Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

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Intracranial mesenchymal tumor with FET-CREB fusion - a unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

https://www.research.manchester.ac.uk/portal/files/87234084/1_s2.0_S1878875019305182_main.pdf

Intracranial Angiomatoid Fibrous Histiocytoma with EWSR1-CREB Family Fusions: A Report of 2 Pediatric Cases.

Angiomatoid fibrous histiocytoma (AFH) is a rare and slow-growing soft tissue lesion that typically arises in the extremities of young patients.

Microscopically, AFH is characterized by pseudovascular, blood-filled spaces that are surrounded by a multinodular proliferation of spindle and/or round cells and lymphoid cuffs. However, there is a wide morphological spectrum, including a myxoid variant. Examples with a prominent myxoid matrix are rare and may pose great diagnostic difficulty.

Specific gene fusions have been found to play a significant role in AFH tumorigenesis. Gene fusions of Ewing sarcoma breakpoint region 1 (EWSR1) with members of the cAMP response element-binding protein family (CREB) of transcription factors (CREB1, activating transcription factor 1 (ATF1), and cAMP response element modulator (CREM)) have been described in histopathologically diverse mesenchymal neoplasms such as AFH, hyalinising clear cell carcinomas of salivary glands, primary pulmonary myxoid sarcoma, and clear cell sarcoma. Classically, EWSR1-CREB is known to be the prominent gene fusion in AFH. Recently, a small series of intracranial mesenchymal tumors with EWSR1-CREB family gene fusions has been reported. These tumors seem to show histologic, immunophenotypic, and cytogenic features similar to those observed in the myxoid variant of AFH; therefore, there is a debate on whether these tumors merely represent a variant of AFH or a novel entity.

This case report is of a 58-year-old woman presenting with the first episode of generalized seizure due to an extra-axial lesion with homogenous contrast enhancement in the right parietal lobe, which was initially diagnosed as a World Health Organization (WHO) grade I meningioma. Following a series of pathological investigations, the diagnosis of an intracranial myxoid variant of AFH was made. This case report illustrates the need to consider the myxoid variant of intracranial AFH in the differential diagnosis of meningioma-like tumors. A high index of suspicion is required if the meningioma behaves abnormally with a much higher recurrence rate.

/pdf/intracranial-myxoid-variant-of-angiomatoid-fibrous-4hkd3jvbsv.pdf

Intracranial Myxoid Variant of Angiomatoid Fibrous Histiocytoma: A Case Report and Literature Review

Background The aim of this study was to highlight the clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma (PPAFH) to assist with a differential diagnosis. Methods There were 10 previous reports in the literature and four new PPAFH cases reviewed in this study. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and DNA and RNA-based next-generation sequencing (NGS) was performed in the four new cases reported here. Results In the four new PPAFH cases, the ages of occurrence were in patients age from 33 to 55 years and tumor sizes were from 1.5 to 8 cm. Three of four (75.0%) tumors were located in the endobronchus. The most common morphological changes included delineated fibrous capsule (100%, 4/4), lymphoplasmacytic cuff (100%, 4/4), and dense or richly lymphoplasmatic infiltration (100%, 4/4). IHC analysis revealed that the tumor cells of four cases expressed vimentin and TLE1, ALK and CD163 or CD68 was positive in three cases, epithelial membrane antigen (EMA), desmin was positive in two cases, and SMA focal positive expression was observed in two cases. EWSR1 gene rearrangement was positive in all PPAFH cases (100%, 4/4) by FISH detections and four cases were confirmed as EWSR1-CREB1 fusion variant by DNA and RNA based NGS. No regional lymph nodes and distal metastasis, recurrences and death of disease after surgical excision were recorded in all four cases. Conclusions PPAFH is a very unusual pulmonary primary mesenchymal tumor and the clinicopathological features are like other unusual sites counterparts, but with a smaller tumor size, related with large airway, with a tendency to exhibit benign biological behavior, with EWSR1 gene rearrangement and higher frequency of EWSR1-CREB1 gene fusion. Key points Significant findings in the study: In comparison with "classic somatic" and nonpulmonary visceral angiomatoid fibrous histiocytoma, pulmonary primary angiomatoid fibrous histiocytoma display distinct clinicopathological features and prognosis. What this study adds The study provided the pathological differential diagnostic criteria and clinico-pathological features for pulmonary primary angiomatoid fibrous histiocytoma.

Distinct clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma: A report of four new cases and review of the literature.

Broadening the Age of Incidence of Intracranial Angiomatoid Fibrous Histiocytoma With EWSR1-CREM Fusion: A Case Report.

Angiomatoid fibrous histiocytoma (AFH) is a tumour primarily occurring in the extremities which can very rarely occur as an isolated intracranial lesion. We report a case of a 22-year-old woman presenting with generalized seizure and visual field deficit due to an occipital mass, which immunohistochemistry showed to be an AFH.

Lisa Lyons

Papers

Primary intracranial angiomatoid fibrous histiocytoma: a case report and literature review.