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Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases., The treatment of brain metastases is often limited by the ability to diagnose their origins. Here the authors generate DNA methylomes from the three most frequent types of brain metastases, identify epigenetic signatures specific to each type of metastasis and construct a DNA methylation-based classifier (BrainMETH) to advance brain metastasis diagnosis.

Purpose: Pituitary adenomas are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood. Experimental Design: A multiplatform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically resected pituitary adenomas in 48 patients: growth hormone (GH)–secreting (n = 17), adrenocorticotropic hormone (ACTH)–secreting (n = 13, including 3 silent-ACTH adenomas), and endocrine-inactive (n = 18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease-specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation. Results: Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes. Conclusions: Taken together, these data stress the contribution of epigenomic alterations to disease-specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments. This article reveals novel insights into the epigenomics underlying pituitary adenomas and highlights how differences in epigenomic states are related to important transcriptome alterations that define adenoma subtypes. Clin Cancer Res; 24(17); 4126–36. ©2018 AACR.

Tumors of hypothalamic neurons that produce vasopressin are rare. We retrieved all cases of vasopressin-positive tumors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing the first series of such tumors. Clinical, radiologic, and pathologic features were reviewed. Four tumors classified as neurocytomas were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. Three patients had the syndrome of inappropriate antidiuresis; in one of these, a 6-year history was initially considered to be idiopathic. One patient died of progressive disease; 3 had incomplete resections and are being followed. In contrast to these patients with neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 cm mass that was completely resected at transsphenoidal surgery; this tumor was a gangliocytoma producing vasopressin associated with corticotroph hyperplasia. We postulate that the small amount of vasopressin secreted by this mature gangliocytic tumor was locally bound to corticotrophs, resulting in hyperplasia and Cushing disease, without sufficient overproduction to cause systemic effects of vasopressin excess. Hypothalamic neurocytoma is a tumor that can mimic pituitary neuroendocrine tumors and olfactory neuroblastoma but is distinguished by positivity for neurofilaments, NeuN, and TTF-1 and negative staining for adenohypophysial biomarkers. Our cases illustrate that neurocytoma and gangliocytoma are 2 variants of tumors of hypothalamic neurons that can produce vasopressin. The morphologic and proliferative features of these 2 tumor types represent 2 ends of a spectrum; their function also can result in divergent clinical manifestations, one characterized by reduced urine output and the other by the more insidious features of glucocorticoid excess.

Introduction Meckel's cave is a dural-lined cavity in the middle fossa skull base in which lies the Gasserian ganglion, a potential site for tumors and inflammatory lesions. A variety of lesions can be predominantly isolated to Meckel's cave, including extension from head and neck cancers, other malignant tumors, as well as benign lesions. Clinical presentation and imaging findings are often insufficient to establish a diagnosis. Hence, histologic confirmation is required to determine the appropriate treatment strategy. Several surgical approaches have been used to reach this deep-seated area, often with significant morbidity and prolonged recovery. Given advancements in endoscopy and greater facility with the technique, the endoscopic endonasal approach has been used increasingly to reach lesions in the region. Methods A single-institution, retrospective chart review over a 10-year period was performed to identify and describe patients with pathologically differing but imaging-similar lesions with their epicenter in Meckel's cave. Results Of a total of 21 cases of lesions in Meckel's cave approached by an endoscopic endonasal transpterygoid approach, we present 6 patients with imaging-ambiguous lesions involving Meckel's cave that were biopsied via the extended endoscopic endonasal approach. Among this diverse group, pathology included B-cell lymphoma, squamous cell carcinoma, adenocarcinoma, malignant schwannoma, benign schwannoma, and neurosarcoidosis. Conclusions We explore not only the relevance of this approach in the armamentarium of the modern skull-base surgeon but also its limitations and conclude that the endoscopic endonasal approach provides a safe and relatively direct, minimally invasive corridor to many lesions of Meckel's cave.