Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA ...sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.
Abstract
Background
Mature cystic teratoma (MCT) is the most common ovarian germ cell tumor with a typically excellent prognosis. Malignant change in a somatic component of an MCT is rare, occurring ...in approximately 1% of cases, and most commonly occurs in the sixth to seventh decades. Osteosarcoma arising within an MCT is exceedingly rare, with only seven previously reported cases. The median age affected is 54 years. At presentation, the tumor is often large with intra-abdominal metastases. The prognosis is dismal, with only one long-term survivor. We are reporting on the clinical, radiographic, and cytohistologic features of the eighth documented case of an osteosarcoma arising in an MCT.
Case Report
A 29-year-old female with a medical history of scimitar syndrome (partial anomalous pulmonary venous return) presented to the emergency room with pelvic pain concerning for ovarian torsion. Computed tomography showed a 14-cm cystic, solid, and fatty mass of the left ovary consistent with an atypical dermoid cyst. She underwent laparoscopic surgery notable for filmy adhesions and friability of the mass. Microscopically, the cyst was composed of dermal elements while the solid component demonstrated lobules of malignant cartilage in addition to osteoid production. The tumor cells stained positively for SATB2 and vimentin and were negative for EMA, cytokeratin AE1/AE3, S100, SALL4, PLAP, and OCT3/4. The abdominal fluid was positive for bizarre malignant cells that were strongly SATB2 positive. A subsequent PET scan highlighted extensive metastatic peritoneal deposits. The patient received one round of chemotherapy before dying 46 days after diagnosis.
Conclusion
Osteosarcoma arising in an MCT is a rare and aggressive malignancy with almost all cases resulting in death within months after diagnosis. While not entirely specific, SATB2 immunohistochemistry in conjunction with cytohistomorphology can aid in making the correct diagnosis, particularly in cytologic specimens where background tumor matrix is not present.
Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by upregulation of type I interferon response. It is associated with increased mortality and severe disabilities. Janus ...Kinase (JAK) inhibitors have shown effectiveness in treatment of AGS through blocking the downstream effects of interferon activation. We illustrate post-mortem histopathologic findings in a patient with AGS who received baricitinib treatment for a duration of over 4 years, initiating at a remarkably young age of 2 months. We observed global cerebral atrophy, markedly diminished white matter, abundant calcifications involving supratentorial white matter, basal ganglia, dentate nuclei, and brainstem. This study showed profound central nervous system (CNS) sequelae despite early initiation of treatment. Our findings highlight the potential necessity for therapeutic options with enhanced CNS bioavailability.
Abstract BACKGROUND Choroid plexus tumors (CPTs) consist of a diverse group of neoplasms, more prevalent in children. They include choroid plexus papillomas (CPPs, grade 1), atypical choroid plexus ...papillomas (aCPPs, grade 2), and choroid plexus carcinomas (CPCs, grade 3). Traditional grading of CPTs relies on histologic assessment, but morphologic criteria for determining tumor grade are subjective. Evidence suggests incorporation of clinical, radiologic, and molecular characteristics may increase diagnostic accuracy. Here, we investigated the multi-modal associations of CPT subtypes to develop a classification system to aid in CPT subtype diagnostics. METHODS We aggregated an integrative dataset that consists of digitized whole-slide images, NGS sequencing panels, methylation arrays, and magnetic resonance spectroscopy (MRS) spectra from in-house and publicly available data sources (n=110). We tested for clinically significant associations and established multi-modal profiles of CPT subtypes, as well as a machine-learning classifier to predict multi-modal based CPT subtypes. RESULTS CPT subtypes exhibit distinct characteristics across modalities with consistent correlations across anatomy, molecular, and metabolic datasets. Computer-vision models achieved high accuracy (89.7%) in classifying CPT subtypes using H&E images. Ki-67 immunostaining displayed increased reactivity in CPC compared to CPP and aCPP (p = 0.007, ANOVA). Methylation-based classifications confidently predicted CPP and CPC subtypes, while aCPP tumors clustered with either CPP or CPC due to the lack of a defined subtype. Molecular variants (i.e. TP53, MYCN) were significantly associated with CPC (p = 0.007, ANOVA). Metabolites such as inositol (p = 0.031) and choline (p = 0.004) were associated with CPT grade based on MRS-spectra. CONCLUSION Multi-modal analysis reliably separates CPTs by grade. The study underscores the significance of integrating multi-modal datasets in refining the accuracy of diagnosis and prognosis of CPTs. Continued research will focus on a multi-modal approach to improve prediction of aggressive behavior and understanding of inherent metabolic heterogeneity of CPT subtypes.
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