Wilms Tumor
Clear Cell Sarcoma
Rhabdoid Tumors of the Kidney
Neuroepithelial Tumors of the Kidney
Desmoplastic Small Round Cell Tumor of the Kidney
Cystic Partially Differentiated Nephroblastoma
Multilocular Cystic Nephroma
Mesoblastic Nephroma
Renal Cell Carcinoma
Nephroblastomatosis

Wilms Tumor

Although most patients with a histologic diagnosis of Wilms tumor fare well with current treatment, approximately 10% of patients have histopathologic features that are associated with a poorer prognosis, and, in some types, with a high incidence of relapse and death. Wilms tumor can be separated into two prognostic groups on the basis of histopathology:

• Favorable histology: Histologically, Wilms tumor mimics development of a normal kidney consisting of three cell types: blastemal, epithelial (tubules), and stromal. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties. While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance and therefore do not direct the initial therapy.[1]



• Anaplastic histology: Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. There are two histologic criteria for anaplasia, both of which must be present for the diagnosis. They are the presence of multipolar polyploid mitotic figures with marked nuclear enlargement and hyperchromasia. Anaplasia correlates best with responsiveness to therapy rather than to aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. This is the reason why focal anaplasia and diffuse anaplasia are differentiated, both pathologically and therapeutically. Focal anaplasia is defined as the presence of one or a few sharply localized regions of anaplasia within a primary tumor. Focal anaplasia does not confer a poor prognosis, while diffuse anaplasia does.[2-4]



• Nephrogenic rests: Many Wilms tumors appear to arise from abnormally retained embryonic kidney precursor cells arranged in clusters termed nephrogenic rests. The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests are classified into intralobar nephrogenic rests (ILNR) and perilobar nephrogenic rests (PLNR) types. Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a pre-neoplastic condition.[1] Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma should be considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.[5]

Clear cell sarcoma of the kidney (CCSK) is not a Wilms tumor variant, but it is an important primary renal tumor associated with a significantly higher rate of relapse and death than favorable histology Wilms tumor. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. The classic pattern of CCSK is defined by nests or cords of cells separated by regularly spaced fibrovascular septa.[6] Dysregulation of the epidermal growth factor receptor pathway has been demonstrated in CCSK.[7] Previously, relapses have occurred in long intervals after the completion of chemotherapy (up to 10 years), however with current therapy relapses after 3 years are uncommon.[8] The brain has emerged as a frequent site of recurrent disease.[9,10]

Rhabdoid tumors (RT) are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney and central nervous system (atypical teratoid/rhabdoid tumor), although RTs can also arise in most soft-tissue sites. Initially they were thought to be a rhabdomyosarcomatoid variant of Wilms tumor when they occurred in the kidney.

Histologically, the most distinctive features of rhabdoid tumors of the kidney (RTK) are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions. A distinct clinical presentation with fever, hematuria, young age (mean 11 months), and high tumor stage at presentation suggests a diagnosis of RTK.[11] RTK tends to metastasize to the lungs and the brain. As many as 10% to 15% of patients with RTK also have central nervous system lesions.[12]

RT in all anatomical locations have a similar molecular origin. Mutation or deletion of both copies of the hSNF5/ INI1 gene that maps to chromosome band 22q11.2 is observed in approximately 70% of primary tumors. An additional 20% to 25% of tumors have reduced expression at the RNA or protein level, indicative of a loss-of-function event. The INI1 protein is a component of the SWI/SNF chromatin remodeling complex (group of genes involved in cell signaling, growth, and differentiation). Identical mutations may give rise to a brain or kidney tumor. Germline mutations of INI1 have been documented for patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[13,14] In most cases, the mutations are de novo, and not inherited from a parent. Germline mosaicism has been suggested for several families with multiple affected siblings. It does appear that those patients with germline mutations have the worst prognosis.[15]

Neuroepithelial tumors of the kidney (NETK) are extremely rare and demonstrate a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with penetration of the renal capsule, extension into the renal vein, and metastases.[16,17] Primary NETK consist of primitive neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts . Within NETK, focal, atypical histologic features have been seen including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[16,18] (Refer to the PDQ summary on Ewings Family of Tumors for more information about neuroepithelial tumors.)

Desmoplastic small round cell tumor of the kidney is a rare, small, round' blue tumor of the kidney. It is diagnosed by its characteristic EWS-WT1 translocation.[19] For more information about desmoplastic small round cell tumor of the kidney, please refer to the PDQ Childhood Soft Tissue Sarcoma Treatment summary.

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%) with unique pathologic and clinical characteristics. It is composed entirely of cysts and their thin septa are the only solid portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or epithelial cell type. Several pathologic features distinguish this neoplasm from standard Wilms tumor. Patients with stage I disease have a 100% survival rate with surgery alone. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[5]

Multilocular cystic nephromas (MCN) are benign lesions consisting of cysts lined by renal epithelium. These lesions can occur bilaterally and a familial pattern has been reported. MCN has been associated with pleuropulmonary blastomas, so radiographic imaging studies of the chest should be followed in patients with MCN.[20]

Mesoblastic nephroma (MN) comprises about 5% of childhood kidney tumors. The median age of diagnosis is 2 months and over 90% of cases appear within the first year of life. Twice as many males are diagnosed as females. The diagnosis should be questioned when applied to individuals over 2 years of age. When diagnosed in the first 7 months of life, the 5 year event-free survival (EFS) and overall survival rates are 94% and 96%, respectively.[21]

Grossly, MN appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. They can be divided into two major types: classic and cellular. Classic mesoblastic nephromas are often diagnosed by prenatal ultrasound or within 3 months after birth and closely resemble infantile fibromatosis.[22] Infantile fibrosarcoma and cellular mesoblastic nephroma contain the same t(12;15)(p13;q25) chromosomal translocation suggestive of a potential linkage.[23] The risk for recurrence within mesoblastic nephromas is closely associated with the presence of a cellular component and with stage.[22]

Malignant epithelial tumors arising in the kidneys of children account for more than 5% of new pediatric renal tumors; therefore, they are more common than CCSK or RTK. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, occurs rarely in children less than 15 years of age. In the older age group of adolescents (15—19 years of age), approximately two-thirds of renal malignancies are RCC.[24] The annual incidence rate is approximately 4 per 1 million children compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher. RCC in young patients has a different genetic and morphologic spectrum than that seen in older adults.[25-28] RCC may be associated with von Hippel-Lindau (VHL) disease, a hereditary condition in which blood vessels within the retina and cerebellum grow excessively.[25] The gene for VHL is located on chromosome 3p25-26 and is a tumor-suppressor gene whose function is lost in patients with the syndrome. Screening for the VHL gene is available.[29] RCC has also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the kidney.[30,31] Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[31] A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors. A significant number of RCC tumors in children have Xp11.2 translocations,[28,32] and there is a subset that appears to be genetically related to alveolar soft part sarcoma.[33] A rare subtype of RCC, renal medullary carcinoma, may be associated with sickle cell hemoglobinopathy.[34] Renal medullary carcinomas are highly aggressive malignancies characterized clinically by a high stage at the time of detection, with widespread metastases and lack of response to chemotherapy and radiotherapy. Survival ranges from 2 weeks to 15 months, with a mean survival of 4 months.[34,35]

RCCs have been described in patients several years after diagnosis and therapy for neuroblastoma.[36] Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear-cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either one of these categories. Childhood RCCs are more frequently of the papillary subtype (20% to 50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma and metanephric adenofibroma. More recently, the genetic translocations can be used as the basis for subgrouping with many involving Xp11.2 resulting in the overexpressed transcription factor genes TFE3 or TFEB. These Xp11.2-translocation carcinomas are recognized as a distinct entity but resemble clear cell RCCs. One of these fusion variants of RCC is identical to the genetic change in alveolar soft-part sarcoma, however, the genetic pathways to pathogenesis are not the same in these two disease (with genetic features similar to those in adults with gains of chromosome 7 and 17) and of the Xp11 translocation type or the related t(6;11) translocation type.[25,28,37,38]

RCC may present with an abdominal mass, abdominal pain, or hematuria. In a series of 41 children with RCC, the median age was 124 months with 46% presenting with localized stage I and stage II, 29% with stage III, and 22% with stage IV disease using the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. Event-free survival and overall survival (OS) were each about 55% at 20 years post treatment. Patients with stage I and stage II disease had an 89% OS rate, while those with stage III and stage IV disease had a 23% OS rate at 20 years posttreatment. [30] An important difference between the outcomes in children and adults with RCC is the prognostic significance of local lymph node involvement. Adults presenting with RCC and involved lymph nodes have a 5-year OS of approximately 20%, but the literature suggests that 72% of children with RCC and local lymph node involvement at diagnosis (without distant metastases) survive their disease.[39] In another series of 49 patients from a population-based cancer registry, the findings were essentially confirmed. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 16% were unclassified, and 6% had clear cell subtype. Survival at 5 years was 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.[40]

Some nephrogenic rests may become hyperplastic which may produce a thick "rind" of blastemal or tubular cells that enlarge the kidney. The diagnosis may be made radiographically, most readily by magnetic resonance imaging, in which the homogeneity of the hypointense rind-like lesion on contrast-enhanced imaging differentiates it from Wilms tumor. Biopsy often cannot discriminate Wilms tumor from these hyperplastic nephrogenic rests. If left untreated, they may regress or differentiate following the administration of chemotherapy. Current recommendations are for treatment with vincristine and dactinomycin until nearly complete resolution as determined by imaging. Even with treatment with vincristine and dactinomycin, about half of children will develop Wilms tumor, within an average of 36 months after diagnosis. In a series of 52 patients, three patients died of recurrent Wilms tumor.[41] In treated children, as many as one-third of Wilms tumors are anaplastic, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical. Patients are followed by imaging at a maximum interval of 3 months for a minimum of 7 years. Given the high incidence of bilaterality and the subsequent Wilms tumors, renal-sparing surgery is indicated.[41]

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