TY - JOUR
T1 - DICER1-associated central nervous system sarcoma in children
T2 - comprehensive clinicopathologic and genetic analysis of a newly described rare tumor
AU - Kamihara, Junne
AU - Paulson, Vera
AU - Breen, Micheál A.
AU - Laetsch, Theodore W.
AU - Rakheja, Dinesh
AU - Shulman, David S.
AU - Schoettler, Michelle L.
AU - Clinton, Catherine M.
AU - Ward, Abigail
AU - Reidy, Deirdre
AU - Pinches, R. Seth
AU - Weiser, Daniel A.
AU - Mullen, Elizabeth A.
AU - Schienda, Jaclyn
AU - Meyers, Paul A.
AU - DuBois, Steven G.
AU - Nowak, Jonathan A.
AU - Foulkes, William D.
AU - Schultz, Kris Ann P.
AU - Janeway, Katherine A.
AU - Vargas, Sara O.
AU - Church, Alanna J.
N1 - Funding Information:
Comparison of the tumor mutational burden in the DCS series and the other DICER1-associated tumors used a Wilcoxon rank-sum test for unpaired data. Comparison of the rate of TP53 and KRAS variants between the DCS and other DICER1-associated tumors was done using Fisher’s exact test. Statistical support was provided by the ICCTR Biostatistics and Research Design Center at Harvard Medical School.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary “DICER1-associated central nervous system sarcoma” (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3–15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic “organoid” features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
AB - The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary “DICER1-associated central nervous system sarcoma” (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3–15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic “organoid” features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
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U2 - 10.1038/s41379-020-0516-1
DO - 10.1038/s41379-020-0516-1
M3 - Article
C2 - 32291395
AN - SCOPUS:85083807643
SN - 0893-3952
VL - 33
SP - 1910
EP - 1921
JO - Modern Pathology
JF - Modern Pathology
IS - 10
ER -