Abstract

In this review, we summarize the clinical, histopathological, and molecular features of central nervous system (CNS) tumors with BCOR internal tandem duplication, intracranial mesenchymal tumor with FET/CREB fusion, CNS CIC-rearranged sarcomas and primary intracranial sarcoma DICER1-mutant, now included in the 2021 WHO classification of CNS tumors. Possible relationships between tumors occurring in the CNS and their systemic counterparts are discussed.

Introduction

In recent years, large molecular studies have permitted a better classification of undifferentiated, poorly differentiated round cell tumors, mainly under the definition of CNS-PNETs, or spindle cell neoplasms occurring in the CNS ¹. One important result of these studies was the widening of the spectrum of “mesenchymal” neoplasms potentially occurring in the CNS; this group includes now mesenchymal tumor with FET/CREB fusion, CIC-rearranged sarcomas and DICER1-mutant intracranial sarcoma. Furthermore, these analyses led to the identification of neuroepithelial tumors which share a common genetic background with pediatric sarcomas, like CNS tumors with BCOR internal tandem duplication (BCOR ITD).

Even though many aspects of biology of these rare tumors have been better defined, some intriguing issues are still to be definitively addressed, and especially their exact relationships with their systemic counterparts.

Incidence, distribution and localisation

Although a large number of cases have been progressively documented in recent years, these neoplasms are rare and precise information regarding their incidence and prevalence in general population is still not available. Based on available literature, the two most frequently reported entities seem to be mesenchymal tumor with FET/CREB fusion and the CNS tumor BCOR ITD ².

Intracranial mesenchymal tumor with FET/CREB fusion occurs more frequently in adult population: in a large series, the median patient age at presentation was 17 years with a predominance in the female population ³. They are mainly extra-axial or intraventricular tumors, localized, in particular, in hemispheric meninges, the falx and the tentorium ^3-5.

In the CNS, tumor in the BCOR ITD and CIC-rearranged sarcoma affect mainly the pediatric population: infants for CNS tumor BCOR ITD (mean age 3.5 years) ⁶, while adolescents and young adult (usually ≤ 21 years) for CIC-rearranged sarcoma. CNS tumors BCOR ITD showed predominantly a cerebellar localization, especially in younger patients (< 5 years old), although they can also occur in cerebral hemispheres ^2,6,7; CNS CIC-rearranged sarcomas may show variable localization including cases at spinal level ^1,8-10.

The mean age of patients with primary DICER1-mutant intracranial sarcoma is 6 years with a wide range of age and predominant intracranial localization ^11-14.

Integrated diagnosis

A combined histopathological- and molecular-based approach is often necessary to reach the final diagnosis. A variable histopathological spectrum and an unspecific immunohistochemical profile are common, hindering an easy recognition in routine diagnostic neuropathology.

Intracranial mesenchymal tumor with FET/CREB fusion is a mesenchymal neoplasm characterized by the presence of fusion of a FET RNA-binding protein family gene (usually EWSR1, rarely FUS) with a member of the CREB transcription factors family (CREB1, ATF1, or CREM). Such cases have been reported in the past as angiomatoid fibrous histiocytoma of the meninges (AFH) or intracranial myxoid mesenchymal tumors (IMMT) ^3,15-22. They may display extremely variable histopathological features, including presence of myxoid stroma, desmoplastic areas, epithelioid and spindle cell cytology ^3,15-22 (Fig. 1). Angiomatous areas and intralesional inflammatory infiltrates are common, as seen in AFH of soft tissues ^3,4,16. Meningioma-like areas and amianthoid fibers can be detected. The immunophenotype of tumor cells is variable. The cells may often express vimentin, EMA and CD99 and could be CD68 and CD163 positive ^3,19-22. A common and unique feature is a focal immunoreactivity for desmin ^3-5,18-22. Cytokeratins, glial markers, melanocytic markers are usually negative³. These tumors show often a low proliferative activity ²⁰, but cases with increased proliferative and mitotic activity have been reported ^4,19,21. The final diagnosis relies on the identification of translocation involving FET family genes with CREB transcription factors genes. Notably, epithelioid features seem to be associated to EWSR1-ATF1 fusions ^3,21. Because molecular alterations involving EWSR1 are not specific and can be identified in other CNS tumors, extreme caution must be used in the interpretation of results obtained with FISH-based methods: a further confirmation of the presence of a specific FET-CREB fusion with other methods should be recommended. Intracranial mesenchymal tumor with FET/CREB fusion may present additional mutations in several genes, including BRAF ²².

CNS tumor BCOR ITD is as a malignant neoplasm characterized by a predominantly solid or microcystic growth pattern, glial-like cytology, a dense capillary network, formation of pseudo-rosettes, and by the presence of an ITD in exon 15 of the BCOR gene. Differently from other entities described herein, this tumor is considered to derive from a neuroepithelial cell of origin (see below) and therefore included in the CNS embryonal tumors along to medulloblastoma, ETMR and ATRT ².

This neoplasm can present variable neuropathological features and immunohistochemical profile. CNS tumor BCOR ITD often resembles a glial neoplasm and can show solid, microcystic or perivascular architecture, often with a prominent, dense vascular stroma (Fig. 2). The cells, usually round or oval, often appear embedded in a glioma-like fibrillary stroma; Homer-Wright rosettes can be found; the tumor may show in part an infiltrative growth pattern; usually these neoplasms display high proliferative and mitotic activity ^6,23-25.

The differential diagnosis, given the common occurrence in the posterior fossa in children, should include medulloblastoma, ependymomas and ETMR. From an immunohistochemical point of view, the neoplasm, usually CD56 and vimentin positive, may present a variable expression of glial markers such as GFAP, OLIG2 and S100 but may also show positivity for NeuN; the expression of other neuronal markers is uncommon ^6,23-25. SATB2, BCL2 and TLE1 as well as pan-NTRK are usually positive ²⁶. The widespread positivity for BCOR, EGFR and Cyclin D1 is helpful but BCOR over-expression is unspecific and can be encountered in numerous other CNS neoplasms, including high-grade gliomas ²⁷. The definitive diagnosis relies on the identification of the presence of duplication in the 15 exon of BCOR gene (Fig. 3). Notably, several BCOR alterations have been also described in other CNS neoplasms, including mutations and fusions ²⁷. Mutations have been identified in retinoblastomas, in various glial tumors, particularly those with high-grade histology, including high-grade astroblastomas. Moreover, BCOR genetic alterations were also found in about 5% of medulloblastomas being apparently more common in infantile SHH-medulloblastoma subgroup ²⁷.

CIC-rearranged sarcoma of the CNS is a high-grade, poorly differentiated neoplasm defined by the presence of a fusion of CIC with different partner genes (such as NUTM1 and DUX4) ². They show histopathological features similar to their systemic soft tissue counterpart ¹⁰: CIC-rearranged sarcomas are formed by undifferentiated round cells arranged in nests or showing a more solid growth pattern; necrosis is common; epithelioid or spindle cell cytology as long as desmoplastic or myxoid stroma have been also described ²⁸ (Fig. 4). In most cases, the differential diagnosis includes other round cell neoplasms, like rhabdomyosarcoma and Ewing’s sarcoma. WT1 and ETV4 positivity, a weak CD99 expression and negativity for NKX2-2 and FLI1 stainings can be very helpful to orientate the diagnosis ^28,29. Heterogeneous ERG/CD31 co-expression in a subset of CIC-rearranged sarcoma may be a potential pitfall in differential diagnosis with vascular tumors ³⁰. Expression of pan-cytokeratin, smooth muscle actin, and neurofilament protein has been reported ^8,28. The final diagnosis relies on demonstrating CIC-rearrangement using FISH, NGS- or RT-based methods.

Primary intracranial sarcoma DICER1-mutant composed of spindle or pleomorphic tumor cells, with evidence of myogenic and occasionally of chondroid differentiation. The tumors show often spindle cell cytology with anaplastic features, focal rhabdomyoblastic differentiation, foci of primitive embryonal-type tissue and in some cases chondroid differentiation ^11,31-34 (Fig. 5). The presence of eosinophilic globules is also a typical feature ¹¹ : they are PAS+ and are stained with alpha-1-antitrypsin. The tumor shows patchy expression of muscular markers (like desmin and myogenin) highlighting the rhabdomyosarcomatous component. Nuclear positivity for TLE1 expression ³⁵ and loss of H3K27me3 were observed in primary intracranial sarcoma DICER1-mutant ^12,35: therefore, these tumors may be included in the differential diagnosis of high-grade cellular malignant spindle cell neoplasms with loss of H3K27me3 (in particular MPNST) ¹². The histology of primary intracranial sarcoma DICER1-mutant overlaps considerably with other DICER1-associated tumors, notably to type II/III pleuropulmonary blastoma (PPB): therefore, distinguishing primary intracranial sarcoma, DICER1-mutant from metastatic PPB is pivotal ³¹.

Information, if any, on a possible presence of a DICER1 syndrome or presence of other DICER1-related neoplasms in clinical history of the patient significantly may further facilitate the neuropathological approach to diagnosis. Confirmation of presence of DICER1 mutation in sporadic cases is mandatory for the final diagnosis.

Taxonomy and oncogenesis

The most intriguing issue for these CNS neoplasms in particular for CNS BCOR ITD, CIC-rearranged sarcoma and for intracranial mesenchymal tumor with FET/CREB fusion is the relationship with their systemic counterparts.

Tumors harboring BCOR-internal tandem duplication represent a histologically heterogeneous group of neoplasms, comprising CNS tumors and sarcomas; the latter group includes clear cell sarcomas of the kidney (CCSK), high-grade endometrial stromal sarcomas (HG-ESS), myxoid mesenchymal tumor of infancy (PMMTI) and undifferentiated round cell sarcoma (URCS) in bone and soft tissues ^36,37.

BCL-6 transcriptional corepressor (BCOR) (located at Xp11.4) encodes a protein which functions as a corepressor bounding to BCL-6 and forming part of the Polycomb Repressive Complex 1 which through ubiquitination leads epigenetic silencing ²⁷. Besides ITD, various alterations affecting BCOR gene have been described: they include fusions (i.e., BCOR-CCNB3, BCOR-MAML3 and ZC3H7B-BCOR), mutations and internal tandem duplications (ITD) ²⁷.

The main similarities between CNS and non-CNS tumors BCOR ITD neoplasms are clinical and include the median age of the patients at the time of diagnosis, the local presentation and the poor prognosis. The histopathology, however, varies greatly and depends on the tissue and site of occurrence ^26,38.

Moreover, CNS tumors BCOR ITD and BCOR ITD sarcomas present close but distinct transcriptomic signature and DNA methylation profile, suggesting the possibility of a common, acquired oncogenic pattern in distinct cell types within specific tissues. Notably, expression analysis revealed that the CNS BCOR ITD group seems to be enriched in genes expressed in neuro-glial cells whereas BCOR ITD sarcomas predominantly expressed embryonal/developmental genes: this correlate well at histopathological level, with the evidence that CNS tumors BCOR ITD, but not BCOR ITD sarcomas express neuro-glial markers (like GFAP, Olig2, Neu-N). The difference in molecular signatures is probably dependent on their different cell of origin. As previously mentioned, the putative origin of CNS BCOR ITD from neuroepithelial cells led to the inclusion of this tumor among CNS embryonal tumors, rather than mesenchymal neoplasms in WHO classification of CNS tumors.

The relationships between intracranial mesenchymal tumors with FET/CREB fusion and their systemic counterpart is more difficult be addressed.

Soft tissue AFH, pulmonary CREB sarcoma and intracranial mesenchymal tumors with FET/CREB fusion share many features but also present some differences at histopathological level (i.e. desmin expression) ⁴. Methylation profiling analysis added interesting information on taxonomy of those tumors occurring in the CNS. CNS tumors seem to be different from their soft tissue counterparts, suggesting the existence of two epigenetic subgroups ^4,39. The first subgroup includes tumors that have epigenomic similarities with the systemic AFH and SFT and have mostly EWSR1-ATF1 and ESWR1-CREB1 fusions; these tumors occur mostly in adolescents and young adults, show a spindle cell cytology and a hemangioma-like vascularity. The second subgroup includes tumors with epigenomic similarities with the clear cell sarcoma of soft tissue (CCS) enriched in cases mostly with ESWR1-CREM and FUS-CREM fusions; they occur in early childhood and show a round or epithelioid/rhabdoid morphology and lack of hemangioma-like features ³⁹.

There is no sufficient evidence to distinguish CIC-rearranged sarcoma in the CNS from histologically and genetically similar tumors in other extra CNS tissues.

Despite a similar histopathology, the majority of intracranial sarcomas with CIC-rearrangement studied to date showed NUTM1 and LEUTX as the fusion partner, whereas those in extracranial bone and soft tissue had DUX4, FOXO4 and NUTM2A as the fusion partner ^10,40,41. CIC gene product encodes a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. Gene truncation (besides fusions) may be also sufficient to enable an oncogenic de-repression of transcription.

Primary intracranial sarcoma, DICER1-mutant, as previously indicated, overlaps considerably in terms of histopathology with other DICER1-associated tumors particular with PPB. These tumors occur in a specific genetic setting defined by mutations in the DICER1 gene (either somatic or germline as part of the DICER1 syndrome). DICER1 syndrome is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous germline mutation of DICER1 gene (chromosome 14, region q32.13) that increases the risk of development of different types of malignant and benign tumors ⁴². Patients with DICER1 syndrome commonly develop pleuropulmonary blastoma (PPB), multinodular goiter, ovarian Sertoli-Leydig cell tumors, and rarely CNS tumors including ETMR, pituitary blastoma and pineoblastoma ⁴². The DICER1 gene encodes an RNase III endoribonuclease that facilitates the activation of the RNA-induced silencing complex essential for double stranded-RNA and mi-RNA processing. Disruption of this pathway results in alterations in protein expression and in cell proliferation as well as derangement of cell differentiation and DNA repair ³¹. DICER1 behaves as either a tumor suppressor gene due to loss-of-function mutations or an oncogene, due to gain-of-function mutations. It retained function as a haploinsufficient tumor-suppressor gene with the loss of one allele leading to tumor progression, but loss of both alleles having an inhibitory effect for tumor development; therefore, one intact allele is needed for cell survival ³¹.

Recent investigations revealed that some genetic alterations seem to be more common in intracranial DICER1-mutant sarcoma compared with other DICER1-associated tumors; they include TP53 inactivation and activating alterations of genes in the RAS pathway (KRAS and NF1) ¹¹. Moreover, it seems that primary intracranial sarcoma, DICER1-mutant, may have a significantly higher tumor mutational burden in comparison to other DICER1-related tumors ¹².

Prognosis and outcome

Given their rarity, it is difficult to draw any assumptions in term of outcome and prognosis.

CIC-rearranged sarcoma and CNS tumor BCOR ITD show generally aggressive clinical behavior ⁸; the initial therapeutic strategy is mainly multimodal including most often the first-line surgery, radiotherapy and adjuvant chemotherapy ⁶. However, cases with prolonged survival have been described ^6,43. For CIC-rearranged sarcoma, it remains uncertain whether the specific fusion partner may influence the biology and therefore the prognosis of the patients with these tumors.

The clinical course of intracranial mesenchymal tumor with FET/CREB fusion is unpredictable, ranging from cases with a relatively indolent behavior, to tumors prone to rapid recurrence ³.

The prognosis for patients with DICER1-mutant primary intracranial sarcoma remains unknown, because only limited data clinical for patient with long-term follow-up are available. Moreover, the possible prognostic relevance of tumors arising in the settings of germline DICER1 mutations has not been defined There is no evidence that the presence of a germline or somatic mutation may influence the prognosis of a patient with DICER1-mutant intracranial sarcoma.

Conclusions

In conclusion, the WHO classification of CNS tumors 2021 now includes new entities among the groups of mesenchymal non-meningothelial tumors and embryonal tumors. These tumors share specific molecular and histopathological features. Given their rarity in the CNS, particular awareness is needed for practicing neuropathologists to suspect the presence of such tumors in routine neuropathology: a combined histopathological and molecular-based approach is therefore necessary to pinpoint the final diagnosis.

AKNOWLEDGMENTS

Special thanks to Prof. Caterina Giannini for providing histopathological images of the CIC-rearranged sarcoma case and to Dr. Isabella Giovagnoni e Dr. Sabina Barresi for the BCOR ITD exon 15 graphics.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

FUNDING

None.

ETHICAL CONSIDERATION

None.

AUTHORS’ CONTRIBUTIONS

MG conceived the manuscript; CP and MG drafted the manuscript; FG provided iconographic material; all authors revised and approved the final version of the manuscript.

Figures and tables

Figure 1.Histopathological features of intracranial mesenchymal tumors with FET/CREB fusion. A case of intracranial mesenchymal tumors with FET/CREB fusion, in the posterior fossa of a 60 years old patient, showed dense cellularity and spindle cell cytology, alternating with myxoid areas (A-B). Angiomatous vessels were present at the periphery (C). Another case, showed a more solid, fibro-histiocytic histology (D) with abundant inflammatory infiltrates at its periphery (E). The tumor was partially positive for desmin (F). Another tumor, occurred in a 55 years old patient and localized in the frontal meninges, showed delicate myxoid features (H). Prominent vascularity and inflammatory infiltrates were present (arrow)(I). All tumors presented EWSR1 rearrangement in FISH analysis.

Figure 2.Histopathological features of CNS tumor BCOR ITD. A CNS Tumor BCOR ITD affecting the cerebellum in a two-year-old boy. The tumor presented with solid or microcystic growth pattern (A, C). The cells were embedded in a fibrillary stroma and appeared arranged around vascular structures (B, D). The tumor was partially OLIG2 positive (E) and diffusely BCOR positive (F).

Figure 3.BCOR Internal Tandem Duplication (BCOR ITD). Schematic plot of internal tandem duplication in BCOR exon 15 (BCOR ITD) at chromosome X (in A). In OGM Circle Plot (Access Software, Bionano Technologies) chromosomal rearrangement are shown as green line (fusion) involving parts of BCOR gene (in B.). The in-frame fusion (depicted in light blue, arrow) affects the BCOR PUFD domain leading to an altered PCGF1-binding affinity, dysregulating transcription (in C.).

Figure 4.Histopathological features of CIC-rearranged sarcoma. A CIC-rearranged sarcoma (harboring a CIC-LEUTX fusion) occurred in the spinal cord of a 4 years old boy. The tumor was extramedullary. The tumor was composed of large epithelioid cells with abundant cytoplasm (A). Necrotic changes were present (B).

Figure 5.Histopathological features of DICER1-mutant sarcoma. A DICER1-mutant intracranial sarcoma in a 18 years old female patient localized in the temporal lobe. The tumor showed high cellularity, partial spindle cell cytology and myxoid stroma (A, B). Pleomorphic cells and hyaline globules were seen (C) along as highly cellular round cell undifferentiated areas (D): here focal myogenin positive staining was present (E). Partial loss of H3K27me3 was found (F). The tumor harbored a DICER1 p.E1813A mutation.

References

1. Sturm D, Orr BA, Toprak UH. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 2016; 164:1060-1072. DOI
2. Louis DN, Perry A, Wesseling P. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021; 23:1231-1251. DOI
3. Sloan EA, Chiang J, Villanueva-Meyer JE. Intracranial mesenchymal tumor with FET-CREB fusion – A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms. Brain Pathol. 2021;31. DOI
4. Tauziède-Espariat A, Sievers P, Larousserie F. An integrative histopathological and epigenetic characterization of primary intracranial mesenchymal tumors, FET:CREB-fused broadening the spectrum of tumor entities in comparison with their soft tissue counterparts. Brain Pathol. 2022; 32(1)DOI
5. Komatsu M, Yoshida A, Tanaka K. Intracranial myxoid mesenchymal tumor with EWSR1-CREB1 gene fusion: a case report and literature review. Brain Tumor Pathol. 2020; 37:76-80. DOI
6. Ferris SP, Velazquez Vega J, Aboian M. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication – a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol. 2020; 30:46-62. DOI
7. Le Loarer F, Baud J, Azmani R, Michot A, Karanian M, Pissaloux D. Advances in the classification of round cell sarcomas. Histopathology. 2022; 80:33-53. DOI
8. Ito M, Ishikawa M, Kitajima M. A case report of CIC-rearranged undifferentiated small round cell sarcoma in the cerebrum. Diagn Cytopathol. 2016; 44:828-832. DOI
9. Yamada S, Muto J, De Leon JCA. Primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation: a similar cytological appearance as its soft tissue counterpart but no lobulation in association with desmoplastic stroma. Brain Tumor Pathol. 2020; 37:111-117. DOI
10. Le Loarer F, Pissaloux D, Watson S. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am J Surg Pathol. 2019; 43:268-276. DOI
11. Koelsche C, Mynarek M, Schrimpf D. Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations. Acta Neuropathol. 2018; 136:327-337. DOI
12. Kamihara J, Paulson V, Breen MA. DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor. Mod Pathol. 2020; 33:1910-1921. DOI
13. de Kock L, Priest JR, Foulkes WD, Alexandrescu S. An update on the central nervous system manifestations of DICER1 syndrome. Acta Neuropathol. 2020; 139:689-701. DOI
14. Warren M, Hiemenz MC, Schmidt R. Expanding the spectrum of dicer1-associated sarcomas. Mod Pathol. 2020; 33:164-174. DOI
15. Dunham C, Hussong J, Seiff M, Pfeifer J, Perry A. Primary Intracerebral Angiomatoid Fibrous Histiocytoma. Am J Surg Pathol. 2008; 32:478-484. DOI
16. Hansen JM, Larsen VA, Scheie D. Primary intracranial angiomatoid fibrous histiocytoma presenting with anaemia and migraine-like headaches and aura as early clinical features. Cephalalgia. 2015; 35:1334-1336. DOI
17. Sciot R, Jacobs S, Calenbergh F Van. Primary myxoid mesenchymal tumour with intracranial location: report of a case with a EWSR1 - ATF1 fusion. Histopathology. 2018; 72:880-883. DOI
18. Gareton A, Pierron G, Mokhtari K. ESWR1-CREM Fusion in an Intracranial Myxoid Angiomatoid Fibrous Histiocytoma-Like Tumor: A Case Report and Literature Review. J Neuropathol Exp Neurol. 2018; 77:537-541. DOI
19. Ballester LY, Meis JM, Lazar AJ. Intracranial Myxoid Mesenchymal Tumor With EWSR1-ATF1 Fusion. J Neuropathol Exp Neurol. 2020; 79:347-351. DOI
20. Kao Y-C, Sung Y-S, Zhang L. EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location. Am J Surg Pathol. 2017; 41:482-490. DOI
21. Vizcaino MA, Giannini C, Chang HT, Kipp BR, Fritchie K, Vaubel R. Intracranial angiomatoid fibrous histiocytoma with rhabdoid features: a mimic of rhabdoid meningioma. Brain Tumor Pathol. 2021; 38:138-144. DOI
22. Bale TA, Oviedo A, Kozakewich H. Intracranial myxoid mesenchymal tumors with EWSR1 - CREB family gene fusions: myxoid variant of angiomatoid fibrous histiocytoma or novel entity?. Brain Pathol. 2018; 28:183-191. DOI
23. De Lima L, Sürme MB, Gessi M. Central nervous system high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)—case-based reviews. Child’s Nerv Syst. 2020; 36:1589-1599. DOI
24. Haberler C, Reiniger L, Rajnai H. Case of the month 1-2019: CNS high-grade neuroepithelial tumor with BCOR alteration. Clin Neuropathol. 2019; 38:4-7. DOI
25. Appay R, Macagno N, Padovani L. HGNET-BCOR Tumors of the Cerebellum. Am J Surg Pathol. 2017; 41:1254-1260. DOI
26. Bouchoucha Y, Tauziède-Espariat A, Gauthier A. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family. J Pathol Clin Res. 2022; 8(3):217-232. DOI
27. Astolfi A, Fiore M, Melchionda F. BCOR involvement in cancer. Epigenomics. 2019; 11(7):835-855. DOI
28. Donahue JE, Yakirevich E, Zhong S. Primary Spinal Epidural CIC-DUX4 Undifferentiated Sarcoma in a Child. Pediatr Dev Pathol. 21(4):411-417. DOI
29. Antonescu CR, Owosho AA, Zhang L. Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol. 2017; 41:941-949. DOI
30. Kojima N, Arai Y, Satomi K. Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall. Mod Pathol April. 2022. DOI
31. González IA, Stewart DR, Schultz KAP. DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma. Mod Pathol. 2022; 35:4-22. DOI
32. Lee JC, Villanueva-Meyer JE, Ferris SP. Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta Neuropathol. 2019; 137:521-525. DOI
33. Das A, Roy P, Modi SK. Germline DICER1-mutant intracranial sarcoma with dual chondroid and spindle cell morphology and pulmonary metastases treated with multimodal therapy. Pediatr Blood Cancer. 2019; 66:e27744. DOI
34. Sakaguchi M, Nakano Y, Honda-Kitahara M. Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a “spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant”. Brain Tumor Pathol. 2019; 36:174-182. DOI
35. Alexandrescu S, Meredith DM, Lidov HG. Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin-like enhancer 1 in primary intracranial sarcoma, DICER1-mutant. Histopathology. 2021; 78:265-275. DOI
36. Kao Y-C, Sung Y-S, Zhang L. Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy. Am J Surg Pathol. 2016; 40:1009-1020. DOI
37. Ueno-Yokohata H, Okita H, Nakasato K. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet. 2015; 47:861-863. DOI
38. Yoshida Y, Nobusawa S, Nakata S. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol. 2018; 28:710-720. DOI
39. Sloan EA, Gupta R, Koelsche C. Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas. Brain Pathol November. 2022; 32:e13037. DOI
40. Louis DN, Wesseling P, Aldape K. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol. 2020; 30:844-856. DOI
41. Hu W, Wang J, Yuan L. Case Report: A Unique Case of Pediatric Central Nervous System Embryonal Tumor Harboring the CIC-LEUTX Fusion, Germline NBN Variant and Somatic TSC2 Mutation: Expanding the Spectrum of CIC-Rearranged Neoplasia. Front Oncol. 2020; 10:598970. DOI
42. Foulkes WD, Bahubeshi A, Hamel N. Extending the phenotypes associated with DICER1 mutations. Hum Mutat. 2011; 32:1381-1384. DOI
43. Bremer J, Kottke R, Johann PD. A single supratentorial high-grade neuroepithelial tumor with two distinct BCOR mutations, exceptionally long complete remission and survival. Pediatr Blood Cancer. 2020; 67:e28384. DOI