Wilms tumour

Key points

1 in 10,000

Clonal expansion of nephrogenic rest

Genetics

WT1 deletions/mutations

LOH 1p/16q - increased risk of relapse

Associations

Beckwith-Wiedemann Syndrome (BWS)

Wilms Tumour, Aniridia, Genitourinary anomalies, and Range of developmental delays (WAGR)

Denys-Drash

Perlman syndrome

Fanconi Anaemia

Simpson-Golabi-Behemel

Isolated hemihypertrophy

Horseshoe kidney

Mnemonic by risk:

Divining Wilms Probability For Bewildering Syndromes

5 - 10% present with von Willebrand disease - either a genetic deficiency or a defective von Willebrand facto r- will sometimes respond to desmopressin therapy - if not successful, cryoprecipitate (concentrated von Willebrand factor) can be used. Resolves permanently only after excision of the tumour

Imaging

Metastases

- Unusual metastatic sites (i.e. not lung or liver) - Rhabdoid, Clear cell sarcoma

- Pulmonary metastasis in patient <2 years - Rhabdoid (rarity of stage 4 Wilms in this age)

Staging

Stage I

• Tumour limited to the kidney or surrounded by a fibrous pseudocapsule outside normal kidney contours

• Renal capsule or pseudocapsule may be infiltrated but not reaching the outer surface, completely resected

• Tumour may protrude into the pelvic system and dip into the ureter, not infiltrating walls

• Renal sinus vessels not involved

• Intrarenal vessels may be involved

Stage II

• Tumour extends beyond the kidney or penetrates renal capsule/pseudocapsule into perirenal fat, completely resected

• Infiltrates renal sinus and/or invades blood and lymphatic vessels outside renal parenchyma, completely resected

• Infiltrates adjacent organs or vena cava, completely resected

• Surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery

Stage III

• Incomplete excision, tumour extends beyond resection margins (gross or microscopic tumour remains)

• Any abdominal lymph nodes involved

• Tumour rupture before or during surgery

• Tumour penetrated peritoneal surface

• Tumour implants on peritoneal surface

• Tumour thrombi at resection margins of vessels or ureter, or removed piecemeal by surgeon

Stage IV

• Haematogenous metastases (lung, liver, bone, brain)

• Lymph node metastases outside the abdominopelvic region

Stage V

• Bilateral renal tumours at diagnosis

• Each side substaged according to above classifications

  
  

Histology

Favourable -blastemal, stromal, epithelial (triphasic most characteristic)

Unfavourable - anaplastic (Focal/diffuse, marker of tumour resistance rather than aggression - focal better prognosis)

Chemotherapy for stage 1-3

Pre op: 4 weeks Actinomycin (A) + Vincristine (V)

Post op:

Low risk histology + completely necrotic + stage 1 - no further chemo

Intermediate risk + stage 1 - 4 weeks AV

Low/Intermediate risk + preop tumour volume <500ml + stage 2/3 - 27 weeks AV

Intermediate risk + preop tumour volume >500ml + stage 2 or above - 27 weeks AVD (Actinomcyin + Vincristine + Doxorubicin)

High risk - 4 drug regimen Cyclophosphamide + dox, then Etoposide + Carboplatin - 34 weeks

Radiotherapy for Stage 3 and Stage 2 with diffuse anaplasia

Chemotherapy for stage 4

Pre op chemo - 6 weeks AVD

Post op chemo - 27 weeks AVD, or 34 weeks 4 drug if high risk or if unable to clear mets

RT to unresected mets

Operative principles

Complete tumour nephrectomy

Mobilise colon

Stay outside tumour capsule

Ligate and divide ureter as low as possible

Divide vessels

Sample lymph nodes - ideally >7

Avoid rupture - traditionally open surgery with large incision

If rupture: Document site and likely spread in detail - for radiotherapy planning

Nephron sparing surgery (NSS) for:

Bilateral WT

Single kidney

Syndromic e.g. BWS

10 Criteria for NSS in unilateral disease:

1. Tumour restricted to one pole of kidney or peripheral at mid-kidney

2. Volume < 300 ml at diagnosis

3. No pre-operative rupture

4. No intraluminal tumour on pre-operative imaging in renal pelvis

5. No invasion of surrounding organs

6. No thrombus in the renal vein or vena cava

7. No multifocal tumour

8. Excision can be performed with oncological safe margin

9. Kidney remnant is expected to show remaining function

10. At least 66% of renal tissue should be spared after the tumour resection with a margin of

healthy tissue, to give any worthwhile protection against hyper perfusion. If this is in

doubt pre-operative DMSA may be able to define expected post-operative function.

Summary:

1. Is it possible?

2. Will it have safe margins?

3. Is the remaining tissue adequate and worth preserving?

Complications

If relapses occur, then will usually happen within <18 months

50% in tumour bed, 50% are pulmonary

End stage renal failure in 1% at 20 years, 10% if bilateral

Doxorubicin - 5% risk of cardiac failure at 20 years

Platinum agents - ototoxicity

Alkylating agents (cyclophosphamide, ifosfamide, melphalan) - gonadal impairment

80-90% survival for stage 1-2

Standard scenario

Renal mass - Concern is malignancy

Differentials:

Wilms

NB

RCC or CMN depending on age

Ensure resuscitated

History

Onset of symptoms

Paraneoplastic features e.g. Hypercalcaemia, bleeding (vWF)

Tumour syndromes - BWS, Denys Drash

Family history

Examination

Mass

Systemic - anaemia

Dysmorphia e.g. Macroglossia and long face - BWS

Genitalia + eyes - WAGR

Investigation

USS - to confirm

Bloods - anaemia + infection markers, renal function, calcium, LDH

Urinary catecholamines

CT chest/abdomen

DMSA scan if bilateral lesions or if partial nephrectomy is planned

ECHO cardiogram (if doxorubicin to be used)

GFR (if carboplatin to be used)

Oncology MDT - management as per Umbrella protocol

Decision for biopsy

≥ 7 years - risk of RCC in 5%

<6 months - mesoblastic nephroma, Rhabdoid

Urinary infection or Septicaemia - Xanthogranulomatous Pyelonephritis

- Hypercalcaemia - mesoblastic nephroma, Rhabdoid

- LDH raised - Neuroblastoma

- Raised urinary catecholamines - Neuroblastoma

- Radiological features not consistent with WT

Plan for open tumour nephrectomy after neoadjuvant chemotherapy

Follow up

Regular abdominal exam

Tests for chemo toxicity

CXR + abdo USS every 3 months until age 7 (CXR every 2 months if intermediate or high risk histology)

Special scenario - Stage 5 Bilateral Wilms or unilateral and nephroblastomatosis or single kidney

Refer to CCLG National Renal tumour Advisory panel

Screen for cancer presdisposition syndrome

Extend neoadjuvant chemo - 6 weeks AV or AVD if metastases then re-image

Partial response - continue AV/AVD for further 6 week

If no effect or progression, do further 6 weeks Etoposide + carboplatin

Do DMSA

Operate if nephron-sparing surgery possible for at least 1 kidney - operate 2 weeks apart - starting with kidney with most function

NSS one side and nephrectomy other is acceptable

If at operation NSS found not possible either side - take tru-cut biopsies and close

Post op chemo - 24 weeks AV or AVD

Favourable disease can have radiotherapy if positive margins, but anaplasia must have complete resection

If BL nephrectomy needed - place haemodialysis line, peritoneal dialysis not suitable for several weeks

Needs to be 2 years tumour free before transplant

Special scenario - Wilms with IVC thrombus

Initial imaging to evaluate thrombus extent

Classify infra-, retro- or supra-hepatic, or intra-atrial

Is IVC patent

If thrombus on a pedicle - IVC filter before chemotherapy to prevent fatal embolus

If thrombus causing cardiac/hepatic failure and unable to have chemotherapy - upfront surgery

Chemotherapy - standard 6 week course - no benefits to extended course in Meta-analysis

Re-image and reclassify - assess for IVC patency

If IVC not patent - MR Angiogram to identify which vessels (usually retroperitoneal) the kidneys are using as collaterals

Plan nephrectomy + IVC thrombectomy

Joint case with experienced oncology surgeon or vascular surgeon

Isolate IVC, sling above and below tumour, and contralateral renal vein

Thrombus level:

Supra-hepatic or Intra-atrial - cardiac surgeons may need to do cardiopulmonary bypass or get supra-diaphragmatic control

Retro-hepatic - mobilise liver, gain infra-diaphragmatic control

Infra-hepatic - control above thrombus

Nephrectomy as standard - place clamps, open IVC

If thrombus adherent but some flow, piecemeal intimal dissection or cavectomy with graft reconstruction

If thrombus adherent but no flow - cavectomy, preserving developed collaterals of contralateral kidney (Renaud 2001)

Special scenario - Ruptured Wilms tumour

Resuscitate patient

Discuss imaging with radiologist

If active bleed - request embolisation - if not possible and continuing bleeding, may need upfront nephrectomy

If stable - bedrest, daily Hb

Start chemotherapy when settled

Special scenario - Nephroblastomatosis

Nephrogenic rests persisting after 36 weeks gestation

4 categories:

• Perilobar (PLNB)

• Intralobar (ILNB)

• Combined

• Universal

All four categories are associated with WT

Perilobar NB (PLNB) is linked to synchronous bilateral WT

Intralobar NB (ILNB) is associated with metachronous WT

Manage in MDT

Will likely need VCR + ActD due to high risk of WT

Nephron sparing surgery if persistent after chemotherapy

Special scenario - Cystic Wilms tumour

Typically respond poorly to chemotherapy

Should consider primary nephrectomy

High risk of rupture - if biopsy needed it should be taken with care

The tumour should be handled carefully intra-op

References

CCLG CLINICAL MANAGEMENT GUIDELINES: RENAL TUMOURS To be used in conjunction with the Umbrella Study Protocol

Boam TD, Gabriel M, Shukla R, Losty PD. Impact of neoadjuvant chemotherapy on thrombus viability in patients with Wilms tumour and caval extension: systematic review with meta-analysis. BJS Open. 2021 May 7;5(3):zrab020. doi: 10.1093/bjsopen/zrab020. PMID: 34052849; PMCID: PMC8164777.

Morris L, Squire R, Sznajder B, van Tinteren H, Godzinski J, Powis M. Optimal neoadjuvant chemotherapy duration in Wilms tumour with intravascular thrombus: A literature review and evidence from SIOP WT 2001 trial. Pediatr Blood Cancer. 2019 Nov;66(11):e27930. doi: 10.1002/pbc.27930. Epub 2019 Jul 24. PMID: 31339231.

Brown EG, Engwall-Gill AJ, Aldrink JH, Ehrlich PF, Fawcett A, Coakley BA, Rothstein DH, Rich BS, Glick RD, Baertschiger RM, Roach JP, Lautz TB. Unwrapping Nephrogenic Rests and Nephroblastomatosis for Pediatric Surgeons: A Systematic Review Utilizing the PICO Model by the APSA Cancer Committee. J Pediatr Surg. 2023 Nov;58(11):2128-2134. doi: 10.1016/j.jpedsurg.2023.07.011. Epub 2023 Aug 1. PMID: 37625940.