Wilms Tumor
Clear Cell Sarcoma
Rhabdoid Tumors of the Kidney
Neuroepithelial Tumors of the Kidney
Cystic Partially Differentiated Nephroblastoma
Mesoblastic Nephroma
Renal Cell Carcinoma
Diffuse Hyperplastic Perilobar Nephroblastomatosis
Current Clinical Trials

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. There is no anaplasia in the tumor.



• Anaplastic histology: Wilms tumor may be focal or diffuse (extreme cellular pleomorphism and atypia).[1] Focal anaplasia does not confer a poor prognosis, while diffuse anaplasia does. Anaplasia is associated with resistance to chemotherapy and may still be detected after preoperative chemotherapy.[2-4]

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 arborizing fibrovascular septa.[5]

Initially thought to be a rhabdomyosarcomatoid variant of Wilms tumor, rhabdoid tumors of the kidney (RTK) are a distinctive and highly malignant tumor type. The most distinctive features of RTK are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions. The cell of origin is unknown. A distinct clinical presentation with fever, hematuria, young age (mean 11 months), and high tumor stage at presentation suggests a diagnosis of RTK.[6] RTK tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with RTK also have central nervous system lesions.[7,8]

The characteristic molecular lesion found in RTK is loss-of-function mutations of the hSNF5/INI1 gene, which is located at chromosome band 22q11.2.[9,10] This same molecular abnormality is found in tumors of the central nervous system termed atypical teratoid and rhabdoid tumors without the kidney involvement.[9,10] Some patients with rhabdoid tumors have constitutional mutations of the hSNF5/INI1 gene,[9,11] and these children are at increased risk for second primary brain tumors.[12]

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.[13,14] Primary NETK consist of primitive neuroectodermal tumors characterized by CD99 (MIC-2) immunostaining and the EWS/FLI-1 or closely related gene fusion products and small cell carcinomas characterized by chromogranin positivity. The two subtypes may be difficult to distinguish. Within both types of NETK, focal, atypical histologic features have been seen including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[13] (Refer to the PDQ summary on Ewings Family of Tumors for more information about neuroepithelial tumors.)

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%) with unique pathologic and clinical characteristics. 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.[15]

Mesoblastic nephroma comprises about 5% of childhood kidney tumors, with twice as many males diagnosed as females. About half of all mesoblastic nephromas are of the classic histologic subtype and are often diagnosed by prenatal ultrasound or within 3 months after birth.[16] The cellular subtype is commonly found in older infants and often has a t(12;15) (p13;q25) translocation and/or chromosome 11 trisomy, cytogenetic abnormalities shared with congenital fibrosarcoma.[17]

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, representing fewer than 3% of renal cancers in children younger than 15 years.[18] Renal cancers occur much less frequently in the 15- to 19-year-old age group than in younger children; however, among this older age group, approximately two-thirds of renal malignancies are RCC.[18] 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.[19-22] RCC may be associated with von Hippel-Lindau disease, a hereditary condition in which blood vessels within the retina and cerebellum grow excessively.[19] The gene for von Hippel-Lindau is located on chromosome 3p25-26 and is a tumor-suppressor gene whose function is lost in patients with the syndrome. RCC has also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the kidney.[23-25] Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[24] 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,[22] and there is a subset that appears to be genetically related to alveolar soft part sarcoma. RCC may be associated with sickle cell disease and/or neuroblastoma.[26,27]

Pediatric RCC differs histologically from the adult counterparts. RCC tumors can be divided into two subgroups consisting of the clear cell lesions and papillary RCC. The clear cell lesions are the true conventional adult-type RCC, complete with abnormalities of chromosome 3p25. The second subgroup of pediatric RCCs are the classic papillary type, which are common in children and show the same genetic features as those found in adults (gains of chromosome 7 and 17). About half of patients with the papillary subtype have genetic alterations in Xp11.2 involving TFE3.[22,28] RCC may present with an abdominal mass, abdominal pain, or hematuria.[29] 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 posttreatment. 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. 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.[30] In another series of 49 patients from a population-based cancer registry, the findings were essentially confirmed.[31] 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.[31]

In diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), the cortical surface of one or both kidneys is composed of hyperplastic nephroblastic tissue in whole or in part. 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 DHPLN unless the interface between DHPLN and normal renal tissue is included. Wilms tumor has a characteristic fibrous pseudocapsule, while DHPLN does not. If left untreated, most children with DHPLN will develop Wilms tumor. Current recommendations are for treatment with vincristine and actinomycin-D until nearly complete resolution of DHPLN as determined by imaging. Even with treatment with vincristine and actinomycin-D, about half of children will develop Wilms tumor, within an average of 36 months after diagnosis of DHPLN. Despite this, the overall survival rate for these children is approximately 50%. In a series of 52 patients, three patients died of recurrent Wilms tumor.[32] In treated DHPLN 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 bilateral DHPLN and the subsequent Wilms tumors, renal-sparing surgery is indicated.[32]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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