Renal Cell Carcinoma (RCC)
Incidence of RCC
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 clear cell sarcoma of the kidney or rhabdoid tumors of the kidney. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, is rare in children younger than 15 years. In the older age group of adolescents (aged 15–19 years), approximately two-thirds of renal malignancies are RCC. The annual incidence rate is approximately 4 cases per 1 million children, compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher.
Conditions Associated With RCC
Conditions associated with RCC include the following:
- von Hippel-Lindau (VHL) disease: VHL disease is an autosomal dominant condition in which blood vessels in the retina and cerebellum grow excessively. The gene for VHL disease is located on chromosome 3p26 and is a tumor-suppressor gene, which is either mutated or deleted in patients with the syndrome.
Screening for the VHL gene is available. To detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm and renal-sparing surgery can be performed, annual screening with abdominal ultrasound or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years.
- Tuberous sclerosis: In tuberous sclerosis, the renal lesions may actually be epithelioid angiomyolipoma (also called perivascular epithelioid cell tumor or PEComa), which is associated with aggressive or malignant behavior and expresses melanocyte and smooth muscle markers.[5,6]
- Familial RCC: Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3. A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.
Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial RCC occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[8,9]
- Renal medullary carcinoma: A rare subtype of RCC, renal medullary carcinoma may be associated with sickle cell hemoglobinopathy. 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 radiation therapy.[ Level of evidence: 3iiA] Survival is poor and ranges from 2 weeks to 15 months, with a mean survival of 4 months.[10-13]
- Hereditary leiomyomatosis: Hereditary leiomyomatosis (of skin and uterus) and RCC is a distinct phenotype caused by dominant inheritance of a mutation in the fumarate hydratase gene. Screening for RCC starting as early as age 5 years has been recommended.[14,15]
- Second malignant neoplasm: RCCs have been described in patients several years after diagnosis and therapy for pediatric malignancies such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, and leiomyosarcoma.[16-21] Early detection and resection may improve survival in these patients.
Genetic Testing for Children and Adolescents With RCC
Indications for germline genetic testing of children and adolescents with RCC to check for a related syndrome are described in Table 7.
|Indication for Testing||Tumor Histology||Gene Test||Related Syndrome|
|VHL = von Hippel-Lindau.|
|aAdapted from Linehan et al.|
|Multifocal RCC or VHL lesions||Clear cell||VHL gene||von Hippel-Lindau syndrome|
|Family history of clear cell RCC or multifocal RCC with absent VHL mutation||Clear cell||Chromosome 3 gene translocations||Hereditary non-VHL clear cell RCC syndrome|
|Multifocal papillary RCC or family history of papillary RCC||Papillary||MET gene||Hereditary papillary RCC syndrome|
|Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothorax||Chromophobe or oncocytic or clear cell||Germline sequence BHD gene||Birt-Hogg-Dubé syndrome|
|Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomata||Type 2 papillary or collecting duct carcinoma||FH gene||Hereditary leiomyomata/RCC syndrome|
|Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytoma||Clear cell or chromophobe||SDHB gene, SDHC gene, SDHD gene||Hereditary paraganglioma/pheochromocytoma syndrome|
Xp11 Translocations Associated With RCC
Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of RCC in children. They are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:
- ASPSCR in t(X;17)(p11.2;q25).
- PRCC in t(X;1)(p11.2;q21).
- SFPQ in t(X;1)(p11.2;p34).
- NONO in inv(X;p11.2;q12).
- Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).
Another less-common translocation subtype, t(6;11)(p21;q12), involving a fusion Alpha/TFEB, induces overexpression of transcription factor EB (TFEB). The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.
Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. The postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[25,26]
Controversy exists as to the biological behavior of the translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[27-29] The outcomes for these patients are being studied in the ongoing COG-AREN03B2 (NCT00898365) Biology and Classification Study. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC. Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC.
Histology of RCC
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 of these categories. Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.
Prognosis and Prognostic Factors for RCC
The primary prognostic factor for RCC is stage of disease. In a series of 41 children with RCC, the median age was 10 years, with 46% presenting with localized stage I and stage II disease, 29% with stage III disease, and 22% with stage IV disease, according to the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. Event-free survival (EFS) 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. In another series of 49 patients from a population-based cancer registry, the findings were similar. 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.
Clinical Features and Diagnostic Evaluation
RCC may present with the following:
- Abdominal mass.
- Abdominal pain.
Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors. (Refer to the Stage Information for Renal Cell Cancer section of the Renal Cell Cancer Treatment summary for more information about the staging evaluation.)
Standard Treatment Options for RCC
Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. OS rates for all patients with RCC range from 64% to 87%. The 5-year survival rates for pediatric RCC is 90% or higher for stage I, higher than 80% for stage II, 70% for stage III, and lower than 15% for stage IV. Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment.
Standard treatment options for RCC include the following:
Radical nephrectomy with lymph node dissection
The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.
Renal-sparing surgery with lymph node dissection
Renal-sparing surgery may be considered for carefully selected patients with low-volume localized disease. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies.[26,36]
As with adult RCC, there is no standard treatment for unresectable metastatic disease in children. The response to radiation is poor, and chemotherapy is not effective. Immunotherapy with such agents as interferon-alpha and interleukin-2 may have some effect on cancer control. Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor.
Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. Case reports of pediatric and adolescent patients with a TFE3 RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[38,39] (Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information on the use of targeted therapies.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood renal cell carcinoma. 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.
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