Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 1174
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size

  Table of Contents    
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 94-98
Miscellaneous newly recognized types of CNS tumors in the WHO CNS5 classification (other than gliomas, glioneuronal and embryonal tumors)

Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Click here for correspondence address and email

Date of Submission24-Oct-2021
Date of Decision08-Dec-2021
Date of Acceptance10-Jan-2022
Date of Web Publication11-May-2022


In this review, we describe salient features of a few of the newer entities recognized in the fifth edition of World Health Organization (WHO) classification of central nervous system (CNS) tumors. While most of these have been offshoots of the deoxyribonucleic acid (DNA) methylation profiling of CNS tumors with distinct profiling such as desmoplastic myxoid tumor (DMT) of the pineal region, SMARCB1-mutant, these also demonstrate subtle, distinct morphological features, which should be carefully searched for to diagnose them.

Keywords: Newer entities in CNS tumors

How to cite this article:
Chatterjee D, Gupta K. Miscellaneous newly recognized types of CNS tumors in the WHO CNS5 classification (other than gliomas, glioneuronal and embryonal tumors). Indian J Pathol Microbiol 2022;65, Suppl S1:94-8

How to cite this URL:
Chatterjee D, Gupta K. Miscellaneous newly recognized types of CNS tumors in the WHO CNS5 classification (other than gliomas, glioneuronal and embryonal tumors). Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:94-8. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/94/345031

   Introduction Top

The fifth edition of World Health Organization (WHO) classification of central nervous system (CNS) tumors introduces new tumor types and subtypes, some based on novel diagnostic technologies such as deoxyribonucleic acid (DNA) methylome profiling. The article provides key features of a few newer entities in the non-glioma, glioneuronal tumors, and embryonal tumors group.

Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant

A desmoplastic myxoid tumor (DMT), SMARCB1 mutant, is a recently recognized tumor entity that characteristically occurs in the pineal region.[1] Although there are only a few reported cases of this entity, DMT shows characteristic clinical, histological, and molecular features.[2]

DMT occurs over a wide age range. Thomas et al.[2] (2020) reported seven cases of DMT, the age ranged from 15 to 61 years. It can affect both genders equally. All published cases of DMT are reported in the pineal region.[2],[3],[4]

DMT is unencapsulated and shows variable histomorphology[2] with a combination of myxoid areas admixed with desmoplastic stroma. The tumor cells are arranged as small clusters, single-cell patterns, or in cords. A focally whorling pattern of arrangement may be seen. The tumor cells are oval to spindled to epithelioid in shape and show a moderate amount of cytoplasm. Mitosis is usually infrequent. The cells are embedded in a pale, basophilic myxoid matrix. However, Matsumura et al.[4] described a case of DMT without the presence of myxoid stroma. The presence of rhabdoid cells is very rarely reported.[2] Other common features include the presence of thick-walled, hyalinized, and elongated blood vessels and focal calcification. Mitotic activity is very low (<1/10 high power fields (HPF)). Lymphocytic infiltrate within the desmoplastic stroma is a prominent finding.[2]

The tumor cells show strong membranous positivity for epithelial membrane antigen (EMA) and diffuse cytoplasmic vimentin expression. They are negative for cytokeratin, glial fibrillary acidic protein (GFAP), and brachyury. They show a strong and diffuse cluster of differentiation 34 (CD34) expression.[2] Also characteristically they show loss of nuclear INI-1 expression while being retained in the endothelial cells and the infiltrating lymphocytes, which act as an internal control. Kiel-67 (Ki-67) proliferation index is usually low (<3%).[2] However, some cases may show elevated proliferation index.[4]

SMARCB1 gene deletion (homozygous or heterozygous) is the genetic alteration noted in most cases. They do not show EWSR1 gene rearrangement. On methylation profiling, this tumor shows similarity with the atypical teratoid rhabdoid tumor (ATRT-MYC) cluster.[2]

The clinical behavior of this tumor is not very well known as only very few cases have been reported in the literature. Thomas et al.[2] reported that out of seven patients in their series, three were alive with stable disease at 4 years, one patient had disease progression, and three patients died.

Primary intracranial sarcoma, DICER mutated

The common mesenchymal tumors that involve CNS are meningiomas and solitary fibrous tumor/hemangiopericytoma (SFT/HPC), both of which primarily affect the leptomeninges. Other mesenchymal tumors can be rarely seen in the CNS, especially in children.[5] There are rare reports of sarcomas of various lineages, such as rhabdomyosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, Ewing's sarcoma, angiosarcoma, etc., arising in the intracranial location. However, many a times, sarcomas in the intracranial location do not show any specific lineage of differentiation and are hence reported as sarcoma, not otherwise specified.

Based on the methylation profile of a wide range of intracranial neoplasms, a group of mesenchymal tumors was identified showing a methylation profile similar to rhabdomyosarcoma of the uterus. Hence, they were initially described as primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features.[6],[7] On performing next-generation sequencing, however, these cases were found to have a high frequency of DICER1 gene mutation. Subsequently, based on further reports and extended immuno-profiling, this group of tumors was named as primary intracranial sarcoma, DICER1 mutated.[1],[7]

The DICER1 gene is located on chromosome 14q32.12 and encodes an RNA endoribonuclease. This is involved in the production of microRNA and thus plays an important role in gene expression.[8] DICER1 gene mutation has been described in various benign and malignant tumors, such as pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, etc. Germline DICER1 mutation, also known as DICER1 syndrome, is associated with an increased risk of developing various benign and malignant neoplasms.[9]

Primary intracranial sarcoma, DICER1 mutated is seen mostly in children (median age 6 years), although it can affect patients over a wide age range. Both genders are almost equally affected. The preferred site is in a supratentorial location and is located intra-axially.[6] They can be seen in the setting of neurofibromatosis type 1.[10]

The histological examination shows a wide variation of morphology. The commonest pattern of growth is “patternless,” followed by fascicular growth, whorling, and sheeting pattern. The individual cells are oval to spindle-shaped, and show frequent mitosis. Koelsche et al.[6] in their original description, reported the presence of rhabdomyoblasts or rhabdomyoblast-like cells in all cases. However, Lee et al.[10] did not identify ant strap cell or rhabdomyoblast in their series. Rather, they described the presence of intracytoplasmic eosinophilic globules in all three cases. Necrosis is a common finding. Focal cartilaginous differentiation may be seen in some cases but other heterologous differentiation such as adipocytic or osteoid differentiation are not reported. These cases were initially diagnosed as pleomorphic sarcoma, not otherwise specified, or embryonal rhabdomyosarcoma.[6]

This tumor shows variable immunoprofile. Desmin is usually expressed in the majority of cases (patchy), while myogenin and smooth muscle actin positivity may be seen in a minority of cases. They are negative for GFAP, cytokeratin, EMA, S100, CD34, and oligodendrocyte transcription factor 2 (OLIG2). Expression of P53 is usually diffuse.[6],[7],[10] Alexandrescu et al.[11] explored further molecular and immunohistochemical aspects of this tumor and reported patchy to diffuse loss of H3K27me3 expression and nuclear transducin-like enhancer 1 (TLE1) expression in all their cases.

These cases show frequent DICER1 mutation, most of which are missense types. They can also show KRAS, NF1, NRAS, and FGFR4 gene mutation in variable frequency. Epidermal growth factor receptor (EGFR) amplification has also been described. TP53 mutation is a frequent finding.[6] These are associated with an aggressive clinical course. However, since there are very few reported cases and long-term follow-up information is lacking in most of the studies, further biological and clinical information is required to predict the outcome of this entity.

Intracranial mesenchymal tumor, FET-CREB fusion-positive

Fusion of FET (FUS, EWSR1, and TAF15) family of RNA-binding proteins (EWSR1 or FUS) to the CREB (cyclic AMP response element-binding protein) family of transcription factors, which includes activating transcription factor 1 (ATF1), CREB1, and cAMP-responsive element modulator (CREM), results in the development of a spectrum of mesenchymal tumors, which shows a wide variation in presentation, location, and morphology. The tumors showing this genetic fusion include angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma of soft tissue, clear cell sarcoma of the gastrointestinal tract, primary pulmonary myxoid sarcoma, hyalinizing clear cell carcinoma of the salivary gland, and a subset of malignant mesotheliomas.[12],[13],[14],[15],[16] The clinical behavior of these entities is highly variable, ranging from benign to highly aggressive malignant tumors. In recent times, FET-CREB fusion has been described in intracranial tumors as well. These tumors were variably named as intracranial AFH or intracranial myxoid mesenchymal tumor (IMMT).[17],[18] Kao et al.[17] reported four young patients with IMMT (two intra-axial and two meningeal), out of which one showed EWSR1-CREM fusion, one displayed EWSR1-ATF1 fusion, and two showed EWSR1-CREB1 gene fusions. Subsequently, Bale et al.[18] reported three cases of IMMT in young patients showing EWSR1-CREB family gene fusion. Based on the morphological, immunohistochemical, and molecular features, they proposed that this tumor may represent a myxoid variant of AFH or could be a novel entity. It was further realized that these entities share similar histologic, clinical, and molecular features, hence they are now termed as an intracranial mesenchymal tumor, FET-CREB fusion-positive.[1],[19]

Intracranial mesenchymal tumor, FET-CERB positive is usually seen in children and young adults (median age 17 years), although it has been rarely described in the older age group. There is a female predilection. They are mostly extra-axial, seen in the meninges or intraventricular location. Most of the reported cases are in the supratentorial location, although other sites like cerebello-pontine angle, and the spinal cord may be involved. Radiologically, they appear as circumscribed, lobulated mass with solid-cystic appearance, showing uniform contrast enhancement. A dural tail may be observed, resembling meningioma.[19]

These tumors show a wide histologic spectrum. They have a lobulated or sheet-like arrangement of cells, the lobules being separated by thick fibrous septa. There is an abundant matrix, which includes a combination of thick collagenous to abundant myxoid stroma; however, the stromal component may be lacking in some cases. The tumor cells are round, oval, spindled to stellate shaped, some cases may exhibit epithelioid/rhabdoid morphology. Mitotic activity is usually low and necrosis is an uncommon finding. Whorling may be seen in some cases, resembling meningioma. Occasional cases show epithelioid tumor cells arranged in cords in a myxoid stroma, mimicking chordoid meningioma. Other findings include dense lymphoplasmacytic cuffing at the periphery of the tumor, collection of dilated and thin-walled blood vessels, and hemosiderin deposition, indicating prior intratumoral hemorrhage. Blood-filled pseudoangiomatous spaces, which are seen in extra-cranial soft tissue AHF, are not seen in this group of tumors.[18],[19] Sloan et al.[19] described some of the morphological features more commonly associated with specific gene fusions. Tumors with EWSR1-ATF1 fusion commonly show epithelioid/rhabdoid morphology while tumors with EWSR1-CREB1 fusion frequently show mucin-rich stroma, stellate/spindle cell morphology, and hemangioma-like vessels.

These tumors show desmin, CD99, and EMA expression, while S100, CD68, and synaptophysin expression is variable.[19] Bale et al.[18] described diffuse GLUT-1 expression in their series. They are negative for GFAP, myogenin, and human melanoma black-45 (HMB-45). INI-1 expression is retained. Ki-67 labeling index is usually low (<5%).

These tumors show variable prognoses. Local recurrence is common, especially in cases with incomplete resection. The median overall survival is greater than 60 months and the 5-year survival rate is approximately 91%.[19]

CIC-rearranged sarcoma

Capicua transcriptional repressor (CIC)-rearranged sarcomas which commonly arise in the deep soft tissue,[20] may sometimes involve the neuraxis.[21] Irrespective of location, these uniformly contain an oncogenic gene fusion of CIC transcriptional repressor with various partners including DUX4 (commonest), FOXO4, LEUTX, NUTM1, or NUTM2A.[22],[23] The majority of CNS CIC-rearranged sarcoma fusions are associated with NUTM1 in comparison to peripheral tumors which show CIC-DUX4 rearrangement.[23] They have a preference for adolescents and young adults, but can be seen in older patients also. They arise in both cranial and spinal compartments.[24]

The histological features are similar to the extra-cranial counterparts. They are composed of sheets of highly undifferentiated small round cells arranged in variably lobulated growth patterns, and desmoplastic stroma.[24] The tumor cells are round cells interspersed with epithelioid/spindle cell morphology as well. They have prominent nucleoli and eosinophilic cytoplasm. Myxoid change in the background stroma is common. Foci of necrosis may be encountered. Interestingly, regardless of the fusion partner of the CIC gene, the morphology remains the same.[23],[25]

CNS CIC-rearranged sarcomas express patchy and weak CD99 with variable immunoreactivity for WT1 and ETV4.[24] NKX2-2 is typically negative, which helps in distinguishing these tumors from Ewing sarcoma. Sarcomas with CIC-NUTM1 fusion express NUT protein. INI-1 expression is retained and helps in excluding ATRT.

The current data on these tumors is not adequate enough to reliably predict their biological behavior, however, the soft tissue examples are characterized by a highly aggressive course.[26]

   Conclusions Top

In summary, we have described the salient features of some rare and newly recognized entities enlisted in the WHO CNS 5 classification and discussed their differentials [Table 1] each of which has distinct molecular alterations and subtle specific morphological features; awareness regarding which is essential for their diagnosis.
Table 1: Salient features of rare and newly recognized entities enlisted in the WHO CNS 5 classification

Click here to view

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.  Back to cited text no. 1
Thomas C, Wefers A, Bens S, Nemes K, Agaimy A, Oyen F, et al. Desmoplastic myxoid tumor, SMARCB1-mutant: Clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults. Acta Neuropathol 2020;139:277-86.  Back to cited text no. 2
Wang YE, Chen JJ, Wang W, Zhang AL, Zhou W, Wu HB. A case of desmoplastic myxoid tumor, SMARCB1 mutant, in the pineal region. Neuropathology 2021;41:37-41.  Back to cited text no. 3
Matsumura N, Goda N, Yashige K, Kitagawa M, Yamazaki T, Nobusawa S, et al. Desmoplastic myxoid tumor, SMARCB1-mutant: A new variant of SMARCB1-deficient tumor of the central nervous system preferentially arising in the pineal region. Virchows Arch 2021;479:835-9.  Back to cited text no. 4
Al-Gahtany M, Shroff M, Bouffet E, Dirks P, Drake J, Humphreys R, et al. Primary central nervous system sarcomas in children: Clinical, radiological, and pathological features. Childs Nerv Syst 2003;19:808-17.  Back to cited text no. 5
Koelsche C, Mynarek M, Schrimpf D, Bertero L, Serrano J, Sahm F, et al. Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations. Acta Neuropathol 2018;136:327-37.  Back to cited text no. 6
Sakaguchi M, Nakano Y, Honda-Kitahara M, Kinoshita M, Tanaka S, Oishi M, et al. 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;36:174-82.  Back to cited text no. 7
Foulkes WD, Priest JR, Duchaine TF. DICER1: Mutations, microRNAs and mechanisms. Nat Rev Cancer 2014;14:662-72.  Back to cited text no. 8
Robertson JC, Jorcyk CL, Oxford JT. DICER1 syndrome: DICER1 mutations in rare cancers. Cancers (Basel) 2018;10:143.  Back to cited text no. 9
Lee JC, Villanueva-Meyer JE, Ferris SP, Sloan EA, Hofmann JW, Hattab EM, et al. 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;137:521-5.  Back to cited text no. 10
Alexandrescu S, Meredith DM, Lidov HG, Alaggio R, Novello M, Ligon KL, et al. Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin-like enhancer 1 in primary intracranial sarcoma, DICER1-mutant. Histopathology 2021;78:265-75.  Back to cited text no. 11
Antonescu CR, Katabi N, Zhang L, Sung YS, Seethala RR, Jordan RC, et al. EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosomes Cancer 2011;50:559-70.  Back to cited text no. 12
Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: A recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res 2006;12:5356-62.  Back to cited text no. 13
Jeon YK, Moon KC, Park SH, Chung DH. Primary pulmonary myxoid sarcomas with EWSR1-CREB1 translocation might originate from primitive peribronchial mesenchymal cells undergoing (myo) fibroblastic differentiation. Virchows Arch 2014;465:453-61.  Back to cited text no. 14
Rossi S, Szuhai K, Ijszenga M, Tanke HJ, Zanatta L, Sciot R, et al. EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res 2007;13:7322-8.  Back to cited text no. 15
Kao YC, Lan J, Tai HC, Li CF, Liu KW, Tsai JW, et al. Angiomatoid fibrous histiocytoma: Clinicopathological and molecular characterisation with emphasis on variant histomorphology. J Clin Pathol 2014;67:210-5.  Back to cited text no. 16
Kao YC, Sung YS, Zhang L, Chen CL, Vaiyapuri S, Rosenblum MK, et al. EWSR1 fusions with CREB family transcription factors define a novel myxoid mesenchymal tumor with predilection for intracranial location. Am J Surg Pathol 2017;41:482-90.  Back to cited text no. 17
Bale TA, Oviedo A, Kozakewich H, Giannini C, Davineni PK, Ligon K, et al. Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions: Myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol 2018;28:183-91.  Back to cited text no. 18
Sloan EA, Chiang J, Villanueva-Meyer JE, Alexandrescu S, Eschbacher JM, Wang W, et al. 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:e12918.  Back to cited text no. 19
Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 2006;15:2125-37.  Back to cited text no. 20
Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 2016;164:1060-72.  Back to cited text no. 21
Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre JM, et al. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 2012;51:207-18.  Back to cited text no. 22
Le Loarer F, Pissaloux D, Watson S, Godfraind C, Galmiche-Rolland L, Silva K, et al. Clinicopathologic features of CIC-NUTM1 sarcomas, a new molecular variant of the family of CIC-fused sarcomas. Am J Surg Pathol 2019;43:268-76.  Back to cited text no. 23
Yamada S, Muto J, De Leon JCA, Kumai T, Ito K, Murayama K, et al. 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;37:111-7.  Back to cited text no. 24
Sugita S, Arai Y, Aoyama T, Asanuma H, Mukai W, Hama N, et al. NUTM2A-CIC fusion small round cell sarcoma: A genetically distinct variant of CIC-rearranged sarcoma. Hum Pathol 2017;65:225-30.  Back to cited text no. 25
Antonescu CR, Owosho AA, Zhang L, Chen S, Deniz K, Huryn JM, et al. 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;41:941-9.  Back to cited text no. 26

Correspondence Address:
Kirti Gupta
Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1038_21

Rights and Permissions


  [Table 1]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Article Tables

 Article Access Statistics
    PDF Downloaded18    
    Comments [Add]    

Recommend this journal