Juan Carlos López-Gutiérrez - Unidad de Anomalías Vasculares, Hospital Universitario La Paz. Madrid, España.
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El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
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Juan Carlos López-Gutiérrez - Unidad de Anomalías Vasculares, Hospital Universitario La Paz. Madrid, España.
- 1. Clinical Classification of Vascular Anomalies Controversies and recent advances Juan Carlos Lopez Gutierrez Vascular Anomalies Center La Paz Children´s Hospital Simposio Internacional: Mosaicismo somático en malformaciones vasculares. Madrid, 10 y 11 de mayo de 2018
- 3. In 2018 , 50.000 children are expected to need treatment for a Vascular Anomaly in Europe
- 5. ISSVA classification for vascular anomalies (Approved at the 20th ISSVA Workshop, Melbourne, April 2014) Overview table °defined as two or more vascular malformations found in one lesion * high-flow lesions N.B. The classification tables do not list exhaustively all known vascular anomalies. Some rare "dermatologic" vascular anomalies will be found in dermatology textbooks. The tumor or malformation nature or precise classification of some lesions is still unclear. These lesions appear in a separate provisional list. Vascular anomalies Vascular tumors Vascular malformations Simple Combined ° of major named vessels associated with other anomalies Benign Locally aggressive or borderline Malignant Capillary malformations Lymphatic malformations Venous malformations Arteriovenous malformations* Arteriovenous fistula* CVM, CLM LVM, CLVM CAVM* CLAVM* others See details See list For more details, click on the underlined linksAbbreviations used
- 6. ISSVA classification of vascular tumors I Benign vascular tumors Infantile hemangioma / Hemangioma of infancy see details Congenital hemangioma Rapidly involuting (RICH) *, Non-involuting (NICH), Partially involuting (PICH) Tufted angioma * ° Spindle-cell hemangioma Intramuscular hemangioma (capillary type) Epithelioid hemangioma Pyogenic granuloma (aka lobular capillary hemangioma) Others Hobnail hemangioma Microvenular hemangioma Anastomosing hemangioma Glomeruloid hemangioma Papillary hemangioma Intravascular papillary endothelial hyperplasia Cutaneous epitheliod angiomatous nodule Acquired elastotic hemangioma Littoral cell hemangioma of the spleen Related lesions Eccrine angiomatous hamartoma Reactive angioendotheliomatosis Bacillary angiomatosis Back to overview Type Alt for previous view * 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
- 7. Benign vascular tumors Congenital hemangioma GNAQ / GNA11 Rapidly involuting (RICH) Non-involuting (NICH) Partially involuting (PICH) Tufted angioma GNA14 Epithelioid hemangioma FOS Pyogenic granuloma BRAF / RAS / GNA14 Spindle-cell hemangioma IDH1 / IDH2 Locally aggressive or borderline vascular tumors Kaposiform hemangioendothelioma t(13;16)(q14;p13.3) GNA14 Pseudomyogenic hemangioendothelioma t(7:19)(q22;13) / FOSB Malignant vascular tumors Angiosarcoma (post radiation) MYC Epithelioid hemangioendothelioma CAMTA1 / TFE3 Back to overview Type Alt for previous viewAppendix 2-a causal genes of vascular anomalies
- 8. Capillary malformations (CM) Cutaneous and/or mucosal CM (aka “port-wine” stain ) GNAQ CM with bone and/or soft tissue hyperplasia GNA11 CM with CNS and/or ocular anomalies (Sturge-Weber syndrome) GNAQ CM of CM-AVM RASA1 / EPHB4 Telangiectasia Hereditary hemorrhagic telangiectasia (HHT) HHT1 ENG HHT2 ACVRL1 HHT3 JPHT (juvenile polyposis hemorrhagic telangiectasia) SMAD4 Others Cutis marmorata telangiectatica congenita (CMTC) Nevus simplex / Salmon patch Others Appendix 2-b causal genes of vascular anomalies Back to overview Type Alt for previous view
- 9. Simple vascular malformations II Lymphatic malformations (LM) Common (cystic) LM PIK3CA somatic Macrocystic LM Microcystic LM Mixed cystic LM Generalized lymphatic anomaly (GLA) LM in Gorham-Stout disease Channel type LM Primary lymphedema (different types) G Acquired progressive lymphatic anomaly (acquired progressive "lymphangioma") Others Back to overview some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details clic on G to see genetics Type Alt for previous viewAppendix 2-c causal genes of vascular anomalies
- 10. Lymphatic malformations (LM) Primary lymphedema Nonne-Milroy syndrome FLT4 / VEGFR3 Primary hereditary lymphedema VEGFC Primary hereditary lymphedema GJC2 / Connexin 47 Lymphedema-distichiasis FOXC2 Hypotrichosis-lymphedema-telangiectasia SOX18 Primary lymphedema with myelodysplasia GATA2 Primary generalized lymphatic anomaly (Hennekam lymphangiectasia-lymphedema syndrome) CCBE1 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome KIF11 Lymphedema-choanal atresia PTPN14 Back to overview Appendix 2-d causal genes of vascular anomalies Type Alt for previous view
- 11. Venous malformations (VM) Common VM TEK (TIE2) / PIK3CA somatic Familial VM cutaneo-mucosal (VMCM) TEK (TIE2) Blue rubber bleb nevus (Bean) syndrome VM TEK (TIE2) somatic Glomuvenous malformation (VM with glomus cells) Glomulin Cerebral cavernous malformation (CCM) CCM1 KRIT1 CCM2 Malcavernin CCM3 PDCD10 Familial intraosseous vascular malformation (VMOS) ELMO2 Back to overview Appendix 2-e causal genes of vascular anomalies Type Alt for previous view
- 12. Arteriovenous malformations (AVM) Sporadic MAP2K1 In HHT HHT1 ENG HHT2 ACVRL1 JPHT (juvenile polyposis hem. telangiect.) SMAD4 In CM-AVM RASA1 / EPHB4 Arteriovenous fistulas (AVF) Sporadic MAP2K1 In HHT HHT1 ENG HHT2 ACVRL1 JPHT (juvenile polyposis hemorrhagic telangiectasia) SMAD4 In CM-AVM RASA1 / EPHB4 Back to overview Appendix 2-f causal genes of vascular anomalies Abbreviations used Type Alt for previous view
- 13. Back to overview Vascular malformations associated with other anomalies Klippel-Trenaunay syndrome PIK3CA somatic Parkes Weber syndrome RASA1 Servelle-Martorell syndrome Sturge-Weber syndrome GNAQ Limb CM + congenital non-progressive limb overgrowth GNA11 Maffucci syndrome IDH1 / IDH2 Macrocephaly - CM (M-CM or MCAP) PIK3CA Microcephaly - CM (MICCAP) STAMBP CLOVES syndrome PIK3CA somatic Proteus syndrome AKT1 Bannayan-Riley-Ruvalcaba syndrome PTEN CLAPO syndrome PIK3CA Appendix 2-g causal genes of vascular anomalies Abbreviations used Type Alt for previous view
- 14. Provisionally unclassified vascular anomalies Verrucous hemangioma / Verrucous VM / Verrucous LVM MAP3K3 somatic Angiokeratoma Sinusoidal hemangioma Acral arteriovenous "tumour" Multifocal lymphangioendotheliomatosis with thrombocytopenia / cutaneovisceral angiomatosis with thrombocytopenia (MLT/CAT) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue / "angiomatosis" of soft tissue PTEN Fibro adipose vascular anomaly (FAVA) PIK3CA Back to overview Appendix 2 -h causal genes of vascular anomalies some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Type Alt for previous view
- 15. Appendix 3 infantile hemangioma Back to overview Pattern - focal - multifocal - segmental - indeterminate Different types - superficial - deep - mixed (superficial + deep) - reticular / abortive / minimal growth - others Association with other lesions PHACE association / syndrome Posterior fossa malformations, Hemangioma, Arterial anomalies, Cardiovascular anomalies, Eye anomalies, sternal clefting and ⁄ or supraumbilical raphe LUMBAR (SACRAL, PELVIS) association / syndrome Lower body hemangioma, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies Type Alt for previous view
- 18. IH clinical course markers remain under investigation
- 19. IH clinical course is not classified and best propranolol timing treatment protocols remain unavailable
- 20. FROM LIVER HEMANGIOENDOTHELIOMAS TO HEMANGIOMAS
- 21. • FOCAL..RICH ANALOG…GLUT1- • MULTIFOCAL……….GLUT1+ • DIFFUSSE…………...GLUT1+
- 22. The United Network for Organ Sharing (UNOS) database recorded that a total of 35 children under 1 year of age underwent liver transplantation between 1989 and 2008, because of hemangioma. In contrast, between 2009 and 2017, among 2672 children aged less than 1 year who underwent liver transplantation, none had a diagnosis of hemangioma
- 23. RICH: Rapidly Involuting Congenital Hemangioma
- 28. ISSVA classification of vascular tumors II or 2 Locally aggressive or borderline vascular tumors Kaposiform hemangioendothelioma * ° Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma (PILA), Dabska tumor Composite hemangioendothelioma Pseudomyogenic hemangioendothelioma G Polymorphous hemangioendothelioma Hemangioendothelioma not otherwise specified Kaposi sarcoma Others Malignant vascular tumors Angiosarcoma G Epithelioid hemangioendothelioma G Others Back to overview * 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 Type Alt for previous view
- 31. The spectrum of disease varies greatly between an indolent disease and aggressive disease with widespread metastases. Doyle LA, Fletcher CD, Hornick JL.Nuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics. Am J Surg Pathol.2016 Jan;40(1):94-102 Uncertain biological behaviour of Composite , Retiform, Epithelioid Hemagioendotheliomas
- 32. Composite HE : Third recurrence episode
- 37. 3 years later… metastatic disease
- 38. Similar clinical course in Pediatric and Adult EHE ? Similar clinical course in liver , skin or pulmonary EHE? Literature review identified 24 children with EHE of the liver/lungs. Most presented with multifocal, systemic disease. Four children experienced rapid progression and died. In six children, disease remained stable for years without therapy. Two patients died from progressive EHE 21 and 24 years after first diagnosis. Twelve surgically excised are free of disease Natural evolution of pediatric visceral EHE is variable, and long-term prognosis remains unclear Hettmer S et al. Epithelioid hemangioendotheliomas of the liver and lung in children and adolescents. Pediatr Blood Cancer.2017 Dec;64(12)
- 39. Simple vascular malformations I Capillary malformations (CM) Cutaneous and/or mucosal CM (aka “port-wine” stain ) G CM with bone and/or soft tissue overgrowth G CM with CNS and/or ocular anomalies (Sturge-Weber syndrome) CM of CM-AVM G CM of MICCAP (microcephaly-capillary malformation) CM of MCAP (megalencephaly-capillary malformation-polymicrogyria) Telangiectasia Hereditary hemorrhagic telangiectasia (HHT) (different types) G Others Cutis marmorata telangiectatica congenita (CMTC) Nevus simplex / Salmon patch / “angel kiss”, “stork bite” Others ISSVA classification for vascular anomaliesBack to overview clic on G to see genetics Type Alt for previous view
- 44. No seizures after 1 year under Sirolimus-AAS treatment Better than expected response to Pulse Dye Laser treatment MOST SEVERE PRESENTATION OF STURGE WEBER SME.
- 45. Simple vascular malformations II Lymphatic malformations (LM) Common (cystic) LM G Macrocystic LM Microcystic LM Mixed cystic LM Generalized lymphatic anomaly (GLA) LM in Gorham-Stout disease Channel type LM Primary lymphedema (different types) G ISSVA classification for vascular anomalies
- 47. Infiltration ? Invasion ? Proliferation ? Growth? Enlargement? Dilatation ? “Lymphangiomatosis is a rare disease characterized by diffuse infiltration of lymphangiomas in the lung, bone, and other tissues………” “Diffuse pulmonary lymphangiomatosis has a poor prognosis and is characterized by slow progressive growth of lymphatic……..” “Disseminated lymphangiomatosis is a rare vascular tumor characterized by a proliferation of abnormal lymphatic channels that often involves multiple organ systems………………..” “However, diffuse pulmonary lymphangiomatosis may present as a form of lymphangiectasia, which is characterized pathologically as dilatations of lymphatics without proliferation and without an anastomosing pattern……………………..”
- 48. AGRESSIVE LYMPHATIC MALFORMATIONS: A PROLIFERATIVE DISORDER ? Meijer-Jorna LB et al. Microvascular proliferation in congenital vascular malformations of skin and soft tissue J Clin Pathol. 2007 July; 60(7): 798–803. “Proliferation does not happen in LM…….” The presence of presumed lymphatic channels in bone that is either hypertrophic or shows progressive disappearance is not associated with increased levels of cell turnover or osteocyte activity ( Paula North, 1st GLA-GSD Conference.Bethesda 2013)
- 51. VEIN-LYMPHATIC CONNECTION and LYMPHATIC-LYMPHATIC CONNECTION
- 53. Bilateral LM in neonates have poor prognosis
- 56. 8 months on Sirolimus
- 57. 18 months on Sirolimus
- 58. CHANNEL TYPE LYMPHATIC MALFORMATIONS
- 60. Simple vascular malformations IIb Primary lymphedema Nonne-Milroy syndrome G Primary hereditary lymphedema G Lymphedema-distichiasis G Hypotrichosis-lymphedema-telangiectasia G Primary lymphedema with myelodysplasia G Primary generalized lymphatic anomaly (Hennekam lymphangiectasia-lymphedema syndrome) G Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome G Lymphedema-choanal atresia G Back to overview ISSVA classification for vascular anomalies clic on G to see genetics Type Alt for previous view
- 62. Milroy Disease
- 63. Lymphedema in Sclerosis Tuberosa Complex Lymphedema in Noonan Sme.
- 64. Lymphedema in Parkes-Weber Sme.
- 65. Simple vascular malformations III Venous malformations (VM) Common VM G Familial VM cutaneo-mucosal (VMCM) G Blue rubber bleb nevus (Bean) syndrome VM G Glomuvenous malformation (GVM) G Cerebral cavernous malformation (CCM) (different types) G Familial intraosseous vascular malformation (VMOS) G Others ISSVA classification for vascular anomalies Back to overview some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details clic on G to see genetics Type Alt for previous view
- 67. Caso 1Lopez Gutierrez JC , Ivars M. Fern-shaped patch as a hallmark of blue rubber bleb nevus syndrome in neonatal venous malformations Eur J Pediatr. 2018 Mar 8.
- 68. Blue Rubber Bleb Nevus Syndrome Tumor or Malformation ?
- 71. Simple vascular malformations IV Arteriovenous malformations (AVM) Sporadic In HHT G In CM-AVM G Others Arteriovenous fistula (AVF) (congenital) Sporadic In HHT G In CM-AVM G Others ISSVA classification for vascular anomalies Back to overview Abbreviations used clic on G to see genetics Type Alt for previous view
- 75. Girón-Vallejo O, López-Gutiérrez JC, Fernández-Pineda I Diagnosis and treatment of Parkes Weber syndrome: a review of 10 consecutive patients. Ann Vasc Surg.2013 Aug;27(6):820-5.
- 78. 2006
- 80. 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 Back to overview Abbreviations used * defined as two or more vascular malformations found in one lesion Type Alt for previous view
- 81. MECHANISMS OF SKELETAL HYPERTROPHY OR ATROPHY IN COMBINED VASCULAR MALFORMATIONS REMAIN UNEXPLAINED Patients with PIK3CA mutations can develope overgrowth, simmetry and undergrowth
- 85. ORAL PREPARATION FOR CHILDREN UNDER 35 KGS 0’05mg/kg/ 12h 0’4mgs/ml Solution 2´5 mgs tablet in 60ml 5% glucose
- 86. ISSVA classification for vascular anomalies Back to overview Anomalies of major named vessels (aka "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 Type Alt for previous view
- 87. TGF-β signaling is upregulated in many elastic fiber diseases including Loeys–Dietz, Marfan, and several cutis laxa syndromes but the exact spatio-temporal regulation of TGF-β signaling remains a matter of debate
- 88. Arterial Tortuosity Syndrome is caused by loss-of-function mutations in the SLC2A10 gene
- 90. ISSVA classification for vascular anomalies Provisionally unclassified vascular anomalies Verrucous hemangioma, V venous malformation, V veno lymphatic malformation G Angiokeratoma Sinusoidal hemangioma Acral arteriovenous "tumour" Multifocal lymphangioendotheliomatosis with thrombocytopenia / cutaneovisceral angiomatosis with thrombocytopenia (MLT/CAT) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue / "angiomatosis" of soft tissue (PHOST) G Fibro adipose vascular anomaly (FAVA) G Back to overview clic on G to see genetics some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Type Alt for previous view
- 96. CONCLUSIONS Appropiate classification of a VA remains the best way to achieve the expected therapeutical outcome Multidisciplinary interpretation of findings from diagnostic examinations is mandatory and will improve final results A sense of wonder must guide research by the vascular anomalies specialist as many entities remain to be identified , classified and diagnosed.
- 97. ISSVA classification for vascular anomalies Back to overview Vascular malformations associated with other anomalies Klippel-Trenaunay syndrome: CM + VM +/- LM + limb overgrowth G Parkes Weber syndrome: CM + AVF + limb overgrowth G Servelle-Martorell syndrome: limb VM + bone undergrowth Sturge-Weber syndrome: facial + leptomeningeal CM + eye anomalies +/- bone and/or soft tissue overgrowth G Limb CM + congenital non-progressive limb hypertrophy G Maffucci syndrome: VM +/- spindle-cell hemangioma + enchondroma G Macrocephaly - CM (M-CM / MCAP) G Microcephaly - CM (MICCAP) G CLOVES syndrome: LM + VM + CM +/- AVM + lipomatous overgrowth G Proteus syndrome: CM, VM and/or LM + asymmetrical somatic overgrowth G Bannayan-Riley-Ruvalcaba sd: AVM + VM +macrocephaly, lipomatous overgrowth G CLAPO syndrome: lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth Abbreviations used clic on G to see genetics Type Alt for previous view
- 98. ISSVA classification for vascular anomalies Provisionally unclassified vascular anomalies Verrucous hemangioma, V venous malformation, V veno lymphatic malformation G Angiokeratoma Sinusoidal hemangioma Acral arteriovenous "tumour" Multifocal lymphangioendotheliomatosis with thrombocytopenia / cutaneovisceral angiomatosis with thrombocytopenia (MLT/CAT) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue / "angiomatosis" of soft tissue (PHOST) G Fibro adipose vascular anomaly (FAVA) G Back to overview clic on G to see genetics some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Type Alt for previous view
- 101. Yang CH Orthotopic liver transplant for multifocal lymphangioendotheliomatosis with thrombocytopenia. Pediatr Transplant.2016 May;20(3):456-459.
- 102. Appendix 4 vascular anomalies possibly associated with platelet count / coagulation disorders Back to overview Anomalies Hematological disorders Tufted angioma Kaposiform hemangioendothelioma Profound and sustained thrombocytopenia with profound hypofibrinogenemia, consumptive coagulopathy and elevated D-dimer (Kasabach-Merritt phenomenon) Rapidly involuting congenital hemangioma Transient mild/moderate thrombocytopenia, +/- consumptive coagulopathy and elevated D-dimer Venous malformations / Lymphatic-venous malformations Chronic localized intravascular coagulopathy with elevated D-dimer, +/- hypofibrinogenemia, and +/- moderate thrombocytopenia (may progress to DIC after trauma or operation) Lymphatic malformations Chronic localized intravascular coagulopathy with elevated D-dimer and +/- mild to moderate thrombocytopenia (consider Kaposiform lymphangiomatosis) (may progress to DIC after trauma or operation) Multifocal lymphangioendotheliomatosis with thrombocytopenia / Cutaneovisceral angiomatosis with thrombocytopenia Sustained, fluctuating, moderate to profound thrombocytopenia with gastrointestinal tract bleeding or pulmonary hemorrhage Kaposiform lymphangiomatosis Mild to Moderate thrombocytopenia, +/- hypofibrinogenemia, and D-dimer elevation Type Alt for previous view
- 103. Appendix 1 abbreviations used (excluding gene names) Back to overview AVF arteriovenous fistula AVM arteriovenous malformation CAT cutaneovisceral angiomatosis with thrombocytopenia CAVM capillary arteriovenous malformation CCM cerebral cavernous malformation CLAVM capillary lymphatic arteriovenous malformation CLAPO lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth CLOVES congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/scoliosis and spinal abnormalities CLM capillary lymphatic malformation CLVAVM capillary lymphatic venous arteriovenous malformation CLVM capillary lymphatic venous malformation CM capillary malformation CM-AVM capillary malformation-arteriovenous malformation CMTC cutis marmorata telangiectatica congenita CNS central nervous system CVAVM capillary venous arteriovenous malformation CVM capillary venous malformation DIC disseminated intravascular coagulopathy FAVA Fibro adipose vascular anomaly GLA generalized lymphatic anomaly GSD Gorham-Stout disease GVM glomuvenous malformation HHT hereditary hemorrhagic telangiectasia HI hemangioma of infancy / infantile hemangioma IH infantile hemangioma / hemangioma of infancy INR international normalized ratio JPHT juvenile polyposis hemorrhagic telangiectasia KHE kaposiform hemangioendothelioma KLA kaposiform lymphangiomatosis KMP Kasabach-Merritt phenomenon, LM lymphatic malformation LVM lymphatic venous malformation MCAP megalencephaly-capillary malformation-polymicrogyria M-CM macrocephaly-capillary malformation MICCAP microcephaly-capillary malformation MLT Multifocal lymphangioendotheliomatosis with thrombocytopenia NICH non-involuting congenital hemangioma PHACE posterior fossa malformations, hemangioma, arterial anomalies, cardiovascular anomalies, eye anomalies PHOST PTEN hamartoma of soft tissue PILA papillary intralymphatic angioendothelioma PICH partially involuting congenital hemangioma RICH rapidly involuting congenital hemangioma TA tufted angioma VM venous malformation VMCM venous malformation cutaneo mucosal Type Alt for previous view
- 104. Benign vascular tumors Congenital hemangioma GNAQ / GNA11 Rapidly involuting (RICH) * Non-involuting (NICH) Partially involuting (PICH) Epithelioid hemangioma FOS Spindle-cell hemangioma IDH1 / IDH2 Locally aggressive or borderline vascular tumors Kaposiform hemangioendothelioma t(13;16)(q14;p13.3) Pseudomyogenic hemangioendothelioma t(7:19)(q22;13) FOSB Malignant vascular tumors Angiosarcoma (post radiation) MYC Epithelioid hemangioendothelioma CAMTA1 / TFE3 Back to overview Type Alt for previous viewAppendix 2-a causal genes of vascular anomalies
- 105. Capillary malformations (CM) Cutaneous and/or mucosal CM (aka “port-wine” stain ) GNAQ CM with bone and/or soft tissue hyperplasia GNA11 CM with CNS and/or ocular anomalies (Sturge-Weber syndrome) GNAQ CM of CM-AVM RASA1 / EPHB4 Telangiectasia Hereditary hemorrhagic telangiectasia (HHT) HHT1 ENG HHT2 ACVRL1 HHT3 JPHT (juvenile polyposis hemorrhagic telangiectasia) SMAD4 Others Cutis marmorata telangiectatica congenita (CMTC) Nevus simplex / Salmon patch Others Appendix 2-b causal genes of vascular anomalies Back to overview Type Alt for previous view
- 106. Simple vascular malformations II Lymphatic malformations (LM) Common (cystic) LM PIK3CA? Macrocystic LM Microcystic LM Mixed cystic LM Generalized lymphatic anomaly (GLA) LM in Gorham-Stout disease Channel type LM Primary lymphedema (different types) G Acquired progressive lymphatic anomaly (benign "lymphangioendothelioma") Others Back to overview some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details clic on G to see genetics Type Alt for previous viewAppendix 2-c causal genes of vascular anomalies
- 107. Lymphatic malformations (LM) Primary lymphedema Nonne-Milroy syndrome FLT4 / VEGFR3 Primary hereditary lymphedema VEGFC Primary hereditary lymphedema GJC2 / Connexin 47 Lymphedema-distichiasis FOXC2 Hypotrichosis-lymphedema-telangiectasia SOX18 Primary lymphedema with myelodysplasia GATA2 Primary generalized lymphatic anomaly (Hennekam lymphangiectasia-lymphedema syndrome) CCBE1 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome KIF11 Lymphedema-choanal atresia PTPN14 Back to overview Appendix 2-d causal genes of vascular anomalies Type Alt for previous view
- 108. Venous malformations (VM) Common VM TEK (TIE2) / PIK3CA somatic Familial VM cutaneo-mucosal (VMCM) TEK (TIE2) Blue rubber bleb nevus (Bean) syndrome VM TEK somatic Glomuvenous malformation (VM with glomus cells) Glomulin Cerebral cavernous malformation (CCM) CCM1 KRIT1 CCM2 Malcavernin CCM3 PDCD10 Familial intraosseous vascular malformation (VMOS) ELMO2 Back to overview Appendix 2-e causal genes of vascular anomalies Type Alt for previous view
- 109. Arteriovenous malformations (AVM) Sporadic In HHT HHT1 ENG HHT2 ACVRL1 JPHT (juvenile polyposis hem. telangiect.) SMAD4 In CM-AVM RASA1 / EPHB4 Arteriovenous fistulas (AVF) Sporadic In HHT HHT1 ENG HHT2 ACVRL1 JPHT (juvenile polyposis hemorrhagic telangiectasia) SMAD4 In CM-AVM RASA1 / EPHB4 Back to overview Appendix 2-f causal genes of vascular anomalies Abbreviations used Type Alt for previous view
- 110. Back to overview Vascular malformations associated with other anomalies Klippel-Trenaunay syndrome PIK3CA Parkes Weber syndrome RASA1 Servelle-Martorell syndrome Sturge-Weber syndrome GNAQ Limb CM + congenital non-progressive limb overgrowth GNA11 Maffucci syndrome IDH1 / IDH2 / NPM1 Macrocephaly - CM (M-CM or MCAP) PIK3CA Microcephaly - CM (MICCAP) STAMBP CLOVES syndrome PIK3CA Proteus syndrome AKT1 Bannayan-Riley-Ruvalcaba syndrome PTEN CLAPO syndrome Appendix 2-g causal genes of vascular anomalies Abbreviations used Type Alt for previous view
- 111. Provisionally unclassified vascular anomalies Verrucous hemangioma / V venous malformation / V veno lymphatic malformation MAP3K3 somatic Angiokeratoma Sinusoidal hemangioma Acral arteriovenous "tumour" Multifocal lymphangioendotheliomatosis with thrombocytopenia / cutaneovisceral angiomatosis with thrombocytopenia (MLT/CAT) Kaposiform lymphangiomatosis (KLA) PTEN (type) hamartoma of soft tissue / "angiomatosis" of soft tissue PTEN Fibro adipose vascular anomaly PIK3CA Back to overview Appendix 2 -h causal genes of vascular anomalies some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details Type Alt for previous view
- 112. * 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 ISSVA classification of vascular tumors 1a Benign vascular tumors 1 Infantile hemangioma / Hemangioma of infancy see details Congenital hemangioma G Rapidly involuting (RICH) * Non-involuting (NICH) Partially involuting (PICH) Tufted angioma * ° Spindle-cell hemangioma G Intramuscular hemangioma (capillary type) Epithelioid hemangioma G Pyogenic granuloma (aka lobular capillary hemangioma) Others see details Back to overview Type Alt for previous view
- 113. N.B. reactive proliferative vascular lesions are listed with benign tumors ISSVA classification of vascular tumors 1b Benign vascular tumors 2 Others Honail hemangioma Microvenular hemangioma Anastomosing hemangioma Glomeruloid hemangioma Papillary hemangioma Intravascular papillary endothelial hyperplasia Cutaneous epitheliod angiomatous nodule Acquired elastotic hemangioma Littoral cell hemangioma of the spleen Related lesions Eccrine angiomatous hamartoma Reactive angioendotheliomatosis Bacillary angiomatosis Back to overview Type Alt for previous view
- 114. ISSVA classification for vascular anomalies (Approved at the 20th ISSVA Workshop, Melbourne, April 2014) Overview table °defined as two or more vascular malformations found in one lesion * high-flow lesions N.B. The classification tables do not list exhaustively all known vascular anomalies. Some rare "dermatologic" vascular anomalies will be found in dermatology textbooks. The tumor or malformation nature or precise classification of some lesions is still unclear. These lesions appear in a separate provisional list. Vascular anomalies Vascular tumors Vascular malformations Simple Combined ° of major named vessels associated with other anomalies Benign Locally aggressive or borderline Malignant Capillary malformations Lymphatic malformations Venous malformations Arteriovenous malformations* Arteriovenous fistula* CVM, CLM LVM, CLVM CAVM* CLAVM* others See details See list For more details, click on the underlined linksAbbreviations used
- 115. * 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 ISSVA classification of vascular tumors 1a Benign vascular tumors 1 Infantile hemangioma / Hemangioma of infancy see details Congenital hemangioma G Rapidly involuting (RICH) * Non-involuting (NICH) Partially involuting (PICH) Tufted angioma * ° Spindle-cell hemangioma G Intramuscular hemangioma (capillary type) Epithelioid hemangioma G Pyogenic granuloma (aka lobular capillary hemangioma) Others see details Back to overview Type Alt for previous view
- 116. N.B. reactive proliferative vascular lesions are listed with benign tumors 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 epitheliod angiomatous nodule Acquired elastotic hemangioma Littoral cell hemangioma of the spleen Related lesions Eccrine angiomatous hamartoma Reactive angioendotheliomatosis Bacillary angiomatosis Back to overview Type Alt for previous view
- 117. ISSVA classification of vascular tumors I Benign vascular tumors Infantile hemangioma / Hemangioma of infancy see details Congenital hemangioma Rapidly involuting (RICH) *, Non-involuting (NICH), Partially involuting (PICH) Tufted angioma * ° Spindle-cell hemangioma Intramuscular hemangioma (capillary type) Epithelioid hemangioma Pyogenic granuloma (aka lobular capillary hemangioma) Others Honail hemangioma Microvenular hemangioma Anastomosing hemangioma Glomeruloid hemangioma Papillary hemangioma Intravascular papillary endothelial hyperplasia Cutaneous epitheliod angiomatous nodule Acquired elastotic hemangioma Littoral cell hemangioma of the spleen Related lesions Eccrine angiomatous hamartoma Reactive angioendotheliomatosis Bacillary angiomatosis Back to overview Type Alt for previous view * 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
- 118. ISSVA classification of vascular tumors II or 2 Locally aggressive or borderline vascular tumors Kaposiform hemangioendothelioma * ° Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma (PILA), Dabska tumor Composite hemangioendothelioma Pseudomyogenic hemangioendothelioma G Polymorphous hemangioendothelioma Hemangioendothelioma not otherwise specified Kaposi sarcoma Others Malignant vascular tumors Angiosarcoma G Epithelioid hemangioendothelioma G Others Back to overview * 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 Type Alt for previous view
- 119. Simple vascular malformations I Capillary malformations (CM) Cutaneous and/or mucosal CM (aka “port-wine” stain ) G CM with bone and/or soft tissue overgrowth G CM with CNS and/or ocular anomalies (Sturge-Weber syndrome) CM of CM-AVM G CM of MICCAP (microcephaly-capillary malformation) CM of MCAP (megalencephaly-capillary malformation-polymicrogyria) Telangiectasia Hereditary hemorrhagic telangiectasia (HHT) (different types) G Others Cutis marmorata telangiectatica congenita (CMTC) Nevus simplex / Salmon patch / “angel kiss”, “stork bite” Others ISSVA classification for vascular anomaliesBack to overview clic on G to see genetics Type Alt for previous view
- 120. Simple vascular malformations II Lymphatic malformations (LM) Common (cystic) LM G Macrocystic LM Microcystic LM Mixed cystic LM Generalized lymphatic anomaly (GLA) LM in Gorham-Stout disease Channel type LM Primary lymphedema (different types) G Acquired progressive lymphatic anomaly (benign "lymphangioendothelioma") Others ISSVA classification for vascular anomalies Back to overview some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details clic on G to see genetics Type Alt for previous view
- 121. Simple vascular malformations IIb Primary lymphedema Nonne-Milroy syndrome G Primary hereditary lymphedema G Lymphedema-distichiasis G Hypotrichosis-lymphedema-telangiectasia G Primary lymphedema with myelodysplasia G Primary generalized lymphatic anomaly (Hennekam lymphangiectasia-lymphedema syndrome) G Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome G Lymphedema-choanal atresia G Back to overview ISSVA classification for vascular anomalies clic on G to see genetics Type Alt for previous view
- 122. Simple vascular malformations III Venous malformations (VM) Common VM G Familial VM cutaneo-mucosal (VMCM) G Blue rubber bleb nevus (Bean) syndrome VM G Glomuvenous malformation (GVM) G Cerebral cavernous malformation (CCM) (different types) G Familial intraosseous vascular malformation (VMOS) G Others ISSVA classification for vascular anomalies Back to overview some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy see details clic on G to see genetics Type Alt for previous view
- 123. Simple vascular malformations IV Arteriovenous malformations (AVM) Sporadic In HHT G In CM-AVM G Others Arteriovenous fistula (AVF) (congenital) Sporadic In HHT G In CM-AVM G Others ISSVA classification for vascular anomalies Back to overview Abbreviations used clic on G to see genetics Type Alt for previous view
- 124. 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 Back to overview Abbreviations used * defined as two or more vascular malformations found in one lesion Type Alt for previous view
- 125. ISSVA classification for vascular anomalies Back to overview Anomalies of major named vessels (aka "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 Type Alt for previous view
- 126. ISSVA classification for vascular anomalies Back to overview Vascular malformations associated with other anomalies Klippel-Trenaunay syndrome: CM + VM +/- LM + limb overgrowth G Parkes Weber syndrome: CM + AVF + limb overgrowth G Servelle-Martorell syndrome: limb VM + bone undergrowth Sturge-Weber syndrome: facial + leptomeningeal CM + eye anomalies +/- bone and/or soft tissue overgrowth G Limb CM + congenital non-progressive limb hypertrophy G Maffucci syndrome: VM +/- spindle-cell hemangioma + enchondroma G Macrocephaly - CM (M-CM / MCAP) G Microcephaly - CM (MICCAP) G CLOVES syndrome: LM + VM + CM +/- AVM + lipomatous overgrowth G Proteus syndrome: CM, VM and/or LM + asymmetrical somatic overgrowth G Bannayan-Riley-Ruvalcaba sd: AVM + VM +macrocephaly, lipomatous overgrowth G CLAPO syndrome: lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth Abbreviations used clic on G to see genetics Type Alt for previous view
- 127. Appendix 1 abbreviations used (excluding gene names) Back to overview AVF arteriovenous fistula AVM arteriovenous malformation CAT cutaneovisceral angiomatosis with thrombocytopenia CAVM capillary arteriovenous malformation CCM cerebral cavernous malformation CLAVM capillary lymphatic arteriovenous malformation CLAPO lower lip CM + face and neck LM + asymmetry and partial/generalized overgrowth CLOVES congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/scoliosis and spinal abnormalities CLM capillary lymphatic malformation CLVAVM capillary lymphatic venous arteriovenous malformation CLVM capillary lymphatic venous malformation CM capillary malformation CM-AVM capillary malformation-arteriovenous malformation CMTC cutis marmorata telangiectatica congenita CNS central nervous system CVAVM capillary venous arteriovenous malformation CVM capillary venous malformation DIC disseminated intravascular coagulopathy FAVA Fibro adipose vascular anomaly GLA generalized lymphatic anomaly GSD Gorham-Stout disease GVM glomuvenous malformation HHT hereditary hemorrhagic telangiectasia HI hemangioma of infancy / infantile hemangioma IH infantile hemangioma / hemangioma of infancy INR international normalized ratio JPHT juvenile polyposis hemorrhagic telangiectasia KHE kaposiform hemangioendothelioma KLA kaposiform lymphangiomatosis KMP Kasabach-Merritt phenomenon, LM lymphatic malformation LVM lymphatic venous malformation MCAP megalencephaly-capillary malformation-polymicrogyria M-CM macrocephaly-capillary malformation MICCAP microcephaly-capillary malformation MLT Multifocal lymphangioendotheliomatosis with thrombocytopenia NICH non-involuting congenital hemangioma PHACE posterior fossa malformations, hemangioma, arterial anomalies, cardiovascular anomalies, eye anomalies PHOST PTEN hamartoma of soft tissue PILA papillary intralymphatic angioendothelioma PICH partially involuting congenital hemangioma RICH rapidly involuting congenital hemangioma TA tufted angioma VM venous malformation VMCM venous malformation cutaneo mucosal Type Alt for previous view
- 128. Appendix 3 infantile hemangioma Back to overview Pattern - focal - multifocal - segmental - indeterminate Different types - superficial - deep - mixed (superficial + deep) - reticular / abortive / minimal growth - others Association with other lesions PHACE association / syndrome Posterior fossa malformations, Hemangioma, Arterial anomalies, Cardiovascular anomalies, Eye anomalies, sternal clefting and ⁄ or supraumbilical raphe LUMBAR (SACRAL, PELVIS) association / syndrome Lower body hemangioma, Urogenital anomalies, Ulceration, Myelopathy, Bony deformities, Anorectal malformations, Arterial anomalies, and Renal anomalies Type Alt for previous view
- 129. Síndrome CLAPO
- 133. No response to Sirolimus Response to Vincristine –Ticlopidine – Aspirine and percutaneous biliary diversion Triana PJ, Lopez Gutierrez JC Pancreatic Kaposiform Hemangioendothelioma Not Responding to Sirolimus. European Journal of Pediatric Surgery. 2017;5(1).