Basics
Description
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 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.
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 teratoma
- A 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 teratoma
- Full 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 teratoma
- Complete surgical resection is therapy of choice; close observation and tumor marker evaluation for normalization
- In cases of elevated AFP and incomplete surgical resection, chemotherapy should be offered given risk of microscopic foci of endodermal sinus tumor.
- Teratoma with malignant components
- Surgery plus chemotherapy with etoposide, cisplatin or carboplatin, and bleomycin
- Patients 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.