The use of nuclear morphometry to predict prognosis in pediatric urologic malignancies: A review

Wilms tumor, the most common pediatric urologic malignancy, and genitourinary rhabdomyosarcoma, the most common soft tissue sarcoma of childhood, respresent two of the most commonly diagnosed pediatric urologic malignancies. The introduction and use of multimodal therapy (surgery, radiation, and chemotherapy) by the National Wilms Tumor Study (NWTS) and the Inter-group Rhabdomyosarcoma Study (IRS) groups have greatly improved the survival among children with these malignancies. Present survival rates for Wilms tumor exceed 85% and for rhabdomyosarcoma survival rates are approaching 80% as well. For Wilms tumor, current treatment trends suggest less intense therapy for those children with favorable histology tumors who are considered at relatively low risk for tumor recurrence. Likewise, the significant morbidity associated with the present therapy regimens for rhabdomyosarcomas has prompted investigators to search for individualized management schemes for children with a high probability of responding. The need for accurate criteria to separate these high and low risk groups becomes imperative. In this review we present our work using nuclear morphometry, as a prognostic indicator, to retrospectively predict response to therapy for children with Wilms tumors and genitourinary rhabdomyosarcomas. © 1993 Wiley-Liss, Inc.     

Renal cell carcinoma as a second malignant neoplasm in a patient with non-syndromic hemihypertrophy and previous Wilms tumor

Survivors of childhood Wilms tumors are at an increased risk of second malignant neoplasms. Recently, it has been postulated that renal cell carcinoma is among the malignancies for which this population is at risk. We present the unique case of an adult Wilms tumor survivor with non-syndromic hemihypertrophy (NSHH) who developed renal cell carcinoma. This case highlights the need for close follow-up in two populations: adults who have survived Wilms tumor and those with NSHH.     

Management of pediatric renal tumor: Past and future trials of the Japan Wilms Tumor Study Group

The Japan Wilms Tumor Study group (JWiTS) was founded in 1996 to improve outcomes for children with renal tumor in Japan, and a nationwide multicenter cooperative study was initiated thereafter. JWiTS‐1 (1996–2005) was analyzed, and JWiTS‐2 (2005–2014) is now under analysis; the following problems have been identified and used to decide future study protocol: (i) there has been a decline in survival rate for patients with rhabdoid tumor of the kidney (RTK) and new treatment strategies are required; (ii) the survival rate for bilateral Wilms tumors (BWT) has improved, but results for renal preservation are unsatisfactory; (iii) the prognosis of stage IV favorable nephroblastoma is very good, suggesting that the current protocols provide overtreatment, particularly for patients with lung metastasis; and (iv) no effective biological risk factors exist for predicting the outcome of Wilms tumor, and a study of the genetic changes of these tumors is necessary to determine biological markers for use in risk classification. To solve these issues, the development of a new risk classification of pediatric renal tumors is required. In addition, different study protocols should be developed according to the risk‐based classification of the patients. Further, a new study protocol for BWT began in 2015, and new study protocols are being prepared for RTK, and for Wilms tumor with lung metastasis. In addition, an analysis of biological markers with regard to risk classification is to be performed. Furthermore, to create new protocols for patients with rare renal tumors, international collaboration with Children's Oncology Group and International Society of Pediatric Oncology is necessary.     

Astrocyte elevated gene-1 overexpression in histologically favorable Wilms tumor is related to poor prognosis

ObjectiveAstrocyte elevated gene-1 (AEG-1) is associated with tumorigenesis and progression in various types of human cancers. However, the status of AEG-1 expression and its significance in Wilms tumor are still unclear. In this study, we investigated the expression of AEG-1 and evaluated its clinical and prognostic significance in favorable-histology Wilms tumor (FHWT).Materials and methodsImmunohistochemistry was performed to examine AEG-1 protein expression in paraffin-embedded tissues from 38 FHWT patients. All patients underwent radical nephrectomy from January 2003 to June 2008 with subsequent therapy according to National Wilms Tumor Study Group protocols. Statistical analyses were performed to evaluate the association between AEG-1 expression and clinical parameters.ResultsWe found high AEG-1 expression in 17 of 38 (44.7%) patients. AEG-1 expression was significantly correlated with clinical stage (p = 0.019) and status of recurrence (p = 0.023). Importantly, patients with high AEG-1 expression had a shorter disease-free survival and overall survival compared with those with low AEG-1 expression (p = 0.011 and p = 0.013).ConclusionAEG-1 expression is associated with FHWT outcome in this study, and AEG-1 may represent a novel and valuable predictor for prognostic evaluation of FHWT patients.     

Characterization of a WiT49 cell line derived orthotopic model of Wilms tumor

Wilms tumor is the most common malignant renal tumor in children. However, to date no Wilms tumor mouse model is available due to the lack of Wilms tumor cell lines. Herein for the first time we report an orthotopic xenograft mouse model utilizing the recently described Wilms tumor cell line WiT49. It has a high tumor occurrence rate (85%) without metastasis. Hematoxylin and eosin staining showed it is subcapsular in location and mainly biphasic with stromal and epithelial components while blastemal component is unappreciable. This model provides the prerequisite for the screening and development of new anti‐tumor agents for Wilms tumor. Pediatr Blood Cancer 2010;54:316–318. © 2009 Wiley‐Liss, Inc.     

Pediatric renal tumor epidemiology: Global perspectives,progress, and challenges

Pediatric renal tumors account for 3%–11% of childhood cancers, the most common of which is Wilms tumor or nephroblastoma. Epidemiology plays a key role in cancer prevention and control by describing the distribution of cancer and discovering risk factors for cancer. Large pediatric research consortium trials have led to a clearer understanding of pediatric renal tumors, identification of risk factors, and development of more risk-adapted therapies. These therapies have improved event-free and overall survival for children. However, several challenges remain and not all children have benefited from the improved outcomes. In this article, we review the global epidemiology of pediatric renal tumors, including key consortium and global studies. We identify current knowledge gaps and challenges facing both high and low middle-incomes countries.     

Evaluation of renal function after successful treatment for unilateral,non‐syndromic wilms tumor

Impaired renal function may occur in experimental animals following surgical removal of most functioning renal tissue (“hyperfiltration injury”). Although end‐stage renal disease is uncommon among long‐term survivors of unilateral, non‐syndromic Wilms tumor, concern has been expressed that there may be an increased risk of less serious, but progressive, renal function impairment among these individuals. The recent development of equations for estimating glomerular filtration rate (eGFR) has facilitated the study of renal function in Wilms tumor survivors. However, the estimating equations were developed to categorize individuals with chronic kidney disease and have significant limitations with regard to the accuracy of individual GFR estimates. These limitations must be considered when utilizing the estimating equations in cross‐sectional or longitudinal evaluations of renal function in cohorts of patients who have been treated successfully for Wilms tumor or other childhood cancers. Pediatr Blood Cancer 2013;60:1929–1935. © 2013 Wiley Periodicals, Inc.     

TP53 codon 72 polymorphisms in favorable histology Wilms tumors

In Wilms tumor (WT), mutations in the gene encoding p53, TP53, are correlated with anaplasia; however TP53 variants have not been studied in favorable histology (FH) WTs. A single nucleotide polymorphism of TP53 encoding either arginine or proline at codon 72 is suggested to alter in vitro p53 behavior. Therefore, we analyzed tissue from 23 consecutive patients with FHWT to determine allelic and genotypic frequencies of Pro72 and Arg72 variants and correlate this with clinical outcomes. Interestingly, our cohort showed a statistically significant over-representation of the Arg allele and Arg/Arg genotype. However, the genotypic and allelic frequencies showed no significant correlation with age, stage, or disease recurrence.     

Imaging of pediatric renal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper focused on Wilms tumor and nephrogenic rests

Malignant renal tumors account for approximately 6% of pediatric malignancies, with Wilms tumor (WT) representing approximately 90% of pediatric renal tumors. This paper provides consensus-based imaging guidelines for the initial evaluation of a child with suspected WT and follow-up during and after therapy co-developed by the Children's Oncology Group (COG) Diagnostic Imaging and Society for Pediatric Radiology (SPR) oncology committees. The guidelines for Wilms Tumor Imaging in the Society of International Pediatric Oncology (SIOP) are briefly discussed to highlight some of the differences in imaging approach.     

Renal function after tandem high-dose chemotherapy and autologous stem cell transplantation in children with Wilms tumor

Lee SH, Paik KH, Sung KW, Son MH, Yoo KH, Koo HH, Kim JY, Cho EJ. Renal function after tandem high‐dose chemotherapy and autologous stem cell transplantation in children with Wilms tumor. Pediatr Transplantation 2011: 15: 855–860. © 2011 John Wiley & Sons A/S. Abstract: Despite increasing evidence that tandem HDCT and autoSCT might improve the survival of patients with high‐risk solid tumors, patients with Wilms tumor may be at high risk of acute and chronic renal impairment during and after tandem HDCT/autoSCT because they usually have a single kidney. We investigated the feasibility of tandem HDCT/autoSCT in patients with Wilms tumor, focusing on renal function. Six patients with relapsed/progressed Wilms tumor were assigned to undergo tandem HDCT/autoSCT. One patient developed transient ARF during the first HDCT/autoSCT. All other patients underwent the second HDCT/autoSCT as scheduled. Acute renal dysfunction during the second HDCT/autoSCT was transient and manageable. Indicators of glomerular function such as creatinine clearance, serum creatinine, and albumin excretion were in the normal range at three yr after tandem HDCT/autoSCT. Subclinical tubular dysfunctions, such as increased excretion of β‐N‐acetylglucosaminidase and β2‐microglobulin, were identified at one and three yr after tandem HDCT/autoSCT; however, no patient required treatment for these conditions. These results are helpful to consider tandem HDCT/autoSCT as a treatment option in patients with Wilms tumor. Longer duration of follow‐up and close monitoring of tubular function are required if tandem HDCT/autoSCT is indicated in patients with Wilms tumor.     

Cushing syndrome as a presenting symptom of renal tumors in children

Cushing syndrome as the presenting symptom of a malignant renal tumor in children is rare. We report the first case of paraneoplastic Cushing syndrome due to a Wilms tumor, in which clinical and biological signs of hypercortisolism regressed during preoperative chemotherapy. Additionally, we reviewed the literature on paraneoplastic Cushing syndrome secondary to pediatric renal tumors. Pediatr Blood Cancer 2009;53:211–213. © 2009 Wiley‐Liss, Inc.     

Wilms tumor,AML and medulloblastoma in a child with cancer prone syndrome of total premature chromatid separation and Fanconi anemia

Wilms tumor (WT) is the most common primary renal tumor in childhood. The occurrence of WT in patients with growth retardation, mental retardation and central nervous system abnormalities in association with premature chromatid separation (PCS) and mosaic variegated aneuploidy has been previously described in only 10 patients. Here we report the very rare occurrence of WT with two other malignancies, acute myeloid leukemia and medulloblastoma in association with chromosomal instability. This is a novel presentation of Fanconi anemia with this cytogenetic abnormality. Pediatr Blood Cancer 2009;53:208–210. © 2009 Wiley‐Liss, Inc.     

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.     

Late relapsing Wilms tumor with rhabdomyomatous differentiation

The authors report a patient with abdominally relapsed Wilms tumor with rhabdomyomatous differentiation leading to renal failure and death 9 years after the initial diagnosis. The patient was treated with intensive chemotherapy because of inoperable tumor but no response was obtained. The prognosis of children with Wilms tumor relapsed in abdomen and in previously irradiated fields is poor and intensive chemotherapy protocols for differentiated tumors after chemotherapy will increase the risk of complications without obvious benefit. Pediatr Blood Cancer 2009;52:675–677. © 2008 Wiley‐Liss, Inc.     

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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.     

Wilms’ tumor: unusual manifestations

Wilms’ tumor is an important renal malignancy with which pediatric radiologists must be familiar. Although the imaging features are usually typical for renal masses, unusual imaging features of Wilms’ tumor may confound the imaging physician. This review highlights the less common imaging appearances of Wilms’ tumor which pediatric radiologists may encounter.

     

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.     

Eosinophilic chromophobe renal cell carcinoma in a child with hypospadias

Chromophobe renal cell carcinoma (CRCC) is a distinct variant of renal carcinoma generally affecting adults. We report a case of an unusual CRCC, arising in a male child affected by hypospadias. This case demonstrates that CRCC can occur in the pediatric patients and can be associated with genital tract anomalies such as Wilms tumor.     

Pediatric Renal Tumors: Practical Updates for the Pathologist

Pediatric renal tumors were targeted by the National Wilms Tumor Study Group for 4 decades with extraordinary success. Within this historic context, this review provides a summary of the new Children’s Oncology Group renal tumor protocols that will be opening in the very near future, focusing on their pathologic requirements. All renal tumors must first be registered on the Renal Tumor Classification and Banking Protocol, followed by registration on 1 of 4 primary therapeutic protocols based on histology, stage, and molecular analysis. This requires prompt submission of samples for molecular analysis and central pathologic review. Changes in staging criteria include classification of all tumor spillage as stage III, and requirement of regional lymph node evaluation for eligibility for stage I Wilms tumors (WTs) weighing less than 550 g in infants younger than 24 months and for stage I clear cell sarcoma. Patients with unilateral favorable histology WT with loss of heterozygosity for chromosomes 1p and 16q will receive more aggressive chemotherapy at each stage. Patients with bilateral WT and patients with diffuse hyperplastic perilobar nephroblastomatosis will be eligible for a novel therapeutic protocol requiring pathologic classification based on response of tumor to previous therapy. Stage I anaplastic WT will be targeted with more aggressive chemotherapy than in the past. For the first time, pediatric renal cell carcinoma will be eligible for a cooperative group protocol. All rhabdoid tumors outside the central nervous system will be eligible for a single protocol. In conclusion, these new protocols bring considerable change in their overall organization, in eligibility, and in therapy.     

Tumor biology,biomarkers, and liquid biopsy in pediatric renal tumors

The expansion of knowledge regarding driver mutations for Wilms tumor (WT) and malignant rhabdoid tumor of the kidney (MRT) and various translocations for other pediatric renal tumors opens up new possibilities for diagnosis and treatment. In addition, there are growing data surrounding prognostic factors that can be used to stratify WT treatment to improve outcomes. Here, we review the molecular landscape of WT and other pediatric renal tumors as well as WT prognostic factors. We also review incorporation of circulating tumor DNA/liquid biopsies to leverage this molecular landscape, with potential use in the future for distinguishing renal tumors at the time of diagnosis and elucidating intratumor heterogeneity, which is not well evaluated with standard biopsies. Incorporation of liquid biopsies will require longitudinal collection of multiple biospecimens. Further preclinical research, identification and validation of biomarkers, molecular studies, and data sharing among investigators are crucial to inform therapeutic strategies that improve patient outcomes.