Diagnosis and Discussion:

Integrated diagnosis: Intracranial mesenchymal tumor  (IMT)

Histopathological diagnosis: Overall histopathological features favor CNS Mesenchymal tumor

CNS WHO grade: Not assigned​

Molecular Information: EWSR1::CREM fusion identified.​

Intracranial mesenchymal tumor is  a recently described (a provisional entity), primary intracranial mesenchymal neoplasm usually children and young adults characterized by fusion of a FET RNA-binding protein family gene (usually EWSR1, rarely FUS) with a member of the CREB family of transcription factors (CREB1, ATF1, or CREM) with variable histomorphology and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The identified fusions on sequencing included EWSR1::ATF1, EWSR1::CREB1, EWSR1::CREM, FUS::CREM and SMARCA2::CREM and are divided into 2 subclasses A (mostly EWSR1-ATF1 and EWSR1-CREB1 fusions) and B (enrichment for tumors with CREM as the fusion partner, either EWSR1-CREM or FUS-CREM).  In this case, a MAP2k1 mutation was also present and is of unclear significance. 

Epidemiology

Most cases have been reported in children or young adults, although occasional cases in adults in their fifties and sixties have been recognized.

Clinical presentation

Symptoms from mass effect and specific location occur, including headache, nausea, vomiting, tinnitus, and occasionally seizures or focal neurological deficits. Hemorrhage may occur.  Patients may suffer from anemia. 

Anatomical localization:

Most tumors are extra-axial and more commonly supratentorial.  Locations reported include cerebral convexities, attachment to the meninges, tentorium, cerebellopontine angle, or spinal cord.  Intraventricular examples (like with meningiomas) occur. 

Radiology

IMT tumors are usually circumscribed, extra-axial tumors with dural attachment and compression of the subjacent brain parenchyma. Lobulated growth (often with both solid and cystic components), avid enhancement after contrast administration intratumoral blood products, and substantial peritumoral oedema are other radiological findings. Features mimicking a meningioma on radiology (enhancing dural tail, bony involvement of the overlying skull) may cause difficulties with definitive diagnosis. 

Etiology and Pathogenesis:

At this time, the etiology is unknown and the cell of origin has not been identified.  There is no known association with familial tumor predisposition syndromes.  These tumors harbor fusion of a FET RNA-binding protein family gene (mostly EWSR1) with a member of the CREB family of transcription factors: CREB1, ATF1 or CREM.  The FET::CREB fusion is recognized in many different extracranial neoplasms, including angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue, hyalinizing clear cell carcinoma, of the salivary gland, and gastrointestinal clear cell sarcoma.  The current relationship of IMT to these tumors is unknown. 

Gross findings:

Tumors are combined solid and cystic masses, partially encapsulated, tan-brown in color, with focal areas of hemorrhage and gelatinous components. 

Histologic features:

Histologically, patterns can vary from epithelioid/rhabdoid cells to stellate/spindle cells .  Meningiothelial-like whorls may be present.  Aggregates of thin-walled vessels (like in hemangioma) are frequent.   Usually, a collagenous stroma is present.  Many examples contain a myxoid stroma.  Dense lymphoplasmacytic cuffing at the tumor periphery (mimicking a lymph node) is a frequent finding.  Architecture can vary significantly within a single tumor. 

Immunohistochemistry/Histochemistry: 

Desmin and CD99 are usually positive. Alcian Blue stains the myxoid areas.   EMA can be positive, but the tumors are consistently negative for SSTR2A.  Glial markers, melanoma markers, and cytokeratins are negative.  INI-1 and SMARCA4 (BRG1) expression is retained.  A low proliferation index (Ki-67) is typical.   

Differential diagnosis:

The differential diagnosis includes other meningeal-based neoplasms, especially meningioma.   Sarcomas may also enter the DDx, especially rhabdomyosarcoma.  The presence of characteristic histopathology and a recognized gene fusion is required for definitive diagnosis. 

Prognosis:

Intracranial mesenchymal tumor has two prognostically relevant methylation subclasses.   It has been reported that patients with methylation subclass B tumors have shorter progression‐free survival relative to subclass A tumors (median 4.5 vs. 49 months, p = 0.001). Given the relative nascent recognition of this tumor, the full-spectrum of its  clinical behavior is not completely elucidated, but is known to range from slow growth to rapid recurrences and rarely, cerebrospinal fluid dissemination or systemic metastases, including pulmonary and thoracic lymph nodes or bony metastases to the spine.  Subtotal resection as well as infratentorial location are adverse prognostic factors.   

References:

1. Intracranial mesenchymal tumour, FET::CREB fusion-positive. The 2021 Who classification of the central nervous system (5^th ed.). IARC Press.  Lyon, Fr. 2021

2. Sloan EA 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 Jan 28;31(4):e12918. doi: 10.1111/bpa.12918

3. Rajan S. et al. Intracranial mesenchymal tumor, FET::CREB fusion-positive: an integrative analysis of 81 cases. Neuro Oncol. 2026 Jan 22:noag001.doi: 10.1093/neuonc/noag001.

4. Komatsu M. et. al. Intracranial myxoid mesenchymal tumor with EWSR1-CREB1 gene fusion: a case report and literature review. Brain Tumor Pathol. 2020 Apr;37(2):76-80.