Pediatric Teratomas and Other Germ Cell Tumors Workup
- Author: E Stanton Adkins, III, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
When a germ cell malignancy is suspected, tumor markers should be assessed prior to surgery. If the diagnosis is made after resection, marker studies should be performed as soon as possible thereafter. When tumor marker findings are positive, they should be monitored before each cycle of chemotherapy to determine the response to therapy and check for relapse.
Alpha-fetoprotein (AFP) is present in tumors with the following histologic features:
Fetal liver or endodermal sinus tumor elements
Endodermal sinus tumor
Beta–human chorionic gonadotropin (β -HCG) is present in tumors with the following histologic features:
Lactate dehydrogenase (LDH) isomer of LDH-1 is present in many tumors with the histologic features of an endodermal sinus tumor.
Once the diagnosis has been histologically confirmed, and if chemotherapy is needed, the following tests should be performed:
Complete blood count (CBC), differential, and platelet count
Glomerular filtration rate (GFR) or creatinine clearance rate - These are used to establish baseline renal function prior to platinum-based chemotherapy
Uric acid levels - These are used are used to assess the added risk from tumor lysis
Liver function tests - These include assessment of bilirubin, alkaline phosphatase, alanine aminotransferase, total protein, and albumin levels; they are used to assess possible metastases and determine baseline results prior to chemotherapy
Electrolytes, calcium, and magnesium levels - These should be monitored daily during chemotherapy, and deficiencies should be treated with supplements or changes in intravenous therapy
Diagnostic imaging is an essential part of initial staging, monitoring the response to therapy, and detecting relapse. Different modalities are appropriate at different points in the therapeutic course.
Chest radiography may be used at diagnosis to detect metastasis.
Computed tomography (CT) of the abdomen and pelvis is essential for the staging of abdominal and pelvic tumors at presentation. Follow-up studies may be performed after the third course of chemotherapy, at the conclusion of induction therapy, and at the conclusion of maintenance therapy to monitor the response. CT is needed at relapse to determine the extent and location of the disease.
Magnetic resonance imaging (MRI) of the abdomen and pelvis may be substituted for CT. If so, it should be used throughout therapy to maintain consistency in imaging studies. Yamaoka et al reported that among ovarian teratomas, mature tumors had imaging appearances typical of sebaceous fluid, whereas immature teratomas had multiple foci of fat as well as simple fluid-containing cysts. MRI has also been used to characterize cardiac tumors.
At diagnosis, chest CT is necessary to evaluate the presence and extent of metastatic disease that originates in the abdomen or pelvis. If a thoracic primary tumor is present, CT is used to assess the location and extent of the primary disease.
Bone scanning is a nuclear medicine test that is used to detect metastatic disease. It should be performed at presentation, as well as after the third course of chemotherapy, at the conclusion of induction therapy, and at the conclusion of maintenance therapy.
The remaining tests are optional and may be used as the clinical situation dictates.
CT or MRI of the brain should be performed whenever brain metastases are suspected.
Ultrasonography of the abdomen and pelvis may aid in the detection of ovarian tumor spread and in monitoring certain masses without the risk of ionizing radiation. Testicular ultrasonography may be useful for detecting microliths in testes contralateral to known tumors. These findings signify a high likelihood of neoplasia in situ.
Fluorodeoxyglucose (FDG) positron emission tomography (PET) appears to be most useful in the detection of relapse because other modalities cannot be used to detect the activity of the disease. The presence of elevated tumor marker levels, without the depiction of new disease on CT or MRI, is an indication for FDG-PET.
Pulmonary function studies, including diffusing capacity tests, are used to establish baseline function and determine the risk of bleomycin toxicity.
Brainstem auditory evoked responses (BAERs) or audiograms are assessed, depending on the patient's age, to establish baseline values prior to platinum-based chemotherapy.
Because germ cell tumors may be associated with chromosomal abnormalities (eg, Klinefelter syndrome, mediastinal germ cell tumors), genetic screening is advisable in many cases.
With mature teratoma, sampling of the entire tumor is necessary to ensure that no immature neural elements or occult foci of malignancy are present. The pathologist should evaluate the tumor at 1-cm intervals.
Histologic findings may include the following:
Immature teratoma - Grade 1, one low-power immature region per slide; grade 2, immaturity in four or fewer low-power fields per slide; grade 3, immaturity in more than four low-power fields per slide
Gliomatosis peritonei - These must be thoroughly evaluated at biopsy; if all glial elements are mature, no added risk is present
Germinoma, dysgerminoma, or seminoma - Sheets of polygonal cells separated by fibrous bands; stains with placental alkaline phosphatase in more than 80% of cases
Yolk sac tumor and endodermal sinus tumor - Most common malignancy within a teratoma; infiltrative tumor composed of pseudopapillary, reticular, solid, or vitelline cellular patterns
Choriocarcinoma - Syncytiotrophoblasts and cytotrophoblasts are present; heterozygosity is often absent
Embryonal carcinoma - Grossly smooth with cystic necrosis; anaplasia, mitotic figures, hemorrhage, necrosis; lack of Schiller-Duval bodies
Differentiation of the various subtypes of testicular germ cell tumors may be facilitated by immunohistochemical testing for molecular markers such as Aurora B, GPR30, Nek2, HMGA1, HMGA2, and others. Such markers could represent also useful novel molecular targets for antineoplastic strategies.
Staging of these tumors depends on the organ of origin.
Ovarian tumors are staged according to two different systems. The International Federation of Gynecology and Obstetrics/American Joint Committee on Cancer (FIGO/AJCC) staging system was initially developed for use in adults, and it is most relevant for epithelial malignancies. The Children's Oncology Group (COG) system is specific to germ cell tumors; it was developed specifically for pediatric tumors.
Testicular tumors are staged and treated according to a COG-specific system. Boys who have achieved sexual maturity have tumors that are staged and treated according to adult protocols.
In FIGO/AJCC stage I ovarian tumors, growth is limited to the ovaries. Subcategories are as follows:
IA - Limited to one ovary, no tumor on the external surface, capsule intact
IB - Limited to both ovaries, no tumor on the external surface, capsule intact
IC - Stage IA or IB with ascites or peritoneal washings that contain malignant cells, tumor on the surface, or ruptured capsule
In stage II, growth involves one or both ovaries, with pelvic extension.
In stage III, tumor involves one or both ovaries, with peritoneal implants outside the pelvis or positive retroperitoneal or inguinal nodes. Superficial liver metastasis indicates stage III disease. Tumor is limited to the true pelvis, but histologically proven malignant extension to small bowel or omentum is present.
In stage IV, growth involves one or both ovaries, with distant metastases. If pleural effusion is present, cytologic findings must be positive to indicate stage IV disease. Parenchymal liver metastasis indicates stage IV disease.
In the COG system, ovarian tumors are staged as follows:
Stage I - Tumor is limited to one or both ovaries; peritoneal fluid and washings are negative for tumor; no clinical, radiographic, or histologic evidence of disease is present beyond the ovaries; tumor marker levels return to the reference range after an appropriate postsurgical half-life decline; the presence of gliomatosis peritonei does not worsen the stage
Stage II - Microscopic residual or positive lymph nodes (< 2 cm as measured by pathologist) are present; peritoneal fluid or washings are negative for malignant cells; tumor markers are positive or negative
Stage III - Lymph node or nodes with malignant metastatic nodule (>2 cm as measured by a pathologist) are present; gross residual or biopsy only; contiguous visceral involvement (omentum, intestine, or bladder) is observed; peritoneal washings are positive for malignant cells; tumor markers are positive or negative
Stage IV - Distant metastases, including liver metastases, are present
Testicular tumors are staged as follows:
Stage I - Limited to testis; tumor markers normal after appropriate half-life decline
Stage II - Transscrotal orchiectomy; microscopic disease in scrotum or high in spermatic cord (< 5 cm from proximal end); retroperitoneal lymph node involvement (< 2 cm); increased tumor marker levels after appropriate half-life decline
Stage III - Retroperitoneal lymph node involvement (>2 cm); no visceral or extra-abdominal involvement
Stage IV - Distant metastases; liver metastases
Extragonadal germ cell tumors are staged as follows:
Stage I - Complete resection at any site; en-bloc coccygectomy for sacrococcygeal site; normal tumor margins; tumor marker levels normal or elevated
Stage II - Microscopic residual disease; lymph nodes normal; tumor marker levels normal or elevated
Stage III - Gross residual disease or biopsy only; retroperitoneal nodes normal or involved with metastatic disease; tumor marker levels normal or elevated
Stage IV - Distant metastases, including those to the liver
The COG has proposed modifying their risk classification system to more accurately reflect current knowledge of pediatric germ cell tumors. Those modifications are being tested in current protocols. Treatment groups will undoubtedly be revised as more knowledge is obtained.
As more is learned about the molecular biology of these tumors, risk stratification is likely to be based less on the site of origin or tumor type and more on the molecular abnormalities of each specific tumor.
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