Doctor123.org

Germ Cell Tumors, Pediatric

Basics

Description

- Prophylactic gonadectomy is recommended for streak gonads in the specific syndromes mentioned above because of the increased risk of developing GCTs. - Guidelines on the management of cryptorchidism recommend the following to decrease the future risk of testicular GCT: - Orchidopexy by 18 months of age - Consideration of orchiectomy of an undescended testis in all boys with a normal contralateral testis when orchidopexy is not feasible - Consider orchiectomy or biopsy in a post pubertal boy with cryptorchidism. - Counsel all men with a history of cryptorchidism and/or their parents regarding the long-term risk of testicular cancer.

Germ cell tumors (GCTs) are a heterogeneous group with a suspected common cell of origin, the primordial germ cell.

  • Their location can be gonadal or extragonadal.
  • The numerous histologic subtypes are broadly classified as mature or immature teratomas and malignant GCTs.
  • See "Brain Tumor" chapter for primary CNS GCT.

Epidemiology

The incidence has a bimodal distribution with a smaller peak in early infancy and a larger peak in adolescence.

  • In children younger than 15 years of age, GCTs occur at a rate of 2.4 cases per million children, and they account for 2-3% of all malignancies.
  • Between 15 and 19 years of age, extracranial GCTs account for approximately 14% of cancer diagnoses.
  • Teratomas and germinomas are the predominant histologic subtypes of early infancy and adolescence respectively.
  • Sacrococcygeal teratomas account for 50% of childhood teratomas. They are most prevalent in infants (1:40,000 live births); with a female predominance (4:1)

Risk Factors

  • Sex chromosome abnormalities are associated with an increased risk for GCTs.
  • Klinefelter syndrome is associated with an increased risk of mediastinal GCTs.Approximately 50% of adolescent mediastinal GCTs are associated with a cytogenetic diagnosis of Klinefelter syndrome.
  • Turner syndrome with any portion of Y chromosome material, Swyer syndrome, nonscrotal partial androgen insensitivity, Frasier syndrome, and males with Denys-Drash syndrome are all associated with streak gonads at increased risk for developing GCTs.
  • History of cryptorchidism is associated with an increased risk of testicular GCT.

Genetics

Familial GCT has been described in 1.5-2% of adult GCTs and a similar contribution to adolescent GCTs is presumed.

General Prevention

  • Prophylactic gonadectomy is recommended for streak gonads in the specific syndromes mentioned above because of the increased risk of developing GCTs.
  • Guidelines on the management of cryptorchidism recommend the following to decrease the future risk of testicular GCT:Orchidopexy by 18 months of ageConsideration of orchiectomy of an undescended testis in all boys with a normal contralateral testis when orchidopexy is not feasibleConsider orchiectomy or biopsy in a post pubertal boy with cryptorchidism.Counsel all men with a history of cryptorchidism and/or their parents regarding the long-term risk of testicular cancer.

Etiology

  • GCTs are hypothesized to originate from primordial germ cells containing neoplastic genetic aberrations.
  • Arrested migration of primordial germ cells is presumed to explain the midline location of extragonadal GCTs.
  • The postpubertal peak in the incidence of GCTs suggests hormonal factors are involved in their growth.
  • Isochromosome 12p or i(12)p is present in more than 80% of postpubertal GCTs. GCTs without the i(12)p typically have gain of 12p chromosomal material.Mature and immature ovarian tumors are biologically distinct in their lack of association with the i(12)p.A number of other genetic mutations have been observed in testicular GCTs.
  • Malignant GCTs in children younger than age 4 years typically contain cytogenetic abnormalities of chromosomes 1, 3, 6, and others.The i(12)p is rarely seen in this group.Deletion of 1q36 is present in 80-100% of infantile malignant GCTs in testicular and extragonadal sites.Recurrent genetic changes of infantile yolk sac tumors include loss of 6q24-qter, gain of 20q and 1q, loss of 1p, and c-myc or n-myc amplification.

Diagnosis

History

  • Acute or chronic abdominal pain is the presenting symptom in up to 80% of ovarian GCTs.Vaginal bleeding, amenorrhea, and constipation may also be present.
  • Pediatric testicular tumors typically present as nontender scrotal masses.
  • GCTs can present with severe, acute abdominal or testicular pain secondary to gonadal torsion.
  • A history of abnormal sexual development may be an indication of an underlying sex chromosome abnormality associated with an increased risk of a GCT.
  • Sacrococcygeal teratomas typically present with swelling.Pregnancies may be associated with polyhydramnios or high-output cardiac failure.Other congenital anomalies are seen in up to 18% of patients.
  • Mediastinal tumors can present with respiratory compromise in younger children, whereas adolescents may have a more insidious presentation.

Physical Exam

  • A palpable abdominal mass may be present with an ovarian GCT.
  • A palpable nontender testicular mass is typical of testicular GCT.
  • Sacrococcygeal GCTs can present with a palpable mass or signs of spinal cord compression.
  • Especially in younger children, a mediastinal GCT may present with potentially critical respiratory compromise or superior vena cava syndrome.
  • Inappropriate absence or presence of sexual development may be seen with hormonally active GCTs.

Diagnostic Tests & Interpretation

Lab

  • Serum tumor markers include AFP and beta-hCG help to diagnose, monitor, and stage GCTs.An acute rise can be seen after initiating chemotherapy.
  • Workup should include a CBC and differential, chemistry panel, liver function tests, uric acid, and LDH to evaluate for other malignancies or organ dysfunction.

Imaging

  • Plain radiograph: may reveal mature calcified tissues, such as bone or teeth, within tumor
  • Chest radiograph: shows mediastinal mass
  • CT scan: necessary to evaluate the primary site and regional disease
  • Transscrotal ultrasound: initial imaging of testicular mass, can reveal calcifications or heterogenous features.
  • Prenatal MRI: helpful for prenatal counseling and preoperative planning of fetal sacrococcygeal teratomas
  • Chest CT and bone scan: indicated to evaluate for metastatic disease when malignancy is suspected

Diagnostic Procedures

Tissue is mandatory, since histology is essential to the classification of GCTs.

Pathologic Findings

  • GCTs are broadly classified as teratomas or malignant GCTs.
  • Teratomas contain elements of all three germ cell layers (ectoderm, mesoderm, and endoderm).They can be mature, immature, or immature with malignant elements.
  • Major malignant histologic subtypes include yolk sac tumor, embryonal carcinoma, gonadoblastoma, choriocarcinoma, and mixed malignant GCT.Histologic subtype does not necessarily correlate with tumor biology, patient age, site of origin, or patient prognosis.

Differential Diagnosis

  • Sacrococcygeal: pilonidal cyst, meningocele, lipomeningocele, hemangioma, abscess, bone tumor, epidermal cyst, chondroma, lymphoma, ependymoma, neuroblastoma, glioma
  • Abdominal: Wilms tumor, neuroblastoma, lymphoma, rhabdomyosarcoma, hepatoblastoma, retained twin fetus
  • Vaginal: rhabdomyosarcoma (sarcoma botryoides), clear cell carcinoma
  • Ovarian: cyst, appendicitis, pregnancy, pelvic infection, hematocolpos, sarcoma, lymphoma, other ovarian tumors
  • Testicular: epididymitis, testicular torsion, infarct, orchitis, hernia, hydrocele, hematocele, rhabdomyosarcoma, lymphoma, leukemia, other testicular tumors
  • Mediastinal: Hodgkin and non-Hodgkin lymphoma, leukemia, thymoma

Treatment

Medication

  • The administration of chemotherapy is based on malignant potential, local tumor extent, surgical outcomes, and the patient's medical history.
  • The typical 1st-line chemotherapy regimen for malignant GCTs includes cisplatin, etoposide, and bleomycin or PEB.Cyclophosphamide in addition to PEB is being investigated in the treatment of high-risk GCTs.Cisplatin is associated with a risks of ototoxicity and nephrotoxicity.PEB therapy is associated with a risk of secondary myelodysplasia or acute myeloid leukemia.Bleomycin is associated with a risk of pulmonary toxicity.

Surgery/Other Procedures

  • Every effort should be made to preserve fertility in gonadal teratomas. An experienced pediatric-gynecology oncologic surgeon is critical.
  • Sacrococcygeal teratomaA complete surgical resection including the coccyx is curative.Close postoperative follow-up should include monitoring of tumor markers.Fetal surgery should be considered if signs of hydrops are seen.
  • Mature teratomaFull surgical excision, irrespective of site, is curative in prepubescent patients.Postpubescent patient with testicular teratoma (mature or immature) is at risk for retroperitoneal metastatic recurrence, so adjuvant chemotherapy and retroperitoneal lymph node resection are additional treatment considerations.
  • Immature teratomaComplete surgical resection is therapy of choice; close observation and tumor marker evaluation for normalizationIn cases of elevated AFP and incomplete surgical resection, chemotherapy should be offered given risk of microscopic foci of endodermal sinus tumor.
  • Teratoma with malignant componentsSurgery plus chemotherapy with etoposide, cisplatin or carboplatin, and bleomycinPatients with residual disease should have additional surgery and additional chemotherapy if total resection is not possible.High-dose chemotherapy with autologous stem cell support and radiation are reserved for salvage therapy in recurrent disease.

Ongoing Care

  • Serial physical exams and imaging studies of primary site
  • Tumor markers (AFP or β-hCG) if elevated at diagnosis
  • If chemotherapy or radiation therapy used, need to monitor for secondary malignancies, long term (See "Cancer Therapy Late Effects" chapter); short term, need to monitor blood counts, chemistries, renal function, and audiology

Additional Reading

  • Barksdale EM, Obokhare I. Teratomas in infants and children. Curr Opin Pediatr. 2009;21(3):344-349. [View Abstract]
  • Hedrick HL, Flake AW, Crombleholme TW, et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediar Surg. 2004;39(3):430-438. [View Abstract]
  • Koulouris CR, Penson RT. Ovarian stromal and germ cell tumors. Semin Oncol. 2009;36(2):126-136. [View Abstract]
  • Lakhoo K. Neonatal teratomas. Early Hum Dev. 2010;86(10):643-647. [View Abstract]
  • Mannuel HD, Hussain A. Update on testicular germ cell tumors. Curr Opin Oncol. 2010;22(3):236-241. [View Abstract]

Codes

ICD09

  • 199.1 Other malignant neoplasm without specification of site
  • 238.0 Neoplasm of uncertain behavior of bone and articular cartilage
  • 164.9 Malignant neoplasm of mediastinum, part unspecified
  • 183.0 Malignant neoplasm of ovary

ICD10

  • C80.1 Malignant (primary) neoplasm, unspecified
  • D48.0 Neoplasm of uncertain behavior of bone/artic cartl
  • C38.3 Malignant neoplasm of mediastinum, part unspecified
  • C56.9 Malignant neoplasm of unspecified ovary

SNOMED

  • 402878003 Germ cell tumor (disorder)
  • 281561000 Sacrococcygeal teratoma (disorder)
  • 278042005 Malignant teratoma of mediastinum (disorder)
  • 254869000 malignant germ cell tumor of ovary (disorder)

FAQ

  • Q: What is the chance of cure for immature/malignant teratomas?
  • A: With current chemotherapy as outlined earlier, overall survival is 85-97% (dependent on disease stage).
  • Q: Can a benign tumor recur? If so, can it then be malignant?
  • A: Yes. If there is residual tissue left behind, the tumor can recur. If there were unrecognized areas of malignancy, the recurrence can be a malignant teratoma. The greatest risk for the latter is with the immature teratomas.