# Presentation: 028828

## WILMS’ TUMORGERM CELL TUMORs

**Alan D. Friedman, M.D.**

## Wilms’ Tumor

**Presentation**
**	****mass/pain/hematuria/HTN**
**Associations**
**WAGR - WT1, 11p13**
**Hemi/BW, IGF2, 11p15**
**Inheritance**
**12%  hereditary**
**poor  penetrance**

## Wilms’ Tumor

**Pathology**
**H&E diagnostic**
**FH vs. UH**
**Nephrogenic rests**** - PLNR,  ILNR **
**Nephroblastomatosis**** - HPLN, DHPLN (rx)**
- Hyperplastic are T2 bright vs sclerotic
**Staging**
**I**** -  renal/excised, 37%, 90% RFS**
**II**** -  beyond capsule/excised- 20%, 90% RFS**
**III**** - resid. abd., 20%, 85% RFS**
**IV**** - Distant, 23%, 66% RFS**
**II**** -IV  UH, 66% RFS**

## Wilms’ Tumor

**Metastases**
**nodes, liver, lung**
**Work-up**
**CT abd/chest, CXR, U/S with IVC Doppler, **
**U/A, catechols**
**Surgical approach**
**Excisional Bx after examine other kidney**
**Preserve parenchyma if bilat.**
**if inoperable try again post 6 wks chemo**

## Wilms’ Tumor

**NWTS I, II**
**VCR/ActD better than VCR or ActD;**
**no XRT for St. I, II**
**NWTS III**
**St. I**** -****	****VA, 10 wk = 6m.**
**St. II**** -****	****VA = VA, Adria for 15m, +/- XRT**
**St. III**** -****	****Adria helps; 1000 cGy = 2000 cGy**
**St. IV**** -****	****trend towards CTX benefit**
**UH**** -****	****CTX helps**

## Wilms’ Tumor

**NWTS IV**
**St. I**** -****	****VA = VpiA, 6m.**
**St. II**** -****	****VA = VpiA, 6m = 15m.**
**St. III**** -****	****VA/Adr = VpiA/Adr; 6m = 15m.**
**St. IV, UH**** - CTX benefits UH.**

## Wilms’ Tumor

**NWTS V (POG 9440)**
**St. I**** -****	****VpiA, 18 wks.  Including 0-550 gm.**
**St. II**** -****	****VpiA, 18 wks**
**St. III**** -****	****VpiA/Adr, 1080 cGy, 6 mos**
**St. IV, UH**** - VpiA/Adr, VP16, CTX/ ****	****	****	****       ****	****    MESNA, 1080 cGy**
**Pre-op**** -****	**** VpiA**

## AREN0532

- St I <2 yr, <550gm - Nephrectomy
- St I, II no LOH - EE4A (VCR, ActD)
- St I, II, LOH 1p/16q - DD4A (VCR, ActD, Adria)
- St III no LOH - DD4A, abd XRT
- AREN0533
- St IV (lung), no LOH, RER - DD4A, abd XRT if local III
- St III/IV LOH or IV not RER or non-lung - VAA, C/E, XRT
- AREN03B2 - biology study

## AREN0321 
FA St I-III, DA St I - DD4A (VCR/ActD/Adria)
DA StII-III, DA/FA St IV, rhabdoid, CCSK IV - UH1
(CTX/carbo/VP16, VCR/Adria/CTX)
CCSK I-III - Reg I (CTX/VP16, VCR/Adria/CTX)
DA St IV measurable disease or rhabdoid III-IV - 
(ironotecan/VCR window)
Renal cell carcinoma - surgery only if complete resection

- FA St I-III, DA St I - DD4A (VCR/ActD/Adria)
- DA StII-III, DA/FA St IV, rhabdoid, CCSK IV - UH1
- (CTX/carbo/VP16, VCR/Adria/CTX)
- CCSK I-III - Reg I (CTX/VP16, VCR/Adria/CTX)
- DA St IV measurable disease or rhabdoid III-IV -
- (ironotecan/VCR window)
- Renal cell carcinoma - surgery only if complete resection

## Wilms’ Tumor

**Relapse (POG 9444)**
**Low vs. High Risk**
**Low**** - CTX/VP16/VpiA/Adr, surg., ****	****   XRT**
**High**** - CTX/VP16, CBCDA/VP16, ****	****    surg., XRT, more chemo **
** ****	****	****    ****+/- ABMT.**

## Wilms Tumor

- St  I, FH
- St II, FH
- St III, FH with
- no 1p16q LOH

- St III, FH, LOH
- St IV, FH

- UH
-  rhabdoid
- CCSK

- EE4A - Vcr, ActD (VA)
- DD4A - VA, Adria
- M - VAAdria, CTX/Etop (CE)
- I - VadriaC, CE; UH-1 - adds Carbo to I

- bilateral

- inoperable 1o/+IVC

- DD-4A or UH-1 per
- stage and grade
- consider early RT
- resect week 5+

- St I/II FH: EE-4A
- DD-4A if not respond
- St III/IV FH: DD-4A
- UH: Reg. UH-1
- operate week 5+

- relapse

- initial tx EE-4A

- NWTSG 4942
- Stratum B
- (CyE, VAdrC)

- initial tx DD-4A, I, M, UH-1

- unilateral, resected 1o

- radiation therapy

- St I/II FH - none
- St I/II UH, III - 1080 cGy post-op
-  St III diffuse anapl. 1980 cGy
- St IV - add whole liver or lung
- <18 mos try to avoid lung RT

- (consider surgery of 1o)

-    nephroblastomatosis

-   DHPLN, consider EE-4A;
- others follow MRI, bx if grows

- Auto BMT

- AREN0532
- no tx, EE4A,or DD4A

- AREN0533
- DD4A or M

- AREN0321
- DD4A, I, UH-1

- AREN0321
- surgery, indiv.

- Renal Ca

- Oxaloplatin/5FU

- Cetuximab

- 2nd relapse

- 2nd relapse

- Relapse after no tx give DD4A
-  perAREN0532)

**Must enroll also on Biology Study, AREN03B2**

## Germ Cell Tumors

**3% childhood cancer, peaks at 2 and 20 yrs**
**Often midline; only 5% Sertoli/granulosa/Leydig cell**
**i(12p)/aneuploidy vs. del(6q or 1p) in infants**

**sperm,**
**ovum**

**placenta**

**gastrula**

**yolk sac**

**chorion**

**embryo**

**seminoma,**
**germinoma**

**choriocarcinoma**

**endodermal sinus tumor**

**teratoma**

**embryonal carcinoma**

## Endodermal Sinus
44%, High AFP, sacrum/testes of infants, 
ovary/testes in adolescents
Choriocarcinoma
4%, High HCG which can give signs/sympt.,
is a gestational form
Germinoma (Seminoma, Dysgerminoma)
15%, ovary, undesc. testes, dysgenetic gonads, 
CNS, very XRT sensitive.

**44%, High AFP, sacrum/testes of infants, **
**ovary/testes in adolescents**
**Choriocarcinoma**
**4%, High ********HCG which can give signs/sympt.,**
**is a gestational form**
**Germinoma (Seminoma, Dysgerminoma)**
**15%, ovary, undesc. testes, dysgenetic gonads, **
**CNS, very XRT sensitive.**

- Germ Cell Tumors

## Embryonal Carcinoma
10%, testes, +/- mild AFP

Teratoma
	24%, 3 germ layers, malignant part often neural. 65%benign, 5% immature, 30% malignant.  neonates-sacral;
serosal implants often mature/neural

**10%, testes, +/- mild AFP**
**Teratoma**
**	****24%, 3 germ layers, malignant part often neural. 65%benign, 5% immature, 30% malignant.  neonates-sacral;**
**serosal implants often mature/neural**

- Germ Cell Tumors

## STAGING
St I - Completely resected
St II - Microscopic Residual
St III- Lymph nodes + or gross residual 
St IV - Distant mets (lung, liver, bone, brain)
POOR PROGNOSTIC FACTORS
Mediastinal primary, AFP>10,000 - peds
liver/bone/brain mets/high HCG or LDH
Slowly falling markers or rapid relapse

**St I ****- Completely resected**
**St II ****- Microscopic Residual**
**St III****- Lymph nodes + or gross residual **
**St IV ****- Distant mets (lung, liver, bone, brain)**
**POOR PROGNOSTIC FACTORS**
**Mediastinal primary, AFP>10,000 - peds**
**liver/bone/brain mets/high ********HCG or LDH**
**Slowly falling markers or rapid relapse**

- Germ Cell Tumors

## Surgery
gross resection if feasible
ideal to remove all residual masses > 1 cm, and be aware of growing teratoma syndrome
testes - inguinal incision with high ligation of spermatic cord - remove even if burned out; Retroperitoneal node biopsy if 2-4 cm on CT (to confirm St III) - debated, can follow
sacral - include coccyx in resection
ovary - surgery depends on exent/frozen; remove omentum if nodules present

**gross resection if feasible**
**ideal to remove all residual masses > 1 cm, and be aware of growing teratoma syndrome**
**testes - inguinal incision with high ligation of spermatic cord - remove even if burned out; Retroperitoneal node biopsy if 2-4 cm on CT (to confirm St III) - debated, can follow**
**sacral - include coccyx in resection**
**ovary - surgery depends on exent/frozen; remove omentum if nodules present**

- Germ Cell Tumors

## Radiotherapy
Seminoma very sensitive, 1st line in adults and
CNS lesions, otherwise consider at relapse
Chemotherapy
VAC: 30-50% RFS
PEB:
Cisplatin 20 mg/M2/day x 5
Etoposide 100 mg/M2/day x 5
Bleomycin 15 Units/M2/day x 1 (qwk vs q3wk)

**Seminoma very sensitive, 1st line in adults and**
**CNS lesions, otherwise consider at relapse**
**Chemotherapy**
**VAC: 30-50% RFS**
**PEB:**
**Cisplatin 20 mg/M2/day x 5**
**Etoposide 100 mg/M2/day x 5**
**Bleomycin 15 Units/M2/day x 1 (qwk vs q3wk)**

- Germ Cell Tumors

## POG 9048/49

St. I/II test. < 10 yr; imm. teratoma had surgery alone 82% avoided chemo, 11/11 salvaged  

I/II ovarian; I/II test > 10 yr intermediate risk
EFS 94%

St. III/IV gonadal; I-IV other are high risk,
 EFS 85%

for high-risk, did 200 vs. 100 mg/M2 cisplatin, 
III/IV extragonadal 84%vs 72%, oto+renal toxic

**St. I/II test. < 10 yr; imm. teratoma had surgery alone 82% avoided chemo, 11/11 salvaged  **
**I/II ovarian; I/II test > 10 yr intermediate risk**
**EFS 94%**
**St. III/IV gonadal; I-IV other are high risk,**
** ****EFS 85%**
**for high-risk, did 200 vs. 100 mg/M2 cisplatin, **
**III/IV extragonadal 84%vs 72%, oto+renal toxic**

- Germ Cell Tumors

## CCG AGCT0132-LOW/INT RISK
Stage I (testes or ovary), no therapy
vascular invasion 48% recur, vs 22% if none
II-IV gonadal, II extragonadal: PEB x 3, second
look, repeat PEB x 3 if positive. 
PEB over 3 days, bleo q3 weeks
CCG AGCT01P1-HIGH RISK (closed)
III/IV extragonadal
PEB with increasing cytoxan 
4 cycles, 2nd look, 2 more cycles if positive

**Stage I (testes or ovary), no therapy**
**vascular invasion 48% recur, vs 22% if none**
**II-IV gonadal, II extragonadal: PEB x 3, second**
**look, repeat PEB x 3 if positive. **
**PEB over 3 days, bleo q3 weeks**
**CCG AGCT01P1-HIGH RISK (closed)**
**III/IV extragonadal**
**PEB with increasing cytoxan **
**4 cycles, 2nd look, 2 more cycles if positive**

- Germ Cell Tumors

## SALVAGE THERAPY
VeIP (velban, ifosfamide, cisplatin)
VIP (VP16, ifosfamide, cisplatin)
salvage 25-30% of patients, but high risk patients (mediastinal, platinum refractory, progressive disease on VeIP..., HCG>1,000) do worse

High dose chemotherapy with stem cell rescue
	Einhorn - carboplatin/etoposide x 2:
	63% DFS (116/184)
	Good risk 70%, Inter. 48%, Poor - 32%
carboplatin/etoposide/cytoxan 6/33 poor risk.   

CCG AGCT0521 paclitaxel, ifosfamide, carboplatin 
			         prior to HSC

**VeIP (velban, ifosfamide, cisplatin)**
**VIP (VP16, ifosfamide, cisplatin)**
**salvage 25-30% of patients, but high risk patients (mediastinal, platinum refractory, progressive disease on VeIP..., HCG>1,000) do worse**
**High dose chemotherapy with stem cell rescue**
**	****Einhorn - carboplatin/etoposide x 2:**
**	****63% DFS (116/184)**
**	****Good risk 70%, Inter. 48%, Poor - 32%**
**carboplatin/etoposide/cytoxan 6/33 poor risk.   **
**CCG AGCT0521 ****paclitaxel, ifosfamide, carboplatin **
**	****	****	****         ****prior to HSC**

- Germ Cell Tumors

## Germ Cell Tumors (non-CNS)

- yolk sac tumor, choriocarcinoma, embryonal, malignant teratoma

- germinoma

- Stage I-IV testes <15 yr
- Stage I-III ovarian ≤21
- Stage I-II extragonadal ≤21

- Stage III-IV extragonadal ≤21

- AGCT0132
- St I gonad - no initial tx
- others - PEB x 3
- +3 cycles if path. PR

- PEB x 4
-  +2 cycles if path. PR
- (high-risk study closed)

- PEB x 3-4
- or XRT if older

- relapse post-chemotherapy

- VeIP reinduction x1-2 (Velban, ifosfamide, cisplatin)
- then tandem auto-BMT (etoposide, carboplatin)

- testes ≥ 15

- St I - no tx
- II-IV: PEB with
- weekly bleo

- Stage IV ovarian ≤21

- PEB x 4
- +2 cycles if
- path. PR

- St I-III <1 - consider follow post-surgery, chemo if progress

- _surgery_
- remove 1o initially or at 2nd look
- remove residual mets post.-chemo

- (or AGCT0521- paclitaxel/ifosfamide/carbo x 2,
- then tandem auto-BMT)