ISSVA classification for vascular anomalies (Approved at the 20th ISSVA Workshop, Melbourne, April 2014, last revision May 2018)
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1 ISSVA classification for vascular anomalies (Approved at the 20th ISSVA Workshop, Melbourne, April 2014, last revision May 2018) This classification is intended to evolve as our understanding of the biology and genetics of vascular malformations and tumors continues to grow Over table Vascular anomalies Vascular tumors Vascular malformations Simple Combined of major named vessels associated with other anomalies Benign Capillary malformations CVM, CLM See details See list Locally aggressive or borderline Malignant Lymphatic malformations Venous malformations Arteriovenous malformations* Arteriovenous fistula* LVM, CLVM CAVM* CLAVM* others defined as two or more vascular malformations found in one lesion * high-flow lesions A list of causal genes and related vascular anomalies is available in Appendix 2 The tumor or malformation nature or precise classification of some lesions is still unclear. These lesions appear in a separate provisional list. Abbreviations used 1 For more details, click on the underlined links
2 ISSVA classification of vascular tumors 1a Benign vascular tumors 1 Infantile hemangioma / Hemangioma of infancy Congenital hemangioma Rapidly involuting (RICH) * Non-involuting (NICH) Partially involuting (PICH) Tufted angioma * Spindle-cell hemangioma Epithelioid hemangioma see details GNAQ / GNA11 GNA14 IDH1 / IDH2 FOS Pyogenic granuloma (also known as lobular capillary hemangioma) Others BRAF / RAS / GNA14 see details * some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details many experts believe that tufted angioma and kaposiform hemangioendothelioma are part of a spectrum rather than distinct entities N.B. reactive proliferative vascular lesions are listed with benign tumors Causal genes in blue
3 ISSVA classification of vascular tumors 1b Benign vascular tumors 2 Others Hobnail hemangioma Microvenular hemangioma Anastomosing hemangioma Glomeruloid hemangioma Papillary hemangioma Intravascular papillary endothelial hyperplasia Cutaneous epithelioid angiomatous nodule Acquired elastotic hemangioma Littoral cell hemangioma of the spleen Related lesions Eccrine angiomatous hamartoma Reactive angioendotheliomatosis Bacillary angiomatosis N.B. The tumor nature of some of these lesions is not certain Reactive proliferative vascular lesions are listed with benign tumors
4 ISSVA classification of vascular tumors 2 Locally aggressive or borderline vascular tumors Kaposiform hemangioendothelioma * Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma (PILA), Dabska tumor Composite hemangioendothelioma Pseudomyogenic hemangioendothelioma Polymorphous hemangioendothelioma Hemangioendothelioma not otherwise specified Kaposi sarcoma Others GNA14 FOSB Malignant vascular tumors Angiosarcoma Epithelioid hemangioendothelioma Others (Post radiation) MYC CAMTA1 / TFE3 * some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details many experts believe that tufted angioma and kaposiform hemangioendothelioma are part of a spectrum rather than distinct entities N.B. reactive proliferative vascular lesions are listed with benign tumors Causal genes in blue
5 Capillary malformations (CM) Simple vascular malformations I Nevus simplex / salmon patch, angel kiss, stork bite Cutaneous and/or mucosal CM (also known as port-wine stain) Nonsyndromic CM CM with CNS and/or ocular anomalies (Sturge-Weber syndrome) CM with bone and/or soft tissues overgrowth Diffuse CM with overgrowth (DCMO) Reticulate CM CM of MIC-CAP (microcephaly-capillary malformation) CM of MCAP (megalencephaly-capillary malformation-polymicrogyria) CM of CM-AVM Cutis marmorata telangiectatica congenita (CMTC) Others Telangiectasia* GNAQ GNAQ GNA11 GNA11 STAMBP PIK3CA RASA1 / EPHB4 Hereditary hemorrhagic telangiectasia (HHT)(HHT1 ENG, HHT2 ACVRL1, HHT3, JPHT SMAD4) Others ISSVA classification for vascular anomalies * The CM nature of some subtypes of telangiectasia is debated. Some telangiectasia may be reclassified in other sections in the future Causal genes in blue
6 ISSVA classification for vascular anomalies Simple vascular malformations IIa Lymphatic malformations (LM) Common (cystic) LM * PIK3CA Macrocystic LM Microcystic LM Mixed cystic LM Generalized lymphatic anomaly (GLA) Kaposiform lymphangiomatosis (KLA) LM in Gorham-Stout disease Channel type LM Acquired progressive lymphatic anomaly (so called acquired progressive "lymphangioma") Primary lymphedema (different types) Others * When associated with overgrowth, some of these lesions belong to the PIK3CA-related overgrowth spectrum see details Some of these lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Causal genes in blue
7 ISSVA classification for vascular anomalies Simple vascular malformations IIb Primary lymphedema Nonne-Milroy syndrome Primary hereditary lymphedema FLT4 / VEGFR3 VEGFC Primary hereditary lymphedema GJC2 / Connexin 47 Lymphedema-distichiasis Hypotrichosis-lymphedema-telangiectasia FOXC2 SOX18 Primary lymphedema with myelodysplasia Primary generalized lymphatic anomaly (Hennekam lymphangiectasia-lymphedema syndrome) GATA2 CCBE1 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome KIF11 Lymphedema-choanal atresia PTPN14 Causal genes in blue
8 ISSVA classification for vascular anomalies Simple vascular malformations III Venous malformations (VM) Common VM Familial VM cutaneo-mucosal (VMCM) Blue rubber bleb nevus (Bean) syndrome VM Glomuvenous malformation (GVM) TEK (TIE2) / PIK3CA TEK (TIE2) TEK (TIE2) Glomulin Cerebral cavernous malformation (CCM) (CCM1 KRIT1, CCM2 Malcavernin, CCM3 PDCD10) Familial intraosseous vascular malformation (VMOS) Verrucous venous malformation (formerly verrucous hemangioma) ELMO2 MAP3K3 Others some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Causal genes in blue
9 ISSVA classification for vascular anomalies Simple vascular malformations IV Arteriovenous malformations (AVM) Sporadic In HHT In CM-AVM MAP2K1 (HHT1 ENG, HHT2 ACVRL1, HHT3, JPHT SMAD4) RASA1 / EPHB4 Others Arteriovenous fistula (AVF) (congenital) Sporadic In HHT In CM-AVM MAP2K1 (HHT1 ENG, HHT2 ACVRL1, HHT3, JPHT SMAD4) RASA1 / EPHB4 Others Abbreviations used Causal genes in blue
10 ISSVA classification for vascular anomalies Combined vascular malformations* CM + VM capillary-venous malformation CVM CM + LM capillary-lymphatic malformation CLM CM + AVM capillary-arteriovenous malformation CAVM LM + VM lymphatic-venous malformation LVM CM + LM + VM capillary-lymphatic-venous malformation CLVM CM + LM + AVM capillary-lymphatic-arteriovenous malformation CLAVM CM + VM + AVM capillary-venous-arteriovenous malformation CVAVM CM + LM + VM + AVM capillary-lymphatic-venous-arteriovenous m. CLVAVM Abbreviations used * defined as two or more vascular malformations found in one lesion
11 ISSVA classification for vascular anomalies Anomalies of major named vessels (also known as "channel type" or "truncal" vascular malformations) Affect lymphatics veins arteries Anomalies of origin course number length diameter (aplasia, hypoplasia, stenosis, ectasia / aneurysm) valves communication (AVF) persistence (of embryonal vessel) Abbreviations used
12 ISSVA classification for vascular anomalies Vascular malformations associated with other anomalies Klippel-Trenaunay syndrome: * CM + VM +/- LM + limb overgrowth PIK3CA Parkes Weber syndrome: CM + AVF + limb overgrowth RASA1 Servelle-Martorell syndrome: Sturge-Weber syndrome: limb VM + bone undergrowth facial + leptomeningeal CM + eye anomalies +/- bone and/or soft tissue overgrowth GNAQ Limb CM + congenital non-progressive limb overgrowth GNA11 Maffucci syndrome: VM +/- spindle-cell hemangioma + enchondroma IDH1 / IDH2 Macrocephaly - CM (M-CM / MCAP) * Microcephaly - CM (MICCAP) PIK3CA STAMBP CLOVES syndrome: * LM + VM + CM +/- AVM + lipomatous overgrowth PICK3CA Proteus syndrome: CM, VM and/or LM + asymmetrical somatic overgrowth AKT1 Bannayan-Riley-Ruvalcaba sd: AVM + VM +macrocephaly, lipomatous overgrowth PTEN CLAPO syndrome: * lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth PIK3CA Abbreviations used * these lesions belong to the PIK3CA-related overgrowth spectrum (PROS) see details Causal genes in blue
13 ISSVA classification for vascular anomalies Provisionally unclassified vascular anomalies Intramuscular hemangioma * Angiokeratoma Sinusoidal hemangioma Acral arteriovenous "tumour" Multifocal lymphangioendotheliomatosis with thrombocytopenia / cutaneovisceral angiomatosis with thrombocytopenia (MLT/CAT) PTEN (type) hamartoma of soft tissue / "angiomatosis" of soft tissue (PHOST) Fibro adipose vascular anomaly (FAVA) PTEN PIK3CA * Distinct from infantile hemangioma, from intramuscular common VM, PHOST/AST, FAVA and AVM some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Causal genes in blue
14 Appendix 1 abbreviations used (excluding gene names) AST angiomatosis of soft tissue HHT hereditary hemorrhagic telangiectasia AVF AVM CAT CAVM CCM CLAVM CLAPO CLOVES CLM CLVAVM CLVM CM CM-AVM CMTC CNS arteriovenous fistula arteriovenous malformation cutaneovisceral angiomatosis with thrombocytopenia capillary arteriovenous malformation cerebral cavernous malformation capillary lymphatic arteriovenous malformation lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/scoliosis and spinal abnormalities capillary lymphatic malformation capillary lymphatic venous arteriovenous malformation capillary lymphatic venous malformation capillary malformation capillary malformation-arteriovenous malformation cutis marmorata telangiectatica congenita central nervous system HI IH INR JPHT KHE KLA KMP LM LVM MCAP M-CM MICCAP MLT NICH PHACE hemangioma of infancy / infantile hemangioma infantile hemangioma / hemangioma of infancy international normalized ratio juvenile polyposis hemorrhagic telangiectasia kaposiform hemangioendothelioma kaposiform lymphangiomatosis Kasabach-Merritt phenomenon, lymphatic malformation lymphatic venous malformation megalencephaly-capillary malformation-polymicrogyria macrocephaly-capillary malformation microcephaly-capillary malformation Multifocal lymphangioendotheliomatosis with thrombocytopenia non-involuting congenital hemangioma posterior fossa malformations, hemangioma, arterial anomalies, cardiovascular anomalies, eye anomalies CVAVM capillary venous arteriovenous malformation PHOST PTEN hamartoma of soft tissue CVM capillary venous malformation PILA papillary intralymphatic angioendothelioma DCMO diffuse capillary malformation with overgrowt PICH partially involuting congenital hemangioma DIC disseminated intravascular coagulopathy PROS PIK3CA-related overgrowth spectrum FAVA Fibro adipose vascular anomaly RICH rapidly involuting congenital hemangioma GLA generalized lymphatic anomaly TA tufted angioma GSD Gorham-Stout disease VM venous malformation GVM glomuvenous malformation VMCM venous malformation cutaneo mucosal
15 ACVRL1 Appendix 2a causal genes of vascular anomalies Telangiectasia, AVM and AVF of HHT2 AKT1 Proteus syndrome BRAF Pyogenic granuloma PG CAMTA1 Epithelioid hemangioendothelioma EHE CCBE1 Primary generalized lymphatic anomaly (Hennekam lymphangiectasialymphedema syndrome) ELMO2 Familial intraosseous vascular malformation VMOS ENG Telangiectasia, AVM and AVF of HHT1 EPHB4 CM-AVM2 FLT4 Nonne-Milroy syndrome (gene also named VEGFR3) FOS Epithelioid hemangioma EH FOSB Pseudomyogenic hemangioendothelioma FOXC2 Lymphedema-distichiasis GATA2 Primary lymphedema with myelodysplasia GJC2 Primary hereditary lymphedema Glomulin Glomuvenous malformation GNA11 Congenital hemangioma CH CM with bone and/or soft tissue hyperplasia Diffuse CM with overgrowth DCMO GNA14 Tufted angioma TA Pyogenic granuloma PG Kaposiform hemangioendothelioma KHE GNAQ Congenital hemangioma CH CM "Port-wine" stain, nonsyndromic CM CM of Sturge-Weber syndrome Next page
16 IDH1 IDH2 KIF11 KRIT1 Malcavernin MAP2K1 MAP2K1 MAP3K3 MYC NPM11 PDCD10 PIK3CA Appendix 2b causal genes of vascular anomalies Maffucci syndrome Spindle-cell hemangioma Maffucci syndrome Spindle-cell hemangioma Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome Cerebral cavernous malformation CCM1 Cerebral cavernous malformation CCM2 Arteriovenous malformation AVM (sporadic) Ateriovenous fistula AVF (sporadic) Verrucous venous malformation (somatic) Post radiation angiosarcoma Maffucci syndrome Cerebral cavernous malformation CCM3 Common (cystic) LM (somatic)* Common VM (somatic)* Klippel-Trenaunay syndrome* Megalencephaly-capillary malformation-polymicrogyria (MCAP)* CLOVES syndrome* CLAPO syndrome* Fibro adipose vascular anomaly FAVA * some of these lesions, associated with overgrowth, belong to the PIK3CA related overgrowth spectrum PROS see details Next page
17 Appendix 2c causal genes of vascular anomalies PTEN PTPN14 RAS RASA1 SMAD4 SOX18 STAMBP TEK (TIE2) TFE3 VEGFC VEGFR3 Bannayan-Riley-Ruvalcaba syndrome PTEN (type) Hamartoma of soft tissue / "angiomatosis" of soft tissue Lymphedema-choanal atresia Pyogenic granuloma PG CM-AVM1 Parkes Weber syndrome Telangiectasia, AVM and AVF of Juvenile polyposis hemorrhagic telangiectasia JPHT Hypotrichosis-lymphedema-telangiectasia Microcephaly-CM (MIC-CAP) Common VM (somatic) Familial VM cutaneo-mucosal VMCM Blue rubber bleb nevus (Bean) syndrome (somatic) Epithelioid hemangioendothelioma EHE Primary hereditary lymphedema Nonne-Milroy syndrome (gene also named FLT4)
18 Appendix 3 infantile hemangioma Pattern - focal - multifocal - segmental - indeterminate Different types - superficial - deep - mixed (superficial + deep) - reticular / abortive / minimal growth - others PHACE association / syndrome LUMBAR (SACRAL, PELVIS) association / syndrome Association with other lesions Posterior fossa malformations, Hemangioma, Arterial anomalies, Cardiovascular anomalies, Eye anomalies, sternal clefting and or supraumbilical raphe Lower body hemangioma, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies
19 Appendix 4 vascular anomalies possibly associated with platelet count / coagulation disorders Tufted angioma Anomalies Kaposiform hemangioendothelioma Rapidly involuting congenital hemangioma Venous malformations / Lymphatic-venous malformations Lymphatic malformations Multifocal lymphangioendotheliomatosis with thrombocytopenia / Cutaneovisceral angiomatosis with thrombocytopenia Kaposiform lymphangiomatosis Hematological disorders Profound and sustained thrombocytopenia with profound hypofibrinogenemia, consumptive coagulopathy and elevated D-dimer (Kasabach-Merritt phenomenon) Transient mild/moderate thrombocytopenia, +/- consumptive coagulopathy and elevated D-dimer Chronic localized intravascular coagulopathy with elevated D-dimer, +/- hypofibrinogenemia, and +/- moderate thrombocytopenia (may progress to DIC after trauma or operation) Chronic localized intravascular coagulopathy with elevated D-dimer and +/- mild to moderate thrombocytopenia (consider Kaposiform lymphangiomatosis) (may progress to DIC after trauma or operation) Sustained, fluctuating, moderate to profound thrombocytopenia with gastrointestinal tract bleeding or pulmonary hemorrhage Mild/moderate thrombocytopenia, +/-hypofibrinogenemia, and D-dimer elevation
20 Appendix 5 PIK3CA-related overgrowth spectrum PIK3CA-related overgrowth spectrum (PROS) groups lesions with heterogeneous segmental overgrowth phenotypes -with or without vascular anomalies- due to somatic PIK3CA activating mutations. This spectrum includes: - Fibroadipose hyperplasia or Overgrowth (FAO) - Hemihyperplasia Multiple Lipomatosis (HHML) - Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) syndrome - Macrodactyly - Fibroadipose Infiltrating Lipomatosis / Facial Infiltrative Lipomatosis - Megalencephaly-Capillary Malformation (MCAP or M-CM) - Dysplastic Megalencephaly (DMEG) - Klippel-Trenaunay syndrome
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