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LAPORANLAPORAN KLINIKKLINIK PedomanPedoman untukuntuk ClinicianClinician didi RenderingRendering PediatricPediatric

LAPORANLAPORAN KLINIKKLINIK PedomanPedoman untukuntuk ClinicianClinician didi RenderingRendering PediatricPediatric PerawatanPerawatan

Diagnosis dan Penatalaksanaan infantil Hemangioma

DavidDavidDavid H.H.H. Darrow,Darrow,Darrow, MD,MD,MD, DDS,DDS,DDS, ArinArinArin K.K.K. Greene,Greene,Greene, MD,MD,MD, AnthonyAnthonyAnthony J.J.J. Mancini,Mancini,Mancini, MD,MD,MD, AmyAmyAmy J.J.J. Nopper,Nopper,Nopper, MD,MD,MD, BAGIANBAGIANBAGIAN dermatologi,dermatologi,dermatologi, BAGIANBAGIANBAGIAN ONONON THTTHTTHT --- KEPALAKEPALAKEPALA DAN LEHER BEDAH, dan BAGIAN ON BEDAH PLASTIK

abstrak

hemangioma infantil (IHS) adalah tumor yang paling umum dari masa kanak-kanak. Tidak seperti tumor

lainnya, mereka memiliki kemampuan unik untuk rumit setelah proliferasi, yang sering menimbulkan

penyedia perawatan primer untuk menganggap mereka akan menyelesaikan tanpa intervensi atau

konsekuensi. Sayangnya, bagian dari IHS cepat mengembangkan komplikasi, mengakibatkan rasa sakit,

gangguangangguangangguan fungsional,fungsional,fungsional, atauatauatau disdisdis permanenpermanenpermanen fififi gurement.gurement.gurement. Akibatnya,Akibatnya,Akibatnya, dokterdokterdokter primerprimerprimer memilikimemilikimemiliki tugastugastugas menentukanmenentukanmenentukan

lesi memerlukan konsultasi awal dengan dokter spesialis. Meskipun beberapa ulasan baru-baru ini telah

diterbitkan,diterbitkan,diterbitkan, laporanlaporanlaporan klinisklinisklinis iniiniini adalahadalahadalah fififi pertamapertamapertama berdasarkanberdasarkanberdasarkan masukanmasukanmasukan daridaridari individuindividuindividu yangyangyang mewakilimewakilimewakili banyakbanyakbanyak

spesialisasi yang terlibat dalam pengobatan IH. Tujuannya adalah untuk memperbarui masyarakat pediatrik

IH. Tujuannya adalah untuk memperbarui masyarakat pediatrik Dokumen ini merupakan hak cipta dan milik dari American

Dokumen ini merupakan hak cipta dan milik dari American Academy of Pediatrics dan DewanDewanDewanDewanDewan Direksi.Direksi.Direksi.Direksi.Direksi. SemuaSemuaSemuaSemuaSemua penulispenulispenulispenulispenulis memilikimemilikimemilikimemilikimemiliki fififififi dipimpindipimpindipimpindipimpindipimpin conconconconcon flflflflfl ikikikikik laporanlaporanlaporanlaporanlaporan kepentingankepentingankepentingankepentingankepentingan dengandengandengandengandengan AmericanAmericanAmerican AcademyAcademyAcademy ofofof Pediatrics.Pediatrics.Pediatrics. setiapsetiapsetiap conconcon flflfl ikikik telahtelahtelah diselesaikandiselesaikandiselesaikan melaluimelaluimelalui prosesprosesproses yangyangyang disetujui oleh Dewan Direksi. The American Academy of Pediatrics telah tidak diminta atau diterima keterlibatan komersial apapun dalam pengembangan isi dari publikasi ini.

laporanlaporanlaporan klinisklinisklinis daridaridari AmericanAmericanAmerican AcademyAcademyAcademy ofofof PediatricsPediatricsPediatrics benebenebene fififi ttt daridaridari keahliankeahliankeahlian dandandan sumbersumbersumber daya penghubung internal dan (American Academy of Pediatrics) dan peninjau eksternal. Namun, laporan klinis dari American Academy of Pediatrics mungkin tidak kembalikembalikembali flflfl dlldlldll pandanganpandanganpandangan penghubungpenghubungpenghubung atauatauatau organisasiorganisasiorganisasi atauatauatau instansiinstansiinstansi pemerintahpemerintahpemerintah yangyangyang mereka wakili.

Bimbingan dalam laporan ini tidak menunjukkan kursus eksklusif pengobatan atau berfungsi sebagai standar perawatan medis. Variasi, dengan keadaan individu akun, mungkin tepat.

Semua laporan klinis dari American Academy of Pediatrics secara otomatis berakhir 5 tahuntahuntahun setelahsetelahsetelah publikasipublikasipublikasi kecualikecualikecuali reafreafreaf fififi rmed,rmed,rmed, direvisi,direvisi,direvisi, atauatauatau pensiunpensiunpensiun padapadapada atauatauatau sebelumsebelumsebelum waktu itu.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-2485

DOI:DOI: 10,154210,1542 // peds.2015-2485peds.2015-2485

Pediatrics (Nomor ISSN: Print, 0031-4005; Online, 1098-4275).

Hak cipta © 2015 oleh American Academy of Pediatrics

PENGUNGKAPANPENGUNGKAPANPENGUNGKAPANPENGUNGKAPAN KEUANGAN:KEUANGAN:KEUANGAN:KEUANGAN: ParaParaParaPara penulispenulispenulispenulis telahtelahtelahtelah mengindikasikanmengindikasikanmengindikasikanmengindikasikan bahwabahwabahwabahwa merekamerekamerekamereka tidaktidaktidaktidak memilikimemilikimemilikimemiliki fifififi hubunganhubunganhubunganhubungan

keuangan yang relevan untuk artikel ini untuk mengungkapkan.

POTENSIPOTENSI KONFLIKKONFLIK KEPENTINGAN:KEPENTINGAN: ParaPara penulispenulis telahtelah mengindikasikanmengindikasikan bahwabahwa merekamereka tidaktidak memilikimemiliki potensipotensi

conconcon flflfl ikikik kepentingankepentingankepentingan untukuntukuntuk mengungkapkan.mengungkapkan.mengungkapkan.

DARI American Academy

of Pediatrics

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mengenai penemuan terbaru di IH patogenesis, pengobatan, dan asosiasi klinis dan untuk memberikan

dasar untuk pengambilan keputusan klinis dalam pengelolaan IH.

TATA NAMA

NomenklaturNomenklaturNomenklatur dandandan klasifikasiklasifikasiklasifikasi fififi kationkationkation tumortumortumor pembuluhpembuluhpembuluh darahdarahdarah dandandan malformasimalformasimalformasi telahtelahtelah berevolusiberevolusiberevolusi daridaridaridaridaridaridaridaridaridaridari deskripsideskripsideskripsideskripsideskripsideskripsideskripsideskripsideskripsideskripsideskripsi klinisklinisklinisklinisklinisklinisklinisklinisklinisklinisklinis ((((((((((( “““““““““““ strawberrystrawberrystrawberrystrawberrystrawberrystrawberrystrawberrystrawberrystrawberrystrawberrystrawberry tandatandatandatandatandatandatandatandatandatandatanda lahir,lahir,lahir,lahir,lahir,lahir,lahir,lahir,lahir,lahir,lahir, ”“”“”“”“”“”“”“”“”“”“”“ salmonsalmonsalmonsalmonsalmonsalmonsalmonsalmonsalmonsalmonsalmon Patch,Patch,Patch,Patch,Patch,Patch,Patch,Patch,Patch,Patch,Patch, ”“”“”“”“”“”“”“”“”“”“”“ hemangiomahemangiomahemangiomahemangiomahemangiomahemangiomahemangiomahemangiomahemangiomahemangiomahemangioma kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum,kavernosum, ””””””””””” dandandandandandandandandandandan “““““““““““ PortPortPortPortPortPortPortPortPortPortPort winewinewine stainstainstain “)“)“) terminologiterminologiterminologi berdasarkanberdasarkanberdasarkan fiturfiturfitur selularselularselular mereka,mereka,mereka, sejarahsejarahsejarah alam,alam,alam, dandandan perilakuperilakuperilaku klinis.klinis.klinis. Awalnya digambarkan oleh Mulliken dan Glowacki pada tahun 1982, yang diklasifikasikan terbaruterbaruterbaru dandandan diterimaditerimaditerima secarasecarasecara luasluasluas fififi kationkationkation anomalianomalianomali vaskularvaskularvaskular yangyangyang diadopsidiadopsidiadopsi oleholeholeh MasyarakatMasyarakatMasyarakat InternasionalInternasionalInternasional untukuntukuntuk StudiStudiStudi VascularVascularVascular AnomaliAnomaliAnomali (Tabel(Tabel(Tabel 1).1).1). 111 SistemSistemSistem iniiniini mencakupmencakupmencakup hemangiomahemangiomahemangioma infantil (IH) antara neoplasma vaskuler, yang lesi ditandai dengan proliferasi abnormal dari sel-sel endotel dan arsitektur pembuluh darah yang menyimpang. Sebaliknya, malformasi vaskular adalah anomali struktural dan kesalahan bawaan morfogenesis pembuluh darah.

Meskipun IH adalah neoplasma yang paling umum, kelompok ini juga termasuk tumor seperti hemangioma bawaan, granuloma piogenik, angioma berumbai (TA), dan beberapa jenis hemangioendothelioma. hemangioma bawaan secara biologis dan perilaku berbeda dari IH. sebagaisebagaisebagai rerere flflfl tercermintercermintercermin dalamdalamdalam nama,nama,nama, hemangiomahemangiomahemangioma bawaanbawaanbawaan hadirhadirhadir dandandan sepenuhnyasepenuhnyasepenuhnya terbentukterbentukterbentuk saat lahir; mereka tidak menunjukkan fase proliferasi postnatal

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Pediatri Volume 136, nomor 4, Oktober 2015

karakteristik IH. 2 varian adalah noninvoluting

bawaan hemangioma (nich), yang tetap stabil

tanpatanpatanpa pertumbuhanpertumbuhanpertumbuhan atauatauatau involusi,involusi,involusi, 2,32,32,3 dandandan

berinvolusi dengan cepat hemangioma kongenital

(RICH), yang mengalami fase involusi cepat

dimulaidimulaidimulai padapadapada fififi tahuntahuntahun pertamapertamapertama kehidupankehidupankehidupan (Gambar(Gambar(Gambar

1).1).1). 444 RICHs,RICHs,RICHs, dalamdalamdalam beberapabeberapabeberapa kasus,kasus,kasus, telahtelahtelah dikaitkandikaitkandikaitkan

dengan trombositopenia tetapi dengan lebih

ringan dan lebih transient koagulopati daripada

yang terlihat di fenomena Kasabach-Merritt (KMP;

lihat diskusi yang berikut); jarang, mereka dapat

dikaitkandikaitkandikaitkan dengandengandengan gagalgagalgagal jantungjantungjantung kongestif.kongestif.kongestif. 5,65,65,6 BeberapaBeberapaBeberapa

RICHs menunjukkan involusi lengkap, dan adalah

mungkin bahwa KAYA dan nich kebohongan di

ujung-ujungujung-ujungujung-ujung spektrumspektrumspektrum klinisklinisklinis yangyangyang sama.sama.sama. 7,87,87,8 KeduaKeduaKedua

subtipe dari hemangioma bawaan awalnya

diyakini varian IH yang menunjukkan

pertumbuhanpertumbuhanpertumbuhan prenatalprenatalprenatal sampaisampaisampai UtaraUtaraUtara etetet alalal 999 menunjukkanmenunjukkanmenunjukkan lebih tinggi dalam kulit yang mengandung

bahwa, tidak seperti IH, lesi tidak mengungkapkan

sering terletak di kepala dan leher, cepat

Ini adalah reaktif berkembang biak lesi vaskular

yangyangyang diklasidiklasidiklasi fififi ededed sebagaisebagaisebagai neoplasmaneoplasmaneoplasma vaskulervaskulervaskuler

(Tabel 1). Lesi ini umum diperoleh pembuluh

darah pada kulit dan selaput lendir terutama

mempengaruhi bayi dan anak-anak dan sering

salah didiagnosis sebagai IH. Sekitar 12% terjadi

padapadapada masamasamasa bayi,bayi,bayi, dandandan 42%42%42% hadirhadirhadir selamaselamaselama fififi rstrstrst 555

tahuntahuntahun hidup.hidup.hidup. 101010 granulomagranulomagranuloma piogenikpiogenikpiogenik yangyangyang palingpalingpaling

membesar ke ukuran rata-rata 6,5 ​​mm, sering

mengembangkan basis pedunkulata, dan,

dengan erosi, rentan terhadap pendarahan yang

difdifdifdif fifififi kultuskultuskultuskultus untukuntukuntukuntuk mengontrolmengontrolmengontrolmengontrol (Gambar(Gambar(Gambar(Gambar 2).2).2).2). 10101010

granuloma piogenik terlihat dengan frekuensi yang

malformasi kapiler. Dua neoplasma yang berbeda

lainnya jinak pembuluh darah, kaposiform

hemangioendothelioma (KHE) dan TA, telah

bingung dengan IH. KHE menyajikan terutama

pada masa bayi tetapi dengan rentang usia jauh

lebih luas daripada IH, yang biasanya tampak

dalamdalamdalam fififi bulanbulanbulan pertamapertamapertama kehidupan.kehidupan.kehidupan. KHEKHEKHE dianggapdianggapdianggap

sebagai neoplasma lokal agresif yang biasanya

muncul sebagai massa jaringan dalam, lembut.

LesiLesiLesi iniiniini telahtelahtelah dikaitkandikaitkandikaitkan dengandengandengan KMP,KMP,KMP, 111111 sebuahsebuahsebuah

koagulopati konsumtif berpotensi mengancam

nyawa yang ditandai dengan perangkap platelet

parah. Sebelum KHE digambarkan di awal

1990-an, KMP keliru diduga terjadi dalam

hubungan dengan IH. Histopatologi, KHE

menunjukkanmenunjukkanmenunjukkan dididi fififi lembarlembarlembar infiltratifinfiltratifinfiltratif ramping,ramping,ramping, sel-selsel-selsel-sel

endotel yang melapisi GLUT1negative slitlike

kapiler.kapiler.kapiler. 121212 TATATA adalahadalahadalah tumortumortumor pembuluhpembuluhpembuluh darahdarahdarah jinakjinakjinak

yang terjadi pada bayi, anak-anak, atau orang

dewasa muda dan biasanya terletak pada leher

atauatauatau bagianbagianbagian atasatasatas dada.dada.dada. 131313 PenampilanPenampilanPenampilan klinisklinisklinis merekamerekamereka

adalah variabel dan termasuk eritematosa untuk

lembayung patch, plak, dan nodul. Histopatologi,

TATATA menunjukkanmenunjukkanmenunjukkan welldewelldewellde fififi jumbaijumbaijumbai nednedned kapilerkapilerkapiler padapadapada

dermis yang kekurangan atypia selular atau

GLUT1 positif dan, seperti KHE, dikaitkan dengan

peningkatan pembuluh limfatik dan kecenderungan

untuk KMP. Kedua tumor berperilaku tak terduga

transporter glukosa protein isoform 1 (GLUT1).

granuloma piogenik, juga dikenal sebagai

hemangioma kapiler lobular, bukanlah piogenik

atau granulomatosa.

TABELTABELTABELTABEL 1111 klasifikasiklasifikasiklasifikasiklasifikasi fifififi kasikasikasikasi CutaneousCutaneousCutaneousCutaneous

Vascular Anomali 2014

malformasi vaskular malformasi vena limfatik malformasi kapiler malformasimalformasimalformasi arteriovenosaarteriovenosaarteriovenosa malformasimalformasimalformasi dandandan fififi stulaestulaestulae Campuran (gabungan) malformasi

tumor pembuluh darah

Jinak Infantil hemangioma (IH) hemangioma kongenital (cepat berinvolusi [KAYA]; non-berinvolusi [nich]) lobulated hemangioma kapiler (LCH)

(Piogenik granuloma) *

berumbai angioma (TA) Lainnya

lokal agresif

Kaposiform hemangioendothelioma (KHE) Kaposi sarcoma Lainnya

Ganas

angiosarcoma

Lainnya

Diadaptasi dari Masyarakat Internasional untuk Studi Vascular Anomali 2014,2014,2014, refrefref 111 (issva.org/classi(issva.org/classi(issva.org/classi fififi kation).kation).kation). * Reaktif berkembang biak vaskular lesi

dan dapat tumbuh perlahan-lahan selama bulan

ke tahun, tumbuh dengan cepat, spontan mundur,

atauatauatauatauatau tetaptetaptetaptetaptetap aktifaktifaktifaktifaktif selamaselamaselamaselamaselama bertahun-tahun.bertahun-tahun.bertahun-tahun.bertahun-tahun.bertahun-tahun. 1414141414 ----- 1616161616 TidakTidakTidakTidakTidak

seperti KHE dan TA, IHS tidak berhubungan

dengan trombositopenia atau koagulopati.

malformasi vaskular adalah lesi kongenital, tetapi

beberapa mungkin menjadi jelas secara klinis

hanya di kemudian hari, mungkin karena ectasia

progresifprogresifprogresif lambatlambatlambat yangyangyang dihasilkandihasilkandihasilkan daridaridari intraluminalintraluminalintraluminal flflfl ow.ow.ow.

Mereka menunjukkan tingkat normal pergantian

sel endotel sepanjang sejarah alam mereka, tetapi

berkembang sebagai pasien tumbuh. malformasi

vaskular tidak rumit, dan pertumbuhan mereka

mungkinmungkinmungkin dalamdalamdalam flflfl dipengaruhidipengaruhidipengaruhi oleholeholeh trauma,trauma,trauma, infeksi,infeksi,infeksi,

dandandan perubahanperubahanperubahan hormonal.hormonal.hormonal. klasifikasiklasifikasiklasifikasi fififi kationkationkation

didasarkan pada jenis kapal dominan: kapiler atau

venulocapillary, vena, limfatik, arteri, atau

campuran.campuran.campuran. 171717 SepertiSepertiSeperti neoplasmaneoplasmaneoplasma vaskuler,vaskuler,vaskuler,

nomenklatur malformasi vaskular telah

menyebabkan kebingungan besar. Kapiler atau

venulocapillary malformasi telah memiliki banyak

sebutan alternatif, yang paling umum

““““““ PortPortPortPortPortPort winewinewinewinewinewine stainstainstainstainstainstain ”””””” dandandandandandan ““““““ nevusnevusnevusnevusnevusnevus flflflfl ammeus.ammeus.ammeus.ammeus. ”””” malformasimalformasimalformasimalformasi venavenavenavena seringseringseringsering kelirukelirukelirukeliru untuk IH,

seringseringseringsering kelirukelirukelirukeliru untuk IH, GAMBAR 1 KAYA sepenuhnya terbentuk saat lahir (A) dan

GAMBAR 1

KAYA sepenuhnya terbentuk saat lahir (A) dan kemudian involutes,

sebagiansebagiansebagian besarbesarbesar selamaselamaselama fififi tahuntahuntahun pertamapertamapertama kehidupan.kehidupan.kehidupan. B,B,B, LesiLesiLesi yangyangyang samasamasama

terlihat pada usia 8 bulan.

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Pediatri Volume 136, nomor 4, Oktober 2015

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diistilahkandiistilahkandiistilahkandiistilahkan ““““ hemangiomahemangiomahemangiomahemangioma kavernosumkavernosumkavernosumkavernosum ””””

dandandandandan “““““ hemangiomahemangiomahemangiomahemangiomahemangioma venavenavenavenavena ””””” dalamdalamdalamdalamdalam literaturliteraturliteraturliteraturliteratur (Gambar 3A). malformasi limfatik, yang dibagi lagi menjadi varietas microcystic dan macrocystic atas dasar ukuran kekosongan dominan, mungkin juga keliru untuk IH bila ada perdarahan ke dalam vesikel pada permukaan kulit atau mukosa (Gambar 3B). Lesi ini secara tradisional telah disebut sebagai

tahun, terutama mendahului perbedaan antara IH dan hemangioma bawaan.

““““ hemangiomahemangiomahemangiomahemangioma ”””” jugajugajugajuga telahtelahtelahtelah tidaktidaktidaktidak tepattepattepattepat digunakandigunakandigunakandigunakan untuk menggambarkan, secara umum, varietas lainnya noninfantile hemangioma dan pembuluh darah malformasi.

Highlights dari Bagian ini

Infantil hemangioma (IH) adalah terminologi yang diterima saat ini untuk lesi yang menjadi fokus dari laporan klinis ini.

• hemangioma bawaan secara biologis dan perilaku berbeda dari IH.

granuloma piogenik adalah reaktif berkembang biak lesi vaskular yang diklasidiklasidiklasi fififi ededed sebagaisebagaisebagai neoplasmaneoplasmaneoplasma vaskulervaskulervaskuler dan kadang-kadang dapat salah didiagnosis sebagai IH.

LesiLesiLesi didiagnosisdidiagnosisdidiagnosis sebagaisebagaisebagai “““ hemangiomahemangiomahemangioma kavernosumkavernosumkavernosum ””” biasanya,biasanya,biasanya, padapadapada kenyataannya, dalam IHS atau malformasi vena.

• Fenomena Kasabach-Merritt atau KMP (a koagulopati konsumtif) tidak terkait dengan IH melainkan dengan 2 neoplasma vaskuler lainnya, kaposiform hemangioendothelioma (KHE) dan angioma berumbai (TA).

““““ higromahigromahigromahigroma kistikkistikkistikkistik ”””” atauatauatauatau ““““ lymphangiomas,lymphangiomas,lymphangiomas,lymphangiomas, ”””” sebutansebutansebutansebutan yangyangyangyang tidaktidaktidaktidak akuratakuratakuratakurat menganggap potensi proliferasi, sehingga semakin kebingungan diagnostik.

Penggunaan berbagai nama untuk IH telah mengakibatkan kebingungan diagnostik besar. Misalnya, istilah

““““ hemangiomahemangiomahemangiomahemangioma kapilerkapilerkapilerkapiler ”””” dandandandan ““““ angiomaangiomaangiomaangioma kapilerkapilerkapilerkapiler ”””” telahtelahtelahtelah digunakandigunakandigunakandigunakan untukuntukuntukuntuk merujuk ke sebuah IH yang terletak terutama di dermis dan cerah berwarna merah. Sebaliknya, sebutan ““““““““ cekungcekungcekungcekungcekungcekungcekungcekung ”””””””” atauatauatauatauatauatauatauatau ““““““““ venavenavenavenavenavenavenavena ”””””””” telahtelahtelahtelahtelahtelahtelahtelah tidaktidaktidaktidaktidaktidaktidaktidak tepattepattepattepattepattepattepattepat digunakandigunakandigunakan untukuntukuntuk dedede fififi nenene sebuahsebuahsebuah IHIHIH itu,itu,itu, karenakarenakarena kedalaman di bawah dermis, bisa menanamkan semburat biru pada permukaan kulit. Selain itu, malformasi vena dan limfatik dalam serta arteriovenous

malformasi telah salah didiagnosis sebagai IH mendalam. Akhirnya, berdasarkan prevalensi belaka,belaka,belaka,belaka,belaka, istilahistilahistilahistilahistilah “““““ hemangioma,hemangioma,hemangioma,hemangioma,hemangioma, ””””” tanpatanpatanpatanpatanpa deskripsideskripsideskripsideskripsideskripsi katakatakatakatakata sifatsifatsifatsifatsifatsifatsifat “““““““ kekanak-kanakankekanak-kanakankekanak-kanakankekanak-kanakankekanak-kanakankekanak-kanakankekanak-kanakan ””””””” atauatauatauatauatauatauatau dengandengandengandengandengandengandengan deskriptordeskriptordeskriptordeskriptordeskriptordeskriptordeskriptor “““““““ remaja,remaja,remaja,remaja,remaja,remaja,remaja, ”” telahtelah digunakandigunakan dalamdalam referensireferensi untukuntuk IHIH bagibagi banyak

antara bayi perempuan; Namun, data yang meskipun lebih tua menyarankan femaleto-laki rasio mulai dari 3: 1 sampai 5: 1, penelitian yang lebih baru menunjukkanmenunjukkanmenunjukkan berbagaiberbagaiberbagai 1,4:1,4:1,4: 111 sampaisampaisampai 3:3:3: 1.1.1. 23,2423,2423,24 PerbedaanPerbedaanPerbedaan jenis kelamin tampaknya meningkat di antara anak-anakanak-anakanak-anak dengandengandengan sindromsindromsindrom PHACEPHACEPHACE ((( PPP osteriorosteriorosterior cacatcacatcacat fossa,

HH emangiomas,emangiomas, serebrovaskularserebrovaskular

SEBUAHSEBUAHSEBUAHSEBUAH anomalianomalianomalianomali rterial,rterial,rterial,rterial, CCCC anomalianomalianomalianomali ardiovascularardiovascularardiovascularardiovascular termasuktermasuktermasuk coarctationcoarctationcoarctation aorta,aorta,aorta, dandandan EEE anomalianomalianomali kamu),kamu),kamu), di mana penelitian telah menemukan 9: 1 rasio

perempuan-ke-laki-laki.perempuan-ke-laki-laki.perempuan-ke-laki-laki.perempuan-ke-laki-laki.perempuan-ke-laki-laki. 2525252525 TidakTidakTidakTidakTidak adaadaadaadaada dedededede fififififi penjelasanpenjelasanpenjelasanpenjelasanpenjelasan definitif untuk perbedaan gender ini. Kebanyakan penelitianpenelitianpenelitian melaporkanmelaporkanmelaporkan signisignisigni fififi cantlycantlycantly insideninsideninsiden yangyangyang lebihlebihlebih tinggitinggitinggi padapadapada bayibayibayi putih.putih.putih. 23,24,2623,24,2623,24,26 AtasAtasAtas dasardasardasar

keberhasilan pengobatan IH menggunakan

b-b- TerapiTerapi blocker,blocker, telahtelah diusulkandiusulkan bahwabahwa bayibayi hitamhitamhitam mungkinmungkinmungkin menunjukkanmenunjukkanmenunjukkan beberapabeberapabeberapa bentukbentukbentuk “““ endogenendogenendogen betabetabeta blokade,blokade,blokade, ””” dandandan adaadaada datadatadata biologisbiologisbiologis molekulermolekulermolekuler untukuntuk mendukungmendukung gagasangagasan ini.ini. 2727

Insiden IH meningkat pada bayi prematur, yang mempengaruhi 22% sampai 30% dari bayi dengan beratberatberat kurangkurangkurang daridaridari 111 kg.kg.kg. 24,2824,2824,28 AnalisisAnalisisAnalisis multivariatmultivariatmultivariat telahtelahtelah

mengungkapkan bahwa berat badan lahir rendah (BBLR) adalah penyumbang utama risiko ini; ada peningkatan 25% dalam risiko mengembangkan IH dengandengandengan setiapsetiapsetiap penguranganpenguranganpengurangan 500-g500-g500-g beratberatberat lahir.lahir.lahir. 292929 faktorfaktorfaktor prenatal juga telah diteliti untuk peran mereka dalam IH. Studi berbeda mengenai peningkatan risiko yang dihasilkan dari chorionic villus sampling ibuibuibuibu 24,3024,3024,3024,30 atauatauatauatau amniosentesis,amniosentesis,amniosentesis,amniosentesis, 30,3130,3130,3130,31

30,3130,3130,3130,31 GAMBAR 2 granuloma piogenik memiliki beberapa fitur klinis

GAMBAR 2

granuloma piogenik memiliki beberapa fitur klinis dan histologis mirip dengan IHS, tetapi mereka umumnya lebih kecil, bertangkai, dan lebih mungkin untuk berdarah.

EPIDEMIOLOGI

Studi dari kejadian IH, termasuk studi prospektif dan review menggabungkan 1 penelitian retrospektif dan 2 kohort cross sectional, menunjukkan bahwa 4% sampai 5% dari bayi yangyangyang terpengaruh.terpengaruh.terpengaruh. 18,1918,1918,19 StudiStudiStudi lainlainlain menunjukkanmenunjukkanmenunjukkan bahwa IH diamati dalam 1% hingga 3% bayi baru lahirlahir 20,2120,21

dan setiap peningkatan risiko yang timbul chorionic villus sampling tampaknya terbatas padapadapada prosedurprosedurprosedur yangyangyang dilakukandilakukandilakukan transcervically.transcervically.transcervically. 313131 Faktor-faktorFaktor-faktorFaktor-faktor prenatal lain yang mungkin termasuk usia yang lebih tua ibu, kehamilan ganda kehamilan, plasentaplasentaplasenta previa,previa,previa, dandandan preeklampsia.preeklampsia.preeklampsia. 242424 anomalianomalianomali plasenta, seperti hematoma retroplasenta, infark, dan komunikasi vaskular melebar, juga telahtelahtelah dikaitkandikaitkandikaitkan dengandengandengan perkembanganperkembanganperkembangan IH.IH.IH. 323232 HalHalHal ini berteori bahwa benang merah

dandandan 2,6%2,6%2,6% menjadimenjadimenjadi 9,9%9,9%9,9% daridaridari anak-anak,anak-anak,anak-anak, 22,2322,2322,23 tapitapitapi

kekurangankekurangankekurangan metodelogimetodelogimetodelogi mungkinmungkinmungkin memilikimemilikimemiliki dididi flflfl dipengaruhidipengaruhidipengaruhi

iniiniini fififi Temuan.Temuan.Temuan. IHSIHSIHS lebihlebihlebih umumumumumum

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dalam asosiasi ini adalah hipoksia plasenta.plasenta. 32,3332,33

Meskipun sering disarankan sebagai faktor

risiko, riwayat keluarga IH dilaporkan hanya

12%12% daridari kasuskasus 24;24;

Namun, keluarga pengelompokan telah

dilaporkan.dilaporkan.dilaporkan. 34,3534,3534,35 AsosiasiAsosiasiAsosiasi jugajugajuga dilaporkandilaporkandilaporkan dengandengandengan

penggunaanpenggunaanpenggunaan ibuibuibu daridaridari obatobatobat kesuburan,kesuburan,kesuburan, 363636 penggunaanpenggunaanpenggunaan

eritropoietin,eritropoietin,eritropoietin,eritropoietin,eritropoietin, 3737373737 tingkattingkattingkattingkattingkat pendidikanpendidikanpendidikanpendidikanpendidikan ibu,ibu,ibu,ibu,ibu, 3636363636 presentasipresentasipresentasipresentasipresentasi

sungsang,sungsang,sungsang,sungsang,sungsang,sungsang, 232323232323 dandandandandandan menjadimenjadimenjadimenjadimenjadimenjadi fifififififi pertamapertamapertamapertamapertamapertama lahir.lahir.lahir.lahir.lahir.lahir. 232323232323

Highlights dari Bagian ini

• Insiden pada populasi umum adalah sekitar 5%.

Faktor risiko untuk IH termasuk menjadi putih, menjadi perempuan, dan memiliki berat lahir rendah.

Asosiasi juga dilaporkan dengan usia

yang lebih tua ibu, kehamilan ganda

kehamilan, plasenta previa,

preeklamsia, penggunaan obat

kesuburan atau erythropoietin,

presentasi bokong, dan menjadi fi pertama

presentasi bokong, dan menjadi fi pertama

presentasi bokong, dan menjadi fi pertama

lahir.

PATOGENESIS DAN HISTOPATOLOGI

Patogenesis

Patogenesis IH, meskipun studi intensif, belum sepenuhnya dijelaskan. Baris bukti mendukung asal selular baik dari sel intrinsik endotel progenitor (EPC) atau angioblasts asal plasenta, namun faktor intrinsik dan ekstrinsik juga memberikan kontribusi pemikiran untuk perkembanganperkembangan mereka.mereka. 3838

FaktorFaktorFaktor intrinsikintrinsikintrinsik meliputimeliputimeliputi dididi flflfl pengaruhpengaruhpengaruh faktorfaktorfaktor

angiogenik dan vaskulogenik dalam IH. Faktor

eksternal meliputi hipoksia jaringan dan

perkembanganperkembanganperkembangan fififi gangguangangguangangguan lapangan.lapangan.lapangan. TeoriTeoriTeori EPCEPCEPC

menyatakan bahwa IHS berkembang dari

ekspansi klonal dari EPC yang beredar, sehingga

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Pediatri Volume 136, nomor 4, Oktober 2015

download dari Pediatri Volume 136, nomor 4, Oktober 2015 GAMBAR 3 A, The darah vena yang

GAMBAR 3

A, The darah vena yang terkandung dalam malformasi vena menanamkan rona kebiruan yang dapat menyebabkan misdiagnosis sebagai IH yang mendalam. B, Perdarahan ke dalam vesikel permukaan malformasi limfatik dapat menyebabkan misdiagnosis sebagai IH.

vasculogenesis, atau pembentukan de novo

pembuluhpembuluh darahdarah baru.baru. 39,4039,40

Teori ini didukung oleh penelitian yang menunjukkan angka peningkatan yang beredar EPC dalam sampel darah dari anak-anak dengan

IH.IH.IH. 414141 buktibuktibukti tambahantambahantambahan berasalberasalberasal daridaridari studistudistudi dididi manamanamana sel-sel induk multipoten berasal dari spesimen IH (HemSCs) telah menunjukkan kemampuan untuk rekapitulasirekapitulasirekapitulasirekapitulasi IHIHIHIH manusiamanusiamanusiamanusia didididi immunodeimmunodeimmunodeimmunode fifififi tikustikustikustikus efisien.efisien.efisien.efisien. 42424242

Ini HemSCs dan EPC darah tali berperilaku serupa satu sama lain dalam beberapa uji in vitro, menunjukkan bahwa beredar EPC bisa menjadimenjadimenjadi asalasalasal daridaridari selselsel endotelendotelendotel IH.IH.IH. 424242 KonsepKonsepKonsep yangyangyang IHS berasal dari sirkulasi sel progenitor multipoten bisa menjelaskan beberapa fitur yang mereka berbagi dengan pembuluh darah plasenta, karena disregulasi EPC beredar juga telah terlibat dalam banyak ibu terkait dan kondisi komorbiditas janin (preeklampsia, retinopati prematuritas, dll) . HemSCs juga telah terbuktiterbuktiterbukti memilikimemilikimemiliki potensipotensipotensi adipogenic,adipogenic,adipogenic, 434343 yangyangyang dapat menjelaskan kehadiran adiposit dicatat selama involusi. Stimulus untuk divisi dari EPC tidak diketahui, tetapi mungkin mutasi somatik atau sinyal yang abnormal dari jaringan lokal. Teori asal plasenta menunjukkan bahwa sel-sel progenitor janin timbul dari gangguan plasenta selama kehamilan atau kelahiran.

Konsep ini dikembangkan dari penelitian yang menunjukkan bahwa penanda molekuler karakteristik jaringan plasenta, termasuk GLUT1, antigenantigenantigen LewisLewisLewis Y,Y,Y, merosin,merosin,merosin, Fc-Fc-Fc- ggg reseptor-IIb,reseptor-IIb,reseptor-IIb, indoleamin 2,3-deoxygenase, dan tipe III iodothyronineiodothyronineiodothyronine deiodinase,deiodinase,deiodinase, jugajugajuga hadirhadirhadir dididi IHS.IHS.IHS. 3,93,93,9 buktibuktibukti klinis untuk teori ini disarankan oleh mereka penelitian yang menunjukkan peningkatan insiden IH dalam hubungan dengan chorionic villus sampling, plasenta previa, dan preeklampsia.preeklampsia. 24,30,3124,30,31

Sebuah teori pemersatu menunjukkan bahwa IH hasil dari proliferasi menyimpang dan diferensiasi dari endotelium hemogenic dengan fenotipe saraf puncak dan kapasitas untuk endotel, hematopoetic, mesenchymal, dan diferensiasi neuronal. Ini adalah hipotesis bahwa sel-sel inti plasenta chorionic villus mesenchymal embolisasi bagi perkembangan janin dan bahwa waktu embolisasi ini dalam kaitannya dengan migrasi sel pial neural sepanjang rute somitic mereka menentukan morfologi IH (segmental vs lokal [focal], lihat bagianbagianbagianbagianbagian berjudulberjudulberjudulberjudulberjudul “““““ PenampilanPenampilanPenampilanPenampilanPenampilan klinisklinisklinisklinisklinis “).“).“).“).“). 4444444444

Sitokin niche dalam IH, termasuk faktor pertumbuhan endotel vaskular (VEGFs), insulin-seperti faktor pertumbuhan, tumor necrosisnecrosisnecrosis factorfactorfactor --- terkaitterkaitterkait apoptosis-inducingapoptosis-inducingapoptosis-inducing ligand-osteoprotegerin (TRAIL-OPG)

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jalur, dan sistem renin-angiotensin, kemudian

mengatur pertumbuhan IH dan responnya

terhadapterhadapterhadap terapiterapiterapi farmakologis.farmakologis.farmakologis. 444444 penulispenulispenulis lainlainlain jugajugajuga

telah memeluk

““““““ cerukcerukcerukcerukcerukceruk ”””””” konsep,konsep,konsep,konsep,konsep,konsep, menunjukkanmenunjukkanmenunjukkanmenunjukkanmenunjukkanmenunjukkan bahwabahwabahwabahwabahwabahwa EPCEPCEPCEPCEPCEPC beredarberedarberedarberedarberedarberedar fifififififi ndndndndndnd perjalanan mereka ke lokasi tertentu yang memberikan kondisi yang menguntungkan untuk pertumbuhanpertumbuhanpertumbuhan kekeke dalamdalamdalam jaringanjaringanjaringan placentalike.placentalike.placentalike. 444444 DalamDalamDalam jaringan seperti kulit dan hati, sel-sel progenitor mungkin mengalami sinyal selular dan faktor jaringan lokal diperlukan untuk merangsang perkembangan mereka. Atas dasar proliferasi cepat dari sel endotel, sebelumnya

penyelidikan asal IH difokuskan pada

angiogenesis, yang tumbuhnya sel-sel endotel

dari pembuluh darah yang ada. Studi semacam

telah menunjukkan peningkatan konsentrasi faktor

angiogenikangiogenikangiogenik dididi IH,IH,IH, sepertisepertiseperti dasardasardasar fififi faktorfaktorfaktor

pertumbuhan broblast (bFGF), VEGF-A, faktor

pertumbuhan seperti insulin, dan matriks

metaloprotease (MMP) 9 dalam lesi selama

proliferasi.proliferasi.proliferasi. 454545 JugaJugaJuga dalamdalamdalam fasefasefase ini,ini,ini, penelitipenelitipeneliti telahtelahtelah

mengidentifikasikanmengidentifikasikanmengidentifikasikan fififi ededed indoleaminindoleaminindoleamin

2,3-deoxygenase, protein berpikir untuk memperlambat involusi IH dengan menghambat sitotoksiksitotoksik responrespon T-limfosit.T-limfosit. 4646

Selama involusi, apoptosis sel endotel disertai

dengan downregulation faktor angiogenik,

sedangkan inhibitor angiogenesis seperti

interferoninterferoninterferon bbb dandandan spidolspidolspidol pematanganpematanganpematangan selselsel sepertisepertiseperti

adhesiadhesiadhesi antarantarantar molekulmolekulmolekul 111 diregulasi.diregulasi.diregulasi. 474747 IniIniIni jugajugajuga

telah menunjukkan bahwa berinvolusi IHS

pameran penurunan produksi oksida nitrat,

sebuah potentiator dari jalur VEGF, yang diukur dengan penurunan kadar oksida nitrat sintase endotel.endotel. 4848

Telah dihipotesiskan bahwa hipoksia memicu respon vaskular pada bayi. Seperti dibahas di atas, BBLRBBLRBBLR adalahadalahadalah signisignisigni fififi faktorfaktorfaktor risikorisikorisiko tidaktidaktidak bisabisabisa untukuntukuntuk IH,IH,IH, dan dalam rahim hipoksia merupakan penyebab umum dari BBLR. Tidak mengherankan, ada bukti pemasangan peran hipoksia dalam pengembangan IH. GLUT1, transporter glukosa fasilitatif digunakan sebagai penanda untuk IH,

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adalahadalah sensorsensor pentingpenting hipoksia.hipoksia. 99

GLUT1 telah terbukti diregulasi di zona hipoksia

tumortumortumor mesenkimmesenkimmesenkim dandandan dididi talitalitali pusatpusatpusat --- berasalberasalberasal selselsel

induk mesenchymal manusia dalam kondisi

hipoksia.hipoksia.hipoksia. 49,5049,5049,50 faktorfaktorfaktor HypoxiainducedHypoxiainducedHypoxiainduced diproduksidiproduksidiproduksi

oleh sel endotel tampaknya memainkan peran

pentingpentingpenting dalamdalamdalam lalulalulalu lintaslintaslintas fififi ckingckingcking selselsel progenitorprogenitorprogenitor

untuk jaringan iskemik. Faktor-faktor ini telah

terbukti diregulasi dalam darah (VEGF-A,

MMP-9)MMP-9)MMP-9) dandandan dididi jaringanjaringanjaringan IHIHIH (sel(sel(sel stromastromastroma --- berasalberasalberasal

faktorfaktorfaktor 111 Sebuah,Sebuah,Sebuah, MMP-9,MMP-9,MMP-9, VEGF-A,VEGF-A,VEGF-A, dandandan

hipoksia-induciblehipoksia-inducible factorfactor 11 Sebuah)Sebuah)

daridari anak-anakanak-anak dengandengan berkembangberkembang biakbiak IH.IH. 4141

Selain itu, telah ditunjukkan bahwa penggunaan erythropoietin pada bayi prematur meningkatkan risikorisikorisiko mengembangkanmengembangkanmengembangkan IH.IH.IH. 373737 DenganDenganDengan demikian,demikian,demikian, iskemia jaringan mengakibatkan neovaskularisasi dari beredar EPC telah diusulkan sebagai stimulus mengarah ke pengembanganpengembanganpengembangan daridaridari IH.IH.IH. 414141 SecaraSecaraSecara klinis,klinis,klinis, daerahdaerahdaerah pucatpucatpucat atauatauatau darahdarahdarah menurunmenurunmenurun flflfl owowow dididi kulitkulitkulit telahtelahtelah dicatat mendahului perkembangan IH, lanjut mendukungmendukung hipotesishipotesis ini.ini. 5151

Highlights dari Bagian ini

• dapat berkembang baik dari sel

progenitor endotel intrinsik (EPC)

atau dari angioblasts asal plasenta.

Pertumbuhan IH dipengaruhi oleh

intrinsikintrinsikintrinsik dididi flflfl uences,uences,uences, sepertisepertiseperti faktorfaktorfaktor

angiogenik dan vaskulogenik dalam IH,

dan oleh faktor-faktor eksternal seperti

lapangan.

Sebuah teori pemersatu mengusulkan bahwa beredar EPC bermigrasi ke lokasi di mana kondisi yang menguntungkan untuk pertumbuhan ke dalam jaringan placentalike.

hipoksia jaringan dan perkembangan fi gangguan

hipoksia jaringan dan perkembangan fi gangguan

hipoksia jaringan dan perkembangan fi gangguan

histopatologi

Terlalu proliferatif dan awal IHS involutif yang baik terbatas, massa unencapsulated dengan merah-Totan permukaan potong. Kemudian lesi involutifinvolutifinvolutif yangyangyang fififi brofattybrofattybrofatty dalamdalamdalam konsistensikonsistensikonsistensi dandandan kurangkurangkurang dedede fififi ned.ned.ned. FiturFiturFitur histologishistologishistologis IHIHIH berubahberubahberubah secara dramatis karena mereka melanjutkan mengikuti pelatihan alami mereka presentasi neonatal, pertumbuhan yang cepat, dan involusi berikutnya, membutuhkan interpretasi dalam kontekskontekskontekskontekskonteks klinisklinisklinisklinisklinis yangyangyangyangyang tepat.tepat.tepat.tepat.tepat. 5252525252 ----- 5454545454 TidakTidakTidakTidakTidak adaadaadaadaada garisgarisgarisgarisgaris pemisah yang tajam antara proliferasi dan involusi, dan fitur involusi biasanya hidup berdampingan dengan fitur proliferasi selama banyak proses. Awal IHS fase proliferasi terdiri daridaridari welldewelldewellde fififi ned,ned,ned, massamassamassa unencapsulatedunencapsulatedunencapsulated kapilerkapilerkapiler dilapisi oleh sel endotel gemuk dikelilingi oleh pericytes gemuk tertanam dalam membran basement multilaminated tanpa sel-sel otot polos terkait (Gambar 4). Lesi pada tahap ini mungkin setidaknya focally menyerupai proliferations vaskular lainnya berkembang pesat seperti granuloma piogenik awal. Kapiler berkembang biak disusun dalam lobulus, yang dipisahkandipisahkandipisahkan oleholeholeh halushalushalus fififi septaeseptaeseptae brousbrousbrous atauatauatau oleholeholeh jaringan intervensi normal. Ini kapiler lesi, tergantung pada lokasi jaringan, berbaur nondestructivelynondestructivelynondestructively dengandengandengan supersupersuper fififi otototototot rangkarangkarangka resmiresmiresmi fififi bers,bers,bers, sarafsarafsaraf perifer,perifer,perifer, kelenjarkelenjarkelenjar ludah,ludah,ludah, dandandan adiposit. sel endotel dan pericytes menunjukkan inti bervariasi membesar dan sitoplasma jelas berlimpah.berlimpah.berlimpah.berlimpah.berlimpah. biasanyabiasanyabiasanyabiasanyabiasanya conconconconcon fififififi mitosismitosismitosismitosismitosis guredguredguredguredgured fififififi guresguresguresguresgures relatif banyak (Gambar 1B); dan ekspresi luas penandapenandapenanda proliferasiproliferasiproliferasi sel,sel,sel, sepertisepertiseperti Ki-67,Ki-67,Ki-67, conconcon fififi rmrmrm yang baik pericytes dan sel endotel secara aktif

membagi. Karena IHS fase proliferasi yang tinggitinggitinggitinggitinggi flflflflfl lesilesilesilesilesi ow,ow,ow,ow,ow, meskipunmeskipunmeskipunmeskipunmeskipun biasanyabiasanyabiasanyabiasanyabiasanya tanpatanpatanpatanpatanpa signisignisignisignisigni fififififi tidaktidaktidaktidaktidak bisa arteriovenous shunting, mereka sering berisi diperbesar menguras urat dengan tebal,

dinding asimetris.

Berinvolusi IHS hadir tantangan diagnostik yang berbeda.berbeda.berbeda. mitosismitosismitosis fififi guresguresgures berkurang,berkurang,berkurang, dandandan badan-badanbadan-badanbadan-badan apoptosis dan tiang

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GAMBAR 4 IH fase proliferasi. lobulus baik terbatas dari kapiler erat dikemas terdiri dari sel

GAMBAR 4

IH fase proliferasi. lobulus baik terbatas dari kapiler erat dikemas terdiri dari sel endotel gemuk dan pericytes dipisahkan oleh elemen dermal stroma normal-munculnormal-munculnormal-muncul (hematoxylin(hematoxylin(hematoxylin dandandan eosin;eosin;eosin; MagniMagniMagni asliasliasli fififi kationkationkation 33 100;100; fotofoto courtesycourtesy ofof PaulaPaula Utara,Utara, MD.)MD.)

selsel peningkatanpeningkatan jumlahjumlah selamaselama involusiinvolusi awal.awal. 48,5548,55 kapiler lesi mulai menghilang. Tidak ada bukti daridaridari trombosis,trombosis,trombosis, dandandan dididi flflfl RadangRadangRadang tidaktidaktidak menonjol.menonjol.menonjol. Sebagai hasil involusi, membran dasar lesi kapiler menjadi tebal dan hyalinized dan mengandung bintik puing-puing apoptosis (Gambar 5). Akhirnya yang tersisa dalam stadiumstadiumstadiumstadiumstadium akhirakhirakhirakhirakhir lesilesilesilesilesi longgarlonggarlonggarlonggarlonggar fififififi brousbrousbrousbrousbrous atauatauatauatauatau fififififi brofattybrofattybrofattybrofattybrofatty stroma,stroma,stroma,stroma, yangyangyangyang berisiberisiberisiberisi beberapabeberapabeberapabeberapa sisasisasisasisa ““““ hantuhantuhantuhantu ””””

pembuluh terdiri dari sisa, kerupuk rambak menebal dari bahan membran basement yang berisi puing-puing apoptosis dan tanpa utuh

basement yang berisi puing-puing apoptosis dan tanpa utuh GAMBAR 5 IHIH fasefase involutif.involutif. kapilerkapiler

GAMBAR 5

IHIH fasefase involutif.involutif. kapilerkapiler lesilesi ditetapkanditetapkan dalamdalam longgarlonggar fifi bro-jaringan adiposa dan kurang padat daripada di fase proliferasi. Perhatikan menebal dan membran dasar hyalinized bertabur dengan puing-puing apoptosis,apoptosis,apoptosis, rerere flflfl efektifefektifefektif daridaridari prosesprosesproses involutif.involutif.involutif. sel-selsel-selsel-sel lapisan endotel sisa yang mitotically tidak aktif. (Foto milik Paula Utara, MD)

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Pediatri Volume 136, nomor 4, Oktober 2015

lapisan seluler. Epidermal atrofi dan mendasari fi jaringan

lapisan seluler. Epidermal atrofi dan mendasari fi jaringan

lapisan seluler. Epidermal atrofi dan mendasari fi jaringan

parut fibrosa dapat hadir jika lesi ulserasi pada fase proliferasi. arteri besar dan vena dimodelkan selamaselamaselama tinggitinggitinggi yangyangyang flflfl owowow fasefasefase proliferasiproliferasiproliferasi tidaktidaktidak sepenuhnya mundur ketika tidur kapiler tetes keluar dan dengan demikian sering hadir dalam berinvolusi IH. Fenomena ini, dipasangkan dengan hilangnya aktivitas mitosis endotel, dapat menyebabkan diagnosis histologis keliru sebagai malformasi vaskular. Misdiagnosis biasanya dapat dihindari dengan mempertimbangkan penampilan histologis secara keseluruhan dan riwayat klinis. Pada akhirnya, seperti dibahas di bawah, masalah tersebut dapat diatasi dengan GLUT1 immunoreaction, karena berinvolusi infantil IHS, tetapi tidak malformasi, akan menunjukkan GLUT1 immunopositivityimmunopositivity didi lesi-jenislesi-jenis kapilerkapiler residual.residual. 9,569,56

Highlights dari Bagian ini

Berkembang biak IHS baik dibatasi dan kekurangan kapsul.

BerinvolusiBerinvolusiBerinvolusi IHSIHSIHS adalahadalahadalah fififi brofattybrofattybrofatty dandandan kurangkurangkurang dedede fififi ned.ned.ned.

GLUT1 adalah penanda immunochemical umum digunakan untuk IH.

KLINIS, KOMPLIKASI, DAN ASOSIASI Fase

Pertumbuhan

Pemeriksaan histologis, disertai dengan studi imunohistokimia rutin, menunjukkan bahwa fase proliferasi IHS infantil adalah campuran seluler kompleks dengan melengkapi besar sel endotel, pericytes, sel mast, dan sel dendritik interstitial. mikroskop elektron mengungkapkan sel-sel endotel yang melapisi gemuk lumina kecil dan bertumpu pada membran basement multilaminated yang menyelubungi manset dari pericytes. Sel-sel endotel IH telah dilaporkan immunoreactimmunoreactimmunoreactimmunoreactimmunoreact positifpositifpositifpositifpositif untukuntukuntukuntukuntuk “““““ normalnormalnormalnormalnormal ””””” penandapenandapenandapenandapenanda endotel pembuluh darah darah, seperti CD31, CD34,CD34,CD34, faktorfaktorfaktor VIIIVIIIVIII --- antigenantigenantigen terkaitterkaitterkait (von(von(von WillebrandWillebrandWillebrand factor),factor),factor), dandandan lain-lain.lain-lain.lain-lain. 575757 SaatSaatSaat ini,ini,ini, penandapenandapenanda imunohistokimia yang paling berguna dan banyak digunakan untuk diagnosis IH adalah GLUT1.GLUT1.GLUT1. 9,579,579,57 GLUT1GLUT1GLUT1 SangatSangatSangat diekspresikandiekspresikandiekspresikan oleholeholeh sel endotel dari IHS pada semua tahap evolusi mereka dan tidak diungkapkan oleh anomali vaskular jinak lainnya dan proliferasi reaktif. GLUT1 imunohistokimia sering digunakan untuk membedakan IHS dari neoplasma vaskuler lain dan memberikan bukti yang meyakinkan bahwa IHS memang sebagai biologis yang khas karena mereka khas klinis.

IHS pameran siklus hidup yang khas. pengamatan klinis telah menyarankan bahwa setidaknya ada 2 tahap evolusi dinamis, yaitu, proliferasi dan involusi. Proliferasi terjadi selama masa bayi awal; bertahap spontan involusi atau regresi dimulai dengan usia 1 tahun.tahun.tahun.tahun.tahun. 5858585858 ----- 6565656565 PeriodePeriodePeriodePeriodePeriode menengahmenengahmenengahmenengahmenengah antaraantaraantaraantaraantara proliferasiproliferasiproliferasiproliferasiproliferasi dan involusi selama pertengahan-ke-akhir masa bayi,bayi,bayi,bayi, seringseringseringsering disebutdisebutdisebutdisebut sebagaisebagaisebagaisebagai ““““ datarandatarandatarandataran ””””

fase, lebih mungkin merupakan periode keseimbangan temporer antara sel-sel individual yang berkembang biak dan mereka yangyangyangyangyang menjalanimenjalanimenjalanimenjalanimenjalani involusiinvolusiinvolusiinvolusiinvolusi dandandandandan apoptosis.apoptosis.apoptosis.apoptosis.apoptosis. 5959595959 ----- 6666666666 ProsesProsesProsesProsesProses involusi memakan waktu beberapa tahun dan bervariasi dalam durasi.

Proliferatif Tahap (Hingga 12 Bulan Usia)

YgYgYg memberimemberimemberi pertandapertandapertanda fififi TemuanTemuanTemuan dididi kulitkulitkulit selamaselamaselama masamasamasa bayi awal mungkin termasuk blanching lokal atau makula lokal telangiektasis eritema. Sebagai proliferasi sel endotel terus, IH membesar, menjadi lebih tinggi, dan mengembangkan konsistensi karet. Selama periode ini, IHS sering menunjukkan pucat dan dilatasi pembuluh darah sekitarnya sekitarnya. Selama periode pertumbuhan yang cepat, ulserasi mungkin timbul, menyebabkan rasa sakit dan jaringan parut akhirnya. IHS biasanya memiliki onset klinisklinisklinis merekamerekamereka sebelumsebelumsebelum 444 minggumingguminggu usia.usia.usia. 66,6766,6766,67 MerekaMerekaMereka berkembang biak untuk periode variabel

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e1065

waktu, tergantung sebagian pada morfologi dan

conconcon merekamerekamereka fififi gurasi.gurasi.gurasi. Namun,Namun,Namun, sebagiansebagiansebagian besarbesarbesar

pertumbuhan IH tampaknya terjadi antara 1 dan 2

bulan.bulan.bulan. 686868 SebuahSebuahSebuah studistudistudi prospektifprospektifprospektif besarbesarbesar telahtelahtelah

menunjukkan bahwa 80% dari ukuran IH umumnya

dicapai dengan 3 bulan, dan paling pertumbuhan

selesaiselesaiselesai sekitarsekitarsekitar 555 bulan.bulan.bulan. 666666 MendalamMendalamMendalam IHSIHSIHS munculmunculmuncul

agak kemudian dan tumbuh agak lebih lama

daripadadaripadadaripadadaripada merekamerekamerekamereka supersupersupersuper fifififi rekan-rekanrekan-rekanrekan-rekanrekan-rekan resmi.resmi.resmi.resmi. 66666666

involusi Tahap

Untuk sebagian besar bayi dengan IH, involusi dimulai antara 6 dan 12 bulan. Meskipun proses berlanjut selama bertahun-tahun, mayoritasmayoritas regresiregresi tumortumor terjaditerjadi sebelumsebelum usiausia 4.4. 48,69,7048,69,70

SebagaiSebagaiSebagai IHSIHSIHS rumit,rumit,rumit, kebanyakankebanyakankebanyakan lesilesilesi flflfl attenattenatten dandandan menyusut dari pusat ke luar. Bagi mereka dengandengandengan supersupersuper fififi komponenkomponenkomponen resmi,resmi,resmi, iniiniini disertaidisertaidisertai dengandengandengandengandengan “““““ sentralsentralsentralsentralsentral kliringkliringkliringkliringkliring ””””” atauatauatauatauatau berubanberubanberubanberubanberuban permukaan. Meskipun IHS umumnya menjalani regresiregresiregresiregresi spontan,spontan,spontan,spontan, pengamatanpengamatanpengamatanpengamatan ““““ involusiinvolusiinvolusiinvolusi maksimalmaksimalmaksimalmaksimal ”””” tidak selalu berarti resolusi lengkap. Memang, sekitar 50% sampai 70% dari IHS tekad, meninggalkan perubahan kulit residual, termasuktermasuktermasuk telangiectasia,telangiectasia,telangiectasia, fififi brofattybrofattybrofatty jaringan,jaringan,jaringan, berlebihan kulit, anetoderma, dyspigmentation, atauatau bekasbekas luka.luka. 7171

Highlights dari Bagian ini

IHS biasanya membuat penampilan awal

mereka sebelum 4 minggu usia dan

menyelesaikan sebagian besar pertumbuhan

mereka dengan 5 bulan usia.

• Involusi IHS dimulai sebagai anak mendekati usia 12 bulan. Dalam kebanyakan kasus, mayoritas involusi selesai pada usia 4.

Penampilan klinis

Selama fase proliferasi, IHS dapat diklasifikasikandiklasifikasikandiklasifikasikan fififi ededed atasatasatas dasardasardasar merekamerekamereka

e1066

download dari

dasardasardasar merekamerekamereka e1066 download dari GAMBAR 6 CutaneousCutaneousCutaneousCutaneousCutaneous

GAMBAR 6

CutaneousCutaneousCutaneousCutaneousCutaneous IHSIHSIHSIHSIHS mungkinmungkinmungkinmungkinmungkin diklasidiklasidiklasidiklasidiklasi fififififi ededededed atasatasatasatasatas dasardasardasardasardasar kedalamankedalamankedalamankedalamankedalaman mereka.mereka.mereka.mereka.mereka. A,A,A,A,A, SuperSuperSuperSuperSuper fififififi resmiresmiresmiresmiresmi IHSIHSIHSIHSIHS hanyahanyahanyahanyahanya terlihatterlihatterlihatterlihatterlihat dididididi permukaanpermukaanpermukaanpermukaanpermukaan kulitkulitkulitkulitkulit dandandandandan mungkinmungkinmungkinmungkinmungkin focalfocalfocalfocalfocal (seperti(seperti(seperti(seperti(seperti yangyang ditunjukkan)ditunjukkan) atauatau segmental.segmental. B,B, DeepDeep IHSIHS tidaktidak memilikimemiliki keterlibatanketerlibatan permukaan.permukaan. C,C, Campuran,Campuran, atauatau senyawa,senyawa, IHSIHS memilikimemiliki keduanyakeduanya yangyang supersuper fifi resmi dan komponen yang mendalam.

kedalamankedalamankedalamankedalamankedalaman jaringanjaringanjaringanjaringanjaringan lunak.lunak.lunak.lunak.lunak. 61,62,7261,62,7261,62,7261,62,7261,62,72 SuperSuperSuperSuperSuper fififififi resmiresmiresmiresmiresmi IHS (Gambar 6A) adalah mereka di mana permukaan tumor tampak merah dan ada sedikit atau tidak ada komponen subkutan dilihat; historis, IHS ini telah digambarkan sebagai satu

““““ stroberistroberistroberistroberi ”””” mengetik.mengetik.mengetik.mengetik. DalamDalamDalamDalam IHSIHSIHSIHS (Gambar(Gambar(Gambar(Gambar 6B)6B)6B)6B) adalah mereka yang tumor berada dalam ke permukaan kulit, dan subkutan hasil lokasi mereka di rona permukaan kebiruan atau tidak ada perubahan permukaan jelas; historis, ini telahtelahtelahtelah disebutdisebutdisebutdisebut sebagaisebagaisebagaisebagai ““““ gua,gua,gua,gua, ””””

supersupersuper fififi resmiresmiresmi dandandan dalamdalamdalam IHS.IHS.IHS. PengamatanPengamatanPengamatan iniiniini menunjukkan bahwa IHS mendalam memerlukan waktu yang lebih lama dari pemantauan dibandingkandibandingkandibandingkan merekamerekamereka dengandengandengan supersupersuper fififi morfologimorfologimorfologi resmi.resmi.resmi. SebuahSebuahSebuahSebuahSebuah spesifikspesifikspesifikspesifikspesifik fififififi ccccc subtipesubtipesubtipesubtipesubtipe supersupersupersupersuper fififififi resmiresmiresmiresmiresmi IHIHIHIHIH telahtelahtelahtelahtelah bervariasi disebut sebagai gagal, nonproliferative, arrestedgrowth, minimal-pertumbuhan, baru lahir, retikuler,retikuler,retikuler,retikuler, atauatauatauatau telangiektasistelangiektasistelangiektasistelangiektasis IH.IH.IH.IH. 73737373 ---- 76767676

Jenis IH menyajikan sebagai makula, patch yang

telangiektasis yang mungkin disertai dengan

blanching dari yang terlibat kulit (Gambar 7). Tidak

seperti kebanyakan IHS, IHS gagal kurang memiliki

signisignisigni jelasjelasjelas fififi cantcantcant fasefasefase proliferasi.proliferasi.proliferasi. SekitarSekitarSekitar dua-pertigadua-pertigadua-pertiga

dari lesi ini terletak pada ekstremitas bawah.

Banyak yang disertai dengan lokal, daerah papular

kecil pertumbuhan jaringan pembuluh darah, sering

sekitarsekitarsekitar pinggiran.pinggiran.pinggiran. 777777 GagalGagalGagal shareshareshare IHSIHSIHS dengandengandengan IHSIHSIHS

penanda permukaan karakteristik yang lebih khas

(misalnya,(misalnya,(misalnya, GLUT1),GLUT1),GLUT1), conconcon fififi rmingrmingrming bahwabahwabahwa merekamerekamereka

benar IHS; Namun, fase pertumbuhan mereka

mungkin akan ditangkap. Banyak dari IHS

kadang-kadangkadang-kadang sebelumsebelum usiausia 11 tahun.tahun. 7878

istilah yang kurang tepat yang tidak lagi umum

digunakan. Dikombinasikan, campuran, atau

senyawa IHS (Gambar 6C) adalah mereka di mana

keduakeduakedua yangyangyang supersupersuper fififi resmiresmiresmi dandandan komponenkomponenkomponen dalamdalamdalam

hiduphiduphidup berdampingan.berdampingan.berdampingan. SuperSuperSuper fififi resmiresmiresmi IHSIHSIHS cenderungcenderungcenderung

muncul lebih awal dan mulai rumit lebih cepat

daripada rekan-rekan mereka yang mendalam,

yang, sebaliknya, cenderung muncul kemudian dan

tumbuh selama waktu yang cukup lama sebelum

berinvolusiberinvolusiberinvolusi (rata-rata,(rata-rata,(rata-rata, sekitarsekitarsekitar 111 bulanbulanbulan lebih).lebih).lebih). 62,64,6662,64,6662,64,66 PenyelidikanPenyelidikanPenyelidikan telangiektasis juga rumit lebih cepat,

perbedaanperbedaanperbedaan iniiniini conconcon fififi rmrmrm yangyangyang jadwaljadwaljadwal iniiniini mewakilimewakilimewakili polapolapola

pertumbuhan karakteristik untuk IHS ini daripada

timbultimbultimbul biasbiasbias observasional.observasional.observasional. 666666 SepertiSepertiSeperti bisabisabisa diduga,diduga,diduga,

mereka IHS dengan morfologi campuran memiliki

pola pertumbuhan yang penengah antara

orang-orang yang terkait dengan

Namun demikian, komplikasi seperti ulserasi dapat terjadi. IHS ini mungkin juga segmental dan kadang-kadang memiliki asosiasi sindrom (lihat(lihat(lihat bagianbagianbagian yangyangyang berjudulberjudulberjudul “““ IHIHIH SyndromesSyndromesSyndromes dandandan AsosiasiAsosiasiAsosiasi “).“).“). 797979

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DARI American Academy of Pediatrics

FIGURE 7 Abortive IHs are macular, telangiectatic patches that have failed to fully proliferate. IHSIHSIHS

FIGURE 7

Abortive IHs are macular, telangiectatic patches that have failed to fully proliferate.

IHSIHSIHS jugajugajuga mungkinmungkinmungkin diklasidiklasidiklasi fififi ededed atasatasatas dasardasardasar conconcon anatomianatomianatomi merekamerekamereka fififi gurasigurasigurasi baikbaikbaik sebagaisebagaisebagai lokallokallokal (focal),(focal), segmental,segmental, taktak tentu,tentu, atauatau multifokal.multifokal. 26,80,8126,80,81

Localized (focal) IHs are discrete lesions that

seem to arise from a single focal point, whereas

segmental lesions cover a territory that is

presumed to be determined by embryonic

neuroectodermalneuroectodermalneuroectodermal placodes.placodes.placodes. 828282 SegmentalSegmentalSegmental IHsIHsIHs

tend to involve a larger surface area of skin.

Segmental IHs of the face have been observed

to conform to unique developmental units, which

have been mapped into 4 distinct patterns:

frontotemporal, maxillary, mandibular, and

frontonasalfrontonasalfrontonasal (Fig(Fig(Fig 8).8).8). 828282 LesionsLesionsLesions thatthatthat areareare notnotnot

dedede fififi nitivelynitivelynitively focalfocalfocal ororor segmentalsegmentalsegmental areareare consideredconsideredconsidered indeterminate. Multifocal lesions are focal lesions occurring at more than 1 anatomic site. One large study found that most IHs (67.5%) are localized, whereas the remainder were segmental (13%), indeterminate (16.5%), or multifocalmultifocal (3.6%).(3.6%). 8383

The presence of a large, facial segmental IH is

aaa hallmarkhallmarkhallmark signsignsign ofofof PHACEPHACEPHACE syndrome,syndrome,syndrome, 252525 whereaswhereaswhereas

large segmental IHs of the anogenital and

lumbosacral areas may be associated with

genitourinary system and spinal cord anomalies

asasasasas partpartpartpartpart ofofofofof otherotherotherotherother syndromessyndromessyndromessyndromessyndromes 8484848484 ––––– 8686868686 ((((( seeseeseeseesee sectionsectionsectionsectionsection

entitledentitledentitledentitledentitled “““““ IHIHIHIHIH SyndromesSyndromesSyndromesSyndromesSyndromes andandandandand AssociationsAssociationsAssociationsAssociationsAssociations ”).”).”).”).”). MoreMoreMoreMoreMore

recently, it has been recognized that

extracutaneous manifestations may also arise in

association with segmental IHs involving other

anatomic sites, as part of the so-called

PHACE-withoutfacePHACE-withoutfacePHACE-withoutface phenomenon.phenomenon.phenomenon. 878787 TheseTheseThese

patients may have segmental IHs of the upper

chest, shoulder, or arm in the absence of facial

IH involvement and in conjunction with structural

heart disease, aortic or other major vessel

anomalies, central nervous system and sternal

defects, or eye anomalies.

nervous system and sternal defects, or eye anomalies. FIGURE 8 (A)(A)(A) PatternsPatternsPatterns ofofof

FIGURE 8

(A)(A)(A) PatternsPatternsPatterns ofofof segmentalsegmentalsegmental IHIHIH ofofof thethethe facefaceface extractedextractedextracted fromfromfrom imageimageimage analysisdeanalysisdeanalysisde fififi ned.ned.ned. Seg1Seg1Seg1 (frontotemporal),(frontotemporal),(frontotemporal), Seg2Seg2Seg2 (maxillary),(maxillary),(maxillary), Seg3 (mandibular), and Seg4 (frontonasal). (B) An ulcerated segmental IH in the maxillary distribution.

Multifocal cutaneous IHs are frequently isolated

to the skin but may also serve as markers for

underlyingunderlyingunderlyingunderlyingunderlying hepatichepatichepatichepatichepatic involvementinvolvementinvolvementinvolvementinvolvement (Fig(Fig(Fig(Fig(Fig 9).9).9).9).9). 8888888888 ––––– 9191919191 PreviousPreviousPreviousPreviousPrevious

retrospectiveretrospectiveretrospective reportsreportsreports 26,8126,8126,81 suggestedsuggestedsuggested thatthatthat thethethe

presence of a large or segmental (.5 cm)

cutaneous IH might prove a useful marker for

hepatic IHs. However, results from a large

prospective study suggest that it is the number

of cutaneous IHs rather than their size that is

thethethe moremoremore predictivepredictivepredictive factor.factor.factor. 929292 WhenWhenWhen 555 ororor moremoremore

IHs are present on cutaneous examination,

ultrasonography may be helpful in assessing

potentialpotential hepatichepatic involvement.involvement. 84,9384,93

Hepatomegaly and congestive heart failure

also suggest the presence of liver IH.

Highlights of This Section

• IHsIHsIHs areareare characterizedcharacterizedcharacterized asasas supersupersuper fififi cial,cial,cial,

deep, or mixed and as focal,

multifocal, or segmental.

• SuperSuperSuper fififi cialcialcial IHsIHsIHs appearappearappear earlierearlierearlier andandand

begin involution sooner than their

deeper counterparts.

• Segmental IHs are more

commonly involved in PHACE (see

texttexttext forforfor dedede fififi nition)nition)nition) andandand otherotherother IHIHIH

syndromes and associations.

• The presence of more than 5 focal

IHs suggests a higher risk of hepatic

involvement.

focal IHs suggests a higher risk of hepatic involvement. FIGURE 9 Multifocal cutaneous IHs in a

FIGURE 9

Multifocal cutaneous IHs in a child with IH of the liver.

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Complications

Although most IHs do not require urgent

treatment, a minority may develop

function-threatening or lifethreatening

complications, necessitating therapeutic

intervention. One study determined that

approximately 24% of patients with IH who were

referred to a group of tertiary care dermatology

practices experienced some complication

relatedrelatedrelated tototo theirtheirtheir IH.IH.IH. 848484 ItItIt isisis thereforethereforetherefore prudentprudentprudent forforfor

pediatric providers to remain vigilant of possible

complications and of risk factors that may herald

future complications. Ulceration accounts for the

majority of IH complications; others include

bleeding, visual impairment, auditory

impairment, congestive heart failure, and airway

obstruction.obstruction.obstruction. 848484 GastrointestinalGastrointestinalGastrointestinal bleedingbleedingbleeding hashashas

been reported as a complication of segmental

intestinal hemangiomatosis, in which the IH is

typically situated in the distribution of the

mesentericmesenteric arterialarterial system.system. 9494

The single best predictor of complications and

the need for therapeutic intervention for IH is

morphologicmorphologicmorphologic subtype.subtype.subtype. 848484 FocalFocalFocal IHsIHsIHs havehavehave thethethe

potential to cause complications primarily by

virtue of their location on or near vital structures,

such as the eye (amblyopia, astigmatism), nose

(anatomic distortion and cartilaginous

destruction), ears (anatomic distortion and

cartilaginous destruction), lips (anatomic

distortion and ulceration), airway (obstruction),

or anogenital region (ulceration). On the face,

focal lesions are 3 times more common than

segmentalsegmentalsegmental IHs.IHs.IHs. 818181 SegmentalSegmentalSegmental IHsIHsIHs areareare moremoremore

frequentlyfrequentlyfrequently complicatedcomplicatedcomplicated bybyby ulceration.ulceration.ulceration. 848484 AAA

prospective cohort study in 1058 patients

undertaken to identify clinical characteristics

predicting complications and need for treatment

found, after controlling for size, that segmental

IHs were 11 times more likely than localized IHs

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to develop complications and 8 times more likelylikely toto receivereceive treatment.treatment. 8484

Segmental lesions tend to have longer

proliferativeproliferativeproliferative phases,phases,phases, somesomesome withwithwith signisignisigni fififi cantlycantlycantly

prolonged duration of growth as long as 10 to

444444 months,months,months, andandand maymaymay thereforethereforetherefore requirerequirerequire signisignisigni fififi cantlycantlycantly

longerlonger treatmenttreatment durations.durations. 9494

The size of the IH was also an important

predictor of the need for treatment in the

aforementioned cohort study, although this

analysis did not appear to control for anatomic

subtype.subtype.subtype. 848484 TheTheThe meanmeanmean sizesizesize ofofof complicatedcomplicatedcomplicated IHsIHsIHs

waswas 37.337.3 cmcm 2,2,

comparedcomparedcompared withwithwith 19.119.119.1 cmcmcm 222 forforfor uncomplicateduncomplicateduncomplicated IHs.IHs.IHs.

In addition, IHs that received treatment of any

typetypetype hadhadhad aaa meanmeanmean sizesizesize ofofof 30.430.430.4 cmcmcm 2,2,2, whichwhichwhich waswaswas

11.111.111.1 cmcmcm 222 largerlargerlarger thanthanthan thosethosethose thatthatthat diddiddid notnotnot receivereceivereceive

treatment. However, the mean size of

segmental IHs is approximately 10 times that of

localizedlocalizedlocalized IHs,IHs,IHs, 666666 suggestingsuggestingsuggesting thatthatthat morphologymorphologymorphology maymaymay

indeed be a more important indicator of

potential complications. Anatomic location was

alsoalsoalso aaa predictorpredictorpredictor ofofof complicationscomplicationscomplications dueduedue tototo IH.IH.IH. 848484 FacialFacialFacial

IHs were complicated 1.7 times more frequently

than nonfacial IHs; they were also 3.3 times

more likely than their nonfacial counterparts to

receive some form of therapy, likely because of

concerns for cosmesis. Periocular IHs and

thosethosethosethosethose ininininin thethethethethe “““““ beardbeardbeardbeardbeard ””””” distributiondistributiondistributiondistributiondistribution areareareareare alsoalsoalsoalsoalso moremoremoremoremore

likely to require intervention, as described

below. In 1 study, perineal IHs were the most

likelylikely toto ulcerate.ulcerate. 9595

usually results in scarring, with the risk of

permanentpermanentpermanent disdisdis fififi gurement.gurement.gurement. AsAsAs aaa result,result,result, promptpromptprompt

initiation of therapy is essential in the

managementmanagementmanagement ofofof ulceratingulceratingulcerating IHs.IHs.IHs. TheTheThe specispecispeci fififi ccc

mechanisms resulting in IH ulceration are poorly

understood. It has been hypothesized that

ulceration may develop secondary to increased

tissue hypoxia, which leads to the development

ofofof dermaldermaldermal fififi brosisbrosisbrosis andandand thenthenthen progressesprogressesprogresses tototo

surfacesurfacesurface breakdown.breakdown.breakdown. 989898 InInIn suchsuchsuch cases,cases,cases, earlyearlyearly whitewhitewhite

discoloration of an IH, possibly representing

supersupersuper fififi cialcialcial dermaldermaldermal

fifi brosis,brosis, maymay bebe aa premonitorypremonitory signsign ofof

impendingimpendingimpending ulceration.ulceration.ulceration. 999999 OtherOtherOther proposedproposedproposed

mechanisms include outgrowing of the blood

supply or rapid expansion exceeding the elastic

capabilitiescapabilities ofof thethe skin.skin. 99,10099,100

Several studies have shown that certain subsets

of patients with IHs are at higher risk of

ulceration.ulceration.ulceration. AsAsAs discusseddiscusseddiscussed previously,previously,previously, supersupersuper fififi cialcialcial

and segmental IHs have been found to be at

higherhigherhigherhigherhigherhigher riskriskriskriskriskrisk ofofofofofof ulcerating.ulcerating.ulcerating.ulcerating.ulcerating.ulcerating. 969696969696 –––––– 98,10198,10198,10198,10198,10198,101 InInInInInIn addition,addition,addition,addition,addition,addition, specispecispecispecispecispeci fifififififi

c locations at higher risk of ulceration include

the head, neck, perioral, and perineal/perianal

regionsregionsregionsregionsregions andandandandand intertriginousintertriginousintertriginousintertriginousintertriginous sitessitessitessitessites (Fig(Fig(Fig(Fig(Fig 10).10).10).10).10). 9696969696 ––––– 98,10298,10298,10298,10298,102 TheTheTheTheThe

neck and anogenital regions sustain maceration

and friction, which may contribute to the

development of ulceration. Ulceration has also

been noted to occur more frequently in infants

younger than 4 months, a period of time during

which the IH

Ulceration

Ulceration, or breakdown of the IH skin surface, occurs with an estimated incidence of 5% to 21%.21%. 9696

Ulceration was the most common complication

in a large prospective cohort of children with

IHs,IHs, occurringoccurring inin 16%16% ofof thethe studystudy population.population. 9797

UlcerationUlcerationUlceration cancancan leadleadlead tototo signisignisigni fififi cantcantcant pain,pain,pain,

bleeding, and secondary infection. Ulceration

also

bleeding, and secondary infection. Ulceration also FIGURE 10 Ulcerated segmental IH of the perineal/perianal

FIGURE 10

Ulcerated segmental IH of the perineal/perianal region.

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isisisisis activelyactivelyactivelyactivelyactively proliferating.proliferating.proliferating.proliferating.proliferating. 9696969696 ––––– 9898989898 SeeSeeSeeSeeSee thethethethethe sectionsectionsectionsectionsection

entitledentitledentitledentitledentitled “““““ ManagementManagementManagementManagementManagement ofofofofof UlceratedUlceratedUlceratedUlceratedUlcerated IHIHIHIHIH ””””” forforforforfor aaaaa

discussion in greater detail.

Bleeding

Although concern for potential bleeding in IH is

common among caregivers and providers, it

occurs rarely and almost exclusively in

ulcerated lesions. The majority of bleeding that

occurs in nonulcerated IHs is minor and easily

controllable with pressure. The most common

such scenario is an IH that has sustained minor

surfacesurfacesurface traumatraumatrauma (ie,(ie,(ie, fromfromfrom frictionfrictionfriction ororor aaa fififi ngernail),ngernail),ngernail),

bled minimally, stopped bleeding spontaneously

or with minimal sustained pressure, and

subsequently presents with surface

hemorrhagic crusting.

In a large prospective study of ulcerated IHs,

bleeding occurred in 41% of lesions but was

clinicallyclinicallyclinicallyclinically signisignisignisigni fifififi cantcantcantcant inininin onlyonlyonlyonly 2%2%2%2% ofofofof thesethesethesethese cases.cases.cases.cases. 96,9896,9896,9896,98

SigniSigniSigni fififi cantcantcant bleedingbleedingbleeding requiringrequiringrequiring bloodbloodblood transfusiontransfusiontransfusion

ororor otherotherother interventioninterventionintervention isisis infrequentlyinfrequentlyinfrequently reported.reported.reported. 989898 RareRareRare

instances of lifethreatening bleeding have been

observed, including 1 report of ulceration of a

segmental neck IH into arterial vessels, the

bleeding from which necessitated transfusions,

systemic and topical treatment of the IH,

embolization,embolization, andand surgicalsurgical excision.excision. 102102

Feeding Impairment

Feeding impairment can occur in infants with

IHs involving either the perioral region or the

airway. Infants with ulcerated lip IHs may be

unable to latch onto a nipple secondary to

severesevere pain,pain, whichwhich cancan leadlead toto impairedimpaired feeding.feeding. 103103

Obstructive airway IHs may complicate

breathing and swallowing, also leading to

impairedimpairedimpaired feeding.feeding.feeding. 104104104 InInIn aaa smallsmallsmall casecasecase seriesseriesseries ininin

infants with complicated facial IHs, several with

ulcerated perioral lesions or airway

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IHs had feeding and oral sensory problems thatthat resultedresulted inin failurefailure toto thrive.thrive. 105105

Airway Involvement and Obstruction

Airway IHs can occur in the presence or

absenceabsenceabsence ofofof skinskinskin fififi ndings.ndings.ndings. SymptomaticSymptomaticSymptomatic

obstructive airway IHs, including supra- and

subglottic IHs, usually present with progressive

biphasic inspiratory and expiratory stridor during

thethethe fififi rstrstrst 666 tototo 121212 weeksweeksweeks ofofof ageageage asasas thethethe lesionlesionlesion isisis

proliferating.proliferating. 105105

Affected infants may also rapidly

developdevelop noisynoisy breathingbreathing oror aa hoarsehoarse cry.cry. 106106

TheTheThe cutaneouscutaneouscutaneous fififi ndingsndingsndings associatedassociatedassociated withwithwith

underlying airway involvement, when present,

help to identify those patients at greatest risk of

airwayairwayairwayairway IHs.IHs.IHs.IHs. CutaneousCutaneousCutaneousCutaneous IHsIHsIHsIHs inininin aaaa ““““ beardbeardbeardbeard ””””

distribution,distribution,distribution, dedede fififi nednedned asasas involvinginvolvinginvolving thethethe preauricularpreauricularpreauricular

regions, chin, anterior neck, or lower lip (Fig 11),

havehave beenbeen associatedassociated withwith airwayairway involvement.involvement. 106,107106,107

Infants with IHs within this distribution bilaterally

appear to be at an even higher risk of

bilaterally appear to be at an even higher risk of FIGURE 11 A,A,A,A,A, TheTheTheTheThe

FIGURE 11

A,A,A,A,A, TheTheTheTheThe presencepresencepresencepresencepresence ofofofofof multiplemultiplemultiplemultiplemultiple IHsIHsIHsIHsIHs ininininin thethethethethe “““““ beardbeardbeardbeardbeard ””””” distributiondistributiondistributiondistributiondistribution isisisisis associatedassociatedassociatedassociatedassociated withwithwithwithwith aaaaa higherhigherhigherhigherhigher likelihoodlikelihoodlikelihoodlikelihoodlikelihood ofofofofof airwayairwayairwayairwayairway involvementinvolvementinvolvementinvolvementinvolvement (reproduced(reproduced(reproduced(reproduced(reproduced(reproduced withwithwithwithwithwith permissionpermissionpermissionpermissionpermissionpermission fromfromfromfromfromfrom JJJJJJ Pediatr.Pediatr.Pediatr.Pediatr.Pediatr.Pediatr. 1997;131(4):6431997;131(4):6431997;131(4):6431997;131(4):6431997;131(4):6431997;131(4):643 –––––– 646646646646646646 ©Elsevier).©Elsevier).©Elsevier).©Elsevier).©Elsevier).©Elsevier). 106106106106106106

BBBBB andandandandand C,C,C,C,C, PatientPatientPatientPatientPatient withwithwithwithwith airwayairwayairwayairwayairway involvementinvolvementinvolvementinvolvementinvolvement requiringrequiringrequiringrequiringrequiring tracheotomytracheotomytracheotomytracheotomytracheotomy isisisisis shownshownshownshownshown withwithwithwithwith “““““ beardbeardbeardbeardbeard ””””” involvementinvolvementinvolvementinvolvementinvolvement atatatatat thethethethethe lipliplipliplip andandandandand chinchinchinchinchin (B)(B)(B)(B)(B) as well as the parotid area and neck (C).

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having associated airway involvement; in a recent series in 17 infants with airway IHs, bilateral involvement of the lower facial segment

waswaswas presentpresentpresent ininin 131313 (76%).(76%).(76%). 106,108106,108106,108 EarlyEarlyEarly referralreferralreferral tototo otolaryngology of infants with severe stridor and

a cutaneous IH in the

compromise usually improves with treatment

of both the heart failure and the IH.

Diffuse lesions of the liver may also be associated with severe consumptive hypothyroidism caused by excess production of type 3 iodothyronine deiodinase. Liver IHs are discussed in greater detail in the subsection entitledentitledentitledentitledentitledentitledentitled “““““““ LiverLiverLiverLiverLiverLiverLiver ””””””” ofofofofofofof “““““““ IHsIHsIHsIHsIHsIHsIHs WithWithWithWithWithWithWith SpecialSpecialSpecialSpecialSpecialSpecialSpecial AnatomicAnatomicAnatomicAnatomicAnatomicAnatomicAnatomic Concerns.Concerns. ””

Highlights of This Section

• Segmental IHs are far more likely than focal IHs to result in a complication, usually ulceration.

• Focal IHs cause complications primarily by virtue of their location on or near vital structures.

• Facial IHs cause complications more frequently than nonfacial IHs and are several times more likely to receive some form of therapy.

• Minor bleeding from an ulcerated IH isis common,common, butbut rarelyrarely ofof clinicalclinical signisigni fifi cance; bleeding from a nonulcerated IH is rare.

• PatientsPatients withwith anan extensiveextensive IHIH inin thethe ““ beardbeardbeard ””” distributiondistributiondistribution areareare moremoremore likelylikelylikely tototo have involvement of the airway.

• High-risk periocular IHs are those that are that are larger than 1 cm in diameter, located near the nose, associated with ptosis or eyelid margin change, or displacing the globe.

• Diffuse IH of the liver may be associated with severe consumptive hypothyroidism.

IH Syndromes and Associations

““““ beardbeardbeardbeard ”””” distributiondistributiondistributiondistribution isisisis advisable,advisable,advisable,advisable, becausebecausebecausebecause airway involvement can be life-threatening if diagnosis and treatment are delayed. In less symptomatic children, a high kilovoltage radiograph of the airway may be useful in

identifying subglottic IH. Airway IHs are discussed in greater detail in the subsection underunderunderunderunder “““““ IHsIHsIHsIHsIHs WithWithWithWithWith SpecialSpecialSpecialSpecialSpecial AnatomicAnatomicAnatomicAnatomicAnatomic ConcernsConcernsConcernsConcernsConcerns ””””” entitledentitledentitledentitledentitled

“““ Airway.Airway.Airway. ”””

Visual Impairment and Other Ocular Complications

IHs occurring within the orbit have the potential to cause mechanical ptosis, strabismus, anisometropia, or astigmatism, which can quicklyquickly leadlead toto thethe developmentdevelopment ofof amblyopia.amblyopia. 108108

StudiesStudiesStudiesStudiesStudies havehavehavehavehave identiidentiidentiidentiidenti fififififi ededededed specispecispecispecispeci fififififi ccccc characteristicscharacteristicscharacteristicscharacteristicscharacteristics ofofofofof

periocular IHs, which place the child at higher

risk of amblyopia. These include periocular IHs

that are larger than 1 cm in diameter, nasal

location of the IH, associated ptosis, eyelid

marginmarginmarginmargin change,change,change,change, orororor displacementdisplacementdisplacementdisplacement ofofofof thethethethe globe.globe.globe.globe. 109109109109 –––– 111111111111

Orbital IHs are discussed in greater detail in the

subsectionsubsectionsubsectionsubsectionsubsectionsubsectionsubsection entitledentitledentitledentitledentitledentitledentitled “““““““ EyeEyeEyeEyeEyeEyeEye andandandandandandand OrbitOrbitOrbitOrbitOrbitOrbitOrbit ””””””” underunderunderunderunderunderunder “““““““ IHsIHsIHsIHsIHsIHsIHs

WithWith SpecialSpecial AnatomicAnatomic Concerns.Concerns. ””

Congestive Heart Failure and Hypothyroidism

Although rare, high-output congestive heart failure can occur in infants with large IHs as a result of arteriovenous shunting of a large blood volume through the lesion. This complication has been reported in infants with large cutaneous IHs and RICHs and in those with

diffuse or multifocal hepatic IHs. 91,92,112,113 Symptomatic

diffuse or multifocal hepatic IHs. 91,92,112,113 Symptomatic

diffuse or multifocal hepatic IHs. 91,92,112,113 Symptomatic

infantsinfantsinfants maymaymay presentpresentpresent withwithwith difdifdif fififi cultycultyculty feeding,feeding,feeding, poorpoorpoor growth, heart murmur, or hepatomegaly. The cardiac

A small subset of children with IH will exhibit

associated congenital

anomalies. The best-known such association is PHACE (Online Mendelian Inheritance in Man

606519).606519).606519). 114114114 TheTheThe disorderdisorderdisorder isisis alsoalsoalso referredreferredreferred

to as PHACES to include potential ventral

midlinemidlinemidlinemidlinemidline defects,defects,defects,defects,defects, specispecispecispecispeci fififififi callycallycallycallycally SSSSS ternalternalternalternalternal cleftcleftcleftcleftcleft

and/ or

SSS upraumbilicalupraumbilicalupraumbilical raphe.raphe.raphe. OriginallyOriginallyOriginally describeddescribeddescribed asasas aaa “““ syndrome,syndrome,syndrome, ””” PHACEPHACEPHACE isisis moremoremore appropriatelyappropriatelyappropriately termed an association, although there are recent data suggesting that chromosomal region 7q33 may provide a genetic susceptibility to exhibitexhibit thethe PHACEPHACE phenotype.phenotype. 115115

The spectrum of anomalies in PHACE syndrome and the ipsilateral relationship between such anomalies and cutaneous IH stronglystronglystronglystronglystronglystrongly suggestsuggestsuggestsuggestsuggestsuggest aaaaaa ““““““ developmentaldevelopmentaldevelopmentaldevelopmentaldevelopmentaldevelopmental fifififififi eldeldeldeldeldeld defect,defect,defect,defect,defect,defect, ””””””

whereby an insult at a critical time in embryogenesis gives rise to similar developmentaldevelopmentaldevelopmental outcomes.outcomes.outcomes. 116116116 TheTheThe precisepreciseprecise timingtimingtiming

of such an insult in PHACE syndrome is speculative, but both the anatomic IH patterns and several of the associated structural abnormalitiesabnormalities pointpoint toto changeschanges earlyearly duringduring thethe fifi rstrstrst trimester,trimester,trimester, probablyprobablyprobably withinwithinwithin thethethe fififi rstrstrst 333 tototo 121212

weeks of gestation before or during early vasculogenesis.vasculogenesis.vasculogenesis. 117117117 PHACEPHACEPHACE syndromesyndromesyndrome isisis nownownow understood to be predominantly a congenital vasculopathy. In fact, many of its features can be explained as downstream events of

arteriopathy with resultant ischemia, and it has been hypothesized that vascular dysplasia may be a key or even primary event in the pathogenesispathogenesis ofof PHACEPHACE syndrome.syndrome. 118118

Consensus criteria were recently developed for the diagnosis of PHACE syndrome (Tables 2

andandand 3).3).3). 252525 ClinicalClinicalClinical examinationexaminationexamination ofofof thethethe skinskinskin andandand eyes as well as detailed imaging of the head, neck, and chest are required to make the diagnosis. More than 90% of infants with PHACE syndrome exhibit more than 1 extracutaneous anomaly, although very few manifestmanifestmanifest thethethe completecompletecomplete spectrum.spectrum.spectrum. 119119119 InInIn contrastcontrastcontrast to nonsyndromic IH, PHACE syndrome

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TABLETABLE 22 ConsensusConsensus AlgorithmAlgorithm forfor thethe DiagnosisDiagnosis ofof PHACEPHACE SyndromeSyndrome

PHACE Syndrome

 

Possible PHACE Syndrome

Facial hemangioma

Facial hemangioma

Hemangioma of the

No hemangioma plus

.

5 cm in diameter plus 1

5 cm in diameter plus 1 minor criterion

.

neck or upper torso plus 1 major criterion or 2 minor criteria

2 major criteria

major criterion or 2 minor criteria

Adapted from ref 25.

TABLETABLE 33 ConsensusConsensus DiagnosticDiagnostic CriteriaCriteria forfor PHACEPHACE SyndromeSyndrome OrganOrgan SystemSystem

is more common in full-term singleton infants of normal birth weight, although femalesfemales areare stillstill moremore commonlycommonly affected.affected. 120120

The hallmark of PHACE syndrome is a large, segmental,segmental,segmental, oftenoftenoften supersupersuper fififi cialcialcial IH,IH,IH, characteristicallycharacteristicallycharacteristically located on the face, scalp, and/or neck (Fig 12). PHACEPHACEPHACE syndromesyndromesyndrome ––– associatedassociatedassociated IHsIHsIHs mostmostmost commonly affect facial segments 1 and/or 3, which also confers a particularly high risk of associatedassociated centralcentral nervousnervous systemsystem involvement.involvement. 84,11984,119

 

Major Criteria

Minor Criteria

Cerebrovascular

Anomaly of major cerebral arteries

Persistent embryonic artery other than trigeminal artery Proatlantal intersegmental artery (types 1 and 2) Primitive

DysplasiaDysplasiaDysplasia aaa ofofof thethethe largelargelarge cerebralcerebral arteriesarteries bb Arterial stenosis or occlusion

with or without moyamoya

collaterals Absence or moderate-severe hypoplasia of the large cerebral arteries Aberrant origin or course of thethe largelarge cerebralcerebral arteriesarteries bb

hypoglossal artery Primitive otic artery

Persistent trigeminal artery

Saccular aneurysms of any

cerebral arteries

Structural brain

Posterior fossa anomaly

Enhancing extraaxial lesion with

Dandy-Walker complex or

features consistent with intracranial hemangioma Midline anomalyanomaly cc

unilateral/bilateral cerebellar

hypoplasia/dysplasia

 

NeuronalNeuronal migrationmigration disorderdisorder dd

Cardiovascular

Aortic arch anomaly

Ventricular septal defect Right aortic arch (double aortic arch)

Coarctation of aorta

DysplasiaDysplasia aa

Aneurysm

Aberrant origin of the subclavian artery with or without a vascular ring

Ocular

Posterior segment abnormality

Anterior segment abnormality

Persistent hyperplastic

Microphthalmia

primary vitreous

Sclerocornea

Persistent fetal vasculature

Coloboma

Retinal vascular anomalies

Cataracts

Morning glory disc anomaly Optic nerve hypoplasia Coloboma

 

Peripapillary staphyloma

Ventral or midline

Sternal defect

Hypopituitarism

 

Sternal cleft

Ectopic thyroid

Supraumbilical raphe

Sternal defects

Adapted from ref 25.

 

aa

IncludesIncludes kinking,kinking, looping,looping, tortuosity,tortuosity, and/orand/or dolichoectasia.dolichoectasia.

bb

InternalInternal carotidcarotid artery,artery, middlemiddle cerebralcerebral artery,artery, anterioranterior cerebralcerebral artery,artery, posteriorposterior cerebralcerebral artery,artery, oror vertebrobasilarvertebrobasilar systemsystem

cc

CallosalCallosal agenesisagenesis oror dysgenesis,dysgenesis, septumseptum pellucidumpellucidum agenesis,agenesis, pituitarypituitary malformation,malformation, oror pituitarypituitary ectopia.ectopia.

dd

Polymicrogyria,Polymicrogyria, corticalcortical dysplasia,dysplasia, oror graygray mattermatter heterotopia.heterotopia.

PHACE syndrome is not exceedingly rare, and

probably even more common than

Sturge-WeberSturge-WeberSturge-Weber syndrome.syndrome.syndrome. 121121121 TheTheThe segmentalsegmentalsegmental IHIHIH

associated with PHACE is sometimes confused

with the port wine stain associated with

SturgeWeber syndrome, especially in the

newbornnewbornnewborn periodperiodperiod beforebeforebefore signisignisigni fififi cantcantcant IHIHIH

proliferation or in cases of

““““ minimalminimalminimalminimal growthgrowthgrowthgrowth ”””” IHIHIHIH inininin whichwhichwhichwhich theretheretherethere isisisis anananan

absenceabsenceabsence ofofof signisignisigni fififi cantcantcant proliferation.proliferation.proliferation. TheTheThe riskriskrisk ofofof

PHACE syndrome in an infant presenting with a

large,large, segmentalsegmental IHIH ($22($22 cmcm 2)2)

ofof thethe headhead oror neckneck isis approximatelyapproximately one-third.one-third. 120120

Cerebrovascular anomalies, present in more than 90% of patients, are the most common extracutaneous feature of PHACE syndrome, followed by cardiac anomalies (67%) and structuralstructural brainbrain anomaliesanomalies (52%).(52%). 8484

The most common arterial abnormality in

PHACE syndrome is dysgenesis of the anterior

circulation, particularly within the internal carotid

artery.artery.artery. 119119119 TheTheThe neuroanatomicneuroanatomicneuroanatomic andandand

cerebrovascular anomalies observed in PHACE

may lead to a number of neurologic sequelae,

including motor and speech delays, seizures,

migraine-like headaches, and rarely, arterial

ischemicischemicischemic stroke.stroke.stroke. 121121121 HearingHearingHearing losslossloss (conductive(conductive(conductive ororor

sensorineural) has also been reported in

PHACE syndrome, particularly when the IH

involves the ear and periauricular scalp, which

can be related to the presence of ipsilateral

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FIGURE 12 A, Frontotemporal segmental IH typical of PHACE syndrome. B, Sternal clefting characteristic of

FIGURE 12

A, Frontotemporal segmental IH typical of PHACE syndrome. B, Sternal clefting characteristic of PHACE syndrome (scar is congenital, not surgical).

intracranial IH involving auditory structures. It has been suggested that children with PHACE syndrome and periauricular IH be evaluated withwith bothboth MRIMRI andand audiometricaudiometric testing.testing. 122122

Cardiovascular anomalies are the second most common extracutaneous manifestation of PHACE syndrome. The aortic coarctation observed differs from classic coarctation in that it occurs in a more proximal location, often involves the arteries feeding the upper extremities, and affects longer segments, which may preclude detection based on a blood pressure gradient between the upper and lower extremities. The aortic anomalies in PHACE syndrome are often noted to be particularly unusual and severe, often requiring surgical repair; thus, detailed imaging of the arch isis essential.essential. 123123

Even in asymptomatic infants, MRI or magnetic resonance angiography (MRA) of the head and neck is indicated, especially given the known potential for progressive vasculopathy and resultant ischemic events in a small subset of severelyseverely affectedaffected patients.patients. 124124

Arterial ischemic stroke, a rare but devastating complication, appears to be more likely in patientspatientspatients withwithwith PHACEPHACEPHACE whowhowho exhibitexhibitexhibit signisignisigni fififi cantcantcant narrowing or nonvisualization of large cerebral arteries, especially when more than 1 vessel is involved and/or if there are associated cardiovascular morbidities such as coarctation of thethe aorta.aorta. 125125

Through serial neuroimaging of high-

risk infants, progressive cerebrovascular changes

maymaymay bebebe identiidentiidenti fififi ededed early,early,early, andandand neurosurgicalneurosurgicalneurosurgical

revascularization procedures can be performed to

potentiallypotentiallypotentially reducereducereduce arterialarterialarterial ischemicischemicischemic strokestrokestroke ––– relatedrelatedrelated

morbiditymorbiditymorbidity andandand mortality.mortality.mortality. 125125125 TheTheThe presencepresencepresence ofofof

severe cerebrovascular and/or cardiovascular

arterial anomalies in patients with PHACE

syndrome may preclude the use of propranolol

for treatment of IH in this population, or require

dosedosedose modimodimodi fififi cation.cation.cation. (see(see(see sectionsectionsection entitledentitledentitled

“““ MedicalMedicalMedical TherapyTherapyTherapy forforfor IHIHIH ”).”).”).

LUMBARLUMBARLUMBAR syndromesyndromesyndrome ((( LLL owerowerower bodybodybody IHIHIH andandand otherotherother cutaneouscutaneouscutaneous defects,defects,defects, UUU rogenitalrogenitalrogenital anomaliesanomaliesanomalies andandand ulceration,ulceration,ulceration, MMM yelopathy,yelopathy,yelopathy,

BBBB onyonyonyony deformities,deformities,deformities,deformities, AAAA norectalnorectalnorectalnorectal malformationsmalformationsmalformationsmalformations andandandand

arterialarterialarterial anomalies,anomalies,anomalies, andandand RRR enalenalenal anomalies)anomalies)anomalies) maymaymay bebebe

bestbestbestbest consideredconsideredconsideredconsidered thethethethe ““““ lowerlowerlowerlower halfhalfhalfhalf ofofofof thethethethe bodybodybodybody ””””

variantvariant ofof PHACEPHACE syndrome.syndrome. 8585 LUMBAR has also been previously described under the competing acronyms SACRALSACRALSACRALSACRALSACRALSACRAL 878787878787 (((((( SSSSSS pinalpinalpinalpinalpinalpinal dysraphism,dysraphism,dysraphism,dysraphism,dysraphism,dysraphism, AAAAAA nogenitalnogenitalnogenitalnogenitalnogenitalnogenital anomalies,

CCCC utaneousutaneousutaneousutaneous anomalies,anomalies,anomalies,anomalies, RRRR enalenalenalenal andandandand urologicurologicurologicurologic anomalies, associated with AAAA ngiomangiomangiomangioma ofofofof LLLL umbosacralumbosacralumbosacralumbosacral localization)localization)localization)localization) andandandand PELVISPELVISPELVISPELVIS 86868686 (((( PPPP erinealerinealerinealerineal hemangioma,hemangioma,hemangioma,hemangioma, EE xternalxternal genitaliagenitalia malformations,malformations,

LLLL ipomyelomeningocele,ipomyelomeningocele,ipomyelomeningocele,ipomyelomeningocele, VVVV esicorenalesicorenalesicorenalesicorenal abnormalities,abnormalities,abnormalities,abnormalities,abnormalities, IIIII mperforatemperforatemperforatemperforatemperforate anus,anus,anus,anus,anus, SSSSS kinkinkinkinkin tag).tag).tag).tag).tag). TheTheTheTheThe IHs are usually segmental lumbosacral or anogenital lesions. In an analysis of 24 new patients and a review of 29 published cases, IHs in association with LUMBAR were noted

tototototo bebebebebe segmentalsegmentalsegmentalsegmentalsegmental andandandandand oftenoftenoftenoftenoften “““““ minimalminimalminimalminimalminimal growthgrowthgrowthgrowthgrowth ””””” ininininin morphology.morphology.morphology. 858585 SuchSuchSuch IHsIHsIHs werewerewere oftenoftenoften extensiveextensiveextensive (eg,(eg,(eg, involving the entire leg) and showed additional potential for ulceration and, rarely, underdevelopment of the affected limb. Like PHACE syndrome, the cutaneous IHs and underlying anomalies showed regional correlation. Myelopathies, particularly spinal dysraphism, were the most common extracutaneous anomaly. Interestingly, arterial anomalies were noted in a minority of patients whowhowho werewerewere specispecispeci fififi callycallycally studiedstudiedstudied forforfor suchsuchsuch anomalies,anomalies,anomalies, although the true incidence and long-term risks areareare unknown.unknown.unknown. ImagingImagingImaging isisis region-speciregion-speciregion-speci fififi c;c;c; MRIMRIMRI isisis useful in delineating the extent of lumbosacral involvement and potential myelopathy, whereas additional imaging with MRA may be warranted for infants with extensive lower limb involvement to assess for arterial anomalies.

Highlights of This Section

PHACE syndrome includes features

cerebrovascularcerebrovascularcerebrovascularcerebrovascular AAAA rterialrterialrterialrterial anomalies,anomalies,anomalies,anomalies, CCCC

ardiovascular anomalies including

coarctation of the aorta, and

EE yeye anomalies.anomalies.

• The hallmark of PHACE syndrome

is a large, segmental IH,

characteristically located on the

face, scalp, and/or neck.

The most common extracutaneous

features of PHACE syndrome are

cerebrovascular anomalies, followed

by cardiac anomalies and structural

brain anomalies.

• LUMBAR syndrome may be best

consideredconsideredconsidered thethethe “““ lowerlowerlower halfhalfhalf ofofof thethethe

bodybodybody ””” variantvariantvariant ofofof PHACEPHACEPHACE syndromesyndromesyndrome

and may be associated with

urogenital, anal, skeletal, and spinal

cord anomalies.

of P osterior fossa defects, H emangiomas,

of P osterior fossa defects, H emangiomas,

of P osterior fossa defects, H emangiomas,

of P osterior fossa defects, H emangiomas,

of P osterior fossa defects, H emangiomas,

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IMAGING OF IH

The diagnosis of IH is generally made on the basis of history and clinical appearance. Occasionally, imaging of the lesion may be required when the diagnosis is uncertain, when evaluation of extent is necessary, or when response to therapy needs to be monitored. IH-associated anomalies, such as spinal dysraphism, anogenitourinary anomalies, and PHACE syndrome, are also best imaged with MRI. However, the risk of early exposure to anesthesia is a consideration in determining the urgency and type of imaging for IH. Ultrasonography is a reasonable initial imaging modality for diagnosing IH, because it is inexpensive and does not require sedation. The sonogramsonogramsonogramsonogram generallygenerallygenerallygenerally revealsrevealsrevealsreveals aaaa well-dewell-dewell-dewell-de fifififi nednednedned high-high-high-high- flflflfl ow parenchymal mass with possible shunting. During the involution phase, areas of increased echogenicity (fat replacement) can be seen within the lesions. Gray scale and color Doppler ultrasonography have also demonstrated utility in monitoring the response of IH to medical therapy.therapy.therapy.therapy.therapy. 127127127127127 UltrasonographyUltrasonographyUltrasonographyUltrasonographyUltrasonography isisisisis alsoalsoalsoalsoalso aaaaa goodgoodgoodgoodgood fififififi rst-linerst-linerst-linerst-linerst-line modality to screen patients with multifocal IHs for liver or visceral involvement, although MRI is preferable to assess complicated or extensive visceralvisceral lesions.lesions. 128128

The extent of the lesion and the surrounding anatomy are better shown on MRI. The most useful sequences include T1-weighted images with and without fat saturation, T1-weighted imagesimagesimages withwithwith fatfatfat saturationsaturationsaturation postpostpost ––– gadoliniumgadoliniumgadolinium administration, T2-weighted images with fat saturation,saturation,saturation, andandand flflfl ow-sensitiveow-sensitiveow-sensitive sequencessequencessequences suchsuchsuch asasas gradientgradientgradient echoechoecho ororor MRA.MRA.MRA. 129129129 ProliferatingProliferatingProliferating IHsIHsIHs typicallytypicallytypically appearappearappear asasas well-dewell-dewell-de fififi nednedned massesmassesmasses withwithwith featuresfeaturesfeatures ofofof highhighhigh flflfl owowow andandand intermediateintermediateintermediate signalsignalsignal intensity on T1-weighted images and high signal intensityintensityintensity ononon T2-weightedT2-weightedT2-weighted images.images.images. 130,131130,131130,131 FlowFlowFlow voids may be apparent on T2-weighted and

flfl ow-sensitiveow-sensitive sequences,sequences, alongalong withwith

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high-high-high- flflfl owowow feedingfeedingfeeding arteriesarteriesarteries andandand drainingdrainingdraining veins.veins.veins.

With administration of intravenous gadolinium,

lesion enhancement is usually early, with

intense and uniform enhancement on delayed

images; however, diffuse or multifocal hepatic

lesions may show early enhancement

peripherallyperipherallyperipherally andandand delayeddelayeddelayed fififi llingllinglling centrallycentrallycentrally

(centripetal(centripetal(centripetal enhancement).enhancement).enhancement). 919191 NonenhancingNonenhancingNonenhancing

regions may represent thrombosis or necrosis.

During the involution phase, as deposits of fat

replace the lesion, foci of increased signal can

be seen on T1-weighted images, and

postcontrast images reveal less avid

enhancement. Computed tomography (CT) is

mentioned only because it is occasionally

ordered when a diagnosis of IH is not expected.

CT

fifi ndingsndings areare similarsimilar toto thosethose onon MRI,MRI, includingincluding well-dewell-dewell-de fififi nednedned andandand avidlyavidlyavidly enhancingenhancingenhancing lesionslesionslesions during the proliferating phase and less pronounced enhancement during the involution phase. Although these studies are shorter in duration than MRI (reducing the likelihood that general anesthesia will be necessary), CT carries the disadvantage of exposing young children to ionizing radiation and its attendant risks.

Highlights of This Section

• Imaging of IH is not usually necessary.

• When imaging of IH is performed, ultrasound is generally the preferred modality for diagnosis, whereas MRI is better to assess extent of the lesion.

• Imaging may be required when the diagnosis is uncertain, when evaluation of extent is necessary, when the IH is a possible marker of PHACE or LUMBAR syndrome, or when response to therapy needs to be monitored.

CLINICAL APPROACH TO IH

The traditional clinical approach to IH has been oneoneoneoneoneone ofofofofofof ““““““ benignbenignbenignbenignbenignbenign neglect.neglect.neglect.neglect.neglect.neglect. ”””””” 606060606060 TheTheTheTheTheThe observationobservationobservationobservationobservationobservation that,that,that,that,that,that, as a neoplasm, IH has the unique ability to undergo involution has led many practitioners to believe that the best management is to

“““ leaveleaveleave ititit alonealonealone andandand ititit willwillwill gogogo away.away.away. ””” However, 1 study from a group of referral pediatric dermatology practices suggests that more than one-third of patients with IH require somesomesome sortsortsort ofofof intervention.intervention.intervention. 848484 Hence,Hence,Hence, althoughalthoughalthough thisthisthis numbernumbernumber maymaymay rerere flflfl ectectect referralreferralreferral bias,bias,bias, ititit isisis clearclearclear thatthatthat some IHs are associated with a high risk of complicationscomplicationscomplications ororor permanentpermanentpermanent disdisdis fififi gurement.gurement.gurement. InInIn many such cases, early intervention may be justijustijusti fififi ededed tototo potentiallypotentiallypotentially arrestarrestarrest thethethe growthgrowthgrowth ofofof thethethe lesion, reduce associated complications, and avoidavoidavoid yearsyearsyears ofofof psychosocialpsychosocialpsychosocial concerns.concerns.concerns. TheTheThe fififi rstrstrst consideration in the management of IH is whether intervention is necessary. The indications for intervention include the following:

(1) emergency treatment of potentially lifethreatening complications; (2) urgent treatment of existing or imminent functional impairment, pain, or bleeding; (3) evaluation to identify structural anomalies potentially associated with IH; and (4) elective treatment to reduce the likelihood of long-term or permanent disdisdis fififi gurement.gurement.gurement. LifethreateningLifethreateningLifethreatening lesionslesionslesions includeincludeinclude obstructing IHs of the airway as well as liver IHs associated with high-output congestive heart failure and severe hypothyroidism. Pain and bleeding are examples of urgent sequelae that occur as a result of ulceration; affected children

may have failure to thrive as well. Other examples of functional impairment include

ocular impairment (loss of visual axis leading to deprivation amblyopia, astigmatism,

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FIGURE 13 Uncomplicated IHs. These lesions generally do not require medical or surgical intervention.

FIGURE 13

Uncomplicated IHs. These lesions generally do not require medical or surgical intervention.

strabismus,strabismus,strabismus, visualvisualvisual fififi eldeldeld cuts),cuts),cuts), impairedimpairedimpaired feedingfeedingfeeding because of involvement of the lips or mouth, and reduced mobility because of complicated involvement of the extremities. Structural anomalies of concern include spinal dysraphism associated with lumbosacral IHs as well as anomalies associated with PHACE and other IH “““ syndromes.syndromes.syndromes. ”””

Long-termLong-termLong-term andandand permanentpermanentpermanent disdisdis fififi gurementgurementgurement isisis aaa concern with IHs of certain anatomic sites (eyelid, nasal tip, lip, breast, genitalia) and with severe ulceration, because these will ultimately leave a scar of similar size.

Most IHs are uncomplicated and are not likely to fall into any of these categories (Fig 13); the practice of initial observation or

““““ watchfulwatchfulwatchfulwatchful waitingwaitingwaitingwaiting ”””” isisisis reasonablereasonablereasonablereasonable forforforfor suchsuchsuchsuch lesions. However, because the clinical presentation of IH can change within days, it is prudent for pediatric providers to reexamine frequently, as often as weekly, those children with lesions at high risk of causing functional or cosmetically critical changes, because many uncomplicated lesions may become complicated

onesonesones ininin earlyearlyearly infancy.infancy.infancy. 132132132 ForForFor lesslessless concerningconcerningconcerning IHs, providers may wish to counsel the family regarding changes of importance, such as rapid growth or ulceration, and to establish with the family a means to see the child on short notice if such changes are observed.

Central to the decision of whether to intervene is

aaa discussiondiscussiondiscussion ofofof thethethe risks,risks,risks, benebenebene fififi ts,ts,ts, andandand

alternatives associated with each of these

choices and with each potential intervention.

Proper informed consent from the family is

paramount in achieving a successful and

satisfying physician-patient relationship as well

as a good therapeutic result. Once a decision

has been made to intervene, the second

consideration is which therapeutic modalities

are most appropriate. There is no formula or

algorithm that easily addresses all of the factors

in this decision; as a result, the treatment plan is

customized for each patient. Relevant factors

include age and medical condition of the patient;

growth phase, location, and size of the lesion or

lesions; degree of skin involvement; severity of

complication and urgency of intervention; potential for adverse psychosocial consequences; parental preference; and clinician experience. A Cochrane review found a dearth of well-designed clinical trials on which appropriate interventions for IH could be determined.determined. 133133

Whether IH affects the psychosocial well-being of affected patients, and the age at which it may do so,so,so, isisis uncertain.uncertain.uncertain. SomeSomeSome authorsauthorsauthors suggestsuggestsuggest thatthatthat “““ childrenchildrenchildren

fifififi rstrstrstrst representrepresentrepresentrepresent andandandand rererere flflflfl ectectectect onononon themselvesthemselvesthemselvesthemselves asasasas independent,independent,independent, objectiveobjectiveobjective entitiesentitiesentities ””” ininin thethethe latterlatterlatter halfhalfhalf ofofof thethethe secondsecondsecond yearyearyear ofofof lifelifelife 134134134 andandand thatthatthat thethethe emotionalemotional responsesresponses ofof othersothers maymay affectaffect aa childchild ’’ sss moodmoodmood eveneveneven earlierearlierearlier thanthanthan 121212 monthsmonthsmonths ofofof age.age.age. 135135135 Thus,Thus,Thus, there may be some effect on the child even before entering preschool. In contrast, a review ofofof thethethe existingexistingexisting literatureliteratureliterature ononon psychosocialpsychosocialpsychosocial ramiramirami fififi cationscationscations ofofof IHIHIH waswaswas lesslessless concerning.concerning.concerning. 136136136 AmongAmongAmong thethethe 777 studies cited, questionnaires that were validated butbutbut notnotnot specispecispeci fififi ccc forforfor IHIHIH revealedrevealedrevealed fewfewfew ororor nonono signssignssigns of psychosocial impact in children with IHs. The authors did note that the studies were conducted in small groups of parents, and all werewerewere flflfl awedawedawed ininin oneoneone waywayway ororor another.another.another. InInIn aaa smallsmallsmall study, quality of life among children 5 to 8

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FROM THE AMERICAN ACADEMY OF PEDIATRICS

years of age who had IHs of the head and neck measuring 2 cm or greater was compared with that of normal controls. Although the questionnairesquestionnairesquestionnaires werewerewere notnotnot disease-specidisease-specidisease-speci fififi c,c,c, thethethe authors found no differences in quality-of-life indicesindices oror inin self-perceptionself-perception scores.scores. 137137

Further complicating this subject is the fact that quality-of-life investigations in young children requirerequirerequire proxyproxyproxy reportingreportingreporting thatthatthat oftenoftenoften rerere flflfl ectsectsects qualityqualityquality of life as perceived by the proxy rather than the child.child.child. Thus,Thus,Thus, nonono dedede fififi nitivenitivenitive statementstatementstatement cancancan bebebe mademademade regardingregardingregarding psychosocialpsychosocialpsychosocial ramiramirami fififi cationscationscations ofofof IH;IH;IH; however,however,however, manymanymany clinicianscliniciansclinicians whowhowho specializespecializespecialize ininin thethethe fififi eldeldeld will consider treatment of those IHs projected to bebebe cosmeticallycosmeticallycosmetically signisignisigni fififi cantcantcant beyondbeyondbeyond 444 yearsyearsyears ofofof age.age. 7070

Details related to IH stage have been addressed

in a study examining growth characteristics of

IHs.IHs.IHs. 666666 TheTheThe largestlargestlargest increaseincreaseincrease ininin IHIHIH sizesizesize occurredoccurredoccurred atatat

a mean age of 3 months, and by 5 months of

age both segmental and localized IHs had

reachedreachedreached 80%80%80% ofofof theirtheirtheir fififi nalnalnal size.size.size. AsAsAs aaa result,result,result,

therapy initiated after the early proliferative

phase is less likely to be effective in controlling

the growth of the lesion or in prevention of

complications. Age and stage are also factors in

the effectiveness of pharmacotherapy for IH.

Early experience with systemic steroids for IH

suggested that younger children had a better

responseresponseresponse tototo therapy,therapy,therapy, 138,139138,139138,139 andandand mostmostmost studiesstudiesstudies ofofof

their mechanism of action suggest they inhibit

componentscomponentscomponents ofofof thethethe proliferativeproliferativeproliferative process.process.process. 140140140 SimilarSimilarSimilar

data for propranolol therapy are not yet

available, but proposed mechanisms of its

action also suggest primary activity during

proliferation.proliferation. 139,141139,141

Conversely, recent retrospective studies indicateindicateindicate thatthatthat b-b-b- blockerblockerblocker therapytherapytherapy forforfor IHIHIH cancancan be effective beyond the proliferative phase asas well.well. 142,143142,143

Age and growth phase are also considerations when surgery for IH is being considered. For example, in

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PEDIATRICS Volume 136, number 4, October 2015

patients who have undergone early surgery and

in whom residual IH intentionally or inadvertently

remains postoperatively, there is potential for

additional growth of the lesion after the

procedure. In addition, because IHs are benign

lesions with the potential to involute, surgeons

do not always endeavor to obtain disease-free

margins, instead allowing involution to assist in

achievingachievingachieving thethethe fififi nalnalnal result.result.result. OnOnOn occasion,occasion,occasion, ininin

surgery for wellinvoluted IHs, tissue may even

be left behind intentionally, using the

fifififi brofattybrofattybrofattybrofatty remnantremnantremnantremnant totototo serveserveserveserve asasasas fifififi llerllerllerller totototo preservepreservepreservepreserve

normal tissue contours. Lesion-related factors,

such as location, size, and degree of skin

involvement or ulceration, often dictate the

feasibility of a given treatment modality. For

example, a pedunculated eyelid lesion causing

ptosis or ectropion or a small, ulcerated lesion

that is certain to scar may lend itself better to

early surgical excision rather than medical

therapy. Conversely, an extensively ulcerated

segmental IH or a lesion of the genitalia is more

appropriately addressed with medical therapy.

Parental preference is another critical factor in

treatment selection, more so in elective cases

than in those that are emergencies or urgent

cases. Parents will often have strong feelings,

particularly about surgical intervention or

systemic medical therapy, that will have a major

effect on treatment planning for the child.

Similarly,Similarly,Similarly, thethethe choicechoicechoice ofofof treatmenttreatmenttreatment maymaymay bebebe ininin flflfl uenceduenceduenced

by the experience of the treating provider and

his or her familiarity with the diversity of

potential interventions. For these reasons, it

may be preferable for complicated IHs to be

managed by a practitioner or team who has

experience with all of the available therapeutic

options.

Highlights of This Section

• The indications for intervention for IH include the following:

1. emergency treatment of potentially lifethreatening complications;

2. urgent treatment of existing or imminent functional impairment, pain, or bleeding;

3. evaluation to identify structural anomalies potentially associated with IH; and

4. elective treatment to reduce the likelihood of long-term or permanentpermanentpermanent disdisdis fififi gurement.gurement.gurement.

• There is no algorithm to determine the most appropriate intervention for IH. Factors affecting this choice include the following:

1. age of the patient,

2. growth phase of the lesion,

3. location and size of the lesion,

4. degree of skin involvement,

5. severity of complication and urgency of intervention,

6. potential for adverse psychosocial consequences,

7. parental preference, and

8. physician experience.

MANAGEMENT OF ULCERATED IHS

The management of ulcerated IHs includes

attentionattentionattention tototo woundwoundwound care,care,care, pain,pain,pain, andandand IHIHIH growth.growth.growth. 969696 Unfortunately,Unfortunately,Unfortunately,

there are no high-quality studies to guide care of

the ulcer, and therefore treatment preferences

areare oftenoften basedbased onon casecase experience.experience. 132132

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Approaches to ulcerated IHs are

summarized in Table 4. Some clinicians

liken the managementmanagementmanagement ofofof ulcerationulcerationulceration tototo thatthatthat ofofof supersupersuper fififi cialcialcial burns and suggest culture and diligent wound care. In 1 study, 16% of ulcerated IHs were considered to be infected on clinical grounds, and cultures revealed pathogens in half of these cases.cases. 9898

Reepithelialization may be facilitated by

debriding crusts with the use of warm

compresses. The ulcer is then covered with a

barrier to prevent excessive drying, control pain,

reduce the risk of trauma and potential bleeding,

and reduce the risk of bacterial colonization or

infection. Such treatments may consist of topical

antibiotics or anesthetics, wound dressings,

barrier creams, or all of the above. Most

ulcerations improve with this conservative

approach to wound care. Because ulceration is

usually associated with proliferation of the IH,

therapies to curb its growth are often used.

Several case series have reported successful

treatment of IH ulceration with propranolol

therapy.therapy.therapy.therapy.therapy. 144144144144144 ––––– 146146146146146 TopicalTopicalTopicalTopicalTopical timololtimololtimololtimololtimolol hashashashashas beenbeenbeenbeenbeen reportedreportedreportedreportedreported

tototo bebebe successfulsuccessfulsuccessful forforfor ulceration,ulceration,ulceration, 147147147 butbutbut itsitsits

absorption is unpredictable in this setting.

Systemic steroids may also be a reasonable

alternative.

In refractory cases, pulsed-dye laser (PDL)

therapy may also be effective in managing

ulceratedulceratedulceratedulceratedulcerated IHs.IHs.IHs.IHs.IHs. 96,14896,14896,14896,14896,148 ––––– 150150150150150 InInInInIn aaaaa prospectiveprospectiveprospectiveprospectiveprospective studystudystudystudystudy ininininin

78 children, 91% of the patients responded to

laser therapy with a mean number of

PainPainPain controlcontrolcontrol isisis aaa signisignisigni fififi cantcantcant issueissueissue ininin infantsinfantsinfants withwithwith ulcerated IH. Pain can be severe and can disrupt sleep as well as interfere with daily activities and/ or function. For example, ulceration located on the lips or oral mucosa may affect oral intake or feeding, whereas interference with urination or stooling may be seen in the setting of perineal ulcerations. Oral acetaminophen and cautious use of topical 2.5% lidocaine ointment may be effective in managingmanagingmanaging thethethe painpainpain ofofof ulceration.ulceration.ulceration. 969696 WithWithWith moremoremore severe ulceration, the use of narcotics may be indicated for inadequately controlled pain. Collaboration with experts in pain management may be useful in this high-risk group of infants.

Highlights of This Section

• Management of ulcerated IH

consists primarily of the following: (1)

barrier dressings, (2) pain control,

and (3) control of IH growth.

• Adjuvant therapies may include the following:

1. topical agents, including antibiotics, anesthetics, or wound dressings, and

2. pulsed dye laser.

MEDICAL THERAPY FOR IH

Background

Medical therapy for IH includes both topical and

systemic administration of medications. Topical

agents may be a consideration for smaller, more

supersupersuper fififi cialcialcial IHsIHsIHs ororor thosethosethose forforfor whichwhichwhich systemicsystemicsystemic

therapy is contraindicated. Systemic therapy is

usually initiated for large IHs, those with a high

riskriskrisk ofofof functionalfunctionalfunctional impairmentimpairmentimpairment ororor disdisdis fififi gurement,gurement,gurement,

and those refractory to other initial therapies.

Beginning in the 1960s, systemic and

intralesional steroids were the cornerstone of

medical therapy for IH. Shrinkage of IH with

systemicsystemicsystemic corticosteroidcorticosteroidcorticosteroid therapytherapytherapy waswaswas fififi rstrstrst

observed serendipitously among patients with

hemangioendotheliomas (KMP) treated for

thrombocytopenia in the late 1950s and early

1960s.1960s.1960s. 152152152 InInIn

1967,1967,1967, ZaremZaremZarem andandand EdgertonEdgertonEdgerton 153153153 treatedtreatedtreated 777

consecutive children with oral prednisolone for

enlarging IHs. All 7 experienced cessation of

lesional growth and no rebound growth after

treatment. On the basis of this result, Fost and

EsterlyEsterlyEsterly 138138138 treatedtreatedtreated 666 childrenchildrenchildren withwithwith oraloraloral prednisoneprednisoneprednisone

for extensive IHs. All but 1 had dramatic

regression after only 2 weeks of therapy.

SubsequentSubsequentSubsequent studiesstudiesstudies havehavehave continuedcontinuedcontinued tototo showshowshow efefef fififi cacy,cacy,cacy,

although physicians have raised concerns about

potential

TABLETABLE 44 TreatmentTreatment OptionsOptions inin thethe ManagementManagement ofof UlceratedUlcerated IHIH

Wound Care

Adjuvant Therapies

2.02.02.0 treatments.treatments.treatments. 148148148 Thus,Thus,Thus, PDLPDLPDL therapytherapytherapy hashashas beenbeenbeen used as both monotherapy and as adjunctive therapy in managing ulcerated IHs; however, it has been recommended that laser therapy be used with caution in patients with proliferating IHs because of the risks of atrophic scarring and/orand/orand/or ulceration.ulceration.ulceration. 151151151 SurgicalSurgicalSurgical excisionexcisionexcision maymaymay alsoalsoalso be a consideration for small ulcerations that are poorly responsive to medical therapy.

Dressings

WhiteWhiteWhite petrolatumpetrolatumpetrolatum ––– impregnatedimpregnatedimpregnated gauzegauzegauze

Nonadherent dressings (eg, Mepitel [Mölnlycke

Health Care; Gothenburg, Sweden], Telfa [Covidien/Medtronic; Minneapolis, MN])

Hydrocolloid dressings (eg, DuoDERM

[ConvaTec; Luxembourg])

Topical agents

White petrolatum, Aquaphor [Beiersdorf Inc.;

Hamburg, Germany], Silver sulfadiazine

(Silvadene; Monarch Pharmaceuticals; Bristol, TN)

Antimicrobials

Metronidazole gel

Mupirocin, gentamicin, bacitracin ointment Pain control

Topical

Anesthetics (eg, lidocaine, benzocaine) Oral

Acetaminophen with or without narcotics

Other

Becaplermin gel Topical timolol PDL

Early excision Oral propranolol or steroids

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FROM THE AMERICAN ACADEMY OF PEDIATRICS

adverse effects of steroids

administered in large doses for long periods of

time.

established in randomized trials, and InInIn thethethe latelatelate 1980s1980s1980s andandand earlyearlyearly 1990s,1990s,1990s, interferon-interferon-interferon- aaa showedshowedshowed recommendations for monitoring are still

some promise in the treatment of

steroid-resistant IHs. This drug is a cytokine

produced by leukocytes that play a role in the

innate immune response against viruses. When

syntheticsyntheticsynthetic interferon-interferon-interferon- aaa 2a2a2a waswaswas usedusedused tototo treattreattreat

patients with HIV, an improvement in their

KaposiKaposi sarcomasarcoma lesionslesions waswas noted.noted. 154154

becomebecomebecome thethethe fififi rst-linerst-linerst-line medicalmedicalmedical therapy;therapy;therapy; however,however,however,

optimal dosing, treatment timing and duration,

and risk of complications have not yet been

evolving.evolving.evolving. 161161161 AnAnAn oraloraloral formulationformulationformulation freefreefree ofofof alcohol,alcohol,alcohol,

sugar, and paraben developed for use in

children (Hemangeol; Pierre Fabre, Castres,

France) received approval from the US Food

and Drug Administration in March 2014. There

isisis aaa paucitypaucitypaucity ofofof datadatadata regardingregardingregarding otherotherother b-b-b- adrenergicadrenergicadrenergic

blockers.blockers. 162162

target hemangioma), compared with a 4% rate

amongamongamong thosethosethose treatedtreatedtreated withwithwith placebo.placebo.placebo. 172172172 AnotherAnotherAnother

randomized trial in 40 patients found a marked

improvement in IH volume, redness, and

elevation among those taking propranolol

comparedcomparedcompared withwithwith thosethosethose takingtakingtaking placebo.placebo.placebo. 173173173 InInIn aaa

2011 comprehensive review of the literature,

response to propranolol therapy was evaluated

ininininin 7979797979 articlesarticlesarticlesarticlesarticles butbutbutbutbut quantiquantiquantiquantiquanti fififififi ededededed ininininin onlyonlyonlyonlyonly 6.6.6.6.6. 160160160160160 PositivePositivePositivePositivePositive

responses in all treated patients were reported

in 86% of publications; the remaining 14%

discussed at least some treatment failures. In

total, 19 of 1175 patients in these publications

were reported as treatment failures, suggesting

aa 1.6%1.6% treatmenttreatment failurefailure rate.rate. 160160

Because interferon-induced genes are

upregulated during involution of IH, there was a

theoretical basis for its mechanism of action in

IH,IH,IH, 152152152 andandand anecdotalanecdotalanecdotal reportsreportsreports asasas wellwellwell asasas clinicalclinicalclinical

trialstrialstrials subsequentlysubsequentlysubsequently documenteddocumenteddocumented itsitsits efefef fififi cacycacycacy ininin

vascular lesions, including IHs refractory to

corticosteroidcorticosteroidcorticosteroid therapy.therapy.therapy. 156,157156,157156,157 However,However,However, ititit isisis nownownow

clearclearclear thatthatthat signisignisigni fififi cantcantcant neurologicneurologicneurologic toxicities,toxicities,toxicities,

including impairment of higher cortical and

motor function, can occur and generally

precludeprecludepreclude itsitsits useuseuse asasas aaa fififi rst-linerst-linerst-line therapy.therapy.therapy. InInIn 2008,2008,2008,

Léauté-LabrèzeLéauté-Labrèze etet alal 158158

reported their serendipitous observation

that oral propranolol, a nonselective blocker

of

b-b- adrenergicadrenergic receptorsreceptors usedused forfor decadesdecades toto

treat cardiac disorders in children, is effective

and well tolerated in the management of IH. A

year later, they reported their experience with

32 infants with severe IH who were treated with

propranolol at 2 to 3 mg/kg per day in 2 to 3

divideddivideddivided doses.doses.doses. 159159159 TheseTheseThese infantsinfantsinfants respondedrespondedresponded wellwellwell

with a rapid, consistent, therapeutic effect and

minimal adverse effects. Since that time, there

have been numerous additional reports of the

safe and effective use of propranolol for the

treatment of medically complex as well as

cosmeticallycosmeticallycosmeticallycosmetically signisignisignisigni fifififi cantcantcantcant IHs.IHs.IHs.IHs. 160160160160

Mode of Action in IH

The mode of action of propranolol in the

treatment of IH is unknown. Proposed

mechanisms include vasoconstriction, inhibition

of angiogenesis (via suppression of VEGF-A

and downregulation of MMPs and interleukin

[IL] 6), regulation of the renin-angiotensin

system, and inhibition of nitric oxide production;

propranololpropranololpropranolol ’’’ sss abilityabilityability tototo stimulatestimulatestimulate apoptosisapoptosisapoptosis isisis

Moreover, lightening of the color and softening

of the tumor was noted in most children within

hourshours toto daysdays ofof thethe initialinitial dosedose ofof propranolol.propranolol. 158,159,173,174158,159,173,174

After initiation of propranolol therapy,

progressive improvement has been noted for at

leastleastleast 333 monthsmonthsmonths ininin mostmostmost patients.patients.patients. 158,159,173,174158,159,173,174158,159,173,174 LikeLikeLike

systemic corticosteroids, propranolol appears to

stabilize IHs in their growth phase; however, it

may also be effective after proliferation has

ended. In 1 study that assigned visual analog

scores to IHs in children treated with propranolol

equivocal.equivocal.equivocal.equivocal. 44,49,140,141,159,161,16344,49,140,141,159,161,16344,49,140,141,159,161,16344,49,140,141,159,161,163 –––– 167167167167

InvestigatorsInvestigatorsInvestigators havehavehave shownshownshown thethethe presencepresencepresence ofofof bbb 2-adrenergic2-adrenergic2-adrenergic

receptors on capillary endothelial cells in

proliferating IH, and vascular endothelial cell

growth factors, which are elevated in rapidly

growing IHs, are suppressed in the presence of

at ages 7 to 120 months, more than half of the

patients achieved a greater rate of improvement

ininin theirtheirtheir scoresscoresscores afterafterafter startingstartingstarting thethethe medication.medication.medication. 143143143 OtherOtherOther

authorsauthors havehave alsoalso reportedreported similarsimilar observations.observations. 142,175142,175

b-b-b-b-b-b- adrenergicadrenergicadrenergicadrenergicadrenergicadrenergic receptorreceptorreceptorreceptorreceptorreceptor blockade.blockade.blockade.blockade.blockade.blockade. 158158158158158158 –––––– 160,168160,168160,168160,168160,168160,168 ItItItItItIt hashashashashashas

also been suggested that propranolol may

prevent the differentiation of IH stem cells into

endothelialendothelialendothelial cellscellscells ororor pericytes,pericytes,pericytes, 169169169 reducereducereduce

contractilitycontractilitycontractility ofofof pericytes,pericytes,pericytes, 170170170 and/orand/orand/or promotepromotepromote

adipogenesis.adipogenesis. 140,165,171140,165,171

Pretreatment Assessment, Contraindications, and Risks of Therapy

b-b- AdrenergicAdrenergic BlockersBlockers

For most clinicians treating complicated

IHs, propranolol has

EfEfEf fififi cacycacycacy

In a randomized controlled trial of oral

propranolol in 460 infants aged 1 to 5 months

with IH, patients administered a dose of 3.4

mg/kg per day exhibited a 60% rate of

successful treatment (complete or nearly

complete resolution of the

A complete history and physical examination,

with special attention to the cardiac and

pulmonarypulmonarypulmonary systems,systems,systems, aidaidaid ininin assessingassessingassessing aaa childchildchild ’’’ sss

candidacy for propranolol initiation.

Electrocardiography is often ordered as well,

particularly in younger infants, those with a low

heart rate, and those with an examination or

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TABLETABLE 55 ContraindicationsContraindications andand PotentialPotential

Complications Associated With

Propranolol Therapy Contraindications

Complications

Sinus bradycardia

Sinus bradycardia

Hypotension

Hypotension

Greater than

Diarrhea

fifi rst-degreerst-degree

Cool extremities Sleep disturbance Reactive airways Hypoglycemia/seizures

heart block

Heart failure

Cardiogenic shock

Reactive airways

Hypoglycemia

Hypersensitivity

to propranolol

hydrochloride Adapted

from ref 161.

family history consistent with congenital

heartheartheart disease.disease.disease. 161161161 SomeSomeSome clinicianscliniciansclinicians alsoalsoalso

prefer to have a cardiology consultation

before starting the medication. However,

pretreatment cardiac screening appears to

be of limited value in patients with an

unremarkable cardiac history and

examination.examination.examination.examination.examination. 176176176176176 ––––– 179179179179179 RelativeRelativeRelativeRelativeRelative

contraindications to the use of propranolol

for IH include

generally asymptomatic and do not require

intervention.intervention.intervention. 177177177 LessLessLess commoncommoncommon complicationscomplicationscomplications

include bronchospasm and hypoglycemia, the

latter of which has the potential to induce

seizures.seizures.seizures. 159,161,180,181159,161,180,181159,161,180,181 InInIn aaa systematicsystematicsystematic reviewreviewreview ofofof

propranolol treatment of IH, there were 371 total

adverseadverse effectseffects reportedreported inin 11891189 patients.patients. 182182

Those most commonly reported were sleep

disturbance (136 patients), acrocyanosis (61

patients), hypotension (39 patients, including 5

consideredconsideredconsideredconsidered ““““ symptomaticsymptomaticsymptomaticsymptomatic ”),”),”),”),

bradycardia (8 patients, including 1 considered

symptomatic), and respiratory events including

infections, wheezing, and stridor (35 patients).

Initiation of Therapy and Dosing

Although the optimal setting for the initiation of

propranolol has yet to be established, a

consensus group has suggested that inpatient

hospitalization be considered for infants 8

weeks of age or younger, preterm infants less

thanthan 4848 weeksweeks ’’

cardiogenic shock, sinus bradycardia,

hypotension,hypotension,hypotension, heartheartheart blockblockblock greatergreatergreater thanthanthan thethethe fififi rstrstrst

degree, heart failure, bronchial asthma, and

knownknownknown hypersensitivityhypersensitivityhypersensitivity tototo thethethe drugdrugdrug (Table(Table(Table 5).5).5). 161161161 SpecialSpecialSpecial initiating therapy at a dose of 1 mg/kg per day, with escalation to a target dose of 1 to 3 mg/kg

precautions have been suggested for children

diagnoseddiagnoseddiagnosed withwithwith PHACEPHACEPHACE syndromesyndromesyndrome andandand signisignisigni fififi cantcantcant

intracranial vascular anomalies because of the

made prior to the FDA approval of Hemangeol,

postconceptional age, those with poor social

support, and those with cardiac or pulmonary

riskriskrisk factors.factors.factors. 161161161 TheTheThe groupgroupgroup recommendedrecommendedrecommended

per day, although this recommendation was

theoretically increased risk of acute ischemic

stroke.stroke. 161161

Experience in the management of hundreds

of infants with IH has shown propranolol to

havehavehave ananan excellentexcellentexcellent safetysafetysafety propropro fififi lelele andandand highhighhigh

tolerability. The most commonly reported

adverse effects of propranolol are sleep

disturbance and coolness and mottling of

the distal extremities. The use of

which is dosed maximally at 3.4 mg/kg per day.

The optimal dose for maintenance has yet to be

established.established.established. TheTheThe groupgroupgroup ’’’ sss recommendedrecommendedrecommended dosingdosingdosing

frequency was 3 times daily; however, the drug

has also been dosed twice daily and showed

bothbothbothbothboth safetysafetysafetysafetysafety andandandandand efefefefef fififififi cacy.cacy.cacy.cacy.cacy. 172,183,184172,183,184172,183,184172,183,184172,183,184 BecauseBecauseBecauseBecauseBecause thethethethethe

peak effect of oral propranolol on heart rate and

blood pressure is 1 to 3 hours after

administration, the group suggested that these

measurements be taken at baseline, 1 and 2

hours after the

each dosage increase of $0.5 mg/kg per day.

Heart rates or blood pressure measurements

lower than 2 SDs from the mean suggest the

need for cardiologic evaluation. It should be

noted that, where there was controversy, the

group recommended the most conservative

approach to propranolol initiation. The risk of

hypoglycemia may be reduced by administering

propranolol and feeding children at intervals not

to exceed 8 hours (or 6 hours in younger

infants).infants). 161161

Children with any acute illness, especially one

interfering with normal oral intake or one

associated with vomiting or diarrhea, will

require close monitoring and often a

temporary decrease in dosing or cessation of

therapy.

Duration of Therapy

The most dramatic improvement using

propranolol for IH occurs within 3 to 4 months of

initiation of therapy. However, many

investigators continue therapy until patients

reach an age when IH would normally begin to

regress without treatment. Hence, treatment is

often continued until at least 8 to 12 months of

age, which, in most studies, equated to 3 to 12

monthsmonthsmonths ofofof therapy.therapy.therapy. 160,172160,172160,172 ForForFor discontinuationdiscontinuationdiscontinuation ofofof

therapy, most practitioners taper propranolol

gradually over a period of 1 to 3 weeks,

primarily in an effort to prevent rebound sinus

tachycardia. Rebound growth of IH has been

observed in 6% to 25% of children, often well

afterafterafter theirtheirtheir fififi rstrstrst birthday,birthday,birthday, leadingleadingleading somesomesome clinicianscliniciansclinicians

totototo weanweanweanwean propranololpropranololpropranololpropranolol overoveroverover weeksweeksweeksweeks totototo months.months.months.months. 185185185185 –––– 189189189189

Rebound growth may be more likely in patients

whose IH exhibited a long proliferative stage

andandand aaa largelargelarge subcutaneoussubcutaneoussubcutaneous component.component.component. 185185185 InInIn

such cases, reinitiation of therapy for variable

periods of time may be necessary.

b-b- blockersblockers cancan bebe alsoalso bebe associatedassociated withwith

adverse cardiac effects, including bradycardia

and hypotension, both of which are

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fifi rstrst dose,dose, andand 11 andand 22 hourshours afterafter

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FROM THE AMERICAN ACADEMY OF PEDIATRICS

TopicalTopicalTopical b-b-b- AdrenergicAdrenergicAdrenergic BlockersBlockersBlockers

Several investigators have reported success using topical b-b- blockersblockers inin thethe treatmenttreatment ofof IH.IH. TimololTimolol maleate is a nonselective

b-b- adrenergicadrenergic receptorreceptor inhibitorinhibitor availableavailable inin

a concentration of

0.25% and 0.5%, which has been used by pediatric ophthalmologists in the United States for more thanthanthan 303030 yearsyearsyears asasas aaa fififi rst-linerst-linerst-line therapytherapytherapy ininin childrenchildrenchildren with glaucoma. In recent years, an extended-release gel-forming solution has become available in concentrations of 0.25% and 0.5%. Systemic absorption of the gelforminggelforminggelforming solutionsolutionsolution isisis signisignisigni fififi cantlycantlycantly lowerlowerlower thanthanthan that of the solution, and absorption through intact skin is likely much less than that through thethe conjunctivaeconjunctivae andand lacrimallacrimal duct.duct. 190190

Case reports and case series have shown a good response of IH to twice-daily topical

applicationapplicationapplicationapplicationapplication ofofofofof timolol.timolol.timolol.timolol.timolol. 191191191191191 ––––– 195195195195195 InInInInIn aaaaa randomizedrandomizedrandomizedrandomizedrandomized controlled trial, timolol was more effective than placebo in reducing the size and color intensity

ofofofofof smallsmallsmallsmallsmall supersupersupersupersuper fififififi cialcialcialcialcial IHs.IHs.IHs.IHs.IHs. 196196196196196 LaboratoryLaboratoryLaboratoryLaboratoryLaboratory studiesstudiesstudiesstudiesstudies

were not monitored in the majority of studies, and only 1 infant in 1 large series developed a transient sleep disturbance. Responses were bestbestbest ininin patientspatientspatients whowhowho hadhadhad supersupersuper fififi cialcialcial IHs,IHs,IHs, usedusedused the

0.5% gel-forming solution, and applied the medicationmedicationmedication forforfor moremoremore thanthanthan 333 months.months.months. 195195195 ManyManyMany experts now consider topical timolol gel-forming solution a reasonable consideration for

uncomplicated,uncomplicated,uncomplicated, supersupersuper fififi cialcialcial IHsIHsIHs forforfor whichwhichwhich treatmenttreatmenttreatment isisis desireddesireddesired butbutbut thethethe risk-to-benerisk-to-benerisk-to-bene fififi ttt ratioratioratio

isisis tootootoo greatgreatgreat tototo justifyjustifyjustify systemicsystemicsystemic b-b-b- blockerblockerblocker therapy.therapy.therapy.

However, there are valid concerns regarding the bioavailability of the drug when used topically in neonates and infants, especially in the treatment of larger or ulcerated lesions and thosethose onon oror nearnear mucousmucous membranes.membranes. 190190

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PEDIATRICS Volume 136, number 4, October 2015

Highlights of This Section

• Propranolol, administered orally at a dose of 1 to 3.43.43.4 mg/kgmg/kgmg/kg perperper day,day,day, isisis efefef fififi caciouscaciouscacious ininin reducing the size and color intensity of IH.

• TheTheThe mechanismmechanismmechanism ofofof propranololpropranololpropranolol ’’’ sss effect on IH likely involves several processes, including vasoconstriction, inhibition of angiogenesis, and stimulation of apoptosis.

• Common side effects of propranolol include sleep disturbance and discoloration with cooling of the hands and feet.

• Contraindications to the use of propranolol for IH include cardiogenic shock, sinus bradycardia, hypotension, heart block greater than fifi rst-degree,rst-degree, heartheart failure,failure, bronchial asthma, and known hypersensitivity to the drug.

• A consensus report suggests that heart rate and blood pressure be determined at baseline, 1 and 2 hourshourshours afterafterafter thethethe fififi rstrstrst dosedosedose ofofof propranolol, and 1 and 2 hours after each dosage increase of $0.5 mg/kg per day.

• Administration of propranolol with feedings, and holding doses if oral intake is compromised, reduces the likelihood of hypoglycemia.

Topical application of timolol has shownshownshown efefef fififi cacycacycacy ininin thethethe managementmanagementmanagement ofofof supersupersuper fififi cialcialcial IHs.IHs.IHs.

Corticosteroid Therapy

The precise mechanism of action of glucocorticoids in the treatment of IHs remains largely unknown. Evidence suggests that corticosteroid therapy has several effects on IH, involving both vasculogenesis and adipogenesis.

The diversity of these effects may account for the variability in response, particularly with the

stage of the treated lesion. Steroids inhibit neovesselneovessel growthgrowth inin culturedcultured humanhuman IHIH biopsiesbiopsies 197197 andandand IL-6IL-6IL-6 ––– mediatedmediatedmediated neovascularizationneovascularizationneovascularization ininin aaa ratratrat cornealcornealcorneal model.model.model. 198198198 CorticosteroidsCorticosteroidsCorticosteroids alsoalsoalso inhibitinhibitinhibit thethethe expression of proangiogenic proteins, including

VEGF-A, urokinase plasminogen activator receptor, monocyte chemoattractant protein-1, IL-6, and MMP-1, from human IH stem cells in a murinemurinemurine model.model.model. 40,19740,19740,197 InInIn addition,addition,addition, glucocorticoidsglucocorticoidsglucocorticoids inhibit the antiadipocytic differentiation effect of preadipocytepreadipocytepreadipocyte factorfactorfactor 111 199,200199,200199,200 andandand promotepromotepromote adipogenesis by increasing the expression of

peroxisomeperoxisome proliferatorproliferator activatedactivated receptor.receptor. 201,202201,202

This activity is thought to explain the developmentdevelopmentdevelopment ofofof thethethe fififi brofattybrofattybrofatty residuumresiduumresiduum duringduringduring involution of the vascular components of IH.

Systemic Corticosteroids

Systemic therapy with corticosteroids for large and complicated IHs has, in many centers, been

supplantedsupplantedsupplanted bybyby systemicsystemicsystemic b-b-b- blockers.blockers.blockers.

Nevertheless,Nevertheless,Nevertheless, steroidssteroidssteroids havehavehave playedplayedplayed aaa signisignisigni fififi cantcantcant role in IH management over the past few decades, and properly dosed and monitored, they remain an effective modality in the management of IH, especially in patients in whom

b-b-b-b- blockerblockerblockerblocker therapytherapytherapytherapy isisisis riskyriskyriskyrisky orororor contraindicated.contraindicated.contraindicated.contraindicated. 203203203203 OneOneOneOne

report in 60 children with IHs treated with either 3 or 5 mg/kg per day of oral prednisone found an excellent response in 68% and a good responseresponseresponse ininin 25%;25%;25%; therapytherapytherapy failedfailedfailed ininin 7%.7%.7%. 204204204 AAA systematic literature review showed an 84%

response rate at an average dose of 2.9 mg/kg perperper daydayday ofofof oraloraloral prednisone.prednisone.prednisone. 205205205 AnotherAnotherAnother recentrecentrecent article reported the response to systemic corticosteroidscorticosteroidscorticosteroids waswaswas signisignisigni fififi cantcantcant ininin 30%30%30% tototo 53%53%53% ofofof cases, equivocal in 35% to 40%, and negligible ininin thethethe remainder.remainder.remainder. 206206206 InInIn aaa prospective,prospective,prospective, randomized, investigator-blinded trial comparing prednisolone and propranolol dosed at 2.0 mg/kg per day, the drugs

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showedshowedshowed similarsimilarsimilar efefef fififi cacycacycacy forforfor reducingreducingreducing thethethe areaareaarea ofofof

localized complications involving the overlying

occurs in lesions of the upper eyelid, with 3

symptomatic IH; however, although

prednisolone showed a somewhat faster

response rate, propranolol was better tolerated

withwithwithwith signisignisignisigni fifififi cantlycantlycantlycantly fewerfewerfewerfewer severesevereseveresevere adverseadverseadverseadverse effects.effects.effects.effects. 207207207207

Rebound growth occurs in 14% to 37% during

dose tapering, occasionally requiring the

resumptionresumptionresumption ofofof steroidsteroidsteroid therapy.therapy.therapy. 205205205 ThisThisThis widewidewide

rangerangerange ininin reboundreboundrebound ratesratesrates likelylikelylikely rerere flflfl ectsectsects thethethe variedvariedvaried

duration of corticosteroid therapy reported in the

literature. Optimal dosing of systemic

corticosteroids remains somewhat controversial.

However, although recommendations for

prednisolone dosing have ranged from 2 to 5

mg/mg/mg/ kgkgkg perperper day,day,day, 132,203,204,208,209132,203,204,208,209132,203,204,208,209 optimaloptimaloptimal dosingdosingdosing

appears to be 2 to 3 mg/kg per day. The

duration of therapy depends on response rate

as well as the age of the patient and phase of IH

growth but generally ranges from 4 to 12 weeks

at full dose, followed by tapering over several

months and completion of treatment by 9 to 12

monthsmonths ofof age.age. 132,205132,205

Intralesional Corticosteroids

The effectiveness of intralesional corticosteroid

therapytherapytherapy forforfor problematicproblematicproblematic IHsIHsIHs waswaswas fififi rstrstrst describeddescribeddescribed

ininin 196719671967 bybyby ZaremZaremZarem andandand Edgerton,Edgerton,Edgerton, 153153153 ininin thethethe samesamesame

article in which they reported their success

treating IH with oral corticosteroids.

Subsequently, numerous studies have

suggested that intralesional corticosteroid

injectioninjection isis aa safesafe andand effectiveeffective treatmenttreatment ofof IH.IH. 210210

–– 219219

In general, corticosteroid injection is reserved

for small, bulky, welllocalized IH lesions. Large

ororor diffusediffusediffuse IHsIHsIHs areareare moremoremore difdifdif fififi cultcultcult tototo managemanagemanage withwithwith

intralesional corticosteroids because of the

following: (1) a large volume of injectable steroid

isis moremore likelylikely toto causecause systemicsystemic adverseadverse effectseffects 220220

andandand (2)(2)(2) ititit isisis difdifdif fififi cultcultcult tototo evenlyevenlyevenly distributedistributedistribute thethethe

corticosteroid throughout a large tumor. In

lesionslesionslesionslesionslesions thatthatthatthatthat areareareareare relativelyrelativelyrelativelyrelativelyrelatively flflflflfl atatatatat ororororor supersupersupersupersuper fififififi cial,cial,cial,cial,cial,

intralesional steroid injection carries an

increased risk of

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skin or underlying tissues. However, in

appropriately selected lesions, many authors

consider intralesional corticosteroid injection

an effective intervention, given its

effectiveness and the relatively low frequency

of reported systemic adverse effects at low

dosesdosesdosesdosesdosesdoses (#2(#2(#2(#2(#2(#2 –––––– 333333 mg/kg).mg/kg).mg/kg).mg/kg).mg/kg).mg/kg). 210210210210210210 –––––– 219219219219219219

In most studies, patients were injected with

either triamcinolone alone or a mixture of

triamcinolone and betamethasone, at total

equivalent doses of triamcinolone doses of

, 33 mg/kg,mg/kg, byby usingusing aa 27-27- oror 30-gauge30-gauge needle.needle. 218218 The interval between injections varied from 1 to 66 weeks.weeks. 208208

After corticosteroid injection, large studies have

reported accelerated regression in 77% to 100%

of patients with IH and cessation of growth in

16%16%16%16%16% tototototo 23%.23%.23%.23%.23%. 210210210210210 ––––– 219219219219219 TheTheTheTheThe effectseffectseffectseffectseffects ofofofofof thethethethethe steroidsteroidsteroidsteroidsteroid lastlastlastlastlast

approximatelyapproximatelyapproximately 333 tototo 444 weeksweeksweeks 216216216 andandand thusthusthus patientspatientspatients

may require additional treatments during the

proliferating phase for rebound growth.

Local complications of intralesional

corticosteroids include fat and/or dermal

atrophyatrophyatrophyatrophyatrophy and/orand/orand/orand/orand/or hypopigmentationhypopigmentationhypopigmentationhypopigmentationhypopigmentation (0%(0%(0%(0%(0% ––––– 3%).3%).3%).3%).3%). 213213213213213 –––––

215

Systemic adverse effects, including cushingoid featuresfeaturesfeaturesfeaturesfeaturesfeatures (0%(0%(0%(0%(0%(0% –––––– 3%)3%)3%)3%)3%)3%) 213213213213213213 –––––– 217217217217217217

andandand adrenaladrenaladrenal suppression,suppression,suppression, 220220220 cancancan occuroccuroccur whenwhenwhen

very large doses of intralesional steroids are

given ($5 mg/kg). A more serious complication

of intralesional corticosteroid therapy

TABLETABLE 66 PotentialPotential AdverseAdverse EffectsEffects ofof

Systemic Corticosteroids HPA

cases of retinal embolization having been

reported after an injection of corticosteroids into

IHsIHsIHsIHsIHs ininininin thisthisthisthisthis region.region.region.region.region. 221221221221221 ––––– 223223223223223 ThisThisThisThisThis complicationcomplicationcomplicationcomplicationcomplication likelylikelylikelylikelylikely

results from a combination of high injection

pressurespressurespressures (causing(causing(causing retrograderetrograderetrograde flflfl owowow ofofof thethethe drugdrugdrug

from the eyelid toward the apex of the orbit) and

excessiveexcessive injectioninjection volume.volume. 224224

However, in several large series of intralesional

corticosteroids for periorbital lesions, this

complication was not reported. Avoidance of

this complication is discussed further in the

subsectionsubsectionsubsectionsubsectionsubsection “““““ EyeEyeEyeEyeEye andandandandand OrbitOrbitOrbitOrbitOrbit ””””” underunderunderunderunder

““ IHsIHs WithWith SpecialSpecial AnatomicAnatomic

Concerns.Concerns. ””

Topical Corticosteroids

The use of high-potency topical corticosteroids

ininin IHIHIH isisis usuallyusuallyusually limitedlimitedlimited tototo thin,thin,thin, supersupersuper fififi cialcialcial lesions.lesions.lesions.

In the initial reports in the 1990s, topical

clobetasol propionate was used for periocular

IHsIHsIHsIHsIHs withwithwithwithwith goodgoodgoodgoodgood efefefefef fififififi cacycacycacycacycacy andandandandand nonononono signisignisignisignisigni fififififi cantcantcantcantcant

adverseadverseadverse effects.effects.effects. 225,226225,226225,226 AAA subsequentsubsequentsubsequent

retrospective chart review of 34 infants with

proliferating IHs who had been treated with

high-potency topical steroids found that 35% of

the infants had good response, whereas 38%

hadhadhad aaa partialpartialpartial response.response.response. 227227227 AAA moremoremore recentrecentrecent

comparison of topical mometasone furoate

versus intralesional triamcinolone acetonide in

supersupersuper fififi cialcialcial IHsIHsIHs lesslessless thanthanthan 555 cmcmcm ininin diameterdiameterdiameter

showed that 86.5% (50% excellent,

36.5% good) of patients in the topical group and

95.7% (63.8% excellent,

31.9% good) in the intralesional group respondedresponded toto thethe therapy.therapy. 228228

axis suppression Cushingoid features Growth deceleration Weight gain/increased appetite Hypertension Gastric irritation Irritability Insomnia Immune suppression Cardiomyopathy Steroid myopathy Osteopenia

Ocular adverse effects (glaucoma, cataracts) HPA,

Adverse Effects of Corticosteroid Therapy

Potential systemic adverse effects of

corticosteroids used in the treatment of IH are

presented in Table 6 and are the most common

reasonreasonreason citedcitedcited forforfor usingusingusing propranololpropranololpropranolol asasas fififi rst-linerst-linerst-line

therapy. It should be noted, however, that a few

physiciansphysiciansphysicians havehavehave favoredfavoredfavored thethethe safetysafetysafety propropro fififi lelele ofofof

corticosteroidscorticosteroids overover thatthat ofof propranolol.propranolol. 229229

hypothalamic-pituitary-adrenal.

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Suppression of the

hypothalamicpituitary-adrenal axis has been

observedobserved duringduring therapytherapy withwith bothboth intralesionalintralesional 215215

––––––– 217,220,230,231217,220,230,231217,220,230,231217,220,230,231217,220,230,231217,220,230,231217,220,230,231 andandandandandandand systemicsystemicsystemicsystemicsystemicsystemicsystemic 132,232132,232132,232132,232132,232132,232132,232 ––––––– 236236236236236236236 steroids.steroids.steroids.steroids.steroids.steroids.steroids.

However, incidence estimates for

hypothalamic-pituitary-adrenal axis

suppression vary widely, from

experts.experts.experts.experts.experts. 238238238238238 ––––– 240240240240240 Furthermore,Furthermore,Furthermore,Furthermore,Furthermore, ititititit hashashashashas beenbeenbeenbeenbeen

suggested that infants not receive live vaccines

during long-term corticosteroid therapy and that

clinicians consider checking vaccine titers on

completion of corticosteroid therapy to assess

thethe adequacyadequacy ofof response.response. 237237

1.7%1.7%1.7%1.7%1.7% 222222222222222 tototototo 87%.87%.87%.87%.87%. 234234234234234 Furthermore,Furthermore,Furthermore,Furthermore,Furthermore, althoughalthoughalthoughalthoughalthough

many patients experience abnormal morning

cortisol levels, nearly all appear to normalize

inin aa fewfew months.months. 220,231220,231

Temporary growth deceleration has also been

reportedreportedreported withwithwith bothbothboth intralesionalintralesionalintralesional 218,220,232218,220,232218,220,232 andandand

systemicsystemicsystemic 132,236,237132,236,237132,236,237 steroidsteroidsteroid therapytherapytherapy ofofof IHs.IHs.IHs.

Almost all children experience

Ocular adverse effects of long-term systemic

corticosteroidcorticosteroidcorticosteroid therapytherapytherapy includeincludeinclude cataractscataractscataracts 241,242241,242241,242 andandand

increasedincreasedincreasedincreasedincreased intraocularintraocularintraocularintraocularintraocular pressure,pressure,pressure,pressure,pressure, 242242242242242 ––––– 245245245245245 althoughalthoughalthoughalthoughalthough

neither has been frequently reported among

children in general or among those being

treated for IH in particular. The most serious

ocular adverse effect is that of vision loss

caused by embolic occlusion of the central

retinalretinalretinalretinal arteryarteryarteryartery afterafterafterafter intralesionalintralesionalintralesionalintralesional injection.injection.injection.injection. 221221221221 –––– 223223223223

““““““ catchcatchcatchcatchcatchcatch upupupupupup ”””””” growthgrowthgrowthgrowthgrowthgrowth afterafterafterafterafterafter completioncompletioncompletioncompletioncompletioncompletion ofofofofofof therapy.therapy.therapy.therapy.therapy.therapy. 236236236236236236 GastricGastricGastricGastricGastricGastric

irritationirritationirritationirritationirritation isisisisis seenseenseenseenseen ininininin 21%21%21%21%21% 236236236236236 tototototo 32%32%32%32%32% 234234234234234 ofofofofof patientspatientspatientspatientspatients

taking oral corticosteroids. This adverse effect

However, the actual risk is thought to be quite cancancan bebebe amelioratedamelioratedameliorated bybyby concomitantconcomitantconcomitant useuseuse ofofof HHH 2-2-2- receptorreceptorreceptor low and is primarily related to high injection

antagonists.antagonists.antagonists. 132,215,218132,215,218132,215,218 MildMildMild behavioralbehavioralbehavioral changeschangeschanges

have been seen in up to 29% of infants

receivingreceiving systemicsystemic corticosteroidcorticosteroid forfor IHIH therapy.therapy. 236236

ininininininin thethethethethethethe subsectionsubsectionsubsectionsubsectionsubsectionsubsectionsubsection “““““““ EyeEyeEyeEyeEyeEyeEye andandandandandandand OrbitOrbitOrbitOrbitOrbitOrbitOrbit ””””””” underunderunderunderunderunderunder “““““““ IHsIHsIHsIHsIHsIHsIHs

These include irritability, fussiness, insomnia,

andand personalitypersonality changes.changes. 230,234,236,237230,234,236,237

pressure.pressure. 224,246,247224,246,247

This complication is discussed in greater detail

WithWith SpecialSpecial AnatomicAnatomic Concerns.Concerns. ””

Osteopenia is a known adverse effect of

long-term systemic corticosteroid therapy but is

rarely observed in children with IH, which

presumably is related to the relatively short

duration and nonrepetitive nature of therapy

typically used for the treatment of IHs.

Hypertension is also a risk of systemic

corticosteroid therapy, but the percentage of

affected individuals is unknown and is likely

dose dependent. Immunosuppressive effects of

systemic corticosteroid therapy are well known.

These include increased infection risk, reduced

B- and T-lymphocyte counts, and poor response

toto vaccines.vaccines. 132,218,236,237132,218,236,237

Cutaneous adverse effects of steroids are most

often associated with intralesional and topical

therapy. The most common risks are atrophy

and hypopigmentation, although the former is

often attributable to the IH itself, whereas the

latterlatterlatter isisis usuallyusuallyusually transient.transient.transient. 227,233227,233227,233 OtherOtherOther potentialpotentialpotential

butbutbut unusualunusualunusual risksrisksrisks includeincludeinclude acne,acne,acne, perioriperioriperiori fififi cialcialcial

dermatitis, striae distensae, and hypertrichosis.

In treating bulky IHs with intralesional therapy,

cutaneous complications can be avoided by

keeping the injection well below the dermis.

Given the many potential adverse effects of

glucocorticoid therapy, many physicians will

periodically reevaluate those infants receiving

systemic corticosteroids (oral or intralesional),

withwithwith specispecispeci fififi ccc attentionattentionattention tototo growthgrowthgrowth variablesvariablesvariables andandand

blood pressure. Some physicians will also

reassess adrenal function at the end of therapy

and determine the need for stress doses of

RareRare casescases ofof pneumoniapneumonia attributableattributable toto PneumocystisPneumocystis steroids on cessation of therapy.

cariniicarinii infectioninfection havehave beenbeen reportedreported inin infantsinfants

taking corticosteroids for IH, and prophylaxis of

these patients with

trimethoprim-sulfamethoxazole has been

advocated by some

Highlights of This Section

• DespiteDespiteDespite theirtheirtheir efefef fififi cacy,cacy,cacy, systemicsystemicsystemic

corticosteroids are no longer

consideredconsidered byby mostmost cliniciansclinicians toto bebe fifi

rst-line therapy for IH due to the

associated risk of adverse effects.

• Corticosteroids, administered orally

at a dose of 2 to 3 mg/kg per day,

areareare efefef fififi caciouscaciouscacious ininin reducingreducingreducing sizesizesize andandand

discoloration of IH.

• The mechanism of IH growth

inhibition by corticosteroids likely

involves reduced vasculogenesis

and enhanced adipogenesis.

• Corticosteroids administered

intralesionally and topically also

appear to be effective in certain

subsets of patients with more

localized IH, but their dosing and

safetysafetysafety propropro fififi lelele areareare notnotnot wellwellwell studied.studied.studied.

• Periodic reexamination of children

receiving corticosteroid therapy for

IH has been suggested for

monitoring of growth and blood

pressure as well as changes in the

lesion(s) being treated.

Other Medical Therapies

BeforeBeforeBefore thethethe discoverydiscoverydiscovery ofofof thethethe therapeutictherapeutictherapeutic efefef fififi cacycacycacy of propranolol for IH, several other agents were usedusedused ininin ananan attemptattemptattempt tototo optimizeoptimizeoptimize efefef fififi cacycacycacy andandand safety. This section will focus on 3 agents that have documented utility in the treatment of IH:

vincristine,vincristine,vincristine, interferon-interferon-interferon- a,a,a, andandand imiquimod.imiquimod.imiquimod. Unfortunately,Unfortunately,Unfortunately, thethethe adverseadverseadverse effecteffecteffect propropro fififi leslesles ofofof these agents limit their usefulness, and they are generally reserved as treatments only for recalcitrant lesions. In addition, the potential usefulness of newer angiogenesis inhibitors will be discussed.

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Vincristine

neutropenia, and spastic diplegia. Although

The drug was used 3 times weekly in 10

Vincristine is a plant-derived vinca alkaloid that

impairs mitosis via microtubule formation. It has

traditionally been used as a chemotherapeutic

agent and possesses multiple antiangiogenic

qualities. It induces endothelial cell apoptosis

and is also a potent inhibitor of endothelial cell

growth, migration, and in vitro capillary-like tube

formation.formation.formation. 248248248 GivenGivenGiven thatthatthat endothelialendothelialendothelial cellscellscells alsoalsoalso

possess a high tubulin content, a biological

rationalerationale forfor IHIH sensitivitysensitivity toto vincristinevincristine exists.exists. 249249

MostMostMost reportsreportsreports ononon thethethe efefef fififi cacycacycacy ofofof vincristinevincristinevincristine

address the treatment of patients with vascular

lesions that were not true IHs but rather KHE or

TAsTAs associatedassociated withwith KMP.KMP. 250250

However, vincristine has also been used

successfully in the management of

function-threatening or lifethreatening IHs

(airway,(airway,(airway, orbital,orbital,orbital, ororor hepatic).hepatic).hepatic). 251,252251,252251,252 TheTheThe drugdrugdrug isisis

administered weekly through a central catheter

because of its extreme vesicant and irritative

potential. Adverse effects include irritation,

neurotoxicity,neurotoxicity,neurotoxicity, losslossloss ofofof deepdeepdeep tendontendontendon rerere flflfl exes,exes,exes,

constipation, cranial nerve palsies, and bone

pain. Alopecia, rash, and myelosuppression are

also possible. Reported adverse effects were

transient.transient.transient. 253253253 ThisThisThis drugdrugdrug appearsappearsappears tototo bebebe particularlyparticularlyparticularly

useful in patients with corticosteroid-resistant

KMP,KMP,KMP, butbutbut ititit isisis notnotnot aaa fififi rst-linerst-linerst-line therapytherapytherapy forforfor IH.IH.IH.

Interferon-Interferon- aa

Interferon-Interferon-Interferon- aaa 2a2a2a andandand 2b2b2b havehavehave bothbothboth beenbeenbeen usedusedused

successfullysuccessfullysuccessfullysuccessfullysuccessfully forforforforfor IHIHIHIHIH ininininin children.children.children.children.children. 156,157156,157156,157156,157156,157 Interferon-Interferon-Interferon-Interferon-Interferon- aaaaa isisisisis

given subcutaneously with an initial dose of 1

millionmillionmillion IU/mIU/mIU/m 2,2,2, increasingincreasingincreasing tototo 333 millionmillionmillion UUU dailydailydaily overoverover

thethethe fififi rstrstrst monthmonthmonth ofofof therapytherapytherapy whilewhilewhile monitoringmonitoringmonitoring

neurologic status, white blood cell count, and

liverliverliver functionfunctionfunction status.status.status. 206206206 MostMostMost patientspatientspatients havehavehave

required between 2 and 12 months of therapy.

AdverseAdverseAdverseAdverseAdverse effectseffectseffectseffectseffects areareareareare signisignisignisignisigni fififififi cantcantcantcantcant andandandandand includeincludeincludeincludeinclude flflflflfl ulikeulikeulikeulikeulike

reactions, rash, gastrointestinal symptoms,

transaminitis,

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some have reported response rates of up to

90% in steroid-resistant lesions, the effect is

gradual in onset, and rebound can occur on

discontinuation.discontinuation. 254254

patients and 5 times weekly in 8 patients, with a

meanmean durationduration ofof therapytherapy ofof 1717 weeks.weeks. AllAll supersuper fifi

cial IHs improved, but little or no change

occurred in mixed and deep IHs. Irritation and

crusting were the most common adverse

effects. This study was criticized because of the UpUpUp tototo 20%20%20% ofofof childrenchildrenchildren treatedtreatedtreated withwithwith interferon-interferon-interferon- aaa appearappearappear lacklack ofof aa controlcontrol group.group. 263263

tototo developdevelopdevelop spasticspasticspastic diplegia.diplegia.diplegia. 255255255 ThisThisThis complicationcomplicationcomplication

tends to occur later in the treatment course and

maymay bebe irreversible.irreversible. 256256

Some practitioners initially theorized that only

interferon-interferon-interferon- aaa 2a,2a,2a, ororor perhapsperhapsperhaps thethethe preservativepreservativepreservative ororor

vehicle, were the cause of these symptoms;

however, similar toxicities have also been

reportedreportedreportedreported withwithwithwith interferon-interferon-interferon-interferon- aaaa 2b.2b.2b.2b. 257257257257

GivenGivenGiven thesethesethese concerns,concerns,concerns, interferon-interferon-interferon- aaa isisis generallygenerallygenerally

consideredconsideredconsideredconsidered aaaa ““““ lastlastlastlast resortresortresortresort ””””

treatment, and most physicians prefer to use

propranolol, systemic corticosteroids, or

vincristine before treating with this agent.

Imiquimod (Imidazoquinoline 5%)

ThisThisThis topicaltopicaltopical immune-responseimmune-responseimmune-response modimodimodi fififi ererer

stimulates the innate immune system by

augmenting the production of cytokines,

includingincludingincludingincludingincludingincluding interferonsinterferonsinterferonsinterferonsinterferonsinterferons (((((( a,a,a,a,a,a, b,b,b,b,b,b, andandandandandand g);g);g);g);g);g); IL-10,IL-10,IL-10,IL-10,IL-10,IL-10, IL-12,IL-12,IL-12,IL-12,IL-12,IL-12,

and IL-18; and tumor necrosis factor. These

agents enhance cell-mediated immunity and

induce apoptosis. However, it may well be that

imiquimodimiquimodimiquimod ’’’ sss therapeutictherapeutictherapeutic effecteffecteffect ononon IHIHIH resultsresultsresults fromfromfrom

the inhibition of angiogenesis by these

cytokines. In addition, imiquimod downregulates

proangiogenic factors such as bFGF and

MMP-9 and upregulates other endogenous

angiogenesis inhibitors, including

interferon-inducible protein

10, tissue inhibitor of MMPs, and

thrombospondins.thrombospondins.thrombospondins. 258258258 TopicalTopicalTopical applicationapplicationapplication ofofof

imiquimod has been shown to markedly inhibit

tumortumortumor cellcellcell ––– inducedinducedinduced angiogenesisangiogenesisangiogenesis ininin aaa humanhumanhuman

keratinocytekeratinocyte model.model. 259,260259,260

A subsequent phase II, open-label study followedfollowed 1616 childrenchildren withwith mixedmixed results.results. 264264

Although some proponents of imiquimod

continuecontinuecontinue tototo useuseuse ititit forforfor thethethe treatmenttreatmenttreatment ofofof supersupersuper fififi cialcialcial

IH,IH,IH, irritation,irritation,irritation, crusting,crusting,crusting, andandand occasionallyoccasionallyoccasionally signisignisigni fififi cantcantcant

ulceration noted with treatment seriously limit its