Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64â€‰years (range 1-82) and the overall median survival was 397â€‰days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (pâ€‰=â€‰0.366) or radiation (pâ€‰=â€‰0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease
BACKGROUND:Myxopapillary ependymoma (MPE) is a heterogeneous disease regarding histopathology and outcome. The underlying molecular biology is poorly understood, and markers that reliably predict the patients' clinical course are unknown. METHODS:We assembled a cohort of 185 tumors classified as MPE based on DNA methylation. Methylation patterns, copy number profiles, and MGMT promoter methylation were analyzed for all tumors, 106 tumors were evaluated histomorphologically, and RNA sequencing was performed for 37 cases. Based on methylation profiling, we defined two subtypes MPE-A and MPEB, and explored associations with epidemiological, clinical, pathological, and molecular characteristics of these tumors. RESULTS:MPE-A occurred at a median age of 27 years and were enriched with tumors demonstrating papillary morphology and MGMT promoter hypermethylation. Half of these tumors could not be totally resected, and 85% relapsed within 10 years. Copy number alterations were more common in MPE-A. RNA sequencing revealed an enrichment for extracellular matrix and immune system-related signatures in MPE-A. MPE-B occurred at a median age of 45 years and included many tumors with a histological diagnosis of WHO grade II and tanycytic morphology. Patients within this subtype had a significantly better outcome with a relapse rate of 33% in 10 years (p=3.4e-06). CONCLUSIONS:We unraveled the morphological and clinical heterogeneity of MPE by identifying two molecularly distinct subtypes. These subtypes significantly differed in progression-free survival and will likely need different protocols for surveillance and treatment.
Clinicopathologic and molecular spectrum of testicular sex cord-stromal tumors not amenable to specific histopathologic subclassification
A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4â€‰cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma
PURPOSE/OBJECTIVE:Placental growth factor (PlGF) and its receptor neuropilin 1 (NRP-1) are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma (MB) models. PATIENTS AND METHODS/METHODS:We conducted a phase 1, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved 4 dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3+3 dose-escalation scheme. Subjects received 2 doses of TB-403 (Days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity (DLT) assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics (PK) and detection of pharmacodynamic biomarkers. RESULTS:Fifteen subjects were treated in 4 dose levels. All subjects received 2 doses of TB-403 in cycle 1. Five serious treatment emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed MB subjects experienced stable disease, which persisted for more than 100 days in 4 out of 7 subjects. CONCLUSIONS:TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with MB.
A nine-month-old boy with regression of milestones and severe constipation: an unusual case of a large spinal NTRK1 fusion pilocytic astrocytoma
INTRODUCTION/BACKGROUND:Pilocytic astrocytoma, a World Health Organization grade 1 tumor, is the most common brain tumor in childrenÂ between 5 and 14 years of age and the second most common in children younger than 5 and older than 14.Â Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. Larotrectinib, aÂ selective inhibitor of tropomyosin receptor kinase, has been effective in pediatric tumors with NTRK fusionÂ mutations in children as young as 1-month-old. CASE/METHODS:We share the case of a 9-month-old boy who presented with a 4-month history of regression of his milestones andÂ severe constipation who was found to have a large spinal pilocytic astrocytoma with multiple intracranialÂ periventricular lesions.
DNA Methylation Profiling in Rare Sellar Tumors [Case Report]
The histologic diagnosis of sellar masses can be challenging, particularly in rare neoplasms and tumors without definitive biomarkers. Moreover, there is significant inter-observer variability in the histopathological diagnosis of many tumors of the CNS, and some rare tumors risk being misclassified. DNA methylation has recently emerged as a useful diagnostic tool. To illustrate the clinical utility of machine-learning-based DNA methylation classifiers, we report a rare case of primary sellar esthesioneuroblastoma histologically mimicking a non-functioning pituitary adenoma. The patient had multiple recurrences, and the resected specimens had unusual histopathology. A portion of the resected sellar lesion was profiled using clinically validated whole-genome DNA methylation and classification. DNA was extracted from the tissue, hybridized on DNA methylation chips, and analyzed using a clinically validated classifier. DNA methylation profiling of the lesion showed that the tumor classified best with the esthesioneuroblastoma reference cohort. This case highlights the difficulty in diagnosing atypical sellar lesions by standard histopathological methods. However, when phenotypic analyses were nonconclusive, DNA methylation profiling resulted in a change in diagnosis. We discuss the growing role of DNA methylation profiling in the classification and diagnosis of CNS tumors, finding that utilization of DNA methylation studies in cases of atypical presentation or diagnostic uncertainty may improve diagnostic accuracy with therapeutic and prognostic implications.
DNA methylation profiling identifies subgroups of lung adenocarcinoma with distinct immune cell composition, DNA methylation age, and clinical outcome
PURPOSE/OBJECTIVE:Lung adenocarcinoma (LUAD) is a clinically heterogenous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. EXPERIMENTAL DESIGN/METHODS:We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. RESULTS:Deconvolution of DNA methylation data identified immunologically hot and cold subsets of lung adenocarcinomas. Additionally, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified 6 molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. CONCLUSIONS:Our results demonstrate that DNA methylation signatures can stratify lung adenocarcinoma into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.
Molecular correlates of male germ cell tumors with overgrowth of components resembling somatic malignancies
A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflectingÂ the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies.
Chromosomal instability in adult-type diffuse gliomas
Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a wide variety of cancers, including colorectal carcinoma with mutations in genes such as APC. Recent reports have demonstrated that CIN, driven in part by mutations in genes maintaining overall genomic stability, is found in subsets of adult-type diffusely infiltrating gliomas of all histologic and molecular grades, with resulting elevated overall copy number burden, chromothripsis, and poor clinical outcome. Still, relatively few studies have examined the effect of this process, due in part to the difficulty of routinely measuring CIN clinically. Herein, we review the underlying mechanisms of CIN, the relationship between chromosomal instability and malignancy, the prognostic significance and treatment potential in various cancers, systemic disease, and more specifically, in diffusely infiltrating glioma subtypes. While still in the early stages of discovery compared to other solid tumor types in which CIN is a known driver of malignancy, the presence of CIN as an early factor in gliomas may in part explain the ability of these tumors to develop resistance to standard therapy, while also providing a potential molecular target for future therapies.
Primary Intracranial Sarcoma, DICER1-Mutant Presenting as a Pineal Region Tumor Mimicking Pineoblastoma: Case Report and Review of the Literature