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The pathology of Wilms tumour (nephroblastoma):the International Society of Paediatric Oncologyapproach

G M Vujanic,1 B Sandstedt2

ABSTRACT

In the International Society of Paediatric Oncology renaltumour trials, preoperative chemotherapy has beensuccessfully applied with resulting reduction of tumourrupture and increased favourable stage distribution ofnephroblastoma. Postoperative treatment includeschemotherapy and sometimes radiotherapy in a risk-adapted approach based on histological sub-classificationand stage of the tumour. However, preoperativechemotherapy alters the tumours histological featuresand distribution of subtypes, and makes staging moredifficult. The paper highlights the most common practical

diagnostic difficulties that a pathologist is faced with indealing with pretreated nephroblastomas. It emphasisesthe importance of a systematic, step-by-step analysisbased on adequately sampled material, in order to

accurately sub-classify a nephroblastoma as a low,intermediate or high risk tumour and assign its genuinestage. Finally, it outlines the standard operating procedure

for submission of renal tumours for rapid centralpathology review which allows the treating oncologists toapply the optimal treatment protocol.

Renal tumours comprise 7e8% of all tumours in thefirst 15 years of life. Wilms tumour (WT) ornephroblastoma is by far the most common (w85%of cases), followed by renal cell carcinomas(w3e5%), mesoblastic nephroma (w3%), clear cellsarcoma of the kidney (w3e4%), rhabdoid tumourofthe kidney (w2%) and miscellaneous rare tumours(w2%).1 Accurate histological diagnosis and stagingof these tumours are critical because their treatmentand prognosis are very different. Since they are rare,they still represent a diagnostic and therapeuticchallenge,2 and it is important to treat and studythem through large national and internationalmulticentre collaborative trials which include

centralised pathological review in order to verify thediagnosis and stage of cases entered on the trials.

The first multicentre trial started in 1969 in theUnited States through the National WilmsTumour Study group (NWTS; now part of theChildrens Oncology Group, COG) with the mostimportant objective being the establishment ofoptimal treatment for WT. NWTS/COG have beentreating WTs with surgery first, followed by, ifnecessary, postoperative chemotherapy and radio-therapy.3 On the other hand, preoperative therapyhas been an essential part of the InternationalSociety of Paediatric Oncology (SIOP) treatmentstrategy since its first trials. In the first two trials

(SIOP 1, 1971e

74; and SIOP 2, 1974e

76) preoper-

ative radiotherapy was used. Since the third trial(SIOP 5, 1977e79) it has been replaced withpreoperative chemotherapy which has shown verysimilar results in terms of preventing tumourrupture(s) and inducing more favourable stagedistribution, with more stage I tumours requiringless postoperative therapy (SIOP 5, 1977e79;SIOP 6, 1980e86; SIOP 9, 1987e93; andSIOP 93 01, 1993e2001).4 Due to the differenttherapeutic approaches between the two groups,there are further differences in histological sub-classification and staging (see below), making

a direct comparison of their results complicated.In 1978, Beckwith and Palmer introduced

a histological classification of primarily operatedWTs with two main groupsdanaplastic and non-anaplasticdwhich became a basis for their treat-ment in NWTS/COG trials.5 By studying thecorrelation between the histological features andsurvival of WTs that received preoperative chemo-therapy from the early SIOP trials, it becameapparent that they could be sub-classified into threetreatment groups: favourable, standard andunfavourable histology groups.6 In the more recentclassifications (SIOP 93 01 and the currentSIOP 2001), they have been renamed into low risk,intermediate risk and high risk tumours (table 1).7 8

This concept of stratification of tumours into low,intermediate and high risk groups has later beenfollowed in other tumours of childhood, includingrhabdomysarcomas, neuroblastomas, hepato-blastomas and germ cell tumours.

Further analyses of WT subtypes from SIOPtrials have resulted in removal from or addition ofcertain subtypes to the risk groups. So, forexample, WT with fibroadenoma-like structures,which was earlier regarded as a favourable histologytumour, has disappeared from the newclassification since it has been recognised that it

represented a pattern of growth of some WTsrather than a distinct histological type.9 On theother hand, it has been shown that a tumour sresponse to preoperative chemotherapy is anindicator of good prognosis,10 so completelynecrotic WT has been placed in the low risk tumourgroup (table 1).8 In the current SIOP 2001 trial(2001e), other WT types including epithelial,stromal and regressive (sub)type with >90%necrosis are being investigated since preliminaryresults have indicated that their prognosis is betterthan for other WT types from the intermediate riskgroup.11 12 In the same way, the presence ofa certain amount of blastema after preoperative

chemotherapy clearly indicates its non-

1Department of Histopathology,School of Medicine, CardiffUniversity, Cardiff, UK2Childhood Cancer ResearchUnit, Astrid Lindgrens ChildrensHospital, Karolinska Institutet,Stockholm, Sweden

Correspondence toProfessor G M Vujanic,Department of Histopathology,School of Medicine, CardiffUniversity, Heath Park, CardiffCF14 4XN, UK; vujanic@cf.ac.uk

Accepted 3 August 2009Published Online First16 August 2009

102 J Clin Pathol 2010;63:102e109. doi:10.1136/jcp.2009.064600

Review

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responsiveness to chemotherapy, and blastemal type WT hasbeen shown to be associated with poorer outcome13 and istherefore moved into high risk tumour group.8

According to the SIOP WT 2001 trial protocol, renal tumoursin children are treated withpreoperative chemotherapy consistingof two drugs given over a period of 4 weeks. Unlike in the rest ofthe SIOP, in theUK a histologicaldiagnosismade on percutaneouscutting needle (tru-cut) biopsy is required before preoperativechemotherapy.1 4 1 5 Chemotherapy is followed by surgery andfurther chemotherapy and/or radiotherapy, if necessary,depending on the tumours histological subtype and stage.

The pathologist has a critical role in the following:< Making an accurate histological diagnosis.< Assigning the tumours histological subtype and risk group.

< Making a precise evaluation of the abdominal stage of thetumour (even in children with stage IV disease, local staging iscrucial in determining the use of radiotherapy).

For pathologists, there is one major disadvantage of preoper-ative chemotherapydit significantly alters the histologicalfeatures of WT, resulting in different histological patterns anddistribution of subtypes from those treated with immediatesurgery. In the earlier SIOP study, in the immediately operated

WTs the most common subtype was mixed (45.1%), followed byblastemal (39.4%) and epithelial predominant (15.5%), whereasin tumours that received preoperative chemotherapy, the mostcommon type was regressive (37.6%), followed by mixed(29.4%), stromal (14%), blastemal (9.3%) and epithelialpredominant (3.1%); 6.6% of tumours were completelynecrotic.13 Preoperative chemotherapy is more likely to destroyblastema and (less differentiated) epithelial elements, while itinduces maturation especially in the stromal component, whererhabdomyoblastic differentiation is much more common than inprimarily operated tumours. The typical chemotherapy-inducedchanges of treated WTs are a mixture of coagulative-type necrosisof small round cells or neoplastic tubules consisting of pink,necrotic nuclei, consistent with coagulative necrosis of blastemalcells or neoplastic tubules, fibrosis, hypocellular stromacontaining foamy and/or haemosiderin-laden macrophages, andhaemorrhage.

In order to subtype a WT, a pathologist has to evaluate it ina particular order, as follows: