Mesenchymal tumors are rare soft connective tissue neoplasms (1, 2). These tumors may arise in all organs originating from mesodermal precursor cells and also in the central nervous system (CNS), specifically from the meninges and rarely from CNS parenchyma (2, 3).

The FET family (usually EWSR1, less frequently FUS) gene’s rearrangements with CREB family genes (CREB1, ATF1, and CREM) have been identified as characterizing a specific group of mesenchymal tumors called angiomatoid fibrous histiocytomas (AFH) (4). These are uncommon soft tissue tumors (typically found in the limbs, hands feet, or pelvis of children and young adults), with an incidence of < 0.5% and are classified as low-intermediate growing neoplasms with a favorable prognosis (2, 5).

More recently, intracranial AFH has been described as an intracranial mesenchymal tumor (6–8). AFH is usually treated with surgical removal, and only in cases of incomplete resection may adjuvant radiation therapy or chemotherapy be necessary (5). We hereby present a unique case of an intracranial mesenchymal tumor with EWSR1::CREM fusion transcript with extra CNS metastatic spreads, treated with different local and systemic therapies, leading to prolonged complete remission of the disease after two years of treatment discontinuation and after eight years from tumor diagnosis.

A 27-year-old woman was admitted to an outside hospital’s emergency department due to a headache and vomiting. She had no previous medical history or family history of cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a mass on the right cerebellum that involved the transverse venous sinus ( Figure 1 ). She underwent a partial resection, and the histological diagnosis highlighted a medulloblastoma. Following the diagnosis, the patient was referred to our center. The revised histological findings suggested the possibility of a high-grade glioneuronal tumor (HGG), which was later confirmed after a total secondary resection. Proton beam therapy (PBT) was administered at the surgical site with a total planned dose of 54 Grays (Gy) in 25 sessions, along with concomitant (75 mg/mq/day during PBT) and adjuvant (200 mg/mq/day for five days per month for six months) oral temozolomide. Subsequent MRIs showed complete remission of the disease. After 18 months from the suspension of treatment, a cerebral MRI revealed a local relapse at the surgical site ( Figure 2 ). During the diagnostic workup, two metastatic lung lesions (the larger in the upper lingula segment) were discovered with suspicion of a lesion in the right iliac bone ( Figures 3 , 4 ). The iliac bone biopsy confirmed the diagnosis of HGG, with 40% PD-1 expression on lymphocytes and 30% PD-L1 expression on neoplastic cells ( Figure 5 ). Subsequently, immunotherapy with intravenous nivolumab (3 mg/kg/day) was started every two weeks and continued for two years without any reported toxicity. The patient achieved complete remission in all sites ( Figure 4D ), which was confirmed by a biopsy of the lesion in the right iliac bone, which showed only inflammatory tissue without evidence of neoplastic infiltration. After six months of discontinuing therapy, CT and a positron emission tomography (PET) scan revealed a relapse in the lung lesion and in the right iliac bone lesion ( Figures 3A , 4 ). A biopsy of this bone mass and a review of the previous cerebellar lesion allowed for a reevaluation of the entire case. Morphological features were similar in the primary and metastatic lesions: the tumor consisted of sheets of epithelioid cells with abundant eosinophilic to clear cytoplasm, large nuclei, and prominent nucleoli and showed a marked lymphoplasmacytic infiltrate at the periphery ( Figures 5A, B ). Mitoses were brisk (three mitoses/mm²), and the Ki67 proliferation index was approximately 15%. Although myxoid stroma and blood-filled cystic spaces were not prominent features, the expression of CD99 (membranous), GLUT-1 with a prominent paranuclear/Golgi pattern, focal EMA, and focal GFAP and synaptophysin raised a suspicion of an unusual mesenchymal tumor ( Figure 5 ). A next-generation sequencing (NGS) panel (Archer Custom Fusion Plex Kit, Integrated DNA Technologies, IA) identified the presence of the EWSR1::CREM fusion transcript on both the primary tumor and the metastasis, confirming the diagnosis of metastatic intracranial mesenchymal tumor FET::CREB fusion-positive. ( Figure 6 ).

In accordance with these findings, fluorescent in situ hybridization (FISH) demonstrated the rearrangement of EWSR1.

Additionally, a blood test for cancer predisposition syndromes was conducted using the Twist Custom Panel, which includes assessments for CTNNB1, SMO, PIK3CA, PTEN, ID1, FGFR1, ARID1A, SMARCA4, CHD7, KDM4C, MYC, MYCN, MSH2, TP53, SUFU, PTCH1, PTCH2, ARID1B, and ERBB2 alterations, and no pathogenic/likely pathogenic variants were identified. Based on the previous clinical response to nivolumab, we decided to start a rechallenge treatment. After two cycles, nivolumab was prematurely discontinued due to the development of grade 2 immuno-mediated pneumonia, leading to a decrease in the patient’s performance status (ECOG 2) and iliac bone and lung disease progression. Consequently, PBT was performed on the right iliac bone lesion (with a total planned dose of 59.4 Gy in 48 sessions) with a complete surgical removal of the lung lesion. Thereafter, the patient received consolidation therapy with eight cycles of temozolomide plus irinotecan, achieving a complete remission of the disease.

She is currently still in complete remission with an optimal quality of life, nine years after diagnosis and two years after discontinuation of therapy ( Figure 7 ).

AFH is a rare mesenchymal tumor (0.3% of all soft tissue tumors) (3), defined by a fusion of a FET family gene (usually EWSR1, but rarely FUS) with members of the cAMP Response Element-Binding Protein family (ATF1, CREB1, or CREM) (9). These specific gene fusions play a key role in AFH tumorigenesis (9–11). In 1979, Enzinger described “angiomatoid malignant fibrous histiocytoma” as a new histological entity for the first time (12, 13). Although AFH has been known for more than 40 years, only in 2021 was it included in the WHO CNS classification as an intracranial mesenchymal tumor (13). In fact, AFH usually occurs in the extremities of young adults, more frequently in the second decade of life, with a female prevalence, and is rarely diagnosed in the CNS (14, 15). Clinically, patients with AFH can experience, in addition to local symptoms, systemic non-specific signs such as fever, anemia, and weight loss (6, 7, 16). Regional recurrence rates after surgery are relatively low (approximately 15%), but AFH can occasionally metastasize (the most common sites are lymph nodes, lungs, and liver), especially if it is not completely removed (5, 16).

CNS-AFH represents a rare primary site ( Tables 1 , 2 ), and the longest patient outcomes reported in the literature are five years with a median progression-free survival of 28 months (8, 9, 11). Patients with subtotal resection showed a local recurrence within 12 months. At microscopic histology examination, AFH is characterized by multinodular proliferation of spindle-shaped, or round cells with syncytial growth, forming bundles surrounded by fibrous pseudocapsules, pericapsular lymphoplasmacytic cuffing, and pseudovascular spaces full of blood. Most AFH cases express desmin but lack positivity for myogenin or MyoD, EMA, and CD68 (4, 29). Regrettably, the definitive histological diagnosis of AFH still presents a challenge (3). In the literature, several unusual clinicopathological presentations and histological variants are described (7, 9). The intracranial mesenchymal tumor is one of these variants, characterized by a prominent collagenous stroma with a dense intracellular matrix resembling the myofibroblastic tumor, poorly differentiated carcinoma, or meningioma. Not all cases contain a myxoid matrix (1, 3, 10).

The intracranial mesenchymal tumor’s radiological aspect shows hypointense T1 signal and hyperintense T2 signal lesions with strong enhancement after gadolinium administration (10). Differential diagnoses include meningioma and schwannoma ( Table 3 ) because intracranial mesenchymal tumors mimic an extra-axial lesion with homogeneous contrast enhancement and a small dural tail in T1 fluid-attenuated inversion recovery (FLAIR) (3). Furthermore, the expression of glial and neural markers is a pitfall for glial and glioneuronal tumors.

Tauziède-Espariat et al. described 11 cases of CNS mesenchymal tumors with FET::CREB fusion. Six in total were a specific cluster with DNA methylation, and five showed no relation to any of the other classes but were similar to the clusters of extra-CNS angiomatoid fibrous histiocytomas, clear cell sarcomas, or solitary fibrous tumors. Therefore, the authors demonstrated that intracranial FET::CREB-fused tumors did not present a single molecular tumor entity but a primary intracranial mesenchymal tumor, the FET::CREB-fused family (4). Several other authors reported small groups of intracranial mesenchymal cases: Kao et al. described four children and young adults diagnosed with intracranial mesenchymal tumors with myxoid component and EWSR1::CREB1, EWSR1::CREM, or EWSR1::ATF1 fusions (10); Bale et al. described three pediatric cases with similar histology and fusions (3); Sloan et al. reported a series of 20 cases of intracranial mesenchymal tumors with FET::CREB fusion and comprehensively characterized their radiologic, molecular, and clinicopathologic features. Several other intracranial mesenchymal tumor cases without myxoid component and EWSR1::CREB1 fusion have been reported in the literature ( Tables 1 , 2 ).

The reported treatment was surgical in all cases; nevertheless, adjuvant radiotherapy and sarcoma-based regimens have also been reported (2). Our case confirms that local treatment (including surgery and proton beam therapy) shows the most favorable outcomes and a more promising prognosis (35).

In the case of the patient described, it was initially difficult to make the correct diagnosis, but by expanding the immunohistochemical panel and integrating it with molecular data, the correct diagnosis of intracranial mesenchymal tumor FET::CREB fusion-positive was made. Due to the rarity of the histopathological and molecular features, this case was previously published as part of a series of EWSR1-rearranged intracranial tumors (29). At the onset, we treated our patient according to the diagnosis of HGG. However, the uncommon occurrence of extracranial metastasis led us to identify a personalized treatment approach. We conducted molecular analysis, which revealed high levels of PD-1 and PD-L1 expression. This information allowed us to initiate treatment with nivolumab, making our case the first to be documented to receive immunotherapy in the medical literature. As a result of this therapy, the patient achieved and maintained a partial response for nearly three years. However, it was only after the most recent disease progression and five years after the initial diagnosis that we were able to identify an intracranial mesenchymal tumor with the EWSR1::CREB1fusion transcript. After this diagnosis, the patient received local treatments (surgery for the lung lesion and proton therapy for the bone lesion) along with consolidation with systemic drug therapy. This consolidation regimen consisted of temozolomide and irinotecan, tailored to sarcoma-specific protocols, with good tolerability and outpatient administration.

In conclusion, our case highlights the necessity and mandatory molecular studies workup for these rare diseases, which are crucial for refining personalized therapies and exploring novel treatment options.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) and/or minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

AM: responsible for all published work, FD: responsible for writing paper write, SR, IG, RA, ACan, and MG: critical revision of histological and molecular case diagnosis. ACac and GM: examination, diagnosis and follow-up of the patient, and critical revision of the manuscript. ACar and GMM: critical revision of the manuscript for intellectual content. SC: radiological diagnosis and follow-up of the patient. SV: treatment and follow-up of the patient, and critical revision of the manuscript. All authors contributed to the article and approved the submitted version.