1. Testicular Cancer Germ Cell Tumors
Marc Wygoda
Department of Oncology

2. Testicular Cancer

3. Germ Cell Tumors Most common Solid Tumor in men 20-35
1% of cancers in males
Great impact on “years of life” saved
95% arise in testis
5% are “extra-gonadal”: mediastinum, retroperitoneum, pineal body
Model of a Curable Cancer even in advanced stage
Model of a Cancer with Tumor Markers playing a crucial role in management

4. Risk Factors Age Family history Personal history
Cryptorchidism (undescended testicle)
Association with Infertility (mild)
Klinefelter’s syndrome

5. Age at presentation

6. Symptoms Painless lump or swelling of testicle
Pain or discomfort in a testicle or the scrotum
Breast tenderness or growth
Symptoms of advanced cancer
lower back pain,
abdominal pain,
shortness of breath,
chest pain

7. How is Testicular Cancer Diagnosed?
Physical examination
Ultrasound of Testis
Blood tests / tumor markers
Diagnosis is confirmed by surgically removing the testicle
Needle biopsy not used (except in very specific situations)
CTS of Chest, Abdomen and Pelvis
No role for MRI.
Mild role of PET (only in Seminoma)

8. DICTUM FOR ANY SOLID SCROTAL SWELLINGS
All patients with a solid testicular mass should be regarded as malignant, unless proven otherwise

9. Radical inguinal orchiectomy
Most men are still able to have children after the removal of one testicle
No effect on sexual function
(men with sexual problems after surgery should have their testosterone level checked)
Some men may choose to have an artificial testicle implanted

10. Histologic Subtypes of GCT
SEMINOMA (40%)
Classical (32%)
Anaplastic (4%)
Spermatocytic (4%)
NON SEMINOMA (60%)
Embryonal Ca (25%)
Teratoma (25%)
Yolk sac Tumor
Choriocarcinoma
Embryonal commonly in mixed (20%)
Mixed GCT: 40%

11. Staging
Serum tumor markers (S): AFP, β-HCG, LDH

12. Tumor Markers AFP Half-life: 5-7 days
Produced by several Non Seminoma subtypes (embryonal, teratocarcinoma, yolk sac, mixed tumors)
Never produced by Seminoma or pure choriocarcinoma
Falsely elevated in liver dysfunction, viral hepatitis and ETOH
β-HCG
Half-life: hours
Produced by syncytiotrophoblastic tissue
All choriocarcinomas, 40-60% embryonal, 5-10% seminoma
Falsely elevated in hypogonadism and marijuana use
LDH
Most useful in advanced seminoma & when other markers are not ↑
Many false positives

13. How is Testicular Cancer Treated?
Depends on stage of cancer and type of tumor
More than one treatment may be used
Surgery
Active surveillance
Radiation therapy
Chemotherapy
Patients should talk with their doctor about whether treatment plan could affect sexual function and fertility before treatment begins

14. Seminoma Tend to remain localized or spread only to LN
The disease spreads in an orderly fashion: retroperitoneal LN – (SII). Mediastinal/supraclavicular LN (SIII). Lung and then non pulmonary (brain/bone/liver)
If LN <1cm repeat in 6w if normal → follow marker decline to distinguish between stage 1 and disseminated disease.
Tumor marker analysis should be performed before surgery and, if elevated, 7 days after surgery to determine the half-life kinetics. Tumor markers should be monitored until normalization.

15. Seminoma: stage at diagnosis
stage I: 70-80%
Stage II (Retroperitoneal Nodes): 15-20%
Stage III (Other metastases): 5%

16. For Right & Left Sided Testicular Tumors
Lymph Nodal spread
For Right & Left Sided Testicular Tumors

18. Testis cancer: seminoma stage I Management options
Surveillance only
Adjuvant Radiotherapy
Adjuvant Chemotherapy

19. Surveillance stage 1 seminoma
Relapse rate in surveillance studies:

20. Testicular Lymphatic Drainage

21. Stage I Seminoma adjuvant Radiotherapy Classical “Hockey Stick” Field

22. Adjuvant radiotherapy stage I seminoma
Gy ( ~3 weeks of treatment)
Target: Paraaortic + Ipsilateral Pelvic Nodes
Relapse rate: 0-2%

23. Hadassah experience in stage I adjuvant Radiotherapy
36 patients with stage I seminoma
Post orchiectomy “hockey stick “ irradiation
Gy in 1.5 Gy fractions
Testicular shell was always used
Semen preservation was recommended to all patients

24. Outcome Median follow-up 98 mo No recurrences!
One contralateral second primary GCT
No effect of Radiotherapy on fertility

25. Fertility Outcome 13/36 were not interested in fertility preservation
1/36 was azoospermic prior to diagnosis
1/36 was oligospermic priot to diasgnosis
5/36 were lost to follow-up
10 pts successfully conceived w/o any intervention
The oligospermic pt successfully underwent IVF treatment
other pts have not yet “tested” their fertility

26. Stage II Seminoma - Treatment
Cancer has spread to lymph nodes in the retroperitoneum, but not lymph nodes in other parts of the body
Stage IIA: ≤ 2 cm: Radiotherapy
Stage IIB: 2-5cm: Radiotherapy or Chemotherapy
Stage IIC: >5cm: Chemotherapy
Prognosis: > 95% Cure

27. Stage III-IV Seminoma - Treatment
Chemotherapy

28. Stage I Non Seminoma Management
Surveillance
Adjuvant Chemotherapy
Surgery: RPLND (Retro Peritoneal Lymph Node Dissection)

29. Surveillance for Markers negative stage I Non seminomas
Appropriate for “low risk” patients:
Compliant patient
No vascular/lymphatic invasion
No dominant presence of Embryonal Carcinoma
Regular physical examination, CT scans, chest x-rays, and blood tests (Markers), performed every few months for the first 2 years and less often thereafter
Risk of Relapse is then ~25%
At relapse excellent chances of cure with chemo

30. Adjuvant Chemotherapy for High Risk stage I NSGCT
Definition of High Risk Stage I NSGCT:
Lympho-vascular invasion, or
Embryonal Carcinoma Predominance (≥ 45%)
Natural History:
~ 50% recurrence rate
Moul et al: Cancer Res 54:1, 1994 30

31. RR is 45-50% in VI positive tumors
No VI (n=199)
VI (n=192)
23 publications ( ; 2587 cases) repeatedly confirm overwhelming importance of VI
RR is 45-50% in VI positive tumors
Vergouwe et al JCO 2003 31

32. Hadassah Adjuvant Chemotherapy PEB x2 Protocol
Entry: Feb → June 2011
Eligibility:
High Risk Stage I NSGCT
Normal Chest-Abdomen-Pelvis CTS
AFP and ΒHCG normal, or return to normal according to ½ lives after Orchiectomy
Number of pts: 31
Age: ( median 25 )
Sperm Banking recommended to all pts 32

33. Results Median Follow-Up: 9.4yrs (range: 0.5-19 yrs)
# of Relapses: (3%) (Retroperitoneal mass 3months after PEB Completion in a pt with pure EC without LVI → RPLND: Growing Mature Teratoma)
DFS: 97%
OS: %
3/31 Controlateral Testicular Cancer:
Stage I Embryonal Ca after 3 yrs → NED
Stage IIB Seminoma after 7yrs → XRT → NED
Stage I Mixed GCT (Teratoma + Seminoma) after 19m → NED
No other Secondary Malignancy seen 33

34. Fertility 11/31 pts have not attempted to father children
16/20 pts known to have desired it, were able to impregnate their wives, and to father 34 healthy children (1-4), without need to use their banked sperm.
Overall Fertility Ratio: 80% (85%?) 34

35. Retroperitoneal Lymph node dissection
Morbidity of from disruption of the sympathetic nerves
Morbidity is increased after XRT or chemo because of a desmoplastic reaction
-also morbidities: atalectasis, penumonitis, ileus, lymphocele, pancreatitis
f/u post RPLND:F/u exam, CXR and markers every 2 months for 1 year, and every 4 months for 1 year and then annually (relapse beyond 2 years is rare)
Major morbidity is ejaculatory dysfunction
Modified nerve sparing RPLND preserves function in > 90%
Identify the sympathetic nerves
Dissection is limited to below the level of the IMA on the ipsilateral side only

36. 36

37. 37

38. German Randomized Trial in all stage I NSGCT Risk Grouping by T Stage38

39. German Randomized Trial in all stage I NSGCT Recurrence Free Survival39

40. Stage II to IV Non Seminoma
Chemotherapy
Important role for Surgery to resect post chemo residual mass

41. Advanced Testicular Cancer: Risk Group Classification
Based on tumor location, tumor spread, and serum marker levels
3 groups for both seminoma and non-seminoma
Good risk
Intermediate risk
Poor risk
Patients with poor-risk cancer still have about a 50% chance of successful treatment

42. Non seminoma seminoma Good risk Intermediate risk Poor risk
AFP<1000
60% of non seminoma
HCG<5000
Any HCG
90% of seminoma
LDH<1.5 *ULN
Any LDH
Non-pulmonary mets absent
Gonadal/retroperitoneal primary
Any primary site
AFP 1000 – 10000
Non-pulmonary visceral mets present
Intermediate risk
HCG 5000 – 50000
13%-28% of non seminoma
LDH 1.5 – 10 * ULN
10% of seminoma
Non-pulmonary / visceral mets absent
Gonadal/retroperitoneal
Mediastinal primary:
Visceral mets presents( bone liver brain
AFP>10000 HCG > LDH>10*ULN
Never
Poor risk
16%-26% of non semin.

43. PFS and OS according to risk
5y PFS (%)
5y OS (%)
prognosis
seminoma
Non seminoma
good 82 89 90
92-94
intermediate 67 75 72
80-83
poor 41 71

44. Cancer Treatment: Chemotherapy
Classical Protocol: PEB
Platinum (Cisplatinum)
Etoposide (VP-16)
Bleomycin
Common Side effects may include fatigue, infection, nausea and vomiting, alopecia.
Rare side effects: hearing loss, skin marks, numbness and tingling, lung damage, kidney damage, cardiovascular disease, and secondary cancers
Nowadays very little severe long term side effects

45. Highly Curable Cancer even in Advanced Stage
Before chemo
After chemo

46. Lung mets before and after Chemo

47. Metastatic Seminoma Chemotherapy PEB x 3

48. Post Chemo RPLND Pathological findings
40-45% teratoma
40-45% Necrosis
10-20% viable Tumor

49. PROGNOSIS Seminoma Nonseminoma Stage I 99% 95% to 99% Stage II 95% 90%
Stage III 80% to 85% 70% to 80%

50. Post treatment Follow up
Regular physical examinations and/or medical tests may be required to monitor for the following long-term effects
Effect of bleomycin on lungs
Effect of chemotherapy on kidneys, blood vessels and lipids profile
Effect of cisplatin on nerves, hearing, and the brain
Secondary cancers
Fertility problems
Testosterone levels
Fear of recurrence is common: psychological support

51. Relapse of Testicular Cancer
Still Curable
2nd line Chemotherapy
High Dose Chemo with Stem Cell Rescue
Post chemo Surgery

52. Conclusions Imperial Surgery Turkey/Persia 15th century
Bibliotheque Nationale, Paris 52

53. Testicular Germ Cell tumors
Model of highly curable cancel
Stage I pts have a long term cure rate close to 100%
Low to intermediate burden metastatic pts cure rate: ~90%
Very advanced pts are infrequent: cure rate ~50-60%
Pts can still be cured after relapse

54. Five-Year Survival Progress Against Testicular Cancer
Source: National Cancer Institute

55. תודה רבה !