发生于脊柱的颅内间叶性肿瘤（FET::CREB 融合阳性）：两例报告Intracranial mesenchymal tumor, FET::CREB fusion-positive, presenting in the spinal column: A report of two cases

Scope: PMC open-access full text (CC BY-NC-ND 4.0) — clinical history and imaging, findings, discussion and author contributions, with Figures 1–2. This case letter has no abstract; the data availability statement and references are not included (citation numbers are retained in the text).

CLINICAL HISTORY AND IMAGING

Here, we report two patients with intradural extramedullary masses in the spine. Patient #1 is a 64‐year‐old male who presented with lymphadenopathy and was found to have an intradural extramedullary mass in the cervical spine. The lymphadenopathy was confirmed to be metastatic disease, and he experienced multiple episodes of local and distant recurrence, requiring multiple surgeries. Notably, systemic imaging was negative for additional lesions outside of the spinal mass and cervical lymphadenopathy. The tumor was initially favored to be a metastatic meningioma. Patient #2 is a 59‐year‐old female who presented with difficulties walking and paresthesia. She was found to have an intradural extramedullary mass in the thoracic spine. The mass was resected, and a diagnosis of meningioma was issued at the time. The tumor recurred a few years later and was re‐resected. At presentation for both patients, magnetic resonance imaging (MRI) of the spine showed solitary contrast enhancing lesions which were favored to be meningiomas by radiology (Figure 1).

FINDINGS

Histopathologic examination revealed very different morphology between the two patients, but the morphologic and immunohistochemical findings were fairly consistent between recurrences. For patient 1, the neoplasm was metastatic to a regional cervical lymph node and was composed of monotonous cells with round nuclei, finely granular chromatin, and small nucleoli with amphophilic to clear cytoplasm (Figure 2A,C). For patient 2, much of the tumor showed pseudovascular architecture with moderate atypia, with more focal areas of more lobular growth and syncytial cytoplasm (Figure 2B,D). Meningothelial whorls were not seen in either case. The Ki‐67 proliferation indices ranged from 20% to 30%, with mitotic rates between 7 and 14 mitoses in 10 consecutive high‐powered fields. On immunohistochemistry, both cases showed diffuse positivity for vimentin and CD99, patchy positivity for EMA (Figure 2F), and focal positivity for desmin. The tumor from patient 1 additionally showed strong patchy positivity for pancytokeratin (Figure 2E) and Cam5.2. The neoplasms were both essentially negative for progesterone receptor and SSTR2. Additionally, the tumors were negative for GFAP, OLIG2, synaptophysin, INSM1, inhibin, calretinin, and SF1. Whole‐transcript RNA sequencing demonstrated the presence of an EWSR1::CREM fusion in the tumor from patient #1 and an EWSR1::ATF1 fusion in the tumor from patient #2.

DNA methylation array classification for patient #1 showed no matching classes on the DKFZ v12.8 or NCI/Bethesda v2.0 classifiers, but some of the NCI/Bethesda subanalyses and the UMAP embedding suggested intracranial mesenchymal tumor, subtype A. For patient #2, the tumor showed a low‐confidence match for meningioma on the DKFZ v12.8 classifier and a moderate‐confidence match for intracranial mesenchymal tumor, subtype B, on the NCI/Bethesda v2.0 classifier. A final diagnosis of central nervous system mesenchymal tumor with FET::CREB fusion, not elsewhere classified (NEC), was eventually issued in both cases. The NEC designation was applied due to the extracranial location.

DISCUSSION

Intracranial mesenchymal tumors with FET::CREB fusions are rare neoplasms of the central nervous system (CNS) that have been previously described as “intracranial angiomatous fibrous histiocytoma” or “intracranial myxoid mesenchymal tumor.” This tumor type, now termed intracranial mesenchymal tumor, FET::CREB fusion‐positive (ICMT), was introduced as a provisional entity in the “Mesenchymal, Non‐Meningothelial Tumors” section of the 2021 edition of the WHO Classification of Tumors of the Central Nervous System (CNS) [1]. The morphologic patterns are broad and often include angiomatoid, epithelioid, or myxoid. The immunohistochemical profile is often non‐specific, with variable positivity for desmin, CD99, and EMA reported.

FET::CREB fusions are found in a wide variety of soft tissue tumor entities. The pathogenesis involves in‐frame gene fusions of a FET‐family RNA‐binding protein (EWSR1 or FUS) and a transcription factor from the cAMP response element binding protein (CREB) family, such as ATF1, CREB1, and CREM, which are all functionally related. CREB signaling plays an important role in multiple physiologic processes including the development of the nervous system and neuroplasticity [2]. The role these fusions play in oncogenesis is not entirely clear. CREB plays an important role in multiple physiological processes including the development of the nervous system but more importantly, its activation is directly linked to neuroplasticity which aids in learning and memory processing [3].

Currently, one of the essential diagnostic criteria defined by the 2021 WHO classification is that ICMTs are located intracranially (supratentorial or infratentorial). However, there are other rare reports of extracranial ICMTs. Sloan et al. [4] conducted an extensive study of FET::CREB fusion tumors with 20 patients, of whom 19 were intra‐axial or intraventricular, and one was in the spinal cord. The spinal cord presentation was in a 15‐year‐old female with a thoracic tumor with an EWRS1::CREM fusion; this patient experienced a local recurrence. Similarly, Tauziède‐Espariat et al. presented a cervical spinal ICMT with EWSR1::CREM fusion in a 35‐year‐old female [5], and Kim et al. and Seo et al. presented thoracic spinal ICMTs with the same fusion as well [6, 7]. A recent large series of ICMT also notes rare spinal presentations of this entity, accounting for approximately 6% of identified cases [8].

The previously reported extracranial ICMTs showed extra‐axial cervical and thoracic masses with contrast enhancement. Most cases exhibit histopathologic features characterized by predominantly epithelioid morphology, with cords and clusters of stellate to spindle cells in a mucin/myxoid‐rich background. The tumor cells in the prior three cases were positive for EMA and CD99, with variable staining for desmin. The expression of EMA can sometimes lead to a misdiagnosis of meningioma. The diagnostic dilemma with meningioma is further exacerbated by the absence of ICMT in DFKZ methylation classifier (as of version 12.8), where these tumors often show false matches of variable confidence to meningioma classes.

Here, we present two additional cases of extracranial “intracranial” mesenchymal tumors, which highlight the difficulties in diagnosing ICMT when these tumors present in extracranial locations and exhibit atypical morphologic features. The cases presented here contribute to the understanding that ICMT can occur throughout the neuroaxis and that the intracranial requirement for diagnosis may be unnecessary in future editions of the WHO classification.

AUTHOR CONTRIBUTIONS

S. Patel analyzed the data and wrote the draft. D Marker and T Pearce analyzed the data and reviewed the article. All authors approved the final version of the article.