Childhood Ovarian Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Ovarian Cancer

Most ovarian masses in children are not malignant.[1] The most common malignant neoplasms are germ cell tumors, followed by epithelial tumors, stromal tumors, and then other tumors such as Burkitt lymphoma.[2,3,4,5]

Most malignant ovarian tumors occur in girls aged 15 to 19 years.[6]

References:

1. Lawrence AE, Gonzalez DO, Fallat ME, et al.: Factors Associated With Management of Pediatric Ovarian Neoplasms. Pediatrics 144 (1): , 2019.
2. Morowitz M, Huff D, von Allmen D: Epithelial ovarian tumors in children: a retrospective analysis. J Pediatr Surg 38 (3): 331-5; discussion 331-5, 2003.
3. Schultz KA, Sencer SF, Messinger Y, et al.: Pediatric ovarian tumors: a review of 67 cases. Pediatr Blood Cancer 44 (2): 167-73, 2005.
4. Aggarwal A, Lucco KL, Lacy J, et al.: Ovarian epithelial tumors of low malignant potential: a case series of 5 adolescent patients. J Pediatr Surg 44 (10): 2023-7, 2009.
5. You W, Dainty LA, Rose GS, et al.: Gynecologic malignancies in women aged less than 25 years. Obstet Gynecol 105 (6): 1405-9, 2005.
6. Brookfield KF, Cheung MC, Koniaris LG, et al.: A population-based analysis of 1037 malignant ovarian tumors in the pediatric population. J Surg Res 156 (1): 45-9, 2009.

Stage Information for Ovarian Cancer

The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging system has been used for ovarian cancers (see Table 1).

Table 1. FIGO Staging for Carcinoma of the Ovary^a

Stage		Description
FIGO = Fédération Internationale de Gynécologie et d'Obstétrique.
a Adapted from Berek et al.[1]
I		Tumor confined to the ovary.
IA		Tumor limited to one ovary (capsule intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IB		Tumor limited to both ovaries (capsules intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IC		Tumor limited to one or both ovaries, with any of the following:
	IC1	Surgical spill.
	IC2	Capsule ruptured before surgery or tumor on the surface of the ovary.
	IC3	Malignant cells in the ascites or peritoneal washings.
II		Tumor involves one or both ovaries with pelvic extension (below pelvic brim) or primary peritoneal cancer.
IIA		Extension and/or implants on uterus and/or fallopian tubes.
IIB		Extension to other pelvic intraperitoneal tissues.
III		Tumor involves one or both ovaries or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes.
IIIA1		Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
	IIIA1(i)	Lymph nodes ≤10 mm in greatest dimension.
	IIIA1(ii)	Lymph nodes >10 mm in greatest dimension.
IIIA2		Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes.
IIIB		Macroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes.
IIIC		Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ).
IV		Distant metastasis excluding peritoneal metastases.
IVA		Pleural effusion with positive cytology.
IVB		Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity).

References:

1. Berek JS, Renz M, Kehoe S, et al.: Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 61-85, 2021.

Childhood Epithelial Ovarian Neoplasia

Clinical Presentation, Histology, and Prognosis

The most common presenting symptoms of ovarian tumors in children are dysmenorrhea and abdominal pain.

Ovarian tumors derived from malignant epithelial elements include the following types:

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

There are subtypes within each tumor type. The subtypes include benign tumors, tumors with low malignant potential or borderline tumors, and adenocarcinomas. Most ovarian tumors in pediatric patients are benign and borderline,[1] with rare malignant lesions in adolescent patients.[2] Studies have reported the following:

• In the Italian prospective multicenter study of rare tumors (TREP project), 16 patients were identified during a 14-year period. Eight patients had benign tumors (seven mucinous cystadenoma and one serous cystadenoma), and eight patients had borderline tumors (two serous and six mucinous).[3][Level of evidence C1] No malignant tumors were identified. High levels of cancer antigen 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. Seventy-nine percent of the patients had stage I disease, with a 100% survival rate. Only patients who had small cell anaplastic carcinomas died.[4][Level of evidence C1]
• A series of female patients younger than 19 years with borderline or malignant epithelial ovarian tumors in the Surveillance, Epidemiology, and End Results (SEER) Program database reported the following:[5]
  • There were 114 cases of borderline ovarian tumors identified. Of these, 53.5% were serous histology and 44.8% were mucinous histology. The 10-year overall survival (OS) rate was 97.3% for these patients.
  • There were 140 cases of malignant epithelial ovarian tumors identified. The median age of these patients was 17 years. Mucinous (56.4%) and serous (20.7%) adenocarcinoma were the most common histologies. Most patients had stage I disease (70.2%). Fertility-sparing surgery was commonly performed (rate of uterine preservation for stage I disease, 91.7%). The 5-year OS rate was 93.6% for patients with stage I disease, compared with 48.3% for those with extra-ovarian spread.

Girls with ovarian carcinoma (epithelial ovarian neoplasia) fare better than do adults with similar histology, probably because girls usually present with low-stage disease.[4,5]

The potential association with genetic predisposition (e.g., BRCA variant) in pediatric patients has not yet been studied.

Treatment of Childhood Epithelial Ovarian Neoplasia

Treatment options for nonmalignant childhood 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,[3] of the eight patients with benign tumors, seven patients had stage I disease, and one patient had stage III disease. Of the eight patients with borderline tumors, three patients had stage I disease, and five patients had stage III disease (based on washings and omental implants). All 16 patients were treated with surgery alone. At the time of the report, 15 patients were alive without disease; the one death was not from ovarian cancer.

Treatment options for childhood malignant ovarian epithelial cancer include the following:

1. Surgery.
2. Chemotherapy.

Treatment of malignant ovarian epithelial cancer is stage-related and follows adult protocols, which may include surgery and chemotherapy. For more information, see Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment.

References:

1. Childress KJ, Patil NM, Muscal JA, et al.: Borderline Ovarian Tumor in the Pediatric and Adolescent Population: A Case Series and Literature Review. J Pediatr Adolesc Gynecol 31 (1): 48-54, 2018.
2. Hazard FK, Longacre TA: Ovarian surface epithelial neoplasms in the pediatric population: incidence, histologic subtype, and natural history. Am J Surg Pathol 37 (4): 548-53, 2013.
3. Virgone C, Alaggio R, Dall'Igna P, et al.: Epithelial Tumors of the Ovary in Children and Teenagers: A Prospective Study from the Italian TREP Project. J Pediatr Adolesc Gynecol 28 (6): 441-6, 2015.
4. Tsai JY, Saigo PE, Brown C, et al.: Diagnosis, pathology, staging, treatment, and outcome of epithelial ovarian neoplasia in patients age < 21 years. Cancer 91 (11): 2065-70, 2001.
5. Nasioudis D, Alevizakos M, Holcomb K, et al.: Malignant and borderline epithelial ovarian tumors in the pediatric and adolescent population. Maturitas 96: 45-50, 2017.

Childhood Sex Cord–Stromal Tumors

General Information About Sex Cord–Stromal Tumors

Clinical presentation

The clinical presentation and prognosis of patients with sex cord–stromal tumors vary by histology. In all entities, metastatic spread occurs rarely and, if present, is usually limited to the peritoneal cavity.[1] Distant metastases mostly occur in patients whose disease has relapsed. Some tumors may be associated with hormone secretion—for example, estrogen in granulosa cell tumors or androgens in Sertoli-Leydig cell tumors.[2]

Diagnostic evaluation

In the United States, these tumors may be registered in the International Testicular and Ovarian Stromal Tumor Registry.[3] In Europe, patients are prospectively registered in the national rare tumor groups.[3,4] The recommendations regarding diagnostic work-up, staging, and therapeutic strategy have been harmonized between these registries.[3]

The European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project (Paediatric Rare Tumours Network - European Registry) has published comprehensive recommendations for the diagnosis and treatment of sex cord–stromal tumors in children and adolescents.[5]

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.[1] Histological 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 pathogenic variants and may be a manifestation of familial pleuropulmonary blastoma syndrome.[6] A two-institution study analyzed eight children aged 4 to 16 years who were diagnosed with Sertoli-Leydig cell tumors. All eight tumors were found to harbor somatic hotspot DICER1 variants, and five patients carried germline DICER1 pathogenic variants (two of them had the phenotype of DICER1 syndrome).[7] Individuals with Sertoli-Leydig cell tumor were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry.[8] In total, 191 participants with ovarian Sertoli-Leydig cell tumor were enrolled, with most presenting with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I disease (92%, 175 of 191 patients). Germline DICER1 variant testing results were available for 156 patients; 58% of these patients had a pathogenic or likely pathogenic germline variant. Somatic DICER1 variant testing showed RNase IIIB hotspot variants in 97% (88 of 91) of intermediate- and poorly differentiated tumors.

Prognostic factors

Prognostic factors related to stage and high mitotic count have been identified. In a report from the German Maligne Keimzelltumoren (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.[9]

A study of 44 patients from the European Cooperative Study Group on Pediatric Rare Tumors showed that stage and histopathologic differentiation determined the prognosis of patients with Sertoli-Leydig cell tumors.[10]

Individuals with Sertoli-Leydig cell tumor were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry.[8] In total, 191 participants with ovarian Sertoli-Leydig cell tumor were enrolled. Adjuvant chemotherapy was administered to 40% of patients (77 of 191). Among these patients, nearly all received platinum-based regimens (95%, 73 of 77), and 30% (23 of 77) received regimens that included an alkylating agent. The 3-year recurrence-free survival rate was 93.6% (95% confidence interval [CI], 88.2%–99.3%) for patients with stage IA tumors, compared with 67.1% (95% CI, 55.2%–81.6%) for patients with stage IC tumors and 60.6% (95% CI, 40.3%–91.0%) for patients with stage II to stage IV tumors (P < .001). Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements who were treated with surgery alone were at higher risk of recurrence (hazard ratio [HR], 74.18; 95% CI, 17.99–305.85).

Treatment of childhood sex cord–stromal tumors

Treatment options for childhood 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–stromal tumors.[2]

• Complete surgical resection was achieved in 23 of 38 girls who did not receive adjuvant treatment.
• Two patients who had a complete surgical resection had recurrent disease. 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 have a disease recurrence. Of the four patients who did not receive chemotherapy, all had a recurrence and two died.

Childhood Juvenile Granulosa Cell Tumors

The most common histological subtype of sex cord–stromal tumors in girls younger than 18 years is juvenile granulosa cell tumor (median age, 7.6 years; range, birth to 17.5 years).[11,12] 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.[1,13]

Risk factors

Juvenile granulosa cell tumors have been reported in children with Ollier disease and Maffucci syndrome.[14,15,16]

Clinical presentation

Patients with juvenile granulosa cell tumors present with the following symptoms:[17,18]

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

Treatment of childhood juvenile granulosa cell tumors

Treatment options for childhood juvenile granulosa cell tumors include the following:

1. Surgery.
2. Chemotherapy.

Surgery

As many as 90% of children with juvenile granulosa cell tumors will have low-stage disease (stage I) by FIGO criteria. These patients are usually curable with unilateral salpingo-oophorectomy alone. In one series, 15 of 17 patients underwent fertility-sparing surgery, and only two patients received adjuvant chemotherapy. No recurrences were reported.[19]

Chemotherapy

Patients with spontaneous tumor rupture or malignant ascites (FIGO stage IC2, IC3), advanced disease (FIGO stages II–IV), or tumors with high mitotic activity have a poorer prognosis and require chemotherapy.[2,4,13] Cisplatin-based chemotherapy regimens have been used with some success in both the adjuvant and recurrent disease settings.[4,11,20,21,22]

Childhood Sertoli-Leydig Cell Tumors

Clinical presentation and risk factors

Sertoli-Leydig cell tumor is a common histological subtype of sex cord–stromal tumors. It is rare in young girls and more frequently seen in adolescents. The tumor may secrete androgens and, thus, present with virilization, secondary amenorrhea,[23] or precocious puberty.[24]

These tumors may be associated with Peutz-Jeghers syndrome, but more frequently are a part of the DICER1-tumor spectrum.[6,25,26] Patients with Sertoli-Leydig cell tumors should be evaluated for germline DICER1 pathogenic variants. If a germline DICER1 pathogenic variant is found, regular follow-up for ovarian and other tumors such as thyroid disease (multinodular goiter, carcinoma) should be considered. Genetic counseling should also be considered.[26,27]

Treatment and outcome of childhood Sertoli-Leydig cell tumors

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

1. Surgery.
2. Chemotherapy.

Surgery

Surgery is the primary treatment for Sertoli-Leydig cell tumors and is the only treatment for low-stage disease (FIGO stage IA). The event-free survival rate for these patients is approximately 100%.[2][Level of evidence C1] However, up to 10% of patients may develop metachronous contralateral tumors, particularly in the context of underlying DICER1 germline pathogenic variants.[28]

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 in children.[2,10]

One study reported on 40 women (average age, 28 years) with FIGO stage I or IC Sertoli-Leydig cell tumors of the ovary.[29][Level of evidence C1]

• Of 34 patients with intermediate or poor differentiation, 23 patients received postoperative chemotherapy (most regimens included cisplatin). None of these patients experienced disease recurrence.
• Of the 11 patients who did not receive postoperative chemotherapy, two had disease recurrence. Both of these patients had tumors that were salvaged with chemotherapy.

References:

1. Schneider DT, Jänig U, Calaminus G, et al.: Ovarian sex cord-stromal tumors--a clinicopathological study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch 443 (4): 549-60, 2003.
2. Fresneau B, Orbach D, Faure-Conter C, et al.: Sex-Cord Stromal Tumors in Children and Teenagers: Results of the TGM-95 Study. Pediatr Blood Cancer 62 (12): 2114-9, 2015.
3. Schultz KA, Schneider DT, Pashankar F, et al.: Management of ovarian and testicular sex cord-stromal tumors in children and adolescents. J Pediatr Hematol Oncol 34 (Suppl 2): S55-63, 2012.
4. Schneider DT, Calaminus G, Harms D, et al.: Ovarian sex cord-stromal tumors in children and adolescents. J Reprod Med 50 (6): 439-46, 2005.
5. Schneider DT, Orbach D, Ben-Ami T, et al.: Consensus recommendations from the EXPeRT/PARTNER groups for the diagnosis and therapy of sex cord stromal tumors in children and adolescents. Pediatr Blood Cancer 68 (Suppl 4): e29017, 2021.
6. Schultz KA, Pacheco MC, Yang J, et al.: Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol 122 (2): 246-50, 2011.
7. Yang B, Chour W, Salazar CG, et al.: Pediatric Sertoli-Leydig Cell Tumors of the Ovary: An Integrated Study of Clinicopathological Features, Pan-cancer-Targeted Next-generation Sequencing and Chromosomal Microarray Analysis From a Single Institution. Am J Surg Pathol 48 (2): 194-203, 2024.
8. Nelson AT, Harris AK, Watson D, et al.: Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries. Gynecol Oncol 186: 117-125, 2024.
9. Schneider DT, Calaminus G, Wessalowski R, et al.: Ovarian sex cord-stromal tumors in children and adolescents. J Clin Oncol 21 (12): 2357-63, 2003.
10. Schneider DT, Orbach D, Cecchetto G, et al.: Ovarian Sertoli Leydig cell tumours in children and adolescents: an analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Eur J Cancer 51 (4): 543-50, 2015.
11. Calaminus G, Wessalowski R, Harms D, et al.: Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study. Gynecol Oncol 65 (3): 447-52, 1997.
12. Capito C, Flechtner I, Thibaud E, et al.: Neonatal bilateral ovarian sex cord stromal tumors. Pediatr Blood Cancer 52 (3): 401-3, 2009.
13. Wu H, Pangas SA, Eldin KW, et al.: Juvenile Granulosa Cell Tumor of the Ovary: A Clinicopathologic Study. J Pediatr Adolesc Gynecol 30 (1): 138-143, 2017.
14. Tanaka Y, Sasaki Y, Nishihira H, et al.: Ovarian juvenile granulosa cell tumor associated with Maffucci's syndrome. Am J Clin Pathol 97 (4): 523-7, 1992.
15. Sampagar AA, Jahagirdar RR, Bafna VS, et al.: Juvenile granulosa cell tumor associated with Ollier disease. Indian J Med Paediatr Oncol 37 (4): 293-295, 2016 Oct-Dec.
16. Littrell LA, Inwards CY, Hazard FK, et al.: Juvenile granulosa cell tumor associated with Ollier disease. Skeletal Radiol 52 (3): 605-612, 2023.
17. Kalfa N, Patte C, Orbach D, et al.: A nationwide study of granulosa cell tumors in pre- and postpubertal girls: missed diagnosis of endocrine manifestations worsens prognosis. J Pediatr Endocrinol Metab 18 (1): 25-31, 2005.
18. Gell JS, Stannard MW, Ramnani DM, et al.: Juvenile granulosa cell tumor in a 13-year-old girl with enchondromatosis (Ollier's disease): a case report. J Pediatr Adolesc Gynecol 11 (3): 147-50, 1998.
19. Bergamini A, Ferrandina G, Candotti G, et al.: Stage I juvenile granulosa cell tumors of the ovary: A multicentre analysis from the MITO-9 study. Eur J Surg Oncol 47 (7): 1705-1709, 2021.
20. Vassal G, Flamant F, Caillaud JM, et al.: Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 cases. J Clin Oncol 6 (6): 990-5, 1988.
21. Powell JL, Connor GP, Henderson GS: Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol 81 (1): 113-6, 2001.
22. Schneider DT, Calaminus G, Wessalowski R, et al.: Therapy of advanced ovarian juvenile granulosa cell tumors. Klin Padiatr 214 (4): 173-8, 2002 Jul-Aug.
23. Arhan E, Cetinkaya E, Aycan Z, et al.: A very rare cause of virilization in childhood: ovarian Leydig cell tumor. J Pediatr Endocrinol Metab 21 (2): 181-3, 2008.
24. Choong CS, Fuller PJ, Chu S, et al.: Sertoli-Leydig cell tumor of the ovary, a rare cause of precocious puberty in a 12-month-old infant. J Clin Endocrinol Metab 87 (1): 49-56, 2002.
25. Zung A, Shoham Z, Open M, et al.: Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome. Gynecol Oncol 70 (3): 421-4, 1998.
26. Schultz KA, Harris A, Messinger Y, et al.: Ovarian tumors related to intronic mutations in DICER1: a report from the international ovarian and testicular stromal tumor registry. Fam Cancer 15 (1): 105-10, 2016.
27. Schultz KAP, Williams GM, Kamihara J, et al.: DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clin Cancer Res 24 (10): 2251-2261, 2018.
28. Schultz KAP, Harris AK, Finch M, et al.: DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry. Gynecol Oncol 147 (3): 521-527, 2017.
29. Gui T, Cao D, Shen K, et al.: A clinicopathological analysis of 40 cases of ovarian Sertoli-Leydig cell tumors. Gynecol Oncol 127 (2): 384-9, 2012.

Childhood Small Cell Carcinoma of the Ovary, Hypercalcemia-Type

Small cell carcinomas of the ovary are exceedingly rare and aggressive.[1] The prognosis is poor for these patients. This cancer may be associated with hypercalcemia.[2]

Molecular Features

Somatic and germline SMARCA4 pathogenic variants have been reported in small cell carcinoma of the ovary, hypercalcemia-type. This finding suggests potential molecular and biological similarities to rhabdoid tumors.[3,4,5] However, one study of children with small cell carcinoma of the ovary, hypercalcemia-type, revealed that this tumor appears molecularly distinct from extracranial rhabdoid tumors with either SMARCA4 or SMARCB1 alterations. In this study, tumors underwent genomic analysis that included RNA sequencing (n = 11) and methylation profiling (n = 9). These findings support their continued classification as different tumor types.[6]

For more information about SMARCA4, visit Rhabdoid Tumor Predisposition Syndrome Type 2.

Treatment of Childhood Small Cell Carcinoma of the Ovary, Hypercalcemia-Type

Treatment options for childhood small cell carcinoma of the ovary, hypercalcemia-type, include the following:

1. Aggressive multimodality therapy.
2. Tazemetostat.

Aggressive multimodality therapy

Successful treatment has been reported in a few cases using aggressive therapy, including surgery and high-dose chemotherapy with stem cell rescue.[2,7,8,9][Level of evidence C1]

Tazemetostat

Tazemetostat is an EZH2 inhibitor that demonstrates activity against preclinical models of small cell carcinoma of the ovary with SMARCA4 loss.[10]

Evidence (tazemetostat):

1. Two patients with small cell carcinoma of the ovary and SMARCA4 loss were enrolled in a phase I trial of tazemetostat.[11]
   • One patient achieved a partial response, and one patient achieved prolonged stable disease.
   • The most common toxicities associated with tazemetostat were asthenia, anemia, anorexia, muscle spasms, nausea, and vomiting.

References:

1. Wens FSPL, Hulsker CCC, Fiocco M, et al.: Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Patient Characteristics, Treatment, and Outcome-A Systematic Review. Cancers (Basel) 15 (15): , 2023.
2. Distelmaier F, Calaminus G, Harms D, et al.: Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease. Cancer 107 (9): 2298-306, 2006.
3. Witkowski L, Goudie C, Foulkes WD, et al.: Small-Cell Carcinoma of the Ovary of Hypercalcemic Type (Malignant Rhabdoid Tumor of the Ovary): A Review with Recent Developments on Pathogenesis. Surg Pathol Clin 9 (2): 215-26, 2016.
4. Ramos P, Karnezis AN, Craig DW, et al.: Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 46 (5): 427-9, 2014.
5. Witkowski L, Carrot-Zhang J, Albrecht S, et al.: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 46 (5): 438-43, 2014.
6. Andrianteranagna M, Cyrta J, Masliah-Planchon J, et al.: SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type. J Pathol 255 (1): 1-15, 2021.
7. Pressey JG, Kelly DR, Hawthorne HT: Successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type. J Pediatr Hematol Oncol 35 (7): 566-9, 2013.
8. Christin A, Lhomme C, Valteau-Couanet D, et al.: Successful treatment for advanced small cell carcinoma of the ovary. Pediatr Blood Cancer 50 (6): 1276-7, 2008.
9. Kanwar VS, Heath J, Krasner CN, et al.: Advanced small cell carcinoma of the ovary in a seventeen-year-old female, successfully treated with surgery and multi-agent chemotherapy. Pediatr Blood Cancer 50 (5): 1060-2, 2008.
10. Chan-Penebre E, Armstrong K, Drew A, et al.: Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Mol Cancer Ther 16 (5): 850-860, 2017.
11. Italiano A, Soria JC, Toulmonde M, et al.: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 19 (5): 649-659, 2018.

Treatment Options Under Clinical Evaluation for Childhood Ovarian Cancer

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1- or SMARCA4-Deficient Tumors): This trial is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1- or SMARCA4-deficient tumors. Patients with small cell carcinomas of the ovary, hypercalcemia type, may be eligible for this study.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]

  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Latest Updates to This Summary (03 / 03 / 2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric ovarian cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Ovarian Cancer Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children's Cancer Center and Blood Disorders Harvard Medical School)
• William H. Meyer, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Ovarian Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/ovarian/hp/child-ovarian-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 31846269]

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Last Revised: 2025-03-03