Primary CNS sarcoma, DICER1-mutant with rhabdomyoblastic differentiation arising within the thoracic spine: illustrative case

Abstract

BACKGROUND

Primary CNS sarcoma, DICER1-mutant is almost exclusively found in the supratentorial compartment. Isolated spinal lesions are exceedingly rare.

OBSERVATIONS

The authors present a case of thoracic intradural extramedullary primary CNS sarcoma, DICER1-mutant. An adult male with a remote history of a left cerebellar lesion resection with unknown pathology presented with sensation changes extending caudally from the torso. He subsequently underwent laminectomy and tumor resection of the lesion. The patient experienced recurrence at 1.5 months requiring re-resection for palliative decompression.

LESSONS

Molecular characterization is essential for accurate diagnosis of this rare entity given its substantial overlap with histological mimics. Following resection and tissue identification of the tumor, patients should be monitored closely for local recurrence. While no standardized treatment exists, adjuvant chemoradiation therapy may improve time to progression and overall survival in an otherwise aggressive disease.

https://thejns.org/doi/10.3171/CASE26660

Primary intracranial sarcoma, DICER1-mutant is a recently recognized and highly aggressive mesenchymal neoplasm first designated as a distinct entity in the fifth edition of the WHO Classification of Tumours of the Central Nervous System.^1,2 These tumors occur predominantly in children and young adults, with a median age of approximately 6 years at diagnosis, and are typically located intracranially within the supratentorial compartment.^2,3 Histologically, they demonstrate marked morphological heterogeneity, including spindle cell or pleomorphic morphology, frequent mitotic activity, eosinophilic cytoplasmic globules, and variable rhabdomyoblastic differentiation, which often creates substantial diagnostic overlap with other high-grade sarcomas and malignant CNS neoplasms.^2,4 Molecular characterization has therefore become essential for accurate classification and therapeutic guidance.^1,5

These tumors have been described almost exclusively in intracranial locations, and spinal origin remains exceedingly rare. Here, we present an illustrative case of an intradural extramedullary thoracic spinal cord primary CNS sarcoma, DICER1-mutant causing severe spinal cord compression with rapid postoperative recurrence, highlighting the diagnostic challenges, operative findings, molecular features, and aggressive clinical behavior of this rare tumor type

Illustrative Case

A 46-year-old Hispanic male presented with 1 week of progressively worsening gait instability and lower extremity sensory changes. He had a history of a left-sided cerebellar lesion resected 20 years prior in Mexico with an unknown pathological diagnosis and postoperative management. The patient was unable to provide further details regarding this history. On examination, strength was intact throughout, but he complained of sensation changes bilaterally below his chest. He was also noted to be hyperreflexic in his lower extremities. Bowel and bladder function were preserved. An MRI study of the spine was performed, which revealed a contrast-enhancing mass dorsal to the spinal cord extending from T1 to T4, causing severe cord compression (Fig. 1). Given its close association with the dura on imaging, a dural-based mass was initially suspected. The remainder of his imaging, including a CT study of his head, chest, abdomen, and pelvis, was unrevealing for any other metastatic lesion.

FIG. 1.

T1-weighted precontrast sagittal (A) and axial (B), T2-weighted sagittal (C) and axial (D), T1-weighted postcontrast sagittal (E) and axial (F), and T2-weighted STIR sagittal (G) MR images of the spine obtained before initial resection. The tumor (arrows) measured 7.3 × 1.3 × 1.1 cm.

The patient underwent a thoracic decompression and resection of the lesion. On opening the dura, a pink, encapsulated, friable mass was encountered (Fig. 2). The cranial pole of the mass was noted to be adherent to the pial surface, but the caudal end had a well-defined subarachnoid plane that allowed dissection away from the spinal cord. The mass was gently mobilized along this plane until it became indistinct, at which point the remaining tumor was resected with a combination of suction and manipulation with blunt instruments. Small fragments of tumor were identified entwined with nerve roots at the right lateral recess around T2–3; attempts to reach this residual resulted in changes to neuromonitoring signals that returned on cessation of mobilization, and further resection was abandoned.

FIG. 2.

Intraoperative microscopic views of the tumor after dural opening, demonstrating steps toward resection. Right is cranial, left is caudal. A: View of intradural tumor on initial exposure. B: Debulking and resection using careful blunt dissection of the tumor from the spinal cord. C: Residual tumor caudally. D: Final appearance after completion of maximal safe resection.

The patient awoke with intact strength and continued numbness and tingling distal to his chest. His postoperative course was uncomplicated. After performing a new baseline MRI study (Fig. 3), he was ultimately discharged to an inpatient rehabilitation facility while awaiting further treatment by radiation oncology.

FIG. 3.

T2-weighted sagittal MR image obtained after the initial surgery. The area of resection is denoted by arrows.

Histopathological sections showed a malignant, poorly differentiated neoplasm composed of epithelioid cells with pale eosinophilic cytoplasm, marked nuclear pleomorphism, prominent nucleoli, and occasional hyaline globules (Fig. 4A and B). Sheet-like architecture predominated, but pseudopapillary and pseudoalveolar architecture was focally noted. Brisk mitotic activity (up to 38 mitotic figures in 10 high-power fields) was present. Tumor necrosis was not identified. The tumor cells were positive for desmin (Fig. 4C), myogenin (Fig. 4D), MyoD1 (Fig. 4E), CD56 (not shown), and CD30 (patchy, not shown), and focal immunoreactivity for EMA and CK 8/18 was additionally noted. SSTR2A, CK AE1/AE3, PR, SMA, S100, Sox-10, GFAP, CD45, CD68, CD21, CD34, ALK, D2-40, and calretinin were negative (not shown). The tumor cells demonstrated a null pattern of P53 (Fig. 4F) expression and lost nuclear expression of ATRX (Fig. 4G). INI1 and BRG1 were both retained (Fig. 4H). The differential diagnosis included pleomorphic rhabdomyosarcoma and primary intracranial sarcoma, DICER1-mutant. Molecular studies were pursued for definitive classification.

FIG. 4.

A and B: Hematoxylin and eosin–stained sections showing a malignant, sarcomatoid neoplasm with marked anaplasia (A), patternless architecture, and occasional hyaline globules (B). C–F: The tumor cells were positive for desmin (C), myogenin (D), and MyoD1 (E) and showed a null pattern of P53 expression (F). G:Loss of ATRX expression was additionally noted. H:The tumor clustered with ERMS using t-distributed stochastic neighbor embedding.

Next-generation sequencing (Mayo Clinic Laboratories Neuro-Onc Expanded Panel) revealed two pathogenic DICER1 variants (one with a near-heterozygous variant allele frequency), two NF1 mutations, an activating EGFR mutation, and a nonsense mutation affecting TP53. Numerous gene rearrangements of uncertain significance were additionally identified, indicating chromosomal instability. Chromosomal microarray analysis (Mayo Clinic Laboratories) essentially showed a tetraploid genome with numerous superimposed gains, losses, and stretches of copy-neutral loss of heterozygosity, notably including near-complete loss of the X chromosome (including the ATRX locus). The tumor matched with methylation class rhabdomyosarcoma (confidence score 0.94), subclass embryonal rhabdomyosarcoma (ERMS; 0.935), using the Bethesda classifier (version 3.1, performed and interpreted at the National Institutes of Health/National Cancer Institute). The tumor also clustered with ERMS using unsupervised t-distributed stochastic neighbor embedding (Fig. 4H) and uniform manifold approximation and projection analyses. Although embryonal and pleomorphic rhabdomyosarcoma were both considered as alternatives, this tumor’s morphology and genomic signature are most compatible with primary CNS sarcoma, DICER1-mutant with extensive rhabdomyoblastic differentiation.

One month later, the patient re-presented to our hospital with subjective right lower extremity weakness and worsening thoracic radiculopathy. He was noted to have missed his radiation oncology and medical oncology follow-up appointments. His MRI study demonstrated a localized tumor recurrence essentially to its original size, with new T2 changes within the spinal cord spanning from C6 to T6 (Fig. 5). He was therefore taken urgently to the operating room for re-resection. Intraoperatively, pathology was consistent with recurrent tumor; notably, the mass was noted to be extremely adherent to the pia along its length. Debulking was therefore performed under ultrasound guidance, after which the dura and wound were again closed in a routine fashion without complication.

FIG. 5.

T1-weighted precontrast sagittal (A) and axial (B), T2-weighted sagittal (C) and axial (D), T1-weighted postcontrast sagittal (E) and axial (F), and T2-weighted STIR sagittal (G) MR images of the spine obtained before resection of the recurrent lesion. The recurrent tumor (arrows) measured 5.6 × 1.2 × 1.3 cm prior to resection. Notably, the large amount of subcutaneous and paraspinal enhancement seen in panel E did not correspond to tumor mass intraoperatively.

The patient again awoke neurologically intact aside from persistent thoracic radiculopathy and lower extremity sensory changes. He was ultimately discharged to a skilled nursing facility and is currently receiving salvage radiation therapy (50.4 Gy in 28 fractions).

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

Primary intracranial sarcoma, DICER1-mutant is almost exclusively seen as an isolated intracranial lesion in children and young adults. Our patient presented with symptoms of spinal cord compression due to an isolated lesion within his spinal canal. Although the history of a previously resected cerebellar lesion is notable, its temporal relation with the currently treated spinal lesion makes metastasis from the reported lesion unlikely. Initial review of imaging suggested a broad differential diagnosis, with meningioma and peripheral nerve sheath tumor as leading considerations. Following resection—­without adjuvant radiation therapy or chemotherapy—our patient experienced recurrence at 1.5 months, requiring repeat surgery for palliative decompression.

To our knowledge, only two prior reports have described a primary CNS sarcoma, DICER1-mutant arising within the spinal cord.^6,7 Pasarikovski et al. described a case similar to ours in which an older female developed an intramedullary thoracic lesion without other CNS or systemic findings and underwent resection.⁶ Despite adjuvant radiation treatment, the patient experienced recurrence at 6 months with numerous spinal lesions and diffuse leptomeningeal spread. Schweizer et al. described a case of DICER1-mutant sarcoma arising within the thoracic spine of a 6-week-old male.⁷ After resection, the child was subsequently treated according to the EU-RHAB protocol⁸ with the addition of a MEK inhibitor. He underwent re-resection for a paraspinal residual tumor at 20 months of age and has achieved remission as of 30 months postdiagnosis.

Given this aggressive clinical behavior, published experiences regarding optimal treatment remain limited. Clinically, DICER1-mutant CNS sarcomas are associated with rapid progression, high rates of local recurrence, and poor overall survival despite multimodal therapy incorporating maximal safe resection, radiotherapy, and systemic chemotherapy.^2,3,9 The two largest case series, from Colombia and Peru, have offered limited insight into the treatment of this complex disease. In 2022, Diaz Coronado et al. studied 70 cases of intracranial sarcomas, of which 28 were confirmed to harbor DICER1 mutations.² The median age at presentation was 6 years. All patients received surgery; 57 subsequently received radiotherapy at a median dose of 60 Gy, and 46 of those received adjuvant chemotherapy in the form of either ICE (ifosfamide/cisplatin/etoposide) or VAC (vincristine/actinomycin D/cyclophosphamide). Patients treated with both chemotherapy and radiation therapy had superior 2-year progression-free survival (58%) compared to those treated with radiation therapy only (21%). The overall 2-year survival rates were 70% and 46%, respectively. Similarly, in 2023, Cardona et al. studied 8 patients with DICER1-mutant intracranial sarcomas.³ The median age at presentation for this cohort was 20 years, with a slight male predominance (5 vs 3). Seven cases were supratentorial in location, and 1 was infratentorial. All patients received resection and intensity-modulated radiation therapy to 54 Gy. Seven patients then received ICE therapy, while 1 patient received VAC. All patients experienced local disease recurrence, with a median time to progression of 14.5 months. The median overall survival for this cohort was 30.8 months. The parallel treatment approaches in both series likely reflect a Canadian cohort that suggested efficacy of this regimen for primary CNS sarcomas, although this predated the fifth edition of the WHO classification of DICER1-mutant tumors as a distinct entity.¹⁰ At this time, there is no defined standard of care for this disease.

DICER1-mutant sarcomas arising in the CNS demonstrate a variety of morphological characteristics, including spindle cell or pleomorphic cytomorphology, fascicular or patternless architecture, and cytoplasmic hyaline globules.¹¹ A subset of cases show heterologous rhabdomyoblastic or chondroid differentiation.^9,12 Striking similarity to other DICER1-mutant tumors such as pleuropulmonary blastoma has also been described.¹¹ The hyaline globules show labeling with periodic acid–Schiff and variable expression of myogenic differentiation such as desmin, SMA, myogenin, and occasionally MyoD1.^11,13 TLE1 immunoreactivity, mutant patterns of P53 expression, and loss of ATRX and H3K27me3 are also frequent findings.¹⁴ While isolated cases with SSTR2A expression have been described,¹⁵ GFAP, Olig2, cytokeratins, S100, SOX-10, EMA, and PR are usually absent, allowing distinction from neuroepithelial neoplasms, sarcomatoid carcinoma, melanoma, or anaplastic meningioma.

Because of their rarity and morphological diversity, accurate diagnosis of primary CNS sarcoma, DICER1-mutant routinely requires next-generation sequencing to distinguish these lesions from histological mimics such as ERMS and other high-grade sarcomatoid neoplasms.^5,6,16 DICER1, located on chromosome 14q32.13, encodes an RNase III endoribonuclease that is critical for microRNA processing, posttranscriptional gene silencing, and regulation of cellular differentiation and proliferation.^17,18 Somatic missense mutations affecting the RNase IIIb metal-binding domains were first identified as recurrent oncogenic events in nonepithelial ovarian cancers and subsequently characterized across a spectrum of DICER1-driven neoplasms.¹⁷ In CNS sarcomas, tumors harbor biallelic DICER1 inactivation, typically combining a somatic RNase IIIb hotspot mutation with a second truncating or loss-of-function variant.^2,19 Co-occurring alterations in TP53, ATRX, NF1, KRAS, and PTEN are frequently identified and contribute to the aggressive biological behavior of these lesions.^2,3 Emerging evidence additionally suggests that these tumors may arise from multipotent neural crest–derived precursor cells capable of divergent neural and mesenchymal differentiation, potentially explaining their substantial histological variability.⁷

Primary intracranial sarcoma, DICER1-mutant has been described as having a distinct methylation profile; however, the extent to which these tumors overlap with DICER1-mutant neoplasms that arise outside of the CNS has not been studied.⁵ This patient’s tumor matched with methylation class ERMS, raising the possibility that DICER1-mutant CNS sarcomas with rhabdomyoblastic differentiation share epigenetic features with those that occur outside of the CNS, that is, uterine ERMS arising in the setting of a germline DICER1 mutation. Uterine DICER1-mutant ERMS does share some genomic features in common with DICER1-mutant CNS sarcomas, including genomic instability and concurrent alterations involving the RAS pathway and TP53, which lends additional support to the possibility that these are related entities.²⁰ Studies comparing the morphologic, genomic, and epigenetic features of DICER1-mutant CNS sarcomas and their extra-CNS counterparts would contribute to our understanding of the biology of these tumors and the use of methylation microarray analysis as a diagnostic tool.

Based on our patient’s clinical course, we recommend surgical decompression for spinal manifestations of primary CNS sarcoma, DICER1-mutant, with the goal of gross-total resection while preserving neurological function. Timely adjuvant radiotherapy followed by chemotherapy should then be pursued. Although no established protocol exists, the EU-RHAB⁸ regimen represents a reasonable framework given the limited available evidence. At recurrence, the operative goal shifts to decompression and functional preservation.

Lessons

Primary CNS sarcoma, DICER1-mutant is a rare and emerging clinical entity that very rarely involves the spine. Despite many radiographic and clinical mimics, spinal CNS sarcoma should remain on a clinician’s differential diagnosis when evaluating intradural spinal masses. Additionally, molecular characterization of this disease is necessary to distinguish it from histopathological mimics. While no definitive standardized treatment exists, limited case series suggest that patients who receive gross-total resection and adjuvant chemoradiation therapy may fare somewhat better. Given the disease’s high recurrence rates and poor overall survival, close follow-up is critical, and expeditious delivery of adjuvant therapy should be prioritized.

Acknowledgments

We acknowledge Tala Malo, Vedvignesh Gorjala, and Emad Allam, MD, for their radiographic contributions to this case. We also acknowledge Jigisha P. Thakkar, MD, and Anupama Chundury, MD, for their assistance with the management and care of this patient.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Tsiang, Smith, Arnold. Acquisition of data: Tsiang, Yang, Jani, Smith, Arnold. Analysis and interpretation of data: Tsiang, Jani, Smith, Arnold. Drafting the article: Tsiang, San, Yang, Jani, Smith. Critically revising the article: Tsiang, San, Jani, Smith, Arnold. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Tsiang. Administrative/technical/material support: San, Yang. Study supervision: Arnold.

Correspondence

John T. Tsiang: Loyola University Medical Center, Maywood, IL. jth.tsiang@gmail.com.