1) what should be the mode of diagnosing the pulmonary mets radiologically - for considering to give WLI?
2) If there is a relapse in lungs after completing prior treatment for abdominal disease - what is the management?
3) if after chemotherapy the relapsed lung metastasis disappear radiologically is it required to give WLI in relapsed cases?
No one replied to this post … just refreshing …. please comment.
__WILMS’ TUMOR
Max Wilms’(1899) : German Surgeon and Nephrologist.
Definition: (Nephroblastoma)
Abnormal proliferation of metanephric blastema without normal differentiation into normal tubules and glomeruli.
• Most common malignant tumor of the kidney in childhood, 8% all solid tumors
• Fifth most common pediatric malignancy
Etiology:
The etiology essentially remains unknown
The tumor may arise in 3 clinical settings
(1) Sporadic, most cases
(2) Association with genetic syndromes – 7-10%
With overgrowth Without overgrowth
1) Beckwith wiedman syndrome (8.4) 1) Aniridia (7.6)
2) Hemihypertrophy (33.4) 2) WAGR
3) Perlman Syndrome 3) Denis- Dash sy.
4) Sotos syndrome 4) Familial Wilms
5) Ambiguous Genitalia
(3) Familial, 1-2%, Auto. Dominant not related to WT gene
Biology:
Knudsons two hit theory:
First hit: Nephrogenic rest Second hit: carcinoma
Two class of genetic abnormality
WT1 = 11p13 – loss of function of suppressor gene/WAGR
WT2 = 11p15 – B-W syndrome
Chromosomal abnormalities: 1p, 16q, etc,
PATHOLOGY:
Gross:
WT typically is an intrarenal solid or cystic mass
Displaces the collecting system.
Spherical, Gray or tan color, soft and friable, areas of hemorrhage and necrosis,
Adjacent parenchyma is compressed with a pseudocapsule.
Micro:
Triphasic: Three components
1) Blastemal- Primitive mesenchymal blastema / aggressive but chemosensitive
2) Epithelial- Primitive tubules and glomeruloid structures
3) Stromal- Muscle, Bone, Cartilage and Fat
Anaplasia:
Nuclei > 3 times
Hyperchromasia
Abnormal mitotic figures
Focal anaplasia- <10% in HPF, One region
Diffuse anaplasia- >10% in HPF, More than one region Favourable: No anaplasia
Unfavourable (10%): Diffuse anaplasia, Sarcomatous (Rhabdoid and clear cell)
PRECURSOR LESIONS OF WILMS TUMOR
Nephrogenic rest, which is defined as foci of abnormally persistent nephrogenic cells that can form a wilms’ tumor.
Multiple NR: Nephroblastomatosis.
Two types a) Perilobar NR
b) Intralobar NR
• Wilms tumor can occur without NR
• NR + ve adjacent to tumor- risk of Metachronous tumor
CLINICAL FEATURES:
The mean age at diagnosis is 3.5 years
M: F = 1:1
Mass abdomen: 90 % of cases
Abdominal Pain: 30%
Hematuria- Gross and Microscopic: 25%
Hypertension 25%- Ischemia or renin from the tumor
IVC and RV Involvement: Varicocele, Hepatomegaly, Ascitis
IMAGING:
Ultrasonography:
Identifies mass lesion
Cystic (Hemorrhage, Necrosis), Solid, Calcification
Lymphnode enlargement, Liver mets
Renal vein and IVC involvement
IVU:
Not routinely done
Distorsion of renal contour & splaying of collecting system
Non visualization- Vascular invasion, obstruction of ureter CT/MRI Scannig:
Differential diagnosis of a kidney tumor versus adrenal tumor
(Neuroblastoma)
Controversial about staging
Assesment of contralateral kidney for bilateral tumor: 7% missed (Explore other kidney always)
Liver secs, IVC thrombus, Lymphnodes etc,
Metastatic evaluation:
Chest X-Ray
LFT
Bone scan – Clear cell sarcoma
MRI brain – Rhabdoid tumor
DIFFERENTIAL DIAGNOSIS:
A) Malignant tumors: B) Benign tumors
Neuroblastoma PUJO, MCKD,
Rhabdomyosarcoma Polycystic KD
Lymphoma Mesenteric cyst
Renal cell carcinoma
STAGING
I: Tumor limited to kidney and completely excised, capsule intact
II: Tumor extends beyond the kidney but completely excised
Penetration of capsule
Previous biopsy
Local spillage confined to flank
No residual tumor
III: Residual nonhematogenous tumor confined to abdomen
Lymphnode positive
Diffuse peritoneal contamination
Peritoneal surface implants
Tumor extends beyond surgical margin
Tumor not completely removed due to local infiltration
IV: Hematogenous mets.
LN above diaphragm
Lung, Liver, Bone and Brain
V: Synchronous bil.tumor, each side staged separately from I to III
SURGICAL MANAGEMENT
• Generous transperitoneal incision
• Assess the liver, lymph nodes and other organs
• Exploration of contralateral kidney- palpated
• Radical nephrectomy with regional lymphadenectomy/ sampling
• Gentle handling of tumor, spillage increases local recurrence by 6 times
• Ligation of vessels first
• RV (10%) and IVC ( 5%) – palpated
• IVC involvement – Excess bleeding from collaterals, embolisation of thrombus
• Thrombus below hepatic veins – Thrombectomy
• Massive local spread which preclude radical surgery- Biopsy and chemo
• Complication of surgery:
Small bowel obstruction (7%)
Hemorrhage (6%) asso. with Von Willebrands disease.
Wound infection, hernia (4%)
Vascular complications (2%)
Splenic and intestinal injury (1.5%)
ADJUVANT TREATMENT
Trails: 1) NWTS Trial – North American
I to V
Surgery – Adjuvant treatment
2) SIOP Trial - Europe
Chemo – Surgery – Chemo+ RT
Risk of treating benign lesions 1-5%
NWTS – V: Treatment Protocol
Status RT (rads) Chemo
1) Stage I - FH & Focal/Dif.anaplasia None A+V = 18 wks Stage II – FH (PI)
2) Stage III, IV – FH 1080 A+V+D = 24
Stage II to IV – Focal anaplasia week (PI)
3) Stage II to IV – Diffuse anaplasia 1080 A+V+D+Eto+Cyc
Stage I to IV – CCSK 24 weeks
4) Stage I to IV – RTK 1080 Carbo+ Eto+ Cyclo-24 weeks
A = Actinomycin
V = Vincristine
D = Doxorubicin
Radiotherapy
Old: 2000 rads No RT I FH / UFH
New: 1080 rads II FH
500 to 1000 rads for bed in residual disease
Pulmonary mets
FNAC
Irradiate both lungs - 1200 rads
Pneumocystis prophylaxis
Liver mets
FNAC
Irradiate liver –FH: 2000 rads - UFH: 3000 rads
Complication of Chemotherapy and RT
1) Acute hemorrhagic toxicity
2) Acute GI toxicity and delayed radiation enteritis
3) Hepatic toxicity
4) Late orthopedic complications
5) Renal Problems
6) Pulmonary complications
7) Cardiac toxicity- Doxorubicin
8) Infertility
9) Second Neoplasms - Soft tissue sarcoma, Leukemia
FOLLOW-UP
Chest x-rays and abdominal ultrasonography every 3 months for the first 2 years, every 6 months for another 2 years, and once every 2 years
SURVIVAL (4 year)
With the advent of multimodal therapy, the prognosis of WT is good, and it is considered an example of success in cancer therapy. The overall cure rate approaches 80-85%.
FH: I = 96 % UFH I to III = 68 %
II = 92 % IV = 55 %
III = 84 %
IV = 80 %
PROGNOSTIC FACTORS
• Stage
• Histology
• New
a) Chromosomal abnormalities LOH 16q poor
b) DNA content
c) Cytokines
d) Tumor markers
Hyaluronic acid, Renin etc
BILATERAL WILMS
• Synchronous – 5 %, Metachronous – 0.5 %
• Nephrogenic rests 100 %
Unilateral Bilateral
1) Distribution Unifocal Multifocal
2) Age 3 ½ years 1 ½ years
3) Maternal age 28 yrs 34 yrs
4) Associated anomalies 4 % 45 %
5) Inheritance Sporadic ?Dominant
NWTS recommendation
Initial Surgery
Initial transabdominal, transperitoneal staging laparotomy
No nephrectomy
Partial nephrectomy only if >2/3 parenchyma is saved
Tumor biopsy and sampling of LN done
Chemotherapy
8 to 10 weeks- Second look surgery
Partial nephrectomy, Wedge excision, one side nephrectomy and other side partial nephrectomy
Not possible – close with biopsy
Continue with full chemo or different chemo- 12 wks and RT
Third look surgery
Rarely Bil. Nephrectomy with dialysis, Transplantation after 2 yrs
Overall 3 year survival is 75 %
Failure of the tumor to shrink: Benign element
Skeletal muscle
PREOPERATIVE THERAPY
NWTS Recommendations for preop chemo
1) Bilateral tumors
2) Inoperable at surgical exploration
3) IVC extension above hepatic veins
SIOP: for all patients
1) Decrease the incidence of tumor rupture during surgery
2) Downstages the tumor, requires less intensive chemo
TREATMENT OF RELAPSE
At 3 years: FH: I – 10 %, II – 12 %, III – 22 %, IV – 22 %
UFH: 35 – 45 %
Treatment depends on previous treatment, site of relapse, duration etc,
Individualized: RT/ Chemo/ ABMT
OTHER TUMORS:
1) Clear cell sarcoma of the kidney (CCSK)
3% of renal tumors
Bonemets
Aggressive- renal sinus invasion
Unilateral
2) Rhabdoid tumor of kidney (RTK)
Most aggressive and lethal, 2% of renal tumors
Large cell with acidophilic cytoplasm
Early age- 16 mo
Mets to brain
3) Congenital mesoblastic nephroma (CMN)
Infants- 3.5 mo
Hypercalcemia (RTK)
C/s leiomyoma, no pseudocapsule, good prognosis
No RT / Chemo if completely removed.
1940 – Discovery of Anesthesia and Surgery was done but, survival after 2yrs of Nephrectomy was only 20%.
1950 – Aduvant RT was started survival 50%.
1966 – Actinomycin D was given survival 81%.
Later with combined efforts of Radiotherapist, Surgeons, Chemotherapist & Pathologist with usage of CT drugs (Actinomycin D, Vincristine, Doxorubicin) survival increased to 90% in last 30 yrs.
NORTH AMERICAN TRIAL’S
NWTS – 1: (1969 – 1973)
Conclusions: Post op local RT was not necessary for Grp-I pts.
RT to be given for not more than 10 days.
Adverse prognosis was noted with Anaplasia.
Combination of Actinomycin D & Vincristine
was more effective than either drug alone.
NWTS –2 : (1974 – 1978)
Conclusion: Combination of 2 drugs of CT – more effective.
In grp I pts receiving AMD+VCR, 6 mnths of
therapy was equally efficacious as 15 mnths of
therapy.
Addition of Doxorubicin improved survival for
higher stage patients (II, III,IV).
These early trial’s allowed identification of prognostic factors, that allowed stratification of patients into High risk & Low risk treatment groups.
Accordingly, in L.N +ve, tumor spill Unfavourable Histology –Abdominal Radiation was considered.
NWTS –3 : ( 1979 – 1986)
Conclusion : Attempt was made to decrease the intensity of therapy for the majority of low risk patients, while maintaining overall survival.
Stg – I FH pts – 10wks or 18wks AMD+ VCR without RT
Benefit – considerably decreasing amount of CT administered & as concequence decrease in total duration of treatment.
RFS – 89%, Survival – 95.6%.
Stg – II FH – No RT but still AMD +VCR=AMD/VCR+DOXO cardiotoxic drug doxorubicin is not necessary for successful treatment of this group.
Stg – III FH –RT dose reduced from 20 Gy to 10.8 Gy if Doxorubicin is added.
RFS – 79%, Survival – 80.9%.
NWTS – III : (1979 –1985)
Discovered important prognostic factors.
i) Histology –anaplasia,relapse rate in time
ii) Hematogenous mets.
iii) Lymph node involvement.
iv) Tumor extension.
Adverse prognostic factors (Grundy et al 1989)
Previous treatment with Doxorubicin.
Relapse in <12 mnths.
Intraabdominal recurrence > Abdominal RT is given.
NWST –III relapse at 3 yrs – Results. (D Angio et al)
Stg I – 9.6%, Stg II – 11.8%, Stg III – 22%, Stg IV – 22%
UFH – I/II/III = 36%, IV – 45% (D Angio et al 1989).
NWTS – 4 : (1986 – 1994)
Goal – Continue improving treatment results while decreasing the cost of therapy, through modification of the schedule of drug administration.
Pulse intensive single dose schedule with divided dose treatment regimen using AMD+DOXO (Green et al 1998)
Treatment duration of 6 & 15 mnths were equally effective in Stg II/III/IV FH.
Randomization to 3drug/4 drug. In diffuse anaplasis, Cyclophosphamide improved RFS 27.2% to 54.8%.
Stg IV – 3 drug+pulm. Irradiation of 12Gy.
Stg I/II FH – No RT.
NWTS – 5 : Single arm therapeutic trial.
Study to judge LOH on chromosome 16q & 1p to prdict relapse. NWTS is also evaluatuing potential biologic factors that may predict tumor behavior – LOH
- DNA content by flow cytometry
Ist cohort of patients, <2 yrs age, <550gm tumor treated by surgery alone.
Initially favourable outcome (Larsen 1990 & Green 1994) but later suspended – when no.of relapses were greater in the limit allowed by design of study.
All receive AMD + VCR -2 yr survival 100% (Green 2000).
NWST pre op therapy = i) Bilateral disease.
ii) Disease inoperable at presentation.
iii) Intravascular extention .
iv) Tumor in solitary kidney.
Role of preop therapy --decreases tumor rupture
down stage disease less intensive adjuvant CT
Contralateral tumors might be missed by imaging. Ritchey et al 1995 in NWTS IV 7% were missed by imaging .
SIOP – International Society of Paediatric Oncology
EUROPE multicentric trials.
SIOP trails largely focus on preoperative therapy.
SIOP – 1:__ Sept 1971 – Oct 1974.
398 pts registered children randomised to prenephrectomy RT or immediate Sx.
Graf et al – Post stg –favoured preneph RT. Also with pre op RT, no.of tumor ruptures reduced (32% to 4%).
AMD single/multiple/nil course with RT, No diff in survival.
SIOP – 2 : 1974 – 1976. 138 pts.
Results of Siop 1 reconfirmed. Preop RT – prevents tumor rupture & induces favourable stage distribution thus eliminating post op whole abdomen RT.
SIOP –5 : 1977 – 1979 . 397 pts.
Basis – To determine whether preop chemo could be as effective as radiotherapy in avoiding surgical tumor rupture, jeopardizing survival & dfs.
Results – Preop chemo AMD + VCR equivalent to preop RT + AMD. High proportion of low stages were obtained.
SIOP – 6 : 1980 – 1986 . adopted preop chemo, all pts received AMD+VCR
Risk adopted therapy to limit sequelae- possible.
<1/3rd patients were given RT.
High cure rates 82% DFS 2yr, 85% 5yr sur for entire trial population.
SIOP –9 : 1987 –1991 852 pts.
Main objective – To determine optimal duration of CT to further increase the rate of Stg I tumors . To lower the number of Stg II & III tumors needing more aggressive therapy.
Results –Low total surgiccal complication rate 8%— benefit of tumor volume reduction after preoop CT(Godzinski et al 1998. Blastemal predominant subtype more chemoresistant –to be treated intensively.
Response to preop chemo is of prognostic value.
After 4 wks of preop CT—No significant tumor shrinkage.
Stg II/III FH – 3 drug AMD/VCR/EPIRUBICIN.
Stg II N1/Stg III – RT is necessary (Graf et al 2000).
Anaplasia remained after preop CT even when size decreased.
SIOP 93-01
Aim – to determine whether post op therapy can be omitted in select pts with Stg I disease( Boccon – Gibod 2000).
— whether survival can be improved in high risk pts with use of Etoposide,Ifos,Carboplatin (Graf et el 2000)
— Stg II N0,N1 -AVE CT. Stg III AVE CT.
— Stg IV 6 wks preop CT. Demonstrable residual mets –Sx. If no remission or if patients has a high risk tumor, postop therapy is intensified by applying high risk protocol -carboplat, etoposide, ifos & anthracycline.
Disadv – Risk of giving chemo to benign tumor is 15%. Exact staging is not possible.
Summary of SIOP trials : 4 wks of prenephrectomy chemo without RT results in 56% of patients having StgI disease at Sx. Receive postop chemo & survival 90% , StgII node +ve & StgIII—61% relapse free survival & 75% OAS. A diminished number of patients have received RT in the sequential SIOP trials. Estimated % of pts who recd RT :
Siop 1 = 90 %, Siop 2 = 90%, Siop 5 = 72%, Siop 6 = 64%, Siop 9 = 24%.
If one excludes metastatic disease pts, then only about 16% of SIOP pts recd RT.
This was the best evidence I was aware of till my exams (2004), I dont know if there has been any further advancements.
Nikhilesh
Hi Abhinav,
In answer to question no 1 "what should be the mode of diagnosing the pulmonary mets radiologically - for considering to give WLI?"
When I was in my MD and had prepared for a seminar (which is available at http://www.slideshare.net/santam/management-of-wilms-tumors) I had read that using CT doesnot add much over and above use of X rays to detect Pulmonary nodules in terms of "outcome" [Based on data by the study from Green et al - http://www.jco.ascopubs.org/content/9/10/1776.abstract?ijkey=93b527ec37cc6015629fe2cd7ec0f6eefe337bd9&keytype2=tf_ipsecsha].
That data was based on retrospective reviews. Thanks to your question I searched the net again. Turns out CT should now be indeed considered as the imaging modality of choice for detecting pulmonary metastasis. There are two issues when u consider the use of CT for detection of pulmonary mets:.
- There is significant interobserver variability in quantification of radiological findings in presence of lung mets
- Despite the high sensitivity of CT scans its often doubtful if the lung nodules are benign or malignant
The more recent study on patients on patients treated in the UKW2 trial [http://www.jco.ascopubs.org/content/20/12/2768.full#R6-109705] seems to suggest that CT scan does add to information in stage I patients (at the time of the protocol NWTS recommendation was to stage patients according to abdominal findings in presence of lung nodules on CT in absence of CXR). These patients were treated with vincristine only however. However they did find patients ending up with relapse had a poorer prognosis. Interestingly stage I with pulmonary nodules on CT had poorer EFS as compared to stage IV patients.
Hi Abhinav,
Science direct going down for maintainence did not make the search easier. However I have come across a nice PPT that should answer the two questions - do tell me how u like it
http://www.slideworld.org/ViewSlides.aspx/16228
The basic idea - Give RT for pulmonary relapse
1) What should be the mode of diagnosing the pulmonary mets radiologically - for considering to give WLI?
Santam has answered the first question: CT scan is now regarded as one of the Std Investigations in developed worlds incorporated into all new Wilms protocols.
2) If there is a relapse in lungs after completing prior treatment for abdominal disease - what is the management?
Salvage rates after relapse are dismal, with the majority of children dying from recurrent disease.
If solitary lung nodule relapse —> Early surgical intervention followed by second line chemo (Adjuvant)
Depending on disease free interval there are options on the choice of salvage chemo (re-challenge with previous chemo, ICE, etc )
3) If after chemotherapy the relapsed lung metastasis disappear radiologically is it required to give WLI in relapsed cases?
One of the recent SIOP studies suggested that whole-lung irradiation may not be necessary for successful therapy of patients with stage IV, favorable histology Wilms' tumor if the metastases completely respond to chemotherapy.
Nearly 10% children will develop RT induced interstitial pneumonitis, and a quarter of which died from this. Further more , there is a 93% incidence of musculoskeletal and soft tissue growth abnormalities in patients treated with whole-lung irradiation after more than 10 years of follow-up.
However, in relapsed cases the benefit Vs Harm ratio is in favour of giving WLI since their prognosis is quite dismal and the competing cause of mortality is the disease itself