Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1

Lee, Julieann C.; Villanueva-Meyer, Javier; Ferris, Sean P.; Sloan, Emily A.; Hofmann, J; Hattab, Eyas M.; Williams, Brian J.; Guo, Hua; Torkildson, Joseph; Flórez, Adriana; Ziffle, Jessica Van; Onodera, Courtney; Grenert, James P.; Cho, Soo‐Jin; Horvai, Andrew E.; Jones, David; Pfister, Stefan M.; Koelsche, Christian; Deimling, Andreas von; Korshunov, Andrey; Perry, Arie; Solomon, David A.

doi:10.1007/s00401-019-01960-x

Cited by 59 publications

(48 citation statements)

References 12 publications

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“…Given the most recent diagnosis, it is possible that the other tumours were also DICER1 ‐related. Another patient deserving mention is patient 5, who was affected by neurofibromatosis type 1 (NF1); the occurrence of primary intracranial sarcoma, DICER1 ‐mutant in the context of NF1 was recently described by Lee et al 6 …”

Section: Resultsmentioning

confidence: 99%

“…Two of the patients in this series were found to have DICER1 tumour predisposition syndrome, and the rest of the tumours were sporadic. Lee et al 6 . reported three patients with primary intracranial sarcoma, DICER1 ‐mutant, and this short series highlighted a more diverse histology than initially thought: definitive rhabdomyoblastic differentiation was not present in all of the cases, and cellular pleomorphism was a consistent feature.…”

Section: Introductionmentioning

confidence: 81%

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Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Alexandrescu¹,

Meredith

Lidov³

et al. 2020

Histopathology

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Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin-like enhancer 1 in primary intracranial sarcoma, DICER1-mutant Aims: Primary intracranial sarcoma, DICER1-mutant is a recently described central nervous system tumour with specific genomic and DNA-methylation profiles. Although some of its histological features (focal spindle-cell morphology, intracytoplasmic eosinophilic granules, and focal heterologous differentiation) are common across most reported cases, the presence of significant histological variability and the lack of differentiation pose diagnostic challenges. We aim to further define the immunoprofile of this tumor. Methods and results: We reviewed the clinical history and performed immunohistochemistry for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, SOX2, SOX10, S100, histone H3 trimethylated on lysine 27 (H3K27me3), desmin, myogenin, CD99, epithelial membrane antigen (EMA) and transducin-like enhancer of split 1 (TLE1) on six primary intracranial sarcomas, DICER1-mutant, with appropriate controls. Targeted exome sequencing was performed on all cases. The sarcomas showed diffuse (n = 4), mosaic (n = 1) or minimal (≤5%, n = 1) loss of H3K27 trimethylation and nuclear TLE1 expression (n = 6). Four had immunohistochemical evidence of myogenic differentiation. SOX2, SOX10, S100 and EMA were negative; CD99 expression ranged from focal cytoplasmic (n = 4) to crisp diffuse membranous (n = 2). One tumour had focal cartilaginous differentiation. Similar immunohistochemical findings were observed in a pleuropulmonary blastoma (albeit with focal TLE1 expression), a DICER1-related pineoblastoma, and an embryonal tumour with a multilayered rosette-like DICER1-related cerebellar tumour. Targeted exome sequencing confirmed the presence of pathogenic biallelic DICER1 mutations in all tumours included in this study. Conclusion: We conclude that H3K27me3 and TLE1 immunostains, when utilised in combination, can be helpful diagnostic markers for primary intracranial sarcoma, DICER1-mutant.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 81%

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Alexandrescu¹,

Meredith

Lidov³

et al. 2020

Histopathology

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“…Study inclusion criteria required demonstration of EWSR1 ‐ WT1 fusion either by next‐generation sequencing of genomic DNA, or RT‐PCR detection of the mRNA fusion transcript. Cases 1–4 had sufficient tumor tissue for genetic evaluation on the UCSF500 Cancer Panel, which assesses approximately 500 cancer‐associated genes for mutations, copy number alterations and structural variants including gene fusions ( and Supporting Information Table 1). Paired tumor‐normal sequencing was performed for patient #1 using a buccal swab sample, whereas analysis of tumor tissue only was conducted for patients #2–4.…”

Section: Methodsmentioning

confidence: 99%

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

et al. 2019

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Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra‐abdominally, and are defined by EWSR1‐WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion‐positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6–25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma‐like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1‐WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1‐WT1 fusion provides a definitive diagnosis of DSRCT. Genome‐wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.

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“…Mutations in DICER1 have been identified in sarcomas in many different locations but predominantly in the genitourinary tract 49 . Among the sarcoma types associated with DICER1 alterations are ERMS of the uterine cervix, 34,50‐63 uterine corpus, 50,55,64,65 ovary, 49,66,67 fallopian tube, 67,68 bladder, 50,69,70 and broad ligament, 53 undifferentiated sarcoma of the ovary, 71 ovarian fibrosarcoma, 72 adenosarcoma of the female genital tract, 73‐79 peripheral primitive neuroectodermal tumor of the uterine cervix, 51 anaplastic sarcoma of the kidney, 80,81 soft tissue leiomyosarcoma, 51 intracranial spindle cell sarcomas, 43,65,82 and PPB‐like peritoneal sarcomas 68 …”

Section: Introductionmentioning

confidence: 99%

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Apellaniz-Ruiz

McCluggage

Foulkes

2020

Genes Chromosomes & Cancer

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Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of “new” morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1‐associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

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Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1

Cited by 59 publications

References 12 publications

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

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