Unusual Cancers of Childhood Treatment (PDQ®) 3/4 —Health Professional Version - National Cancer Institute

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

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

Colorectal Carcinoma

Incidence

Carcinoma of the large bowel is rare in the pediatric age group.[77] It is seen in one case per 1 million persons younger than 20 years in the United States annually; fewer than 100 cases are diagnosed in children each year in the United States.[78] From 1973 to 2006, the Surveillance, Epidemiology, and End Results (SEER) database recorded 174 cases of colorectal cancer in patients younger than 19 years.[79] Colorectal carcinoma accounts for about 2% of all malignancies in patients aged 15 to 29 years.[80]

Clinical Presentation

Colorectal tumors can occur in any location in the large bowel. Larger series and reviews suggest that ascending and descending colon tumors are each seen in approximately 30% of cases, with rectal tumors occurring in approximately 25% of cases.[81-83]

Signs and symptoms in children with descending colon tumors include the following:

• Abdominal pain (most common).
• Rectal bleeding.
• Change in bowel habits.
• Weight loss.
• Nausea and vomiting.

The median duration of symptoms before diagnosis was about 3 months in one series.[78,84]

Changes in bowel habits may be associated with tumors of the rectum or lower colon.

Tumors of the right colon may cause more subtle symptoms but are often associated with the following:

• Abdominal mass.
• Weight loss.
• Decreased appetite.
• Blood in the stool
• Iron-deficiency anemia.

Any tumor that causes complete obstruction of the large bowel can cause bowel perforation and spread of the tumor cells within the abdominal cavity.

Diagnostic Evaluation

Diagnostic studies include the following:[85,86]

• Examination of the stool for blood.
• Studies of liver and kidney function.
• Measurement of carcinoembryonic antigen (CEA).
• Various medical imaging studies, including direct examination using colonoscopy to detect polyps in the large bowel. Other conventional radiographic studies include barium enema or video-capsule endoscopy followed by computed tomography of the chest and bone scans.[87]

Histology and Molecular Features

There is a higher incidence of mucinous adenocarcinoma in the pediatric and adolescent age group (40%–50%), with many lesions being the signet ring cell type,[77,78,84,88,89] whereas only about 15% of adult lesions are of this histology. The tumors of younger patients with this histologic variant may be less responsive to chemotherapy. In the adolescent and young adult population with the mucinous histology, there is a higher incidence of signet ring cells, microsatellite instability, and mutations in the mismatch repair genes.[89-91] Tumors with mucinous histology arise from the surface of the bowel, usually at the site of an adenomatous polyp. The tumor may extend into the muscle layer surrounding the bowel, or the tumor may perforate the bowel entirely and seed through the spaces around the bowel, including intra-abdominal fat, lymph nodes, liver, ovaries, and the surface of other loops of bowel. A high incidence of metastasis involving the pelvis, ovaries, or both may be present in girls.[86]

Colorectal cancers in younger patients with noninherited sporadic tumors often lack KRASmutations and other cytogenetic anomalies seen in older patients.[92] In a genomic study that used exome and RNA sequencing to identify mutational differences in colorectal carcinomas of adults (n = 30), adolescents and young adults (n = 30), and children (n = 2), five genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR) were identified that were more frequently mutated in adolescents and young adult patients. These genes contained a damaging mutation and were identified through whole-exome sequencing and RNA sequencing. In addition, higher mutational rates in DNA mismatch and DNA repair pathways, such as MSH2, BRCA2, and RAD9B, were more prevalent in adolescent and young adult samples but the results were not validated by RNA sequencing.[93]

Staging

Most reports also suggest that children present with more advanced disease than do adults, with 80% to 90% of patients presenting with Dukes stage C/D or TNM stage III/IV disease (refer to the Stage Information for Colon Cancer section of the PDQ summary on adult Colon Cancer Treatment for more information about staging).[78,81-85,88,89,94-100]

Treatment and Outcome

Most patients present with evidence of metastatic disease,[84] either as gross tumor or as microscopic deposits in lymph nodes, on the surface of the bowel, or on intra-abdominal organs.[88,94] Of almost 160,000 patients with colorectal cancer included in the National Cancer Database, 918 pediatric patients were identified. Age younger than 21 years was a significant predictor of increased mortality.[89]

Treatment options for childhood colorectal cancer include the following:

1. Surgery: Complete surgical excision is the most important prognostic factor and is the primary goal of surgery, but in most instances, this is impossible. Removal of large portions of tumor provides little benefit for those with extensive metastatic disease.[78] Most patients with microscopic metastatic disease generally develop gross metastatic disease, and few individuals with metastatic disease at diagnosis become long-term survivors.
2. Radiation therapy and chemotherapy: Current therapy includes the use of radiation for rectal and lower colon tumors, in conjunction with chemotherapy using 5-FU with leucovorin.[101] Other agents, including irinotecan, may be of value.[84][Level of evidence: 3iiiA] No significant benefit has been determined for interferon-alfa given in conjunction with 5-FU/leucovorin.[102]
   A recent review of nine clinical trials comprising 138 patients younger than 40 years demonstrated that the use of combination chemotherapy improved PFS and OS in these patients. Furthermore, OS and response rates to chemotherapy were similar to those observed in older patients.[103][Level of evidence: 2A]
   Other active agents used in adults include oxaliplatin, bevacizumab, panitumumab, cetuximab, aflibercept, and regorafenib.[104-107]

Survival is consistent with the advanced stage of disease observed in most children with colorectal cancer, with an overall mortality rate of approximately 70%. For patients with a complete surgical resection or for those with low-stage/localized disease, survival is significantly prolonged, with the potential for cure.[81]

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).

Genetic Syndromes Associated With Colorectal Cancer

About 20% to 30% of adult patients with colorectal cancer have a significant history of familial cancer; of these, about 5% have a well-defined genetic syndrome.[108] Hereditary colorectal cancer has two well-described forms:

• Polyposis (including familial adenomatous polyposis [FAP] and attenuated FAP, which are caused by pathogenic variants in the APC gene; and MUTYH-associated polyposis, which is caused by pathogenic variants in the MUTYH gene).
• Lynch syndrome (often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM.

Other colorectal cancer syndromes and their associated genes include oligopolyposis (POLE, POLD1), FAP3 (NTHL1), juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).

The incidence of these genetic syndromes in children has not been well defined, as follows:

• In one review, 16% of patients younger than 40 years had a predisposing factor for the development of colorectal cancer.[109]
• A later study documented immunohistochemical evidence of mismatch repair deficiency in 31% of colorectal carcinoma samples in patients aged 30 years or younger.[110]
• A retrospective review of patients younger than 18 years in Germany identified 31 patients with colorectal carcinoma.[111] Eleven of the 26 patients who were tested for a genetic predisposition syndrome tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, and two patients with constitutional mismatch repair deficiency). When compared with the patients without a genetic predisposition syndrome, the 11 patients with a genetic predisposition syndrome presented with more localized disease, allowing complete surgical resection and improved outcome (100% survival).

Familial polyposis is inherited as a dominant trait, which confers a high degree of risk. Early diagnosis and surgical removal of the colon eliminates the risk of developing carcinomas of the large bowel.[112] Some colorectal carcinomas in young people, however, may be associated with a mutation of the adenomatous polyposis coli (APC) gene, which also is associated with an increased risk of brain tumors and hepatoblastoma.[113] Familial adenomatous polyposis (FAP) syndrome is caused by mutation of a gene on chromosome 5q, which normally suppresses proliferation of cells lining the intestine and later development of polyps.[114] A double-blind, placebo-controlled, randomized phase I trial in children aged 10 to 14 years with FAP reported that celecoxib at a dose of 16 mg/kg per day is safe for administration for up to 3 months. At this dose, there was a significant decrease in the number of polyps detected on colonoscopy.[115][Level of evidence: 1iiDiv] The role of celecoxib in the management of FAP in children is not clear.

Another tumor suppressor gene on chromosome 18 is associated with progression of polyps to malignant form. Multiple colon carcinomas have been associated with neurofibromatosis type I and several other rare syndromes.[116]

Despite the increased risk of multiple malignancies in families with Lynch syndrome, the risk of malignant neoplasms during childhood in those families does not seem to be increased when compared with the risk in children from non-Lynch syndrome colorectal carcinoma families.[117]

Neuroendocrine Tumors (Carcinoid Tumors)

These tumors, like tracheobronchial adenomas, may be benign or malignant and can involve the lining of the lung, large or small bowel, or liver.[118-123] Most lung lesions are benign; however, some metastasize.[124]

The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[124] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[125] Occasionally, carcinoids may produce ectopic ACTH and cause Cushing disease.[126]

Neuroendocrine Tumors of the Appendix

Clinical Presentation

A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[127][Level of evidence: 3iiDii] The most common primary site was the appendix (36 of 45 cases). No recurrences were observed among the patients with appendiceal primary tumors treated with appendectomy alone, which supports resection of the appendix without hemicolectomy as the procedure of choice.

Most carcinoid tumors of the appendix are discovered incidentally at the time of appendectomy, and are small, low-grade, localized tumors.[128-130]

Treatment

Treatment options for neuroendocrine tumors of the appendix include the following:

1. Appendectomy.

In adults, it has been accepted practice to remove the entire right colon in patients with large carcinoid tumors of the appendix (>2 cm in diameter) or with tumors that have spread to the lymph nodes.[131-134]

Study results suggest that appendectomy alone is sufficient treatment for childhood appendiceal carcinoids regardless of size, position, histology, or nodal or mesenteric involvement and that right hemicolectomy is unnecessary in children. Routine follow-up imaging and biologic studies were not beneficial.[131,134-136]

Evidence (appendectomy alone):

1. The Italian Rare Tumors in Pediatric Age project performed a prospective registry study that evaluated 113 patients with appendiceal neuroendocrine tumors.[135][Level of evidence: 3iiiA] Primary re-excision was not recommended for completely excised tumors smaller than 2 cm except for microscopic/macroscopic residual tumor on the margins of the appendix, in which case cecum resection and pericecal node biopsy was recommended. Decisions about tumors larger than 2 cm were made at the discretion of the primary physicians. However, physicians were discouraged from performing right hemicolectomy unless margins were positive. Of the 113 study participants, 108 had tumors smaller than 2 cm. Thirty-five patients had extension of tumor beyond the appendiceal wall. Five tumors invaded the serosa, and 28 tumors invaded the periappendiceal fat. Margins were clear in 111 of 113 patients.
   • At 41 months of follow-up, 113 of 113 patients were alive.
   • The five patients with tumors larger than 2 cm did well.
   • One patient had resection of the cecum; no residual tumor was found.
   • One patient had a right hemicolectomy (tumor was <2 cm with clear margins, but an octreotide scan was possibly positive; no tumor was found).
   The study concluded that appendectomy alone should be considered curative for most cases of appendiceal neuroendocrine tumors. The procedure of choice is a resection of the appendix without hemicolectomy.
2. A French multicenter study of children younger than 18 years with neuroendocrine tumors of the appendix was carried out by surveying pediatric surgeons from 1988 to 2012. A total of 114 patients were identified. Risk factors for secondary right hemicolectomy were extension into the mesoappendix, positive margins, size larger than 2 cm, and high proliferative index. Eighteen patients met the above criteria and were observed.[136]
   • All patients were alive and disease free at follow-up.
   • In addition, follow-up radiological studies and biological tests were not found to be helpful.
   The investigator's recommendation was that appendectomy alone is sufficient treatment for neuroendocrine tumors of the appendix.
3. A systematic review and meta-analysis of 38 studies of appendiceal carcinoid identified 958 cases with a mean age at presentation of 11.6 years. Tumor size was 2 cm or larger in 85% of the cases. Of the 24 papers that reported the status of the margin of resection, 97% had negative margins. Nodal involvement was reported in ten series and was present in 1.4% of cases, with higher rates seen in patients whose tumors were larger than 2 cm (35%). Vascular involvement was seen in 11% of 510 patients, and invasion of the mesoappendix or periappendiceal fat was reported in 29% of 910 patients.[134]
   • According to the European and American Neuroendocrine Tumor Societies, 189 patients met the criteria for a secondary procedure after initial appendectomy but only 69 patients underwent a secondary procedure (n = 43, hemicolectomy; n = 2, ileocecectomy; n = 1, cecectomy; n = 2, ileocolectomy; n = 21, not specified).
   • Of the 120 patients who did not have a secondary procedure, 91 patients had tumors extending to the mesoappendix, 5 patients had vascular invasion, 4 patients had positive margins, 12 patients had tumors 2 cm or larger, 1 patient had a high proliferative index, and 7 patients had positive lymph nodes. No recurrence was reported in patients who had a secondary procedure or those who were observed. Preoperative and postoperative imaging was not helpful in managing the patients.

Nonappendiceal Neuroendocrine Tumors

Clinical Presentation

A single-institution retrospective review identified 45 cases of carcinoid tumors in children and adolescents between 2003 and 2016.[127][Level of evidence: 3iiDii] Extra-appendiceal primary tumors (n = 9) were associated with a higher risk of metastasis and recurrence.

Nonappendiceal neuroendocrine tumors in the abdomen can occur in the pancreas, stomach, and liver. The most common clinical presentation is an unknown primary site. Nonappendiceal neuroendocrine tumors are more likely to be larger, higher grade, or present with metastases.[137] Larger tumor size has been associated with a higher risk of recurrence.[127]

Clinical experience with nonappendiceal neuroendocrine tumors is reported almost entirely in adults. Histopathology is graded by mitotic rate, Ki-67 labeling index, and presence of necrosis into well-differentiated (low grade, G1), moderately differentiated (intermediate grade, G2) and poorly differentiated (high grade, G3) tumors.[138]

Treatment and Outcome

Treatment options for resectable nonappendiceal neuroendocrine tumors include the following:

1. Surgery.[139]

Treatment options for unresectable or multifocal nonappendiceal neuroendocrine tumors include the following:

1. Embolization.[140]
2. Somatostatin receptor 2 (SSTR2) ligands.[141,142]
3. Peptide receptor radionuclide therapy.[143]
4. mTOR inhibitors.[144]
5. Tyrosine kinase inhibitors.[145]

SSTR2 ligands include octreotide, long-acting repeatable octreotide, and lanreotide. Octreotide is not practical for therapy because of its short half-life, requiring frequent repeated administration. Long-acting repeatable octreotide and lanreotide have been evaluated in prospective, randomized, placebo-controlled trials.[141,142] Patient age was not specified in the first trial, and eligibility was restricted to age 18 years and older in the second trial. Neither agent produced significant objective responses in measurable tumors. Both agents were associated with statistically significant increases in PFS and time-to-progression, and both agents are recommended for the treatment of unresectable nonappendiceal neuroendocrine tumors in adults.

Conventional cytotoxic chemotherapy appears to be inactive.[137]

In one retrospective, single-institution study, the 5-year relapse-free survival rate of nonappendiceal neuroendocrine tumors was 41%, and the OS rate was 66%.[137]

(Refer to the Tracheobronchial Tumors section of this summary for information about tracheobronchial carcinoid tumors.)

Metastatic Neuroendocrine Tumors

Treatment of metastatic carcinoid tumors of the large bowel, pancreas, or stomach becomes more complicated and requires treatment similar to that given for adult high-grade neuroendocrine tumors. (Refer to the PDQ summary on adult Gastrointestinal Carcinoid Tumors Treatment for treatment options in patients with malignant 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).

Gastrointestinal Stromal Tumors (GIST)

Incidence

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract in adults.[146] These tumors are rare in children.[147] Approximately 2% of all GIST occur in children and young adults.[148-150] In one series, pediatric GIST accounted for 2.5% of all pediatric nonrhabdomyosarcomatous soft tissue sarcomas.[151] Previously, these tumors were diagnosed as leiomyomas, leiomyosarcomas, and leiomyoblastomas.

In pediatric patients, GIST are most commonly located in the stomach and almost exclusively affect adolescent females.[150,152,153]

Histology and Molecular Features

Histologically, pediatric GIST have a predominance of epithelioid or epithelioid/spindle cell morphology and, unlike adult GIST, the mitotic rate does not appear to accurately predict clinical behavior.[152,154] The majority of GIST in the pediatric age range have loss of the succinate dehydrogenase (SDH) complex and consequently, lack SDHB expression by immunohistochemistry.[155,156] In addition, these tumors have minimal large-scale chromosomal changes and overexpress the insulin-like growth factor 1 receptor.[157,158]

Activating mutations of KIT and PDGFA, which are seen in 90% of adult GIST, are present in only a small fraction of pediatric GIST.[152,157,159] The lack of SDHB expression in most pediatric GIST implicates cellular respiration defects in the pathogenesis of this disease and supports the notion that this disease is better categorized as SDH-deficient GIST. Furthermore, about 50% of patients with SDH-deficient GIST have germline mutations of the SDH complex, most commonly involving SDHA,[155] supporting the notion that SDH-deficient GIST is a cancer predisposition syndrome and testing of affected patients for constitutional mutations for the SDH complex should be considered.[160] A small percentage of SDH-deficient GIST lack somatic or germline mutations of the SDH complex and are characterized by SDHC promoter hypermethylation and gene silencing and are categorized as SDH-epimutant GIST.[161]

In an observational study carried out at the NCI, 116 patients with presumed wild-type GIST were evaluated, and 95 of these patients had an adequate tumor specimen available for molecular profiling. Among these 95 patients, the investigators identified the following three distinctive subgroups of patients:[162]

• Group 1 (SDH-competent GIST): Group 1 was comprised of 11 patients who were designated as SDH competent because of positive staining of SDHB and lack of mutations on sequencing. All of these patients were adults, the median age was 46 years, and 64% were female. The tumors arose primarily in the small bowel (9 of 11), one patient had metastases to the peritoneum, and one patient had multifocal disease. Mutational analysis of these tumors identified mutations in the BRAF, NF1, CBL, KIT, and ARID1A genes. With a median follow-up of 8 years, three of these patients (27%) died of progressive disease.
• Group 2 (SDHX-mutant GIST): Group 2 was comprised of 63 patients who were SDH deficient and contained mutations in the SDHA (n = 34), SDHB (n = 16), SDHC (n = 12), and SDHD (n = 1) complexes. Of the 38 patients with SDH-mutant GIST who had matching germline and tumor DNA, 31 (82%) had the same mutation detected in the germline and the tumor. This group of patients was younger (median age, 23 years), mostly female (62%), and presented with gastric tumors (100%) and multifocal disease (42%). Metastases at presentation were seen in the lymph nodes (65%), liver (21%), and peritoneum (10%). At a median follow-up from diagnosis of 6 years, only three patients (5%) had died.
• Group 3 (SDHC-epimutant GIST): Group 3 was comprised of 21 patients with SDH-deficient tumors, with SDHC promoter methylation and no structural mutations. The median age at diagnosis was younger (age 15 years) and most patients were female (95%). All tumors arose in the stomach; 72% were multifocal; and metastases were present at diagnosis in the liver (37%), peritoneum (5%), and lymph nodes (38%). At a median follow-up of 7 years, only one patient (5%) with an SDH-epimutant tumor died from disease.

Of the 95 patients that were evaluated at this clinic, 18 patients had syndromic GIST (i.e., Carney triad or Carney-Stratakis syndrome). Among the Carney triad patients, two patients had the complete triad, five patients had SDH mutations, and six patients had epimutant tumors. Seven patients with Carney-Stratakis syndrome had SDH-mutant GIST (n = 6) or SDH-epimutant GIST (n = 1).[162]

Clinical Features

Most pediatric patients with GIST are diagnosed during the second decade of life with anemia-related gastrointestinal bleeding. In addition, pediatric GIST have a high propensity for multifocality (23%) and nodal metastases.[150,152,159] These features may account for the high incidence of local recurrence seen in this patient population. Despite these features, patients have an indolent course characterized by multiple recurrences and long survival.[159]

SDH-deficient GIST can arise within the context of the following two syndromes:[152,163]

• Carney triad. Carney triad is a syndrome characterized by the occurrence of GIST, lung chondromas, and paragangliomas. In addition, about 20% of patients have adrenal adenomas and 10% have esophageal leiomyomas. GIST are the most common (75%) presenting lesions in these patients. To date, no coding sequence mutations of KIT, PDGFR, or the SDH genes have been found in these patients.[150,163,164]
• Carney-Stratakis syndrome. Carney-Stratakis syndrome is characterized by paraganglioma and GIST caused by germline mutations of the SDH genes B, C, and D.[156,165]

Treatment

Once the diagnosis of pediatric GIST is established, referral to medical centers with expertise in the treatment of GIST should be considered, with all samples evaluated for mutations in KIT (exons 9, 11, 13, 17), PDGFR (exons 12, 14, 18), and BRAF (V600E).[166,167]

Treatment options for GIST depend on whether a mutation is detected, as follows:

1. GIST with a KIT or PDGFR mutation: Pediatric patients who harbor KIT or PDGFRmutations are managed according to adult guidelines.
2. SDH-deficient GIST: Approximately one-half of all wild-type GIST patients are SDH-deficient.[168] For most pediatric patients with SDH-deficient GIST, because of its indolent course, surgical resection of localized disease is recommended while avoiding extensive surgery and repeated surgical resections. These recommendations are supported by a study of 76 patients with wild-type GIST who underwent surgery for newly diagnosed and recurrent disease.[168] In this study, only 9% of patients experienced a fatal event, whereas 71% (54 patients) developed recurrence or progression at a median of 2.5 years. For this population, the 1-year event-free survival (EFS) was 73%, the 5-year EFS was 24%, and the 10-year EFS was 16%. Factors associated with an increased risk of recurrence included metastatic disease and elevated mitotic rate; SDH status and extent of surgical resection did not influence the risk of recurrence. Among 33 patients who underwent reoperation for recurrent disease, each subsequent resection was associated with a lower EFS.
   Responses to imatinib and sunitinib in pediatric patients with SDH-deficient GIST are uncommon and consist mainly of disease stabilization.[152,169,170] In a review of ten patients who were treated with imatinib mesylate, one patient experienced a partial response and three patients had stable disease.[152] In the phase III SWOG intergroup trial S0033 (NCT00009906), 20 tumors from patients who were presumed to be wild-type were resequenced.[170] Twelve of these tumors were identified as being SDH mutant, and only one patient (8.3%) experienced a partial response to imatinib.[171] In another study, sunitinib appeared to show more activity, with one partial response and five cases of stable disease in six children with imatinib-resistant GIST.[172] Unlike the adult recommendations, the use of adjuvant imatinib cannot be recommended in children with SDH-deficient GIST.[173]
   Given the indolent course of the disease in pediatric patients, it is reasonable to avoid extensive initial surgeries and to withhold subsequent resections unless they are needed to address only symptoms such as obstruction or bleeding.[147,152]

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 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).
• NCT03165721 (A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine [SGI-110], in Children and Adults With Wild-Type GIST, Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer): Participants will be injected with SGI-110 under the skin each day for 5 days. This cycle will repeat every 28 days. The cycles repeat until toxicity occurs or the disease progresses.

References

1. Ribeiro RC, Figueiredo B: Childhood adrenocortical tumours. Eur J Cancer 40 (8): 1117-26, 2004. [PUBMED Abstract]
2. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72 (11): 3145-55, 1993. [PUBMED Abstract]
3. Michalkiewicz E, Sandrini R, Figueiredo B, et al.: Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22 (5): 838-45, 2004. [PUBMED Abstract]
4. Wieneke JA, Thompson LD, Heffess CS: Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27 (7): 867-81, 2003. [PUBMED Abstract]
5. Redlich A, Boxberger N, Strugala D, et al.: Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial. Klin Padiatr 224 (6): 366-71, 2012. [PUBMED Abstract]
6. Gulack BC, Rialon KL, Englum BR, et al.: Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). J Pediatr Surg 51 (1): 172-7, 2016. [PUBMED Abstract]
7. Berstein L, Gurney JG: Carcinomas and other malignant epithelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, Chapter 11, pp 139-148. Also available online. Last accessed November 20, 2018.
8. Figueiredo BC, Sandrini R, Zambetti GP, et al.: Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43 (1): 91-6, 2006. [PUBMED Abstract]
9. Pianovski MA, Maluf EM, de Carvalho DS, et al.: Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 47 (1): 56-60, 2006. [PUBMED Abstract]
10. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al.: Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 45 (3): 265-73, 2005. [PUBMED Abstract]
11. Rodriguez-Galindo C: Adrenocortical tumors in children. In: Schneider DT, Brecht IB, Olson TA: Rare Tumors in Children and Adolescents. Berlin, Germany: Springer-Verlag, 2012, pp 436-44.
12. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al.: Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. J Clin Oncol 33 (6): 602-9, 2015. [PUBMED Abstract]
13. Ribeiro RC, Sandrini F, Figueiredo B, et al.: An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A 98 (16): 9330-5, 2001. [PUBMED Abstract]
14. Custódio G, Parise GA, Kiesel Filho N, et al.: Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 31 (20): 2619-26, 2013. [PUBMED Abstract]
15. Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998. [PUBMED Abstract]
16. Wijnen M, Alders M, Zwaan CM, et al.: KCNQ1OT1 hypomethylation: a novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors? Pediatr Blood Cancer 59 (3): 565-6, 2012. [PUBMED Abstract]
17. Steenman M, Westerveld A, Mannens M: Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28 (1): 1-13, 2000. [PUBMED Abstract]
18. El Wakil A, Doghman M, Latre De Late P, et al.: Genetics and genomics of childhood adrenocortical tumors. Mol Cell Endocrinol 336 (1-2): 169-73, 2011. [PUBMED Abstract]
19. Figueiredo BC, Stratakis CA, Sandrini R, et al.: Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84 (3): 1116-21, 1999. [PUBMED Abstract]
20. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8 (3): 163-9, 1984. [PUBMED Abstract]
21. van Slooten H, Schaberg A, Smeenk D, et al.: Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55 (4): 766-73, 1985. [PUBMED Abstract]
22. Das S, Sengupta M, Islam N, et al.: Weineke criteria, Ki-67 index and p53 status to study pediatric adrenocortical tumors: Is there a correlation? J Pediatr Surg 51 (11): 1795-1800, 2016. [PUBMED Abstract]
23. Stojadinovic A, Ghossein RA, Hoos A, et al.: Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20 (4): 941-50, 2002. [PUBMED Abstract]
24. Almeida MQ, Fragoso MC, Lotfi CF, et al.: Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 93 (9): 3524-31, 2008. [PUBMED Abstract]
25. West AN, Neale GA, Pounds S, et al.: Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67 (2): 600-8, 2007. [PUBMED Abstract]
26. Pinto EM, Chen X, Easton J, et al.: Genomic landscape of paediatric adrenocortical tumours. Nat Commun 6: 6302, 2015. [PUBMED Abstract]
27. Gönç EN, Özön ZA, Cakır MD, et al.: Need for comprehensive hormonal workup in the management of adrenocortical tumors in children. J Clin Res Pediatr Endocrinol 6 (2): 68-73, 2014. [PUBMED Abstract]
28. Ghazi AA, Mofid D, Salehian MT, et al.: Functioning adrenocortical tumors in children-secretory behavior. J Clin Res Pediatr Endocrinol 5 (1): 27-32, 2013. [PUBMED Abstract]
29. Hanna AM, Pham TH, Askegard-Giesmann JR, et al.: Outcome of adrenocortical tumors in children. J Pediatr Surg 43 (5): 843-9, 2008. [PUBMED Abstract]
30. McAteer JP, Huaco JA, Gow KW: Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg 48 (5): 1025-31, 2013. [PUBMED Abstract]
31. Cecchetto G, Ganarin A, Bien E, et al.: Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Pediatr Blood Cancer 64 (6): , 2017. [PUBMED Abstract]
32. Klein JD, Turner CG, Gray FL, et al.: Adrenal cortical tumors in children: factors associated with poor outcome. J Pediatr Surg 46 (6): 1201-7, 2011. [PUBMED Abstract]
33. Bulzico D, de Faria PA, de Paula MP, et al.: Recurrence and mortality prognostic factors in childhood adrenocortical tumors: Analysis from the Brazilian National Institute of Cancer experience. Pediatr Hematol Oncol 33 (4): 248-58, 2016. [PUBMED Abstract]
34. Leite FA, Lira RC, Fedatto PF, et al.: Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT). Pediatr Blood Cancer 61 (11): 1940-8, 2014. [PUBMED Abstract]
35. Pinto EM, Rodriguez-Galindo C, Choi JK, et al.: Prognostic Significance of Major Histocompatibility Complex Class II Expression in Pediatric Adrenocortical Tumors: A St. Jude and Children's Oncology Group Study. Clin Cancer Res 22 (24): 6247-6255, 2016. [PUBMED Abstract]
36. Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 82 (7): 2027-31, 1997. [PUBMED Abstract]
37. Pinto EM, Rodriguez-Galindo C, Pounds SB, et al.: Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study. J Clin Oncol 35 (35): 3956-3963, 2017. [PUBMED Abstract]
38. Zancanella P, Pianovski MA, Oliveira BH, et al.: Mitotane associated with cisplatin, etoposide, and doxorubicin in advanced childhood adrenocortical carcinoma: mitotane monitoring and tumor regression. J Pediatr Hematol Oncol 28 (8): 513-24, 2006. [PUBMED Abstract]
39. Hovi L, Wikström S, Vettenranta K, et al.: Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report. Med Pediatr Oncol 40 (5): 324-6, 2003. [PUBMED Abstract]
40. Stewart JN, Flageole H, Kavan P: A surgical approach to adrenocortical tumors in children: the mainstay of treatment. J Pediatr Surg 39 (5): 759-63, 2004. [PUBMED Abstract]
41. Hubertus J, Boxberger N, Redlich A, et al.: Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. Klin Padiatr 224 (3): 143-7, 2012. [PUBMED Abstract]
42. Kardar AH: Rupture of adrenal carcinoma after biopsy. J Urol 166 (3): 984, 2001. [PUBMED Abstract]
43. Gonzalez RJ, Shapiro S, Sarlis N, et al.: Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 138 (6): 1078-85; discussion 1085-6, 2005. [PUBMED Abstract]
44. Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007. [PUBMED Abstract]
45. Driver CP, Birch J, Gough DC, et al.: Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15 (6): 527-32, 1998 Nov-Dec. [PUBMED Abstract]
46. Curtis JL, Burns RC, Wang L, et al.: Primary gastric tumors of infancy and childhood: 54-year experience at a single institution. J Pediatr Surg 43 (8): 1487-93, 2008. [PUBMED Abstract]
47. Subbiah V, Varadhachary G, Herzog CE, et al.: Gastric adenocarcinoma in children and adolescents. Pediatr Blood Cancer 57 (3): 524-7, 2011. [PUBMED Abstract]
48. American Cancer Society: Cancer Facts and Figures-2000. Atlanta, Ga: American Cancer Society, 2000.
49. Guilford P, Hopkins J, Harraway J, et al.: E-cadherin germline mutations in familial gastric cancer. Nature 392 (6674): 402-5, 1998. [PUBMED Abstract]
50. Saf C, Gulcan EM, Ozkan F, et al.: Assessment of p21, p53 expression, and Ki-67 proliferative activities in the gastric mucosa of children with Helicobacter pylori gastritis. Eur J Gastroenterol Hepatol 27 (2): 155-61, 2015. [PUBMED Abstract]
51. Ajani JA: Current status of therapy for advanced gastric carcinoma. Oncology (Huntingt) 12 (8 Suppl 6): 99-102, 1998. [PUBMED Abstract]
52. Chung EM, Travis MD, Conran RM: Pancreatic tumors in children: radiologic-pathologic correlation. Radiographics 26 (4): 1211-38, 2006 Jul-Aug. [PUBMED Abstract]
53. Perez EA, Gutierrez JC, Koniaris LG, et al.: Malignant pancreatic tumors: incidence and outcome in 58 pediatric patients. J Pediatr Surg 44 (1): 197-203, 2009. [PUBMED Abstract]
54. Dall'igna P, Cecchetto G, Bisogno G, et al.: Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer 54 (5): 675-80, 2010. [PUBMED Abstract]
55. Brecht IB, Schneider DT, Klöppel G, et al.: Malignant pancreatic tumors in children and young adults: evaluation of 228 patients identified through the Surveillance, Epidemiology, and End Result (SEER) database. Klin Padiatr 223 (6): 341-5, 2011. [PUBMED Abstract]
56. Rojas Y, Warneke CL, Dhamne CA, et al.: Primary malignant pancreatic neoplasms in children and adolescents: a 20 year experience. J Pediatr Surg 47 (12): 2199-204, 2012. [PUBMED Abstract]
57. Papavramidis T, Papavramidis S: Solid pseudopapillary tumors of the pancreas: review of 718 patients reported in English literature. J Am Coll Surg 200 (6): 965-72, 2005. [PUBMED Abstract]
58. Estrella JS, Li L, Rashid A, et al.: Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. Am J Surg Pathol 38 (2): 147-57, 2014. [PUBMED Abstract]
59. Laje P, Bhatti TR, Adzick NS: Solid pseudopapillary neoplasm of the pancreas in children: a 15-year experience and the identification of a unique immunohistochemical marker. J Pediatr Surg 48 (10): 2054-60, 2013. [PUBMED Abstract]
60. Sacco Casamassima MG, Gause CD, Goldstein SD, et al.: Pancreatic surgery for tumors in children and adolescents. Pediatr Surg Int 32 (8): 779-88, 2016. [PUBMED Abstract]
61. Crocoli A, Grimaldi C, Virgone C, et al.: Outcome after surgery for solid pseudopapillary pancreatic tumors in children: Report from the TREP project-Italian Rare Tumors Study Group. Pediatr Blood Cancer : e27519, 2018. [PUBMED Abstract]
62. Maffuz A, Bustamante Fde T, Silva JA, et al.: Preoperative gemcitabine for unresectable, solid pseudopapillary tumour of the pancreas. Lancet Oncol 6 (3): 185-6, 2005. [PUBMED Abstract]
63. Bien E, Godzinski J, Dall'igna P, et al.: Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT). Eur J Cancer 47 (15): 2347-52, 2011. [PUBMED Abstract]
64. Chisholm KM, Hsu CH, Kim MJ, et al.: Congenital pancreatoblastoma: report of an atypical case and review of the literature. J Pediatr Hematol Oncol 34 (4): 310-5, 2012. [PUBMED Abstract]
65. Glick RD, Pashankar FD, Pappo A, et al.: Management of pancreatoblastoma in children and young adults. J Pediatr Hematol Oncol 34 (Suppl 2): S47-50, 2012. [PUBMED Abstract]
66. Honda S, Okada T, Miyagi H, et al.: Spontaneous rupture of an advanced pancreatoblastoma: aberrant RASSF1A methylation and CTNNB1 mutation as molecular genetic markers. J Pediatr Surg 48 (4): e29-32, 2013. [PUBMED Abstract]
67. Isobe T, Seki M, Yoshida K, et al.: Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma. Cancer Res 78 (4): 865-876, 2018. [PUBMED Abstract]
68. Lindholm EB, Alkattan AK, Abramson SJ, et al.: Pancreaticoduodenectomy for pediatric and adolescent pancreatic malignancy: A single-center retrospective analysis. J Pediatr Surg 52 (2): 299-303, 2017. [PUBMED Abstract]
69. Défachelles AS, Martin De Lassalle E, Boutard P, et al.: Pancreatoblastoma in childhood: clinical course and therapeutic management of seven patients. Med Pediatr Oncol 37 (1): 47-52, 2001. [PUBMED Abstract]
70. Belletrutti MJ, Bigam D, Bhargava R, et al.: Use of gemcitabine with multi-stage surgical resection as successful second-line treatment of metastatic pancreatoblastoma. J Pediatr Hematol Oncol 35 (1): e7-10, 2013. [PUBMED Abstract]
71. Dhamne C, Herzog CE: Response of Relapsed Pancreatoblastoma to a Combination of Vinorelbine and Oral Cyclophosphamide. J Pediatr Hematol Oncol 37 (6): e378-80, 2015. [PUBMED Abstract]
72. Hamidieh AA, Jalili M, Khojasteh O, et al.: Autologous stem cell transplantation as treatment modality in a patient with relapsed pancreatoblastoma. Pediatr Blood Cancer 55 (3): 573-6, 2010. [PUBMED Abstract]
73. Jensen RT, Cadiot G, Brandi ML, et al.: ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 95 (2): 98-119, 2012. [PUBMED Abstract]
74. Kulke MH, Benson AB 3rd, Bergsland E, et al.: Neuroendocrine tumors. J Natl Compr Canc Netw 10 (6): 724-64, 2012. [PUBMED Abstract]
75. Lüttges J, Stigge C, Pacena M, et al.: Rare ductal adenocarcinoma of the pancreas in patients younger than age 40 years. Cancer 100 (1): 173-82, 2004. [PUBMED Abstract]
76. Rustgi AK: Familial pancreatic cancer: genetic advances. Genes Dev 28 (1): 1-7, 2014. [PUBMED Abstract]
77. da Costa Vieira RA, Tramonte MS, Lopes LF: Colorectal carcinoma in the first decade of life: a systematic review. Int J Colorectal Dis 30 (8): 1001-6, 2015. [PUBMED Abstract]
78. Saab R, Furman WL: Epidemiology and management options for colorectal cancer in children. Paediatr Drugs 10 (3): 177-92, 2008. [PUBMED Abstract]
79. Ferrari A, Casanova M, Massimino M, et al.: Peculiar features and tailored management of adult cancers occurring in pediatric age. Expert Rev Anticancer Ther 10 (11): 1837-51, 2010. [PUBMED Abstract]
80. Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md: National Cancer Institute, 2006. NIH Pub. No. 06-5767. Also available online. Last accessed January 31, 2019.
81. Kaplan MA, Isikdogan A, Gumus M, et al.: Childhood, adolescents, and young adults (≤25 y) colorectal cancer: study of Anatolian Society of Medical Oncology. J Pediatr Hematol Oncol 35 (2): 83-9, 2013. [PUBMED Abstract]
82. Kim G, Baik SH, Lee KY, et al.: Colon carcinoma in childhood: review of the literature with four case reports. Int J Colorectal Dis 28 (2): 157-64, 2013. [PUBMED Abstract]
83. Sultan I, Rodriguez-Galindo C, El-Taani H, et al.: Distinct features of colorectal cancer in children and adolescents: a population-based study of 159 cases. Cancer 116 (3): 758-65, 2010. [PUBMED Abstract]
84. Hill DA, Furman WL, Billups CA, et al.: Colorectal carcinoma in childhood and adolescence: a clinicopathologic review. J Clin Oncol 25 (36): 5808-14, 2007. [PUBMED Abstract]
85. Pratt CB, Rao BN, Merchant TE, et al.: Treatment of colorectal carcinoma in adolescents and young adults with surgery, 5-fluorouracil/leucovorin/interferon-alpha 2a and radiation therapy. Med Pediatr Oncol 32 (6): 459-60, 1999. [PUBMED Abstract]
86. Kauffman WM, Jenkins JJ 3rd, Helton K, et al.: Imaging features of ovarian metastases from colonic adenocarcinoma in adolescents. Pediatr Radiol 25 (4): 286-8, 1995. [PUBMED Abstract]
87. Postgate A, Hyer W, Phillips R, et al.: Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps. J Pediatr Gastroenterol Nutr 49 (4): 417-23, 2009. [PUBMED Abstract]
88. Ferrari A, Rognone A, Casanova M, et al.: Colorectal carcinoma in children and adolescents: the experience of the Istituto Nazionale Tumori of Milan, Italy. Pediatr Blood Cancer 50 (3): 588-93, 2008. [PUBMED Abstract]
89. Poles GC, Clark DE, Mayo SW, et al.: Colorectal carcinoma in pediatric patients: A comparison with adult tumors, treatment and outcomes from the National Cancer Database. J Pediatr Surg 51 (7): 1061-6, 2016. [PUBMED Abstract]
90. Tricoli JV, Seibel NL, Blair DG, et al.: Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer. J Natl Cancer Inst 103 (8): 628-35, 2011. [PUBMED Abstract]
91. Khan SA, Morris M, Idrees K, et al.: Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg 51 (11): 1812-1817, 2016. [PUBMED Abstract]
92. Bleyer A, Barr R, Hayes-Lattin B, et al.: The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 8 (4): 288-98, 2008. [PUBMED Abstract]
93. Tricoli JV, Boardman LA, Patidar R, et al.: A mutational comparison of adult and adolescent and young adult (AYA) colon cancer. Cancer 124 (5): 1070-1082, 2018. [PUBMED Abstract]
94. Chantada GL, Perelli VB, Lombardi MG, et al.: Colorectal carcinoma in children, adolescents, and young adults. J Pediatr Hematol Oncol 27 (1): 39-41, 2005. [PUBMED Abstract]
95. Durno C, Aronson M, Bapat B, et al.: Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma. Gut 54 (8): 1146-50, 2005. [PUBMED Abstract]
96. Karnak I, Ciftci AO, Senocak ME, et al.: Colorectal carcinoma in children. J Pediatr Surg 34 (10): 1499-504, 1999. [PUBMED Abstract]
97. LaQuaglia MP, Heller G, Filippa DA, et al.: Prognostic factors and outcome in patients 21 years and under with colorectal carcinoma. J Pediatr Surg 27 (8): 1085-9; discussion 1089-90, 1992. [PUBMED Abstract]
98. Radhakrishnan CN, Bruce J: Colorectal cancers in children without any predisposing factors. A report of eight cases and review of the literature. Eur J Pediatr Surg 13 (1): 66-8, 2003. [PUBMED Abstract]
99. Sharma AK, Gupta CR: Colorectal cancer in children: case report and review of literature. Trop Gastroenterol 22 (1): 36-9, 2001 Jan-Mar. [PUBMED Abstract]
100. Taguchi T, Suita S, Hirata Y, et al.: Carcinoma of the colon in children: a case report and review of 41 Japanese cases. J Pediatr Gastroenterol Nutr 12 (3): 394-9, 1991. [PUBMED Abstract]
101. Madajewicz S, Petrelli N, Rustum YM, et al.: Phase I-II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res 44 (10): 4667-9, 1984. [PUBMED Abstract]
102. Wolmark N, Bryant J, Smith R, et al.: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90 (23): 1810-6, 1998. [PUBMED Abstract]
103. Blanke CD, Bot BM, Thomas DM, et al.: Impact of young age on treatment efficacy and safety in advanced colorectal cancer: a pooled analysis of patients from nine first-line phase III chemotherapy trials. J Clin Oncol 29 (20): 2781-6, 2011. [PUBMED Abstract]
104. Saltz LB, Clarke S, Díaz-Rubio E, et al.: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26 (12): 2013-9, 2008. [PUBMED Abstract]
105. Heinemann V, von Weikersthal LF, Decker T, et al.: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (10): 1065-75, 2014. [PUBMED Abstract]
106. Van Cutsem E, Tabernero J, Lakomy R, et al.: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30 (28): 3499-506, 2012. [PUBMED Abstract]
107. Grothey A, Van Cutsem E, Sobrero A, et al.: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 303-12, 2013. [PUBMED Abstract]
108. Gatalica Z, Torlakovic E: Pathology of the hereditary colorectal carcinoma. Fam Cancer 7 (1): 15-26, 2008. [PUBMED Abstract]
109. O'Connell JB, Maggard MA, Livingston EH, et al.: Colorectal cancer in the young. Am J Surg 187 (3): 343-8, 2004. [PUBMED Abstract]
110. Goel A, Nagasaka T, Spiegel J, et al.: Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol 8 (11): 966-71, 2010. [PUBMED Abstract]
111. Weber ML, Schneider DT, Offenmüller S, et al.: Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes. Pediatr Blood Cancer 63 (4): 611-7, 2016. [PUBMED Abstract]
112. Erdman SH: Pediatric adenomatous polyposis syndromes: an update. Curr Gastroenterol Rep 9 (3): 237-44, 2007. [PUBMED Abstract]
113. Turcot J, Despres JP, St Pierre F: Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 2: 465-8, 1959 Sep-Oct. [PUBMED Abstract]
114. Vogelstein B, Fearon ER, Hamilton SR, et al.: Genetic alterations during colorectal-tumor development. N Engl J Med 319 (9): 525-32, 1988. [PUBMED Abstract]
115. Lynch PM, Ayers GD, Hawk E, et al.: The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 105 (6): 1437-43, 2010. [PUBMED Abstract]
116. Pratt CB, Jane JA: Multiple colorectal carcinomas, polyposis coli, and neurofibromatosis, followed by multiple glioblastoma multiforme. J Natl Cancer Inst 83 (12): 880-1, 1991. [PUBMED Abstract]
117. Heath JA, Reece JC, Buchanan DD, et al.: Childhood cancers in families with and without Lynch syndrome. Fam Cancer 14 (4): 545-51, 2015. [PUBMED Abstract]
118. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79 (4): 813-29, 1997. [PUBMED Abstract]
119. Deans GT, Spence RA: Neoplastic lesions of the appendix. Br J Surg 82 (3): 299-306, 1995. [PUBMED Abstract]
120. Doede T, Foss HD, Waldschmidt J: Carcinoid tumors of the appendix in children--epidemiology, clinical aspects and procedure. Eur J Pediatr Surg 10 (6): 372-7, 2000. [PUBMED Abstract]
121. Quaedvlieg PF, Visser O, Lamers CB, et al.: Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients. Ann Oncol 12 (9): 1295-300, 2001. [PUBMED Abstract]
122. Broaddus RR, Herzog CE, Hicks MJ: Neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) presenting at extra-appendiceal sites in childhood and adolescence. Arch Pathol Lab Med 127 (9): 1200-3, 2003. [PUBMED Abstract]
123. Foley DS, Sunil I, Debski R, et al.: Primary hepatic carcinoid tumor in children. J Pediatr Surg 43 (11): e25-8, 2008. [PUBMED Abstract]
124. Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 71 (839): 542-5, 1995. [PUBMED Abstract]
125. Delaunoit T, Rubin J, Neczyporenko F, et al.: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors. Mayo Clin Proc 80 (4): 502-6, 2005. [PUBMED Abstract]
126. More J, Young J, Reznik Y, et al.: Ectopic ACTH syndrome in children and adolescents. J Clin Endocrinol Metab 96 (5): 1213-22, 2011. [PUBMED Abstract]
127. Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
128. Pelizzo G, La Riccia A, Bouvier R, et al.: Carcinoid tumors of the appendix in children. Pediatr Surg Int 17 (5-6): 399-402, 2001. [PUBMED Abstract]
129. Hatzipantelis E, Panagopoulou P, Sidi-Fragandrea V, et al.: Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. J Pediatr Gastroenterol Nutr 51 (5): 622-5, 2010. [PUBMED Abstract]
130. Henderson L, Fehily C, Folaranmi S, et al.: Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. J Pediatr Surg 49 (10): 1513-7, 2014. [PUBMED Abstract]
131. Dall'Igna P, Ferrari A, Luzzatto C, et al.: Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. J Pediatr Gastroenterol Nutr 40 (2): 216-9, 2005. [PUBMED Abstract]
132. Wu H, Chintagumpala M, Hicks J, et al.: Neuroendocrine Tumor of the Appendix in Children. J Pediatr Hematol Oncol 39 (2): 97-102, 2017. [PUBMED Abstract]
133. Boxberger N, Redlich A, Böger C, et al.: Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 60 (1): 65-70, 2013. [PUBMED Abstract]
134. Njere I, Smith LL, Thurairasa D, et al.: Systematic review and meta-analysis of appendiceal carcinoid tumors in children. Pediatr Blood Cancer 65 (8): e27069, 2018. [PUBMED Abstract]
135. Virgone C, Cecchetto G, Alaggio R, et al.: Appendiceal neuroendocrine tumours in childhood: Italian TREP project. J Pediatr Gastroenterol Nutr 58 (3): 333-8, 2014. [PUBMED Abstract]
136. de Lambert G, Lardy H, Martelli H, et al.: Surgical Management of Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Retrospective French Multicenter Study of 114 Cases. Pediatr Blood Cancer 63 (4): 598-603, 2016. [PUBMED Abstract]
137. Boston CH, Phan A, Munsell MF, et al.: A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience. J Pediatr Hematol Oncol 37 (6): 438-42, 2015. [PUBMED Abstract]
138. Enzler T, Fojo T: Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors. Semin Oncol 44 (2): 141-156, 2017. [PUBMED Abstract]
139. Ambe CM, Nguyen P, Centeno BA, et al.: Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience. Cancer Control 24 (5): 1073274817729076, 2017 Oct-Dec. [PUBMED Abstract]
140. Elf AK, Andersson M, Henrikson O, et al.: Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial. World J Surg 42 (2): 506-513, 2018. [PUBMED Abstract]
141. Rinke A, Wittenberg M, Schade-Brittinger C, et al.: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology 104 (1): 26-32, 2017. [PUBMED Abstract]
142. Caplin ME, Pavel M, Ćwikła JB, et al.: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371 (3): 224-33, 2014. [PUBMED Abstract]
143. Brabander T, Teunissen JJ, Van Eijck CH, et al.: Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 30 (1): 103-14, 2016. [PUBMED Abstract]
144. Gajate P, Martínez-Sáez O, Alonso-Gordoa T, et al.: Emerging use of everolimus in the treatment of neuroendocrine tumors. Cancer Manag Res 9: 215-224, 2017. [PUBMED Abstract]
145. Liu IH, Kunz PL: Biologics in gastrointestinal and pancreatic neuroendocrine tumors. J Gastrointest Oncol 8 (3): 457-465, 2017. [PUBMED Abstract]
146. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 22 (18): 3813-25, 2004. [PUBMED Abstract]
147. Pappo AS, Janeway K, Laquaglia M, et al.: Special considerations in pediatric gastrointestinal tumors. J Surg Oncol 104 (8): 928-32, 2011. [PUBMED Abstract]
148. Prakash S, Sarran L, Socci N, et al.: Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 27 (4): 179-87, 2005. [PUBMED Abstract]
149. Miettinen M, Lasota J, Sobin LH: Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29 (10): 1373-81, 2005. [PUBMED Abstract]
150. Benesch M, Wardelmann E, Ferrari A, et al.: Gastrointestinal stromal tumors (GIST) in children and adolescents: A comprehensive review of the current literature. Pediatr Blood Cancer 53 (7): 1171-9, 2009. [PUBMED Abstract]
151. Cypriano MS, Jenkins JJ, Pappo AS, et al.: Pediatric gastrointestinal stromal tumors and leiomyosarcoma. Cancer 101 (1): 39-50, 2004. [PUBMED Abstract]
152. Pappo AS, Janeway KA: Pediatric gastrointestinal stromal tumors. Hematol Oncol Clin North Am 23 (1): 15-34, vii, 2009. [PUBMED Abstract]
153. Benesch M, Leuschner I, Wardelmann E, et al.: Gastrointestinal stromal tumours in children and young adults: a clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). Eur J Cancer 47 (11): 1692-8, 2011. [PUBMED Abstract]
154. Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130 (10): 1466-78, 2006. [PUBMED Abstract]
155. Miettinen M, Lasota J: Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol 53: 514-9, 2014. [PUBMED Abstract]
156. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35 (11): 1712-21, 2011. [PUBMED Abstract]
157. Janeway KA, Liegl B, Harlow A, et al.: Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res 67 (19): 9084-8, 2007. [PUBMED Abstract]
158. Tarn C, Rink L, Merkel E, et al.: Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proceedings of the National Academy of Sciences 105 (24): 8387-92, 2008. Also available onlineExit Disclaimer. Last accessed November 20, 2018.
159. Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008. [PUBMED Abstract]
160. Janeway KA, Kim SY, Lodish M, et al.: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108 (1): 314-8, 2011. [PUBMED Abstract]
161. Killian JK, Miettinen M, Walker RL, et al.: Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med 6 (268): 268ra177, 2014. [PUBMED Abstract]
162. Boikos SA, Pappo AS, Killian JK, et al.: Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2 (7): 922-8, 2016. [PUBMED Abstract]
163. Otto C, Agaimy A, Braun A, et al.: Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Pathol 6: 52, 2011. [PUBMED Abstract]
164. Carney JA: Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. J Clin Endocrinol Metab 94 (10): 3656-62, 2009. [PUBMED Abstract]
165. Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [PUBMED Abstract]
166. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
167. Janeway KA, Weldon CB: Pediatric gastrointestinal stromal tumor. Semin Pediatr Surg 21 (1): 31-43, 2012. [PUBMED Abstract]
168. Weldon CB, Madenci AL, Boikos SA, et al.: Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol 35 (5): 523-528, 2017. [PUBMED Abstract]
169. Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006. [PUBMED Abstract]
170. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002. [PUBMED Abstract]
171. Heinrich MC, Rankin C, Blanke CD, et al.: Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol 3 (7): 944-952, 2017. [PUBMED Abstract]
172. Janeway KA, Albritton KH, Van Den Abbeele AD, et al.: Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer 52 (7): 767-71, 2009. [PUBMED Abstract]
173. Dematteo RP, Ballman KV, Antonescu CR, et al.: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9669): 1097-104, 2009. [PUBMED Abstract]

Genital/Urinary Tumors

In This Section

• Carcinoma of the Bladder
  • Clinical Presentation
  • Risk Factors
  • Histology
  • Treatment and Outcome
  • Treatment Options Under Clinical Evaluation
• Testicular Cancer (Non–Germ Cell)
  • Incidence and Clinical Presentation
  • Prognosis
  • Treatment
  • Treatment Options Under Clinical Evaluation
• Ovarian Cancer (Non–Germ Cell)
  • Epithelial Ovarian Neoplasia
  • Sex Cord–Stromal Tumors
  • Small Cell Carcinoma of the Ovary, Hypercalcemia-Type
  • Treatment Options Under Clinical Evaluation
• Carcinoma of the Cervix and Vagina
  • Incidence, Risk Factors, and Clinical Presentation
  • Treatment and Outcome
  • Treatment Options Under Clinical Evaluation

Unusual pediatric genital/urinary tumors include the following:

• Carcinoma of the bladder.
• Testicular cancer (non–germ cell).
• Ovarian cancer (non–germ cell).
• Carcinoma of the cervix and vagina.

The prognosis, diagnosis, classification, and treatment of these genital/urinary tumors are discussed below. It must be emphasized that these tumors are seen very infrequently in patients younger than 15 years, and most of the evidence is derived from case series.

Carcinoma of the Bladder

Clinical Presentation

Urothelial bladder neoplasms are extremely rare in children; the most common presenting symptom is hematuria.[1]

Risk Factors

Bladder cancer in adolescents may develop as a consequence of alkylating-agent chemotherapy given for other childhood tumors or leukemia.[2-4] The association between cyclophosphamide and bladder cancer is the only established relationship between a specific anticancer drug and a solid tumor.[2]

Histology

Histologic classification of these neoplasms includes the following:

• Urothelial papillomas.
• Papillary neoplasms of low malignant potential.
• Low-grade urothelial carcinoma.
• High-grade urothelial carcinoma.

An alternative designation is transitional cell carcinoma of the bladder. The most common histology is papillary urothelial neoplasm of low malignant potential, while high-grade, invasive urothelial carcinomas are extremely rare in young patients.[4-8]

Treatment and Outcome

Treatment options for childhood bladder cancer include the following:

1. Surgery.

In contrast to adults, most pediatric bladder carcinomas are low grade, superficial, and have an excellent prognosis after transurethral resection.[6-9] Squamous cell carcinoma and more aggressive carcinomas, however, have been reported and may require a more aggressive surgical approach.[7,10-12]

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 Bladder Cancer Treatment for more information.)

Testicular Cancer (Non–Germ Cell)

Incidence and Clinical Presentation

Testicular tumors are very rare in young boys and account for an incidence of 1% to 2% of all childhood tumors.[13,14] The most common testicular tumors are benign teratomas followed by malignant nonseminomatous germ cell tumors. (Refer to the PDQ summary on Childhood Extracranial Germ Cell Tumors Treatment for more information.)

Non–germ cell tumors such as sex cord–stromal tumors are exceedingly rare in prepubertal boys. In a small series, gonadal stromal tumors accounted for 8% to 13% of pediatric testicular tumors.[15,16] Most gonadal stromal tumors present as a painless testicular mass, while 10% to 20% of patients may have endocrine manifestations such as precocious puberty.[17] In newborns and infants, juvenile granulosa cell and Sertoli cell tumors are the most common stromal cell tumor. Juvenile granulosa cell tumors usually present in infancy (median age, 6 days) and Sertoli cell tumors present later in infancy (median age, 7 months). In older males, Leydig cell tumors are more common.[18] Large cell calcifying Sertoli cell tumors may indicate an underlying genetic predisposition, such as Peutz-Jeghers syndrome or Carney complex. These tumors may occur in both testes, and some patients may have a slow and indolent course.[19]

Prognosis

The prognosis for sex cord–stromal tumors is usually excellent after orchiectomy.[17,20,21]; [22][Level of evidence: 3iiiA] In a review of the literature, 79 patients younger than 12 years were identified. No patient had high-risk pathological findings after orchiectomy, and none had evidence of occult metastatic disease, suggesting a role for a limited surveillance strategy.[23][Level of evidence: 3iiiA]

Treatment

Treatment options for testicular cancer (non-germ cell) include the following:

1. Surgery.

There are conflicting data about malignant potential in older males. Most case reports suggest that in pediatric patients, these tumors can be treated with surgery alone.[20][Level of evidence: 3iii]; [24][Level of evidence: 3iiiA]; [17][Level of evidence: 3iiiDii] It is prudent to check alpha-fetoprotein (AFP) levels before surgery. Elevated AFP levels are usually indicative of a malignant germ cell tumor. However, AFP levels and decay in levels are often difficult to interpret in infants younger than 1 year.[25]

Evidence (surgery):

1. In a study of patients prospectively reported to the German Maligne Keimzelltumoren (MAKEI) registry, 42 patients with sex cord–stromal tumors were identified. All tumors were confined to the testes. Patients were treated with surgery alone, according to specific germ cell tumor guidelines.[22][Level of evidence: 3iiiA]
   • There were no recurrences.
2. A French registry identified 11 boys with localized sex cord–stromal testicular tumors. All 11 boys were treated with surgery alone.[26][Level of evidence: 3iA]
   • There were no recurrences.
3. The benign behavior of pediatric non–germ cell testicular tumors has led to reports of testis-sparing surgery.[27-29]

However, given the rarity of this tumor, the surgical approach in pediatrics has not been well defined.

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).

Ovarian Cancer (Non–Germ Cell)

Most ovarian masses in children are not malignant.

The most common neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then other tumors such as Burkitt lymphoma.[30-33]

Most malignant ovarian tumors occur in girls aged 15 to 19 years.[34]

Epithelial Ovarian Neoplasia

Histology, Clinical Presentation, and Prognosis

Ovarian tumors derived from malignant epithelial elements include the following:

• Serous cystomas.
• Mucinous cystomas.
• Endometrial tumors.
• Clear cell tumors.

Within each classification, subtypes include benign tumors, tumors with low malignant potential or borderline tumors, and adenocarcinomas. Most ovarian tumors in the pediatric age range are benign and borderline,[35] with rare malignant lesions in adolescence.[36] Studies have reported the following:

• In the Italian prospective multicenter study of rare tumors (TREP project), of the 16 patients identified over 14 years, 8 patients had benign tumors (7 mucinous cystadenoma and 1 serous cystadenoma) and 8 patients had borderline tumors (2 serous and 6 mucinous).[37][Level of evidence: 3iA] No malignant tumors were identified. High levels of cancer antigen (CA)-125 were detected in 6 of 15 patients.
• In another series of 19 patients younger than 21 years with epithelial ovarian neoplasms, the average age at diagnosis was 19.7 years. Dysmenorrhea and abdominal pain were the most common presenting symptoms. Low malignant potential or well-differentiated tumors were diagnosed in 84% of patients, 79% of the patients had stage I disease with a 100% survival rate, and only those who had small cell anaplastic carcinoma died.[38][Level of evidence: 3iiiA]

Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than do adults with similar histology, probably because girls usually present with low-stage disease.[38,39] The potential association with genetic predisposition (e.g., BRCA mutation) in pediatric patients has not yet been studied.

Treatment

Treatment options for epithelial ovarian neoplasia include the following:

1. Surgery alone.

Treatment of epithelial ovarian neoplasia is based on stage and histology. Most pediatric and adolescent patients have stage I disease. In the TREP study,[37] of the eight patients with benign tumors, seven patients were stage I and one patient was stage III. Of the eight patients with borderline tumors, three patients were stage I and five patients were stage III (on the basis of washings and omental implants). All 16 patients were treated with surgery alone. Fifteen patients are alive without disease; the one death was not from ovarian cancer.

Treatment options for malignant ovarian epithelial cancer include the following:

1. Surgery.
2. Radiation therapy.
3. Chemotherapy.

Treatment of malignant ovarian epithelial cancer is stage-related and follows adult protocols; it may include surgery, radiation therapy, and chemotherapy. (Refer to the PDQ summary on adult Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment for more information.)

Sex Cord–Stromal Tumors

Histology and Molecular Features

Ovarian sex cord–stromal tumors are a heterogeneous group of rare tumors that derive from the gonadal non–germ cell component.[40] Histologic subtypes display some areas of gonadal differentiation and include juvenile (and, rarely, adult) granulosa cell tumors, Sertoli-Leydig cell tumors, and sclerosing stromal tumors. Other histological subtypes, such as steroid cell tumor, sex cord tumor with annular tubules, or thecoma, are exceedingly rare. Ovarian Sertoli-Leydig cell tumors in children and adolescents are commonly associated with the presence of germline DICER1 mutations and may be a manifestation of the familial pleuropulmonary blastoma syndrome.[41]

Clinical Presentation

The clinical presentation and prognosis of sex cord–stromal tumors varies by histology. In all entities, metastatic spread occurs rarely and if present, is usually limited to the peritoneal cavity.[40] Distant metastases mostly occur in relapse situations.[42] Some tumors may be associated with hormone secretion; for example, estrogen in granulosa cell tumors or androgens in Sertoli-Leydig cell tumors.[26]

Diagnostic Evaluation

In the United States, these tumors may be registered in the Testicular and Ovarian Stromal Tumor registry.[43] In Europe, patients are prospectively registered in the national rare tumor groups.[43,44] The recommendations regarding diagnostic work-up, staging, and therapeutic strategy have been harmonized between these registries.[43]

Prognostic Factors

In a report from the German MAKEI study, 54 children and adolescents with prospectively registered sex cord–stromal tumors were analyzed. Forty-eight patients presented with stage I tumors and six patients had peritoneal metastases. While overall prognosis was favorable, patients at risk could be identified by stage (stage Ic, preoperative rupture, stages II and III) and histological criteria such as high mitotic count.[45]

Treatment

Treatment options for sex cord–stromal tumors include the following:

1. Surgery.
2. Chemotherapy.

A French registry identified 38 girls younger than 18 years with ovarian sex cord tumors.[26] Complete surgical resection was achieved in 23 of 38 girls who did not receive adjuvant treatment. Two patients recurred, one patient's tumor responded to chemotherapy, and the other patient died. Fifteen girls had tumor rupture and/or ascites. Eleven of the 15 patients received chemotherapy and did not recur; of the four patients who did not receive chemotherapy, all recurred and two died.

Juvenile Granulosa Cell Tumors

Incidence

The most common histologic subtype in girls younger than 18 years is juvenile granulosa cell tumors (median age, 7.6 years; range, birth to 17.5 years).[46,47] Juvenile granulosa cell tumors represent about 5% of ovarian tumors in children and adolescents and are distinct from the granulosa cell tumors seen in adults.[40,48-50]

Risk Factors

Juvenile granulosa cell tumors have been reported in children with Ollier disease and Maffucci syndrome.[51,52]

Clinical Presentation

Patients with juvenile granulosa cell tumors present with the following:[53,54]

• Precocious puberty (most common; caused by estrogen secretion).
• Abdominal pain.
• Abdominal mass.
• Ascites.

Treatment

Treatment options for juvenile granulosa cell tumors include the following:

1. Surgery. As many as 90% of children with juvenile granulosa cell tumors will have low-stage disease (stage I) by International Federation of Gynecology and Obstetrics (FIGO) criteria and are usually curable with unilateral salpingo-oophorectomy alone.
2. Chemotherapy. Patients with spontaneous tumor rupture or malignant ascites (FIGO stage IC2, IC3), advanced disease (FIGO stages II–IV), and those with high mitotic activity tumors have a poorer prognosis and require chemotherapy.[26,44,55] Use of a cisplatin-based chemotherapy regimen has been reported in both the adjuvant and recurrent disease settings with some success.[44,46,50,56,57][Level of evidence: 3iiiA]

Sertoli-Leydig Cell Tumors

Incidence, Risk Factors, and Clinical Presentation

Sertoli-Leydig cell tumors are rare in young girls and are more frequently seen in adolescents. They may secrete androgens and, thus, present with virilization, secondary amenorrhea,[58] or precocious puberty.[59] These tumors may also be associated with Peutz-Jeghers syndrome, but more frequently are a part of the DICER-1 tumor spectrum.[41,60,61]

Treatment and Outcome

Treatment options for Sertoli-Leydig cell tumors include the following:

1. Surgery. Surgery is the primary treatment for Sertoli-Leydig cell tumors and is the only treatment for low-stage disease (FIGO stage Ia), with essentially 100% event-free survival (EFS).[26][Level of evidence: 3iiiA] However, up to 10% of patients may develop metachronous contralateral tumors, particularly in the context of underlying DICER1 germline mutations.[62]
2. Chemotherapy. Patients with Sertoli-Leydig cell tumors with abdominal spillage during surgery, spontaneous tumor rupture, or metastatic disease (FIGO stages IC, II, III, and IV) are treated with cisplatin-based combination chemotherapy, although the impact of chemotherapy has not been studied in clinical trials.[26,63] An additional study reported on 40 women with FIGO stage I or Ic Sertoli-Leydig cell tumors of the ovary, with an average age of 28 years.[64][Level of evidence: 3iiA] Of 34 patients with intermediate or poor differentiation, 23 patients received postoperative chemotherapy (most regimens included cisplatin); none recurred. Of the 11 patients who did not receive postoperative chemotherapy, two recurred; both had tumors that were salvaged with chemotherapy.

A study of 44 patients from the European Cooperative Study Group on Pediatric Rare Tumors showed that prognosis of Sertoli-Leydig cell tumors was determined by stage and histopathologic differentiation.[63]

Small Cell Carcinoma of the Ovary, Hypercalcemia-Type

Incidence, Molecular Features, and Prognosis

Small cell carcinomas of the ovary are exceedingly rare and aggressive tumors and may be associated with hypercalcemia.[65]

SMARCA4 mutations have been described in these tumors, putting these in the context of rhabdoid tumors.[66]

The clinical course is usually aggressive and prognosis is poor.

Treatment

Treatment options for small cell carcinoma of the ovary include the following:

1. Aggressive multimodality therapy. Successful treatment with aggressive therapy has been reported in a few cases.[65,67][Level of evidence: 3iiB]; [68,69][Level of evidence: 3iiiA]
2. Tazemetostat. Tazemetostat is an EZH2 inhibitor that demonstrates activity against preclinical models of small cell carcinoma of the ovary with SMARCA4 loss.[70] Two patients with small cell carcinoma of the ovary and SMARCA4 loss were enrolled in a phase I trial of tazemetostat; one patient achieved a partial response and one patient achieved prolonged stable disease.[71]

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 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).
• EZH-202 (NCT02601950) (A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma): This is a phase II, multicenter, open-label, single-arm, two-stage study of tazemetostat. Patients receive 800 mg (orally) of tazemetostat twice a day in continuous 28-day cycles. Eligible subjects will be enrolled into one of five cohorts on the basis of their tumor type. Patients aged 16 years and older are eligible for this study.