Mixed odontogenic tumors: A review of the clinicopathological and molecular features and changes in the WHO classification

2533 Background: Primary lesions of the CNS refer to a heterogeneous group of benign or malignant tumors arising in different parts of the brain and spinal cord. According to the 2016 CNS WHO classification, the accurate diagnosis of primary brain tumors requires a layered approach of histologic, anatomic and molecular features to generate an integrated diagnosis with clinical and prognostic significance. However, in the US and worldwide, scarce resources are available to perform all the required tests routinely, so methods that improve pre-test probabilities and decrease false positive results have significant clinical and financial impact. Aims: 1) validate new diagnostic workflows with implementation of modern machine learning/artificial intelligence approaches; 2) design a reliable and interactive computational platform for primary CNS tumor diagnosis. Methods: To achieve these goals we have developed a population model in Rstudio, “La Tabla”, based on the articles from open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. The data of “La Tabla” is comprised of more than 100,000 adult and pediatric cases, including rare brain tumor diagnoses, such as Gangliocytoma, Diffuse Midline Glioma and etc. Results: Boruta package and weights function in R have been used to distinguish the most important features for diagnosis prediction. To visualize correlation between these features (age, ki67 level, tumor location, presence of myxoid areas, calcifications, necrosis and etc.) and all diagnoses in two-dimensional space, we used a t-SNE algorithm. Models trained with decision tree algorithms (randomForest, XGBoost and C5.0) showed high overall accuracy in predicting diagnoses of “La Tabla” (95%, 94% and 92%) and 300 patients at OSUCCC-James (93%, 74% and 87%) in the absence of IHC and molecular data. Neural networks provided by keras and nnet packages predicted diagnoses using just clinical and histological findings with 94% and 88% accuracy on “La Tabla” and James patient databases respectively. Currently, we are building “Shiny” applications with R to deliver easily operated platform for pathologists and physicians. Conclusions: In conclusion, we managed to generate models that are able to diagnose primary brain lesions using basic clinical data (age, gender, tumor location), ki67 levels and distinct features of histological architecture. Most of the models distinguish brain tumors and associated molecular status with high accuracy and will serve as a reliable tool for second opinion in clinical neuro-oncology.

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Defects of the Carney complex gene (PRKAR1A) in odontogenic tumors

Endocrine Related Cancer ◽

10.1530/erc-15-0094 ◽

2015 ◽

Vol 22 (3) ◽

pp. 399-408 ◽

Cited By ~ 4

Author(s):

Sílvia F Sousa ◽

Ricardo S Gomez ◽

Marina G Diniz ◽

Vanessa F Bernardes ◽

Flávia F C Soares ◽

...

Keyword(s):

Protein Expression ◽

Direct Sequencing ◽

Carney Complex ◽

Tumor Formation ◽

Odontogenic Tumors ◽

Maxillary Bone ◽

Synonymous Mutations ◽

Show Evidence ◽

Molecular Therapies ◽

Mixed Odontogenic Tumors

The surgical treatment of some odontogenic tumors often leads to tooth and maxillary bone loss as well as to facial deformity. Therefore, the identification of genes involved in the pathogenesis of odontogenic tumors may result in alternative molecular therapies. ThePRKAR1Agene displays a loss of protein expression as well as somatic mutations in odontogenic myxomas, an odontogenic ectomesenchymal neoplasm. We used a combination of quantitative RT-PCR (qRT-PCR), immunohistochemistry, loss of heterozygosity (LOH) analysis, and direct sequencing of allPRKAR1Aexons to assess if this gene is altered in mixed odontogenic tumors. Thirteen tumors were included in the study: six ameloblastic fibromas, four ameloblastic fibro-odontomas, one ameloblastic fibrodentinoma, and two ameloblastic fibrosarcomas. The epithelial components of the tumors were separated from the mesenchymal by laser microdissection in most of the cases. We also searched for odontogenic pathology inPrkar1a+/−mice.PRKAR1AmRNA/protein expression was decreased in the benign mixed odontogenic tumors in association with LOH at markers around thePRKAR1Agene. We also detected a missense and two synonymous mutations along with two 5′-UTR and four intronic mutations in mixed odontogenic tumors.Prkar1a+/−mice did not show evidence of odontogenic tumor formation, which indicates that additional genes may be involved in the pathogenesis of such tumors, at least in rodents. We conclude that thePRKAR1Agene and its locus are altered in mixed odontogenic tumors.PRKAR1Aexpression is decreased in a subset of tumors but not in all, andPrkar1a+/−mice do not show abnormalities, which indicates that additional genes play a role in this tumor's pathogenesis.

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Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system

Blood ◽

10.1182/blood-2008-10-182782 ◽

2009 ◽

Vol 113 (9) ◽

pp. 1906-1908 ◽

Cited By ~ 104

Author(s):

Olga K. Weinberg ◽

Mahesh Seetharam ◽

Li Ren ◽

Katie Seo ◽

Lisa Ma ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Who Classification ◽

Progression Free Survival ◽

World Health ◽

Multilineage Dysplasia ◽

Molecular Features ◽

Not Otherwise Specified ◽

Cebpa Mutations ◽

Acute Myeloid

Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P = .014), presented with a lower hemoglobin (P = .044), more frequently expressed CD14 (P = .048), and exhibited a decreased frequency of CEBPA mutations (P = .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P < .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

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The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors

Frontiers in Oral Health ◽

10.3389/froh.2021.740788 ◽

2021 ◽

Vol 2 ◽

Author(s):

Letícia Martins Guimarães ◽

Bruna Pizziolo Coura ◽

Ricardo Santiago Gomez ◽

Carolina Cavalieri Gomes

Keyword(s):

Mapk Pathway ◽

Direct Sequencing ◽

Genetic Alterations ◽

Odontogenic Tumors ◽

Genetic Mutations ◽

Cellular Functions ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Allele Specific ◽

Mixed Odontogenic Tumors

Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most odontogenic tumors remains unclear, there have been some advances, recently, in the understanding of the genetic basis of specific odontogenic tumors. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway is intimately involved in the regulation of important cellular functions, and it is commonly deregulated in several human neoplasms. Molecular analysis performed by different techniques, including direct sequencing, next-generation sequencing, and allele-specific qPCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway in odontogenic tumors. Genetic mutations in this pathway genes have been reported in epithelial and mixed odontogenic tumors, in addition to odontogenic carcinomas and sarcomas. Notably, B-Raf proto-oncogene serine/threonine kinase (BRAF) and KRAS proto-oncogene GTPase (KRAS) pathogenic mutations have been reported in a high proportion of ameloblastomas and adenomatoid odontogenic tumors, respectively. In line with the reports about other neoplasms that harbor a malignant counterpart, the frequency of BRAF p.V600E mutation is higher in ameloblastoma (64% in conventional, 81% in unicystic, and 63% in peripheral) than in ameloblastic carcinoma (35%). The objective of this study was to review MAPK/ERK genetic mutations in benign and malignant odontogenic tumors. Additionally, such genetic alterations were discussed in the context of tumorigenesis, clinical behavior, classification, and future perspectives regarding therapeutic approaches.

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Clinical statistical examination of odontogenic tumors according to the new WHO classification in 2005

Journal of Japanese Society of Oral Oncology ◽

10.5843/jsot.18.39 ◽

2006 ◽

Vol 18 (2) ◽

pp. 39-47

Author(s):

Hiromi Nishi ◽

Koichiro Higashikawa ◽

Hiroshi Shimasue ◽

Misato Hiraoka ◽

Miwa Miyauchi ◽

...

Keyword(s):

Who Classification ◽

Odontogenic Tumors

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Compound odontome with unerupted permanent incisor

Ibrahim Medical College Journal ◽

10.3329/imcj.v5i1.9860 ◽

1970 ◽

Vol 5 (1) ◽

pp. 29-31

Author(s):

Mahfujul Haq Khan ◽

Md Manjurul Karim ◽

Sejuty Haque ◽

Saeed Hossein Khan ◽

Mohammad Towfiq Alam

Keyword(s):

Key Words ◽

Lateral Incisor ◽

Odontogenic Tumors ◽

Impacted Tooth ◽

Dental Hard Tissues ◽

Hard Tissues ◽

Delayed Eruption ◽

Mixed Odontogenic Tumors

Odontomas are mixed odontogenic tumors composed of both epithelial and mesenchymal dental hard tissues. They are usually asymptomatic and are often discovered during routine radiography. A case of odontoma in a 21 year old man is described who presented with delayed eruption of upper central and lateral incisor teeth. The odontome was surgically removed followed by re-implantation of preserved extracted lateral incisor and a porcelain crown.Ibrahim Med. Coll. J. 2011; 5(1): 29-31 Key Words: Odontoma; Impacted tooth; Re-implantation.DOI: http://dx.doi.org/10.3329/imcj.v5i1.9860

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Acute Panmyelosis with Myelofibrosis: Clinicopathological and Molecular Features of a Rare Malignant Bone Marrow Disease.

Blood ◽

10.1182/blood.v114.22.3101.3101 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3101-3101

Author(s):

Silke Kapp-Schwoerer ◽

Renate Looser ◽

Franz Schaub ◽

Michael Hummel ◽

Manfred Olschewski ◽

...

Keyword(s):

Bone Marrow ◽

Who Classification ◽

Laboratory Data ◽

Myeloproliferative Neoplasm ◽

Jak2 V617f ◽

Genetic Alterations ◽

Control Group ◽

Stromal Compartment ◽

Molecular Features ◽

Mutational Status

Abstract Abstract 3101 Poster Board III-38 Background Acute panmyelosis with myelofibrosis (APMF) is listed among the category of “AML, not otherwise specified” in the actual WHO classification of hematopoietic tumors. Since specific genetic alterations have not yet been defined, this myeloid neoplasm (MN) remains clinicopathologically assigned. The WHO classification addresses the difficulties concerning the differential diagnosis between APMF, myelodysplastic syndromes (MDS) with excess of blasts and concomitant fibrosis (RAEB-F) and acute megakaryoblastic leukaemia (AMGL). Methods Our files were searched for patients with rapid-onset MN without a prior history of a myeloproliferative neoplasm or a MDS fulfilling the 2008 WHO criteria of APMF. An age- and gender-matched control group of RAEB-F cases with multilineage dysplasia was retrieved for comparison. Our approach included: i) the careful review of morphological, clinical and laboratory data with special regard to the proportion of immature CD34 + precursors/blasts in bone marrow (BM) biopsies; ii) the grading of BM fibrosis according to the European consensus guidelines; iii) the analysis of the JAK2-V617F, the MPL W515L and the GATA1 mutational status, the cytoplasmic localization of nucleophosphamin1 (NPM1) in BM blasts, and the expression the inhibitor of differentiation protein-2 (Id2) in hematopoietic and stroma cells; iv) the evaluation of the prognostic relevance of these parameters. Results Fifty-four patients (32 males, 22 females) with a median age of 66, 9 years from our institutions were diagnosed APMF. Sufficient DNA for allele specific PCR for JAK2 genotyping was obtained from paraffin-embedded EDTA-decalcified BMB specimens from 22 APMF and 14 RAEB-F patients. In addition, an analysis of MPL W515L and GATA1 mutations was performed on 15 APMF cases. The relevant clinicopathological and molecular data are summarized in the table. Semiquantitative evaluation revealed a decreased expression level of Id2 in erythropoiesis of the APMF samples, while Id2 was increased in the stromal compartment. Within the total APMF cohort, patients aged ≤60 years had a longer OS (p=0,013). A comparison between the Kaplan-Meier curves of the APMF patients who underwent hematopietic cell transplantation (HCT) with those treated by conventional chemotherapy clearly showed that HCT significantly improved OS (median survival 6,1 vs. 11,1 months, p=0,005). Within the non-transplanted group, a bone marrow blast count ≤25% was associated with a longer OS (p=0,006). Conclusions Our results point to significant differences between APMF and RAEB-F with regard to OS, MCV, LDH, BM fibrosis and BM blast cells. We detected a higher frequency of mutated JAK2 V616F in the MB samples than generally reported in the literature for other categories of AML or MDS. However, the JAK2 V617F mutation status or an aberrant cytoplasmic NPM1 localization were both not predictive of outcome. In contrast to data published for AMGL, no association between a MPL W515L mutation and APMF was observed. Survival was significantly worse in APMF than in RAEB-F. A rapid diagnosis based on a multiparameter approach and a proper management including the option of HCT even in elderly patients seems mandatory for APMF patients. Targeting the fibrotic BM microenvironment which is characterized by an increased Id2 expression may be considered for future therapeutic strategies. Disclosures Skoda: Genentech Inc.: Consultancy.

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Mixed odontogenic tumors in four young dogs: ameloblastic fibroma and ameloblastic fibro-odontoma

Journal of Veterinary Diagnostic Investigation ◽

10.1177/1040638718812936 ◽

2018 ◽

Vol 31 (1) ◽

pp. 98-102 ◽

Cited By ~ 1

Author(s):

Patrick Huang ◽

Cynthia Bell ◽

Vanessa Wallace ◽

Brian G. Murphy

Keyword(s):

Dental Pulp ◽

Tooth Development ◽

Odontogenic Tumors ◽

Diagnostic Features ◽

Early Stages ◽

Odontogenic Epithelium ◽

Ameloblastic Fibroma ◽

Mixed Odontogenic Tumors

Ameloblastic fibroma (AF) and ameloblastic fibro-odontoma (AFO) are mixed odontogenic tumors (odontogenic tumors with induction) that are reported only rarely in dogs. These tumors are histologically complex and, to a degree, recapitulate the early stages of tooth development, comprising 2 types of tissue: neoplastic odontogenic epithelium, and induced ectomesenchyme (dental pulp). AFOs are distinguished from AFs by the additional presence of hard dental matrices such as dentin. Herein, we describe the key diagnostic features of AF and AFO in 4 young dogs.

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