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ABSTRACT: A coexistence of different renal tumors has rarely been reported. The most commonly described association is of Wilms tumor and renal cell carcinoma. Metanephric adenofibroma has also been associated with Wilms tumor or papillary renal cell carcinoma. Another reported association is metanephric adenoma and papillary renal cell carcinoma with sarcomatoid dedifferentiation. Herein we describe a complex renal tumor containing areas of metanephric adenofibroma, Wilms tumor, and undifferentiated renal cell carcinoma in a previously healthy 18-year-old boy. The tumor showed histologic and immunohistochemical features of these 3 different tumors, offering additional support to the view that these 3 tumors are related.
Pediatric and Developmental Pathology 06/2011; 15(1):65-70. · 0.99 Impact Factor
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Marry M van den Heuvel-Eibrink,
Harm van Tinteren,
Harriet Rehorst,
Aurore Coulombe,
Catharine Patte,
Beatriz de Camargo,
Jan de Kraker,
Ivo Leuschner,
Rieneke Lugtenberg,
Kathy Pritchard-Jones,
Bengt Sandstedt,
Filippo Spreafico,
Norbert Graf, Gordan M Vujanic
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ABSTRACT: Survival data of malignant rhabdoid tumour of the kidney (MRTK) registered in SIOP trials, advocating preoperative chemotherapy, are not available.
To evaluate characteristics, response and survival of MRTK patients registered in recent SIOP protocols.
An evaluation of all MRTK patients treated from 1993 to 2005 (SIOP trials 93-01 and 2001) was performed. Data were obtained from study specific case record forms and entered centrally in a database.
Hundred and seven patients were identified (57 male), with a median age at diagnosis of 13 months (interquartile range 6-27 months), and a median follow-up time of 60 months. Left and right kidneys were equally affected. Tumour stage distribution was stage I (6%), stage II (22%), stage III (43%), stage IV (22%) and stage V (3%). Stage IV patients included 17 with pulmonary metastasis (8 lung-only) and 12 with multiple organ metastases (bone, brain and liver). Primary surgery was the upfront treatment approach in 22/107 patients (21%), by which 19 patients reached a complete remission (CR). Median difference in tumour volume before and after preoperative chemotherapy was 69 ml (interquartile range: 4.5-158.0, P < 0.0001), indicating marked chemosensitivity. The 5-year event-free survival (EFS) of the total group was 22% (95% CI: 15-33) and overall survival 26% (95% CI: 18-37). Most events (86%) occurred within the first 2 years after diagnosis. Younger age at diagnosis was an important adverse prognostic factors for survival. In contrast, tumour volume at diagnosis, nor volume reduction was associated with outcome.
MRTK has a poor outcome especially in young and advanced-stage disease patients. Neither tumour volume at diagnosis, nor pre-operative chemosensitivity are prognostic factors for survival.
Pediatric Blood & Cancer 05/2011; 56(5):733-7. · 1.89 Impact Factor
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ABSTRACT: Mesoblastic nephroma (MN) is a rare tumour which occurs mainly in early infancy and for which primary nephrectomy is the treatment of choice. This study aimed to assess surgical complications and outcomes in this patient group and to re-evaluate the age threshold of 6 months for recommending primary nephrectomy.
A retrospective file review of all cases of MN registered in UK Children's Cancer and Leukaemia Group renal tumour trials between October 1991 and March 2008. Data from the trials were compared with data held by the National Registry of Childhood Tumours, Oxford.
Forty-seven (3.5%) confirmed cases of MN were found among 1346 registered renal tumours. Median age at diagnosis was 30 days (range birth-3.8 years). MN was significantly more common in the first 3 months of life compared to between 3 and 6 months (33 vs. 2 cases). Seven cases occurred between 6 months and 1 year and only five cases occurred beyond 1 year of age. There was a significant difference in the age of diagnosis by histological subtype. There were 11 complications in the series; no registered patient developed a recurrent tumour; and all were alive at last follow-up.
Outcome for children with MN is excellent at all ages, with little indication for adjuvant chemotherapy. Children presenting at <3 months of age, should be treated by primary nephrectomy. In those presenting aged >3 months, alternative diagnoses should be considered, especially in the presence of surgical risk factors.
Pediatric Blood & Cancer 05/2011; 56(5):744-8. · 1.89 Impact Factor
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ABSTRACT: Wilms tumour (WT) has various subtypes that are correlated with prognosis and require distinct therapy. Stromal predominant (SpWT) and epithelial WT (EpWT) have previously been associated with a good outcome. The current analysis describes the outcome and (tumour) characteristics of all patients with SpWT, EpWT, including highly differentiated epithelial type (HDET), treated according to the International Society of Pediatric Oncology (SIOP) 93-01 study.
All children older than 6 months and below 18 years of age with localized or metastatic WT and intermediate risk (IR) histology or HDET treated with pre-operative chemotherapy were included in the present analysis.
A total of 1,389 eligible patients had IR or HDET histology: 1% HDET, 4% EpWT, 10% SpWT, and 85% other IR. For EpWT/HDET, 93% had stage I/IIN-, 5-year EFS was 90.2% and overall survival of (OS) 98.4%, as compared to 84.0% and 92.5% in other IR histology (NS). Stage I EpWT/HDET had a significant better outcome than stage I of other IR. In SpWT 82% of cases had stage I/IIN-; 5-year EFS was 94.3% and OS 99.2%, significantly better compared to other IR histology. All patients with stage I are alive (2/149 relapses); 3/52 stage IIN-, 2/21 stage IIN+/III, and 6/12 stage IV patients relapsed (1 deceased per stage group).
The good outcome for EpWT and SpWT generally is very good which may be related to low age and low stage in most cases. A reduction of treatment intensity and/or duration may be justified especially for low stage SpWT that has an EFS close to 100%.
Pediatric Blood & Cancer 08/2010; 55(2):233-8. · 1.89 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) and its receptor Met are known to play diverse roles in both organogenesis and cancer. Wilms' tumor (WT) is a prototype for the link between abrogated development and neoplasia, with dysregulation of growth factor/receptor pathways playing key roles. Despite this, an understanding of the HGF/Met axis in the process is lacking.
Observing copy number alterations at the loci for these genes in WTs and their precursor lesions nephrogenic rests, we examined protein expression by immunohistochemistry and investigated the effects of HGF on an in vitro model of kidney development.
HGF was preferentially expressed in the blastemal cells of nephrogenic rests but not WTs. Met expression was infrequent and restricted to well-differentiated epithelial cells and stroma in both lesions. In an independent cohort of favorable histology WTs on a tissue microarray, HGF was expressed in 15 of 193 (8%) cases and correlated with a predominance of epithelial cells, whereas Met expression was observed in 25 of 179 (14%) cases and was associated with stromal subtypes. In a mouse mesonephric cell line model, we observed Met expression in culture conditions reflecting both mesenchymal and epithelial differentiation, whereas HGF was up-regulated in association with acquisition of a more epithelial-like phenotype. This could be mimicked by exogenous exposure of mesenchymal-like cells to recombinant HGF.
These data show that the relatively infrequent expression of HGF and Met in WT tumorigenesis reflects their roles in nephrogenesis, particularly the mesenchymal-to-epithelial transition, rather than a dependence on oncogenic signaling pathways.
Clinical Cancer Research 04/2009; 15(8):2723-30. · 7.74 Impact Factor
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Raisa Vuononvirta,
Neil J Sebire,
Anthony R Dallosso,
Jorge S Reis-Filho,
Richard D Williams,
Alan Mackay,
Kerry Fenwick,
Anita Grigoriadis,
Alan Ashworth,
Kathy Pritchard-Jones,
Keith W Brown, Gordan M Vujanic,
Chris Jones
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ABSTRACT: Perilobar nephrogenic rests (PLNRs) are abnormally persistent foci of embryonal immature blastema that have been associated with dysregulation at the 11p15 locus by genetic/epigenetic means and are thought to be precursor lesions of Wilms tumor. The precise genomic events are, however, largely unknown.
We used array comparative genomic hybridization to analyze a series of 50 PLNRs and 25 corresponding Wilms tumors characterized for 11p15 genetic/epigenetic alterations and insulin-like growth factor-II expression.
The genomic profiles of PLNRs could be subdivided into three categories: those with no copy number changes (22 of 50, 44%); those with single, whole chromosome alterations (8 of 50, 16%); and those with multiple gains/losses (20 of 50, 40%). The most frequent aberrations included 1p- (7 of 50, 14%) +18 (6 of 50, 12%), +13 (5 of 50, 10%), and +12 (3 of 50, 6%). For the majority (19 of 25, 76%) of cases, the rest harbored a subset of the copy number changes in the associated Wilms tumor. We identified a temporal order of genomic changes, which occur during the insulin-like growth factor-II/PLNR pathway of Wilms tumorigenesis, with large-scale chromosomal alterations such as 1p-, +12, +13, and +18 regarded as "early" events. In some of the cases (24%), the PLNRs harbored large-scale copy number changes not observed in the concurrent Wilms tumor, including +10p, +14q, and +18.
These data suggest that although the evidence for PLNRs as precursors is compelling, not all lesions must necessarily undergo malignant transformation.
Clinical Cancer Research 01/2009; 14(23):7635-44. · 7.74 Impact Factor
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ABSTRACT: In SIOP trials, Wilms' tumors were labeled as stage II by the presence of nonviable and/or viable tumor in the renal sinus and/or perirenal fat. The aim of this study was to determine if this approach was justified. Stage II Wilms' tumors were reviewed to establish whether staging was due to viable or nonviable tumor, and this was related to clinical outcome. One hundred sixty-nine patients were included: 40 had stage II due to the presence of nonviable tumor and 129 due to viable tumor. Postoperatively, 29 patients were undertreated: 7 with nonviable and 22 with viable stage II tumors. No undertreated patient with nonviable stage II relapsed or died (event-free survival [EFS] and overall survival [OS] 100%), whereas 3 of 22 with viable stage II relapsed, and 2 of them died (EFS 86%, OS 91%). Of 140 correctly treated patients, only 1 of 33 nonviable stage II patients relapsed and died (EFS and OS 97%); 8 of 107 patients with viable stage II relapsed (EFS 92%), and 3 of them died (OS 97%). The presence of nonviable tumor in the renal sinus and/or perirenal fat does not predict an adverse outcome in Wilms' tumors, and alone it does not warrant designation to stage II.
Pediatric and Developmental Pathology 10/2008; 12(2):111-5. · 0.99 Impact Factor
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ABSTRACT: 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.
Pathology 03/2008; 40(2):217-27. · 2.38 Impact Factor
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ABSTRACT: To investigate the presence and prognostic relevance of KIT expression in paediatric renal tumours, and to determine whether receptor overexpression is associated with gene amplification and/or mutation.
Immunohistochemistry without antigen retrieval for CD117 was carried out on tissue microarrays consisting of 274 Wilms' tumours, 13 clear cell sarcomas of the kidney (CCSK), 10 mesoblastic nephromas (MN), and 7 rhabdoid tumours of the kidney (RTK). In addition, gene copy number was investigated by chromogenic in situ hybridisation (CISH), and overexpressing tumours were sequenced for KIT mutations in exons 9, 11, 13 and 17.
Only 8/200 (4.0%) Wilms' tumours exhibited any degree of moderate-strong KIT staining in any of their assessable cell types. This small group of KIT-positive tumours had a shorter time to relapse (p = 0.0044, log-rank test). There were no positive MNs or RTKs; however 3/11 (27.3%) CCSKs were strongly positive, with an additional two cases weakly reactive. No cases exhibited gene amplification or mutation.
KIT overexpression in rare in Wilms' tumours, although does appear to confer a worse prognosis, in particular for patients primarily treated with preoperative chemotherapy. CCSKs are associated with an increased expression of KIT, however, in the absence of gene amplification and/or activating mutation. The potential of anti-KIT therapeutic strategies in the treatment of paediatric renal tumours appears to be limited.
Journal of clinical pathology 12/2007; 60(11):1226-31. · 2.43 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We sought to evaluate these variables in pediatric renal tumors.
We screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, we further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN.
Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, we identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases.
Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.
Clinical Cancer Research 09/2007; 13(15 Pt 1):4360-4. · 7.74 Impact Factor
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Larry L Wang,
Elizabeth J Perlman, Gordan M Vujanic,
Craig Zuppan,
Marie-Anne Brundler,
C Ronny L H Cheung,
Monica L Calicchio,
Steven Dubois,
Marc Cendron,
Joyce L Murata-Collins,
Gail D Wenger,
Donna Strzelecki,
Frederic G Barr,
Tucker Collins,
Antonio R Perez-Atayde,
Harry Kozakewich
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ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor that generally manifests as abdominal paraserosal masses and affects mainly male adolescents and young adults. When presenting within visceral organs, the diagnosis of DSRCT poses significant difficulties.
Four primary renal DSRCT in children diagnosed during a 3-year period are the basis of this report. The medical records and pathologic material were reviewed, including immunohistochemical, ultrastructural, and cytogenetic/molecular studies.
The age at presentation was 6 to 8 years, and all children presented with a left renal mass. The tumors measured 3.7 to 13.4 cm and consisted of nests, cords, or sheets of small undifferentiated cells with foci of necrosis and calcification. Desmoplasia was not seen. Tumor cells were immunopositive for vimentin, WT-1 (monoclonal and polyclonal), desmin, cytokeratin, and epithelial membrane antigen. A distinct paranuclear dotlike pattern was observed with vimentin and desmin. Tumor cells possessed rare or focal immunoreactivity for platelet derived growth factor-A and transforming growth factor-beta3, which have been implicated in the pathogenesis of desmoplasia in DSRCT. The EWS-WT1 t(11;22)(p13;q12) translocation was demonstrated in all 4 tumors by fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction.
DSRCT should be considered in the differential diagnosis of renal tumors composed of small round cells. Undifferentiated morphology and lack of desmoplasia contribute to the difficulty in its recognition. Ancillary studies such as immunohistochemistry may suggest the diagnosis, but cytogenetic and molecular genetic studies are required for confirmation.
American Journal of Surgical Pathology 05/2007; 31(4):576-84. · 4.35 Impact Factor
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Rachael Natrajan,
Suzanne E Little,
Jorge S Reis-Filho,
Lara Hing,
Boo Messahel,
Paul E Grundy,
Jeffrey S Dome,
Toni Schneider, Gordan M Vujanic,
Kathy Pritchard-Jones,
Chris Jones
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ABSTRACT: The most well established molecular markers of poor outcome in Wilms' tumor are loss of heterozygosity at chromosomes 1p and/or 16q, although to date no specific genes at these loci have been identified. We have previously shown a link between genomic gain of chromosome 1q and tumor relapse and sought to further elucidate the role of genes on 1q in treatment failure.
Microarray-based comparative genomic hybridization identified a microamplification harboring a single gene (CACNA1E) at 1q25.3 in 6 of 76 (7.9%) Wilms' tumors, correlating with a shorter relapse-free survival (P = 0.0044, log-rank test). Further characterization of this gene was carried out by measuring mRNA and protein expression as well as stable transfection of HEK293 cells.
Overexpression of the CACNA1E transcript was associated with DNA copy number (P = 0.0204, ANOVA) and tumor relapse (P = 0.0851, log-rank test). Immunohistochemistry against the protein product Ca(V)2.3 revealed expression localized to the apical membrane in the distal tubules of normal kidney but not to the metanephric blastemal cells of fetal kidney from which Wilms' tumors arise. Nuclear localization in 99 of 160 (61.9%) Wilms' tumor cases correlated with a reduced relapse-free survival, particularly in cases treated with preoperative chemotherapy (P = 0.009, log-rank test). Expression profiling of stably transfected HEK293 cells revealed specific up-regulation of the immediate early response genes EGR1/EGR2/EGR3 and FOS/FOSB, mediated by activation of the MEK/ERK5/Nur77 pathway.
These data identify a unique genetic aberration with direct clinical relevance in Wilms' tumor relapse and provide evidence for a potential novel mechanism of treatment resistance in these tumors.
Clinical Cancer Research 01/2007; 12(24):7284-93. · 7.74 Impact Factor
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ABSTRACT: Most Wilms' tumors are of low stage, favorable histology, and have a high likelihood of cure with current multimodal therapy. Despite this, there remains a group of patients whose tumors recur for whom intensive salvage regimens result in survival of only 50%. Fitting a Cox proportional hazards model to microarray-based comparative genomic hybridization (aCGH) data on 68 Wilms' tumor samples, we identified a significant correlation between increased copy number at chromosome 15q26.3 insulin-like growth factor I receptor (IGFIR) and tumor relapse (adjusted P = 0.014). Wilms' tumors (13%) exhibited a low-level gain corresponding to three to four copies of the gene by aCGH analysis, 9 of 10 of which exhibited high IGFIR mRNA levels. Although IGFIR protein expression was restricted to the epithelial cells of fetal kidney and Wilms' tumors in most cases, 12% of tumors were also found to express IGFIR in the blastemal compartment. Blastemal IGFIR protein expression was associated with an increased copy number and a shorter relapse-free survival time (P = 0.027, log-rank test). In addition to the membrane localization, IGFIR was localized to the perinuclear region of the blastemal cells in 6% of Wilms' tumors. These data provide evidence that an increase in IGFIR gene copy number results in aberrant expression in the blastemal compartment of some Wilms' tumors and is associated with an adverse outcome in these patients. These findings suggest the possibility of use of targeted agents in the therapy of these children.
Cancer Research 01/2007; 66(23):11148-55. · 7.86 Impact Factor
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Christopher Mitchell,
Kathy Pritchard-Jones,
Rosemary Shannon,
Carolyn Hutton,
Suzanne Stevens,
David Machin,
John Imeson,
Anna Kelsey, Gordan M Vujanic,
Peter Gornall,
Jenny Walker,
Roger Taylor,
Pat Sartori,
Juliet Hale,
Gill Levitt,
Boo Messahel,
Helen Middleton,
Richard Grundy,
Jon Pritchard
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ABSTRACT: To determine if patients receiving preoperative chemotherapy with vincristine and actinomycin D for non-metastatic Wilms' tumour have a more advantageous stage distribution and so need less treatment compared to patients who have immediate nephrectomy, without adversely affecting outcome.
Between 1991 and 2001, a total of 205 patients with newly diagnosed non-metastatic renal tumours, of which 186 had Wilms' histologies, were randomly assigned either to immediate surgery or to 6 weeks preoperative chemotherapy and then delayed surgery. Both groups of children received postoperative chemotherapy according to tumour stage and histology determined at the time of nephrectomy.
There was a significant improvement in the stage distribution for patients with Wilms' histologies receiving delayed surgery compared to those having immediate nephrectomy (stage I: 65.2% versus 54.3%; stage II: 23.9% versus 14.9%; stage III: 9.8% versus 29.8%, chi2 test for trend=7.02, p=0.008). This improvement resulted in 20% fewer children receiving radiotherapy or doxorubicin yet event-free and overall survivals at 5 years of 79.6% and 89.0%, respectively, were similar in the two groups.
Six weeks of preoperative chemotherapy with vincristine and actinomycin D results in a significant shift towards a more advantageous stage distribution and hence reduction in therapy, while maintaining excellent event free and overall survival in children with non-metastatic Wilms' tumour. Around 20% of survivors were therefore spared the late-effects of doxorubicin or radiotherapy. Our results suggest that all children with non-metastatic Wilms' tumour should receive chemotherapy prior to tumour resection.
European Journal of Cancer 11/2006; 42(15):2554-62. · 5.54 Impact Factor
