ORIGINAL RESEARCH

Disease characteristics and survival outcomes of extragonadal

primary germ cell tumour in two Canadian tertiary cancer centres

Jenny J. Ko, MD; Tehmina Asif, MD; Haocheng Li, MD; Nimira Alimohamed, MD; Phuong Thao Nguyen,

MD; Daniel Y.C. Heng, MD

Department of Medical Oncology, Abbotsford Cancer Centre, Abbotsford, BC, Canada; Department of Medical Oncology, Saskatchewan Cancer Agency, Saskatoon, SK, Canada; Departments of Oncology

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

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

-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

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,

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

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-

3,14

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 30‒40% 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,

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

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%)

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

1 (3%)

5 (16%)

4 (12%)

22 (69%)

2 (12%)

15 (88%)

2 (40%)

1 (20%)

1 (13%)

3 (37%)

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%)

1 (20%)

7 (88%)

2 (25%)

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

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

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.

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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-

1,17

EGCTs, achieved long-term DFS.

Furthermore, patients

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

2,23

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

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-

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^-⁴¹Further

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-

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

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 15‒30% 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.

9-31

Importantly, three

reported in GGCT patients (0‒46%).

patients had Grade 3‒5 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