Slide 1

Non-seminoma germ cell tumorsPresented by:Sarah M. Al MuhaisenR5 URO residentObjectivesSubtypes.Markers.

Types of treatment:ChemoSurveillance.RPLND.

Recurrence ? 2nd line of therapy !

TypesEmbryonal carcinoma: 25%Yolk sac.Choriocarcinoma.Teratoma.

Mixed 60 % !EmbryonalHighly malignant Aggressive Mets.Least differentiated primitive epithelial cells.Areas of necrosis or hemorrhage and poorly defined capsule.

AFP & HCG.

ChoriocarcinomaMay present w/ distant mets, despite small intratesticular primary !

When mets occur vascular invasion.Commenest Lung & brain catastrophinc hemorrhage with chemo

often presents w/ palpable nodule: due to hemorrhagechorio is always hemorrhagic, but hemorrhage is not always chorio !

Chorio !

Cont. ChoriocarcinomaGross central hemorrhage + viable grayish white tumour at periphery

Microscopic 2 distinct and appropriately oriented cell types: syncytiotrophoblasts and cytotrophoblasts.

HCG

Yolk sac (Endodermal sinus)Common in kids.Adults Mixed.Embryoid bodies (Schiller-Duval) resembles 1-2 weeks embryos, < 1 mm in diameter, consist of a cavity surrounded by loose mesenchyma containing syncytiotrophoblasts and cytotrophoblasts.

AFP ONLY !

Syncitortophoblast, areas of hemorrhage & necrosis

Teratoma> 1 germ cell layer in all stages of maturation and differentiation.

Mature: benign structures from normal ectoderm, mesoderm, and endoderm most common testis tumour in kids !

Immature: consist of undifferentiated primitive tissue from each of the 3 cell layers.

Mostly N. markes or mild HCG.

Adults mixed.

Resistant to chemo !

Growing teratoma syndrome !

Somatic malignant transformationRhabdomyosarcomaAdenocarcinomaPNET

What is the most common testis tumor of infants and children?

Mature teratoma (43%)RMS (26%)epidermoid cyst (10%)yolk sac (8%)germ cell tumors (6%)

Mixed tumors60%The most frequent combination is embryonal carcinoma, yolk sac, teratoma, and syncytiotrophoblasts.

Metastatic deposits associated with teratomas usually contain embryonal carcinoma (80%).

From dependence to independence ..

Be PROACTIVEMarkers2 main classes:(1) Oncofetal substances associated with embryonic development (AFP and -hCG).(2) Cellular enzymes, such as LDH and placental like alkaline phosphatase (PLAP).

Why ?Diagnosis, staging, monitoring of treatment response, prognosis & recurrence of GCT.

AFP dominant serum protein of the early embryo,. HCG is secreted by the placenta.

Both fall to barely detectable levels soon after birth 1 year.

Trophoblastic AFP. Syncytiotrophoblastic cells HCG.

-FetoproteinT1/2 5-7 days.Embryonal, yolk sac & teratocarcinoma.

Causes of AFP:Malignancy: testis, liver, pancreas, stomach.Normal pregnancy.Benign liver disease: drugs (chemo, anaesthetics, antiepileptics), viral hepatitis, EtOH abuse.Ataxia telangectasia.Tyrosinemia.

HCGT1/2 24-36 hours.Composed of and polypeptide chains.Pituitary H. (LH, FSH, TSH) possess subunits.

HCG (False +ve) castration or hypogonadism.Testosterone / 72 hrs. Normal !

in choriocarcinoma, embryonal & 15% of seminoma.

Causes of HCGPregnancy.Malignancy: testis, liver, pancreas, stomach, lung, breast, kidney, bladder.Marijuana smokers.Hypogonadism.

LDH5 isoenzymes mainly type I.

Monitoring.

Bulk.15 % of advanced NSGCT Normal markers !!!

markers after orchidectomy systemic diseseas chemo ! (R/O other causese of ).

Markers after Rx. (all types) if not, incomplete response

After orchidectomy repeat within 4 x T ! After RAD or chemo ??Recurrence Chemical >> clinical detection !Begin with the end in mind .. Develop a personal centered principle missions .. & extend the mission to a GOAL !

Serum MarkersS0: LDH 6 cm.% of MIB staining.Pt. age.

Absence of RF Mets < 20 % !CS I Surveillance. RPLND. 1ry chemotherapy.Surveillance70-80% of NSGCT R cured with orchidectomy - ve RF !Survey > 5 yrs risk of 2ry malignany ? Radiation ! 90 % will occur in the 1st 2 yrs.1-5 % in 5 yrs.If Relapse Intensive therapy > therapy at Dx. Def. Relapse: markers.Retroperitoneal bulky mass > 3 cm. (75 %)Distant mets.

RPLNDThe most common site Landing zone.20% Teratoma, resistant to chemo.Spare 75% of adjuvant chemo unless N2-3 or +ve RF.Obviate the need of routine surveillance CT.Major Sx., needs an experienced surgeon but long term morbidity.

W ve RF RPLND +/- adjuvant chemo 100 % long term cancer specific survival.(Donohue et al, 1993; Hermans et al, 2000; Stephenson et al, 2005b).Bilateral template nerve sparingRec. < 2 %.Antegrade ejaculation > 90 %.

(Jewett, 1990; Donohue et al, 1998; Stephenson et al, 2005b; Eggener et al, 2007b; Subramanian et al, 2010)

RPLND Bulky L.N (pN2-3) > 2 cm Adjuvant chemo.

BEPx 2 or EP x 2 Rec 49 % 2 % but no difference in survival. (Williams et al. 1987b)1ry chemotherapyAfter orchidectomy to relapse.

Disadvantages:Retroperitoneal mass could be teratoma radioresistant!Long term surveillance CT.Long term CVS toxicity & a risk for 2ry malignancy.Less amenable for salvage therapy if Rec. occur .

CS I S markers & -ve imaging post orchidectomy.Chemo BEP x 4cancer spicific survival is 90 %

(Culine et al, 1996; International Germ Cell Consensus Classification, 1997)

Treatment selection for CS I risk surveillance.

risk RPLND if markers R ve.Chemo Surveillance least !

Think win/win .. In cases win/win can not be achieved, accept the fact that no deal could be the best alternative !

CS II A & II BRPLND +/- adjuvant chemotherapy.v.sInduction chemotherapy +/- post chemo RPLND.

Both R accepted option w survival > 95 % The arguments in favor of RPLND13-35 % pts. Have ve L.N avoid chemo 30 % R teratoma ?Long term sp. Survival +/- RPLND is 98-100 %.(Pizzocaro, 1987; Donohue et al, 1995; Weissbach et al, 2000; Stephenson et al, 2007)

Avoid chemo in 50 %Preseve ejaculation in 90 %

Disadvantage needs experience surgeon, 50% will req. further chemo, 15 % will have persistent disease The arguments in favor of induction chemotherapy60-80 % complete response with PCS.Cancer sp. Survival is 98-100 %.

(Peckham and Hendry, 1985; Logothetis et al, 1987; Socinski et al, 1988; Ondrus et al, 1992; Horwich et al, 1994; Lerner et al, 1995; Culine et al, 1997; Debono et al, 1997; Weissbach et al, 2000; Stephenson et al, 2007).

Long term toxicity & risk of relapse !The consensus is that CS II A & B with markers (AFP & HCG) + bulky L.N > 3 cm chemo ! Otherwise RPLND ! Seek 1st to understand, then to be understood .. Listening is not a simple echoing, its putting yourself in others prospective !

CS II C & IIICHEMO !BEP x 4Chemo for good riskBEP x 3 & EP x 4 in good risk by IGCCCG & 5 yrs overall survival is 91-94 %.(International Germ Cell Consensus Classification, 1997; van Dijk et al, 2006).

All randomized trial comparing carboplatin to cisplatin cisplatin was superior in outcomes.(Bajorin et al, 1993; Bokemeyer et al, 1996b, 2004; Horwich et al, 1997, 2000).

Bleomycin can safely be omitted in good risk gp.Chemo for intermediate & poor risk gp.BEP x 4 5-year survival rate is 79% and 48%, Respectively !(International Germ Cell Consensus Classification, 1997).

VIP hematological & GU toxicity.VIP x 4 substitute BEP x 4 in : Compromised pulmonary function.Who will undergo chest Sx. To remove residual mass (PCS).

Synergize ..Through mutual trust & understanding, you may solve conflicts & find a better solution

Postchemotherapy Residual Masses in NSGCTClassifications:(1) Complete response (CR), normal markers & resolution of radiographic disease (residual masses 1 cm).(2) Normal markers with persistent radiographic tumor(partial remission).(3) Partial remissionmarkers +ve. (4) Disease progression.

3 & 4 2nd line (salvage) chemo !Residual mass > 1 cm PCS.What about 1 & 2 ?Observation vs. PCS if residual mass > 3 cm.

Residual mass H/P:Necrosis 40% Relapse after PCS is 10 % only !Teratoma 45%.Viable GCT 15%.

Long term survival is 75-90 % in PCS for residual teratoma.(Toner et al, 1990; Hartmann et al, 1997b; Sonneveldet al, 1998; Stenning et al, 1998; Carver et al, 2007c).

If teratoma Malignant transformation (Rhabdomyosarcoma) PCS ONLY, chemoresistant !

Size of tumor reduction w chemo predicts wether its a tumor or teratoma.2 cm or smaller 6 % GCT vs, 30% teratoma !

NO ROLE FOR FDG-PET in assessing NSGCT post chemo residual mass !

RPLND should always be done B4 chemo !If RPLND necrosis, Post chemo mass can be followed with 5 yrs. survival of 75% .

(Fox 7 Collegues 1993)Sharpen the saw, take a time out through renewal of physical, mental, social, emotional dimensions .. & maintain balance between them.

Relapsing NSGCTChemo naive.Early relapse (< 2 yrs.)Late relapse.Chemo naiveInduction chemo.CS I, II A & B , mass < 3 cm & normal markers Chemo or RPLND (if teratoma was present in the 1ry tumor)

Post chemo (Early relapse < 2 yrs.)Poor prognosis Unable to achieve complete response (within 6 months).

Overall survival 38 %. 3 yrs progression free survival with the 2nd line chemo 51 %.

(International Prognostic Factors Study Group et al, 2010).TIP x 4 or VIPx 4 No randomized trial comparing their efficacy, so both R standard.

HDCT ( dose chemo Rx.) Failed to improve survival.

Post chemo residual massMarkers R ve post 2nd line chemo Surgery !

H/P :Viable GCT 53 % Necrosis 26 %.Teratoma 21 %.

5 yrs survival is 44-61 % (Fox et al, 1993; Hartmannet al, 1997b; Donohue et al, 1998; Stenning et al, 1998)

Viable GCT poor prognosis which wont be changed with further chemo Desperation SurgeryReceived 2 lines of chemo.Markers R still +ve.Single/ resectable retroperitoneal mass.

single-institution case series, 47-60% normal markers postoperatively and long-term survival is 33-57% +/- post op chemo.

(Wood et al, 1992; Murphy et al, 1993; Eastham et al, 1994; Albers et al, 2000; Beck et al, 2005).

Postchemotherapy NSGCT RelapseLate> 2 yrs.3 % of all NSGCT.Bx. (if markers ve).Viable malignancy 60-90% ! (Most common Yolk sac).Teratoma 20 %Malignant transformation (adenocarcinoma).

Risk factors for late relapse ?Hx. Of prior relapse.Presence of Teratoma in PCS.Failure to control the retroperitoneal disease.

Rearely responsive to chemo Sx. !

Unresectable TIP !(Kondagunta et al, 2005).