Publications by authors named "David N Louis"

203 Publications

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.

Neuro Oncol 2021 Jun 29. Epub 2021 Jun 29.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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http://dx.doi.org/10.1093/neuonc/noab106DOI Listing
June 2021

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis.

Cell 2021 Mar 15;184(5):1281-1298.e26. Epub 2021 Feb 15.

Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.
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http://dx.doi.org/10.1016/j.cell.2021.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935772PMC
March 2021

Atretic cephalocele: report of an infrequent dermatopathologic finding.

J Cutan Pathol 2021 Jan 20. Epub 2021 Jan 20.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1111/cup.13824DOI Listing
January 2021

High Seroprevalence of Anti-SARS-CoV-2 Antibodies in Chelsea, Massachusetts.

J Infect Dis 2020 11;222(12):1955-1959

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

SARS-CoV-2 antibody testing allows quantitative determination of disease prevalence, which is especially important in high-risk communities. We performed anonymized convenience sampling of 200 currently asymptomatic residents of Chelsea, the epicenter of COVID-19 illness in Massachusetts, by BioMedomics SARS-CoV-2 combined IgM-IgG point-of-care lateral flow immunoassay. The seroprevalence was 31.5% (17.5% IgM+IgG+, 9.0% IgM+IgG-, and 5.0% IgM-IgG+). Of the 200 participants, 50.5% reported no symptoms in the preceding 4 weeks, of which 24.8% (25/101) were seropositive, and 60% of these were IgM+IgG-. These data are the highest seroprevalence rates observed to date and highlight the significant burden of asymptomatic infection.
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http://dx.doi.org/10.1093/infdis/jiaa579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499676PMC
November 2020

Clinical sensitivity and interpretation of PCR and serological COVID-19 diagnostics for patients presenting to the hospital.

FASEB J 2020 10 28;34(10):13877-13884. Epub 2020 Aug 28.

Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

The diagnosis of COVID-19 requires integration of clinical and laboratory data. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic assays play a central role in diagnosis and have fixed technical performance metrics. Interpretation becomes challenging because the clinical sensitivity changes as the virus clears and the immune response emerges. Our goal was to examine the clinical sensitivity of two most common SARS-CoV-2 diagnostic test modalities, polymerase chain reaction (PCR) and serology, over the disease course to provide insight into their clinical interpretation in patients presenting to the hospital. We conducted a single-center, retrospective study. To derive clinical sensitivity of PCR, we identified 209 PCR-positive SARS-CoV-2 patients with multiple PCR test results (624 total PCR tests) and calculated daily sensitivity from date of symptom onset or first positive test. Clinical sensitivity of PCR decreased with days post symptom onset with >90% clinical sensitivity during the first 5 days after symptom onset, 70%-71% from Days 9 to 11, and 30% at Day 21. To calculate daily clinical sensitivity by serology, we utilized 157 PCR-positive patients with a total of 197 specimens tested by enzyme-linked immunosorbent assay for IgM, IgG, and IgA anti-SARS-CoV-2 antibodies. In contrast to PCR, serological sensitivity increased with days post symptom onset with >50% of patients seropositive by at least one antibody isotype after Day 7, >80% after Day 12, and 100% by Day 21. Taken together, PCR and serology are complimentary modalities that require time-dependent interpretation. Superimposition of sensitivities over time indicate that serology can function as a reliable diagnostic aid indicating recent or prior infection.
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http://dx.doi.org/10.1096/fj.202001700RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461169PMC
October 2020

cIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors.

Brain Pathol 2020 09 23;30(5):863-866. Epub 2020 Jun 23.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT-NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT-NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.
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http://dx.doi.org/10.1111/bpa.12866DOI Listing
September 2020

Roses and rosettes-the two sides of James Homer Wright.

Proc (Bayl Univ Med Cent) 2020 Apr 19;33(2):286-292. Epub 2019 Dec 19.

James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical SchoolBostonMassachusetts.

James Homer Wright is a distinguished figure in the history of pathology and one of the founders of the discipline in the hospitals of Harvard Medical School. While he has been recognized as a highly accomplished investigative pathologist, historical sources have described him as austere, formidable, forbidding, disheartening, and gruff. Wright once did something seemingly so impulsive that it astonished his colleagues. When he heard a beautiful Norwegian contralto named Aagot Lunde perform, he anonymously sent her roses on a daily basis until she eventually agreed to meet him. They fell in love, married, and lived happily together until Aagot's death. This article paper explores the lives and careers of J. Homer Wright and Aagot Lunde Wright using unique archival materials as well as newspaper and magazine coverage of their life and travels together. After their marriage, Aagot soon stopped performing, but Mrs. Wright continued as a New England socialite for about a decade, which also coincided with the timeframe in which J. Homer made almost all of his important discoveries. James Homer Wright was covertly a romantic who thrived academically when supported by his wife, both of their families, and close friends.
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http://dx.doi.org/10.1080/08998280.2019.1695498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155993PMC
April 2020

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

Brain Pathol 2020 07 19;30(4):844-856. Epub 2020 Apr 19.

Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.
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http://dx.doi.org/10.1111/bpa.12832DOI Listing
July 2020

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.

Cell 2019 08 18;178(4):835-849.e21. Epub 2019 Jul 18.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, 1090, Austria.

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
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http://dx.doi.org/10.1016/j.cell.2019.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703186PMC
August 2019

A half century of change in diagnostic neuropathology: from the giants of yore to current brain tumor classification.

Authors:
David N Louis

Hum Pathol 2020 01 11;95:161-168. Epub 2019 Jul 11.

James Homer Wright Pathology Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. Electronic address:

The first issue of Human Pathology contains a laudatory review of one of the most treasured books in the history of neuropathology: Neurological Clinicopathological Conferences of the Massachusetts General Hospital, a collection of neurological cases that appeared first in the New England Journal of Medicine in the 1940s, 1950s, and 1960s. Each patient history is discussed by well-known neurologists, neurosurgeons, and neuropathologists. Review of these cases provides a framework to explore diagnostic shifts that have occurred over the past half century. Importantly, while the discussants of these cases were great diagnosticians, they were somewhat limited by the methods available to them at the time; subsequent novel technologies provided opportunities for new insights that were made by the next generation of experts. Today's pathologists (whether neuropathologists or any other pathology subspecialists) are similarly skilled at diagnosis, although their diagnoses are now more often made on biopsies (rather than autopsies) and informed by pre-operative imaging studies as well as post-operative molecular analyses. In turn, one would conclude that, even in the face of future technological changes brought about by disruptive innovations like artificial intelligence and deep molecular analyses, a need will continue for the expertise of pathologists and other clinical diagnosticians.
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http://dx.doi.org/10.1016/j.humpath.2019.06.006DOI Listing
January 2020

Data Sets for the Reporting of Tumors of the Central Nervous System: Recommendations From The International Collaboration on Cancer Reporting.

Arch Pathol Lab Med 2020 02 20;144(2):196-206. Epub 2019 Jun 20.

From the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Dr Louis); the Department of Pathology, Amsterdam Universities Medical Center/VUmc CCA Brain Tumor Center, Amsterdam, the Netherlands (Dr Wesseling); he Department of Pathology, Princess Máxima Center for Pediatric Oncology, and University Medical Center Utrecht, Utrecht, the Netherlands (Dr Wesseling); Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, United Kingdom (Dr Brandner); the Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom (Dr Brandner); the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Dr Brat); the Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee (Dr Ellison); the Department of Radiology, Oncology and Anatomic Pathology, University La Sapienza, Rome, Italy (Dr Giangaspero); RCCS Neuromed, Pozzilli, Isernia, Italy (Dr Giangaspero); the Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky (Dr Hattab); the Department of Laboratory Medicine & Pathobiology, The Hospital for Sick Children, Toronto, Ontario, Canada (Dr Hawkins); Project Management Office, Royal College of Pathologists of Australasia, Sydney, Australia (Ms Judge);he Departments of Pathology, Neurology, and Neurosurgery, University of Colorado, Aurora (Dr Kleinschmidt-DeMasters); the Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan (Dr Komori); the Department of Pathology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan (Dr Komori); Alfred Anatomical Pathology and NNF, Victorian Brain Bank, Carlton, Victoria, Australia (Dr McLean); Institute of Neuropathology, University Hospital Münster, Münster, Germany (Dr Paulus); Division of Neuropathology, Department of Pathology, University of California, San Francisco (Dr Perry); the Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany (Dr Reifenberger); German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany (Dr Reifenberger); the Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (Dr Weller); and the Department of Histopathology, Addenbrookes Hospital, Cambridge, United Kingdom (Dr Rous); ICCR Steering Group Representative (Dr Rous).

Context.—: Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR).

Objective.—: To develop standardized templates for brain tumor diagnostic pathology reporting.

Design.—: As a response to the 2016 updated 4th edition of the (World Health Organization) (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner.

Results.—: The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO.

Conclusions.—: The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world.
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http://dx.doi.org/10.5858/arpa.2018-0565-OADOI Listing
February 2020

cIMPACT-NOW: a practical summary of diagnostic points from Round 1 updates.

Brain Pathol 2019 07 22;29(4):469-472. Epub 2019 May 22.

Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M-mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH-mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH-wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH-wildtype/H3-wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAF mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary.
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http://dx.doi.org/10.1111/bpa.12732DOI Listing
July 2019

PIK3CA activating mutations are associated with more disseminated disease at presentation and earlier recurrence in glioblastoma.

Acta Neuropathol Commun 2019 04 29;7(1):66. Epub 2019 Apr 29.

Perlmutter Cancer Center, New York University Langone Health and School of Medicine, New York, USA.

Phosphatidylinositol 3-kinase signaling promotes cell growth and survival and is frequently activated in infiltrative gliomas. Activating mutations in PIK3CA gene are observed in 6-15% of glioblastomas, although their clinical significance is largely undescribed. The objective of this study was to examine whether PIK3CA mutations are associated with a specific clinical phenotype in glioblastoma. We retrospectively reviewed 157 consecutive newly diagnosed glioblastoma patients from December 2009 to June 2012 who underwent molecular profiling consisting of targeted hotspot genotyping, fluorescence in situ hybridization for gene amplification, and methylation-specific PCR for O-methylguanine-DNA methyltransferase promoter methylation. Molecular alterations were correlated with clinical features, imaging and outcome. The Cancer Genome Atlas data was analyzed as a validation set. There were 91 males; median age was 58 years (range, 23-85). With a median follow-up of 20.9 months, median progression-free survival (PFS) and estimated overall survival (OS) were 11.9 and 24.0 months, respectively. Thirteen patients (8.3%) harbored PIK3CA mutation, which was associated with younger age (mean 49.4 vs. 58.1 years, p = 0.02). PIK3CA mutation correlated with shorter PFS (median 6.9 vs. 12.4 months, p = 0.01) and OS (median 21.2 vs. 24.2 months, p = 0.049) in multivariate analysis. A significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions, was observed (46.2% vs. 11.1%, p = 0.004). In conclusion, despite the association with younger age, PIK3CA activating mutations are associated with earlier recurrence and shorter survival in adult glioblastoma. The aggressive course of these tumors may be related to their propensity for disseminated presentation.
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http://dx.doi.org/10.1186/s40478-019-0720-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487518PMC
April 2019

Characterization of applicants for residency training in pathology: Does diversity exist?

Ann Diagn Pathol 2019 Jun 10;40:23-25. Epub 2019 Feb 10.

Harvard Medical School, Boston, MA, USA; Pathology Service, Massachusetts General Hospital, Boston, MA, USA.

Context: A diverse workforce has been shown to improve productivity and innovation. The level of diversity among pathology residency applicants has not previously been reported.

Objective: This study aims to characterize the applicants at an academic pathology department to gain a better understanding of diversity among them.

Design: Between 2015 and 2017, data from a tertiary care center were analyzed for gender, US and international medical school, USMLE scores, and self-identified racial or ethnic group. For 2017, data was compared to that published by the Association of American Medical Colleges (AAMC).

Results: There were 1293 pathology applicants with 48-49% being female. The overall underrepresented minority (URM) applicant pool in pathology represented 12.6%, 9.5%, and 11.1% of our applicants for 2015, 2016, and 2017, respectively. URMs from US medical schools alone represented 4.7%, 3.7%, and 4.5% of our applicants for 2015, 2016, and 2017, respectively. The percentage of 2017 US medical school graduates applying to any US pathology training program was 22.2% versus 38.7% applying to pathology at our center (p ≤0.001). URM applicants for pathology from US medical schools were significantly lower than URM applicants to all AAMC medical specialties (p = 0.035). Among our pathology applicants in 2017, USMLE I scores and number of applicants with any publications were higher for non-URMs compared to URMs (p = 0.048 and p = 0.046, respectively).

Conclusion: No significant difference related to gender was identified among our applicants while racial/ethnic groups remain underrepresented with significantly fewer URM applicants from US medical schools compared to published AAMC data for all medical specialties.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.02.010DOI Listing
June 2019

cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF mutation.

Acta Neuropathol 2019 04 8;137(4):683-687. Epub 2019 Mar 8.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

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http://dx.doi.org/10.1007/s00401-019-01987-0DOI Listing
April 2019

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Acta Neuropathol 2019 02 24;137(2):307-319. Epub 2018 Dec 24.

Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme.
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http://dx.doi.org/10.1007/s00401-018-1952-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513906PMC
February 2019

Implementing the DICOM Standard for Digital Pathology.

J Pathol Inform 2018 2;9:37. Epub 2018 Nov 2.

Harvard Medical School, Boston, MA, USA.

Background: Digital Imaging and Communications in Medicine (DICOM) is the standard for the representation, storage, and communication of medical images and related information. A DICOM file format and communication protocol for pathology have been defined; however, adoption by vendors and in the field is pending. Here, we implemented the essential aspects of the standard and assessed its capabilities and limitations in a multisite, multivendor healthcare network.

Methods: We selected relevant DICOM attributes, developed a program that extracts pixel data and pixel-related metadata, integrated patient and specimen-related metadata, populated and encoded DICOM attributes, and stored DICOM files. We generated the files using image data from four vendor-specific image file formats and clinical metadata from two departments with different laboratory information systems. We validated the generated DICOM files using recognized DICOM validation tools and measured encoding, storage, and access efficiency for three image compression methods. Finally, we evaluated storing, querying, and retrieving data over the web using existing DICOM archive software.

Results: Whole slide image data can be encoded together with relevant patient and specimen-related metadata as DICOM objects. These objects can be accessed efficiently from files or through RESTful web services using existing software implementations. Performance measurements show that the choice of image compression method has a major impact on data access efficiency. For lossy compression, JPEG achieves the fastest compression/decompression rates. For lossless compression, JPEG-LS significantly outperforms JPEG 2000 with respect to data encoding and decoding speed.

Conclusion: Implementation of DICOM allows efficient access to image data as well as associated metadata. By leveraging a wealth of existing infrastructure solutions, the use of DICOM facilitates enterprise integration and data exchange for digital pathology.
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http://dx.doi.org/10.4103/jpi.jpi_42_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236926PMC
November 2018

Financially effective test algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma.

Neuro Oncol 2019 05;21(5):596-605

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines.

Methods: To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing.

Results: In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P < 0.0001, log-rank). The radiologic phenotype in the EGFR-amplified tumors includes diffusion restriction (15%, P = 0.02), >5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally.

Conclusion: EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.
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http://dx.doi.org/10.1093/neuonc/noy201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502496PMC
May 2019

Localized crystal-storing histiocytosis of the posterior fossa.

Neuropathology 2018 Oct 31;38(5):529-534. Epub 2018 Jul 31.

Department of Pathology, University of Washington, Seattle, Washington, USA.

Crystal-storing histiocytosis (CSH) is an uncommon histiocytic proliferation reported to involve diverse organs and tissues, but involvement of the central nervous system (CNS) is rare. In most cases CSH is identified in association with underlying lymphoproliferative, plasma cell diseases or rarely with various inflammatory or infectious conditions. CSH is characterized by the cytoplasmic accumulation of crystalline material in histiocytes, most commonly of kappa immunoglobulin light chain. We report a unique case of localized CSH involving the left cerebellum and caudal brain stem in a young man with a history of gout but without known lymphoproliferative or plasma cell disorders. Awareness of this entity is important diagnostically, but also to ensure appropriate management and follow-up, particularly in the absence of apparent underlying malignancy.
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http://dx.doi.org/10.1111/neup.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172157PMC
October 2018

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

Acta Neuropathol 2018 07 23;136(1):153-166. Epub 2018 Apr 23.

Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII), and WHO grade IV glioblastoma, IDH-mutant (GBM). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII and AAIII have lost their significance. In contrast, GBM still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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http://dx.doi.org/10.1007/s00401-018-1849-4DOI Listing
July 2018

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

Science 2018 04;360(6386):331-335

Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.
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http://dx.doi.org/10.1126/science.aao4750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949869PMC
April 2018

A feast of reviews about brain and pituitary tumor pathology.

Authors:
David N Louis

Brain Tumor Pathol 2018 Apr;35(2):49-50

Massachusetts General Hospital and Harvard Medical School, Boston, USA.

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http://dx.doi.org/10.1007/s10014-018-0315-2DOI Listing
April 2018

Grading of Diffuse Astrocytic Gliomas: A Review of Studies Before and After the Advent of IDH Testing.

Semin Neurol 2018 02 16;38(1):19-23. Epub 2018 Mar 16.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Estimating the malignancy level of tumors is key to management, and has been part of oncology practice for the past ∼100 years. A central aspect of assessing malignancy level is based on histological "grading"-a process in which a pathologist evaluates microscopic features of a tumor and interprets those findings in light of large prognostic studies. For the diffuse astrocytic gliomas, there have been many such studies over the past century and these have proven useful in estimating prognosis for patients. With the advent of molecular genetics, molecular diagnostic testing has been added to histological evaluation in the armamentarium of the pathologist, and the recent World Health Organization (WHO) Classification of Tumors of the Central Nervous System encourages testing for isocitrate dehydrogenase (IDH) gene status in the classification of diffuse astrocytic gliomas. The present review catalogues a large series of diffuse astrocytic glioma grading studies over the past few decades, and compares the prognostic value of such grading schema before and after the emergence of IDH testing. The review concludes that novel approaches to diffuse astrocytic tumor grading are required in the era of IDH testing.
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http://dx.doi.org/10.1055/s-0038-1636430DOI Listing
February 2018

A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle.

Nat Commun 2018 02 23;9(1):810. Epub 2018 Feb 23.

Department of Pathology, University of California, San Francisco, CA, 94143, USA.

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.
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http://dx.doi.org/10.1038/s41467-018-02826-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824822PMC
February 2018

Correction.

J Radiol Case Rep 2017 Oct 31;11(10). Epub 2017 Oct 31.

Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, Houston, TX, USA.

[This corrects the article on p. 8 in vol. 10.].
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http://dx.doi.org/10.3941/jrcr.v11i10.3328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741321PMC
October 2017

Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations.

Neuro Oncol 2017 Nov;19(12):1640-1650

Department of Pathology; Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines.

Methods: From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods.

Results: In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine.

Conclusion: The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.
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http://dx.doi.org/10.1093/neuonc/nox120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716163PMC
November 2017