genito-urinary rhabdomyosarcomas - ipso · genito-urinary rhabdomyosarcomas yves heloury. pediatric...

Genito-urinary rhabdomyosarcomas

Yves Heloury

Pediatric oncology: systematic approach

• Know the prognostic factors and risk stratification of RMS

• Understand the principles of treatment of RMS

• Understand the place of surgery and radiotherapy for the

local control of GU RMS

• Identify the long term sequelae

Objectives

Pediatric oncology: systematic approach

• RMS: general considerations

• Genito-urinary RMS• paratesticular RMS

• Bladder/Prostate RMS

• vaginal RMS

• uterine RMS

• Not discussed• rare localizations

• recurrences

• metastatic RMS

Presentation

• Progress achieved by the cooperatives studies

– IRSG and COG-STS

– ESSG (SIOP MMT, CWS, ICG)

• Goal: tailoring the treatment to risks factors to maintain or improve survival with a decrease of morbidity

RMS

• Definition

– Soft tissue malignant tumor arising from immature mesenchymal cells commited to skeletal muscle lineage

– 40% of soft tissue sarcomas in children

RMS

• Predisposing conditions

– Li-Fraumeni syndrome (constitutional p53 mutations)

– Neurofibromatosis, type 1

– Beckwith- Weidemann syndrome

– Costello syndrome

– Ionizing radiation

RMS

• Before the biopsy or primary resection: imaging studies of the mass

(US for paratesticular, MRI for BP and vagina)

• After the diagnostic of RMS: extension of the disease• Chest x-ray

• CT of chest and abdomen (LN)

• Bone scan

• Bilateral bone marrow aspirates and biopsies

Place of PET scan to be defined

RMS- Disease evaluation

• Age

– Children aged 1 to 9

years have the best

prognosis

RMS- Risk assessment

• Age (IRS-IV)

• Estimated 5 years EFS

• infants: 57%

• 1 to 9 years: 81%

• > 10 years: 68%


Malempati S , Cancer 2011;117:3493-501


Favorable Unfavorable

Histology Embryonal Alveolar

Primary site Orbit, non PM head

and neck, GU non BP,

biliary tree

PM, BP, extremities,

other

Tumor size < 5 cm > 5 cm

Lymph nodes Absent Present

Metastasis Absent Present

Extent of surgery Resectable Unresectable

•WHO pathologic classification

– Embryonal

• Spindle cell (paratesticular)

• Botryoid (vagina, bladder)

• Typical

• Anaplastic

– Alveolar

• Typical

• solid

– Pleomorphic

Botryoid and spindle cell subtypes are associated with very favorable outcomes


Alveolar

Embryonal

•WHO pathologic classification

– Embryonal

• Spindle cell (paratesticular)

• Botryoid (vagina, bladder)

• Typical

• Anaplastic

– Alveolar

• Typical

• solid

– Pleomorphic

Botryoid and spindle cell subtypes are associated with very favorable outcomes


Botryoid

Spindle cell

• Alveolar RMS

– Specific translocation (Barr FG J Mol Diagn 2006;8,202-8)

• PAX3 gene: 59%

• PAX7 gene: 19%

– Prognostic value of negative translocation: discordant publications • Williamson D, J Clin Oncol 2010;28:2151-8

• Stegmaier S, Pediatr Blood Cancer 2011;57:406-14

• Embryonal RMS: loss of genomic material from the short arm of chromosome 11

• Value of gene expression profiling? (Davicioni ,E J Clin Oncol, 2010;28:1240-6)

Importance of tissue collection ( fresh and frozen tissue)







biliary tree


other





• Primary site







biliary tree


other





Risk assessmentSurgico-pathologic group system (COG)

Group Definition

I (13% of all patients)

Paratesticular

Localized tumor completely removed

with pathologically clear margins and no

regional LN involvement

II (20% of all patients)

Localized tumor grossly removed with

(a)microscopic disease at the margin

(b) involved, grossly removed regional LN

(c) both (a) and (b)

III (48% of all patients)

Bladder/prostate and vagina

Localized tumor with gross residual

disease after incomplete removal or

biopsy only

IV (18% of all patients)Distant metastases at diagnosis

• Low risk (survival ~ 90%)

– All embryonal tumors except those in unfavorable primary sites that have been incompletely resected

– GU: paratesticular and vagina

• Intermediate risk (survival ~ 65%)– All non metastatic alveolar tumors (paratesticular ?)

– Embryonal tumors in unfavorable sites that have been incompletely resected

– GU: Bladder/prostate

• High risk (survival ~ 20%)

– Metastatic tumors

RMS- Risk stratification

• Systemic disease– chemotherapy for all the children (VAC, IVA, …)

• Local disease– Surgery

– Radiotherapy

But chemotherapy can be sufficient to obtain a CR

RMS- Treatment principles

• Management and overall treatment philosophy is different in SIOPMMT and COG-STS trials

– MMT• Primary objective is to reduce the use of radiation therapy and radical surgery

• OS is the primary end point, accepting the possibility of an inferior EFS and the necessity for second-line salvage therapy for relapse

– COG-STS• Primary objective is to employ local therapy soon after initial chemotherapy

• EFS is the target end point

Donaldson SS, J Clin Oncol 2005;23:2586-7


• Management and overall treatment philosophy is different in SIOPMMT and COG-STS trials

– Superior EFS and better OS in IRSG than MMT 89

– OS and EFS largely similar for non-bladder/prostate genito-urinary RMS

– For bladder/prostate RMS, OS was similar (86%-IRS vs 80%-SIOP) but EFS was worse in SIOP trial (65%) compare to IRS (79%)

– Lower morbidity for survivors in MMT?


• Initial surgery

– Resection of the tumor if complete microscopic resection, provided that major functional/cosmetic impairment will not result (paratesticular)

– Other situations: biopsy (open, core biopsy, endoscopy)

– Pretreatment reexcision in some paratesticular tumors with incorrect approach (20/96- Stewart RJ, J Clin Oncol 2003;21/793-8)

• Delayed primary resection to obtain a complete microscopic resection


• Radiotherapy

– Indications

• Embryonal RMS with residual disease

• Alveolar RMS

– Dose (COG)

• Group II: 41 Gy

• Group III: 50.4 Gy


• Low-risk patients: all embryonal except

unfavorable site with incomplete resection (gross residual disease)

– Chemotherapy

• VA or VAC in COG (22 weeks)

• IVA in SIOP (16 weeks)

– Radiotherapy for microscopic, locoregional or gross residual tumor


• Intermediate-risk patients: all non metastatic alveolar and embryonal in unfavorable site with incomplete resection

– COG-ARST0531

• Chemotherapy: VAC or VAC alternating with Vincristine- Ifosfamide (42 weeks)

• Radiotherapy at week 4 (36 to 50.4 Gy)


• High-risk patients: metastatic RMS

– VAC remains the base of the treatment

– Many treatment options under evaluation as the prognosis

remains poor (lower than 50% of 5-year survival rate)


• Diagnosis

– Painless scrotal mass

– AFP, HCG normal

– Reactional hydrocele

– Delay

• < 10 years: 3 weeks

• > 10 years: 3 months

Paratesticular RMS

• Diagnosis: US

– Enlarged intrascrotal

extratesticular mass

– Abdominal extension

Paratesticular RMS

• Surgery: inguinal radical orchiectomy

– Incision can be extended towards the scrotum in very large scrotal masses

– Primary control of the cord

– En bloc excision

Correct initial surgical approach: 52% (Stewart R, J Clin Oncol

2003;21:793-8)

Paratesticular RMS

Surgery: inguinal radical orchiectomy

Paratesticular RMS

• Indications of hemi-scrotectomy

– Tumor fixation or invasion

– Previous transscrotal biopsy

– Not systematic after initial scrotal approach

Paratesticular RMS

• Retroperitoneal nodes

– Thin cut abdominal and

pelvic CT with contrast

– PET?

Paratesticular RMS

• Retroperitoneal lymph nodes

– Pathologic in 24% in IRS III

– COG

• > 10 years: systematic retroperitoneal sampling

• < 10 years- positive CT: retroperitoneal sampling

• < 10 years- negative CT: no sampling

– SIOP: sampling if positive CT scan

Paratesticular RMS

• Ipsilateral staging retroperitoneal

node dissection

– Minimally invasive surgery

– Trans or retroperitoneal approach in

the lateral position

– Nerve sparring technique

– Identical dissection above the IMA

Paratesticular RMS

Paratesticular RMS

Stewart RJ, J Clin Oncol 2003;21/793-8

• Patient demographics: 74% < 5 years

• Tumor characteristics: 85% localized embryonal RMS

• Size: 64% > 5 cm

• Nodal involvement: 7%

• Localization

– Bladder: 59%

– Prostate: 29%

Rodeberg DA, Int J Cancer 2011;128:1232-9

Bladder/Prostate RMS

• Clinical presentation

– Abdominal mass

– Urinary retention

• Initial management: drainage of urine

– Urethral catheter

– JJ stent if ureterohydronephrosis related to direct compression by a large pelvic mass


• Biopsy (+++)

– Cystoscopy

– percutaneous

• Initial surgery: 12%

– tumors located at the dome of the bladder

– 5% of gross complete resection (Rodeberg)


• After initial biopsy: chemotherapy

• Local control: EBRT for COG (50.4 Gy at week 4) and CW (32 to 45 Gy)

• Residual mass after completion of treatment (CT and RT)

– 67% non viable

– Initial conservative management

– Value of PET- scan ?

Raney B, J Pediatr Surg 2010;45:2160-8

Rodeberg DA, J Clin Oncol 2009;27:3705-11


41

– SIOP

• prolonged chemotherapy (2° line if necessary) to try to obtain CR ( disappeance of tumor correlates with non viable tumor)

• If PR (55%), surgery and/or radiotherapy (EBRT or brachytherapy)

Combined Conservative surgery & Brachytherapy (H. Martelli. J Pediatr Surg 2009; 44:190-6)

– 26 boys with bladder-prostate RMS

– Tumors limited to trigone and prostate

– 22 IRS-III (+4 meta)

– Local Treatment : partial cystectomy, partial prostatectomy or both + brachytherapy

– 24/26 alive in 1st CR at 5 years

– excellent functional results 41


2 year-old boy with prostate RMSMRI at diagnosis

Clinical case- Pr H. MARTELLI-Paris


MRI after 7 courses of chemotherapy



Left prostatectomy + brachytherapy

Iridium 192- 2 loops surrounding the prostate- low dose rate (5-7 days)- 60 Gy


• Functional results

– Preservation of the bladder in 70-80%

– Exenteration for recurrences or progression

– Prostatectomies: risks of incontinence and impotence

– Functional bladder after high doses of RT (>40 Gy)?

– Long term follow-up (continence- UDS, erections, ejaculations)


• Age

• early childhood (76% < 3 years- Walterhouse DO, Pediatr Blood Cancer, 2011;57:76-83)

• unusual > 5 years

• Symptoms

• Bleeding

• Introital mass

• Biopsy (80% botryoid)

• Evaluation of extent by EUA and MRI

Initial radical surgery is never indicated

Vaginal RMS

• Prolonged chemotherapy

• Evaluation between 12-31 weeks

• No residual tumor: no radiotherapy

• No prognostic value of mature rhabdomyoblasts

• Residual tumor

• Excision if conservative

• Others: Radiotherapy (EBRT or brachytherapy)

Vaginal RMS

• Sequelae (Spunt SL, J Clin Oncol 2005;23:7143-51)

• 26 female patients with pelvic RMS

• Median follow-up: 20.3 years

• Grade ¾ late effect by patient: 3

• 54% required late surgery

• More median late effect for patients with RT

Vaginal RMS

•COG experience (Walterhouse DO, Pediatr

Blood Cancer, 2011;57:76-83)

• Decrease dose of cyclophosphamide

• Decrease indications EBRT

• Increase relapse rate

• OS stable

Vaginal RMS

• Brachytherapy (IGR experience)

• Low dose rate brachytherapy: 50-60 Gy delivered in 5-6 days on

the residual tumor

• Indication: tumors smaller than 40 mm

• Previous oophoropexy ( laparoscopic transposition in the latero-

colic spaces

Vaginal RMS

• Brachytherapy (IGR experience)

• Results similar to EBRT: OS 91% (Magné N, Int J Gynecol Cancer 2006)

• Long term: 20 patients older than 12 years

– Spontaneous puberty: 17

– Normal menses: 12

– Pregnancies: 4 in 3 women

Vaginal RMS

Vaginal RMS

• Age: adolescents

• Treatment based on chemo and radiotherapy

• For cervix RMS, place for radical abdominal trachelectomy to avoid irradiation of the uterine cavity (Kayton ML, J Pediatr

Surg 2009;44:862-7)

Uterine RMS

Uterine RMS

(Kayton ML, J Pediatr Surg 2009;44:862-7)

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