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

Doros LA, Rossi CT, Yang J, Field A, Williams GM, Messinger Y, Cajaiba MM, Perlman EJ, A Schultz K, Cathro HP, Legallo RD, LaFortune KA, Chikwava KR, Faria P, Geller JI, Dome JS, Mullen EA, Gratias EJ, Dehner LP, Hill DA - Mod. Pathol. (2014)

Bottom Line: We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

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.

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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)).
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fig5: 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)).

Mentions: A 21-month-old girl had a 6.6 cm cystic and solid mass of the left kidney, which was composed of multiple cysts lined by cuboidal/hobnail epithelium with loose subepithelial mesenchyme without overtly sarcomatous features, but in adjacent areas there was a spindle cell sarcoma pattern with anaplasia and pleomorphism (Figure 5). No primitive tubular or other epithelial elements were seen. Immunohistochemically, the immature mesenchyme and solid sarcomatous foci were reactive for desmin, and there was no nuclear WT1 expression. DICER1 testing on formalin-fixed, paraffin-embedded tumor tissue identified a c.5427G>A; G1809R somatic missense mutation.


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

Doros LA, Rossi CT, Yang J, Field A, Williams GM, Messinger Y, Cajaiba MM, Perlman EJ, A Schultz K, Cathro HP, Legallo RD, LaFortune KA, Chikwava KR, Faria P, Geller JI, Dome JS, Mullen EA, Gratias EJ, Dehner LP, Hill DA - Mod. Pathol. (2014)

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)).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117822&req=5

fig5: 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)).
Mentions: A 21-month-old girl had a 6.6 cm cystic and solid mass of the left kidney, which was composed of multiple cysts lined by cuboidal/hobnail epithelium with loose subepithelial mesenchyme without overtly sarcomatous features, but in adjacent areas there was a spindle cell sarcoma pattern with anaplasia and pleomorphism (Figure 5). No primitive tubular or other epithelial elements were seen. Immunohistochemically, the immature mesenchyme and solid sarcomatous foci were reactive for desmin, and there was no nuclear WT1 expression. DICER1 testing on formalin-fixed, paraffin-embedded tumor tissue identified a c.5427G>A; G1809R somatic missense mutation.

Bottom Line: We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

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.

Show MeSH
Related in: MedlinePlus