Gonadal (Testicular and Ovarian Tumors)

Authors: Ayda G. Nambayan, DSN, RN, St. Jude Children’s Research Hospital Erin Gafford, Pediatric Oncology Education Student, St. Jude Children’s Research Hospital; Nursing Student, School of Nursing, Union University Content Reviewed by: Guillermo L. Chantada, MD, Hospital JP Garrahan, Buenos Aires, Argentina Cure4Kids Release Date: 1 September 2006

At 4 weeks gestation, germ cells begin to develop in the yolk sac in an undifferentiated state. These primordial germ cells migrate to the gonadal ridge by the 6th week of gestation, and descend into the pelvis or scrotal sac.This migratory route explains the midline location of most extra-gonadal germ cell tumors (intracranial, mediastinal, retroperitoneal or sacrococcygeal).

(A -1 ) Germ cell neoplasms arise either from the primordial germ cells (gonadal) or indirectly through embryonic or extra-embryonic differentiation (extra-gonadal). The stromal tumors arise from the primitive sex cords of either the ovary or the testicles, and the rare epithelial tumors arise from the coelomic epithelium that have undergone neoplastic transformations.

Though the morphology of each type of germ cell tumor is similar in all locations (whether gonadal or extragonadal), the morphologic type and biological characteristics vary depending on the site of origin and age of the patient. There are three (A – 2) biologically distinct subsets of germ cell tumors: - tumors of the adolescent testis and ovary - extragonadal germ cell tumors of older children - tumors of infants and young children

Testicular Germ Cell Tumors:

Approximately 7% of all germ cell tumors are testicular and 75% of all (A – 3) testicular tumors have a germ cell origin. Though 90% are localized, metastatic disease can occur in the lymph nodes of the chest and retroperitoneum.

Risk factors include undescended testes; and patients who have orchidopexy should be examined for occurrence of testicular tumors. Most commonly, patients present with a painless, irregular scrotal mass, often associated with hydroceles or inguinal hernias.

Most testicular tumors are noted during routine examination or observed by the child’s caretaker. These tumors are irregular, non-tender scrotal masses. In some cases, a hydrocele and inguinal hernia may also be present.

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Diagnostic Workup:

 Complete history of illness to evaluate for associated symptoms such as constipation, vomiting, genitourinary symptoms.  Physical exam to assess for masses, inguinal hernias, hydoceles  Ultrasound to determine cystic versus solid characteristics and detect calcifications; localize the scrotal mass, and differentiate between simple and reactive hydrocele.  Assessment of serum tumor markers AFP and β-hCG, which are often elevated, since most testicular tumors are of the yolk pathology. These serum markers serve as the basis for staging and monitoring treatment efficacy.  Metastatic evaluation including CT scan, and ultrasound of the pelvis, abdomen and pelvis; chest X-ray, and bone scintigraphy.

Staging for Testicular Cancers:

A (A – 4) staging system developed by the Pediatric Oncology Group and the Children’s Cancer Group that accounts for tumor markers and the trans-scrotal surgery of the tumors.

Ovarian Tumors:

Ovarian tumors represent approximately 1% of childhood malignancies and are often seen during the first and second decades of life. Two -thirds of all ovarian tumors are of germ cell origin, most commonly benign teratomas. (A – 5) Malignant ovarian tumors include dysgerminoma, yolk sac (endodermal sinus), embryonal carcinoma, mixed germ cell tumor, and immature teratoma.

Patients often complain of abdominal distention, varying degrees of acute and chronic abdominal pain, and a palpable abdominal mass. Other symptoms include enuresis, constipation, amenorrhea, precocious puberty, and vaginal bleeding.

Diagnostic Workup:

 Complete history of illness to evaluate for associated symptoms such as vaginal bleeding, amenorrhea, and a review of the menstrual history, if applicable, should be done.  Physical exam to assess for (A – 6) abdominal mass and presence of secondary sex characteristics (presence of precocious puberty)  Ultrasound to evaluate pelvic masses, localize adnexal masses, differentiate between solid and cystic masses, and to detect calcifications.  Abdominal and pelvic CT scans to define the site of origin, tumor extent, presence of calcifications, fat and metastatic disease  Assess serum tumor markers AFP, β-hCG, carcinoembryonic antigen, and CA-125. These serum markers serve as basis for staging and monitoring treatment efficacy.  Metastatic evaluation by CT scan, ultrasound of the pelvis, abdomen and pelvis, chest X- ray, CT and bone scintigraphy. CNS imaging may be necessary in patients with disseminated disease.

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Staging for Ovarian Cancers:

A staging system currently used for ovarian cancers in the adult population developed by the (A-7) International Federation of Gynecology and Obstetrics (FIGO) serves as a basis for a simpler system being used by the (A-8) Pediatric Oncology Group/Children’s Cancer Group (POG\CCG) in their cooperative studies.

Treatment:

Treatment for germ cell tumors should be multimodal and individualized. Surgical resection is the treatment of choice in treating benign germ cell tumors and is also important in treating malignant tumors if removal does not sacrifice vital structures. In cases of tumors that are unresectable, chemotherapy can sometimes be used to debulk some tumors so that they can be resected. Young patients with completely excised testicular yolk sac tumors whose AFP values return to normal after surgery, may be managed without adjuvant therapy and monitored closely with serial AFP levels for early detection of relapse.

Standard agents currently used in the Germ Cell Tumor Protocols include cisplatin (platinol), etoposide (VP – 16), and bleomycin (PEB). Newer agents include ifosfamide (Ifex), carboplatin, and topotecan. Even though dysgerminomas are exquisitely radiosensitive, this modality has been recently replaced by chemotherapy in most cases. The introduction of effective chemotherapy has greatly improved the prognosis of germ cell tumors. Relapsing patients with chemosensitive disease can be rescued with higher dose chemotherapy.

Future Directions:

The challenges for germ cell tumors include further understanding these diverse tumors through risk groupings, identification of molecular and genetic alterations associated with these tumors, and the development of novel therapies with lower toxicity and fewer late effects than current drugs.

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Helpful Web links:

Lucile Packard Children’s Hospital at Stanford, Palo Alto, CA http://www.lpch.org/diseaseHealthInfo/healthLibrary/oncology/gct.html

St. Jude Children's Research Hospital http://www.stjude.org/disease-summaries/0,2557,449_2167_7407,00.html eMedicine.com – Teratomas and Other Germ Cell Tumors http://www.emedicine.com/ped/topic3023.htm eMedicine.com - Germ Cell Tumors http://www.emedicine.com/med/topic863.htm

The National Cancer Institute This website contains comprehensive information on extracranial germ cell tumors. http://jncicancerspectrum.oxfordjournals.org/cgi/pdq/jncipdq;CDR0000062854

Related www.Cure4kids.org Seminars

Seminar #658 Ovarian Masses in Pediatric Age Groups Himesh Gupta, MD, Stephen Shochat, MD, Joseph D. Khoury, MD and Fredric Hoffer, MD https://www.cure4kids.org/seminar/658

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APPENDIX:

A – 1 Histogenesis of the Gonadal Tumors

Embryonic Gonads Mesenchymal Tissue

Primordial germ cell Celomic epithelium : Dysgerminoma Sex-cord stromal Epithelial tumors tumors Embryonal differentiation Embryonal carcinoma

Extra-embryonic tumors Endodermal sinus tumor Embryonic tumors Choriocarcinoma Teratoma Polyembryoma

Distribution and Characteristics of Germ Cell Tumors:

Germ Cell Median Age Pathology Clinical Tumor Presentation

Gonadal Pre-adolescents & Dysgerminomas Palpable abdominal Ovarian adolescents Yolk sac tumors mass (10 – 14 years) Immature teratoma Abdominal distention Malignant mixed germ cell tumors Varying degree of acute Embryonal carcinomas or chronic abdominal pain. - depending on patient age, histology and the presence of ovarian torsion

Infants Endodermal sinus tumor (yolk sac) Testicular Adolescents teratomas Irregular, non tender scrotal mass

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Germ Cell Median Age Pathology Clinical Tumor Presentation

Extragonadal Infancy Endodermal sinus tumor (Yolk sac) Variable – depending upon Sacrococcygeal Embryonal location and histology Benign Teratoma Immature Malignant

Children Teratoma Coughing Mediastinal Adolescents Embryonal carcinoma Wheezing anterior Endodermal sinus tumor (yolk sac) Dyspnea superior Choriocarcinoma Chest pain especially in large posterior tumors

Under 2 years Benign or malignant Abdominal pain Abdominal Constipation Retroperitoneum Urinary difficulties Stomach Omentum Liver Children Germinomas Headaches Intracranial Non-germinomas Visual disturbances Pineal Mixed with yolk sac Incoordination Suprasellar Choriocarcinoma Diabetes Insipidus Infrasellar Teratocarcinoma Hypopituitaris, Anorexia Precocious puberty

Infants Usually benign Variable, depending upon Head and Neck location Oral cavity Pharynx Orbit Neck Upper jaw Under 3 years Usually malignant Blood-tinged vaginal Vaginal discharge

Castleberry, R. et.al. Germ Cell Tumors in Principles and Practice of Pediatric Oncology, Pizzo, P. and Poplack, D. (Eds). Lippincott-Raven Press

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A – 2 Biological Subsets and corresponding molecular\genetic alterations

Biological Subsets Molecular and genetic alterations Testis: C-kit expression Tumors of the adolescent testis and ovary Multiple copies of i(12p) LOH 12q13, 12q22, 11p13, 11p15 K-ras and N-ras mutation

Ovary: C-kit expression MGF expression Aneuploidy Extra-gonadal germ cell tumors of older children Increased copies if the x chromosome Diploidy and tetraploidy Presence of i(12p) in some pineal tumors Tumors of infants and young children Biologic similarity between gonadal and extragonadal tumors Diploid with normal karyotypes Chromosomal abnormalities in 1, 3 and 6 Deletion of 1p36

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A – 3 Clinical Features of Pediatric Testicular Tumors

Tumor Type Median Age Clinical Features Endodermal Sinus Tumor 2 years Most common malignant tumor of the testes AFP, tumors are histologically pure 85% are in stage I chemotherapy used in higher stage and recurrent disease Teratoma 3 years Histologically poorly differentiated – amenable to surgery alone

Embryonal Carcinoma Late teens Uncommon in young children AFP + hCG managed with lymphadenectomy + chemotherapy + radiation therapy (based on stage) Teratocarcinoma Late teens 80% Stage I with 75% survival rate with surgery alone advanced disease requires multimodal therapy Gonadoblastoma 5 to 10 years Associated with sexual maldevelopment syndrome Treatment of choice -Bilateral resection of the gonads Others (Seminoma, mixed germ ---- rare in children cell tumor, choriocarcinoma) Castleberry, R. et.al. Germ Cell Tumors in Principles and Practice of Pediatric Oncology, Pizzo, P. and Poplack, D. (Eds). Lippincott-Raven Press

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A – 4 Testicular Cancer Staging System Pediatric Oncology Group/Children’s Cancer Group (POG/CCG)

Stage Extent of Disease Stage I Limited to the testes Complete resection by high inguinal orchiectomy or transscrotal orchiectomy without spill No clinical, radiographic, or histologic evidence of disease beyond the testes Tumor markers normal after appropriate post-surgical half-life decline; patients with normal or unknown markers at diagnosis must have a negative ipsilateral retroperitoneal node dissection to confirm Stage I Stage II Transscrotal orchiectomy with gross spill of the tumor Microscopic disease in scrotum or high in spermatic cord (< 5cm from proximal end) Retroperitoneal lymph node involvement (< 2cm) Increased tumor markers after appropriate half life Stage III Retroperitoneal lymph node involvement (>2cm) No visceral or extra-abdominal involvement Stage IV Distant metastases including the liver

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A – 5 Clinical Features of Pediatric Ovarian Tumors:

Tumor Median Age Features Dysgerminoma 16 years Rapid development Highly radiosensitive with excellent survival rates 14-25% with other germ cell elements Endodermal sinus tumor 18 years  AFP, 75% Stage I high risk for relapse chemotherapy given to all patients Teratoma Mature (solid, cystic) 10 -15 years Surgery mainstay of treatment Neuroglial implants may occur with solid or cystic types

Immature 11 -14 years Amount of neuroepithelium determines grade Prognosis inversely related to stage and grade  AFP in 30% of cases Embryonal carcinoma 14 years 47% prepubertal; hCG and precocious puberty present; chemotherapy indicated Malignant mixed germ 16 years 40% pre-menarche; 30% sexually precocious cell tumor AFP and hCG may be increased Gonadoblastoma 8 – 10 years Associated with dysgenetic gonads and sexual maldevelopment; treatment of choice – removal of both gonads Other (polyembryoma; ----- Rare in children choriocarcinoma) Castleberry, R. et.al. Germ Cell Tumors in Principles and Practice of Pediatric Oncology, Pizzo, P. and Poplack, D. (Eds). Lippincott-Raven Press

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A – 6 Ovarian Mass – presence of a pelvic mass, right lower quadrant

Resected Ovarian Mass - teratoma (Himesh Gupta, MD, St. Jude Children's Research Hospital)

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A – 7 International Federation of Gynecology and Obstetrics (FIGO) Staging for Ovarian Tumors

Stage I: Tumor limited to the Ovaries

Stage IA: Limited to 1 ovary; no ascites. No tumor on external surface; capsule intact Stage IB: Limited to both ovaries; no ascites. No tumor on external surfaces; capsule intact Stage IC: Limited to one or both ovaries; tumor present on surface of one or both ovaries; or with capsule ruptured; or with positive ascites or positive peritoneal washings.

Stage II: Tumor involving one or both ovaries with pelvic extension

Stage IIA: Extension and/or metastases to uterus and/or tubes only. Stage IIB Extension to other pelvic tissues Stage IIC: As in IIA or IIB with positive ascites or positive peritoneal washings; or with capsule ruptured.

Stage III: Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes; extension to small bowel or omentum; superficial liver metastases.

Stage IIIA: Limited to true pelvis grossly with negative nodes but histologically confirmed microscopic seeding of abnormal peritoneal surfaces. Stage IIIB: Limited to one or both ovaries with negative nodes but histologically confirmed implants of abdominal peritoneal surfaces, none > 2 cm in diameter. Stage IIIC Abdominal implants >2cm diameter and/or positive retroperitoneal or inguinal nodes.

Stage IV: Tumor of one or both ovaries with distant metastases outside the peritoneal cavity; parenchymal liver metastases; pleural effusion, if present, must have positive cytology.

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A – 8 Staging of Ovarian Germ Cell Tumors: Pediatric Oncology Group (POG) /Children’s Cancer Group (CCG)

Stage Extent of Disease Stage I Limited to ovary or ovaries; peritoneal washings negative for malignant cells No clinical, radiographic, or histological evidence of disease beyond ovaries Tumor markers normal after appropriate post surgical half-life decline The presence of gliomatosis peritonei (peritoneal nodules composed of glial cells with no malignant elements) does not upstage patient. Stage II Microscopic residual or positive lymph nodes (<2cm) Peritoneal washings negative for malignant cells Tumor markers positive or negative The presence of gliomatosis peritonei does upstage patient Stage III Lymph node with malignant metastatic nodule (>2cm) Gross residual or biopsy only Contiguous viscera; involvement of omentum, intestines, bladder Peritoneal washings positive for malignant cells Tumor markers positive or negative Stage IV Distant metastases including liver

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Acknowledgments:

Cure4Kids.org International Outreach Program St. Jude Children's Research Hospital 332 N. Lauderdale St. Memphis, TN 38105-2794

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