Renal tumours of childhood: an update

Pathology (February 2008) 40(2), pp. 217–227

DIAGNOSTIC TUMOURAL HISTOPATHOLOGY

Renal tumours of childhood: an update GORDAN M. VUJANIC´*

AND

ADRIAN K. CHARLES{

*Paediatric Pathology, School of Medicine, Cardiff University, United Kingdom, {Pathwest, Princess Margaret Hospital, Subiaco, Western Australia

Summary The role of the pathologist has been fundamental in the progress of the treatment of paediatric renal tumours. There are different philosophies in the treatment of these tumours, and there have been many recent advances in the areas of chemotherapy, identification of new entities, prognostic histological criteria following treatment and molecular prognostic and diagnostic features. This review discusses the different approaches of the different treatment protocols from Europe and North America, and reviews staging criteria, prognostic criteria and also the different tumour entities. Key words: Renal tumours, nephroblastoma, Wilms’ tumour, childhood tumours, histology. Received 11 October, revised 23 October, accepted 23 October 2007

INTRODUCTION The last 40 years have seen a large change in the management and diagnosis of paediatric renal tumours and this has been reflected in a greatly improved prognosis. The role of the pathologist is fundamental in the management of these tumours and pathologists have been crucial in many recent developments. The establishment of national and international groups with treatment protocols designed to improve and research the management of children with cancer, the formation of specialised paediatric oncology units with multidisciplinary teams, central pathology review, and good statistical support have been key components in the improved treatment of these children. The role of Bruce Beckwith and the National Wilms’ Tumor Study group (NWTS) in the United States, the Socie´te´ Internationale d’Oncologie Pe´diatrique (SIOP) and United Kingdom Children’s Cancer Study group (UKCCSG) pathologists in Europe, and groups elsewhere, have led to recognition of many new entities (Table 1), histological subtypes, refinement in pathological staging systems (Table 2), histological prognostic features following chemotherapy, increasing use of molecular diagnostic techniques and also insights into tumour biology.1 This has led to treatment protocols based on prognostic indices to optimise an individual’s therapy to balance the risks of inadequate treatment with iatrogenic morbidity. The majority (over 90%) of patients can now look forward to a long term cure. This has changed the emphasis of treatment from cure to reducing the burden of long term therapy-related sequelae from surgery, chemotherapy and radiation, such as infertility, secondary tumours, scoliosis

and cardiomyopathy. End stage renal failure is not common, apart from the patients with multifocal disease where renal sparing therapy regimens are planned, and patients with syndromes such as Denys-Drash, WAGR (Wilms’ tumour/aniridia/genitourinary anomalies/mental retardation syndrome) and, to a lesser extent, those with hypospadias or genitourinary abnormalities.2 The treatment of clear cell sarcoma of the kidney with adriamycin/ doxorubicin has now transformed the prognosis of this tumour to close to that of Wilms’ tumour. The current major clinical challenges include developing new therapies for current therapy-resistant disease, such as the high stage anaplastic Wilms’ tumour, persisting blastemal type (after pre-operative chemotherapy) Wilms’ tumour, the relapsed chemo-resistant Wilms’ tumours and higher stage rhabdoid tumours.3,4 Improved radiological investigation techniques are also changing practice. For pathologists, awareness of the different tumour types, staging criteria, prognostic histological features both before and after therapy, and handling of surgical material to enable the child to benefit from the best therapy is crucial. New diagnostic modalities such as gene array may take an important role in diagnosis and prognosis before long.5 This review is to provide information on the current state of pathologists’ management of paediatric renal tumours, reviewing the major entities, handling of the tumour with particular attention being paid to recent changes in staging, recognition of the use of post-chemotherapy changes as prognostic information, mention of some newer entities and use of molecular techniques for both diagnosis and prognosis. As in many tumours, the mainstay of diagnosis remains H&E stained slides. These patients should be managed in tertiary referral centres as the evidence is clear that prognosis for the child is improved at such centres. Unlike adults with cancers, the majority of children with cancer are entered into trials, and correct pathological examination and retention of tissue can be very important in enabling a child to be registered.

OVERVIEW OF THE TREATMENT OF PAEDIATRIC RENAL TUMOURS: THE MAIN INTERNATIONAL APPROACHES The management of paediatric renal tumours depends crucially upon histological type and stage. Internationally there have been different approaches to treatment of these tumours.6–8 In the United States [NWTS or more recently the Childrens’ Oncology Group (COG) which has formed from the separate tumour groups in North America] renal

Print ISSN 0031-3025/Online ISSN 1465-3931 # 2008 Royal College of Pathologists of Australasia DOI: 10.1080/00313020701813776

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Pathology (2008), 40(2), February

tumours are treated with primary nephrectomy, followed by further therapy if necessary (small tumours would have surgery only). In Europe, children older than 6 months of age with typical imaging features of Wilms’ tumour are treated with pre-operative chemotherapy, followed by surgery and further chemotherapy and/or radiotherapy as indicated by the pathological assessment.9–11 There have been few studies to assess the difference between these two approaches. The NWTS/COG approach gives a better pathological view of the untreated tumour, and allows more accurate staging, but provides little information on tumour response to the therapy. The European/SIOP approach, however, gives important information on the tumour’s response to the chemotherapy. In some cases the original stage may be difficult to assess, and in some cases of completely necrotic tumours, the diagnosis may be difficult.12 In the UK, the SIOP protocol is followed but it also includes a pre-chemotherapy biopsy since it has been shown that in around 12% of tumours that

TABLE 1

Paediatric renal tumours

Tumour

Frequency

Wilms’ tumour and related Nephrogenic rests Cystic partially differentiated nephroblastoma, cystic nephroma Probably related Metanephric tumours: metanephric adenoma, metanephric adenofibroma, metanephric stromal tumour Mesoblastic nephroma, classical, cellular and mixed Clear cell sarcoma of kidney Rhabdoid tumour of kidney Renal cell carcinoma Translocation associated renal cell carcinoma Renal medullary cell carcinoma Post neuroblastoma renal cell carcinoma Post Wilms’ tumour renal cell carcinoma Papillary carcinoma Lymphoma of kidney Angiomyolipoma Primitive neuroectodermal tumour of kidney Synovial sarcoma Ossifying renal tumour of infancy Others (embryonal sarcoma, anaplastic sarcoma, etc)

TABLE 2

80–85%

*5% *5% *2% *5%

Rare Rare Very rare Rare

radiologically were considered to be Wilms’ tumours, the biopsy showed another tumour type.13 Another study suggested that biopsy followed by chemotherapy compared with primary nephrectomy had a similar overall survival, but a reduction in the chemotherapeutic exposure.14 Surgery following chemotherapy usually means smaller, less friable tumours resulting in less surgical morbidity and mortality.8 As will be discussed later, children with multiple renal tumours or in a syndrome associated with multiple renal tumours are treated with renal sparing surgery, often following a needle biopsy diagnosis. Adults with Wilms’ tumour should be treated on the same protocols as children, with good results.15

HANDLING OF THE NEPHRECTOMY SPECIMEN The tumour nephrectomy specimen should be received fresh, with care taken to identify the vascular and ureteric margins and to ensure the renal capsule is not stripped.16 The surface is usually best inked after the specimen has been photographed, measured and weighed, but before being bivalved, to demonstrate the relationship between the kidney and the tumour, and to allow tumour and kidney tissue to be taken for biological studies (cytogenetics of tumour and frozen tissue of tumour and normal kidney for assessment of loss of heterozygosity for chromosome 1p and 16q in the tumour). The initial sections must be taken in such a way that staging assessment following fixation is not compromised. Parallel slices of around 15–20 mm thick are made and the tumour fixed. Staging is best assessed following fixation. Photographs or photocopying the tumour slices can allow blocks and biological samples to be mapped. The whole of one slice should be blocked, with additional blocks from grossly different areas. Particular care to sample the interface between the renal capsule, tumour capsule, tumour and residual kidney is important to assess if the renal capsule is intact. The renal sinus is often very distorted, but sections here are important to identify sinus involvement by tumour.17 Care to examine the residual kidney for lesions that may be nephrogenic rests is also important. If the tumour appears to be stage 1 and no lymph nodes are identified macroscopically, then the hilar fat should be very fully sampled as some of these

Current staging criteria in COG and SIOP trials

Stage*

COG (primary nephrectomy)

SIOP (after pre-operative chemotherapy)

Stage I

Tumour confined to kidney within intact renal capsule. No previous biopsy (COG). Vessels of sinus clear. Hilar lymph nodes examined and negative. Tumour fully resected, but tumour extends through the capsule, or into soft tissue of renal sinus or in blood vessels beyond renal parenchyma. Residual disease in abdomen, due to rupture, spillage, tumour biopsy, tumour in abdominal lymph nodes, or tumour is fragmented and full excision uncertain. Haematogenous metastases, or tumour in lymph nodes outside the abdomen Bilateral disease, each side staged as above

Tumour confined to kidney within intact (pseudo) capsule. Vessels of sinus clear. (Non-viable tumour in the sinus/ perirenal fat ignored for staging purposes.) Tumour fully resected, but tumour extends through the (pseudo) capsule, or into soft tissue of the renal sinus or in blood vessels beyond renal parenchyma. As COG, but necrotic tumour in lymph nodes assessed as positive even if no viable tumour. Also the presence of non-viable tumour at any resection margins. Haematogenous metastases, or tumour in lymph nodes outside the abdomen Bilateral disease, each side staged as above

Stage II Stage III Stage IV Stage V

*The pathological staging of Wilms’ tumours varies between the United States COG protocol and the SIOP protocol. The main difference is that staging is after therapy in the SIOP which means that some tumours that were probably higher stage at presentation are at a lower stage at resection.

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tumours are undiagnosed stage 3 tumours (due to lymph node metastases). The key points in the examination of the tumour are tumour type and stage. Tumour weight and measurements, and the determination of the presence of nephrogenic rests are also important points to note. It is important to recognise that tumour ‘float’ (where small fragments of tumour tend to break off the tumour mass and rest on the surface of the specimen) is common in blastemal Wilms’ tumours, and so care should be taken to prevent this upstaging a tumour. There may be extensive vascular permeation by tumour. There may be an inflammatory reaction outside the renal capsule, but if there is no viable tumour tissue (after extensive sampling of such an area) this will not upstage the tumour. The presence of Tamm-Horsfall protein and tubular epithelium in lymphatics and local lymph nodes is well recognised and does not upstage the tumour.18 There is evidence of considerable discrepancy in diagnosing and staging of these tumours between the local institution and expert review of around 20%; rapid central pathology review is being recommended in new trials.19,20 There has been a recent change in the assessment of pulmonary metastases. Smaller lung nodules (under 10 mm in size) may be sampled at the time of initial nephrectomy, as a significant number are not metastases, and so the disease may not be a stage IV (see below). Renal cell carcinomas are staged by the COG using the TNM system. Core biopsies need to be triaged to ensure there is sufficient for a histological diagnosis, but material for cytogenetics, frozen tissue and molecular studies should be kept if possible.

WILMS’ TUMOUR Wilms’ tumour is one of the most common malignant solid extracranial tumours of childhood. It is very uncommon in adults.21 The tumour is usually sporadic but in around 10% of cases is associated with various syndromes or congenital anomalies.22 These include the WT1 associated syndromes (WAGR23,24 and Denys-Drash25), the overgrowth syndromes (Beckwith-Wiedemann,26 Perlman,27 hemihypertrophy28 and others), and syndromes associated with genetic changes including trisomy 18 and 13.29 Increased DNA mutation syndromes such as Fanconi and variegated

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aneuploidy syndrome30,31 have an increased risk of developing Wilms’ tumour. Familial Wilms’ tumours do occur, although they are relatively uncommon (*1–2% of cases).32 Around 5% of patients have bilateral tumours. Bilateral tumours are more common in syndromic cases, who usually present at a younger age. The different syndromes tend to have different types of nephrogenic rests (see later)33 with intralobar rests tending to be associated with the WT1 group, younger children, and a Wilms’ tumour showing more stromal type features.34 A study of non-syndromic children with Wilms’ tumours has shown constitutional WT1 mutations in around 2%; these children tended to present earlier, and have stromal predominant tumours.35 Children with Wilms’ tumours tend to have a heavier birthweight than average, apart from the WAGR patients.23 Genitourinary abnormalities, including horseshoe kidneys, are more common in patients with Wilms’ tumour,36 although there is no clearly increased risk in multicystic kidney disease.37 There appear to be differences in the international incidence of Wilms’ tumours, the associated type of nephrogenic rests (see below), and the underlying genetics.38 The histological appearances of untreated Wilms’ tumour are very variable, with blastemal, epithelial or stromal predominant tumours or more often a mixture of all three types (Fig. 1). The blastemal predominant tumours (as assessed prior to chemotherapy) tend to present with a higher stage than the epithelial or stromal predominant tumours.39 The pure epithelial tumours can be difficult to distinguish form papillary carcinoma, or metanephric adenoma, and the pure blastemal tumours can be difficult to distinguish from other small round blue cell tumours. As the SIOP tumours have received chemotherapy and the COG tumours have not, the criteria for sub-classifying them are different and it is important to emphasise that, for example, terms such as epithelial/stromal predominant Wilms’ tumours (in COG terminology), are not synonyms for epithelial/stromal type Wilms’ tumours (in SIOP terminology).11 The diagnosis of Wilms’ tumour histologically is usually straightforward, apart from the blastemal cases which may show rosettes and often have a serpiginous growth pattern. Immunohistochemistry is not usually helpful in making a positive diagnosis; most blastemal cells will show WT1 positivity, although some cases with WT1 mutations will be negative. Patchy desmin, vimentin,

FIG. 1 Wilms’ tumour showing the classical triphasic pattern of blastema, tubules and stroma, recapitulating nephrogenesis (medium power). FIG. 2 Wilms’ tumour following therapy (medium power). This case is showing marked teratoid changes with cartilage, mucinous and rhabdomyomatous differentiation. FIG. 3 Wilms’ tumour showing anaplasia. The large cells are usually apparent at medium power, and the atypical mitotic figure is demonstrated in the insert (high power).

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cytokeratin, and CD99 may be present. Immunohistochemistry is generally used to exclude another tumour entity. Following pre-operative chemotherapy, Wilms’ tumours show a considerable histological change from the nontreated tumour, usually with loss of the blastemal elements and less response to differentiated epithelial/stromal elements. The tumour’s response to chemotherapy is of prognostic importance.11,40,41 In many, but particularly in blastemal tumours, there is massive necrosis and apoptosis and shrinkage of the tumour, and a (virtually) completely necrotic tumour has an excellent prognosis.41 However, some blastemal type Wilms’ tumours, even without anaplasia, fail to show the same response and these are now classified as high risk tumours under the SIOP protocol. Another pattern seen in pre-treated tumours is maturation and differentiation of the tumour, often producing features reminiscent of a teratoma with mesenchymal, ectodermal (squamous) and endodermal (bowel)-like structures (Fig. 2). Mucus secreting glands, well differentiated skeletal muscle fibres, squamous epithelium, cartilage, bone and other mature tissue more commonly seen in teratomas may be present. The stromal predominant tumours, particularly the fetal rhabdomyomatous sub-type may show no shrinkage at all with therapy but show maturation.42,43 The genetics of Wilms’ tumours is complex44 and there appears to be a considerable degree of genetic heterogeneity, with different tumour suppressor genes, different genetic mechanisms, losses and gains of chromosomal material, some translocations, and importantly methylation and imprinting changes, particularly involving the 11p15 (the Beckwith-Wiedemann locus).45 Recently a gene on chromosome X, WTX, has been found to be inactivated in around 30% of Wilms’ tumours.46 Epidemiological studies suggest at least three types of genetic pathways in Wilms’ tumour pathogenesis.34 There are also at least three genes related to the 2% or so of patients with a family history of Wilms’ tumour.32 Prognostic features The main prognostic features of Wilms’ tumour are the stage and presence of anaplasia, in both COG and SIOP trials, but for SIOP important prognostic features also include assessment of the histological response to therapy and the amount of persisting blastemal tissue.11 Evidence of multifocal nephrogenic rests indicates a risk of developing bilateral disease. Anaplasia is the only unfavourable histological feature in Wilms’ tumours with primary nephrectomy.47 It occurs in around 5% of Wilms’ tumour patients, but tends to occur in older children. The criteria for diagnosing anaplasia include the finding of atypical (tri- or multipolar) mitoses, marked nuclear enlargement (at least three times the size of adjacent cells) and hyperchromasia (Fig. 3).48 These tumours are generally aneuploid. The anaplasia may be focal or diffuse. Recognition that anaplasia reflects a chemo-resistant tumour feature means that the definitions of focal and diffuse anaplasia have been amended from the original criteria.49 Focal anaplasia is now defined as a localised lesion which is known to be completely resected. Diffuse anaplasia includes multi-focal anaplasia, anaplasia in an extrarenal site, in a random biopsy, and presence of

Pathology (2008), 40(2), February

focal anaplasia and marked nuclear unrest (see below) elsewhere in the tumour. The new definitions have prognostic significance.49,50 Some tumours show nuclear changes that do not amount to anaplasia (called nuclear unrest). This does not at the moment alter the treatment, but does mean that the case should be carefully reviewed for anaplasia. There appears a higher risk of recurrence with unrest, but the overall prognosis appears to be the same as for non-anaplastic tumours.51 Anaplasia is associated with a poor prognosis, especially at the higher stage, and still represents a diagnostic problem at the institutional level.47 Anaplasia is associated with p53 mutations,52 and is often positive using p53 immunohistochemical staining. Anaplasia is not ablated or caused by previous therapy, and anaplasia may actually be easier to detect in pre-treated cases due to loss of the chemo-sensitive elements. The histological subtype, such as blastemal or stromal predominance on biopsies prior to therapy does not affect prognosis, but is correlated with stage.39 The histology of the tumour following therapy offers prognostic information. Intermediate risk tumours include those tumours where at least one-third of the residual tumour mass contains viable tumour of epithelial and stromal type (these must constitute greater than two-thirds of the viable tumour with 510% blastema), or mixed type.11 In contrast, those tumours resected following chemotherapy with significant amounts of persisting blastema (defined as at least one-third of the tumour mass being viable and this composed of greater than two-thirds blastema) require more aggressive therapy. Those tumours showing complete response with necrotic tumour only require a less intensive regimen.41 Other histological features of prognostic importance are the identification of perilobar nephrogenic rests in children presenting with Wilms’ tumour under the age of 1 year, who are at particular risk of developing metachronous tumours.53,54 The identification of necrotic lymph nodes, with no viable tumour present, as well as the finding of non-viable tumour at the resection margins, is regarded as stage III in the SIOP trial (Table 3). In this era of effective chemotherapy, there is a conceptual change in that the inherent aggressiveness of a tumour may be completely overcome if the therapeutic response is very good.39 Children with stage IV disease with lung metastases whose lung lesions show a good response as assessed by radiology after 6 weeks of therapy are also spared further therapy. CT detected lung lesions should be considered for biopsy, as not all such lesions are tumour.55 Relapse to the lungs alone appears to be a less adverse prognostic factor than metastases to the TABLE 3 Age and likely renal tumour Age (years)

Most common

Possible

Rare

Birth 51 1–5 5–10 11–15

MN WT, MN WT WT WT, RCC

WT RTK, CCSK CSSK CSSK, RCC PNET

RTK MN (up to 3 years), RTK

CSSK, clear cell sarcoma of kidney; MN, mesoblastic nephroma; RTK, rhabdoid tumour of kidney; WT, Wilms’ tumour.

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liver or elsewhere.56 Relapse to the central nervous system may also be a poor prognostic feature.57 Children under 2 years of age with small (5550 g), favourable histology, stage 1 Wilms’ tumours appear to do well with surgical treatment only.53 A COG trial of surgery only as initial therapy was stopped as the trial had very cautious trial stopping rules for the number of children expected to relapse. However the children who relapsed responded very well to further therapy including chemotherapy. This good response was presumably because the tumours had not been exposed to chemotherapeutic agents previously. Therefore, the overall outcome of this trial was very favourable and a large majority of the children benefited by only being exposed to surgical therapy. Children over the age of 4 years appear to have a higher relapse rate.58 Loss of heterozygosity (LOH) of 16q and 1p have also been found to be poor prognostic markers, independent of p53 mutations, and this information is included in the latest COG trials and alters therapy if there is a change at both loci.59 Several studies have also shown monosomy of chromosome 22 to be an adverse finding.39,60 Other features including telomerase activity,61 and vascular growth factors and changes have also been shown to influence the prognosis, but are not used to alter therapy. Children with germline WT1 and the WAGR syndrome are at increased risk of renal failure.54,62 Extrarenal Wilms’ tumour There are occasional reports of retroperitoneal, uterine and closely related sites with Wilms’ tumour, presumably related to mesonephric development. These are treated as renal tumours.63 There are also reports of Wilms’ tumour within teratomas. Another interesting association is nephrogenic tissue associated with spinal dysraphism.64 Ongoing issues with Wilms’ tumours Although the treatment of Wilms’ tumour has led to an overall impressive cure rate, there are several outstanding clinical issues that are being addressed. The debate and practice of preoperative chemotherapy, or primary surgery for unilateral disease, is still important.65 Patients with multiple nephrogenic rests run a high risk of requiring

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dialysis and studies are underway to refine protocols with renal sparing surgery to keep as much functional kidney tissue as possible.66 It must be remembered that although metachronous tumours develop in these cases, each tumour has not been exposed in its proliferative phase to the previous chemotherapies, and therefore the later tumours respond more like de novo tumours than a relapsed tumour (which is obviously a chemo-resistant clone). The use of partial nephrectomy for unilateral tumours has a role in limited cases.67 There is also a requirement for developing novel agents for the treatment of anaplastic Wilms’ tumours and Wilms’ tumours which have failed to respond to therapy. There is also a large interest in the long-term follow-up of all children after cancer. There are often long-term sequelae, such as therapy-associated acute myelogenous leukaemia,68 cardiac failure (generally after doxorubicin and lung field irradiation),69 infertility and radiation changes.70 There are of course significant psychological traumas to the whole family. Nephrogenic rests The precursor lesions to Wilms’ tumour are nephrogenic rests (NRs)33,71 which are seen in around 40% of Wilms’ tumours.34 It is likely that the remainder of Wilms’ tumours arise from rests but overgrow them, analogous to the adenoma-carcinoma sequence in the bowel. There are two types of rests which appear to arise due to alterations and disturbance of renal development with persisting blastema which normally is lost at 35 weeks of gestational age. Perilobar NRs are at the edge of the renal lobes, and intralobar NRs (Fig. 4) are located within the lobes or deep in the medulla. The two types may be sporadic, but may be part of a syndrome. Intralobar rests tend to be seen with the WT1 mutation syndromes, whereas perilobar rests appear to be associated with the hemihypertrophy and similar syndromes. Beckwith-Wiedemann syndrome may be associated with both, but often has perilobar rests and also has a characteristic medullary change, the Beckwith medulla.72 The two types of rests have a different malignant potential. There are also racial differences with fewer perilobar rests seen in the Japanese population.38 Management of cases with multiple nephrogenic rests can be difficult, with multiple imaging studies and recurrent surgery and chemotherapy, and it can be difficult, if not sometimes impossible, to be certain of whether a lesion

FIG. 4 Polypoid intralobar nephrogenic rest within the pelvicalyceal system (medium power). FIG. 5 Metanephric adenoma (medium power). The typical interface with the kidney is demonstrated. The tumour cells have the characteristic small, dark cells, forming tiny tubules, with occasional psammoma bodies. FIG. 6 Cellular mesoblastic nephroma (medium power). Note the infiltration of the adjacent kidney and the entrapped renal tubules.

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is a growing nephrogenic rest or a Wilms’ tumour.73–76 Probably in an actively growing lesion, this is a semantic question, and chemotherapy appears to reduce the risk of developing a Wilms’ tumour if one is not already present.77 An entity which is sometimes confused with nephrogenic rests is the embryonal hyperplasia of Bowman’s capsular epithelium (EHBCE), which is usually seen in children’s kidneys, generally after dialysis.78 Perilobar nephrogenic rests may also be seen associated with renal dysplasia, but there appears to be no increased risk of Wilms’ tumour in renal dysplasia. Cystic partially differentiated nephroblastoma and cystic nephroma Cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN) are related entities. They tend to occur in younger children, with a male predominance.79 Both are composed of well defined, multicystic tumours, with no macroscopically solid areas.80 The thin fibrous septa are lined by usually hobnailed epithelium. The only difference between the two entities is the presence of microscopic nodules of blastema deep to the epithelium in CPDN and this almost certainly reflects a spectrum of tumours, merging with multicystic Wilms’ tumour with macroscopically obvious nodules at one end and cystic nephroma at the other. There may be heterologous solid elements such as rhabdomyoblasts. Areas resembling these lesions may be seen in some intralobar nephrogenic rests and Wilms’ tumours, and patients with both Wilms’ tumour and cystic nephroma are described.81 Total nephrectomy is sufficient treatment.79,82 Cystic nephroma in infants has to be distinguished from the adult tumour with the same name (but also called mixed epithelial and stromal tumour and cystic hamartoma of the renal pelvis83), and also localised cystic disease of the kidney. There are several reports noting the association of cystic nephroma and pleuro-pulmonary blastoma.84–86

METANEPHRIC TUMOURS The metanephric group of tumours includes metanephric adenoma,87 metanephric adenofibroma88 and metanephric stromal tumour.89 These renal tumours are rare. Metanephric stromal tumour needs to be particularly considered when making a diagnosis of classic type mesoblastic nephroma in a child over 3 years of age. The lesion has characteristic hypo- and hypercellular areas (resulting in a nodular appearance on low power view), concentric collarettes of tumour around entrapped tubules and blood vessels which may show angiodysplasia, and glial tissue may be seen in the stroma. The vascular involvement can lead to surgical difficulties, with fragile arteries. The adenoma has a strong similarity to some types of nephrogenic rest, but occurs usually in young adults, and may be associated with polycythaemia. It has a striking interface with the kidney (Fig. 5). These tumours generally behave in a benign fashion, although the epithelial component may show papillary carcinoma or Wilms’ tumour, and occasional cases of metastasis have been described.90,91 Metanephric adenoma can be difficult to distinguish from epithelial predominant Wilms’ tumour and there may be a close pathogenetic relationship.92

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MESOBLASTIC NEPHROMA This is the most common tumour diagnosed antenatally or in the neonatal period and does not occur after the age of 3 years (Table 3).93,94 There are two main types of tumour, the classical and the cellular variant (Fig. 6), but some tumours show features of both subtypes. The cellular variant has the same genetic changes as infantile fibrosarcoma, namely the t(12:15)(p13;q25) translocation involving the ETV6 and NTRK395 and trisomy 11.96,97 In one study the mixed tumours also contained the same translocation by both fluorescent in situ hybridisation (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR),98 whereas other studies showed no positive results in the mixed cellular and classical tumours.99,100 Interestingly, this translocation is not unique to these infantile tumours, and is also seen in secretory breast carcinomas.101 The tumours may show considerable infiltration of the kidney, often extending into the adjacent tissues. The tumour may recur locally and patients rarely present with metastases,94 which all develop within 12 months of the diagnosis.102 Surgery is regarded as the treatment of choice, even in stage II tumours, whereas chemotherapy can be considered in stage III tumours.94 This tumour needs to be distinguished from the metanephric stromal tumour, which has a scalloped rather than infiltrating junction with the residual kidney, and shows perivascular cuffing and vascular changes (see above). The cellular mesoblastic nephroma can have cells mimicking rhabdoid tumour. So-called adult mesoblastic nephromas are now recognised to have represented other tumours such as metanephric stromal tumour, cystic hamartoma of the renal pelvis/mixed epithelial and stromal tumour.83,103

CLEAR CELL SARCOMA OF KIDNEY Clear cell sarcoma of kidney (CSSK) has a similar age distribution to Wilms’ tumours, although it is extremely rare in the neonatal period, and shows a male to female predominance of around 2:1.104 Recently some reports have suggested a translocation, t(10;17), in CCSK, suggesting its possible role in tumorigenesis.105,106 There are no specific immunohistochemical markers for CCSK, and its cell of origin is unclear. The characteristic histological features are the ‘chickenwire’ vascular pattern and the open, rather bland looking nuclei, although the mitotic rate may be quite brisk.107 Around the blood vessels a more spindled cell population is often seen (Fig. 7). The tumour may appear at low power to be well demarcated, but has an infiltrative border with the adjacent kidney. Although first identified by its tendency to bone metastasis,108,109 most metastases are to local lymph nodes at presentation; however, the bone is the most common site for presentation with metastatic relapse.104 Brain metastases are well recognised. The introduction of doxorubicin has resulted in a marked improvement in the prognosis of this tumour.110

RHABDOID TUMOUR OF KIDNEY Rhabdoid tumour of kidney is a particularly aggressive and chemotherapy resistant tumour, which occurs in infancy

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FIG. 7 Clear cell sarcoma of kidney showing the classical vascular pattern (medium power). In this case the spindle cell component adjacent to the blood vessels is very evident. FIG. 8 Rhabdoid tumour of kidney (high power). The non-cohesive nature of the tumour cells and the prominent nucleoli are typical and the inclusions are focally readily apparent.

and is very uncommon over 3–4 years of age.111,112 It may be associated with hypercalcaemia. It can be quite variable in its histology, and to add to the confusion, Wilms’ tumours and other tumours may have rhabdoid-like areas.113 It has a rather non-cohesive and infiltrative appearance, but the classical rhabdoid feature of eosinophilic cytoplasmic inclusions may be seen only focally. The more characteristic feature is the large nucleus with prominent nucleoli (Fig. 8). The immunophenotype is variable, but the cytoplasmic inclusion is usually positive for vimentin, and may show cytokeratin, and epithelial membrane antigen (EMA) positivity.112 Membranous CD99 positivity may be seen (personal observation). Recently the identification of the gene INI, which acts as a tumour suppressor gene, has identified a group of tumours of infants that have rhabdoid features, the renal and extrarenal rhabdoid tumours (soft tissue and liver in particular), and the atypical teratoid rhabdoid tumour of the brain.114 Interestingly, there appears to be different genetic changes of INI in tumours from the different sites,115 and there may be further loci.116 Immunohistochemisty to detect the absence of the otherwise ubiquitously expressed protein product of this gene in tumour cells (compared with positive internal controls such as endothelial cells) provides useful screening for these tumours, as most other tumours are positive.117,118 The only other tumours that are reported with lack of INI staining include the medullary carcinoma of the kidney, and some proximal type epithelioid sarcomas.118 Both of these tumours often show rhabdoid features, and the proximal epithelioid sarcoma has also been reported to have chromosome 22q abnormalities. A particular differential diagnosis in older children is the medullary cell carcinoma, (see below). Rhabdoid features can be seen in other tumour entities, including mesoblastic nephroma and Wilms’ tumour, and the distinction can be difficult. Rhabdoid tumour is also associated with the development of a posterior fossa brain tumour. It is recognised that 10–15% of these children have a germline mutation, explaining the association of the development of the brain tumour with the rhabdoid tumour,119 and also some familial rhabdoid tumour families are now well recognised.120 The outlook for patients in higher stages is dismal with only very limited success with modern therapy.121 Children under the age of 1 year have an extremely poor prognosis,

especially at higher stages, however, older children do show a better outcome.122

RENAL CELL CARCINOMA Renal cell carcinomas are uncommon, comprising around 5% of all paediatric renal tumours. Renal cell carcinomas that occur in older children and young adults tend to have a distinctive histology and genetic changes.123 These are associated with specific translocations124 involving chromosomal loci Xp11.2 and 1q21 (the PRCC and TEF3 genes),125–127 or the closely related t(6;11) tumours128,129 and these form 33% or more of paediatric renal carcinomas. They typically have a nested appearance, but may be papillary. The identification of TFE3 or TFEB immunohistochemically is a useful way of detecting these tumours in paraffin material.130 They are also usually negative or only focally positive for cytokeratin and EMA, but positive for CD10. Other translocation variants involving t(X;17) have been described.125,131,132 A number of these tumours occur as post-chemotherapy tumours, including after neuroblastoma, and Wilms’ tumours.133 Papillary carcinoma can also occur in older children.134 Carcinomas of the kidney need to be considered in children with von HippelLindau, and tuberous sclerosis. In the latter condition the epithelioid variant of angiomyolipoma may have a worrying appearance. Renal cell carcinomas with lymph node metastases generally appear to have a better prognosis in children.17 Medullary cell carcinoma is a highly aggressive tumour, often with rhabdoid features occurring in children and young adults with sickle cell trait or disease. Immunohistochemistry for INI may be negative as described above.135,136 There is a definite association of renal cell carcinoma developing after neuroblastoma, not necessarily after therapy. Initial reports noted a typical oxyphil appearance but the pattern can be less obvious.137 Renal cell carcinoma following Wilms’ tumour has also been described.133,138

PRIMITIVE NEUROECTODERMAL TUMOUR (PNET) OF KIDNEY This entity tends to occur in older children and young adults.139 It can be mistaken for blastemal Wilms’ tumour, which may show some rosette formation. The tumours

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typically show strong CD99 membranous staining, Fli-1 is often present, and WT1 is negative.140 The use of molecular techniques to detect the Ewings/PNET translocations by FISH or RT-PCR can be crucial in making the distinction.141 Other rare entities such as small cell carcinoma may also need to be considered in the differential diagnosis.

LYMPHOMA OF KIDNEY Primary involvement of the kidney by lymphoblastic or Burkitt’s lymphoma is well recognised in children, and may present as multifocal disease.

OTHER ENTITIES A number of other rare tumours have been recognised in the kidney. Some of them are organ specific, whereas others have been known in other sites and have recently been recognised in the kidney (some thanks to the application of molecular techniques). Angiomyolipoma is associated with tuberous sclerosis (this tumour may increase in size, and present after starting the oral contraceptive pill). Synovial sarcoma has presented as a renal tumour142 as well as desmoplastic small round cell tumour.143 Juxtaglomerular cell tumour144 and ossifying renal tumour of infancy145 are rare tumours. Cystic embryonal sarcoma146,147 is also described, although tumours such as PNET and synovial sarcoma need to be excluded in the differential diagnosis. Anaplastic sarcoma of the kidney has recently been described.148 Mixed epithelial and stromal tumour of the kidney149 (also called adult type mesoblastic nephroma, cystic hamartoma of the renal pelvis and other synonyms) has also been described in childhood. Renal medullary dysplasia associated with Beckwith-Wiedemann syndrome may also mimic a tumour.150

CONCLUSION The correct pathological approach and diagnosis of paediatric renal tumours is crucial in the management of children presenting with renal tumours. There are still reports of considerable variation in the diagnosis of the tumour compared with central review. As there is still ongoing development and refinement of these entities, with several new entities further delineated over the last decade of so, central review and entering these tumours into trials is still very important. There are likely to be further developments as the growing use of molecular markers provides additional prognostic information, some of which may inform the histological interpretation. The role of the histologist is going to remain crucial in this area for a considerable time, but there will be growing use of additional diagnostic tests to refine our reports and thereby direct the treatment of the child. Address for correspondence: Dr A. K. Charles, Pathwest, Princess Margaret Hospital, Roberts Road, Subiaco, WA 6008, Australia. E-mail: [email protected]

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