Management of Testicular
Dr. Mohd Waseem Raza
Moderator- Dr. Subhash Gupta
1-2 % of all male malignancies.
Most common malignancy in young adult males (aged 15-40 years)
2 to 3% Testicular Tumour are bilateral
Worldwide Incidence is 1.5/lakh (Globocan 2008)
Incidence in India 0.5/lakh (Globocan 2008)
Right testis: along the IVC inter-aortocaval region
pre-aortic & para-aortic lymph nodes, with possible
cross-over within the retroperitoneum
Left testis: Preaortic and para-aortic lymph nodes
around the left renal hilum inter-aortocaval nodes
mostly without cross-over
Retroperitoneal lymph nodes are located anterior to the
T11 to L4 vertebral bodies concentrated at the L1–L3
Nodal spread to ipsilateral iliac chain is ~3%
Scrotal skin: lymphatics drain into the inguinal and
external iliac nodes.
Aetiology of testicular tumour
Cryptorchidism - 5-fold increase in incidence.
Eutopic (descended) testis-10%
(Pottern et al. J Natl Cancer Inst. 1985;74:377-381; Swerdlow AJ, Higgins CD, Pike MC. Risk of
testicular cancer in cohort of boys with cryptorchidism. BMJ. 1997;314:1507-1511)
Family history - increases the likelihood of developing testicular GCT.
[Dieckmann 1997; Chia 2009; Lutke Holzik 2004; Polednak 1996;Westergaard
Risk of developing a new contralateral primary tumor - 2%
Subfertility , infertility, and testicular feminization.
[Richiardi 2004; Raman 2005; Møller 1999; Jacobsen 2000; Guazzieri 1985]
Marijuana use -- 2 fold increased incidence of NSGCT
[Daling 2009; Trabert 2011]
Altered intrauterine hormonal environment
Mediastinal GCTs : more common in Klinefelter’s syndrome patients .
Testicular Tumour & Molecular Biology
Proto-oncogenes in Germ Cell Tumours
c-erb B-1 and c-erb b-2
(Shuin T et al. Differential expression of protooncogenes in human germ cell tumors of the testis.
Cancer 1994 Mar 15;73(6):1721-7)
Molecular Biology cont..
11, 13 and 18
7, 8 and X
Most consistent structural chromosomal abnormality is an
Spermatocytic seminomas-- Gain of chromosome 9
Looijenga LH et al. Pathogenesis of testicular germ cell tumours. Reviews of
Reproduction (1999) 4, 90–100
Diagnostic and Staging work up
b) Clinical Examination
c) Radiological procedure - USG / CT ± MRI ± Bone Scan
d) Tumour Markers - β HCG, AFP, LDH
e) Pathology of Tumour Specimen
Painless Swelling of One Gonad
Dull Ache or Heaviness in Lower Abdomen
Acute Scrotal Pain-10%
Present with Metatstasis -10%
- Neck Mass / Cough / Anorexia / Vomiting / Back Ache/ Lower limb
Rarely - Infertility
Dictum For Any Solid Scrotal Swellings: All patients with a solid, Firm
Intratesticular Mass that cannot be Transilluminated should be regarded as
Malignant unless otherwise proved
ultrasound – B/L testis- confirms a solid testicular mass.
CT scans of the abdomen and pelvis with chest imaging by either CT or
• Lymph nodes measuring > 5 mm in a landing zone are suspicious for
metastatic disease in a patient with a known testicular tumor.
• If iodinated contrast dye is contraindicated
• Useful for defining vascular anatomy before surgical management of
bulky retroperitoneal masses
Bone scan and brain imaging (CT or MRI) are not part of routine staging.
Positron emission tomography (PET) -not useful in routine staging.
Neither small lesions nor teratoma can be identified by PET (false
negative) and inflammatory processes such as sarcoidosis often
demonstrate fluorodeoxyglucose avidity (false positive).
(de Wit M, Brenner W, Hartmann M, et al. Ann Oncol. 2008;19:1619-1623; Oechsle K,
Hartmann M, Brenner W, et al. J Clin
( Alfafetoprotein ) ( Human Chorionic
Normal:<16 ngm / Has α and β polypeptide chain
Half Life: 5 to 7 d
Normal: < 1 ng / ml
Half Life: 24 to 36 hours
Raised AFP :
Raised β HCG Pure embryonal ca
100 % - Choriocarcinoma
60% - Embryonal ca
Yolk sac Tumour
55% - Teratocarcinoma
25% - Yolk Cell Tumour
7% - Seminomas
N=105 - 333 IU/L
metastatic seminoma- 80% and
Elevated -50% of seminomas at
presentation (half-life of 24
AFP Not raised is Pure Choriocarcinoma or Pure
Role of Tumour Markers
Helps in Diagnosis - 80 to 85% of Testicular Tumours have Positive
Indicates histology of Tumour
Royal Marsden staging system
Limited to testis
Nodes <2 cm
Nodes 2–5 cm
Nodes 5–10 cm
Nodes >10 cm
Nodes above and below diaphragm
AJCC 7th Edition
Primary tumor cannot be assessed.
No evidence of primary tumor (e.g., histologic scar in testis).
Intratubular germ cell neoplasia (carcinoma in situ).
Tumor limited to the testis and epididymis without vascular/lymphatic invasion;
tumor may invade into the tunica albuginea but not the tunica vaginalis.
Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or
tumor extending through the tunica albuginea with involvement of the tunica
Tumor invades the spermatic cord with or without vascular/lymphatic invasion.
Tumor invades the scrotum with or without vascular/lymphatic invasion.
Regional lymph nodes cannot be assessed.
No regional lymph node metastasis.
Metastasis with a lymph node mass ≤2 cm ; or multiple lymph nodes, none >2 cm in
Metastasis with a lymph node mass >2 cm but not >5 cm ; or multiple lymph nodes,
any one mass >2 cm but not >5 cm in greatest dimension.
Metastasis with a lymph node mass >5 cm in greatest dimension.
No distant metastasis.
Nonregional nodal or pulmonary
Distant metastasis other than to
nonregional lymph nodes and lung.
Serum Tumor Markers (S) Required for Staging
Marker studies not available or not performed.
Marker study levels within normal limits.
LDH <1.5 × N and hCG (mIu/ml) <5,000 and AFP (ng/ml) <1,000.
LDH 1.5–10 × N or hCG (mIu/ml) 5,000–50,000 or AFP (ng/ml)
LDH >10 × N or hCG (mIu/ml) >50,000 or AFP (ng/ml) >10,000.
N indicates the upper limit of normal for the LDH assay.
IGCCCG Prognostic System for Advanced-Stage GCT
Requires gonadal or retroperitoneal
primary tumor, absence of NPVM, and ≥ 1
following: HCG 5000-50,000 mIU/dL, AFP
1000-10,000 ng/dL, or LDH 1.5-10.0 x ULN
Requires any of the following: mediastinal 41
primary tumor site, presence of NPVM,
50,000 mIU/dL, AFP > 10,000 ng/dL, or
LDH > 10 x ULN
Requires all of the following: gonadal or
retroperitoneal primary tumor, absence
NPVM, HCG < 5000 mIU/dL, AFP < 1000
ng/dL, and LDH < 1.5 x ULN
IGCCCG Prognostic System for Advanced-Stage GCT
Absence of NPVM
Presence of NPVM
International Germ Cell Consensus Classification Group: a prognostic
factor-based staging system for metastatic germ cell cancers. J Clin
Sperm banking must be discussed with the patients before undergoing any
therapeutic intervention that may compromise fertility including RT ,Surgery
Management of testicular tumor is combined modality treatment.
Various treatment modalities are:
• All patients
• done via an inguinal incision, with cross
clamping of spermatic cord vasculature and
delivery of testis into the surgical field.
• Scrotal violation, increased local/regional
recurrence, but no difference in distant
recurrence rate or overall survival.
Stage wise management of seminoma
• Indication: Pts. who can comply.
• Sites for relapses
– Retroperitoneum- 76-94%
– Mediastinum- 5-15%
Whether All Stage I patients should be
considered for surveillance?
Prognostic Factors for Relapse in Stage I Seminoma
Managed by Surveillance: A Pooled Analysis
Pooled Data of 638 patients(Princess Margaret Hospital, Danish Testicular
Cancer Study Group, Royal Marsden Hospital, and Royal London Hospital)
• Median follow-up -7.0 years
• Multivariate predictors for relapse:
1) tumor size > 4 cm and
2) invasion of rete testis
– If tumor < 4 cm then age less than 30 independent risk factor
Risk of relapse - no risk factors: 12%; one risk factor: 16%; both risk
– If tumor < 4 cm, risk relapse if > 30 yo: 11%; if age < 30 yo: 20%
Warde et al. J Clin Oncol 2002:4448-4452.
"Long-term outcome of postorchiectomy surveillance
for Stage I testicular seminoma."
20% rete testis invasion, 45% >4cm. Median F/U 12.1 years, 3 lost to
Relapse-free rate: 5-years 83%, 10-years 80%, 15-years 80%
Relapse site: 88% (15/17) below diaphragm.
Predictor for relapse: invasion of rete testis (HR 3.5, p= 0.03)
(Choo R, Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):736-40.)
Median F/U 34 months
100 with no risk factors
treated with surveillance
214 patients with risk factors
(tumor >4 cm, rete testis
involvement) had carboplatin
AUC=7 x 2
5-year DFS: surveillance 94%, chemo 96%.
Relapses: surveillance 6%, chemo 3% (0.8% if tumor >4cm, 9.1% if rete testis,
6% if both).
Median time to relapse 9 months (4-28 months)
Aparicio Jet al. Risk-adapted management for patients with clinical stage I seminoma: the
Second Spanish Germ Cell Cancer Cooperative Group study.J Clin Oncol. 2005 Dec
Median f/u 34 mo
84 pts (37%) with no risk
factors treated with
44 pts (19%) had tumor > 4 cm, 25 (11%)
with rete testis, 74 (33%) had both. Only
the latter group (both risk factors)
received treatment w/ carboplatin x 2.
All others received surveillance only.
16 relapses (7%) for pts on surveillance; 1 relapse (1.4%) for pts on
3 yr DFS 88% (surveillance group), 98% (adjuvant carboplatin group).
For 2 risk factors: carboplatin. For 0-1 risk factors: observation
Aparicio J et al.Risk-Adapted Treatment in Clinical Stage I Testicular
Seminoma: The Third Spanish Germ Cell Cancer Group Study. J Clin Oncol.
2011 Oct 31
Validation study failed to identify rete testis invasion as prognostic on
univariate analysis and neither variable was prognostic on multivariate
Chung PW, Daugaard G, Tyldesley S, et al. Program and abstracts of the 46th American Society of
Clinical Oncology Annual Meeting; June 4 - 8, 2010; Chicago, Illinois. Abstract 4535
Compliance with follow-up is a concern for this patient population.
In one study, as many as 21% of patients were lost to follow-up within 5.5
Alomary I, Samant R, Gallant V. Treatment of stage I seminoma: a 15-year review. Urol Oncol.
• Stage I surveillance
H&P, labs every 3–4 months for 3 years,
every 6 months for years 4–7,
CT abdomen and pelvis at each visit.
CXR at alternate visits up to 10 years
Adjuvant RT for Stage I Seminoma
Historically, seminoma was treated with orchiectomy + inguinal/paraaortic RT, and sometimes also mediastinal RT
Prophylactic mediastinal RT was abandoned due to increased cardiac
mortality in the 1960's and 1970's
Para-aortic fields plus ipsilateral iliac LNs ("dog leg") at 30/15 became
Dog-Leg vs. Para-aortic
– Randomized. 478 men with Stage I to PA or Dog-Leg.
– RT 30 Gy. Median F/U 4.5 years
Dog Leg RT
3YR RELAPSE FREE
PELVIC RELAPSE FREE
Para Aortic RT
Relapse: 9 in each group (NS), but pelvic recurrences 0 DL vs. 4 PA
(Fossa SD, J .MRC.Clin Oncol. 1999 Apr;17(4):1146.)
MRC Trial TE 18,
Post orchiectomy --- Paraaortic
radiation (dogleg for patients
with prior inguinal surgery)
2-year relapse rate of 3-4%. 1 death (allocated to 20 Gy)
Toxicity: At 4 weeks, 20 Gy significantly better (moderate/severe
lethargy 5% vs. 20%); at 12 weeks no difference
Jones WG et al.J Clin Oncol. 2005 Feb 20;23(6):1200-8
Other Dose Fractions
25.5 Gy /15# /3 weeks, 20 Gy /10# /2weeks results in excellent survival
and freedom from relapse
Nausea occurs more frequently when a higher daily dose per fraction is
Niewald M, et al. Low-dose radiotherapy for Stage I seminoma longterm results. Int J Radiat Oncol Biol Phys
Reduction in RT Field size
Superior edge of para-aortic field
– 80/163 patients, Stage I seminoma.
– Treated with PA field extending from T11/T12 (vs historical T10/T11)
– Median dose 20 Gy. ;Median F/U 7.1 years
– Outcome: 5-year RFS 95%; no relapse above T12
– Dosimetry: Median reduction of treated volume 16% (13-21%)
– Conclusion: Recommended to minimize risk of radiation-related late
(Bruns F. Adjuvant radiotherapy in stage I seminoma: is there a role for
further reduction of treatment volume?" Acta Oncol. 2005;44(2):142-8.)
Position and immobilization
– Supine, arms placed by the pt. side and legs straight, with feet
stabilized with a foam wedge underneath the knees.
– Body cast can also be used for immobilization
– Position penis out of field
– Contra-lateral testis is shielded with a lead clamshell device.
Mean dose values to the contra lateral testicle.
PA + IL iliac
1.86 cGy 3.89 cGy
0.65 cGy 1.48 cGy
– Superior: T11–T12 interspace
– Inferior: L5–S1 interspace
– Lateral: transverse process
– For left testis: cover renal hilum
– 20 Gy in 10# to para-aortic ± pelivic
lymph node by ap-pa field
Elective para-aortic field for stage I
Nodal CTV and Contouring for Seminoma stage I
Contour the IVC and aorta separately
from 2 cm below the top of the kidneys
down to the point where these blood
Posterior view of para-aortic fields.
Wilder RB et al. Radiotherapy treatment planning for testicular seminoma.
IJROBP 2012 Jul 15;83(4):e445-52
Adjuvant CT for stage I Seminoma
Chemotherapy is preferred in patients with a horseshoe (pelvic) kidney,
inflammatory bowel disease, or a history of radiotherapy
Multiple nonrandomized trials have been published using either a single
or 2 cycles of carboplatin.
RT vs. Chemo
MRC TE19/EORTC 30982
14 countries. N=1447, Stage I.
Median F/U 4 years
1 cycle carboplatin
Radiation (PA or DL )
20Gy/10 - 30Gy/15).
3 Yr Relapse Free Survival
Distant 57 %
Pelvic 31 %
74 % Para Aortic
Second testicular tumors
- Oliver RT et al. Radiotherapy versus single-dose carboplatin in adjuvant
treatment of stage I seminoma: a randomised trial. Lancet. 2005 Jul 2329;366(9482):293-300
Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC
Median FU 6.5 yrs
1 death from seminoma in RT arm.
Pts receiving >= 99% of the AUC 7 dose had RFS of 96.1% vs 92.6% of those
who had lower doses (p=0.08).
Reduction of contralateral GCTs with carbo (carbo n=2 vs RT n=15; HR 0.22).
Conclusion: confirmed non-inferiority of single dose carboplatin vs RT;
reduced risk of 2nd GCT.
Criticism - it was designed to exclude a 3% relapse risk in the carboplatin arm- the
main goal consequently not being achieved.
Oliver RT, J Clin Oncol. 2011 Mar 10;29(6):957-962.
Increased relapse risk with the single-dose carboplatin regimen, as seen in
one prospective study (9% vs 0%)
[Dieckmann KP et al : Adjuvant treatment of clinical stage I seminoma: is a single course of
carboplatin sufficient?Urology 2000, 55(1):102-6]
Current recommendation is to administer either a single carboplatin dose
(that must be properly dosed with the help of renal scintigraphy) or two
cycles spaced three weeks apart.
% OF PTS
1 ×CARBO - 5 -9 %
2×CARBO - 0 – 3
4% @ 5 yrs
NODES 74 -94%
DISTANT METS PARA AORTIC
99 – 100%
SEMINOMA STAGE 2
• Depends on bulk of retroperitoneal nodes
• Radiotherapy treatment of choice in stage 2a & 2b (node <
5cm), 25 to 35 Gy
• Disease specific survival rate 97 – 100%
• Reccurance rate < 10% ,MC site SCF & mediastinum.
• CT + RT = RT alone (patterson et al, 2001)
Superior: T11–T12 interspace
Inferior: mid-obturator foramen
Lateral: transverse process down to
L5–S1 interspace then diagonally to
the lateral edge of the acetabulum,
then vertically downward to the
median border of the obturator
For left testis: cover renal hilum
Paraaortic and ipsilateral inguinal field for
stage II left testicular seminoms, with
inclusion of the rental hilus.
Modifed Dog Leg Field
"Radiotherapy for stages IIA/B testicular seminoma: final report of a
prospective multicenter clinical trial."
RT to para-aortic and high ipsilateral iliac LNs
Median F/U 5.8 years
Stage IIA (n=66)
Stage IIB (n=21)
30 Gy/ 15#
Toxicity: Grade 3 nausea 8-10%; no late toxicity
Conclusion: RT for Stage IIA-B seminoma, with reduced portals,
yields excellent tumor control and no late toxicity
(Classen J, J Clin Oncol. 2003 Mar 15;21(6):1101-6.)
Modified Dog Leg Field cont..
The German Testicular Cancer Study Group – also support modified field
in their prospective trials.
[Schmidberger H. 1997, Bamberg M. 1999, Classen J,2003]
European Germ Cell Cancer Consensus Group recommends that the
inferior border of dog-leg fields should be placed at the upper border of
the acetabulum in patients with no prior history of pelvic surgery.
Stage II a25Gy in 20 # by AP-PA
Stage II b & IIc
25 Gy in 20 #
10 Gy in 5 #
Dog Leg Modified to cover common iliac
CTV1 + Iliac vessels down to the
upper border of the acetabulum.
1.2-cm expansion on the iliac
vessels and included in CTV1.
The PTV1 is created as previously
Wilder RB et al. Radiotherapy treatment planning for testicular seminoma.
IJROBP 2012 Jul 15;83(4):e445-52
Contour the retroperitoneal
adenopathy (i.e., the gross
GTV + 0.8cm = CTV2
CTV2 + 0.5cm =PTV2
PTV2 + 0.7cm = Block Edge
By coning down after 20 Gy,
one reduces toxicity.
Multileaf collimator blocks for the boost
Chemotherapy for stage IIa & IIb
72 pts (18-Stage IIA, 54-Stage IIB)
Median f/u 71 m
4 cycles of
3 cycles of BEP (bleomycin,
83% achieved CR, 17% PR.
5-yr PFS 100% and 87% for Stage IIA and IIB. 5-yr OS 95%
Conclusion: Chemotherapy is a highly effective and well-tolerated
treatment for patients with stage IIA or IIB seminoma
(Spanish Germ Cell Cancer Group Garcia-Del-Muro X, J Clin Oncol. 2008 Nov 20;26(33):54165421.)
• Stage 2c ( node > 5cm)
• Systemic chemo is the treatment of choice, RT is a option but
relapse rate is 30%.
• If nodes > 10 cm RT relapse rate is 40 %.
• CT of choice is BEP x 3/EP x 4
Seminoma Stage 3
Treatment is BEP × 3 cycles or EP × 4 cycles
Einhorn and colleagues demonstrating that the fourth cycle was
associated with excess toxicity but with no increased cancer-specific
BE500P x 4 cycles
BE500P for 3
Cisplatin based regimen was superior to the carboplatin arm
[Bajorin 1993; Bokemeyer 1996; Horwich 1997; Horwich 2000]
3 x BEP vs 4 x EP
E500P x 4 cycles vs B90E500P x 3 cycles
To test equivalence
primary endpoint of favorable response rate was similar
between the 2 arms (97% vs 95%; P = .34)
No statistically significant differences were found in 4-year
event-free survival (P = .135) or overall survival (P = .096)
E500P for 4 cycles arm had more episodes of neutropenia,
febrile neutropenia rate (7% vs 5%) and the use of growth factors (36% vs
29%) were equivalent.
Neurologic (P = .006) and dermatologic (P =.001) toxicities were more frequent
with B90E500P for 3 cycles
Culine S, Kerbrat P, Kramar A, et al. Refining the optimal chemotherapy regimen for
good-risk metastatic nonseminomatous germ-cell tumors: a randomized trial of the
Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP). Ann
Salvage After CT
• Residual mass regress in about a month in 80%.
Stage II / III
BEP x 3 or EP x 4
Post Chemotherapy residual Mass
< 3 cm
Resect /Salvage RT
Follow up schedule for seminoma
• After RT for stage I seminoma
H&P, labs (AFP, b-HCG, LDH), and CXR every 3–4 months for year 1,
every 6 months for year 2,
Pelvic CT annually for 3 years for patients treated with PA-only RT (not
needed if PA and pelvic RT)
Stage wise management of Non-seminoma
Post orchidectomy options are:
STAGE 1 (50%)
Survival close to 100%
• Risk factors for relapse
• Venous invasion
• Presence of undifferentiated elements
• Absence of yolk sac elements
– Follow up tumor markers, phy examination, cxr monthly 1 yr, 2m – 2 yr, 3m – 3 yr,
6m – 4&5 yr.
– CT abd & pelvis monthly for 1 yr, 4m – 2 yr , 6m – 3 yr, yearly 4- 5 yr
RPLND is offered to stage I nonseminoma patients :
1. with LVI in the primary tumor
2. to noncompliant patients
• The presence of (LVI), is associated with a 45% to 55% of recurrence vs
15% to 20% for patients without this risk factor
[Colls 1999; Daugaard 2003; Gels 1995]
Retro peritoneal lymph node
• Include the precaval, retrocaval,
paracaval, interaortocaval, retroaortic,
preaortic, para-aortic, and common iliac
lymph nodes bilaterally.
• Retrograde ejaculation.
• With modern nerve-sparing techniques,
the incidence has declined to rates of 5%.
Stephenson Aj et al Curr Treat Options
Adjuvant chemotherapy for stage I NSGCT
• Failure of postorchiectomy markers to normalize (stage IS) indicates
the presence of systemic disease, often outside the
retroperitoneum and requires primary management with systemic
Trials evaluating 1 or 2 cycles of bleomycin, etoposide, and cisplatin (BEP)
in all T2N0-T4N0 demonstrated continuous disease-free survival and
overall survival rates of 95% and 99%, respectively
Cullen MH, et al. Short-course adjuvant chemotherapy in high-risk stage I
nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin
Median time to relapse is 6 month with almost all relapse < 2 yrs.
ADJ CT(BEP *2)
98 – 99%
nodes, 25% lung
STAGE IIc /III
Chemotherapy (BEP x 4)
Note: - Radiation therapy only for palliation in metastatic disease.
De Wit 1995*
De Wit 1998*†
†Trial performed exclusively in nonseminoma, intermediate-risk patients.
Stage I patients are subdivided into low risk, (20% relapse rate) or high risk,
(40–50% relapse rate), according to absence or presence of vascular,
(lymphatic or venous) invasion.
20% to 30% of patients will develop progressive disease following initial
chemotherapy with or without surgery and will require salvage therapy
Conventional doses of cisplatin plus ifosfamide plus either vinblastine
(VeIP) or paclitaxel (TIP) are the most commonly used regimens.
Complications : Radiotherapy
Acute--nausea, vomiting, diarrhea
Late--small bowel obstruction, chronic diarrhea, peptic ulcer disease
(<2% with <35 Gy)
Second cancers: 5–10% increased risk
With testicular shielding, most patients will have oligospermia by 4
months that lasts ~1 year
Infertility: 50% of patients have subfertile counts on presentation or after
surgery. After RT, 30% able to have children
Most common curable malignancy of young adults.
Seminoma > nonseminoma
Surgery is the main modality of treatment followed by Radiotherapy & or
chemotherapy for seminoma and chemotherapy & RPLND for
Surveillance for patients who are compliant
Follow-up is recommended to detect second primary tumors, local or
distant recurrences, and to monitor for potential long-term side effects