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Diagnosis and Discussion: Case 1148

Final Diagnosis

Primary central nervous system mesenchymal tumor with FET::CREB fusion, NEC*

*not else classified (NEC) designation due to extracranial location

Discussion

Intracranial mesenchymal tumor (IMT) with a FET-CREB fusion is a rare neoplasm of the central nervous system (CNS) that has been previously described as intracranial angiomatous fibrous histiocytoma.

Clinically, these tumors produce mass effect symptoms depending on the location. Symptoms that are reported include headache, nausea, vomiting, tinnitus, seizures, and focal neurological deficits. Most cases occur in children or young adults, although cases in adults in their 6th and 7th decades have been reported [1]. Currently the WHO 2021 edition defines these tumors as “intracranial” and are seen mostly extra-axially or intraventricularly. MRI demonstrates a circumscribed extra-axial neoplasm with attached to meninges or dura with compression of adjacent brain, often mimicking meningioma [2].

This tumor is characterized at the molecular level by an in-frame gene fusion involving FET family RNA-binding proteins (EWSR1 or FUS) and transcription factors from the CREB family, such as ATF1, CREB1, and CREM [3, 4]. FET-CREB fusions are seen in: angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma of soft tissue (CCS), 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 lacking BAP1 and NF2 alterations [5].

Histologically, these tumors demonstrate a wide morphological spectrum. The architecture ranges from syncytial or sheet-like growth to reticular cord-like structures, with a subset of tumors containing fibrous septa separating nodules of tumour cells. Tumour cell morphology is varied and may depend on gene fusion. CREB1 mutations show stellate and spindle-cell morphology with mucin-rich stroma or collagenous stroma. ATF1 mutations may show an epithelioid or rhabdoid morphology [5, 6]. The immunohistochemical profile is variable, with reported immunoreactivity for EMA, CD99 and desmin. Tumors are mostly negative for the following markers: meningothelial markers (SSTR2A), glial markers (OLIG2 and GFAP), keratins (CAM5.2) and muscle/vessel markers (myogenin, MYOD1, myoglobin, SMA, MSA and CD34), melanocytic markers (melan-A and HMB45), and STAT6.

In conclusion, this case demonstrates a rare presentation of an “extracranial” intracranial mesenchymal tumor. The following points can be considered: (1) The current 2021 WHO classification requires an intracranial location for the diagnosis of ICMT. This case is an example of a rare extracranial presentation of that entity. There are rare case reports of extracranial ICMTs, specifically, Tauziède-Espariat et al documents ICMT in the cervical region of the spinal cord with EWSR1::CREM gene fusion [7], (2) the morphology of these neoplasms is varied and can present as angiomatoid, epithelioid, or myxoid with a non-specific immunochemical staining pattern and lastly (3) DNA methylation array classification is not always reliable in identifying these tumors. Epigenetically, they closely resemble meningiomas, which can lead to diagnostic uncertainty unless fusion sequencing or alternative methylation classifiers are used.

References

  1. Komatsu M, Yoshida A, Tanaka K, Matsuo K, Sasayama T, Kojita Y, Kanda T, Kodama Y, Itoh T, Hirose T. Intracranial myxoid mesenchymal tumor with EWSR1-CREB1 gene fusion: a case report and literature review. Brain Tumor Pathol. 2020 Apr;37(2):76-80. doi: 10.1007/s10014-020-00359-x. Epub 2020 Mar 25. PMID: 32215804.
  2. Alshareef MA, Almadidy Z, Baker T, Perry A, Welsh CT, Vandergrift WA 3rd. Intracranial Angiomatoid Fibrous Histiocytoma: Case Report and Literature Review. World Neurosurg. 2016 Dec;96:403-409. doi: 10.1016/j.wneu.2016.09.059. Epub 2016 Sep 22. PMID: 27667574.
  3. Sciot R, Jacobs S, Calenbergh FV, Demaerel P, Wozniak A, Debiec-Rychter M (2018) Primary myxoid mesenchymal tumour with intracranial location: report of a case with a EWSR1-ATF1 fusion. Histopathology 72:880–883.
  4. Bale TA, Oviedo A, Kozakewich H, Giannini C, Davineni PK, Ligon K, Alexandrescu S (2018) Intracranial myxoid mesenchymal tumors with EWSR1-CREB family gene fusions. myxoid variant of angiomatoid fibrous histiocytoma or novel entity? Brain Pathol 28:183–191.
  5. Sloan EA, Chiang J, Villanueva-Meyer JE, Alexandrescu S, Eschbacher JM, Wang W, Mafra M, Ud Din N, Carr-Boyd E, Watson M, Punsoni M, Oviedo A, Gilani A, Kleinschmidt-DeMasters BK, Coss DJ, Lopes MB, Raffel C, Berger MS, Chang SM, Reddy A, Ramani B, Ferris SP, Lee JC, Hofmann JW, Cho SJ, Horvai AE, Pekmezci M, Tihan T, Bollen AW, Rodriguez FJ, Ellison DW, Perry A, Solomon DA. 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 Jul;31(4):e12918. doi: 10.1111/bpa.12918. Epub 2021 Jan 28. PMID: 33141488; PMCID: PMC8089120.
  6. Komatsu M, Yoshida A, Tanaka K, Matsuo K, Sasayama T, Kojita Y, Kanda T, Kodama Y, Itoh T, Hirose T. Intracranial myxoid mesenchymal tumor with EWSR1-CREB1 gene fusion: a case report and literature review. Brain Tumor Pathol. 2020 Apr;37(2):76-80. doi: 10.1007/s10014-020-00359-x. Epub 2020 Mar 25. PMID: 32215804.
  7. Tauziède-Espariat A, Pierron G, Guillemot D, Benevello C, Pallud J, Benzakoun J, Hasty L, Métais A, Chrétien F, Varlet P. An extracranial CNS presentation of the emerging "intracranial" mesenchymal tumor, FET: CREB-fusion positive. Brain Tumor Pathol. 2023 Jan;40(1):35-39. doi: 10.1007/s10014-022-00443-4. Epub 2022 Sep 15. PMID: 36107277.