Symptoms may include abnormalities of heart rhythm, enlargement of the heart, fluid in the pericardial sac, and congestive heart failure. Some patients present with sudden death. Successful treatment may require surgery, including transplantation, and chemotherapy appropriate for the type of cancer that is present.[93,94,95]; [Level of evidence: 3iiA]
Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life. Fewer than 300 cases in children have been reported.
This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[98,99,100] These tumors can spread over the surface of organs, without invading far into the underlying tissue, and may spread to regional or distant lymph nodes. Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.[101,102] In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation. The amount of exposure required to develop cancer is unknown, and there is no information about the risk for children exposed to asbestos.
Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive or for those that recur. In general, the course of the disease is slow, and long-term survival is common. Diagnostic thoracoscopy should be considered in suspicious cases to confirm diagnosis.
Radical surgical resection has been attempted with mixed results. Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[100,105] Pain is an infrequent symptom; however, radiation therapy may be used for palliation of pain.
Papillary serous carcinoma of the peritoneum is sometimes mistaken for mesothelioma. This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel.
(Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)
Abdominal cancers include adrenocortical tumors, carcinomas of the stomach, cancer of the pancreas, colorectal carcinomas, carcinoid tumors, and gastrointestinal stromal tumors. The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series. (Refer to the Renal Cell Carcinoma section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors for more information.)
Carcinoma of the Adrenal Cortex
Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior. Their incidence in children is extremely low (only 0.2% of pediatric cancers). Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[2,3] In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million. Internationally, however, the incidence of adrenocortical tumors appear to vary substantially. The incidence of adrenocortical tumors is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[5,6,7] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[8,9,10,11] Female gender is consistently predominant in most studies, with a female to male ratio of 1.6 to 1.
Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe, and in 95% of the Brazilian cases. Germline TP53 mutations are almost always the predisposing factor. In the non-Brazilian cases, relatives of children with adrenocortical tumors often, though not invariably, have a high incidence of other non-adrenal cancers (Li-Fraumeni syndrome), and germline mutations usually occur within the region coding for the TP53 DNA-binding domain (exons 5 to 8, primarily at highly conserved amino acid residues). In the Brazilian cases, in contrast, the patients' families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed. Patients with Beckwith-Wiedemann and hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors. However, less than 1% of children with adrenocortical tumors have these syndromes. The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.
Unlike adult adrenocortical tumors, histologic differentiation of adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,9] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenoma and carcinoma appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation. Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[18,19] However, morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[21,22] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from characteristics, such as venous, capsular, or adjacent organ invasion; tumor necrosis; mitotic rate; and the presence of atypical mitoses.
Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[3,9] Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) due to excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3,9,23] Likewise, nonfunctional tumors are rare (<10%) and tend to occur in older children. Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.
In patients with localized disease, age between 0 and 3 years, virilization alone, normal blood pressure, disease stage I, absence of spillage during surgery, and tumor weight no greater than 200 grams were associated with a greater probability of survival. In a Cox regression model analysis, only stage I, virilization alone, and age 0 to 3 years were independently associated with a better outcome. Available data suggest that tumor size is especially important in children; patients with small tumors have an excellent outcome with surgery alone, regardless of histologic features. The overall probability of 5-year survival for children with adrenocortical tumors is reported to be 54% to 74%.[3,9,10,23,24]
Treatment of adrenocortical tumors
At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.
Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used; surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[7,25,26] An aggressive surgical approach of the primary tumor and all metastatic sites is recommended when feasible. Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (approximately 20% of initial resections and 43% of resections after recurrence).[3,10] When the diagnosis of adrenocortical tumor is suspected, laparotomy and a curative procedure are recommended rather than fine-needle aspiration, to avoid the risk of tumor rupture. Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.
Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[1,25] A retrospective analysis in Italy and Germany identified 177 adult patients with adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 to 5 g per day. In a review of 11 children with advanced adrenocortical tumors treated with mitotane and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was around 4 g/m2, and therapeutic levels were achieved after 4 to 6 months of therapy.
The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. One study reported three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.
(Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)
Carcinoma of the Stomach
Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual. In one series, gastric cancer in children younger than 18 years accounted for 0.11% of all gastric cancer cases seen over an 18-year period. The frequency and death rate from stomach cancer has declined worldwide for the past 50 years with the introduction of food preservation practices such as refrigeration.
The tumor must be distinguished from other conditions such as non-Hodgkin lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach. Symptoms include vague upper abdominal pain, which can be associated with poor appetite and weight loss. Other symptoms may include nausea, vomiting, change in bowel habits, poor appetite, weakness, and Helicobacter pylori infection.[33,35] Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread. Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to confirm the diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.
Treatment should include surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as fluorouracil (5-FU) and irinotecan. Other agents that may be of value are the nitrosoureas with or without cisplatin, etoposide, doxorubicin, or mitomycin C.
Prognosis depends on the extent of the disease at the time of diagnosis and the success of treatment that is appropriate for the clinical situation. Because of the rarity of stomach cancer in the pediatric age group, little information exists regarding the treatment outcomes of children.
(Refer to the PDQ summary on adult Gastric Cancer Treatment for more information.)
Cancer of the Pancreas
Malignant pancreatic tumors are rare in children and adolescents with an incidence of 0.46 cases per 1 million (younger than 30 years).[37,38,39,40] Tumors included in this general category can arise at any site within the pancreas. Cancers of the pancreas may be classified as adenocarcinomas, squamous cell carcinomas, acinic cell carcinomas, liposarcomas, lymphomas, papillary-cystic carcinomas, pancreatoblastomas, malignant insulinomas, glucagonomas, and gastrinomas.[41,42,43,44,45] Several cases of primitive neuroectodermal tumor of the pancreas have been reported in children and young adults. Pancreatoblastoma is reported to be associated with Beckwith-Wiedemann syndrome and Cushing syndrome.[47,48]
Most malignant pancreatic tumors are carcinomas and do not secrete hormones, although some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.[40,41,49] If the tumor interferes with the normal function of the islet cells, patients may have watery diarrhea or abnormalities of salt balance. Both carcinoma of the pancreas and pancreatoblastoma can produce active hormones and can be associated with an abdominal mass, wasting, and pain.[50,51,52] At times, there is obstruction of the head of the pancreas, which is associated with jaundice and gastrointestinal bleeding. Elevation of alpha-fetoprotein has been seen in pancreatoblastoma and acinar cell carcinoma.[44,53,54,55]
Diagnosis of pancreatic tumors is usually established by biopsy, using laparotomy or a minimally invasive surgery (e.g., laparoscopy). A diagnosis can be achieved only after ruling out various benign and cancerous lesions.
Solid pseudopapillary neoplasm of the pancreas is a rare tumor of borderline malignancy that has been reported in children but more commonly occurs in young women.[56,57,58,59] Treatment consists of complete tumor resection (ideally without biopsy). Metastases may occur, but in general, prognosis is good following surgery alone.[45,60,61]; [Level of evidence: 3iiA]; [Level of evidence: 3iiDi]
Treatment includes various surgical procedures to remove the pancreas and duodenum or removal of part of the pancreas. Complete resection is usually possible and long-term survival is likely, though pancreatoblastoma has a high recurrence rate.[42,53]; [Level of evidence: 3iiA] For pediatric patients, the effectiveness of radiation therapy is not known. Chemotherapy may be useful for treatment of localized or metastatic pancreatic carcinoma. The combination of cisplatin and doxorubicin has produced responses in pancreatoblastoma prior to tumor resection.[65,66] Postoperative treatment with cisplatin, doxorubicin, ifosfamide, and etoposide has also produced responses in patients with pancreatoblastoma, although surgery is the mainstay of therapy.; [Level of evidence: 3iiiA] Other agents that may be of value include 5-FU, streptozotocin, mitomycin C, carboplatin, gemcitabine, and irinotecan. Response rates and survival rates generally are not good.
(Refer to the PDQ summary on adult Pancreatic Cancer Treatment for more information.)
Carcinoma of the large bowel is rare in the pediatric age group. It is seen in one per 1 million persons younger than 20 years in the United States annually, and fewer than 100 cases are diagnosed in children each year in the United States. From 1973 to 2006, the SEER database recorded 174 cases of colorectal cancer in patients younger than 19 years.
In children, 40% to 60% of tumors arise on the right side of the colon, in contrast to adults who have a prevalence of tumors on the left side. Most reports also suggest that children present with more advanced disease and have a worse outcome.[68,70,71,72,73,74,75,76,77,78,79,80,81,82]
Most tumors in the pediatric age group are poorly differentiated mucin-producing carcinomas and many are of the signet ring cell type,[68,71,75] whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. In the adolescent and young adult population, colorectal cancers have a higher incidence of mucinous histology, signet ring cells, microsatellite instability, and mutations in the mismatch repair genes. These tumors arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls. Colorectal cancers in younger patients have a high incidence of microsatellite instability, and noninherited sporadic tumors in younger patients often lack KRAS mutations and other cytogenetic anomalies seen in older patients.
Genetic syndromes associated with colorectal cancer
About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome. The incidence of these syndromes in children has not been well defined. In one review, 16% of patients younger than 40 years had a predisposing factor for the development of colorectal cancer. A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger. The most common genetic syndromes associated with the development of colorectal cancer are shown in Tables 3 and 4.
Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminates the risk of developing carcinomas of the large bowel. Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma. The familial APC syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps. A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with familial adenomatous polyposis (FAP) reported that celecoxib at a dose of 16 mg/kg/day is safe for administration for up to 3 months. At this dose, there was a significant decrease in the number of polyps detected on colonoscopy.[Level of evidence: 1iiDiv] The role of celecoxib in the management of FAP is not known.
Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I and several other rare syndromes.
Presenting symptoms are nonspecific and include abdominal pain, weight loss, change in bowel habits, anemia, and bleeding; the median duration of symptoms was about 3 months in one series.[68,71,94] Changes in bowel habits may be associated with tumors of the rectum or lower colon. Tumors of the right colon may cause more subtle symptoms but are often associated with an abdominal mass, weight loss, decreased appetite, and blood in the stool. Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.
Diagnostic studies that may be of value include examination of the stool for blood, studies of liver and kidney function, measurement of carcinoembryonic antigen, and various medical imaging studies, including direct examination using colonoscopy to detect polyps in the large bowel. Other conventional radiographic studies include barium enema or video-capsule endoscopy followed by computed tomography of the chest and bone scans.[81,84,95]
Most patients present with evidence of metastatic disease, either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[73,75] Complete surgical excision is the most important prognostic factor and should be the primary aim of the surgeon, but in most instances this is impossible; removal of large portions of tumor provides little benefit for the individuals with extensive metastatic disease. Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.
Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using 5-FU with leucovorin. Other agents, including irinotecan, may be of value.[Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alpha given in conjunction with 5-FU/leucovorin. A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved progression-free and overall survival (OS) in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.
(Refer to the PDQ summaries on adult Colon Cancer Treatment and Rectal Cancer Treatment for more information.)
These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[99,100,101,102,103,104] Most lung lesions are benign; however, some metastasize.
Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, localized tumors; simple appendectomy is the therapy of choice.[106,107] For larger (>2 cm) tumors or tumors that have spread to local nodes, cecectomy or rarely, right hemicolectomy, is the usual treatment. It has become accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (>2 cm in diameter) or with tumors that have spread to the nodes; however, this practice remains controversial. A MEDLINE search did not find any documented cases of childhood localized appendiceal carcinoid in children younger than 18 years with complete resection who relapsed. Treatment of metastatic carcinoid tumors of the large bowel or stomach becomes more complicated and requires treatment similar to that given for colorectal carcinoma. (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors for therapeutic options in patients with malignant carcinoid tumors.)
The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver. Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms. Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.
Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults. These tumors are rare in children. Approximately 2% of all GIST occur in children and young adults;[114,115,116] in one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas. Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas. In pediatric patients, GIST are most commonly located in the stomach and usually occur in adolescent females.[118,119]
Pediatric GIST can arise within the context of tumor predisposition syndromes. Approximately 10% of pediatric cases of GIST are associated with Carney triad or Carney-Stratakis syndrome.[118,120]
Familial GIST and neurofibromatosis 1–associated GIST occur in patients older than 40 years.[119,124,125]
Histology and molecular genetics
Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, their mitotic rate does not appear to accurately predict clinical behavior.[118,126] Most pediatric patients with GIST present during the second decade of life with anemia-related gastrointestinal bleeding. In addition, pediatric GIST have a high propensity for multifocality (23%) and nodal metastases.[118,127] These features may account for the high incidence of local recurrence seen in this patient population.
Pediatric GIST is biologically different from adult GIST. Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only 11% of pediatric GIST.[118,127,128] In addition, unlike adult KIT mutant GIST, pediatric GIST have minimal large-scale chromosomal changes and the expression of insulin-like growth factor 1 receptor (IGF1R) expression is significantly higher and amplified in these patients, suggesting that administration of an IGF1R inhibitor might be therapeutically beneficial in these patients.[128,129]
Recent studies have revealed that about 12% of patients with wild-type GIST and a negative history of paraganglioma have germline mutations in the SDHB or C gene. In addition, using immunohistochemistry, SDHB expression is absent in all pediatric wild-type GIST, implicating cellular respiration defects in the pathogenesis of this disease. Furthermore, these findings support the notion that pediatric patients with wild-type GIST should be offered testing for constitutional mutations for the SDH complex. The routine use of immunohistochemistry has documented lack of SDHB expression in 94% of children younger than 20 years with wild-type GIST and some investigators now favor the term SDH-deficient GIST. This group of patients lack KIT, PDGFR, and BRAF mutations in the primary tumor and lack SDHB immunoreactivity in the tumor. SDH-deficient GIST more commonly affects females, has an indolent clinical course, and occurs in the stomach.
Treatment of GIST
Once the diagnosis of pediatric GIST is established, it is recommended that patients be seen at centers with expertise in the treatment of GIST and that all samples be subjected to mutational analysis for KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[131,132]
Treatment of GIST varies based on whether a mutation is detected:
A randomized clinical trial in adults demonstrated that administration of adjuvant imatinib mesylate improved event-free survival in adult patients with GIST but this benefit was restricted to those with KIT exon 11 and PDGFR mutations, and thus the use of this agent in the adjuvant setting in pediatric wild-type GIST cannot be recommended. Responses to imatinib and sunitinib in pediatric patients with wild-type GIST are uncommon and consist mainly of disease stabilization.[118,134,135] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease. In another study, the clinical activity of sunitinib in six children with imatinib-resistant GIST was reported as one partial response and five stable disease.
Genital/urinary tumors include carcinoma of the bladder, non-germ cell testicular cancer, non-germ cell ovarian cancer, and carcinoma of the cervix and vagina. The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below. It must be emphasized that these tumors are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.
Carcinoma of the Bladder
Carcinoma of the bladder is extremely rare in children. The most common carcinoma to involve the bladder is papillary urothelial neoplasm of low malignant potential, which generally presents with hematuria.[1,2] In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have a good prognosis following transurethral resection.[2,3,4,5,6] Squamous cell and more aggressive carcinomas, however, have been reported and may require a more aggressive surgical approach.[7,8] Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.[9,10] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.
(Refer to the PDQ summary on adult Bladder Cancer Treatment for more information.)
Testicular Cancer (Non-Germ Cell)
Testicular tumors are very rare in young boys and account for an incidence of 1% to 2% of all childhood tumors.[11,12] The most common testicular tumors are benign teratomas followed by malignant non-seminomatous germ cell tumors. (Refer to the PDQ summary on Childhood Extracranial Germ Cell Tumors for more information.) Non-germ cell tumors such as sex cord–stromal tumors are exceedingly rare in prepubertal boys. In a small series, gonadal stromal tumors accounted for 8% to 13% of pediatric testicular tumors.;  In newborns and infants, juvenile granulosa cell tumors are the most common stromal cell tumor. In older males, Leydig cell tumors are more common. Stromal cell tumors have been described as benign in young boys.[16,17,18]
There are conflicting data about malignant potential in older males. Most case reports suggest that in the pediatric patients, these tumors can be treated with surgery alone.[Level of evidence: 3iii]; [Level of evidence: 3iiiA]; [Level of evidence: 3iiiDii] However, given the rarity of this tumor, the surgical approach in pediatrics has not been well studied.
Ovarian Cancer (Non-Germ Cell)
The majority of ovarian masses in children are not malignant. The most common neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then miscellaneous tumors such as Burkitt lymphoma.[20,21,22,23] The majority of ovarian tumors occur in girls aged 15 to 19 years.
Epithelial ovarian neoplasia
Ovarian tumors derived from malignant epithelial elements include: adenocarcinomas, cystadenocarcinomas, endometrioid tumors, clear cell tumors, and undifferentiated carcinomas. In one series of 19 patients younger than 21 years with epithelial ovarian neoplasms, the average age at diagnosis was 19.7 years. Dysmenorrhea and abdominal pain were the most common presenting symptoms; 79% of the patients had stage I disease with a 100% survival rate, and only those who had small cell anaplastic carcinoma died. Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than adults with similar histology, probably because girls usually present with low-stage disease.
Treatment is stage-related and may include surgery, radiation, and chemotherapy with cisplatin, carboplatin, etoposide, topotecan, paclitaxel, and other agents.
Sex cord–stromal tumors
Ovarian sex cord–stromal tumors are a heterogeneous group of rare tumors that derive from the gonadal non-germ cell component. Histologic subtypes display some areas of gonadal differentiation and include juvenile granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. Ovarian sex-cord stromal tumors in children and adolescents are commonly associated with the presence of germline DICER1 mutations and may be a manifestation of the familial pleuropulmonary blastoma syndrome.
The most common histologic subtype in girls younger than 18 years is juvenile granulosa cell tumors (median age, 7.6 years; range, birth to 17.5 years).[29,30] Juvenile granulosa cell tumors represent about 5% of ovarian tumors in children and adolescents and are distinct from the granulosa cell tumors seen in adults.[27,31,32,33] Most patients with juvenile granulosa cell tumors present with precocious puberty. Other presenting symptoms include abdominal pain, abdominal mass, and ascites. Juvenile granulosa cell tumors has been reported in children with Ollier disease and Maffucci syndrome.
As many as 90% of children with juvenile granulosa cell tumors will have low-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I) and are usually curable with unilateral salpingo-oophorectomy alone. Patients with advanced disease (FIGO stage II–IV) and those with high mitotic activity tumors have a poorer prognosis. Use of a cisplatin-based chemotherapy regimen has been reported in both the adjuvant and recurrent disease settings with some success.[29,33,36,37,38]
Sertoli-Leydig cell tumors are rare in young girls but may present with virilization  or precocious puberty.[40,41] These tumors may also be associated with Peutz-Jeghers syndrome.
Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia. Successful treatment with aggressive therapy has been reported in a few cases.[Level of evidence: 3iiB]; [44,45][Level of evidence: 3iiiA]
Carcinoma of the Cervix and Vagina
Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence with fewer than 50 reported cases.[23,46] Two-thirds of the cases are related to the exposure of diethylstilbestrol in utero. The median age at presentation is 15 years, with a range of 7 months to 18 years, and with most patients presenting with vaginal bleeding.
Adults with adenocarcinoma of the cervix or vagina will present with stage I or stage II disease 90% of the time. In children and adolescents, there is a high incidence of stage III and stage IV disease (24%). This difference may be explained by the practice of routine pelvic examinations in adults and the hesitancy to perform pelvic exams in children.
The treatment of choice is surgical resection, followed by radiation therapy for residual microscopic disease or lymphatic metastases. The role of chemotherapy in management is unknown, although drugs commonly used in the treatment of gynecologic malignancies, carboplatin and paclitaxel, have been used. The 3-year event-free survival (EFS) for all stages is 71% ± 11%; for stage I and stage II, the EFS is 82% ± 11%, and for stage III and stage IV, the EFS is 57% ± 22%.
Other rare childhood cancers include multiple endocrine neoplasia syndromes and Carney complex, skin cancer, chordoma, and cancer of unknown primary site. The prognosis, diagnosis, classification, and treatment of these other rare childhood cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.
Multiple Endocrine Neoplasia (MEN) Syndromes and Carney Complex
MEN syndromes are familial disorders that are characterized by neoplastic changes that affect multiple endocrine organs. Changes may include hyperplasia, benign adenomas, and carcinomas. There are two main types of MEN syndrome: type 1 and type 2. Type 2 can be further subdivided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma.
Clinical features and diagnosis of MEN syndromes
The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 5.
Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors. Mutation testing should be combined with clinical screening for patients and family members with proven at-risk MEN 1 syndrome. It is recommended that screening for patients with MEN 1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography (CT) of the abdomen every 1 to 3 years.
A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN 2A and MEN 2B syndromes.[7,8,9]
Guidelines for genetic testing of suspected patients with MEN2 syndrome, as well as the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer, have been published.[14,15]
Treatment of MEN syndromes
Relatives of patients with MEN 2A should undergo genetic testing in early childhood, before the age of 5 years. Carriers should undergo total thyroidectomy as described above with autotransplantation of one parathyroid gland by a certain age.[20,24,25,26]
Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children, since there is a high incidence of bilateral disease.
Hirschsprung disease has been associated in a small percentage of cases with the development of neuroendocrine tumors such as medullary thyroid carcinoma. RET germline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[29,30,31] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. It has been recommended that patients with Hirschsprung disease be screened for mutations in RET exon 10 and consideration be given to prophylactic thyroidectomy if such a mutation is discovered.[31,32,33]
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN 2A and MEN 2B.)
In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with vandetanib, a selective inhibitor of RET, VEGFR, and EGFR, versus placebo, vandetanib administration was associated with significant improvements in progression-free survival, response rate, disease control rates, and biochemical response.
The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17. The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[37,38,39] There are guidelines that may be followed for screening patients with Carney complex.
For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.
Pheochromocytoma and Paraganglioma
Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into: (1) sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines, and (2) parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.[40,41]
It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (see Table 7). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of subjects have disease by age 26 years.[42,43,44]
Immunohistochemical SDHB staining may help triage genetic testing; tumors of patients with SDHB, SDHC, and SDHD mutations have absent or very weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[46,47] Therefore, immunohistochemical SDHB staining can help identify potential carriers of a SDH mutation early, thus obviating the need for extensive and costly testing of other genes.
Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with symptoms of excess catecholamine production, including hypertension, headache, perspiration, palpitations, tremor, and facial pallor. These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half the patients. These symptoms can also be induced by exertion, trauma, labor and delivery, induction of anesthesia, surgery of the tumor, foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder). Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression, but also may be asymptomatic and diagnosed incidentally.
Paraganglioma and pheochromocytoma in children and adolescents
Paraganglioma and pheochromocytoma are exceedingly rare in the pediatric and adolescent population, accounting for only approximately 20% of all cases.[48,49]
Younger patients have a higher incidence of bilateral adrenal pheochromocytoma and extra-adrenal paraganglioma, and a germline mutation can be identified in close to 60% of patients. Therefore, genetic counseling and testing is always recommended in young patients. The pediatric and adolescent patient appears to present with symptoms similar to those of the adult patient, although with a more frequent occurrence of sustained hypertension. The clinical behavior of paraganglioma and pheochromocytoma appears to be more aggressive in children and adolescents and metastatic rates of up to 50% have been reported.[41,49,50]
In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline mutation that involved the SDHB (n = 27; 55%), SDHD (n = 4; 8%), VHL (n = 6; 12%), or NF1 (n = 2; 4%) genes. The germline mutation rates for patients with nonmetastatic disease were lower than those observed in patients who had evidence of metastases (64% vs. 87.5%). Furthermore, among patients with metastatic disease, the incidence of SDHB mutations was very high (72%) and most presented with disease in the retroperitoneum; five died of their disease. All patients with SDHD mutations had head and neck primary tumors. In another study, the incidence of germline mutations involving RET, VHL, SDHD and SDHB in patients with nonsyndromic paraganglioma was 70% for patients younger than 10 years and 51% among those aged 10 to 20 years. In contrast, only 16% of patients older than 20 years had an identifiable mutation. It is important to remember that these two studies did not include systematic screening for other genes that have been recently described in paraganglioma and pheochromocytoma syndromes such as KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX (see Table 7).
These findings suggest that younger patients with extra-adrenal nonsyndromic pheochromocytoma and paraganglioma are at high risk for harboring SDHB mutations and that this phenotype is associated with an earlier age of onset and a high rate of metastatic disease. Early identification of young patients with SDHB mutations using radiographic, serologic, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB mutation. In addition, approximately 12% of pediatric GIST patients have germline SDHB, SDHC, or SDHD mutations in the context of Carney-Stratakis syndrome.
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging.
Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when the diagnosis of a s