DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma

Abstract

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, whereas 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.

Figure 1

Unusual Wilms tumor in patient with germline DICER1 mutation and subsequent PPB. (a) Sheets of loose primitive blastemal cells and nodules of cartilage, (b) Primitive cartilage nodule emerging from primitive mesenchyme on left; (c) primitive spindled cells with skeletal muscle differentiation; (d) array of primitive tubules resembling seen primitive tubules in classic Wilms tumor (H&E; original magnification × 200 (a–d).

Figure 2

Malignant transformation of cystic nephroma in a 10 year-old boy. (a) Low power view of complex cystic spaces and variable stromal cellularity; (b) medium power view of cyst septa lined by plump, cuboidal, ‘hobnail,' epithelium with subepithelial layer of primitive cells (cambium layer). This pattern is remarkably similar to the Type I, cystic PPB. (c, d) High power views of atypical, primitive cells beneath the epithelium; (e, f) recurrent solid tumor with spindle cell sarcomatous and anaplastic patterns ((H&E; original magnification × 100 (a), × 200 (b, e); × 400 (c, d, f)).

Figure 3

Malignant transformation of cystic nephroma in a 20 year-old woman. (a) Low power view of renal mass with variably sized cystic spaces and focal areas of increased stromal cellularity; (b) medium power view of cyst with plump cuboidal epithelium and loose subepithelial mesenchyme; (c) medium power view of septa lined by plump cuboidal epithelium and subepithelial collection of primitive cells (cambium layer); (d) recurrent solid tumor with diffuse anaplasia ((H&E; original magnification × 100 (a), × 400 (b, d); × 200 (c)).

Figure 4

Malignant transformation of cystic nephroma in a 26-month-old child. (a) Low power view showing multiple rounded cysts with increased septal cellularity; (b) high power view showing subepithelial spindle cell proliferation; (c) nodules of primitive cells intermixed with loose rhabdomyosarcomatous tumor tissue; (d) area with more advanced skeletal muscle differentiation; (e, f) nodules of malignant cartilage in background of anaplastic sarcoma (H&E; original magnification × 100 (a), × 400 (b, d, e, f), × 200 (c)).

Figure 5

Renal sarcoma with cystic nephroma-like cysts in a 21 month old child. (a) Low power view of large cystic structures with loose, pale subepithelial zone; (b, c) medium power view of cysts adjacent to solid sarcomatous areas; (d) high-grade spindle cell sarcoma; (e) anaplastic tumor cells with markedly atypical enlarged, hyperchromatic nuclei and cytoplasmic hyaline globules; (f) desmin immunohistochemistry highlighted cells in the anaplastic areas. (H&E; original magnification × 100 (a), × 200 (b, c), × 400 (d, e); anti-desmin immunostain × 400 (f)).