Annals of Oncology 21 (Supplement 5): v140–v146, 2010
doi:10.1093/annonc/mdq176clinical practice guidelines
Testicular seminoma: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
H.-J. Schmoll1, K. Jordan1, R. Huddart2, M. P. Laguna Pes3, A. Horwich2, K. Fizazi4 & V. Kataja5
On behalf of the ESMO Guidelines Working Group*
1Department of Oncology/Haematology/Haemostaseology, University Hospital Halle, Halle, Germany; 2Department of Academic Radiotherapy, Institute of Cancer
Research, Royal Marsden Hospital, Sutton Hospital, UK; 3Department of Urology, AMC University Hospital, Amsterdam, The Netherlands; 4Department of Medicine,
Institute Gustave Roussy, Villejuif, France; 5Department of Oncology, Kuopio University Hospital, Kuopio and Vaasa Central Hospital, Vaasa, Finland
incidence
The incidence of testicular cancer in Europe is rising, with
doubling every 20 years. The current incidence is 6.3/100 000/
year, with the highest rate in Northern European countries
(6.8/100 000/year). The death rate is very low (0.38 cases/
100 000/year). Of testicular tumours, 40% are seminomas and
60% non-seminomas.
Invasive testicular cancer develops from carcinoma in situ
(CIS)/testicular intraepithelial neoplasia (TIN), often found in
the residual non-malignant testicular tissue. In a random
biopsy, 2%–5% of testicular cancer patients have CIS in the
contralateral testis. This is in accordance with a 2%–3% rate of
synchronous contralateral or metachronous testicular cancer.
diagnosis
The diagnosis is based on histology of the testicular mass
removed by inguinal orchiectomy or by testis-conserving
surgery [IV, B].
Biopsy or, instead, high b-human chorionic gonadotropin
(b-HCG) without biopsy in patients presenting with
extragonadal tumour syndrome (patients with HCG >200
should be regarded as non-seminoma) [IV, B].
In advanced and rapidly progressive disease requiring urgent
chemotherapy, diagnosis may be based on typical clinical
picture and possible marker elevation alone.
Germ cell tumour may present extragonadally in the
retroperitoneum or mediastinum in a minority of cases. In one-
third of these patients there is CIS in the testis and one-third
has scar tissue (‘burned out tumour’), leaving one-third of the
patients having definitive primary extragonadal germ cell
tumour without affecting the testicle. These patients present
with undifferentiated (adeno)carcinoma of unknown origin,
mostly with typical marker elevation and/or elevated copy
number of chromosome i12p, which is specific for germ cell
tumours.
staging and risk assessment
Full blood count, creatinine, electrolytes and liver enzymes
should be obtained. Tumour markers [a-fetoprotein (AFP),
b-HCG and lactate dehydrogenase (LDH)] are needed for
confirmation of pure seminoma and for risk assessment
according to UICC/IGCCCG stage and prognostic index.
Markers are taken before orchiectomy and repeated
a minimum of 7 days after orchiectomy. Pure classical
seminoma does not secrete AFP; however, in some cases
elevated levels of HCG may be present.
Patients with raised AFP should be managed as for non-
seminoma, even if histology is pure seminoma.
Testicular sonography (7.5 MHz transducer) should be
conducted, also noting the size of the contralateral testis.
Thoracic CT scan (not mandatory for seminoma stage I),
abdomen and pelvis [III, B]. MRI of the central nervous system
is needed only in advanced stages or with symptoms. Bone scan
should be conducted in case of indirect indicators for
involvement (e.g. symptoms).
PET scanning does not contribute in early stages of seminoma
[I, B], but is a possible option for stages II/III, in particular for
defining treatment strategy in case of residual tumour.
If fertility is an issue, the following is recommended:
determination of total testosterone, lutenizing hormone (LH)
and follicle-stimulating hormone (FSH) (determined before
operation), semen analysis and sperm banking (before
operation or chemotherapy).
In case of a borderline lymph node size in imaging
(normal <1 cm), CT scan should be repeated 6 weeks later
before defining definitive treatment strategy. If imaging is
normal, tumour marker decline should be monitored until
normalization in order to discriminate stage I and disseminated
disease.
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: April 2002, last update January
2010. This publication supercedes the previously published version—Ann Oncol 2009;
20 (Suppl 4): iv83–iv88.
Conflict of interest: Professor Schmoll has reported no conflicts of interest; Dr Jordan
has reported that she is a speaker for MSD Germany; Professor Huddart, Dr Laguna
Pes, Professor Horwich, Professor Fizazi and Dr Kataja have reported no conflicts of
interest.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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Definition of stage and risk classification must be done
according to the UICC/American Joint Committee on Cancer
(AJCC) and IGCCCG classification (Table 1).
For histology, the World Health Organization (WHO)
classification must be used and the report must specify the
tumour localization, size, multiplicity, extension of tumour
(e.g. in rete testis or other tissue), pT category (UICC),
histopathological type (WHO) and presence of
syncytiotrophoblasts. In pluriform tumours, each individual
component should be described, with percentage presence or
absence of vascular invasion (venous or lymphatic) and
presence of TIN.
treatment of primary tumour
Orchiectomy is standard of care and partial orchiectomy may
be performed in specific indications [II, B].
Surgery of the primary should be performed before any
further treatment, unless there is life-threatening
metastatic disease and clear clinical diagnosis of germ cell
tumour by marker elevation which requires immediate
chemotherapy.
Tumour marker analysis should be performed before surgery
and, if elevated, 7 days after surgery to determine the half-life
kinetics. Tumour markers should be monitored until
normalization. Markers should be taken after surgery, even if
normal.
radical orchiectomy
Radical orchiectomy is performed through an inguinal incision
[II, A]. Any scrotal violation for biopsy or open surgery should
be strongly avoided. Tumour-bearing testis is resected with the
spermatic cord at the level of the internal inguinal ring.
A frozen section is recommended in doubtful cases (of small
tumours) before definitive surgery [II, B], to allow organ-
sparing surgery.
organ-preserving surgery/partial orchiectomy
Radical orchiectomy may be avoided and replaced by organ
preserving surgery; however, only in highly experienced centres
and, in particular, in the case of synchronous bilateral testicular
tumours, metachronous contralateral (second) testicular
tumour, tumour in a solitary testis and sufficient endocrine
function, and contralateral atrophic testis.
After local resection the spared testicular tissue always
contains TIN, which can be destroyed by adjuvant
radiotherapy. This can and should be delayed in patients who
wish to father children, but for a period as short as possible.
contralateral biopsy for diagnosis of TIN
Some 3%–5% of testicular cancer patients have TIN in the
contralateral testis with the highest risk (‡34%) with testicular
atrophy (volume <12 ml) and age <40 years, and in patients with
extragonadal germ cell tumour prior chemotherapy (‡33%), but
only in 10% post-chemotherapy. If untreated, invasive testicular
tumour develops in 70% of the TIN-positive testis within 7 years.
The sensitivity and specificity of one random biopsy for the
detection of TIN is very high. Therefore, patients should be
informed about the potential risk of TIN and a contralateral
biopsy should be offered. However, patients themselves should
be given the opportunity to decide whether a biopsy should be
done or only monitoring performed—assuming the same high
level of survival (nearly 100%) whatever strategy is chosen.
If the patient has had chemotherapy a biopsy should not be
taken <2 years from treatment.
treatment of TIN
If TIN has been diagnosed the options include immediate
definitive treatment, surveillance with delayed active treatment
or no treatment. The strategy should be chosen by the
patient depending on the individual needs, in particular if
fertility is an issue. However, fertility potential is often very low
in this group of patients. If fertility has to be maintained,
definitive treatment should be delayed and substituted by active
surveillance until conception followed by either active
treatment or further surveillance. If fertility is not relevant,
irradiation with 16–20 Gy (2 Gy fraction, five�times per week)
[III] should be performed (the strongest evidence is for 20 Gy).
In patients with TIN and no gonadal tumour (incidental
diagnosis, e.g. by biopsy for infertility or extragonadal germ cell
tumours) orchiectomy is preferred over irradiation, because of
potential damage to the contralateral, non-affected testis by
scattered radiation.
For TIN in patients receiving chemotherapy, chemotherapy
eradicates TIN in two-thirds of patients. Therefore, treatment
for TIN is only indicated if re-biopsy after chemotherapy is
considered; however, not earlier than 2 years after
chemotherapy. Instead of definitive treatment for TIN, it is
strongly suggested to follow up the patient by monitoring
alone, including the possibility of a (re)biopsy.
treatment of stage I
Some 75% of patients with seminoma have stage I disease, with
a survival of >99% independent of the chosen strategy. Most
important is to minimize the burden of treatment as much as
possible. Active (adjuvant) treatment should be avoided and
substituted by active surveillance independent of the individual
risk for relapse (Table 2).
The relapse rate at 5 years is 12%, 16% and 32% in patients
without risk factors, with one risk factor and with two risk
factors (tumour size ‡4 cm; invasion of the rete testis),
respectively [II, B]. In 97%, relapse occurs in the
retroperitoneal or high iliac lymph nodes. Late relapse is
possible even after 10 years in very rare cases.
A risk-adapted strategy with selection of adjuvant treatment
according to the individual risk is currently being investigated
and still experimental.
With surveillance strategy as standard approach, up to 88%
of the standard patient population does not need any treatment
after the local tumour ablation. Only if surveillance is not
applicable, the equally effective alternatives are either adjuvant
carboplatin (one cycle, area under the curve 7) [I, A] or
adjuvant radiotherapy (20 Gy in 2 Gy fractions; para-aortic
fields) (for field description see Table 3).
Annals of Oncology clinical practice guidelines
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clinical practice guidelines Annals of Oncology
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Both options deliver the burden of active systemic or
local treatment to 100% of the patients and, in addition, full
PEB chemotherapy to 3%–5% of the patients because of
relapse after adjuvant treatment. Since with any modality
(surveillance only or adjuvant carboplatin or radiation) the
survival is ‡98%. Surveillance offers the lowest burden of
overall treatment.
treatment of stage IIA (lymph nodes
1–2 cm)/borderline IIB (lymph nodes
2–2.5 cm)
Clinical stage IIA seminoma should be verified beyond standard
imaging, e.g. by fine-needle biopsy, before initiation of systemic
chemotherapy.
Standard treatment is para-aortic and ipsilateral iliac
radiotherapy to 30 Gy in 2 Gy fractions (Table 3).
Chemotherapy (PEB for three cycles or PE for four cycles, if
there are arguments against bleomycin) is an equivalent option
with different and more acute toxicities, but probably less risk
for secondary cancer.
treatment of stage IIB (lymph nodes
2.5–5 cm)
PEB for three cycles is standard (3- or 5-day schedule). If there
are arguments against bleomycin [reduction in lung capacity,
emphysema, severe (ex)smokers, etc.] then four cycles of PE are
used (Table 2).
For patients refusing or otherwise non-candidates for
chemotherapy, para-aortic and ipsilateral iliac field
radiotherapy to 36 Gy in 2 Gy fractions is standard
(Table 3).
treatment of advanced seminoma
stage IIC/III
Chemotherapy with PEB is standard treatment (Table 2): three
cycles for good prognosis patients (3- or 5-day schedule) and
four cycles for intermediate prognosis patients (5-day schedule)
(see below).
In case of an increased risk for bleomycin-induced lung toxicity,
three cycles of PEB in good prognosis patients may be substituted
by four cycles of PE. In patients with intermediate prognosis the
substitution of bleomycin by ifosfamide, without increasing the
number of cycles, seems to be an appropriate option [I, B].
Chemotherapy consists of PEB given as a 5- or 3-day
schedule for good prognosis patients and as 5-day schedule
for intermediate prognosis patients [I, B]. The 5-day schedule
is cisplatin 20 mg/m2 (30–60 min), days 1–5; etoposide 100 mg/
m2 (30–60 min), days 1–5; bleomycin 30 mg (absolute)
bolus, days 1, 8 and 15. The 3-day protocol is cisplatin 50
mg/m2 (30–60 min), days 1–2; etoposide 165 mg/m2 (30–60
min), days 1–3; bleomycin 30 mg (absolute) bolus, days
1, 8 and 15.
In the case of complete response, follow-up only is required.
In cases of residual tumour >3 cm, a PET scan (a minimum of 6
weeks after chemotherapy) is recommended, whereas it is only
Table 3. Radiation doses and fields for early stage seminoma
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optional in residual lesion <3 cm (in lesions <3 cm predictive
value is less proven).
If PET scan is positive there is strong evidence for residual
active tumour and resection should be considered. If PET scan
is negative, follow-up only without active treatment is needed.
If no PET is done, lesions >3 cm can be either resected or
followed only until resolution or progression.
salvage treatment
relapse after radiation of early stages of seminoma
Chemotherapy is the treatment of choice (standard
chemotherapy as in stage IIC/III). In cases with localized, small
volume relapse (re)irradiation may be considered instead of
chemotherapy, in particular if the interval has been long and it
is not a disseminated relapse.
relapse after primary chemotherapy
salvage chemotherapy. Relapse after a longer (>3 months)
period following initial favourable response does not always
represent a platinum-resistant situation. Cisplatin is part of
salvage treatment protocols, preferably together with
additional agents that have not been used in the first-line
treatment.
After second-line and, in some cases, also after third-line
treatment, chemosensitivity may still be present.
Standard first-line salvage chemotherapy is standard dose
VIP (etoposide, ifosfamide, cisplatin), TIP or VeIP. There is no
proven benefit of high-dose chemotherapy for first- or second-
line salvage treatment.
In refractory patients, e.g. those who never reach a marker-
negative complete response after first-line treatment or have no
favourable response after salvage treatment, no standard
treatment can be recommended. Gemcitabine/paclitaxel may be
considered as an option. High-dose chemotherapy in this
setting is highly experimental and should only be performed in
clinical trials. Surgery should be part of the strategy, in
particular in those patients with localized or late relapse with
poor response to chemotherapy. Patients should be included in
clinical trials and referred to expert centres whenever possible.
response evaluation for metastatic
disease
The treatment effect must be monitored by appropriate
measures (chest X-ray, CT scan and markers) at 1 month after
end of treatment [IV, B]. In the case of residual mass a PET
scan is recommended [II].
follow-up
The recommended follow-up schedules are very pragmatic and
have never been validated. Table 4 gives an exemplary
programme.
note
Levels of Evidence [I–V] and Grades of Recommendation
[A–D] as used by the American Society of Clinical Oncology
are given in square brackets. Statements without grading were
considered justified standard clinical practice by the experts and
the consensus conference panel.
acknowledgements
The manuscript is based on the results of an expert panel
discussion, organized and financed by an educational grant of
the European Society of Medical Oncology (ESMO) in
Table 4. Follow-up for seminoma
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association with the ESMO Symposium on Testicular Cancer,
EIS in May 2008 and was performed as a formal expert
consensus conference. Members of the consensus conference
panel are H.-J. Schmoll (Chair), Germany; M.P. Laguna
(Co-chair), The Netherlands; K. Fizazi (Co-chair), France;
A. Horwich (Co-chair), UK; P. Albers, Germany; W. Albrecht,
Germany; F. Algaba, Spain; A. Bamias, Greece; I. Bodrogi,
Hungary; G. Cohn-Cedermark, Sweden; S. Culine, France;
M. Cullen, UK; G. Daugaard, Denmark; M. De Santis, Austria;
R. De Wit, The Netherlands; G. Derigs, Germany; K.
Dieckmann, Germany; J.P. Droz, France; L. Einhorn, USA;
A. Fle´chon, France; S. Fossa, Norway; J. Garcia del Muro
Solans, Spain; T. Gauler, Germany; L. Ge´czi, Hungary; J.R.
Germa Lluch, Spain; S. Gillessen, Switzerland; M.
Gosporadowicz, Canada; M. Hartmann, Germany; R. Huddart,
UK; M. Jewett, Canada; J. Joffe, UK; K. Jordan, Germany;
V. Kataja, Finland; O. Klepp, Norway; C. Kollmannsberger,
Canada; S. Krege, Germany; L. Looijenga, The Netherlands;
G.M. Mead, UK; A. Necchi, Italy; C. Nichols, USA; N. Nicolai,
Italy; T. Oliver, UK; D. Ondrus, Slovak Republic; W. Osterhuis,
The Netherlands; L. Paz-Ares, Spain; T. Powles, UK; T. Pottek,
Germany; E. Rajpert-De Meyts, Denmark; G. Rosti, Italy;
G. Rustin, UK; R. Salvioni, Italy; H. Schmidberger, Germany;
F. Sedlmayer, Austria; A. Sella, Israel; C. Sippel, Germany;
N.E. Skakkebaek, Denmark; R. Souchon, Germany; A. Sohaib,
UK; S. Tjulandin, Russia; A.W. van den Belt-Dusebout, The
Netherlands; H. von der Maase, Denmark; P. Warde, Canada;
L. Wood, Canada.
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2. Oliver RT, Mason MD, Mead GM et al. Radiotherapy versus single-dose
carboplatin in adjuvant treatment of stage I seminoma: a randomi