Composite Wilms Tumor and Renal Cell Carcinoma

We report the largest series of 18 cases of an uncommon composite renal tumor comprised of Wilms tumor (WT) and renal cell carcinoma (RCC). The tumors were identified by rereviewing WT with "unusual" epithelial components. The age at presentation ranged from 3 months to 11 years (median: 3.7 y), with 13/18 (72%) patients under the age of 5 years, and only 3/18 (17%) older than 10 years of age. There was a striking (2:1) female predominance. All tumors presented as a renal mass that measured from 5 to 18 cm (median 9.3 cm) on gross examination. Histologically, the ratio between WT and RCC components varied from 99%:1% to 5%:95%, respectively. There was a marked prevalence of anaplastic WT (39% vs. ~10% in large cohorts of WTs), and papillary RCC (89% vs. ~20% in large pediatric RCC series). The papillary RCC component included subtypes not previously described in children (biphasic squamoid alveolar RCC and sarcomatoid RCC). Most tumors were stage III (10/18, 56%), which is significantly higher than in large cohorts of WT (~20%). The most common reason for local stage III diagnosis was lymph node metastases with PRCC component (6/11, 55%). Five patients were treated with primary nephrectomy, and 13 with preoperative chemotherapy for WT. Postoperative treatment was tailored according to WT and/or RCC histology and stage. Twelve patients (12/18, 67%) relapsed between 7 months and 12 years after diagnosis (7/12, 58%, within 1 y; there were 2 very late relapses at 5.5 y and 12 y after the diagnosis). In 7/12 (58%) cases, the site of relapses was the lung. Histology of the relapse was available in 10 cases, including 4 cases with both WT and PRCC components, 3 cases with WT component only, 2 cases with RCC component only, and 1 case with WT relapse in the contralateral kidney and PRCC in the lung. Thirteen patients were alive at the last follow-up, including 6 patients who had event-free survival (median follow-up 1.9 y, range 0.4 to 3.1 y) and 7 patients who relapsed but survived (median follow-up 6 y, range 2 to 18 y). All 5 deaths were related to progressing relapsed disease. Immunohistochemical studies allowed RCC subtyping and showed statistically significant differential expression between the WT versus RCC components. In the WT component, we found a higher expression of WT1 ( P =0.007), CD57 ( P =0.002), and SALL4 ( P =0.04), whereas CK7 ( P =0.004) and P504 ( P =0.002) were higher in RCC. Co-expression of WT1 and CD56 was identified in both components in 61% cases, suggesting a close relationship between RCC and WT components. p53 overexpression was present in 5/12 (42%) tested WT and 4 RCC (33%). Molecular studies confirmed the clonal relationship of all paired samples with sufficient neoplastic content for comparison. Recurrent genomic alterations included mutations in TP53 (6/8, 75%) as well as genes involved in the PI3K/mTOR pathway (5/8, 63%) and cell cycle regulation (3/8, 38%). In addition, all tumors with sufficient neoplastic content were negative for microsatellite instability with a low tumor mutation burden. Our study described the characteristics of composite renal tumors combining WT and RCC, highlighting several unusual and specific features. Its behavior appeared to be more aggressive than that of WT or RCC alone, and we propose that it should be recognized as a separate entity, which may require different treatment from WT or RCC alone.