sábado, 6 de julio de 2019

Unusual Cancers of Childhood Treatment (PDQ®) 5/6 —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



Genital/Urinary Tumors

Unusual pediatric genital/urinary tumors include the following:
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 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
(Refer to the PDQ summary on adult 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 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

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 DICER1-tumor spectrum.[41,60,61] Patients with Sertoli-Leydig cell tumors should be evaluated for germline DICER1mutations. If a germline DICER1 mutation is found, regular follow-up for ovarian and other tumors such as thyroid disease (multinodular goiter, carcinoma) and genetic counseling should be considered.[61,62]
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.[63]
  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.[26,64] 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.[65][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.[64]

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.[66]
SMARCA4 mutations have been described in these tumors, putting these in the context of rhabdoid tumors.[67]
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.[66,68][Level of evidence: 3iiB]; [69,70][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.[71] 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.[72]

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 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  • 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.

Carcinoma of the Cervix and Vagina

Incidence, Risk Factors, and Clinical Presentation

Adenocarcinoma of the cervix and vagina is rare in childhood and adolescence, with fewer than 50 reported cases.[33,73] Two-thirds of the cases are related to exposure to diethylstilbestrol in utero.
The median age at presentation is 15 years, with a range of 7 months to 18 years, and most patients present with vaginal bleeding. Adults with adenocarcinoma of the cervix or vagina will present with stage I or stage II disease 90% of the time. In children and adolescents, there is a high incidence of stage III and stage IV disease (24%). This difference may be explained by the practice of routine pelvic examinations in adults and the hesitancy to perform pelvic exams in children.

Treatment and Outcome

Treatment options for carcinoma of the cervix and vagina include the following:
  1. Surgery.
  2. Radiation therapy, for residual microscopic disease or lymphatic metastases.
The treatment of choice is surgical resection,[74] followed by radiation therapy for residual microscopic disease or lymphatic metastases. The role of chemotherapy in management is unknown, although drugs commonly used in the treatment of gynecologic malignancies, carboplatin and paclitaxel, have been used.[75]
The 3-year EFS for all stages is 71% ± 11%; for stage I and stage II, the EFS is 82% ± 11%, and for stage III and stage IV, the EFS is 57% ± 22%.[73]

Treatment Options Under Clinical Evaluation

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