Wilms tumour

• Wilms tumour (nephroblastoma) is the most common malignant kidney tumour of childhood and the fourth most common childhood cancer overall.
• It is a cancer of the developing kidney: a disorganised mass of embryonic renal tissue, which explains why it occurs almost exclusively in young children.
• Most children are diagnosed between ages 2 and 4, and 80% are under 5 when it is found. ^[1]
• It usually declares itself as a single, smooth abdominal or flank mass that does not cross the midline; some children also have haematuria or hypertension.
• Imaging, especially renal ultrasonography followed by CT or MRI, confirms a renal origin and the extent, and Wilms tumour rarely contains calcification, unlike neuroblastoma, which often does.
• With nephrectomy and stage- and histology-stratified chemotherapy (plus radiotherapy in selected cases), the 5-year relative survival is about 93%. ^{[6] [1]}
• Children with predisposing syndromes need regular renal ultrasonography, because the tumour is often found earlier and at a lower stage when it is looked for. ^[6]

By the end of this page you should be able to:

1. State what Wilms tumour is and why it is called nephroblastoma.
2. Explain the roles of WT1 and WT2 and name the three classic syndromes that go with them.
3. Recognise the typical presentation and say how it differs from neuroblastoma on imaging.
4. Stage a Wilms tumour and link stage to the chance of cure.
5. Outline how surgery, chemotherapy and radiotherapy are combined in the two major treatment strategies (upfront nephrectomy, or preoperative chemotherapy).
6. Plan surveillance of a child who is at increased risk.

Wilms tumour is not a single entity but a family of tumours that share embryonal renal features. The two principal approaches to it, used on opposite sides of the Atlantic, are the Children's Oncology Group (COG/NWTSG) protocol, which begins with surgery, and the International Society of Paediatric Oncology (SIOP) protocol, which gives 4 to 6 weeks of chemotherapy first. ^{[3][5] [1]}

"Nephroblastoma" and "Wilms tumour" are used interchangeably; this page uses "Wilms tumour" because it is what most clinicians say.

Wilms tumour is an orphan disease in global terms but the commonest solid kidney cancer of childhood. In North America and Europe the incidence is roughly 9.7 cases per million children under 15 and 13.5 cases per million infants. ^[6] It is the most prevalent primary renal tumour and the most common intra-abdominal solid tumour of childhood, and overall the fourth most common childhood malignancy. ^{[1] [2]}

• Age. The peak is between ages 2 and 4, and 80% of children are diagnosed before age 5. ^[1] An onset before age 2, or after age 6, is unusual and should raise the possibility of a bilateral or predisposition-related tumour. ^[6]
• Sex. Both sexes are affected; some series report a slight female excess.
• Bilateral disease. Wilms tumour appears in both kidneys in about 5 to 10% of cases, either at presentation or as a later metachronous tumour. ^{[1] [2]}
• Syndromic cases. About 10% of Wilms tumours occur in children with a recognised congenital condition or genitourinary anomaly. ^[1]
• Prognosis overall. The 5-year relative survival for children under 20 with Wilms tumour is 93%. ^[6]

The kidney develops by reciprocal signalling between the ureteric bud and the metanephric mesenchyme. Nephrogenic rests are nests of embryonic renal cells that remain in the kidney after 36 weeks of gestation and are thought to be the precursor lesions of Wilms tumour. ^[1] They are seen in roughly 25 to 40% of unilateral Wilms tumours and in essentially all bilateral cases. ^[1] Intralobar rests (inside the renal lobule) are associated with WAGR and Denys-Drash syndromes; perilobar rests (at the edge of the lobule) with Beckwith-Wiedemann syndrome.

• WT1, on chromosome 11p13, codes for a zinc-finger transcription factor needed for the transition of renal mesenchyme to epithelium. It is a tumour suppressor: loss of both copies, or mutation, allows embryonic renal cells to survive when they should have differentiated. WT1 changes are the basis of WAGR and Denys-Drash syndromes and of some sporadic tumours.
• WT2, on chromosome 11p15, is not a classical gene but a region subject to genomic imprinting (only one parental copy is normally expressed). Loss of imprinting or uniparental disomy at 11p15.5, as in Beckwith-Wiedemann syndrome, raises insulin-like growth factor 2 (IGF2) and predisposes to Wilms tumour and other embryonal tumours. About 13 of 437 children (3%) with sporadic Wilms tumour but no growth disorder carry a constitutional 11p15 abnormality, so molecular testing of blood for 11p15 changes is increasingly advised even in apparently non-syndromic cases. ^{[6] [2]}

About 8% of children with Beckwith-Wiedemann spectrum develop a malignancy, most often Wilms tumour or hepatoblastoma. ^[6] Children with WAGR or Denys-Drash have the highest risk and the youngest age at diagnosis.

A few other conditions (Perlman, Simpson-Golabi-Behmel, Bloom, DICER1, isolated hemihypertrophy and others) also raise the risk at various levels; some are grouped as low risk (under 5%). ^[6]

Wilms tumour is an experiment in development gone wrong rather than a conventional adult carcinoma. The arrest happens at the moment the kidney's embryonic mesenchyme should turn into renal tissue:

1. Proliferation without differentiation. Inactivated or mutated WT1 stalls the mesenchymal-epithelial transition, leaving a pool of undifferentiated blastemal cells.
2. Growth inside the renal capsule. The tumour pushes the non-neoplastic kidney to one side and is surrounded by a pseudocapsule, which is why it presents as a smooth, well-circumscribed flank mass that does not cross the midline.
3. Vascular involvement. Wilms tumour has a striking tendency to grow into the renal vein and the inferior vena cava. About 4% present with involvement of the inferior vena cava or right atrium, and 11% with renal vein involvement. ^{[6] [1]}
4. Metastasis. The commonest distant sites are the lungs, followed by the liver, bone and, in clear cell sarcoma of the kidney (a different tumour that once was grouped with Wilms), the brain. Sixty to 70% of patients already have metastatic disease at presentation in the highest-risk histology groups, but most Wilms tumours are found before that. ^[1]

Renal masses in Wilms tumour can also be hormonally active: renin release explains the hypertension that some children show at presentation.

Most children are picked up by a parent or an incidental abdominal ultrasound. The child is often well and has been growing normally. Features reported in roughly the following frequencies:

• Asymptomatic abdominal or flank mass (most common). A painless swelling noticed while bathing or dressing, which is smooth, rounded and firm and does not cross the midline. ^{[1] [2]}
• Haematuria. Microscopic or (less often) visible blood in the urine, when the tumour breaks into the collecting system. About 2% of cases involve the ureter, and gross haematuria with a non-functioning kidney or hydronephrosis should raise that possibility. ^[6]
• Abdominal or loin pain. Less common, usually implying capsular stretch, bleeding into the tumour or rupture.
• Hypertension. A minority are hypertensive at diagnosis, probably from renin release by the tumour or from renal ischaemia.
• Systemic symptoms. Fever, weight loss and malaise are more characteristic of neuroblastoma; they are uncommon in Wilms tumour and should prompt a search for a non-renal or infectious cause.

• A firm, smooth flank or upper-abdominal mass that usually does not cross the midline and moves a little with respiration.
• Blood pressure should be measured; if hypertension is present it should be recorded and treated.
• Hepatomegaly, bony tenderness or proptosis would suggest a neuroblastoma with metastases rather than Wilms tumour.

A suddenly enlarging abdomen, pain, anaemia or hypotension suggest haemorrhage into or from the tumour, which carries a risk of tumour spill at surgery and implies a higher stage. Preoperative chemotherapy is sometimes chosen specifically to reduce this risk.

The main differential for an abdominal mass of this sort is neuroblastoma, which is an adrenal/sympathetic-chain tumour that usually presents younger, often crosses the midline and frequently calcifies. The contrast is summarised below.

Other tumours in the differential include clear cell sarcoma and rhabdoid tumour of the kidney, and hepatoblastoma and teratoma for non-renal upper abdominal masses. ^{[6] [1]}

Ultrasound is usually the first test. It confirms that the mass is renal, shows cystic, haemorrhagic or necrotic change, and looks for thrombus in the renal vein or inferior vena cava. ^[7] Most Wilms tumours are solid, heterogeneous masses that displace the kidney's collecting system.

CT or MRI of the abdomen and pelvis defines the tumour's size, local extent, vascular invasion and nodal disease; CT of the chest looks for pulmonary metastases. MRI is the most sensitive modality for thrombus in the renal vein and inferior vena cava and for spinal extension in neuroblastoma. ^[6][7] MRI is often used at follow-up to limit radiation exposure. ^[7]

• Urine catecholamines (vanillylmandelic acid and homovanillic acid) help to exclude neuroblastoma.
• Renal function, full blood count and coagulation screen before any operation.
• Cystoscopy is suggested by gross haematuria, a non-functioning kidney or hydronephrosis, because about 2% of cases involve the ureter; such a tumour should be resected en bloc. ^[6]
• Bone and brain imaging are reserved for the small group of children with features suggesting specific sarcomas rather than standard Wilms tumour.
• Biopsy is not performed for a resectable unilateral tumour on COG/NWTSG protocols, because biopsy would upstage the tumour. It is considered when imaging leaves the diagnosis in doubt or when preoperative chemotherapy is needed before nephrectomy. ^[4][6]

The diagnosis is confirmed on the resected tumour: a triphasic (or biphasic) blastemal-epithelial-stromal tumour with primitive small round blue cells. Anaplasia (large hyperchromatic nuclei with atypical mitoses) is found in about 5% of tumours and confers an unfavourable outlook; it may be focal or diffuse, with diffuse anaplasia the most problematic. ^[1][2] Favourable histology still makes up the large majority of cases.

Nephrogenic rests are multiple in bilateral disease (100%) and in about 25 to 40% of unilateral tumours. ^[1]

NCI COG data give the approximate distribution at presentation as stage I in 43% of patients, stage II in 20% and stage III in 21%; stages IV and V are less common. ^[6]

Survival figures are the approximate five-year overall survival from the Neagu review and are only a guide; they assume modern risk-stratified treatment. ^[2]

Separate from the stage question there are two overarching philosophies. A systematic review of the comparative studies found that SIOP's preoperative chemotherapy produced intraoperative spillage of 0% versus 22.2% (one series), while NWTS/COG delivered 100% diagnostic accuracy in the single study reporting it, but the evidence is drawn from a handful of single-centre studies in developing countries and cannot be over-generalised. ^[5]

• COG/NWTSG (North America). Upfront transperitoneal nephrectomy, exploration and sampling of lymph nodes, en bloc excision without rupture or biopsy, then stage-directed chemotherapy, with radiotherapy to the tumour bed for stage III disease. A biopsy is deliberately avoided because it would upstage the tumour, and routine resection of the contralateral kidney is not required if imaging is adequate.
• SIOP (Europe and much of the world). 4 to 6 weeks of preoperative chemotherapy to shrink the tumour, reduce spillage at surgery and convert unresectable disease; then delayed nephrectomy and postoperative chemotherapy or radiotherapy directed by stage and response. Preoperative chemotherapy in SIOP trials reduced spillage from over 20% to about 5%. ^{[6] [1]}

• Nephrectomy. Radical nephrectomy through a midline (or transverse) incision, which gives access to both renal vessels and the contralateral kidney; a flank incision gives too little exposure. The tumour is resected en bloc with the kidney, ureter and any thrombus, ideally before manipulating the mass, to avoid embolising tumour thrombus. ^[4][6]
• Lymph nodes. Regional nodes are sampled even when they look normal, because nodal status determines stage; a tumour cannot be called stage I without nodal sampling.
• Chemotherapy. The backbone is vincristine and dactinomycin for lower stages, with doxorubicin added for higher stages, anaplastic histology or metastatic disease; intensified regimens are used for stage IV and bilateral disease. ^[6] An 18-week course (for example the EE-4A regimen) suffices for some early-stage, favourable-histology patients; more intensive therapy runs longer. Dactinomycin is withheld or has its timing adjusted if there is significant renal impairment. ^[1]
• Radiotherapy. Given to the tumour bed for stage III local disease and for anaplastic histology (and to metastatic sites, in particular the lungs). Doses depend on age and on whether the disease is local, metastatic or relapsed; in current practice the range used is roughly 10 to 20 Gy for local disease. ^[2]
• Radiotherapy delay matters: in one large series a delay of greater than 14 days in starting postoperative radiotherapy was associated with higher mortality for non-metastatic disease. ^[6]

Bilateral Wilms tumour is usually treated with preoperative three-drug chemotherapy (vincristine, dactinomycin and doxorubicin), nephron-sparing surgery as soon as the tumours are operable, ideally within 12 weeks of diagnosis, and then postoperative chemotherapy directed by the histology of each kidney. ^[6] In the AREN0534 trial this approach gave a 4-year event-free survival of 81% and an overall survival of 95% for children with bilateral tumours. ^[6] Renal-sparing strategies are essential here, because bilateral disease and its treatment together are the main route to end-stage renal failure after Wilms tumour. ^[1]

Relapses after current first-line therapy now occur late and uncommonly; where they occur, standard options include salvage chemotherapy with ifosfamide, carboplatin and etoposide, high-dose chemotherapy with stem-cell support and local control. ^[6]

• Tumour spill during operation, which historically up-stages a tumour to stage III and necessitates radiotherapy.
• Thrombus. Undiagnosed caval thrombus that begins to move during surgery is a surgical emergency; preoperative identification and a planned approach prevent pulmonary embolism.
• Postoperative: intestinal obstruction, wound dehiscence; atrial arrhythmias and stroke are rare but reported.
• Renal. Loss of renal parenchyma plus nephrotoxic therapy (both surgery and chemotherapy) can cause progressive kidney disease; surveillance of renal function is needed lifelong in bilateral or WT1-related disease.
• Late effects. Survivors carry risks of second neoplasms, cardiac dysfunction (particularly after anthracycline and/or radiotherapy), intestinal obstruction and premature ovarian insufficiency; those treated with vincristine and dactinomycin alone had mortality comparable to the general population in a large survivor study. ^[6]

Wilms tumour is one of the triumphs of modern paediatric oncology:

• The overall 5-year relative survival for children under 20 is 93%. ^[6]
• Stage I favourable-histology tumours are effectively cured (over 95%).
• Anaplastic histology worsens prognosis, diffuse anaplasia most of all; clear cell sarcoma and rhabdoid tumour of the kidney, which used to be taught alongside Wilms, are now staged and treated separately and do worse than favourable-histology Wilms.
• Favourable features include small, localised, completely resected tumours without anaplasia; adverse features include anaplasia, loss of heterozygosity on 1p or 16q and unfavourable histology. ^[6]
• Early recurrence (relapse within about 2 years) carries a worse outlook than the original diagnosis, while late recurrence is uncommon with current regimens.

Children with predisposing conditions are the group to watch, and the emphasis is on finding the tumour early, when it is small and unmassive.

Who is screened. The NCI stratifies syndromic risk as follows: greater than 20% (high) for WAGR spectrum and Denys-Drash; 5 to 20% (moderate) for Frasier, Beckwith-Wiedemann and Simpson-Golabi-Behmel among others; under 5% (low) for Bloom, DICER1, isolated hemihypertrophy and a long tail of other conditions. ^{[6] [3]}

How. Renal ultrasonography every 3 months during the risk period for that syndrome, with physical examination: 5 years for WT1-related syndromes and 8 years for Beckwith-Wiedemann syndrome. ^[6] For Beckwith-Wiedemann spectrum, screening until age 7 picks up close to 95% of Wilms tumours, and screening begins at birth in most programmes, with concurrent serum AFP and ultrasound screening for hepatoblastoma. ^{[6] [2][3]}

Effect. Children with Beckwith-Wiedemann who are screened present at an earlier age and stage, and small tumours detected this way are candidates for renal-sparing surgery. ^[6]

• Newborns and infants. Congenital mesoblastic nephroma, not Wilms tumour, is the usual renal tumour of the newborn. It is usually cured by nephrectomy alone; cellular variants are more aggressive and may need adjuvant therapy. ^{[6] [1]}
• Bilateral disease. See the stage V section above; nephron-sparing strategies take priority, and any child with a predisposition to further tumours may receive earlier and more frequent imaging. ^[4][6]
• Horseshoe kidney and solitary kidney. Wilms tumour does occur in these settings, and renal-sparing approaches are preferred whenever feasible. ^[6]
• Adults. Wilms tumour is rare in adults and the diagnosis is easily missed; pathology review by a paediatric renal tumour centre is advised.

• Ultrasound is the one imaging test that matters first: it confirms a renal mass and often distinguishes it from neuroblastoma by the lack of calcification and the mass not crossing the midline. ^[5][7]
• Where preoperative chemotherapy and multidisciplinary care are available, a SIOP-style approach lets a smaller, less haemorrhagic (and lower-stage) tumour be operated on later, which is helpful when theatre lists, blood products or pathology are scarce. ^[5][6]
• Misdiagnosis of Wilms tumour as another small round cell tumour has been reported in up to 17.4 to 21.7% of cases in some resource-limited series, so when a registry system allows, histology review is valuable. ^[5]
• For children with curable disease, an incomplete course of chemotherapy is worse than none: abandoning treatment mid-course is the single most common reason children die of Wilms tumour in low-resource settings. ^[5]
• Long-term follow-up and survivorship (renal function, blood pressure, fertility, second malignancies) must be planned from the start, because it is the most neglected part of care.

• Wilms tumour (nephroblastoma) is the most common childhood kidney cancer and the fourth most common childhood malignancy overall.
• Peak age is 2 to 4 years; 80% of cases are diagnosed before age 5. ^{[1] [2]}
• It arises from abnormally persistent embryonic renal tissue (nephrogenic rests), driven by WT1 loss and WT2 imprinting abnormalities. ^[1][6]
• The three classic syndromes are WAGR (high risk, WT1 deletion on 11p13), Denys-Drash (high risk, WT1 missense) and Beckwith-Wiedemann (moderate risk, 11p15 imprinting defect). ^[1][6]
• Presentation is usually an asymptomatic flank mass that does not cross the midline; haematuria, abdominal pain, hypertension and rupture are less common. ^[1][6]
• Renal ultrasonography leads, followed by CT or MRI for staging; thrombus in the renal vein or inferior vena cava must be specifically sought. ^[6][7]
• Wilms tumour rarely calcifies, unlike neuroblastoma, which calcifies in 80 to 90% of cases, crosses the midline and occurs in younger children. ^{[7] [6]}
• Stage predicts outcome: stage I greater than 95%, stage II greater than 90%, stage III 80 to 90%, stage IV 70 to 80%. ^[2]
• The two standard strategies are upfront nephrectomy (COG/NWTSG) and preoperative chemotherapy followed by delayed nephrectomy (SIOP). ^[3]
• Treatment is nephrectomy and stage-stratified chemotherapy with vincristine, dactinomycin and, for higher stages, doxorubicin, plus radiotherapy (about 10 to 20 Gy for local stage III or anaplastic disease). ^{[2][6] [1]}
• Bilateral (stage V) disease is managed with three-drug preoperative chemotherapy, nephron-sparing surgery and response-directed treatment; a modern protocol gives 81% 4-year event-free and 95% survival. ^[6]
• At-risk children (WAGR, Denys-Drash, Frasier, Beckwith-Wiedemann and others) are followed with renal ultrasonography every 3 months until 5 years for WT1-related syndromes and 8 years for Beckwith-Wiedemann. ^{[6] [3]}
• Under current regimens the overall 5-year relative survival is 93%. ^[6]

• Neuroblastoma
• Clear cell sarcoma of the kidney
• Beckwith-Wiedemann syndrome and WAGR spectrum
• Paediatric abdominal mass and renal presentation
• Congenital mesoblastic nephroma