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Chordoid meningioma is a morphological variant of meningioma designated as WHO grade 2. However, the recurrence rates varied widely in different case series, and to date, a unifying molecular genetic signature has not been identified. Among 1897 meningiomas resected at our institution, we identified 12 primary chordoid meningiomas from 12 patients. Histologically, all 12 cases had predominant (> 50%) chordoid morphology. Ten were otherwise grade 1, and two were also atypical. We performed DNA global methylation profile, copy number variation analysis, and targeted next-generation sequencing on 11 chordoid meningiomas, and compared to those of 51 non-chordoid, mostly high grade meningiomas. The chordoid meningiomas demonstrated a unique methylation profile in tSNE, UMAP, and hierarchical heatmap clustering analyses of the most differentially methylated CpGs. The most common copy number variation in chordoid meningioma was loss of 1p (7/11, 64%). Three chordoid meningiomas had 2p loss, which was significantly higher than the non-chordoid control cohort (27% vs 7.2%, p = 0.035). 22q loss was only seen in the two cases with additional atypical histological features. Chordoid meningiomas were enriched in mutations in chromatin remodeling genes EP400 (8/11,73%) KMT2C (4/11, 36%) and KMT2D (4/11, 36%), and showed low or absent NF2, TERT, SMO, and AKT1 mutations. Prognosis wise, only one case recurred. This case had atypical histology and high-grade molecular features including truncating NF2 mutation, 1p, 8p, 10, 14, 22q loss, and homozygous deletion of CDKN2A/B. Progression free survival of chordoid, otherwise grade 1 meningioma was comparable to non-chordoid WHO grade 1 meningioma (p = 0.75), and significantly better than chordoid WHO grade 2 meningioma (p = 0.019). Conclusion: the chordoid histology alone may not justify a universal WHO grade 2 designation. Screening for additional atypical histological or molecular genetic features is recommended.

Identification of molecular genetic alterations has become an important part of diagnosis and care of patients with brain tumors. Comparisons of immunohistochemistry (IHC) with DNA sequencing techniques have suggested that IHC is useful for identifying surrogates of mutations in gliomas; however, studies of the efficacy are relatively few. Our aim was to compare IHC in our neuropathology laboratory with a commercially available next-generation sequencing (NGS) platform, Tempus xT. We studied 212 immunohistochemically stained sections of gliomas to identify mutations of isocitrate dehydrogenase (IDH), p53, BRAF, the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), and histone H3. Tempus xT NGS confirmed the IHC diagnosis of IDH1/R132H in 102 of 102 patients (100%), BRAF/V600E in 14 of 14 (100%) patients and H3/K27M in 10 of 10 (100%) patients. For p53, NGS confirmed the IHC diagnosis of mutation in 47 of 53 (87%) patients. For 6 patients, IHC was interpreted as wild-type while NGS indicated a mutation. NGS confirmed the IHC diagnosis of ATRX mutation in 29 of 31 (94%) patients. In 1 patient, IHC predicted a mutation that was not confirmed by NGS, and in another, IHC predicted wild-type, but NGS showed mutant. In 2 other patients, IHC diagnosis of ATRX mutation was equivocal; 1 was mutant and 1 was wild-type by NGS. Our single-center study suggests that IHC for IDH1/R132H, BRAF/V600E, and H3/K27M is highly reliable and may be used confidently in clinical practice. IHC for p53 and ATRX mutations is often reliable but possibly problematic, and genetic studies may be necessary to determine astrocytic or oligodendroglial differentiation.

Background Rathke cleft cysts (RCCs) are known sellar/suprasellar lesions that can grow and become symptomatic. For most asymptomatic lesions, stability is a typical outcome of surveillance; however, random relapse or cyst size fluctuation may also be observed. The conventional treatment for growing cysts is transsphenoidal removal. Methods A literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. For significance, all journals were screened. Only records of tissue diagnosed RCCs with changes in size were included. Age and sex at diagnosis, size of the lesion, symptoms (if any), pituitary dysfunction, follow-up period, and size reduction were included in the data items. Results A total of 4 articles where selected after the second exclusion method. Three articles where case series and one was a case report. Eight total patients where histologically proven to have Rathke cleft cysts which fluctuated in size without intervention. Conclusion This review shows that RCCs can decrease or fluctuate in size following a dynamic process that is not fully understood. In the absence of symptoms, a larger cyst or an absolute increase in a cyst size, which may traditionally provoke an early surgical intervention, should be assessed and managed carefully to avoid potentially unneeded surgical morbidity.

Distant spread of pituitary adenoma outside the sellar/suprasellar region is classified as pituitary carcinoma. Cerebrospinal fluid (CSF)-born spread of pituitary adenoma can occur after tumor cell spillage into the CSF space after surgery, irradiation, or apoplexy and is not necessarily related to intrinsic tumor biology.To systematically review the literature and describe the clinical characteristics and treatment strategies of patients with pituitary carcinomas. We further present 2 cases from our institution.A single-center retrospective review of patients with pituitary adenoma spread to distant intracranial locations between 2000 and 2020 was performed. Electronic databases were searched from their inception to May 25, 2021, and studies describing patients with pituitary spread to distant locations were included.Of 1210 pituitary adenoma cases reviewed, 2 (0.16%) showed tumor spread to distant locations. We found 134 additional cases (from 108 published articles) resulting in a total of 136 cases (61.9% were male). The time to tumor spread ranged between 0 and 516 months (median: 96 months). The follow-up duration ranged between 0 and 240 months (median: 11.5 months). All but 2 patients (98.5%) underwent surgical resection before adenoma spread. The 2 exceptions included a patient with evidence of an apoplectic event on autopsy and another patient with leptomeningeal pituitary spread but an unclear history of apoplexy. Elevated tumor markers were not linked to poor outcomes.Distant spread of pituitary adenoma may occur after surgery, irradiation, or apoplexy. It is not necessarily associated with a malignant clinical course.

BackgroundHigh-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.MethodsWe measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival.ResultsElevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P ConclusionsThe data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome.Key Points1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.

Mucoepidermoid carcinoma (MEC) is the most common primary salivary gland malignancy. While salivary gland neoplasia is rare in children, MEC is much more likely to occur in the pediatric population than Warthin tumor, a common benign salivary gland neoplasm associated with smoking and older age. The recently-reported Warthin-like variant of MEC bears a striking histologic resemblance to Warthin tumor, representing a potential diagnostic pitfall. Therefore, low-power observation of Warthin-like features in pediatric salivary gland tumors should prompt careful diagnostic consideration of Warthin-like MEC. Two cases of Warthin-like MEC in the parotid glands of teenaged patients were identified in the archives of the Department of Pathology at Children’s Medical Center in Dallas, Texas. Surgical material for each case was reviewed and both diagnoses were verified. Fluorescence in situ hybridization (FISH) for CRTC1–MAML2 fusion was performed in both cases. Histologically, neither tumor exhibited the classic bilayer of oncocytic epithelial cells characteristic of Warthin tumor. Instead, the neoplastic epithelial cells exhibited architectural and cytologic atypia, with mucous cells interspersed. CRTC1–MAML2 gene fusions were identified via FISH and confirmed the diagnosis of MEC in both cases. Of note is that the second patient’s tumor recurred with features of conventional MEC, indicating the potential for Warthin-like MEC to undergo this morphologic change. The present cases illustrate that Warthin-like MEC, like conventional MEC, may occur in the pediatric population. Pediatric and head and neck pathologists must be aware of this variant’s existence and diagnostic criteria to avoid misdiagnosis as benign Warthin tumor.

Cancers reprogram their metabolism and the resulting alterations in metabolite abundance can be monitored in patients noninvasively using proton magnetic resonance spectroscopy (MRS). We evaluated glutamine, glycine and 2-hydroxyglutarate (2HG) in 27 adult subjects with gliomas (17 male and 10 female; age 22 - 69, median 39 years) using optimized MRS at 3T (PRESS TE 97ms) and examined their association with post-gadolinium enhancement, cell proliferation rate (MIB-1 labeling index), and overall survival of patients. The tumors included 9 glioblastomas (3 IDH mutated and 6 IDH wildtype), 10 astrocytomas (7 IDH mutated and 3 IDH wildtype), and 8 oligodendrogliomas (IDH mutated). The concentrations of glutamine and glycine were both significantly higher in enhancing tumors than in non-enhancing tumors (p=0.001 and 0.0001, respectively). The concentrations of glutamine and glycine were both positively correlated with MIB-1 (p=4E-5 and 1E-7, respectively). The sum of glutamine and glycine levels showed stronger association with MIB-1 (p=5E-10, r=0.89). In the Kaplan-Meier overall survival analysis, the survival was significantly shorter in patients with glutamine levels higher than 4.1 mM than those with concentrations less than 4.1 mM (p=0.02). For glycine, the patients with higher than 2.4 mM showed association with poor survival (p=0.03). The sum of glutamine and glycine levels showed stronger association with overall survival (p=0.008, cutoff 8.5mM). 2HG level greater than 0.5 mM was associated with long survival (p=0.01). We tested metabolic ratios to 2HG, in which 2HG estimates less than 1 mM were put as 1 mM (avoiding infinite ratios arising from null 2HG cases). The glutamine/2HG, glycine/2HG, and (glutamine+glycine)/2HG showed strong association with overall survival (p=2E-4, 2E-5 and 4.5E-7, respectively). Our data suggest that increased metabolism of glutamine and glycine is closely associated with rapid cell proliferation and poor survival, suggesting the metabolites are imaging biomarkers of glioma aggressiveness.

Noonan syndrome is a genetic condition with a heterogeneous phenotype and multisystem involvement. The pathogenesis of this disorder has been attributed to the mutations in the RAS/MAPK signaling pathway involved in cell proliferation and differentiation. The most common clinical presentations are related to cardiovascular abnormalities with congestive heart failure as the most common mechanism of death. We present the autopsy findings from a Noonan syndrome patient who died as a result of an unusual form of right ventricular obstruction associated with a rare PTPN11 variant previously reported without details of the cardiac findings. Discussion follows that includes overview of the incidence, genetic causes, types of right-sided obstructive lesions, PTPN11 genotype—cardiac phenotype correlations, and other potential mechanisms that may contribute to disease heterogeneity.

Pleomorphic xanthoastrocytoma (PXA) is a slow-growing neoplasm that predominantly affects the pediatric and young adult population. This neoplasm has a good prognosis, with a median 10-year survival rate of 70%. The majority of tumors are supratentorial and arise in the temporal lobe, while spinal tumors are extremely rare, with only 8 reported cases. Molecular perturbations involving the MAPK/ERK signaling pathway have been described in PXAs. The most common mutation is BRAF V600E in 60%-80% of cases. Other mechanisms activating this pathway in the absence of this mutation are rare and include CRAF (RAF1) fusion genes. We report a PXA case in the cervical spinal cord of a 49-year-old man with slowly progressive coordination difficulties and extremity numbness. The tumor was negative for the V600E mutation, but 2 RNA sequencing platforms detected a QKI-RAF1 fusion (t(6; 3)(q26; p25)), which has not been previously reported in PXAs. This fusion is known to activate MAPK/ERK and PI3K/mTOR signaling. Although first- and second-generation RAF inhibitors are predicted to be ineffective, this fusion may be targetable by the novel RAF inhibitor LY3009120 and to some extent by the MEK inhibitor trametinib. Genetic analysis to screen for MAPK/ERK pathway mutations is warranted on PXAs negative for the V600E mutation.

Adult brainstem gliomas are difficult to classify based on radiologic and histologic features. A K27M mutation in histone 3 has been described to identify high-grade midline gliomas associated with a particularly unfavorable prognosis. While initially considered a pediatric entity, it is now known that H3K27M-mutant brainstem gliomas occur in all age groups, but they are less well understood in adults. We studied clinical, radiologic, and pathologic features of 25 brainstem gliomas diagnosed at our institution between 1994 and 2017 in subjects at least 18 years old. Seven tumors (28%) were positive for the H3K27M mutation, and their median overall survival was significantly shorter than in the H3-wildtype group (p = 0.004). Although the mutation was invariably associated with a poor prognosis, our study also illustrates the radiologic and pathologic heterogeneity in this molecular tumor subtype. The results showed that H3K27M-mutant status and clinically aggressive course cannot be ruled out based on low-grade histology on the initial biopsy, exophytic growth, only focal or minimal enhancement or an extrapontine location, such as midbrain or medulla. These results favor an integrated approach employing a combination of clinical, radiologic, histologic features as well as H3K27M immunohistochemistry for the diagnostic subclassification of adult brainstem gliomas.

Malignant tumors reprogram cellular metabolism, resulting in altered concentration of some metabolites. We measured glycine (GLY) and 2-hydroxyglutarate (2HG) in 37 adult subjects with gliomas noninvasively using proton magnetic resonance spectroscopy and examined their association with immunochemical analyses of tumor biopsies and overall patient survival. MRS data were acquired using optimized point-resolved spectroscopy (PRESS TE 97ms) at 3T and the millimolar concentrations of metabolites were estimated with reference to water. The GLY concentration was positively correlated with MIB-1 proliferation index (p=1.7×10−7). The GLY estimation was inversely correlated with expression of glycine decarboxylase (GLDC) (p=0.02), without showing significant correlation with expression of serine hydroxymethyltransferase 2 (SHMT2). There was a strong association between elevated GLY and breakdown of blood-brain barrier, as indicated by higher GLY in post-gadolinium enhancing tumors than in non-enhancing tumors (p=10−6). In contrast, 2HG did not show significant correlation with MIB-1 index or post-gadolinium enhancement. In Kaplan-Meier survival analysis, patients with GLY level above 2.5 mM were significantly associated with poor survival (log-rank p value 0.003; median survival 8.8 months), compared to those with GLY level below 2.5 mM. The hazard ratio of the high-GLY tumors with respect to the low-GLY tumors was 6.7. 2HG level lower than a detection threshold (1 mM), which may represent IDH wildtype tumors, was associated with poor survival (p=0.01). In addition, we performed Kaplan-Meier analysis for the GLY-to-2HG ratio. 2HG estimates less than 1 mM were put as unity. Tumors with GLY/2HG > 2 showed strong association with poor survival (p=5.2×10−9; medial survival 5.4 months), with a 12-fold higher hazard rate compared to those with GLY/2HG < 2. Together, our data suggest that GLY-mediated one-carbon metabolism may underlie rapid cell proliferation in malignant gliomas and that elevation of GLY provides a noninvasive imaging biomarker predictive of cell proliferation and patient outcome.