We reviewed 351 cases of clear cell sarcoma of the kidney (CCSK), including 182 cases entered on National Wilms Tumor Study Group (NWTSG) trials 1-4 for which clinical follow-up information was available. Tumors were restaged using NWTS 5 criteria. Mean age at diagnosis in the NWTS group was 36 months with a range of 2 months to 14 years. The male to female ratio was 2:1. Typical gross features included large size (mean diameter 11.3 cm), a mucoid texture, foci of necrosis, and prominent cyst formation. Nine major histologic patterns were identified (classic, myxoid, sclerosing, cellular, epithelioid, palisading, spindle, storiform, and anaplastic); virtually all tumors contained multiple patterns that blended with one another. Immunohistochemical stains were performed on 45 cases; only vimentin was consistently immunoreactive. Consistently negative results with other antibodies helped exclude other tumors in the differential diagnosis; all CCSKs were cytokeratin-negative, including epithelioid tumors that mimicked Wilms tumor, and MIC2-negative, including cellular tumors that mimicked primitive neuroectodermal tumor. The p53 gene product was rarely overexpressed in non-anaplastic CCSKs, but strikingly overexpressed in two of three anaplastic CCSKs. Overall survival was 69%. Multivariate analysis revealed four independent prognostic factors for survival: treatment with doxorubicin, stage, age at diagnosis, and tumor necrosis. Of note, stage 1 patients had a remarkable 98% survival rate. No other histologic or clinical variable independently correlated with survival.
Clear cell sarcoma of the kidney (CCSK), an uncommon renal neoplasm of childhood, nonetheless represents one of the most common unfavorable histology tumors entered on National Wilms Tumor Study Group (NWTSG) clinical protocols. Approximately 20 new cases of CCSK are diagnosed each year in the United States. 3 CCSK was initially recognized as a distinct clinicopathologic entity by Kidd in 1970, who noted its propensity to metastasize to bone. 15 The distinctive histopathologic features of CCSK were reported simultaneously in 1978 by Morgan and Kidd, 22 Marsden and Lawler, 19 and Beckwith and Palmer. 5 These reports confirmed the propensity to metastasize to bone, the poor clinical outcome, and the sarcomatous, nonepithelial nature of the tumor. The tremendous morphologic diversity that CCSK can show, ranging from epithelioid to spindle cell patterns, has been emphasized in later writings. 4,23
Since its initial description, several small series of CCSK have been published. Early studies emphasized that even low-stage tumors had a poor prognosis, adding to the tumor's fearsome reputation. 30,32 Subsequently, results from the first three NWTS trials suggested that the addition of doxorubicin (Adriamycin) to vincristine and dactinomycin improved the 6-year relapse-free survival for patients with CCSK, although the difference did not reach statistical significance. 10 Nonetheless, all patients with CCSK on NWTS trial 5 are now treated with doxorubicin regardless of stage. While this approach has decreased the importance of accurate staging, the essential role of doxorubicin in therapy emphasizes the need for pathologists to accurately identify CCSK. Failure to recognize a tumor as a CCSK could deprive a child of optimal chemotherapy.
Immunohistochemical studies have been performed with the hope of establishing a unique profile that distinguishes CCSK from other lesions in the differential diagnosis. These have generally shown that CCSKs are reactive for vimentin but little else. 17,18,25 However, the possibility of cytokeratin expression in epithelioid areas of CCSK has not been addressed. This issue is highlighted by isolated reports of epithelial differentiation in CCSK, both in primary 16,31 and cultured tumors. 13 In addition, one study found a high frequency of p53 protein overexpression in these tumors as determined by immunohistochemistry, suggesting frequent mutations in this gene. 6
Diagnostic criteria for the renal tumors of childhood have evolved over the years. Recognition of new entities, such as metanephric stromal tumor, 2 embryonal sarcoma of the kidney, 7 primary renal peripheral neurorectodermal tumor (PNET), 29 and cystic hamartoma of the renal pelvis, 27 has allowed previously recognized tumors, such as congenital mesoblastic nephroma, to become more sharply defined. Staging criteria have also changed over the course of the NWTS. Finally, immunohistochemical studies have become more reliable and adaptable to archival material using the heat-induced epitope retrieval method. With these considerations in mind, we have reviewed all cases of CCSK available at the NWTSG Pathology Center, which holds the largest collection of pediatric renal tumors in existence. The goals of this study were to define more sharply the clinicopathologic and immunohistochemical spectra of CCSK, and to search for clinical and pathologic variables of prognostic import.