Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA.

Diffuse midline glioma (DMG) is a highly malignant childhood tumor with an exceedingly poor prognosis and limited treatment options. The majority of these tumors harbor somatic mutations in genes encoding histone variants. These recurrent mutations correlate with treatment response and are forming the basis for molecularly guided clinical trials. The ability to detect these mutations, either in circulating tumor DNA (ctDNA) or cerebrospinal fluid tumor DNA (CSF-tDNA), may enable noninvasive molecular profiling and earlier prediction of treatment response. Here, the authors review ctDNA and CSF-tDNA detection methods, detail recent studies that have explored detection of ctDNA and CSF-tDNA in patients with DMG, and discuss the implications of liquid biopsies for patients with DMG.

Intracranial temporal bone angiomatoid fibrous histiocytoma: illustrative case.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare, slowly progressive neoplasm that most commonly occurs in soft tissues. AFH rarely occurs in bone such as the calvaria. The authors present a case of AFH in the petrous temporal bone, which, to their knowledge, is the first case of AFH in this location. OBSERVATIONS: A 17-year-old girl presented with worsening positional headaches with associated tinnitus and hearing loss. Imaging demonstrated an extraaxial mass extending into the right cerebellopontine angle, with erosion of the petrous temporal bone, with features atypical for a benign process. The patient underwent retrosigmoid craniotomy for tumor resection. Pathology was consistent with a spindle cell tumor, and genetic testing further revealed an EWSR1 gene rearrangement, confirming the diagnosis of AFH. The patient was discharged with no complications. Her symptoms have resolved, and surveillance imaging has shown no evidence of recurrence. LESSONS: The authors report the first case of AFH in the petrous temporal bone and only the second known case in the calvaria. This case illustrates the importance of the resection of masses with clinical and imaging features atypical of more benign entities such as meningiomas. It is important to keep AFH in the differential diagnosis for atypical masses in the calvaria and skull base.

Pigmented epithelioid melanocytoma: a rare lytic bone lesion involving intradural extension and subtotal resection in a 14-month-old girl.

Pigmented epithelioid melanocytomas (PEMs) are low-grade, intermediate-type borderline melanocytic tumors with limited metastatic potential. To date, PEMs have been treated via gross-total resections. Postoperative recurrence and mortality are rare. This case highlights a unique presentation of a PEM that involved bone destruction and intradural infiltration, which required a subtotal resection. To the authors' knowledge, this is the first report of a PEM extending through the dura and necessitating subtotal resection, which is contrary to the standard of care, gross-total resection. Surveillance imaging 10 months after resection remained negative for clinical and radiological recurrence.

Liquid biopsy for diffuse intrinsic pontine glioma: an update.

Diffuse intrinsic pontine glioma (DIPG), otherwise known as diffuse midline glioma with H3K27M mutation, is a devastating brainstem glioma without a cure. Efforts are currently underway to better optimize molecular diagnoses through biological sampling, which today remains largely limited to surgical biopsy sampling. Surgical intervention is not without its risks, and therefore a preference remains for a less invasive modality that can provide biological information about the tumor. There is emerging evidence to suggest that a liquid biopsy, targeting biofluids such as CSF and blood plasma, presents an attractive alternative for brain tumors in general. In this update, the authors provide a summary of the progress made to date regarding the use of liquid biopsy to diagnose and monitor DIPG, and they also propose future development and applications of this technique moving forward, given its unique histone biology.

Clinical and biological significance of adamantinomatous craniopharyngioma with CTNNB1 mutation.

OBJECTIVE: The Wnt/ß-catenin signaling pathway is strongly implicated in the pathogenesis of adamantinomatous craniopharyngioma (adaCP). However, there is no evidence that the CTNNB1 mutation activates the target gene of Wnt/ß-catenin signaling, and it is unknown whether it affects the tumorigenesis of adaCP. To assess the effect of the CTNNB1 mutation of adaCP, the authors analyzed the correlation between the mutation and clinical, radiological, pathological, and biological findings. METHODS: Between 2003 and 2015, 42 patients (24 male and 18 female, median age 42 years) with either papillary craniopharyngioma (papCP) or adaCP underwent tumor resection at the authors' institution. BRAF V600E and CTNNB1 in papCP and adaCP samples were sequenced by next-generation sequencing and the Sanger method, and mRNA expression levels of Axin2 and BMP4 were evaluated by RT-PCR. Axin2, BMP4, ß-catenin, and BRAF expression were evaluated by immunohistochemistry. Other data were collected from clinical reports. RESULTS: The BRAF V600E mutation was detected in all 10 cases of papCP (100%). CTNNB1 exon 3 mutations were detected in 21 of 31 (68%) cases of adaCP, excluding 1 case for which there were no available sequence data. The mRNA expression level of Axin2 was significantly higher in adaCPs with a CTNNB1 mutation than in those without (p < 0.05). The immunohistochemical findings of Axin2 and BMP4 did not correlate with CTNNB1 mutation positivity. When patients who received adjuvant radiation therapy were excluded, progression-free survival was shorter in the mutation-positive group than in the mutation-negative group (log-rank test, p = 0.031). Examination of clinical characteristics and immunohistochemical findings of adaCPs showed that there was no significant correlation between CTNNB1 mutation positivity and age, sex, tumor volume, gross-total resection, optic tract edema, calcification, or T1 signal intensity of cyst fluid on MRI, ß-catenin, and MIB-1 index. CONCLUSIONS: These results raise the possibility that the CTNNB1 mutation in adaCP may be associated with disease recurrence, and genes related to the Wnt/ß-catenin signaling pathway might represent a therapeutic target.

RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance.

OBJECTIVE Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease. The authors conducted a genetic study of really interesting new gene (RING) finger protein 213 ( RNF213); actin alpha 2 ( ACTA2); BRCA1/BRCA2-containing complex subunit 3 ( BRCC3); and guanylate cyclase 1, soluble, alpha 3 ( GUCY1A3) as well as a clinical phenotype analysis in Chinese MMD patients to determine whether genetic differences are responsible for the different clinical features that appear in MMD in different ethnicities. METHODS A panel was designed to identify disease-causing mutations in MMD genes and those involved in related disorders ( RNF213, ACTA2, BRCC3, and GUCY1A3). The panel was used to detect disease-causing mutations in 255 Chinese MMD patients. Genotype and allele frequencies were compared between patients and 300 controls. A mutation segregation analysis was performed in 34 families, and genotype-phenotype correlations were made. RESULTS Twenty-seven rare missense variants of RNF213 were identified and were not found in controls. Among them, p.R4810K was identified in 31.4% of patients (80 of 255) with MMD. Significantly higher frequencies of the A allele and G/A genotype of p.R4810K were observed in MMD patients compared with controls (χ2 = 104.166, p < 0.000). Twenty-five rare variants were identified in 10.6% of patients (27 of 255) without p.R4810K variants. Segregation analysis supported an association between MMD and 3 variants. No possible disease-causing mutations were identified in ACTA2, BRCC3, or GUCY1A3. Compared with patients without the rare variants in RNF213, the p.R4810K heterozygous patients were younger at diagnosis (25 vs 29 years old, p = 0.049) and had more familial cases (24% vs 4.4%, p = 0.000), ischemic cases (81.3% vs 67.5%, p = 0.037), and involvement of the posterior cerebral artery (52% vs 32.5%, p = 0.007). CONCLUSIONS RNF213 is the major susceptibility gene in Chinese MMD patients. The spectrum of rare variants identified in Chinese MMD patients was diverse. Compared to patients without the rare variants in RNF213, the p.R4810K heterozygous patients exhibited different clinical features.