We present a case involving a 71-year-old female with a past medical history of hypertension and osteoarthritis who presented with a 2-month history of progressive bilateral lower extremity weakness, paresthesia and hyperalgesia. MRI of the thoracic spine demonstrated a 60 mm intradural intramedullary expansile lesion spanning C7–T3, with avid contrast enhancement and surrounding vasogenic edema (Figure 1A). Remaining central nervous system (CNS)/body imaging demonstrated no further lesions. The differential diagnosis included ependymoma, astrocytoma and spinal metastases.

Figure 1.

Radiographic evolution of primary DICER1-mutant CNS sarcoma of the spinal cord. (A) Preoperative sagittal contrast-enhanced T1-weighted MRI (CE T1W MRI) reveals a 60 mm intradural, intramedullary expansile lesion (arrows) extending from C7 to T3, with associated vasogenic edema. (B) Sagittal CE T1W MRI obtained at 6 months follow-up shows extensive leptomeningeal dissemination and multiple new metastatic lesions (arrows) involving the brainstem, cervical and thoracic spinal cord.

The patient underwent intramedullary tumor resection. Histopathology revealed a highly cellular neoplasm comprised of sheets of pleomorphic cells, including spindle and giant cells, focal eosinophilic cytoplasmic globules (Figure 2A–B), a fine reticulin network, numerous mitoses and a Ki-67 proliferative index of 40% (Figure 2C). Immunohistochemistry (IHC) demonstrated strong CD56/Neural Cell Adhesion Molecule (NCAM) (Figure 2D) and regional Glial Fibrillary Acidic Protein (GFAP) (Figure 2E) and S100 staining, suggesting partial neural differentiation, as well as regional desmin immunolabeling. The tumor nuclei exhibited strongly positive p53, loss of ATRX (Figure 2F) and retained H3K27me3 expression. The tumor cells were immuno-negative for IDH1^R132H, Epithelial Membrane Antigen (EMA), synaptophysin, neurofilament and myogenin.

Figure 2.

H&E-stained sections (A, B) showing pleomorphic tumor cells, focally containing eosinophilic cytoplasmic globules (B, arrows); immunohistochemistry showing elevated Ki-67 proliferative index (C), strong CD56/NCAM (D) and regional GFAP (E) immunostaining and loss of ATRX expression in tumor nuclei (F). (Original magnifications A × 63, B × 100, C–F × 40).

Targeted next-generation sequencing (NGS) identified a pathogenic DICER1 loss-of-function variant (c.5438A > G, p.[Glu1813Gly]), known as E1813G, in the RNase IIIb catalytic domain, with a variant allele frequency of 0.56, supporting a heterozygous mutation. Additionally, an ATRX loss-of-function variant (c.979G > T, p.[Glu327]) and a TP53 missense variant (c.747G > T, p.[Arg249Ser]) were detected. No pathogenic variants were found in IDH1/2, H3F3A, HIST1H3B or BRAF, and the MGMT promoter was unmethylated. Methylation-based profiling using the DKFZ CNS and NIH Bethesda classifiers ^{Reference Capper, Jones and Sill1,Reference Kamihara, Paulson and Breen2} confirmed a strong match to the “Primary Intracranial Sarcoma, DICER1-Mutant” class, with classification scores of 0.819 and 0.813, respectively. Copy number variation analysis revealed losses in chromosomes 9/11/19/21, with segmental losses on 2q/3p/4q/6q/10p/16p/17q/18p/18q, gain of chromosomes 1/5/12/20 and segmental gain of 7p/10q/16q/17p. This genomic signature is consistent with previously reported DICER1-mutant CNS sarcomas. ^{Reference Capper, Jones and Sill1,Reference Koelsche, Mynarek and Schrimpf3}

Adjuvant radiotherapy to the tumor cavity and adjacent expansile edematous spinal cord with a dose of 54 Gy in 30 fractions was delivered. Once the diagnosis of primary DICER1-mutant CNS sarcoma was confirmed, the consensus from a multidisciplinary discussion including members from several institutions recommended no further adjuvant systemic therapy given the tumor type and mutational signature, in conjunction with the treatment she had already received. Surveillance 6-month MR demonstrated new diffuse leptomeningeal enhancement along the surface of the spinal cord, with numerous new lesions throughout the brainstem, cervical and thoracic spine (Figure 1B). The DICER1 loss-of-function variant E1813G detected in the patient’s tumor as a probable heterozygous mutation is a known “hot-spot” residue in the RNase IIIb catalytic domain, responsible for posttranslational gene regulation. Although such variants might possibly act in a dominant-negative fashion, the patient’s grandson had a pleuropulmonary blastoma (PPB) at the age of 4 years, with negative DICER1 germline testing at the time of diagnosis, but with the variant detected in his grandmother’s tumor now reintroducing concern of a DICER1 tumor predisposition syndrome. In light of this family history, targeted DICER1 analysis was performed in the patient, and repeat testing was initiated in her grandson. Germline analysis of the patient’s peripheral blood did not reveal any pathogenic DICER1 variants, and the tumor mutation was absent in the germline specimen, confirming its somatic origin. The grandson has since undergone repeated clinical germline testing for DICER1 with consistently negative results. Although germline testing has thus far been negative, the coexistence of a DICER1-mutant CNS sarcoma in the proband and a family history of PPB remains highly suggestive of DICER1 predisposition. For this reason, referral to clinical genetics was advised, with the possibility of considering pursuing additional or research-based germline analyses to account for cryptic or currently undetectable pathogenic variants.

This report represents the first documented case of a primary DICER1-mutant CNS sarcoma within the spinal cord, expanding its recognized anatomical spectrum beyond intracranial locations. DICER1-mutant CNS sarcomas are rare, high-grade mesenchymal neoplasms recently recognized in the 2021 World Health Organization Classification of Tumors of the CNS. They occur almost exclusively intracranially in the cerebral hemispheres of children and young adults. ^{Reference Kamihara, Paulson and Breen2} These tumors result from biallelic inactivation of the DICER1 gene, typically involving a germline loss-of-function variant paired with a somatic “hotspot” mutation in DICER1’s RNase IIIb domain, although “de novo” DICER1 mutations can also occur, ultimately impairing miRNA biogenesis and disrupting cellular differentiation. ^{Reference Foulkes, Priest and Duchaine4} The DICER1 gene (14q32.13) encodes a type III ribonuclease essential for miRNA processing, chromatin remodeling and apoptosis. ^{Reference Foulkes, Priest and Duchaine4} Histologically, they exhibit undifferentiated spindle or pleomorphic morphology, often showing focal rhabdomyoblastic differentiation and eosinophilic cytoplasmic globules. ^{Reference Koelsche, Mynarek and Schrimpf3} These tumors present significant diagnostic challenges due to their rarity and histopathologic overlap with other high-grade CNS neoplasms. In the present case, IHC revealed partial neural differentiation, consistent with a previously reported case ^{Reference Yao, Duan, Feng, Yan and Qi5} of DICER1-mutant CNS sarcoma. Spindle cell morphology, eosinophilic cytoplasmic globules and a high Ki-67 proliferative index are characteristic features of DICER1-mutant sarcomas; however, definitive diagnosis requires molecular confirmation. ^{Reference Kamihara, Paulson and Breen2} NGS identified the pathogenic DICER1 mutation in the RNase IIIb domain, and methylation profiling demonstrated a high-confidence match to the unique epigenetic signature of DICER1-mutant sarcomas, ^{Reference Capper, Jones and Sill1,Reference Kamihara, Paulson and Breen2} thereby establishing the final diagnosis. Clinically, DICER1-mutant sarcomas exhibit an aggressive disease course, with rapid progression and a high recurrence rate following resection. ^{Reference Cardona, Chamorro Ortiz and Ruíz-Patiño6} Although adjuvant chemotherapy followed by radiotherapy has shown potential benefit in intracranial DICER1-mutant sarcomas, ^{Reference Cardona, Chamorro Ortiz and Ruíz-Patiño6} treatment paradigms remain undefined, particularly for lesions arising within the spinal cord. Surveillance strategies are therefore essential for monitoring tumor recurrence and progression. ^{Reference Bakhuizen, Hanson and van der Tuin7} In parallel, germline testing informs genetic counseling and screening for DICER1-associated malignancies in at-risk individuals in affected families. ^{Reference Schultz, Williams, Kamihara, Stewart, Harris and Bauer8}