The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, while others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and “hotspot” missense mutation rates which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

PURPOSE To characterize the epidemiology, histology, radiographic features and surgical approach of pediatric and adolescent renal cell carcinoma (pRCC). PATIENTS AND METHODS pRCC cases prospectively enrolled on the Children's Oncology Group study AREN03B2 underwent central pathology, radiology, surgery and oncology review. RESULTS As of June 2012, of 3250 patients enrolled on AREN03B2, 120 (3.7%) had unilateral RCC (median age 12.9 years, range 1.9-22.1; 52.5% female). Central review classified these as translocation morphology (56), papillary (20), renal medullary carcinoma (13), chromophobe (4), oncocytoma (1), conventional clear cell (1), and RCC not otherwise specified (25). Lymph node (LN) involvement (N+) was found in 35/73 (47.9%) cases for which LN were sampled, including 19/40 (47.5%) with primary tumors < 7cm. Using a size cut-off of 1cm, imaging detection of N+ had a sensitivity of 57.14% [(20/35); 95% CI: 39.35%, 73.68%] and specificity of 94.59% [(35/37); 95% CI: 81.81%, 99.34%]. Distant metastases were present in 23 (19.2%). Initial surgery was radical nephrectomy (RN) in 88 (73.3%), nephron-sparing surgery (NSS) in 18 (15.0%), and biopsy in 14 (11.7%). Patients undergoing NSS compared to RN were less likely to have LNs sampled (6/18 (33.3%) vs. 65/88 (73.9%), p-value = 0.002). CONCLUSIONS Translocation RCC is the most common form of pediatric and adolescent RCC. Nodal disease is common and seen with small primary tumors. Imaging has a high specificity but relatively low sensitivity for detection of such lymph node disease. Failure to sample LNs results in incomplete staging and potentially inadequate disease control for younger RCC patients.

Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5-year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high-risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children’s Oncology Group, is presented.