Testicular Cancer

1. Testicular Ca
Dr. Edmond Wong
EAU 2010
EAU 2011
EGCCCG 2008 (EU)
1

2. Epidemiology
• 1-1.5% of male neoplasm
• 5% of urological tumors
• 3-6 new case per 100,000 male/ year
• Increasing trend towards increase incidence
• 1-2% bilateral
• Histological variance:
– Germ cell tumors (90%)
– Non- GCT (10%)
• Peak incidence:
– 30s for seminoma
– 40s for pure seminoma
– Familial clustering among sibilings
2

3. Risk factors
1. Familial hx of Ca testis in 1st degree relative
(father/brother)
2. History of cryptorchidism
3. Infertility
4. Klinefelter’s syndrome
5. Contralateral tumor or Tin
6. HIV
7. Maternal oestrogen exposure
8. Race: scandanavian
3

4. Genetics
• Specific genetic marker: Isochromosome of the
short arm of chromosome 12 – i(12p) in all germ
cell tumors
• Intratubular germ cell neoplasia (testicular
intraepithelial neoplasia, Tin) : same
chromosomal change with alterantion in p53
locus (66%)
• Deregulation in pluripotent programme of fetal
germ cells (markers: M2A, C-KIT,
OCT4/NANOG)
4

5. Germ Cell Tumors
Seminoma (40% of all GCTs):
– Typical/ Classic (85%)
– Anaplastic (5-10%)
– Spermatocytic (2-12%)
• Nonseminomatous
tumour
– embryonal cell carcinoma
– yolk sac tumor
– teratoma
– choriocarcinoma
5

6. Pathology: WHO classification
6

7. Classic Seminoma
• Peak at 30s, also in > 60s
• Composed of islands/ sheets of relatively large
cells with clear cytoplasm and densely staining
nuclei
• Syncystiotrophoblastic element in 10 – 15 %
– correspond to β-hCG production
• Lymphocystic infiltration
in 20 %
• Slow growth rate
7

8. Anaplastic seminoma
• Morphology similar to that of classic / typical
seminoma
• Characteristics being more aggressive and
potentially more lethal:
– Higher mitotic activity
– Higer local invasion
– Increased rate of metastatic spread
– Higher rate of β-hCG production
• Inguinal orchiectomy + RT is equally effective
in controlling both anaplastic and classic
seminoma
8

9. Spermatocytic seminoma
• Composed of cells with variable size and
deeply pigmented cytoplasm, resemble
different phase of maturing spermatogonia
• Metastatic potential: extremely low
• Prognosis is accordingly favorable
9

10. Embryonal carcinoma
• Highly malignant
• Small, rounded, but irregular mass invading the tunica
vaginalis testis, may involve contiguous cord
structures
• Cut surface: a variegated, grayish white, fleshy tumor,
often with areas of necrosis or hemorrhage and a
poorly defined capsule
• Histology: distinctly malignant epithelioid cells
arranged in glands or tubules; cytoplasm pale or
vacuolated, and the nuclei rounded with coarse
chromatin and one or more large nucleoli
10

11. Choriocarcinoma
• May occur as a palpable nodule; the size
depends on the extent of local hemorrhage
• May present with advanced distant metastasis
but a paradoxically small intratesticular lesion
• Histology: two distinct and appropriately
oriented cell types must be demonstrated:
– syncytiotrophoblasts (large, multinucleated cells)
– cytotrophoblasts (closely packed, intermediate-sized, uniform
cells)
11

12. Teratoma
• More than one germ cell layer in various stages of
maturation and differentiation
• Mature and immature elements
• Variably sized cysts containing gelatinous, mucinous,
or hyalinized material interspersed with islands of solid
tissue often containing cartilage or bone
• Histology: the cysts may be lined by squamous,
cuboidal, columnar, or transitional epithelium, and the
solid component may contain any combination of
cartilage; bone; intestinal, pancreatic, or liver tissue;
smooth or skeletal muscle; and neural or connective
tissue elements
12

13. Yolk sac tumor
• The most common testis tumor of infants and children
• In adults, it occurs most frequently in combination with
other histologic types
• Responsible for the production of AFP
• Histology: composed of epithelioid cells that form
glandular and ductal structures
• Embryoid bodies: measuring < 1 mm in diameter,
consist of a cavity surrounded by loose mesenchyma
containing syncytiotrophoblasts and cytotrophoblasts,
resembling 1- to 2-week-old embryos
13

14. History:
• History related to the mass
- Duration, painful/painless, change in size, previous history of genitalia surgery, sexual
history, trauma, associated urinary tract symptoms
• Previous relevant history and risk factor(s)
- Cryptorchidism (Undescend 4-13x risk)
- Family History (6-8x risk)
- Racial Origin (Highest in Scandinavia)
- Maternal exposure of estrogen (2.8-5.3x risk)
- Subfertility (1.6-20x risk)
- Contralateral testicular tumour (5-10% risk)
- HIV
14

15. Clinical examination
• General:
– SC LN
– Palpable abdominal mass
– Gynaecomastia (7%) more common in NSGTC
– Back and flank pain (11%)
• Scrotum:
– Painless , unilateral mass in scrotum
– Reduction in testis size precede testicular tumor
– Casual finding of intrascrotal mass
– Scrotal pain (20%)
– Local pain (27%)
– Mimic orchioepididymitis (10%)
15

16. Extragoadal Ca testis
• 1/3 ITGCN
• 1/3 USG testis reveal burned out tissue
• 1/3 Primary extragonadal germ cell tumor
• Supported by elevated AFP / beta-hCG
• Dx must be confirmed by bx of
extragonadal mass
• Histology of undifferentiated Ca 
immunohistological marker (isochrom i
12p)
16

17. Blood test
• Serum marker has prognostic value:
– AFP (produced by yolk sac cells) : ½ life 5 day
• Increase in 50-70% of NSGCT
– hCG (expression of trophoblasts): ½ life 36hr
• Increase in 40-60% of NSGCT
• Increase in 30% of Seminomas
– 90% NSGCT present with rise both marker
• LDH (marker of tissue destruction)
– For pt with metastatic disease
– Elevated in 10 - 20% of seminomas, correlating with tumor burden
– Useful in monitoring of Rx response in advanced seminoma
– Increase in 51% of ca testis
• Other marker :
– PLAP (placental like alkaline phosphatase): monitoring pt with pure
seminoma
• -ve maker do not exclude the dx of GCT
• AFB, hCG & LDH in advanced cancer is mandatory , while PLAP is
optional
17

18. Imaging of testis
• Scrotal USG: > 7.5 MHz
– Confirm presence of testicular mass
– Diff intra or extratesticular
– Explore contralateral testis
– Sensitivity (100%)
– Also indicated in pt with retroperitoneal or visceral mass & elevated hCG or AFP
– FU of contralateral testis on FU pt at risk
• Seminoma :
– a homogeneous hypoechoic, intratesticular mass; larger lesions may be more
inhomogeneous
– calcifications and cystic areas are less common
• Nonseminomatous tumour :
– may contain microcalcifications and areas of hemorrhage, typically
heterogeneous in appearance
– teratoma elements: may demonstrate well-defined structures of ectodermal
derivation
18

19. Testicular microcalcifications
• Divided into classic and limited:
– Classic: presence of five or more microliths on one or more
images of the testes
• Aassociated in both benign and malignant conditions:
– Klinefelter syndrome
– male pseudohermaphroditism
– Down syndrome
– subfertility
– infertility
– cryptorchism
– hypogonadism
– fragile X syndrome
– pseudoxanthoma elasticum
– pulmonary microlithiasis
19

20. CT scan of the abdomen and pelvis with IV
and oral contrast
• To identify metastatic disease to the retroperitoneal
lymph nodes (sensitivity 70-80%)
• Understages approximately 15-20% of patients
thought to be at stage I
• Left-sided NSGCTs – LN bounded by left renal vein,
left ureter, IMA and aorta
• Right-sided tumors – interaortocaval LN at the level of
L2 ( Echelon LN )
• Lymphatic drainage cross over from right to left, and
20% of right-sided NSGCTs, lymph node involvement
is found on the left side
20

21. Chest XR / CT
• to help identify any possible pulmonary
metastases
• the only thoracic examination in seminoma when
retroperitoneal and pelvic CT are -ve
• Chest CT is recommended for NSGCT
• Chest CT increases the sensitivity of diagnosis,
but the presence of small, benign granulomas of
the lung may be misdiagnosed as metastatic
disease in as many as 30% of patients with
clinically low-stage disease
21

22. • MRI:
– Higher SV (100%) and SP (95%) than USG
for diagnosis
– Able to differentiate Seminomatous from non-
seminomatour tumors
– No adv over CT
• PET :
– No adv over CT, because both are insensitive
for microscopic LN metastasis
22

23. 23

24. Inguinal exploration and
orchidectomy
• Should be performed within 1 week
• Immediate orchidectomy with division of spermatic cord
at internal inguinal ring must be performed if tumor is
found
– scrotal skin lymphatics are different from testicular lymphatics and
drain into the inguinal nodes
– perform all orchidectomies for solid masses through an inguinal
route to avoid tumor spill into the inguinal drainage basin
– If a patient is explored scrotally, subsequent therapy may
necessitate hemiscrotectomy and radiation treatment of the inguinal
nodes
• If dx not clear: testicular bx is taken for frozen section
• In case of disseminated disease or life-threatening
metastasis  up-front chemotherapy and then
orchidectomy later when clinically stabilized
24

25. Before orchidectomy
Discuss the issue of:
• Sperm banking
• Contralateral testicular biopsy (10%) in no risk
 (34%) in risk gp (refer to TIN)
• Testicular prothesis:
– Prothesis infection (2%) may delay post-op chemo
– Extrusion from scrotum (5%)
– Scrotal contraction or migration (3%)
– Chronic pain (3%)
– Hematoma (< 1%)
25

26. Radical Inguinal Orchidectomy
• Inguinal incision
• Cord isolation
• Pedicle control with a non-crushing vascular clamp
• Dissection of the spermatic cord with 1 – 2 cm into the
internal spermatic ring
• Leave a long nonabsorbable tie on the patient side of
the spermatic cord. This is to facilitate identification if
retroperitoneal lymph node dissection (RPLND)
becomes necessary and the patient requires
dissection of the remaining spermatic cord structures
from the abdominal exposure.
26

27. Organ sparing surgery
• Contraindication: presence of non-tumoral contralateral
testis
• Indications:
– Bilateral testicular tumors
– Metachronous contralateral tumors
– Tumor in solitary testis with normal pre-op testosterone level
– Tumor volume <30% of testicular volume
• Rate of Tin is high (82%)
• If TIN is found  RT
• All patient must be treated with Adj RT (20Gy) at some
point (after fathering of children)
27

28. 28

29. Pathological exam of testis
• Mandatory pathology requirements:
– Macroscopic features: side, testis size, max tumor size ,
macroscopic features of epididymis, spermatic cord and TV
– Sampling : 1cm2 section for every cm of tumor diameter (include
parenchyma, albuginea and epididymis) with selection of
suspected area. At least 1 proximal and 1 distal section of
spermatic cord + any suspected area
– Microscopic features: Histological types WHO 2004:
• Peri-tumoural venous and/or lymphatic invasion
• Albuginea, TV, rete testis, epididymis or spermatic cord invasion
• Intratubular germ cell neoplasia(Tin) in non-tumor parenchyma
– pT category according to TNM 2002
– Immunohistochemical studies: in seminoma and mixed germ cell
tumor, AFP & hCG
29

30. • Advisable immunohistochemical markers: in
case of doubts:
– Seminoma : Cytokeratin (CAM 5.2) , PALP, c-kit
– Intratubular germ cell tumor: PALP, c-kit
– Other markers: Chromogranine A (Cg A) , Ki-1(MIB-1)
30

31. 31

32. CIS (Tin)
• Testicular Intra-epitheralial neoplasia (TIN) or Intratubular germ-cell
neoplasia (ITGCN)
• Pre-invasive testicular germ-cell lesion (CIS)
• Precursor of all GCT except spermatocytic seminoma
• Incidence in general population : 1%
• Incidence of contralateral (10%) & metachronous (2.5%) Tin
• 50% progression to GCT in 5 yr, 70% in 7 yr
• Does not raised tumor marker
• Presence has no bearing in overall prognosis in tumor bearing testis
• Histology:
– malignant germ cell lining seminiferous tubules containing Sertoli cells in
single row
– nuclear pleomorphism and intact basement membrane
– Tubules: smaller diameter , thickened wall, absent spermatogenesis
32

33. • Contralateral bx to rule out presence of Tin (not for all
patient)
• Indication for contralateral biopsy: 34% risk
– Testicular volume < 12ml
– Age < 40
– Hx of cryptorchidism (3%)
– Poor spermatogenesis (Johnson Score 1-3) : hx of infertility (1%)
• Other risk factors:
– Extra-gonadal GCT (40%)
– 45 XO karyotype
• Double biopsy is preferred to increase sensitivity:
– Upper and lower pole , able to dx with 99% accuracy
– Preserved in Stieve’s or Bouin’s solution
• Testicular bx in pt with extragonadal GCT:
– 1/3 will have TIN in one or both testis
– Routine bx of bilateral testis is not recommended , because they
will have received chemo which eradicate most TIN already
– If indicated , perform before chemo or 2-year after chemo
33

34. 34

35. Txn of Tin: In contralateral testis / affected single testis
after organ preserving surgery
• Surveillance:
– Interval btw TIN and testicular ca is long (justified)
– have not complete family, Fu PE & USG yearly
• Local RT
– 20Gy in single fraction of 2Gy , 5 day/week
– Need testosterone replacement
– < 20Gy have lower frequency of complete eradication
• Orchidectomy:
– loss of fertility and need of testosterone
– Will result in infertility  must be counseled for sperm banking
• Post-orchidectomy chemo given:
– 2/3 have ITGCN eradicated , bx at least 2 yr after complete
chemo
– If still have ITGCN  RT vs orchidectomy
35

36. Txn of TIN: pt without gonadal
tumors
• Normal contralateral testis 
orchidectomy
• RT may impair fertility of contralateral
unaffected testis (scattered radiation)
36

37. Txn of TIN: Pt schedule for chemo
• 2/3 will be eradicate by chemo alone
• Delay RT to avoid extensive damage to
Leydig cell
• Bx after chemo: alone after 2 year
• If persisted  managed as above
37

38. 38

39. Screening of Ca testis
• Stage and prognosis is directly related to
early diagnosis
• Self PE by affected individual is advisable
39

40. Staging
• To determine metastatic or occult disease:
– ½ life kinetics of serum tumor markers
– Nodal pathway must be screened
– Presence of visceral need to be rule out
40

41. Staging
• AJCC 2002 TNM classification
• Royal Marsden Staging System
– Stage I: confined to testis
– Stage II: retroperitoneal LN involvement (A, B, C, D)
– Stage III: Supra-diaphragmatic & visceral met with
vary degree of tumor marker
– Stage IV: Disseminated disease (liver, lung, bone)
• Boden-Gibbs classification
– A – confined to testis
– B – regional LN metastasis
– C – Above diaphragm or extralymphatic metastasis
41

42. Test for staging
• Serial blood sampling
• CXR
• CT Abd + Pelvis (+/- Chest)
• Abdomen + retroperitoneal USG
• MRI
• PET scan
42

43. Serum marker
• ½ life of AFP: 5-7 days
• ½ life of hCG: 3 days
• Post-orchidectomy
– Serial marker evaluation to determine ½ life kinetic
– Marker in Stage I disease should decrease until normalization
– Elevated marker  metastatic disease
– Normal maker does not rule out presence of tumor metastasis
– Should be measure every week after orchidectomy
• Post-orchidectomy markers are important in risk
classification according to IGCCCG
• Post-Chemo: persistence marker  poor prognostic
value
43

44. AFP (Alpha-fetoprotein)
• Expressed by trophoblastic elements
• 50 - 70% of teratomas, yolk sac tumors
• Not produced by pure choriocarcinoma
and pure seminoma
• T1/2: 3-5 days
• Normal <10 ng/mL
44

45. Falsely raised AFP level
• Tobacco smoking (AFP increases by about 10%)
(Bartels 1993, Bernstein 1989, Cuckle 1990,
Thomsen 1983, Spencer 1993)
• Binge-drinking of alcohol or long-term alcoholism
• Non-germ cell malignancies (hepatocellular carcinoma
and other gastrointestinal malignancies)
• Benign hepatic conditions (hepatitis, Cirrhosis)
• Inflammatory bowel disease
• Ataxia Telangiectasia
• Wiscott-Aldrich syndrome (eczema-thrombocytopenia-
immunodeficiency syndrome)
• Wilson's Disease
45

46. β-hCG
• Expressed by syncytiotrophoblastic
elements
• Choriocarcinomas (100%), teratomas
(40%) and seminomas (10%)
• T1/2: 24-36h
• Beta-subunit measured
• Normal < 5 mIU/mL
46

47. Falsely raised β-hCG level
• Marijuana use
• Human anti-mouse antibodies (HAMA) or
heterophilic antibodies eg in IgA deficient
individuals
• Duodenal ulcers
• Cirrhosis of the liver
• Inflammatory bowel disease
47

48. Imaging
• Supracalvicular LN: physical examination
• CXR:
– Routine thorax examination
– AP + lat CXR as the only investigation in CT -ve seminoma (EAU GL)
• CT thorax:
– best way to assess thorax and mediastinal LN
– Mandatory in all pt with NSGCT & Seminoa with +ve Abd CT scan
– Recommend in NSGCT because 10% with small subpleural LN not visible in CXR
– High SV but low SP
• Retroperitoneal + mediastinal LN : CT
– Sensitivity: 70%
– SV & NPV increase with 3mm threshold to define metastatic node in landing zones
– Rate of understaging : 30%
– New generation CT does not improve SV
• MRI:
– Similar result as CT in detection of retroperitoneal LN
– Helpful when CT or USG inconclusive/ contraindicated
• PET scan:
– not enough evidence in staging
– For FU pt with seminoa with any residual mass at least 4 weeks after Chemo (to decide on
WW vs active treatment)
• CT brain or spine, bone scan or liver USG: in case of suspected metastasis
• CT or MRI brain in NSGCT with widespread lung metastasis
48

49. 49

50. 50

51. 51

52. 52

53. 53

54. Stage I
• 80% of seminoma, 55% of NSGCT
• 5% NSGCT will be in Stage IS
• If RPLND was performed in all stage IS pt
 nearly all patient will have pathological
stage II disease (pN+)
54

55. Stage IA
• Primary tumor limited to testis and epididymis
(T1)
• No evidence of microscopic vascular or
lymphatic invasion by tumor cell on microscopy
• No sign of metastases on clinical exam or
imaging
• Post-orchidectomy serum tumor marker level
within normal limits
• Marker should be assess until normalization
55

56. Stage IB
• More locally invasive primary tumor (T2-4)
• Not sign of metastastic disease
56

57. Stage IS
• Persistently elevated (usually increasing)
serum tumor marker level after
orchidectomy (S1-3)
• Evidence of subclinical metastatic disease
(or possibly second GCT in remaining
testis)
• If serum marker are declining in expected
½ life  FU until normalization
57

58. 1997 IGCCCG
• A prognostic factor-based staging system for
metastatic Ca Testis base on clinical
independent adverse factors
• Categories pt into : good, intermediate, poor
prognosis
• NO Poor prognostic group in Seminoma
• Factors used:
– Primary Histology
– Location of primary tumor
– Location of metastases
– Pre-chemotherapy marker levels in serum
58

59. 59

60. 60

61. seminoma Non-seminomatous germ cell
tumour
good intermediate Good Intermediate Poor
5 yr PFS 82% 67% 89% 75% 41%
5 yr survival 86% 72% 92% 80% 48%
61

62. 62

63. Prognostic risk factors
• Stage I Seminoma: predictor for relapse
– Tumor size > 4cm
– Invasion of rete testis
• Stage I NSGCT:
– Vascular invasion of primary tumor in blood or
lymphatic vessels (occult metastases)
– Proliferation rate (by MIB-1 immunostaining) >70%
– embryonal carcinoma > 50% (predict vascular
invasion)
63

64. 64

65. Fertility associated issue
• Sperm abnormality are common in Ca testis
• Chemotherapy and RT  impair fertility
• Pre-treatment fertility assessment:
– Testosterone
– LH & FSH level
– Semen analysis & cryopreservation should be offered
• Cryopreservation should be done before or after
orchidectomy , and before chemotherapy
• Life long testosterone supplement in case of
bilateral orchidectomy & low testosterone after
txn of Tin
65

66. Testosterone replacement &
contraception
• Testosterone replacement should be offer
after bilateral orchidectomy to maintain
sexual fxn and avoid late toxicity from
hypogonadism
• After unilateral orchidectomy:
– Tesosterone replacement depends on
testosterone level and clinical symptom
• Contraception should be suggest during
and 1 yr after Chemo or RT
66

67. Txn: Stage I (T1-4 N0M0)
seminoma
• 80% seminoma present as stage I
• Cure rate approach 100%
• 15-20% retroperitoneal met
• 5% present with distant metastasis
• 15-20% have subclinical retroperitoneal metastasis &
will relapse after orchidectomy
• Risk of relapse raised to 30% if both risk factor present
• Options after orchidectomy included:
1. Surveillance
2. Adjuvant chemotherapy
3. Adjuvant RT
– (RPLND)
• A risk- adapted approached is recommended
67

68. Surveillance: Stage I seminoma
• Risk of relapse: 15-20% (12%) in 5 yr
• TF: Up to 88% can be txn with orchidectomy alone
• Consider in patient without risk factors
• Most common relapse site: infra-diaphragmatic / high iliac LN (97%)
• Surveillance protocol : Princess Margret Hospital (Toronto)
– CT : 0-3 yr (Q4m), 4-6yr (Q6m), 7-10yr (Yearly)
– Marker: each visit
– CXR: alt visit
• Txn of relapse under surveillance:
– 70% of relapse can be txn with RT alone (low vol disease)
– 20% relapse after RT Then will salvage chemo
• CSS: 97-100%, 5yr DFS > 90% in Spanish GCCCG with this risk adapted
approach
• Adv: No side effect of RT or chemo
• Drawback:
– Need for more intensive FU (imaging for at least 5 yr)
– Greater psychological burden
– Small but significant risk of relapse after 5 yr  support for long term surveillance
68

69. Chemotherapy: Stage I seminoma
• MRC TE 19 trial : joint MRC + EORTC 1 cycle of carboplatin (AUC7) vs RT
(Lancet 2005, Oliver)
– LN relapse: Retroperitoneal (Chemo) , pelvic (RT)
– No significant difference in after 4 yr :
• Recurrence rate
• Time to recurrence
• Survival
• Thus adj carboplatin is an alternative to RT or surveillance in Stage I
seminoma
• Adv over RT
– Ease of administration
– Shorter time to deliver adj treatment
– Reduction of contralateral testis tumor
– Less lethargic and less likely to take time off work when compared with RT
(Lancet 2005, Oliver)
• Disadv:
– Myelotoxicity & gonadotoxicity
• 1 course reduce risk of relapse to 3%
• 2 course of carboplatin further reduce relapse rate to 1% [Aparico JCO
2005]  for pt with both risk factors (invade rete testis, > 4cm)
69

70. Radiotherapy: Stage I seminoma
• Seminoma are extremely radiosensitive
• Site:
– Para-aortic (PA) field or para-aortic + ipsilateral iliac node hockey stick field (Dog-leg)
– Upper edge of T11 to lower edge of L5
– Lateral field margin: renal hilum
– Medial field margin: processus transversus of L spine
• Dose: 20-24 Gy (2Gy x 5/week for 2 week)
• Reduce relapse rate to only 1-3% (same as chemo)
• Recurrence: outside irradiated field (supradiaphragmatic LN or lung) or left renal
hilum
• PA irradiation of supra-diaphragmatic LN not recommended
• Extend: MRC TE 10 trial [Fossa JCO 1999]
– Standard : RT to PA for Stage I (T1-3) with undisturbed LN drainage
– Reduce acute toxicity & improve sperm count in 18m vs traditional dog-leg field
– However higher relapse rate in iliac LN: 2% in right side
• Dosage : MRC TE 18 [Fossa Eur J Cancer 2001]
– Equivalence recurrent rate with 20Gy vs 30Gy
– Side effect:
• Severe RT long-term toxicity: <2%
• GI: 5% GU : 60%
• Risk of RT:
– Radiation scatter  reduce fertility (need shielding of contralateral testis)
– RT-induced secondary non-germ cell malignancy (Ca stomach , testis)
– Moderate long term GI side effect
70

71. RPLND
• Not recommended for stage I seminoma
• Prospective non- randomised study:
[Warszawski Scan J Urol Nephrol 1997]
– RT vs RPLND, stage I seminoma
– Result: trend towards higher incidence of
retroperitoneal relapses (9.5%) in RPLND
71

72. Risk adapted approach
• High risk of occult metastatic disease: [Warde JCO 2001]
– Tumor > 4cm
– Rete tesits invasion
• Risk of occult disease:
– Both risk factors: 32%
– No risk factors: 12%
• Risk of relapse: No risk factor: 6 %
• Risk of relapse in pt of both risk factor treated with carboplatin :
3.3%
• Thus: Txn of high risk gp with Chemo /RT will reduce recurrence
from >30% to 3%
72

73. 73

74. 74

75. 75

76. Txn: NSGCT Stage I
• After orchidectomy: normalized marker with –ve CT
• Risk of relapse:
– 20% subclinical metastasese and will relapse if surveillance alone after
orchidectomy
– Of those relapse: 80% in 1st year
– 50% with vascular infiltration will develop metastasis vs 15-30% without vascular
infiltration
• Cure rate ~99%
• Options of post orchidectomy NSGCT :
1. Surveillance
2. Primary chemotherapy
3. Retroperitoneal LND
• Again: risk adapted approached is recommended
– Low risk (13%)  surveillance
– High risk (64%)  Chemo or RPLND
• Cure rate of 100% is achieved
76

77. Surveillance: NSGCT Stage I
• Indication: Low risk patient with no vascular invasion
• Cumulative relapse rate: 20%
• Time of relapse:
– 80% within 12m FU
– 12% during 2nd year
– 6% during 3rd
– 1% in 4th or 5th year, or even later
• 60% relapse in retroperitoneum, 30% in lung, 10% marker only
– 35% have normal tumor marker level at relapse
– 10% presented with large-volume recurrent disease
• FU schedule:
– CT : 0, 3, 12 m
• Surveillance is still advocated because:
– Improvement in clinical staging and Fu methods
– Availability of effective salvage cisplatin-base chemo
– Post-chemo surgery
• Thus, surveillance can be offered to pt with non-risk stratified clinical stage I
NSGCT as long as they are compliant and well informed
• Txn of relapse on surveillance: 2 BEP
• Overall cure rate: >98%
77

78. Primary Chemotherapy: NSGCT Stage I
• Indication: High risk patient with vascular invasion
• 2 course of PEB (cisplatin , etoposide & bleomycin) as
primary treatment of high risk patient (> 50% risk of
relapse)
• Reduce relapse rate to : 3% (from 50%)
• Adv:
– Very little long-term toxicity
– Do not affect fertility or sexual activity
• Disadv:
– Beware of slow-growing retroperitoneal teratomas  risk of late
chemoresistant cancer relapse
– Cryopreservation before chemo is recommended
• Cost analysis: different results, but low frequency of Fu
CT can reduce cost
78

79. RPLND: NSGCT Stage I
• Indication: High risk patient with vascular invasion
• RPLND:
– LN met (30%)  PS2 (then should txn as Stage II)
• Fu only : 30% relapse outside abd/pelvis
• 2 more course ciaplatin base chemo (2x BEP) : < 2% relapse
– No LN met (70%)  PS1
• With vascular invasion  30% relapse
• Without vascular invasion  10% relapse
• Risk of relapse after properly performed RPLND (<2%) mostly lung
• Other risk: ejaculatory disturbance (6%)
• FU: less frequent CT than surveillance
• Lap RPLND: Not recommended as standard procedure
• RPLND vs 1 course of PEB: AUO Trial AH 01/94 [Alber JCO08]
– PEB significantly increase 2yr recurrence-free survival (99% vs 92%)
– Irrespective of vascular invasion or not
– 1x BEP is better then RPLND in stage I disease
79

80. Risk-adapted mx
• No vascular invasion (50-70%):
– surveillance : 30 % relapse
• Vascular invasion(30%):
– Surveillance: 50% relapse
– 2 cycles of PEB
• Result : Swedish-Norwegian Testicular Cancer Project (SWENOTECA)
– Median FU of 4.7 yr
– Relapse rate: 3.2% with vascular invasion treated with only one adjuvant PEB
80

81. Mechanism of antegrade ejaculation
• Antegrade ejaculation requires the coordination of three separate events:
– (1) closure of the bladder neck (sympathetic)
– (2) seminal emission (sympathetic)
– (3) ejaculation (antegrade propulsion of semen)
• Relaxation of external shpincter (parasymthetic)
• Contraction of bulbocavernosus muscle (somatic via pudendal nerve)
• The sympathetic fibers : T12 to L3 thoracolumbar spinal cord.
• In the midretroperitoneum after leaving the sympathetic trunk
• Fibers converge toward the midline and form the hypogastric plexus near the
takeoff of the inferior mesenteric artery (IMA) just above the aortic bifurcation.
• Hypogastric plexus  pelvic plexus to innervate the seminal vesicles, vas deferens,
prostate, and bladder neck
• Ejaculation is mediated by nerves originating at the sacral and lumbar spinal cord
• Pudendal somatic innervation from S2 to S4 causes relaxation of the external urethral
sphincter and rhythmic contractions of the bulbourethral and perineal muscles
• Paravertebral sympathetic ganglia, postganglionic sympathetic fibers T2-L4, and their
convergence at the hypogastric plexus are most crucial in the preservation of
antegrade ejaculation
• The highest rates of preserved ejaculation are reported with “nerve-sparing” RPLND,
in which the sympathetic chains, the postganglionic sympathetic fibers, and the
hypogastric plexus are prospectively identified, meticulously dissected, and preserved
81

82. RPLND
• 3 main setting of RPLND
• RPLND I:
– Prophylactic LND in NSGCT stage I (none shown on
CT and RPLND)
– More common in US then Europe
• RPLND II:
– Resection of (low-vol) retroperitoneal LN in NSGCT
– When CT show LN or LN +ve during RPLND I
• RPLND III:
– Resection of post-chemo mass or
– Resection of post-RPLND I/II mass after primary txn
of metastatic NSGCT/seminoma
82

83. RPLND
• Standard RPLND:
– Excised all retroperitoneal lymphoid tissue
• Modified/ nerve-sparing RPLND:
– Aim to excised lymphoid tissue most likely to have
met disease
– To spare the nerve control of ejaculation
• Note: RPLND of left is less extensive and does
not cross to Rt because Rt  Lt lymphatic
spread is more common than Lt  Rt
83

84. 84

85. RPLND I (Rt side)
• Rt renal hilum
  along medial border of Rt
ureter
  till Rt common iliac artery
  along Rt CIA & aorta to the
Rt of origin of IMA
  medial border of Lt ureter
  Lt renal artery
  back to Rt renal hilum
Note:
• To excised LN behind great
vessels (30% involved)
• Lumber A&V has to be divided
85

86. RPLND I (Left side)
• Jxn of IVC & Rt RV
 down Rt border of
IVC
 to level of origin of
IMA
 down Lt CIA to pt
where Lt ureter cross
 Up along medial
border of Lt ureter
 to Lt RV
86

87. RPLND II/III
• Bilateral
• RPLND II
– Extend below IMA &
above renal artery
• RPLND III
– Complete bilateral +
removal of any LN
mass
– May involve renal
vessels , mediastinum
or resection of great
vessels
87

88. Complications of RPLND
• Recurrence rate: 10%
• Loss of ejaculation: 7%
• Late complication : 5%
– Chylous ascites
– Renal artery or SMA damage
– Bowel damage/ colostomy/ colectomy
– Bowel obstruction
– Pulmonary embolism
– German testis study Gp 2003
88

89. 89

90. 90

91. 91

92. CSIS : persistent elevated tumor
markers
• Serum tumor marker should be FU according to
expected half life until level fall into reference
value
• If persistent elevated  RPLND  87% will
have LN +ve
• USG of contra lateral testis must be performed
• Txn:
– 3 course of PEB & FU as CS1B (high risk)
– RPLND
92

93. Metastatic Germ Cell tumor
• Treatment of metastatic GCT depends on:
– Histology of primary tumor
– Prognostic group by IGCCCG
93

94. Low-volume disease (Stage IIA/B)
• Stage IIA Seminoma
– Standard: Radiation
– Dose: 30 Gy (2Gy at 5 fraction per week)
– Field: PA + ipsilateral Iliac (hockey-stick field)
– Upper field: upper border of thoracic vertebra
– Lower field: upper border of ipsilateral acetabulum
– 6yr relapse free survival: 95%
– OS: 100%
• Stage II B Seminoma:
– RT: 36Gy
• Lateral border include metastatic LN with safety margin of 1-1.5cm
• 6 yr relapse free survival : 90%
• OS: 100%
– Chemo: (4x etoposide + cisplatin (EP) or 3x PEB in good prognosis)
• CI of bleomycin (< 40 age, smoker, risk of pulmonary fibrosis)
• More toxic in the short term
94
• Similar level of disease control

95. Stage IIA/B seminoma: After RT or Chemo
Fu with CT at 3months
• Residual mass after chemo /RT is uncommon
• If no residual mass/ <3cm: Fu CT 6/12
• If residual mass > 3cm: PET CT 4-6week after
chemo
• PET CT +ve  Biopsy:
– +ve: RPLND : reserve for globular mass but not for
retroperitoneal fibrosis
– or slavage Chemo/ RT
95

96. 96

97. Stage IIA/B NSGCT
• Cure rate: 98%
• Clinical IIA with –ve marker (1-2cm)
– Pure embryonal carcinoma: immediate chemo
– Teratoma or mixed tumor: either
1. Surveillance : CT at 6 week
a) Shrinking lesion observed
b) No change  RPLND
c) Growing lesion  teratoma or undifferentiated
» No increase maker  RPLND
» Increase marker  3x BEP (txn as metastatic disease) +/- resection
of residual tumor
2. RPLND final patho stage
– PS I: FU
– PS IIA/B : either
» surveillance  Chemo if recur (30%) (4 BEP)
» Chemo: 2 BEP (7% recur)
– CT : if node still present  2 BEP
97

98. Stage IIA Marker +ve / IIB NSGCT
1. No elevate tumor marker: good prognosis
– Chemo: 3 BEP / 4 EP
2. Elevated tumor marker: intermediate and poor prognostic
– 4x BEP or
– 4x PEI/ VIP (cisplatin , etoposide & ifosfamide)
3. RPLND if not willing for chemo
– Metastases  adj 2 cycles of PEB
• Then post Chemo Surveillance: 4-6 week image FU
– Shrinking lesion (<1cm) observed
– Stable or growing (>1cm)  marker
• Normalized : RPLND
• Plateau tumor marker  teratoma /undifferentiated malignant tumor 
RPLND
• Elevated tumor marker salvage Chemo: PEI/VIP or TIP (Paclitaxel,
ifosfamide & cisplatin)
• Primary RPLND & Chemo are comparable in terms of outcome
• Cure rate : 98%
98

99. FU for NSGCT
• RPLND is mandatory for residual mass >
1cm
• No role of PET scan (vs seminoma)
• For post chemo RPLND:
– 50% necrosis
– 35% mature teratoma
– 15% viable cancer
99

100. 100

101. Advanced metastatic disease
(Stage IIC / III)
• Txn of seminoma and NSGCT is the same
• Primary treatment: 3 or 4 cycle of PEB (depend
risk classification)
• PEB proven superiority to PVB (cisplatin ,
vinblastin & bleomycin)
• 3-day regimen as effective as 5-day , but asso
with increase toxicity
101

102. Good prognosis gp
• Standard treatment:
– 3 cycles of PEB , or if bleomycin CI
– 4 cycles of EP
• Given without dose reduction at 21-day intervals
• Delay cycle 3d for each only in:
– Fever with WBC < 1000/mm3
– Thrombocytopenia < 100, 000/IU
• G-CSF:
– No indication for prophylatic application
– Prophylaxis in case of infectious complication during
chemo
102

103. Intermediate prognosis gp
• 5 yr survival rate: 80%
• Standard treatment:
– 4 cycles of PEB
• Other trial:
– EORTC Genitourinary Tract Cancer
Cooperative Group trial with PEB vs PEB +
paclitaxel
103

104. Poor risk Gp
• Only in NSGCT
• 5yr progression-free survival: 50%
• Standard treatment:
– 4 cycles of PEB
– 4 cycles of PEI (cisplatin, etoposide, ifosfamide)
• same effect, more myelotoxic
• Consider in pt CI to bleomycin (compromised P fxn)
• Pt with slow marker decline  poorer prognosis
• No recommendation on pt with KS < 50%,
extended liver or pulmonary infiltration
104

105. Restaging and further txn
• By imaging and re-evaluation of tumor markers
• Marker decline & tumor regression  complete
chemo at 3/ 4 cycle
• Marker decline but tumor growing:
– Complete induction therapy
– Tumor resection
• Marker growth after 2 course of chemo:
– Crossover therapy on new drug trails
• Low-level marker plateau post-txn:
– Observe to see whether normalization occur
– Salvage chemo if marker rise again
105

106. Residual tumor resection
• Seminoma:
– Residual mass should NOT be resected
irrespective of size
– Fu PET + tumor marker
• Residual mass > 3cm: do PET
• Residual mass < 3cm : optional
– Salvage therapy on progression (chemo ,
surgery , RT)
106

107. Residual tumor resection: Non-seminoma
• After PEB induction chemo: RPLND will reveal
– 50% contain mature teratoma
– 40% contain necrotic-fibrotic tissue
– 10% residual mass contain cancer
• NO imaging to differentiate all three
• Thus: Residual tumor resection is mandatory:
– Complete remission after chemo (no visible tumor)  no need resection
– Visible tumor mass but normal marker  Surgical resection
– Persistent retro-peritoneal disease  Resection of all primary
metastatic site within 4-6 weeks of complete chemo (NS approach)
• Extend of resection:
– If possible , all massess should be resected, because complete
resection is more critical than recourse to post-op chemo
– Resection of contralateral pulmonary lesion is not mandatory if patho
exam of lesion from first lung show complete necrosis
107

108. Consolidation chemo after 2nd
surgery
• If resection show necrosis or mature
teratoma  no further treatment
• If incomplete resection / immature
teratoma
– Adj 2 cycle of conventional dose cisplatin
base chemo to poor prognosis pt
– Caution cumulative dose of bleomycin
– If only < 10% vital tumor resected, no benefit
on adj chemo to prevent further relapse
108

109. Systemic salvage txn for relapse or
refractory disease
• Seminoma:
– 4 cycle : PEI/VIP (etoposide , ifosfamide , cisplatin)
– 4 cycle: TIP (paclitaxel, ifosfamide, cisplatin)
– 4 cycle: VeIP (vinblastine, ifosfamide, cisplatin)
– Not sure if high dose chemo will help
• Non-seminoma: same as for seminoma
• Cisplatin-based salvage chemo after 1st line  50%
long term remission rate
• Prognostic indicator for response to slavage therapy
– Location & histology of primary tumor
– Response to 1st line treatment
– Duration of remission
– Level of AFP & hCG at relapse
109

110. 110

111. • Salvage VeIP not superior to conventional
dose cisplatin-base combination
• Use of >3 agents  increase toxicity but
not treatment outcome
• High dose chemo offered no advantage as
first salvage treatment in good prognosis
patient
• Other options: Paclitaxel & gemcitabine
111

112. Late relapse
• Definition: pt relapse >2yr after chemo for
metastatic disease
• If feasible , should undergo immediate radical
surgery for all lesion (undifferentiated GCT,
mature teratoma or secondary non-germ cell
cancer)
• Salvage chemo according to bx histology if
lesions not completely resectable
• Secondary surgery if response to chemo
• RT for unresectable , localized refractory
disease
112

113. Salvage surgery
• Residual tumor after salvage
chemotherapy
• Resected 4-6weeks after marker
normalization or plateau
• If maker progression: resection of residual
tumor (desperation surgery)
• If complete resection : 25% long term
survival may be achieved
113

114. Brain metastasis
• 10% advance Ca present with brain met
• Long term survival 5yr
– Brain met at diagnosis (30%)
– Brain met as recurrent disease (2-5%)
• Txn:
– Chemotherapy
– Consolidation RT (even in total response after
chemo)
– Surgery in solitary metastasis
114

115. 115

116. 116

117. 117

118. Prognosis
• All stages have at least a 90% cure rate
• Stage I : 98-100%
• Stage II (B1/B2 nonbulky) : 98-100%
• Stage II (B3 bulky) and stage III : 90% complete
response to chemotherapy &
86% durable response rate to chemotherapy
118

119. Prognostic risk factors
Pathological (for Stage 1)
• For seminoma:
– Tumor size > 4cm
– Invasion of the rete testis
• For non-seminoma:
– Vascular/ lymphatic in or peri-tumoural invasion
– Proliferation rate > 70%
– Percentage of embryonal carcinoma > 50%
Clinical (for metastatic disease)
• Primary location
• Elevation of tumor marker levels
• Presence of non-pulmonary visceral metastasis
119

120. 120

121. FU after curative treatment
• Most recurrence occur in first 2 years
• Late relapse beyond 5 yr, thus yearly Fu for life
is advocated
• After RPLND , recurrence in retroperitoneum is
rare, most relapse in chest
• CT thorax has higher predictive value then CXR
• Result of therapy dependent on bulk of disease,
thus intensive strategy to detect asymptomatic
disease is justifiable
• There is risk of secondary malignancies after RT
or Chemo
121

122. Recommended minimal FU schedule in:
stage 1 seminoma
Year 1 Year 2 Year 3-4 Year 5-10
Physical 3x 3x 2x/yr 1x/yr
Exam
Tumor 3x 3x 2x/yr 1x/yr
markers
Chest XR 2x 2x 1x/yr 1x/yr
Abd + pel 2x 2x 1x/yr 1x/yr
CT
122

123. Recommended minimal FU schedule in a
surveillance policy: stage 1 non-seminoma
Year 1 Year 2 Year 3-5 Year 6-10
Physical 4x 4x 2x/yr 1x/yr
Exam
Tumor 4x 4x 2x/yr 1x/yr
markers
Chest XR 2x 2x
Abd + pel 2x (3 & 12
CT mo)
123

124. Recommended minimal FU schedule after
RPLND/ adj chemo: stage 1 non-seminoma
Year 1 Year 2 Year 3-5 Year 6-10
Physical 4x 4x 2x/yr 1x/yr
Exam
Tumor 4x 4x 2x/yr 1x/yr
markers
Chest XR 2x 2x
Abd + pel 1x 1x
CT
124

125. Recommended minimal FU schedule in
advanced NSGCT & seminoma
Year 1 Year 2 Year 3-5 Thereafter
Physical 4x 4x 2x/yr 1x/yr
Exam
Tumor 4x 4x 2x/yr 1x/yr
markers
Chest XR 4x 4x 2x/yr 1x/yr
Abd + pel 2x 2x 1x/yr 1x/yr
CT
Chest CT As indicated
Brain CT As indicated
125

126. 126

127. Testicular Stromal Tumors
• 2-4% of adult testicular tumors
• Only Leydig cell & Sertoli cell tumor are of clinical
relevance
• Classification WHO 2004:
127

128. Leydig cell turmors
• Epidemiology:
– 1% of adult, 3% of child testicular tumor
– 30-60s in adult, similar incidence in every decade ;Children: 3-9
yr
– 3% bilateral , found in Klinefelter syndrome
– 10 % malignant
• Pathology:
– Most common type of sex cord/ gonadal stromal tumor
– Gross: solid, yellow to tan , hemorrhage/necrosis (30%) , well
outline & 5cm
– Micro: polygonal cell, eosinophilic cytoplasm , Reinke crystals,
regular nucleus, solid arrangement & capillary strom
– Cell: vimentin, inhibin, protein S-100, steroid hormones,
calretinin & focal cytokeratin
128

129. 129

130. Leydig cell tumor: diagnosis
• Presentation:
– Painless enlarged testis
– USG incidental finding
– Gynaecomastia (30%)
– Bilateral 3%
– Metastasis (10-20%) : risk factor (older age)
– Must distinguished from multinodular tumor-like lesions of the
androgenital syndrome
• Diagnosis:
– Tumor marker (AFP, hCG , LDH, PLAP) : always –ve
– Hormone:
• High oestrogen & oestradiol
• Low testosterone & increase LH & FSH
– USG of both testis: well-deifine, small , hypoechoic lesion with
hypervascularisation (no different from GCT)
– CT chest & abdomen
130

131. Leydig cell tumor: Treatment & FU
• Highly recommend to performed organ-sparing
orchiectomy in small intraparenchymal lesion
• If histological sign of malignancy 
orchidectomy + RPLND
• If no sign of malignancy after ordhidectomy 
FU CT (not need tumor marker)
• Metastatic disease: poor response to RT or
chemo  poor survival
131

132. Sertoli Cell Tumor
• Epidmiology:
– < 1% of testicular tumor
– Mean age: 45 yr, rare < 20
– Pt with androgen insensitivity syndrome & Peutz- Jegher
syndrome
• Pathology:
– Gross: well circumscribed, yellow , tan or white, 3.5cm
– Micro: eosinophilic to pale with vacuolated cytoplasm, regular
nuclei with grooves
– Tubular or solid arragment, cord-like or retiform pattern
– Cell : vimentin, cytokeratin ,inhibin (40%) ,Protein S-100 (30%
132

133. 133

134. Diagnosis
• Presentation:
– Most are unilateral and unifocal
– Bilateral 40% , multifocal (30%)
– Metastatsis : 12%
– Tumor marker always –ve
– Hormonal disorder infrequent
– Young man with large cell calcifying form : Carney’s complex,
Peutz-Jegher sydrome , endocrine disorder (40%)
• Diagnosis:
– Tumor markers
– Hormones
– USG both testis: hypoechoic (cannto diff from GCT)
• Large tumor: brightly echogenic foci due to calcification
– CT Chest & abdomen
134

135. Treatment
• highly recommended to proceed with an organ-
sparing approach in small intraparenchymal
testicular lesions until final histology is available
• Esp in pt with: gynaecomastia or hormonal
disorders or typical imaging on ultrasound
(calcifications, small circumscribed tumours)
• Tumor with histological sign of malignancy:
– Orchidectomy + RPLND
• FU: CT
• Metastatic disease: poor response to RT or
Chemo , poor survival
135

136. Granulosa cell tumor
• Juvenile type:
– Benign
– Most frequent congenital testicle tumor
– 6 % of prepubertal testicular tumor
– Charateristic Cystic appearance
• Adult type:
– Homogeneous , yellow-grey tumor
– Elongated cell with grooves with microfollicular and
Call-Exner body arrangement
– 20% malignant, > 7cm
136

137. Medication use in Ca Testis
• Cisplatin
• Etoposide
• Bleomycin
• Ifosfomide
• Vinblastin
137

138. 138

139. 139

140. 140