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CASE
19
https://t.me/med1917
Growing teratoma syndrome
in testis cancer
Jennifer Clark, Thomas A. Lee, and
Vijay A.C. Ramani
Expert commentary Vijay A.C. Ramani
Case history
A fit and well 24- year- old man presented with a right- sided testicular mass and back
pain of approximately 6 months’ duration. He was working as a plasterer, was unmarried with no children, and living with his mother. He smoked 15– 20 cigarettes
per day and denied drinking alcohol. At the time of presentation, he had palpable
abdominal and supraclavicular lymph node masses. Tumour markers were considerably elevated with an alpha- fetoprotein (AFP) level of 996 ng/ mL and a beta
human chorionic gonadotropin (β- hCG) level of 6620 ng/ mL. He had an obviously
abnormal- feeling right testis and testicular ultrasound confirmed a heterogeneous
mass suspicious for malignancy.
He was advised of the likely diagnosis of testicular cancer and, following adequate counselling and sperm banking, he underwent a right radical inguinal orchidectomy. Radical orchidectomy was performed via an inguinal approach and the
spermatic cord transected at the internal ring. Insertion of testicular prosthesis was
discussed with him preoperatively but he opted against this.
Learning point Epidemiology and aetiology
Epidemiology
Primary testicular cancer accounts for around 1% of all male cancers and 5% of all urological
cancers and is the commonest solid organ cancer in men aged between 20 and 45 years. Nonseminomatous germ- cell tumours (NSGCTs) are commoner between the ages of 20 and 35 years,
whereas seminoma is more common between the ages of 35 and 45 years. Incidence has been
increasing in Western societies and is currently around 3– 10/ 100,000 per year. Mortality is low
(0.3/ 100,000) and has fallen significantly since the introduction of platinum- based chemotherapy
in 1975.
Aetiology
● Age: rare <15 and >60 years (yolk sac tumour and lymphoma more common respectively for these
groups).
● Race: white Caucasians at highest risk (white males in US 3× as likely as black males to develop
testicular cancer).
186 Challenging Concepts in Urological Surgery
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● Cryptorchidism: 5– 10% of patients with testicular cancer have history of cryptorchidism; 3× risk
and 6× risk of testicular cancer in men who underwent orchidopexy before or after 13 years of age
respectively.
● Germ cell neoplasia insitu (GCNIS): 50% will develop invasive germ cell testicular cancer within
5 years.
● Hereditary: 4× increased risk over population if father diagnosed with testicular cancer, 8×
increased risk if brother diagnosed.
● HIV: increased risk of seminoma.
● Previous testicular cancer: 1– 2% of testicular cancers are bilateral. 12× increased risk of
metachronous testicular cancer.
Clinical tip Pretreatment
fertility assessment should
be offered
All patients of reproductive age
should be offered a pretreatment
fertility assessment including
testosterone, luteinizing
hormone, and follicle- stimulating
hormone levels plus semen
analysis and cryopreservation.2
All centres should have a fasttrack arrangement for semen
cryopreservation to avoid any delay
in management. In cases where
the patient has life- threatening
complications of metastatic
disease, there may not be time for
this before commencing urgent
chemotherapy.
Compiled from EAU guidelines on testis cancer 2019.
Histological examination confirmed the presence of a 35 mm postpubertal type
cystic teratoma with the presence of germ cell neoplasia in situ (GCNIS) (Figure 19.1).
There was no lymphovascular invasion and the rete testis, epididymis, and spermatic
cord were free of tumour. He was staged at pT1NxMx (see ‘Learning point’ box on
TNM staging)— teratoma postpubertal type.
Expert comment Preoperative essentials
Serum tumour markers
This allows baseline reading and monitoring after orchidectomy and throughout systemic therapy.
AFP and β- hCG must decrease according to their half- lives (5– 7 days and 2– 3 days, respectively)
in the absence of metastatic or contralateral disease. Persistence or rise of serum tumour markers
1
Figure 19.1 Histology from orchidectomy specimen demonstrating GCNIS within tubules and the cystic
lining of the teratoma.
187Case 19 Growing teratoma syndrome in testis cancer
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after orchidectomy indicates the presence of micro- or macro- metastatic disease. Lactate
dehydrogenase (LDH) is not a specific marker but may indicate the extent of tumour burden
in metastatic disease.
Sperm banking
All centres should have a fast- track service for sperm banking, which should be done before
orchidectomy wherever possible. A small percentage (4%) of patients can be azoospermic3
after orchidectomy, although some reports indicate this could be higher. This allows fertility
planning in azoospermic patients and arrangements for onco- testicular sperm extraction
(onco- TESE) at an appropriate centre.
Testicular prosthesis
Insertion of a testicular prosthesis should be offered to patients and it can be inserted at the
time of orchidectomy without increased risk of infectious complication.4 Clinical factors such
as extreme size of primary tumour and condition of scrotum, significant metastatic disease
requiring urgent chemotherapy, and poorly controlled diabetes may contraindicate primary
insertion of a prosthesis.
Contralateral testis biopsy
The risk of contralateral GCNIS is 5%. High- risk groups should be offered contralateral testis
biopsy and centres should have specialist multidisciplinary team (SMDT) consensus with
oncologists for the management of GCNIS. Age <40 years and testis atrophy (<12 mL)
increases the risk of GCNIS to 18%5 and these patients should be targeted for contralateral
testis biopsy.
The patient underwent a staging computed tomography (CT) scan with contrast
of the thorax, abdomen, and pelvis showing a bulky conglomerate retroperitoneal
nodal mass, which displaced the inferior vena cava (IVC) and completely encased
the aorta measuring 14.7 × 8.3 cm. He had no suspicious pulmonary nodules and
no bone lesions but did have thrombus in the left internal jugular and subclavian
veins (Figure 19.2).
Figure 19.2 Initial CT findings of retroperitoneal nodal mass encasing major vessels.
188 Challenging Concepts in Urological Surgery
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Learning point TNM staging of testis cancer
See Table 19.1.
Table 19.1 Tumour, lymph node, and metastases (TNM) staging system
T— primary tumour N— regional lymph nodes M— distant metastasis
Tx Primary tumour not
assessed
T0 No evidence of primary
tumour
Tis Intratubular germ cell
neoplasia (ITGCN)
T1 Limited to testis/
epididymis without
lymphovascular
invasion (LVI), no
involvement of tunica
vaginalis
T2 Limited to testis/
epididymis with LVI or
involvement of tunica
vaginalis
T3 Invasion of spermatic
cord with/ without LVI
T4 Invasion of scrotum
with/ without LVI
Adaptation of TNM staging from EAU guidelines (2020).
Nx Regional nodes not
N0 No evidence of regional
N1 Metastasis of 5 or fewer
N2 Lymph node metastasis
or
Metastasis of >5 lymph
N3 Lymph node metastasis
assessed
node metastasis
lymph nodes (none
>2 cm in maximum
diameter)
of between 2 and 5 cm
maximum diameter
nodes (none >5 cm in
maximum diameter)
of >5 cm maximum
diameter
1
Mx Distant metastasis not
assessed
M0 No evidence of
distant metastasis
M1a Metastasis to
non- regional
lymph nodes or
lungs
M1b Distant metastasis
other than to
non- regional
lymph nodes or
lungs
Learning point Classification
of teratomas (2016)
It is important to note that
teratomas are classified based on
whether or not they originated
from GCNIS.
Germ cell tumours derived
from GCNIS
● Teratoma postpubertal type.
● Teratoma with somatic- type
malignancy.
Germ cell tumours unrelated
to GCNIS
● Teratoma prepubertal type:
7
– Dermoid cyst.
– Epidermoid cyst.
– Well- differentiated
neuroendocrine tumour
(monodermal teratoma).
● Mixed teratoma and yolk sac
tumour prepubertal type.
Learning point World Health Organization 2016 histopathological classification of germ
cell tumours
See Table 19.2.
Table 19.2 World Health Organization 2016 histopathological
classification of germ cell tumours
GCNIS derived Non- GCNIS derived
Seminoma Spermatocytic tumour
Embryonal carcinoma Yolk sac tumour (prepubertal)
Yolk sac tumour: Teratoma (prepubertal)
— Sarcomatoid yolk sac tumour
Trophoblastic:
— Choriocarcinoma
— Other trophoblastic tumours
Teratoma (postpubertal)
Adaptation of Williamson SR et al.
6
Expert comment Postpubertal and prepubertal teratomas
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One of the main modifications of the 2016 World Health Organization classification of testis tumours
is the clarification of the origin of postpubertal and prepubertal teratoma from GCNIS.
6
It is important to remember that postpubertal teratomas are associated with GCNIS and have a
significant potential to develop metastasis containing both teratomatous and non- teratomatous germ
cell elements. This case presented is an illustration of this and the vast majority of adult teratomas
should be managed as malignant germ cell tumours. Management of postpubertal teratomas based
on the presence or absence of mature or immature elements has no prognostic value as even the
‘mature teratoma’ in the postpubertal setting has its origins in GCNIS.
Prepubertal teratomas, on the other hand, are characterized by more organized structure, lack of
cytological atypia or GCNIS, or impaired spermatogenesis and have not been reported to metastasize.
In rare cases, a prepubertal teratoma can be diagnosed in postpubertal testis based on documented
histopathological features.
8
Post orchidectomy, the patient’s AFP level peaked at 3077 ng/ mL with an β- hCG
concentration of just over 18,000 and an LDH level of 440 IU/ L. His case was discussed
in the regional germ cell multidisciplinary team (MDT) meeting and the final staging
was confirmed as pT1N3M0 S2. For prognostic and treatment purposes, this placed
him in the intermediate- risk group (S2).
Learning point Serum tumour markers
See Table 19.3.
Table 19.3 Serum tumour markers staging system
189Case 19 Growing teratoma syndrome in testis cancer
S— serum tumour markers
Sx Serum markers not assessed
S0 Normal serum markers
LDH (U/ I)
β- hCG (mIU/ mL)
AFP (ng/ mL)
S1 <1.5× normal and <5000 and <1000
S2 1.5– 10× normal or 5000– 50,000 or 1000– 10,000
S3 >10× normal or >50,000 or >10,000
Adaptation of TNM staging from EAU guidelines (2020).
1
Evidence base Prognostic- based system for metastatic germ cell cancer
See Table 19.4.
Table 19.4 Prognostic- based staging system for metastatic germ cell cancers
Good prognosis group
NSGCT (56% of cases) Seminoma (90% of cases)
●
5- year progression- free survival (PFS) 89%
●
5- year overall survival (OS) 92%
●
5- year PFS 82%
●
5- year OS 86%
All of the following: All of the following:
●
Testis/ retroperitoneal primary
●
No non- pulmonary visceral metastases
●
AFP < 1000 ng/ mL
●
hCG < 5000 mIU/ mL
●
LDH <1.5× normal
●
Any primary site
●
No non- pulmonary visceral metastases
●
Normal AFP
●
Any level of hCG
●
Any level of LDH
(continued)
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Table 19.4 Continued
Intermediate prognosis group
NSGCT (28% of cases) Seminoma (10% of cases)
●
5- year PFS 75%
●
5- year OS 80%
Any of the following: All of the following:
●
Testis/ retroperitoneal primary
●
No non- pulmonary visceral metastases
●
AFP 1000— 10,000 ng/ mL
●
hCG 5000— 50,000 mIU/ mL
●
LDH 1.5– 10× normal
Poor prognosis group
NSCGT (16% of cases) Seminoma
●
5- year PFS 41% No patients classified as poor prognosis
●
5- year OS 48%
Any of the following:
●
Mediastinal primary
●
Non- pulmonary visceral metastases
●
AFP > 10,000 ng/ mL
●
hCG > 50,000 mIU/ mL
●
LDH > 10× normal
Adapted from International Germ Cell Cancer Collaborative Group (IGCCCG).
●
5- year PFS 67%
●
5- year OS 72%
●
Any primary site
●
Non- pulmonary visceral metastases
●
Normal AFP
●
Any hCG
●
Any LDH
9
After discussion in the MDT, a plan was made for treatment with four cycles of 5- day
bleomycin, etoposide, and cisplatin (BEP) under the care of the medical oncology
team. Pretreatment, he underwent audiology and pulmonary function tests alongside
full blood work. He was admitted to a dedicated young person’s oncology unit for the
treatment and had a peripherally inserted central catheter line inserted. Apart from
side effects of nausea and fatigue, the patient tolerated chemotherapy well.
Evidence base Evidence for BEP in metastatic NSGCT
Standard treatment of metastatic NSGCT with three to four cycles of BEP chemotherapy depends
on the histology of the primary tumour and the prognostic subgroup as defined by the International
Germ Cell Cancer Collaborative Group.
De Wit et al., as part of the EORTC Genitourinary Tract Cancer Cooperative Group, reported a
randomized study comparing four cycles of etoposide, ifosfamide, cisplatin (VIP) to four cycles of BEP
in patients with intermediate- prognosis NSGCT.10 There were no differences in relapse rate, diseasefree rate, and overall survival rate. The VIP regimen was more toxic with regard to bone marrow
function with no improved effectiveness.
Clinical tip Pre- chemotherapy testing
● Audiological studies: cisplatin ototoxicity can result in high- frequency hearing loss.
● Pulmonary function tests: bleomycin can cause potentially life- threatening pulmonary interstitial
fibrosis in up to 10% of patients.
● Renal function tests: cisplatin can lead to nephrotoxicity so pre- and post- chemotherapy renal
function testing as well as hydration during treatment is imperative.
● Liver function tests: etoposide can cause elevation in alanine transaminase levels, in particular when
used in conjunction with an alkylating agent such as cisplatin, and liver function should be monitored.
● Cardiac function: cisplatin has been reported as a risk for arrhythmia and myocarditis. In older
patients or those at risk, echocardiography may be recommended.
Figure 19.3 CT scan demonstrating progression in size of tumour mass and cystic components.
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Unfortunately, shortly following completion of chemotherapy, despite normalization of his tumour markers, the patient was admitted with ongoing back pain,
nausea, vomiting, and suspected small bowel obstruction. His nutritional status was
poor and he described significant weight loss. He was managed with a nasogastric
tube, intravenous fluids, and total parenteral nutrition.
A further CT of the abdomen and pelvis with contrast was performed (Figure
19.3) which showed progression of the bulky mixed density retroperitoneal lymphadenopathy to 16.6 × 8.3 cm, causing obstruction of the third and fourth parts
of the duodenum. There was also progressive thrombus within the left brachiocephalic vein.
The patient’s case was re- discussed at the germ cell MDT and he was listed for
laparotomy and bilateral template retroperitoneal lymph node dissection (RPLND).
191Case 19 Growing teratoma syndrome in testis cancer
NSCGT
● Any residual mass >1 cm diameter and normalized serum tumour markers.
● Any residual mass <1 cm diameter and plateauing serum tumour makers.
● Residual mass <1 cm diameter and mature teratoma in primary orchidectomy specimen.
● Residual mass with negative or plateauing markers after salvage chemotherapy.
● Desperation RPLND for patients with chemoresistant masses which are completely resectable.
Clinical tip Indications for post- chemotherapy RPLND
Seminoma
● Patients with residual mass >3 cm should undergo fluorodeoxyglucose (FDG) positron emission
tomography (PET) (risk of viable cancer 12– 30%):
– PET negative → surveillance.
– PET positive → SMDT discussion regarding radiotherapy/ further chemotherapy/ surgery.
Compiled from ESMO Consensus Conference 2018.
Expert comment Surgical decision- making in the MDT
Decisions in the testis MDT regarding surgery should be based on (1) indications, (2) timing,
and (3) procedure (TIP).
11
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Indications
NSGCT: patients with a post- chemotherapy (usually BEP) residual mass >1 cm and normal or
plateauing tumour markers should undergo RPLND. The indications are summarized in the earlier
‘Clinical tip’ box. The final histology following RPLND shows viable cancer or mature teratoma in up
to 10% and 50% of patients, respectively. Approximately 40% of patients have fibrotic or necrotic tissue
in the final specimen and currently there are no tests to identify these patients. Particular attention
should be paid to those patients with postpubertal ‘mature’ teratoma in the orchidectomy specimen
due to its unique biological behaviour as explained previously and a case is made for excising residual
masses <1 cm.
Seminoma: in general, surgery is rarely indicated in metastatic seminoma post chemotherapy. An
FDG- PET scan has a high negative predictive value in patients with residual masses. The possibility
of necrosis in post- chemotherapy seminoma masses <3 cm in size are very high and surgery is not a
standard of care in these patients. For masses >3 cm in size, an FDG- PET scan is advised at least 6 weeks
after completion of chemotherapy. Progression or persistence of β- hCG is an indication for second- line
chemotherapy. RPLND is reserved as a last resort after SMDT discussions and appraisal of options
including radiotherapy. A case can be made for undertaking this surgery in very specialized and small
number of centres due to intense fibrosis and severe induration that is invariably present in such patients.
Expert comment Surgical decision- making in the MDT 2
Timing
RPLND should be performed within 6– 8 weeks of completion of chemotherapy. Delays in surgery
lead to inferior survival and the possibility of needing reinduction chemotherapy.
12,13
Patients can present with metastasis at various sites— particularly the retroperitoneum and lungs. The
management is personalized to each patient and there is a variation in policy at different testis centres
but, in general, the following factors need to be taken into account:
● There is a histopathological discordance:
- Of 20% between lung metastasis in both lungs but this can be as low as 5% if necrosis is found at
first lung resection and tumour markers normal
- Of approximately 10% between retroperitoneal and lung resection when necrosis only is present
in the retroperitoneum.
16
14,15
● If RPLND is performed first then the histology can be used to determine the need for thoracotomy.
The reverse strategy is unlikely to be sufficiently predictive.
Expert comment Surgical decision- making in the MDT 3
Procedure
It is not justifiable to carry out a lumpectomy and a decision has to be made regarding performing a
bilateral RPLND (the case presented here), right or left template RPLND, or a bilateral nerve- sparing
RPLND. The type of dissection is determined at the SMDT and is based on the location and extent
of the residual disease. Radical dissection must not be compromised but a nerve- sparing template
dissection should be considered where appropriate to lessen risk of ejaculatory dysfunction.
Post- chemotherapy RPLND is usually challenging and the surgical approach to the residual masses
depends on their location— in particular, the involvement of retrocrural area and presence of
significant disease above the renal hilum. It is possible to determine the extent of resection in terms of
the need for a nephrectomy or aortic/ IVC excision and graft replacement or liver resection or psoas
excision. The surgical team should be equipped and prepared to do this at specialized centres capable
of multidisciplinary surgery.
17
17.2; he was seen by a dietician and commenced on total parenteral nutrition to try
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and prevent further weight loss and maintain his physical condition. He struggled
with pain and had developed an opioid dependence, which was very challenging to
manage on the ward. The pain team were involved early and his pain was managed
with pregabalin and modified- release morphine.
Postoperatively, the patient was managed on the high dependency unit and then
stepped down to ward level care on the ‘young oncology unit’. There were significant challenges managing his postoperative pain and, despite involvement of
the pain team, the patient remained on high- dose opioids for many months after
discharge.
Expert comment Operative note: bilateral RPLND to achieve radical excision
Following an epidural, general anaesthetic, and insertion of central and arterial lines, the abdomen
was opened with a midline incision. The colon was completely mobilized and dissection
commenced with the coeliac axis and the superior mesenteric artery freed from the adjacent cystic
structure. The third part of the duodenum was tethered to the mass and partially released. The
splenic vein was then identified and the left renal vein carefully dissected along its length and a
significant component of the mass separated from the left renal hilum. Painstaking mobilization
was required to separate the superior aspect of the mass from the proximal aorta and left and right
renal arteries. The aortal and IVC were completely dissected and encircled proximally so that they
could be controlled. Similar dissection was carried out distally at the iliac vessels to allow control if
needed.
The IVC was plastered onto the left side of the mass and careful dissection was undertaken with the
right renal vein preserved. Meticulous ligation of multiple right- and left- sided lumbar veins was
required to fully release the IVC.
The circumferential mass was gradually released from the aorta, with three sets of lumbar arteries
ligated. Due to the sheer bulk of the mass, it could not be removed en bloc so was split in line with
the inferior mesenteric artery. This allowed a more controlled separation of the right side of the mass
from the aorta, spine, and psoas and the right side of the mass could be removed.
The lower third of the aorta was densely plastered to the mass and a plane had to be painstakingly
developed. The inferior mesenteric artery was transfixed and divided at its origin to allow mobilization.
The mass was densely adherent to the left and right iliac veins and compressing them. Lengthy
dissection was undertaken to allow control of these vessels in case of bleeding. The masses were
excised on both sides in this bilateral template.
The inter aortocaval aspect of the mass was mobilized and the right hilum preserved. Posterior
mobilization of the left side mass could then be completed and it was excised with no further visible
disease. Haemostasis was carefully checked and minor bleeding points managed with Prolene®
sutures. Lymph fluid leakage was underrun with Monocryl®, the colon replaced, and posterior
retroperitoneum reconstructed. A drain was inserted and the abdomen closed.
The final histology report described an extensive conglomerate of five masses in
one resection specimen weighing >10 kg (Figure 19.4). The microscopic appearances
were consistent with teratoma containing mature elements in the form of cysts lined
by glandular and/ or squamous epithelium in addition to fibromuscular stroma but
with no evidence of neoplasia. This finding is typical of the growing teratoma syndrome (GTS).
193Case 19 Growing teratoma syndrome in testis cancer
Clinical tip Involvement of
young person’s services
A diagnosis of cancer and the
impact of subsequent treatments
(especially major surgery that
may impact sexual function and
fertility) can be very challenging
psychologically for a young
person. Their lives, expectations,
and understanding may be
quite different to older people.
Involvement of psychological
services and expertise on a ‘young
oncology unit’ aimed at young
people is therefore essential to
provide support that may be
outside of the surgeon’s remit to
provide.
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