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

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

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Unusual Cancers of Childhood Treatment

General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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.[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 therapies 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%.[1] 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.)

The tumors discussed in this summary are diverse; the discussion is 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 fewer than two in a year. Most of these tumors are more frequent in adults with cancer; thus, much of the information about these tumors may also be sought through sources relevant to adults with cancer.


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. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

Head and Neck Cancers

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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.[1] 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

Nasopharyngeal carcinoma (NPC) 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. NPC is very uncommon in children younger than 10 years, but increases in incidence to 0.8 and 1.3 per million per year in children aged 10 to 14 years and in children aged 15 to 19 years, respectively.[4,5] There is a higher frequency of this tumor in North Africa and Southeast Asia.

Nasopharyngeal carcinoma occurs in association with Epstein-Barr virus (EBV), the virus associated with infectious mononucleosis.[6] The virus can be detected in biopsy specimens of these cancers, and tumor cells can have EBV antigens on their cell surface. Three histologic subtypes are recognized by the World Health Organization (WHO). Type 1 is squamous cell carcinoma, type 2 is nonkeratinizing carcinoma, and type 3 is undifferentiated carcinoma. Children with NPC are more likely to have WHO type 2 or type 3 disease.[5]

This cancer most frequently spreads to lymph nodes in the neck, which may alert the patient, parent, or physician to the presence of this tumor. The tumor may also spread to the nose, mouth, and pharynx, causing snoring, epistaxis, obstruction of the eustachian tubes, or hearing loss; it may also invade the base of the skull, causing cranial nerve palsy or difficulty with movements of the jaw (trismus). Distant metastatic sites may include the bones, lungs, and liver. The location of the primary tumor can be determined by direct inspection of the nasopharynx. 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 infections draining into the lymph nodes of the neck.

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 a mirror, examination by a neurologist, and magnetic resonance imaging of the head and neck can be used to determine the extent of the primary tumor. Evaluation of the chest and abdomen by computed tomography and bone scan should also be performed to determine whether there is metastatic disease. The levels of EBV and antibody to EBV should also be measured.[2,7]

Tumor staging is performed utilizing the tumor-node-metastasis classification system of the American Joint Committee on Cancer (AJCC).[8] The majority (>90%) of children and adolescents with NPC present with advanced disease (stage III/IV or T3/T4).[9] Metastatic disease at diagnosis is uncommon (stage IVC). Outcome is directly related to the stage of the disease, with overall survival ranging from 80% for stage I and stage II to 40% for stage III.[10] Other factors associated with an inferior outcome include node size larger than 6 cm, radiation dose less than 60 Gy, and poor response to chemotherapy.[10] A retrospective analysis of data from the Surveillance Epidemiology and End Results (SEER) program reported that patients younger than 20 years had a higher risk of developing a second malignancy, a higher incidence of advanced stage disease when compared with older patients, and a superior outcome after controlling for stage.[5] The overall survival of children and adolescents with NPC is 83%, compared with 62% in adults.[5]

Surgery has a limited role in the management of nasopharyngeal carcinoma because the disease is usually considered unresectable due to extensive local spread.

High-dose radiation therapy alone has had a role in the management of low-stage nasopharyngeal carcinoma, but studies in both children and adults show that combined modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.[10,11,12,13,14] In a meta-analysis of studies adding chemotherapy to radiation therapy in adults with nasopharyngeal carcinoma, concomitant chemotherapy plus radiation therapy offered a significant benefit for survival, locoregional disease control, and reduction in distant metastases.[13] Neoadjuvant chemotherapy resulted in a significant reduction in locoregional recurrence only, while postradiation chemotherapy did not offer any benefit. In children, two studies utilizing preradiation chemotherapy with methotrexate, cisplatin, 5-fluorouracil (5-FU), and leucovorin with or without recombinant interferon-beta reported response rates of more than 90%.[15,16] Initial chemotherapy with cisplatin and docetaxel prior to radiation in young patients with nasopharyngeal carcinoma is associated with objective responses and favorable outcomes after radiation therapy.[17][Level of evidence: 3iiiDiv] Radiation therapy doses utilized in both studies were approximately 60 Gy. Additional drug combinations that have been used in children with nasopharyngeal carcinoma include bleomycin with epirubicin and cisplatin, cisplatin and fluorouracil, and cisplatin with methotrexate and bleomycin.[3] Incorporation of high-dose-rate brachytherapy into the chemoradiation therapy approach has been reported, but its role in the management of nasopharyngeal carcinoma in children is unknown.[18,19]

A preliminary report of the use of EBV-specific cytotoxic T-lymphocytes revealed minimal toxicity and evidence of significant antitumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.[20] (Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)

Treatment options under clinical evaluation

  • COG-ARAR0331: This Children's Oncology Group trial is evaluating the efficacy of induction chemotherapy with cisplatin plus 5-FU followed by concomitant chemotherapy (cisplatin) plus radiation therapy with amifostine as a radioprotectant in patients with AJCC stages IIB to IV nasopharyngeal carcinoma. Patients with stages I to IIA disease will receive only radiation therapy with amifostine.


Esthesioneuroblastoma (olfactory neuroblastoma) is a very rare, small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.[21,22,23,24] Most children present with a nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe, with associated symptoms. There appears to be a male predominance, and the average age of presentation is in adolescence. The youngest child reported with this diagnosis was aged 2 years. Metastatic disease is uncommon. The long-term survival rate appears to be approximately 60% to 80%. Local recurrences may occur later in life.

A retrospective analysis of data from the Surveillance, Epidemiology, and End Results program identified 311 patients with esthesioneuroblastoma.[25] Patients were staged by the extent of the tumor. Disease limited to the nasal cavity was considered the lowest stage and involvement of regional lymph nodes or metastasis was considered the highest stage. This staging system correlated well with outcome. 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.[26]

The mainstay of treatment has been surgery and radiation.[27] Newer techniques such as endoscopic sinus surgery, stereotactic radiosurgery, and proton-beam therapy (charged-particle radiation therapy) may play a role in the management of this tumor.[28]

Reports indicate the increasing use of neoadjuvant or adjuvant chemotherapy.[21,22,29,30,31]; [32][Level of evidence: 3iii] Chemotherapy regimens that have been used with efficacy include etoposide (VP-16) with ifosfamide and cisplatin;[33] vincristine, actinomycin D, and cyclophosphamide without doxorubicin; ifosfamide/etoposide; cisplatin plus etoposide or doxorubicin; [29] and irinotecan plus docetaxel.[34][Level of evidence: 3iiA]

Thyroid Tumors

Tumors of the thyroid are classified as adenomas or carcinomas.[35,36,37,38,39] 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 of these 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.

The annual incidence of thyroid cancers is low in children younger than 15 years (2.0 per million people), accounting for approximately 1.5% of all cancers in this age group.[4] Thyroid cancer incidence is higher in children aged 15 to 19 years (17.6 per million people), and it accounts for approximately 8% of cancers arising in this older age group.[4] Most thyroid carcinomas occur in girls.[40]

Patients with thyroid cancer usually present with a thyroid mass with or without cervical adenopathy.[41,42,43,44] When compared to pubertal adolescents, prepubertal children had a more aggressive presentation with a greater degree of extrathyroid extension, lymph node involvement, and lung metastases. However, outcome was similar in the prepubertal and adolescent groups.[45]

There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.[46,47] 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.[48] 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 Syndrome section of this summary for more information.)

The American Thyroid Association Taskforce [49] has developed guidelines for management of thyroid nodules in older adolescents and adults, but it is not yet known how to apply these guidelines to thyroid nodules in children.[35]

Initial evaluation of a child or adolescent with a thyroid nodule should include an ultrasound of the thyroid. 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.[50,51,52,53] Open biopsy or resection may be preferable for young children as well.

Various histologies account for the general diagnostic category of carcinoma of the thyroid,[54] but the vast majority of tumors are differentiated. These tumors comprise papillary carcinoma (60%–75%),[47] follicular carcinoma (10%–20%), medullary carcinoma (5%–10%), and anaplastic carcinoma (<1%). Papillary carcinoma often has multicentric origins and a very high rate of lymph node metastasis (70%–90%).[54] Follicular carcinoma may be sporadic or familial and medullary carcinoma is usually familial.[55] Follicular carcinoma is usually encapsulated and has a higher incidence of bone and lung metastasis. Follicular carcinoma and papillary carcinoma (often referred to as differentiated thyroid cancer) generally have a benign course, with a 10-year survival rate of more than 95%.[56] Fifty percent of medullary thyroid carcinomas in adults and children have hematogenous metastases at diagnosis.[57] 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.[58] (Refer to the Multiple Endocrine Neoplasia Syndromes (MEN) and Carney Complex section of this summary for more information.)

Surgery by an experienced thyroid surgeon is the treatment required for all thyroid neoplasms.[56] For patients with papillary or follicular carcinoma, total or near-total thyroidectomy plus cervical lymph node dissection, when indicated, is the most common surgical approach.[41] For patients with obvious metastatic disease or heavy nodal invasion, total thyroidectomy and treatment with radioactive iodine is indicated. For patients with an isolated nodule in the thyroid, treatment may involve only a lobectomy.[41,59] During the 4- to 6-week period following surgery, patients who undergo total or near-total thyroidectomy will develop hypothyroidism. 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 29 mCi) is administered for total thyroid destruction. If there is evidence of nodal or disseminated disease, higher doses (100 to 200 mCi) of I-131 are required. In children, the I-131 dose may be adjusted for weight and other age-dependent safety factors.[60,61] After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress thyrotropin (TSH) production.[62]

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.[63] Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary.[64] 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.[35] 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.[65,66,67,68]

Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[64,69,70] 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.[37,71,72] Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation.[73] 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.[74] (Refer to the PDQ summary on adult Thyroid Cancer Treatment for more information.)

Oral Cancers

Cancer of the oral cavity is extremely rare in children and adolescents.[75,76] The incidence of cancer of the oral cavity has increased in adolescent and young adult females.[77] The vast majority (>90%) of tumors and tumor-like lesions in the oral cavity are benign.[78,79,80,81] 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 histiocytoma [LCH]). Malignant tumors are found in 0.1% to 2% of a series of oral biopsies performed in children [78,79] and 3% to 13% of oral tumor biopsies.[80,81] 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.[82][Level of evidence: 3iiA]

The most common type of primary oral cancer in adults, squamous cell carcinoma (SCC), is extremely rare in children. Only occasional case reports are found in the literature.[83] 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 human papillomavirus infection.[84,85,86,87,88,89,90,91] Most reported cases of SCC managed with surgery alone have done well without recurrence.[92]

Treatment of benign oral tumors is surgical. Management of malignant tumors is dependent on histology and may include surgery, chemotherapy, and radiation.[93] LCH 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.)

Salivary Gland Tumors

Most salivary gland neoplasms arise in the parotid gland.[94,95,96,97,98,99] 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 on very rare occasions may be malignant.[100]

Sialoblastomas are usually benign tumors presenting in the neonatal period but can rarely metastasize.[101] Chemotherapy regimens with carboplatin, epirubicin, vincristine, etoposide, dactinomycin, doxorubicin, and ifosfamide have produced responses in two children with sialoblastoma.[102]; [103][Level of evidence: 3iiiDiv]

The malignant lesions include mucoepidermoid carcinoma,[104] acinic cell carcinoma, rhabdomyosarcoma, adenocarcinoma, and undifferentiated carcinoma. These tumors may occur after radiation therapy and chemotherapy are given for treatment of primary leukemia or solid tumors.[105,106] Radical surgical removal is the treatment of choice, whenever possible, with additional use of radiation therapy and chemotherapy for high-grade tumors or tumors that have spread from their site of origin.[104,107,108] Prognosis for patients with these tumors is generally good.[97,109,110,111] (Refer to the PDQ summary on adult Salivary Gland Cancer Treatment for more information.)

Laryngeal Cancer and Papillomatosis

Benign tumors of the larynx are rare. Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[112,113] 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.[114] Squamous cell carcinoma of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation.[115] 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 human papillomavirus (HPV), most commonly HPV-6 and HPV-11.[116] The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6.[117] 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.[118] Malignant degeneration may occur with development of cancer in the larynx and squamous cell lung cancer.

This condition is not cancerous, and primary treatment is surgical ablation with laser vaporization.[119] Frequent recurrences are common. Lung involvement, though rare, can occur.[118] If a patient requires more than four surgical procedures per year, treatment with interferon may be considered.[120] 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.[121] 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 the NUT Gene

Researchers have described a group of young patients with midline carcinomas with a very poor prognosis. The tumors arise in midline epithelial structures including the thymus, mediastinum, airway structures, and bladder. They show squamous differentiation. Tumors from 8 of 11 patients contained a balanced chromosomal translocation t(15;19) involving the BRD4 and the NUT genes. These patients had no response to chemotherapy and died very quickly. Tumors from the remaining three patients had a chromosomal break in the NUT gene on chromosome 15 but had normal chromosome 19. These patients were older and had a slightly longer survival than the eight patients with t(15;19).[122]

There is no established treatment for midline tract carcinoma.


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Thoracic Cancers

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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.[1]

Breast Cancer

The most frequent breast tumor seen in children is a fibroadenoma.[2] 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.[3] 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.[3]

Breast cancer has been reported in both males and females younger than 21 years.[4,5,6,7,8,9] 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.[10] 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- and 10-year survival rates were 63% and 54%, respectively.

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.[8,11,12,13] Carcinomas are more frequent than sarcomas. Mammograms 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.)

Bronchial Tumors

Primary lung tumors are rare in children and histologically quite diverse.[1] 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, including the following:[14,15,16,17,18]

  • Carcinoid tumor (most frequent).
  • Mucoepidermoid carcinoma.
  • Adenoid cystic carcinoma (least frequent).

Carcinoid tumors account for 80% to 85% of all bronchial tumors in children.[14,15,16,17,18] Epithelial cancers of the lung are rare in children. When they do occur, they tend to be of advanced stage with prognosis dependent on both histology and stage.[19]

The presenting symptoms are usually because of an incomplete bronchial obstruction with a cough, recurrent pneumonitis, and 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 as long as 4 to 5 years.[20]

Metastatic lesions are reported in approximately 6% of cases and recurrences occur in 2% of cases. Atypical carcinoid tumors are rare but more aggressive with 50% of patients presenting with metastatic disease at diagnosis.[19,21] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[22] Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread. Bronchial tumors of all histologic types are associated with an excellent prognosis in children, even in the presence of local invasion.[23,24]

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.[25]

Conservative pulmonary resection, including sleeve segmental resection when feasible, with the removal of the involved lymphatics, is the treatment of choice.[26,27] 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

Pleuropulmonary blastoma (PPB) is a rare and highly aggressive pulmonary malignancy in children. PPB appears to progress through the following stages:

  • 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. However, there have been reports of type I transitioning directly to type III.[28,29]
  • Type II: A cystic and solid neoplasm.
  • Type III: A purely solid neoplasm.[30,31] Cerebral metastasis occurs in up to 50% of patients with type III tumors.[32]

An association between congenital lung cysts and PPB has been reported, although cytogenetic and molecular studies can help distinguish the nonneoplastic congenital cystic adenomatoid malformation from PPB.[33,34,35,36,37] Comparative genomic and fluorescent in situ hybridization methods have identified gain of chromosome 8q as the main recurrent chromosomal abnormality in pleuropulmonary blastoma.[38,39] A family history of cancer in close relatives has been noted for many young patients affected by this tumor.[40,41] In addition, PPB has been reported in siblings.[42] There has been a reported association between PPB and cystic nephroma.[43,44]

The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the mediastinum, diaphragm, and/or pleura.[36,45] The tumors may recur or metastasize, in spite of primary resection.[29,31] 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 PPB by reducing the risk of recurrence.[30,46] Achieving total resection of the tumor at any time during treatment is associated with improved prognosis.[36] Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, doxorubicin, and irinotecan.[47] High-dose chemotherapy with stem cell rescue has been used without success.[48] 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.[30]

Evidence suggests a close histologic relationship between a type 4 cystic adenomatoid malformation and a type I PPB.[49,50] Complete surgical lobectomy is adequate treatment for these patients, but close observation is recommended.

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:[51]

  • Type I: Surgery alone for select cases; adjuvant chemotherapy may decrease recurrences.[30,51]
  • Type II and Type III: Surgery followed by chemotherapy.[47]

An independent group of researchers has established a registry and resource Web site for this rare tumor.[51]

Esophageal Tumors

Esophageal cancer is rare in the pediatric age group, though it is relatively common in older adults.[52] Symptoms are related to difficulty in swallowing and associated weight loss. Most of these tumors are squamous cell carcinomas, though sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma. 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 generally is 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.[53,54,55] 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.[56,57] 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.[58,59] Endocrine (hormonal) disorders including hyperthyroidism, Addison disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.[60]

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, though 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,[60] 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.[55,60,61,62,63] 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%.[63,64] Response rates are lower for patients with thymic carcinoma, but 2-year survival rates have been reported to be as high as 50%.[65]

A group of young patients with midline carcinomas with a very poor prognosis has been reported. The tumors arise in midline epithelial structures including the thymus, airway structures, and bladder. They exhibit squamous differentiation. Tumors from 8 of 11 patients exhibited a balanced chromosomal translocation t(15;19) involving the BRD4 and NUT genes. These patients had no response to chemotherapy and died very quickly. Tumors from the remaining three patients had a chromosomal break in the NUT gene on chromosome 15 but had normal chromosome 19. These patients were older and had a slightly longer survival than the eight patients exhibiting t(15;19).[66]

Cardiac Tumors

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.[67] The most common primary heart tumors in children are rhabdomyomas and fibromas.[68,69] 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).[68,70,71,72] 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.[73,74,75] A mutation of the PRKAR1A gene is noted in more than 90% of the cases.[73,76] Primary malignant pediatric heart tumors are rare but may include malignant teratomas, rhabdomyosarcomas, chondrosarcomas, and other sarcomas.[68]

The distribution of cardiac tumors in the fetal and neonatal period is different, with more benign teratomas occurring.[70] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[70] 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.[77] 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.[78]

Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, and carcinoma of other sites.[68] 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, which may include transplantation, and chemotherapy appropriate for the type of cancer that is present.[79,80,81]; [67][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.[82]

This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[83,84,85] 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.[86,87] In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.[88] 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.[82] Radical surgical resection has been attempted with mixed results.[89] Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[85,90] 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.[91] 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.)


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29. Hill DA, Jarzembowski JA, Priest JR, et al.: Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol 32 (2): 282-95, 2008.
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31. Miniati DN, Chintagumpala M, Langston C, et al.: Prenatal presentation and outcome of children with pleuropulmonary blastoma. J Pediatr Surg 41 (1): 66-71, 2006.
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36. Indolfi P, Bisogno G, Casale F, et al.: Prognostic factors in pleuro-pulmonary blastoma. Pediatr Blood Cancer 48 (3): 318-23, 2007.
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38. de Krijger RR, Claessen SM, van der Ham F, et al.: Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma. Mod Pathol 20 (11): 1191-9, 2007.
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47. Ohta Y, Fujishima M, Hasegawa H, et al.: High therapeutic effectiveness of postoperative irinotecan chemotherapy in a typical case of radiographically and pathologically diagnosed pleuropulmonary blastoma. J Pediatr Hematol Oncol 31 (5): 355-8, 2009.
48. de Castro CG Jr, de Almeida SG, Gregianin LJ, et al.: High-dose chemotherapy and autologous peripheral blood stem cell rescue in a patient with pleuropulmonary blastoma. J Pediatr Hematol Oncol 25 (1): 78-81, 2003.
49. MacSweeney F, Papagiannopoulos K, Goldstraw P, et al.: An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol 27 (8): 1139-46, 2003.
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57. Yaris N, Nas Y, Cobanoglu U, et al.: Thymic carcinoma in children. Pediatr Blood Cancer 47 (2): 224-7, 2006.
58. Souadjian JV, Enriquez P, Silverstein MN, et al.: The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 134 (2): 374-9, 1974.
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61. Carlson RW, Dorfman RF, Sikic BI: Successful treatment of metastatic thymic carcinoma with cisplatin, vinblastine, bleomycin, and etoposide chemotherapy. Cancer 66 (10): 2092-4, 1990.
62. Niehues T, Harms D, Jürgens H, et al.: Treatment of pediatric malignant thymoma: long-term remission in a 14-year-old boy with EBV-associated thymic carcinoma by aggressive, combined modality treatment. Med Pediatr Oncol 26 (6): 419-24, 1996.
63. Casey EM, Kiel PJ, Loehrer PJ Sr: Clinical management of thymoma patients. Hematol Oncol Clin North Am 22 (3): 457-73, 2008.
64. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996.
65. Loehrer PJ Sr, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001.
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Abdominal Cancers

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 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 are classified as carcinomas and adenomas.[1,2,3,4,5,6] These tumors occur throughout the pediatric age group, including the fetus and newborn.[7] Adrenocortical tumors may be hormonally active or inactive. Adenomas are generally benign, whereas adrenocortical carcinomas frequently secrete hormones and may cause the patient to develop masculine traits, irrespective of the patient's gender. Pediatric patients with adrenocortical carcinoma often have Li-Fraumeni syndrome, which is an inherited condition that predisposes family members to multiple cancers, including breast cancer, rhabdomyosarcoma, and osteosarcoma.[8] A variety of p53 mutations associated with Li-Fraumeni syndrome have been observed in North American children with adrenocortical carcinoma, whereas in a southern Brazilian population, a distinctive p53 mutation predisposes to this disease.[1,9] Children with Beckwith-Wiedemann syndrome [10] or hemihypertrophy [11] are at an increased risk of developing carcinoma of the adrenal cortex (as well as Wilms tumor, hepatoblastoma, and other rare cancers) in the first several years of life.

These tumors spread locally to the lymph nodes and can also involve the kidneys, lungs, bones, and brain.[12] Surgical removal should be attempted but may not always be possible if the tumor has spread widely. Additional treatment may include the use of an artificial hormone that blocks the masculinizing effects of the tumor [13] or chemotherapy using cisplatin, 5-fluorouracil (5-FU), and etoposide.[4,14] A retrospective analysis in Italy and Germany identified 177 patients with adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 to 3 grams per day of mitotane and was associated with fewer toxic side effects than doses of 3 to 5 grams per day.[15,16] The prognosis for patients who have small, completely resected tumors generally is excellent, but prognosis can be poor for patients who have large primary tumors or metastatic disease at diagnosis.[3,17] Tumor stage has been identified as a significant prognostic factor in children with adrenocortical tumors. When possible, surgical reexcision should be attempted for local tumor recurrences and for inferior vena caval tumor invasion.[18] Adrenal tumors can present as incidental findings (incidentalomas), and these tumors should be thoroughly evaluated.[19] (Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)

Treatment options under clinical evaluation

  • COG-ARAR0332: This Children's Oncology Group trial is evaluating the treatment of adrenocortical tumors with surgery and lymph node dissection. Patients with advanced disease will receive multiagent chemotherapy. Patients with stage I or stage II disease will have resection and retroperitoneal lymph node sampling (I) or dissection (II). Patients with stage III and stage IV disease will receive chemotherapy before resection. The chemotherapy is cisplatin, doxorubicin, etoposide, and oral mitotane.

Carcinoma of the Stomach

Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[20] 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.[21] 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.[20] Symptoms include vague upper abdominal pain, which can be associated with poor appetite, and weight loss. Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread. Other symptoms may include nausea, vomiting, change in bowel habits, poor appetite, weakness, and Helicobacter pylori infection.[22] 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 5-FU and irinotecan.[23] 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.[24] 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

Pancreatic tumors are rare in children and adolescents and carry a variable prognosis.[25,26,27] 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.[28,29,30] Several cases of primitive neuroectodermal tumor of the pancreas have been reported in children and young adults.[31] Most pancreatic tumors do not secrete hormones, though some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.[28,32] 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 abdominal mass, wasting, and pain.[33,34,35] 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.[36,37] Pancreatoblastoma is reported to be associated with Beckwith-Wiedemann syndrome and Cushing syndrome.[38,39]

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.[40,41,42,43] Treatment consists of complete tumor resection (ideally without biopsy). Metastases may occur, but in general, prognosis is good following surgery alone.[44,45]; [46][Level of evidence: 3iiDi]

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. 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.[29,36]; [47][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.[48,49] Postoperative treatment with cisplatin, doxorubicin, ifosfamide, and etoposide has also produced responses in patients with pancreatoblastoma.[50][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.)

Colorectal Carcinoma

Carcinoma of the large bowel is rare in the pediatric age group; it is seen in only one per 1 million persons younger than 20 years in the United States annually.[51] Forty percent to 60% of the tumors arise on the right side in children in contrast to adults who have a prevalence of tumors on the left side.[52] Colon cancer in children is often associated with a family cancer syndrome.[53,54,55] There is an increasing risk of colorectal carcinoma in members of families with a family history of intestinal polyposis, which can lead to the development of multiple adenomatous polyps.[56] Juvenile polyps are not associated with an increased incidence or risk of cancer.

Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminate the risk of developing carcinomas of the large bowel.[57] 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.[58] 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.[59] 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.[60][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 also been associated with progression of polyps to a malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I and several other rarer syndromes.[61]

The histologic types of colorectal cancer include adenocarcinomas, mucinous or colloid adenocarcinomas, signet ring adenocarcinomas, and scirrhous tumors. Most tumors in the pediatric age group are mucin-producing carcinomas,[51,62,63] 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. 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.[64]

Colorectal carcinoma usually presents with symptoms related to the site of the tumor.[62] Changes in bowel habits are 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.

Because of its rarity, colorectal carcinoma is rarely diagnosed in a pediatric patient; however, vague gastrointestinal symptoms should alert the physician to investigate this possibility. 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.[64,65,66]

Most patients present with evidence of metastatic disease,[62] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[63,67] 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.[51] 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.[68] Other agents that may be of value include irinotecan.[62][Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alpha given in conjunction with 5-FU/leucovorin.[69] (Refer to the PDQ summaries on adult Colon Cancer Treatment and Rectal Cancer Treatment for more information.)

Carcinoid Tumors

These tumors, like bronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[70,71,72,73,74,75] Most lung lesions are benign; however, some metastasize.[76] 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.[77] 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.[78] Treatment of metastatic carcinoid tumors of the large bowel or stomach becomes more complicated and requires treatment similar to that given for colorectal carcinoma. The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[76] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[79] (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors for more information.)

Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[80] These tumors are rare in children. Approximately 2% of all GIST occur in children and young adults;[81,82,83] in one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[84] Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas. GIST can arise within the context of four tumor predisposition syndromes:

  • Carney triad is a syndrome characterized by the occurrence of GIST, lung chondromas, and paragangliomas. In addition, about 20% of patients have adrenal adenomas and 10% have esophageal leiomyomas. GIST are the most common presenting lesions (75%). To date, no coding sequence mutations of KIT, PDGFR, or the SDH genes have been found in these patients.[83,85]
  • Carney-Stratakis syndrome is characterized by paraganglioma and GIST due to germline mutations of the succinate dehydrogenase genes B, C, and D.[86]
  • Neurofibromatosis type I (NF1).[87]
  • Familial GIST.[88,89]

Approximately 10% of pediatric patients with GIST are associated with Carney triad or Carney-Stratakis syndrome and they have a better prognosis.[89] Familial GIST and NF1-associated GIST occur in patients older than 40 years.[87,88]

Pediatric patients with GIST are usually female (74%) and have tumors that are most commonly located in the stomach (85%).[89] 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.[89,90] Most pediatric patients with GIST present during the second decade of life with anemia-related gastrointestinal bleeding. In addition, GIST have a high propensity for multifocality (23%) and nodal metastases.[89,91] These features may account for the high incidence of local recurrence seen in this patient population. Pediatric GIST are 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;[89,91,92] unlike adult KIT mutant GIST, they have minimal large-scale chromosomal changes.[92] It has been demonstrated that insulin-like growth factor 1 receptor (IGF1R) expression is significantly higher and amplified in wild-type pediatric GIST when compared to adult GIST, suggesting that administration of an IGF1R inhibitor might be therapeutically beneficial in these patients.[93]

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.[94] In the presence of KIT or PDGFR mutations, published adult guidelines for management of these tumors may be followed. For most pediatric patients with wild-type GIST, however, complete surgical resection of localized disease is recommended as long as it can be accomplished without significant morbidity (i.e., gastrectomy). Given the indolent course of the disease in pediatric patients, it is reasonable to withhold extensive and mutilative surgeries and carefully observe children with locally recurrent or unresectable asymptomatic disease.[89] A randomized clinical trial demonstrated that administration of adjuvant imatinib mesylate improved event-free survival in adult patients with GIST. However, because no pediatric trials have been conducted and pediatric tumors might be less sensitive to imatinib mesylate, the use of this agent in the adjuvant setting in pediatric GIST cannot be recommended.[95] For patients who progress or have symptoms, a trial of imatinib mesylate appears warranted.[89,96,97] The experience with this agent in pediatric GIST is limited. In a review of 10 patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[89] 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.[98][Level of evidence: 3iiDiii]


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Genital / Urinary Tumors

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 (PUNLMP), which generally presents with hematuria.[1] In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have a good prognosis following transurethral resection.[2,3,4] Squamous cell and more aggressive carcinomas, however, have been reported.[5,6] Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.[7,8] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.[7] (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.[9] 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 stromal tumors are exceedingly rare in prepubertal boys. In a small series, gonadal stromal tumors accounted for 8% to 13% of pediatric testicular tumors.[10]; [11] In newborns and infants, juvenile granulosa cell tumors (JGCT) are the most common stromal cell tumor.[12] In older males, Leydig cell tumors are more common. Stromal cell tumors have been described as benign in young boys.[13,14] There are conflicting data about malignant potential in older males. Most case reports suggest that in the pediatric patient, these tumors can be treated with surgery alone. However, given the rarity of this tumor, the surgical approach in pediatrics has not been well studied.[13][Level of evidence: 3iii]; [15][Level of evidence: 3iiiA]

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.[16,17,18] The majority of ovarian tumors occur in girls aged 15 to 19 years.[19] Ovarian tumors derived from malignant epithelial elements include: adenocarcinomas,[20] cystadenocarcinomas, endometrioid tumors, clear cell tumors, and undifferentiated carcinomas. Treatment is stage-related and may include surgery, radiation, and chemotherapy with cisplatin, carboplatin, etoposide, topotecan, paclitaxel, and other agents. 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.[21] (Refer to the PDQ summaries on Childhood Extracranial Germ Cell Tumors, adult Ovarian Epithelial Cancer Treatment, and adult Ovarian Low Malignant Potential Tumor Cancer Treatment for more information.)

Ovarian sex cord-stromal tumors are a heterogeneous group of rare tumors that derive from the gonadal nongerm cell component.[22] Histologic subtypes display some areas of gonadal differentiation and include JGCT, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. The most common type in girls younger than 18 years is JGCT (median age, 7.6 years; range, birth to 17.5 years).[23,24] JGCT represent about 5% of ovarian tumors in children and adolescents and are distinct from the granulosa cell tumors seen in adults.[22,25,26,27] Most patients with JGCT present with precocious puberty.[28] Other presenting symptoms include abdominal pain, abdominal mass, and ascites. JGCT has been reported in children with Ollier disease and Maffucci syndrome.[29] As many as 90% of children 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.[23,27,30,31,32] Sertoli-Leydig cell tumors are rare in young girls but may present with virilization [33] or precocious puberty.[34,35] These tumors may also be associated with Peutz-Jegher syndrome.[36] Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia.[37] Successful treatment with aggressive therapy has been reported in a few cases.[37][Level of evidence: 3iiB]; [38,39][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.[40] 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 [41] followed by radiation therapy for residual microscopic disease or lymphatic metastases. The role of chemotherapy in management is unknown, though drugs commonly used in the treatment of gynecologic malignancy, 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 EFS is 82% ± 11%, and for stage III and stage IV EFS is 57% ± 22%.[40]


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3. Serrano-Durbá A, Domínguez-Hinarejos C, Reig-Ruiz C, et al.: Transitional cell carcinoma of the bladder in children. Scand J Urol Nephrol 33 (1): 73-6, 1999.
4. Fine SW, Humphrey PA, Dehner LP, et al.: Urothelial neoplasms in patients 20 years or younger: a clinicopathological analysis using the world health organization 2004 bladder consensus classification. J Urol 174 (5): 1976-80, 2005.
5. Sung JD, Koyle MA: Squamous cell carcinoma of the bladder in a pediatric patient. J Pediatr Surg 35 (12): 1838-9, 2000.
6. Lezama-del Valle P, Jerkins GR, Rao BN, et al.: Aggressive bladder carcinoma in a child. Pediatr Blood Cancer 43 (3): 285-8, 2004.
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10. Pohl HG, Shukla AR, Metcalf PD, et al.: Prepubertal testis tumors: actual prevalence rate of histological types. J Urol 172 (6 Pt 1): 2370-2, 2004.
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12. Carmignani L, Colombo R, Gadda F, et al.: Conservative surgical therapy for leydig cell tumor. J Urol 178 (2): 507-11; discussion 511, 2007.
13. Agarwal PK, Palmer JS: Testicular and paratesticular neoplasms in prepubertal males. J Urol 176 (3): 875-81, 2006.
14. Dudani R, Giordano L, Sultania P, et al.: Juvenile granulosa cell tumor of testis: case report and review of literature. Am J Perinatol 25 (4): 229-31, 2008.
15. Thomas JC, Ross JH, Kay R: Stromal testis tumors in children: a report from the prepubertal testis tumor registry. J Urol 166 (6): 2338-40, 2001.
16. Morowitz M, Huff D, von Allmen D: Epithelial ovarian tumors in children: a retrospective analysis. J Pediatr Surg 38 (3): 331-5; discussion 331-5, 2003.
17. Schultz KA, Sencer SF, Messinger Y, et al.: Pediatric ovarian tumors: a review of 67 cases. Pediatr Blood Cancer 44 (2): 167-73, 2005.
18. Aggarwal A, Lucco KL, Lacy J, et al.: Ovarian epithelial tumors of low malignant potential: a case series of 5 adolescent patients. J Pediatr Surg 44 (10): 2023-7, 2009.
19. Brookfield KF, Cheung MC, Koniaris LG, et al.: A population-based analysis of 1037 malignant ovarian tumors in the pediatric population. J Surg Res 156 (1): 45-9, 2009.
20. Lovvorn HN 3rd, Tucci LA, Stafford PW: Ovarian masses in the pediatric patient. AORN J 67 (3): 568-76; quiz 577, 580-84, 1998.
21. Tsai JY, Saigo PE, Brown C, et al.: Diagnosis, pathology, staging, treatment, and outcome of epithelial ovarian neoplasia in patients age < 21 years. Cancer 91 (11): 2065-70, 2001.
22. Schneider DT, Jänig U, Calaminus G, et al.: Ovarian sex cord-stromal tumors--a clinicopathological study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch 443 (4): 549-60, 2003.
23. Calaminus G, Wessalowski R, Harms D, et al.: Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study. Gynecol Oncol 65 (3): 447-52, 1997.
24. Capito C, Flechtner I, Thibaud E, et al.: Neonatal bilateral ovarian sex cord stromal tumors. Pediatr Blood Cancer 52 (3): 401-3, 2009.
25. Bouffet E, Basset T, Chetail N, et al.: Juvenile granulosa cell tumor of the ovary in infants: a clinicopathologic study of three cases and review of the literature. J Pediatr Surg 32 (5): 762-5, 1997.
26. Zaloudek C, Norris HJ: Granulosa tumors of the ovary in children: a clinical and pathologic study of 32 cases. Am J Surg Pathol 6 (6): 503-12, 1982.
27. Vassal G, Flamant F, Caillaud JM, et al.: Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 cases. J Clin Oncol 6 (6): 990-5, 1988.
28. Kalfa N, Patte C, Orbach D, et al.: A nationwide study of granulosa cell tumors in pre- and postpubertal girls: missed diagnosis of endocrine manifestations worsens prognosis. J Pediatr Endocrinol Metab 18 (1): 25-31, 2005.
29. Gell JS, Stannard MW, Ramnani DM, et al.: Juvenile granulosa cell tumor in a 13-year-old girl with enchondromatosis (Ollier's disease): a case report. J Pediatr Adolesc Gynecol 11 (3): 147-50, 1998.
30. Powell JL, Connor GP, Henderson GS: Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol 81 (1): 113-6, 2001.
31. Schneider DT, Calaminus G, Wessalowski R, et al.: Therapy of advanced ovarian juvenile granulosa cell tumors. Klin Padiatr 214 (4): 173-8, 2002 Jul-Aug.
32. Schneider DT, Calaminus G, Harms D, et al.: Ovarian sex cord-stromal tumors in children and adolescents. J Reprod Med 50 (6): 439-46, 2005.
33. Arhan E, Cetinkaya E, Aycan Z, et al.: A very rare cause of virilization in childhood: ovarian Leydig cell tumor. J Pediatr Endocrinol Metab 21 (2): 181-3, 2008.
34. Baeyens L, Amat S, Vanden Houte K, et al.: Small cell carcinoma of the ovary successfully treated with radiotherapy only after surgery: case report. Eur J Gynaecol Oncol 29 (5): 535-7, 2008.
35. Choong CS, Fuller PJ, Chu S, et al.: Sertoli-Leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12-month-old infant. J Clin Endocrinol Metab 87 (1): 49-56, 2002.
36. Zung A, Shoham Z, Open M, et al.: Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome. Gynecol Oncol 70 (3): 421-4, 1998.
37. Distelmaier F, Calaminus G, Harms D, et al.: Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease. Cancer 107 (9): 2298-306, 2006.
38. Christin A, Lhomme C, Valteau-Couanet D, et al.: Successful treatment for advanced small cell carcinoma of the ovary. Pediatr Blood Cancer 50 (6): 1276-7, 2008.
39. Kanwar VS, Heath J, Krasner CN, et al.: Advanced small cell carcinoma of the ovary in a seventeen-year-old female, successfully treated with surgery and multi-agent chemotherapy. Pediatr Blood Cancer 50 (5): 1060-2, 2008.
40. McNall RY, Nowicki PD, Miller B, et al.: Adenocarcinoma of the cervix and vagina in pediatric patients. Pediatr Blood Cancer 43 (3): 289-94, 2004.
41. Abu-Rustum NR, Su W, Levine DA, et al.: Pediatric radical abdominal trachelectomy for cervical clear cell carcinoma: a novel surgical approach. Gynecol Oncol 97 (1): 296-300, 2005.

Other Rare Childhood Cancers

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.[1] 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 (FMTC). The most salient clinical and genetic alterations of the MEN syndromes are shown in Table 1.

Table 1. MEN Syndromes with Associated Clinical and Genetic Alterations

Syndrome Clinical Features/Tumors Genetic Alterations
MEN type 1: Werner syndrome[2] Parathyroid 11q13 (MEN1 gene)
Pancreatic islets: Gastrinoma 11q13 (MEN1 gene)
Pituitary: Prolactinoma 11q13 (MEN1 gene)
Other associated tumors: Carcinoid 11q13 (MEN1 gene)
MEN type 2A: Sipple syndrome Medullary thyroid carcinoma 10q11.2 (RET gene)
Parathyroid gland
MEN type 2B Medullary thyroid carcinoma 10q11.2 (RET gene)
Mucosal neuromas
Intestinal ganglioneuromatosis
Marfanoid habitus
Familial medullary thyroid carcinoma Medullary thyroid carcinoma 10q11.2 (RET gene)

The MEN 1 syndrome, also referred to as Werner syndrome, is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two of the three endocrine tumors listed in the table above are present. Less common tumors associated with this syndrome include adrenocortical tumors, carcinoid tumors, lipomas, angiofibromas, and collagenomas. The first manifestation of the disease in 90% of patients is hypercalcemia; the most common cause of morbidity and mortality in these patients is the development of gastrinomas, leading to Zollinger-Ellison syndrome.[2,3] 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.[4] Mutation testing should be combined with clinical screening for patients and family members with proven at-risk MEN 1 syndrome.[5] There are guidelines that may be followed for screening patients with MEN 1 syndrome. Treatment of patients with MEN 1 syndrome is based on the type of tumor.

MEN 2A is characterized by the presence of two or more endocrine tumors (see Table 2) in an individual or in close relatives.[6]RET mutations in these patients are usually confined to exons 10 and 11. MEN 2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[6,7,8] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[9] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus. A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in such patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[9] There are guidelines that may be followed for screening patients with MEN 2 syndromes.

FMTC is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases. (See Table 2.)

Table 2. Clinical Features of MEN 2 Syndromes

MEN 2 Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease
MEN 2A 95% 50% 20% to 30%
MEN 2B 100% 50% Uncommon
FMTC 100% 0% 0%

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.[10,11,12] The management of medullary thyroid cancer in children from families having the MEN 2 syndromes relies on presymptomatic detection of the RET proto-oncogene mutation responsible for the disease. For children with MEN 2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a mutation is identified. [12,13,14,15,16,17] 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.[17,18,19,20] Because of the increased virulence of medullary thyroid carcinoma in children with MEN 2B and in those with mutations in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[9,14,21]; [22][Level of evidence: 3iiiDii] 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.[23,24,25] 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.[25,26,27]

The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17.[28] 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.[28,29,30] There are guidelines that may be followed for screening patients with Carney complex.

The outcome of patients with the MEN 1 syndrome is generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors. The outcome for patients with the MEN 2A syndrome is also generally good, yet the possibility exists for recurrence of medullary thyroid carcinoma and pheochromocytoma.[31,32,33] Patients who have the MEN 2B syndrome have a worse outcome primarily due to more aggressive medullary thyroid carcinoma. Prophylactic thyroidectomy has the potential to improve the outcome in MEN 2B, but there are no long-term outcome reports published to date. For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

Refer to the PDQ summary on Genetics of Medullary Thyroid Cancer for more information about MEN 2A and MEN 2B.

Treatment options under clinical evaluation

  • NCI-07-C-0189: This phase I/II NCI trial is investigating vandetanib, an orally available tyrosine kinase receptor inhibitor, for patients aged 5 years to 18 years, with hereditary thyroid medullary carcinoma.[34,35]

Skin Cancer (Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma)

Melanoma is the most common skin cancer in children, followed by basal cell and squamous cell carcinomas (SCCs).[36,37,38,39,40,41,42,43,44] There are approximately 425 cases of melanoma diagnosed each year in the United States in patients younger than 20 years, representing about 1% of all new cases of melanoma that are diagnosed annually in this country.[45] Melanoma annual incidence in the United States (2002–2006) increased with age, from 1 to 2 per million in children younger than 10 years to 4.1 per million in children aged 10 to 14 years and 16.9 per million in children aged 15 to 19 years.[46] Melanoma accounts for about 8% of all cancers seen in children aged 15 to 19 years.[46] The incidence of pediatric melanoma (in children younger than 20 years) increased by 1.7% per year between 1975 and 2006;[46] increased ambient ultraviolet radiation increases the risk of the disease.[47]

Conditions associated with an increased risk of melanoma in children and adolescents include giant melanocytic nevi, xeroderma pigmentosum (a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations),[40] immunodeficiency, immunosuppression, and Werner syndrome.[48] Other phenotypic traits that are associated with an increased risk of melanoma in adults have been documented in children and adolescents with melanoma and include exposure to ultraviolet sunlight, red hair, blue eyes,[49,50,51,52] poor tanning ability, freckling, dysplastic nevi, increased number of melanocytic nevi, and family history of melanoma.[53,54,55] Neurocutaneous melanosis is an unusual condition associated with large or multiple congenital nevi of the skin in association with meningeal melanosis or melanoma; approximately 2.5% of patients with large congenital nevi develop this condition, and those with increased numbers of satellite nevi are at greatest risk.[56,57]

Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is stage dependent.[58] In pediatric melanoma, however, thickness does not appear to correlate with outcome in localized invasive disease.[47,59,60,61] In addition, pediatric melanoma appears to have a higher incidence of nodal involvement and this feature does not appear to have an impact on survival.[62,63] However, it is unclear how these findings truly affect clinical outcome since some series have included patients with atypical melanocytic lesions.[64,65] In a study of sentinel lymph node biopsies in children and adolescents, 25% were positive (compared with 17% in adults). However, only 0.7% of lymph nodes found on complete lymph node dissection were positive for melanoma. In this study, mortality was infrequent but was confined to sentinel lymph node–positive patients.[66][Level of evidence: 3iiA] Children younger than 10 years who have melanoma often present with poor prognostic features, are more often non-white, have head and neck primary tumors, and more often have syndromes that predispose them to melanoma.[47,58,60]

Basal cell carcinomas generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure.[67] These tumors may be multiple and exacerbated by radiation therapy.[68] Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare disorder with a predisposition to the development of early-onset neoplasms, including basal cell carcinoma, ovarian fibroma, and desmoplastic medulloblastoma.[69,70,71,72] SCCs are usually reddened lesions with varying degrees of scaling or crusting, and they have an appearance similar to eczema, infections, trauma, or psoriasis.

Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Basal and squamous cell carcinomas are generally curable with surgery alone, but the treatment of melanoma requires greater consideration because of its potential for metastasis. The width of surgical margins in melanoma is dictated by the site, size, and thickness of the lesion and ranges from 0.5 cm for in situ lesions to 2 cm or more for thicker lesions.[40] To achieve negative margins in children, wide excision with skin grafting may become necessary in selected cases. Examination of regional lymph nodes using sentinel lymph node biopsy has become routine in many centers[73,74] and is recommended in patients with lesions measuring more than 1 mm in thickness or in those whose lesions are 1 mm or less in thickness and have unfavorable features such as ulceration, Clark level of invasion IV or V, or mitosis rate of 1 per mm2 or higher.[73,75,76] Lymph node dissection is recommended if sentinel nodes are involved with tumor, and adjuvant therapy with high-dose interferon-alpha-2b for a period of 1 year should be considered in these patients.[40,73,77,78,79] Clinically benign melanocytic lesions can sometimes pose a significant diagnostic challenge, especially when they involve regional lymph nodes.[80,81,82]

The diagnosis of pediatric melanoma may be difficult and many of these lesions may be confused with the so-called melanocytic tumors of unknown metastatic potential (MELTUMP).[83] These lesions are biologically different from melanoma and benign nevi.[83,84] Novel diagnostic techniques are actively being used by various centers in an attempt to differentiate melanoma from these challenging melanocytic lesions. For example, the absence of BRAF mutations or the presence of a normal chromosomal complement with or without 11p gains strongly argues against the diagnosis of melanoma.[85,86] In contrast, the use of FISH probes that target four specific regions in chromosomes 6 and 11 can help classify melanoma correctly in over 85% of the cases.[87]HRAS mutations have been described in some cases of Spitz nevi but they have not been described in Spitzoid melanoma. The presence of a HRAS mutation may aid in the differential diagnosis of Spitz nevus and Spitzoid melanoma.[88]

Overall 5-year survival of children and adolescents with melanoma is approximately 90%.[47,58,60] Approximately three-fourths of all children and adolescents present with localized disease and have an excellent outcome (>90% 5-year survival). The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[47,60] In one study, the outcome for patients with metastatic disease was favorable,[47] but this figure was not duplicated in another study from the National Cancer Database.[60] For patients with metastatic disease, prognosis is poor and single-agent chemotherapy with dacarbazine, temozolomide, sorafenib,[89] or interleukin-2, or biochemotherapy may be used.[90,91] Newer therapies, such as ipilimumab, have been tested in very limited numbers of children and results are not yet available.[92] (Refer to the PDQ summary on adult Skin Cancer Treatment for more information.)


Chordoma is a very rare tumor of bone that arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum. The incidence in the United States is approximately one case per one million people per year, and only 5% of all chordomas occur in patients younger than 20 years.[93] In children and adolescents, chordomas are more likely to arise in the skull base rather than in the sacrum, making them relatively inaccessible to complete surgical excision. Most pediatric patients have the conventional or chondroid variant of chordoma.[93,94] Patients usually present with pain, with or without neurologic deficits such as cranial or other nerve impairment. Diagnosis is straightforward when the typical physaliferous (soap-bubble-bearing) cells are present. Differential diagnosis is sometimes difficult and includes dedifferentiated chordoma and chondrosarcoma. Standard treatment includes surgery, which is not commonly curative because of difficulty in obtaining clear margins, and external radiation therapy. The best results have been obtained using proton-beam therapy (charged-particle radiation therapy).[95,96]; [97][Level of evidence: 3iiiDiii] Recurrences are usually local but can include distant metastases to lungs or bone. Children younger than 5 years appear to have a worse outlook than older patients.[93,98,99] The survival rate in children and adolescents ranges from about 50% to 80%.[93,99] There is no known effective cytotoxic agent or combination chemotherapy for this disease. Imatinib mesylate has been shown to have antitumor activity in adults with chordoma,[100] and its effect might be the result of inhibition of phosphorylation and activation of PDGFR alpha, beta, and KIT receptors.[101] This therapy has not been tested in children with chordoma.

Cancer of Unknown Primary Site

Cancers of unknown primary site (CUPs) present as a metastatic cancer for which a precise primary tumor site cannot be determined.[102] As an example, lymph nodes at the base of the skull may enlarge in relationship to a tumor that may be on the face or the scalp but is not evident by physical examination or by radiographic imaging. Thus, modern imaging techniques may indicate the extent of the disease but not a primary site. Tumors such as adenocarcinomas, melanomas, and embryonal tumors such as rhabdomyosarcomas and neuroblastomas may have such a presentation. Because of the age-related incidence of tumor types, embryonal histologies are more common in children.

For all patients who present with tumors from an unknown primary site, treatment should be directed toward the specific histopathology of the tumor and should be age appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.[102] Studies in adults suggest that positron emission tomography (PET) imaging can be helpful in identifying CUPs, particularly in patients whose tumors arise in the head and neck area.[103] In addition, molecular assignment of tissue of origin using molecular profiling techniques is feasible and can aid in identifying the putative tissue of origin in about 60% of patients with CUPs.[104] It is still unclear, however, whether these techniques can improve the outcomes or response rates of these patients, and no pediatric studies have been conducted.[105]

Chemotherapy and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending on the histologic findings, symptoms, and extent of tumor) should be initiated as early as possible.


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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of unusual cancers of childhood. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board. Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Unusual Cancers of Childhood Treatment are:

  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
  • R. Beverly Raney, MD (Consultant)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Carlos Rodriguez-Galindo, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Unusual Cancers of Childhood Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/unusual-cancers-childhood/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2011-05-19

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