Pretreatment, ultrasound-guided cutting needle biopsies in childhood renal tumors

BACKGROUND: The current International Society of Paediatric Oncology (SIOP)-10 protocol does not allow pretreatment histological classification of low-stage renal tumors in children for fear of needle tract recurrences. The aims of this retrospective study were to evaluate the safety, sensitivity, and specificity of ultrasound-guided cutting needle biopsies (UCNB) performed at our institution in pediatric patients with renal tumors. PROCEDURE: Of 28 pediatric patients presenting with a renal tumor between 1988 and 1996, 25 underwent biopsy with the Biopty biopsy instrument (needle diameter 1.2 mm). The preoperative biopsy and nephrectomy slides were reviewed by a SIOP reference pathologist. The patients' hospital records were reviewed and biopsy complications were noted. RESULTS: At review of the nephrectomy slides, the diagnoses were: Wilms tumor (16 patients), with anaplasia in one case, rhabdoid tumor (2 patients), neuroblastoma (2 patients), mesoblastic nephroma (2 patients), clear cell sarcoma (1 patient), malignant teratoma (1 patient), and renal cell carcinoma (1 patient). No needle tract recurrence or other major complication was observed. The only complication was local pain at the biopsy site, which occurred in 24% (6/25) of the cases. The sensitivity of UCNB was 76% (19/25); five biopsies did not yield diagnostic material and one was not concordant. All cases of Wilms tumor were correctly diagnosed by UCNB, but only 33% (3/9) of the other tumors. CONCLUSIONS: In all cases of Wilms tumor a correct diagnosis was made. The overall sensitivity was 76%. UCNB proved to be a safe procedure that was not associated with needle tract recurrence or other serious complications.     

Needle track recurrence after biopsy of non-metastatic Wilms tumour

A 2-year-old girl presented with a left-sided Wilms tumour. She was randomised to have a needle biopsy and preoperative chemotherapy according to the United Kingdom Children's Cancer Study Group (UKCCSG) protocol, a trial of preoperative chemotherapy in biopsy-proven Wilms tumour versus immediate nephrectomy (UK 9101). A nephrectomy was performed 6 weeks later. Six months later she presented with an abdominal wall recurrence at the needle biopsy site, which was resected. The value of needle biopsy in localised Wilms tumour is debated.     

Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9

BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.     

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??Childhood kidney tumors account for about 7% of all childhood cancers. Most childhood kidney tumors are Wilms tumor??but in the 15- to 19-year age group??most tumors are renal cell carcinoma. In medically developed countries??clinical trials in Wilms tumor??WT?? have resulted in overall survival rates of greater than 90%. Children’s Oncology Group Renal Tumor Committee??COG-RTC?? is one of the clinical study groups internationally known for its clinical research in childhood kidney tumor. Its standard treatment for children with Wilms tumor consists of initial nephrectomy??when feasible?? followed by chemotherapy and??in some patients??radiation therapy. This summary reviewed peer-reviewed??evidence-based reports about the treatment for Wilms tumor published recently and intended to be a resource to assist clinicians who care for children with Wilms tumor.     

The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China

Purpose : This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). Methods : We collected and analyzed clinical data concerning patients aged <15 years with favorable histology (FH) WTs treated at the Sun Yat‐Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. Results : We enrolled 97 patients with FH WTs (median follow‐up, 71.5 months; range, 22.2‐170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P = .010). Five‐year event‐free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5‐year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P = .001) and OS (P = .017). Conclusions : Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT–diagnosed prechemotherapy may have prognostic relevance. Further research into other potential confounding variables are required to determine whether such patients warrant altered risk‐stratified therapy.     

Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients

BACKGROUND: This study provides insight into the clinical behavior, diagnostic complexities, and long-term management of patients with hyperplastic perilobar nephroblastomatosis (HPLN). PROCEDURE: Fifty-two patients with HPLN with available long-term follow-up were retrospectively analyzed for pathologic, radiologic, and clinical features. RESULTS: The mean age at diagnosis was 16 months; the lesions were bilateral in 49 patients. Of 33 patients who initially underwent diagnostic biopsy and adjuvant chemotherapy, 18 (55%) developed Wilms tumor (WT) at a mean of 35 months from diagnosis. Of 16 patients whose initial therapy included nephrectomy and adjuvant therapy, three (19%) developed WT at a mean of 36 months from diagnosis. All three patients who underwent initial diagnostic biopsy and received no adjuvant therapy during their initial course developed WT 4, 4, and 10 months following diagnosis. 24/52 patients developed either a single (13 patients) or multiple (11 patients) WT throughout their course; 8/24 (33%) of WT were anaplastic. The time from initial diagnosis to the development of the last WT ranged from 13 to 116 months (mean 42 months). Three children with HPLN died of WT at 3, 5, and 6 years of age; 2/3 were anaplastic. CONCLUSIONS: HPLN is a self-limited, pre-neoplastic proliferative process associated with a high risk of developing WT. The accurate diagnosis and the choices of therapy during the often-complex course of HPLN depend on the availability and accurate interpretation of a combination of pathologic, radiologic, and clinical information. When such information is appropriately obtained, the long-term survival of patients with HPLN is excellent.     

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group

PURPOSE: This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. PATIENTS AND METHODS: The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. RESULTS: Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. CONCLUSIONS: The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.     

Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?

Cheng E, Fustino N, Klesse L, Chinnakotla S, Sanghavi R. Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?
Pediatr Transplantation 2011: 15: E187–E191. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant lymphoproliferative disorder is a life‐threatening neoplasm that can occur after orthotopic liver transplant. We report a 14‐month‐old female status‐post OLT with an atypical presentation of PTLD as a solitary renal mass. At eight‐wk post‐transplant, she presented with elevated transaminases, CMV counts (73 000 copies/mL), and EBV counts (35 000 copies/mL). CT scan revealed a solid heterogeneously enhancing right renal mass measuring 2.6 × 2.4 × 3.3 cm. The radiological diagnosis was Wilms tumor, although PTLD could not be excluded. Complete resection of a Wilms tumor is potentially curative. A needle biopsy would upstage the malignancy and result in radiochemotherapy that is deleterious to a liver graft. The mass was not amenable to partial nephrectomy. A total nephrectomy, given life‐long nephrotoxic immunosuppressants, was an unfavorable option. Thus, needle biopsy was performed. Histology confirmed monoclonal, EBV‐associated PTLD and diffuse large B‐cell lymphoma. Her therapy included immunosuppression reduction, cyclophosphamide, steroids, and anti‐CD20 monoclonal antibody. Concomitantly, she received Cytogam and gancyclovir. Complete remission was achieved three months after chemotherapy. This case illustrates that young age, CMV infection, and EBV infection are strong risk factors for PTLD. With such risk factors present, any mass or lesion in a solid organ transplant patient should be considered PTLD until proven otherwise.     

Image-guided percutaneous biopsy of musculoskeletal lesions in children

Background Percutaneous core needle biopsy (PCNB) of musculoskeletal lesions can provide early and definitive diagnosis and guide decisions on management. The technique is less invasive than open biopsy and has a low complication rate. Objectives The purpose of this study was to assess the diagnostic accuracy and safety of image-guided PCNB of musculoskeletal lesions in children. Materials and methods Retrospective review of the medical records of patients referred for PCNB of musculoskeletal lesions was performed. Data collected included tumor type and complication rates. Lesion “hit” or “missed”, and core adequacy and ability to reach a definitive pathological diagnosis were reviewed and used to determine whether the biopsy was overall successful or unsuccessful. Results A total of 127 biopsies were performed in 111 patients. Of the 127 PCNB procedures, 114 “hit” the lesion and 13 “missed,” and 120 of the cores provided for analysis were deemed adequate for pathological interpretation and 7 were deemed inadequate. A definitive pathological diagnosis was possible in 97 of the 127 PCNB preocedures and not possible in 30. Overall 76% of the PCNB procedures were successful. The diagnostic success of biopsy in primary malignant tumors was significantly higher (92%) than in primary benign tumors (65%; P = 0.008). Six minor complications resulted from PCNB. Conclusion This study showed that PCNB is accurate and safe for the diagnosis of musculoskeletal lesions in pediatric patients, and its results are comparable to those in adult studies.     

Teratoid Wilms' tumor, an important variant of nephroblastoma

PurposeThe teratoid histologic variant of Wilms’ tumor is rare, with only 15 prior reported cases. We review these and report an additional case in which a cytogenetic abnormality was identified that has not previously been reported in a teratoid Wilms’ tumor.Materials and methodsA medline search revealed 15 previously reported cases of the teratoid variant of Wilms’ tumor. We summarized the characteristics of these cases with attention to radiologic appearance, stage, laterality, histology, response to chemotherapy and outcomes.ResultsCharacteristic radiologic features suggesting teratoid Wilms’ tumor were calcific densities and stippling, or areas of attenuation indicating adipose tissue. The majority of teratoid Wilms’ tumor patients had a high tumor stage at presentation (50% stage III or greater). The incidence of bilateral tumors was 38%. Chemotherapy was administered in nine cases and in only one (11%) was there a cytoreductive response. Four deaths (25%) occurred amongst these patients.ConclusionsTeratoid Wilms’ tumors appear to present with a high stage, increased incidence of bilaterality and have a high mortality rate. Treatment strategies should focus on total surgical extirpation, including metastatic sites when feasible, due to this entity's limited response to chemotherapy.     

Tumor de Wilms: revisión de nuestra experiencia en los últimos 15 años

Introduction

Wilms’ tumour is the most frequent renal tumour in children. Multi-modal treatment includes chemotherapy and surgery, with or without radiotherapy. The survival is excellent, with rates exceeding 90%. A review is presented on our experience over the last 15 years of treating Wilms’ tumour in Hospital Niño Jesús, Madrid.

A rare case of intrarenal teratoma in a 6-month-old male

We report a rare case of an intrarenal teratoma in a 6-month-old male. Following biopsy, he was successfully managed with a primary nephrectomy. This patient presented as would a Wilms tumor. According to SIOP guidelines, the diagnosis of Wilms tumor is made on clinical and imaging information only, prior to neoadjuvant chemotherapy. This patient was investigated, according to UK (CCLG) guidelines, with a biopsy prior to treatment and therefore avoided unnecessary chemotherapy.     

Advances in the clinical management of high-risk Wilms tumors

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors’ view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.     

Introduction to the genetics of primary renal tumors in children

Wilms tumor can be explained only partially by the “two hit” model that was originally developed for retinoblastoma. Heterogeneity of two kinds, operates. The first is that four other primary tumors are regularly observed in children, and the second is that Wilms tumor itself appears to represent more than one genetic entity. All five of these primary renal tumors arise from primary or secondary mesenchyme, renal blastema, or renal epithelium. Mesoblastic nephroma, and possibly clear cell sarcoma, may have some genetic affinity with Wilms tumor, but rhabdoid tumor of the kidney and renal carcinoma do not. At least three different genes seem to be important in the origin of Wilms tumor. One, WT1, whose mutations may be associated with aniridia, may follow the “two hit” model in that there are cases in which both copies of the gene are defective or lost, as expected for a tumor suppressor gene. A second gene, which is associated with Beckwith-Wiedemann Syndrome (BWS) and which has not been cloned, appears to be imprinted in females, and may have an oncogene function. It is evidently activated by gain of a paternal allele or by loss of the inactive, but possibly trans-sensing, maternal allele. Activation of the insulin-like growth factor II gene may be a final common pathway for mutation in both WT1 and BWS. A third gene is unlinked to either of the other two, but its location and function are unknown. It shares with WT1 specificity for Wilms tumor, which is not true of the BWS gene. © 1993 Wiley-Liss, Inc.     

Advances in the clinical management of high-risk Wilms tumors

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors’ view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.     

Wilms’ Tumor—Lessons and Outcomes—A 25-Year Single Center UK Experience

Wilms’ tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985–2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases—after immediate (n = 5/37), 13.5% vs delayed nephrectomy—(n = 3/57), 5.2%; X ² P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred—hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed “late malignancies” —thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including “late onset,” second malignancies deserve special consideration.     

Management of Wilms tumors in Drash and Frasier syndromes

Background

Children with WT1 gene‐related disorders such as Denys–Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end‐stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron‐sparing surgery was beneficial.

Procedure

We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007.

Results

We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate‐risk tumors and one high‐risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron‐sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft‐tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end‐stage renal disease‐related complications. The median follow‐up time for the 18 survivors was 136 months (range, 17–224 months).

Conclusion

Most Wilms tumors in children with WT1‐related disorders were early‐stage and intermediate‐risk tumors, with a young age at diagnosis. In patients without end‐stage renal disease, nephron‐sparing surgery should be considered for delaying the onset of renal failure. Pediatr Blood Cancer 2009;52:55–59. © 2008 Wiley‐Liss, Inc.     

New definitions of focal and diffuse anaplasia in Wilms tumor: the International Society of Paediatric Oncology (SIOP) experience

BACKGROUND: Unlike the original definitions of focal (FA) and diffuse anaplasia (DA) in Wilms tumor (WT), recently redefined FA and DA proved to be of prognostic significance. The aim of the study was to analyze WT from the SIOP file, the majority of which were treated with preoperative chemotherapy, in order to investigate whether chemotherapy influenced the presence of anaplasia, whether the new definitions were applicable to these tumors, and whether they were of prognostic significance. PROCEDURE: The unilateral anaplastic WT of children up to 16 years of age from the SIOP 6 and 9 nephroblastoma trials and studies were first classified according to the original definitions and analyzed. Then they were reclassified and analyzed according to the new definitions. RESULTS: Anaplasia was diagnosed in 86 (5.5%) of 1,554 unilateral WT. The age at diagnosis ranged from 9 to 175 months (median, 63) and more than half of children were over 5 years of age. From 15% to 85% of the tumor mass showed chemotherapy-induced changes. Blastemal anaplasia was seen in 74, stromal in 23, and epithelial in 22 cases. According to the original definitions, FA was diagnosed in 55 (64%) and DA in 31 (36%) cases. In total, 48% children were alive and well, including 53% with FA and 39% with DA (P = 0.23). When reclassified, 39 old FA cases were moved to the new DA group, resulting in 70 (81%) DA and 16 (19%) FA cases. The female-to-male ratio for FA changed from 1.9:1 to 1:1 while remained unchanged for DA. The percentage of FA stage I cases increased from 31% to 44%, while it decreased from 25% to 6% for stage III. For other stages it remained virtually unchanged. The overall 4-year actual survival was 75% for FA and 41% for DA (P = 0.03). CONCLUSIONS: Preoperative chemotherapy did not obliterate or produce anaplasia. The new definitions were applicable to pretreated cases and they were of prognostic significance.     

Bilateral Wilms tumor in a boy with severe hypospadias and cryptochidism due to a heterozygous mutation in the WT1 gene

Mutations in the WT1 gene causing Wilms tumors were first reported in WAGR syndrome (Wilms tumor, Aniridia, Genitourinary malformation, mental Retardation) and Denys Drash syndrome (pseudohermaphroditism, Wilms tumor, nephropathy), but only in a few patients with hypospadias and cryptorchidism without other signs of Denys Drash (DDS) or WAGR syndrome WT1 mutations were identified. We report a boy, who was born in 1989 with hypospadias and bilateral cryptorchidism. Previous karyotyping and endocrine studies had ruled out any known cause of male pseudohermaphroditism. Subsequently, he developed a bilateral Wilms tumor, which was detected by palpation at the age of 15 months during a routine visit by the general pediatrician. Because of its extensive size, surgery and chemotherapy were needed for treatment. Analysis of the WT1 gene was performed 5 y after diagnosis and revealed a C to T transition in one allele generating a stop codon at codon 362 and subsequently leading to a truncated protein with loss of its ability to bind to DNA. No signs of DDS or WAGR syndrome are present in the boy. The work up of this patient and the so far known few comparable cases from the literature lead to the conclusion that in newborns with severe urogenital malformations not due to known chromosomal or endocrine disorders mutational screening of the WT1 gene should be performed, to evaluate the high risk of developing a Wilms tumor. We favor mutational screening in these patients as an easy tool for investigation, because in the future it will probably decrease the necessity of frequent control visits in patients without a WT1 mutation.     

Decrease in LDL receptor-related protein expression and function correlates with advanced stages of Wilms tumors

BACKGROUND: The molecular processes responsible for the invasive phenotype of pediatric Wilms tumors (WT) are poorly understood. A candidate WT suppressor gene (WT1) has been found mutated in a number of these pediatric kidney tumors. However, the disruption of normal WT1 protein function cannot solely explain WT growth. The aim of the present study is to identify new molecular players that regulate the invasive character of WT. PROCEDURE: Fresh frozen samples from 45 renal tumors of Wilms were obtained from the National Wilms Tumor Study Group's Biological Samples Bank. Gelatin zymography, Western blotting, and immunodetection were used to compare tissue biopsies originating from the infiltrating (stage III), metastatic (stage IV), and anaplastic phenotype of Wilms tumors (WT). RESULTS: The expression of the low-density lipoprotein receptor-related protein (LRP) diminished in stage IV and anaplastic WT. Moreover, the expression of RAP, an LRP intracellular chaperone, was also decreased. The diminished expression of LRP and RAP correlated with increased levels of several known extracellular ligands that LRP usually recycles from the extracellular matrix (ECM) environment, including PAI-1, MMP-9, and TIMP-1. The proteolytic processing of MT1-MMP, a functional regulator of LRP, also correlated with the WT invasive phenotype. CONCLUSIONS: The low expression of LRP, whose function is regulated by MT1-MMP and whose activity in recycling ECM-associated proteolytic enzymes becomes drastically diminished in advanced stages of WT, may in part explain the acquired invasive potential of the developing WT pediatric cancer.