Precursor lesions of Wilms tumor: Clinical and biological implications

Nephrogenic rests (NR) are persistent embryonal remnants in the kidney that are apparent precursors of Wilms tumor (WT). Nephroblastomatosis (Nbl) denotes multiple or diffuse NR. Two major categories of NR have been recognized to date, perilobar (PLNR) and intralobar (ILNR). A dynamic classification of NR according to their recognized developmental fates is presented. Dormancy, maturation, involution, hyperplastic overgrowth, and neoplastic induction are the common fates of NR. Hyperplastic NR are far more common than formerly recognized, and are frequently confused with WT, especially in cases of multicentric and bilateral tumors. Biopsy is of limited value in distinguishing hyperplastic NR from WT, and the use of surgery in cases of Nbl requires careful consideration, as its role can in many cases be reduced or supplanted due to the effectiveness of modern imaging techniques and chemotherapy. An understanding of the natural history of NR and Nbl is essential for rational patient care decisions, and is important for understanding the molecular biology of WT. © 1993 Wiley-Liss, Inc.     

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes

Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.     

Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumor

A new classification and terminology is proposed for precursor lesions of Wilms' tumor (WT), based upon morphology and natural history. The generic term nephrogenic rest (NR) is used for all WT precursors. Two major categories of NR are recognized: perilobar (PLNR) and intralobar (ILNR). Nephroblastomatosis signifies the presence of multiple or diffuse NRs. Nephroblastomatosis can be classified into four categories: (a) perilobar (PLNR only); (b) intralobar (ILNR only; (c) combined (PLNR and ILNR); and (d) universal. The individual rests can be subdivided into (a) nascent or dormant NRs; (b) maturing or sclerosing NRs; (c) hyperplastic NRs; and (d) neoplastic NRs. Of 282 evaluable unilateral WT specimens, 28.4% were definitely rest-positive, and an additional 12.4% were probably positive, with equal prevalence of PLNRs and ILNRs. Median age at diagnosis of WT was 36 months with PLNRs, 16 months with ILNRs, and 12 months if both types were present. PLNRs were strongly associated with synchronous bilateral WTs, and ILNRs with metachronous contralateral WTs. ILNRs were associated with aniridia and Drash syndrome, whereas PLNRs were more commonly found with hemihypertrophy and/or Beckwith-Wiedemann syndrome. The delineation of two distinct categories of WT precursors suggests pathogenetic heterogeneity for WTs. The biological and clinical implications of NRs are considered in the context of this classification.     

Clinical presentation of rhabdoid tumors of the kidney

PURPOSE: We designed this study to differentiate the clinical presentation, particularly the incidence of hematuria, of a rhabdoid tumor of the kidney (RTK), a rare but highly malignant tumor, from a Wilms tumor. PATIENTS AND METHODS: We reviewed patient flow charts from the National Wilms Tumor Study Group and queried participating hospitals to obtain additional information regarding presenting symptoms and laboratory data for fifty patients. Patient ages ranged from 2 days to 3.5 years with a mean of 11 months. We documented the presence of gross and microscopic hematuria, fever, and hypercalcemia. RESULTS: Whereas 75% of children with rhabdoid tumor of the kidney (RTK) had stage III (44%), IV (27%), or V (4%) tumors, 67% of children with Wilms tumors had stage I (41%) or II (26%) tumors. Either gross or microscopic hematuria was present in 84.4% (27/32) of the patients with RTK. Gross hematuria was present in 59% (22/37) of children with RTK compared with 18% previously reported with Wilms tumor. Microscopic hematuria was present in 76% (22/29) of children with RTK compared with 24% previously reported with Wilms tumor. Fever was found in 44% (16/36) of children with RTK, compared with 22% of children previously reported with Wilms tumor. Hypercalcemia was seen 26% (6/23) of children with RTK. CONCLUSION: Although diagnosis of any renal mass still must be confirmed with histopathologic features, a distinct clinical presentation with fever, hematuria, a young age, and high-tumor stage at presentation suggests the diagnosis of RTK.     

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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.     

Extrarenal testicular Wilms’ tumor in a 3-year-old child

We report an extremely rare case of extrarenal testicular Wilms’ tumor in a 3-year-old boy with intrabdominal undescended left testis. The patient was admitted because of pain and vomiting, with evidence of a huge abdominal mass. At surgery a large tumor arising from the intrabdominal testis was found. Histology showed the classical triphasic Wilms’ tumor elements: epithelial, mesenchymal and blastemal areas. Extrarenal Wilms’ tumors account for only 3 % of all Wilms’ tumors and just ~100 cases have been reported in literature. Testicular origin is anecdotic. We present histomorphological, histogenetic, clinical, diagnostic, prognostic and therapeutic features of this rare tumor.     

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.     

Epidemiology of Wilms tumor

Wilms tumor affects approximately one child per 10,000 worldwide before the age of 15 years. Incidence rates appear to be slightly elevated for U.S. and African Blacks in comparison to Whites, but are only half as great among Asians. Several case-control studies have suggested that paternal occupational or maternal hormonal exposures during pregnancy may increase the risk of Wilms tumor, but small numbers of subjects and inconsistencies in the patterns of exposures do not permit firm conclusions to be drawn. It is unlikely that such environmental exposures play a major role in the etiology of Wilms tumor. The median age-at-onset of Wilms tumor is 38 months in the U.S. National Wilms Tumor Study series, with cases in girls occurring on average 6 months later than in boys. Patients with bilateral tumors, aniridia, cryptorchism/hypospadias, Beck-with-Wiedemann syndrome, or intralobar nephrogenic rests tend to be diagnosed much younger than average (median 17–27 months). Those with familial disease or multicentric tumors have intermediate age-at-onset distributions, while those with perilo-bar nephrogenic rests are diagnosed at older ages. The epidemiologic features suggest that somatic mosaicism, rather than a germ-line mutation, may be responsible for some of the bilateral and multicentric cases. © 1993 Wiley-Liss, Inc.     

Cancer occurrence in Southeast Asian children in California

OBJECTIVES: To estimate misclassification of ethnicity and cancer incidence in Southeast Asian children using the population-based California Cancer Registry. METHODS: Asian race/ethnicity was evaluated using lists of Asian surnames. Average annual incidence rates (per million) for 1988 to 1992 were calculated for non-Hispanic white, black, Hispanic, and Asian children (age <15 years). Proportional incidence ratios (PIRs) for 1988 to 1995 were used to compare Southeast Asian children to non-Hispanic white children. RESULTS: Of the Asian children, 4.2% (30/722) were misclassified by subgroup, predominantly Hmong listed as Laotian. The Asian cancer rate was 134.2 versus 159.2 for non-Hispanic whites. The germ cell tumor rate was higher in Asians (9.9) than in non-Hispanic whites (4.8), but the Wilms tumor rate was two-thirds lower (3.1 vs. 9.2). The rates of Hodgkin lymphoma and central nervous system tumors were lower (2.8 vs. 5.6 and 20.0 vs. 33.8) in Asians than non-Hispanic whites. Compared with non-Hispanic whites, the PIR for Wilms tumor in Southeast Asian children was reduced (PIR = 0.1). Southeast Asian children had increased PIRs for Burkitt lymphoma (PIR = 2.6) and leukemias not classified as acute lymphocytic leukemia or acute nonlymphocytic leukemia (PIR = 3.5). CONCLUSIONS: Accurate race/ethnicity classification of Southeast Asian children is a concern. Marked differences were found in the incidence and PIRs of specific cancers among Southeast Asian children, other Asian children, and other children in California.     

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.     

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.     

Current management of Wilms' tumor in children

PurposeWilms’ tumor is the most common renal tumor in children. Outcomes have improved dramatically over the past few decades, but important treatment questions remain. These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current treatment of Wilm's tumor.Materials and methodsThe medical literature and results of all cooperative group studies reporting treatment of children with Wilms’ tumor were reviewed.ResultsOverall survival exceeds 90% for most patients with nephroblastoma. However, outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral tumors it continues to be defined.ConclusionsCurrent protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and mortality rates.     

Recent advances in Wilms tumor genetics

The past decade has witnessed substantial growth in our knowledge of the genes and loci that are altered in Wilms tumor. Although Wilms tumor was one of the original paradigms of Knudson's two-hit model of cancer formation, it has become apparent that several genetic events contribute to Wilms tumorigenesis. Recent research has identified targets and regulators of the first Wilms tumor gene, WT1, has uncovered several candidate genes at the second Wilms tumor locus, WT2, and has identified two familial Wilms tumor loci, FWT1 and FWT2. The recent discovery of activating beta-catenin mutations in some Wilms tumors has also implicated the Wnt signaling pathway in this neoplasm. Recurrent abnormalities of other loci, including 16q, 1p, and 7p, have indicated that these sites may harbor Wilms tumor genes. An enhanced understanding of these and other genetic lesions will provide the foundation for novel targeted Wilms tumor therapies.     

Clear cell sarcoma of the kidney in children: experience in a developing country

Introduction  

Clear cell sarcoma of the kidney (CCSK) is a rare tumour comprising 4% of primary renal tumours in children. It has a unique constellation of chromosomal and molecular features and should no longer be viewed as an unfavourable histological variant of Wilms tumour. Little is known of its clinical presentation and pathological profile in children living in a developing country.     

Ossifying Renal Tumor of Infancy: A Clinicopathologic Study of Nine Cases

We studied nine ossifying renal tumors of infancy (ORTI), including all five previously reported cases. There were eight boys and one girl ranging in age from 6 days to 14 months. Cross hematuria was the presenting sign in all nine patients. Eight tumors arose in the left kidney and six in the upper pole. All seven patients with follow-up information were free of recurrence. All lesions were attached to a renal papilla and presented mainly within the calyceal lumen. Two resembled staghorn calculiclinically. All tumors contained varying proportions of osteoid, osteoblastic cells, and spindle cells. The spindle cell component had features strongly suggesting that they represented hyperplastic intralobar nephrogenic rests (ILNR). The proportion of osteoid and degree of osseous maturation increased with increasing age of the patient. ORTI is a distinctive clinicopathologic entity, possibly representing a distinctive interaction between ILNR in the renal papilla with distal collecting duct or urothelial cells in the developing kidney.     

Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice.

BACKGROUND: Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented. METHODS: The available literature was reviewed. RESULTS: The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future. CONCLUSIONS: The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3-4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.     

PILOMATRIXOMA: A not uncommon Hamartoma of Infancy and Childhood

With few exceptions, accounts of this symptomless subcutaneous lesion have been concerned with the unique histological features and its occurrence in adults. This report of 37 pilomatrixomas in 35 children draws attention to the incidence in the paediatric age group and to the clinical features which are so constant and characteristic that the correct diagnosis can, in almost all cases, be made before excision.     

Comparative genomic hybridization analysis of clear cell sarcoma of the kidney

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is a rare malignant pediatric tumor, distinguished from the Wilms tumor by its characteristic histologic features and a more aggressive clinical behavior with a tendency to metastasize to bone. Genetic studies on CCSK are limited and no consistent findings have been reported. PROCEDURE: We examined four cases of CCSK for presence of consistent genetic alterations using comparative genomic hybridization (CGH). This is the first report concerning CGH analysis of CCSK. RESULTS: Three of the tumors showed no chromosome gains or losses. One of the tumors had gains of 1 q and the terminal end of 11 q. CONCLUSIONS: These results are consistent with previous findings of limited chromosomal changes in CCSK karyotypes. Gain of 1 q in CCSK warrants further investigation. Copy number gains of 1 q have been repeatedly demonstrated in soft tissue and bone sarcomas, as well as other tumors, implying the presence of genes involved in tumor development and/or progression.