1. Campbell’s Chapter 29 Neoplasms of the Testis Brent Zamzow D.O.

2. Introduction Most common malignancy in males 15-35 Survival
<50% prior to 1970
>95% in 1997
Improved survival:
Accurate tumor markers
Effective chemo
Modifications of surgical technique
Mostly radiosensitive
Backup treatments if primary treatments fail

3. WHO Classification of Testicular Tumors
Germ Cell Tumors
Precursor lesions-intratubular malignant germ cells (carcinoma in situ)
Tumors of one histologic type (pure forms)  
Seminoma    
Variant-seminoma with syncytiotrophoblastic cells  
Spermatocytic seminoma    
Variant-spermatocytic seminoma with sarcoma 
Embryonal carcinoma  
Yolk sac tumor  
Polyembryoma  
Trophoblastic tumors    
Choriocarcinoma    
Choriocarcinoma with other cell types   
Placental site trophoblastic tumor  
Teratoma    
Mature teratoma    
Dermoid cyst    
Immature teratoma    
Teratoma with malignant areas
Tumors of more than one histologic type (mixed forms)-specify types and estimate percentage
Sex Cord/Gonadal Stromal Tumors
Pure forms 
Leydig's cell tumor  
Sertoli's cell tumor    
Large-cell calcifying Sertoli's cell tumor    
Lipid-rich Sertoli's cell tumor
Granulosa cell tumor 
Adult-type granulosa cell tumor  
Juvenile-type granulosa cell tumor
Tumors of thecoma/fibroma group
Incompletely differentiated sex cord/gonadal stromal tumors
Mixed forms
Unclassified Forms
Tumors Containing Both Germ Cell and Sex Cord/Gonadal Stromal Elements
Gonadoblastoma
Mixed germ cell-sex cord/gonadal stromal tumors, unclassified
Miscellaneous Tumors
Carcinoid tumor
Tumors of ovarian epithelial types
Lymphoid and Hematopoietic Tumors
Lymphoma
Plasmacytoma
Leukemia
Tumors of Collecting Ducts and Rete
Adenoma
Carcinoma
Tumors of the Tunica, Epididymis, Spermatic Cord, Supporting Structures, and Appendices
Adenomatoid tumor
Mesothelioma  
Benign  
Malignant
Melanotic neuroectodermal
Desmoplastic small round cell tumor
Soft Tissue TumorsUnclassified TumorsSecondary TumorsTumor-like Lesions
Nodules of immature tubules
Testicular lesions of adrenogenital syndrome
Testicular lesions of androgen-insensitivity syndrome
Nodular precocious maturation
Specific orchitis
Nonspecific orchitis
Granulomatous orchitis
Malakoplakia
Adrenal cortical rest
Fibromatous peritonitis
FuniculitisResidue of meconium peritonitis
Sperm granuloma
Vasitis nodosa
Sclerosing lipogranuloma
Gonadal splenic fusion
Mesonephric remnants
Endometriosis
Epidermal cyst
Cystic dysplasia
Mesolithial cyst
Others

4. Classification Germ Cell Tumors (GCT) >50% GCT are mixed Seminoma
Classic or Typical
Anaplastic
Spermatocytic
Nonseminoma
Embryonal Cell Carcinoma
Yolk Sac Tumor
Teratoma
Choriocarcinoma
>50% GCT are mixed

5. Normal testis
Sertoli cells straight arrow, leydig cells curved arrow

6. Classic Seminoma 82-85% of seminomas Mostly men in 30’s
Rarely occurs in adolescents or infants
Clear cytoplasm, dense nucleus
Synctiotrophoblasts in 10-15%
Elevated B-HCG in 10%
hCG up to 500 ng/mL
Lymphocytes in 20%

7. Classic Seminoma
Lymphocytes, fried egg apperance

8. Anaplastic Seminoma 5-10% of seminomas Greater mitotic activity
Higher rate of local invasion
Increased rate of metastasis
Higher rate of B-HCG production
Stage for stage – treatment outcomes same as classic seminoma
Classification no longer used
Only higher metastatic potential

9. Anaplastic Seminoma
Pleomorphism, hyperchromasia

10. Spermatocytic Seminoma
3 sizes of cells
9% of seminomas
50% older than 50
Very low metastatic potential
Prognosis favorable
Orchiectomy only

11. Spermatocytic Seminoma

12. Seminoma Painless testicular mass Testis size normal or smaller in 15%
Age
35-55 classic seminoma
Peak 35-39
>60 spermatocytic seminoma
Most common germ cell tumor in men >65
Rare before 10

13. Nonseminomatous Germ Cell Tumors (NSGCTs)
Embryonal
Choriocarcinoma
Teratoma
Yolk Sac
Mixed

14. Embryonal Carcinoma Small, hard, irregular mass Age 25-35
Smallest germ cell tumor
40% <2cm
Invades tunica vaginalis
Often close to rete testis
Gray/white with necrosis or hemorrhage
Highly malignant

15. Embryonal
Overlapping nuclei, anaplastic cells, pappilary projections

16. Embryonal Tumor Markers
Can have elevated hCG & AFP
Synctiotrophoblasts common in stroma
hCG not elevated in pure embryonal
AFP usually due to yolk sac elements

17. Choriocarcinoma Commonly present metastatic Usually a peripheral mass
Central hemorrhage
Must have synctiotrophoblasts & cytotrophoblasts
1-2% of tumors
hCG elevated in >99%
Age 20-30
Worst prognosis

18. Choriocarcinoma
C-cytotrophoblasts, arrow-syncytiotrophoblasts

19. Teratoma Derived from ectoderm, mesoderm, endoderm
2 or more embryonic germ cell layers in various stages of maturation
Can contain bone, cartilage, intestinal, pancreatic, liver, muscle, neural cells
Lined by any cell type
Large, lobulated, nonhomogeneous
Rarely can get malignant teratoma
Histologically benign

20. Teratoma
respiratory epithelium – arrowheads , curved arrow bone (mesoderm), straight arrows – mucin producing glands (endoderm)

21. Teratoma Classifications 3% of adult, 38% of children
Mature
Immature
With malignant transformation
Simple epidermoid cysts
3% of adult, 38% of children
Elevated AFP 20-25%
Age 25-35
Epidermoid cysts – benign
Metastatic teratoma resistant to chemo & radiation

22. Yolk Sac Tumor Other names Most common testis tumor age 0-10
Endodermal Sinus Tumor
Adenocarcinoma of the infantile testis
Juvenile Embryonal Carcinoma
Orchioblastoma
Most common testis tumor age 0-10
Slow growing mass
25% have hydrocele
AFP elevated in >90%
In adult mixed tumors, 1/3 have yolk sac elements

23. Yolk Sac Tumor Yellow, mucinous
Higher incidence of hematogenous spread
Treatment
>80% confined to testis & cured by radical orchiectomy
Low-volume retroperitoneal lymph node involvement – RPLND
Advanced disease – chemo
Residual mass unresponsive to chemo – radiation
Survival 87% for all stages

24. Yolk sac
Arrows = AFP reaction

25. Mixed Tumors 60% of tumors Most frequent mixed tumor
Embryonal, seminoma, yolk sac, teratoma & syncytiotrophoblasts
Document % of volume for each type
AFP & hCG can be elevated
Age 10-30
Managed as NSGCT

26. Intratubular Germ Cell Neoplasia: CIS of Testis
Precursor to all GCTs except spermatocytic seminoma
Risk Factors
Contralateral testis w/ unilateral ca (2-38%)
Cryptorchidism (5-6%)
Infertility (1%)
Extragonadal GCT (35-50%)
Intersex (25-100%)
Evenly distributed through testis
Open biopsy is reliable
US unreliable
Treatment Options
Observation – treatment of choice
Orchiectomy
Radiation (European treatment)
Chemo ineffective
Treatment depends on age, b/l or unilateral, atrophy, physician’s philosophy. Progression may take 15 years. Some may screen intersex or other high risk

27. Epidemiology of GCTs Incidence Laterality
Lifetime risk white male – 1 in 500
1/3 risk for American blacks
Highest incidence – Scandinavia, Switzerland, Germany, New Zealand
Lowest incidence – Asia, Africa
Laterality
2-3% are bilateral
More common on R
Cryptorchidism more common on R

28. Etiology Cryptorchidism 7-10% of tumors had cryptorchidism
1940 – 48x higher risk
1980 – 3-14x higher risk
5-10% cryptorchidism make tumor in other side
Structural abnormalities seen in cryptorchid testis at 3 years
Orchiopexy does not prevent cancer, allows clinical surveillance
Trauma not causative, just makes you go to doctor. Hormones – estrogen exposure DES,

29. Pathogenesis Tunica albuginea – barrier to spread
½ of NSGCT present as metastatic
Complete spontaneous regressions rare
Consider all adult GCT malignant
Infantile teratoma is benign
Lymphatic mets is common in all GCTs
Choriocarcinoma – lymph & vascular

30. Patterns of Spread Predictable (except for choriocarcinoma)
Spermatic cord has 4-8 lymph channels
Right-sided tumors
Interaortocaval at level of L2 body
Can cross from R to L
Left-sided tumors
Para-aortic between L ureter, L renal vein, aorta, origin of IMA
NSGCT – doubling time days
85% of those who die from GCT, die within 2yrs of orchiectomy

31. Presentation Signs & symptoms
Usually painless lump
30-40% c/o heaviness or dull ache
10% acute pain
10% present with metastatic manifestations
Neck mass, cough, nausea, vomiting, lumbar pain, bone pain
Gynecomastia is present in 5% of GCTs
Any hypoechoic area on US w/i tunica suspicious for tumor
Gynecomastia is systemic endocrine manifestation – hCG, prolactin, estrogen, androgens, still undefined relationship.

32. Staging
Based on pathology of primary tumor & imaging of chest & retroperitoneum
Understage 20% (Stage I undergoing RPLND)
10-15% have undetectable nodal mets
5-10% relapse at extranodal sites

33. Staging Systems American Joint Committee on Cancer (AJCC) – 1997, 2002
TNMS system
Stage grouping
Stage 0, Ia, Ib, Is, IIa, IIb, IIc, III
Stage I
No nodes, no mets
Stage II
Positive regional nodes
Stage III
Nonregional nodes or pulmonary mets

34. Imaging CXR CT MRI – no benefit PET Scan – no benefit over CT
PA & lateral CXR should be initial radiologic procedures CT
Abdominal CT is best test to look for retroperitoneal mets
Do after orchiectomy
If CXR or abdominal CT is abnormal, get chest CT
MRI – no benefit
PET Scan – no benefit over CT
Cannot detect microscopic disease

35. Tumor Markers Draw tumor markers prior to orchiectomy
Alpha-fetoprotein (AFP)
Serum protein of early embryo
Human Chorionic Gonadotropin (hCG)
Secreted by placenta
Lactic Acid Dehydrogenase (LDH)
Placental Alkaline Phosphatase (PLAP) & Gamma-Glutamyl-Transpeptidase (GGTP)
Low sensitivity

36. AFP Early levels 5-7 day half life Can be elevated in:
In fetus produced by fetal yolk sac, liver, GI tract
Highest levels at weeks gestation
At 1 year declines to low adult levels
5-7 day half life
Can be elevated in:
Testis, liver, pancreas, stomach, lung ca
Normal pregnancy
Benign liver disease
Ataxia-telangiectasia
Tyrosinemia
Never elevated in pure choriocarcinoma or seminoma
Pure embryonal
Teratocarcinoma
Yolk sac
Combined

37. HCG Has alpha & beta subunits
Alpha subunit similar to FSH, LH, TSH
Beta subunit is distinct
Secreted by placenta to maintain corpus luteum
Syncytiotrophoblastic cells produce hCG in GCTs
24-36 hour half life
Elevated in all choriocarcinoma, 40-60% of embryonal, 5-10% of seminomas
Can be elevated in:
Marijuana smokers
Liver, pancreas, stomach, lung, breast, kidney, bladder ca
Elevated LH - false positive HCG
LH may cross react with HCG assays causing false positive

38. LDH High levels in muscle, liver, kidney, brain
High false positive rate
Most useful as a marker for bulky disease

39. Tumor Markers NSGCTs Be careful
Elevated AFP 50-70%
Elevated hCG 40-60%
Elevated either or both 90%
10% of advanced disease will have normal tumor markers
Be careful
Elevated AFP can be from liver dysfunction
Elevated hCG can be from hypogonadism & marijuana
Normal markers does not mean no residual disease
10-20% after chemo & RPLND for bulky disease have viable tumor despite normal markers
Degree of AFP or hCG elevation is proportional to tumor burden

40. Treatment of GCTs Radical orchiectomy for local control
Offer sperm banking prior to surgery
>50% have mets, so most require further treatment
Treat retroperitoneal lymph nodes
Large retroperitoneal mets – chemo initially
65-85% seminomas confined to testis
60-70% nonseminomas present as recognizable metastatic disease

41. Partial Orchiectomy Option for Careful frozen sections
Organ confined tumor <2cm
Especially incidentally found, nonpalpable
Solitary testis or w/ B/L tumors
Careful frozen sections
Can use crushed ice, gentle occlusion of spermatic cord

42. Stage I Seminoma 15-25% staging error Radiation – treatment of choice
20-25 Gy to para-aortic nodes
5-year disease free survival >95%
Long-term side effects
Infertility, GI, 2nd malignancy
3% relapse (outside retroperitoneum) & need chemo
Chemotherapy
Carboplatin x1-2 experimental
Surveillance
Optimum surveillance protocol unknown
Give option for <6cm, no vascular invasion, normal hCG, compliant, <34
15-20% will relapse & require XRT or chemo
Stage I = no nodes, survival is same with surveillance & XRT, surveillance more common due to increased risk of secondary malignancy

43. Stage IIa & IIb Seminoma
XRT
Ipslilateral external iliac, b/l common iliac, paracaval, para-aortic, cisterna chyli
Avoid kidney
Shield contralateral testis
5-yr disease free survival 80%
3% relapse
Chemo
If nodes close to kidney
Stage 2a&b, retroperitoneal nodes <5cm

44. Stage IIc & III Seminoma
Before platinum – radiation
Cisplatin-based chemo now treatment of choice
Bleomycin, Etoposide, Cisplatin (BEP) x3–4
Etoposide, Cisplatin (EP) x4
90% complete response to chemo at 4yrs
10% relapse after initial chemo response
Postchemo residual retroperitoneal mass
Well-delineated, >3cm – resect
Mass = GCT, then salvage chemo (vinblastine, ifosfamide, cisplatin)
Otherwise observation
IIC node >5cm, III is nonregional node or pulmonary mets, response numbers are all over the place

45. NSGCTs Low Stage High Stage Surveillance Chemo RPLND
Good vs. Poor risk

46. RPLND
1948
Retroperitoneal nodes are first & sometimes only areas of mets
Gold Standard of staging
Modified template RPLND
Most likely areas to be involved
Minimize side effects
Infertility, ejaculatory dysfunction

48. Stage I NSGCTs Radiation - not used in North America, relapse rate 24%
Surveillance
Option for low risk:
No vascular/lymphatic invasion (<T2)
<40% embryonal
Motivated, reliable pts
Relapse 28%, survival 99%
Protocol
CXR, tumor markers q1mo x1yr, q2mo x1yr, q3-6mo up to 10 more yrs
CT q2-3mo x2yrs, q6mo up to 10yrs
Chemo – BEP x2-3
Option for low or high risk:
T2 or higher (vascular/lymphatic invasion)
>40% embryonal
Modified template RPLND
If negative, then observe
70% of RPLNDs find no disease
If <2cm nodes (N1), observe or adjuvant chemo – BEP x2 or EP x2
If >2cm nodes (N2), adjuvant chemo – BEP x2 or EP x2
5-10% relapse outside field of RPLND
staging is inaccurate in at least 25% & only way to accurately stage is RPLND

49. Stage IIa & IIb NSGCTs Bilateral RPLND Chemo – BEP x3 or EP x4
N1 (nodes <2cm) – observe or adjuvant chemo – BEP x2
N2 (nodes 2-5cm) – adjuvant chemo – BEP x2
Chemo – BEP x3 or EP x4
If post-orchiectomy tumor markers elevated
If nodes >3cm
Stage IIa&b – nodes <2, 2-5cm

50. Stage IIc & III NSGCTs Low Risk No nonpulmonary visceral mets
AFP <1000, hCG <5000, and LDH <1.5x normal
Intermediate Risk
Markers between low & high risk
High Risk
Nonpulmonary visceral mets
AFP >10,000, hCG >50,000, or LDH >10x normal
Chemo tailored to this classification

51. Stage IIc & III NSGCTs Low risk High risk Chemo – BEP x3 or EP x4
92% 5-yr survival
High risk
Chemo – BEP x4 or B/isosfamide/P
48% 5-yr survival

52. Stage IIc & III NSGCTs After Chemo
Complete response (normal tumor markers, no residual mass)
Observe
10% relapse & need salvage chemo
Partial response (normal tumor markers, residual mass)
Full B/L RPLND & resect residual mass
10-20% GCT – salvage chemo
40-50% teratoma – observe or resect
40% necrosis – observe
Poor response (elevated tumor markers or no shrinkage of mass)
Salvage chemo, high dose chemo & autologous bone marrow transplant
25% long term survival
Growing teratoma syndrome, can transform into sarcoma or adenocarcinoma. If partial response, can omit RPLND if >90% response & no teratoma in primary tumor.

53. Chemo & XRT Toxicity 2nd Malignancy Bleomycin Etoposide Cisplatin
Up to 18% 25yrs after XRT
Chemo
Higher long-term incidence of leukemia, melanoma, lymphoma, colon, stomach, kidney, prostate, bladder, thyroid, rectum, pancreas, connective tissue cancers
Bleomycin
Pulmonary Toxicity
Etoposide
Myelosuppression
Cisplatin
Nephrotoxicity – also Carboplatin
Low Magnesium
Neurotoxicity & Ototoxicity

54. Other Testicular Tumors
Extragonadal Germ Cell Tumors
Mediastinum, retroperitoneum, sacroccygeal region, pineal gland
Leydig Cell Tumor
Sertoli Cell Tumor
Gonadoblastoma
Lymphoma

55. Leydig Cell Tumors 1-3% of testicular tumors 10% malignant
Average survival – 3 years if malignant
Reinke’s crystals – red extracellular lobular crystals
Presentation
Precocious puberty in kids
Elevated testosterone, urinary 17-ketosteroids
Mass
Impotence, gynecomastia
Treatment
Radical orchiectomy & surveillance
Endocrine w/u

56. Leydig Cell Tumor

57. Sertoli’s Cell Tumors <1% testicular tumors
Most common testicular tumor in dogs
10% malignant
Any age
Radical orchiectomy
RPLND if metastatic

58. Others Gonadoblastoma Epidermoid Cyst Rete Testis Adenocarcinoma
0.5% testicular tumors
80% are in phenotypically female pts
Good prognosis
Epidermoid Cyst
1% testicular tumors
? Monolayer teratoma
Benign
Rete Testis Adenocarcinoma
Age 20-80
Very malignant
Adrenal Rest Tumor
B/L tumor, CAH – remission w/ corticoid treatment
Lymphoma
5% testicular tumors
Most common secondary tumor
Most common testicular tumor in age >50
½ are B/L

59. THE END