Testicular Cancer Germ Cell Tumors

1
Testicular CancerGerm 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)
• Klinefelters 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

Mixed GCT 40
11
Staging

• Serum tumor markers (S) AFP, ß-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
• ß-HCG
• Half-life 24-36 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/supraclavi
  cular LN (SIII). Lung and then non pulmonary
  (brain/bone/liver)
• If LN lt1cm 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

• Lymph Nodal spread
• For Right Left Sided Testicular Tumors

17
(No Transcript)
18
Testis cancer seminoma stage IManagement
options

• Surveillance only
• Adjuvant Radiotherapy
• Adjuvant Chemotherapy

19
Surveillancestage 1 seminoma

• Relapse rate in surveillance studies

20
Testicular Lymphatic Drainage
21
Stage I Seminoma adjuvant RadiotherapyClassical
Hockey Stick Field
22
Adjuvant radiotherapystage I seminoma

• 22.5-25 Gy ( 3 weeks of treatment)
• Target Paraaortic Ipsilateral Pelvic Nodes
• Relapse rate 0-2

23
Hadassah experience in stage Iadjuvant
Radiotherapy

• 36 patients with stage I seminoma
• Post orchiectomy hockey stick irradiation
• 22.5-24 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 gt5cm Chemotherapy
• Prognosis gt 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 Chemotherapyfor 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 541, 1994
31
No VI (n199) VI (n192)

• 23 publications (1979-2001 2587 cases)
  repeatedly confirm overwhelming importance of VI
• RR is 45-50 in VI positive tumors

Vergouwe et al JCO 2003
32
Hadassah Adjuvant Chemotherapy PEB x2 Protocol

• Entry Feb. 1993 ? June 2011
• Eligibility
• High Risk Stage I NSGCT
• Normal Chest-Abdomen-Pelvis CTS
• AFP and ?HCG normal, or return to normal
  according to ½ lives after Orchiectomy
• Number of pts 31
• Age 15-53 ( median 25 )
• Sperm Banking recommended to all pts

33
Results

• Median Follow-Up 9.4yrs (range 0.5-19 yrs)
• of Relapses 1 (3)
  (Retroperitoneal mass
  3months after PEB Completion in a pt with pure EC
  without LVI ? RPLND Growing Mature Teratoma)
• DFS 97
• OS 100
• 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

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?)

35
Retroperitoneal Lymph node dissection

• Major morbidity is ejaculatory dysfunction
• Modified nerve sparing RPLND preserves function
  in gt 90
• Identify the sympathetic nerves
• Dissection is limited to below the level of the
  IMA on the ipsilateral side only

36
(No Transcript)
37
(No Transcript)
38
German Randomized Trialin all stage I NSGCTRisk
Grouping by T Stage
39
German Randomized Trialin all stage I
NSGCTRecurrence Free Survival
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
AFPlt1000 60 of non seminoma
HCGlt5000 Any HCG 90 of seminoma
LDHlt1.5 ULN Any LDH
Non-pulmonary mets absent Non-pulmonary mets absent
Gonadal/retroperitoneal primary Any primary site
AFP 1000 10000 Non-pulmonary visceral mets present Intermediate risk
HCG 5000 50000 Any HCG 13-28 of non seminoma
LDH 1.5 10 ULN Any LDH 10 of seminoma
Non-pulmonary / visceral mets absent Gonadal/retroperitoneal Any primary site
Mediastinal primary Visceral mets presents( bone liver brain AFPgt10000 HCG gt 50000 LDHgt10ULN Never Poor risk 16-26 of non semin.
43
PFS and OS according to risk
5y PFS () 5y PFS () 5y OS () 5y OS ()
prognosis seminoma Non seminoma 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 Cancereven in Advanced Stage
Before chemo
After chemo
46
Lung mets before and after Chemo
47
Metastatic SeminomaChemotherapy PEB x 3
48
Post Chemo RPLNDPathological 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
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
Progress Against Testicular Cancer
Five-Year Survival
Source National Cancer Institute
55
???? ??? !