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Unusual Cancers of Childhood Treatment (PDQ®)

Health Professional Version
Last Modified: 04/03/2014

Thoracic Cancers

Breast Cancer
        Fibroadenoma
        Malignant breast tumors
Lung Cancer
Bronchial Tumors
        Histology
        Prognosis
        Clinical presentation and diagnostic evaluation
        Treatment
Pleuropulmonary Blastoma
        Types of pleuropulmonary blastoma
        Risk factors
        Clinical presentation and diagnostic evaluation
        Treatment
Esophageal Tumors
        Incidence and histology
        Clinical presentation and diagnostic evaluation
        Treatment
Thymoma and Thymic Carcinoma
        Incidence and risk factors
        Clinical presentation
        Treatment
Cardiac Tumors
        Histology
        Risk factors
        Clinical presentation and diagnostic evaluation
        Treatment
Mesothelioma
        Incidence and risk factors
        Prognosis
        Diagnostic evaluation
        Treatment

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

Fibroadenoma

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

Malignant breast tumors

Incidence, epidemiology, and treatment

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

Treatment of adolescents and young adults

Breast cancer is the most frequently diagnosed cancer among adolescent and young adult (AYA) women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses.[12] Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different than in older women and correlates with a worse prognosis.[13] Treatment in the AYA group is similar to that in older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.[14]

Female survivors of Hodgkin lymphoma

There is an increased lifetime risk of breast cancer in female survivors of Hodgkin lymphoma who were treated with radiation to the chest area; however, breast cancer is also seen in patients who were treated for any cancer that was treated with chest irradiation.[9,15-18] Carcinomas are more frequent than sarcomas. Mammograms with adjunctive breast magnetic resonance imaging (MRI) should start at age 25 years or 10 years postexposure to radiation therapy (whichever came last). (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.) Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with the human immunodeficiency virus).

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

Lung Cancer

Primary lung tumors are rare in children and histologically quite diverse.[1] When epithelial cancers of the lung occur, they tend to be of advanced stage with prognosis dependent on both histology and stage.[19]

The majority of pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5.[20] While primary pulmonary tumors are rare in children, the majority of these tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign.[21] These tumors may respond to the ALK inhibitor crizotinib in the presence of ALK translocations.[22][Level of evidence: 3iiiDiv]

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

Bronchial Tumors

Histology

Bronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of bronchial tumors on occasion display a malignant behavior. There are three histologic types:[23-28]

  • Carcinoid tumor (most frequent). Carcinoid tumors account for 80% to 85% of all bronchial tumors in children.[23-27]
  • Mucoepidermoid carcinoma.
  • Adenoid cystic carcinoma (least frequent).
Prognosis

Bronchial tumors of all histologic types are associated with an excellent prognosis in children, even in the presence of local invasion.[29,30]

Clinical presentation and diagnostic evaluation

The presenting symptoms of a cough, recurrent pneumonitis, and hemoptysis are usually due to an incomplete bronchial obstruction. Because of difficulties in diagnosis, symptoms are frequently present for months, and, occasionally, children with wheezing have been treated for asthma with delays in diagnosis as long as 4 to 5 years.[31]

Metastatic lesions are reported in approximately 6% of carcinoid tumors, and recurrences are reported in 2% of cases. Atypical carcinoid tumors are rare but more aggressive with 50% of patients presenting with metastatic disease at diagnosis.[19,32] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[33] Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread.

Treatment

The management of bronchial tumors is somewhat controversial because bronchial tumors are usually visible endoscopically. Biopsy of 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.[34]

Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[35,36] Adenoid cystic carcinomas (cylindroma) have a tendency to spread submucosally, and late local recurrence or dissemination has been reported. In addition to en bloc resection with hilar lymphadenectomy, a frozen section examination of the bronchial margins should be performed in children with this lesion. Neither chemotherapy nor radiation therapy is indicated for bronchial tumors, unless evidence of metastasis is documented.

Pleuropulmonary Blastoma

Types of pleuropulmonary blastoma

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. Pleuropulmonary blastoma 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.[37,38]
  • Type II: A cystic and solid neoplasm. Cerebral metastasis may occur in 11% of patients.[39]
  • Type III: A purely solid neoplasm.[40,41] Cerebral metastasis occurs in up to 50% of patients with Type III tumors.[39]
Risk factors

Approximately one-third of families affected by pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the Pleuropulmonary Blastoma Family Tumor and Dysplasia Syndrome. Germline mutations in the DICER1 gene are considered the major genetic determinant of the complex.[42,43] Importantly, while DICER1 mutations cause a wide range of phenotypes, pleuropulmonary blastoma does not occur in all families with DICER1 mutations; therefore, the term DICER1 syndrome is generally used for these families. Also, most mutation carriers are unaffected, indicating that tumor risk is modest.[43]

A family history of cancer in close relatives has been noted for many young patients affected by this tumor.[44,45] In addition, pleuropulmonary blastoma has been reported in siblings.[46]

There has been a reported association between pleuropulmonary blastoma and cystic nephroma, ciliary body medulloepithelioma of the eye, and primary ovarian neoplasms, particularly ovarian sex cord–stromal tumors.[43,47-50]

Clinical presentation and diagnostic evaluation

The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the heart/great vessels, mediastinum, diaphragm, and/or pleura.[51,52] The International Pleuropulmonary Blastoma Registry identified 11 cases of Type II and Type III pleuropulmonary blastoma with tumor extension into the thoracic great vessels or the heart. Radiographic evaluation of the central circulation should be performed in children with suspected or diagnosed pleuropulmonary blastoma to identify potentially fatal embolic complications.[53]

Treatment

Achieving total resection of the tumor at any time during treatment is associated with improved prognosis.[52] The tumors may recur or metastasize, in spite of primary resection.[38,41] The cerebral parenchyma is the most common metastatic site.[39]

Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma, and adjuvant chemotherapy may benefit patients with Type I pleuropulmonary blastoma by reducing the risk of recurrence.[40,54] Chemotherapeutic agents may include vincristine, cyclophosphamide, dactinomycin, doxorubicin, and irinotecan.[55,56] Data from the International Pleuropulmonary Blastoma Registry suggest that adjuvant chemotherapy may reduce the risk of recurrence.[40]

Radiation, either external beam or P-32, may be used when the tumor cannot be surgically removed.

High-dose chemotherapy with stem cell rescue has been used without success.[57]

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 the following:[58]

  • Type I: Surgery alone for select cases; adjuvant chemotherapy may decrease recurrences.[40,58] Evidence suggests a close histologic relationship between a Type 4 cystic adenomatoid malformation and a Type I pleuropulmonary blastoma.[59,60] Complete surgical lobectomy is adequate treatment for these patients, but close observation is recommended.
  • Type II and Type III: Surgery followed by chemotherapy.[55]

An independent group of researchers has established a registry and resource Web site for this rare tumor.[58]

Esophageal Tumors

Incidence and histology

Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[61,62] Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma.

Clinical presentation and diagnostic evaluation

Symptoms are related to difficulty in swallowing and associated weight loss. Diagnosis is made by histologic examination of biopsy tissue.

Treatment

Treatment options for esophageal carcinoma include either external-beam intracavitary radiation therapy or chemotherapy agents commonly used to treat carcinomas: platinum derivatives, paclitaxel, and etoposide. Prognosis is generally poor for this cancer, which rarely can be completely resected.

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

Thymoma and Thymic Carcinoma

A cancer of the thymus is not considered a thymoma or a thymic carcinoma unless there are neoplastic changes of the epithelial cells that cover the organ.[63-65] 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.

Incidence and risk factors

Thymoma and thymic carcinomas are very rare in children.[66-68] In the Tumori Rari in Età Pediatrica registry, only eight cases were identified over a 9-year period.[69] A review of 73 cases of anterior mediastinal tumors using the SEER Registry of the National Cancer Institute identified thymic epithelial tumors as having the worst survival rate at 10 years from diagnosis; better survival rates occurred in patients with lymphomas and germ cell tumors.[70]

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.[71,72] Endocrine (hormonal) disorders including hyperthyroidism, Addison disease, and panhypopituitarism can also be associated with a diagnosis of thymoma.[73]

Clinical presentation

These neoplasms are usually located in the anterior mediastinum and are usually discovered during a routine chest x-ray. Symptoms can include cough, difficulty with swallowing, tightness of the chest, chest pain, and shortness of breath, although nonspecific symptoms may occur. These tumors generally are slow growing but are potentially invasive, with metastases to distant organs or lymph nodes. Staging is related to invasiveness.

Treatment

Surgery is performed with the goal of a complete resection and is the mainstay of therapy.[74]

Radiation therapy is used in patients with invasive thymoma or thymic carcinoma.[73]

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.[65,69,73,75-77] 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%.[77,78] Response rates are lower for patients with thymic carcinoma, but 2-year survival rates have been reported to be as high as 50%.[79]

Sunitinib has yielded clinical responses in four adult patients with thymic carcinoma.[80]

Cardiac Tumors

Histology

Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%;[81] in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%.[82] The most common primary tumors of the heart are benign and include rhabdomyoma, myxoma, teratoma, and fibroma.[83-85] Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[83,86-89]

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.[90-92] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[90,93]

Primary malignant pediatric heart tumors are rare but may include malignant teratoma, lymphoma, and various sarcomas such as rhabdomyosarcoma, angiosarcoma, chondrosarcoma, and infantile fibrosarcoma.[83,94]

Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, melanoma, leukemia, thymoma, and carcinomas of various sites.[81,83]

Risk factors

The distribution of cardiac tumors in the fetal and neonatal period is different when compared with older patients, with two-thirds of teratomas occurring during this period of life.[86] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[86,95] A retrospective review of 94 patients with cardiac tumors detected by prenatal or neonatal echocardiography showed that 68% of the patients exhibited features of tuberous sclerosis.[96] 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.[97]

Clinical presentation and diagnostic evaluation

Patients may be asymptomatic but about two-thirds of patients have symptoms that may include abnormalities of heart rhythm, enlargement of the heart, fluid in the pericardial sac, congestive heart failure, syncope, stroke, and respiratory distress.[85] Some patients present with sudden death.[98][Level of evidence: 3iiiA]

The utilization of new cardiac MRI techniques can identify the likely tumor type in the majority of children.[99] However, histologic diagnosis remains the standard for diagnosing cardiac tumors.

Treatment

Successful treatment may require surgery, debulking for progressive symptoms, cardiac transplantation, and chemotherapy that is appropriate for the type of cancer that is present.[100-102]; [103][Level of evidence: 3iiA] Although some lesions such as rhabdomyomas can regress spontaneously, some practitioners recommend prophylactic resection to prevent mass-related complications.[82,85,95]; [104][Level of evidence: 3iiDiii] Treatment with the mTOR inhibitor everolimus has been reported to be associated with a decrease in the size of rhabdomyomas in patients with tuberous sclerosis.[95] Complete surgical excision of other lesions offers the best chance for cure, with postoperative complications seen in about one-third of patients and postoperative mortality rates in less than 10% of patients.[82,85] In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.[85] Cardiac sarcomas have a poor outcome and can be treated with multimodal therapy; the use of preoperative chemotherapy may be of value in reducing tumor volume prior to surgery.

Mesothelioma

Incidence and risk factors

Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life.[105] Fewer than 300 cases in children have been reported.[106]

This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[107-109] 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.[110,111] In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.[112] The amount of exposure required to develop cancer is unknown, and there is no information about the risk for children exposed to asbestos.

Prognosis

Benign and malignant mesotheliomas cannot be differentiated using histologic criteria. A poor prognosis is associated with lesions that are diffuse and invasive and with those that recur. In general, the course of the disease is slow, and long-term survival is common.

Diagnostic evaluation

Diagnostic thoracoscopy should be considered in suspicious cases to confirm diagnosis.[105]

Treatment

Radical surgical resection has been attempted with mixed results.[113] Treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[109,114,115] 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.[116] 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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