Wednesday, August 21, 2019

Unusual Cancers of Childhood Treatment (PDQ®) 3/7 –Health Professional Version - National Cancer Institute

Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Unusual Cancers of Childhood Treatment (PDQ®)–Health Professional Version

Thoracic Cancers

Unusual pediatric thoracic cancers include the following:
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

Fibroadenoma is the most frequent breast tumor seen in children.[2,3] Sudden rapid enlargement of a suspected fibroadenoma is an indication for needle biopsy or excision, as rare transformation leading to malignant phyllodes tumors has been reported.[4]
Other benign lesions include tubular adenoma, benign phyllodes tumor, and benign fibroepithelial neoplasm.[5]
Treatment of Fibroadenoma
Treatment options for fibroadenoma include the following:
  1. Observation. Many tumors will regress without a need for surgical resection.[3,5]
Treatment options for phyllodes tumors include the following:
  1. Wide local excision without mastectomy.[4]

Breast Cancer

Incidence and Outcome
Breast cancer has been reported in both males and females younger than 21 years.[6-12] A review of the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute shows that 75 cases of malignant breast tumors in females aged 19 years or younger were identified from 1973 to 2004.[13] 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%.
A National Cancer Database report described 181 cases of breast malignancy in patients aged 21 years and younger; 65% of patients had invasive carcinoma and the remaining patients had sarcoma or malignant phyllodes. In this study, the authors compared the pediatric patients with the adult patients and found that pediatric patients were more likely to have an undifferentiated malignancy, more advanced disease at presentation, and more variable management. Outcomes between children and adults were similar.[14]
A subsequent report from the SEER database (1973–2009) discovered 91 girls aged 10 to 20 years with breast cancer, predominantly carcinomas (57% invasive, 5.5% in situ) and sarcomas (37%, mostly phyllodes tumors). The mortality rate was 46.6% for patients with regional disease and 18.7% for patients with localized disease. The mortality rates for the patients in this study were higher than the rates for premenopausal and postmenopausal women, although the sample size was small.[15][Level of evidence: 3iiA]
While rare, breast cancer has also been described in males. In a review of the National Cancer Database, 677 male adolescents and young adults were diagnosed with breast cancer during the period of 1998 to 2010; most patients (82%) had invasive disease. Age younger than 25 years and absence of nodal evaluation at the time of surgery were associated with worse outcomes.[12]
Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with HIV).
Risk Factors
Risk factors for breast cancer in adolescents and young adults (AYA) include the following:
  1. Previous malignancy. A retrospective review of the American College of Surgeons National Cancer Database from 1998 to 2010 identified 106,771 patients aged 15 to 39 years with breast cancer.[16] Of these patients, 6,241 (5.8%) had experienced a previous histologically distinct malignancy. Patients with breast cancer as a subsequent neoplasm had a significantly decreased 3-year overall survival (OS) (79% vs. 88.5%, P < .001), with subsequent neoplasm status identified as an independent risk factor for increased mortality (hazard ratio, 1.58; 95% confidence interval, 1.41–1.77).
  2. Chest irradiation. There is an increased lifetime risk of breast cancer in female survivors of Hodgkin lymphoma who were treated with radiation to the chest area; however, breast cancer is also seen in patients who were treated for any cancer that was treated with chest irradiation.[10,17-20][Level of evidence: 1A] Carcinomas are more frequent than sarcomas.
    Mammograms with adjunctive breast magnetic resonance imaging (MRI) start at age 25 years or 10 years postexposure to radiation therapy (whichever came last). (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for more information about secondary breast cancers.)
Treatment of Breast Cancer in Adolescents and Young Adults
Breast cancer is the most frequently diagnosed cancer among AYA women aged 15 to 39 years, accounting for about 14% of all AYA cancer diagnoses.[21] Breast cancer in this age group has a more aggressive course and worse outcome than in older women. Expression of hormone receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2) on breast cancer in the AYA group is also different from that in older women and correlates with a worse prognosis.[16,22]
Treatment of the AYA group is similar to that of older women. However, unique aspects of management must include attention to genetic implications (i.e., familial breast cancer syndromes) and fertility.[23,24]
(Refer to the PDQ summary on adult Breast Cancer Treatment or the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

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.[25] Most primary lung tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign.[26] A review of primary malignant epithelial lung tumors using the National Cancer Data Base found that the most common primary malignant pediatric lung neoplasms were carcinoid tumors (63%) followed by mucoepidermoid carcinoma of the lung (18%).[27]
Most pulmonary malignant neoplasms in children are due to metastatic disease, with an approximate ratio of primary malignant tumors to metastatic disease of 1:5.[28]
The following are the most common malignant primary tumors of the lung:

Tracheobronchial Tumors

Histology
Tracheobronchial tumors are a heterogeneous group of primary endobronchial lesions, and although adenoma implies a benign process, all varieties of tracheobronchial tumors on occasion display malignant behavior. The following histologic types have been identified (refer to Figure 4):[29-35]
  • Carcinoid tumor (neuroendocrine tumor of the bronchus). Carcinoid tumors account for 80% to 85% of all tracheobronchial tumors in children.[29-33]; [36][Level of evidence: 3iiA] It is the most common tracheobronchial tumor.
  • Mucoepidermoid carcinoma. A slow-growing vascular polypoid mass of the airway that is the second most common (10%) pediatric tracheobronchial tumor.
  • Inflammatory myofibroblastic tumors. These low-grade benign tumors account for 1% of pediatric tracheobronchial tumors, are commonly located in the upper trachea, and rarely metastasize.
  • Rhabdomyosarcoma.
  • Granular cell tumors. Malignant transformation has not been documented in pediatric patients.
ENLARGEDrawing showing the most representative primary tracheobronchial tumors in children: myofibroblastic inflammatory tumor, carcinoid, rhabdomyoma, granular cell tumor, and mucoepidermoid K.
Figure 4. The most representative primary tracheobronchial tumors are described with their more frequent location. Reprinted from Seminars in Pediatric SurgeryExit Disclaimer, Volume 25, Issue 3, Patricio Varela, Luca Pio, Michele Torre, Primary tracheobronchial tumors in children, Pages 150–155, Copyright (2016), with permission from Elsevier.
Prognosis
With the exception of rhabdomyosarcoma, tracheobronchial tumors of all histologic types are associated with an excellent prognosis after surgical resection in children, even in the presence of local invasion.[37,38]; [39][Level of evidence: 2A]
Clinical Presentation and Diagnostic Evaluation
The presenting symptoms of a tracheobronchial tumor are usually caused by an incomplete tracheobronchial obstruction and include the following:
  • Cough.
  • Recurrent pneumonitis.
  • Hemoptysis.
Because of difficulties in diagnosis, symptoms are frequently present for months, and, occasionally, children with wheezing have been treated for asthma, with delays in diagnosis for as long as 4 to 5 years.[40]
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.[25,41] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[42] Octreotide nuclear scans may demonstrate uptake of radioactivity by the tumor or lymph nodes, suggesting metastatic spread.
The management of tracheobronchial tumors is somewhat controversial because tracheobronchial tumors are usually visible endoscopically. Biopsy of these lesions may be hazardous because of the risk of hemorrhage. New endoscopic techniques have allowed biopsy to be performed safely;[34,43] however, endoscopic resection is not recommended except in highly selected cases.[35,43,44] 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.[45]
Treatment
Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[46,47]; [39][Level of evidence: 2A] Chemotherapy and radiation therapy are not indicated for tracheobronchial tumors, unless evidence of metastasis is documented or the tumor is the rhabdomyosarcoma histologic type.
Treatment options for tracheobronchial tumors, according to histologic type, are as follows:
  1. Carcinoid tumor (neuroendocrine tumor of the bronchus). Surgical resection with lymph node sampling is the treatment of choice. OS is 95%.[48,49]
  2. Mucoepidermoid carcinoma. The recommended treatment is open surgical resection and lymph node sampling. Endoscopic resection is not recommended.[35,50]
  3. Inflammatory myofibroblastic tumors. Surgery is the treatment of choice. However, if the tumor is ALK mutation-positive, treatment with crizotinib may be effective.[35,51-53]
  4. Rhabdomyosarcoma. Mutilating surgery is not indicated. This tumor is very responsive to chemotherapy and radiation therapy, even with lymph node metastasis.[35]
  5. Granular cell tumors. Surgical resection is based on morbidity risk.[35,54,55]
(Refer to the Neuroendocrine Tumors [Carcinoid Tumors] section of this summary for information about neuroendocrine carcinoid tumors.)
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Pleuropulmonary Blastoma

Types of Pleuropulmonary Blastoma
Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy that can present as a pulmonary or pleural mass. In most cases, pleuropulmonary blastoma is associated with germline mutations of the DICER1 gene. The International Pleuropulmonary Blastoma RegistryExit Disclaimer is a valuable resource for information on this rare malignancy.[56,57]
The following three subtypes of pleuropulmonary blastoma have been identified:
  • Type I: A purely lung cystic neoplasm with subtle malignant changes that typically occurs in the first 2 years of life and has a good prognosis. The median age at diagnosis for Type I tumors is 8 months, and it has a slight male predominance. Transition from Type I to Type III occurs; however, a significant proportion of Type I lesions may not progress to Type II and Type III tumors.[57,58]
    Histologically, these tumors appear as a multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface, with skeletal differentiation in one-half of the cases.[58] This form of disease can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts.
  • Type Ir: A purely cystic tumor that lacks a primitive cell component. The r designation signifies regression or nonprogression. Type Ir was originally recognized in older siblings of pleuropulmonary blastoma patients, but can be seen in very young children. A lung cyst in an older individual with a DICER1 mutation or in a relative of a pleuropulmonary blastoma patient is most likely to be Type Ir.[57]
    In the Pleuropulmonary Blastoma Registry experience, most Type I and Ir cysts are unilateral (74%), half are unifocal, and 55% are larger than 5 cm. Pneumothorax may be present at diagnosis in up to 30% of Type I and Ir pleuropulmonary blastoma cases.[57]
  • Type II: Type II exhibits both cystic and solid components. The solid areas have mixed blastomatous and sarcomatous features; most of the cases exhibit rhabdomyoblasts, and nodules with cartilaginous differentiation are common.[59]
    Anaplasia is present in up to 60% of the cases.[60] In the Pleuropulmonary Blastoma Registry, the median age at diagnosis was 35 months, and distant metastases were present at the time of diagnosis in 7% of cases.[57]
  • Type III: A purely solid neoplasm, with the blastomatous and sarcomatous elements described above, and the presence of anaplasia in 70% of cases.[60-62]
    Median age at diagnosis in the Pleuropulmonary Blastoma Registry was 41 months, and distant metastases were present in 10% of patients at the time of diagnosis.[57]
The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50-year period (refer to Table 3).[57]
Table 3. Relative Proportions and Features of Pleuropulmonary Blastomaa
 Type IType IrType IIType II/III or III
aAdapted from Messinger et al.[57]
Relative proportion of pleuropulmonary blastoma cases33%35%32%
Presence of germline DICER1mutation62%63%75%
Median age at diagnosis (months)8473541
5-year overall survival89%100%71%53%
Prognostic Factors
In a comprehensive analysis of 350 patients reported by the Pleuropulmonary Blastoma Registry, only two prognostic factors were identified: the type of pleuropulmonary blastoma and the presence of metastatic disease at diagnosis.[57] (Refer to Table 3.) In three additional small cohort series, the ability to perform a complete surgical resection was also identified as a prognostic factor.[63-65]
The presence of a germline DICER1 mutation is not a prognostic factor.[57]
Risk Factors
Close to two-thirds of patients with pleuropulmonary blastoma have a germline DICER1mutation. Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the DICER1 syndrome.[66-68] Most mutation carriers are unaffected, indicating that tumor risk is modest.[67]
Germline DICER1 mutations have been associated with the following:[66-70]
  • Cystic nephroma and Wilms tumor. Up to 10% of pleuropulmonary blastoma cases have been reported to develop cystic nephroma or Wilms tumor, which are the most relevant associated malignancies. These tumors are also more prevalent among family members.[71]
  • Ovarian sex cord–stromal tumors (especially Sertoli-Leydig cell tumor).
  • Multinodular goiter.
  • Uterine cervix embryonal rhabdomyosarcoma.
  • Nasal chondromesenchymal hamartoma.
  • Renal sarcoma.
  • Pulmonary sequestration.
  • Juvenile intestinal polyps.
  • Ciliary body medulloepithelioma.
  • Medulloblastoma.
  • Pineoblastoma.
  • Pituitary blastoma.
  • Seminoma.
The penetrance of DICER1 mutations associated with each pathologic condition is not well understood, but lung cysts, pleuropulmonary blastoma, and thyroid nodules are the most commonly reported manifestations in individuals who have loss-of-function mutations.[70] Most associated conditions occur in children younger than 10 years, although ovarian tumors and multinodular goiters are described in children and adults aged up to 30 years.[68,70] Surveillance and screening recommendations have been proposed.[70]
Surveillance
As with other cancer predisposition conditions, before individuals with DICER1 mutations are screened, factors that must be considered include typical age of onset of each disease, potential benefits of early detection, and risks and availability of screening modalities. A consensus panel convened by the International Pleuropulmonary Blastoma Registry has proposed guidelines for surveillance. In addition to imaging-based surveillance, individuals and families can be counseled at each visit regarding potential signs and symptoms of DICER1-associated conditions and undergo appropriate age-specific and gender-specific preventive screening studies.[70]
Clinical Presentation
Presenting symptoms are not specific, and commonly include the following:
  • Respiratory distress.
  • Fever.
  • Chest pain.
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.[63,64] Tumor embolism is a known risk, and radiographic evaluation of the central circulation is performed to identify potentially fatal embolic complications.[72]
Treatment
There are no standard treatment options. Current treatment regimens for these rare tumors have been informed by consensus opinion.
Treatment options for pleuropulmonary blastoma include the following:
  1. Surgery.
  2. Adjuvant chemotherapy.
A complete surgical resection is required for cure.[63]
Data from the International Pleuropulmonary Blastoma Registry and from the European Cooperative Study Group in Pediatric Rare Tumors (EXPeRT) suggest that adjuvant chemotherapy may reduce the risk of recurrence.[57]; [64][Level of evidence: 3iiiA] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.[57,64,73]
Some general treatment considerations from the Pleuropulmonary Blastoma Registry include the following:[56,57]
  1. Type I and Type Ir: Surgery is the treatment of choice for Type I and Type Ir pleuropulmonary blastoma. In the Pleuropulmonary Blastoma Registry series, the 5-year disease-free survival (DFS) and OS were 82% and 91%, respectively. Approximately 10% of the cases may progress to Type II or Type III after surgery, but adjuvant chemotherapy does not appear to have an impact on the rate of progression and survival.[57,64]
  2. Type II and Type III: A multimodal sarcoma approach is recommended for Types II and III pleuropulmonary blastoma, usually including rhabdomyosarcoma regimens and either upfront or delayed surgery.[57,64,65] Anthracycline-containing regimens appear to be superior.[64] The respective 5-year DFS and OS were 59% and 71% for Type II and 37% and 53% for Type III.[57] The role of radiation therapy is not well defined. While the use of radiation did not impact survival in the pleuropulmonary blastoma registry series, only 20% of patients with Types II and III received it.[57] Approximately 50% of relapses occur in the brain.[57]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Esophageal Tumors

Incidence and Histology

Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[74,75] Most of these tumors are squamous cell carcinomas, although sarcomas can also arise in the esophagus. The most common benign tumor is leiomyoma.

Risk Factors, Clinical Presentation, and Diagnostic Evaluation

Risk factors include caustic ingestion, gastroesophageal reflux, and Barrett esophagus.[75] 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 the following:[75]
  1. External-beam intracavitary radiation therapy.
  2. Chemotherapy (agents commonly used to treat carcinomas such as platinum derivatives, paclitaxel, and etoposide).
  3. Surgery.
Prognosis is generally poor for this cancer, which rarely can be completely resected.

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
(Refer to the PDQ summary on adult Esophageal Cancer Treatment for more information.)

Thymoma and Thymic Carcinoma

Thymoma and thymic carcinoma originate within the epithelial cells of the thymus, resulting in an anterior mediastinal mass. The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component, whereas, a thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as thymic carcinoma or type C thymoma. Thymic carcinomas have a higher incidence of capsular invasion and metastases.[76-78] Other tumors that involve the thymus gland include lymphomas, germ cell tumors, carcinomas, and carcinoids. Hodgkin lymphoma and non-Hodgkin lymphoma may also involve the thymus and must be differentiated from true thymomas and thymic carcinomas.

Thymoma

Incidence and Outcome
Primary tumors of the thymus are exceptionally rare in children; very few pediatric series have been reported.[76,79-81]
The following studies have reported on outcomes associated with thymoma:
  • A review of the SEER registry from 1973 to 2008 identified 73 cases of malignant anterior mediastinal tumors in patients younger than 20 years.[79] Of these cases, 32% were thymoma, 29% were non-Hodgkin lymphoma, and 22% were Hodgkin lymphoma. Patients with thymoma had a worse survival at 10 years than did patients with lymphoma. Patients with thymoma who were treated in an earlier era from 1973 to 1989 had a 10-year survival rate of 18%; patients who were treated between 1991 and 2008 had a 75% survival rate. Presence of metastatic disease and treatment without surgery were associated with a worse outcome.
  • A review of 48 published cases of thymoma in patients younger than 18 years, excluding thymic carcinoma, found an association between stage of disease and survival; it also suggested guidelines for treatment. The overall 2-year survival in this series was 71%.[80]
  • The European Cooperative Study Group for Pediatric Rare Tumors identified 16 children with thymoma between 2000 and 2012.[81] Complete resection was achieved in 11 of 16 patients with thymoma. Fourteen of the 16 patients with thymoma were alive and well at a median of 5 years from diagnosis.
Clinical Presentation
These neoplasms are usually located in the anterior mediastinum and discovered during a routine chest x-ray. Symptoms may include the following:[80]
  • Cough.
  • Difficulty with swallowing.
  • Tightness of the chest.
  • Chest pain.
  • Shortness of breath
  • Superior vena cava syndrome.
About 40% of adults with thymoma have one or more paraneoplastic disorders during their lifetime.[82,83] The most common associated disorder is myasthenia gravis, which occurs in approximately 30% of adult patients.[82] This disorder has also been reported in children and is important to recognize it before a thoracotomy of a suspected thymoma. Various other paraneoplastic syndromes have been found to be associated with thymoma. These include pure red cell aplasia, hypogammaglobulinemia, nephrotic syndrome, and autoimmune or immune disorders such as scleroderma, dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and thyroiditis. Endocrine disorders associated with thymoma include hyperthyroidism, Addison disease, and panhypopituitarism.[82-84]
Treatment
Treatment options for thymoma include the following:
  1. Surgery. Surgery is the mainstay of therapy and an attempt should be made to resect all disease.[85]
  2. Radiation therapy. Thymoma is relatively radiosensitive, and radiation therapy is recommended for patients with unresectable or incompletely resected invasive disease.[84] Radiation dosage recommendations are based on the age of the child and the extent of tumor invasion. Total doses of 45 Gy to 50 Gy are recommended for control of clear or close margins, 54 Gy for microscopically positive margins, and doses of at least 60 Gy for patients with bulky residual disease.[86]
  3. Chemotherapy. 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.[76,84,87] 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%.[86-89]
  4. Octreotide. Because thymoma shows high uptake of indium In 111–labeled octreotide, trials using this somatostatin analogue have been conducted in patients with refractory disease. In an Eastern Cooperative Oncology Group phase II trial of 42 patients, 4 patients had partial responses to octreotide alone and 8 patients responded with the addition of prednisone to octreotide.[90]
  5. Sunitinib. In an open-label phase II study of sunitinib in adult patients with refractory thymoma, partial responses were observed in 6% of patients with thymoma, and stable disease was achieved in 75% of patients with thymoma.[91]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Thymic Carcinoma

The European Cooperative Study Group for Pediatric Rare Tumors identified 20 patients with thymic carcinoma between 2000 and 2012.[81] Complete resection was achieved in 1 of 20 patients with thymic carcinoma. Five patients with thymic carcinoma survived. Five-year OS for patients with thymic carcinoma was 21.0%.
Treatment
Treatment options for thymic carcinoma include the following:
  1. Surgery. Surgery is the mainstay of therapy and an attempt should be made to resect all disease.[85]
  2. Radiation therapy. Thymic carcinoma is relatively radiosensitive, and radiation therapy is recommended for patients with unresectable or incompletely resected invasive disease.[84] Radiation dosage recommendations are based on the age of the child and the extent of tumor invasion. Total doses of 45 Gy to 50 Gy are recommended for control of clear or close margins, 54 Gy for microscopically positive margins, and doses of at least 60 Gy for patients with bulky residual disease.[86]
  3. Chemotherapy (as described for thymoma). Response rates are lower for patients with thymic carcinoma, but 2-year survival rates have been reported to be as high as 50%.[89,92,93]
  4. Sunitinib. In an open-label phase II study of sunitinib in adult patients with refractory thymic carcinoma, partial responses were observed in 26% of patients with thymic carcinoma and stable disease was achieved in 65% of patients with thymic carcinoma.[91]
(Refer to the PDQ summary on adult Thymoma and Thymic Carcinoma Treatment for more information on the treatment of thymoma and thymic carcinoma.)
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Cardiac Tumors

Histology

Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%;[94] in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%.[95]
The most common primary tumors of the heart are benign and include the following:[96-98]
  • Rhabdomyoma.
  • Myxoma.
  • Teratoma.
  • Fibroma.
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[96,99-102]
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.[103-105] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[103,106]
Primary malignant pediatric heart tumors are rare and include the following:[96,107-109]
  • Malignant teratoma.
  • Lymphoma.
  • Various sarcomas, including rhabdomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, and infantile fibrosarcoma.
Secondary tumors of the heart include metastatic spread of rhabdomyosarcoma, other sarcomas, melanoma, leukemia, thymoma, and carcinomas of various sites.[94,96]

Risk Factors

The distribution of cardiac tumors in the fetal and neonatal period is different from that in older patients, with two-thirds of teratomas occurring during this period of life.[99] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[99,110] 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.[111] In another study, 79% of patients (15 of 19) 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.[112]

Clinical Presentation and Diagnostic Evaluation

Patients may be asymptomatic and present with sudden death,[113][Level of evidence: 3iiiA] but about two-thirds of patients have symptoms that may include the following:
  • Abnormalities of heart rhythm.
  • Enlargement of the heart.
  • Fluid in the pericardial sac.
  • Congestive heart failure.
  • Syncope.
  • Stroke.
  • Respiratory distress.[98]
The utilization of new cardiac MRI techniques can identify the likely tumor type in some children.[114] 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.[115-117]; [118][Level of evidence: 3iiA] In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.[98]
Treatment options for cardiac tumors, according to tumor type or resectability, are as follows:
  1. Rhabdomyoma. Although some lesions such as rhabdomyomas can regress spontaneously, some practitioners recommend prophylactic resection to prevent mass-related complications.[95,98,110]; [119][Level of evidence: 3iiDiii] Treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus has been reported to be associated with a decrease in the size of rhabdomyomas in patients with tuberous sclerosis.[110,120,121]
  2. Sarcoma. Cardiac sarcomas have a poor outcome and can be treated with multimodal therapy; the use of preoperative chemotherapy and/or radiation therapy may be of value in reducing tumor volume before surgery.
  3. Other tumor types. 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.[95,98]
  4. Unresectable tumor. Radiation therapy is a rare treatment option for patients with unresectable disease. Radiation therapy is used with the intent of preventing progression because it is unlikely to produce full disease resolution.[122-125]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Mesothelioma

Incidence, Risk Factors, and Clinical Presentation

Mesothelioma is extremely rare in childhood, with only 2% to 5% of patients presenting during the first two decades of life.[126] Fewer than 300 cases in children have been reported.[127]
Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.[128,129] The amount of exposure required to develop cancer is unknown. In adults, these tumors have been associated with exposure to asbestos, which was used as building insulation.[130] There is no information about the risk for children exposed to asbestos.
This tumor can involve the membranous coverings of the lung, the heart, or the abdominal organs.[131-133] 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.

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.[126]

Treatment

Treatment options for malignant mesothelioma include the following:
  1. Surgery.
  2. Chemotherapy.
  3. Radiation therapy.
Radical surgical resection has been attempted with mixed results.[134] In adults, a multimodal therapy including extrapleural pneumonectomy and radiation therapy after combination chemotherapy with pemetrexed-cisplatin may achieve durable responses.[135][Level of evidence: 2A] However, this approach remains highly controversial.[136] In children, treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[133,137-139]
Hyperthermic chemotherapy has been used to treat adults with pleural mesothelioma.[140,141]
Pain is an infrequent symptom; however, if pain occurs, radiation therapy may be used for palliation.
Papillary serous carcinoma of the peritoneum may be mistaken for mesothelioma.[142] 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.

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
(Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)
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