ORIGINAL RESEARCH  
Disease characteristics and survival outcomes of extragonadal  
primary germ cell tumour in two Canadian tertiary cancer centres  
1
2
3
4
Jenny J. Ko, MD; Tehmina Asif, MD; Haocheng Li, MD; Nimira Alimohamed, MD; Phuong Thao Nguyen,  
5
4
MD; Daniel Y.C. Heng, MD  
1
2
3
Department of Medical Oncology, Abbotsford Cancer Centre, Abbotsford, BC, Canada; Department of Medical Oncology, Saskatchewan Cancer Agency, Saskatoon, SK, Canada; Departments of Oncology  
4
5
and Community Health Sciences, University of Calgary, Calgary, AB, Canada; Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada; Department of Medical Oncology, Royal  
Inland Cancer Centre, Kamloops, BC, Canada  
Cite as: Can Urol Assoc J 2016;10(5-6):E165-70. http://dx.doi.org/10.5489/cuaj.3357  
Published online May 12, 2016.  
Introduction  
Extragonadal germ cell tumours (EGCTs) comprise a heteroge-  
Abstract  
neous group of primary germ cell tumours with distinct natural  
history and responses to different treatment modalities. The  
incidence of EGCTs is estimated at 1.9–3.4/1 000 000. EGCTs  
1
Introduction: Extragonadal germ cell tumours (EGCTs) are a hetero-  
geneous group with distinct natural history and responses to treat-  
ment modalities. We sought to evaluate characteristics and survival  
outcomes in men with EGCTs.  
Methods: We performed a retrospective analysis on a consecutive  
list of men diagnosed with EGCT in two Albertan cancer centres  
between 1990 and 2013. Demographic characteristics and out-  
comes, stratified by primary site, were evaluated.  
often occur in the midline of the body, with the three most com-  
mon sites in the anterior mediastinum, retroperitoneum, and  
1,2  
pineal gland. Epidemiologic studies suggest that although  
similar in morphologic appearance, the embryonic and  
genetic initiating events of EGCTs may be distinct from the  
1
-4  
gonadal germ cell tumours (GGCTs). EGCTs, especially  
of the mediastinal origin, are often marked by inferior sur-  
vival outcomes compared to GGCTs, as well as hematologic  
neoplasms (acute myeloid leukemia and malignant histio-  
cytosis) and systemic mast cell disease that are unrelated to  
Results: Sixty-nine cases were identified. The median age was  
2
9 (range 15–76) and 48 cases (70%) were non-seminomatous.  
Twenty-four (35%) belonged to International Germ Cell Cancer  
Collaborative Group (IGCCCG) favourable risk group, 14 (20%) to  
intermediate, and 31 (45%) to poor. Thirty (43%) had mediastinal  
primary (MPs); 29 were treated with first-line bleomycin, etopo-  
side, and cisplatin (BEP). Seventeen (57%) relapses occurred, of  
which three patients achieved long-term survival. Seventeen (25%)  
had a central nervous system (CNS) primary, with eight (47%)  
classic germinoma. Seven (41%) received primary chemotherapy  
alone; 5 (29%) received primary radiotherapy alone, and 5 (29%)  
received both. Nineteen (28%) had a retroperitoneal primary (RPs)  
and received first-line chemotherapy; all but two received BEP  
and eight (42%) had surgical resection. Three (5%) had other or  
unknown primary. Five-year overall survival (OS) and disease-free  
survival for all patients were 56% and 44%, respectively; for MPs,  
5
,6  
treatment effect.  
The usual treatment for EGCTs has been platinum-based  
chemotherapy regimen, such as bleomycin, etoposide and  
cisplatin (BEP), followed by surgical resection of residual  
7
tumours, if feasible. Previously published retrospective stud-  
ies have suggested efficacy of chemotherapy in achieving  
complete response and long-term survival in both semi -  
nomatous and non-seminomatous germ cell tumours of  
8-12  
extragonadal origin. Patients with relapse can be salvaged  
with high-dose chemotherapy with stem cell support similar  
to disease relapse in GGCTs, although prospective, random-  
1
3,14  
4
5
4% and 34%; for CNS primary, 76% and 53%; for RPs, 58% and  
3%. Factors that correlated with decreased OS were elevated  
ized data are lacking.  
There is substantial variability in  
the case volume and surgical expertise among centres and a  
multidisciplinary care in a specialized tertiary cancer centre  
alpha fetoprotein (AFP) (p<0.001) or human chorionic gonado-  
tropin (HCG) (p=0.001), lactate dehydrogenase (LDH) levels  
7,15  
is essential in the treatment of EGCTs. Even with optimal  
(
p=0.028), bone metastasis (p<0.001), lung metastasis (p<0.001),  
treatments, survival varies among different primary sites and  
can range from five-year survival of 3040% in the medi-  
astinal EGCTs to 90% in germinoma of the central nervous  
and IGCCCG poor risk (p=0.001).  
Conclusions: EGCT is a rare, but important subset of GCT. Patients  
with EGCTs, despite aggressive treatments, still have poorer out-  
comes than gonadal primary.  
4,11,16,17  
system.  
ment of EGCTs in Canadian patients are scarce.  
To date, however, published data on the treat-  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
2016 Canadian Urological Association  
E165  
©
Ko et al.  
The objectives of our study were to evaluate patient, dis-  
patients, as well as three subgroups stratified by primary site.  
Among 30 patients (43%) with MPs with 5 years of fol-  
lowup, 5/8 patients (63%) with seminomatous and 6/19  
(32%) with non-seminomatous MPs achieved long-term  
survival. One patient died due to bleomycin lung toxicity  
after two cycles of BEP. Upfront or salvage high-dose che-  
motherapy with autologous stem cell support was used in 11  
patients, of which three (27%) survived 5 years. Seventeen  
(57%) relapses occurred; most were high-risk (n=2, 13%)  
or very high-risk (n=15, 87%) by the IGCCCG2 criteria.18  
Fifteen (88%) received salvage chemotherapy with (n=1) or  
without (n=14) radiation therapy (RT), most commonly pacli-  
taxel, ifosfamide and cisplatin (TIP) (n=8). Other regimens  
included upfront salvage high-dose chemotherapy with stem  
cell support (n=3), BEP (n=2), and vinblastine, ifosfamide  
and cisplatin (VeIP, n=2). Two patients had resection of  
residual mass after salvage therapy, all of which contained  
viable non-teratomatous GCTs. Three patient (20%) with  
relapse achieved long-term survival.  
Seventeen patients (25%) had a CNS primary, of which  
eight (47%) were classic germinoma; five (29%) had  
IGCCCG intermediate- or poor-risk disease. Seven (41%)  
received primary chemotherapy alone; five (29%) received  
primary RT alone; five (29%) patients received both. Among  
those with 5 years of followup, 6/7 patients (86%) with CNS  
germinoma and 5/8 (63%) with non-seminomatous CNS pri-  
mary achieved long-term survival. One patient passed away  
due to possible bleomycin lung toxicity five months after  
BEP regimen. Five patients (29%) relapsed, of whom three  
patients (60%) achieved long-term survival.  
ease, and treatment characteristics and survival outcomes  
in male patients diagnosed with EGCTs in two Canadian  
tertiary cancer centres.  
Methods  
We performed a retrospective analysis on a consecutive  
list of all male patients diagnosed with EGCT and treated  
in Alberta. All cases of GCTs in the two tertiary cancer cen-  
tres (Tom Baker Cancer Centre, Calgary, AB; Cross Cancer  
Institute, Edmonton, AB) were reviewed; all consecutive  
cases in which treating physicians made the diagnosis of  
and proceeded with treatments for EGCT were included.  
All cases underwent attempts at pathologic diagnosis with  
either fine-needle, core-needle or excisional biopsy; 17  
patients had non-diagnostic pathology and were diagnosed  
and treated as EGCT based on tumour markers or clinical  
presentation. Electronic and paper charts were obtained and  
reviewed by the study coordinators using the pre-specified  
data template. Data for patients treated in Edmonton were  
only available between January 1, 2002 and December 31,  
2
010, while all data were accessible for patients treated in  
Calgary between January 1, 1990 and December 31, 2013.  
Disease relapse was determined if there was a rise in tumour  
markers or radiologic progression after the first-line cura-  
tive therapy was finished; post-chemotherapy resection of  
residual tumour was considered to be part of the first-line  
therapy and was not counted as relapse.  
Data were transferred from Excel to Stata S/E Version  
1
3 for analysis. Categorical variables were expressed as a  
Nineteen patients (28%) had a RP. Five (26%) were  
accompanied by other visceral or mediastinal lymph node  
metastases. Most (n=15, 79%) had non-seminoma. All  
received first-line chemotherapy; all but two received BEP.  
Eight (42%) patients had upfront or salvage surgical resec-  
tion, seven of which were found with viable tumour. All  
eight patients (42%) who relapsed had non-seminoma and  
died within one year of relapse. None of the RP patients  
received salvage high-dose chemotherapy with autologous  
stem cell support at the time of the first recurrence; only one  
patient received salvage high-dose chemotherapy after sal-  
vage chemotherapy failure, but eventually died from relapse.  
The most common salvage therapy was TIP (n=3), followed  
by VeIP (n=2), etoposide (EP) (n=1), and upfront salvage  
high-dose chemotherapy with stem cell support (n=1).  
Lastly, three patients (5%) had other (n=1 for prostate, n=1  
for intraperitoneal) or unknown primary (n=1). The patient  
with the prostate seminomatous primary achieved long-term  
complete remission (CR) after first-line chemotherapy, while  
the other two passed away despite treatment.  
frequency and percentage; patient age was expressed as  
mean and range. Overall survival (OS) was defined as the  
date of diagnosis to the date of death or last followup visit,  
with patients censored at their last followup visit. Disease-  
free survival (DFS) was defined as the date of diagnosis to  
the date of relapse, progression, death, or last followup visit  
and similarly censored at last followup visit. OS and DFS  
curves in the entire cohort and the following subgroups,  
stratified by the primary site, were estimated by Kaplan-  
Meier method with log-rank test to compare the differences  
among central nervous system (CNS), mediastinal (MP), and  
retroperitoneal primary (RP) sites. Hazard ratios for the risk  
group stratification (e.g. International Germ Cell Cancer  
Collaborative Group [IGCCCG]) were modeled by univari-  
ate Cox regression. A p value <0.05 was considered to be  
statistically significant.  
Results  
Between 1990 and 2013, 69 patients in two Albertan tertiary  
cancer centres were diagnosed with EGCT. Table 1 sum-  
marizes patient, disease and treatment characteristics for all  
The Kaplan-Meier curves of OS and DFS, stratified by  
the IGCCCG risk groups, are shown in Fig. 1. One patient  
is excluded for losing followup information. The five-year  
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Characteristics and outcomes of EGCT  
Table 1: Patient, disease, and treatment characteristics of the overall cohort and stratified by primary site  
Variable  
Overall (n=69)  
Mediastinal (n=30)  
CNS (n=17)  
Retroperitoneal (n=19)  
Age (range)  
29 (15–76)  
29 (16–55)  
21 (15–51)  
39 (21–76)  
IGCCCG risk groups  
Favourable  
24 (35%)  
14 (20%)  
31 (45%)  
0
12 (71%)  
1 (6%)  
10 (53%)  
4 (21%)  
5 (26%)  
Intermediate  
9 (30%)  
21 (70%)  
Poor  
4 (23%)  
Tumour characteristics  
Seminoma  
21 (30%)  
48 (70%)  
9 (1.5–26)  
9 (30%)  
21 (70%)  
12 (5–22)  
8 (47%)  
9 (53%)  
3 (1.5–4)  
4 (21%)  
15 (79%)  
10 (2–26)  
Non-seminoma  
Primary tumour size, median in cm (range)  
Tumour markers  
Elevated alpha-fetoprotein  
23 (33%)  
17 (57%)  
13 (43%)  
12 (40%)  
3 (18%)  
1 (6%)  
3 (16%)  
7 (37%)  
6 (32%)  
Elevated beta-human chorionic  
gonadotropin  
22 (32%)  
Elevated lactate dehydrogenase  
Treatments  
22 (32%)  
4 (23%)  
Surgical resection  
First-line chemotherapy  
BEP  
25 (36%)  
64 (93%)  
15 (50%)  
30 (100%)  
29 (97%)  
4/29 (14%)  
3 (10%)  
2 (12%)  
12 (71%)  
5 (29%)  
8 (42%)  
19 (100%)  
17 (89%)  
4/17 (24%)  
2 (11%)  
53 (77%)  
Bleomycin lung toxicity  
First-line RT  
10/53 (19%)  
15 (22%)  
1/5 (20%)  
10 (59%)  
Relapse  
Patients with relapse  
32 (46%)  
17 (57%)  
5 (29%)  
8 (42%)  
Prognostic score at relapse (IGCCCG2)18  
Very low  
Low  
Intermediate  
High  
0
1 (3%)  
5 (16%)  
4 (12%)  
22 (69%)  
0
0
0
2 (12%)  
15 (88%)  
0
0
2 (40%)  
2 (40%)  
1 (20%)  
0
1 (13%)  
3 (37%)  
0
Very high  
4 (50%)  
Treatments  
Salvage chemotherapy  
Salvage radiation therapy  
High-dose chemotherapy with  
autologous stem cell support  
25 (78%)  
8 (25%)  
6 (19%)  
15 (88%)  
3 (18%)  
5 (29%)  
2 (40%)  
2 (40%)  
1 (20%)  
7 (88%)  
2 (25%)  
0
BEP: bleomycin, etoposide, and cisplatin; IGCCCG: International Germ Cell Cancer Collaborative Group; RT: radiation therapy.  
OS (5YOS) and DFS (5YDFS) for all patients were 56% and  
4%, respectively. The 5YOS and DFS for MPs were 44%  
and 34%, respectively; for CNS primary, 76% and 53%; for  
RPs, 58% and 53% (Fig. 2). Significant differences among the  
Goss et al previously published a single-institution experience  
of 37 patients with EGCTs treated in a tertiary cancer centre  
4
19  
in Toronto, ON. The six-year OS for seminomatous EGCTs  
was 88%, while for non-seminomatous EGCTs, 53%. Our  
study shows a comparable results in all subgroups except in  
seminomatous MPs, with lower than expected 5YOS of 63%.  
Among the nine cases of seminomatous MPs in our cohort,  
three cases underwent resection of residual disease, which  
were fibrosis and/or necrotic tissues; four cases relapsed after-  
wards. This finding, despite the small number of patients, is  
unusual in gonadal seminoma. This may reflect inherent che-  
moresistance of MP-GCTs; however, unlike gonadal GCTs, in  
which orchiectomy specimens are obtained, tissue biopsies  
in MP-GCTs are typically inadequate and prone to potential  
sampling issues. Therefore, one hypothesis is that there is  
some degree of misclassification of non-seminoma into semi-  
noma. While the same may be true for other EGCTs, we did  
5
YOS (p=0.006) and 5YDFS (p=0.002) were noted among  
different primary sites, with the CNS primary showing the  
best survival and MP, worst. The factors that correlated with  
OS were elevated alpha fetoprotein (AFP) (p=<0.001) and/  
or human chorionic gonadotropin (HCG) levels (p=0.001),  
lactate dehydrogenase (LDH) levels (p=0.028), lung metastasis  
(p=<0.001), bone metastasis (p=<0.001), and IGCCCG risk  
group (p=0.001).  
Discussion  
To the authors’ knowledge, our study comprises the largest  
published Canadian cohort of patients with EGCTs to date.  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
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Ko et al.  
Fig. 1. Kaplan-Meier curve of (a) overall survival and (b) disease-free survival, for the overall cohort. X-axis in months; FAV: IGCCCG favourable risk group; INT:  
intermediate risk group; POOR: poor risk group.  
not note significant discrepancy between our outcomes and  
those reported in the literature for other primary sites when  
stratified by seminoma vs. non-seminoma except in MPs.  
Our results showed that the outcomes of EGCTs remain  
inferior to those of GGCTs, even in RP and CNS primary.  
This is contrary to other smaller studies that show generally  
15,20,21  
favourable prognosis for RP and CNS GCTs.  
However,  
these studies included too few non-seminomatous RP or CNS  
primary to make a meaningful comparison to our cohort.  
Larger studies, on the other hand, showed that 88% of  
Fig. 2. Kaplan-Meier curve of the overall survival (a) and disease-free survival (b), for the overall cohort and subgroups by primary site; X-axis in months; All: all  
patients with EGCT; CNS: intracranial primary GCT; MP: mediastinal primary GCT; RP: retroperitoneal primary GCT.  
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Characteristics and outcomes of EGCT  
seminomatous EGCTs, but only 45% of non-seminomatous  
nine of 26 patients who experienced postoperative com-  
plications were attributed to respiratory failure from bleo-  
1
1,17  
EGCTs, achieved long-term DFS.  
Furthermore, patients  
3
2
with non-seminomatous RPs had survival just as poor as  
those with MPs, an intriguing finding given that there exists  
evidence that RPs may simply represent GGCTs with burnt-  
mycin. None of the patients who received chemotherapy  
regimens other than BEP had respiratory complications. This  
finding underscores the importance of bleomycin avoidance  
in patients with potential risk factors for respiratory failure or  
anticipated surgical resection of residual tumours.  
In our cohort with CNS primary, there were seven cases  
of complete response and long-term survival with first-line  
chemotherapy alone without RT or surgical resection. CNS  
GCTs comprise a unique group of GCTs, with no uniform  
standards of care. In particular, our cohort contained a large  
proportion of suspected or confirmed non-germinoma. Data  
on non-germinomatous CNS tumours, including evidence  
2
2,23  
out gonadal primary.  
Inferior survival in EGCTs may be  
in part due to relative insensitivity to cisplatin-based che-  
motherapy and aggressive pathology inherent in EGCTs. For  
example, Pectasides et al showed that non-seminomatous  
EGCTs had a greater degree of p53, MIB-1, and COX-2  
overexpression compared with matched cohorts of GGCTs  
and seminomatous EGCTs, demonstrating potential biologic  
2
4
differences. Recent large trials, such as EORTC 30983 and  
GETUG 13, reported improved DFS, but similar OS with  
more intensive chemotherapy regimens in patients with  
for optimal treatment, are lacking due to their rarity and dif-  
2
5,26  
33,34  
high-risk GGCT.  
More studies are needed to elucidate  
ficulties in accurate histopathologic diagnosis.  
Generally  
whether more intensive chemotherapy or targeted therapy  
can improve outcomes in patients with EGCTs.  
accepted treatments include radiation therapy with or with-  
out chemotherapy, with favourable survival in classic ger-  
minoma, but less favourable in mixed histopathology.35-37  
At least one study reports a favourable prognosis and ger-  
minoma-like pathology in patients who achieve complete  
response with chemotherapy, but it is unknown whether a  
combined modality is superior to a single modality treat-  
ment. Even though in vitro studies have shown therapeutic  
concentrations of bleomycin and etoposide, the penetration  
of cisplatin into the intracranial space is limited.39-41 Further  
studies are needed to clarify the role of first-line radiation  
and chemotherapy in primary CNS GCTs.  
Salvage therapy in our patients with relapsed disease, espe-  
cially of RPs, also did not seem as effective as that reported  
in GGCT. In literature, about 19% of patients with recurrent  
EGCT achieve long-term DFS (11% mediastinal, 30% retro-  
27  
peritoneal). Our study included a high proportion of non-  
seminoma, especially in the retroperitoneal group, with less  
frequent use of high-dose chemotherapy with stem cell sup-  
port. In our cohort, TIP was most frequently used for salvage  
chemotherapy, while VIP (etoposide, ifosfamide and cisplatin)  
or VeIP regimens are commonly used in other centres, both  
38  
27,28  
as upfront and salvage therapy.  
Also, none of our patients  
with RPs received high-dose chemotherapy with stem cell  
support after first relapse, perhaps due to a perception that  
salvage chemotherapy may be sufficient for relapse. However,  
most of our patients who had salvage surgery had viable non-  
teratomatous malignancy in the surgical pathology. Given  
these findings, for selected patients with MP- and RP-GCTs  
who relapse — especially within one year of first-line therapy  
Conclusion  
In summary, EGCT is a rare, but important subset of GCTs.  
Patients with EGCT, in particular non-seminomatous, have  
poorer outcomes compared with gonadal primary despite  
aggressive treatments. Non-seminomatous EGCTs demon-  
strate relative chemo-resistance and further studies are need-  
ed to identify optimal upfront and salvage treatment options.  
aggressive, upfront salvage therapies, such as high-dose  
chemotherapy with stem cell support, may be appropriate.  
Our results confirm the rates of bleomycin lung toxicity  
in 1530% of the patients treated with BEP, similar to those  
Competing interests: Dr. Ko has received honoraria from Janssen. Dr. Alimohamed has received  
honoraria from Astellas and Bayer. Dr. Heng has been an Advisory Board member for Bayer, GSK,  
Novartis, and Pꢀzer. The remaining authors declare no competing ꢀnancial or personal interests.  
2
9-31  
Importantly, three  
reported in GGCT patients (046%).  
patients had Grade 35 respiratory failure, possibly due to  
bleomycin exposure, with no clear risk factors otherwise. In  
our study, almost all patients with MPs and RPs received BEP  
as first-line therapy. While the BEP regimen is the standard of  
care in GGCTs and is most established in the management of  
EGCTs, there is some evidence to suggest that this regimen  
may interfere with optimal surgical management and post-  
operative outcomes due to bleomycin-related lung toxicity.  
For example, in a large case series of surgical resection of  
residual disease in the EGCT patients, Kesler et al reported  
that nine of 10 patients who had postoperative mortality and  
This paper has been peer-reviewed.  
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CUAJ • May-June 2016 • Volume 10, Issues 5-6