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Gonadal (Testicular and Ovarian Tumors)

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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Gonadal (Testicular and Ovarian Tumors)

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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Gonadal (Testicular and Ovarian Tumors)

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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Gonadal (Testicular and Ovarian Tumors)

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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Gonadal (Testicular and Ovarian Tumors)
Embryonic Gonads Mesenchymal Tissue

APPENDIX:

  • A – 1
  • Histogenesis of the Gonadal Tumors

  • Primordial germ cell
  • Celomic epithelium

:

  • Dysgerminoma
  • Sex-cord stromal

tumors
Epithelial tumors
Embryonal differentiation Embryonal carcinoma

Extra-embryonic tumors
Endodermal sinus tumor

  • Choriocarcinoma
  • Embryonic tumors

Teratoma Polyembryoma

Distribution and Characteristics of Germ Cell Tumors: Germ Cell Tumor

  • Median Age
  • Pathology
  • Clinical

Presentation

Gonadal

  • Pre-adolescents & Dysgerminomas
  • Palpable abdominal

  • mass
  • Ovarian
  • adolescents
  • Yolk sac tumors

  • (10 – 14 years)
  • Immature teratoma

Malignant mixed germ cell tumors Embryonal carcinomas
Abdominal distention Varying degree of acute or chronic abdominal pain. - depending on patient age, histology and the presence of ovarian torsion

Infants Adolescents
Endodermal sinus tumor (yolk sac)

  • teratomas
  • Testicular

Irregular, non tender scrotal mass

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Gonadal (Testicular and Ovarian Tumors)

Germ Cell Tumor

  • Median Age
  • Pathology
  • Clinical

Presentation

Extragonadal

  • Infancy
  • Endodermal sinus tumor (Yolk sac)

Embryonal
Variable – depending upon

  • location and histology
  • Sacrococcygeal

Benign Teratoma Immature Malignant

  • Children
  • Teratoma
  • Coughing

Mediastinal anterior superior

  • Adolescents
  • Embryonal carcinoma

Endodermal sinus tumor (yolk sac) Choriocarcinoma
Wheezing Dyspnea Chest pain especially in large

  • tumors
  • posterior

Under 2 years

Children

  • Benign or malignant
  • Abdominal pain

Constipation Urinary difficulties
Abdominal Retroperitoneum Stomach Omentum Liver

  • Germinomas
  • Headaches

Intracranial Pineal Suprasellar Infrasellar
Non-germinomas Mixed with yolk sac Choriocarcinoma Teratocarcinoma
Visual disturbances Incoordination Diabetes Insipidus Hypopituitaris, Anorexia Precocious puberty

  • Infants
  • Usually benign
  • Variable, depending upon

  • location
  • Head and Neck

Oral cavity Pharynx Orbit Neck Upper jaw

  • Under 3 years
  • Usually malignant
  • Blood-tinged vaginal

  • discharge
  • Vaginal

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

Go Back

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Gonadal (Testicular and Ovarian Tumors)

  • 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

Tumors of infants and young children
Increased copies if the x chromosome Diploidy and tetraploidy Presence of i(12p) in some pineal tumors 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) 80% Stage I with 75% survival rate with surgery alone advanced disease requires multimodal therapy Associated with sexual maldevelopment syndrome Treatment of choice -Bilateral resection of the gonads
Teratocarcinoma Gonadoblastoma
Late teens 5 to 10 years

  • ----
  • Others (Seminoma, mixed germ

cell tumor, choriocarcinoma) rare in children

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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Gonadal (Testicular and Ovarian Tumors)

  • Testicular Cancer Staging System
  • A – 4

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
Transscrotal orchiectomy with gross spill of the tumor Microscopic disease in scrotum or high in spermatic cord (< 5cm from proximal end)
Stage II
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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Gonadal (Testicular and Ovarian Tumors)

Clinical Features of Pediatric Ovarian Tumors:

Median Age Features

A – 5

Tumor

  • Dysgerminoma
  • 16 years
  • Rapid development

Highly radiosensitive with excellent survival rates 14-25% with other germ cell elements  AFP, 75% Stage I high risk for relapse chemotherapy given to all patients
Endodermal sinus tumor 18 years 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 cell tumor

  • 16 years
  • 40% pre-menarche; 30% sexually precocious

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; choriocarcinoma)

  • -----
  • Rare in children

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

Go Back

  • 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)

Go Back

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Gonadal (Testicular and Ovarian Tumors)

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

  • Stage I:
  • Tumor limited to the Ovaries

Stage IA: Stage IB: Stage IC:
Limited to 1 ovary; no ascites. No tumor on external surface; capsule intact Limited to both ovaries; no ascites. No tumor on external surfaces; capsule intact 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: Stage IIB Stage IIC:
Extension and/or metastases to uterus and/or tubes only. Extension to other pelvic tissues 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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  • Mature Teratomas

    Mature Teratomas

    MATURE TERATOMAS 30% Ovarian tumors Mostly dermoid cysts May be seen at any age Complications: infection, torsion, rupture with pseudomalignant change outside ovary, melanosis peritonei, hemolytic anemia, limbic encephalitis Dermoid Cyst Dermoid Cyst Dermoid Cyst with Abundant Brain Dermoid Cyst Sieve –Like Pattern Cerebellum Fetal Cartilage (not immature!) Selected Home Truths 1. If it looks like a fibroid grossly do not put through any sections. You will just end up confused! (AT Hertig, M.D.) 2. Nothingggg looks more malignant on high power than normal proliferative endometrium (AT Hertig, M.D.) 3. If it grossly looks like a dermoid cyst, it is a dermoid cyst! UNCOMMON TISSUES IN DERMOID Salivary gland 16% Thyroid 13% GI epithelium 12% Lung 3% Retina 2% PttProstate 1% Pituitary 1% Pancreas 1% From Blackwell et al. Am J Obset Gynecol 51:151, 1946 MALIGNANT CHANGE IN DERMOID CYST • About 1% of cases, disproportionately in postmenopausal years • Great majjyority are sq uamous cell carcinoma • Others are mostly melanoma and rare sarcomas • Thorough sampling to show association with dermoid can be crucial • Theoretically includes mucinous tumors but by convention they are considered separately Squamous Cell Ca in Dermoid Squamous Cell Ca in Dermoid Struma with Dermoid Cystic Struma Cystic Struma Cystic Struma Solid Struma Struma Carcinoid Insular Carcinoid PRIMITIVE GERM CELL TUMORS Dysgerminoma Yolk sac tumor Embryonal carcinoma Choriocarcinoma Immature Teratoma Polyembryoma Mixed forms (mostly 1 and 2) Remember some, mostly 1, arise out
  • Klinefelter Syndrome and Germ Cell Tumors: Review of the Literature Kimberley Bonouvrie1,2 , Jutte Van Der Werff Ten Bosch2,3 and Machiel Van Den Akker2,3*

    Klinefelter Syndrome and Germ Cell Tumors: Review of the Literature Kimberley Bonouvrie1,2 , Jutte Van Der Werff Ten Bosch2,3 and Machiel Van Den Akker2,3*

    Bonouvrie et al. International Journal of Pediatric Endocrinology (2020) 2020:18 https://doi.org/10.1186/s13633-020-00088-0 REVIEW Open Access Klinefelter syndrome and germ cell tumors: review of the literature Kimberley Bonouvrie1,2 , Jutte van der Werff ten Bosch2,3 and Machiel van den Akker2,3* Abstract Objective: The most common presentation of Klinefelter syndrome (KS) is infertility and features of hypogonadism. Currently no consensus exists on the risk of malignancy in this syndrome. Several case reports show an incidence of extragonadal germ cells tumors (eGCT) of 1.5 per 1000 KS patients (OR 50 against healthy population). Malignant germ cell tumors are rare in children. They account for 3% of all children cancers. Young patients with a germ cell tumor are not routinely tested for Klinefelter syndrome. This can therefore result in underdiagnosing. Literature data suggest a correlation between eGCT and KS. To the best of our knowledge there is no precise description of the primary locations of germ cell tumors in KS patients. The purpose of this study is to evaluate age groups and primary locations of extragonadal germ cell tumors in Klinefelter patients. With this data we investigate whether it is necessary to perform a cytogenetic analysis for KS in every eGCT patient. Study design: This study is based on case report publications in PubMed/Medline published until march 2020 that described “Klinefelter Syndrome (MeSH) AND/OR extragonadal germ cell tumors”. Publications were included when patients age, location and histology of the germ cell tumor was known. Two double blinded reviewers selected the studies.Results: 141 KS patients with eGCTs were identified.

  • OVARIAN GERM CELL TUMORS Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines

    OVARIAN GERM CELL TUMORS Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines OVARIAN GERM CELL TUMORS Executive Summary Ovarian germ cell tumors (OGCTs) are derived from primordial germ cells of the ovary. These tumors affect both adults and children and therefore the recommendations apply to the EML lists for both adults and children (regimen distinctions are included in the present briefing). OGCTs include dysgerminomas and nondysgerminomas, which are subdivided to immature teratoma, embryonal cell carcinoma, yolk sac tumors, primary ovarian (nongestational) choriocarcinomas, polyembryoma, and mixed germ cell tumors. OGCTs comprise of 2-3% of all malignant ovarian tumors registered globally, with highest rates in young women of 15 to 30 years old [1]. Since 1990, the standard regimen for OGCT treatment has been a combination of bleomycin, etoposide and cisplatin, referred to as “BEP” regimen. The standard of care in the United States, Europe, and other high-income settings is a combination of the three chemotherapy agents plus surgery. This allows to achieve a survival rate of 95-100% at 5 years among patients receiving adjuvant BEP regimen after surgery for stage I disease, and 70-85% among patients with metastatic disease (II-IV stages) on BEP regimen [2,3]. The chance of survival without chemotherapy is 0%. Addition of filgrastim to chemotherapy when a patients’ absolute neutrophil count decreases to less than 500 prevents the occurrence of severe neutropenia and infection. Using filgrastim helps to maintain appropriate dose intensity, which is vital in the treatment of germ cell tumors, as well as other curable tumors.

  • Therapeutic Challenges for Cisplatin-Resistant Ovarian Germ Cell Tumors

    cancers Review Therapeutic Challenges for Cisplatin-Resistant Ovarian Germ Cell Tumors Ugo De Giorgi 1,*, Chiara Casadei 1, Alice Bergamini 2, Laura Attademo 3, Gennaro Cormio 4, Domenica Lorusso 5, Sandro Pignata 3 and Giorgia Mangili 2 1 Department of Medical Oncology and Hematology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; [email protected] 2 Department of Obstetrics and Gynaecology, San Raffaele Scientific Institute, 20132 Milan, Italy; [email protected] (A.B.); [email protected] (G.M.) 3 Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80138 Naples, Italy; [email protected] (L.A.); [email protected] (S.P.) 4 Gynecologic Oncology Unit, IRCCS Istituto Oncologico Giovanni Paolo II, 70124 Bari, Italy; [email protected] 5 Gynecologic Oncology Unit, Department of Woman, Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; [email protected] * Correspondence: [email protected] Received: 28 August 2019; Accepted: 15 October 2019; Published: 17 October 2019 Abstract: The majority of patients with advanced ovarian germ cell cancer are treated by cisplatin-based chemotherapy. Despite adequate first-line treatment, nearly one third of patients relapse and almost half develop cisplatin-resistant disease, which is often fatal. The treatment of cisplatin-resistant disease is challenging and prognosis remains poor. There are limited data on the efficacy of specific chemotherapeutic regimens, high-dose chemotherapy with autologous progenitor cell support and targeted therapies. The inclusion of patients in clinical trials is strongly recommended, especially in clinical trials on the most frequent male germ cell tumors, to offer wider therapeutic opportunities.