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Wilms tumour – 2015

UPDATED JUNE 2015

1. GENERAL INFORMATION

1.1    Incidence and mortality

Wilms tumour (WT) (or nephroblastoma) is a rare malignancy of the kidney, however representing the most frequent type of renal tumour (accounting for approximately 90% of the cases) in people with less than 15 years of age. According to RARECAREnet project, there are on average 600 new cases of WT a year in Europe (RARECAREnet). For the period 2000-2007, the European crude incidence rate of WT was 1.3 per million per year. In children incidence is higher with a crude rate of 7. Incidence is higher in girls than boys (Pastore 2006). The peak incidence occurs between 2 and 3 years of age, with 95% of children being diagnosed before the age of 10 years. During the period 2000-2007 the annual age-standardised incidence rate (per million) ranged between 2.0 and 1.2 in Central and Eastern European countries, respectively. During the period 1995-2007 a slight incidence increase, not significantly, was reported (RARECAREnet).  In the period 1978-1997, WT increased by 0.7% per year, however a significant increasing trend was observed only in age group 1-4 (Pastore 2006).
In 2012, 132 deaths for kidney cancer were estimated in European children (GLOBOCAN).

1.2  Survival

Five-year survival from WT for children diagnosed in all Europe in 2005-2007 was 90%, ranging from 94% (Central Europe) to 84% (Eastern Europe) (Gatta 2014). The prognosis for children with WT has improved dramatically as the result of advances in surgical techniques, and careful pre- and post-operative management, anaesthesia, and supportive care.  Children in the age 0-3 years at diagnosis had a more favourable prognosis than those diagnosed later. Five year survival improved during the period 1978-1997 (Pastore 2006); than, in the period 1999-2007 survival stabilised (Gatta 2014).

1.3 Prevalence

In Europe (EU27), at the beginning of 2008 about 18,150 people lived with a diagnosis of WT (Gatta 2012). 54% of all prevalent cases had survived more than 15 years after diagnosis (slightly less than 10.000 cases at the beginning of 2008); they are usually considered cured of their cancer.

1.4 Risk Factors

Due to the early age at diagnosis, environmental exposure from as early as preconception through pregnancy and the postnatal period is warranted, as well as the parental exposure. The most relevant are parental exposure to pesticide, maternal history of hypertension during pregnancy, and high weight at birth.
A recent meta-analysis (Chu 2010) evaluated the maternal exposure to pesticide, concluding for a significant higher risk of 40%. Regarding paternal exposure to pesticide, a study among farm in Brazil (Sharpe 1995) exposed at any time prior preconception estimated a significant risk of 4; a study on male and female farm owners using pesticide spraying equipment were found to have an high incidence of WT than expected based on rates in the general rural population (SIR = 2.5) (Kristensen 1996).
Paternal exposure to hydrocarbons and metals including lead during various periods as the hairdressing chemical were examined with some studies reporting high risk of WT in their children (Chu 2010).
From 4 to 10% of cases with WT is associated with high birth-weight (Chu 2010).  The large Swedish national cohort study found an association only in girls and with a disease onset before 5 years, but not over (Crump 2014).
The meta-analysis by Chu at al. estimated that 1.2% of WT cases is attributable to a maternal history of hypertension (Chu 2010).
A small proportion of WT cases appear to be heritable. Approximately 1.5% of patients in a large series had one or more family member (siblings or cousins) with WT (Coppes 1994; Sharpe 1995). Some congenital disorders and genetic conditions have been linked to WT. The risk is increased in children with:

  • the Beckwith-Wiedemann syndrome, an overgrowth syndrome associated with macroglossia, omphalocele, macrosomia, and visceromegaly;
  • the Simpson-Golabi-Behmel syndrome, an X-linked foetal overgrowth disorder caused by mutations in the glypican 3 gene;
  • the Perlman syndrome, the Denys-Drash syndrome and the WAGR syndrome. The WAGR syndrome (WT, aniridia, genitourinary malformations, and mental retardation) led to the identification of one of the WT genes. The genetic predisposition may also explain the very low incidence of WT cases after the age of 10 years (less than 3%).

Prenatal ionising radiation (in utero) from diagnostic x-rays was found in association with increased risk of WT only in one large study in the UK (Bithell 1975).
Several epidemiologic studies have investigated occupational, environmental, and lyfe style factors as risk factors for WT.
Factors for which evidence is limited include high birth weights: the association with birth weight over 4,000 grams has been reported in some studies (Sharpe 1995; Leisenring 1994; Yeazel 1997). Prenatal ionising radiation (in utero) from diagnostic x-rays was found in association with increased risk of WT only in one large study in the UK (Bithell 1975).  Few studies have suggested that children of fathers exposed as welders or mechanics  have increased risk of WT (Sharpe 1995). Pesticides have also been linked with increased risk (Zahm 1998). The studies reviewed by Zahm and Ward suggested that both childhood insecticide exposures and parental pesticide exposures before birth increase increase the risk of developing WT. However, these results were not confirmed by a recent review (Infante-Rivard 2007) based on further 6 studies. Three of them were negative and the others positive, all the observed risks were not statistically significant. The review emphasised the  importance of accurate exposure assessment and the need to consider the gene-environment interactions.
Factors for which evidence is inconsistent include maternal consumption of coffee and tea and maternal use of hair dye use, both during pregnancy. Studies on maternal medication use, even during pregnancy, reported associations with various drugs including hormones, antibiotics, dipyrone, metaclopramide, pethrane anaesthesia during delivery. Most of these results were found only in a single study (Sharpe 1995; Lindblad 1992; Sharpe 1996).

2. PATHOLOGY AND BIOLOGY

2.1 Pathology

Generally, WT usually occurs as a large, well-delimited mass in the kidney. On cut section, it can be solid or cystic, with areas of necrosis and haemorrhage. About 5% of children have bilateral disease and 7% have multicentric unilateral disease.
Microscopically, it is formed of three basic components that are blastema, epithelium and stroma (sarcomatous component) (Figure 1) (Argani 2003). The blastemal component is markedly cellular, morphologically undifferentiated, and formed of small, round to oval cells. The epithelial component tends to form more or less differentiated tubular and/or glomerular structures, but can also feature a number of other differentiated epithelia. In rare cases it gives origin to a renal cell carcinoma. The stromal (sarcomatous) component is usually formed by undifferentiated mesenchyma, but it can also show a distinct differentiation, usually a rhabdomyosarcomatous differentiation.
The typical immunophenotype of WT is nuclear immunoreactivity for WT1 (180 and C19), marked and diffuse in the blastemal and epithelial components, while it is variable in the sarcomatous component (Figure 1). Vimentin is present in all components. Coexpression of keratins marks the epithelial component, while the stromal component coexpresses desmin and myogenin in rhabdomyosarcomatous areas.
Seven per cent of WTs are anaplastic (Faria 1996). Anaplasia is a morphological marker of resistance to conventional therapies, neither induced nor modified by therapy itself. Microdissection studies have demonstrated an impairment of p53-induced apoptosis in anaplastic areas due to TP53 mutations  (Beniers 2001). Immunocytochemically, p53 immunoreactivity is present in anaplastic areas (Figure 1).

Figure 1.

tumore di wilms_figura1

Anaplasia is strictly defined on morphologic parameters as the simultaneous presence of:

  • atypical, generally multipolar mitoses;
  • nuclei which enlarged to at least three times the size of those in the adjacent cells of the same type;
  • hyperchromasia of the enlarged nuclei.

Anaplasia is classified into focal (1-4 clearly defined foci into the primary tumour) or diffuse, on topographical principles (Faria 1996). Not chemotherapy pre-treated WTs without anaplasia are usually referred as “favourable-histology” tumours. The presence of anaplasia usually occurs in children older than 3 years.
Previous treatment can induce changes in morphology or stage of the tumours (Vujanić 2009). The neoplastic component can undergo necrosis or post-treatment changes can occur, such as fibrosis, sclerohyalinosis, or fibrohistiocytic reactions with haemosiderin. Otherwise, the tumour can remain as a residual viable mass and appears unchanged or undergoes differentiation. The blastemal component can differentiate – resembling epithelium or stroma, the epithelial component may become “atrophic”, with differentiated tubular and glomerular structures and cysts lined by epithelium, and the stromal component may undergo maturation to a rhabdomyomatous component.
The nomenclature of WT varies in untreated and pre-treated tumours. Basically, in untreated tumours, the definition of the type (monophasic, biphasic, or triphasic type) is only a descriptive classification of the relative percentages of the three components. The nomenclature in pre-treated tumours follows the SIOP classification, with strict codified parameters, and bears prognostic significance as it is the basis for stratification into risk categories (Table 1) (Vujanić 2002). The nomenclature and significance of the presence of anaplasia is the same in both situations, namely pre-treated or primarily operated tumours.
The precursors of WT are nephrogenic rests, which are present in the parenchyma outside the neoplastic mass in 30-45% of kidneys with WT (reviewed in Fukuzawa 2007). They are defined as persistence of foci of nephrogenic cells after the 36th week of pregnancy. They are classified into perilobar and intralobar, and are related to a risk of synchronous or metachronous development of WT in the opposite kidney.

Table 1. Revised SIOP working classification of renal tumours of childhood (2001).

 

For pre-treated cases
I. Low risk tumours Cystic partially differentiated nephroblastoma
Completely necrotic nephroblastoma
II. Intermediate risk tumours Nephroblastoma – epithelial type
Nephroblastoma – stromal type
Nephroblastoma – mixed type
Nephroblastoma – regressive type
Nephroblastoma – focal anaplasia
III. High risk tumours Nephroblastoma – blastemal type
Nephroblastoma – diffuse anaplasia

2.2 Biology

The observation that sporadic WT cases differ from those that are familial in terms of  age of onset and the frequency of bilateral presentation, led Knudson and Strong to propose that WT develops as a consequence of two rate-limiting events (two “hits”), which subsequently were identified as the bi-allelic inactivation of a tumour suppressor gene (Knudson 1972).
The WT1 gene located on chromosome 11p13, which plays an important role in kidney embryogenesis (Pritchard-Jones 1990), perfectly fits within this model. In fact, patients affected with the WAGR (Wilms tumour, aniridia, genitourinary abnormalities, and mental retardation) or the Denys-Drash syndromes, both predisposing to WT, carry germline heterozygous deletions or point mutations of WT1, which is completely inactivated in tumour DNA (reviewed in Little 1997). However, inactivating mutations of the WT1 gene are detectable only in a small fraction – not exceeding 15% – of sporadic WTs without congenital anomalies (Little 1997; Schumacher 1997; Little 2004; Perotti 2005). Interestingly, 50 to 75% of WT1-mutant WTs carry mutations also of the CTNNB1 gene, which codes for β-catenin, an important transcription regulator of the WNT/β-catenin pathway. However, such mutations are not usually detectable in WTs with wild-type WT1 alleles (Maiti 2000; Li 2004). In the latter group, a number of studies, including cytogenetics, loss of heterozygosity, and comparative genomic hybridization analyses, have revealed the involvement of different chromosomal regions. These include 11p15, where a cluster of imprinted genes, among which H19 and IGF2, is mapped (Reeve 1989; Rainier 1993; Ogawa 1993); 1p, 11q, 16q, 22q (Maw 1992; Grundy 1994; Radice 1995; Klamt 1998; Hing 2001; Höglund 2004; Ruteshouser 2007), and 7p, where two candidate WT suppressor genes, PTH1 and POU6F2, have been identified (Vernon 2003; Perotti 2004).
Recently, mutations affecting aminoacid residue Q177 of SIX1 and SIX2 have been described in 4.3-7% of WTs and mutations in miRNA processing genes (miRNAPGs) DROSHA and DGCR8 have been identified in 8.1-15% of WTs (Walz 2015, Wegert 2015).

3. DIAGNOSIS

Renal masses in children may be discovered during routine clinical examination or incidentally during the course of diagnostic or therapeutic procedures for other causes. Renal tumours are rare in the paediatric population and include a spectrum of diseases that may challenge the clinician in choosing the optimal treatment. Most children with WT are brought to medical attention because of abdominal swelling or the presence of an abdominal mass. Abdominal pain, hypertension, gross haematuria, or fever are other possible signs at diagnosis. Hypertension is present in about 25% of patients. A thorough review of the patient’s clinical history and physical examination may reveal additional signs or symptoms to aid in the diagnosis.
The differential diagnosis for renal masses in children includes both benign and malignant conditions. The most common malignant paediatric renal tumours are WT, clear cell sarcoma of the kidney, rhabdoid tumour of the kidney, mesoblastic nephroma, and renal cell carcinoma. As the therapy approach is different for these different entities, it is of paramount importance to obtain an histological diagnosis, through nephrectomy or with a biopsy in those cases in which primary chemotherapy is planned. However, there are cases in which the radiological picture is highly revealing of WT that the biopsy might be omitted. Neuroblastoma, especially those typically arising from the adrenal gland, or benign processes (polycystic kidney disease, renal abscess, hydronephrosis) may produce clinical and radiographic findings similar to the ones produced by renal tumours.
If a renal tumour is suspected, diagnostic imaging studies play a central role in the evaluation of initial extent of disease and for planning surgery or monitoring the response to therapy. Parameters that should be carefully evaluated are the extent of the tumour within and behind the kidney, involvement of the contralateral kidney, the presence of intravascular tumour thrombosis (renal and cava venis), and  the presence of retroperitoneal lymph nodes (Slovis 2008; Owens 2008).
The initial radiographic study is an abdominal ultrasound examination (standard procedure). Either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen is recommended to further evaluate the nature and the extent of the mass. This examination is of importance for adequate planning of surgery. In addition, these cross-sectional images may demonstrate small lesions in the contralateral kidney, thus avoiding further, unnecessary surgical exploration (standard basis).
Despite thorough clinical and radiographic evaluation, some renal masses will remain indeterminate, and their management is subject to individual clinical opinions. Careful correlation of clinical and imaging findings may facilitate the pre-operative diagnosis of most renal lesions. An emphasis on the multidisciplinary approach is essential to the evaluation of these patients, including the paediatrician, paediatric radiologist, paediatric surgeon, paediatric oncologist and radiotherapist, and pathologist.
The clinical relevance of small lung nodules detected only on CT scan but not on chest radiograph remains to be elucidated. Retrospective studies of the prognostic significance of CT-only lung nodules in WT patients have yielded conflicting results (Wilimas 1997; Green 1991; Meisel 1999; Grundy 2012). In the past, two alternative treatment approaches were recommended in these cases (i.e., as truly metastatic patients or according to local tumour stage), dependently on physician’s choice. More recently, the additional therapy – especially concerning indications to whole lung radiotherapy – is based on the quality of response of the lung nodule to a phase of chemotherapy, on a type 3 level of evidence.
WT most commonly metastasises to the lungs and regional lymph nodes, less frequentlu to and liver. The presence/absence of metastases should be evaluated at presentation, on the basis of imaging studies.

4. STAGING

Staging is currently one of the most important prognostic indicators for WT. The staging system incorporates clinical, surgical and pathological information, as standard evidence. The current definition of stage is depicted in Table 2.
The debate over the correct stage definition of those patients with local tumour spillage (spontaneous, intraoperative or due to a needle biopsy) continues. Since the demonstration of increased relapse rate in patients with spillage or rupture previously classified as stage II (thus as “minor” rupture), treated according to NWTS-4 and -5) where the overall survival was not significantly different (D’Angio 2003; Shamberger 1999), the current attitude of North American researchers is to classify these tumours as stage III, on a type 3 level of evidence (Perlman 2005).

Table 2. Staging system for Wilms tumour.
STAGE I Tumour confined to the kidney and completely resected.
No penetration of the renal capsule or involvement of renal sinus vessels
STAGE II Tumour extends beyond the kidney but is completely resected (negative margins and lymph nodes).
At least one of the following has occurred:

  • penetration of the renal capsule;
  • invasion of the renal sinus vessels;
  • biopsy of tumour prior to removal
STAGE III Gross or microscopic residual tumour remains post-operatively,including inoperable tumour;
positive surgical margins; spillage of tumour pre-operatively or intraoperatively;
regional lymph node metastases; or transacted tumour thrombus
STAGE IV Haematogeneous metastases or lymph node metastases
outside the abdomen (e.g., lung, liver, bone, brain)
STAGE V Bilateral renal Wilms tumour

5. PROGNOSIS

Currently, the recognised prognostic factors in children with WT are disease stage and tumour histological features on a type C basis. Advanced tumour stage at the time of diagnosis is associated with increased risk of recurrence and mortality on a type C basis. The most important histological predictor of response and survival in untreated WT is the presence of diffuse anaplasia, on a type C basis. Pathological examination is necessary to distinguish between focal and diffuse anaplasia (Beckwith 1996). Despite patients with focal anaplasia had a better prognosis than those with diffuse anaplasia in oldest North American studies (Faria 1996), in the more recent protocol this data has been reconsidered. Children with stage II to IV WT with diffuse anaplasia have a poor prognosis, on a type C basis (Green 1994). When anaplastic foci are completely removed in stage I tumour, the outcome is more favourable, on a type R basis (Faria 1996; Beckwith 1996). Recent studies provided evidence that TP53 mutational analysis might improve risk stratification in diffuse anaplastic WT (Maschietto 2014). Anaplastic tumours with TP53 mutations and/or 17p loss had an increased risk of recurrence and death compared to tumours lacking TP53 abnormalities.
While stage and anaplasia have been identified as prognostic indicators independent of whether patients are treated by immediate surgery or surgery after preoperative chemotherapy, the SIOP trials have allowed studies to be undertaken of drug-induced regression as prognostic factors (Vujanić 2002; van den Heuvel-Eibrink 2015). Tumours which show massive necrosis seem to be associated with a better outcome, while the persistence of a large amount of blastemal component after pre-operative chemotherapy is an adverse prognostic factor, on a type 3 level of evidence. These findings are considered as individual prognostic parameters in those patients who receive pre-operative chemotherapy, and are currently adopted in the SIOP protocols as factors influencing the choice of therapy.
The prognostic relevance of certain genetic abnormalities has been controversially discussed in the literature (Dome 2002). There is evidence for loci which may be associated to more aggressive tumours, namely allele loss (LOH) on chromosomes 1p, 7p, 11q, 16q and 22q. Independent studies have assessed the predictive value of some of these abnormalities (Grundy 1994; Grundy 1998; Klamt 1998; Bown 2002). Colleagues from the North America have reported that LOH for both chromosomes 1p and 16q identifies a subset of WT patients who have a significantly increased risk of relapse and death, on a type 3 level of evidence (Grundy 2005). The effect of LOH on outcome in the National Wilms Tumour Study-5 was most apparent among people who had LOH for both 1p and 16q. Compared to the four-year RFS percentage for patients with stages I/favourable histology (FH) or II/FH with no LOH (85.7%), the four-year RFS percentages were 68.7% (LOH 1p an 16q) (p = 0.001).
A gain of chromosome 1q has been recently demonstrated to be associated with an increased rate of recurrence, on a type 3 level of evidence (Hing 2001; Gratias 2013).
Age less than 2 years at diagnosis has been broadly correlated with a better outcome on a type 3 level of evidence (Green 1993; Pritchard-Jones 2003).
Recent data point towards the prognostic impact of LOH on chromosome 1p (Spreafico 2013), and of copy number gain of chromosome 1q (Perotti 2012; Gratias 2013). Furthermore, MYCN gain has been demonstrated to be associated with anaplasia, and with poorer relapse-free and overall survival, independent of histology (Williams 2015). Intriguingly, also the combination of SIX1 or SIX2 and miRNAPGs mutations has been described as resulting in poor outcome (Walz 2015), and it is associated to high-risk blastemal-type WT (Wegert 2015).

6. TREATMENT

During the last three decades, the international cooperative groups conducted sequential studies of treatment for children with WT. Regardless of the timing of surgery (upfront versus post-chemotherapy), the North American (previously organised in the National Wilms Tumor Study Group, and currently named Children’s Oncology Group (COG) and the SIOP (International Society of Paediatric Oncology) groups have highlighted three drugs that are highly effective for WT: vincristine, actinomycin-D and doxorubicin. The combination, duration of treatment, and mode of administration of these drugs have been refined through extensive trials. Other drugs that have been recommended for higher-risk or non-responding patients are etoposide, carboplatin, and either cyclophosphamide or ifosfamide, on a type C basis (Pein 1994; Spreafico 2008). Two-drug chemotherapy (vincristine plus actinomycin) is used for stage I or II tumours, whereas doxorubicin and radiation therapy are added for stages III and IV, on a type C basis. Only a minority of high-risk tumours (namely, diffuse anaplastic and blastemal-type after pre-operative chemotherapy) needs adjunctive drugs.
Radiotherapy is currently used in selected cases, mainly when the tumour has loco-regional extension, or when there is residual tumour after surgery, on a type C basis (i.e., stage III). Even if pulmonary radiotherapy indicated in patients with lung metastases at diagnosis is under critical re-evaluation, current approaches claim for omission of whole lung radiotherapy in cases displaying complete remission of lung metastases after neo-adjuvant chemotherapy, on a type C basis (Verschuur 2012).

6.1 North American Studies

Current therapy for WT in North America has evolved through five completed studies of the NWTS group (reviewed in Neville 2000; Grundy 2005). NWTS has sought to refine adjuvant therapy, with each study intensifying the therapy provided for high-risk patients and decreasing or modifying the therapy for low-risk patients. All the trials were based on the cornerstone of primary nephrectomy, followed by adjuvant chemotherapy, and radiotherapy as indicated. In addition, the latest protocols were specifically focused on prospectively test tumour-associated molecular features as prognostic biomarkers (Dome 2013).
Since the first NWTS study protocol (launched in 1969), the combination of vincristine and actinomycin D has been acknowledged as being more effective than drug alone, and thus became the benchmark of therapy for achieving a favourable outcome (D’Angio 1976). The NWTS-2 protocol (1975-1978) found that the addition of doxorubicin improved survival for higher-stage patients (D’Angio 1981). In the NWTS-3 protocol (1979-1986), the role of doxorubicin was further elucidated, demonstrating that this potentially cardiotoxic drug was not essential in non-anaplastic stage II tumours, being subsequently omitted (D’Angio 1989). For stage III patients, the dose of irradiation to the flank was reduced to 10.8 Gy. The NWTS-3 protocol randomly assigned stage I children to treatment with vincristine and actinomycin D for either 10 weeks or 6 months; the reviewed 16-year RFS rates were 88.9% for patients treated for 10 weeks and 92.5% for patients treated for 6 months (p = 0.08) (Green 2004).
To sum up, the major conclusions from NWTS-1, -2, -3 were:

  • post-operative flank radiotherapy is unnecessary for children with stage I or II/favourable histology, when treated with vincristine plus actinomycin D;
  • cyclophosphamide showed no benefit in stage IV/favourable histology tumours, while improved RFS and OS rate in children with stage II to IV anaplastic WTs.

The NWTS-4 protocol (1986-1994) evaluated efficacy, toxicity and costs of administration of different regimens of drugs, namely “pulse-intensive” regimens (Green 1998a). The NWTS 4 documented that 6-month treatment is as effective as 15-month treatment in stage II to IV non-anaplastic WT. The 2-year RFS in NWTS-4 exceeded 91%.
The recently-closed NWTS-5 protocol prospectively tested the influence of tumour-specific LOH for chromosomes 1p and 16q on outcome, identifying a subset of patients with favourable-histology WT who have a significantly increased risk of relapse and death (see section «Prognosis»), on a type 3 level of evidence (Grundy 2005).
The treatment strategy for metastatic WT (without anaplasia) is less standardised. Generally, the therapy includes chemotherapy with vincristine, actinomycin D, and doxorubicin as a standard coice, while abdominal radiation therapy is restricted to those with local stage III tumour. Both the COG and the SIOP current protocols are adopting a response-based approach in lung radiotherapy decision making, omitting radiotherapy for cases with rapid complete response of lung metastases after neoadjuvant chemotherapy, on a type C basis.
The results from NWTS-3 for children with stage IV/favourable histology WT demonstrated no statistically significant improvement in 4-year RFS or OS resulting from the addition of cyclophosphamide to the three-drug regimen.

6.2 International Society of Pediatric Oncology (SIOP)

The SIOP trials largely focused on the issue of pre-operative therapy. The use of pre-operative chemotherapy is considered to be of benefit because it reduces the risk of tumour rupture during surgery on a type 1 level of evidence (Lemerle 1976; Mitchell 2006), induces a favourable stage distribution, with 60% of patients with stage I disease requiring less adjuvant therapy on a type 3 level of evidence and selects good responders among patients with stage IV disease on a type 3 level of evidence .
The SIOP conducted different trials and studies aimed at developing a treatment strategy tailored to the primary chemotherapy-induced response in the tumour. Other goals of pre-operative chemotherapy are to decrease surgical morbidity, and to reduce the rate of tumour ruptures, resulting in a higher percentage of patients with a  lower tumour stage (this is the concept of “downstaging”). Downstaging aims to lower the number of stage III tumours requiring more aggressive therapy.
The first two SIOP trials and studies (1971-74, and 1974-76) provided the rationale for employing pre-operative therapy, showing that pre-treatment reduced the rate of tumour rupture and predisposed towards a good stage scoring after surgery (Lemerle 1976). The other early SIOP studies investigated the best pre-operative treatment modality, concluding that a two-drug regimen with vincristine and actinomycin D was effective and well tolerated (reviewed in Graf 2000). It was demonstrated that only a short post-operative treatment was necessary in stage I patients, while intensification of chemotherapy by adding an anthracycline was employed in stage II (lymph node negative) patients, because of an higher rate of abdominal relapses in this group (Tournade 1993). Risk-adapted therapy – as designed in SIOP 6 – resulted in an 82% 2-year RFS rate and a 89% 5-year OS rate for the series as a whole. In the subsequent SIOP-9 (1987-1991) a primary aim was to determine the optimum duration of pre-operative chemotherapy. This trial showed that 4 weeks were as effective as 8 weeks in terms of stage distribution, but not concerning tumour shrinkage (Tournade 2001). The 4-year EFS was 87% for stages I to III, and 65% for stage IV, with an OS of 90% (stages I-III) and 81% (stage IV).
A retrospective analysis of SIOP 1993-2001 data showed that post-chemotherapy histological classification of the tumours in low, intermediate, and high-risk was most important (Graf 2000; de Kraker 2004). The current SIOP classification includes in low-risk group children with completely necrotic WT, mesoblastic nephroma, and cystic partially differentiated nephroblastoma. The intermediate-risk group consists of five histological types (epithelial, stromal, mixed and regressive type, and focal anaplasia). Included in the high-risk tumour group are blastemal-type WT and diffuse anaplasia type.
The contemporary SIOP 2001 trial and study has prospectively tested in a randomised fashion the role of adding doxorubicin in stage II and III intermediate-risk patients. Respective data significantly showed that doxorubicin could be safely omitted for stage II and III, without jeopardising overall survival rate for intermediate-risk patients. Current standard adjuvant therapy in SIOP 2001 for stage II and III (intermediate-risk) tumours has consequently moved to the combination of vincristine and actinomycin D alone, without doxorubicin.
In the case of stage IV patients,  SIOP adopts a response-adapted risk stratification, so that lung irradiation can be avoided for children with rapidly responding lung metastases, on a type 3 level of evidence (Verschuur 2012). The results of a trial within the SIOP-6 study showed that patients in complete remission after chemotherapy (and in some cases after metastasectomy) did not need irradiation to the lungs (Tournade 1993).
In conclusion, the individuality of the SIOP approach allowed assessment of the histopathological features that chemotherapy had induced in tumour cells, establishing the efficacy of the drugs used in vivo.

6.3 United Kingdom Children’s Cancer and Leukaemia Group

The United Kingdom Children’s Cancer and Leukaemia Group summarised their combined experience to evaluate the benefits of immediate surgery versus pre-operative chemotherapy. In the earlier studies the approach was to perform a primary nephrectomy (Pritchard 1995; Mitchell 2000), the group then performed a randomised comparison of the two diverse methods (Mitchell 2000), while more recently the group has joined the ongoing SIOP 2001 trial and study.
The first study (1980-1986) included a non-randomised trial of single-agent vincristine for children with stage I/favourable histology WT; the 3-year EFS rate was 90%, and the OS 96% (Pritchard 1995). The second UKW trial (1988-1991) confirmed an excellent outcome for stage I tumours treated with only 10 weekly vincristine (Mitchell 2000). More recent analysis has documented that the excellent outcome in stage I WT  is not achieved in children aged 4 years or older. The UKW3 randomised trial addressed the question of whether pre-operative chemotherapy achieved a higher rate of success in children with low stage disease  and  reduced the overall burden of treatment (Mitchell 2006).  Despite a low recruitment, they were able to demonstrate that about 15% of patients can be shifted from stage III to stage I tumours with pre-operative chemotherapy.

6.4 Italian Association of Paediatric Haematology and Oncology (AIEOP)

The benchmark of the Italian studies has been the primary nephrectomy approach, with adjuvant therapy based on tumour stage and histology, on a type C basis.
The second AIEOP study (Protocol CNR-AIEOP-92, 1992-1998) provided the basis for the therapy regimens that are currently adopted in Italy. Stage-adapted adjuvant chemotherapy for non-anaplastic WT was:

  • stage I-II, weekly vincristine and low-intensive actinomycin D every 4 weeks, up to either 8 or 25 weeks, respectively;
  • stage III, 8-weekly vincristine, actinomycin D (week 1, 3, 5, 7), doxorubicin (week 3, 7) followed by delayed irradiation to the flank and additional three-drug chemotherapy for total one year duration.

Children with stage II to IV either focal or diffuse anaplastic tumours received one year of chemotherapy employing ifosfamide, etoposide and carboplatin as additional drugs, plus radiation therapy. The 5-year OS and EFS for the whole series were 88% and 79%, respectively. EFS (OS) by stage were 87% (93%) for stage I; 81% (93%) for stage II; 75% (82%) for stage III; 61% (75%) for stage IV. Unfavourable histology WTs, rhabdoid tumours and clear cell sarcomas of the kidney had a 67% EFS (Spreafico 2006).
The subsequent contemporary AIEOP-WT-2003 protocol aimed at reducing chemotherapy for stage I/II WT, and improving the outlook for stage III/IV WT (balancing radiotherapy timing/indications and doxorubicin dose reduction), and for anaplastic tumours. Treatment was assigned as follows:

  • stage I (including anaplastic cases) and II receive either 6-week or 22-week vincristine/actinomycin-D chemotherapy, respectively;
  • stage III receives 34-week three-drug chemotherapy and abdominal radiotherapy;
  • stage IV receives pre-operative 6-week three-drug chemotherapy, abdominal and/or metastatic sites radiotherapy (the last one based on metastatic-response modulation) plus three-drug chemotherapy.

For stage II-IV anaplastic cases, an intensified regimen based on alternating courses of ifosfamide/D and carboplatin/etoposide was designed. Five-year DFS and OS for non-anaplastic WT were 86% ±2 and 94% ±1, respectively.
DFS (OS) according to tumour stage are:

  • stage I: 90% ±3 (97% ±2);
  • stage II, 86% ±3 (94% ±2);
  • stage III, 88% ±4 (97% ±2);
  • stage IV, 75% ±6 (86% ±5).

For 33 metastatic complete responders to pre-operative three-drug chemotherapy, for whom lung radiotherapy was omitted, DFS (OS) was 83% ±7 (96% ±4) compared with 65% ±9 (73.5% ±9) for incompletely responders. DFS (OS) was 70% ±7 (74% ±7) in 43 cases with diffuse anaplastic tumours.

6.5 Bilateral disease

Synchronous bilateral WTs occur in 5-7% of patients. The management presently recommended is initial chemotherapy, on a type C basis. Initial biopsy can be omitted in selected cases, when the imaging evaluation is highly suggestive of WT, on a type C basis (Perlman 2005; Owens 2008; Indolfi 2013). Primary excision of the tumour masses should not be attempted. A first tumour response re-evaluation is ideally performed after 6 weeks of double-agent chemotherapy (vincristine, actinomycin-D) to determine whether response has been sufficiently adequate to allow conservative tumour resection, with preservation of a substantial amount of normal renal tissue, on a type 3 level of evidence.
In cases of requirement of further tumour reduction, additional courses of the same chemotherapy regimen can be administered before surgery. It is under discussion whether intensifying pre-operative chemotherapy (namely adding additional drugs) might be of benefit in allowing a higher rate of nephron-sparing surgical procedures. However, it is worth noting that prolonging primary chemotherapy phase may result in an increased risk of developing anaplastic foci within the tumour. In case of persistent non response to primary chemotherapy, it is preferable to proceed with a surgical exploration, on a type C basis. When failure of the mass to shrink is not due to persistent viable tumour, but to the presence of necrosis, fibrosis, or skeletal muscle differentiation or stromal elements, in some cases an early surgical incisional biopsy or resection may identify anaplastic histology and limit the duration of chemotherapy for children with bilateral WT and anaplasia (Hamilton 2006).
When planning definitive surgery, partial nephrectomy or wedge excision of the tumour should be considered, on a type C basis, but only if complete tumour resection can be obtained and part of either or both of the kidneys can be salvaged (Davidoff 2008).
Post-operative chemotherapy should be continued in relation to stage and histological features of the tumour, based on SIOP risk grouping, on a type C basis (Vujanić 2002).

6.6 Surgery

Surgery remains a crucial part of treatment for renal tumours, providing local primary tumour control and information for adequate tumour histology and staging. Trans-peritoneal radical nephrectomy is the mainstay of treatment for most patients with WT, on standard evidence. To ensure optimal patient outcome, the surgical management of the children must be appropriate, removing the tumour without rupture or spill, and determining correctly the intra-abdominal extent of the tumour (Ehrlich 2005). Sampling of regional lymph nodes is standard. Extensive lymph node resection is not recommended, on a type 3 level of evidence, but the absence of node biopsy may result in under-staging and under-treatment of the tumour, and may result in an increased risk of local recurrence (Shamberger 1999). It is not clear how many lymph nodes should be sampled to achieve reliable staging. Furthermore, the data reported by Shamberger et al. provided evidence that tumour spill by the surgeon increases the risk of local disease recurrence. In Shamberger’s work, the largest relative risk for local relapse in NWTS-4 was observed in children with stage III tumours, in children with diffuse anaplasia, and in children reported to have tumour spill during surgery.
Nephron sparing surgery has been advocated in monolateral WT cases to decrease the risk of hyperfiltration injury and, thus, the risk of late renal failure in successfully treated patients with WT. The risk of end-stage renal disease in children with unilateral, non-syndromic WT treated on the NWTS group protocols is 0.7% (Green 2013a). Partial nephrectomy, when technically feasible, is indicated for those cases with bilateral disease and in those with unilateral tumour where the patient has urological disorders or syndromes predisposing to nephroblastoma, on a type C basis. The role of renal sparing surgery in patients with bilateral tumours is clear, but for children with and without any risk of developing contralateral metachronous tumours further clairification is needed.

7. LATE SEQUELAE

Generally, late complications are a consequence of treatment type and intensity; the use of radiotherapy and anthracyclines increases the risk of these complications. Some clinically significant late sequelae possibly occurring in WT survivors include cardiac toxicity, reproductive problems, musculoskeletal effects, renal dysfunction, and the development of second malignant neoplasms (Mertens 2001; Curry 2006; Wright 2009; Green 2013b).
Heart failure is the commonest late effect of doxorubicin, and can occur many years after treatment. The cumulative incidence of congestive heart failure was 4.4% 20 years after diagnosis among National Wilms Tumour Studies participants who received doxorubicin as part of their initial therapy, and it was 17.4% among patients who received doxorubicin for an initial or subsquent relapse (Green 2001). Female sex, cumulative doxorubicin dose, and left flank radiation therapy were significant risk factors for congestive heart failure. Cardiac toxicity depends on drug total cumulative dose, although some myocyte damage has been seen to develop after low dose treatment (Kremer 2002). Severe heart dysfunction has not been detected in survivors receiving a total dose less than 250 mg/m2 and current protocols take this cumulative dose into account as the recommended limit, on a type C basis. A regular echocardiogram is standard option for survivors treated with doxorubicin, whether it is given with or without pulmonary radiotherapy.
Fertility and pregnancy outcome are both compromised in females receiving whole abdominal irradiation in which both ovaries and/or the uterus are within the treatment field, compared with the non irradiated group, on a type 3 level of evidence. Male fertility is generally not at risk.
Long-term studies have reported renal impairments uncommon in unilateral nephrectomy survivors, so that total nephrectomy is still the standard option (Green 2013; Spreafico 2014). Life-long evaluation of renal function is recommended pnly for children with conditions known to predispose to renal dysfunction.
The type and distribution of second cancers following WT suggests that patients treated with radiotherapy are at greater risk compared to those not given radiation (Breslow 2005). The cumulative risk of a second malignant neoplasm among participants in the National Wilms Tumour Studies was 1.6% 15 years after diagnosis. These patients should be appropriately counselled about their risk and offered, whenever available, clinical surveillance to achieve early diagnosis. A recent analysis from the NWTS database showed that female survivors of WT who were treated with chest radiotherapy had a high risk of developing early breast cancer, with nearly 15% developing invasive disease by age 40 (Lange 2014). Careful medical and epidemiological monitoring of survivors can provide critical information to further optimise therapy while minimising long-term sequelae.

8. FOLLOW-UP

Although no studies have been carried out to evaluate the most effective schedule to follow patients treated for WT, the aim of an organised follow-up programme are:

  • detection of relapse at a stage at which salvage treatment has the best chance of efficacy;
  • monitoring and treating therapy-related toxicities;
  • early diagnosis of metachronous WT in children who may be predisposed to such an event;
  • detection of secondary malignancies.

Most relapses (about 90%) occur in the first 2 years after diagnosis and the remainder in the next 2 years (Malogolowkin 2013).
The first site of recurrence is the lung, so that chest radiograph must be performed routinely at regular intervals until approximately 5 years post-diagnosis. Children with WT-predisposing syndromes or with nephrogenic rests require longer follow-up, because the remaining kidney(s) continue to be at risk for several years.
The current AIEOP recommendation for follow-up of patients treated for WT are the following:

  • clinical examination and chest x-ray every 2 months during treatment and in the subsequent first year, every 3 months in the second year, every 4 months in the third year, every 6 months in the fourth year;
  • post-operative abdominal ultrasound every 4 months in the first 2 years, every 6 months in the third year then yearly
  • in stage III patients abdominal ultrasound should be performed every 2 months during first year, every 3 months in the second, every 4 months in the third year, then yearly;
  • echocardiogram at the baseline, then for several years for patients treated with doxorubicin  and/or whole lung radiotherapy;
  • pulmonary function test at the baseline then for several years for patients treated with whole lung irradiation.

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Dr. Davide Biasoni (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address: davide.biasoni@istitutotumori.mi.it

Dr. Paola Collini (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:paola.collini@istitutotumori.mi.it

Dr. Lorenza Gandola (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:lorenza.gandola@istitutotumori.mi.it

Prof. Norbert Graf (Reviewer)
University Hospital for Children – Homburg, Germany

Dr. Alfonso Marchianò (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:alfonso.marchiano@istitutotumori.mi.it

Dr. Carlo Morosi (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:carlo.morosi@istitutotumori.mi.it

Dr. Daniela Perotti (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:daniela.perotti@istitutotumori.mi.it

Dr. Luigi Piva (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:luigi.piva@istitutotumori.mi.it

Dr. Filippo Spreafico (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address: filippo.spreafico@istitutotumori.mi.it

Dr. Monica Terenziani (Author)
Fondazione IRCCS “Istituto Nazionale dei Tumori” – Milan, Italy
e-mail address:monica.terenziani@istitutotumori.mi.it