Sunday, April 7, 2019

Unusual Cancers of Childhood Treatment (PDQ®) 2/4 —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




Laryngeal Cancer and Papillomatosis

Childhood Laryngeal Cancer

Histology
Tumors of the larynx are rare. The most common benign tumor is subglottic hemangioma.[160] Malignant tumors, which are especially rare, may be associated with benign tumors such as polyps and papillomas.[161,162]
Clinical Presentation
These tumors may present with the following:
  • Hoarseness.
  • Difficulty swallowing.
  • Enlargement of the lymph nodes of the neck.
Treatment of Childhood Laryngeal Cancer
Rhabdomyosarcoma is the most common pediatric malignant tumor of the larynx and is treated with chemotherapy and radiation therapy.[163] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Squamous cell carcinoma of the larynx in children is managed in the same manner as it is in adults with carcinoma at this site, using surgery and radiation therapy.[164] Laser surgery may be the initial treatment used for these lesions. (Refer to the PDQ summary on Laryngeal Cancer Treatment [Adult] for more information about treatment of laryngeal cancer in adults.)
Treatment Options Under Clinical Evaluation for Childhood Laryngeal Cancer
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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Childhood Laryngeal Papillomatosis

General Information
Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is associated with human papillomavirus (HPV) infection, most commonly HPV-6 and HPV-11.[165,166] The presence of HPV-11 appears to correlate with a more aggressive clinical course than does the presence of HPV-6.[167]
These tumors can cause hoarseness because of their association with wart-like nodules on the vocal cords, and they may rarely extend into the lung, producing significant morbidity.[168] Malignant degeneration may occur, with development of cancer in the larynx and squamous cell lung cancer.
Treatment of Childhood Laryngeal Papillomatosis
Papillomatosis is not cancerous, and primary treatment is surgical ablation with laser vaporization.[169] Frequent recurrences are common. Lung involvement, although rare, can occur.[168]
If a patient requires more than four surgical procedures per year, other interventions may be necessary, including the following:
  • Interferon therapy.[170]
  • Immunotherapy with HspE7, a recombinant fusion protein that has shown activity in other HPV-related diseases. A pilot study suggested a marked increase in the amount of time between surgeries.[171]
  • Laser therapy combined with intralesional bevacizumab.[172]
The effectiveness of intralesional cidofovir has not been conclusively demonstrated.[173]
The role of checkpoint inhibitors, such as PD-1 inhibitors, is currently being investigated.[174] Reports with small numbers of patients have documented that in selected cases, the administration of a quadrivalent HPV vaccine can be associated with a complete remission and an increase in the intersurgical interval.[175,176] In contrast, other reports have not documented a therapeutic effect of the quadrivalent HPV vaccine.[177]
Treatment Options Under Clinical Evaluation for Childhood Laryngeal Papillomatosis
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:
  • NCT02632344 (Pembrolizumab for HPV-associated Recurrent Respiratory Papilloma Patients With Laryngeal, Tracheal, and/or Pulmonary Involvement): In this research study, the investigators are determining whether pembrolizumab can restore the natural ability of the immune system to recognize and eliminate HPV-infected cells from the body. Pembrolizumab will be administered at a dose of 200 mg as a 30-minute intravenous infusion every 3 weeks. Treatment will be administered on day 1 of each cycle.

Midline Tract Carcinoma Involving the NUT Gene (NUT Midline Carcinoma)

Molecular Features

NUT midline carcinoma is a very rare and aggressive malignancy genetically defined by rearrangements of the NUT gene. In most cases (75%), the NUT gene on chromosome 15q14 is fused with the BRD4 gene on chromosome 19p13, creating chimeric genes that encode the BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 on chromosome 9q34 or to NSD3 on chromosome 8p11;[178] these tumors are termed NUT-variant.[179]

Clinical Presentation and Outcome

Childhood midline tract carcinomas (NUT midline carcinomas) arise in midline epithelial structures, typically mediastinum and upper aerodigestive tract, and present as very aggressive undifferentiated carcinomas, with or without squamous differentiation.[180,181] Although the original description of this neoplasm was made in children and young adults, individuals of all ages can be affected.[179] A retrospective series with clinicopathologic correlation found that the median age at diagnosis of 54 patients was 16 years (range, 0.1–78 years).[182]
The outcome is very poor, with a median survival of less than 1 year. Preliminary data suggest that NUT-variant tumors may have a more protracted course.[179,180]

Treatment of Childhood Midline Tract Carcinoma

Treatment options for childhood midline tract carcinoma include the following:
  1. Chemotherapy.
  2. Surgery.
  3. Radiation therapy.
Treatment of childhood midline tract carcinoma involving the NUT gene (NUT midline carcinoma) has included a multimodal approach with systemic chemotherapy, surgery, and radiation therapy. Cisplatin, taxanes, and alkylating agents have been used with some success; however, while early response is common, tumor progression occurs early in the course of the disease.[183]; [182][Level of evidence: 3iiiB] In a report from the NUT Midline Carcinoma Registry, 40 patients with primary tumors in the head and neck were evaluable. Two-year overall survival was 30%. The three long-term survivors (35, 72, and 78 months) underwent primary gross-total resection and received adjuvant therapy.[181][Level of evidence: 3iiA]
Preclinical studies have shown that the NUT-BRD4 fusion is associated with globally decreased histone acetylation and transcriptional repression; studies have also shown that this acetylation can be restored with histone deacetylase inhibitors, resulting in squamous differentiation and arrested growth in vitro and growth inhibition in xenograft models. Response to vorinostat has been reported in two separate cases of children with refractory disease, suggesting a potential role for this class of agents in the treatment of this malignancy.[184,185] The BET bromodomain inhibitors represent a promising class of agents that is being investigated for adults with this malignancy.[178]

Treatment Options Under Clinical Evaluation for Childhood Midline Tract Carcinoma

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 are examples of national and/or institutional clinical trials that are 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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
  • NCT01587703 (A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma and Other Cancers): This study is evaluating the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762, a BET bromodomain inhibitor, as well as the tolerability and clinical activity, in patients with NUT midline carcinoma and other solid tumors. Patients aged 16 years and older are eligible for this study.
  • NCT01987362 (A Two Part, Multicenter, Open-label Study of TEN-010 Given Subcutaneously): This is a phase I, nonrandomized, dose-escalating, open label, multicenter study of patients aged 18 years and older with histologically confirmed advanced solid tumors with progressive disease requiring therapy or NUT midline carcinoma. This study is evaluating the safety, tolerability, and pharmacokinetics of TEN-010, a small molecule bromodomain inhibitor.

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  132. Rutt AL, Hawkshaw MJ, Lurie D, et al.: Salivary gland cancer in patients younger than 30 years. Ear Nose Throat J 90 (4): 174-84, 2011. [PUBMED Abstract]
  133. Allan BJ, Tashiro J, Diaz S, et al.: Malignant tumors of the parotid gland in children: incidence and outcomes. J Craniofac Surg 24 (5): 1660-4, 2013. [PUBMED Abstract]
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  138. Thariat J, Vedrine PO, Temam S, et al.: The role of radiation therapy in pediatric mucoepidermoid carcinomas of the salivary glands. J Pediatr 162 (4): 839-43, 2013. [PUBMED Abstract]
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  141. Rahbar R, Grimmer JF, Vargas SO, et al.: Mucoepidermoid carcinoma of the parotid gland in children: A 10-year experience. Arch Otolaryngol Head Neck Surg 132 (4): 375-80, 2006. [PUBMED Abstract]
  142. Kupferman ME, de la Garza GO, Santillan AA, et al.: Outcomes of pediatric patients with malignancies of the major salivary glands. Ann Surg Oncol 17 (12): 3301-7, 2010. [PUBMED Abstract]
  143. Aro K, Leivo I, Mäkitie A: Management of salivary gland malignancies in the pediatric population. Curr Opin Otolaryngol Head Neck Surg 22 (2): 116-20, 2014. [PUBMED Abstract]
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  147. Techavichit P, Hicks MJ, López-Terrada DH, et al.: Mucoepidermoid Carcinoma in Children: A Single Institutional Experience. Pediatr Blood Cancer 63 (1): 27-31, 2016. [PUBMED Abstract]
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  149. Verma J, Teh BS, Paulino AC: Characteristics and outcome of radiation and chemotherapy-related mucoepidermoid carcinoma of the salivary glands. Pediatr Blood Cancer 57 (7): 1137-41, 2011. [PUBMED Abstract]
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  151. Ryan JT, El-Naggar AK, Huh W, et al.: Primacy of surgery in the management of mucoepidermoid carcinoma in children. Head Neck 33 (12): 1769-73, 2011. [PUBMED Abstract]
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  153. Grant SR, Grosshans DR, Bilton SD, et al.: Proton versus conventional radiotherapy for pediatric salivary gland tumors: Acute toxicity and dosimetric characteristics. Radiother Oncol 116 (2): 309-15, 2015. [PUBMED Abstract]
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  155. Drilon A, Siena S, Ou SI, et al.: Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 7 (4): 400-409, 2017. [PUBMED Abstract]
  156. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018. [PUBMED Abstract]
  157. Irace AL, Adil EA, Archer NM, et al.: Pediatric sialoblastoma: Evaluation and management. Int J Pediatr Otorhinolaryngol 87: 44-9, 2016. [PUBMED Abstract]
  158. Prigent M, Teissier N, Peuchmaur M, et al.: Sialoblastoma of salivary glands in children: chemotherapy should be discussed as an alternative to mutilating surgery. Int J Pediatr Otorhinolaryngol 74 (8): 942-5, 2010. [PUBMED Abstract]
  159. Scott JX, Krishnan S, Bourne AJ, et al.: Treatment of metastatic sialoblastoma with chemotherapy and surgery. Pediatr Blood Cancer 50 (1): 134-7, 2008. [PUBMED Abstract]
  160. Bitar MA, Moukarbel RV, Zalzal GH: Management of congenital subglottic hemangioma: trends and success over the past 17 years. Otolaryngol Head Neck Surg 132 (2): 226-31, 2005. [PUBMED Abstract]
  161. McGuirt WF Jr, Little JP: Laryngeal cancer in children and adolescents. Otolaryngol Clin North Am 30 (2): 207-14, 1997. [PUBMED Abstract]
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  165. Kashima HK, Mounts P, Shah K: Recurrent respiratory papillomatosis. Obstet Gynecol Clin North Am 23 (3): 699-706, 1996. [PUBMED Abstract]
  166. Derkay CS, Wiatrak B: Recurrent respiratory papillomatosis: a review. Laryngoscope 118 (7): 1236-47, 2008. [PUBMED Abstract]
  167. Maloney EM, Unger ER, Tucker RA, et al.: Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 132 (7): 711-5, 2006. [PUBMED Abstract]
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  169. Andrus JG, Shapshay SM: Contemporary management of laryngeal papilloma in adults and children. Otolaryngol Clin North Am 39 (1): 135-58, 2006. [PUBMED Abstract]
  170. Avidano MA, Singleton GT: Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 112 (2): 197-202, 1995. [PUBMED Abstract]
  171. Derkay CS, Smith RJ, McClay J, et al.: HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial. Ann Otol Rhinol Laryngol 114 (9): 730-7, 2005. [PUBMED Abstract]
  172. Sidell DR, Nassar M, Cotton RT, et al.: High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 123 (3): 214-21, 2014. [PUBMED Abstract]
  173. Chadha NK, James A: Adjuvant antiviral therapy for recurrent respiratory papillomatosis. Cochrane Database Syst Rev 12: CD005053, 2012. [PUBMED Abstract]
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  175. Young DL, Moore MM, Halstead LA: The use of the quadrivalent human papillomavirus vaccine (gardasil) as adjuvant therapy in the treatment of recurrent respiratory papilloma. J Voice 29 (2): 223-9, 2015. [PUBMED Abstract]
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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]
Treatment of Fibroadenoma
Treatment options for fibroadenoma include the following:
  1. Observation. Many tumors will regress without a need for surgical resection.[3]
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.[5-11] 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.[12] 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.[13]
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.[11]
Breast tumors may also occur as metastatic deposits from leukemia, rhabdomyosarcoma, other sarcomas, or lymphoma (particularly in patients who are infected with the 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.[14] 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.[9,15-18][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.[19] 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.[14,20]
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.[21,22]
(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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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.[23] Most primary lung tumors are malignant. In a review of 383 primary pulmonary neoplasms in children, 76% were malignant and 24% were benign.[24] 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%).[25]
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.[26]
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):[27-33]
  • Carcinoid tumor (neuroendocrine tumor of the bronchus). Carcinoid tumors account for 80% to 85% of all tracheobronchial tumors in children.[27-31] 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 Surgery, 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.[34,35]; [36][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.[37]
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.[23,38] There is a single report of a child with a carcinoid tumor and metastatic disease who developed the classic carcinoid syndrome.[39] 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;[32,40] however, endoscopic resection is not recommended except in highly selected cases.[33,40,41] 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.[42]
Treatment
Conservative pulmonary resection, including sleeve segmental resection, when feasible, with the removal of the involved lymphatics, is the treatment of choice.[43,44]; [36][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%.[45,46]
  2. Mucoepidermoid carcinoma. The recommended treatment is open surgical resection and lymph node sampling. Endoscopic resection is not recommended.[33,47]
  3. Inflammatory myofibroblastic tumors. Surgery is the treatment of choice. However, if the tumor is ALK mutation-positive, treatment with crizotinib may be effective.[33,48-50]
  4. Rhabdomyosarcoma. Mutilating surgery is not indicated. This tumor is very responsive to chemotherapy and radiation therapy, even with lymph node metastasis.[33]
  5. Granular cell tumors. Surgical resection is based on morbidity risk.[33,51,52]
(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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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 Registry is a valuable resource for information on this rare malignancy.[53,54]
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.[54,55]
    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.[55] 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.[54]
    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.[54]
  • 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.[56]
    Anaplasia is present in up to 60% of the cases.[57] 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.[54]
  • Type III: A purely solid neoplasm, with the blastomatous and sarcomatous elements described above, and the presence of anaplasia in 70% of cases.[57-59]
    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.[54]
The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50-year period (refer to Table 3).[54]
Table 3. Relative Proportions and Features of Pleuropulmonary Blastomaa
Type IType IrType IIType II/III or III
aAdapted from Messinger et al.[54]
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.[54] (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.[60-62]
The presence of a germline DICER1 mutation is not a prognostic factor.[54]
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.[63-65] Most mutation carriers are unaffected, indicating that tumor risk is modest.[64]
Germline DICER1 mutations have been associated with the following:[63-67]
  • 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.[68]
  • 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.
DICER1 mutations appear to have a low penetrance, with pleuropulmonary blastoma, cystic nephroma, and multinodular goiter being the most frequently reported manifestations. 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.[65,67] Surveillance and screening recommendations have been proposed.[67]
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.[60,61] Tumor embolism is a known risk, and radiographic evaluation of the central circulation is performed to identify potentially fatal embolic complications.[69]
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.[60]
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.[54]; [61][Level of evidence: 3iiiA] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.[54,61,70]
Some general treatment considerations from the Pleuropulmonary Blastoma Registry include the following:[53,54]
  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.[54,61]
  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.[54,61,62] Anthracycline-containing regimens appear to be superior.[61] The respective 5-year DFS and OS were 59% and 71% for Type II and 37% and 53% for Type III.[54] 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.[54] Approximately 50% of relapses occur in the brain.[54]
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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Esophageal Tumors

Incidence and Histology

Esophageal cancer is rare in the pediatric age group, although it is relatively common in older adults.[71,72] 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.[72] 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:[72]
  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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
(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.[73-75] 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.[73,76-78]
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.[76] 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%.[77]
  • The European Cooperative Study Group for Pediatric Rare Tumors identified 16 children with thymoma between 2000 and 2012.[78] 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:[77]
  • 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.[79,80] The most common associated disorder is myasthenia gravis, which occurs in approximately 30% of adult patients.[79] 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.[79-81]
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.[82]
  2. Radiation therapy. Thymoma is relatively radiosensitive, and radiation therapy is recommended for patients with unresectable or incompletely resected invasive disease.[81] 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.[83]
  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.[73,81,84] 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%.[83-86]
  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.[87]
  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.[88]
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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Thymic Carcinoma

The European Cooperative Study Group for Pediatric Rare Tumors identified 20 patients with thymic carcinoma between 2000 and 2012.[78] 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.[82]
  2. Radiation therapy. Thymic carcinoma is relatively radiosensitive, and radiation therapy is recommended for patients with unresectable or incompletely resected invasive disease.[81] 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.[83]
  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%.[86,89,90]
  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.[88]
(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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Cardiac Tumors

Histology

Cardiac tumors are rare, with an autopsy frequency of 0.001% to 0.30%;[91] in one report, the percentage of cardiac surgeries performed as a result of cardiac tumors was 0.093%.[92]
The most common primary tumors of the heart are benign and include the following:[93-95]
  • Rhabdomyoma.
  • Myxoma.
  • Teratoma.
  • Fibroma.
Other benign tumors include histiocytoid cardiomyopathy tumors, hemangiomas, and neurofibromas (i.e., tumors of the nerves that innervate the muscles).[93,96-99]
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.[100-102] A mutation of the PRKAR1A gene is noted in more than 90% of the cases of Carney complex.[100,103]
Primary malignant pediatric heart tumors are rare and include the following:[93,104,105]
  • Malignant teratoma.
  • Lymphoma.
  • Various sarcomas, including rhabdomyosarcoma, angiosarcoma, 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.[91,93]

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.[96] Multiple cardiac tumors noted in the fetal or neonatal period are highly associated with a diagnosis of tuberous sclerosis.[96,106] 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.[107] 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.[108]

Clinical Presentation and Diagnostic Evaluation

Patients may be asymptomatic and present with sudden death,[109][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.[95]
The utilization of new cardiac MRI techniques can identify the likely tumor type in most children.[110] 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.[111-113]; [114][Level of evidence: 3iiA]
Treatment options for cardiac tumors, according to tumor types, are as follows:
  1. Rhabdomyoma. Although some lesions such as rhabdomyomas can regress spontaneously, some practitioners recommend prophylactic resection to prevent mass-related complications.[92,95,106]; [115][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.[106,116,117]
  2. Sarcoma. 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 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.[92,95]
In one series, 95% of patients were free from cardiac tumor recurrence at 10 years.[95]

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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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.[118] Fewer than 300 cases in children have been reported.[119]
Mesothelioma may develop after successful treatment of an earlier cancer, especially after treatment with radiation.[120,121] 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.[122] 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.[123-125] 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.[118]

Treatment

Treatment options for malignant mesothelioma include the following:
  1. Surgery.
  2. Radiation therapy.
  3. Chemotherapy.
Radical surgical resection has been attempted with mixed results.[126] In adults, a multimodal therapy including extrapleural pneumonectomy and radiation therapy after combination chemotherapy with pemetrexed-cisplatin may achieve durable responses.[127][Level of evidence: 2A] However, this approach remains highly controversial.[128] In children, treatment with various chemotherapeutic agents used for carcinomas or sarcomas may result in partial responses.[125,129-131]
Hyperthermic chemotherapy has been used to treat adults with pleural mesothelioma.[132,133]
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.[134] 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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
(Refer to the PDQ summary on adult Malignant Mesothelioma Treatment for more information.)

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Abdominal Cancers



Unusual pediatric abdominal cancers include the following:
The prognosis, diagnosis, classification, and treatment of these abdominal cancers are discussed below. It must be emphasized that these cancers are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series. (Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors for information about kidney tumors.)

Adrenocortical Carcinoma

Adrenocortical tumors encompass a spectrum of diseases with often seamless transition from benign (adenoma) to malignant (carcinoma) behavior.

Incidence

The incidence of adrenocortical tumors in children is extremely low (only 0.2% of pediatric cancers).[1] Adrenocortical tumors appear to follow a bimodal distribution, with peaks during the first and fourth decades.[2,3] Childhood adrenocortical tumors typically present during the first 5 years of life (median age, 3–4 years), although there is a second, smaller peak during adolescence.[4-6]
In children, 25 new cases are expected to occur annually in the United States, for an estimated annual incidence of 0.2 to 0.3 cases per 1 million individuals.[7] Internationally, however, the incidence of adrenocortical tumors appears to vary substantially. It is particularly high in southern Brazil, where it is approximately 10 to 15 times that observed in the United States.[8-11]
Female sex is consistently predominant in most studies, with a female to male ratio of 1.6:1.0.[3,5,6]

Risk Factors

Germline TP53 mutations are almost always the predisposing factor. The likelihood of a TP53 germline mutation is highest in the first years of life and diminishes with age. Predisposing genetic factors have been implicated in more than 50% of the cases in North America and Europe and in 95% of the Brazilian cases. [12]
  • In the non-Brazilian cases, relatives of children with adrenocortical tumors often, although not invariably, have a high incidence of other nonadrenal cancers (Li-Fraumeni syndrome). Germline mutations usually occur within the region coding for the TP53 DNA-binding domain (exons 5 to 8, primarily at highly conserved amino acid residues).[10,12]
  • In the Brazilian cases, the patients’ families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed.[11,13] In a Brazilian study, neonatal screening for the TP53 R337H mutation, which is prevalent in the region, identified 461 (0.27%) carriers among 171,649 of the newborns who were screened.[14] Carriers and relatives younger than 15 years were offered clinical screening. Adrenocortical tumors identified in the screening participants were smaller and more curable than the tumors found in carriers who did not elect to participate in screening.
Patients with Beckwith-Wiedemann and hemihyperplasia syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors.[15] Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome.[16] However, less than 1% of children with adrenocortical tumors have these syndromes.[17]
The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.[18]

Histology

Unlike adult adrenocortical tumors, histologic differentiation of pediatric adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,4] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenomas and carcinomas appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation.[19]
Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[20-22]
Morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.[23] IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[24,25] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from tumor characteristics, such as tumor necrosis, mitotic rate, the presence of atypical mitoses, and venous, capsular, or adjacent organ invasion.[11,22,23]

Molecular Features

A study performed on 71 pediatric adrenocortical tumors (37 in a discovery cohort and 34 in an independent cohort) provided a description of the genomic landscape of pediatric adrenocortical carcinoma.[26]
  • IGF2 overexpression. The most common genomic alteration, present in approximately 90% of cases, was copy number loss of heterozygosity for 11p15 with retention of the paternal allele resulting in IGF2 overexpression.
  • TP53 mutations. TP53 mutations were commonly observed. Twelve of 71 cases had the Brazilian founder R337H TP53 germline mutation. Excluding the Brazilian founder mutation cases, TP53 germline mutations were observed in approximately one-third of cases, with somatic TP53 mutations observed in approximately 10% of the remaining cases, such that approximately 40% of non-Brazilian cases had TP53 mutations. Among cases with TP53 mutations, chromosome 17 loss of heterozygosity with selection against wild-type TP53 was present in virtually all cases.
  • ATRX mutations. ATRX genomic alterations (primarily structural variants) were present in approximately 20% of cases. All ATRX alterations occurred in the presence of TP53alterations. The co-occurrence of TP53 and ATRX mutations correlated with advanced stage, large tumor size, increased telomere length, and poor prognosis.
  • CTNNB1 mutations. Activating CTNNB1 mutations were found in approximately 20% of cases and were mutually exclusive with TP53 germline alterations.

Clinical Presentation

Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[3,4]
  • Virilization. Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) caused by an excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients.[11,27]
  • Hyperestrogenism. Hyperestrogenism can also occur.[28]
  • Cushing syndrome. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3-5,11,29]
Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.[11]
Nonfunctional tumors are rare (<10%) and tend to occur in older children.[3]

Prognostic Factors

Overall, adverse prognostic factors for adrenocortical carcinoma include the following:
  • Large tumor size. Tumor weight higher than 200 g or tumor volume greater than 200 cm3 have been associated with a worse outcome.[30,31] Patients with small tumors have an excellent outcome when treated with surgery alone, regardless of histologic features.[6,32,33]
  • Metastatic disease.[6,30,31,33]
  • Age. Age older than 4 or 5 years.[3,6,30,31,33]
  • Microscopic tumor necrosis.[33]
  • Para-aortic lymph node involvement.[33]
  • Incomplete resection or spillage during surgery.[6,30,31]
  • Low HLA class II antigen expression. A low expression of the HLA class II antigens HLA-DRA, HLA-DPA1, and HLA-DPB1 has been associated with older age, larger tumor size, presence of metastatic disease, and worse outcome.[34] In pediatric patients, increased expression of MHC class II genes, especially HLA-DPA1, is associated with a better prognosis.[35]
Stage I disease appears to be associated with a better prognosis.[33]
The overall probability of 5-year survival for children with adrenocortical tumors depends on stage and ranges from greater than 80% for patients with resectable disease to less than 20% for patients with metastases.[3-5,29-32,36]
A portion of patients with adrenocortical carcinoma do not have a germline TP53 mutation. A retrospective review of children with adrenocortical carcinoma identified 60 patients without germline TP53 mutations.[37] There was a strong female predominance (female to male ratio, 42:18) in this group of patients. Three-year progression-free survival (PFS) was 71.4%, and overall survival (OS) was 80.5%. Prognostic factors for this group were the same as the factors identified in previous analyses that did not segregate for TP53 germline status. Unfavorable prognostic features included older age, higher disease stage, heavier tumor weight, presence of somatic TP53 mutations, and higher Ki-67 labeling index. Ki-67 labeling index and age remained significantly associated with PFS after adjusting for stage and tumor weight.

Treatment

At the time of diagnosis, two-thirds of pediatric patients have limited disease (tumors can be completely resected), and the remaining patients have either unresectable or metastatic disease.[3]
Treatment of childhood adrenocortical tumors has evolved from the data derived from the adult studies, and the same guidelines are used. Surgery is the most important mode of therapy, and mitotane and cisplatin-based regimens, usually incorporating doxorubicin and etoposide, are recommended for patients with advanced disease.[10,11,38,39]; [5][Level of evidence: 3iiiA]
Treatment options for childhood adrenocortical tumors include the following:
  1. Surgery: An aggressive surgical approach toward the primary tumor and all metastatic sites is recommended when feasible.[40,41] Because of tumor friability, rupture of the capsule with resultant tumor spillage is frequent (approximately 20% of initial resections and 43% of resections after recurrence).[3] When the diagnosis of adrenocortical tumor is suspected, laparotomy and a curative procedure are recommended rather than fine-needle aspiration, to avoid the risk of tumor rupture.[41,42] Laparoscopic resection is associated with a high risk of rupture and peritoneal carcinomatosis; thus, open adrenalectomy remains the standard of care.[43]
  2. Mitotane and cisplatin-based regimens: In adults, mitotane is commonly used as a single agent in the adjuvant setting after complete resection.[38] Little information is available about the use of mitotane in children, although response rates appear to be similar to those seen in adults.[1,38]
    • A retrospective analysis in Italy and Germany identified 177 adult patients with completely resected adrenocortical carcinoma. Recurrence-free survival was significantly prolonged by the use of adjuvant mitotane. Benefit was present with 1 g to 3 g per day of mitotane and was associated with fewer toxic side effects than doses of 3 g to 5 g per day.[44] (Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment for more information.)
    • In a review of 11 children with advanced adrenocortical tumors treated with mitotane and a cisplatin-based chemotherapeutic regimen, measurable responses were seen in seven patients. The mitotane daily dose required for therapeutic levels was approximately 4 g/m2, and therapeutic levels were achieved after 4 to 6 months of therapy.[38]
    • In the GPOH-MET 97 trial, mitotane levels greater than 14 mg/L correlated with better survival.[5,11]
The use of radiation therapy in pediatric patients with adrenocortical tumors has not been consistently investigated. Adrenocortical tumors are generally considered to be radioresistant. Furthermore, because many children with adrenocortical tumors carry germline TP53 mutations that predispose to cancer, radiation may increase the incidence of secondary tumors. One study reported that three of five long-term survivors of pediatric adrenocortical tumors died of secondary sarcoma that arose within the radiation field.[11,45]
(Refer to the PDQ summary on adult Adrenocortical Carcinoma Treatment 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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Gastric (Stomach) Cancer

Incidence

Primary gastric tumors in children are rare, and carcinoma of the stomach is even more unusual.[46] In one series, gastric cancer in children younger than 18 years accounted for 0.11% of all gastric cancer cases seen over an 18-year period.[47] 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.[48] Rare cases of familial diffuse gastric cancer associated with CDH1 germline mutations have been reported in adolescents.[49]

Clinical Presentation and Diagnostic Evaluation

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.[46] Symptoms of carcinoma of the stomach include the following:
  • Vague upper abdominal pain, which can be associated with poor appetite and weight loss.
  • Nausea and vomiting.
  • Change in bowel habits.
  • Poor appetite.
  • Weakness.
  • Helicobacter pylori infection.[47,50]
  • Anemia. Many individuals become anemic but otherwise show no symptoms before the development of metastatic spread.
Fiberoptic endoscopy can be used to visualize the tumor or to take a biopsy sample to confirm the diagnosis. Confirmation can also involve an x-ray examination of the upper gastrointestinal tract.

Treatment and Outcome

Treatment options for gastric carcinoma include the following:
  1. Surgery.
  2. Radiation therapy and chemotherapy.
Treatment includes surgical excision with wide margins. For individuals who cannot have a complete surgical resection, radiation therapy may be used along with chemotherapeutic agents such as fluorouracil (5-FU) and irinotecan.[51] 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.[47] Because of the rarity of stomach cancer in the pediatric age group, little information exists regarding the treatment outcomes of children.
(Refer to the Gastrointestinal Stromal Tumors [GIST] section of this summary for information about the treatment of GIST.)

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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

Cancer of the Pancreas

Malignant pancreatic tumors are rare in children and adolescents, with an incidence of 0.46 cases per 1 million individuals younger than 30 years.[52-55]
The primary pancreatic tumors of childhood can be classified into the following four categories:

Solid Pseudopapillary Tumor of the Pancreas

Incidence
Solid pseudopapillary tumor of the pancreas, also known as Frantz tumor, is the most common pediatric pancreatic tumor, accounting for up to 70% of cases in most institutional series.[54,56] This tumor has low malignant potential and most commonly affects females of reproductive age (median age, 21 years), with a predilection for blacks and East Asians.[52,54,57] There is no known genetic or hormonal factor to explain the strong female predilection, although it has been noted that all tumors express progesterone receptors.[58]
Histology
Histologically, the tumors are characterized by a combination of solid, pseudopapillary, and cystic changes. The fragility of the vascular supply leads to secondary degenerative changes and cystic areas of hemorrhage and necrosis. The cells surrounding the hyalinized fibrovascular stalks form the pseudopapillae.[52] A highly specific paranuclear dot-like immunoreactivity pattern for CD99 has been described.[59]
Clinical Presentation
Solid pseudopapillary tumor of the pancreas is a very friable tumor, and tumor rupture and hemoperitoneum have been reported.[52,54,57] Tumors can occur throughout the pancreas and are often exophytic. On imaging, the mass shows typical cystic and solid components, with intratumoral hemorrhage and a fibrous capsule.[52]
Outcome
The outcome of solid pseudopapillary tumors of the pancreas is excellent, with 10-year survival rates exceeding 95%.[58]
Treatment
Treatment options for solid pseudopapillary tumor of the pancreas include the following:
  1. Surgery.
  2. Chemotherapy.
Treatment of solid pseudopapillary tumor of the pancreas is surgical; however, preoperative and operative spillage is not unusual.[60] Whipple procedures (pancreaticoduodenectomy) are often necessary, but non-Whipple pancreatic-sparing resections may be possible utilizing a pancreatico-jejunostomy procedure. Surgery is usually curative, although local recurrences occur in 5% to 15% of the cases.[57] A retrospective review of the Italian Pediatric Rare Tumor Registry identified 43 pediatric patients diagnosed with solid pseudopapillary tumor of the pancreas between 2000 and 2018.[61][Level of evidence: 3iiA] The median age at diagnosis was 13.2 years (range, 7–18 years). Only one patient presented with metastatic disease. At follow-up (median, 8.4 years; range, 0–17 years), one recurrence occurred in a patient who had intraoperative rupture, and all patients were alive.
Metastatic disease, usually in the liver, may occur in up to 15% of the cases.[52,54,57-59] Single-agent gemcitabine has been reported to be effective in cases of unresectable or metastatic disease.[62]

Pancreatoblastoma

Incidence and Risk Factors
Pancreatoblastoma accounts for 10% to 20% of all pancreatic tumors during childhood. It is the most common pancreatic tumor of young children and typically presents in the first decade of life, with a median age at diagnosis of 5 years.[52,63]
Patients with Beckwith-Wiedemann syndrome have an increased risk of developing pancreatoblastoma; this syndrome is identified in up to 60% of cases of pancreatoblastoma developing during early infancy and in 5% of children developing pancreatoblastoma later in life.[64] Pancreatoblastoma has also been associated with familial adenomatous polyposis syndromes.[65]
Histology and Molecular Features
This tumor is thought to arise from the persistence of the fetal analog of pancreatic acinar cells. Pathology shows an epithelial neoplasm with an arrangement of acinar, trabecular, or solid formations separated by dense stromal bands.[52] CTNNB1 and IGF2 gene mutations have been described in some cases, suggesting that pancreatoblastoma might result from alterations in the normal pancreas differentiation.[66,67]
Clinical Presentation
Although approximately one-half of the cases originate in the head of the pancreas, jaundice is uncommon. Close to 80% of the tumors secrete alpha-fetoprotein, which can be used to measure response to therapy and monitor for recurrence.[63] In some cases, the tumor may secrete adrenocorticotropic hormone (ACTH) or antidiuretic hormone, and patients may present with Cushing syndrome and the syndrome of inappropriate antidiuretic hormone secretion.[64] Metastases are present in 30% to 40% of the patients, usually involving liver, lungs, and lymph nodes.[63]
Outcome
Using a multimodality approach, close to 80% of patients can be cured.[63]
Treatment
Treatment options for pancreatoblastoma include the following:
  1. Surgery.
  2. Chemotherapy.
Surgery is the mainstay in the treatment of pancreatoblastoma, and a complete surgical resection is required for cure. Because of the common origin in the head of the pancreas, a Whipple procedure is usually required.[60,68]
For large, unresectable, or metastatic tumors, preoperative chemotherapy is indicated; pancreatoblastoma commonly responds to chemotherapy, and a cisplatin-based regimen is usually recommended. The PLADO regimen, which includes cisplatin and doxorubicin, is the most commonly used regimen, and treatment is modeled after the management of hepatoblastoma, with two to three cycles of preoperative therapy, followed by resection and adjuvant chemotherapy.[54,63,65,69]
Although radiation therapy has been used in unresectable or relapsed cases, its role in the treatment of microscopic disease after surgery has not been defined.[65]
Response has been seen for patients with relapsed or persistent pancreatoblastoma treated with gemcitabine in one case [70] and vinorelbine and oral cyclophosphamide in two cases.[71]
High-dose chemotherapy with autologous hematopoietic stem cell rescue has been reported to be effective in selected cases.[54,72]

Islet Cell Tumors

Incidence and Risk Factors
Islet cell tumors represent approximately 15% of pediatric pancreatic tumors in most series.[54,56,73] These tumors usually present in middle age and may be associated with multiple endocrine neoplasia type 1 (MEN1) syndrome; less than 5% of islet cell tumors occur in children.[52]
Clinical Presentation
The most common type of functioning islet cell tumor is insulinoma, followed by gastrinoma.
  • Insulinoma. Patients with insulinoma present with fasting hyperinsulinic hypoglycemia; in young children, presentation may include behavioral problems, seizures, or coma.
  • Gastrinoma. Gastrinoma presents with Zollinger-Ellison syndrome, with recurrent peptic ulcers in uncommon locations, and diarrhea due to gastric hypersecretion. While most insulinomas are benign, a significant proportion of gastrinomas are malignant.[73]
  • ACTHoma and VIPoma. Other less common tumors seldom seen in children are the ACTHoma, which presents as Cushing syndrome, and the VIPoma, which presents as Verner-Morrison syndrome.
Nonfunctioning tumors are extremely rare in pediatrics, except when associated with MEN1. Islet cell tumors are typically solitary; when multiple tumors are present, the diagnosis of MEN1 syndrome should be considered.
On imaging, these tumors are usually small and well defined. Somatostatin receptor scintigraphy is useful for the location of islet cell tumors; however, only 60% to 70% express somatostatin receptor.[52]
Treatment
Treatment options for islet cell tumors include the following:
  1. Surgery.
  2. Chemotherapy.
  3. Mammalian target of rapamycin (mTOR) inhibitor therapy.
Treatment of islet cell tumors includes medical therapy for control of the syndrome and complete surgical resection.[60] For patients with malignant tumors and unresectable or metastatic disease, chemotherapy and mTOR inhibitors are recommended.
The management of these tumors in children follows the consensus guidelines established for adult patients.[73,74] (Refer to the PDQ summary on adult Pancreatic Neuroendocrine Tumors [Islet Cell Tumors] Treatment for more information.)

Pancreatic Carcinoma

Incidence and Risk Factors
Pancreatic carcinomas (acinar cell carcinoma and ductal adenocarcinoma) are extremely rare in children. These malignancies represent less than 5% of pediatric pancreatic tumors and include the following:[54,56]
  • Acinar cell carcinoma. Although rare in pediatrics, acinar cell carcinoma is more common than ductal cell adenocarcinoma, the most common pancreatic carcinoma in adults. Acinar cell carcinoma is considered to be the adult counterpart of pancreatoblastoma, and histological differentiation between both entities may be difficult.[52]
  • Ductal adenocarcinoma. Ductal adenocarcinoma is rare in the first four decades of life and even rarer during childhood and adolescence.[75] Ductal adenocarcinoma is associated with several cancer predisposition syndromes, such as hereditary pancreatitis (PRSS1 mutations), familial atypical mole and multiple melanoma (CDKN2mutations), Peutz-Jeghers syndrome and other hereditary nonpolyposis colon carcinomas (STK11 and germline mismatch repair genes), and syndromes associated with DNA repair gene mutations (such as BRCA2 and ATM).[76]
Clinical Presentation
Presenting symptoms are nonspecific and are related to local tumor growth. However, 4% to 15% of adult patients with acinar cell carcinoma may present with a lipase hypersecretion syndrome, manifesting as peripheral polyarthropathy and painful subcutaneous nodules.
Treatment
(Refer to the PDQ summary on adult Pancreatic Cancer Treatment for information about the treatment of pancreatic 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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).
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