GERM CELL TUMOURS OF THE TESTIS by Nwabueze.ppt

GERM CELL TUMOURS OF THE TESTIS by Nwabueze

1. GERM CELL TUMOURS OF
THE TESTIS
UROLOGY UNIT
UNTH
8/8/07

2. Case Summary
By Dr. S. N. Okeke

3. Biodata
•Name: Mr. A.P
•Age: 36yrs
•Sex: Male
•Marital Status: Single
•Occupation: Civil servant
•Address: Delta State

4. Presenting Complaint
•Recurrent ® inguinal mass x 10 months.

5. HPC
•Was seen at SOP on 15/03/07 with the above
complaint
•Born with absent ® testis in the hemiscrotum.
•Associated small lump in the ® groin.
•He never sought medical attention till 4yrs
prior to presentation when the lump started
increasing in size.

6. Cont’d
•2yrs later he had ® groin exploration.
•No histology was done.
•The surgical wound healed satisfactorily.
•However 10months after surgery, a new growth
appeared at the surgical site.
•The growth increased in size.
•Became painful 2wks afterwards, with radiation to the
lower back.
•No trauma to the lump.
•No pain in any other part of the body.

7. Cont’d
•There was no obvious change in the size of
the contralateral well descended testis.
•No abdominal swelling. No chronic cough.
•He had lost about 10kg in the preceding
3months.
•No change in bowel habit.
•No urinary symptoms

8. •The rest of the history was not contributory.

9. On Examination
•Young man. No obvious distress. Afebrile.
Not pale. Anicteric. No peripheral lymph
adenopathy. No pedal oedema.
•Vital signs: stable
•Chest: Clear.

10. Abdomen
•Flat. Moved with respiration.
•A surgical scar at the ® groin
•An ovoid mass was deep to the scar.
4x4cm. Hard. Non tender. With definite
margins. Not attached to skin. Not attached
to underlying muscle.
•DRE: Essentially normal

11. Ext. Genitalia
•Hypoplastic ® hemiscrotum
•Absent ® testis.
•Well developed undescended left testis of
adequate volume.
•No hypospadias.
•No chordee

12. Diagnosis
•Recurrent ® testicular tumour in an
undescended testis

13. Investigations
•FBC. S/E/U/C: normal
•CXR-PA view: normal
•Abdominopelvic u/s scan:
-Retroperitoneal masses,the largest, about
the size of his kidney 7x5cm
-Ectopic (pelvic) ® kidney
•CT scan: Not done
•AFP & Beta-hCG: normal

14. On 23/04/07
•He had excision biopsy of the ® groin mass.
•Histology: Seminoma – Classic variant
•Diagnosis: seminoma (classic variant) stage
IIB (at least)

15. •He was worked up for Cytotoxic therapy by the oncology
unit.
•One week ago, he had 1
st
course of :
IV Cisplatin 20mg/sqm (35mg). for 5days.
Tab Etoposide 120mg/sqm (200mg) for 5days.
He had no untoward effects.
Next course is to follow in 3weeks.
He is to have a total of 6 courses.
After the complete dose of chemoRx, he will be reassessed
for residual disease. Radiotherapy is to follow.
Thank you.

16. SURGICAL ANATOMY
OF THE
TESTIS
BY
Dr Okezie Mbadiwe

17. •Ovoid,firm,intrascrotal
•5 by 2.5 by 2.5cm
•20g
•Tunica albuginea
•Tunica vaginalis
•Epididymis

18. COVERINGS OF THE TESTIS

19. •Blood supply: Testicular aa
Minimal Anastomosis with Ductal and Cremasteric aa
•Venous Drainage
Panpiniform plexus
Left testicular vein: Lt. Renal vein
Right testicular: IVC
•Lymphatic drainage
Para-aortic nodes (L2)
Connections with mediastinal and Cervical nodes
•Nerve: Sympathetic (T10)

20. STRUCTURE
•T. Albuginea
•Mediastinum testis
•200 – 300 lobules
•Each lobule: 1 – 4 tubules
(Semniferous tubules)
•Rete testis
•Supporting cells (sertoli)
•Interstitial cells (Leydig)

21. DESCENT OF THE TESTIS
•Genital ridge: Germ cells from yolk sac
•Gubernaculum testis
•Processus vaginalis

22. THANK YOU

23. PATHOLOGY
BY
DR. I.I. NNABUGWU

24. INTRODUCTION
•Testicular cancer is the most common
malignancy in young men 15-35yrs.
•One of the most curable solid neoplasms
applying multimodal therapy of
malignancies.
•Germ cells: Pluripotent
•Germ cell tumours: constitute 90-95% of all
primary testicular cancers.

25. Epidemiology
•Incidence: 3.7/100,000 American Whites
0.9/100,000 American Blacks
0.1/100,000 Nigeria. Magoha (1995)
•Age: 0-10yrs: mainly yolksac tumours
20-40yrs: mainly seminoma
•Race: scandinavian countries, USA & UK, Africa &Asia
•Genetics: No obvious genetic abnormality identified yet.
•Right tumours slightly more than left tumours
•Bilaterality: 2-3% of cases
Similar or different histology
Simultaneously or successively.

26. Classification.
•6 major attempts since 1940.
•WHO (1998) classification:
Precursor lesions: Ca. in situ
Tumours of one histologic type (pure form)
1.Seminoma. 2.Embryonal Ca
3.Yolk sac tumour 4.Polyembryoma
5.Trophoblastic tumours
6.Teratoma: Mature teratoma, Dermoid cyst,
Immature teratoma,teratocarcinoma
Mixed tumours

27. Clinical Classification
•Seminoma
•Non seminoma

28. Seminomas
•Classic: 82-85% of seminoma,
•Spermatocytic: 2-12%
•Anaplastic: 5-10%
•Age range: 20-40yrs
•Rare in adolescents and infants
•5-10% produce beta-hCH(syncytiotrophoblast)
•Commonest histology in Undescended testis

29. Yolk sac Tumour
•Most common testis tumour of infants
•Produces AFP
•a.k.a endodermal sinus tumour
•Adenocarcinoma of infantile testis

30. Predisposing Factors
•Undescended testis: may be due to
-Gonadal dysgenesis
-Abnormal Germ cell morphology
-Endocrine dysfunction
-Elevated temperature
-Impaired blood supply
•Increased risk of cancer (3-14X general
population)

31. Cont’d
•7-10% of testicular GCT occur in undescent.
•5-10% of patients with undescent develop
cancer in contralateral well descended testis.
•Orchidopexy does not prevent carcinogenesis
•Ectopic testis is not a predisposing condition.

32. Other Predisposing Conditions
•Trauma
•Atrophy
•Hormone administration (e.g) DES and
pregnancy

33. Natural History
•All germ cell tumours are malignant or
potentially so.
•Following malignant transformation
-CIS
-Invasive Ca
-Lymphatic spread
-Haematogenous spread
•Spread is predictable except for chorioCa.

34. Cont’d
•Rapid growth with (doubling time 10-30days
for NSGCT)
•Bleeding or Necrosis
•Spontaneous regression is extremely rare if
ever.

35. Biochemical substances secreted
•AFP: Yolksac tumour, Embryonal Ca,
Teratocarcinoma.
•Beta-hCG: ChorioCa, Embryonal Ca
•Lactate Dehydrogenase (LDH)
•Placental Alkaline phosphatase
•Human chorionic somatomammotropin.

36. Staging TNMS
•According to AJCC &UICC
•pTis: Intratubular ca. in situ
•pTo: No tumour identified
•pTx: Tumour cannot be assessed
•pT1: Lim. to testis/epid. No vasc/lymph. involv.
•pT2: Lim. To testis/epid. Vasc./lymph. involv. Or
invading tunica vaginalis
•pT3: Invades spermatic cord +/- vasc/lym. invas.
•pT4: Scrotal invas. +/- vasc./lymph. invas.

37. Nodal status
•Nx: Cannot be assessed
•N0: No regional lymph node
•N1: Single or multiple nodes 2cm or less.
•N2: Single or mult. nodes >2cm & <(=)5cm
•N3: Node(s) > 5cm.

38. Distant mets.
•M0: No evidence
•M1: Non regional nodal or Pulm. Mets.
•M2: Non pulm. visceral mets.

39. Serum Tumour Markers
LDH hCG(mIU/ml) AFP(ng/ml)
S0 N/< N/< N/<
S1 <1.5xN <5000 <1000
S2 1.5-10xN 5000-50,000 1000-10,000
S3 >10xN >50,000 >10,000

40. Staging Cont’d
•Clinically: stage O: pTIS
stage I: Confined to scrotum
stage II: Regional lymph node.
stage III: Distant metastasis

41. Prognostic factors
•Tumour burden
•Number of metastatic sites
•Level of tumour markers hCG, AFP & LDH

42. Conclusion
•Thank you

43. CLINICAL FEATURES &
INVESTIGATIONS
BY
DR. A.D. OKOH

44. CLINICAL FEATURES
SUBDIVISIONS
1. Incidental dx
2. Hormonal manifestations
3. Localized dx
4. Metastatic dx

45. INCIDENTAL DX
Asymptomatic
Discovered during inv. for other reasons e.g.
infertility, undescended testis
FXS OF HORMONAL
MANIFESTATIONS
A. SYMPTOMS
Breast enlargement – effect of tumour hCG secretion

B. SIGN
Gynaecomastia

46. FXS OF LOCALIZED DX
A. SYMPTOMS
Scrotal/Testicular swelling : usu. painless; occ.
painful
B. SIGNS
Testicular mass
 Consistency
Homogenous - Seminoma
Inhomogenous - NSGCT
 Non-tender usu.
 Intra-scrotal
 Hydrocele – associated wth it occ.

47. FEATURES OF METASTATIC DX
A. SYMPTOMS
Loss of appetite (anorexia)
Weakness (anaemia)
Wt. loss (asthenia)
Yellowness of eyes (jaundice)
Bone pain/swelling & bone # (spontaneous/trauma)
Abd. pain & swelling
Cough , chest pain , SOB

48. B. SIGNS
LYMPHADENOPATHY
Left supraclavicular
Inguinal
CHEST
Fxs of pleural effusion & pulmonary pathologies
ABD
Hepatomegaly & ascites
Para-aortic LNE
MSK
Bone swellings & tenderness , # evidence
CNS
Cerebral mets - Altered consciousness
Spinal mets - motor & sensory system dysfxn

49. INVESTIGATIONS
To :
Assist in diagnosis
Check for complications & stage the dx
Plan tx modalities
IMAGING STUDIES
Testicular USS
Abd/pelvic USS
CXR

50. Skeletal survey
Radioisotope bone scan
CT Scan/MRI
 Brain
 Chest
 Abdomen
 Scrotal
PET

51. TUMOUR MARKERS
Alpha-fetoprotein
Beta subunit hCG
Lactate dehydrogenase
Placental ALP (PLAP)
Gamma glutamyl transpeptidase (GGT)
OTHERS
FBC + ESR
SEUCr
LFT
Mantoux test

52. DIFFERENTIAL
DIAGNOSIS
Epididymitis
Hydrocele
Non-Hodgkin lymphoma
Spermatocele
Testicular torsion
Varicocele

53. TREATMENT
BY
DR. B.S. MAKAMA

54. OUTLINE
Factors determining tx modalities
Modalities of tx
Tx of CIS of the testis
Fertility in pxs wth GCT
Basis of sensitivity of GCT to DNA
damaging agents
Conclusion

55. TX OF GCT OF THE TESTIS
Tx depends on the ff factors :
 Histological type of the tumour
 Seminoma GCT
 Non-seminomatous GCT
 Stage of the dx
 TNM
 Boden & Gibb
 Memorial Sloan-Kettering Cancer Centre
 Royal Masden Hospital
 Clinical
Low stage dx (T1 - T3 & N1 - N2)
Advanced stage dx (T4/N3/M1)

56.  Prediction of metastatic potential (MP)
A. NSGCT
 Vascular/lymphatic invasion
 Extent of primary tumour (T-stage)
 Embryonal Ca : 30 – 40 % of tumour vol.
 Absence of yolk sac tumour
N/B :
 Low risk metastatic potential - Surveillance
 High risk metastatic potential - Option of either :
RPLND or
Chemotherapy

57. B. Seminomas
Predictors of MP for lower stage SGCT
 Tumour size
 Vascular & lymphatic invasion
 Elevated Beta hCG
 Prognostic staging for metastatic GCT
 Good prognosis
 Intermediate prognosis
 Poor prognosis

58. TREATMENT
Multimodal approach
Platinium based chemotherapy
Impt. implications of predictable pathways of LN
drainage
30 – 40 % of pxs wth stage 1 NSGCT have
occult metastasis
MODALITIES OF TX
 Surgery
 Radical Inguinal orchidectomy +/-
 RPLND

59.  Adjuvant Radiotherapy (RT)
 Adjuvant Chemotherapy
SURGERY
Radical orchidectomy : including clinically
advanced dx
POST-RADICAL ORCHIDECTOMY TX
MODALITIES :
Surveillance
RPLND
RT
Chemotherapy

60. SURVEILLANCE PRINCIPLES IN
STAGE 1TC
Strong commitment of both pt &
physician
 Various protocols have been
developed :
1
st
yr – Pt seen @ mthly intervals
2
nd
yr – Pt seen @ 2 mthly intervals
3
rd
yr – Pt seen @ 3 mthly interval

61. Years 4 to 7 – Pt seen @ 6 mthly
intervals
for :
 O/E
 CT Scan abdomen/pelvis
 CXR
 Tumour markers

62. SURVEILLANCE OF STAGE 1 SEMINOMA
Post-tx options are :
RT
Surveillance
Adjuvant RT remains current tx of choice
 Surveillance/RT ~ 100% cure in stage 1
seminoma post-orchidectomy irrespective of
approach
SURVEILLANCE OF STAGE 1 NSGCT
 Ultimate survival appears less c.f. RPLND
 Despite this either is advocated

63. 
Surveillance appropriate for :
 Clinical stage 1 wthout relapse risk
factor
 Surveillance protocol motivated pts
 Pts understanding risk of non-
compliance to follow- up schedule

64. ADJUVANT TX POST-RAD.
ING. ORCHIDECTOMY

RPLND
 RPLND – I :

Confined to pts wth
only clinically stage I
dx confirmed intra-op
Surgical Technique
 Template

65. Nerve sparing

Survival ~ 100%
 Relapse outside
retroperitoneum
 Salvaged by
chemotherapy

66. 
RPLND – II
 Stage IIA or IIB dx
 Clinically demonstrable or
 Visible @ surgery
 Relapse usu. Outside peritoneum
LAPAROSCOPIC RPLND : Currently only for staging

RPLND – III

Resection of residual dx
 Indicated in pts who failed primary tx
 Performed both for Seminoma & NSGCT

67. ADJUVANT RT
SEMINOMA
 Low Stage
 RT std adjuvant tx
 Sensitive to low dose radiation
 2,500 - 3,500 cGy
 Given over 3 wks
 To peri-aortic + ipsilat. Inguino-pelvic LN
 95% five yr survival
 Advanced Stage
 Sometimes used for residual dx after chemotx

68.  Advanced Stage
 Combination chemotherapy
 BVP proved effective
 ~ 90% dx free in 4 yrs
NSGCT
 Low Stage
N/B : Primary chemotherapy
 Survival for 2 cycles of BEP ~ 95 – 100%
 No randomised studies against RPLND
 Long term effects on young adults unclear

69. NSGCT
 Higher doses (4,000 – 5,000 cGy)
 Long term morbidity
N/B: NSGCT are sensitive to chemotherapy
 Falling out of favour as 1
st
line tx
ADJUVANT CHEMOTHERAPY
SEMINOMA
 Low Stage
 Efficacy comparable to adjuvant RT, wth single
agent – Carboplatin
 Pt quality of life – same
 May gain wider acceptance in the future

70. CHRONIC TOXICITY
6 categories :
 Nephrotoxicity – Cisplatin
 CVS – Bleomycin +/- Vinblastine
Raynaud’s phenomenom
Occlusive vasc. dx
 Neurotoxicity – Cisplatin + Vinblastine
 Chronic periph. neuropathy
 Impaired auditory fxn

71.  Pulmonary – Bleomycin
 Pneumonitis
 Pulmonary fibrosis
Second malignancy :
 Both 2
nd
GCT + Non-GCT
 Fertility
 Oligospermia
 Azoospermia
N/B : Adjuvant chemotherapy can also be used in
low stage dx

72. Advanced Stage
A. Good Risk Pt
TX GOALS
 Maintain high cure rates
 Reduce tx related toxicity
Generally receive
 4 cycles of EP or
 3 cycles of BEP
N/B : Bleomycin is essential in good risk if
only 3 cycles of chemotx are given
 80 - 90% dx free rates

73. B. Poor Risk Pt
 5 yr survival – 48%
 Recently high dose chemotx wth
autologous bone marrow
transplant (ABMT) or
 Peripheral stem cell support
 4 cycles of BEP + 2 cycles of Etoposide
+ Carboplatin + ABMT

74. SALVAGE FOR RELAPSED TC
SALVAGE CHEMOTHERAPY
Current std is wth Ifosfamide based regimen as
1
st
line e.g. VIP, BEPI
 PROGNOSTIC FACTORS FOR SALVAGE
CHEMOTX
 Favourable
 Prior complete response to Cisplatin based regimen
 Testis as primary site
 Unfavourable
 Initial incomplete response to Cisplatin based regimen
 Primary mediastinal site

75. SALVAGE SURGERY
Aggressive surgery may offer a reasonable
alternative
SALVAGE RT
RT + high dose chemotherapeutic regimens wth
ABMT

76. TX OF CIS OF THE TESTIS
CIS progresses to invasive dx
TX OPTIONS
 Orchidectomy
 RT
 Chemotx
 Observation
N/B : Low dose radiation is currently being investigated
FERTILITY IN PTS WTH TESTIS CA
 Young adult men affected, hence fertility a concern
 Defective spermatogenesis in 25% of pts @
presentation

77. 
50% hypofertile post-
orchidectomy prior to adjuvant tx
Adjuvant tx further impairs
fertility
50% returns to normal sperm
count @ 2yrs ff chemotx
25% remain azoospermic

78. Only 35% achieve paternity ff
chemotx
 76% paternity ff RPLND – I
 Cryo-preservation of semen
b/4 chemotx
 Assisted reproductive
techniques (ART) e.g. ICSI

79. BASIS OF SENSITIVITY OF TC TO
DNA - DAMAGING
AGENTS
 When equivalent freq. of strand breaks are
produced the testicular cell lines die more
readily
 Damaged DNA leads to increase P53
 P53 increase transcription of Waf-1 &
Mdm-2 protein
 Waf-1 a potent inhibitor of cyclin-
dependent kinase which causes cell cycle
arrest @ G1

80. Over-expressed myc, myb or EZF, and
elevated P53 may lead to apoptosis
 GCT cells have higher levels of apoptosis
promoting proteins - Bax and lower levels
of suppressor of apoptosis – Bcl – 2
 Bax:Bcl-2 ratio determines response to
cell damage for either apoptosis or repair
 ? P53 up-regulates Bax & down-regulates
Bcl-2

81. PREVENTION

People should be encouraged to do
regular self-examination of the
testis esp. in the high risk group
 Monitor tumour markers for
testicular tumour

82. CONCLUSION
At present there are a no. challenges facing
physicians responsible for the care of pts
wth GCT
Ongoing devt. in the field of molecular
biology are likely to enhance our
understanding of the aetiology &
pathogenesis of GCT in the future, and
hopefully the prevention of these
fascinating tumours in the new millenium

83. THANK YOU & GOD BLESS !