ABSTRACT
Vascular anomalies are a heterogeneous group of disorders that are currently classified based on their clinical and histological characteristics. Over the past decade, there have been significant advances in molecular genetics that have led to identification of genetic alterations associated with vascular tumors, vascular malformations, and syndromes. Here, we describe known genetic alterations in vascular anomalies, discuss when and how to test, and examine how identification of causative genetic mutations provides for better management of these disorders through improved understanding of their pathogenesis and increasing use of targeted therapeutic agents in order to achieve better outcomes for our patients.
Subject(s)
Neoplasms, Vascular Tissue , Vascular Diseases , Vascular Malformations , Humans , Mutation , Neoplasms, Vascular Tissue/genetics , Vascular Malformations/diagnosis , Vascular Malformations/genetics , Vascular Malformations/therapyABSTRACT
Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role.
Subject(s)
Blood Vessels/abnormalities , Glycolysis , Hexokinase/metabolism , Neoplasms, Vascular Tissue/metabolism , Pericytes/metabolism , A549 Cells , Animals , Blood Vessels/metabolism , Blood Vessels/pathology , Cardiac Myosins/genetics , Cardiac Myosins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Endothelial Cells/metabolism , Gene Expression Regulation, Neoplastic , Hexokinase/genetics , Humans , Mice , Mice, Inbred C57BL , Myosin Light Chains/genetics , Myosin Light Chains/metabolism , Neoplasms/metabolism , Neoplasms, Vascular Tissue/drug therapy , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Tumor Microenvironment/physiology , Up-Regulation , rho-Associated KinasesABSTRACT
An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.
Subject(s)
Bone Neoplasms/genetics , Epithelioid Cells/metabolism , Neoplasms, Vascular Tissue/genetics , Oncogene Proteins, Fusion/genetics , Adolescent , Adult , Aged , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Epithelioid Cells/pathology , Female , Humans , Male , Middle Aged , NFATC Transcription Factors/genetics , Neoplasms, Vascular Tissue/metabolism , Neoplasms, Vascular Tissue/pathology , Oncogene Proteins, Fusion/metabolism , RNA-Binding Protein EWS/genetics , RNA-Binding Protein FUS/geneticsABSTRACT
In this article, the authors have reviewed all the recent news regarding how the discovery of some novel and recurrent molecular and genetic changes has modified the classification of some entities and have addressed to the description of new variants of vascular tumors. And even more important, the authors also reviewed on how these findings, in addition to gain insight into the tumoral biology, portend significant clinical consequences not only regarding to their diagnosis but also to their management and prognosis because some of these mutations are potential targets for treatment. The authors have also highlighted immunohistochemical markers can help us as a surrogate marker of those molecular alterations.
Subject(s)
Neoplasms, Vascular Tissue/diagnosis , Skin Neoplasms/diagnosis , Humans , Neoplasms, Vascular Tissue/classification , Neoplasms, Vascular Tissue/genetics , Pathology, Molecular/methods , Pathology, Molecular/trends , Skin Neoplasms/classification , Skin Neoplasms/geneticsABSTRACT
BACKGROUND: High probability of metastasis limited the long-term survival of patients with hepatocellular carcinoma (HCC). Our previous study revealed that Galectin-3 was closely associated with poor prognosis in HCC patients. METHODS: The effects of Galectin-3 on tumour metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. RESULTS: Galectin-3 showed a close correlation with vascular invasion and poor survival in a large-scale study in HCC patients from multiple sets. Galectin-3 was significantly involved in diverse metastasis-related processes in HCC cells, such as angiogenesis and epithelial-to-mesenchymal transition (EMT). Mechanistically, Galectin-3 activated the PI3K-Akt-GSK-3ß-ß-catenin signalling cascade; the ß-catenin/TCF4 transcriptional complex directly targeted IGFBP3 and vimentin to regulate angiogenesis and EMT, respectively. In animal models, Galectin-3 enhanced the tumorigenesis and metastasis of HCC cells via ß-catenin signalling. Moreover, molecular deletion of Galectin-3-ß-catenin signalling synergistically improved the antitumour effect of sorafenib. CONCLUSIONS: The Galectin-3-ß-catenin-IGFBP3/vimentin signalling cascade was determined as a central mechanism controlling HCC metastasis, providing possible biomarkers for predicating vascular metastasis and sorafenib resistance, as well as potential therapeutic targets for the treatment of HCC patients.
Subject(s)
Carcinoma, Hepatocellular/pathology , Galectin 3/physiology , Liver Neoplasms/pathology , beta Catenin/genetics , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/mortality , Cell Adhesion/genetics , Cell Line, Tumor , Cell Movement/genetics , Disease Progression , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/mortality , Neoplasms, Vascular Tissue/secondary , Survival Analysis , Tissue Array Analysis , Wnt Signaling Pathway/genetics , beta Catenin/metabolismABSTRACT
Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.
Subject(s)
Biomarkers, Tumor , Bone Neoplasms/classification , Epithelioid Cells , Neoplasms, Vascular Tissue/classification , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biopsy , Bone Neoplasms/chemistry , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Differentiation , Child , Child, Preschool , Disease-Free Survival , Epithelioid Cells/chemistry , Epithelioid Cells/pathology , Female , Gene Fusion , Gene Rearrangement , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Italy , Male , Middle Aged , Neoplasms, Vascular Tissue/chemistry , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Polymerase Chain Reaction , Predictive Value of Tests , Risk Assessment , Risk Factors , Young AdultABSTRACT
Vascular anomalies are classified as either tumors or malformations based on clinical findings rendered through radiologic evaluation, physical exam, and histologic interpretation. These findings comprise the phenotype of the disorder. Recently, advances in the molecular genetics of vascular anomalies have shed light on the genotype of these disorders. These phenotype/genotype characterizations will provide a more precise classification of vascular anomalies and identify potential therapeutic targets for expanded treatment options in the future. In this chapter, we will review the phenotype/genotype characterizations and the possible therapeutic pathways for targeted pharmacologic therapy.
Subject(s)
Molecular Diagnostic Techniques , Neoplasms, Vascular Tissue/genetics , Vascular Malformations/genetics , Antineoplastic Agents/therapeutic use , Genetic Predisposition to Disease , Humans , Molecular Targeted Therapy , Neoplasms, Vascular Tissue/diagnostic imaging , Neoplasms, Vascular Tissue/drug therapy , Phenotype , Precision Medicine , Predictive Value of Tests , Vascular Malformations/diagnostic imaging , Vascular Malformations/drug therapySubject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Neoplasms, Vascular Tissue/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Skin Neoplasms/genetics , Biopsy , Child, Preschool , DNA Mutational Analysis , Exome/genetics , Female , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Gain of Function Mutation , Humans , Neoplasms, Vascular Tissue/diagnosis , Neoplasms, Vascular Tissue/pathology , Proto-Oncogene Proteins p21(ras)/metabolism , Skin/blood supply , Skin/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/pathologyABSTRACT
Hepatic small vessel neoplasm (HSVN) is a recently described infiltrative vascular neoplasm of the liver, composed of small vessels. Although the infiltrative nature can mimic angiosarcoma, HSVN are thought to be benign or low-grade neoplasms because they lack cytologic atypia and increased proliferation. To characterize the molecular pathogenesis of HSVN, we performed both targeted panel sequencing and exome sequencing on 18 benign or low-grade vascular neoplasms in the liver including 8 HSVN, 6 classic cavernous hemangioma (CH), and 4 variant lesions (VL) with overlapping features between HSVN and CH. All 18 lesions had simple genomes without copy number alterations. In total, 75% (6/8) of HSVN demonstrated known activating hotspot mutations in GNAQ (2/8, p.Q209H) or GNA14 (4/8, p.Q205L), and the remaining 2 had the same missense mutation in GNAQ, p.G48L, which has not been previously described. 25% (1/4) of VL had a hotspot GNAQ p.Q209H mutation and another VL had a GNAQ p.G48L mutation. Known pathogenic mutations were not identified in any of the 6 CH. These data suggest that HSVN share a similar molecular biology to several other vascular lesions (congenital hemangioma, tufted angioma, anastomosing hemangioma, lobular capillary hemangioma, and kaposiform hemangioendothelioma) recently reported to have GNAQ, GNA11, or GNA14 mutations.
Subject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Liver Neoplasms/genetics , Neoplasms, Vascular Tissue/genetics , Adult , Aged , Female , Humans , Male , Middle Aged , MutationABSTRACT
Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung, and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1-CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately 6 years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical, and molecular cytogenetic findings. Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Hemangioendothelioma, Epithelioid/genetics , Hemangioendothelioma, Epithelioid/pathology , Neoplasms, Vascular Tissue/genetics , Adult , Biomarkers, Tumor/genetics , Calcium-Binding Proteins/metabolism , Female , Hemangioendothelioma, Epithelioid/diagnosis , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Neoplasms, Vascular Tissue/pathology , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Trans-Activators/metabolism , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Translocation, Genetic/geneticsABSTRACT
Class 3 semaphorins were discovered as a family of axon guidance molecules, but are now known to be involved in diverse biologic processes. In this study, we investigated the anti-angiogenic potential of SEMA3E and SEMA3F (SEMA3E&F) in infantile hemangioma (IH). IH is a common vascular tumor that involves both vasculogenesis and angiogenesis. Our lab has identified and isolated hemangioma stem cells (HemSC), glucose transporter 1 positive (GLUT1(+)) endothelial cells (designated as GLUT1(sel) cells) based on anti-GLUT1 magnetic beads selection and GLUT1-negative endothelial cells (named HemEC). We have shown that these types of cells play important roles in hemangiogenesis. We report here that SEMA3E inhibited HemEC migration and proliferation while SEMA3F was able to suppress the migration and proliferation in all three types of cells. Confocal microscopy showed that stress fibers in HemEC were reduced by SEMA3E&F and that stress fibers in HemSC were decreased by SEMA3F, which led to cytoskeletal collapse and loss of cell motility in both cell types. Additionally, SEMA3E&F were able to inhibit vascular endothelial growth factor (VEGF)-induced sprouts in all three types of cells. Further, SEMA3E&F reduced the level of p-VEGFR2 and its downstream p-ERK in HemEC. These results demonstrate that SEMA3E&F inhibit IH cell proliferation and suppress the angiogenic activities of migration and sprout formation. SEMA3E&F may have therapeutic potential to treat or prevent growth of highly proliferative IH.
Subject(s)
Endothelial Cells/drug effects , Gene Expression Regulation, Neoplastic , Membrane Proteins/pharmacology , Neoplastic Stem Cells/drug effects , Neovascularization, Pathologic/prevention & control , Nerve Tissue Proteins/pharmacology , Semaphorins/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Hemangioma/blood supply , Hemangioma/genetics , Hemangioma/pathology , Humans , Infant , Neoplasms, Vascular Tissue/blood supply , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Recombinant Proteins/pharmacology , Signal Transduction , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolismSubject(s)
Blood Vessels/abnormalities , Neoplasms, Vascular Tissue/classification , Vascular Malformations/classification , Arteriovenous Malformations/classification , Arteriovenous Malformations/diagnosis , Arteriovenous Malformations/physiopathology , Diagnosis, Differential , Gastrointestinal Neoplasms/diagnosis , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/metabolism , Hemangioendothelioma/diagnosis , Hemangioendothelioma/metabolism , Hemangioma/classification , Hemangioma/complications , Hemangioma/metabolism , Hemangioma, Capillary/classification , Hemangioma, Capillary/congenital , Hemangioma, Capillary/embryology , Humans , Infant, Newborn , Kasabach-Merritt Syndrome/diagnosis , Kasabach-Merritt Syndrome/etiology , Kasabach-Merritt Syndrome/metabolism , Lymphatic Abnormalities/classification , Lymphatic Abnormalities/diagnosis , Lymphatic Abnormalities/genetics , Lymphatic Abnormalities/pathology , Neoplasms, Vascular Tissue/diagnosis , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Nevus, Blue/diagnosis , Remission, Spontaneous , Sarcoma, Kaposi/diagnosis , Sarcoma, Kaposi/metabolism , Skin Neoplasms/classification , Skin Neoplasms/complications , Skin Neoplasms/congenital , Skin Neoplasms/diagnosis , Skin Neoplasms/metabolism , Syndrome , Vascular Malformations/diagnosis , Vascular Malformations/genetics , Vascular Malformations/pathologyABSTRACT
The c-myc proto-oncogene is involved in various cellular processes including cell growth, proliferation, and apoptosis. Overexpression and deregulated expression of the gene have been previously linked to several lineage-unrelated, aggressive, and poorly differentiated tumors. The expression of c-myc has also been implicated in hematopoiesis and has been shown to play a crucial role in angiogenesis via a vascular endothelial growth factor-dependent mechanism. This gives c-myc a dual oncogenic function in that tumor growth requires both cell proliferation and angiogenesis to ensure survival and confer an effective malignancy. Amplification of c-myc has been recently reported to be a recurrent genetic alteration in angiosarcomas secondary to irradiation and/or chronic lymphedema. Of note, however, no c-myc gene abnormalities have been demonstrated in cases of primary angiosarcomas or postradiation atypical vascular lesions. More recently, our own experience indicates that c-myc amplification is not normally found in the Kaposi sarcoma and cannot be correlated with expression of the c-Myc protein. This comprehensive review outlines the structure, normal functions, and effects of the deregulated expression of c-myc with particular emphasis on its role in angiogenesis and select cutaneous vascular neoplasms.
Subject(s)
Neoplasms, Vascular Tissue/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Skin Neoplasms/metabolism , Biopsy , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Neoplasms, Vascular Tissue/genetics , Neoplasms, Vascular Tissue/pathology , Neovascularization, Pathologic , Predictive Value of Tests , Prognosis , Protein Conformation , Proto-Oncogene Mas , Proto-Oncogene Proteins c-myc/chemistry , Proto-Oncogene Proteins c-myc/genetics , Signal Transduction , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Structure-Activity RelationshipABSTRACT
This article provides an update on vascular neoplasms. New immunohistochemical markers for the diagnosis of vascular neoplasms tumor 1, infantile hemangiomas, myopericytomas, perivascular epithelial cell tumors, acquired elastotic hemangiomas, vascular proliferations in radiated skin, and new histopathologic variants of AIDS-related Kaposi sarcoma are explored.
Subject(s)
Neoplasms, Radiation-Induced/pathology , Neoplasms, Vascular Tissue/metabolism , Neoplasms, Vascular Tissue/pathology , Perivascular Epithelioid Cell Neoplasms/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Cell Cycle Proteins , Claudins/genetics , Claudins/metabolism , Hemangioma, Capillary/pathology , Humans , Neoplasms, Vascular Tissue/genetics , Neoplastic Syndromes, Hereditary/pathology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA Splicing Factors , Sarcoma, Kaposi/pathology , Skin Neoplasms/geneticsABSTRACT
Historically, vascular malformations were not thought to be the result of genetic abnormalities because most of those presenting clinically are sporadic. However, research in this field has expanded over the last decade, leading to the identification of genetic defects responsible for several inherited forms of vascular malformations and associated syndromes, which has shed light on the pathogenesis of sporadic lesions. This advancement in the field has not only enhanced diagnostic capabilities but also improved our understanding of the potential role of complex genetic mechanisms in vascular malformation development. This article focuses on genetic contributions of vascular malformations in the context of syndromes and the tests that are available.
Subject(s)
Arteriovenous Malformations/genetics , Blood Vessels/abnormalities , Lymphatic Abnormalities/genetics , Arteriovenous Malformations/diagnosis , Capillaries/abnormalities , Congenital Abnormalities/genetics , Humans , Infant, Newborn , Intracranial Arteriovenous Malformations/genetics , Lymphatic Vessels/abnormalities , Neoplasms, Vascular Tissue/genetics , Neovascularization, Pathologic/genetics , SyndromeABSTRACT
RET mutations play an important role in the development of human neuroendocrine tumors. The prevalence of the RET polymorphism G691S of exon 11 is higher in patients with medullary thyroid carcinoma (MTC) as compared to the general population. A weak association between RET polymorphisms and sporadic papillary thyroid carcinoma (PTC) has also been described. We hereby describe the association of MTC, bronchial carcinoid tumor, and PTC in a familial setting. A 75-yr-old woman developed MTC 7 yr after successful treatment of a bronchial carcinoid. Serum calcitonin was 12.9 pg/ml with a peak response to pentagastrin (151.0 pg/ml). The patient underwent total thyroidectomy and a genetic mutational analysis of the RET gene. Histological evaluation confirmed MTC with no evidence of lymph nodes involvement. After thyroidectomy serum calcitonin was <2.0 pg/ml. A germline missense mutation at codon 691 in exon 11 of the RET gene was found. The mutational analysis was extended to the patient's offspring, and her daughter was found to bear the G691S polymorphism of RET. Wild type RET gene was found in the son. The daughter, who showed a nodular goiter, autoimmune thyroiditis and normal serum calcitonin, also underwent thyroidectomy. Histologic examination of the thyroid revealed an incidental PTC. This is the first description of a bronchial carcinoid tumor occurring in association with MTC. The occurrence of apparently unrelated NET in the same subject, or within a family, should be regarded as a challenge for deeper investigations into the possible oncogenic role of this genetic alteration.
Subject(s)
Bronchial Neoplasms/genetics , Carcinoid Tumor/genetics , Carcinoma, Medullary/genetics , Carcinoma, Papillary/genetics , Neoplasms, Vascular Tissue/genetics , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Adult , Aged , Base Sequence , DNA Mutational Analysis , Female , Germ-Line Mutation , Humans , Male , Mutation, Missense , Pedigree , Polymorphism, GeneticABSTRACT
Primary aortic tumours are very rare. To our knowledge, only 120 cases had been reported in the world literature. Their clinical presentation is not specific. They are usually diagnosed at aortic surgery or by post-mortem examination. Intimal sarcoma is the most frequent histological type. We report a case of intimal sarcoma of the thoracic aorta diagnosed on autopsy of a 48-year-old man victim of sudden death. The main problem raised by intimal sarcoma lies in its poor differentiation or lack of differentiation. Thus, the pathologist must perform a phenotypic analysis as complete as possible of this tumor.
Subject(s)
Aorta, Thoracic/pathology , Aortic Diseases/pathology , Neoplasms, Vascular Tissue/pathology , Sarcoma/pathology , Aortic Diseases/genetics , Cell Division , Death, Sudden , Humans , Male , Middle Aged , Neoplasms, Vascular Tissue/genetics , PolyploidyABSTRACT
Vascular anomalies, divided into vascular tumors and vascular malformations, are localized defects of angiogenesis. Hemangiomas appear soon after birth, grow quickly, and then spontaneously, but slowly, disappear. In contrast, vascular malformations are congenital defects of vascular development that grow proportionately with the child. Most vascular anomalies are considered non-hereditary. However, due to detailed analysis inherited forms have been observed, which has led to identify mutations in three genes causing familial vascular malformations: in the angiopoietin receptor TIE2 in mucocutaneous venous malformations (VMCM), in glomulin in glomuvenous malformations (GVM) and in RASA1 in the newly recognized phenotype capillary malformation-arteriovenous malformation (CM-AVM). Identification of the causative genes has permitted more precise diagnosis and differential diagnosis, evaluation of phenotypic variability among patients with a proven mutation, study of used treatments in more homogeneous patient groups, and elucidation of the etiopathogenic mechanisms behind vascular malformations. Further studies are needed to unravel the role of genetic variations in the various vascular malformations and to unravel the precise molecular mechanisms that lead to development of these vascular lesions. This should provide development of new-targeted therapies.
Subject(s)
Blood Vessels/abnormalities , Neoplasms, Vascular Tissue/etiology , Adaptor Proteins, Signal Transducing/genetics , Arteriovenous Malformations/etiology , Arteriovenous Malformations/genetics , Capillaries/abnormalities , Diagnosis, Differential , Genetic Variation/genetics , Hemangioma/etiology , Hemangioma/genetics , Humans , Lymphatic Vessels/abnormalities , Mutation/genetics , Neoplasms, Vascular Tissue/genetics , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/genetics , Phenotype , Receptor, TIE-2/genetics , Tacrolimus Binding Proteins/genetics , p120 GTPase Activating Protein/geneticsABSTRACT
Genetic factors play a critical role in the pathogenesis of vascular anomalies. Significant advances have been made in recent years in identifying the genetic and molecular determinants of a variety of vascular anomalies using a molecular genetic approach. Several genes for vascular anomalies have been identified. These genes include AGGF1 for Klippel-Trenaunay syndrome, RASA1 for capillary malformations, KRIT1, MGC4607, PDCD10 for cerebral cavernous malformations, glomulin for glomuvenous malformations, TIE2 for multiple cutaneous and mucosal venous malformations, VEGFR-3, FOXC2, NEMO, SOX18 for lymphedema or related syndromes, ENG, ACVRLK1, MADH4 for HHT or related syndromes, NDP for Coats' disease, Notch3 for CADASIL, and PTEN for Proteus Syndrome. These findings have made genetic testing possible in some clinical cases, and may lead to the development of therapeutic strategies for vascular anomalies. Furthermore, these studies have identified critical genes involved in vascular morphogenesis, and provided fundamental understanding of the molecular mechanisms underlying vasculogenesis and angiogenesis.
Subject(s)
Arteriovenous Malformations/genetics , Neoplasms, Vascular Tissue/genetics , HumansABSTRACT
AIMS: To determine the expression of WT1 in endothelial proliferations and tumours. Endothelial cells are derived from angioblasts which differentiate into bone marrow stem cells (BMSC). BMSC are characterized by the constitutive expression of the WT1 gene and we have postulated that its expression may be maintained during the differentiation of angioblasts to endothelial cells. METHODS AND RESULTS: The expression of WT1 was studied in human umbilical vein-derived (HUVEC) and brain microvascular endothelial cells (HBME) as well as in a Kaposi sarcoma (KS) cell line in vitro. Forty-two human skin biopsy samples of endothelial proliferations and tumours were analysed for the protein expression of WT1 using the monoclonal antibodies for wt-WT1 (6F-H2) and its 17AA+ variant (2C12). WT1 expression was detectable in HUVEC and KS cells and all WT1 splice variants examined (17AA+/- KTS+/-) were detectable in KS cells, while the 17AA+/- and KTS- variants were present in HUVEC. Immunohistochemical analysis of the 42 human skin biopsy samples revealed cytoplasmic WT1 expression using wild-type specific antibody (6FH2) in microvessels, which is maintained during neoangiogenesis (inflammation, haemorrhage, peritumoral angiogenesis). Around one-third of haemangiomas (3/10) and non-HIV-Kaposi sarcomas (7/18) expressed the WT1 protein in the cytoplasm of tumour cells compared with its frequent expression in angiosarcomas (7/8) using the same antibody (6FH2). The nuclear 17AA+ isoform of WT1 was detectable at protein level in a small proportion of KS cases exclusively (3/7). CONCLUSION: Our data suggest that WT1 protein expression is maintained during angiogenesis and malignant transformation of endothelial cells and can be considered as a new endothelial marker.