Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of unusual cancers of childhood. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Incidence of unusual childhood cancers.
• Treatment options for unusual childhood cancers.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

The National Cancer Institute 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.

Cancer in children and adolescents is rare. 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 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.^[1] 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.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 Late Effects of Treatment for Childhood Cancer summary 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.

References

Head and Neck Cancers

Head and neck cancers include nasopharyngeal carcinoma, esthesioneuroblastoma, thyroid tumors, mouth cancer, salivary gland cancer, laryngeal carcinoma, papillomatosis, and respiratory tract carcinoma involving the NUT gene on chromosome 15. The prognosis, diagnosis, classification, and treatment of these head and neck cancers are discussed below.

Nasopharyngeal Carcinoma

Nasopharyngeal cancer arises in the lining of the nasal cavity and pharynx.^[1][2] This tumor accounts for about one-third of all cancers of the upper airways. The incidence of this tumor is approximately 1 in 100,000 persons younger than 20 years in the United States.^[3] 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.^[4] 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. Type 1 is squamous cell carcinoma, type 2 is nonkeratinizing carcinoma, and type 3 is undifferentiated carcinoma.

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, the lungs, and the liver. The location of the primary tumor can be made 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 presents with epistaxis, 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.^[1][5]

Tumor staging is performed utilizing the tumor-node-metastasis (TNM) classification system of the American Joint Committee on Cancer (AJCC).^[6] The majority (>90%) of children and adolescents with nasopharyngeal carcinoma present with advanced disease (stage III/IV or T3/T4).^[7] 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.^[8] 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.^[8]

Surgery has a limited role in the management of nasopharyngeal carcinoma since the disease is usually considered unresectable because of extensive local spread. High-dose radiation therapy alone may have a role in the management of low-stage nasopharyngeal carcinoma; however, studies in both children and adults have shown that combined modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.^{[8][9][10][11]} 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.^[11] 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, and leucovorin with or without recombinant interferon-beta reported response rates of more than 90%.^[12][13] Radiation therapy doses utilized in both studies were approximately 60 Gy. Additional drug combinations that have been used in children with nasopharyngeal carcinoma include BEP (bleomycin, epirubicin, and cisplatin), PF (cisplatin, fluorouracil), and PMB (cisplatin, methotrexate, and bleomycin).^[2] Incorporation of high-dose-rate brachytherapy into the chemoradiotherapy approach has been reported, but its role in the management of nasopharyngeal carcinoma in children is unknown.^[14][15]

A preliminary report of the use of Epstein-Barr virus-specific cytotoxic T-lymphocytes revealed minimal toxicity and evidence of significant anti-tumor activity in patients with relapsed or refractory nasopharyngeal carcinoma.^[16] (Refer to the PDQ summary on Nasopharyngeal Cancer Treatment for more information.)

Treatment options under clinical evaluation

• ARAR0331: This Children's Oncology Group trial (COG-ARAR0331) is evaluating the efficacy of induction chemotherapy with cisplatin plus 5-fluorouracil 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

Esthesioneuroblastoma (olfactory neuroblastoma) is a very rare, small round-cell tumor arising from the nasal neuroepithelium that is distinct from primitive neuroectodermal tumors.^[17][18][19] 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 mainstay of treatment has been surgery and radiation. Newer techniques such as endoscopic sinus surgery and radiosurgery may play a role in the management of this tumor.^[20] A retrospective analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program identified 311 patients with esthesioneuroblastoma.^[21] 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.^[22] Recent reports indicate increasing use of neoadjuvant chemotherapy.^{[17][18][23][24]} Chemotherapy regimens that have been used with efficacy include VIP (etoposide [VP-16], ifosfamide, and cisplatin [Platinol]),^[25] VAC (vincristine + actinomycin D + cyclophosphamide) without doxorubicin (Adriamycin), ifosfamide/etoposide, and cisplatin plus etoposide or doxorubicin.^[23] The long-term survival rate appears to be approximately 60% to 80%. Local recurrences may occur later in life.

Thyroid Tumors

Tumors of the thyroid are classified as adenomas or carcinomas.^{[26][27][28][29][30]} 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.

Although rare, thyroid cancers represent about 1.5% of all tumors seen in the pediatric age group. Most thyroid carcinomas occur in girls.^[31] Patients with thyroid cancer usually present with a thyroid mass with or without cervical adenopathy.^[32][33][34] There is an excessive frequency of thyroid adenoma and carcinoma in patients who previously received radiation to the neck.^[35][36] 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 (ATA) Taskforce ^[37] 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.^[26]

Initial evaluation of a child or adolescent with a thyroid nodule should include an ultrasound of the thyroid and a radionuclide scan. Most thyroid nodules are cold or hypofunctional. Tests of thyroid function are usually normal, but thyroglobulin can be elevated. Fine needle aspiration (FNA) is the initial diagnostic approach, though experience in FNA in pediatric hospitals may be limited, in which case open biopsy or lobe resection should be considered.^[38][39] 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,^[40] but the vast majority of tumors are differentiated. Papillary carcinoma represents 60% to 75% of these tumors,^[36] follicular carcinoma 10% to 20%, medullary carcinoma 5% to 10%, and anaplastic carcinoma less than 1%. Follicular carcinoma may be sporadic or familial and medullary carcinoma is usually familial.^[41] Papillary carcinoma often has multicentric origins and a very high rate of lymph node metastasis (70%–90%).^[40] Follicular carcinoma is usually encapsulated and has a higher incidence of bone and lung metastasis. Follicular carcinoma and papillary carcinoma generally have a benign course, with a 10-year survival rate of more than 95%.^[42] Fifty percent of medullary thyroid carcinomas in adults and children have hematogenous metastases at diagnosis.^[43] 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.^[44]

Surgery by an experienced thyroid surgeon is the treatment required for all thyroid neoplasms.^[42] Total or near-total thyroidectomy plus cervical lymph node dissection, when indicated, is the most common surgical approach.^[32] For patients with obvious metastatic disease or heavy nodal invasion, total thyroidectomy and treatment with radioactive idodine is indicated. For patients with an isolated nodule in the thyroid, treatment may involve only a lobectomy.^[32][45] During the 4- to 6-week period following surgery, patients who received a total thyroidectomy may develop hypothyroidism. A radioactive iodine (I-131) scan is then performed to search for residual, functionally active neoplasms. 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 (100–200 mCi) of I-131 are required. After surgery and radioactive iodine therapy, hormone replacement therapy must be given to compensate for the lost thyroid hormone and to suppress TSH production.^[46]

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.^[47] Periodic evaluations are required to determine whether there is metastatic disease involving the lungs. Lifelong follow-up is necessary.^[48] Thyroglobulin, T4, and thyrotropin (TSH) levels should be evaluated periodically to determine whether replacement hormone is appropriately dosed.

Patients with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.^[48][49][50] 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.^[28][51][52] 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.^[53] Recurrent papillary thyroid cancer is usually responsive to treatment with radioactive iodine ablation.^[54] Even patients with a tumor that has spread to the lungs may expect to have no decrease in life span after appropriate treatment. (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.^[3][55] The vast majority (>90%) of tumors and tumor-like lesions in the oral cavity are benign.^{[56][57][58][59]} 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 ^[56][57] and 3% to 13% of oral tumor biopsies.^[58][59] Malignant tumor types include lymphomas (especially Burkitt) and sarcomas (including rhabdomyosarcoma and fibrosarcoma). 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.^[60][61] Adolescents with an oral SCC should be screened for Fanconi anemia.^[62][63]

Treatment of benign oral tumors is surgical. Management of malignant tumors is dependent on histology and may include surgery, chemotherapy, and radiation.^[64] LCH may require other treatment besides surgery. (Refer to the PDQ summaries on adult Oropharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.)

Salivary Gland Tumors

Most salivary gland neoplasms arise in the parotid gland.^{[65][66][67][68][69]} 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. Sialoblastomas are usually benign tumors presenting in the neonatal period, but can rarely metastasize.^[70] The malignant lesions include mucoepidermoid carcinoma,^[71] 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.^[72][73] 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.^[71][74][75] Prognosis for patients with these tumors is generally good.^{[68][76][77][78]} (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.^[79][80] 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. SCC of the larynx should be managed in the same manner as in adults with carcinoma at this site, with surgery and radiation.^[81] 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.^[82] The presence of HPV-11 appears to correlate with a more aggressive clinical course than HPV-6.^[83] This condition is not cancerous, and primary treatment is surgical ablation with laser vaporization.^[84] Frequent recurrences are common. If a patient requires more than four surgical procedures per year, treatment with interferon should be considered.^[85] 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.^[86] These results, however, must be confirmed in a larger randomized trial. These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords and may rarely extend into the lung, producing significant morbidity. Malignant degeneration may occur, with development of cancer in the larynx and squamous cell lung cancer. (Refer to the PDQ summary on adult Laryngeal Cancer Treatment for more information.)

Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15

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 exhibit squamous differentiation. Tumors from 8 of 11 patients exhibited 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 exhibiting t(15;19).^[87]

Thoracic Cancers

Thoracic cancers include breast cancer, bronchial adenomas, bronchial carcinoid tumors, pleuropulmonary blastoma, esophageal tumors, thymomas, thymic carcinomas, tumors of the heart, and mesothelioma. The prognosis, diagnosis, classification, and treatment of these thoracic cancers are discussed below.

Breast Cancer

The most frequent breast tumor seen in children is a fibroadenoma.^[1] 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.^[2] 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.^[2]

Carcinomas have been reported in both males and females younger than 21 years.^{[3][4][5][6][7][8]} 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.^{[7][9][10][11]} (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.) Carcinomas are more frequent than sarcomas. Mammograms should start at age 25 years or 10 years postexposure to radiation therapy (whichever came last). Treatment options include radiation, chemotherapy, and surgery for children and adolescents with breast cancer. 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 [HIV]). (Refer to the PDQ summary on adult Breast Cancer Treatment for more information.)

Bronchial Tumors

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. The most frequent type is a carcinoid tumor; this is followed by mucoepidermoid carcinoma and adenoid cystic carcinoma. Carcinoid tumors account for 80% to 85% of all bronchial tumors in children.^{[12][13][14][15][16]} 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. 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.^[17] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.^[18] 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.^[19][20] The management of bronchial tumors is somewhat controversial because all 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.^[21] 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.^[17]

Conservative pulmonary resection with the removal of the involved lymphatics is the treatment of choice. Sleeve segmental bronchial resection is possible in children and when feasible, is the treatment of choice.^[22][23] 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 is a rare and highly aggressive pulmonary malignancy in children. Pleuropulmonary blastoma appears to progress through stages with the earliest stage (type I) being a purely lung cystic neoplasm with subtle malignant changes, typically occurring in the first 2 years of life with a good prognosis, followed by the more aggressive stages: type II (cystic and solid neoplasm) and type III (purely solid neoplasm) stages.^[24][25] There have been reports of type I transitioning directly to type III.^[26] Cerebral metastasis occurs in up to 50% of patients with type III tumors.^[27] An independent group of researchers has established a registry and resource web site for this rare tumor.^[28] An association between congenital lung cysts and pleuropulmonary blastoma has been reported, although cytogenetic and molecular studies can help distinguish the nonneoplastic congenital cystic adenomatoid malformation from pleuropulmonary blastoma.^{[29][30][31][32][33]} The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the mediastinum, diaphragm, and/or pleura.^[32][34] The tumors may recur or metastasize, in spite of primary resection.^[25][35] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma, and adjuvant chemotherapy may benefit patients with type I pleuropulmonary blastoma by reducing the risk of recurrence.^[24][36] Achieving total resection of the tumor at any time during treatment is associated with improved prognosis.^[32] Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, and doxorubicin. High-dose chemotherapy with stem cell rescue has been used without success.^[37] Radiation, either external beam or P-32, may be used when the tumor cannot be surgically removed. A family history of cancer in close relatives has been noted for many young patients affected by this tumor.^[38] In addition, there has been a reported association between pleuropulmonary blastoma and cystic nephroma.^[39][40] Data from the International Pleuropulmonary Blastoma Registry suggest that adjuvant chemotherapy may reduce the risk of recurrence.^[24]

Esophageal Tumors

Esophageal cancer is rare in the pediatric age group, though it is relatively common in older adults.^[41] 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 with the platinum derivatives, paclitaxel, and etoposide, agents commonly used to treat carcinomas. 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.^[42][43] The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component. 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 rare in adults and children.^[44][45] Various diseases and syndromes are associated with thymoma, including myasthenia gravis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, and pure red-cell aplasia.^[46] Endocrine (hormonal) disorders including hyperthyroidism, Addison disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.^[47]

These neoplasms are usually located in the front part of the chest 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.

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 exhibit squamous differentiation. Tumors from 8 of 11 patients exhibited 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 exhibiting t(15;19).^[48]

Radiation therapy is necessary for patients with invasive thymoma or thymic carcinoma, even with a complete resection.^[47] 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, cisplatin, and paclitaxel.^[47][49][50] The prognosis for patients with invasive thymoma or thymic carcinoma usually is poor, though significantly higher rates of survival have been reported for patients with tumors that are not locally invasive. (Refer to the PDQ summary on adult Thymoma and Thymic Carcinoma Treatment for more information.)

Tumors of the Heart

The most common tumors of the heart are benign and include myxomas, rhabdomyomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).^[51][52] Primary tumors of the heart may include benign and malignant teratomas, rhabdomyosarcomas, hemangiomas, and chondrosarcomas. Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.^[51] In a retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography, 68% of the patients exhibited features of tuberous sclerosis.^[53] In another study, 79% (15/19) 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.^[54] Other tumors of the heart can include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, and carcinoma of other sites. Symptoms include abnormalities of heart rhythm, enlargement of the heart, fluid in the pericardial sac, and congestive heart failure. Successful treatment may require surgery, which may include transplantation, and chemotherapy appropriate for the type of cancer that is present.^[55][56]

Mesothelioma

Mesothelioma is extremely rare in childhood with only 2% to 5% of patients presenting during the first two decades of life.^[57]

This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.^[58] 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.^[59][60] In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.^[61] 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.^[57] Radical surgical resection has been attempted with mixed results.^[62] Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.^[63] 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.^[64] This tumor generally involves all surfaces lining the abdominal organs, including the surfaces of the ovary. Treatment includes surgical resection whenever possible and use of chemotherapy with agents such as cisplatin, carboplatin, and paclitaxel. (Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)

Abdominal Cancers

Abdominal cancers include adrenocortical tumors, carcinomas of the stomach, cancer of the pancreas, colorectal carcinomas, carcinoid tumors, and gastrointestinal stromal cell tumors. The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below. 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]} 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.^[6] 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][7] Children with Beckwith-Wiedemann Syndrome ^[8] or hemihypertrophy ^[9] 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.^[10] 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 ^[11] or chemotherapy using cisplatin, 5-fluorouracil (5-FU), and etoposide.^[4][12] 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 g/day of mitotane and was associated with fewer toxic side effects than doses of 3 to 5 g/day.^[13][14]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][15] 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.^[16] Adrenal tumors can present as incidental findings (incidentalomas), and these tumors should be thoroughly evaluated.^[17] (Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)

Treatment options under clinical evaluation

• 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 IIIand stage IV disease will receive chemotherapy before resection. The chemotherapy is cisplatin, doxorubicin, etoposide, and oral mitotane.

Carcinoma of the Stomach

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.^[18] The tumor must be distinguished from other conditions such as non-Hodgkin lymphoma, malignant carcinoid, leiomyosarcoma, and various benign conditions or tumors of the stomach. Symptoms include vague upper abdominal pain, which can be associated with poor appetite, and weight loss. 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.^[19] 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.^[20] 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.^[21] Because of the rarity of stomach cancer in the pediatric age group, little information regarding the treatment outcomes of children exists. (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.^[22] 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.^[23][24][25] Several cases of primitive neuroectodermal tumor of the pancreas have been reported in children and young adults.^[26] Most pancreatic tumors do not secrete hormones, though some tumors secrete insulin, which can lead to symptoms of weakness, fatigue, hypoglycemia, and coma.^[23][27] 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.^[28][29][30] 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.^[31][32] Pancreatoblastoma is reported to be associated with the Beckwith-Wiedemann syndrome and Cushing syndrome.^[33][34]

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.^[35][36] Treatment consists of complete tumor resection (ideally without biopsy). Metastases may occur, but in general, prognosis is good following surgery alone.^[37][38]

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.^[24][31] 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.^[39][40] 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, as it is seen in only one person per 1 million younger than 20 years in the United States annually.^[41] 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.^[42] Colon cancer in children is often associated with a family cancer syndrome.^[43][44] 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.^[45] 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.^[46] 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.^[47] 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.^[48] 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.^[49]

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,^[50] 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.^[51]

Colorectal carcinoma usually presents with symptoms related to the site of the tumor. 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 followed by computed tomography of the chest and bone scans.^[50][51]

Most patients present with evidence of metastatic disease, either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.^[52] Complete surgical excision should be the primary aim of the surgeon, but in most instances this is impossible; removal of large portions of tumor provides little benefit for the individuals with extensive metastatic disease. Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.

Current therapy includes the use of radiation for rectal and lower-colon tumors, in conjunction with chemotherapy using 5-FU with leucovorin.^[53] Other agents that may be of value include irinotecan and oxaliplatin. No significant benefit has been determined for interferon-alpha given in conjunction with 5-FU/leucovorin.^[54] (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 or the large or small bowel.^{[55][56][57][58][59]} Most lung lesions are benign; however, some metastasize.^[60] Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, are small, localized tumors and simple appendectomy is the therapy of choice.^[61] 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.^[62] 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.^[60] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.^[63] (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors for more information.)

Gastrointestinal Stromal Cell Tumor

Gastrointestinal stromal cell tumor (GIST) is a mesenchymal tumor of the intestinal tract that typically occurs in adults older than 40 years. These tumors are rare in children. Only 1.4% of all patients with GISTs are children and young adults.^[64] Many of these tumors were previously diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas. Younger patients with GISTs are usually female and commonly present in the second decade of life with anemia-related gastrointestinal bleeding. In children, most tumors are in the stomach and may be localized or multifocal. Carney triad is associated with gastric GIST in a small number of children and in an association with extra-adrenal paraganglioma and pulmonary chondroma. A familial variant of pediatric GIST has not been established. The association of KIT mutations in adults with GIST is as high as 90%; imatinib mesylate has been found to be effective therapy in these patients. GIST in adolescents and young adults has a heterogeneous presentation; some patients have tumors with mutations in KIT or PDGFA, which suggests that these tumors may respond to imatinib mesylate.^[65][66] Pediatric GIST is probably biologically different from adult GIST, since KIT and PDGFA mutations are rarely detected in pediatric GIST tumors.^[67] Clinical response to targeted therapies such as imatinib mesylate has not been proven. Complete surgical resection of localized disease should be the initial treatment in pediatric GIST. No chemotherapy regimen has been effective in the treatment of GIST, and in the absence of mutations in KIT, imatinib mesylate is not recommended as adjuvant therapy. The clinical course of GIST is variable, with an excellent prognosis in children with localized disease and an indolent, slowly progressive course in children with liver and lymph node metastatic disease. Because of the variable expression of mutations in KIT or PDGFA, all patients with GISTs should have their tumors examined for these mutations.^[64][65][66]

Genital/Urinary Tumors

Genital/urinary tumors include carcinoma of the bladder, ovarian cancer, and carcinoma of the cervix and vagina. The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below.

Carcinoma of the Bladder

Carcinoma of the bladder is extremely rare in children. The most common carcinoma to involve the bladder is transitional cell carcinoma, which generally presents with hematuria.^[1] In contrast to adults, most bladder carcinomas are low grade, superficial, and have a good prognosis following transurethral resection.^[1][2][3] Squamous cell and more aggressive carcinomas, however, have been reported.^[4][5] Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.^[6][7] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.^[6] One of the most important risk factors for bladder cancer in adults is cigarette smoking, which may be associated with as many as 50% of these cancers in men and 33% in women.^[7] (Refer to the PDQ summary on adult Bladder Cancer Treatment for more information.)

Ovarian Cancer

The majority of ovarian masses in children are not neoplastic. The most common neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then miscellaneous tumors such as Burkitt lymphoma.^[8][9] Ovarian tumors derived from malignant epithelial elements include: adenocarcinomas,^[10] 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.^[11] (Refer to the PDQ summaries on Childhood Extracranial Germ Cell Tumors, adult Ovarian Epithelial Cancer Treatment, and 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.^[12] Histologic subtypes display some areas of gonadal differentiation and include juvenile granulosa cell tumors (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, 6 months to 17.5 years in one study).^[13] JGCT represent about 5% of ovarian tumors in children and adolescents and are distinct from the granulosa cell tumors seen in adults.^{[12][14][15][16]} Most patients present with precocious puberty.^[17] Other presenting symptoms include abdominal pain, abdominal mass, and ascites. JGCT has been reported in children with Ollier disease and Maffucci syndrome.^[18] 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.^{[13][16][19][20][21]}

Carcinoma of the Cervix and Vagina

Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence with fewer than 50 reported cases.^[22] 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 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 ^[23] 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%.^[22]

Other Rare Childhood Cancers

Other rare childhood cancers include multiple endocrine neoplasia syndrome, skin cancer, chordoma, and cancer of unknown primary site. The prognosis, diagnosis, classification, and treatment of these other rare childhood cancers are discussed below.

Multiple Endocrine Neoplasia Syndrome

These syndromes are familial disorders that are characterized by neoplastic changes in more than one endocrine organ.^[1] Changes may include hyperplasia, benign adenomas, and carcinomas. There are distinct genetic disorders with characteristic clinical presentations referred to as multiple endocrine neoplasia (MEN) 1, MEN 2a, and MEN 2b. An additional complex is referred to as the Carney complex, which is an association of MEN associated with heart and skin tumors.^[2]

The MEN 1 syndrome, also referred to as Werner syndrome, may involve tumors of the pituitary gland, the parathyroid, and adrenal, gastric, and pancreatic structures, which may secrete hormones such as insulin. The gene for this syndrome is located on chromosome 11q13. Mutation testing should be combined with clinical screening for patients and family members with proven "at risk" MEN 1.^[3] The MEN 2a syndrome (Sipple syndrome) is associated with medullary thyroid carcinoma, parathyroid hyperplasia, adenomas, and pheochromocytoma. The MEN 2b syndrome is associated with medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, and pheochromocytomas, mucosal neuromas, and ganglioneuromas.^[4][5] Patients with the MEN 2b syndrome may have a slender body build, long and thin extremities, a high arch palate, and pectus excavatum or pes cavus. The face may be characterized by thick lips because of mucosal neuromas. Such patients can also be identified by performing a pentagastrin stimulation test or by genetic screening in families known to be affected.

A germline mutation in the ret oncogene (tyrosine-kinase receptor) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN 2a and MEN 2b syndromes.^[6][7][8] The current 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. Children with MEN 2a should undergo prophylactic total thyroidectomy between the age of 5 and 8 years.^{[8][9][10][11][12]} Relatives of patients with MEN 2a should undergo genetic testing in early childhood, before the age of 5 years. Carriers should undergo total thyroidectomy with autotransplantation of one parathyroid gland by a certain age, depending on the type of mutation found.^[13][14][15] Because of the increased virulence of medullary thyroid carcinoma in children with MEN 2b, it is recommended that these children undergo prophylactic thyroidectomy in infancy.^[10][16] 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.

The Carney complex includes the association of primary pigmented nodular adrenocortical disease with blue nevi of the skin and mucosa and a variety of additional endocrine or nonendocrine tumors. There may be myxomas of the skin or breast and tumors of peripheral nerve sheath origin.^[2]

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.^[17][18][19] 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.

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

Melanoma is thought to be the most common skin cancer in children, followed by basal cell and squamous cell carcinomas (SCCs).^{[20][21] [22][23][24][25][26][27]} The incidence of melanoma in children and adolescents represents approximately 1% of the new cases of melanoma that are diagnosed annually in this country. In most instances, melanoma in the pediatric population is similar to that of adults in relation to site of presentation, symptoms, description, spread, and prognosis, but thickness does not appear to have prognostic significance.^{[26] [28]}Melanoma may grow more rapidly in prepubescent children than in older individuals and may present with more atypical clinical features in children than in adults.^[29][30] Analysis of the National Cancer Data Base identified 3,159 patients aged 1 year to 19 years with melanoma. Most of the patients (90%) were 10 years or older. More girls (56%) were seen than boys. Younger age and higher stage conferred a worse prognosis.^[28]

The greatest cause of skin cancer of any type is exposure to the ultraviolet portion of sunlight.^{[31][32][33][34]} Other causes may be related to chemical carcinogenesis, radiation exposure, immunodeficiency, or immunosuppression. The person who is most likely to develop a melanoma is easily sunburned, has poor tanning ability, and generally has light hair, blue eyes, and pale skin. Worldwide, there is an increasing incidence of both melanoma and nonmelanoma skin cancers. Melanoma presents as a relatively flat, dark-colored lesion, which may enlarge, penetrate the skin, or metastasize.

Melanomas may be congenital.^[23] They are sometimes associated with large congenital black spots known as melanocytic nevi,^[35] which may cover the trunk and thigh.^[36][37][38] Melanomas can also develop in individuals with xeroderma pigmentosum, a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations. Individuals with xeroderma pigmentosum may also develop other skin cancers, including SCCs and basal cell carcinomas.^[24] Children with hereditary immunodeficiencies have an increased lifetime risk of developing melanoma.

Neurocutaneous melanosis is an unusual condition associated with large or multiple congenital nevi of the skin and melanin deposits within the central nervous system. These deposits may be detected by magnetic resonance imaging of the brain or spinal cord. Dysplastic nevi occur in about 5% of the U.S. population and are potential precursors of melanoma.^[24] Individuals with atypical moles, which include raised lesions that may bleed and various color hues (e.g., brown, tan, pink, black), are at an increased risk of having melanoma and of having children affected by these premalignant lesions.

Basal cell carcinomas generally appear as raised lumps or ulcerated lesions, usually in areas with previous sun exposure. These tumors may be multiple and exacerbated by radiation therapy.^[39] 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.^{[40] [41][42][43]} 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. Surgery for melanoma depends on the size, site, level of invasion, and metastatic extent or stage of the tumor.^[24] Wide excision with skin grafting may become necessary. The current recommendation is that surgical resection include a 2-cm-deep margin for melanoma lesions, with examination of the regional lymph nodes draining the site of the melanoma. This procedure may require the injection of a radioisotope, following its distribution, and then performing excision of the associated regional lymph nodes (sentinel lymph node [SLN] biopsy technique).^[44][45] This requires injection of a vital blue stain and radioisotope into the skin to characterize the pattern of lymph node drainage. Lymph node dissection is necessary if sentinel nodes are involved with the tumor; however, if there is no spread of the disease beyond the lymph nodes, adjuvant therapy with interferon-alpha-2b alone may be recommended for a period of 1 year.^[24][46][47] Finding the tumor-involved regional lymph node (via SLN biopsy) may clarify the suspicion of melanoma in diagnostically difficult situations such as Spitz nevus with significant atypia at the primary site.^[44] However, on the basis of reports of clinically benign melanocytic lesions involving regional lymph nodes, the prognostic value of SLN biopsy is unclear.^[48] SLN biopsies have shown an increased frequency of benign nodal nevi, which might mimic metastasis of melanoma and, therefore, may raise potential diagnostic and therapeutic issues.^[49] For individuals with metastatic disease, a combination of cisplatin, vinblastine, imidazole carboxamide, interleukin-2 (IL2), and interferon-alpha-2b has been proposed.^[24]

Overall 5-year survival of children and adolescents with melanoma is approximately 91%.^[50] Most children and adolescents present with localized disease (68%–78%) and have an excellent outcome (96% 5-year survival). In a Surveillance, Epidemiology, and End Results (SEER) study, the 5-year survival for those with nodal or distant metastases was 77% and 57%, respectively.^[50] The prognosis of children and adolescents with melanoma has been previously reported to be similar to that of adults with similar stage disease, with the prognosis depending on the tumor thickness and the extent of spread at the time of diagnosis.^[51][52] However, the outcomes for children and adolescents noted in the SEER study are substantially better for those with nodal or distant metastases than the outcomes for adults in similar stages. One study compared young patients (≤20 years) with adult patients and found a higher incidence of lymph node metastases in the younger patients versus case-matched adult patients (18% vs. 10%), but, the 10-year cause-specific survival rates were similar between the two groups (89% and 79%respectively).^[53] The reason for this difference is unknown, though it is speculated that in children some cases were classified as stage III on the basis of what may have been an intranodal nevus.^[48] Factors associated with worse survival from melanoma include male gender, unfavorable location of primary tumor, and regional or distant metastases.^[50] Refer to the PDQ summary on adult Skin Cancer Treatment for more information.

Treatment options under clinical evaluation

There are two melanoma trials available to patients aged 10 years or older. Both of these trials are combination adult/pediatric trials.

• E1697 (ECOG):^[54] Phase III trial of 4 weeks of high-dose interferon-alpha-2b in stages T3 to T4 or N1 melanoma.
• S0008 (SWOG):^[55] Phase III trial of high-dose interferon-alpha-2b versus cisplatin, vinblastine, and dacarbazine plus IL2 in patients with high-risk melanoma.

Chordoma

Chordoma is a rare tumor 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 1 million people per year. In American children and adolescents, chordomas are more likely to arise in the clivus, especially in females, rather than in the sacrum, which is more common among adult males.^[56] 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,^[57][58] but this is currently available only in Loma Linda, California, and Boston, Massachusetts. Recurrences are usually local but can include distant metastases to lungs or bone. Children younger than 5 years may have a worse outlook than older patients.^[59][60] The survival rate in children and adolescents is about 50% at 4 years from diagnosis.^[60] There is no known effective cytotoxic agent or combination chemotherapy for this disease, but there is a report of temporary regression after ifosfamide and doxorubicin therapy in a 19-month-old child.^[61]

Cancer of Unknown Primary Site

These cancers present as a metastatic cancer for which a precise primary tumor site cannot be determined.^[62] 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, the treatment should be considered in relation to the pathology of the tumor and should be appropriate for the general type of cancer initiated, irrespective of the site or sites of involvement.^[62] Chemotherapy and radiation therapy treatments appropriate and relevant for the general category of carcinoma or sarcoma (depending upon the histologic findings, symptoms, and extent of tumor) should be initiated as early as possible.

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Changes to This Summary (04/02/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Head and Neck Cancers

Added Louis et al. as reference 15.

Added text to state that a meta-analysis study of patients with esthesioneuroblastoma indicates that higher histopathologic grade and metastases to the cervical lymph nodes may confer adverse prognostic factors (cited Dulguerovet et al. as reference 22).

Added text to state that The American Thyroid Association Taskforce 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 (cited Dinauer et al. and Cooper et al. as references 26 and 37, respectively).

Added Vasko et al. as reference 27.

Added Reinhard et al. as reference 63.

Thoracic Cancers

Added text to state that pleuropulmonary blastoma appears to progress through stages with the earliest stage with subtle malignant changes, followed by the more aggressive types. Cerebral metastasis occurs in up to 50% of patients with type III tumors (cited Shivastava et al. and Priest et al. as references 26 and 27, respectively).

Abdominal Cancers

Added Kletter et al. as reference 34.

Added text to state that pediatric gastrointestinal stromal cell tumors (GIST) are probably biologically different from adult GIST, since certain mutations are rarely detected in pediatric GIST (cited Janeway et al. as reference 67).

Other Rare Childhood Cancers

Added Griffin et al. as reference 39.