DOI: 10.
1093/annonc/mdf669
Extragonadal germ cell tumors
H.-J. Schmoll
Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany
Introduction
Germ cell cancer is the most common malignancy in men aged
15–35 years; 5% of the malignant germ cell tumors are of
extragonadal origin [1]. An extragonadal germ cell tumor
(EGGCT) is by definition a germ cell neoplasm displaying
one of the histologies associated with gonadal origin, but
located outside of the gonads. This specific clinical entity was
first described in the 19th century [2, 3]. Histological, serolog-
ical and cytogenetic characteristics of EGGCTs are similar to
those of primary testicular germ cell tumors, but major differ-
ences in clinical behavior suggest that gonadal and extra-
gonadal tumors are biologically different (Table 1). In
particular, this is true of primary mediastinal EGGCTs and
tumors originating in the sacrococcygeal or pineal region; in
contrast, tumors arising in the retroperitoneum are more often
associated with premalignant lesions in one of the testes and
behave clinically in a manner very similar to that of the prim-
ary testis counterpart. Also male patients with carcinoma of
unknown primary (CUP syndrome) with undifferentiated hist-
ology and typical germ cell tumor serum markers, as well as
Table 1. Clinical and biological features of extragonadal germ cell
tumors with respect to gonadal germ cell tumors [11]
Features shared with gonadal germ cell tumors
• Occurrence in young adults, mostly men
• Midline locations
• Metastasis to lung, liver and bone
• Seminomatous and nonseminomatous histological subtypes
• Elevated serum tumor markers (β-HCG, AFP)
• i(12p) karyotypic abnormality
• Sensitivity to cisplatin-based combination chemotherapy
Features distinct from gonadal germ cell tumors
• Increased tumor bulk at presentation
• Anterior superior mediastinal predominance
• Predominance of nonseminomatous germ cell tumors
• High frequency in patients with Klinefelters’s syndrome
• High frequency of development of hematological malignancies
(mediastinal primaries only)
AFP, α-fetoprotein; β-HCG, β human chorionic gonadotropin.
© 2002 European Society for Medical Oncology
presentation in the midline structures, belong to the group of
EGGCT. However, in practice it may be difficult to distin-
guish extragonadal tumors from metastatic tumors where the
primary testis lesion has regressed, e.g. in some cases a scar is
found in the testis probably representing a ‘burn-out’ or
‘autoinfarcted’ primary [4]. Furthermore, it is unclear whether
the presence of a carcinoma in situ or intraepithelial germ cell
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neoplasia represents a primary tumor lesion resulting in meta-
static deposits e.g. in the mediastinum or retroperitoneum, or
whether this testicular lesion represents a general premalig-
nant or malignant change of germ cells at any location distrib-
uted in the body, leading to an extragonadal malignant tumor.
Biology and genetics
It is generally accepted that EGGCTs follow the same prin-
ciples of development from primordial germ cells as primary
gonadal germ cell tumors. While their migration from the yolk
sac-endoterm to the genital ridge which occurs in the midline,
aberrant midline migration might enable primordial germ
cells to lodge in the site where extragonadal germ cell tumors
are commonly found. Accordingly, the cytogenetic finding of
one or multiple copies of the short arm of chromosome 12p
with the loss of the long arm of chromosome 12 is seen in
nearly all germ cell cancers of primary gonadal and extra-
gonadal origin [5, 6]. This concept, however, is challenged by
findings from serial sections in human embryos and murine
embryos [7, 8], which failed to find any evidence of misplaced
germ cells outside of the gonads. Furthermore, it has been
recently shown that ectopically placed primordial germ cells
detected in sections of murine embryos undergo apoptosis [9].
Chaganti et al. [10] compared the clonal cytogenetic changes
in a group of primary extragonadal tumors with a group of pri-
mary gonadal tumors, with the hypothesis that if these tumors
truly represented de novo transformations of primordial germ
cells in a nongonadal environment, then their genetic and
cytogenetic profile may be different from those of gonadal
germ cell tumors. Although the two groups differed signifi-
cantly in the pattern of differentiation, neither specific chromo-
somal aberrations, including increased 12p copy number, nor
the incidence of recurring break points were significantly
different between the two groups. These finding led to an
alternative suggestion that some form of reverse migration of
occult carcinoma in situ lesions in the testis could occur;
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according to this hypothesis extragonadal tumors would also
be of gonadal origin [10]. The potential development of malig-
nant gonadal and extragonadal germ cell tumors is described
in Figure 1, which has been adapted from Chaganti et al. [6].
However, neither of these two series explain the striking pre-
dominance of malignancy in male EGGCTs in comparison
with females who predominantly have EGGCTs and germ cell
tumors of the ovaries that are benign [11].
TIN (or carcinoma in situ, cis) cells are regarded as the pre-
cursors of all male germ cell tumors; however, it is unclear
how cis cells undergo the molecular changes leading to high
DNA content and the typical chromosomal aberrations seen
in this cancer. The molecular changes associated with the
development of germ cell tumors are still not clearly under-
stood. However, it is clear from the universal cytogenetic find-
ing of increased 12p copy number that this chromosomal
molecular profiling, CGH analysis, etc. Of particular interest
is an amplification of the proximal 12p11.2-12 region which
includes the genes ras-k2, SOX5 and JAW1, as well as cycline
CCND2 mapped to the 12p13 region, which could be the best
candidate for the 12p3 gene in normal testicular genesis and
malignant germ cell development [12] and growth. The most
likely target cell for transformation during germ cell develop-
ment may be a cell with replicated chromosomes that
expresses wild-type p53, harbors DNA breaks and which may
be prone to apoptosis. Such a stage is represented by the
zytogene-pachytene spermatocyte at which a ‘recombination
checkpoint’ appears to operate which can provide an apoptotic
trigger in the presence of an unresolved DNA double-strand
break. This stage is temporally the longest phase during
spermatogenesis with the cell cycle machinery halted to allow
the recombinational events to complete. It also contains repli-

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change is a key event. Candidate driver genes are currently in cated DNA, and based on murine data, wild-type p53 protein
the process of being identified using the techniques of is temporally expressed at this stage. According to this model

Figure 1. Genetics and biology of male germ cell (GC) tumors [7]. A diagrammatic representation of male GC development during a normal life span
and the proposed model of GC transformation. The key genetic events that underlie normal male GC fate and embryonal development are shown with
respect to their spatial and temporal relationships. Germ cell tumor development is depicted in the context of normal GC biology.

aberrant chromatid exchange events associated with crossing
over the zytogene-pachytene may lead to increased 12p copy
number and overexpression of cyclin D2. Such a cell may
escape a recombination checkpoint-associated apoptotic
response through the oncogenic effect of cycline D2, leading
to aberrant re-initiation of cell cycle and genomic instability.
In germ cells that have, under follicle-stimulating hormone
(FSH) stimulation, re-entered the cell cycle after cycline D2
activation, downstream events such as a loss of tumor suppres-
sor genes induced by genomic instability could lead to neo-
plastic progression. Candidate suppressor genes are Rb1,
DCC and NME (for a review see Chaganti and Houldsworth
[6]). An overview of this hypothetical development of germ
cell tumors is given in Figure 1.
Except for a few described cases of germ cell tumors diag-
nosed in fathers and twins, there is no evidence for familiar
inheritance. However, there is a clear association between
EGGCT and Klinefelter’s syndrome and a possible associ-
ation with Down’s and Li–Fraumeni syndromes. Klinefelter’s
syndrome is a male genetic disorder characterized by the
47,XXY karyotype, small and soft testis, sterility, eunuchoid
habitus, gynecomasty, high levels of FSH, a 20-fold increased
risk for breast cancer and an increased risk of EGGCT primary
gonadal germ cell tumors. These tumors mainly occur in
young children, with a peak in incidence at 10 years, before
that of gonadal germ cell tumors. It is, however, unclear
whether the development of germ cell tumors in patients with
Klinefelter’s syndrome is the result of primary genetic abnor-
mality, errors during embryonic development or abnormal
hormonal milieu priming premalignant tumor cells into malig-
nant tumor growth.
Histopathology
Like their counterparts of gonadal origin, EGGCTs occur in
several characteristic histological patterns that reflect the
stages of normal embryonic and fetal development with semi-
nomatous (‘germinoma/dysgerminoma’) and nonsemino-
matous germ cell tumors including endodermal sinus tumor,
yolk sac tumor, embryonal carcinoma, choriocarcinoma and
mature or immature teratoma. Histopathological pattern and
tumor marker expression of α-fetoprotein (AFP), β human
chorionic gonadotropin (β-HCG) and alkaline phosphatase, as
well as LDH, follow the same pattern as primary gonadal
germ cell tumors.
Whereas the proportion of seminomatous and nonsemino-
matous germ cell tumors in primary gonadal tumors is more or
less equal, in EGGCTs seminomatous histology is seen in
only 20–24% of EGGCTs. In a cumulated series of 635 cases
with EGGCTs collected from 11 different institutions, there
were 104 and 524 patients with seminomatous and non-
seminomatous extragonadal germ cell tumors, respectively
[13]. There is no predominance of either histology in patients
267
with primary mediastinal or primary retroperitoneal semino-
matous or nonseminomatous extragonadal germ cell tumors.
Clinical presentation
The most common localization of EGGCTs is in the mediast-
inum and retroperitoneum. Beyond this the tumors can arise in
the pineal region, sacrococcygeal region and also in the pros-
tate, vagina, orbita, liver and gastrointestinal tract (Table 2).
Because of the rarity of the other localizations of EGGCTs,
this chapter only reports on primary mediastinal and retro-
peritoneal EGGCTs.
The most conclusive data regarding clinical presentation
and treatment results derive from a recent meta-analysis rep-
resenting the largest published series of EGGCTs with
635 patients [13]. Patients with mediastinal EGGCT had in
particular dyspnea (25%), chest pain (23%) and cough (17%)
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at initial presentation, followed by fever (13%), weight loss
(11%), vena cava occlusion syndrome and fatigue/weakness
(6%). Less frequent than expected was chest pain, cervical
nodes (2%), hemoptysis, hoarseness and dysphagea (1%
each). In patients with a tumor in a primary retroperitoneal
location, the lead symptoms are abdominal (29%) and back
pain (14%), followed by weight loss (9%), fever (8%), vena
caval or other thrombosis (9%), palpable abdominal tumor
(6%), cervical nodes (4%), scrotal edema (5%), gynecomastia
and dysphagea (3%).
The pattern of age distribution for seminomatous and non-
seminomatous EGGCTs is comparable with gonadal tumors,
with a median age of onset of 33, 41, 28 and 30 years for media-
stinal seminoma, retroperitoneal seminoma, mediastinal
nonseminoma and retroperitoneal nonseminoma, respect-
ively. Half of the patients with extragonadal seminomatous
tumors have elevated β-HCG and/or LDH; in extragonadal
nonseminomatous tumors there seems to be a different pattern
between mediastinal and retroperitoneal EGGCTs with 74%
of the mediastinal tumors presenting with elevated AFP and
Table 2. Anatomical locations of extragonadal germ
cell tumors (EGGCTs) [11]
Common
• Mediastinum
• Pineal and suprasellar regions
• Sacrococcyx (infants and young children only)
Controversial
• Retroperitoneum (metastatic versus true EGGCT?)
Very rare
• Vagina
• Prostate
• Liver and gastrointestinal tract
• Orbita
268

38% with elevated HCG, whereas 50% of the primary retro-
peritoneal tumors have elevated AFP, but 74% have elevated
HCG (Tables 3 and 4). The size of the mediastinal tumor is
nearly double that of nonseminomatous tumors, 9 cm (range
7–30) in comparison with 5 cm (range 1–20) in mediastinal
seminoma, whereas the size of retroperitoneal EGGCTs is
comparable in both histologies. Metastases are less frequent at
diagnosis with seminomatous EGGCTs (40% of patients)
compared with nonseminomatous EGGCTs (50% for
mediastinal and 76% for retroperitoneal nonseminomatous
EGGCTs). The pattern of metastases outside of the primary
tumor location varies depending on the location of the primary
tumor and its histology; mediastinal seminomas mostly have
metastatic deposits in the cervical lymph nodes whereas
mediastinal nonseminoma is associated in particular with lung
metastases in 27% of patients. Retroperitoneal seminoma is
lymph nodes in 6%, whereas retroperitoneal nonsemino-
matous tumors have a high frequency of lung metastases
(49%), abdominal (34%), or cervical lymph nodes (18%) and
liver metastases (25%). The proportion of patients with two or
more metastatic sites follows the patients with primary
gonadal origin and typical pattern of poor prognosis germ cell
tumors, with 48% in retroperitoneal nonseminomas EGGCTs
versus 15% in retroperitoneal seminomas. Accordingly about
90% of patients with seminomatous EGGCTs have good
prognosis [International Germ Cell Cancer Collaboration
Group (IGCCCG) classification] whereas about 50% of the
primary retroperitoneal nonseminomatous tumors present
with poor prognostic features.
Diagnosis

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found in the retroperitoneal primary tumor lymph node meta-
stases in 26%, mediastinal lymph nodes in 12% and cervical
Table 3. Clinical characteristics of a series of 104 patients with
extragonadal seminoma [15]
Since EGGCTs are not clinically evident with a primary
gonadal tumor, in virtually all patients the diagnosis is led by
the symptoms induced by the growing mediastinal or retro-
peritoneal tumor mass. Fine needle cytology or histology
through percutaneous or mediastinoscopic biopsy reveals

Mediastinal Retroperitoneal
seminoma seminoma Table 4. Characteristics of 524 patients with extragonadal
nonseminomatous germ cell cancer [13]
No. of patients 51 52
Size of primary, cm (range) 4.6 (1–20) 7.2 (1–25) Mediastinal Retroperitoneal
Age, years (range) 33 (18–65) 41 (23–70) nonseminoma nonseminoma

Site of metastases No. of patients 287 227

Lung 4% 6% Size of primary, cm 9 (0.7–30) 8 (1–25)

(range)
Abdominal LN 8% 26%
Age, years (range) 28 (14–51) 30 (16–79)
Liver 2% 6%
Site of metastases
Cervical LN 25% 6%
Lung 27% 49%
Bone 4% 6%
Abdominal LN+ 8% 34%
CNS – –
Liver 8% 25%
Paratracheal LN 2% 12%
Cervical LN 8% 18%
Other 2% 6%
Bone 4% 3%
Prognosis group
CNS 4% 5%
Good 94% 88%
Other 13% 12%
Intermediate 6% 12%
No. of metastatic sites
Serum tumor markers
0 51% 24%
HCG, ng/ml (range) 8.5 (1–89) 4 (1–90)
1 34% 28%
Elevation >2 43% 34%
≥2 16% 48%
LDH, U/l (range) 523 (160–2019) 542 (80–8555)
Tumor marker at
Elevation >200 U/l 43% 68% diagnosis
No. of metastatic sites APF, ng/ml (range) 2.548 (1–500 000) 25 (1–123 000)
0 59% 54% Elevation 74% 51%
1 35% 31% β-HCG, mlU/ml (range) 5 (1–3.138 × 106) 335 (1–9.99 × 106)
≥2 6% 15% Elevation 38% 74%
LDH, IU/l (range) 489 (90–3,427%) 834 (140–9,970%)
HCG, human chorionic gonadotropin; LDH, lactate dehydrogenase;
LN, lymph nodes. Elevation 52% 61%
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either seminomatous or nonseminomatous elements but

sometimes only the term ‘undifferentiated carcinoma’ is
recorded by the pathologist. The determination of serum
markers and request for immunopathology with specific germ
cell markers in the pathological specimen should result in the
diagnosis of EGGCT in almost all cases.

Testicular biopsy
A testis primary is excluded by sonographic investigation of
the testis. Several reports have described the presence of a
testicular intraepithelial neoplasia (TIN) or microscopic scar
in the testis of patients with EGGCT. The largest biopsy series
is reported in the above-mentioned meta-analysis [13] with 71
patients (11% of the whole series) undergoing biopsy. Three
per cent showed a sertoli cell only syndrome, 31% athrophic
or fibrotic testis and in 9% TIN was evident with a higher

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proportion in primary retroperitoneal EGGCTs than in medi-
astinal tumors. Further to this observation, 12 of 524 non-
seminomatous EGGCTs and four of 104 seminomatous
EGGCTs developed metachronous testicular tumors, mostly
seminoma, after a median follow-up of 6 years [14]. Although
according to this data the standard incidence ratio (SIR) is
greatly increased (SIR 62) in comparison with patients with
primary testis tumors resulting in a 10% cumulative risk at 10
years after diagnosis of EGGCT, these metachronous testicu-
lar tumors are highly curable due to the limited stage at presen-
tation and their mostly seminomatous histology. A routine
bilateral testicular biopsy of patients with EGGCT is therefore
not justified.
Prognosis
Primary mediastinal and retroperitoneal extragonadal semi-
nomatous germ cell tumors have an equivalent prognosis as
their primary gonadal counterpart, with a 5-year survival of
88% (Table 5 and Figure 2) in a meta-analysis of 104 patients
[15]. The same parameters which identified patients with
gonadal seminomatous tumors as having a good or inter-
mediate prognosis, including levels of HCG or LDH, presence
of nonpulmonary visceral metastases or primary mediastinal
tumor, also predict the individual prognosis in seminomatous
tumor of primary extragonadal origin.
Figure 2. Calculated overall survival rates of (A) 104 nonseminomatous
EGGCT patients and (B) 524 nonseminomatous extragonadal germ cell
tumor (EGGCT) patients according to the primary tumor location [13].
Nonseminomatous EGGCTs have a worse prognosis than
seminomatous EGGCTs with a 5-year survival rate of 62% for
retroperitoneal and 45% for mediastinal nonseminomatous
EGGCTs (Figure 2). Accordingly, the complete response
(CR) rate including partial response with marker normaliza-
tion is lower than in seminomatous EGGCT with 68% for
retroperitoneal and 64% for mediastinal primary, and the
relapse rate is much higher at 50% and 52%, respectively
(Table 5). Also, the analysis according to the IGCCCG classi-
fication shows that patients with primary retroperitoneal
EGGCT and good/intermediate prognostic features belong to
the category of poor prognosis, with a 5-year survival of only
59% and 61% [13]. These data clearly indicate that not only do
mediastinal EGGCTs have a poor prognosis and should be
treated accordingly, but that retroperitoneal EGGCTs also
belong to the poor prognosis group even if they fulfil the
IGCCCG criteria of good or intermediate prognosis. Since the
response and survival data are based on a meta-analysis of the
largest number of patients ever reported in an EGGCT trial,

Table 5. Treatment outcome in a cumulative series of 635 patients with EGGCT [13]

No. of patients CR/PR (%) Relapse (%) 5-year OS (%) 5-year PFS (%)
Mediastinal seminoma 48 94 6 88 88
Retroperitoneal seminoma 46 88 17 88 77
Mediastinal nonseminoma 286 64 52 45 44
Retroperitoneal nonseminoma 226 68 50 62 45

CR, complete response, OS, overall survival; PR, partial response; PFS, progression-free survival.
270
the results probably reflect the true situation better than single
center studies; however, most studies reported results which
are relatively consistent with these data [16–22].
The conclusions from the data are as follows:
• Patients with seminomatous EGGCTs should be treated
according to their prognostic classification (IGCCCG),
with three cycles of cisplatin, etoposide, bleomycin (PEB)
for good prognosis patients and four cycles of PEB for
intermediate prognosis patients.
• Patients with nonseminomatous EGGCTs, retroperitoneal
location and good/intermediate prognosis (IGCCCG)
should be treated with three cycles of PEB, and patients
with poor prognosis with four cycles of PEB.
• Patients with nonseminomatous EGGCTs and a medi-
astinal location all belong to the poor prognosis group and
should be treated accordingly with four cycles of PEB.
The role of high-dose chemotherapy
No prospective studies have investigated the role of high-dose
chemotherapy in first-line treatment of extragonadal tumors.
In a meta-analysis of 524 patients with nonseminomatous
germ cell tumors, 59 patients (13%) were treated with high-
dose chemotherapy [13]. No specific data of this subgroup,
which would be the largest series of high-dose chemotherapy
in this specific disease type, is yet available. However, in the
univariate analysis for prognostic factors high-dose chemo-
therapy obviously was not a significant prognostic factor for
improved survival. Sixty-four patients out of another series of
235 patients with mainly poor prognostic criteria (IGCCCG)
treated with initial sequential high-dose chemotherapy with
cisplatinum plus intermediate high-dose etoposide and ifosfa-
mide plus stem cell rescue had extragonadal germ cell tumors,
with a 5-year survival reported to be higher than with standard
dose platinum-based combination chemotherapy [23]. This
has resulted in the inclusion of these patients with primary
mediastinal or poor prognosis retroperitoneal germ cell
tumors into the current European Organisation for Research
and Treatment of Cancer (EORTC) study, which is comparing
four cycles of standard dose PEB with one cycle of standard
etoposide, ifosfamide, cisplatin (VIP) followed by three
cycles of high-dose VIP plus stem cell rescue. The result of
this study will probably highlight more precisely the role of
high-dose chemotherapy for this specific patient population.
The role of radiation
As reported in the meta-analysis by Bokemeyer et al. [13] the
relapse rate in patients with bulky extragonadal seminoma
treated with radiation alone is relatively high, in accordance
with the retrospective analysis of other earlier studies. There-
fore, radiation therapy, as part of the treatment strategy of
advanced seminoma and in particular extragonadal seminoma,
has been abandoned. However, for salvage treatment in cases
of otherwise untreatable disease, e.g. definitive progression
under chemotherapy, radiotherapy is the treatment of choice
and will be actively used—at least for sometime—in the
majority of patients. Salvage radiotherapy is therefore an
important measure for some patients with otherwise refractory
disease suffering from locoregional problems, such as super-
ior vena cava obstruction, bronchus obstruction, cases of resi-
dual disease after salvage surgery, as well as CNS metastases.
The role of secondary surgery
Due to poor prognosis in many patients with retroperitoneal
EGGCTs and the specific localization of primary mediastinal
EGGCT, surgery is a very important part of the treatment
strategy. In the above-mentioned series [13] secondary sur-
gery after chemotherapy has been performed in about 50% of
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extragonadal seminomatous tumors revealing necrosis in only
92% of the resected patients; 49% of patients with mediastinal
EGGCT underwent secondary resection of residual tumor
mass in the mediastinum resulting in viable germ cell tumor in
34% and non-germ cell tumor elements in 1.4%, major
teratoma in 26% and necrotic tissue in 37%. In nonseminoma-
tous retroperitoneal EGGCT, 45% of the patients underwent
secondary surgery, mainly of the retroperitoneal residuum;
viable undifferentiated tumor was found in 25%, major
teratoma in 16% and necrotic tissue in 59% of patients. These
data are in accordance with data of a recent series from
Memorial Sloan-Kettering Cancer Center with 32 patients
presenting with mediastinal EGGCT [24] and clearly indicate
that secondary surgery is an integral part of the treatment strat-
egy in patients with EGGCT and is mandatory in the case of
residual mass, which is true for about 50% of the patient
population.
Salvage chemotherapy
The outcome of patients relapsing after primary chemo-
therapy for EGGCTs is very poor and probably worse than
patients with primary gonadal nonseminomatous testicular
cancer and poor prognostic features. From a collected series
of 142 patients treated prospectively in 11 European and
American centers in an era when cisplatinum was widely used,
only 19% of patients were long-term disease-free after stand-
ard or high-dose salvage chemotherapy followed by addi-
tional surgical resection of residual tumors in some patients
[25]. Primary mediastinal location and cisplatinum-refractory
patients have been identified as independent factors predicting
a negative outcome with standard or high-dose salvage
chemotherapy. In this series, 28% of 79 patients with medi-
astinal and 41% of patients with retroperitoneal extragonadal
germ cell tumors received high-dose chemotherapy at relapse.
The median survival time was 15 months for patients treated
with high-dose chemotherapy and 11 months for patients
treated with standard-dose salvage chemotherapy protocols;

although the survival curves are in favor of high-dose chemo-
therapy, there is no statistically significant difference between
both groups in terms of median and long-term survival.
These data are in accordance to results from individual small
series where long-term survival in patients relapsing after
chemotherapy of a mediastinal germ cell tumor have only
rarely been observed. In conclusion, currently there is no role
for high-dose chemotherapy as salvage treatment at the time
of relapse after initial remission, or in cases of primary
cisplatinum resistance, in patients with mediastinal and prob-
ably also retroperitoneal extragonadal germ cell tumors. The
data from a prospective randomized trial of the European
Group for Blood and Marrow Transplantation comparing
standard cisplatinum-based salvage chemotherapy with high-
dose salvage chemotherapy also including patients with
extragonadal germ cell tumors are eagerly awaited [26].
Second malignancies
The cumulative risk of development of metachronous testicu-
lar cancer 10 years after diagnosis of EGGCT is about 10%
according to the results from a meta-analysis by Hartmann
et al. [14]. The rate of metachronous testicular cancer is higher
among patients with nonseminomatous EGGCTs and retro-
peritoneal EGGCTs (14%), than in patients with semino-
matous EGGCTs (1.4%) or seminomatous mediastinal
EGGCTs (6.2%). This represents an increased standard inci-
dence ratio (SIR), derived from the incidence of metachronous
testicular cancer in the primary gonadal testis cancer popu-
lation of 62 (95% confidence interval 36–99). However, most
cases of metachronous testicular cancer in these patients are of
seminomatous histology, which is also true in patients with
primary nonseminomatous EGGCT, and is therefore associ-
ated with a good prognosis.
The risk of developing secondary non-germ cell solid
tumors is not increased with an incidence of 2% after a median
follow-up of 55 months [27]. However, there is an increased
risk, in patients with mediastinal EGGCT, of developing acute
megacaryoblastic leukemia or myelodysplasia with abnormal
megacaryocytes (2% of patients). With a standard incidence
ratio of 250 in comparison with a normal age matched general
population [28, 29]. The median time to onset of hemato-
logical neoplasia is 6 months (range 0–47) and the median
survival after diagnosis of the hematological malignancy
is short at 5–6 months, due to the poor biology of these
leukemias, despite autologous or allogenic bone marrow trans-
plantation. The secondary leukemias are clearly different cyto-
genetically from leukemias induced by alkylating agents or
topoisomerase II inhibitors with typical cytogenetic find-
ings of a germ cell tumor, in particular the presence of an
isochromosome 12p. Interestingly, leukemias only appear
in patients with primary nonseminomatous mediastinal
EGGCTs, not in patients with primary retroperitoneal
EGGCTs.
271
Conclusions
Extragonadal germ cell tumors are a very interesting tumor
entity with specific biological and clinical characteristics. The
prognosis is excellent in cases of seminomatous histology
independent of the localization of the EGGCT in either the
mediastinum or retroperitoneum. Unfortunately the majority
of patients (80%) have nonseminomatous EGGCTs and
thereby have poor prognosis which is independent of the
primary location of the nonseminomatous EGGCT. Standard
cisplatinum-based chemotherapy plus additional secondary
surgery in half of all patients is the basis of the treatment
strategy. Salvage chemotherapy including high-dose chemo-
therapy has no significant impact on long-term survival; how-
ever, this must be prospectively investigated.
Due to the poor prognosis and several potential clinical
problems associated with the disease and treatment, these
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patients should be treated primarily in specialized centers.
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