The document discusses testicular cancer and provides details on its epidemiology, classification, staging, diagnosis, and disease management. Some key points: - Testicular cancer peaks in the third decade for non-seminoma and fourth decade for seminoma. Risk factors include cryptorchidism, family history, and subfertility. - Germ cell tumors are divided into seminoma and non-seminomatous tumors including embryonal carcinoma, teratoma, and choriocarcinoma. - Stage I disease accounts for 75-80% of seminoma and 55% of non-seminoma cases at diagnosis. Serum tumor markers and imaging help determine diagnosis and staging.

1. Testicular Cancer
Dr. Perviz Hacıyev
uroloq.com
1

2. Epidemiology
• Testicular cancer represents 1% of male neoplasms and 5% of tm
• 1-2% bilateral, and the predominant is germ cell tm (90-95%)
• Peak incidence:
- 3rd decade for non-seminoma,
- 4th decade for pure seminoma.
• A specific genetic marker (an isochromosome of the 12p) - in all
histological types of germ cell tumours and in TIN.
• Alterations in the p53 locus have been identified in 66% of cases
of testicular TIN
2

3. Epidemiology
• Risk factors
- testicular dysgenesis syndrome (i.e. cryptorchidism, hypospadias,
decreased spermatogenesis evidenced by subor infertility)
- familial history of testicular tm (1st-gr relatives)
- presence of a contralateral tumour or TIN
• Very tall men seem to have a higher risk of GCT, while short stature
is protective
3

4. Epidemiology
• Risk factors
- 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
4

5. Classification
• Germ cell tumours
- Intratubular germ cell neoplasia, unclassified type (IGCNU)
- Seminoma (including cases with syncytiotrophoblastic cells)
- Spermatocytic seminoma (mention if there is a sarcomatous
component)
- Embryonal carcinoma
- Yolk sac tumour
- Choriocarcinoma
- Teratoma (mature, immature, with malignant component)
- Tumours with more than one histological type (specify
percentage of individual components).
5

6. Classification
• Sex cord/gonadal stromal tumours
- Leydig cell tumour
- Malignant Leydig cell tumour
- Sertoli cell tumour
- lipid-rich variant
- sclerosing
- large cell calcifying
- Malignant Sertoli cell tumour
- Granulosa cell tumour
- adult type
- juvenile type
- Thecoma/fibroma group of tumours
- Other sex cord/gonadal stromal tumours - incompletely differentiated - mixed
- Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma),
• Miscellaneous non-specific stromal tumours
- Ovarian epithelial tumours
- Tumours of the collecting ducts and rete testis
- Tumours (benign and malignant) of non-specific stroma
6

7. 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
7

8. 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
8

9. 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
9

10. 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
10

11. 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
11

12. 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)
12

13. 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
13

14. 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
14

15. Staging and Classification
• The mean serum half-life of AFP 5-7 days and hCG is 2-3days
15

16. Staging and Classification
• 75-80% of seminoma patients, and about 55% of patients with
NSGCT cancer have stage I disease at diagnosis
• True stage IS is found in about 5% of non-seminoma patients.
16

17. Staging and Classification
17

18. Staging and Classification
18

19. Staging and Classification
19

20. Staging and Classification
20

21. Staging and Classification
21

22. Staging and Classification
22

23. Diagnosis
- Painless unilateral scrotal mass,
- Casual US finding or revealed by a scrotal trauma
- Scrotal pain 27% (as first sptm in 20%)
- Gynaecomastia 7% (more in non-seminomatous).
- Back and flank pain 11%
- Mimic orchioepididymitis 10%
- US sensitivity is almost 100%
23

24. Diagnosis
• Serum tumour markers:
- AFP
- serum protein of embryo
- fetal yolk sac and liver
- serum t1/2: 5-7 days
- hCG (expression of trophoblasts);
- LDH (lactate dehydrogenase)
24

25. Diagnosis
AFP
- Serum protein of embryo
- Fetal yolk sac and liver
- Serum t1/2: 5-7 days
- in 50-70% with
- Yolk sac tumor
- Embryonal ca
- Mixed tumor
- Not produced by
- Choriocarcinoma
- Seminoma
- Elevated in
- Testicular ca
- Liver ca
- Pancreatic ca
- Lung ca
- Stomach ca
- Hepatitis
- Cirrhosis
- 10% inc in smokers
25

26. Diagnosis
Beta-HCG
- Excretion production of placenta
- Syncytiotrophoblast cells
- Serum t1/2: 2-3 days
- Choriocarcinoma ~100%
- Teratomas 40%
- Embryonal carcinoma 40-60%
- Seminoma 10-30%
- Elevated in
- Testicular ca
- Liver ca
- Pancreatic ca
- Lung ca
- Stomach ca
- Breast ca
- Renal CC
- Bladder ca
- Ovarian ca
- Marijuana use
26

27. Diagnosis
PLAP
(Placental Like Alkaline Phosphatase)
- Elevated Levels:
- Stage 1 seminoma 30-50%
- Advanced seminoma 100%
- increased 10-fold in smokers
27

28. Diagnosis
Serum tumour markers:
- Markers should be determined before, and 5-7 days after,
orchiectomy:
- AFP are increased in 50-70% and hCG in 40-60% of patients with
NSGCT.
- About 90% of NSGCT present with a rise in one or two of the
markers.
- LDH may be elevated in 80% of patients with advanced testicular
cancer
28

29. Diagnosis
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
- Diagnosis must be confirmed by bx of extragonadal mass
- Histology of undifferentiated Ca → immunohistological marker
(isochrom i 12p)
29

30. Diagnosis
Pathology
• Advisable immunohistochemical markers, in cases of doubt, are:
• in seminoma: cytokeratins (CAM 5.2), PLAP, c-kit;
• in intratubular germ cell neoplasia: PLAP, c-kit;
• other advisable markers: chromogranin A (Cg A), Ki-67 (MIB-1)
30

31. Organ-sparing Surgery
• Organ-sparing surgery is not indicated in the presence of non-
tumoural contralateral testis,
• Organ preserving surgery can be performed when tumour volume is
less than 30% of the testicular volume and surgical rules are
respected. In those cases, the rate of associated TIN is high (82%)
- synchronous bilateral testicular tumours
- metachronous contralateral tumours
- in a tumour in a solitary testis with normal pre-operative
testosterone levels
31

32. Testicular Intraepithelial Neoplasia
(TIN)
• Contralateral incidence of TIN is 9% , Incidence in general population :
1%
• Contralateral metachronous testicular tumours 2.5%
• Biopsy of the contralateral testis should be offered to patients at high
risk for contralateral TIN (34% Risk)
- testicular volume < 12 mL,
- cryptorchidism or poor spermatogenesis (Johnson Score 1-3).
- A contralateral biopsy is not necessary in patients older than 40 years
without risk factors.
- Once TIN is diagnosed, local radiotherapy (16-20 Gy in fractions of 2
Gy) is the treatment of choice in the case of a solitary testis
- Double Biopsy is preferred(upper and lower pole)
- If TIN is diagnosed and the contralateral testis is healthy, the options
for management are orchiectomy or close observation (with a 5-year
risk of developing TC of 50%,70% in 7 years)
32

33. Testicular Intraepithelial Neoplasia
(TIN)
33

34. Testicular Intraepithelial Neoplasia
(TIN)
34

35. Testicular Microlithiasis
- Seen in up to 0.6% of patients undergoing USG
- Prevelance in general population 5.1-5.6%
- Present in about 50% of men with a germ cell tumour
- Associations:
- testicular germ cell tumour
- Kleinfelter syndrome, Down syndrome
- cryptorchidism
- testicular infarct
- infertility
- 8x risk of GCT in symptomatic testicles
- no risk has in asymptomatic testicles
- Annual USG follow up only if a risk factors:( until age 55)
- personal/family history of germ cell tumour
- maldescent
- orchidopexy
- testicular atrophy
35

36. Testicular Microlithiasis
36

37. Diagnosis
CT
- sensitivity 70-80%
- Understages 15-20% 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
- 20% of right-sided NSGCTs, lymph node involvement is found
on the left side
37

38. Diagnosis
38

39. Diagnosis
39

40. Risk factors for metastatic relapse in stage I
GCT
• For seminoma stage I absence of both factors indicated a low recurrence rate (6%)
• For non-seminoma stage I, vascular invasion of the primary tumour in blood or
lymphatic vessels is the most important predictor of occult metastatic disease.
40

41. Disease Management
Stage I Germ cell tumours
• 80% of seminoma,
• 55% of NSGCT
• 5% NSGCT will be in Stage IS
• If RPLND was performed in all stage IS patients nearly
all patient will have pathological stage II disease (pN+)
41

42. Disease Management
Stage I seminoma
• 15-20% subclinical metastatic disease
• Surveillance:
- Relapse rates is 15-20% at 5 years
- In patients with low risk (tumour size < 4 cm and no rete testis
invasion), the recurrence under surveillance is as low as 6%
- 70% of patients with relapse are suitable for treatment with
radiotherapy alone
- Patients who relapse after salvage radiotherapy can be
effectively treated with chemotherapy
42

43. Disease Management
Stage I seminoma
• Surveillance:
- Follow up Princess Margret Hospital (Toronto)
- CT : 0-3 yr (Q4m), 4-6yr (Q6m), 7-10yr (Yearly)
- Marker: each visit
- CXR: all visit
- The overall cancer-specific survival rate reported under
surveillance performed by experienced centres is 97-100% for
seminoma stage I
43

44. Disease Management
Stage I seminoma
• Surveillance:
Mok and Warde, Hematol Oncol Clin 201144

45. Disease Management
Stage I seminoma
• Adjuvant chemotherapy:
- EORTC MRC TE 19 trial:
- 1x carboplatin vs adjuvant RT,
- no significant difference in recurrence rate, time to
recurrence and survival after a median follow-up of 4 years
- 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)
45

46. Disease Management
Stage I seminoma
• Adjuvant radiotherapy:
- Adjuvant RT to a para-aortic field or to a para-aortic and
ipsilateral iliac nodes, with moderate doses (total 20-24 Gy,2Gy x
5/week for 2 week), will reduce the relapse rate to 1-3%
- Adjuvant irradiation of supradiaphragmatic lymph nodes is not
indicated in seminoma stage I.
- Trial of 20 Gy versus 30 Gy PA radiation in stage I seminoma
showed equivalence for both doses in terms of recurrence rates
- In young patients (< 40 yrs) adjuvant radiotherapy should no
longer be used.
- Contraception should be suggest during and 1 year after Chemo
or RT
46

47. Disease Management
Stage I seminoma
• RPLND:
- In a prospective, non-randomised study comparing
radiotherapy and RPLND in stage I seminoma, there was a
trend towards a higher incidence of retroperitoneal relapses
(9.5%) after RPLND as primary treatment. Therefore, this
policy should not be recommended in stage I seminoma
47

48. Disease Management
Stage I seminoma
• Risk-adapted treatment:
- 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%
- Txn of high risk gp with Chemo /RT will reduce recurrence from
>30% to 3%
- Patients in the high-risk group treated with carboplatin
experienced a 1.4% - 3.2% relapse rate at mean follow up of 34
months
48

49. Disease Management
Stage I seminoma
49

50. Disease Management
NSGCT clinical stage I
• Surveillance:
- Indication: Low risk patient with no vascular invasion
- Relapse rate of about 28-30%
- 60% of relapses are in the retroperitoneum. 30% in lung, 10% marker only
- 35% have normal tumor marker level at relapse
- 11% presented with large-volume recurrent disease
- Follow up schedule: CT : 0, 3, 12 m
50

51. Disease Management
NSGCT clinical stage I
• Surveillance:
Mok and Warde, Hematol Oncol Clin 2011
51

52. Disease Management
NSGCT clinical stage I
• Adjuvant chemotherapy:
- CS1 NSGCT have a 14-48% risk of recurrence after orchiectomy.
- Indication: High risk patient with vascular invasion
- Relapse rates after chemo 2.7%
- 2 cycles of cisplatin-based adjuvant chemotherapy do not seem
to adversely affect fertility or sexual activity
- German Testicular Study Group 2008:
- nerve-sparing RPLND vs 1 x BEP
- CS 1 NSGCT without risk-adaption
- Adjuvant chemotherapy significantly increased the 2-year
recurrence-free survival to 99.41% (in RLND 92.37%)
52

53. Disease Management
NSGCT clinical stage I
• Adjuvant chemotherapy:
- SWENOTECA:
- Recommended one course of BEP in LVI+ patients., while
patients with LVI- chose between surveillance and BEP x 1
- The relapse-rate of patients who received BEP x 1 at 5 years was
3.2% for patients LVI+
- and 1.6% for patients LVI-
- After a median follow-up of 8.1 years the relapse rate was
- 2.3% for all
- 3.4% for LVI+
- 1.3% for LVI-
53

54. Disease Management
NSGCT clinical stage I
• Adjuvant chemotherapy:
Powles, Hematol Oncol Clin 2011
54

55. Disease Management
NSGCT clinical stage I
• RPLND:
- AUO trial AH 01/94 by the German Testicular Cancer Study Group.
- RPLND vs 1xBEP
- BEP 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
- RPLND:
- LN met (30%) → PS2 (then should txn as Stage II)
- Follow up 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
55

56. Disease Management
NSGCT clinical stage I
• Risk-adapted treatment:
- Risk-adapted treatment is based on the risk factor, vascular invasion.
- No vascular invasion (50-70%):
- surveillance : 30 % relapse
- Vascular invasion (30%):
- Surveillance: 50% relapse
- 2 cycles of PEB is option
- Result : Swedish-Norwegian Testicular Cancer Project (SWENOTECA)
- Median FU of 4.7 yr
- Relapse rate: 3.2% with VI treated with only 1xPEB
- Patients with absent VI are recommended a surveillance
- 1 cycle of BEP is recommended in patients with VI
- In cases of relapse after BEP x 1, 3 courses of BEP are recommended.
56

57. Disease Management
NSGCT clinical stage I
• RPLND:
Powles, Hematol Oncol Clin 2011
57

58. Disease Management
NSGCT clinical stage I
• RPLND:
- The presence of vascular invasion, predominant embryonal
carcinoma, pT category as well as a high number of and
extranodal extension in metastatic nodes may be associated
with an increased risk of recurrence in PS2 cases without
adjuvant chemotherapy.
58

59. Disease Management
NSGCT clinical stage I
59

60. Disease Management
60

61. Disease Management
Metastatic germ cell tumours
• CS1S with (persistently) elevated serum tumour markers:
- If the marker level increases after orchiectomy, the patient has
residual disease.
- If RPLND is performed, 87% will have LN+
- USG of contralateral testis must be performed
- Treatment
- 3 x BEP , follow as CS1B patients (high risk)
- RPLND
61

62. Disease Management
Metastatic germ cell tumours
• Low Clinical Stage
- I = Normal markers and no evidence of disease on CT-scan
(<0.5 cm)
- IIA = <2 cm retroperitoneal nodes
- IIB = 2-5 cm retroperitoneal nodes
• Advanced Clinical Stage (≥StageIIC)
- Same treatment for seminoma and non-seminoma:
- `Good prognosis` 3 x BEP
- `Intermediate and poor prognosis` 4 x BEP
62

63. Disease Management
• Stage IIA/B seminoma:
- Standard: Radiotherapy, Dose: 30 Gy (2Gy at 5 fraction per week)
- relapse rates of 9-24%
- increased risk of cardiovascular events and second malignancies
- The radiation dose delivered in stage IIA and IIB is approximately 30 Gy and 36
Gy, respectively.
- The standard radiation field compared with stage I will be extended from the
PA region to the ipsilateral iliac field.
- In stage IIB, the lateral borders should include the metastatic lymph nodes
with a safety margin of 1.0-1.5 cm.
- This technique yields a relapse-free survival in stage IIA and IIB of 92% and
90%, respectively.
- Overall survival is almost 100%
- Dose reduction to 27 Gy has been associated with 11% of relapses
63

64. Disease Management
• Stage IIA/B seminoma:
- Chemotherapy;
- 3 x BEP or 4 x EP in cases with Cx to bleomycin
- no randomised studies comparing RT vs chemotherapy.
- Single-agent carboplatin is not an alternative to standard EP
or BEP chemotherapy for metastatic disease
64

65. Disease Management
• Stage IIA/B seminoma:
65

66. Disease Management
• Stage IIA/B non-seminoma:
- Treatment should start with initial chemotherapy in all advanced cases of NSGCT
except for stage II NSGCT disease without elevated tumour markers, which
alternatively can be managed by primary RPLND or surveillance to clarify stage
- If surveillance is chosen, one follow-up evaluation after 6 weeks is indicated to
document whether the lesion is growing, remaining stable or shrinking
- A shrinking lesion is probably non-malignant in origin and should be observed
further.
- A stable or growing lesion indicates either teratoma or an undifferentiated
malignant tumour.
- If the lesion is growing without a corresponding increase in the tumour markers
AFP or beta-hCG, RPLND represents the first option to be performed by an
experienced surgeon because of suspected viable disease or teratoma
- Patients with a growing lesion and a concomitant increase in the tumour
markers require primary chemotherapy with BEP according to the treatment
algorithm for patients with metastatic disease
- An alternative to the surveillance strategy in marker-negative II A/B non-
seminoma with suspicion of an undifferentiated malignant tumour is a (CT-
guided) biopsy, if technically possible
66

67. Disease Management
• Stage IIA/B non-seminoma:
- Cure rate: 98%
- Clinical IIA with – marker (1-2cm)
- Pure embryonal carcinoma: immediate chemo
- Teratoma or mixed tumor: either
1. Surveillance : CT at 6 week
- Shrinking lesion→ observed
- No change → RPLND
- 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
67

68. Disease Management
• Stage IIA/B non-seminoma:
- Clinical IIA marker+/ IIB
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 → teratoma /undifferentiated malignant tumor → RPLND
- Elevated → salvage Chemo: PEI/VIP or TIP (Paclitaxel, ifosfamide & cisplatin)
- Primary RPLND & Chemo are comparable in terms of outcome
- Cure rate : 98%
68

69. Disease Management
• Follow up for non-seminoma:
- 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
69

70. Disease Management
• Stage IIA/B non-seminoma:
70

71. Disease Management
Metastatic disease (stage IIC and III)
• Primary chemotherapy:
• Good prognosis risk group - Seminoma
- 3 x BEP or 4 x EP
• Intermediate prognosis risk group - Seminoma
- 4 x BEP or etoposide, cisplatin, ifosfamide (VIP) (in the case
of contraindications to bleomycin).
71

72. Disease Management
Metastatic disease (stage IIC and III)
• Primary chemotherapy:
• Good prognosis risk group - NSGCT
- 3 x BEP or 4 x EP (if Bleomycin ci)
- This regimen has proven superior to cisplatin, vinblastine and
bleomycin (PVB)
- 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
72

73. Disease Management
Metastatic disease (stage IIC and III)
• Primary chemotherapy:
• Intermediate prognosis risk group - NSGCT
- 5-year survival rate of about 80%.
- 4 x BEP
- A randomised trial has compared 4 x BEP to 4 x BEP with the
addition of paclitaxel (T-BEP) and did not show a significant
improvement in OS. The overall toxicity with T-BEP was higher
than with BEP and thus it cannot be recommended as a
standard approach.
73

74. Disease Management
Metastatic disease (stage IIC and III)
• Primary chemotherapy:
• Poor prognosis risk group - NSGCT
- The 5-year progression-free survival is 45 - 50%.
- 4 x BEP
- Four cycles of cisplatin, etoposide and ifosfamide (PEI) have the same
effect, but are more myelotoxic
- GETUG 13:
- Patients with an unfavourable tumour marker decline after one cycle
of BEP should be switched to a more intensive chemotherapy
regimen.
- Patients with extended pulmonary infiltration are at risk for acute
respiratory distress syndrome: adapting the doses of the BEP regimen
in the first cycle of chemotherapy (only 3 days of EP without
bleomycin) was suggested to reduce the risk of early death in this
setting
74

75. Disease Management
BEP regimen (interval 21 days)
75

76. Restaging
- 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
76

77. Residual Tumour Resection
• Seminoma
- < 3 cm at follow-up (<10% viable cancer)
- > 3 cm (12-30% viable cancer): Pet-scan
- if PET negative: follow-up
- if PET positive: surgery
• NSGCT
- Any residual mass should be removed
- Nerve sparing procedure should be performed if possible
77

78. Residual Tumour Resection
78

79. Residual Tumour Resection
79

80. Residual Tumour Resection
• Seminoma:
- A residual mass of seminoma should not be primarily resected, irrespective of the size, but
controlled by imaging investigations and tumour markers
- FDG-PET:
- FDG-PET has a high negative predictive value in patients with residual masses after treatment
of seminoma.
- False positive results are less frequent when scans are scheduled >2 months after
chemotherapy.
- In patients with residuals of > 3 cm, FDG-PET should be performed in order to gain more
information on the viability of these residuals.
- In patients with residuals of < 3 cm, the use of FDG-PET is optional
- In the case of a post-chemotherapy mass that is still positive at reclassification FDG-PET with
no volume increase, a second FDG-PET should be performed 6 weeks later.
- In progressive disease (i.e. a growing mass which up-takes contrast medium at CT scans or
radionuclide tracer at FDG-PET), salvage therapy is indicated (usually chemotherapy or
radiotherapy)
- Patients with persistent and progressing hCG elevation after 1st line chemotherapy should
immediately proceed with salvage chemotherapy.
- Progressing patients without hCG progression should undergo histological verification (e. g. by
biopsy or mini-invasive or open surgery) before salvage chemotherapy is given
80

81. Residual Tumour Resection
• Non-seminoma:
- Following first-line BEP chemotherapy, only 6-10% of residual
masses contain viable cancer, 50% contain mature teratoma,
and 40% contain necrotic-fibrotic tissue
- FDG-PET is not indicated to re-stage patients after
chemotherapy
- In cases of complete remission after 1st line chemotherapy (no
visible tumour), tumour resection is not indicated
- Residual tumour resection is mandatory in all patients with a
residual mass > 1 cm in the short axis at cross-sectional CT
imaging
- The role of surgery is debated in patients with retroperitoneal
residual lesions < 1 cm. There is still a risk of residual cancer or
teratoma although the vast majority of patients (> 70%)
harbour fibro-necrotic tissue
81

82. Residual Tumour Resection
• Non-seminoma:
- The alternative is to put patients with residual disease < 1 cm on an
observation protocol based on recurrence data of 6-9% depending
on the time of follow-up
- Patients treated with 1st line chemotherapy should be informed
about this life-long risk of recurrence in the order of 10% before
consenting to observe residual lesions < 1 cm.
- 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
82

83. Residual Tumour Resection
Indications for Postchemotherapy RPLND
83

84. Disease Management
Chemotherapy after secondary surgery:
- After resection of necrosis or mature/immature teratoma, no
further treatment is required
- In cases of incomplete resection of viable cancer, two adjuvant
cycles of conventionally dosed cisplatin-based chemotherapy
may be given in certain subgroups (e.g. ‘poor prognosis’
patients)
84

85. Disease Management
Systemic salvage treatment for relapse or refractory disease:
- Cisplatin-based combination salvage chemotherapy will result
in long-term remissions in about 50% of the patients who
relapse after first-line chemotherapy, but the results are highly
dependent on several prognostic factors
- The regimens of choice are four cycles of a triplet regimen
including cisplatin and ifosfamide plus a third agent: etoposide
(PEI/VIP), paclitaxel (TIP), or potentially gemcitabine (GIP)
- Due to their potentially lethal risk of haematological toxicity,
these regimens should be used with G-CSF support and by
well-trained oncologists.
85

86. Disease Management
Systemic salvage treatment 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
86

87. Disease Management
Standard PEI/VIP, TIP and GIP chemotherapy (interval 21 days)
87

88. Disease Management
The International Prognostic Factors Study Group Score
5 risk groups:
- very low risk = -1 points; low risk = 0 points; intermediate-risk = 1-2 points, high risk =
3-4 points; very high risk > 5 points
88

89. Disease Management
Second relapse:
- For patients having received two series of conventionally dosed
therapy (firstline and first salvage), HD chemotherapy with
autologous stem cell support should be used. Even with HD-
therapy the curative chance is only 20-25%
- Refractory disease: Patients relapsing within 4-8 weeks after
platinum-based therapy or who are progressing despite
platinum-based therapy as well as those relapsing shortly after
HD-CTX are considered cis-platinum refractory.
- For those patients, combinations of gemcitabine and oxaliplatin
or the triple combination of gemcitabine, oxaliplatin and
paclitaxel have resulted in response rates of 25-45%.
- Those patients with a good response undergoing subsequent
resection of residual tumour lesions may still have a 15-20%
chance of long-term cure
89

90. Disease Management
Second relapse:
- Late relapse (> 2 years after end of first-line treatment): Late
Relapse is defined as recurrence more than 2 years following
cure after chemotherapy for metastatic TC, with, or without,
residual tumour surgery and occurs, according to a pooled
analysis, in 1.4% and 3.2% in seminoma and non-seminoma
patients, respectively
- If feasible, all lesions of late relapsing nonseminoma patients
should be removed by radical surgery.
90

91. Disease Management
Treatment of brain metastases:
- Brain metastases occur in the frame of a systemic relapse and
rarely as an isolated relapse.
- Long term survival 5yr
- Brain met at diagnosis (30%)
- Brain met as recurrent disease (2-5%)
- Treaatment:
- Chemotherapy
- Consolidation RT (even in total response after chemo)
- Surgery in solitary metastasis
91

92. Disease Management
92

93. Follow-up
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
93

94. Follow-up
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
94

95. Follow-up
- Most recurrences in first 2 years
- Late relapses can occur beyond 5 years, and therefore yearly
follow-up for life may be advocated
- After RPLND, relapse in the retroperitoneum is rare, the most
likely site of recurrence being the chest
- CT of the chest has a higher predictive value than plain
radiography chest
- Longer follow-up in patients after radiotherapy and chemotherapy
is justified to detect late toxicities (e.g. cardio-vascular, endocrine).
95

96. Follow-up
Follow-up: stage I non-seminoma
- Approximately 5% of patients with CS1 NSGCT present with
elevated levels of tumour markers after orchiectomy, and up to
25-30% relapse during the first 2 years
- Follow-up investigations during surveillance:
- relapses will occur in 30% of cases
- Of these relapses, 80% will occur in the first 12 months after
orchiectomy, and approximately 12% during the second year.
- The median time to relapse is 6 months (range 1-62 months),
but relapses after 3-5 years, and even later, can still occur,
with an annual rate of 4%
- approximately 70% of patients have evident metastases in the
retroperitoneum, and 10% in the mediastinum and lungs
96

97. Follow-up
Follow-up: stage I non-seminoma
- Follow-up investigations during surveillance:
97

98. Follow-up
Follow-up: stage I non-seminoma
- Follow-up after nerve-sparing RPLND:
- Retroperitoneal relapse after a properly performed nerve-
sparing RPLND is rare.
- Pulmonary relapses occur in 10-12% of patients, and more
than 90% of those relapses occur within 2 years of RPLND
98

99. Follow-up
Follow-up: stage I non-seminoma
- Follow-up after adjuvant chemotherapy:
- relapse rate of about 3%
- In a randomised trial with one course of BEP versus RPLND,
the relapse rate with adjuvant chemotherapy was 1% (Albers P,
J Clin Oncol 2008)
99

100. Follow-up
Follow-up: stage I seminoma
- The majority of patients with seminoma (70-80%) present with
clinical stage I disease at diagnosis.
- In 15-20% of cases, there is nodal radiological involvement at
the level of the retroperitoneum
- 5% of patients present with distant metastasis.
- The relapse rate varies between 1% and 20%, depending on the
post-orchiectomy therapy chosen.
100

101. Follow-up
Follow-up: stage I seminoma
- Follow-up after radiotherapy:
- Low doses of radiotherapy (20-24 Gy) limited to the
retroperitoneal or the paraaortic and ipsilateral field achieve
an OS rate of approximately 99% at 5-10 years
- The rate of relapse is 1-2% and the most common time of
presentation is within 18 months of treatment
101

102. Follow-up
Follow-up: stage I seminoma
- Follow-up during surveillance:
- The actuarial risk of relapse at 5 years ranges between 6%
(low risk) and 20%
- There is no increased risk of death.
- The median time to relapse ranges from 12-18 months, but
up to 29% of relapses can develop later than this
- The sites of relapse are the PA lymph nodes in up to 82% of
cases
102

103. Follow-up
Follow-up: stage I seminoma
- Follow-up after adjuvant chemotherapy:
- One or two courses of carboplatin-based chemotherapy is an
effective alternative treatment in stage I seminoma
- The relapse rate is 1.9-4.5%
103

104. Follow-up
Follow-up: stage I seminoma
104

105. Follow-up
Follow-up: metastatic disease
105

106. Long-term Toxicities after cure for testicular
cancer
- Treatment-induced Second malignant neoplasms usually occur
after the first 10 years
- RT-related SMN are primarily localised within or close to the RT
field (colon, stomach, pancreas, bladder and the urinary tract)
- Fung et al. demonstrated that modern cisplatin-based
chemotherapy was associated with a 40% increased risk of a solid
SMN
- Chemotherapy exposed TCSs have a nearly 3-fold increased risk
of dying of pulmonary diseases than the normal population
- Bleomycin-induced lung toxicity may affect 7% to 21% of
patients in the long-term, resulting in death in 1%-3%
106

107. Long-term Toxicities after cure for testicular
cancer
- Paclitaxel-induced acute neuropathy consists of an acute pain
syndrome, which usually develops within three days of paclitaxel
administration, or within a week
- Cisplatin-induced ototoxicity comprises tinnitus and hearing
impairment
- Cisplatin-based chemotherapy may lead to long-term renal
function impairment in 20-30% of TCSs
107

108. TESTICULAR STROMAL TUMOURS
Leydig cell tumours:
- 1-3% of adult, 3% of testicular tumours in children
- 3% are bilateral, about 8% of patients with Klinefelter
- 10-30% with gynaecomastia
- 10% malignant
- Most common type of sex cord/ gonadal stromal tumor
- Tumour markers allways negative
108

109. TESTICULAR STROMAL TUMOURS
Sertoli cell tumours:
- Malignancy 10 - 22%.
- Tumour markers are always negative
- Bilateral 40% , multifocal (30%)
- Metastatsis : 12%
- Three subtypes have been described
- Classic Sertoli cell tumour
- Large cell calcifying form with characteristic calcifications
- Sclerosing form
- Young man with large cell calcifying form : Carney’s complex,
Peutz-Jegher sydrome , endocrine disorder (40%)
109

110. TESTICULAR STROMAL TUMOURS
Granulosa cell tumour:
- 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
110