Download CME_Testis Cancer_Erik Mayer_Accepted - Spiral

Primary testicular tumours and management of Clinical
Stage 1 Testicular Cancer
Elsie Ellimah Mensah1, David Nicol2, Erik Mayer1, 2
1 Imperial College London
2 Royal Marsden Hospitals
Introduction
Testicular cancer comprises 1% of cancers in men but is the commonest malignancy in young men
aged 15-40 in Western populations.[1] The incidence has risen over the last 40 years globally.
Mortality rates in Westernised countries is reducing reflecting improved therapeutic options and
multidisciplinary specialist centre management.[2] With excellent cure rates there is an increasing
focus on minimising treatment related side effects and morbidity.
Classification of testicular tumours
Testicular cancers are classified as germ cell tumours (GCTs) or sex cord-stromal tumours.
Approximately 95% are GCTs [3] which are further classified as seminomatous germ cell tumours
(SGCT) or non-seminomatous germ cell tumours (NSGCT) with the latter usually containing a mixture
of histological sub-types [4].
Sex cord-stromal tumours comprise <5% of testicular tumours. The most relevant subtypes clinically
are leydig cell tumours, which represent 70% of cases, and sertoli cell tumours.[5]
Demographics
The peak incidence for SGCT is 30-40 years and 20-30 years for NSGCT. [6] Leydig cell tumours
commonly present between the third and sixth decades of life with an earlier peak in children aged
3-9 years. Sertoli cell tumours are rare and occur most frequently in men in their 40’s. [7]
Wide geographical variation in incidence rates is reported with lowest in Egypt and highest in
Northern Europe.[6] These variations are likely to be influenced by both genetic susceptibility and
environmental risk factors. Even within Northern Europe incidence varies, for example Denmark has
twice the incidence of Finland.[8] Increasing incidence has been documented in specific Eastern
European countries (e.g. Slovenia and Slovakia), suggesting environmental risk factor changes.[8]
Risk Factors and Aetiology
The aetiology of GCTs is not fully understood. Intra-testicular germ cell neoplasia (ITGCN), also
termed carcinoma in situ (CIS) is the accepted precursor. It is hypothesised that early disturbances in
the differentiation of immature foetal germ cells initiates a cascade of changes leading to ITGCN
which subsequently progresses to tumour formation generally in the post-pubertal period.[9]
Cryptorchidism, hypospadias and low sperm counts are well documented risk factors or associations
with GCTs. Collectively grouped under the term testicular dysgenesis syndromes, they may reflect an
unfavourable environment during testicular development in the prenatal stage (figure 1).
Figure 1: The testicular dysgenesis pathway. Reproduced with kind
permission from [10].
Cryptorchidism is associated with a 4-8 times greater risk of developing testicular cancer. An
alternative to the testicular dysgenesis pathway is that the maldescended testicle is exposed to an
abnormal environment which subsequently leads to the formation of CIS and testicular cancer.
Some studies have reported increased testicular tumour risk in patients who have had delayed
orchidopexy compared with those who had it at a younger age. These findings have however not
been shown in other studies and thus both theories remain valid albeit unproven. [6]
First degree relatives of patients with GCTs have a 4-8 fold increase in the risk - supporting a genetic
contribution to a shared genetic and environmental risk model. Familial factors that have been
postulated include an activation mutation in the KIT gene which has been detected in some sporadic
and familial tumours, particularly bilateral tumours.[10,11]
A previous testicular tumour is a further risk factor for GCTs with a cumulative rate of approximately
5% reported.[6,12]. This closely reflects the incidence of CIS when biopsy of the contralateral testis is
performed at time of initial presentation.
Testicular microlithiasis is frequently present in patients with GCTs although also common in the
general population. In the absence of other risk factors, such as personal/family history of GCTs or
cryptorchidism, microlithiasis is not an independent risk factor. [13]
Increased oestrogen exposure during prenatal development has been postulated as an underlying
factor in the genesis of GCTs and a possible explanation for the changing variation in incidence.[14]
Potential causes include plastics common in western environments and increased output of urinary
oestrogens secondary to oral contraceptive pill use in women. It has been suggested that Bisphenol
A (BPA), a known oestrogenic compound used in plastic manufacture and present in the resin lining
of canned food and some dental sealants, may via hormonal effects, disrupt endocrine pathways
during foetal development.[15] The finding of free BPA in human cord blood supports this
hypothesis by confirming maternal absorption and placental transfer.[16] Current research is
exploring pathways by which increased oestrogen exposure may have a carcinogenic effect.
Transmembrane G protein receptor (GPER) is a promotor of oestrogen activity in germ cells[9] with
potential roles in spermatogenesis and testicular development. In vitro BPA accelerates seminoma
cell proliferation. This effect is obliterated by the addition of a specific GPER antagonist suggesting
that BPA may have an effect on germ cell proliferation via GPER.[15]
As with all cancers GCTs are likely to have both initiators and promoters. Foetal events are likely to
underpin the former. The fact that the vast majority of GCT present after puberty suggest that
hormonal changes associated with this event may promote progression from CIS. Xenograft models
of human GCTs have demonstrated that manipulation of the gonadotropin axis including FSH and LH
significantly influences tumour growth supporting this hypothesis.[17]
Clinical Assessment
Testicular cancer usually manifests as a painless testicular lump although patients may uncommonly
present with testicular pain, minor trauma or even epididymo-orchitis. The initial history should
include identification of risk factors encompassing cryptorchidism as well as personal or family
history of testicular tumours. Clinical examination must include the scrotum and a general
assessment for signs of metastatic disease. These may include lymphadenopathy or a palpable
abdominal mass. Respiratory tract signs may indicate pulmonary metastasis which necessitates
urgent intervention.
Serum tumour markers (alpha-fetoprotein (AFP), lactate dehydrogenase (LDH) and human chorionic
gonadotrophin (b-HCG)) should be routinely measured. Whilst negative results do not exclude GCT
these are useful adjuncts for diagnosis and when raised pre-operatively, are critical to assessing
response to treatment. Tumour markers can also be normal at presentation but rise with
subsequent systemic relapse or the development of contralateral tumour.
AFP is produced by yolk sac cells and has a serum half-life of 3-5 days. It is produced in early
development of the liver and not specific to testicular tumours with elevations in hepatocellular
carcinoma, hepatic dysfunction and substance abuse misuse. Elevated levels with GCTs indicating a
non-seminomatous component. It is raised in up to 70% of NSGCT.
B-HCG is a glycoprotein expressed by syncytiotrophoblasts and is raised in germ cell tumours
particularly choriocarcinoma. The normal value is <5ng/ml (there may be local laboratory variability)
with a half-life of 24-36 hours. Both SGCT and NSGCT can produce b-HCG with very high levels
(>300ng/ml) restricted to NSGCT[4]. B-HCG is present in urine forming the basis of urine pregnancy
tests; which may be utilised in emergency departments as a tool to help make a GCT diagnosis. This
tool has also been used in austere medical environments such as in the military.[18] It has been
suggested that cannabis or marijuana use spuriously elevates HCG; this is not supported by current
literature. [19,20]
LDH is a less specific marker merely reflecting tumour burden as its concentration is proportional to
tumour volume. It is raised in up to 80% of SGCT and 60% of NSGCT.
It is useful to assess serum testosterone levels at baseline. This may assist counselling patients if
androgen supplementation is a possibility post-orchidectomy, e.g. atrophic contralateral testis.
Stromal tumours typically present similarly to GCT although may also produce symptoms such as
gynaecomastia reflecting endocrine dysfunction. When these signs are present luteinising hormone
(LH) and follicle stimulating hormone (FSH) should also be assessed.
Testicular ultrasonography is an import adjunct to scrotal examination. It can differentiate intratesticular from extra-testicular masses, determine the presence multiple testicular lesions and
evaluate the contralateral testicle. A 7-10MHz high frequency transducer is used and the assessment
should be done in at least 2 planes. SGCT are usually homogenous hypo-echoic lesion(s) occasionally
replacing the entire testicle. NSGCT are often heterogeneous with poorly defined margins reflecting
their mixed histology with cystic components suggesting teratomatous elements. [21]
When testicular cancer is clinically diagnosed, CT imaging of the chest/abdomen and pelvis will be
required for staging purposes. This may be delayed until after surgery although chest x-ray is
required prior to orchidectomy to exclude significant pulmonary metastasis.
Initial Management
Following assessment of patients with a diagnosis of clinical stage 1 an inguinal orchidectomy should
be performed. This confirms the diagnosis, including local staging information and provides
histological prognostic features.
Orchidectomy is a confronting prospect psychologically for the patient [22] and
thus standard practice is to offer a testicular prosthesis. This can be performed concurrently at time
of orchidectomy or as an interval procedure. An important caveat is for those patients known to
need, or at high-risk of needing, adjuvant chemotherapy i.e. clinical stage II to IV or very high tumour
markers. The risk of prosthesis-related infection is in the order of 1-2% and if it occurs, the need for
its removal and antibiotics, will delay chemotherapy. Insertion of testicular prosthesis at the time of
radical orchidectomy (synchronous prosthesis insertion) has been shown to be safe. [23]
Dissatisfaction related to the cosmetic outcome may occur and hence more realistic expectations
may be achieved if the patient is able to see samples of available prostheses.[24] Other risks
associated with prosthesis insertion are extrusion (although rare when inserted through a groin
incision), migration, haematoma formation and chronic pain. Concerns have been raised regarding
the long-term safety of silicone based testicular implants and this has led to the development of
saline filled implants. The long term safety and efficacy data on these is still unknown.[25]
Organ-sparing surgery may be considered in selected patients. Currently accepted oncological
indications are synchronous bilateral tumours and metachronous contralateral tumours.[26] Current
EAU testicular tumour guidelines recommend that this may be considered in cases where the
tumour represents <30% of the testicle. Adjuvant treatment in the form of radiotherapy delivered to
the remnant testicular tissue (18-20 Gy) is used to address residual ITGCN and reduce the risk of
local recurrence. [7] Irradiation at this dose affects fertility whilst preserving leydig cell function to
allow normal testosterone production. [27] Testosterone replacement will be required in patients
who do suffer impaired leydig cell function. Likewise, patients with an atrophic contralateral testicle
may also require testosterone supplementation and it is in this sub-group of patients that organsparing surgery can be considered in order to try and preserve endogenous endocrine function.
Irradiation following organ-sparing surgery has been shown to be effective at treating ITGCN and
preventing disease relapse. [28]
Fertility is of concern to patients and must therefore be addressed. Patients with GCTs, even prior to
treatment are more likely to have abnormal semen parameters.[29] Sperm banking prior to
orchidectomy is not an absolute requirement but is preferable if the contralateral testis is atrophic.
This should not delay oncological treatment unduly and thus these discussions should start early in
the patient pathway when possible. None of the chemotherapeutic agents routinely used in the
management of testicular germ cell tumours (carboplatin, bleomycin, etoposide and cisplatin) cause
long term infertility when used in the first line setting. [30] Recovery usually occurs within 1-5 years
although may take longer if patients have low pre-treatment sperm counts. Recovery may not occur,
however, if patients have subsequent courses of chemotherapy.[30] Sperm banking should be done
before chemotherapy [30] but may still be feasible up to 14 days after initiation of the first cycle.
[31]
The human fertilisation and embryology authority (HFEA) is the independent body regulating human
embryology and fertilisation treatment and research in the United Kingdom. Under the Human
Fertilisation and Embryology Act HFEA licences and regulates clinics with a strict code of conduct to
which they must adhere.[34]
Prior to sperm storage, patients should have the opportunity to discuss the process including costs
and storage time limits. Currently, sperm storage for people who are about to undergo treatment
likely to impair fertility is funded by the NHS based on local Clinical Commissioning Group (CCG)
acceptance criteria. Patients who do not meet their local CCG criteria may self-fund as NHS patients
and the currently quoted price for sperm freezing and storage for the first year is about £300. [33]
The standard storage time limit is 10 years in the United Kingdom. Patients must undergo screening
for infectious disease including HIV, Hepatitis B and C. They will need to provide written consent for
sperm storage and will have the opportunity to detail wishes on issues such as the fate of sperm if
they die or are unable to make decisions including whether partners can use the samples at a later
date. Patients must understand that there is no guarantee of sperm quality after thawing and sperm
may be damaged in the freezing process. There are also options for cryopreservation of testicular
tissue in specialised centres as well as opportunities for sperm retrieval at the time of surgery in
cases of obstructive azoospermia.
‘Cancer patients’ are more likely than ‘infertility patients’ to use or continue storage of banked
samples, [34] but even in this group utilisation of the cryopreserved sperm is low (<10%). [35]
Staging
Local staging of testicular tumours is completed with histological assessment of the orchidectomy
specimen. Clinical staging is determined by confirming the presence or absence of metastatic
disease by cross-sectional imaging (CT chest, abdomen and pelvis) as well as post orchidectomy
serum tumour markers levels. Additional imaging, including bone and/or brain is undertaken if
clinically indicated based on symptoms.
GCTs metastasise in a predictable and systematic manner from the primary site to retroperitoneal
lymph nodes to distant sites, most commonly lungs and posterior mediastinum. The lymphatic
drainage is such that right-sided testicular tumours drain first to the inter-aortocaval region,
followed by precaval and paracaval nodes. Left-sided tumours on the other hand drain to the
preaortic and para-aortic lymph nodes and then to the inter-aortocaval nodes.[36] Contralateral
spread (cross-over) is commonly seen for right-sided tumours but is rare for left-sided tumours. Sex
cord-stromal tumours metastasise in a similar pattern. Involvement of the pelvic lymph nodes can
occur either because of scrotal invasion by the primary tumour, a high-burden of retroperitoneal
lymph node disease which is postulated to cause retrograde spread to the iliac node chain or in
cases where the anatomical normal lymphatic drainage has been disrupted as a consequence of
previous inguino-scrotal surgery such as orchidopexy for maldesceded testicle.
Staging systems commonly in clinical use include the TNM system for staging malignant disease and
the Royal Marsden Hospital testicular cancer staging system which is widely used in the United
Kingdom.[37] For the TNM system, “T” relates to the primary tumour after orchidectomy, “N” to the
lymph node status which is determined either on clinical imaging or following pathological
assessment of lymph nodes (suffix p used), and “M” relates to metastasis. For the Royal Marsden
system, a stage I – IV classification is described as shown. (Table 1)
Stage 1 testicular cancers can be further classified as 1A or 1B.


Stage 1A: Primary tumour limited to testis and epididymis. No lymphatic or vascular invasion,
no metastasis. Tumour markers return to normal post orchidectomy.
Stage 1B: Locally invasive, not metastatic
“Stage 1” disease more accurately refers to clinical stage 1 (CS1) disease based on the orchidectomy
specimen, normalisation tumour markers after surgery and absence of metastatic disease on
imaging. Pathological stage 1(PS1) refers to CS1 patients who undergo retroperitoneal lymph node
dissection (RPLND) following orchidectomy with no histological node involvement.
Approximately 80% of SGCT and 55% of NSGCT patients present with CS1 disease.[38] These
tumours are highly curable thus the need to determine which treatment options preserve the high
cure rate whilst minimising harm to the patient.
Table 1: Royal Marsden Staging System for Testicular Cancer
STAGE
DESCRIPTION
I
Confined to the testis and peritesticular tissue
IM
Rising concentrations of serum tumour markers without evidence of metastatic disease
II
Abdominal nodal metastasis
A
<2cm
B
2-5cm
C
>5cm
III
Supradiaphragmatic nodal metastasis
M
Mediastinal
N
Supraclavicular, cervical or axillary
O
No abdominal node metastasis
(Node stage as decribed for stage II above)
IV
Disseminated disease
Lung

L1
<3 metastasis

L2
≥3 metastasis, <2cm diameter

L3
≥3 metastasis, one or more >2cm diameter
H+
Liver metastasis
Br+
Brian metastasis
Bo+
Bone metastasis
Management of CS1 disease post orchidectomy
Observational studies looking at the patterns of disease relapse in CS1 disease have demonstrated
high survival rates with active surveillance alone (99% 5-year disease specific survival). [39] Although
surveillance, therefore, is a popular management option it is important to identify the sub-group of
patients who are at increased risk of distant disease relapse and would therefore benefit from
adjuvant therapy. The majority of relapses occur within 2 years for NSGCT and 3 years for SGCT.
Seminomatous germ cell tumours (SGCT)
Contemporary data shows that 14% of patients with SGCT have occult metastatic disease and will
relapse on surveillance.[40] For SGCT, tumour size and rete testis invasion are prognostic risk factors
for identifying patients at greatest risk of relapsing. [41,42] Tumour size is a continuous variable and
thus the larger the tumour size, the greater the risk of relapse. For the purposes of risk stratifying
patients, a tumour size >4cm is generally accepted as the cut off for high-risk of relapse. Patients
without either of the two risk factors have <3% relapse rate on surveillance as compared with 21% if
risk factors are present (overall relapse rate of 14% in a non-risk stratified group). [40]
Seminoma cells are very radio-sensitive and CS1 SGCT patients have historically been treated with
adjuvant retroperitoneal radiotherapy [40]. The low risk of occult metastatic disease however means
that this approach is unnecessary in the vast majority of patients and yet exposes them to treatment
related side effects. The risk of radiation induced secondary malignancies is an important
concern.[43] Adjuvant radiotherapy is not currently recommended in the management of CS1 SGCT
by the European Association of Urologists (EAU) and certainly not in patients under 40 years.[44]
For patients at high-risk of relapse, the current recommendation for adjuvant treatment is one cycle
of carboplatin chemotherapy at AUC 7 based on evidence from the joint Medical Research Council
(MRC) and the European Organisation for Research and Treatment of Cancer (EORTC) randomised
trial of carboplatin versus radiotherapy for stage 1 seminoma.[45] The results confirmed the noninferiority of this single dose carboplatin regimen when assessing relapse-free survival rates. There
was also a significant reduction in the medium term risk of second germ cell tumours in the
carboplatin arm. This approach has been confirmed by the SWENOTECA trial.[40]
Occasionally patients at low risk of recurrence may have adjuvant chemotherapy recommended.
This may be prompted by concerns about compliance with, or practicality undertaking, follow-up or
where if relapse occurred, standard treatment may be problematic due to comorbidities. In these
circumstances it is therefore considered advantageous to reduce the risk of relapsing disease as
much as possible.
Non Seminomatous Germ Cell Tumours (NSGCT)
Post orchidectomy management options for CS1 NSGCT are surveillance, adjuvant chemotherapy
and RPLND. The presence of lymphovascular invasion (LVI) in the testicular tumour is the most
widely accepted adverse prognostic risk factor in NSGCT. Risk of relapse with LVI is 25-50%
compared to 12-15% without and thus adjuvant treatment should be considered if present. [40,46]
Standard adjuvant chemotherapy comprised two cycles of bleomycin, etoposide and cisplatin (BEP).
Specific toxicity risks are associated with this regimen; Bleomycin can cause interstitial pneumonitis
with subsequent pulmonary fibrosis. [47] This occurs in 10% of patients with risk factors including
age (over 40), increasing dose, renal insufficiency and smoking .[48] Etoposide is associated with an
increased risk of developing secondary malignancies (leukaemia) and Cisplatin is associated with
hearing impairment. To minimise toxicity risks without compromising efficacy there is some
evidence to support one cycle of BEP instead of two. The SWENOTECA trial reported excellent
results for BEP X 1 cycle in their CS1 NSGCT cohort. They reported a relapse rate of 3.2% for high-risk
patients (patients with LVI) and 1.6% for low risk patients (without LVI). [40] This new evidence has
thus led to a change in EAU recommendations from 2 cycles of BEP chemotherapy to 1 cycle in the
latest guideline update. [44]
Primary RPLND has been explored as an option for CS1 NSGCT with the premise of selecting out
patients who are truly PS1 and also reducing the burden, cumulative radiation exposure and
financial impact of imaging during follow-up. RPLND allows accurate pathological staging and thus
ensures more appropriate subsequent treatment in patients found to have PS2 disease and has a
potentially curative role in this cohort. The retroperitoneum is the initial and sometimes solitary site
of metastatic spread and relapses in the retro-peritoneum are rare following a well performed
RPLND.[36] Improvements in surgical techniques and better understanding of the patterns of
lymphatic drainage in testicular tumours has meant that the morbidity associated with RPLND has
greatly improved.[49] 20 - 30% of patients who have undergone RPLND are found to have
retroperitoneal metastasis, upstaging them to PS2. [50] These CS1, but occult PS2 have the potential
to be under-treated if surveillance is used based on a CS1 profile. Lymphovascular invasion is,
however, a robust predictor of the likelihood of occult PS2 and therefore developing a
‘relapse’.[50,51] Randomised trials have additionally demonstrated that RPLND is inferior to
chemotherapy at preventing recurrence in a non-risk stratified patient cohort. [52] In those patients
that recurred after RPLND alone, a proportion relapsed in the retroperitonem alone, probably
resulting from the use of a unilateral template only at RPLND. A significant proportion also relapsed
outside of the retroperitoneum.
Based on the available evidence, surveillance is a recommended option for CS1 patients without
lymphovascular invasion in the primary tumour, and where there are no concerns with compliance
with follow-up. For patients at high risk of recurrence, adjuvant BEP chemotherapy is recommended.
A well-defined role for RPLND in CS1 patients remains unclear.
Sex cord-stromal tumours
Approximately 10% of sex cord-stromal testicular tumours are malignant and can metastasise. [5,53]
The prognostic factors associated with malignancy are size greater than 5cm, necrosis,
moderate/severe nuclear atypia, angiolymphatic invasion, infiltrating margins and >3 mitotic
features per 10 high power fields. [5,7] When faced with small hypo-echoic masses and where
stromal tumours are suspected, an organ sparing approach should be considered if possible due to
the high likelihood that these tumours are benign. Stromal tumours are relatively non responsive to
chemotherapy or radiotherapy and the prognosis for patients with distant metastasis is poor. [7]
RPLND, therefore, has an important role in CS1 disease when histological features associated with
malignancy are present.
Follow Up
Ideally follow up should identify relapse at an early stage minimising harm and burden to patients.
There is currently no universal protocol for follow up of testicular cancer patients. Follow up
protocols depend on the initial, and any adjuvant treatment option used and will thus differ for
patients managed on surveillance, chemotherapy or primary RPLND. As follow up is risk stratified
based, this can be less intense if adjuvant therapy has been employed.
NSGCT
There is a need for strict adherence to follow up protocols over several years and this requires
significant motivation from patients. In patients with LVI, the relapse rate can be as high as 50%.

Surveillance
90% of relapses occur within the first 2 years[7] and these occur preferentially in the
retroperitoneum followed by mediastinum and the lung. The protocol recommended by the
EAU guidelines is shown in table 2.[44]
Table 2: Recommended minimum follow-up schedule in a surveillance policy: stage I nonseminoma. (Reproduced with kind permission from [44])
Procedure
Year
1
2
3
4-5
Physical
examination
4 times
4 times
4 times
Once/yr
Tumour markers
4 times
4 times
4 times
Once/yr
Once
Once
(24 mths)
(36 mths)
Plain radiography of Twice
chest
Abdominopelvic CT

Twice
(3mths, 12
mths)
RPLND
The relapse rate after a well performed RPLND is rare. The recommended protocol by the
EAU is similar to the surveillance policy above but CT is recommended yearly for 5 years.

Adjuvant chemotherapy
As previously discussed, the relapse risk in these patients is very low and similar to the
RPLND cohort in trials. As such the recommended follow up protocol is as per RPLND
patients above.[44]
The Royal Marsden Hospital’s follow up protocol is similar to that described above. There is
a greater intensity of investigations in the first year with more frequent chest x-rays and
serum tumour marker assessments as 80% of relapses will occur in the first year. With
regards to CT imaging, only abdominal scanning is recommended unless the pelvis is deemed
to be high risk (scrotal breech or previous inguinoscrotal surgery). [54]
SGCT
Relapse rates depend on whether any adjuvant treatment is used. Seminoma tumours are very
sensitive to chemotherapy and radiotherapy and thus relapse following adjuvant treatment is
uncommon. Secondly, measurements of serum tumour markers are a less reliable means of
monitoring for relapse as only 30% of seminoma patients will have elevated HCG levels at diagnosis
or during treatment. [7] The EAU follow up recommendation is shown in table 3.[44]
Table 3: Recommended minimum follow-up schedule for post-orchidectomy surveillance,
radiotherapy or chemotherapy: stage I seminoma. Reproduced with kind permission from [44].
Procedure
Year
1
2
3-5
Physical
examination
3 times
3 times
Once/yr
Tumour markers
3 times
3 times
Once/yr
Plain
Twice
Twice
Twice
Twice
Chest radiography
Abdominopelvic CT
36 and 60
mths
Stromal Tumours
There is little data on optimal follow up regimes for these tumours due to low numbers and the lack
of follow up data in the literature.
Conclusions
Despite being an uncommon male cancer, testicular cancer remains very important in the 15-40 ages
and the cure rate remains excellent irrespective of adjuvant treatment used. This therefore permits
the “luxury” of controversies in what, if any, adjuvant treatment should be used, bearing in mind the
need not to over-treat or overburden this group of young men with treatments that will be mostly
unnecessary albeit potentially harmful.
CME Questions
1. Accepted independent risk factors for testicular GCT include the following except;
a) Cryptorchidism
b) Testicular microlithiasis
c) Affected first degree relative
d) Hypospadias
e) Low sperm counts
Answer: b. In the absence of other risk factors, testicular microlithiasis is not an independent
risk factor for testicular GCT.
2. Regarding organ-sparing surgery, which of the following is untrue?
a) Adjuvant radiotherapy is used post-operatively to address ITGCN in the remnant
testicular tissue.
b) Can be considered for tumours involving up to 50% of the testicle
c) May be considered in synchronous bilateral tumours.
d) Testosterone replacement may sometimes be required.
e) Patients with an atrophic contralateral testicle may require testosterone
supplementation.
Answer: b; Organ sparing surgery may be considered for tumours involving <30% of the
testicle.
3. Regarding Seminomatous GCT, which of the following is untrue?
a) Seminoma cells are highly radiosensitive
b) Adjuvant radiotherapy is recommended for most patients.
c) The adjuvant chemotherapy regime currently recommended is a single cycle of
carboplatin.
d) Tumour size and rete testis invasion are known prognostic risk factors.
e) Low risk patients with clinical stage 1 have <3% risk of recurrence with surveillance.
Answer: b. Radiotherapy is not recommended as adjuvant treatment.
4. Regarding non seminomatous germ cell tumours, which of the following is true?
a) The recommended adjuvant chemotherapy regime is 1 cycle of carboplatin.
b) Rete testis invasion is the most predictive adverse risk factor
c) NSGCT’s seldom metastasize to the retroperitoneum.
d) Adjuvant BEP (Bleomycin, etoposide and cisplatin) chemotherapy is recommended
for high risk patients.
e) Low dose chemotherapy is recommended for patients without adverse risk factors.
Answer: d. The latest EAU recommendation is 1 cycle of BEP as adjuvant chemotherapy in
patients with vascular invasion.
5. Regarding testicular GCT, which of the following is untrue?
a) The incidence is rising globally
b) They may contain a mixture of histological subtypes.
c) Sperm banking prior to orchidectomy is not an absolute requirement.
d) The peak incidence for seminomatous GCT is 30-40 years.
e) Cure rates overall are relatively poor.
Answer: e. Cure rates for testicular cancer are excellent.
6. In the clinical assessment of testicular tumours which of the following is true?
a) Tumour markers are rarely normal at presentation
b) Elevated LDH levels are diagnostic for non-seminomatous GCT.
c) Elevated AFP levels indicate a non-seminomatous component.
d) Chest CT is essential prior to orchidectomy.
e) Negative tumour marker results exclude a diagnosis of testicular GCT.
Answer: c.
Bibliography
1
Chia VM, Quraishi SM, Devesa SS, et al. International trends in the incidence of testicular
cancer, 1973-2002. Cancer Epidemiol Biomarkers Prev 2010;19:1151–9. doi:10.1158/10559965.EPI-10-0031
2
Chowdhury S, Rudman S. Global incidence and outcome of testicular cancer. 2013;:417–27.
3
Ghazarian a a, Trabert B, Devesa SS, et al. Recent trends in the incidence of testicular germ
cell tumors in the United States. Andrology 2014;:1–6. doi:10.1111/andr.288
4
Stenman U-H, Alfthan H, Hotakainen K. Human chorionic gonadotropin in cancer. Clin
Biochem 2004;37:549–61. doi:10.1016/j.clinbiochem.2004.05.008
5
Silberstein JL, Bazzi WM, Vertosick E, et al. Clinical outcomes of local and metastatic testicular
sex cord-stromal tumors. J Urol 2014;192:415–9. doi:10.1016/j.juro.2014.01.104
6
Manecksha RP, Fitzpatrick JM. Epidemiology of testicular cancer. BJU Int 2009;104:1329–33.
doi:10.1111/j.1464-410X.2009.08854.x
7
Albers P, Albrecht W, Algaba F, et al. EAU guidelines on testicular cancer: 2011 update. Eur
Urol 2011;60:304–19. doi:10.1016/j.eururo.2011.05.038
8
Trabert B, Chen J, Devesa SS, et al. International patterns and trends in testicular cancer
incidence, overall and by histologic subtype, 1973-2007. Andrology 2014;:1–8.
doi:10.1111/andr.293
9
Chimento A, Sirianni R, Casaburi I, et al. GPER Signaling in Spermatogenesis and Testicular
Tumors. Front Endocrinol (Lausanne) 2014;5:30. doi:10.3389/fendo.2014.00030
10
Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in
situ: genetic and environmental aspects. Hum Reprod Update 2006;12:303–23.
doi:10.1093/humupd/dmk006
11
Rapley E a, Hockley S, Warren W, et al. Somatic mutations of KIT in familial testicular germ
cell tumours. Br J Cancer 2004;90:2397–401. doi:10.1038/sj.bjc.6601880
12
G AJ, Abildgaard N, Johansen B. Risk of Bilateral Testicular Germ Cell Cancer in Denmark :
Munck-Hansen , Lene Hesse. 1991;83:4288–92.
13
Richenberg J, Belfield J, Ramchandani P, et al. Testicular microlithiasis imaging and follow-up:
guidelines of the ESUR scrotal imaging subcommittee. Eur Radiol Published Online First: 15
October 2014. doi:10.1007/s00330-014-3437-x
14
Sharpe RM. The “oestrogen hypothesis” - Where do we stand now? Int. J. Androl. 2003;26:2–
15. doi:10.1046/j.1365-2605.2003.00367.x
15
Chevalier N, Bouskine A, Fenichel P. Bisphenol A promotes testicular seminoma cell
proliferation through GPER/GPR30. Int J Cancer 2012;130:241–2. doi:10.1002/ijc.25972
16
Vandenberg LN, Maffini M V, Sonnenschein C, et al. Bisphenol-A and the great divide: a
review of controversies in the field of endocrine disruption. Endocr. Rev. 2009;30:75–95.
doi:10.1210/er.2008-0021
17
Douglas ML, Richardson MM, Nicol DL. Testicular germ cell tumors exhibit evidence of
hormone dependence. Int J Cancer 2006;118:98–102. doi:10.1002/ijc.21330
18
Carstairs SD. Diagnosis of testicular cancer with a urine pregnancy test in an austere military
medical environment. Am J Emerg Med 2013;31:1615. doi:10.1016/j.ajem.2013.08.010
19
Braunstein GD, Buster JE, Soares JR, et al. Pregnancy hormone concentrations in marijuana
users. Life Sci 1983;33:195–9. doi:10.1016/0024-3205(83)90413-7
20
Braunstein GD, Thompson R, Gross S, et al. Marijuana use does not spuriously elevate serum
human chorionic gonadotropin levels. Urology 1985;25:605–6. doi:10.1016/00904295(85)90290-0
21
Gottlieb RH, Oka M. Radiology Sonography of the Scrotum 1. ;i.
22
Skoogh J, Steineck G, Cavallin-Ståhl E, et al. Feelings of loss and uneasiness or shame after
removal of a testicle by orchidectomy: A population-based long-term follow-up of testicular
cancer survivors. Int J Androl 2011;34:183–92. doi:10.1111/j.1365-2605.2010.01073.x
23
Robinson R, Tait C, Clarke N, et al. Is it Safe to Insert a Testicular Prosthesis at the Time of
Radical Orchidectomy for Testis Cancer - an Audit of 904 Men Undergoing Radical
Orchidectomy. BJU Int Published Online First: 28 August 2014. doi:10.1111/bju.12920
24
J. ADSHEAD, B. KHOUBEHI JW and GR. Testicular implants and patient satisfaction : a
questionnaire-based study of men after orchidectomy for testicular cancer. 2001;:559–62.
25
Bodiwala D, Summerton DJ, Terry TR. Testicular prostheses: development and modern usage.
Ann R Coll Surg Engl 2007;89:349–53. doi:10.1308/003588407X183463
26
Giannarini G, Dieckmann K-P, Albers P, et al. Organ-sparing surgery for adult testicular
tumours: a systematic review of the literature. Eur Urol 2010;57:780–90.
doi:10.1016/j.eururo.2010.01.014
27
Bazzi WM, Raheem O a, Stroup SP, et al. Partial orchiectomy and testis intratubular germ cell
neoplasia: World literature review. Urol Ann 2011;3:115–8. doi:10.4103/0974-7796.84948
28
Heidenreich A, Weissbach L, Höltl W, et al. Organ sparing surgery for malignant germ cell
tumor of the testis. J Urol 2001;166:2161–5. doi:10.1097/00005392-200209000-00064
29
Fraietta R, Spaine DM, Bertolla RP, et al. Individual and seminal characteristics of patients
with testicular germ cell tumors. Fertil Steril 2010;94:2107–12.
doi:10.1016/j.fertnstert.2009.12.021
30
Party 2007 working. The effects of cancer treatment on reproductive functions Guidance on
management. 2007.
31
Gates R. Oncology nursing secrets. 3rd ed. Elsevier Health Sciences 2008.
32
HFEA. Code of Practice. 2011;26.
33
Homerton University Hospital. Price list for self funding NHS patients.
http://www.homerton.nhs.uk/our-services/services-a-z/f/fertility-centre/price-lists/
34
Johnson MD, Cooper AR, Jungheim ES, et al. Sperm banking for fertility preservation: a 20year experience. Eur J Obstet Gynecol Reprod Biol 2013;170:177–82.
doi:10.1016/j.ejogrb.2013.06.021
35
Williams DH. Sperm banking and the cancer patient. Ther Adv Urol 2010;2:19–34.
doi:10.1177/1756287210368279
36
Stephenson AJ, Sheinfeld J. The role of retroperitoneal lymph node dissection in the
management of testicular cancer. Urol Oncol 2004;22:225–33; discussion 234–5.
doi:10.1016/j.urolonc.2004.04.029
37
Dalal PU, Sohaib S a, Huddart R. Imaging of testicular germ cell tumours. Cancer Imaging
2006;6:124–34. doi:10.1102/1470-7330.2006.0020
38
Oldenburg J, Aparicio J, Beyer J, et al. Personalizing, not patronizing: The case for patient
autonomy by unbiased presentation of management options in stage I testicular cancer. Ann
Oncol 2014;:mdu514 – . doi:10.1093/annonc/mdu514
39
Kollmannsberger C, Tandstad T, Bedard PL, et al. Patterns of Relapse in Patients With Clinical
Stage I Testicular Cancer Managed With Active Surveillance. J Clin Oncol 2014;:1–7.
doi:10.1200/JCO.2014.56.2116
40
Cohn-Cedermark G, Stahl O, Tandstad T. Surveillance vs. adjuvant therapy of clinical stage I
testicular tumors - a review and the SWENOTECA experience. Andrology 2014;:1–8.
doi:10.1111/andr.280
41
Shelley MD, Burgon K, Mason MD. Treatment of testicular germ-cell cancer: a cochrane
evidence-based systematic review. Cancer Treat Rev 2002;28:237–53. doi:10.1016/S03057372(02)00059-2
42
Aparicio J, Maroto P, García Del Muro X, et al. Prognostic factors for relapse in stage I
seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the
Spanish Germ Cell Cancer Group (SGCCG). Ann Oncol 2014;25:2173–8.
doi:10.1093/annonc/mdu437
43
Van den Belt-Dusebout AW, de Wit R, Gietema JA, et al. Treatment-specific risks of second
malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol
2007;25:4370–8. doi:10.1200/JCO.2006.10.5296
44
Albers P, Albrecht W, Algaba F, et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol
Published Online First: August 2015. doi:10.1016/j.eururo.2015.07.044
45
Oliver RTD, Mead GM, Rustin GJS, et al. Randomized trial of carboplatin versus radiotherapy
for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC
TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011;29:957–62.
doi:10.1200/JCO.2009.26.4655
46
Dong P, Liu Z-W, Li X-D, et al. Risk factors for relapse in patients with clinical stage I testicular
nonseminomatous germ cell tumors. Med Oncol 2013;30:494. doi:10.1007/s12032-013-0494y
47
O’Sullivan JM. Predicting the risk of bleomycin lung toxicity in patients with germ-cell
tumours. Ann Oncol 2003;14:91–6. doi:10.1093/annonc/mdg020
48
Singhera M, Lees K, Huddart R, et al. Minimizing toxicity in early-stage testicular cancer
treatment. Expert Rev Anticancer Ther 2012;12:185–93. doi:10.1586/era.11.212
49
Jacobsen N-EB, Foster RS, Donohue JP. Retroperitoneal lymph node dissection in testicular
cancer. Surg Oncol Clin N Am 2007;16:199–220. doi:10.1016/j.soc.2006.10.003
50
Albers P, Siener R, Kliesch S, et al. Risk factors for relapse in clinical stage I nonseminomatous
testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. J Clin
Oncol 2003;21:1505–12. doi:10.1200/JCO.2003.07.169
51
Heinzelbecker J, Gross-Weege M, Weiss C, et al. Microvascular invasion of testicular
nonseminomatous germ cell tumors: implications of separate evaluation of lymphatic and
blood vessels. J Urol 2014;192:593–9. doi:10.1016/j.juro.2014.02.2569
52
Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph
node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in
the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO
trial AH 01/94. J Clin Oncol 2008;26:2966–72. doi:10.1200/JCO.2007.12.0899
53
Acar C, Gurocak S, Sozen S. Current treatment of testicular sex cord-stromal tumors: critical
review. Urology 2009;73:1165–71. doi:10.1016/j.urology.2008.10.036
54
Van As NJ, Gilbert DC, Money-Kyrle J, et al. Evidence-based pragmatic guidelines for the
follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer 2008;98:1894–
902. doi:10.1038/sj.bjc.6604280