Primary hypothyroidism presenting as neuropsychiatric symptoms and pituitary enlargement in a young woman: illustrative case.

BACKGROUND: Pituitary adenomas are the most common cause of pituitary enlargement and can potentially warrant surgical intervention. However, there are physiological causes of pituitary enlargement that can be reversed with hormone replacement alone. OBSERVATIONS: A 29-year-old female presented with acute onset paranoia to the psychiatry department. A computed tomography scan of the head revealed a 2.3 cm sellar mass with confirmation on magnetic resonance imaging. Testing showed a markedly elevated thyroid-stimulating hormone 1,600 µIU/mL (0.470-4.200 µIU/mL), suggesting pituitary hyperplasia. Treatment with levothyroxine replacement resulted in marked improvement in symptoms and resolution of pituitary hyperplasia on four month follow up. LESSONS: This rare presentation of severe primary hypothyroidism highlights the importance of evaluating for physiological causes of pituitary enlargement.

Staged endovascular treatment of a coexisting parasellar aneurysm and endoscopic resection of a pituitary macroadenoma: illustrative case.

BACKGROUND: Intracranial aneurysms and pituitary adenomas are relatively common pathologies that, in rare instances, may concurrently present. Their management poses considerable clinical and technical challenges. OBSERVATIONS: The authors present a case of a 66-year-old female patient with a fusiform aneurysm of the left internal carotid artery associated with a symptomatic pituitary macroadenoma that had been causing visual deficits for the past several years. She underwent successful placement of flow diverter stents across her aneurysm, followed by routine dual antiplatelet therapy to maintain stent patency. She underwent frequent serial radiographic, endocrine, and ophthalmological evaluations during this time to ensure stability of her pituitary adenoma. Following confirmation of aneurysm obliteration and subsequent de-escalation of antiplatelet medications to aspirin monotherapy, her tumor was subsequently resected via an endoscopic endonasal approach in a delayed fashion. LESSONS: The authors review the literature regarding management of these concurrent pathologies and describe the aspects of the case that led them to their chosen treatment strategy. An algorithm is proposed regarding the management of parasellar aneurysms with a concurrent diagnosis of pituitary tumor pathology.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Genetic characterization of an aggressive optic nerve pilocytic glioma.

Optic nerve glioma (ONG) is a rare, typically slow-growing WHO I grade tumor that affects the visual pathways. ONG is most commonly seen in the pediatric population, in association with neurofibromatosis type 1 syndrome. However, sporadic adult cases may also occur and may clinically behave more aggressively, despite benign histopathology. Genetic characterization of these tumors, particularly in the adult population, is lacking. A 39-year-old female presented with 1 month of progressive left-sided visual loss secondary to a enhancing mass along the left optic nerve sheath. Initial empiric management with focal radiotherapy failed to prevent tumor progression, prompting open biopsy which revealed a WHO I pilocytic astrocytoma of the optic nerve. Whole-exome sequencing of the biopsy specimen revealed somatic mutations in NF1,FGFR1 and PTPN11 that may provide actionable targets for molecularly guided therapies. Genetic characterization of ONG is lacking but is needed to guide the management of these rare but complex tumors. The genomic alterations reported in this case contributes to understanding the pathophysiology of adult sporadic ONG and may help guide future clinical prognostication and development of targeted therapies.

SPONTANEOUS RESOLUTION OF PRIMARY HYPERCORTISOLISM OF CUSHING DISEASE AFTER PITUITARY HEMORRHAGE.

OBJECTIVE: To describe a case of spontaneous resolution of primary hypercortisolism from Cushing disease (CD) due to pituitary apoplexy (PA). METHODS: Clinical, laboratory, and pathologic information are described. RESULTS: A 59-year-old female presented with a headache, a 2.3 cm sellar mass with a questionable hemorrhagic component, and clinical signs of hypercortisolism. On further evaluation, she had an increased 24-hour urine free cortisol, abnormal serum cortisol during a low dose dexamethasone suppression test, and an elevated plasma adrenocorticotropic hormone (ACTH), consistent with pituitary CD. As she was being prepared for surgical resection, she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism, and a repeat magnetic resonance imaging scan showed shrinkage of the sellar mass. She has been managed conservatively since and remains in clinical/biochemical remission until present time, 18 months following her initial presentation. CONCLUSION: We report a case of spontaneous resolution of CD from symptomatic hemorrhage within an ACTH-secreting pituitary adenoma, or PA. This has been rarely reported in the medical literature. The fact that she did not pass through a phase of adrenal withdrawal, makes us suspect a residual functional adenoma within or around the sella which may eventually grow, causing her disease to recur, as has been reported. Hence, continued monitoring will be required.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

This corrects the article DOI: 10.1038/ncomms14433.

Longitudinal analysis of treatment-induced genomic alterations in gliomas.

BACKGROUND: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. METHODS: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case. RESULTS: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency. CONCLUSIONS: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.

Integrated genomic characterization of IDH1-mutant glioma malignant progression.

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis.

BACKGROUND: Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. METHODS: We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. RESULTS: We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. CONCLUSIONS: We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Surgical navigation for meningioma surgery.

The use of surgical navigation systems (SNSs) is well established in intracranial surgery for gliomas and metastases yet some doubt its benefit in surgery for intracranial meningiomas. In this chapter we review the authors' experiences and literature on how use of surgical navigation may be useful in craniotomy for intracranial mengingiomas. With the exception of small convexity meningiomas, finding the tumor is not a common problem. The most important issues where the capabilities of SNS can be used to the surgeon's advantage are optimizing the bone and dural opening, avoiding arterial and venous structures, defining the frontal air sinuses and determining one's location within a large tumor devoid of landmarks. Contemporary SNS can provide instantaneous localization and orientation information, as well as utilize multimodality imaging that is required to address these problems and is an effective means of optimizing surgery for many intracranial meningiomas.