Testicular cancer
Badrinath R. Konety, MD
Classification
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Germ Cell Tumors (GCTs)
Gonadal Stromal tumors
Tumors with GCT + Stromal elements
Hematopoeitic/Lymphoid
Tumors of Rete Testis
Adnexal tumors
GCT - Introduction
• Most common in men 15-35 yrs
• Paradigm for multimodality treatment
• Survival < 50% (1970) to > 95% (1997)
• Focus on decreased morbidity
GCT - Epidemiology
• Around 7000 new cases
in USA
• 90-95% of all testicular
primary neoplasms
• Most common solid
tumors of men age 20
to 34 years
• 2-3 % bilateral
• Cryptorchidism
3-14 times ↑ risk
5-10% contralateral
orchiopexy helps
detection
• Trauma
• Atrophy
• Hormones (mothers on
estrogens)
Classification GCTs
Seminoma
Classic
Anaplastic
Spermatocytic
Non Seminoma
Embryonal carcinoma
Yolk Sac
Choriocarcinoma
Teratoma
Mixed NSGCTs
Clinical Manifestations
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Painless testis swelling/lump
Acute pain (10%)
Reactive hydrocele
Metastatic disease - 40-50% pts
– Respiratory / GI / Back pain / DVT etc
• Gynecomastia – 5%
• Physical Exam - Testicular self exam
• Scrotal Ultrasonography
Seminoma
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Enlarged painless testis
35-70% of all GCTs. PLAP + in 90%
Can be bilateral either synchronous or metachronous
Classic
85%, age 30-50
syncitiotrophoblasts (15%) = b HCG
• Anaplastic
5-10% more aggressive, 1/3rd of all deaths from seminoma, more bHCG
• Spermatocytic
2-10%, no metastasis, >40yrs.
Most common GCT in men > 65 yrs
10% of metastatic seminoma has NSGCT elements
Campbell-Walsh Urology, Elsevier, Philadelphia, PA
NSGCTs
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Embryonal
Choriocarcinoma
Teratoma
Yolk Sac
Mixed
Embryonal Carcinoma
• 40% of all GCTs have EC
elements
• Usually < 2 cm, VI, LI adverse
prognosis
• Syncitiotrophoblastic cells
adjacent to EC cells, produce b
HCG
• If AFP ↑, usually from coexistent yolk sac
• EC cells do not secrete either
AFP or bHCG
• Age 25-35 yrs
• Hard, irregular testis, normal
size
Teratoma
• < 5% in adults, 40% in
children
• By definition, 2 or more
germ cell layers
• Endo – mucus secreting
• Meso – Bone cartilage,
muscle
• Ecto – squamous, neural
• AFP in 25% (mucinous or
hepatoid differentiation)
Mature teratoma with cartilege
Teratoma
• Most often seen 10-30y
• Benign in children
• Can undergo malignant
transformation in adults
to sarcoma, squamous
carcinoma or
adenocarcinoma
• Resistant to
chemoradiation
• Metastatic teratoma –
most often embryonal
Immature teratoma
Choriocarcinoma
• 1-2%, pure or mixed
• Pure CC – hemorrhagic
mass with viable tumor
cells at periphery
• Syncitiotrophoblasts +
cytotrophoblasts
• Necrosis and
hemorrhage
• B HCG  > 99%
• Decades 2 and 3
• No testis swelling, small
nodule
• Usually present with distant
mets – lung and /or brain
• Hematogenous mets most
common
Mixed GCTs
• 60% of all GCTs
• Even if seminoma present, treat as NSGCT
• Serum tumor markers may or may not be
elevated
Yolk Sac tumor (Embryonal Carcinoma
of infants and children )
Most common prepubertal testis tumor
AFP ↑ >90% of pts
Hydrocele in 25% pts
Pattern of mets different in children (more
hematogenous spread)
• Confined to testicle in 80% of cases
• Low volume RP disease - RPLND
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Intratubular Germ Cell Neoplasia
(ITGCN)
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Adjacent to germ cell tumor: 98%
Cryptorchidism: 2-8%
Prior germ cell tumor (contralateral testis): 5%
50% risk of developing GCT in 5y
Treat with observation, XRT (20 Gy) or orchiectomy
Chemo reduces risk but still 25% - 45% risk of GCT at
10y (Christensen et al. Ann. Oncol. 1998)
• Can be precursor to all types of GCT except
spermatocytic seminoma
GCT – Unique Features
• Chemo and radiation
• Retroperitoneum is usually
sensitive
the first and only site of
• Capacity to differentiate
metastatic disease
• Consistent pattern of
• Landing zones for rightmetastasis
sided tumors:
– Interaortocaval, precaval
• Ability to produce marker
lymph nodes
substances (AFP/HCG)
• NSGCT: unique potential for • Landing zones for left-sided
tumors:
teratomatous
– Para-aortic, left hilar
differentiation
lymph nodes
• High growth rates 10-30
days
Right to Left Crossover extremely common
Clinical Staging TNMS
• Findings at Inguinal Orchiectomy
– Histology, size, extent of invasion, LVI
• Imaging
– Chest and Retroperitoneum
– CT scan with IV contrast
– PET CT more accurate for seminoma rather than NSCGT
• Serum Tumor Markers
– AFP, bHCG , LDH
NSCGT
• Choriocarcinoma – can have brain mets
• Brain mets can bleed during chemo
• Check head CT particularly in patient with very
high bHCG and choriocarcinoma
Serum markers
• AFP ↑ in 50% , b HCG ↑ in 50% with NSGCT
• 90% of NSGCT have either one marker ↑
• 10-15% will have neg markers even in advanced
disease
• Normalization of markers after treatment ≠ absence
of disease in 10-20% pts
AFP - AlphaFetoProtein
• Half-life of 5-7 days
• Elevated in embryonal, yolk-sac, mixed
• Excludes diagnosis of seminoma/pure
choriocarcinoma
• False positive with liver disease (hepatitis,
cirrhosis) and drug abuse (alcohol, cocaine)
• Can be elevated in hepatocellular, pancreatic,
stomach, and lung cancers
b HCG- Human Chorionic
Gonadotrophin
• Half Life of 24-36 hours
• Assay cross reactive with β subunit of LH (↑in
castration du to high GnRH)
• Also ↑ in liver, pancreas, stomach breast, lung
cancers and marijuana smokers
• ↑ in chorio/embyronal/ seminoma (10%)
LDH
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Produced by liver, muscle
>200 U/dl
Can be elevated in various types of GCT
Good marker for seminoma
Testes sparing surgery
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Controversial
Mass <2cm
Simultaneous bilateral tumors
Solitary testicle with normal testosterone
Biopsy adjacent parenchyma (80% ITGCN)
Can treat remaining testicle with 20Gy of XRT
Scrotal violation
• Local recurrence higher (2.9% vs 0.4%) (Capelouto et
al. J. Urol. 1995)
• Seminoma – extend radiation portal to include
groin and scrotum area
• NSCGT – excise scar and cord remnant
• Extensive groin resection or hemiscrotectomy
not required especially after chemo
NSCGT stage I
• 20-30% occult RP mets
• LVI and Embryonal predominance (45-90% ) are
risk factors
• Absence of yolk sac and MIB-1 + staining >70% ↑
risk
• ↑ rate of mets from 35-70%
• Surveillance
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28% relapse and 1.4% mortality
90% relapses <2y, most in RP
Chemo if large mass and ↑ markers
RPLND if nl markers and small mass
NSCGT stage I – RPLND
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Full bilateral template
<2% local recurrence
Curative in 60-90% with IIa
Needs adjuvant chemo for >IIa
100% curative for teratoma
Lower recurrence free survival compared to
primary chemo 92% vs 99% (Albers et al. JCO 2008)
Stage I NSCGT - chemo
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2 cycles of BEP
Best single modality cure rate
Does not treat teratoma
Long term surveillance
Late toxicity
Under treats >IIb disease
Guidelines:
Low risk stage I – surveillance
High risk stage I – surveillance/chemo/RPLND
Stage IIa-b
• RPLND
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Upto 1/3 neg nodes
Treats teratoma
Only 2 cycles chemo
Avoids chemo in upto
50%
• Chemo
– 60-80% avoid surgery
– Treatment in community
– CSS >95%
Stage IIc and III NSCGT
• Risk based chemo
– Good risk
• BEP x 3 or EP x 4
– Intermediate and Poor risk
• BEP x 4
• BEP x 3 = EP x 4 (94% vs 91% 5y RFS Culine et al. An Oncol
2007)
Risk
Criteria
Good
Test/RP primary + no non pulm visceral mets + AFP <1000, bHCG
<5000, LDH <1.5x normal
Intermediate
Test/RP primary + no non-pulm visceral mets + AFP 1000-10,000
OR bHCG 5000-50,000 OR LDH 1.5x to 10x normal
Poor
Mediastinal primary OR non-pulm visceral mets OR AFP >10,000
OR bHCG >50,000 OR LDH >10x normal
PC- RPLND
• Indicated mass >1cm
negative markers
• Lower relapse after PC
RPLND
• Better response to second
line chemo
• <1cm mass, no teratoma
in primary and good risk
disease – observe CSS
>96% (Ehrlich et al. JCO 2010)
Path
Frequency
Fibrosis
40%
Teratoma
45%
Tumor
15%
PC relapse
• Prognostic characterstics
– >10% of specimen with tumor
– Intermediate or poor risk GCT
– Incomplete resection
• Accepted salvage regimens add 4 cycles
– Vinblastine, Ifosfamide,Platinum (VIP),
– Paclitaxel, Ifosfamide, Platinum (TIP),
– Vinblastine, Etoposide, Ifosfamide, Platinum (VeIP)
• High dose appears to be = std dose
• Growing teratoma – stop and resect
PC masses
• Post second line chemo mass
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53% viable tumor; 21% teratoma
No benefit of post RPLND chemo
Complete resection less feasible
Desperation surgery (RPLND only)
• Late relapse >2y (3%)
– 54-88% tumor (yolk sac most common)
– 12-28% teratoma
– 10% malignant transformation (adenoca most
common)
– Poor response to second line chemo
Seminoma- Clinical Stage I options
5 year survival > 95%
Adjuvant XRT 20-30 Gy (preferred in US)
Paraaortic / Hockey stick field
Primary chemotherapy (1-2 cycles carboplatin)
Long term toxicity, recurrence rate 3-5%
• Treat Clinical stage I S with primary chemo
Active Surveillance – low risk (<4cm, no LVI)
Rigorous follow up/compliance/ imaging related radiation
exposure
17% RELAPSE at 15 months, OS similar
Seminoma risk factors
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Size (> or < 4cm)
Rete testes invasion
LVI – not important
No poor risk category
High risk stage I – 2 cycles vs 1 cycle chemo
(Aparicio J et al. JCO 2011)
Risk
Criteria
Good risk
Any primary + no non pulm visceral mets + normal
markers
Intermediate risk
Any primary + presence of non pulmonary visceral mets +
normal markers
Seminoma treatment
Stage
treatment
Stage IIa
XRT 35Gy
Stage IIb
XRT or Chemotherapy (EP x 4 or BEP x 3)
Stage IIc
Risk based chemotherapy (EP x 4 or BEP x3)
Stage III
Risk based chemotherapy (EP x 4 or BEP x 3)
RP/pelvic recurrence after dog leg XRT <1% - no
need for follow up CT
RP recurrence after chemo – same (need CT f/u)
3-5% relapse after 1 cycle carboplatin
Seminoma post chemo mass
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60-80% will have residual masses
Majority will resolve over 12-18 months
90% necrosis and 10% viable tumor
Mass <3cm – observe
Mass >3cm – evaluate with PET
– If PET positive then RPLND (very difficult)
Seminoma - relapse
• Surveillance failures – dog leg XRT
• Bulky adenopathy - chemotherapy
Toxicity of chemo/XRT
Early
Late
Very late
Fatigue
Raynauds
Secondary malignancies
Myelosuppression
Neuropathy
CV disease
Neuropathy
Hearing loss
GI disease
Hearing loss
Hypogonadism
Infection
Infertility
Mortality (upto 4.4%)
RPLND Templates
Avoid dissection below IMA on contralateral side
Reducing Extra-Template Residual
Disease
• Inclusion of all infrahilar regions except the
contralateral iliac would reduce residual postRPLND disease to:
2% for right-sided templates
3% for left-sided templates
• 3-32% can have disease outside templates
Eggener et al, J Urol, 2007, Carver et al. JCO 2007
RPLND: Technique Matters
• Paracolic recurrences occur following incomplete excision of the
spermatic cord
• Re-operative RPLND has a higher morbidity rate and adversely
impacts survival
• Nerve-sparing is essential to achieve antegrade ejaculation
– Sympathetic chain
– Paravertebral sympathetic ganglia
– Post-gangionic fibers T2-L4
Kantzavelos, Urology, 2003 Donohue et al, Semin Urol Oncol, 1998
Chang, J Urol, 2002
McKiernan, Urology, 2003
What about RPLND following chemotherapy
for metastatic disease?
• Full bilateral RPLND is currently the standard of care
• Several groups have recommended omitting PC-RPLND in men with a
clinical complete response to chemotherapy
• Modified templates have been suggested in the post-chemotherapy
setting with limited supporting data
• Redo RPLND associated with worse survival (55% vs 84%) (Donahue et al. Sem.
Urol. Oncol. 1998)
Ehrlich, BJU, 2006
Donohue, Urol Oncol, 2003
Permpongkosol, Urology, 2007
Post-chemo residual mass
Small post-chemo mass
Daneshmand et al. Urol. Oncol. 2011
Limited Post-Chemotherapy Resections are Associated
with Decreased Disease Specific Survival
All patients
Fibrosis
Overall
Complete RPLND (n=459)
Complete RPLND (n=459)
Complete RPLND (n=227)
Resection of Mass (n=20)
Resection of Mass (n=45)
Resection of Mass (n=45)
p<0.001
P<0.001
Carver et al, JCO 2007
p=0.002
Complications
• Remember all complications !!!
• Injury to any intraabdominal structures –
Bowel (duodenum), pancreas
• vasculature (renal, SMA, IMA etc…), cisterna
chylli – chylous ascites
• Ureter
• Perioperative complications related to prior
chemotherapy
• Ejaculatory dysfunction
Avoid complications
• Careful fluid resuscitation in post chemo
patients
• Low inspired O2
• Spinal cord ischemia due to aortic
mobilization (1%)
• Ileus/bowel obstruction
• Pancreatitis
Non GCT tumors
• Leydig cell tumor
– 25% occur in kids
– Present with painless mass and precocious
puberty
– In adults feminizing characteristics
– 90% benign 10% malignant (almost all in
adults)
– Orchiectomy is treatment
– Mets poor response to XRT/chemo (Mitotane)
• Sertoli cell
Non GCT
– 1% or tumors 90% benign
– Orchiectomy and RPLND if mets
• Granulosa cell
– Benign, orchiectomy
• Gonadoblastoma
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Intersex and mixed gonadal dysgenesis
Female with amenorrhea or cryptorchid male
GCT elements can metastasize
Bilateral orchiectomy
Hematologic malignancies
• Lymphoma
– Most common in men >60y age
– Could be primary or recurrent
– Orchiectomy
• Leukemia
– Testes sanctuary site
– Common in children
– Bilateral in 50%
– Rx with chemo/XRT
A recently married, 25-year-old man, had a radical orchiectomy
for embryonal cell carcinoma. There was lymphatic invasion in
the rete testis. Serum markers, chest and abdominal CT scans
are normal. His semen analysis shows the volume of 3 ML, 25
million sperm per ML, motility 60%, and 50% normal forms. The
patient and his wife want the treatment that gives the best
chance for fertility, as well as the best cancer control. He should
be advised to undergo
A.
B.
C.
D.
E.
Radiotherapy
Surveillance
Modified retroperitoneal lymphadenectomy
Bilateral retroperitoneal lymphadenectomy
Platinum based combination chemotherapy
A 24-year-old man is treated for stage III mixed germ cell tumor
of the right testis by inguinal orchiectomy, four cycles of BEP
chemotherapy, and post-chemotherapy bilateral RPLND. He
remains disease-free with normal serum tumor markers for four
years. Current physical examination and serum HCG are
normal. Serum AFP is 27 mg/dl (normal less than 10 mg/dl), and
a CT scan of the chest, abdomen, and pelvis demonstrates a
solitary 2 cm mass in the right retrocrural area. The next step is
A.
B.
C.
D.
E.
Observation
Repeat AFP after IM testosterone.
Additional BEP chemotherapy
Salvage chemotherapy
Excision of the mass
A 27-year-old man has bulky retroperitoneal adenopathy
following radical orchiectomy for a mixed germ cell tumor. His
chest x-ray is normal. Serum beta-HCG and AFP are markedly
elevated. Liver enzymes are slightly elevated and the patient
relates a history of ethanol excess. He receives three cycles of
BEP. Restaging reveals a 3 cm retroperitoneal mass, a normal
chest x-ray, and normal serum beta-HCG. However, the serum
AFP is 20 IU/ML (normal equals 0-9). The next step is
A.
B.
C.
D.
E.
Retroperitoneal lymph node dissection.
CT-guided needle biopsy
Salvage chemotherapy
Serial markers and CT scans
External beam radiotherapy
A 26 -year-old man undergoes orchiectomy for seminoma. A CT
scan of the retroperitoneum and tumor markers are
negative. He elects surveillance. The most accurate statement
regarding his outcome over the next 2 years is:
A. 5% risk of visceral relapse
B. Similar to patients treated with radiation
therapy
C. 40% risk of relapse with nonseminomatous
elements
D. 5% risk of retroperitoneal node relapse
E. 50% risk of pulmonary relapse
Modified RPLND preserves fertility in most patients by
sparing which of the following structures?
A.
B.
C.
D.
E.
Internal iliac arteries.
Genitofemoral nerve.
Postganglionic sympathetic nerve fibers.
Seminal vesicles.
Pelvic parasympathetic plexus.
For a 2.5 cm residual retroperitoneal mass post
chemotherapy for advanced pure seminoma
(pretreatment retroperitoneal mass 8 cm in diameter)
the optimal next step in management is:
A. Consolidation radiotherapy.
B. Second time chemotherapy.
C. Excision of the residual mass.
D. Surveillance.
E. Autologous marrow transplant and further
chemotherapy.
A 64 -year-old man has painless right testicular swelling of 3
months duration. Urinalysis is normal, and testicular ultrasound
reveals an enlarged right testis. The most likely diagnosis is:
A.
B.
C.
D.
E.
Lymphoma.
Chronic lymphocytic leukemia.
Spermatocystic seminoma.
Teratocarcinoma.
Embryonal carcinoma.