DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.
Junne KamiharaVera PaulsonMicheál A BreenTheodore W LaetschDinesh RakhejaDavid S ShulmanMichelle L SchoettlerCatherine M ClintonAbigail WardDeirdre ReidyR Seth PinchesDaniel A WeiserElizabeth A MullenJaclyn SchiendaPaul A MeyersSteven G DuBoisJonathan A NowakWilliam D FoulkesKris Ann P SchultzKatherine A JanewaySara O VargasAlanna J ChurchPublished in: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (2020)
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.
Keyphrases
- end stage renal disease
- high grade
- chronic kidney disease
- ejection fraction
- copy number
- newly diagnosed
- prognostic factors
- healthcare
- peritoneal dialysis
- gene expression
- autism spectrum disorder
- dna methylation
- young adults
- bone marrow
- patient reported outcomes
- health insurance
- pain management
- locally advanced
- genome wide
- radiation induced
- mesenchymal stem cells