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Renal tumours of childhood: an overview
MINI-SYMPOSIUM: PAEDIATRIC PATHOLOGY
Renal tumours of childhood: an overview
Primary renal tumours of childhood
Gordan M Vujanic´
Abstract The diagnosis, management and prognosis of paediatric renal tumours have significantly improved over the last 40 years. Pathologists have played a significant role in these developments through their work in multicentre national and international trials and studies, by recognizing new tumour entities, as well as favourable and unfavourable histological features of different tumours. Over the last few years, a number of new tumour entities have been recognized in the kidney due to the application of molecular techniques, but also on the basis of their characteristic clinicopathological features recognized by studying large series of tumours from national and international trials. In addition to histology and stage, in recent trials some molecular genetic abnormalities have been introduced for treatment stratification of patients with Wilms tumour.
Relative percentage
Wilms tumour Without anaplasia With anaplasia Mesoblastic nephroma Clear cell sarcoma Rhabdoid tumour Renal cell carcinoma Others
85 80 5 2e3 3 2 5 3
Table 1
current SIOP 2001 classification distinguishes three treatment groups of tumours, including low-, intermediate- and high-risk tumours (Table 2).5 The tumour stage is the critical factor for determining treatment and its accurate assignment is one of the most essential and demanding tasks of the pathologist. The staging criteria have changed over time as the significance of different findings have become apparent.6e8
Keywords children; clear cell sarcoma; mesoblastic nephroma; renal cell carcinoma; renal tumours; rhabdoid tumour; Wilms tumour
Wilms tumour (nephroblastoma)
Introduction
Wilms tumour is usually diagnosed in young children (the mean age for males is 36.5 months and for females 42.5 months). It is uncommon in neonates and infants,1,9 and only occasionally occurs in adults.10 Other unique features of WT are that in 5e10% of patients it occurs as bilateral disease (more common in cases associated with syndromes),11 it is familial in 1e2% of cases,12 and it exceptionally rarely occurs as an extra-renal tumour.13 It is typically sporadic but in around 10% of cases it is associated with different syndromes or congenital anomalies.14 Histologically, classical (mixed) WT consist of three components: blastemal, epithelial and stromal (Figure 1a). These components may be present in various proportions and each one may show a different line and degree of differentiation, resulting in innumerable histological appearances. However, many WTs contain only one or two components and preoperative chemotherapy, which is given in the SIOP trials, may alter original histological features by destroying (usually) blastemal cells and inducing maturation of other components.15 Blastema represents the least differentiated component, consisting of small to medium sized undifferentiated cells which may show a number of patterns, including diffuse (Figure 1b), serpentine, nodular and basaloid patterns. The epithelial component may show primitive epithelial components such as rosettes, moderately to well-differentiated tubules (Figure 1c), or well-differentiated glomeruli-like structures. The stromal component may include undifferentiated mesenchymal cells but also well-differentiated smooth and skeletal muscle cells (Figure 1d), fat tissue, cartilage and bone (more commonly seen in tumours in patients who received preoperative chemotherapy). Depending on the percentages of the individual components, WTs are subclassified into subtypes.5 If none of the components is predominant (i.e. is
Renal tumours of childhood are rare, comprising only about 7% of all tumours in children up to 15 years of age,1 and the vast majority of 100 or so diagnosed annually in the UK are Wilms tumours (WTs) or nephroblastomas (Table 1). Therefore, a practising paediatric pathologist can be expected to see very few, especially non-WTs, making the accurate diagnosis and staging difficult.2 Therefore, it is important that these tumours are studied in multicentre trials, as has been happening in the USA through the Children’s Oncology Group (COG, former National Wilms Tumor Study [NWTS]) and in Europe through the International Society of Paediatric Oncology (SIOP) since the 1970s. These groups have different treatment strategies and classifications but their survival results are remarkably similar.3 The COG/NWTS treatment strategy includes primary nephrectomy followed by postoperative therapy, whereas in the SIOP trials children older than 6 months of age with tumours showing typical imaging features of WT are treated with preoperative chemotherapy followed by nephrectomy and further postoperative therapy, depending on histological subtype and stage. In the UK, the SIOP trial protocol is followed, but in addition a pretreatment cutting needle biopsy is taken for histological diagnosis of a tumour.4 It is important to bear in mind that as histological criteria for subtyping and staging WTs in the COG/ NWTS and SIOP classifications differ, it is not possible to simply compare the results type-for-type and stage-for-stage. The
Gordan M Vujanic´ MD PhD FRCPath is Professor of Paediatric Pathology and Honorary Consultant in Paediatric Pathology at the School of Medicine, Cardiff University, Cardiff, UK.
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percentages of the other components, is regarded as mixed-type WT, too. Consequently, epithelial or stromal type are predominantly composed of epithelial or stromal elements, but contain less than 10% of blastema. These differentiated tumours (epithelial and stromal type WTs) occur at a younger age, which is probably one of the reasons why WTs at a younger age have a better prognosis.16 In primarily operated WTs, the only histological feature of adverse prognostic significance is anaplasia, which is found in about 5% of cases.17 Anaplasia may occur in any cell type (but is extremely rare in the stromal component, especially on its own, i.e. not associated with anaplasia in the blastemal and/or epithelial component). It is defined as the presence of large atypical multipolar mitoses (Figure 2a), together with marked nuclear enlargement and hyperchromasia (Figure 2b).18 Anaplasia is further subclassified as focal (FA) and diffuse anaplasia (DA). FA is defined as the presence of anaplastic changes in one or a few sharply defined foci within the primary tumour, without evidence of marked nuclear atypia elsewhere in the tumour. DA is defined as non-localized anaplasia and/or anaplasia beyond the original tumour capsule; FA with marked nuclear atypia elsewhere in the tumour; anaplasia that is not clearly demarcated from non-anaplastic tumour; anaplasia in intrarenal vascular extensions, extrarenal invasive sites or metastases; and anaplasia in a random biopsy sample.18 In the latest COG trial, FA and DA are regarded as high-risk tumours,
SIOP Working classification of renal tumours of childhood I Low risk tumours Mesoblastic nephroma Cystic partially differentiated nephroblastoma Completely necrotic Nephroblastoma II Intermediate risk tumours Nephroblastoma e epithelial type Nephroblastoma e stromal type Nephroblastoma e mixed type Nephroblastoma e regressive type Nephroblastoma e focal anaplasia III High risk tumours Nephroblastoma e blastemal type Nephroblastoma e diffuse anaplasia Clear cell sarcoma of the kidney Rhabdoid tumour of the kidney IV Others Table 2
not occupying more than two-thirds of the tumour), the tumour is designated as mixed, but in the SIOP classification any tumour which contains greater than 10% of blastema, irrespective of the
Different histological patterns of Wilms tumour: a mixed pattern with blastemal, epithelial and stromal elements; b diffuse blastemal pattern; c epithelial pattern with moderately differentiated tubules; and d stromal pattern with marker rhabdomyoblastic differentiation. Figure 1
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Anaplastic Wilms tumour with a atypical multipolar mitosis and b marked nuclear enlargement and hyperchromasia. Figure 2
subclassified into dormant, sclerosing and hyperplastic NRs, and they may regress to fibrous tissue or progress to WT. Perilobar NRs are found at the periphery of the renal lobe and are composed of epithelial, stromal and blastemal structures (Figure 3a). They are associated with overgrowth syndrome (hemihypertrophy, BeckwitheWiedemann syndrome) and have a low malignant potential. Intralobar NRs occur within the renal lobe and are usually bland with the adjacent kidney (Figure 3b). They usually contain abundant stroma and are better organized than WT. Intralobar NRs are often associated with WAGR (Wilms’ tumour, aniridia, genitourinary anomalies, mental retardation) and DenyseDrash syndromes.21 There seems to be a considerable degree of heterogeneity in the genetics of WT,22,23 with different tumour suppressor genes and different genetic mechanisms, with losses and gains of chromosomal material, some translocations, and methylation and imprinting changes, particularly involving the 11p15 locus (the BeckwitheWiedemann locus).22,23 Recently, a WTX gene on chromosome X was identified to be inactivated in around 30% of WT.24 Epidemiological studies suggest at least three types of genetic pathway in WT pathogenesis.22,23 In the last completed NWTS trial, it was shown that loss of heterozygosity on both
whereas in the latest SIOP classification FA is subclassified in the intermediate-risk group, and DA in the high-risk group.5 Anaplasia is associated with a poor prognosis, especially at the higher stage, and is still a diagnostic problem at the institutional level.17 Preoperative chemotherapy does not obliterate or induce anaplasia, and it may actually help its detection due to loss of the chemosensitive elements. It is associated with p53 mutations, and is often positive on p53 immunohistochemical staining.19 In addition to DA, in the SIOP classification of WTs treated with preoperative chemotherapy, blastemal-type WT is also subclassified into the high risk group, since its relapse-free survival was as poor as for DA in the SIOP9/GPOH study.5,15 The prognosis of WT depends on its histology and stage. WT most commonly metastasizes to the lungs and lymph nodes, whereas bone and brain metastases are rare. The overall survival for patients with WT is now over 90%; therefore, at present the focus is reduction of treatment in order to reduce therapy-related sequelae.8 Nephrogenic rests (NRs) are abnormally persistent (after 36 weeks of gestation) foci of embryonal cells that are capable of developing into WT. NRs are found in 30e40% of WTs,20 and are subclassified into perilobar and intralobar NRs, depending on their localization within the renal lobe. Both types are further
a Perilobar nephrogenic rests and b intralobar nephrogenic rests. Figure 3
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kidney (RTK). The diagnosis should be reached by looking for other characteristic features of these tumours. Interestingly, there seems to be an association between CN and pleuropulmonary blastoma.27,28
Mesoblastic nephroma Mesoblastic nephroma (MN) accounts for w2e3% of all paediatric renal neoplasms and is now regarded as a low-grade fibroblastic sarcoma of the kidney. It is the commonest congenital renal tumour, with 90% of cases presenting in the first year of life, whereas it virtually never occurs after 3 years of age.29 Histologically, it may exhibit classical, cellular type and mixed pattern. The classical type closely resembles infantile fibromatosis and consists of spindled cells arranged in intersecting fascicles (Figure 5a), and usually it infiltrates the renal parenchyma, especially in the hilus. The cellular type consists of densely packed plump, round cells with vesicular nuclei and a small to moderate amount of cytoplasm (Figure 5b). It is usually sharply circumscribed and does not infiltrate the renal parenchyma.30 It shares the same genetic abnormality as infantile fibrosarcoma: a t(12;15)(p13;q25) translocation with resultant ETV6eNTRK3 fusion.31 MN is treated with complete surgical excision, resulting in excellent survival.32 Rare local recurrences, particularly of cellular type, are due to incomplete resection, and exceptionally rare cases of distant metastases have been reported. They all develop within 12 months after the diagnosis, so patients should be followed up closely for at least 1 year.33 The differential diagnosis includes metanephric stromal tumour, clear cell sarcoma of the kidney and stromal-type WT. As no specific immunohistochemical markers for MN exist, the diagnosis should be reached by taking into account the clinical and histological features of these tumours.
Figure 4 Cystic partially differentiated nephroblastoma consisting entirely of cysts and their septa, which contain small islands of blastema.
chromosomes 16q and 1p, identified in approximately 5% of patients with non-anaplastic WT, was associated with an unfavourable outcome,25 and this has been introduced in treatment stratification in the recently launched trial.6
Cystic renal tumours Cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN) are rare, completely cystic renal tumours which share the same histological features, including sharp demarcation from the renal parenchyma. They consist of cysts of different shapes and sizes, with the septa as the only solid areas, and they may contain tubules and, in CPDN, foci of blastema (Figure 4).26 As they are treated with surgery only, it is important to distinguish them from other renal tumours which may show a very prominent cystic pattern (but are virtually never completely cystic), such as pretreated WTs, mesoblastic nephroma, clear cell sarcoma of the kidney (CCSK) and even rhabdoid tumour of the
Clear cell sarcoma of the kidney Clear cell sarcoma of the kidney (CSSK) represents w3% of renal tumours of childhood. Its peak incidence is between 2 and 4 years of age, and it shows a male-to-female predominance of
Mesoblastic nephroma: a classical type, consisting of fascicles of bland spindle cells and with infiltration of the adjacent renal parenchyma and b cellular type, consisting of densely packed cells. Figure 5
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Clear cell sarcoma of the kidney showing different patterns aed and a characteristic vascular network b. Figure 6
around 2:1.34 Histologically, CCSK shows a wide histological spectrum of different patterns, including classical, epithelioid, spindled, sclerosing, palisading, myxoid, cystic and pleomorphic, which explains why it is the most frequently misdiagnosed renal tumour of childhood (Figure 6). Different patterns are usually found within the same tumour. The classical pattern is characterized by well-defined cords or nests of undifferentiated large cells with bland, empty-looking nuclei containing finely dispersed chromatin and usually no nucleoli. However, this pattern is seen in only w30% of cases. The most distinguishing feature is the ‘chickenwire’, delicate vascular network (Figure 6b), which can be easily recognized on CD34 staining. Another characteristic and diagnostically helpful feature of CCSK is its delicate infiltration of the adjacent renal parenchyma at the kidneyetumour interface, with entrapment of non-neoplastic tubules at the periphery of the tumour.34 No specific immunohistochemical and genetic features associated with CCSK have been identified.34,35 Recently, a t(10;17) translocation was reported in CCSK, suggesting its possible role in tumorigenesis.36 In another study, nerve growth factor receptor was strongly positive in 100% of CCSKs, making it the first potentially useful marker for CCSK.37 The most common metastases of CCSK at presentation are to local lymph nodes (w30%),34 but the bone is the commonest site for metastatic relapse.34 The introduction of doxorubicin has resulted in a striking improvement in the prognosis of stage IeIII tumour.38
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Rhabdoid tumour of the kidney Rhabdoid tumor of the kidney (RTK) accounts for about 2% of paediatric renal tumours. The mean age at diagnosis is 1 year, and the median age is 11 months. Over 80% of cases are diagnosed in the first 2 years of life, and the diagnosis is dubious after the age of 5 years.39 The tumour is associated with hypercalcaemia and synchronous or metachronous brain tumours. Characteristic
Figure 7 Rhabdoid tumour of the kidney composed of large, non-cohesive cells with large nuclei and prominent nucleoli, with prominent intracytoplasmic inclusion.
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Metanephric tumours including a metanephric stromal tumour showing nodular appearance due to hypo- and hyper-cellular areas and b metanephric adenoma, composed of small, well-differentiated tubules, with no capsule between the tumour and the kidney. Figure 8
histological features are the presence of large, non-cohesive tumour cells with eccentric large nuclei and very prominent eosinophilic central nucleoli (present in virtually all cases), and hyaline intracytoplasmatic inclusions (often seen only focally) (Figure 7). In addition to the classical pattern, the tumour may show numerous other patterns, including classical, sclerosing, epithelioid, clear cell sarcoma-like, lymphomatoid, vascular, pseudopapillary and cystic patterns.39,40 Immunohistochemically, in addition to vimentin (positive in all cases), RTK coexpresses different markers, including desmin, myoglobin, EMA, NSE, neurofilaments, S100 protein and CD99 (which are usually focally positive and not present in all cases).39,40 However, the diagnostic immunohistochemical feature is absence of immunoreactivity for INI1 marker in the tumour cell nuclei. Genetic abnormalities of hSNF5/INI1 tumour suppressor gene on chromosome 22q11e12 has been identified in children with renal and extra-renal rhabdoid tumours, and the atypical teratoid rhabdoid tumour of the brain.41 The differential diagnosis of RTK includes renal medullary carcinoma (INI1 is also negative in this tumour), cellular mesoblastic nephroma with rhabdoid cells, CCSK, blastemal WT, EWS/PNET and rhabdmomyosarcoma. RTK is a highly invasive, lethal neoplasm which gives early metastases in lung, lymph nodes, liver, bone and brain. The prognosis is very poor with 80e90% of patients dying within a few months of the diagnosis,39,40 but it appears to be better for older children.42
treated with surgery only and has the same excellent prognosis as MN.43 MAF occurs in children and young adults and exhibits a mixture of stromal elements (identical to those in MST) and well-defined areas of immature epithelium (tubules and papillae).44 Finally, MA is more commonly found in adults than in children. It is usually small (up to 2 cm) and composed of monotonous small, closely-packed tubules which show no mitoses. Characteristically, there is no capsule between the tumour and the adjacent renal parenchyma (Figure 8b).45 It may be difficult to distinguish from epithelial-predominant WT and there may be a close pathogenetic relationship.46
Renal cell carcinomas Renal cell carcinomas (RCCs) represent around 5% of all paediatric renal tumours, hence they are more common than MN, CCSK or RTK. They show distinguishing histological and genetic features from RCCs seen in adults.47,48 These tumours are defined by several different translocations.49 A group of Xp11.2-translocation carcinomas resulting from fusion of the TFE3 gene50 (which includes a total of five gene fusions) is now recognized as a separate entity in the latest World Health
Metanephric tumours Metanephric tumours comprise a spectrum of rare, recently recognized entities, including metanephric stromal tumour (MST),43 metanephric adenofibroma (MAF)44 and metanephric adenoma (MA).45 Histologically, MST is a pure stromal tumour showing characteristic hypo- and hyper-cellular areas (resulting in a nodular appearance on low power view) (Figure 8a), concentric collarettes of tumour around entrapped tubules and blood vessels which may show angiodysplasia. It occurs from 2 days to 156 months of age (median 13 months) and it should be considered in the differential diagnosis of stromal tumours in children older than 3 years of age, when MN does not occur. It is
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Figure 9 Renal cell carcinoma associated with Xp11.2 translocation showing papillary architecture with large cells with abundant granular eosionophilic cytoplasm.
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Organization classification.51 Histologically, they show a typical nested appearance, but may also be papillary, composed of cells with granular eosinophilic cytoplasm or clear cells (Figure 9). Immunohistochemically, tumour cells show strong nuclear positivity for TFE3, which is diagnostic.52 A t(6;11)-translocation RCC is another translocation-associated paediatric RCC which has been rarely reported, and is seems to be less aggressive than Xp11.2-translocation RCC.53 Histologically, they feature nests and small acini of polygonal epithelioid cells with well-defined cell borders, separated by a thin-capillary vasculature, but also another population of smaller epithelioid cells clustered around nodules of hyaline basement membrane material.54 A number of these tumours occur as post-chemotherapy tumours, including after neuroblastoma and WT.55 Papillary carcinoma can also occur in older children.56 Carcinomas of the kidney need to be considered in children with von HippeleLindau disease and tuberous sclerosis. RCCs with lymph node metastases generally appear to have a better prognosis in children. Renal medullary carcinoma is a rare, highly aggressive tumour occurring in children and young adults with sickle cell trait or disease.57 Microscopically, it is very infiltrative, and is composed of large cells with large, vesicular nuclei and prominent nucleoli (rhabdoid features), usually accompanied by a marked acute and chronic inflammatory infiltrate and stromal desmoplasia.57,58 Interestingly, tumour cells may be negative for INI1 marker. Patients usually present with widespread metastases and show no response to chemo- or radio-therapy, resulting in a poor survival (mean 4 months).57,58 A rare form of RCC developing after neuroblastoma has been described, showing unusual oncocytoid histological features with solid and papillary pattern.59 RCC following WT has also been described.
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Other entities A number of other rare tumours have been recently identified in the kidney. Some have been recognized by the application of molecular biology techniques, such as primitive neuroectodermal tumour,60 synovial sarcoma61 and desmoplastic small round cell tumour,62 whereas others, such as anaplastic sarcoma of the kidney63 and mixed epithelial and stromal tumour of the kidney,64 have been recognized on the basis of their characteristic clinicopathological features observed by examination of large series of cases from the multicentre studies.
Conclusion Renal tumours of childhood are a fascinating group of tumours where huge progress in classification, treatment and understanding of molecular biology has been made. This has only been possible because of close collaboration between patients, clinicians and pathologists, and their participation in national and international multicentre trials where clinical, epidemiological and pathological data have been systematically and meticulously collected and studied. Since these tumours are rare, they still represent a diagnostic problem and central pathology review in multicentre trials is essential for assigning the appropriate treatment. Molecular biology markers are likely to play an even more important role in future trials. A
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21 Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of nephrogenic rests and Wilms tumors. J Pediatr Hematol Oncol 2007; 29: 589e94. 22 Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002; 14: 5e11. 23 Pritchard-Jones K, Vujanic G. Multiple pathways to Wilms tumor: how much is genetic? Pediatr Blood Cancer 2006; 47: 232e4. 24 Rivera MN, Kim WJ, Wells J, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 2007; 315: 642e5. 25 Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorablehistology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2005; 23: 7312e21. 26 Joshi VV, Beckwith JB. Multilocular cyst of the kidney (cystic nephroma) and cystic, partially differentiated nephroblastoma. Terminology and criteria for diagnosis. Cancer 1989; 64: 466e79. 27 Boman F, Hill DA, Williams GM, et al. Familial association of pleuropulmonary blastoma with cystic nephroma and other renal tumors: a report from the International Pleuropulmonary Blastoma Registry. J Pediatr 2006; 149: 850e4. 28 Bouron-Dal Soglio D, Harvey I, Yazbeck S, Rypens F, Oligny LL, Fournet JC. An association of pleuropulmonary blastoma and cystic nephroma: possible genetic association. Pediatr Dev Pathol 2006; 9: 61e4. 29 van den Heuvel-Eibrink MM, Grundy P, Graf N, et al. Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: a collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms Tumor Study Groups. Pediatr Blood Cancer 2008; 50: 1130e4. 30 Murphy WM, Grignon DJ, Perlman EJ. Kidney tumors in children. In: Tumors of the kidney, bladder, and urinary structures. Atlas of tumor pathology, 4th Series, Fascicle 1. Washington, DC: Armed Forces Institute of Pathology; 2004. p. 57e64. 31 Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 1998; 58: 5046e8. 32 Furtwaengler R, Reinhard H, Leuschner I, et al. Mesoblastic nephroma - a report from the Gesellschaft fur Padiatrische Onkologie und Hamatologie (GPOH). Cancer 2006; 106: 2275e83. 33 Beckwith JB. Letter to editor. Pediatr Pathol 1993; 13: 886e7. 34 Argani P, Perlman EJ, Breslow NE, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 2000; 24: 4e18. 35 Schuster AE, Schneider DT, Fritsch MK, et al. Genetic and genetic expression analyses of clear cell sarcoma of the kidney. Lab Invest 2003; 83: 1293e9. 36 Brownlee NA, Perkins LA, Stewart W, et al. Recurring translocation (10;17) and deletion (14q) in clear cell sarcoma of the kidney. Arch Pathol Lab Med 2007; 131: 446e51. 37 Bonadio J, Perlman EJ. Immunohistochemical analysis of 61 clear cell sarcomas on the kidney for a panel including NGFR and CD99. Book of Abstracts from the Society for Pediatric Pathology Annual Meeting, 2008: A26. 38 Seibel NL, Li S, Breslow NE, et al. Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2004; 22: 468e73. 39 Weeks DA, Beckwith JB, Mierau GW, Luckey DW. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms’ Tumor Study Pathology Center. Am J Surg Pathol 1989; 13: 439e58.
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40 Vujanic GM, Sandstedt B, Harms D, Boccon-Gibod L, Delemarre JF. Rhabdoid tumour of the kidney: a clinicopathological study of 22 patients from the International Society of Paediatric Oncology (SIOP) nephroblastoma file. Histopathology 1996; 28: 333e40. 41 Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol 2004; 28: 1485e91. 42 Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms’ Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 2005; 23: 7641e5. 43 Argani P, Beckwith JB. Metanephric stromal tumor. Report of 31 cases of a distinctive pediatric renal neoplasm. Am J Surg Pathol 2000; 24: 917e26. 44 Arroyo MR, Green DM, Perlman EJ, Beckwith JB, Argani P. The spectrum of metanephric adenofibroma and related lesions. Clinicopathologic study of 25 cases from the National Wilms Tumor Strudy Group Pathology Centre. Am J Surg Pathol 2001; 25: 433e44. 45 Davis Jr CJ, Barton JH, Sesterhenn IA, Mostofi FK. Metanephric adenoma. Clinicopathological study of fifty patients. Am J Surg Pathol 1995; 19: 1101e14. 46 Argani P. Metanephric neoplasms: the hyperdifferentiated, benign end of the Wilms tumor spectrum? Clin Lab Med 2005; 25: 379e92. 47 Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007; 31: 1149e60. 48 Bruder E, Passera O, Harms D, et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004; 28: 1117e32. 49 Argani P. The evolving story of renal translocation carcinomas. Am J Clin Pathol 2006; 126: 332e4. 50 Argani P, Ladanyi M. Translocation carcinomas of the kidney. Clin Lab Med 2005; 25: 363e78. 51 Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Tumours of the urinary system and male genital organs: pathology and genetics. World Health Organisation classification of tumours. Lyon: IARC; 2004. 52 Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003; 27: 750e61. 53 Argani P, Lae M, Hutchinson B, et al. Renal carcinomas with the t(6;11) (p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005; 29: 230e40. 54 Argani P, Ladanyi M. Recent advances in pediatric renal neoplasia. Adv Anat Pathol 2003; 10: 243e60. 55 Argani P, Lae M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006; 24: 1529e34. 56 Renshaw AA, Granter SR, Fletcher JA, Kozakewich HP, Corless CL, Perez-Atayde AR. Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes. Am J Surg Pathol 1999; 23: 795e802. 57 Davis Jr CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995; 19: 1e11. 58 Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology 2002; 60: 1083e9.
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59 Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999; 23: 772e80. 60 Parham DM, Roloson GJ, Feely M, Green DM, Bridge JA, Beckwith JB. Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol 2001; 25: 133e46. 61 Argani P, Faria PA, Epstein JI, et al. Primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg Pathol 2000; 24: 1087e96. 62 Wang LL, Perlman EJ, Vujanic GM, et al. Desmoplastic small round cell tumor of the kidney in childhood. Am J Surg Pathol 2007; 31: 576e84. 63 Vujanic GM, Kelsey A, Perlman EJ, Sandstedt B, Beckwith JB. Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 2007; 31: 1459e68. 64 Hara N, Kawaguchi M, Murayama S, Maruyama R, Tanikawa T, Takahashi K. Mixed epithelial and stromal tumor of the kidney in a 12-year-old girl. Pathol Int 2005; 55: 670e6.
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Renal tumours of childhood, especially non-Wilms’ tumours, are rare, making them difficult to accurately diagnose and stage Wilms tumour has an excellent prognosis with over 90% overall survival (all stages together) Two subtypes of Wilms tumour with a poor prognosis are diffuse anaplasia and blastemal type Wilms tumour is the only renal tumour of childhood associated with nephrogenic rests and clinical syndromes There is a considerable degree of genetic heterogeneity in the genetics of Wilms tumour Cellular mesoblastic nephroma and infantile fibrosarcoma represent the same tumour entity Renal and extrarenal rhabdoid tumours are the same entity Renal cell carcinomas comprise around 5% of all paediatric renal tumours and show distinguishing histological and genetic features from renal cell carcinomas in adults
Ó 2009 Elsevier Ltd. All rights reserved.
Renal tumours of childhood: an overview
Primary renal tumours of childhood
Gordan M Vujanic´
Abstract The diagnosis, management and prognosis of paediatric renal tumours have significantly improved over the last 40 years. Pathologists have played a significant role in these developments through their work in multicentre national and international trials and studies, by recognizing new tumour entities, as well as favourable and unfavourable histological features of different tumours. Over the last few years, a number of new tumour entities have been recognized in the kidney due to the application of molecular techniques, but also on the basis of their characteristic clinicopathological features recognized by studying large series of tumours from national and international trials. In addition to histology and stage, in recent trials some molecular genetic abnormalities have been introduced for treatment stratification of patients with Wilms tumour.
Relative percentage
Wilms tumour Without anaplasia With anaplasia Mesoblastic nephroma Clear cell sarcoma Rhabdoid tumour Renal cell carcinoma Others
85 80 5 2e3 3 2 5 3
Table 1
current SIOP 2001 classification distinguishes three treatment groups of tumours, including low-, intermediate- and high-risk tumours (Table 2).5 The tumour stage is the critical factor for determining treatment and its accurate assignment is one of the most essential and demanding tasks of the pathologist. The staging criteria have changed over time as the significance of different findings have become apparent.6e8
Keywords children; clear cell sarcoma; mesoblastic nephroma; renal cell carcinoma; renal tumours; rhabdoid tumour; Wilms tumour
Wilms tumour (nephroblastoma)
Introduction
Wilms tumour is usually diagnosed in young children (the mean age for males is 36.5 months and for females 42.5 months). It is uncommon in neonates and infants,1,9 and only occasionally occurs in adults.10 Other unique features of WT are that in 5e10% of patients it occurs as bilateral disease (more common in cases associated with syndromes),11 it is familial in 1e2% of cases,12 and it exceptionally rarely occurs as an extra-renal tumour.13 It is typically sporadic but in around 10% of cases it is associated with different syndromes or congenital anomalies.14 Histologically, classical (mixed) WT consist of three components: blastemal, epithelial and stromal (Figure 1a). These components may be present in various proportions and each one may show a different line and degree of differentiation, resulting in innumerable histological appearances. However, many WTs contain only one or two components and preoperative chemotherapy, which is given in the SIOP trials, may alter original histological features by destroying (usually) blastemal cells and inducing maturation of other components.15 Blastema represents the least differentiated component, consisting of small to medium sized undifferentiated cells which may show a number of patterns, including diffuse (Figure 1b), serpentine, nodular and basaloid patterns. The epithelial component may show primitive epithelial components such as rosettes, moderately to well-differentiated tubules (Figure 1c), or well-differentiated glomeruli-like structures. The stromal component may include undifferentiated mesenchymal cells but also well-differentiated smooth and skeletal muscle cells (Figure 1d), fat tissue, cartilage and bone (more commonly seen in tumours in patients who received preoperative chemotherapy). Depending on the percentages of the individual components, WTs are subclassified into subtypes.5 If none of the components is predominant (i.e. is
Renal tumours of childhood are rare, comprising only about 7% of all tumours in children up to 15 years of age,1 and the vast majority of 100 or so diagnosed annually in the UK are Wilms tumours (WTs) or nephroblastomas (Table 1). Therefore, a practising paediatric pathologist can be expected to see very few, especially non-WTs, making the accurate diagnosis and staging difficult.2 Therefore, it is important that these tumours are studied in multicentre trials, as has been happening in the USA through the Children’s Oncology Group (COG, former National Wilms Tumor Study [NWTS]) and in Europe through the International Society of Paediatric Oncology (SIOP) since the 1970s. These groups have different treatment strategies and classifications but their survival results are remarkably similar.3 The COG/NWTS treatment strategy includes primary nephrectomy followed by postoperative therapy, whereas in the SIOP trials children older than 6 months of age with tumours showing typical imaging features of WT are treated with preoperative chemotherapy followed by nephrectomy and further postoperative therapy, depending on histological subtype and stage. In the UK, the SIOP trial protocol is followed, but in addition a pretreatment cutting needle biopsy is taken for histological diagnosis of a tumour.4 It is important to bear in mind that as histological criteria for subtyping and staging WTs in the COG/ NWTS and SIOP classifications differ, it is not possible to simply compare the results type-for-type and stage-for-stage. The
Gordan M Vujanic´ MD PhD FRCPath is Professor of Paediatric Pathology and Honorary Consultant in Paediatric Pathology at the School of Medicine, Cardiff University, Cardiff, UK.
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percentages of the other components, is regarded as mixed-type WT, too. Consequently, epithelial or stromal type are predominantly composed of epithelial or stromal elements, but contain less than 10% of blastema. These differentiated tumours (epithelial and stromal type WTs) occur at a younger age, which is probably one of the reasons why WTs at a younger age have a better prognosis.16 In primarily operated WTs, the only histological feature of adverse prognostic significance is anaplasia, which is found in about 5% of cases.17 Anaplasia may occur in any cell type (but is extremely rare in the stromal component, especially on its own, i.e. not associated with anaplasia in the blastemal and/or epithelial component). It is defined as the presence of large atypical multipolar mitoses (Figure 2a), together with marked nuclear enlargement and hyperchromasia (Figure 2b).18 Anaplasia is further subclassified as focal (FA) and diffuse anaplasia (DA). FA is defined as the presence of anaplastic changes in one or a few sharply defined foci within the primary tumour, without evidence of marked nuclear atypia elsewhere in the tumour. DA is defined as non-localized anaplasia and/or anaplasia beyond the original tumour capsule; FA with marked nuclear atypia elsewhere in the tumour; anaplasia that is not clearly demarcated from non-anaplastic tumour; anaplasia in intrarenal vascular extensions, extrarenal invasive sites or metastases; and anaplasia in a random biopsy sample.18 In the latest COG trial, FA and DA are regarded as high-risk tumours,
SIOP Working classification of renal tumours of childhood I Low risk tumours Mesoblastic nephroma Cystic partially differentiated nephroblastoma Completely necrotic Nephroblastoma II Intermediate risk tumours Nephroblastoma e epithelial type Nephroblastoma e stromal type Nephroblastoma e mixed type Nephroblastoma e regressive type Nephroblastoma e focal anaplasia III High risk tumours Nephroblastoma e blastemal type Nephroblastoma e diffuse anaplasia Clear cell sarcoma of the kidney Rhabdoid tumour of the kidney IV Others Table 2
not occupying more than two-thirds of the tumour), the tumour is designated as mixed, but in the SIOP classification any tumour which contains greater than 10% of blastema, irrespective of the
Different histological patterns of Wilms tumour: a mixed pattern with blastemal, epithelial and stromal elements; b diffuse blastemal pattern; c epithelial pattern with moderately differentiated tubules; and d stromal pattern with marker rhabdomyoblastic differentiation. Figure 1
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Anaplastic Wilms tumour with a atypical multipolar mitosis and b marked nuclear enlargement and hyperchromasia. Figure 2
subclassified into dormant, sclerosing and hyperplastic NRs, and they may regress to fibrous tissue or progress to WT. Perilobar NRs are found at the periphery of the renal lobe and are composed of epithelial, stromal and blastemal structures (Figure 3a). They are associated with overgrowth syndrome (hemihypertrophy, BeckwitheWiedemann syndrome) and have a low malignant potential. Intralobar NRs occur within the renal lobe and are usually bland with the adjacent kidney (Figure 3b). They usually contain abundant stroma and are better organized than WT. Intralobar NRs are often associated with WAGR (Wilms’ tumour, aniridia, genitourinary anomalies, mental retardation) and DenyseDrash syndromes.21 There seems to be a considerable degree of heterogeneity in the genetics of WT,22,23 with different tumour suppressor genes and different genetic mechanisms, with losses and gains of chromosomal material, some translocations, and methylation and imprinting changes, particularly involving the 11p15 locus (the BeckwitheWiedemann locus).22,23 Recently, a WTX gene on chromosome X was identified to be inactivated in around 30% of WT.24 Epidemiological studies suggest at least three types of genetic pathway in WT pathogenesis.22,23 In the last completed NWTS trial, it was shown that loss of heterozygosity on both
whereas in the latest SIOP classification FA is subclassified in the intermediate-risk group, and DA in the high-risk group.5 Anaplasia is associated with a poor prognosis, especially at the higher stage, and is still a diagnostic problem at the institutional level.17 Preoperative chemotherapy does not obliterate or induce anaplasia, and it may actually help its detection due to loss of the chemosensitive elements. It is associated with p53 mutations, and is often positive on p53 immunohistochemical staining.19 In addition to DA, in the SIOP classification of WTs treated with preoperative chemotherapy, blastemal-type WT is also subclassified into the high risk group, since its relapse-free survival was as poor as for DA in the SIOP9/GPOH study.5,15 The prognosis of WT depends on its histology and stage. WT most commonly metastasizes to the lungs and lymph nodes, whereas bone and brain metastases are rare. The overall survival for patients with WT is now over 90%; therefore, at present the focus is reduction of treatment in order to reduce therapy-related sequelae.8 Nephrogenic rests (NRs) are abnormally persistent (after 36 weeks of gestation) foci of embryonal cells that are capable of developing into WT. NRs are found in 30e40% of WTs,20 and are subclassified into perilobar and intralobar NRs, depending on their localization within the renal lobe. Both types are further
a Perilobar nephrogenic rests and b intralobar nephrogenic rests. Figure 3
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kidney (RTK). The diagnosis should be reached by looking for other characteristic features of these tumours. Interestingly, there seems to be an association between CN and pleuropulmonary blastoma.27,28
Mesoblastic nephroma Mesoblastic nephroma (MN) accounts for w2e3% of all paediatric renal neoplasms and is now regarded as a low-grade fibroblastic sarcoma of the kidney. It is the commonest congenital renal tumour, with 90% of cases presenting in the first year of life, whereas it virtually never occurs after 3 years of age.29 Histologically, it may exhibit classical, cellular type and mixed pattern. The classical type closely resembles infantile fibromatosis and consists of spindled cells arranged in intersecting fascicles (Figure 5a), and usually it infiltrates the renal parenchyma, especially in the hilus. The cellular type consists of densely packed plump, round cells with vesicular nuclei and a small to moderate amount of cytoplasm (Figure 5b). It is usually sharply circumscribed and does not infiltrate the renal parenchyma.30 It shares the same genetic abnormality as infantile fibrosarcoma: a t(12;15)(p13;q25) translocation with resultant ETV6eNTRK3 fusion.31 MN is treated with complete surgical excision, resulting in excellent survival.32 Rare local recurrences, particularly of cellular type, are due to incomplete resection, and exceptionally rare cases of distant metastases have been reported. They all develop within 12 months after the diagnosis, so patients should be followed up closely for at least 1 year.33 The differential diagnosis includes metanephric stromal tumour, clear cell sarcoma of the kidney and stromal-type WT. As no specific immunohistochemical markers for MN exist, the diagnosis should be reached by taking into account the clinical and histological features of these tumours.
Figure 4 Cystic partially differentiated nephroblastoma consisting entirely of cysts and their septa, which contain small islands of blastema.
chromosomes 16q and 1p, identified in approximately 5% of patients with non-anaplastic WT, was associated with an unfavourable outcome,25 and this has been introduced in treatment stratification in the recently launched trial.6
Cystic renal tumours Cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN) are rare, completely cystic renal tumours which share the same histological features, including sharp demarcation from the renal parenchyma. They consist of cysts of different shapes and sizes, with the septa as the only solid areas, and they may contain tubules and, in CPDN, foci of blastema (Figure 4).26 As they are treated with surgery only, it is important to distinguish them from other renal tumours which may show a very prominent cystic pattern (but are virtually never completely cystic), such as pretreated WTs, mesoblastic nephroma, clear cell sarcoma of the kidney (CCSK) and even rhabdoid tumour of the
Clear cell sarcoma of the kidney Clear cell sarcoma of the kidney (CSSK) represents w3% of renal tumours of childhood. Its peak incidence is between 2 and 4 years of age, and it shows a male-to-female predominance of
Mesoblastic nephroma: a classical type, consisting of fascicles of bland spindle cells and with infiltration of the adjacent renal parenchyma and b cellular type, consisting of densely packed cells. Figure 5
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Clear cell sarcoma of the kidney showing different patterns aed and a characteristic vascular network b. Figure 6
around 2:1.34 Histologically, CCSK shows a wide histological spectrum of different patterns, including classical, epithelioid, spindled, sclerosing, palisading, myxoid, cystic and pleomorphic, which explains why it is the most frequently misdiagnosed renal tumour of childhood (Figure 6). Different patterns are usually found within the same tumour. The classical pattern is characterized by well-defined cords or nests of undifferentiated large cells with bland, empty-looking nuclei containing finely dispersed chromatin and usually no nucleoli. However, this pattern is seen in only w30% of cases. The most distinguishing feature is the ‘chickenwire’, delicate vascular network (Figure 6b), which can be easily recognized on CD34 staining. Another characteristic and diagnostically helpful feature of CCSK is its delicate infiltration of the adjacent renal parenchyma at the kidneyetumour interface, with entrapment of non-neoplastic tubules at the periphery of the tumour.34 No specific immunohistochemical and genetic features associated with CCSK have been identified.34,35 Recently, a t(10;17) translocation was reported in CCSK, suggesting its possible role in tumorigenesis.36 In another study, nerve growth factor receptor was strongly positive in 100% of CCSKs, making it the first potentially useful marker for CCSK.37 The most common metastases of CCSK at presentation are to local lymph nodes (w30%),34 but the bone is the commonest site for metastatic relapse.34 The introduction of doxorubicin has resulted in a striking improvement in the prognosis of stage IeIII tumour.38
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Rhabdoid tumour of the kidney Rhabdoid tumor of the kidney (RTK) accounts for about 2% of paediatric renal tumours. The mean age at diagnosis is 1 year, and the median age is 11 months. Over 80% of cases are diagnosed in the first 2 years of life, and the diagnosis is dubious after the age of 5 years.39 The tumour is associated with hypercalcaemia and synchronous or metachronous brain tumours. Characteristic
Figure 7 Rhabdoid tumour of the kidney composed of large, non-cohesive cells with large nuclei and prominent nucleoli, with prominent intracytoplasmic inclusion.
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Metanephric tumours including a metanephric stromal tumour showing nodular appearance due to hypo- and hyper-cellular areas and b metanephric adenoma, composed of small, well-differentiated tubules, with no capsule between the tumour and the kidney. Figure 8
histological features are the presence of large, non-cohesive tumour cells with eccentric large nuclei and very prominent eosinophilic central nucleoli (present in virtually all cases), and hyaline intracytoplasmatic inclusions (often seen only focally) (Figure 7). In addition to the classical pattern, the tumour may show numerous other patterns, including classical, sclerosing, epithelioid, clear cell sarcoma-like, lymphomatoid, vascular, pseudopapillary and cystic patterns.39,40 Immunohistochemically, in addition to vimentin (positive in all cases), RTK coexpresses different markers, including desmin, myoglobin, EMA, NSE, neurofilaments, S100 protein and CD99 (which are usually focally positive and not present in all cases).39,40 However, the diagnostic immunohistochemical feature is absence of immunoreactivity for INI1 marker in the tumour cell nuclei. Genetic abnormalities of hSNF5/INI1 tumour suppressor gene on chromosome 22q11e12 has been identified in children with renal and extra-renal rhabdoid tumours, and the atypical teratoid rhabdoid tumour of the brain.41 The differential diagnosis of RTK includes renal medullary carcinoma (INI1 is also negative in this tumour), cellular mesoblastic nephroma with rhabdoid cells, CCSK, blastemal WT, EWS/PNET and rhabdmomyosarcoma. RTK is a highly invasive, lethal neoplasm which gives early metastases in lung, lymph nodes, liver, bone and brain. The prognosis is very poor with 80e90% of patients dying within a few months of the diagnosis,39,40 but it appears to be better for older children.42
treated with surgery only and has the same excellent prognosis as MN.43 MAF occurs in children and young adults and exhibits a mixture of stromal elements (identical to those in MST) and well-defined areas of immature epithelium (tubules and papillae).44 Finally, MA is more commonly found in adults than in children. It is usually small (up to 2 cm) and composed of monotonous small, closely-packed tubules which show no mitoses. Characteristically, there is no capsule between the tumour and the adjacent renal parenchyma (Figure 8b).45 It may be difficult to distinguish from epithelial-predominant WT and there may be a close pathogenetic relationship.46
Renal cell carcinomas Renal cell carcinomas (RCCs) represent around 5% of all paediatric renal tumours, hence they are more common than MN, CCSK or RTK. They show distinguishing histological and genetic features from RCCs seen in adults.47,48 These tumours are defined by several different translocations.49 A group of Xp11.2-translocation carcinomas resulting from fusion of the TFE3 gene50 (which includes a total of five gene fusions) is now recognized as a separate entity in the latest World Health
Metanephric tumours Metanephric tumours comprise a spectrum of rare, recently recognized entities, including metanephric stromal tumour (MST),43 metanephric adenofibroma (MAF)44 and metanephric adenoma (MA).45 Histologically, MST is a pure stromal tumour showing characteristic hypo- and hyper-cellular areas (resulting in a nodular appearance on low power view) (Figure 8a), concentric collarettes of tumour around entrapped tubules and blood vessels which may show angiodysplasia. It occurs from 2 days to 156 months of age (median 13 months) and it should be considered in the differential diagnosis of stromal tumours in children older than 3 years of age, when MN does not occur. It is
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Figure 9 Renal cell carcinoma associated with Xp11.2 translocation showing papillary architecture with large cells with abundant granular eosionophilic cytoplasm.
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Organization classification.51 Histologically, they show a typical nested appearance, but may also be papillary, composed of cells with granular eosinophilic cytoplasm or clear cells (Figure 9). Immunohistochemically, tumour cells show strong nuclear positivity for TFE3, which is diagnostic.52 A t(6;11)-translocation RCC is another translocation-associated paediatric RCC which has been rarely reported, and is seems to be less aggressive than Xp11.2-translocation RCC.53 Histologically, they feature nests and small acini of polygonal epithelioid cells with well-defined cell borders, separated by a thin-capillary vasculature, but also another population of smaller epithelioid cells clustered around nodules of hyaline basement membrane material.54 A number of these tumours occur as post-chemotherapy tumours, including after neuroblastoma and WT.55 Papillary carcinoma can also occur in older children.56 Carcinomas of the kidney need to be considered in children with von HippeleLindau disease and tuberous sclerosis. RCCs with lymph node metastases generally appear to have a better prognosis in children. Renal medullary carcinoma is a rare, highly aggressive tumour occurring in children and young adults with sickle cell trait or disease.57 Microscopically, it is very infiltrative, and is composed of large cells with large, vesicular nuclei and prominent nucleoli (rhabdoid features), usually accompanied by a marked acute and chronic inflammatory infiltrate and stromal desmoplasia.57,58 Interestingly, tumour cells may be negative for INI1 marker. Patients usually present with widespread metastases and show no response to chemo- or radio-therapy, resulting in a poor survival (mean 4 months).57,58 A rare form of RCC developing after neuroblastoma has been described, showing unusual oncocytoid histological features with solid and papillary pattern.59 RCC following WT has also been described.
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Other entities A number of other rare tumours have been recently identified in the kidney. Some have been recognized by the application of molecular biology techniques, such as primitive neuroectodermal tumour,60 synovial sarcoma61 and desmoplastic small round cell tumour,62 whereas others, such as anaplastic sarcoma of the kidney63 and mixed epithelial and stromal tumour of the kidney,64 have been recognized on the basis of their characteristic clinicopathological features observed by examination of large series of cases from the multicentre studies.
Conclusion Renal tumours of childhood are a fascinating group of tumours where huge progress in classification, treatment and understanding of molecular biology has been made. This has only been possible because of close collaboration between patients, clinicians and pathologists, and their participation in national and international multicentre trials where clinical, epidemiological and pathological data have been systematically and meticulously collected and studied. Since these tumours are rare, they still represent a diagnostic problem and central pathology review in multicentre trials is essential for assigning the appropriate treatment. Molecular biology markers are likely to play an even more important role in future trials. A
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21 Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of nephrogenic rests and Wilms tumors. J Pediatr Hematol Oncol 2007; 29: 589e94. 22 Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002; 14: 5e11. 23 Pritchard-Jones K, Vujanic G. Multiple pathways to Wilms tumor: how much is genetic? Pediatr Blood Cancer 2006; 47: 232e4. 24 Rivera MN, Kim WJ, Wells J, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 2007; 315: 642e5. 25 Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorablehistology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2005; 23: 7312e21. 26 Joshi VV, Beckwith JB. Multilocular cyst of the kidney (cystic nephroma) and cystic, partially differentiated nephroblastoma. Terminology and criteria for diagnosis. Cancer 1989; 64: 466e79. 27 Boman F, Hill DA, Williams GM, et al. Familial association of pleuropulmonary blastoma with cystic nephroma and other renal tumors: a report from the International Pleuropulmonary Blastoma Registry. J Pediatr 2006; 149: 850e4. 28 Bouron-Dal Soglio D, Harvey I, Yazbeck S, Rypens F, Oligny LL, Fournet JC. An association of pleuropulmonary blastoma and cystic nephroma: possible genetic association. Pediatr Dev Pathol 2006; 9: 61e4. 29 van den Heuvel-Eibrink MM, Grundy P, Graf N, et al. Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: a collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms Tumor Study Groups. Pediatr Blood Cancer 2008; 50: 1130e4. 30 Murphy WM, Grignon DJ, Perlman EJ. Kidney tumors in children. In: Tumors of the kidney, bladder, and urinary structures. Atlas of tumor pathology, 4th Series, Fascicle 1. Washington, DC: Armed Forces Institute of Pathology; 2004. p. 57e64. 31 Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 1998; 58: 5046e8. 32 Furtwaengler R, Reinhard H, Leuschner I, et al. Mesoblastic nephroma - a report from the Gesellschaft fur Padiatrische Onkologie und Hamatologie (GPOH). Cancer 2006; 106: 2275e83. 33 Beckwith JB. Letter to editor. Pediatr Pathol 1993; 13: 886e7. 34 Argani P, Perlman EJ, Breslow NE, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 2000; 24: 4e18. 35 Schuster AE, Schneider DT, Fritsch MK, et al. Genetic and genetic expression analyses of clear cell sarcoma of the kidney. Lab Invest 2003; 83: 1293e9. 36 Brownlee NA, Perkins LA, Stewart W, et al. Recurring translocation (10;17) and deletion (14q) in clear cell sarcoma of the kidney. Arch Pathol Lab Med 2007; 131: 446e51. 37 Bonadio J, Perlman EJ. Immunohistochemical analysis of 61 clear cell sarcomas on the kidney for a panel including NGFR and CD99. Book of Abstracts from the Society for Pediatric Pathology Annual Meeting, 2008: A26. 38 Seibel NL, Li S, Breslow NE, et al. Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2004; 22: 468e73. 39 Weeks DA, Beckwith JB, Mierau GW, Luckey DW. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms’ Tumor Study Pathology Center. Am J Surg Pathol 1989; 13: 439e58.
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40 Vujanic GM, Sandstedt B, Harms D, Boccon-Gibod L, Delemarre JF. Rhabdoid tumour of the kidney: a clinicopathological study of 22 patients from the International Society of Paediatric Oncology (SIOP) nephroblastoma file. Histopathology 1996; 28: 333e40. 41 Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol 2004; 28: 1485e91. 42 Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms’ Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 2005; 23: 7641e5. 43 Argani P, Beckwith JB. Metanephric stromal tumor. Report of 31 cases of a distinctive pediatric renal neoplasm. Am J Surg Pathol 2000; 24: 917e26. 44 Arroyo MR, Green DM, Perlman EJ, Beckwith JB, Argani P. The spectrum of metanephric adenofibroma and related lesions. Clinicopathologic study of 25 cases from the National Wilms Tumor Strudy Group Pathology Centre. Am J Surg Pathol 2001; 25: 433e44. 45 Davis Jr CJ, Barton JH, Sesterhenn IA, Mostofi FK. Metanephric adenoma. Clinicopathological study of fifty patients. Am J Surg Pathol 1995; 19: 1101e14. 46 Argani P. Metanephric neoplasms: the hyperdifferentiated, benign end of the Wilms tumor spectrum? Clin Lab Med 2005; 25: 379e92. 47 Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007; 31: 1149e60. 48 Bruder E, Passera O, Harms D, et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004; 28: 1117e32. 49 Argani P. The evolving story of renal translocation carcinomas. Am J Clin Pathol 2006; 126: 332e4. 50 Argani P, Ladanyi M. Translocation carcinomas of the kidney. Clin Lab Med 2005; 25: 363e78. 51 Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Tumours of the urinary system and male genital organs: pathology and genetics. World Health Organisation classification of tumours. Lyon: IARC; 2004. 52 Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003; 27: 750e61. 53 Argani P, Lae M, Hutchinson B, et al. Renal carcinomas with the t(6;11) (p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005; 29: 230e40. 54 Argani P, Ladanyi M. Recent advances in pediatric renal neoplasia. Adv Anat Pathol 2003; 10: 243e60. 55 Argani P, Lae M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006; 24: 1529e34. 56 Renshaw AA, Granter SR, Fletcher JA, Kozakewich HP, Corless CL, Perez-Atayde AR. Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes. Am J Surg Pathol 1999; 23: 795e802. 57 Davis Jr CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995; 19: 1e11. 58 Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology 2002; 60: 1083e9.
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59 Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999; 23: 772e80. 60 Parham DM, Roloson GJ, Feely M, Green DM, Bridge JA, Beckwith JB. Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol 2001; 25: 133e46. 61 Argani P, Faria PA, Epstein JI, et al. Primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg Pathol 2000; 24: 1087e96. 62 Wang LL, Perlman EJ, Vujanic GM, et al. Desmoplastic small round cell tumor of the kidney in childhood. Am J Surg Pathol 2007; 31: 576e84. 63 Vujanic GM, Kelsey A, Perlman EJ, Sandstedt B, Beckwith JB. Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 2007; 31: 1459e68. 64 Hara N, Kawaguchi M, Murayama S, Maruyama R, Tanikawa T, Takahashi K. Mixed epithelial and stromal tumor of the kidney in a 12-year-old girl. Pathol Int 2005; 55: 670e6.
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Renal tumours of childhood, especially non-Wilms’ tumours, are rare, making them difficult to accurately diagnose and stage Wilms tumour has an excellent prognosis with over 90% overall survival (all stages together) Two subtypes of Wilms tumour with a poor prognosis are diffuse anaplasia and blastemal type Wilms tumour is the only renal tumour of childhood associated with nephrogenic rests and clinical syndromes There is a considerable degree of genetic heterogeneity in the genetics of Wilms tumour Cellular mesoblastic nephroma and infantile fibrosarcoma represent the same tumour entity Renal and extrarenal rhabdoid tumours are the same entity Renal cell carcinomas comprise around 5% of all paediatric renal tumours and show distinguishing histological and genetic features from renal cell carcinomas in adults
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