Extragonadal Germ Cell Tumors
Author: Issam Makhoul, MD, Assistant Professor, Department of Medicine, Division of
Hematology/Oncology, University of Arkansas for Medical Sciences
Coauthor(s): Brendan Curti, MD, Consulting Staff, Department of Medicine, Division of
Hematology-Oncology, The Oregon Clinic; Kush Sachdeva, MD, Private Practice, Souther
Oncology Hematology Associates, South Jersey Hospital system June 30, 2004
Background: Extragonadal germinal cell syndromes are rare tumors affecting predominantly
young males. They are characterized by their location on the midline from the pineal gland to the
coccyx. They produce a rich symptomatology and may reach large volumes if they arise in silent
areas. Histologically, they mirror their gonadal counterparts with which they share the same
chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result
in high rates of long-term survival and even cure.
Pathophysiology: Controversy remains regarding the origin of extragonadal germ cell tumors
(EGGCTs). These tumors can be found anywhere on the midline, particularly the
retroperitoneum, the anterior mediastinum, the sacrococcyx, and the pineal gland. Other less
common sites include the orbit, suprasellar area, palate, thyroid, submandibular region, anterior
abdominal wall, stomach, liver, vagina, and prostate. The classical theory suggests that germ cell
tumors (GCTs) in these areas are derived from local transformation of primordial germ cells
misplaced during embryogenesis.
A recent alternative theory suggests that primary mediastinal presentations represent reverse
migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in
origin. According to this theory, the differences in phenotypes expressed by mediastinal germ
cell tumors (MGCTs) and gonadal GCTs may be explained by differences in the cellular
environment between the gonad and the anterior mediastinum. Some retroperitoneal EGGCTs
may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the
primary tumour.
To explain the origin of CIS cells, 2 models have been proposed. The first suggests that fetal
gonocytes whose development into spermatogonia is blocked may undergo abnormal cell
division and then invasive growth mediated by postnatal and pubertal gonadotrophin stimulation.
The second model postulates that the most likely target cell for transformation is the zygotenepachytene spermatocyte. During this stage of germ cell development, aberrant chromatid
exchange events associated with crossing over can occur. Normally, these cells are eliminated by
apoptosis. In occasional cells this crossing over may lead to increased 12p copy number and
overexpression of cyclin D2. The cell carrying this abnormality is relatively protected against
apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of cell cycle
and genomic instability.
Malignant transformation of germ cells is the result of a multistep process of genetic changes.
One of the earliest events is the increased copy number of 12p, either as 1 or more copies of
i(12p) or as tandem duplications of chromosome arm 12p. This abnormality is found in CIS
lesions as well as more advanced disease. Further studies indicate that the CCND2 gene is
present at chromosome band 12p13 and CCND2 is overexpressed in most GCTs, including CIS.
Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S
checkpoint.
Hematologic malignancies frequently are associated with MGCTs. Embryologically,
hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up
30% of MGCTs, providing a possible basis for this association.
Recently the balance of the p53-mdm2 interaction was shown to be disrupted in intracranial
germ cell tumors (ICGCTs). mdm2 sequesters p53 and inhibits its function as G1-S checkpoint
controller and apoptosis inducer. In normal cells, mdm2 availability is controlled by ARF, the
product of the p14ARF gene located on INK4a/ARF locus, which binds with mdm2 and induces
its degradation. Mutation of ARF, reported in 71% of ICGCTs, results in mdm2 accumulation
and functional impairment of p53. This abnormality was reported in 90% of seminomatous and
55% of nonseminomatous intracranial germ cell tumors (NS-ICGCTs) examined.
Frequency:

In the US: EGGCTs represent 5-10% of all GCTs.

Internationally: In Norway, a recent study by Dueland et al estimated the incidence of
EGGCTs at 0.5 per 100,000 per year. This represents about 2% of the number of
testicular cancers reported for the same period. ICGCTs represent 0.3-3.4% of primary
intracranial tumors in Western countries and 2.1-12.7% in Japan.
Mortality/Morbidity: For patients receiving intensive chemotherapy, 5-year survival rates of
40-65% have been reported. Extragonadal seminomas carry the best survival rates. Mortality due
to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal
germ cell tumors (NS-EGGCTs).

Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors
(NS-GCTs) 60-70%. NS-GCTs include yolk-sac tumors, embryonal carcinomas,
choriocarcinomas, teratomas, and nonteratomatous combined GCTs.

The most common site of EGGCTs is the mediastinum (50-70%) followed by the
retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than
5%).

Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in
45%, sarcoma in 5%, and viable germ cell cancer in 26%. However, the smaller the
residual mass, the lower the chance that it harbors viable tumor cells.
Sex: In children, benign and malignant EGGCTs occur equally in males and females. In adults,
only benign EGGCTs (teratomas) occur at equal frequency in both sexes; more than 90% of
malignant EGGCTs occur in males.
History: Symptoms vary depending on the site and the size of the tumor. Those arising in
nonvital organs can reach large sizes before becoming symptomatic, but small tumors may result
in significant symptoms if they obstruct, compress, or rupture into important structures.

Mediastinal germ cell tumors
o
The mediastinum is the most common site of EGGCTs (50-70%). MGCTs
account for 1-15% of adult anterior mediastinal tumors. Mature teratomas
represent 60-70% of MGCTs. Malignant MGCTs (30-40%) are divided between
seminomas (40%) and NS-GCTs (60%). Although 90-100% of malignant GCTs
are symptomatic, only 50% of teratomas produce symptoms. Nonseminomatous
mediastinal germ cell tumors (NS-MGCTs) are faster growing and metastasize
earlier than mediastinal seminomas.
o
Although their incidence peaks in the third decade, several cases have been
reported in patients older than 60 years.
o
MGCT patients may present with (in decreasing order) chest pain, dyspnea,
superior vena cava syndrome, cough, postobstructive pneumonia, weight loss,
fever, night sweats, dysphagia, shoulder or arm pain, vocal cord paralysis, and
hoarseness. In one third of patients the anterior mediastinal mass is an incidental
finding of a routine chest x-ray (in most of these cases a benign tumor is found).
o
Metastases to locoregional lymph nodes or to distant sites, such as the lungs,
liver, or bone, may be present in 20-50% of cases on presentation. Distant
metastases are seen only in malignant MGCTs.
o
Mature teratoma rupture, teratoma with malignant transformation, and
hematologic malignancies may complicate MGCTs (see Complications).

Retroperitoneal germ cell tumors
o
The second most common site of EGGCTs (30-40%), after the mediastinum, is
the retroperitoneum. Retroperitoneal germ cell tumors (RGCTs) represent 10% of
all malignant primary retroperitoneal tumors.
o
Often patients with RGCTs present late, after their tumors have reached large
dimensions.
o
Presenting symptoms are abdominal mass with or without pain, backache, and
weight loss. Loss of ejaculation was reported in one case.

Intracranial germ cell tumors
o
Very rare tumors of the adolescent and young adult, ICGCTs are localized
preferentially to the pineal and suprasellar regions. However, other midline
structures can be involved. Although seminomas (60% of ICGCTs) have a
predilection for the suprasellar region, embryonal carcinomas, yolk-sac tumors,
and choriocarcinomas mainly occur in the pineal region.
o
Pineal tumors present with headache, nausea, and vomiting because of increased
intracranial pressure; they require early ventriculoperitoneal (VP) shunting.
Deterioration of intellectual functions, gait abnormalities with frequent falls, and
sphincteric incontinence are common. Choreic movements and ataxia of the limbs
with spastic weakness appear in later stages of Parinaud syndrome.
o
In suprasellar tumors, precocious pseudopuberty, diabetes insipidus with or
without anterior pituitary dysfunctions (eg, adrenocorticotropic hormone [ACTH]
deficiency), central hypothyroidism, growth hormone (GH) deficiency, and
hypogonadism may be seen. Decreased visual acuity, visual field defect, diplopia,
obesity, psychosis, and obsessive-compulsive symptoms also have been reported.
o
Recently, a case of primary spinal seminoma was reported in a patient with
Klinefelter syndrome.

Sacrococcygeal germ cell tumors
o
In the literature to date, 17 cases have been reported.
o
Pain and bowel habit change are the main symptoms. Severe arthropathy of
peripheral joints and evidence of hypertrophic osteoarthropathy were reported in
one case.

Extragonadal germ cell cancer syndrome
o
Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in
young males. Histologically, these tumors are poorly differentiated carcinomas
with atypical features.
o
The germ cell origin of these tumors is suggested by the typical abnormalities of
chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG)
and/or alpha-fetoprotein (AFP).
Physical: Complete physical examination is required.

MGCTs may be silent. Dullness caused by atelectasis or pleural effusion and localized
wheezes because of airway compression may be present.

A large abdominal mass may be palpated in RGCTs.

In suprasellar ICGCTs, decreased visual acuity and visual field defects, obesity, or signs
of endocrine deficiencies may be present.

In pineal tumors, Parinaud syndrome (ie, paralysis of conjugate upward gaze, slightly
dilated pupils that react on accommodation but not to light, with a lesion at the level of
the superior colliculi) can be present. Gait abnormalities, papilledema, and grasp reflex
because of hydrocephalus are present variably. Plantar reflexes are sometimes extensor.
Lab Studies:

Tumor markers bhCG and AFP
o
These tumor markers provide diagnostic, staging, and prognostic information.
Check these levels before and then at regular intervals after therapy.
o
Choriocarcinoma, embryonal carcinoma, and a minority of seminomas (<10%)
produce bhCG. Neoplasms with which bhCG elevation can be seen are prostate,
bladder, ureteral, and renal cancers. The levels of bhCG in the cerebrospinal fluid
of patients with primary ICGCT were elevated more frequently than in the plasma
before treatment and became detectable prior to any increase of the serum values
in case of relapse.
o
AFP elevations are seen in yolk-sac tumors and embryonal carcinoma. Pure
seminomas and pure choriocarcinomas do not produce AFP. Pregnancy,
hepatocellular carcinoma, cirrhosis, and hepatitis also may be associated with
increased levels of AFP.

o
The half-life of bhCG is 24 hours, and that of AFP is 4-6 days.
o
AFP, bhCG, or both are elevated in approximately 85% of NS-GCTs.
Lactate dehydrogenase (LDH) is a nonspecific marker. Its level correlates well with the
tumor burden and with the number of i(12p) copies.

Placental alkaline phosphatase is used in some centers as a marker and is useful in the
immunohistochemical characterization of midline tumors.

Cytogenetic analysis of patients with MGCTs reveals trisomy 8 in 16% of cases and
Klinefelter syndrome (XXY) in 14-20% of cases. However, the most common karyotype
abnormality is i(12p), present in 38% of patients. The presence of this abnormality helps
identify midline GCTs presenting as poorly differentiated carcinomas with atypical
features.

Obtain baseline evaluation of pituitary function (ie, thyroid-stimulating hormone,
cortisol, GH, follicle-stimulating hormone, luteinizing hormone, prolactin) before
treatment and then at regular intervals in patients with ICGCTs.

Evaluation of blood counts, liver function tests, and kidney functions before therapy and
after recovery is necessary.
Imaging Studies:

Testicular ultrasound: This should be ordered whenever a malignant GCT is diagnosed to
rule out a gonadal primary.

CT scan of the chest, abdomen, and pelvis
o
Mature teratomas appear as heterogeneous cystic, well-defined, anterior
mediastinal masses with walls of different thicknesses. Calcifications are present
in approximately one quarter, with a bone or a tooth rarely identifiable. The
combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior
mediastinal mass is highly specific for mature teratoma.
o
Seminomas present as bulky, lobulated, homogeneous, anterior mediastinal
masses. Although invasion of adjacent organs is uncommon, metastases to
regional lymph nodes and bone can be seen. Calcifications are rare.
o
NS-MGCTs appear as irregular, anterior mediastinal masses, often with
extensive, central heterogeneous areas of low attenuation caused by necrosis,
hemorrhage, and/or cyst formation. Adjacent organ involvement and metastases
to regional lymph nodes as well as to distant sites may occur.

Chest x-ray shows enlargement of the mediastinum on the anteroposterior view. The
lateral view reveals the anterior location of the mass.

CT scan or MRI of the brain shows pineal seminoma as a discrete mass that usually
reaches 3-4 cm in diameter. It compresses the superior colliculi and sometimes the
superior surface of the cerebellum and narrows the sylvian aqueduct. Obstructive
hydrocephalus may be evinced by the presence of dilated ventricles and interstitial
edema.
Other Tests:

Assess neuropsychologic status in children before they undergo cranial radiation and at
regular intervals thereafter.

Perform formal visual examination in patients with suprasellar/hypothalamic tumors.

Biopsy of the tumor mass
o
Histologic confirmation of GCT may be obtained by open biopsy of an abdominal
mass, anterior median sternotomy of a mediastinal mass, and neuroendoscopy of a
pineal tumor. Fine-needle aspiration frequently establishes the diagnosis,
obviating the need for open biopsy. Pathologic studies help determine the
histologic subtype, the presence of non–germ cell elements, or the rare cases of
marker-positive non–small cell lung cancer.
o
Tumor marker elevation in the appropriate clinical setting makes the diagnosis of
GCTs highly likely. Chemotherapy can be initiated in these cases without tissue
diagnosis if a need for immediate treatment is present.
Histologic Findings: EGGCTs show the same histologic features as gonadal GCTs.
Staging: Clinical staging of MGCT

Stage I - Well-circumscribed tumor with or without focal adhesions to the pleura or
pericardium but without microscopic evidence of invasion into adjacent organ

Stage II - Tumor confined to the mediastinum with macroscopic and/or microscopic
evidence of infiltration into adjacent structures

Stage III - Tumor with metastases
o
Stage IIIA - With metastases to intrathoracic organs
o
Stage IIIB - With extrathoracic metastases
Medical Care: Treatment modality is determined by the site and the histologic type of the
primary tumor. Seminomas are very sensitive to chemotherapy and radiotherapy. NS-GCTs are
less sensitive to these modalities and may require surgery for resection of a postchemotherapy
residual mass. Prior to the availability of cisplatin-based chemotherapy, cure rates for NS-GCTs
were less than 10%. Surgery is the only treatment for teratomas.

MGCTs: Cisplatin-based chemotherapy has made a significant improvement in treatment
of seminoma of the mediastinum.
o
Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the
current standard of care. Radiotherapy can be used after chemotherapy in bulky
mediastinal seminomas.
o
In NS-MGCT, 4 cycles of BEP also are recommended. If the serum tumor
markers remain elevated, give salvage chemotherapy. If the CT scan shows
residual disease with or without tumor marker elevation, perform surgical
resection followed by 2 cycles of chemotherapy. The nature of the salvage and
postsurgical chemotherapy remains debated. Intensive cisplatin-based
chemotherapy followed by resection of residual tumor was shown to yield
survival rates of 48-73% in NS-MGCTs.
o
Walsh et al reported on the experience at M. D. Anderson Cancer Center over 5
years with 20 patients treated for NS-MGCTs. Of those treated, 11 patients had
received no prior chemotherapy, and 9 patients were referred following treatment
at other facilities for salvage therapy after progression of their tumors.

Patients received combination chemotherapy with alternating sequential
courses comprising, first, bleomycin, vincristine, and cisplatin (BOP);
followed in 7 days by cisplatin, cyclophosphamide, doxorubicin
(Adriamycin) (CISCA); followed in 14 days by cisplatin, vincristine,
methotrexate, and bleomycin (POMB); followed in 10 days by
actinomycin, cyclophosphamide, and etoposide (ACE).

In addition to this regimen, etoposide, ifosfamide, and cisplatin (VIP) also
were used in the salvage group.

Major toxic effects occurred in all these patients, including neuropathy,
ototoxicity, mucositis, cytopenias, and renal toxicity.

The 2-year survival rate of the entire group was 58%. However, the 2-year
survival rate for the previously untreated group was 72%, whereas it was
39% for the salvage group.

Intensification of the chemotherapy was achieved by decreasing the
interval between cycles and by alternating drugs from course to course.
This was made possible by the systemic use of hematopoietic growth
factors. Stem cell rescue has been used in certain centers to achieve dose
intensification.
o
Recently, data from 75 patients treated at Indiana University for NS-MGCTs were
analyzed.

Of those treated, 48 patients received BEP, 9 patients received VIP, 9
patients received VIP/Velban (vinblastine) and bleomycin (VeB), and the
rest were treated with different cisplatin-containing regimens.

No significant difference in survival was reported between those who
received BEP and those who received VIP.

Of the 62 patients (58%) who underwent surgical resection of a residual
mass, 36 are long-term survivors. Overall survival rate for the group is
48%.

None of the 17 patients whose disease relapsed after or progressed on
first-line chemotherapy and surgery could achieve complete remission
despite salvage therapy with cisplatin-based regimens, high-dose
chemotherapy, paclitaxel, or oral etoposide.

ICGCTs: The standard treatment for ICGCTs has been radiotherapy, either alone
(seminomas) or in combination with chemotherapy (NS-GCTs).
o
A wide range of survival rates (37-100%) is reported after radiation. However,
because of its long-term toxicity, attempts were made to use lower doses of
craniospinal irradiation (CSI) in combination with chemotherapy. Regardless of
the type of the initial treatment, combined modality therapy comprising radiation
and chemotherapy is the recommended salvage therapy for relapse.
o
Radiation therapy varies in intensity from CSI with boost (the most intense), to
whole brain irradiation with boost, ventricular irradiation with boost, and focal
irradiation alone (the least intense).
o
Event-free survival rate (EFS) of 90% for patients with seminomas who received
only CSI was reported by Calaminus et al. Chemotherapy alone resulted in an
EFS of 53%, although the follow-up period was short and the number of patients
was limited in this group. Patients receiving combined modality achieved an EFS
of about 92%. In nonseminomas, EFS was affected by the cumulative dose of
cisplatin. Patients who received a cumulative dose of 400 mg/m2 had an EFS of
86%. Those who received 200 mg/m2 had a significantly lower EFS, 56%. The 2
groups were observed for 46 and 65 months, respectively.
o
Balmaceda and colleagues reported on 71 patients treated by chemotherapy alone
for ICGCTs (45 seminomas and 26 NS-GCTs). Diagnosis was established by
resection (approximately 50% of patients) or biopsy. Patients were evaluated after
4 cycles of carboplatin, etoposide, and bleomycin. If complete response (CR) was
achieved, 2 more cycles were given. Surgery alone resulted in 3 CR. Of 68
patients, 39 achieved CR after chemotherapy alone. Of the 29 patients with partial
response (PR), 10 achieved CR with intensified chemotherapy and 3 more after
second surgery, bringing the number of CRs to 55 (78%). Although response to
chemotherapy was not affected by the histologic type (81% for nonseminomas vs
82% for seminomas), long-term survival differed significantly by histologic type
(84% for seminomas vs 62% for nonseminomas). Treatment mortality rate was
10%.
o
The optimal role for surgery remains to be defined. Because of the risk of
intraspinal metastases related to surgery or even to stereotactic biopsy, a sandwich
protocol using preoperative chemotherapy, followed by surgery, then
postoperative chemotherapy was suggested. Surgery is indicated only if a residual
mass is present after chemotherapy. Such a protocol uses BEP preoperatively and
VIP postoperatively. The tumor marker elevation in NS-GCT obviates the need
for surgical biopsies.
o
Third ventriculostomy via neuroendoscopy can be performed to drain obstructive
hydrocephalus. This procedure prevents peritoneal seeding related to VP shunt.

RGCTs: Primary chemotherapy with 4 cycles of BEP is recommended for both
seminomas and nonseminomas, with excision of residual mass in nonseminomas.
o
Pectasides reported on 16 patients with RGCTs, 11 with NS-GCTs and 5 with
seminomatous GCTs. Cisplatin-based (or carboplatin-based) chemotherapy
resulted in complete or PR in 14 patients. Ten patients underwent surgery,
bringing the number of patients with CR to 14 (87.5%); 9 of them are long-term
survivors (56.25%).
o
Nichols recommends primary abdominal radiotherapy for patients with smallvolume retroperitoneal seminomas (abdominal mass <5 cm) and chemotherapy
for patients with larger volume disease (abdominal mass >10 cm). Patients with
intermediate disease may be treated with either modality.

Sacrococcygeal GCTs have a poor prognosis. Long-standing remission is attained in only
31% of patients treated with multiagent chemotherapy.
Surgical Care: Surgery is the primary and only effective modality in teratomas. It also is used as
primary or secondary treatment of NS-EGGCTs. The current standard of care is surgery if a
residual mass is present after neoadjuvant chemotherapy. Used in this setting, chemotherapy
allows translation of PRs into CRs and evaluation of the chemosensitivity of the tumor.
However, the size of residual mass for which surgery is indicated remains controversial. In the
experience at the Memorial Sloan-Kettering Cancer Center, 5 of 20 patients underwent surgery
for residual mass after receiving chemotherapy or radiotherapy for retroperitoneal seminoma. No
viable seminoma was found in masses less than 3 cm. Therefore, they recommend surgical
resection for residual tumors greater than 3 cm to ascertain the need for subsequent
chemotherapy.
No further chemotherapy is recommended if the final pathology is consistent with mature
teratoma or necrotic tissue. Additional postoperative chemotherapy is given if the patient is
found to have viable tumors. Although the same chemotherapy used preoperatively may be used
after surgery, it is reasonable to switch to another drug combination.
The surgical resection should include all gross disease with en bloc resection of all involved
structures that can be sacrificed. Orchiectomy or testicular biopsy is not required unless testicular
examination and/or ultrasound findings are suggestive or frankly abnormal.

MGCT: Midline sternotomy is the most common approach, followed by posterolateral
thoracotomy. Partial pericardial resection is required in most cases. Thymectomy is
performed routinely because the thymus often is replaced totally by tumor. Dissection of
the aorta and sometimes resection of certain veins occasionally are required to achieve
complete resection.

RGCT: Midline, transverse, or oblique transperitoneal approaches have been used to
remove RGCTs. Excision via a thoracoabdominal extraperitoneal approach has been
suggested recently. The alleged benefits of this approach are more ready removal of the
primary tumor and its possible intrathoracic extensions, avoidance of paralytic ileus, and
decreased risk of ejaculatory dysfunction.

Pineal GCT: En bloc resection of the pineal mass is performed via the supracerebellar
infratentorial approach.
Drug Category: Chemotherapeutic agents -- Regardless of the tumor location and whenever
chemotherapy is considered, a BEP combination is the treatment of choice (BEP for 4 cycles at
3-wk intervals). VIP has been used as salvage therapy for progressive disease or as postoperative
therapy following resection of residual mass containing viable tumor. Vinblastine occasionally
has replaced etoposide if the latter was used in the initial regimen.
Cisplatin (Platinol) -- Platinum-containing
compound that exerts antineoplastic effect by
covalently binding to DNA with preferential
binding to N-7 position of guanine and adenosine.
Can react with 2 different sites on DNA to
Drug Name
produce cross-links. Platinum complex also can
bind to nucleus and cytoplasmic protein. A
bifunctional alkylating agent, once activated to
aquated form in cell it binds to DNA, resulting in
interstrand and intrastrand cross-linking.
Modify dose on basis of CrCl. Avoid use if CrCl
<60 mL/min.
Adult Dose
Pediatric Dose
20 mg/m2/d IV infusion over 20-60 min for 5 d
q21d
Not established
Documented hypersensitivity; preexisting renal
Contraindications insufficiency; myelosuppression; hearing
impairment
Increases toxicity of bleomycin and ethacrynic
Interactions
acid; aminoglycosides and amphotericin B
increase nephrotoxicity; bleomycin, cytarabine,
methotrexate, and ifosfamide may accumulate
because of decreased renal excretion; may
enhance cytotoxicity of etoposide; mesna and
sodium thiosulfate directly inactivate cisplatin;
dipyridamole increases cytotoxicity by enhancing
cellular uptake
Pregnancy
D - Unsafe in pregnancy
Administer adequate hydration before and for 24
h after dosing to reduce risk of nephrotoxicity;
adverse effects include bone marrow suppression,
nausea, vomiting, mucositis, and high-frequency
hearing loss; major dose-limiting toxic effect is
peripheral neuropathy; can cause acute or chronic
Precautions
renal failure in as many as one third of patients
treated, but usually can be prevented by vigorous
hydration and saline diuresis; renal tubular
wasting of potassium and magnesium are
common (monitor closely); cellulitis and fibrosis
rarely have occurred after extravasation; avoid
aluminum needles
Etoposide (Toposar, VePesid) -- Inhibits
topoisomerase II and causes DNA strand
breakage, causing cell proliferation to arrest in
Drug Name
late S or early G2 portion of cell cycle. Prodrug
activated by dephosphorylation.
Reduce dose in hepatic (increased total bilirubin
[TB]) and renal (decreased CrCl) impairment.
100 mg/m2 IV daily for 5 d; repeat cycle every 3
wk
Adult Dose
TB 1.5-3 mg/dL: 50% dose reduction
TB 3.1-4.9 mg/dL: 75% dose reduction
TB >5 mg/dL: Avoid use
CrCl 15-50 mL/min: 25% dose reduction
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; IT administration
may cause death
May prolong effects of warfarin and increase
clearance of methotrexate; has additive effects
with cyclosporine in cytotoxicity of tumor cells;
Interactions
clearance decreased by high dose of cyclosporine
(serum concentration >2000 ng/mL), leading to
increased risk of neutropenia; zidovudine
increases serum concentration, resulting in
increased toxicity
Pregnancy
D - Unsafe in pregnancy
Bleeding, severe myelosuppression, nausea,
Precautions
vomiting, hypotension, allergic reaction, and
alopecia may occur
Bleomycin (Blenoxane) -- Glycopeptide antibiotic
that acts by intercalating and binding to guanosine
and cytosine portions of DNA. May induce
Drug Name
single- or double-stranded DNA breaks by ability
to form oxygen free radicals.
Test dose is optional: 1-2 U IV/IM prior to full
dose.
30 U IV bolus weekly on days 2, 9, and 16; repeat
Adult Dose
q21d; modify dose based on CrCl
CrCl 20-30 mL/min: 50% of normal dose
CrCl <20 mL/min: 40% of normal dose
Pediatric Dose
Not established
Documented hypersensitivity; significant renal
Contraindications function impairment; compromised pulmonary
function
Interactions
Pregnancy
May decrease plasma levels of digoxin and
phenytoin; cisplatin may increase toxicity
D - Unsafe in pregnancy
Caution in renal impairment; possibly secreted in
breast milk; may cause mutagenesis and
pulmonary toxicity (10%); idiosyncratic reactions
Precautions
similar to anaphylaxis (1%) may occur; monitor
for adverse effects during and after treatment;
erythema, rash, vesiculations, hyperpigmentation,
stomatitis, alopecia, and nail changes may occur
Ifosfamide (Ifex) -- Alkylating agent—2 major
metabolites are produced after its activation in
Drug Name
liver. Ifosfamide mustard, by its ability to crosslink DNA strands, responsible for therapeutic
effect. Acrolein related to bladder toxicity.
Adult Dose
Pediatric Dose
Contraindications
1200 mg/m2/d IV continuous infusion d 1-5
Not established
Documented hypersensitivity; depressed bone
marrow function; uncontrolled infection
Phenobarbital, phenytoin, chloral hydrate, and
Interactions
other drugs that interfere with cytochrome P-450
activity may alter effects
Pregnancy
D - Unsafe in pregnancy
May cause hemorrhagic cystitis and severe
myelosuppression; caution in renal function
impairment or compromised bone marrow
reserve; nausea, vomiting, diarrhea, and
Precautions
occasionally constipation may occur; CNS toxic
effects include somnolence, confusion, depressive
psychosis, and hallucinations; seizures and coma
occasionally may occur; use mesna concomitantly
at dose of 1200 mg/m2/d IV continuous infusion
days 1-6
Drug Name
Vinblastine (Velban) -- Vinca alkaloid, inhibits
microtubule formation, which in turn disrupts
formation of mitotic spindle, causing cell
proliferation to arrest at metaphase.
Reduce dose by 50% in patients with TB >3
mg/dL. Dose reduction not required in impaired
renal function.
Adult Dose
0.11 mg/kg IV days 1 and 2
Pediatric Dose
3 mg/m2 IVP every 2-4 wk
Contraindications
Documented hypersensitivity; bone marrow
suppression
May reduce plasma phenytoin levels; mitomycin-
Interactions
C may increase toxicity significantly; avoid
heparin and furosemide
Pregnancy
D - Unsafe in pregnancy
Caution in impaired liver function and
neurotoxicity; when patient is receiving
mitomycin-C, monitor closely for shortness of
breath and bronchospasm; very irritating (a
vesicant) and should be given exclusively via side
Precautions
port of freely flowing IV; if extravasation occurs,
antidote is hyaluronidase (Wydase); warm
compresses should be applied at site of
extravasation; adverse effects include
myelosuppression, alopecia, nausea, vomiting,
anorexia, constipation, and paresthesia
Further Outpatient Care:

Detection of late recurrences (>2 y after treatment discontinuation), development of
testicular tumors several years after the initial diagnosis of EGGCTs, and treatmentrelated complications justify prolonged periods of follow-up care with clinical evaluation,
tumor markers, and imaging studies.

In children (and probably in adults) with ICGCTs, obtain baseline intelligence quotient
(IQ) and achievement tests before starting radiotherapy. Perform follow-up intellectual
assessments at 1 year after completion of radiation, then at 2, 3, and 5 years, and if any
intellectual deterioration is noted. Evaluate hearing if intellectual deterioration occurs.
Evaluation of thyroid, corticotropin, gonadotropin, prolactin, and GH functions is
obtained before and regularly after radiation therapy.
Complications:

Growing teratoma syndrome is the increase in tumor size during or after chemotherapy
for MGCT or RGCT and only mature teratoma at histologic analysis of the resected
tumor specimen. Mature teratoma component is present in the majority of the primary
tumors (86%). The major risk factor for this complication is the completeness of the
surgical resection of the primary tumor, because it was seen in only 4% of the patients
who underwent complete resection compared to 83% of those patients who had partial
resection. Complete surgical resection is the treatment of choice.

Rupture of a mature teratoma as a result of the digestive enzymes secreted by intestinal
mucosa or pancreatic tissue into the bronchi or lung may result in hemoptysis or
expectoration of hair or sebum. Rupture into the pleura or pericardium leads to
pericardial or pleural effusion.

Teratoma with malignant transformation is a rare complication of MGCT. The most
common transformations are different kinds of sarcomas, glioblastomas,
nephroblastomas, neuroblastomas, adenocarcinomas, and hematologic malignancies.

The incidence of hematologic malignancies in patients with NS-MGCTs is 200- to 300fold higher than in matched controls.
o
The median time from the diagnosis of the GCT to the diagnosis of the
hematologic malignancy is 6 months (range 0-47 mo). Acute myelogenous
leukemia and myelodysplasia with megakaryocyte lineage abnormalities are the
most common disorders.
o
Patients present with pancytopenia, isolated thrombocytopenia, splenomegaly,
and/or hepatomegaly. Flushing and syncope are suggestive of systemic
mastocytosis, another unusual hematologic malignancy complicating MGCTs.
o
The clinical course is very aggressive, with a median survival of 5 months.
Predictors of the subsequent occurrence of leukemia are mediastinal localization
of the GCT and endodermal sinus tumor and teratocarcinoma histologic types.
Bone marrow biopsy should not be delayed if cytopenia persists or recurs after the
initial chemotherapy period.

Chemotherapy-related complications may be immediate or delayed.
o
Nausea and vomiting became less common with the advent of 5hydroxytryptamine 3 (5-HT3) antagonists. Postcisplatin delayed emesis is better
treated by oral administration of metoclopramide, benzodiazepine, and
dexamethasone for 2-4 days.
o
A certain degree of cisplatin-related nephrotoxicity is almost always present and
is cumulative. Hypomagnesemia is common, requiring supplementation for
prolonged periods of time in some patients.
o
Arthralgias, myalgias, peripheral neuropathy, and paralytic ileus are common
toxic effects of vinblastine. However, since replacement of vinblastine with
etoposide in first-line therapy began, these complications are no longer seen.
Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. It
rarely requires hearing aids.
o
Neutropenic fever and severe thrombocytopenia are relatively uncommon with
etoposide and cisplatin (EP) as first-line chemotherapy. The addition of
bleomycin and salvage chemotherapy results in significant increase of these
complications (50%), requiring the prophylactic use of hematopoietic growth
factors after the first episode of neutropenic fever.
o
Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated
patients) and is dose and age dependent (rate is higher in patients >70 y and after
a cumulative dose >1200 IU or 400 mg). The progression to pulmonary fibrosis is
uncommon and occasionally fatal (1%). Although carbon monoxide diffusing
capacity may not predict clinically significant lung damage, its use was
recommended along with chest x-ray as a screening test in patients treated with
bleomycin. If radiographic changes or a decrease of diffusing capacity of lung for
carbon monoxide (DLCO) greater than 30% is detected, discontinue the drug.
o
Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction
were reported after use of bleomycin.
o
Accelerated coronary artery disease is a well-recognized complication of
mediastinal radiotherapy.
o
Infertility is seen in as many as 50% of patients after chemotherapy. Standard
bilateral retroperitoneal lymph node dissection almost always is associated with
retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior
approaches decrease, but do not abolish, this adverse effect.
o
The frequency of etoposide-related secondary leukemia is dose dependent. It is
seen in less than 0.5% of patients who received a total dose less than 2000 mg/m2
and in about 6% of those who received more than 3000 mg/m2. Abnormalities of
chromosome band 11q23 are very common in this setting. Latency period varies
from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric
cancers, and soft-tissue sarcomas is increased slightly after combined radiation
and chemotherapy. Latency period is about 10 years or more.
o
Weijl et al reported a high rate of thromboembolic events (8.4%) during
chemotherapy in 179 patients with GCTs. Liver metastases and high-dose
corticosteroids were identified as risk factors for these complications.

With the achievement of prolonged survival for patients with ICGCTs, researchers
became increasingly aware of long-term effects of cranial radiation on intellectual and
endocrine functions.
o
These complications are correlated with the total dose and fraction sizes of
irradiation and are correlated conversely to the patient's age at the time of
treatment. Concomitant chemotherapy increases the risk of toxicity.
o
Verbal IQs and reading skills are affected to a lesser degree than performance IQs
or mathematic ability. Personality changes include anxiety, depression, lability,
belligerence, hypersexuality, reduced attention span, memory, and reasoning
ability.
o
GH deficiency with growth retardation and hypothyroidism are much more
common than gonadotropin and corticotropin deficiencies.
o
Leukoencephalopathy, hearing loss, and second malignancies (20-y cumulative
probability of about 12% for the latter) are increased after cranial irradiation.
Prognosis:

Analysis of available data on 5862 patients with GCTs resulted in development of a
classification system by the International Germ Cell Collaborative Group (IGCCG). This
system categorizes tumors on the basis of histologic type (seminomas have better
prognosis than nonseminomas), localization of metastases (retroperitoneal and testicular
portend better prognosis than mediastinal and intracranial GCTs), and initial levels of
serum AFP, bhCG, and LDH (the higher the tumor markers the worse the effect on
survival).

Nonseminoma
o
Good prognosis is indicated by all of the following:

Testis/retroperitoneal primary

No nonpulmonary visceral metastases

Good markers - AFP <1000 ng/mL, bhCG <1000 IU/L, and LDH <1.5 X
upper limit of normal (N)

Includes 56% of nonseminomas, which have a 5-year progression-free
survival rate (PFS) of 89% and 5-year survival rate of 92%
o
Intermediate prognosis is indicated by all of the following:

Testis/retroperitoneal primary

No nonpulmonary visceral metastases

Any of AFP >1000 and <10,000 ng/mL, bhCG >5000 and <50,000 IU/L,
or LDH >1.5 X N and <10 X N

Includes 28% of nonseminomas, which have a 5-year PFS of 75% and 5year survival rate of 92%
o
Poor prognosis is indicated by any of the following:

Mediastinal primary

Nonpulmonary visceral metastases

Poor markers - Any of AFP >10,000 ng/mL, bhCG >50,000 IU/L, or LDH
>10 X N

Includes 16% of nonseminomas, which have a 5-year PFS of 41% and 5year survival rate of 48%

Seminoma
o
Good prognosis is indicated by the following:

Any primary site

No nonpulmonary visceral metastases

Normal AFP, any bhCG, any LDH

Includes 90% of seminomas, which have a 5-year PFS of 92% and 5-year
survival rate of 88%
o
Intermediate prognosis is indicated by the following:

Any primary site

Nonpulmonary visceral metastases

Normal AFP, any bhCG, any LDH

Includes 10% of seminomas, which have a 5-year PFS of 67% and 5-year
survival rate of 72%
o

Poor prognosis: No patients are classified as having poor prognosis.
Ganjoo analyzed the data from 75 patients treated at Indiana University for NS-MGCTs
with chemotherapy followed by surgery. Tumor marker elevation prior to or after
chemotherapy was not found to be an independent prognostic variable for survival.
However, the presence of visceral metastases and especially postchemotherapy pathology
were the most important predictors of survival.

The Institut Gustave-Roussy prognostic model based on tumor marker levels was not
able to accurately classify their group of 38 patients treated for NS-MGCT. The use of
etoposide seemed not to make any difference in survival. Although patients who were
able to receive dose-intensive chemotherapy fared better, this did not reach statistical
significance. Extrapulmonary metastases remained the sole significant parameter in longterm survival.

Patients with MGCT have a poor prognosis owing to at least the following 3 factors:
MGCTs are not as sensitive as other GCT to chemotherapy, bulky disease increases the
risk of poor outcome in the short term owing to respiratory failure, and hematologic
malignancies are linked to a very unfavorable prognosis.
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