High-grade meningiomas: biology and implications

The epochal developments in the treatment of meningioma—microsurgery, skull base techniques, and radiation therapy—will be appended to include the rational application of targeted and immune therapeutics, previously ill-fitting concepts for a tumor that has traditionally been a regarded as a surgical disease. The genomic and immunological architecture of these tumors continues to be defined in ever-greater detail. Grade I meningiomas are driven by NF2 alterations or mutations in AKT1, SMO, TRAF7, PIK3CA, KLF4, POLR2A, SUFU, and SMARCB1. Higher-grade tumors, however, are driven nearly exclusively by NF2/chr22 loss and are marked by infrequent targetable mutations, although they may harbor a greater mutation burden overall. TERT mutations may be more common in tumors that progress in histological grade; SMARCE1 alteration has become a signature of the clear cell subtype; and BAP1 in rhabdoid variants may confer sensitivity to pharmacological inhibition. Compared with grade I meningiomas, the most prominent alteration in grade II and III meningiomas is a significant increase in chromosomal gains and losses, or copy number alterations, which may have behavioral implications. Furthermore, integrated genomic analyses suggest phenotypic subgrouping by methylation profile and a specific role for PRC2 complex activation. Lastly, there exists a complex phylogenetic relationship among recurrent high-grade tumors, which continues to underscore a role for the most traditional therapy in our arsenal: surgery.

Download Full-text

Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma

The Bone & Joint Journal ◽

10.1302/0301-620x.102b12.bjj-2020-0810.r1 ◽

2020 ◽

Vol 102-B (12) ◽

pp. 1752-1759

Author(s):

Yusuke Tsuda ◽

Kim Tsoi ◽

Jonathan D. Stevenson ◽

Minna Laitinen ◽

Peter C. Ferguson ◽

...

Keyword(s):

Disease Progression ◽

Histological Grade ◽

External Validation ◽

Surgical Margin ◽

Calibration Plot ◽

High Grade ◽

Dedifferentiated Chondrosarcoma ◽

Study Population ◽

Grade Ii ◽

Definitive Surgery

Aims Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma. Methods The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot. Results In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit. Conclusion Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: Bone Joint J 2020;102-B(12):1752–1759.

Download Full-text

Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155416675850 ◽

2016 ◽

Vol 65 (2) ◽

pp. 93-103 ◽

Cited By ~ 11

Author(s):

Arthur William Alvarenga ◽

Luis Eduardo Machado ◽

Bruna Roz Rodrigues ◽

Fernanda Cristina Sulla Lupinacci ◽

Paulo Sanemastu ◽

...

Keyword(s):

Histological Grade ◽

Mammalian Target Of Rapamycin ◽

Experimental Models ◽

High Grade ◽

Ki 67 ◽

Protein Partners ◽

Phosphorylated Akt ◽

Grade Ii ◽

Human Astrocytomas

The mammalian target of rapamycin (mTOR) binds to several protein partners and forms two complexes, termed mTOR complexes 1 and 2 (mTORC1/2), that differ in components, substrates, and regulation. mTORC2 contains the protein Rapamycin-insensitive companion of mTOR (RICTOR); phosphorylates kinases of the AGC family, such as Akt; and controls the cytoskeleton. Even though the regulation of mTORC2 activity remains poorly understood, the hyperactivation of this signaling pathway has been shown to contribute to the oncogenic properties of gliomas in experimental models. In this work, we evaluated expression and phosphorylation of Akt, and expression of RICTOR and Ki-67 in 195 human astrocytomas of different grades (38 cases of grade I, 49 grade II, 15 grade III, and 93 grade IV) and 30 normal brains. Expression and phosphorylation of Akt increased with histological grade and correlated with a worse overall survival in glioblastomas (GBMs). RICTOR was overexpressed in grade I and II astrocytomas and demonstrated a shift to nuclear localization in GBMs. Nuclear RICTOR was associated to increased proliferation in GBMs. Our results point to an increase in total and phosphorylated Akt in high-grade gliomas and to a possible role of RICTOR in proliferations of high-grade GBM cells.

Download Full-text

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms22116083 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6083

Author(s):

Aintzane Rueda-Martínez ◽

Aiara Garitazelaia ◽

Ariadna Cilleros-Portet ◽

Sergi Marí ◽

Rebeca Arauzo ◽

...

Keyword(s):

Mendelian Randomization ◽

Clear Cell ◽

Association Studies ◽

Epidemiological Data ◽

Epidemiological Studies ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Genomic Analyses ◽

Gynecological Disorder ◽

Robust Evidence

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.

Download Full-text

Clear cell histology portends a worse prognosis than other WHO grade II histologies

Journal of Neuro-Oncology ◽

10.1007/s11060-020-03668-5 ◽

2021 ◽

Author(s):

Pranay Soni ◽

Jianning Shao ◽

Arbaz Momin ◽

Diana Lopez ◽

Lilyana Angelov ◽

...

Keyword(s):

Clear Cell ◽

Who Grade ◽

Grade Ii ◽

Worse Prognosis

Download Full-text

Stereology in Grading and Prognosis of Canine Cutaneous Mast Cell Tumors

Veterinary Pathology ◽

10.1177/0300985820985138 ◽

2021 ◽

pp. 030098582098513

Author(s):

Mafalda Casanova ◽

Sandra Branco ◽

Inês Berenguer Veiga ◽

André Barros ◽

Pedro Faísca

Keyword(s):

Mast Cell ◽

Clinical Outcome ◽

Prognostic Value ◽

Histological Grade ◽

Intraobserver Variability ◽

Low Grade ◽

High Grade ◽

Mast Cell Tumors ◽

Cutaneous Mast Cell ◽

Grade Iii

Canine cutaneous mast cell tumors (ccMCTs) are currently graded according to Patnaik and Kiupel grading schemes. The qualitative and semiquantitative parameters applied in these schemes may lead to inter- and intraobserver variability. This study investigates the prognostic value of volume-weighted mean nuclear volume ([Formula: see text]), a stereological estimation that provides information about nuclear size and its variability. [Formula: see text] of 55 ccMCTs was estimated using the “point-sampled intercept” method and compared with histological grade and clinical outcome. The clinical history of dogs treated with surgical excision alone was available for 30 ccMCTs. Statistical differences in [Formula: see text] were found between grade II ([Formula: see text]= 115 ± 29 µm3) and grade III ccMCTs ([Formula: see text]= 197 ± 63 µm3), as well as between low-grade ([Formula: see text]= 113 ± 28 µm3) and high-grade ccMCTs ([Formula: see text]= 184 ± 63 µm3). An optimal cutoff value of [Formula: see text] ≥ 150 µm3 and [Formula: see text] ≥ 140 µm3 was determined for grade III and high-grade ccMCTs, respectively. In terms of prognosis, [Formula: see text] was not able to predict the clinical outcome in 42% of the cases; however, cases with [Formula: see text]<125 µm3 had a favorable outcome. These results indicate that, despite having limited prognostic value when used as a solitary parameter, [Formula: see text] is highly reproducible and is associated with histological grade as well as with benign behavior.

Download Full-text

Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas

Cancer Research ◽

10.1158/0008-5472.can-08-3913 ◽

2009 ◽

Vol 69 (9) ◽

pp. 4036-4042 ◽

Cited By ~ 118

Author(s):

Kuan-Ting Kuo ◽

Bin Guan ◽

Yuanjian Feng ◽

Tsui-Lien Mao ◽

Xu Chen ◽

...

Keyword(s):

Copy Number ◽

Molecular Genetic ◽

Low Grade ◽

High Grade ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Genetic Changes ◽

Dna Copy Number Alterations ◽

Serous Tumors

Download Full-text

Clear Cell Carcinomas of the Mullerian System: Does the Pathogenesis Vary Depending on Their Nuclear Grade and Their Association with Endometriosis? An Immunohistochemical Analysis

Pathology Research International ◽

10.1155/2012/674748 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Ahmad Alduaij ◽

Katrine Hansen ◽

Tahreem A. Karim ◽

Cunxian Zhang ◽

Michelle M. Lomme ◽

...

Keyword(s):

Clear Cell ◽

Immunohistochemical Analysis ◽

Nuclear Grade ◽

High Grade ◽

Ki 67 ◽

High Nuclear Grade ◽

Positive Immunostaining

Clear cell carcinomas (CCC) of the mullerian system are considered high grade tumors, but morphologically, the cells of CCC show both low and high grade features. The aims of the current study were to categorize CCC into low and high nuclear grade types, correlate their association with endometriosis, and then observe possible variations in pathogenesis based on their expression of p53 and Ki-67. We studied 41 pure mullerian CCCs and designated each as either a high (HNG) or low (LNG) nuclear grade tumor. Morphologically, 17 (41%) CCCs were LNG and 24 (59%) were HNG. Nine (38%) HNG and 2 (12%) LNG tumors showed positive immunostaining with p53. Endometriosis was associated with 8 (47%) LNG tumors and 8 (33%) HNG CCCs. Of the 11 cases with p53 alteration, 4 (1 LNG and 3 HNG) were associated with endometriosis. Conclusions: HNG CCCs, irrespective of their association with endometriosis, have alterations of p53. In general, LNG ovarian and endometrial CCCs, irrespective of their association with endometriosis/adenomyosis, are less likely to show p53 alteration. It appears that mullerian CCCs may have variable pathogenesis depending on their nuclear grade and association with endometriosis. A larger study is needed to validate these findings.

Download Full-text

PATH-15. PROTEOMIC SIGNATURES PREDICT GRADE IN PEDIATRIC AND YOUNG ADULT INFILTRATIVE ASTROCYTOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.650 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii427-iii427

Author(s):

Richard T Graham ◽

Blake E Sells ◽

Jessica Fleming ◽

Joseph P McElroy ◽

Erica H Bell ◽

...

Keyword(s):

Young Adult ◽

Molecular Mechanisms ◽

Unsupervised Clustering ◽

Validation Dataset ◽

Clinical Test ◽

High Grade ◽

Lasso Regression ◽

Grade Ii ◽

Grade Iii ◽

Protein Signature

Abstract BACKGROUND Infiltrative astrocytomas in children and young adults pose a treatment challenge due to the difficulty of achieving gross total resection and tumor resistance to irradiation and chemotherapy. Histopathologic grade is an essential part of determining prognosis and treatment, but it is subjective and provides limited understanding of the molecular mechanisms underlying tumor development and progression. METHODS We performed liquid chromatography/mass spectrometry (LC/MS-MS) on 28 FFPE samples of primary infiltrative astrocytomas (10 grade II, 8 grade III and 10 grade IV – WHO classification) from Nationwide Children’s Hospital (NCH). Initial unsupervised clustering was performed. Lasso regression yielded a protein signature separating low- and high-grade tumors which was validated using a similar cohort of pediatric and young adult infiltrative astrocytomas from the Proteomic Data Commons (PDC) (n=28) of the National Cancer Institute. RESULTS Unsupervised clustering of NCH samples essentially recapitulated grade and lasso regression yielded a 10-protein signature that distinguished grade II from grade III/IV tumors. This 10-protein signature when applied to the PDC validation dataset, accurately predicted grade for 89.3% of the tumors (p=0.00014). CONCLUSIONS We identified a quantitative protein signature that can reliably distinguish between low- and high-grade infiltrative astrocytomas from FFPE tissue. Further validation will enable the development an objective prognostic proteomic clinical test that complements and may outperform current histopathological strategies. Additionally, proteomic profiling of tumors will clarify the molecular mechanisms contributing to treatment resistance and tumor progression and help identify novel treatment targets. Independent functional validation and characterization of proteins is ongoing.

Download Full-text

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

Rhinology Journal ◽

10.4193/rhino15.382 ◽

2016 ◽

Vol 54 (3) ◽

pp. 278-286

Author(s):

J. Perez-Escuredo ◽

A. Lopez-Hernandez ◽

M. Costales ◽

F. Lopez ◽

S.P. Ares ◽

...

Keyword(s):

Clinical Outcome ◽

Copy Number ◽

Genetic Alterations ◽

Intestinal Type ◽

Dust Exposure ◽

Copy Number Alterations ◽

A Genome ◽

Sinonasal Adenocarcinoma ◽

Gains And Losses ◽

Microarray Cgh

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

Download Full-text