Testicular ca [edmond]

1

Testicular Ca

Dr. Edmond WongEAU 2010EAU 2011

EGCCCG 2008 (EU)

2

Epidemiology

• 1-1.5% of male neoplasm• 5% of urological tumors• 3-6 new case per 100,000 male/ year• Increasing trend towards increase incidence• 1-2% bilateral• Histological variance:

– Germ cell tumors (90%)– Non- GCT (10%)

• Peak incidence: – 30s for seminoma– 40s for pure seminoma– Familial clustering among sibilings

3

Risk factors

1. Familial hx of Ca testis in 1st degree relative (father/brother)

2. History of cryptorchidism3. Infertility4. Klinefelter’s syndrome5. Contralateral tumor or Tin6. HIV7. Maternal oestrogen exposure8. Race: scandanavian

4

Genetics

• Specific genetic marker: Isochromosome of the short arm of chromosome 12 – i(12p) in all germ cell tumors

• Intratubular germ cell neoplasia (testicular intraepithelial neoplasia, Tin) : same chromosomal change with alterantion in p53 locus (66%)

• Deregulation in pluripotent programme of fetal germ cells (markers: M2A, C-KIT, OCT4/NANOG)

5

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

6

Pathology: WHO classification

7

Classic Seminoma

• Peak at 30s, also in > 60s• Composed of islands/ sheets of relatively large c

ells 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

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

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

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

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

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

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 glan

dular and ductal structures• Embryoid bodies: measuring < 1 mm in diameter, cons

ist of a cavity surrounded by loose mesenchyma containing syncytiotrophoblasts and cytotrophoblasts, resembling 1- to 2-week-old embryos

14

History:

• History related to the mass

- Duration, painful/painless, change in size, previous history of genitalia surgery, sexual history, trauma, associated urinary tract symptoms

• Previous relevant history and risk factor(s)

- 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

15

Clinical examination

• General: – SC LN– Palpable abdominal mass– Gynaecomastia (7%) more common in NSGTC– Back and flank pain (11%)

• Scrotum: – Painless , unilateral mass in scrotum– Reduction in testis size precede testicular tumor– Casual finding of intrascrotal mass– Scrotal pain (20%)– Local pain (27%)– Mimic orchioepididymitis (10%)

16

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• Dx must be confirmed by bx of

extragonadal mass• Histology of undifferentiated Ca

immunohistological marker (isochrom i 12p)

17

Blood test• Serum marker has prognostic value:

– AFP (produced by yolk sac cells) : ½ life 5 day• Increase in 50-70% of NSGCT

– hCG (expression of trophoblasts): ½ life 36hr• Increase in 40-60% of NSGCT • Increase in 30% of Seminomas

– 90% NSGCT present with rise both marker• LDH (marker of tissue destruction)

– For pt with metastatic disease – Elevated in 10 - 20% of seminomas, correlating with tumor burden– Useful in monitoring of Rx response in advanced seminoma– Increase in 51% of ca testis

• Other marker : – PLAP (placental like alkaline phosphatase): monitoring pt with pure

seminoma• -ve maker do not exclude the dx of GCT • AFB, hCG & LDH in advanced cancer is mandatory , while PLAP is

optional

18

Imaging of testis• Scrotal USG: > 7.5 MHz

– Confirm presence of testicular mass– Diff intra or extratesticular– Explore contralateral testis– Sensitivity (100%)– Also indicated in pt with retroperitoneal or visceral mass & elevated hCG or AFP– FU of contralateral testis on FU pt at risk

• Seminoma :– a homogeneous hypoechoic, intratesticular mass; larger lesions may be more inh

omogeneous– calcifications and cystic areas are less common

• Nonseminomatous tumour :– may contain microcalcifications and areas of hemorrhage, typically heterogeneou

s in appearance– teratoma elements: may demonstrate well-defined structures of ectodermal deriv

ation

19

Testicular microcalcifications

• Divided into classic and limited:– Classic: presence of five or more microliths on one or more ima

ges of the testes

• Aassociated in both benign and malignant conditions: – Klinefelter syndrome

– male pseudohermaphroditism

– Down syndrome

– subfertility

– infertility

– cryptorchism

– hypogonadism

– fragile X syndrome

– pseudoxanthoma elasticum

– pulmonary microlithiasis

20

CT scan of the abdomen and pelvis with IV and oral contrast

• To identify metastatic disease to the retroperitoneal lymph nodes (sensitivity 70-80%)

• Understages approximately 15-20% of patients thought to be 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, and 20% of right-sided NSGCTs, lymph node involvement is found on the left side

21

Chest XR / CT

• to help identify any possible pulmonary metastases

• the only thoracic examination in seminoma when retroperitoneal and pelvic CT are -ve

• Chest CT is recommended for NSGCT• Chest CT increases the sensitivity of diagnosis,

but the presence of small, benign granulomas of the lung may be misdiagnosed as metastatic disease in as many as 30% of patients with clinically low-stage disease

22

• MRI: – Higher SV (100%) and SP (95%) than USG

for diagnosis– Able to differentiate Seminomatous from non-

seminomatour tumors– No adv over CT

• PET : – No adv over CT, because both are insensitive

for microscopic LN metastasis

23

24

Inguinal exploration and orchidectomy

• Should be performed within 1 week• Immediate orchidectomy with division of spermatic cord

at internal inguinal ring must be performed if tumor is found– scrotal skin lymphatics are different from testicular lymphatics and dr

ain into the inguinal nodes– perform all orchidectomies for solid masses through an inguinal rout

e to avoid tumor spill into the inguinal drainage basin – If a patient is explored scrotally, subsequent therapy may necessitat

e hemiscrotectomy and radiation treatment of the inguinal nodes

• If dx not clear: testicular bx is taken for frozen section• In case of disseminated disease or life-threatening

metastasis up-front chemotherapy and then orchidectomy later when clinically stabilized

25

Before orchidectomy

Discuss the issue of:• Sperm banking• Contralateral testicular biopsy (10%) in no risk

(34%) in risk gp (refer to TIN)• Testicular prothesis:

– Prothesis infection (2%) may delay post-op chemo– Extrusion from scrotum (5%)– Scrotal contraction or migration (3%)– Chronic pain (3%)– Hematoma (< 1%)

26

Radical Inguinal Orchidectomy

• Inguinal incision• Cord isolation • Pedicle control with a non-crushing vascular clamp• Dissection of the spermatic cord with 1 – 2 cm into the

internal spermatic ring• Leave a long nonabsorbable tie on the patient side of t

he spermatic cord. This is to facilitate identification if retroperitoneal lymph node dissection (RPLND) becomes necessary and the patient requires dissection of the remaining spermatic cord structures from the abdominal exposure.

27

Organ sparing surgery

• Contraindication: presence of non-tumoral contralateral testis

• Indications: – Bilateral testicular tumors– Metachronous contralateral tumors– Tumor in solitary testis with normal pre-op testosterone level– Tumor volume <30% of testicular volume

• Rate of Tin is high (82%)• If TIN is found RT • All patient must be treated with Adj RT (20Gy) at some

point (after fathering of children)

28

29

Pathological exam of testis

• Mandatory pathology requirements: – Macroscopic features: side, testis size, max tumor size ,

macroscopic features of epididymis, spermatic cord and TV– Sampling : 1cm2 section for every cm of tumor diameter (include

parenchyma, albuginea and epididymis) with selection of suspected area. At least 1 proximal and 1 distal section of spermatic cord + any suspected area

– Microscopic features: Histological types WHO 2004: • Peri-tumoural venous and/or lymphatic invasion• Albuginea, TV, rete testis, epididymis or spermatic cord invasion• Intratubular germ cell neoplasia(Tin) in non-tumor parenchyma

– pT category according to TNM 2002– Immunohistochemical studies: in seminoma and mixed germ cell

tumor, AFP & hCG

30

• Advisable immunohistochemical markers: in case of doubts: – Seminoma : Cytokeratin (CAM 5.2) , PALP, c-kit– Intratubular germ cell tumor: PALP, c-kit– Other markers: Chromogranine A (Cg A) , Ki-1(MIB-1)

31

32

CIS (Tin)• Testicular Intra-epitheralial neoplasia (TIN) or Intratubular germ-cell

neoplasia (ITGCN)• Pre-invasive testicular germ-cell lesion (CIS) • Precursor of all GCT except spermatocytic seminoma• Incidence in general population : 1%• Incidence of contralateral (10%) & metachronous (2.5%) Tin • 50% progression to GCT in 5 yr, 70% in 7 yr• Does not raised tumor marker• Presence has no bearing in overall prognosis in tumor bearing testis• Histology:

– malignant germ cell lining seminiferous tubules containing Sertoli cells in single row

– nuclear pleomorphism and intact basement membrane– Tubules: smaller diameter , thickened wall, absent spermatogenesis

33

• Contralateral bx to rule out presence of Tin (not for all patient)

• Indication for contralateral biopsy: 34% risk– Testicular volume < 12ml– Age < 40– Hx of cryptorchidism (3%)– Poor spermatogenesis (Johnson Score 1-3) : hx of infertility (1%)

• Other risk factors: – Extra-gonadal GCT (40%)– 45 XO karyotype

• Double biopsy is preferred to increase sensitivity:– Upper and lower pole , able to dx with 99% accuracy – Preserved in Stieve’s or Bouin’s solution

• Testicular bx in pt with extragonadal GCT: – 1/3 will have TIN in one or both testis– Routine bx of bilateral testis is not recommended , because they

will have received chemo which eradicate most TIN already– If indicated , perform before chemo or 2-year after chemo

34

35

Txn of Tin: In contralateral testis / affected single testis after organ preserving surgery

• Surveillance: – Interval btw TIN and testicular ca is long (justified) – have not complete family, Fu PE & USG yearly

• Local RT – 20Gy in single fraction of 2Gy , 5 day/week– Need testosterone replacement– < 20Gy have lower frequency of complete eradication

• Orchidectomy: – loss of fertility and need of testosterone– Will result in infertility must be counseled for sperm banking

• Post-orchidectomy chemo given:– 2/3 have ITGCN eradicated , bx at least 2 yr after complete

chemo– If still have ITGCN RT vs orchidectomy

36

Txn of TIN: pt without gonadal tumors

• Normal contralateral testis orchidectomy

• RT may impair fertility of contralateral unaffected testis (scattered radiation)

37

Txn of TIN: Pt schedule for chemo

• 2/3 will be eradicate by chemo alone

• Delay RT to avoid extensive damage to Leydig cell

• Bx after chemo: alone after 2 year

• If persisted managed as above

38

39

Screening of Ca testis

• Stage and prognosis is directly related to early diagnosis

• Self PE by affected individual is advisable

40

Staging

• To determine metastatic or occult disease: – ½ life kinetics of serum tumor markers– Nodal pathway must be screened– Presence of visceral need to be rule out

41

Staging

• AJCC 2002 TNM classification• Royal Marsden Staging System

– Stage I: confined to testis– Stage II: retroperitoneal LN involvement (A, B, C, D)– Stage III: Supra-diaphragmatic & visceral met with

vary degree of tumor marker– Stage IV: Disseminated disease (liver, lung, bone)

• Boden-Gibbs classification– A – confined to testis– B – regional LN metastasis– C – Above diaphragm or extralymphatic metastasis

42

Test for staging

• Serial blood sampling

• CXR

• CT Abd + Pelvis (+/- Chest)

• Abdomen + retroperitoneal USG

• MRI

• PET scan

43

Serum marker

• ½ life of AFP: 5-7 days• ½ life of hCG: 3 days• Post-orchidectomy

– Serial marker evaluation to determine ½ life kinetic– Marker in Stage I disease should decrease until normalization– Elevated marker metastatic disease– Normal maker does not rule out presence of tumor metastasis– Should be measure every week after orchidectomy

• Post-orchidectomy markers are important in risk classification according to IGCCCG

• Post-Chemo: persistence marker poor prognostic value

44

AFP (Alpha-fetoprotein)

• Expressed by trophoblastic elements

• 50 - 70% of teratomas, yolk sac tumors

• Not produced by pure choriocarcinoma and pure seminoma

• T1/2: 3-5 days

• Normal <10 ng/mL

45

Falsely raised AFP level

• Tobacco smoking (AFP increases by about 10%) (Bartels 1993, Bernstein 1989, Cuckle 1990,

Thomsen 1983, Spencer 1993) • Binge-drinking of alcohol or long-term alcoholism• Non-germ cell malignancies (hepatocellular carcinoma a

nd other gastrointestinal malignancies)• Benign hepatic conditions (hepatitis, Cirrhosis)• Inflammatory bowel disease • Ataxia Telangiectasia• Wiscott-Aldrich syndrome (eczema-thrombocytopenia-i

mmunodeficiency syndrome)• Wilson's Disease

46

β-hCG

• Expressed by syncytiotrophoblastic elements

• Choriocarcinomas (100%), teratomas (40%) and seminomas (10%)

• T1/2: 24-36h

• Beta-subunit measured

• Normal < 5 mIU/mL

47

Falsely raised β-hCG level

• Marijuana use

• Human anti-mouse antibodies (HAMA) or heterophilic antibodies eg in IgA deficient individuals

• Duodenal ulcers

• Cirrhosis of the liver

• Inflammatory bowel disease

48

Imaging• Supracalvicular LN: physical examination• CXR:

– Routine thorax examination– AP + lat CXR as the only investigation in CT -ve seminoma (EAU GL)

• CT thorax: – best way to assess thorax and mediastinal LN– Mandatory in all pt with NSGCT & Seminoa with +ve Abd CT scan– Recommend in NSGCT because 10% with small subpleural LN not visible in CXR– High SV but low SP

• Retroperitoneal + mediastinal LN : CT– Sensitivity: 70%– SV & NPV increase with 3mm threshold to define metastatic node in landing zones– Rate of understaging : 30%– New generation CT does not improve SV

• MRI: – Similar result as CT in detection of retroperitoneal LN– Helpful when CT or USG inconclusive/ contraindicated

• PET scan: – not enough evidence in staging– For FU pt with seminoa with any residual mass at least 4 weeks after Chemo (to decide on

WW vs active treatment) • CT brain or spine, bone scan or liver USG: in case of suspected metastasis• CT or MRI brain in NSGCT with widespread lung metastasis

49

50

51

52

53

54

Stage I

• 80% of seminoma, 55% of NSGCT

• 5% NSGCT will be in Stage IS

• If RPLND was performed in all stage IS pt nearly all patient will have pathological stage II disease (pN+)

55

Stage IA

• Primary tumor limited to testis and epididymis (T1)

• No evidence of microscopic vascular or lymphatic invasion by tumor cell on microscopy

• No sign of metastases on clinical exam or imaging

• Post-orchidectomy serum tumor marker level within normal limits

• Marker should be assess until normalization

56

Stage IB

• More locally invasive primary tumor (T2-4)

• Not sign of metastastic disease

57

Stage IS

• Persistently elevated (usually increasing) serum tumor marker level after orchidectomy (S1-3)

• Evidence of subclinical metastatic disease (or possibly second GCT in remaining testis)

• If serum marker are declining in expected ½ life FU until normalization

58

1997 IGCCCG

• A prognostic factor-based staging system for metastatic Ca Testis base on clinical independent adverse factors

• Categories pt into : good, intermediate, poor prognosis

• NO Poor prognostic group in Seminoma• Factors used:

– Primary Histology– Location of primary tumor– Location of metastases– Pre-chemotherapy marker levels in serum

59

60

61

seminoma Non-seminomatous germ cell tumour

good intermediate Good Intermediate Poor

5 yr PFS 82% 67% 89% 75% 41%

5 yr survival 86% 72% 92% 80% 48%

62

63

Prognostic risk factors

• Stage I Seminoma: predictor for relapse– Tumor size > 4cm– Invasion of rete testis

• Stage I NSGCT: – Vascular invasion of primary tumor in blood or

lymphatic vessels (occult metastases) – Proliferation rate (by MIB-1 immunostaining) >70%– embryonal carcinoma > 50% (predict vascular

invasion)

64

65

Fertility associated issue

• Sperm abnormality are common in Ca testis• Chemotherapy and RT impair fertility• Pre-treatment fertility assessment:

– Testosterone– LH & FSH level– Semen analysis & cryopreservation should be offered

• Cryopreservation should be done before or after orchidectomy , and before chemotherapy

• Life long testosterone supplement in case of bilateral orchidectomy & low testosterone after txn of Tin

66

Testosterone replacement & contraception

• Testosterone replacement should be offer after bilateral orchidectomy to maintain sexual fxn and avoid late toxicity from hypogonadism

• After unilateral orchidectomy: – Tesosterone replacement depends on

testosterone level and clinical symptom

• Contraception should be suggest during and 1 yr after Chemo or RT

67

Txn: Stage I (T1-4 N0M0) seminoma

• 80% seminoma present as stage I• Cure rate approach 100%• 15-20% retroperitoneal met• 5% present with distant metastasis• 15-20% have subclinical retroperitoneal metastasis &

will relapse after orchidectomy• Risk of relapse raised to 30% if both risk factor present• Options after orchidectomy included:

1. Surveillance2. Adjuvant chemotherapy3. Adjuvant RT– (RPLND)

• A risk- adapted approached is recommended

68

Surveillance: Stage I seminoma• Risk of relapse: 15-20% (12%) in 5 yr • TF: Up to 88% can be txn with orchidectomy alone• Consider in patient without risk factors• Most common relapse site: infra-diaphragmatic / high iliac LN (97%)• Surveillance protocol : Princess Margret Hospital (Toronto)

– CT : 0-3 yr (Q4m), 4-6yr (Q6m), 7-10yr (Yearly) – Marker: each visit– CXR: alt visit

• Txn of relapse under surveillance: – 70% of relapse can be txn with RT alone (low vol disease)– 20% relapse after RT Then will salvage chemo

• CSS: 97-100%, 5yr DFS > 90% in Spanish GCCCG with this risk adapted approach

• Adv: No side effect of RT or chemo• Drawback:

– Need for more intensive FU (imaging for at least 5 yr) – Greater psychological burden– Small but significant risk of relapse after 5 yr support for long term surveillance

69

Chemotherapy: Stage I seminoma• MRC TE 19 trial : joint MRC + EORTC 1 cycle of carboplatin (AUC7) vs RT

(Lancet 2005, Oliver) – LN relapse: Retroperitoneal (Chemo) , pelvic (RT)– No significant difference in after 4 yr :

• Recurrence rate• Time to recurrence• Survival

• Thus adj carboplatin is an alternative to RT or surveillance in Stage I seminoma

• Adv over RT – Ease of administration– Shorter time to deliver adj treatment– Reduction of contralateral testis tumor – Less lethargic and less likely to take time off work when compared with RT (Lanc

et 2005, Oliver)• Disadv:

– Myelotoxicity & gonadotoxicity• 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)

70

Radiotherapy: Stage I seminoma• Seminoma are extremely radiosensitive• Site:

– Para-aortic (PA) field or para-aortic + ipsilateral iliac node hockey stick field (Dog-leg)– Upper edge of T11 to lower edge of L5– Lateral field margin: renal hilum – Medial field margin: processus transversus of L spine

• Dose: 20-24 Gy (2Gy x 5/week for 2 week)• Reduce relapse rate to only 1-3% (same as chemo)• Recurrence: outside irradiated field (supradiaphragmatic LN or lung) or left renal

hilum• PA irradiation of supra-diaphragmatic LN not recommended• Extend: MRC TE 10 trial [Fossa JCO 1999]

– Standard : RT to PA for Stage I (T1-3) with undisturbed LN drainage– Reduce acute toxicity & improve sperm count in 18m vs traditional dog-leg field– However higher relapse rate in iliac LN: 2% in right side

• Dosage : MRC TE 18 [Fossa Eur J Cancer 2001]– Equivalence recurrent rate with 20Gy vs 30Gy– Side effect:

• Severe RT long-term toxicity: <2%• GI: 5% GU : 60%

• Risk of RT: – Radiation scatter reduce fertility (need shielding of contralateral testis) – RT-induced secondary non-germ cell malignancy (Ca stomach , testis)– Moderate long term GI side effect

71

RPLND

• Not recommended for stage I seminoma

• Prospective non- randomised study: [Warszawski Scan J Urol Nephrol 1997]– RT vs RPLND, stage I seminoma– Result: trend towards higher incidence of

retroperitoneal relapses (9.5%) in RPLND

72

Risk adapted approach• 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%• Thus: Txn of high risk gp with Chemo /RT will reduce recurrence

from >30% to 3%

73

74

75

76

Txn: NSGCT Stage I• After orchidectomy: normalized marker with –ve CT• Risk of relapse:

– 20% subclinical metastasese and will relapse if surveillance alone after orchidectomy

– Of those relapse: 80% in 1st year– 50% with vascular infiltration will develop metastasis vs 15-30% without vascular

infiltration• Cure rate ~99% • Options of post orchidectomy NSGCT :

1. Surveillance2. Primary chemotherapy3. Retroperitoneal LND

• Again: risk adapted approached is recommended– Low risk (13%) surveillance– High risk (64%) Chemo or RPLND

• Cure rate of 100% is achieved

77

Surveillance: NSGCT Stage I• Indication: Low risk patient with no vascular invasion• Cumulative relapse rate: 20%• Time of relapse:

– 80% within 12m FU– 12% during 2nd year– 6% during 3rd

– 1% in 4th or 5th year, or even later• 60% relapse in retroperitoneum, 30% in lung, 10% marker only

– 35% have normal tumor marker level at relapse– 10% presented with large-volume recurrent disease

• FU schedule: – CT : 0, 3, 12 m

• Surveillance is still advocated because: – Improvement in clinical staging and Fu methods– Availability of effective salvage cisplatin-base chemo– Post-chemo surgery

• Thus, surveillance can be offered to pt with non-risk stratified clinical stage I NSGCT as long as they are compliant and well informed

• Txn of relapse on surveillance: 2 BEP• Overall cure rate: >98%

78

Primary Chemotherapy: NSGCT Stage I

• Indication: High risk patient with vascular invasion• 2 course of PEB (cisplatin , etoposide & bleomycin) as

primary treatment of high risk patient (> 50% risk of relapse)

• Reduce relapse rate to : 3% (from 50%) • Adv:

– Very little long-term toxicity– Do not affect fertility or sexual activity

• Disadv:– Beware of slow-growing retroperitoneal teratomas risk of late

chemoresistant cancer relapse– Cryopreservation before chemo is recommended

• Cost analysis: different results, but low frequency of Fu CT can reduce cost

79

RPLND: NSGCT Stage I• Indication: High risk patient with vascular invasion• RPLND:

– LN met (30%) PS2 (then should txn as Stage II)• Fu 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

• Risk of relapse after properly performed RPLND (<2%) mostly lung• Other risk: ejaculatory disturbance (6%)• FU: less frequent CT than surveillance• Lap RPLND: Not recommended as standard procedure• RPLND vs 1 course of PEB: AUO Trial AH 01/94 [Alber JCO08]

– PEB 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

80

Risk-adapted mx• No vascular invasion (50-70%):

– surveillance : 30 % relapse• Vascular invasion(30%):

– Surveillance: 50% relapse– 2 cycles of PEB

• Result : Swedish-Norwegian Testicular Cancer Project (SWENOTECA)– Median FU of 4.7 yr– Relapse rate: 3.2% with vascular invasion treated with only one adjuvant PEB

81

Mechanism of antegrade ejaculation• Antegrade ejaculation requires the coordination of three separate events:

– (1) closure of the bladder neck (sympathetic)– (2) seminal emission (sympathetic) – (3) ejaculation (antegrade propulsion of semen)

• Relaxation of external shpincter (parasymthetic) • Contraction of bulbocavernosus muscle (somatic via pudendal nerve)

• The sympathetic fibers : T12 to L3 thoracolumbar spinal cord. • In the midretroperitoneum after leaving the sympathetic trunk• Fibers converge toward the midline and form the hypogastric plexus near the takeof

f of the inferior mesenteric artery (IMA) just above the aortic bifurcation. • Hypogastric plexus pelvic plexus to innervate the seminal vesicles, vas deferens,

prostate, and bladder neck • Ejaculation is mediated by nerves originating at the sacral and lumbar spinal cord• Pudendal somatic innervation from S2 to S4 causes relaxation of the external urethral

sphincter and rhythmic contractions of the bulbourethral and perineal muscles • Paravertebral sympathetic ganglia, postganglionic sympathetic fibers T2-L4, and their

convergence at the hypogastric plexus are most crucial in the preservation of antegrade ejaculation

• The highest rates of preserved ejaculation are reported with “nerve-sparing” RPLND, in which the sympathetic chains, the postganglionic sympathetic fibers, and the hypogastric plexus are prospectively identified, meticulously dissected, and preserved

82

RPLND

• 3 main setting of RPLND• RPLND I:

– Prophylactic LND in NSGCT stage I (none shown on CT and RPLND)

– More common in US then Europe• RPLND II:

– Resection of (low-vol) retroperitoneal LN in NSGCT– When CT show LN or LN +ve during RPLND I

• RPLND III:– Resection of post-chemo mass or– Resection of post-RPLND I/II mass after primary txn o

f metastatic NSGCT/seminoma

83

RPLND

• Standard RPLND:– Excised all retroperitoneal lymphoid tissue

• Modified/ nerve-sparing RPLND: – Aim to excised lymphoid tissue most likely to have me

t disease– To spare the nerve control of ejaculation

• Note: RPLND of left is less extensive and does not cross to Rt because Rt Lt lymphatic spread is more common than Lt Rt

84

85

RPLND I (Rt side) • Rt renal hilum along medial border of Rt ur

eter till Rt common iliac artery along Rt CIA & aorta to the

Rt of origin of IMA medial border of Lt ureter Lt renal artery back to Rt renal hilum

Note: • To excised LN behind great ve

ssels (30% involved)• Lumber A&V has to be divided

86

RPLND I (Left side)• Jxn of IVC & Rt RV down Rt border of I

VC to level of origin of

IMA down Lt CIA to pt

where Lt ureter cross Up along medial b

order of Lt ureter to Lt RV

87

RPLND II/III• Bilateral• RPLND II

– Extend below IMA & above renal artery

• RPLND III– Complete bilateral + re

moval of any LN mass– May involve renal vess

els , mediastinum or resection of great vessels

88

Complications of RPLND

• Recurrence rate: 10%• Loss of ejaculation: 7%• Late complication : 5%

– Chylous ascites– Renal artery or SMA damage– Bowel damage/ colostomy/ colectomy– Bowel obstruction– Pulmonary embolism

– German testis study Gp 2003

89

90

91

92

CSIS : persistent elevated tumor markers

• Serum tumor marker should be FU according to expected half life until level fall into reference value

• If persistent elevated RPLND 87% will have LN +ve

• USG of contra lateral testis must be performed• Txn:

– 3 course of PEB & FU as CS1B (high risk) – RPLND

93

Metastatic Germ Cell tumor

• Treatment of metastatic GCT depends on: – Histology of primary tumor– Prognostic group by IGCCCG

94

Low-volume disease (Stage IIA/B)• Stage IIA Seminoma

– Standard: Radiation– Dose: 30 Gy (2Gy at 5 fraction per week) – Field: PA + ipsilateral Iliac (hockey-stick field)– Upper field: upper border of thoracic vertebra– Lower field: upper border of ipsilateral acetabulum– 6yr relapse free survival: 95%– OS: 100%

• Stage II B Seminoma: – RT: 36Gy

• Lateral border include metastatic LN with safety margin of 1-1.5cm• 6 yr relapse free survival : 90%• OS: 100%

– Chemo: (4x etoposide + cisplatin (EP) or 3x PEB in good prognosis) • CI of bleomycin (< 40 age, smoker, risk of pulmonary fibrosis) • More toxic in the short term• Similar level of disease control

95

Stage IIA/B seminoma: After RT or Chemo

Fu with CT at 3months• Residual mass after chemo /RT is uncommon• If no residual mass/ <3cm: Fu CT 6/12• If residual mass > 3cm: PET CT 4-6week after

chemo• PET CT +ve Biopsy:

– +ve: RPLND : reserve for globular mass but not for retroperitoneal fibrosis

– or slavage Chemo/ RT

96

97

Stage IIA/B NSGCT• Cure rate: 98%• Clinical IIA with –ve marker (1-2cm)

– Pure embryonal carcinoma: immediate chemo– Teratoma or mixed tumor: either

1. Surveillance : CT at 6 weeka) Shrinking lesion observedb) No change RPLNDc) 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

98

Stage IIA Marker +ve / IIB NSGCT

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 tumor marker teratoma /undifferentiated malignant tumor

RPLND• Elevated tumor marker salvage Chemo: PEI/VIP or TIP (Paclitaxel,

ifosfamide & cisplatin) • Primary RPLND & Chemo are comparable in terms of outcome• Cure rate : 98%

99

FU for NSGCT

• 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

100

101

Advanced metastatic disease (Stage IIC / III)

• Txn of seminoma and NSGCT is the same• Primary treatment: 3 or 4 cycle of PEB (depend

risk classification) • PEB proven superiority to PVB (cisplatin ,

vinblastin & bleomycin)• 3-day regimen as effective as 5-day , but asso

with increase toxicity

102

Good prognosis gp

• Standard treatment: – 3 cycles of PEB , or if bleomycin CI– 4 cycles of EP

• Given without dose reduction at 21-day intervals• 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

103

Intermediate prognosis gp

• 5 yr survival rate: 80%

• Standard treatment: – 4 cycles of PEB

• Other trial: – EORTC Genitourinary Tract Cancer Cooperati

ve Group trial with PEB vs PEB + paclitaxel

104

Poor risk Gp

• Only in NSGCT• 5yr progression-free survival: 50%• Standard treatment:

– 4 cycles of PEB– 4 cycles of PEI (cisplatin, etoposide, ifosfamide)

• same effect, more myelotoxic• Consider in pt CI to bleomycin (compromised P fxn)

• Pt with slow marker decline poorer prognosis• No recommendation on pt with KS < 50%,

extended liver or pulmonary infiltration

105

Restaging and further txn

• 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

106

Residual tumor resection

• Seminoma: – Residual mass should NOT be resected

irrespective of size – Fu PET + tumor marker

• Residual mass > 3cm: do PET• Residual mass < 3cm : optional

– Salvage therapy on progression (chemo , surgery , RT)

107

Residual tumor resection: Non-seminoma• After PEB induction chemo: RPLND will reveal

– 50% contain mature teratoma– 40% contain necrotic-fibrotic tissue– 10% residual mass contain cancer

• NO imaging to differentiate all three• Thus: Residual tumor resection is mandatory:

– Complete remission after chemo (no visible tumor) no need resection– Visible tumor mass but normal marker Surgical resection– Persistent retro-peritoneal disease Resection of all primary

metastatic site within 4-6 weeks of complete chemo (NS approach) • Extend of resection:

– If possible , all massess should be resected, because complete resection is more critical than recourse to post-op chemo

– Resection of contralateral pulmonary lesion is not mandatory if patho exam of lesion from first lung show complete necrosis

108

Consolidation chemo after 2nd surgery

• 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

109

Systemic salvage txn 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

110

111

• Salvage VeIP not superior to conventional dose cisplatin-base combination

• Use of >3 agents increase toxicity but not treatment outcome

• High dose chemo offered no advantage as first salvage treatment in good prognosis patient

• Other options: Paclitaxel & gemcitabine

112

Late relapse

• Definition: pt relapse >2yr after chemo for metastatic disease

• If feasible , should undergo immediate radical surgery for all lesion (undifferentiated GCT, mature teratoma or secondary non-germ cell cancer)

• Salvage chemo according to bx histology if lesions not completely resectable

• Secondary surgery if response to chemo• RT for unresectable , localized refractory

disease

113

Salvage surgery

• Residual tumor after salvage chemotherapy

• Resected 4-6weeks after marker normalization or plateau

• If maker progression: resection of residual tumor (desperation surgery)

• If complete resection : 25% long term survival may be achieved

114

Brain metastasis

• 10% advance Ca present with brain met• Long term survival 5yr

– Brain met at diagnosis (30%)– Brain met as recurrent disease (2-5%)

• Txn: – Chemotherapy – Consolidation RT (even in total response after

chemo) – Surgery in solitary metastasis

115

116

117

118

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

119

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

120

121

FU after curative treatment

• Most recurrence occur in first 2 years• Late relapse beyond 5 yr, thus yearly Fu for life

is advocated• After RPLND , recurrence in retroperitoneum is

rare, most relapse in chest• CT thorax has higher predictive value then CXR• Result of therapy dependent on bulk of disease,

thus intensive strategy to detect asymptomatic disease is justifiable

• There is risk of secondary malignancies after RT or Chemo

122

Recommended minimal FU schedule in: stage 1 seminoma

Year 1 Year 2 Year 3-4 Year 5-10

Physical Exam

3x 3x 2x/yr 1x/yr

Tumor markers

3x 3x 2x/yr 1x/yr

Chest XR 2x 2x 1x/yr 1x/yr

Abd + pel CT

2x 2x 1x/yr 1x/yr

123

Recommended minimal FU schedule in a surveillance policy: stage 1 non-seminoma

Year 1 Year 2 Year 3-5 Year 6-10

Physical Exam

4x 4x 2x/yr 1x/yr

Tumor markers

4x 4x 2x/yr 1x/yr

Chest XR 2x 2x

Abd + pel CT

2x (3 & 12 mo)

124

Recommended minimal FU schedule after RPLND/ adj chemo: stage 1 non-seminoma

Year 1 Year 2 Year 3-5 Year 6-10

Physical Exam

4x 4x 2x/yr 1x/yr

Tumor markers

4x 4x 2x/yr 1x/yr

Chest XR 2x 2x

Abd + pel CT

1x 1x

125

Recommended minimal FU schedule in advanced NSGCT & seminoma

Year 1 Year 2 Year 3-5 Thereafter

Physical Exam

4x 4x 2x/yr 1x/yr

Tumor markers

4x 4x 2x/yr 1x/yr

Chest XR 4x 4x 2x/yr 1x/yr

Abd + pel CT

2x 2x 1x/yr 1x/yr

Chest CT As indicated

Brain CT As indicated

126

127

Testicular Stromal Tumors

• 2-4% of adult testicular tumors• Only Leydig cell & Sertoli cell tumor are of clinical

relevance• Classification WHO 2004:

128

Leydig cell turmors

• Epidemiology: – 1% of adult, 3% of child testicular tumor– 30-60s in adult, similar incidence in every decade ;Children: 3-9

yr– 3% bilateral , found in Klinefelter syndrome– 10 % malignant

• Pathology: – Most common type of sex cord/ gonadal stromal tumor– Gross: solid, yellow to tan , hemorrhage/necrosis (30%) , well

outline & 5cm– Micro: polygonal cell, eosinophilic cytoplasm , Reinke crystals,

regular nucleus, solid arrangement & capillary strom– Cell: vimentin, inhibin, protein S-100, steroid hormones,

calretinin & focal cytokeratin

129

130

Leydig cell tumor: diagnosis• Presentation:

– Painless enlarged testis– USG incidental finding– Gynaecomastia (30%) – Bilateral 3%– Metastasis (10-20%) : risk factor (older age) – Must distinguished from multinodular tumor-like lesions of the

androgenital syndrome• Diagnosis:

– Tumor marker (AFP, hCG , LDH, PLAP) : always –ve– Hormone:

• High oestrogen & oestradiol• Low testosterone & increase LH & FSH

– USG of both testis: well-deifine, small , hypoechoic lesion with hypervascularisation (no different from GCT)

– CT chest & abdomen

131

Leydig cell tumor: Treatment & FU

• Highly recommend to performed organ-sparing orchiectomy in small intraparenchymal lesion

• If histological sign of malignancy orchidectomy + RPLND

• If no sign of malignancy after ordhidectomy FU CT (not need tumor marker)

• Metastatic disease: poor response to RT or chemo poor survival

132

Sertoli Cell Tumor

• Epidmiology: – < 1% of testicular tumor– Mean age: 45 yr, rare < 20– Pt with androgen insensitivity syndrome & Peutz- Jegher

syndrome

• Pathology: – Gross: well circumscribed, yellow , tan or white, 3.5cm– Micro: eosinophilic to pale with vacuolated cytoplasm, regular

nuclei with grooves– Tubular or solid arragment, cord-like or retiform pattern– Cell : vimentin, cytokeratin ,inhibin (40%) ,Protein S-100 (30%

133

134

Diagnosis

• Presentation: – Most are unilateral and unifocal– Bilateral 40% , multifocal (30%)– Metastatsis : 12% – Tumor marker always –ve– Hormonal disorder infrequent– Young man with large cell calcifying form : Carney’s complex,

Peutz-Jegher sydrome , endocrine disorder (40%)• Diagnosis:

– Tumor markers– Hormones– USG both testis: hypoechoic (cannto diff from GCT)

• Large tumor: brightly echogenic foci due to calcification– CT Chest & abdomen

135

Treatment

• highly recommended to proceed with an organ-sparing approach in small intraparenchymal testicular lesions until final histology is available

• Esp in pt with: gynaecomastia or hormonal disorders or typical imaging on ultrasound (calcifications, small circumscribed tumours)

• Tumor with histological sign of malignancy: – Orchidectomy + RPLND

• FU: CT • Metastatic disease: poor response to RT or

Chemo , poor survival

136

Granulosa cell tumor

• 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

137

Medication use in Ca Testis

• Cisplatin

• Etoposide

• Bleomycin

• Ifosfomide

• Vinblastin

138

139

140