classification pathogenesis and treatment of benign ... · vascular anomalies in children with a...

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Classification, Pathogenesis Classification, Pathogenesis and Treatment of Benign and Treatment of Benign

Vascular Anomalies in ChildrenVascular Anomalies in ChildrenWith a review of the pathology

Martin C. Mihm Jr., MDMartin C. Mihm Jr., MDDirector, Melanoma ProgramDirector, Melanoma Program

Brigham and Women’s HospitalBrigham and Women’s HospitalHarvard Medical SchoolHarvard Medical School

Conflict of Interest

Chairman Scientific Advisory Board –Caliber I.D. Inc.

Member Scientific Advisory Board – MELA Sciences IncSciences Inc.

Vascular anomalies are either Vascular anomalies are either hemangiomas or malformationshemangiomas or malformations

10% of all children are born 10% of all children are born with a vascular birthmarkwith a vascular birthmark

90% resolve by age 2; the90% resolve by age 2; the 90% resolve by age 2; the 90% resolve by age 2; the remaining are either a remaining are either a problematic problematic hemangiomahemangioma(infantile), or type of (infantile), or type of hemangiomahemangioma (NICH/RICH) or a (NICH/RICH) or a vascular malformation (the vascular malformation (the most common is a port wine most common is a port wine stain)stain)

Facial hemangioma

Facial Port Wine Stain

Mulliken & Young (1988)

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HemangiomasHemangiomas--Clinical PresentationClinical Presentation Typically Typically infantile infantile hemangiomashemangiomas appearappear

3 to 4 weeks after birth3 to 4 weeks after birth

Start as a flat Start as a flat blanched lesion blanched lesion

Begin proliferation Begin proliferation at 4 to 6 weeksat 4 to 6 weeks

Can be both Can be both superficial/deep superficial/deep

Waner and Suen (1999)Waner and Suen (1999)

Hemangioma “before” signs of proliferation

Hemangioma during proliferation

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Infantile Hemangioma, Proliferative phase

Infantile Hemangioma, Proliferative phase

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Infantile Hemangioma:

Involution

Infantile Hemangioma, Mid-Involution

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Infantile Hemangioma, End-stage

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One prominent One prominent histological feature histological feature of infantile of infantile hemangiomas, the hemangiomas, the presence of presence of endoneurial endoneurial pseudoinvasion, pseudoinvasion, led us to led us to investigate bloodinvestigate blood--nerve barrier nerve barrier competency in competency in these lesions.these lesions.

GLUT1GLUT11.1. One of a family of facilitative glucose One of a family of facilitative glucose

transporter protein isoforms, each with a transporter protein isoforms, each with a limited tissue distribution in vivo.limited tissue distribution in vivo.

2. Expression found in normal tissues highly2. Expression found in normal tissues highly2. Expression found in normal tissues highly 2. Expression found in normal tissues highly restricted to erythrocytes, perineural cells, restricted to erythrocytes, perineural cells, endothelial cells at bloodendothelial cells at blood--tissue barriers as tissue barriers as brain, nerve and placenta, and some brain, nerve and placenta, and some epithelial barriers.epithelial barriers.

3. Up3. Up--regulation in many malignant cells, regulation in many malignant cells, but not in benign tumors.but not in benign tumors.

Pyogenic Granuloma

GLUT1

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Hemangioma

Lesion Gene Locus Pathway Therapy

IH VEGFR3; PDGFR-beta; FLT4;

5p31-33 VEGF receptor pathway; EC proliferation;

Propranolol; acebutolol; corticosteroids;

VEGFR2; TEM8

p ;tubular morphogenesis; sprouting integrin-like receptor

Uebelhoer M., Boon LM, ikkula M. CSH Perspectives; 2012

Preferred Treatment of Infantile Hemangiomas Early proliferating superficial lesions, especially segmental, should be treated with pulse dye laser or topicals

Steroids are still preferred for intralesional injection into small focal hemangiomas since propranolol has not been found to be effective when injected directly into a lesion

Propranolol is first line oral/systemic treatment for large, disfiguring and problematic segmental and focal hemangiomas

Surgery is considered for lesions that fail drug and/or laser therapy or when a vital structure is impaired and there is insufficient time to wait for drug therapy to take effect

Labreze, de la Roque, Hubiche, Boralevi, Bordeau Children’s Labreze, de la Roque, Hubiche, Boralevi, Bordeau Children’s Hospital, June 2008 (Hospital, June 2008 (New England Journal of MedicineNew England Journal of Medicine) 358) 358--26492649--26512651

C

GLUT1 Le Y

The Unique Vascular Phenotype of Infantile Hemangioma

FcgammaRIIFcgammaRII MEROSIN

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GLUT1 LeY

PLACENTA

FcγIlR MEROSIN

POSSIBLE MECHANISMS FOR SHARED POSSIBLE MECHANISMS FOR SHARED HEMANGIOMAHEMANGIOMA--PLACENTAL PHENOTYPEPLACENTAL PHENOTYPE

1. Embolization1. Embolization of placentallyof placentally--derived vascular cells or derived vascular cells or precursors to fetal tissues during gestation or birth (North precursors to fetal tissues during gestation or birth (North P. et al.; P. et al.; Hum PathHum Path; 2001; Mihm MC. Nelson S. ; 2001; Mihm MC. Nelson S. Cutaneous PatholCutaneous Pathol; 2010).; 2010).

2. 2. Colonization by angioblasts Colonization by angioblasts (Boye E. et al.; (Boye E. et al.; JCI; 2001)JCI; 2001)aberrantly “switched” to the placental phenotype by either:aberrantly “switched” to the placental phenotype by either:

a. Somatic mutation.a. Somatic mutation.b. Abnormal local inductive influences. b. Abnormal local inductive influences.

3. Infantile hemangioma 3. Infantile hemangioma stem cellsstem cells give rise to both give rise to both endothelial and pericytic cells. (Boscolo E. et al.; endothelial and pericytic cells. (Boscolo E. et al.; Arteriosclr Thromb Vasc BiolArteriosclr Thromb Vasc Biol; 2013); 2013)

Recent Investigations (Cont.)Recent Investigations (Cont.)

Striking similarities of transcriptomes between Striking similarities of transcriptomes between placenta and hemangioma when studying placenta and hemangioma when studying hierarchical and nonhierarchical clustering hierarchical and nonhierarchical clustering analysis of >7,800 genes from a variety of analysis of >7,800 genes from a variety of tissuestissues

Comparing the two studying arrays of 21 Comparing the two studying arrays of 21 endothelial cell genes in 1000 polymporphisms, endothelial cell genes in 1000 polymporphisms, great similarities were found. (Barnes et al. great similarities were found. (Barnes et al. PNAS, 2005)PNAS, 2005)

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Vascular MalformationsVascular MalformationsHigh FlowHigh Flow

Arteriovenous MalformationsArteriovenous Malformations Arteriovenous FistulasArteriovenous Fistulas

Low FlowLow Flow

LymphaticLymphatic CapillaryCapillary VenousVenous MixedMixed

Arteriovenous Malformation

HIGH FLOW

Lymphatic Malformation

LOW FLOW

Most cases occur sporadicallyMost cases occur sporadically Heritable AVMs have been associated with a Heritable AVMs have been associated with a

cutaneous capillary malformation and hereditary cutaneous capillary malformation and hereditary hemorrhagic telangiectasia (HHT)hemorrhagic telangiectasia (HHT)

Arteriovenous Malformations

g g ( )g g ( ) ArterioArterio--venous fistulae are commonly trauma venous fistulae are commonly trauma

associatedassociated Lesions present as often small pulsatile Lesions present as often small pulsatile

cutaneous plaques or nodules with overlying cutaneous plaques or nodules with overlying normal or Port Wine Stainnormal or Port Wine Stain--like skinlike skin

HHTHHT--associated AVMs involve endoglin associated AVMs involve endoglin and activin receptorand activin receptor--like kinase 1 geneslike kinase 1 genes

Loss of function results in impaired TGFLoss of function results in impaired TGF--beta signaling necessary for AVbeta signaling necessary for AV


beta signaling, necessary for AV beta signaling, necessary for AV differentiationdifferentiation

The cutaneous capillary malformation The cutaneous capillary malformation associated with AVM involve mutations in associated with AVM involve mutations in RASA 1 that affects the RAS/MAP Kinase RASA 1 that affects the RAS/MAP Kinase pathwaypathway

Whitehead KJ et al. 2013; CHS Perspectives on medicine

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AVM

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AVM involving the skin

AVM HistopathologyAVM Histopathology

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NIDUS

artery

NIDUS

vein

TheoryTheory

Relative or absolute absence of preRelative or absolute absence of pre--capillary sphincters/sphincter control.capillary sphincters/sphincter control.

Results in continuous shunting of blood Results in continuous shunting of blood across the nidusacross the nidusacross the nidus.across the nidus.

This in turn results in expansion of the This in turn results in expansion of the nidus, venous dilatation and arterial nidus, venous dilatation and arterial hypertrophy.hypertrophy.

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Primary nidus Primary nidus –– capillary malformationcapillary malformation Arterial hypertrophy and venous Arterial hypertrophy and venous

dilatationdilatation--secondary changessecondary changesN f li i ll diff ti tiN f li i ll diff ti ti

TheoryTheory

No way of clinically differentiating No way of clinically differentiating between primary nidus and secondary between primary nidus and secondary changes.changes.

Difficulty in determining “tumor margins”, Difficulty in determining “tumor margins”, assuming that the nidus is fixed.assuming that the nidus is fixed.

Treatment of AVMsTreatment of AVMs Requires multidisciplinary Requires multidisciplinary

team approach with team approach with Interventional Radiologist and Interventional Radiologist and SurgeonSurgeon

Goal is to manage, attempt to Goal is to manage, attempt to curecure

Embollization/AngiographicEmbollization/Angiographic

SclerotherapySclerotherapy

Combination with surgery. Combination with surgery. Must remove the NIDUSMust remove the NIDUS

All tissue must be removedAll tissue must be removedWaner & Suen (1999)

ArteriovenousArteriovenous MalformationMalformation


AVM RASA1 5q13-22 Ras/MAPK inhibiton; Cell motility; Survival

mTOR inhibitors? Ras inhibitors?Survival inhibitors?


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Glomulovenous Glomulovenous MalformationMalformation

“Glomangioma”“Glomangioma”GlomangiomaGlomangioma

Differential diagnosis in infancy:– Blue Rubber Bleb Nevus Syndrome– Leukemia Cutis (Blueberry Muffin Syndrome)

Venous Malformations

Glomulovenous MalformationGlomulovenous Malformation

– Venous Malformations

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Glomulovenous MalformationGlomulovenous Malformation


Glomuvenous Malformation

GLMN 1p21-22 SMC differentiation

P t i

? mTOR inhibitors

; Protein synthesis/ degradation; TGF-beta, HGF pathways


Low Flow Low Flow –– Lymphatic Lymphatic MalformationMalformation

Lymphatic malformations (cystic Lymphatic malformations (cystic hygroma or lymphangioma are hygroma or lymphangioma are classified as microcystic, classified as microcystic, macrocystic, or mixed. macrocystic, or mixed.

Most lymphatic malformations Most lymphatic malformations (approximately 75%) occur in the (approximately 75%) occur in the cervicofacial region. cervicofacial region.

The overlying skin can be healthy, The overlying skin can be healthy, or it may have tiny characteristic or it may have tiny characteristic vesicles. vesicles.

Lymphatic MalformationsLymphatic Malformations

Lesions often first present or become Lesions often first present or become more extensive at times of hormonal more extensive at times of hormonal change, such as puberty, or associated change, such as puberty, or associated with infectionwith infectionwith infectionwith infection

Recurring infections lead to extensive Recurring infections lead to extensive growth and often require prophylactic growth and often require prophylactic antibioticsantibiotics

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LYMPHATIC MALFORMATIONS

Lymphatic MalformationLymphatic Malformation

Lymphatic MalformationLymphatic Malformation

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Lymphatic Malformation, Macrocystic Lymphatic Malformation, Macrocystic (Cystic Hygroma)(Cystic Hygroma)

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Management of Lymphatic Management of Lymphatic MalformationsMalformations

Surgical resectionSurgical resection

Laser therapyLaser therapy

OK 432OK 432 OK 432OK 432

Management with Management with antibioticsantibiotics

Studies currently Studies currently underway with Rapamycin underway with Rapamycin and Viagra (Sildenafil)and Viagra (Sildenafil)

Before

After numerous surgeries

Low Flow Low Flow –– Capillary MalformationCapillary MalformationPort Wine StainsPort Wine Stains

Also known as port wine Also known as port wine stainsstains

Sometimes referred to as Sometimes referred to as venular malformationsvenular malformations

Present at birth as a flat Present at birth as a flat red/purple birthmarkred/purple birthmark

Never regressNever regress

Some can thicken, Some can thicken, cobble, and cause tissue cobble, and cause tissue overgrowthovergrowth

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PORT WINE STAIN

Port Wine Stain Dermal Venulocapillary Malformation

Mature Port Wine Stain: Cobblestoning and Nodularity

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Port Wine Stain TreatmentPort Wine Stain Treatment

Laser treatmentLaser treatment Sometimes Sometimes

require tissue require tissue debulkingdebulkingdebulkingdebulking

Photos courtesy of www.birthmark.org

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Pulse Dye Laser (PDL) is current treatment Pulse Dye Laser (PDL) is current treatment of choiceof choice

Selectively destroys subsurface targets Selectively destroys subsurface targets without inducing thermal damage in without inducing thermal damage in


adjacent normal tissueadjacent normal tissue PDL first generation used 577 nm. PDL first generation used 577 nm.

wavelength and 300 us. pulse durationwavelength and 300 us. pulse duration Now 585 nm. wavelength available for Now 585 nm. wavelength available for

adult PWS treatmentadult PWS treatment

Angiogenesis inhibitor Rapamycin (RPM) Angiogenesis inhibitor Rapamycin (RPM) has been combined with PDL to potentially has been combined with PDL to potentially enhance PWS therapeutic outcomeenhance PWS therapeutic outcome

RPM can suppress theRPM can suppress the


RPM can suppress the RPM can suppress the VEGF/PI3K/AKT/mTOR pathway and VEGF/PI3K/AKT/mTOR pathway and inhibit reperfusion of blood vessels post inhibit reperfusion of blood vessels post PDL in PWS patientsPDL in PWS patients

Further study is needed for more efficient Further study is needed for more efficient therapeutic modalitiestherapeutic modalities

Venous MalformationVenous Malformation Clinical FeaturesClinical Features Incidence is 1 in 5,000 to 1 in 10,000 personsIncidence is 1 in 5,000 to 1 in 10,000 persons Thrombosis common and associated with pain Thrombosis common and associated with pain

as well as clinical nodularityas well as clinical nodularityO i l d i l di Kli lO i l d i l di Kli l Occur in complex syndromes including KlippelOccur in complex syndromes including Klippel--Trenaunay, Maffucci, and Blue Rubber Bleb Trenaunay, Maffucci, and Blue Rubber Bleb Nevus syndromeNevus syndrome

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Low Flow Low Flow -- Venous Venous MalformationsMalformations

Venous Malformations are Venous Malformations are usually soft and easily usually soft and easily compressible softcompressible soft--tissue mass tissue mass that is associated with bluish that is associated with bluish skin discoloration. skin discoloration.

Increasing engorgement with Increasing engorgement with dependency is typical.dependency is typical.

These birthmarks can be These birthmarks can be small and localized or small and localized or extensive and involve the extensive and involve the entire extremity or body entire extremity or body part.part.

Venous Malformation

GLUT1

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Venous Malformation TreatmentVenous Malformation Treatment

Surgical resectionSurgical resection EmbollizationEmbollization SclerotherapySclerotherapy RapamycinRapamycin NdYagNdYag LaserLaser

Venous MalformationVenous MalformationLesion Gene Locus Pathway Therapy

VM TIE2/TEK 9p21 Tyrosine kinase receptor; EC migration, proliferation, survival; SMC recruitment; Vascular sprouting; Maturation, stability;

TIE2 inhibitors?

, y;Hematopoietic quiescence


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Low Flow Low Flow –– Mixed MalformationMixed Malformation LymphoLympho--venous malformations are often referred to as mixed venous malformations are often referred to as mixed

lesions. lesions.

They contain both abnormal lymphatic and venous channels.They contain both abnormal lymphatic and venous channels.

They may be scattered in one extremity or may be a focal They may be scattered in one extremity or may be a focal malformationmalformation

Treatment consists of embollization, sclerotherapy, Treatment consists of embollization, sclerotherapy, compression management and lasercompression management and laser

Orhan Konez (2008)

Malformation SyndromesMalformation Syndromes

Shortcut to Geoffforstudy010.lnk

Sturge-Weber SyndromeKlippel-Trenaunay Syndrome

KlippelKlippel--TrenaunayTrenaunay SyndromeSyndrome Affects one or more limbs or trunk Affects one or more limbs or trunk

region.region.

Triad of stain, tissue hypertrophy, and Triad of stain, tissue hypertrophy, and bone overgrowthbone overgrowth

Most cases girth of limb is larger but in Most cases girth of limb is larger but in some cases the nonsome cases the non--affected limb can be affected limb can be clinically smallerclinically smaller

Stain is different than typical port wine Stain is different than typical port wine stainstain

Lateral Marginal Vein varicosity Lateral Marginal Vein varicosity diagnosticdiagnostic

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KTS Treatment/ManagementKTS Treatment/Management

CompressionCompressionWater therapyWater therapy LaserLaser

El ti f t itEl ti f t it Elevation of extremityElevation of extremity Low dose aspirinLow dose aspirin Debulking when Debulking when

necessarynecessary Amputation as a last Amputation as a last

resortresort VBF Birthmarks Fact Booklet

SturgeSturge--Weber SyndromeWeber SyndromeInvolves 3 components, vascular stain of the V1 (eye area), calcification on the brain, and glaucoma from increased ocular pressure

30% to 70% of individuals with a stain in30% to 70% of individuals with a stain in the V1 region are suspect for SWS

Brain involvement may be unilateral or bilateral

A typical vascular nevus

SturgeSturge--Weber SyndromeWeber Syndrome

Ellison D., Neuropathology; 3rd Ed.

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Bilateral meningeal angiomatosis.



Coronal slices of a surgical specimen show the narrowed dark granular cortical


ribbon.


Microscopy shows the abnormal leptomeningeal venous plexus and a linear array of


linear array of superficial calcifications in the thin atrophic cortex.


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Severe astrogliosis with Rosenthal fiber formation and many calcospherites in the


superficial cortex.


The leptomeningeal venous angioma lacks elastic fibers.



Vascular Tumors and Vascular Tumors and Malformations associated with Malformations associated with

CoagulopathyCoagulopathy MildMild--toto--moderate chronic consumptive moderate chronic consumptive

coagulopathycoagulopathy –– large venous andlarge venous andcoagulopathycoagulopathy large venous and large venous and lymphatic malformationslymphatic malformations

Severe thrombocytopenia due to platelet Severe thrombocytopenia due to platelet trapping (Kasabachtrapping (Kasabach--Merritt phenomenon)Merritt phenomenon)–– kaposiform hemangioendothelioma and kaposiform hemangioendothelioma and tufted angiomatufted angioma

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Kaposiform hemangioendotheliomaKaposiform hemangioendothelioma

Infantile hemangioma TA KHE

Kasabach-Merritt Phenomenon

GLUT1 positive

No KMP

GLUT1 negative

+/- KMP

TA

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KHE

KHE

KHE

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Intramuscular “Hemangiomas”

Large vessel malformations (mostly venous)

Small vessel type (vascular malformations or tumors?)or tumors?)

Mixed small and large vessel type No infantile hemangiomas

Intramuscular “Hemangiomas”

Most are low-flow venous malformations.

Th ll l “ ll l” t i i i f til The cellular, “small-vessel” type mimic infantile hemangioma in histology somehat, but are negative for GLUT1, etc. These present as “masses” by MRI and typically show angiographic and/or clinical features of AV-shunting. They are clinically consistent with vascular malformations and do not regress.

Intramuscular venous malformation

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Intramuscular venous malformation

Intramuscular “hemangioma”

In SummaryIn Summary Vascular tumors of childhood represent a number Vascular tumors of childhood represent a number

of distinct entities with diverse etiologies of distinct entities with diverse etiologies –– many many with diagnostic histopathological features.with diagnostic histopathological features.

Some lesions continue to defy classification and Some lesions continue to defy classification and are best viewed as complex, dynamic processes are best viewed as complex, dynamic processes responding to as yet unidentified factors. For responding to as yet unidentified factors. For these, the object for the pathologist is not to these, the object for the pathologist is not to “pigeon hole”, but to describe as accurately as “pigeon hole”, but to describe as accurately as possible. possible.

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Everyone has the right to look Everyone has the right to look normalnormal

Photos courtesy of VBF

AcknowledgmentsAcknowledgments Paula North, MD, PhDPaula North, MD, PhD Milton Waner, MDMilton Waner, MD Teresa O, MDTeresa O, MD Adriano Piris, MDAdriano Piris, MD Ignacio Ignacio CarpinteroCarpintero, MD, MD Larry Larry EichenfieldEichenfield, MD, MD IlonaIlona FriedenFrieden, MD, MD Christine Lian, MDChristine Lian, MD Labib Zakka, MDLabib Zakka, MD Linda Linda RozellRozell--Shannon, PhDShannon, PhD

Thank you for your kind Thank you for your kind attentionattention

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