Case Report: DICER1-mutant primary intracranial sarcoma with concurrent TP53, PDGFRA, and KEAP1 somatic mutations in a 5.5-year-old boy

Abstract

DICER1-mutant primary intracranial sarcoma (DICER1-mutant PIS) is a rare and aggressive central nervous system (CNS) malignancy primarily affecting pediatric patients. We report the case of a 5.5-year-old boy who presented with non-specific prodromal symptoms, including recurrent dizziness and progressive vomiting. Brain neuroimaging revealed a cystic-solid mass in the frontal lobe, characterized by heterogeneous contrast enhancement, significant perilesional edema, and intratumoral hemorrhage. Histopathological examination of the tumor demonstrated marked cellular pleomorphism, atypical mitoses, and distinctive intracytoplasmic eosinophilic globules. Next-generation sequencing confirmed the presence of the canonical hotspot DICER1 p.E1705K alteration, along with concurrent pathogenic mutations in TP53, PDGFRA, and KEAP1. Additionally, somatic SMARCB1 allelic loss due to loss of heterozygosity was identified. Due to its insidious clinical presentation and overlapping morphological characteristics, DICER1-mutant PIS is often challenging to diagnose accurately, and no standardized therapeutic guidelines currently exist. The patient underwent subtotal surgical resection followed by adjuvant chemoradiotherapy. However, intracranial disease progression and the development of new metastatic lesions were observed during long-term follow-up. This case underscores the critical importance of prompt and definitive molecular diagnosis, individualized multidisciplinary treatment approaches, and extended regular surveillance for this high-grade malignancy. It provides valuable real-world evidence that can inform the clinical management of similar rare DICER1-mutant PIS cases.

1. Introduction

DICER1-mutant primary intracranial sarcoma (DICER1-mutant PIS) is an uncommon primary malignant CNS tumor predominantly affecting children and adolescents. It is thought to originate from primitive intracranial non-meningeal mesenchymal progenitor cells. The 5th edition of the WHO Classification of Central Nervous System Tumors (2021) classifies DICER1-mutant PIS within the category of mesenchymal, non-meningothelial tumors involving the CNS (tumors of uncertain differentiation). This tumor constitutes less than 1% of all primary pediatric intracranial neoplasms (1). Clinical presentation and imaging characteristics of DICER1-mutant PIS are non-specific, and its histologic features are highly variable. Currently, published case series worldwide are limited, resulting in an incomplete understanding of its epidemiology, radiology, pathology, immunoprofile, and molecular landscape.

In the present study, we report a pediatric case of DICER1-mutant PIS and comprehensively outline its clinical, radiological, histopathological, and molecular features. A review of the pertinent published literature is also included to enhance diagnostic recognition among neurosurgeons and diagnostic pathologists.

2. Case description

A previously healthy 5.5-year-old boy was hospitalized for persistent dizziness lasting over one month and worsening emesis over three consecutive days. The dizziness began spontaneously a month before admission, without identifiable triggers, and occasionally resolved on its own. The patient experienced intermittent vomiting, but no convulsions, altered consciousness, or motor dysfunction. Two weeks prior to hospitalization, febrile symptoms developed. Three days before admission, the frequency of vomiting increased to 1–2 episodes per day, accompanied by lethargy and decreased responsiveness, which led to inpatient admission. A preoperative brain MRI scan, including pre- and post-contrast sequences, revealed a roughly round, space-occupying lesion measuring 4.1 cm × 3.9 cm × 3.8 cm within the right frontal lobe.

The tumor displayed a relatively well-defined yet irregularly contoured border. It exhibited heterogeneous signal intensity and contained two distinct cystic degenerative foci. These foci appeared hypointense on T1-weighted imaging (T1WI; Figure 1a) and hyperintense on T2-weighted imaging (T2WI; Figure 1b). Significant perilesional vasogenic edema was present, leading to compression of the adjacent brain parenchyma and a leftward midline shift. Post-contrast MRI revealed marked and heterogeneous enhancement (Figure 1c). Preoperative systemic evaluation, which included chest–abdominal CT and whole-body bone scintigraphy, ruled out both extracranial metastasis and synchronous systemic primary tumors. However, spinal and craniospinal MRI and CSF cytology were not obtained at initial diagnosis, which precluded complete staging for leptomeningeal dissemination.

Figure 1.

Preoperative brain MRI findings of the lesion. (a) T1WI shows hypointense cystic degeneration; (b) T2WI shows hyperintense cystic components with marked perilesional edema; (c) Post-contrast T1WI shows prominent heterogeneous tumor enhancement (arrowhead).

After a rigorous preoperative assessment confirmed no surgical contraindications, subtotal resection of the right frontal mass was performed with intraoperative microscopic navigation. Intraoperatively, the tumor was found to have extensive infiltration, ill-defined margins, and close proximity to eloquent cortical areas, making gross-total resection unsafe. Therefore, a subtotal resection with maximal safe excision was performed. Macroscopically, the resected specimen measured 6 cm × 5 cm × 1.5 cm and presented a friable, gray-brown cut surface with multifocal hemorrhage and cystic degeneration (Figure 2a). Histologically, tumor cells were observed growing in diffuse sheets and intersecting fascicles, consisting of round, spindle-shaped, and irregular neoplastic cells (Figure 2b). These cells possessed abundant eosinophilic or pale, clear cytoplasm (Figure 2c). The tumor nuclei exhibited marked pleomorphism, prominent nucleoli, and multinucleated giant tumor cells (Figure 2d). Frequent mitotic figures, including both typical and atypical forms, were readily identifiable (Figure 2e). Characteristic intracytoplasmic eosinophilic globules, varying in size, were diffusely distributed throughout the tumor parenchyma (Figure 2f).

Figure 2.

Gross morphology and histopathology of the tumor. (a) Gross specimen showing hemorrhage and cystic degeneration; (b) Tumor cells arranged in diffuse sheets and intersecting fascicles (H&E ×100); (c) Tumor cells with abundant eosinophilic or clear cytoplasm (H&E ×200); (d) Tumor nuclei showing marked pleomorphism, prominent nucleoli, and multinucleated giant cells (H&E ×200) (arrowhead); (e) Numerous typical and atypical mitotic figures (H&E ×200) (arrowhead); (f) Characteristic eosinophilic cytoplasmic globules of variable size diffusely distributed in the tumor parenchyma (H&E ×200) (arrowhead). (g–i) Immunohistochemical staining. (g) vimentin (+) (×100); (h) Ki-67 index 60% (×100); (i) p53 (+) (×100).

Immunohistochemistry results: diffuse positive expression of vimentin (Figure 2g), ATRX, INI1, BRG1, MAP2, CD99, Nestin, H3K27me3, and TLE1; focal weak immunoreactivity for desmin, MyoD1, and myogenin; Ki-67 labeling index was approximately 60% (Figure 2h); and diffuse nuclear p53 overexpression was observed (Figure 2i). All tested markers—including GFAP, EMA, S100, pan-cytokeratin (pan-CK), SALL4, and BRAF V600E—were entirely negative. Targeted next-generation sequencing identified pathogenic somatic alterations in DICER1 (c.5113G>A, p.Glu1705Lys; c.4005C>G, p.Tyr1335*), KEAP1 (c.1429_1430insGG, p.Gly477fs*23), PDGFRA (c.2525A>T, p.Asp842Val), and TP53 (c.814G>A, p.Val272Met), along with loss of heterozygosity at the SMARCB1 locus. The tumor mutational burden was 0.55 mutations/Mb. Furthermore, no pathogenic or likely pathogenic germline variants associated with inherited cancer predisposition syndromes were identified. This confirms that the tumorigenesis was sporadic and somatically driven, rather than being indicative of constitutional DICER1 syndrome.

One month after surgery, the child received proton beam therapy (total dose, 56 Gy in 28 fractions; target delineation not specified). Subsequently, adjuvant chemotherapy was administered: cycle 1—cyclophosphamide, 1500 mg/m²; carboplatin, 400 mg/m²; and vincristine, 1.5 mg/m² (all given on day 1); cycle 2—ifosfamide, 1.8 g/m²; and etoposide, 0.1 g/m² (days 1–5), initiated one month later. The two cycles were alternated, completing a total of eight cycles. Before cycle 9, MRI revealed a new lesion in the left thalamus, indicating intracranial progression. Spinal and craniospinal MRI and CSF cytology were not performed due to the patient’s deteriorating clinical condition and parental refusal; thus, salvage therapy was switched to ifosfamide, 1.5 g/m²; etoposide, 0.1 g/m²; and cisplatin, 25 mg/m² (days 1–3). At ten months after surgery, the patient remained alive.

3. Discussion

DICER1-mutant PIS, a recently recognized, rare, high-grade intracranial sarcoma, was formally integrated into the 2021 WHO Classification of Central Nervous System Tumors. This aggressive malignancy predominantly affects pediatric patients, with a median age of onset around 6 years, and typically originates in supratentorial regions, particularly the frontal lobe (2). Although a tumor with overlapping histomorphological features was described in 1996 (3), the modern molecular entity of DICER1-mutant PIS was definitively established in 2018 by Koelsche et al., who characterized its distinctive genomic profile and DNA methylation signature using multi-omics approaches, thereby coining the now widely accepted term “DICER1-mutant primary intracranial sarcoma” (4, 5). Given its infrequent occurrence, subtle onset, and non-specific clinical manifestations, DICER1-mutant PIS is frequently misdiagnosed or underdiagnosed. Consequently, no standardized diagnostic or therapeutic guidelines have been established. Currently, a definitive diagnosis relies on a comprehensive evaluation encompassing clinical presentation, neuroimaging features, histomorphology, immunophenotype, and molecular analyses (6).

Somatic, dominant-negative hotspot mutations concentrated within the RNase IIIb domain of DICER1 represent the primary oncogenic driver in pediatric DICER1-mutant PIS. The most frequently observed hotspot substitutions include p.Glu1705Lys (p.E1705K), p.Asp1709Asn (p.D1709N), and p.Gly1809Arg (p.G1809R) (7). Located on chromosome 14q32.13, DICER1 encodes a crucial endoribonuclease vital for the biogenesis of mature miRNAs. Mutations in the RNase IIIb domain disrupt the physiological cleavage of precursor miRNAs, leading to the loss of 5p-arm mature miRNAs and, via an Argonaute-dependent strand-switch mechanism, a concurrent gain-of-function upregulation of full-length, functional 3p-arm miRNAs. This imbalance subsequently results in the dysregulation of mRNA expression, which in turn promotes the activation of oncogenes or the inactivation of tumor suppressors, ultimately driving malignant transformation (8, 9). Therefore, RNase IIIb hotspot alterations may represent a useful molecular marker for DICER1-mutant PIS diagnosis, though their diagnostic value should be interpreted in conjunction with clinical, histopathological, and methylation profiling data.

The present case lacked genome-wide DNA methylation profiling, which is currently regarded as the gold-standard confirmatory assay for the “sarcoma, CNS, DICER1-mutant” methylation class as originally delineated by Koelsche et al. (4). This limitation stemmed from constrained intraoperative tissue availability and institutional resource restrictions at the time of diagnosis. Although the concurrent presence of the canonical DICER1 p.E1705K hotspot mutation, rhabdomyosarcomatous morphology with eosinophilic cytoplasmic globules, and a supportive immunophenotype collectively provides compelling diagnostic evidence, the absence of methylation data introduces a residual degree of diagnostic uncertainty and precludes refined subclassification within the broader CNS sarcoma methylation family. This caveat should be taken into account when interpreting the current findings. For future suspected cases, methylation array analysis is strongly recommended whenever technically and logistically feasible, as it would substantially enhance diagnostic confidence and enable accurate classification using the international CNS tumor methylation classifier.

A key limitation is incomplete initial staging: spinal/craniospinal MRI and CSF cytology were omitted at diagnosis, precluding baseline assessment of leptomeningeal dissemination. When a new left thalamic lesion emerged during follow-up, these tests were again deferred due to clinical deterioration and parental refusal. As a result, neuraxis involvement and leptomeningeal spread remain undetermined. This limits accurate disease burden assessment and may have underestimated the initial risk. For future DICER1-mutant PIS cases, comprehensive neuraxis imaging and CSF evaluation should be performed whenever clinically feasible to guide risk-adapted therapy.

DICER1-mutant PIS is frequently misdiagnosed as various intracranial mesenchymal or neuroepithelial tumors because of its indolent onset, nonspecific imaging features, and spindle-cell proliferation. The differential diagnosis is detailed below:

1. Gliosarcoma (designated as a histological variant of IDH-wildtype glioblastoma in the WHO CNS5 classification): Features biphasic differentiation into glial and sarcomatous components; the glial compartment is GFAP- and Olig2-positive with wild-type IDH status, whereas the sarcomatous component expresses vimentin but lacks myogenic markers; DICER1 RNase IIIb hotspot mutations are absent.

2. Intracranial embryonal rhabdomyosarcoma: Occurs predominantly in toddlers; rhabdomyoblastic tumor cells show positivity for desmin and focal/variable positivity for MyoD1 and myogenin, with retained INI1 expression; canonical DICER1 hotspot mutations are undetectable.

3. Anaplastic meningioma (CNS WHO grade 3): Originating from arachnoid cap cells, this entity is characterized by meningeal whorls, an elevated mitotic index, and geographic tumor necrosis. It exhibits EMA positivity and variable (often reduced or lost in high-grade cases) PR expression, vimentin expression, and absence of GFAP.

4. Solitary fibrous tumor (CNS WHO grade 3): Defined by staghorn-type vasculature and ovoid to spindle-shaped cells with diffuse nuclear STAT6 immunoreactivity; no pathogenic DICER1 RNase IIIb variants are detected.

5. Malignant peripheral nerve sheath tumor (MPNST): Fascicles of spindle cells with wavy or comma-shaped nuclei are evident. Approximately half of cases exhibit focal S100 and SOX10 expression, and about 50% show loss of nuclear H3K27me3 expression. DICER1 sequencing yields negative results (10).

6. Atypical teratoid/rhabdoid tumor (AT/RT): Occurs predominantly in infants and is composed of primitive small round blue cells and rhabdoid cells with complete loss of INI1 or BRG1 protein expression; DICER1 RNase IIIb hotspot mutations are consistently absent.

Despite overlapping morphological and immunohistochemical features with other histological mimics, DICER1 RNase IIIb hotspot mutations are frequently encountered in DICER1-mutant PIS and have not been reported in the other differential diagnostic entities listed above, although confirmatory data from larger cohorts are still needed (4). Therefore, targeted sequencing of the DICER1 RNase IIIb domain is essential to confirm a diagnosis of DICER1-mutant PIS and rule out histological mimics.

No universally established therapeutic protocol currently exists for DICER1-mutant PIS. Gross-total resection remains the preferred initial treatment to minimize residual tumor burden and mitigate the risk of local recurrence. However, if complete resection is surgically unachievable, subtotal resection is performed. Existing clinical data indicate that postoperative concurrent chemoradiotherapy effectively extends overall survival, with pediatric populations demonstrating superior survival benefits (2, 11), thereby supporting a comprehensive, multimodal management approach for DICER1-mutant PIS. Due to the extreme rarity of this disease, the clinical effectiveness of targeted therapy and immune checkpoint inhibition is not yet clearly understood. However, our NGS analysis identified two actionable genomic alterations. First, a PDGFRA p.D842V mutation—resistant to imatinib and sunitinib but highly sensitive to avapritinib (12)—supports off-label use of avapritinib or enrollment in basket trials. Second, biallelic DICER1 inactivation (p.E1705K + p.Y1335*) confirms tumor dependence on DICER1 loss and suggests downstream RAS/MAPK activation. In our patient’s case, the tumor mutational burden was 0.55 mutations/Mb—substantially lower than the mean TMB of 12.9 mutations/Mb reported in a cohort of pediatric DICER1-associated central nervous system sarcoma (DCS) (13). This low TMB, together with the algorithmic inference of microsatellite stability (MSS; note that dedicated MSI/MMR testing was not performed, and this inference requires confirmatory validation), suggests limited efficacy of single-agent immune checkpoint blockade in this tumor type. Nevertheless, the translational significance of TMB in this rare entity remains unclear and warrants further investigation in larger cohorts. Therefore, small-molecule inhibitors targeting the DICER1 pathway represent a promising avenue for future therapeutic development (14). Finally, consistent and long-term imaging surveillance is crucial for the early identification of recurrence or distant metastasis, enabling prompt intervention and ultimately improving clinical outcomes.

4. Conclusions

This case report comprehensively details the complex clinical, histopathological, and molecular features of DICER1-mutant PIS, underscoring the critical role of extensive molecular profiling for accurate diagnosis in routine clinical practice. The DICER1 RNase IIIb hotspot mutation serves as the primary diagnostic biomarker for DICER1-mutant PIS. While combined surgical resection and adjuvant chemoradiotherapy represent the current favored upfront treatment approach, a universally established standard is lacking, and tumor progression is frequently observed in patients who undergo subtotal resection. Further multicenter, cumulative case-based studies are essential to refine standardized diagnostic criteria and develop personalized therapeutic strategies for this rare, high-grade pediatric sarcoma.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the Health Research Project of the Kunming Municipal Health and Family Planning Commission (2023-01-04-001); the Kunming Health Science and Technology Personnel Training Project [2024-SW (Reserve Talents)-17]; and the Medical Technology Center [2025-SW (Technology) -10].

Data availability statement

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

Ethics statement

The studies involving humans were approved by The Ethics Committee of Kunming Children’s Hospital Affiliated to Kunming Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions

HW: Supervision, Writing – review & editing, Investigation, Writing – original draft, Visualization. JZ: Data curation, Validation, Funding acquisition, Writing – original draft, Writing – review & editing. MW: Writing – original draft, Writing – review & editing, Methodology, Investigation. LL: Supervision, Writing – original draft, Writing – review & editing, Visualization. SP: Investigation, Resources, Writing – review & editing, Writing – original draft. YX: Conceptualization, Supervision, Writing – review & editing, Writing – original draft, Resources.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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