Abstract

Background: Primary intracranial sarcomas (PIS) are rare tumors with mesenchymal origins. These tumors have a heterogeneous clinical presentation and are associated with a poor prognosis.

Case Description: This report highlights the complexities associated with PIS by focusing on a 26-year-old male with recurrent tumor growth facing unique challenges regarding diagnosis and treatment options . A high-grade spindle-celled neoplasm with sarcomatous features characterized the patient’s tumor. There were additional morphologic changes, including multinucleated giant cells and rare foci with eosinophilic spheroids. Genomic analysis revealed a DICER1-associated PIS. Treatment involved endovascular embolization, multiple surgical interventions, intrathecal etoposide injections, and oral pazopanib with adjuvant radiation therapy.

Conclusion: This case additionally highlights an unusual association between PIS and anomalous hypervascularity, refractory hemorrhage, and subdural effusions, a presentation that is increasingly being reported in this type of tumor.

Keywords: DICER-1, Hematoma, Primary intracranial sarcoma, Tumor, Vascular fistula, DICER-1 mutation, Vascular malformation

INTRODUCTION

Primary intracranial sarcomas (PIS) are rare tumors that originate from multipotent primitive mesenchymal cells within leptomeninges or dura.[ 2 ] These tumors have been diagnosed in individuals aged 3–71. However, they are more often encountered in individuals younger than 50, with a median age of 28–31 years.[ 5 , 17 ] The prevalence of PIS ranges from 0.1% to 4.3%. PIS are more likely to be located in the supratentorial compartment, with the frontal and temporal lobes being the most common regions of presentation.[ 10 , 23 ] However, they have also been described in the occipital lobe, clivus, and cerebellopontine angle.[ 17 ] Symptoms are most commonly related to the location of PIS with the most common symptoms including headache, dizziness, loss of vision, paresthesias, and hearing loss.[ 5 ] Increasingly, a hemorrhagic presentation is also being anecdotally reported.

The prognosis of PIS is poor, with an overall 5-year survival rate of 33.4% with a mean survival time estimated at 15.5 months.[ 23 ] Approximately 40% of individuals diagnosed with PIS will have metastasis, which contributes to the poor prognosis.[ 2 ] Approximately 25% of patients have a recurrence of tumors, and more than 75% die secondary to disease progression.[ 10 ] Intracranial sarcomas are remarkably diverse, with the most common types being fibrosarcoma, intracranial synovial sarcoma, and mesenchymal chondrosarcoma.[ 10 ] Prior history of radiation to the cranium may be present in some cases.[ 15 ]

Diagnosis of PIS is typically based on clinical, pathological, and imaging features. Common imaging findings include contrast enhancement, diffusion restriction, hemorrhage, meningeal extension, and necrosis.[ 2 , 5 , 14 ] However, imaging is often non-specific, and diagnosis is not achieved until a biopsy confirms mesenchymal origins. Immunohistochemistry (IHC) is often positive for vimentin and negative for neuronal and glial markers.[ 2 ] The tumors are described as having highly proliferative, spindle-shaped cells with a lack of developed cell-cell junctions.[ 2 ] Recent advancements in next-generation sequencing have aided in the identification of diagnostic and clinically relevant targets. Genetic studies have identified mutations in genes such as NRAS, PIK3CA, BAP1, KDR, BLM, and CNV deletions of SMARCB1.[ 5 ]

Treatment often includes a combination of surgery, radiotherapy, and chemotherapy.[ 2 , 10 ] Gross total resection (GTR) is often the first choice, and patients who undergo GTR tend to have a better survival rate. Furthermore, surgical intervention provides the opportunity for biopsy diagnosis as well as tailored adjuvant therapy with tumor-specific chemotherapy and/or radiation. One of the more common chemotherapy treatments is the ifosfamide, carboplatin, and etoposide (ICE) regimen consisting of ICE.[ 13 ] Additional chemotherapy options include VP-16, carboplatin, vincristine, and cyclophosphamide.[ 2 ]

CASE PRESENTATION

The patient was a 26-year-old male with a history of anxiety, alcohol, and cannabis use disorder who presented at an outside institution for severe headaches. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed right frontoparietal intracranial hemorrhage with mass effect requiring emergent decompressive craniectomy [ Figure 1 ]. The patient was later transferred to our institution for a higher level of care. The initial working diagnosis based on the patient’s age, intracerebral hemorrhage (ICH), and imaging findings was a ruptured arteriovenous malformation (AVM). A digital subtraction angiogram (DSA) was completed which demonstrated evidence of venous congestion and arteriopathy in the region of the ICH; however, there was no definite (AVM) nidus identified.

Figure 1:

Computed tomography without contrast (a) and T2-weighted magnetic resonance imaging (b) demonstrating large right frontoparietal intraparenchymal hematoma measuring 8.2 × 6.1 × 5.1 cm.

While no definite evidence of AVM was encountered on the first DSA, there was still concern for an underlying vascular malformation that the large hemorrhage may have compressed. An underlying hemorrhagic tumor was also considered in the differential; however, the initial MRI showed only lobulated areas of enhancement along the margin of the hemorrhage. To evaluate the possibility of metastatic disease, the patient received CT imaging of the chest, abdomen, and pelvic regions, which were negative. As the patient was neurologically stable and had already undergone decompression, no further surgical intervention was performed, and the patient was eventually transferred to rehab.

One month later, the patient was re-presented with acute onset nausea, vomiting, increased lethargy, and aphasia. Repeat imaging revealed an increased size of the right frontoparietal hematoma [ Figure 2 ]. An external ventriculostomy drain was placed, and neurointerventional radiology performed a transcatheter embolization of an abnormal distal anterior cerebral artery branch supplying an area of parenchymal phase hypervascularity using liquid embolic material [ Figure 3 ]. During this procedure, microcatheter runs noted a small amount of arteriovenous shunting; however, there was no definitive evidence of an AVM or arteriovenous fistula.

Figure 2:

Axial computed tomography of the head (a) without contrast and (b) T2-weighted magnetic resonance imaging demonstrating large right frontoparietal intraparenchymal hematoma measuring 7.1 × 6.9 × 5.8 cm with evidence of edema.

Figure 3:

(a) Baseline cerebral angiogram showing parenchymal phase hypervascularity within fed primarily by a distal branch of the right pericallosal artery (parenchymal tumor blush); and (b) interventional radiology embolization with associated reduction in hypervascularity (red arrow).

Given the repeat hemorrhage, persistent neurologic deficits, and mass effect, the patient was brought to the operating room for evacuation of the hemorrhage and resection of any underlying cause. Through a right frontal craniotomy, the hematoma was evacuated, and an abnormal mass was encountered deep within the right frontal lobe. The mass was biopsied, and intraoperative pathology was concerning for the malignant tumor. The tumor was debulked down to the ventricular surface, and near total resection was achieved.

Immediate postoperative imaging showed a residual tumor centered at the left paramedian frontal lobe [ Figure 4a ]. In <3 weeks, the residual tumor grew significantly with associated hemorrhage and mass effect [ Figure 4b ]. A second operation was completed urgently for recurrent tumor resection, with only a small amount of residual tumor left after surgery. Due to the malignant nature of the tumor, radiation was initiated, after which the patient began improving and was discharged. Despite this initial progress, the patient presented to the emergency room about 4 months later with acute onset headache and altered mentation. Imaging demonstrated residual tumor growth, which was resected for a 3^rd time. The patient once again recovered, but then 2 months later presented with disease progression evidenced by extensive extra-axial metastatic lesions along the left cerebral convexity, basal cisterns, bilateral cerebellopontine angles, fourth ventricular outflow tract with leptomeningeal enhancement throughout the brainstem, and obstructive hydrocephalus [ Figure 4c ]. Despite aggressive surgical management and adjuvant radiation, the patient eventually passed away from disease progression.

Figure 4:

(a) T1-weighted magnetic resonance imaging (MRI) demonstrating post-surgical changes with residual enhancing tumor along the margin of the surgical bed. (b) T1-weighted MRI showing residual tumor growth 2 weeks later. Heterogenous, multilobulated tumor now measuring 6.8 × 6.2 × 6.3 cm. (c) T1-weighted magnetic resonance imaging demonstrating diffuse leptomeningeal enhancement.

Pathology

Initial histological examination of the tumor revealed a high-grade spindle-celled neoplasm with sarcomatous features (World Health Organization [WHO] grade IV). There were additional areas with pleomorphic changes, including multinucleated giant cells, eosinophilic spheroids, and regions with a fibrillary background [ Figure 5 ]. Marked tumor vascularity was noted with lakes of blood and necrosis, including those of vessel walls [ Figure 6 ].

Figure 5:

(a-c) Histological demonstration of resected tumor demonstrating a highly cellular (>80%), spindle celled, sarcomatous neoplasm with a fibrillary background, regional pseudopalisading necrosis, and pleomorphic changes including multinucleated, bizarre giant cells, and eosinophilic spheroids.

Figure 6:

(a and b) Histological demonstration of marked tumor vascularity with regional hemorrhage.

On immunohistochemistry (IHC) staining, the tumor was positive for vimentin, with patchy reactivity for reticulin. However, since there was no clear indication of its lineage or subtype, samples were sent for genomic analysis, and deoxyribonucleic acid methylation profiling was performed. The methylation profile on the Heidelberg classifier (version 11b6 and 12b6) and National Cancer Institute/Bethesda classifier indicated a high-grade PIS DICER1-mutant. Further, tumor profiling was pursued and a notable biomarker included a pathogenic variant on platelet-derived growth factor receptor alpha.

Adjuvant therapy

After the second surgery for tumor resection, the patient received five fractions of radiation utilizing intensity-modulated radiation therapy. Chemotherapy options were also discussed with the patient and his family. However, the patient was not willing to receive blood products based on religious beliefs, which limited aggressive chemotherapy approaches. Thus, the traditional approach of treating intracranial sarcomas with ICE was avoided due to the risk of myelosuppression. Instead, the patient began treatment with etoposide biweekly for 6 weeks (0.5 mg, intrathecal). The patient tolerated etoposide well, and due to the molecular profile of the patient’s tumor, oral pazopanib was added to the patient’s regimen.

DISCUSSION

The purpose of this report is to highlight a relatively new entity described in the 2021 WHO central nervous system (CNS) five classifications of CNS tumors that pose challenges in clinical and morphologic diagnosis and require additional molecular investigations for confirmation. This entity also tends to present with catastrophic hemorrhage at times and is often seen in younger individuals. Besides the obvious spindle-celled pleomorphic architecture of a sarcoma, one additional hallmark is the finding of eosinophilic globules, although their presence can be patchy and may be easily overlooked without extensive sampling and evaluation in multiple sections. The index case itself did not reveal these eosinophilic globules in the initial resection, and only a detailed analysis of a subsequent resection specimen revealed the abnormality in a small focus.

DICER1 mutation syndrome is an autosomal dominant predisposition to several types of cancer secondary to a mutation in an RNase III endonuclease.[ 3 ] While DICER1 syndrome has been associated with pituitary blastomas and pineoblastomas,[ 8 ] there is no official association existing between DICER1 syndrome and intracranial sarcomas.[ 19 , 20 ] However, there is a growing body of literature describing somatic DICER1-associated mutations independent of the genomic DICER syndrome. The DICER1 mutation may represent a spectrum of PIS in which several subclassifications have been made. Furthermore, it has been proposed that PIS with DICER1 mutations represent a fairly heterogeneous group of tumors, some of which may fall under the category of DICER1 syndrome, while other PIS may represent a different DICER1-related pathology specific to a spectrum of sarcomatous tumors.[ 8 , 9 ]

Koelsche et al. proposed a subtype of PIS termed spindle cell sarcoma with rhabdomyosarcoma-like features (SCS-RMSDICER1), which had a significant association with DICER1 mutation in 22 cases.[ 12 ] This variant has been reported by Sakaguchi et al. as well, who reported two pediatric patients with SCS-RMS-DICER1, and Alexandrescu et al. reported five such cases.[ 1 , 18 ] SCS-RMS-DICER1 were described as having focal clusters of rhabdomyoblasts, with immature spindle cells and eosinophilic globules situated in a predominantly fascicular background. IHC revealed myoglobin, vimentin, and focal desmin reactivity.[ 12 , 18 ]

Kamihara et al. reported DICER1-associated CNS sarcomas, which had a significant association with DICER1 mutation in six cases. These tumors were spindle cells with brisk mitotic activity in a fascicular background. There was evidence of eosinophilic globules and regions of cartilaginous formations. These cells were poorly differentiated but showed focal positivity for myogenic markers. Finally, there was evidence of palisading necrosis in one of the patients.[ 11 ] Alexandrescu et al. and Das et al. each independently described one patient who had a description fitting the chondroid differentiation.[ 1 , 7 ]

Finally, Yao et al. described a third set of DICER1-associated PIS that bore similarity to the histological description of the other subclassifications of DICER1-associated PIS that showed dense, spindled cells with eosinophilic globules. However, Yao et al. noted that PIS has a unique positive IHC for neurogenic markers.[ 22 ]

The significant hypervascularity and large ICH associated with the tumor presented in this case report created significant difficulties in diagnosis. The association of PIS with subdural effusions or hematomas is not unusual, although there are only limited descriptions in the literature. As pathologists and clinicians recognize more awareness of this entity and its association with the DICER-1 alteration, more anecdotal (but unpublished) descriptions are reported. Of the 16 patients reported by Al-Gahtany et al., three were reported to have tumors with associated hypervascularity on angiogram, with an additional patient reported to have intratumoral and intraventricular hemorrhage mimicking the appearance of an AVM on imaging.[ 2 ] Vasoya et al. also reported a case of a pediatric patient with bilateral chronic subdural hematomas with an associated subdural mass, which, on resection and histological analysis, was revealed to be an undifferentiated sarcoma.[ 21 ] Bailey and Ingraham described two fibrosarcomas, which contained a fluid-filled sac at the center of each tumor, which was initially taken for subdural hematomas.[ 4 ] Cinalli et al. described two pediatric cases presenting with rapidly progressive ICH, which on imaging appeared to be secondary to subdural fluid collections. However, after the initial evacuation of the hematoma, the patients exhibited refractory symptoms and recurrent symptoms of ICH. Surgical intervention revealed PIS in each case.[ 6 ] Finally, Nejat et al. described a subdural rhabdomyosarcoma which presented as a subdural hematoma refractory to treatment. Again, after craniotomy, a PIS was discovered.[ 16 ] Thus, there appears to be a rare but considerable association between PIS and anomalous hypervascularity with refractory hemorrhage.

CONCLUSION

DICER1-associated PIS is a rare, characteristically heterogeneous subset of sarcomas. These intracranial sarcomas have been described with myogenic, chondroid, and neurogenic differentiation. Despite advancements in understanding the molecular landscape of these tumors, the overall prognosis for DICER1-associated PIS remains poor, emphasizing the urgency for continued research. Furthermore, there appears to be a noteworthy association between PIS and anomalous hypervascularity, resulting in these tumors presenting as hemorrhagic lesions, adding a level of complexity to the diagnosis and management of these difficult cases.

Ethical approval

The Institutional Review Board approval is not required.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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