A recurrent SMARCB1/INI-1-deficient poorly differentiated chordoma in the posterior cranial fossa of a 2-year-old female

To the Editor: Chordoma is a rare primary malignant bone tumor, which usually includes three subtypes: classic, chondroid, and dedifferentiated.1 In 2020, the 5th edition of World Health Organization Classification of Soft Tissue and Bone Neoplasms classified poorly differentiated chordoma (PDC) as a special subtype of chordoma.2 Atypical histological features for classical chordoma, highly aggressive clinical course, unique immunohistochemical features with absent INI1 expression, and exclusive genetic alteration with the inactivation of the SMARCB1/INI1 gene make PDC different from other tumors. Herein, we present a rare case of recurrent pediatric PDC in the posterior cranial fossa. A 2-year-old female was referred to our hospital with the complaint of being unable to walk for more than 10 days. She had a surgical history of a posterior cranial fossa mass, with a pathological diagnosis of clear cell meningioma in a local hospital 2 months prior. Magnetic resonance imaging showed a mass with slight hypointensity on T1-weighted and slight hyperintensity on T2-weighted image scanning, and significant inhomogeneous contrast enhancement (Figure 1A) in the left cerebellar hemisphere-pontine pedis region-cervical vertebral canal. Subtotal tumor resection was performed. Grossly, the resected specimen measured about 2.5 × 2 × 0.7 cm. Histologically, rhabdoid, spindled, and epithelioid cells with abundant clear or eosinophilic cytoplasm and pleomorphic nuclei with prominent nucleoli were arranged in sheets or nests (Figure 1B,C). Focal tumor necrosis (Figure 1D), mitoses, and lymphocyte infiltration (Figure 1E) were also observed. Immunohistochemically, the tumor cells were strongly positive for brachyury (Figure 1F), pan-cytokeratin, and epithelium membrane antigen (Figure 1G), and negative for S-100, INI1 (Figure 1H), glial fibrillary acidic protein, desmin, progesterone receptor, and α-smooth muscle actin. The Ki-67 proliferation index was approximately 30%. Enhanced copy number variation analysis by Illumina DNA methylation arrays revealed deletion of chromosome 4p and partial deletion of chromosome 22q (Figure 1I). The final diagnosis was SMARCB1/INI-1-deficient PDC (SIDPDC) as demonstrated by histopathology and genome-wide DNA methylation profiling. Radiation therapy was administered after surgery. The child died a month after the second excision. Written informed consent was obtained from her parents. SIDPDC mostly affects children.3 Except for eight cases in adults, the literature includes only 62 pediatric SIDPDC cases, with 34 females and 28 males (average age: 5.4 years) including our case.3-6 Tumor locations are clivus or skull base (n = 52), cervical spine (n = 5), sacrococcygeal bone (n = 2), dura (n = 1), and the posterior fossa (n = 2). Computed tomography scans mainly show osteolytic and destructive bone masses. Magnetic resonance imaging scans usually show hypointensity on T1-weighted and hyperintensity on T2-weighted images with enhancement on contrast imaging.3 SIDPDC is characterized by focal rhabdoid morphology, increased cell density, solid growth patterns, evident cell atypia, and abundant mitotses with positive brachyury expression and absent INI1 expression.4 Genetic study reveals homozygous or heterozygous SMRACB1 gene loss. DNA methylation profiling is helpful for the diagnosis and differential diagnosis, but it is seldom reported in SIDPDC. Unsupervised clustering analysis shows SIDPDC loss of homozygosity or heterozygosity at chromosome 22q, resulting in inactivation of the SMARCB1/INI1 gene, different from both classical chordoma and atypical teratoid/rhabdoid tumors, which harbor point mutations of the SMARCB1/INI1 gene.4, 7, 8 Surgical resection with radiotherapy and chemotherapy is the first-choice treatment modality. Adjuvant radiotherapy and chemotherapy have effects on both progression-free survival and overall survival in PDC patients in univariate and/or multivariate analyses.1 The prognosis has been dismal with a median overall survival of 13 months in children.2 Zhang et al. analyzed the transcriptome of 90,691 single cells in the first single-cell RNA sequencing of skull base chordoma and identified several targets that could potentially be translated into therapy. They found that a stem-like cluster targeting drug, YL-13027, as a TGF-βR1 inhibitor, combined with PD-1 inhibitor, may be a new therapeutic strategy for the treatment of patients with skull base chordoma.9 Ngo and Postel-Vinay suggested that immunotherapy (including immune checkpoint inhibitors) may represent a promising treatment strategy for SMARCB1-deficient tumors.10 The EZH2 inhibitor tazemetostat has been in clinical trials for SMARCB1/INI-1-deficient tumors, and has been approved by the United States Food and Drug Administration for the treatment of advanced epitheloid sarcoma.11 The drug might be promising for the treatment of SIDPDC. In summary, we present the first posterior cranial fossa SIDPDC with genome-wide DNA methylation profiling study. Improved prognosis for patients with SIDPDC is urgent and will rely on further research. The authors declare no conflicts of interest.