JOURNAL READING

Keloid & Hypertropic Scar

Pembimbing:
dr. Rahimah, Sp.KK

Oleh:
Fladinish Sinta Aurora Pambudi (C37 - 202110401011093)

KSM ILMU KULIT DAN KELAMIN

RSUD HAJI PROVINSI JAWA TIMUR
FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH MALANG
2022
 LEMBAR PENGESAHAN

JOURNAL READING

The Most Current Algorithms for the

Treatment and Prevention of Hypertrophic
Scars and Keloids: A 2020 Update of the
Algorithms Published 10 Years Ago

Jurnal dengan judul “The Most Current Algorithms for the Treatment
and Prevention of Hypertrophic Scars and Keloids: A 2020 Update of the
Algorithms Published 10 Years Ago” telah diperiksa dan disetujui sebagai salah
satu tugas dalam rangka menyelesaikan studi kepaniteraan klinik Dokter Muda di
Bagian Ilmu Penyakit Penyakit Kulit Rumah Sakit Umum Haji Surabaya.

Surabaya, 12 Oktober 2022

Pembimbing,

dr. Rahimah, Sp.KK

 KATA PENGANTAR

Assalamualaikum Warahmatullahi Wabarakatuh

Puji syukur penulis panjatkan kepada Tuhan Yang Maha Esa, karena atas
berkat dan rahmat-Nya, penulis telah menyelesaikan penyusunan jurnal dengan
judul “The Most Current Algorithms for the Treatment and Prevention of
Hypertrophic Scars and Keloids: A 2020 Update of the Algorithms Published
10 Years Ago”.

Penyusunan jurnal ini bertujuan untuk memenuhi salah satu syarat kelulusan
pada program pendidikan profesi dokter pada Fakultas Kedokteran Universitas
Muhammadiyah Malang yang dilaksanakan di RSU Haji Surabaya. Ucapan terima
kasih kepada dr. Rahimah, Sp.KK selaku dokter pembimbing. Terima kasih atas
bimbingan, saran, petunjuk dan waktunya serta semua pihak terkait yang telah
membantu sehingga penulis dapat menyelesaikan penyusunan referat ini.

Penulis menyadari penyusunan jurnal ini masih jauh dari kesempurnaan.

Dengan kerendahan hati, penulis mohon maaf yang sebesar-besarnya dan
mengharapkan kritik dan saran yang membangun. Semoga penyusunan referat ini
dapat bermanfaat bagi semua pihak.

Wassalamualaikum Warahmatullahi Wabarakatuh

Surabaya, 12 Oktober 2022

Penulis
 TOPIK SPESIAL

Algoritma Terkini untuk Perawatan dan Pencegahan Bekas

Luka Hipertrofik dan
Keloid: Pembaruan Algoritma 2020Diterbitkan 10
Tahun Lalu
Rei Ogawa, MD, Ph.D.
Latar Belakang: Pada tahun 2010, Jurnal ini menerbitkan tinjauan komprehensif saya, yaitu literatur tentang
Tokyo, Jepang bekas luka hipertrofik dan keloid. Dalam artikel itu, saya mempresentasikan algoritma berbasis bukti untuk
pencegahan dan pengobatan bekas luka patologis refrakter ini.
Dalam dekade berikutnya, kemajuan substansial telah dibuat di lapangan, termasuk banyak uji acak terkendali
baru. Untuk mencerminkan hal ini, saya telah memperbarui ulasan saya.

Metode: Semua studi dievaluasi untuk kualitas metodologis. Karakteristik dasar pasien diekstraksi bersama
dengan intervensi dan keluaran mereka. Tinjauan sistematis, meta-analisis, dan tinjauan komprehensif
disertakan jika tersedia.

Hasil: Faktor risiko yang memicu skar hipertrofik dan pertumbuhan keloid meliputi faktor lokal (tekanan
pada luka/bekas luka), faktor sistemik (mis., hipertensi), faktor genetik (mis., polimorfismenukleotida
tunggal), dan faktor gaya hidup.
Pengobatan bekas luka hipertrofik tergantung pada keparahan kontraktur jaringan parut: jika parah,
pembedahan adalah pilihan pertama. Jika tidak, terapi konservatif diindikasikan. Perawatankeloid tergantung
pada apakah mereka kecil dan tunggal atau besar dan ganda.
Keloid kecil dan tunggal dapat diobati secara radikal dengan pembedahan dengan terapi adjuvant(misalnya
radioterapi) atau terapi konservatif multimodal. Untuk keloid besar dan multipel, operasipengurangan
volume dan jumlah adalah pilihan. Terlepas dari pengobatannya, pasien harus ditindaklanjuti dalam jangka
panjang. Terapi konservatif, termasuk lembaran gel, fiksasi pita, ageneksternal topikal dan injeksi, agen
oral, dan terapi rias, harus diberikan berdasarkan kasus per kasus.
Kesimpulan: Uji acak terkendali pada manajemen bekas luka patologis telah meningkat tajam selama
dekade terakhir. Meskipun penelitian-penelitian ini mengalami berbagaiketerbatasan, penelitian-penelitian
tersebut telah sangat meningkatkan manajemen bekas luka hipertrofik dan keloid. Uji coba berkualitas
tinggi di masa depan kemungkinan akan meningkatkan algoritme perawatan keloid dan bekas luka
hipertrofik saat ini lebih lanjut. (Plast. Reconstr.Surg. 149: 79e, 2022.)

bekas luka refrakter.1 Sejak itu, banyak uji acak

Pada 2010, jurnal ini menerbitkan tinjauan mengenai terkendali pada manajemen bekas luka patologis dan
bekas luka hipertrofi dan keloid serta algoritma pedoman2-5 telah diterbitkan. Untuk mencerminkan
pengobatan dan pencegahan untuk kemajuan yang cukup besar ini, saya
telah mengubah ulasan dan algoritme saya (Gbr. 1 dan 2).
Dari Departemen Bedah Plastik, Rekonstruksi dan Estetika, Nippon
Medical School.
Diterima untuk publikasi 15 Mei 2020; diterima 12 Mei 2021.
Pengungkapan: Tidak ada pengungkapan keuangan yangharus
dibuat.
Hak Cipta © 2021 Penulis. Diterbitkan oleh Wolters Kluwer Health, Inc.
atas nama American Society of Plastic Surgeons. Seluruh hakcipta. Ini
adalah artikel akses terbuka yang didistribusikan di bawahketentuan
Creative Commons Attribution Non Commercial-No Derivatives License Dengan membaca artikel ini, Anda berhak mengklaim
4.0 (CCBY-NC-ND), di mana diperbolehkan untuk mengunduh dan 1 (satu) jam Kredit Keselamatan Pasien Kategori 2.
membagikan karya asalkan dikutip dengan Anggota ASPS dapat mengklaim kredit ini dengan
benar. Karya tidak dapat diubah dengan cara apa pun atau
masuk ke Dasbor
digunakan secara komersial tanpa izin dari jurnal. PlasticSurgery.org, mengeklik “Submit CME”, dan mengisi form
DOI: 10.1097/PRS.0000000000008667

www.PRSJournal.com 79e
 Bedah Plastik dan Rekonstruksi • Januari 2022

Gambar 1. Algoritma pengobatan untuk bekas luka hipertrofik (HSs). Bekas luka pertama-tama harus dinilai untuk tingkat kontraktur bekas luka.Jika
kontrakturnya parah, operasi yang menghilangkan kontraktur adalah pilihan pertama. Jika kontrakturnya ringan, bekas luka dapat direseksi seluruhnya;
namun, terapi multimodal non-bedah juga merupakan pilihan.

80e
Machine Translated by Google

Volume 149, Nomor 1 • Bekas Luka Hipertrofik dan Keloid

Gambar 2. Algoritma pengobatan keloid. Metode pengobatan yang dipilih untuk keloid tergantung pada apakah keloid itu kecil tunggal
atau besar dan multipel. Keloid kecil dan tunggal dapat diobati secara radikal dengan pembedahan dengan terapi adjuvant (termasuk terapi
radiasi); sebagai alternatif, mereka dapat diobati dengan terapi multimodal non-bedah. Untuk keloid besar dan multipel, operasi
pengurangan volume dan jumlah adalah pilihan.

81e
 Bedah Plastik dan Rekonstruksi • Januari 2022
PERKEMBANGAN BARU PADA DECADE
LALU
Dekade terakhir terjadi pertumbuhan yang luar biasa dalam
pemahaman kita tentang bagaimana bekas luka hipertrofik dan
keloid berkembang. Akibatnya, bekas luka hipertrofik dan
keloid saat ini telah
diketahui disebabkan oleh peradangan kronis pada dermis
retikuler. Faktor risiko yang terkait dengan bekas
luka hipertrofik serta perkembangan dan peningkatan keloid
telah diidentifikasi, sehingga membantu optimalisasi dan
efektivitas pengobatan.
Beberapa kemajuan besar dalam mencegah dan mengobati
bekas luka hipertrofik dan keloid telah dibuat, yaitu sebagai
berikut. Pertama, plester deprodone propionate (steroid yang
lebih kuat) ditemukan dapat mencegah dan mengobati bekas
luka hipertrofik dan keloid dengan sangat efektif. Kedua,
metode bedah telah dioptimalkan untuk setiap daerah tubuh,
sehingga meningkatkan hasil kosmetik dan fungsional,
keamanan, dan tingkat kekambuhan. Ketiga, protokol terapi
radio pascaoperasi telah disesuaikan, membuatnya lebih aman
sekaligus tetap efektif. Algoritma sebelumnya telah sangat
ditingkatkan dengan dimasukkannya modalitas ini. Saya
mengantisipasi bahwa bukti berkualitas tinggi lebih lanjut
untuk modalitas ini, dan modalitas baru tambahan, akan
muncul dalam dekade berikutnya.
DIAGNOSIS BEKAS LUKA HIPERTROFIK
DAN KELOID
Diagnosis Banding
Bekas luka hipertrofik dan keloid adalah kelainan
fibroproliferatif pada lapisan dermis retikuler: lapisan ini
menunjukkan peradangan terus menerus, angiogenesis yang
berlebihan, dan akumulasi kolagen yang melimpah.
Dibandingkan dengan bekas luka hipertrofik klasik, keloid
klasik menyebar secara agresif,jarang sembuh secara
spontan, dan, pada tingkat
histologis, mengandung kolagen keloid, sedangkan bekas luka
hipertrofik hanya memiliki nodul. Namun, banyak bekas luka
memiliki gambaran klinis dan patologis dari keloid klasik dan
bekas luka hipertrofik. Ini menunjukkan bahwa bekas luka
hipertrofik klasik dan keloid adalah manifestasi kutub dari
kelainan kulit yang sama, di antaranya terdapat spektrum
intermediet.
Perbedaan klinis dan histologis antara bekas luka
hipertrofik klasik dan keloid mungkin mencerminkan
perbedaan dalam intensitas dan durasi peradangan dermis
retikuler. Perbedaan-perbedaan ini pada gilirannya
dapat mencerminkan keberadaan dan tingkat keparahan faktor
risiko lokal, sistemik, genetik, dan gaya hidup
82e
Perbedaan Diagnosis Internasional Bekas Luka
Hipertrofik dan Keloid
Keloid klasik sangat dipengaruhi oleh genetika.8–13Ini
sebagian menjelaskan perbedaan etnis dalam kerentanan
keloid: keloid umum terjadi di Afrika (5 hingga10 persen
terkena), lebih jarang di Asia (0,1 hingga 1 persen), dan jarang
di Orang Eropa/Amerika Utara (<0,1 persen).14
Perbedaan etnis ini berarti bahwa dokter di daerah tertentu
memiliki lebih banyak pengalaman dengan keloid daripada
yang lain. Kesan saya, diperoleh melalui menghadiri banyak
konferensi bekas luka internasional, bahwa ini dapat
mempengaruhi diagnosis dokter. Jadi, di negara-negara Barat,
sebagian besar bekas luka abnormal adalah bekas luka
hipertrofik klasik: akibatnya, dokter Barat sering mendiagnosis
bekas luka sebagai keloid jika mereka menunjukkan
penyebaran kecil. Namun, dokter Afrika melihat banyak pasien
dengan keloid klasik: akibatnya, mereka sering mendiagnosis
semua bekas
luka sebagai bekas luka hipertrofik kecuali jika mereka
tumbuh dengan cepat. Ini harus dipertimbangkan ketika
meninjau literatur internasional.
Diagnosis Banding Bekas Luka Hipertrofik dan Keloid
dari Penyakit dengan gambaran klinis yang mirip
Bekas luka hipertrofik dan diagnosis keloid sering
didasarkan pada gambaran klinis saja. Namun, tumor
ganas seperti dermatofibrosarcoma protuberans15-18dan giant-
cell fibroblastoma19
dapat salah didiagnosis secara klinis sebagai keloid. Selain
itu, analisis dari 378 bekas luka hipertrofik dan keloid
menunjukkan bahwa 1,06 persen adalah penyakit
lain.20 Jadi, biopsi diperlukan jika dicurigai keganasan.20-22
PENCEGAHAN POST OP LUKA
HIPERTROFIK DAN KELOID
Pasien dengan bekas luka hipertrofik dan riwayat keloid
berada pada risiko tinggi, seperti juga pasien dengan satu atau
lebih dari faktor risiko berikut (perhatiankhusus harus
dilakukan selama dan setelah operasi).
Faktor risikoLokal
Bekas luka hipertrofik dan keloid sering terjadi pada
tempat yang sering teregang oleh gerakan tubuh sehari-hari,
termasuk sendi utama, dada anterior, skapula, dan p erut
bagian bawah.23 Sebaliknya, bekas luka hipertrofikdan keloid
jarang terjadi pada kulit kepala dan tungkai bawah anterior. ,
di mana tegangan regangan rendah.23 Hal ini karena regangan
luka memperpanjang dan memperburuk
Volume 149, Nomor 1 • Bekas Luka Hipertrofik dan Keloid
peradangan, sehingga memicu bekas luka hipertrofik dan
pembentukan keloid
Untuk mencegah pembentukan bekas luka hipertrofik dan
pembentukan keloid setelah pembedahan pada daerah tubuh yang
rentan, harus digunakan teknik bedah yang membatasi ketegangan
dermal, yaitu, flap, Z-plasties, dan jahitan reduksi tarikan subkutan
dan fasia dalam. Selain itu, peregangan luka pascaoperasi harus
dibatasi oleh bahan fiksasi seperti pita kertas, lembaran gel, gel,
atau garmen dan garmen bebat kompresi. Semua didukung oleh
analisis meta/uji acak terkendali. Mengenaipita kertas, uji acak
terkendali26 menunjukkan bahwa fiksasi pita kertas mengurangi
risiko bekas luka hipertrofik setelah operasi caesar sebesar 13,6
kali lipat.
Mengenai lembaran gel, meta-analisis pada 20 percobaan27
menyimpulkan bahwa lembaran gel silikon dapat mencegah bekas
luka hipertrofik dan pembentukan keloid pada orang yang rentan
bekas luka dengan luka yang baru sembuh; namun, mereka
berkomentar bahwa kualitas uji coba buruk.27 Sebuah tinjauan
baru-baru ini pada 10 uji coba memiliki kesimpulan yang serupa.28
Mengenai gel, uji acak terkendali29 menunjukkan bahwa gel
silikon mengurangi pigmentasi bekas luka sternotomi, eritema,
kekerasan, tinggi, dan nyeri serta gatal. Hal ini dikonfirmasioleh
sebuah tinjauan.28 Mengenai terapi kompresi, meta-analisis
dari 12 percobaan menegaskan bahwa terapi kompresi 15sampai
25-mmHg mengurangi ketebalan luka bakar, eritema, dan
kekerasan.30
Semua pasien yang menjalani operasi pada areatubuh yang rentan
harus dimonitor secara ketat untuk mencari bekas luka hipertrofik
dan keloid selama 3 sampai 12 bulan.
Jika indurasi diamati, pita steroid dan plester harus dimulaidan
diganti dengan injeksi steroid jika indurasi terjadi.
Sistemik
Faktor sistemik termasuk hormon estrogen wanita31:sebuah
studi cross-sectional besar menunjukkan bahwa keloid dapat
mendominasi pada wanita.32 Selain itu, vasodilatasi yang
diinduksi estrogen dapat memperburuk luka dan peradangan
bekas luka: memang, bekas luka hipertrofik dan keloid
memburuk selama kehamilan33,34 dan membaik setelah
melahirkan. Faktor sistemik lainnya adalah hipertensi, yang
dapat memperburuk bekas luka
hipertrofik dan keloid.35 Selain itu, penyakit hipersitokinemia
(misalnya penyakit Castleman) dapat sangat memperburuk bekas
luka hipertrofik dan keloid.36,37 Oleh karena itu, pembedahan pada
pasien hamil, hipertensi, dan hipersitokinemia harus dilakukan
dilakukan dengan teknik bedah dan fiksasi luka yang dijelaskan di
atas, diikuti dengan pemantauan ketat.
Genetik
Seperti yang disebutkan, keloid seringkali sangatdipengaruhi
oleh faktor genetik, termasuk etnis14 dan
gen familial: beberapa kasus keluarga rentan keloid telah
dilaporkan.38,39 Selain itu, beberapa polimorfisme nukleotida
tunggal terkait dengan keloid40-42: empat
mempromosikan keloidogenesis40 dan satu terkait dengankeloid
parah.41
Beberapa penyakit genetik berhubungan dengan genesis
keloid, termasuk sindrom Rubinstein-Taybi43,44:sebuah studi
potong lintang44 melaporkan bahwa 24 persen dari pasien
tersebut memiliki keloid yang tumbuh secara spontan.
Eksostosis herediter ganda juga terkait dengan keloidogenesis
Faktor risiko ini tidak dapat dihindari. Dengan demikian,
pasien dengan riwayat keluarga dan penyakit genetik harus dirawat
dengan hati-hati selama dan setelah operasi.
Frekuensi yang relatif rendah dari polimorfisme nukleotida
tunggal terkait keloid berarti bahwa pengujiannya tidak praktis.
Gaya Hidup
Beberapa faktor gaya hidup dapat memperburukperadangan luka dan
bekas luka akibat pembedahan, termasuk aktivitas fisik peregangan luka
yang berat. Atlet dan pekerja kasar harus mengistirahatkan luka mereka.
Diet tertentu dan mandi air panas bisa memperburuk peradangan akibat
pembedahan46: pengalaman saya dengan ribuan pasien menunjukkan bahwa
mereka sering mengalami gatal dan nyeri setelah
mengonsumsi makanan panas dan pedas atau mandi air panas.
DETEKSI DINI DAN LINI PERTAMA
PENGOBATAN LUKA
HIPERTROFIK DAN KELOID
Bekas luka hipertrofik dan keloid harus dideteksi lebih awal
karena dapat memberikan respons yang baik terhadapterapi
konservatif. Seperti yang akan dibahas nanti, terapi konservatif
lini pertama untuk bekas luka hipertrofik dan keloid dalam
pedoman bahasa Jepang 20195 adalah aplikasi plester atau plester
steroid jangka panjang/terus menerus. Plester steroid (deprodone
propionate) yang kuat secara efektif memudarkan bekas luka
hipertrofik awal
dan keloid5,31,47,48 tetapi hanya tersedia di Jepang.47Namun demikian,
jika diterapkan sangat dini dan terus- menerus, pita pasang
fludroxycor yang lebih lemah pun dapat memudarkan bekas luka
hipertrofik dan keloid awal.5
PENGOBATAN BEKAS LUKA HIPERTROFI
Bekas luka hipertrofik terdeteksi beberapa minggu setelah
cedera (Gbr. 1). Membesar dari 3 sampai 6 bulan; jika faktor
risiko kecil, mereka kemudian mendatar dan mengecil secara
spontan. Proses ini dapat dipercepat dengan terapi konservatif
berikut, yang mengurangi volume bekas luka hipertrofik dan
menekan rasa sakit dan gatal.
Bekas luka hipertrofik jarang memerlukan pembedahan kecuali
jika terjadi kontraktur dan menyebabkan disfungsi sendi 49,50;
dalam hal ini, operasi rekontruktif direkomendasikan
83e
 Bedah Plastik dan Rekonstruksi • Januari 2022
Terapi Kompresi
Sebuah meta-analisis baru-baru ini (12 uji acak terkendali)
menunjukkan bahwa terapi kompresi 15 hingga25 mmHg
mengurangi ketebalan luka bakar dan hipertrofik,eritema, dan
kekerasannya.30
Terapi kompresi dapat meningkatkan penyembuhan luka
melalui vasokonstriksi lokal yang membatasi inflamasi akibatluka
bakar.
Lembar Gel
Lembaran gel lembut dan berperekat. Sebuah meta
27
analisis (20 percobaan) melaporkan bahwa dengan diberikan
lembaran gel terus menerus meningkatkan pematangan bekas luka
hipertrofi. Sebuah meta-analisis baru51 pada pertanyaan ini sedang
berlangsung: akan menarik untuk mempelajari temuan mereka.
Jenis bahan mungkin tidak penting: uji acak terkendali52
menunjukkan bahwa lembaran
gel matriks silikon dan hidrokoloid mengurangi dimensi bekas luka
hipertrofik dengan baik. Yang lebih penting mungkin adalah
pendidikan pasien: uji acak terkendali53 pada pasien luka bakar dan
bekas luka hipertrofik menunjukkan bahwa instruksi yang dibagikan
dalam selebaran dan kaset video meningkatkan efektivitas
pengobataan lembaran gel.
Analisis komputer menunjukkan bahwa lembaran gel dapat
mencegah pembentukan bekas luka hipertrofik dan mendorong
pematangan bekas luka hipertrofik dengan membatasi luka dan
ketegangan bekas luka.54
Pijat bekas luka
Uji acak terkendali pada rehabilitasi luka bakar
memiliki hasil yang bertentangan, dan meta- analisis dari 10 uji acak
terkendali menyimpulkan bahwa bukti pendukungnya lemah.55 Saya
menyarankan agar berhati-hati mengenai terapi pijat. Penyembuhan
luka berhubungan dengan peradangan awal yang biasanya perlahan-
lahan berkurang. Pada titik ini, pijatan dapat meningkatkan maturasi
bekas luka. Namun, pada pasien yang memiliki faktorr isiko,
peradangan justru meningkat alih-alih mereda. Karena pijatan dapat
meregangkan bekas luka, hal itu dapat menyebabkan
dan memperburuk bekas luka hipertrofik dan keloid. Dengan
demikian, pijat bekas luka pada pasien berisiko tinggi harus
dihindari.
Injeksi Kortikosteroid
Meta-analisis terbaru dari empat hingga 14 percobaan, 28,56,57 meta-
analisis jaringan dari 23 percobaan, 58 tinjauan sistematis dari 11 studi,
59
tinjauan komprehensif, 60,61
dan beberapa uji acak terkendali baru62,63
menunjukkan bahwa kortikosteroid intralesi dapat menginduksi
84e
Regresi 50 hingga 100 persen dari bekas luka hipertrofik dan keloid.
Sebuah panel ahli internasional merekomendasikan triamcinolone
acetonide pada dosis 2,5 sampai 40 mg/area.64Suntikan mungkin
bekerja dengan mengurangi produksi sitokin inflamasi.65 Namun,
kerugiannya termasuk nyeri akibat injeksi, efek samping sistemik
(misalnya, disfungsi menstruasi, supresi adrenokortikal ,66 dan katarak
dan glaukoma), dan efek samping lokal (misalnya, penipisan dan
atrofi kulit, jerawat steroid, dilatasi pembuluh darah kapiler, dan
hipopigmentasi).
Pita dan Plaster Kortikosteroid
Pita dan plester kortikosteroid adalah alternatif tanpa rasa sakit
dari suntikan kortikosteroid. Ketika 60 pasien bekas luka hipertrofik
dan keloid diobati dengan pita fludroxycortide (steroid lemah), 20
persen dari 30 orang dewasa dan 80 persen dari 30anak-anak
menunjukkan manfaat pada bekas luka dan eritema dan pruritus
setelah 12 bulan. Respon pediatrik yang kuat mungkin mencerminkan
kulit yang lebih tipis.
Ketika 24 orang dewasa yang tidak responsif dialihkan ke plester
deprodon propionat (steroid yang lebih kuat), 70,8
persen menunjukkan peningkatan fitur bekas luka setelah 6
bulan.47,67 Studi observasional lain dan pengalaman klinis
yang baik dengan pita dan plester steroid telah menjadikannya andalan
protokol manajemen bekas luka.31
Akibatnya, pedoman Jepang5 baru-baru ini merekomendasikanbahwa
pita dan plester kortikosteroid harus menjadi lini pertama bekas luka
hipertrofik dan terapi keloid. Gambar 3 menggambarkan bekas luka
hipertrofik yang dirawat dengan plester deprodon propionat. Pita dan
plester harus digunakan terus menerus sedini mungkin5 selama
minimal 3 bulan. Jika tidak berhasil, itu harus diganti dengan
perawatan yang lebih kuat.
Salep dan Krim Kortikosteroid
Uji acak terkendali pada kortikosteroid
salep dan krim hanya sedikit, tetapi studi seri kasus68 menunjukkan
bahwa injeksi triamsinolon asetonide pada bekas luka hipertrofik dan
tempat eksisi keloid dikombinasikan dengan aplikasi salep
kortikosteroid 6 bulan dua kali sehari menghasilkan tingkat keloid dan
bekas luka hipertrofik kekambuhan sebesar 14,3 persen dan 16,7
persen, masing-masing.
Hasil ini dan pengalaman klinis yang baik baru-baru ini
menyebabkan beberapa masyarakat Jepang tentang luka bakardan
bekas luka 5.69 merekomendasikan salep kortikosteroid
dan bahan krim untuk luka bakar dermal superfisial70 dan
pencegahan dan pengobatan bekas luka hipertrofi.5
Namun, karena salep dan krim kortikosteroid harus dioleskan
empat kali sehari untuk
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Volume 149, Nomor 1 • Bekas Luka Hipertrofik dan Keloid

Gbr. 3. Pengobatan bekas luka hipertrofik dengan plester deprodon propionat. (Kiri)
Tampilan pra-perawatan. (Kanan) Tiga tahun setelah menggunakan plester deprodon propionat. Seorangwanita
50 tahun memiliki beberapa bekas luka hipertrofik akibat persalinan sesar. Dia diberi plester deprodon
propionat dan diminta untuk menerapkannya 24 jam per hari sampai pemberitahuan selanjutnya. Dia
diinstruksikan untuk melepasnya saat mandi dan kemudian merekatkannya kembali. Ketika plester kehilangan
kelengketannya, maka diganti dengan plester baru. Setelah 6 bulan,bekas luka menjadi lunak. Setelah 3 tahun,
bekas luka menjadi benar-benar rata dan warnanya mendekati warna kulit di sekitarnya.

menghasilkan e fek sep erti pad a peng aplika sian pita steroid dan
plester,67 diperlukan edukasi pemakaian kepada pasien.
Laser
Dua ulasan70,71 dan sebuah meta-analisis72 menunjukkan bahwa
laser pulsed-dye secara signifikan mengurangi eritema dan pruritus
hipertrofik bekas luka73-77 karena panjang gelombangnya(585 hingga 595
nm) mencapai daerah angiogenik bekas luka hipertrofi: panasnya
mengurangi aliran darah bekas luka hipertrofik dan juga mengurangi
peradangan. Neodymium:yttrium- aluminium garnet laser (532/1064
nm) memiliki efek yang sama, seperti yang ditunjukkan oleh sebuah
review,71 sebuah meta-analisis,72 studi kasus-seri,48,78 dan uji acak
terkendali79
Uji acak terkendali menunjukkan bahwa laser fraksional karbon dioksida
nonablatif/ablatif tidak memiliki efek
menguntungkan.80,81 Terapi laser ablatif penuh tidak direkomendasikan
untuk bekas luka patologis karena angka kekambuhan yang tinggi.82,83
Kontraktur bekas luka seperti itu harus dihilangkan melalui
pembedahan. Hal tersebut juga mempercepat pematangan jaringan
parut hipertrofik di sekitarnya. Bekas luka hipertrofik kecil dan linier
dapat diobati dengan reseksi lengkap.Semua operasi bekas luka
hipertrofi harus melibatkan teknik pembebasan tegangan,5
termasuk Z-plasty, 84 W-plasty, 85 dan flap lokal.86–89
Gambar 4 menunjukkan kontraktur bekas luka hipertrofik yang
dirawat dengan Z-plasty.
Satu uji acak terkendali menunjukkan bahwa jahitan yang
dapat diserap / tidak dapat diserap tidak berbeda
dalam risikonya menjadi bekas luka hipertrofik,90 tetapi lainnya91
menunjukkan bahwa jahitan yang tidak dapat diserap mengurangi
frekuensi bekas luka hipertrofik. Metode penjahitan mungkin
lebih penting daripada bahannya: pengalaman klinis 92 menunjukkan
bahwa jahitan reduksi-tegangan mengurangi bekas lukahipertrofi dan
jaringan parut keloid dan kekambuhan karena mengurangi ketegangan
dermal.6,92,93

Operasi Terapi Bekas Luka Hipertrofik Lainnya

Ketika bekas luka hipertrofik terjadi di dekat atau pada Terapi lain telah diusulkan untuk bekas luka hipertrofik.
sendi, kontraksinya dapat menyebabkan disfungsi sendi Beberapa mungkin juga cocok untuk

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Gambar 4. Pengobatan kontraktur bekas luka traumatis antara jari dan telapak tangan dengan menggunakan Z-plasty. (Kiri) Pandangan sebelum operasi. (Tengah)Segera setelah
operasi. (Kanan) Delapan belas bulan setelah operasi. Seorang anak laki-laki berusia 10 tahun mengalami trauma pada jari manis dan telapak tangan kirinya. Sebuah bekas luka
hipertrofik dengan kontraktur bekas luka ringan berkembang. Karena lebar bekas lukanya sempit, bekas luka itu bisa dihilangkanseluruhnya. Setelah itu, Z-plasties ditempatkan di
atas sendi dan lipatan utama di telapak tangan. Setelah operasi, peradangan berkurang dengan lancar. Bekas luka menjadi matang selama tahun berikutnya.

keloid. Namun, evidence basednya masih rendah. Salah satunya
adalah transplantasi jaringan adiposa dengan menggunakan teknik
lipotransfer dan lipoinjection. Ulasan baru-baru ini94 mencatat
bahwa sel punca yang diturunkan dari adiposa dapat
mengeluarkan faktor trofik yang mengubah ekspresi mediator
fibrotik dan remodeling. Bukti terlalu terbatas untuk membenarkan
perubahan dalam praktek klinis. Sebuah tinjauan baru-baru ini95
dari studi seri kasus menunjukkan bahwa terapi cryo aman dan
mengurangi bekas luka yang dengan baik, meskipun dengan
beberapa efek samping (depigmentasi, kekambuhan, nyeri).
Meta-analisis dan ulasan terbaru28 menunjukkan bahwa injeksi
5-fluorouracil efektif sebagai terapi tunggal tetapi dalam
mengurangi bekas luka hipertrofik dan keloid serta eritema lebih
baik bila dikombinasikan dengan injeksi triamcinolone acetonide.
Injeksi toksin botulinum tipe A (Botox; Allergan, Inc., Dublin,
Irlandia) intralesi dapat memperbaiki dan mencegah bekas luka
hipertrofik dan keloid dengan menekan ketegangan jaringan parut
dan aktivitas fibroblas.96 Uji coba terkontrol acak terbaru 97,98
menunjukkan bahwa injeksi Botox pascaoperasi mencegah
perkembangan jaringan parut hipertrofik. Sebuah meta- analisis
dari 14 studi57
menunjukkan bahwa, dibandingkan dengan plasebo, injeksi Botox
secara signifikan memperbaiki bekas luka hipertrofik dan
penampilan dan lebar keloid.
Sebuah meta-analisis99 dari lima percobaan menunjukkan
bahwa suntikan bleomycin mengurangi bekas luka hipertrofik
dan keloid lebih efektif daripada suntikan triamcinolone
acetonide dan/atau 5-fluorouracil. Ulasan 14-studi tentang gel
ekstrak bawang merah topikal
(obat antiinflamasi nonsteroid) melaporkan bahwa ada 11 yang
memberikan efek menguntungkan pada bekas luka hipertrofikdan
keloid.100
Tranilast oral (obat anti alergi) memperbaiki penyakit
inflamasi dengan sedikit efek samping. Telah lama digunakan
di Jepang untuk mengobati bekas luka hipertrofik dan keloid.5,101-103
Uji coba terkontrol secara acak menunjukkan
bahwa tranilast memperbaiki bekas luka hipertrofik dan
keloid serta mengurangi kemerahan bekas luka hipertrofik
pascaoperasi yang baru.104
PENGOBATAN KELOID
Perawatan keloid dimulai dengan menentukan jumlah dan
ukuran keloid (Gbr. 2): ini menunjukkan kekuatan faktor risiko
keloid pasien.1
Jika keloid kecil dan tunggal ketegangan kulit
mungkin menjadi factor risikonya. Namun, jika ada keloid
multipel atau besar, faktor genetik dan sistemik harus
dipertimbangkan, terutama jika keloid berada di daerah tubuh
yang berbeda. Keloid tunggal atau kecil dapat diobati denganterapi
konservatif. Keloid yang tebal, besar, multipel harus
dinilai untuk pembedahan ditambah terapi adjuvant karena
responnya buruk terhadap obat topikal. Dokter harus hati-hati
mendiskusikan pilihan terapi dengan pasien dan menetapkantujuan
pengobatan.
Peradangan keloid umumnya memburuk dari waktu ke waktu.
Karena pijat bekas luka, laser ablatif, dan monoterapi bedah
memicu peradangan dan memperburuk keloid, maka hal tersebut
harus dihindari.

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Lembar Gel
Meta-analisis O'Brien dan Jones27 menunjukkan
bahwa lembaran gel silikon saja dapatmengurangi
ketebalan keloid dan eritema.
Injeksi Kortikosteroid
Banyak penelitian menunjukkan bahwa suntikan
kortikosteroid intralesi menginduksi regresi keloid Namun,
menggabungkan injeksi kortikosteroid dengan 5-fluorouracil,
pulsed-dye laster, atau cryother apy memiliki
hasil yang lebih baik daripada injeksi kortikosteroid saja.70
memberikan efek yang baik pada keloid105 dan mengurangi
kekambuhan hingga 14,3 persen bila diterapkan pascaoperasi.68
Namun, memiliki kekurangan, yaitu krim mudah terhapus.
Krioterapi
Ulasan terbaru 56.106 menunjukkan bahwa cryotherapy
(monoterapi atau dengan injeksi triamcinolone acetonide) efektif
mengurangi ukuran keloid.
Metode cryotherapy termasuk kontak langsung,107
semprotan, 107-109 dan jarum intralesi. 109.110
Namun, evidence base-nya terbatas pada studi seri kasus.106

Pita Kortikosteroid dan Plester

Seperti halnya bekas luka hipertrofik, pitadan plester
kortikosteroid adalah terapi keloid lini pertama dalam
5
pedoman Jepang 2019. Aplikasi jangka panjangdan terus
menerus melembutkan dan kemudian
47, e6fe7efektif dan mengurangi kekambuhan pasca operasi.58-60
meratakan massa. Ini juga mengurangi pruritus dan eritema.
Gambar 5 menunjukkan keloid yang dirawat dengan plester steroid.
Namun, berdasarkan pengalaman saya, keloid yang berkembang
pesat tidak dapat dihentikan hanya dengan pita steroid dan
plester, dan terapi ini harus dikombinasikandengan suntikan
triamsinolon asetonid atau metode lain.
Keuntungan terbesar dari pita steroid dan plester adalah tidak
menimbulkan rasa sakit dan sedikit efek samping. Plester steroid
kuat (deprodone propionate), yang hanya tersedia di Jepang, lebih
efektif daripada pita fludroxycortide.Ini harus tersedia di seluruh
dunia untuk mengobati bekas luka patologis.
Salep dan Krim Kortikosteroid
Studi seri kasus menunjukkan bahwa beberapa
aplikasi krim kortikosteroid harian memiliki hasil yang sangat baik
Agen Antitumor dan Imunosupresif
Meta-analisis terbaru, ulasan, dan uji acak terkendali 58-60
menunjukkan bahwa injeksi 5-
fluorourasil intra esional adalah monoterapi keloid yang
Mereka juga menunjukkan bahwa 5-fluorourasil secara
efektif mengurangi elevasi keloid dan eritema ketika
dikombinasikan dengan triamcinolone acetonide
injections.58-60 Sebuah meta-analisis99 melaporkan bahwa injeksi
bleomycin meningkatkan keloid lebih efektifdaripada
triamcinolone acetonide dan/atau injeksi 5-flu orouracil.
Operasi
Keloid kecil dapat direseksi secara radikal. Keloid besar dan
multipel mungkin cocok untuk eksisi parsial dan mengurangi
ketebalan area atau jumlah keloid. Reseksi radikal harus selalu
dikombinasikan dengan
terapi adjuvan (misalnya terapi radiasi) karena pembedahansaja
menghasilkan kekambuhan 45 sampai 100 persen.

Gambar 5. Pengobatan keloid dengan plester deprodon propionat. (Kiri) Tampilan sebelum perawatan. (Kanan)Tiga tahun
setelah memulai plester deprodon propionat. Seorang wanita 40 tahun terdapat keloid di bahu kirinya sebagai akibat dari
folikulitis. Dia dirawat dengan plester deprodon propionat selama 24 jam/hari. Pasien mengganti plaster setiap hari dan
terus menggunakannya selama 3 tahun. Enam bulan setelah memulai terapi ini, bekas luka menjadi lunak. Dalam 3 tahun
berikutnya, bekas luka menjadi hampir rata.

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64
Pembedahan harus melibatkan teknik bebas tegangan, yaitu, jahitan
reduksi tarik-tarik subkutan dan fasialdalam,31,92,93 Z-plasties,111-113
dan transfer flap lokal.114
Jahitan reduksi tarik mengangkat tepi luka dengan mulus dan
membebaskan tegangan dermal.31,92,93
Pengalaman klinis kami 112 menunjukkan bahwa mereka membantu
mengurangi tingkat kekambuhan.
Mengenai Z-plasty, studi kasus seri keloid dinding dada
depan111 dan keloid lengan atas113
menunjukkan bahwa eksisi, penjahitan pengurangan ketegangan, Z-plasty,
dan radioterapi menyebabkan tingkat kekambuhan masing- masing 10,6
dan 5,3 persen, pada 24 bulan.
Semua kekambuhan yang mudah dipadamkan dengan plester steroid
dan suntikan. Gambar 6 menggambarkan keloid jerawat dinding dada
yang dirawat dengan Z-plasty.
Pilihan flap tergantung pada daerah yang terkena.
Sebuah studi seri kasus menunjukkan bahwa tidak satu pun dari 10 besar
keloid dinding dada anterior kambuh setelah reseksi parsial atautotal
dan rekonstruksi flap
Flap lebih unggul dari cangkok kulit: yang terakhir tidak meluas pasca
operasi dan dapat menghasilkan bekas luka patologis yang mengelilingi
cangkok kulit. Saat menggunakan flap, tempat donor harus menjalani
terapi multimodal untuk mencegah keloid baru.114Gambar 7 menunjukkan
keloid skapula yang dirawat dengan flap seperti kapak.
Daerah khusus adalah telinga. Eksisi baji direkomendasikan untuk
keloid daun telinga.5 Sebuah studi kasus 112.115 keloid daun
telinga menunjukkan bahwa eksisi baji dan radioterapi menghasilkan4,7
persen
kekambuhan pada 18 bulan. Eksisi inti direkomendasikan
diperbaiki untuk keloid kartilago auricular.5 Sebuah studi kasus116
menunjukkan bahwa eksisi inti lobus telinga dan keloid auricular
ditambah suntikan steroid menghasilkan tingkat kekambuhan 9,5 persen
pada 22 bulan.
Demikian pula, studi seri kasus lain117 menunjukkan bahwa

Gambar 6. Pengobatan keloid akne dinding dada dengan menggunakan Z-plasty dan radioterapi pasca operasi.(Atas, kiri)
Pandangan sebelum operasi. (Atas, kanan) Segera setelah eksisi keloid total. (Di bawah, kiri)
Segera setelah operasi. (Bawah, kanan) Dua tahun setelah operasi. Seorang pria 60 tahun mengembangkankeloid dinding
dada sebagai akibat dari jerawat. Itu dipotong sepenuhnya dan luka ditutup dengan Z-plasties untuk melepaskan
ketegangan pada bekas luka. Pembedahan diikuti dengan terapi radio berkas elektron (18
Gy, dalam tiga fraksi, selama 3 hari). Peradangan turun dengan lancar dan bekas luka menjadi matang selama18 bulan.

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Volume 149, Nomor 1 • Bekas Luka Hipertrofik dan Keloid

Gambar 7. Pengobatan keloid folikulitis skapula dengan menggunakan kapak flap dan radioterapi
pascaoperasi. (Atas, kiri) Pandangan sebelum operasi. (Atas, kanan) Segera setelah eksisi keloid total dan
desain flap. (Bawah, kiri) Segera setelah operasi. (Bawah, kanan) Dua tahun setelah operasi. Seorang pria 70
tahun memiliki keloid di skapula. Mereka dipotong sepenuhnya dan direkonstruksi dengan menggunakan flap
seperti kapak. Setelah operasi, bekas luka diradiasi (18 Gy,
dalam tiga fraksi, selama 3 hari). Inflamasi menurun dan bekas luka menjadi matur selama 18 bulan.

total dan eksisi inti menyebabkan kekambuhan 8,1 dan 0
persen, masing-masing. Gambar 8 menggambarkan keloid
aurikularis inti yang dirawat dengan eksisi.
Terapi radiasi
Radioterapi secara efektif mengobati atau mencegah keloid
dengan menekan angiogenesis dan juga peradangan.118
Monoterapi radiasi harus disediakan untuk pasien yang lebih tua
atau mereka yang memiliki keloid besar karena memerlukan dosis
radiasi yang besar. Hal tersebut akan segera mengurangi rasa sakit
dan gatal dan perlahan-lahan memperbaiki warna dan ketebalan
bekas luka di tahun berikutnya.31
Radioterapi sangat efektif sebagai adjuvan bedah.
Meta-analisis terbaru dari 72 studi
menunjukkan bahwa operasi plus radioterapi dikaitkan dengan
lebih sedikit kekambuhan (22 persen) daripada monoterapi
radiasi (37 persen). Khususnya, tingkat operasiplus radioterapi ini
lebih tinggi daripada tingkat di pusat kami (<10 persen).112 Ini
mungkin mencerminkan fakta bahwa studi yang diperiksa meta-
analisis diterbitkan dari tahun 1957 hingga 2014.112
Penyempurnaan dalam teknik operasi, radioterapi, dan perawatan
pasca operasi mungkin
semuanya berkontribusi pada tingkat kekambuhan yang rendah.
Sinar-X superfisial atau orthovoltage (foton) pernah
digunakan,120.121 tetapi banyak institusi sekarang

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Gambar 8. Pengobatan keloid auricular dengan menggunakan metode eksisi inti dan radioterapi pasca operasi. (Kiri) Pandangan sebelum
operasi. (Tengah) Flap dibuat pada keloid setelah core dilepas. (Kanan) Dua tahun setelah operasi. Seorang wanita 20 tahun mengalami
keloid aurikularis. Sebuah flap dirancang di sisi anterior keloid dan intinya telah dihapus. Flap dijahit menggunakan jahitan polipropilen 6-0.
Setelah operasi, situs itu diiradiasi (15 Gy, dalam dua fraksi, selama 2 hari).Peradangan turun dengan lancar dan bekas luka menjadi matang
selama 18 bulan.

lebih memilih instrumen berkas elektron (-ray) karena efek samping
organ internal yang lebih sedikit.122–124 Brachytherapylaju dosis tinggi
(terutama sinar-ÿ) semakin banyak
digunakan,125.126 tetapi keamanannya untuk organ dalam harus
dipelajari lebih lanjut.
Dosis maksimum biologis efektif untuk keloid adalah 30 Gy.127-129
Dosis melebihi ini tidak memiliki keuntungan dalam kemanjuran dan
hanya meningkatkan risiko karsinogenesis ary kedua. Mengingat bahwa
situs tubuh bervariasi dalam kerentanan kekambuhan, dosis efektif
biologis 30-Gy tidak selalu diperlukan.Fasilitas kami memanfaatkan ini
untuk lebih mengurangi risiko cinogenesis mobil sekunder: kami
menerapkan iradiasi pasca operasi spesifik-situs tubuh untuk keloid,
yaitu, 18 Gy dalam tiga fraksi selama 3 hari (dosis efektif secara
biologis, sekitar 30 Gy) ke situs dengan kekambuhan tinggi, 8 Gy
dalam satu fraksi selama 1 hari ke daun telinga, dan 15 Gy dalam dua
fraksi selama 2 hari ke bagian tubuh lainnya.112
TINDAK LANJUT JANGKA PANJANGPASCA
PENGOBATAN DARI LUKA HIPERTROFIK
DAN KELOID
Bekas luka hipertrofik yang telah diobati dan pasien dengan keloid
harus diedukasi tentang manajement bekas luka dan tindak lanjut
jangka panjang. Tindak lanjut yang ketat memungkinkan deteksi dini
dan pengobatan kekambuhan yang masih kecil dapat merespon dengan
baik terhadap pita steroid, plester, atau injeksi. Dengan demikian,pasien
harus ditindaklanjuti selama lebih dari 18 sampai 24 bulan.
Tindak lanjut dapat berhenti ketika bekas luka rata dan lembut.
Pasien dengan bekas luka hipertrofik dan keloid sering
mengalamistres psikologis yang dapat memperburuk bekas luka
mereka. Mereka dapat memanfaatkan terapi rias atau kamuflase136–139
karena mereka meningkatkan penampilan kosmetik dan mendorong
perubahan fisiologis yang bermanfaat.

Lebih dari 70 tahun, hanya ada sedikit laporan kasus KESIMPULAN

karsinogenesis maligna setelah radioterapi keloid. 129–134 Sebagian
besar, tidak jelas apakah ini adalah kasus karsinogenesis sekunder
yang sebenarnya. Selain itu, survei135dari ahli onkologi radiasi di
seluruh dunia menunjukkan bahwa lebih dari 90 persen menganggap
keloid sebagai indikasi radioterapi yang dapat diterima. Jadi, sebelum
mengecualikan kemungkinan radioterapi keloid, ahli bedah harus
mendiskusikanmasalah ini dengan ahli onkologi radiasi.129
Dalam dekade terakhir, banyak penelitian berkualitas tinggitelah
dilakukan, dan level evidence based untuk banyak regimen
pengobatan atau pencegahan telah diperkuat. Seperti yang
tercermin dalam ulangan ulasan saya di sini, perubahan
ini telah mengarah pada strategi manajemen bekas luka patologisyang
sekarang secara efektif dan aman mencegah, menghilangkan, atau
memperbaiki bekas luka.
Namun, mengingat perbedaan etnis dalam kecenderungan bekas
luka patologis, algoritma pencegahan dan pengobatanharus
dioptimalkan

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Volume 149, Nomor 1 • Bekas Luka Hipertrofik dan Keloid
untuk setiap ras manusia melalui internasional
kolaborasi.
Rei Ogawa, MD, Ph.D.
Departemen Bedah Plastik, Rekonstruksi,
dan Estetika
Sekolah Kedokteran Nippon1-
1-5 Sendagi Bunkyo-ku
Tokyo 113-8603, Jepang
r.ogawa@nms.ac.jp
REFERENSI
1. Ogawa R. Algoritma terbaru untuk pengobatan dan pencegahan bekas luka
hipertrofik dan keloid. Plast Reconstr Surg. 2010;125:557–568.
2. Emas MH, Berman B, Clementoni MT, Gauglitz GG, Nahai F, Murcia
C. Rekomendasi klinis internasional yang diperbarui pada
manajemen bekas luka: Bagian 1. Mengevaluasi bukti.
Bedah Dermatol. 2014;40:817–824.
15.
3. Monstrey S, Middelkoop E, Vranckx JJ, dkk. Pedoman praktis
manajemen bekas luka yang diperbarui : Tindakan non-invasif dan
invasif. J Plast Reconstr Aesthet Surg. 2014;67:
1017–1025.
4. Seegenschmiedt MH, Micke O, Niewald M, dkk.; Kelompok Koperasi
Jerman untuk Radioterapi Penyakit Jinak (GCG-BD). Pedoman DEGRO
untuk radioterapi gangguan non-maligna: Bagian III. Gangguan
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107. Har-Shai Y, Amar M, Sabo E. Krioterapi intralesi untuk meningkatkan involusibekas
luka hipertrofik dan keloid.
Plast Reconstr Surg. 2003;111:1841–1852.
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baru yang didukung oleh studi eksperimental [koreksi yang diterbitkan muncul
di Regen Perbaikan Luka. 2007;15:163]. RegenPerbaikan Luka . 2006;14:18–
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operasi untuk keloid dinding dada anterior : Analisis terhadap 141 pasien. Plast
Reconstr Surg Glob Open 2019;7:e2177.
112. Ogawa R, Tosa M, Dohi T, Akaishi S, Kuribayashi S. Eksisi bedah dan
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Reconstr Surg Glob Open 2019;7:e2496.
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Plast Reconstr Surg Glob Open 2016;4:e1049.
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telinga: Analisis 174 lesi pada 145 pasien. Plast Reconstr Surg. 2013;132:818e–
825e.
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Sebuah studi percontohan kemanjuran keloidektomi dengan flap fillet intidan
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Bedah Dermatol. 2013;39:1514–1519.
117. Ogawa R, Akaishi S, Dohi T, Kuribayashi S, Miyashita T, Hyakusoku H.
Analisis perawatan bedah 63 keloid pada bagian tulang rawan daun telinga:
Efektivitas metode eksisi inti. Plast Reconstr Surg. 2015;135:
868–875.
118. Ogawa R, Akaishi S. Disfungsi endotel mungkin memainkan peran kuncidalam
patogenesis keloid dan bekas luka hipertrofik: Keloid dan bekas luka
hipertrofik mungkin merupakan gangguan vaskular. Hipotesis Med
2016;96:51–60.
119. Mankowski P, Kanevsky J, Tomlinson J, Dyachenko A, Luc M.
Mengoptimalkan radioterapi untuk keloid: Sebuah tinjauan sistematismeta-
analisis membandingkan tingkat kekambuhan antara modalitas
radiasi yang berbeda. Ann Plast Surg. 2017;78:
403–411.
120. Norris JE. Terapi sinar-x superfisial dalam manajemen keloid: Sebuah studi
retrospektif dari 24 kasus dan tinjauan literatur. Plast Reconstr Surg.
1995;95:1051–1055.
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sinar-X pascaoperasi. Dermatologi
1983;167:90–93.
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122. Akita S, Akino K, Yakabe A, dkk. Gabungan eksisi bedah dan terapi radiasiuntuk
pengobatan keloid. J Craniofac Surg. 2007;18:1164–1169.
123. Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T.
Terapi penyinaran berkas elektron pasca operasi untuk keloid dan bekas luka
hipertrofik: Studi retrospektif terhadap 147 kasus yang diikuti selama lebih dari 18
bulan. Plast Reconstr Surg.
2003;111:547–553; diskusi 554-555.
124. Ogawa R, Miyashita T, Hyakusoku H, Akaishi S, Kuribayashi S, Tateno A.
Protokol radiasi pasca operasi untuk keloid dan bekas luka hipertrofik: Analisis
statistik dari 370 situs yang diikuti selama lebih dari 18 bulan. Ann Plast Surg.
2007;59:688–691.
125. Kuribayashi S, Miyashita T, Ozawa Y, dkk. Iradiasi pasca-keloidektomi
menggunakan brakiterapi superfisial dosis tinggi. J Radiat Res.
2011;52:365–368.
126. Goutos I, Ogawa R. Brachytherapy dalam manajemen ajuvan bekas lukakeloid:
Tinjauan literatur. Luka Bakar Sembuhkan. 2017;3:2059513117735483.
127. Guix B, Henríquez I, Andrés A, Finestres F, Tello JI, Martínez A. Pengobatankeloid
dengan brachytherapy dosis tinggi: Sebuah studi tujuh tahun. Int J Radiat Oncol
Biol Phys. 2001;50:167-172.
128. Jones K, CD Lebih Lengkap, Luh JY, dkk. Laporan kasus dan ringkasan literatur:
Keloid perineum raksasa yang diobati dengan radioterapi pasca-eksisi. Dermatol
BMC. 2006;6:7.
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keloid dapat diterima? Risiko karsinogenesis akibat radiasi . PlastReconstr
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Reconstr Surg (1946) 1953;12:86–89.
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135. Leer JW, van Houtte P, Davelaar J. Indikasi dan jadwal pengobatan untukiradiasi
penyakit jinak: Sebuah survei.
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Operasi Plast Wajah. 2012;28:536–540.
 SPECIAL TOPIC
The Most Current Algorithms for the Treatment
and Prevention of Hypertrophic Scars and
Keloids: A 2020 Update of the Algorithms
Published 10 Years Ago
Rei Ogawa, M.D., Ph.D.

Background: In 2010, this Journal published my comprehensive review of the litera-

Tokyo, Japan ture on hypertrophic scars and keloids. In that article, I presented evidence-based
algorithms for the prevention and treatment of these refractory pathologic scars.
In the ensuing decade, substantial progress has been made in the field, including
many new randomized controlled trials. To reflect this, I have updated my review.
Methods: All studies were evaluated for methodologic quality. Baseline char-
acteristics of patients were extracted along with the interventions and their
outcomes. Systematic reviews, meta-analyses, and comprehensive reviews were
included if available.
Results: Risk factors that promote hypertrophic scar and keloid growth include
local factors (tension on the wound/scar), systemic factors (e.g., hypertension),
genetic factors (e.g., single-nucleotide polymorphisms), and lifestyle factors.
Treatment of hypertrophic scars depends on scar contracture severity: if severe,
surgery is the first choice. If not, conservative therapies are indicated. Keloid
treatment depends on whether they are small and single or large and multiple.
Small and single keloids can be treated radically by surgery with adjuvant therapy
(e.g., radiotherapy) or multimodal conservative therapy. For large and multiple
keloids, volume- and number-reducing surgery is a choice. Regardless of the
treatment(s), patients should be followed up over the long term. Conservative
therapies, including gel sheets, tape fixation, topical and injected external agents,
oral agents, and makeup therapy, should be administered on a case-by-case basis.
Conclusions: Randomized controlled trials on pathologic scar management
have increased markedly over the past decade. Although these studies suffer
from various limitations, they have greatly improved hypertrophic scar and
keloid management. Future high-quality trials are likely to improve the current
hypertrophic scar and keloid treatment algorithms further.  (Plast. Reconstr.
Surg. 149: 79e, 2022.)

I
n 2010, this Journal published my review on
hypertrophic scars and keloids and the treat-
ment and prevention algorithms for these
From the Department of Plastic, Reconstructive and Aesthetic
Surgery, Nippon Medical School.
Received for publication May 15, 2020; accepted May 12,
2021.
Copyright © 2021 The Authors. Published by Wolters Kluwer
Health, Inc. on behalf of the American Society of Plastic
Surgeons. All rights reserved. This is an open-access article dis-
tributed under the terms of the Creative Commons Attribution-
Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND),
where it is permissible to download and share the work provided
it is properly cited. The work cannot be changed in any way or
used commercially without permission from the journal.
DOI: 10.1097/PRS.0000000000008667
refractory scars.1 Since then, many randomized
controlled trials on pathologic scar management
and guidelines2–5 have been published. To reflect
these considerable advancements, I have reprised
my review and the algorithms (Figs. 1 and 2).
Disclosure: There are no financial disclosures to be
made.
By reading this article, you are entitled to claim
one (1) hour of Category 2 Patient Safety
Credit. ASPS members can claim this credit by
logging in to PlasticSurgery.org Dashboard, click-
ing “Submit CME,” and completing the form.

www.PRSJournal.com 79e
 Plastic and Reconstructive Surgery • January 2022

Fig. 1. Treatment algorithm for hypertrophic scars (HSs). The scar should first be assessed for the degree of scar contracture.
If the contracture is severe, surgery that releases the contracture is the first choice. If the contracture is mild, the scar can be
resected completely; however, nonsurgical multimodal therapy is also a choice.

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Volume 149, Number 1 • Hypertrophic Scars and Keloids

Fig. 2. Treatment algorithm for keloids. The selected treatment method for keloids depends on whether the keloids are
small and single or large and multiple. Small and single keloids can be treated radically by surgery with adjuvant therapy
(including radiation therapy); alternatively, they could be treated with nonsurgical multimodal therapy. For large and mul-
tiple keloids, volume- and number-reduction surgery is a choice.

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 Plastic and Reconstructive Surgery • January 2022
NEW DEVELOPMENTS IN THE PAST
DECADE
The past decade has seen a remarkable
growth in our understanding of how hypertro-
phic scars and keloids develop and progress.
Consequently, hypertrophic scars and keloids are
now known to be caused by chronic inflammation
in the reticular dermis. Risk factors associated
with hypertrophic scar and keloid development
and aggravation have been identified, thereby
aiding treatment optimization and effectiveness.
Several major advancements in preventing and
treating hypertrophic scars and keloids have been
made, as follows. First, deprodone propionate (a
stronger steroid) plaster was found to both pre-
vent and treat hypertrophic scars and keloids very
effectively. Second, surgical methods have been
optimized for each body region, thereby improv-
ing cosmetic and functional outcome, safety, and
recurrence rates. Third, the postoperative radio-
therapy protocol has been fine-tuned, making it
safer while remaining equally effective. The previ-
ous algorithm has been greatly improved by the
inclusion of these modalities. I anticipate that
further high-quality evidence for these modalities,
and additional new modalities, will emerge in the
next decade.
HYPERTROPHIC SCAR AND KELOID
DIAGNOSIS
Differential Diagnosis
Hypertrophic scars and keloids are fibropro-
liferative disorders in the reticular dermis layer:
this layer exhibits continuous inflammation,6
excessive angiogenesis, and abundant collagen
accumulation. Compared to classic hypertrophic
scars, classic keloids spread aggressively, rarely
resolve spontaneously, and, at the histologic level,
contain keloidal collagen, whereas hypertrophic
scars only have nodules. However, many scars
bear the clinical and pathologic features of both
classic keloids and hypertrophic scars. This sug-
gests that classic hypertrophic scars and keloids
are polar manifestations of the same skin disor-
der, between which lies a spectrum of intermedi-
ate scars.
The clinical and histologic differences
between classic hypertrophic scars and keloids
probably reflect differences in the intensity and
duration of reticular dermis inflammation. These
differences in turn may reflect the presence and
severity of local, systemic, genetic, and lifestyle
risk factors.6,7
82e
International Differences in Hypertrophic Scar
and Keloid Diagnosis
Classic keloids are strongly driven by genet-
ics.8–13 This partly explains ethnic differences
in keloid susceptibility: keloids are common in
Africans (5 to 10 percent are affected), less com-
mon in Asians (0.1 to 1 percent), and rare in
Europeans/North Americans (<0.1 percent).14
These ethnic differences mean that physi-
cians in certain regions have more experience
with keloids than others. It is my impression,
gained through attending many international
scar conferences, that this can influence phy-
sician diagnoses. Thus, in Western countries,
most abnormal scars are classic hypertro-
phic scars: consequently, Western physicians
often diagnose scars as keloids if they exhibit
minor spreading. However, African physicians
see many patients with classic keloids: conse-
quently, they often diagnose all scars as hyper-
trophic scars unless they grow rapidly. This
should be taken into account when reviewing
international literature.
Differential Diagnosis of Hypertrophic Scars and
Keloids from Similarly Appearing Diseases
Hypertrophic scar and keloid diagnosis is
often based on clinical features alone. However,
malignant tumors such as dermatofibrosarcoma
protuberans15–18 and giant-cell fibroblastoma19
can be misdiagnosed clinically as keloids.20
Moreover, analysis of 378 hypertrophic scars and
keloids showed that 1.06 percent were other dis-
eases.20 Thus, biopsy is warranted if malignancy is
suspected.20–22
PREVENTION OF POSTSURGICAL
HYPERTROPHIC SCARS AND KELOIDS
Patients with a hypertrophic scar and keloid
history are at high risk, as are patients with one
or more of the following risk factors (special care
must be taken during and after surgery).
Risk Factors
Local
Hypertrophic scars and keloids occur fre-
quently on sites that are frequently stretched
by daily body movements, including the major
joints, anterior chest, scapula, and lower abdo-
men.23 By contrast, hypertrophic scars and keloids
occur rarely on the scalp and anterior lower leg,
where stretching tension is low.23 This is because
stretching a wound prolongs and worsens its
Volume 149, Number 1 • Hypertrophic Scars and Keloids
inflammation, thereby provoking hypertrophic
scar and keloid formation.24–26
To prevent hypertrophic scar and keloid for-
mation after surgery on susceptible body regions,
surgical techniques that limit dermal tension
should be used, namely, flaps, Z-plasties, and
subcutaneous and deep fascial tensile-reduction
sutures. Moreover, postsurgical wound stretching
should be limited by fixation materials such as
paper tape, gel sheets, gels, or compression ban-
dages and garments. All are supported by meta-
analyses/randomized controlled trials. Regarding
paper tape, a randomized controlled trial26 dem-
onstrated that paper tape fixation reduced the
hypertrophic scar risk after cesarean section by
13.6-fold. Regarding gel sheets, a meta-analysis on
20 trials27 concluded that silicone gel sheets may
prevent hypertrophic scar and keloid formation
in scar-prone people with newly healed wounds;
however, they commented that trial quality was
poor.27 A recent review on 10 trials had similar
conclusions.28 Regarding gels, a randomized con-
trolled trial29 showed that silicone gel reduces
sternotomy scar pigmentation, erythema, hard-
ness, height, and pain and itchiness. This was
confirmed by a review.28 Regarding compression
therapy, a meta-analysis of 12 trials confirmed that
15- to 25-mmHg compression therapy reduces
burn scar thickness, erythema, and hardness.30
All patients undergoing surgery on suscep-
tible body areas should be monitored closely for
hypertrophic scars and keloids for 3 to 12 months.
If induration is observed, steroid tape and plaster
should be started and replaced with steroid injec-
tion if the induration prevails.
Systemic
Systemic factors include the female hormone
estrogen31: a large cross-sectional study showed that
keloids may predominate in women.32 Moreover,
estrogen-induced vasodilation could worsen
wound and scar inflammation: indeed, hypertro-
phic scars and keloids worsen during pregnancy33,34
and improve after delivery. Another systemic factor
is hypertension, which may aggravate hypertrophic
scars and keloids.35 Moreover, hypercytokinemic
diseases (e.g., Castleman disease) can greatly
worsen hypertrophic scars and keloids.36,37 Thus,
surgery on pregnant, hypertensive, and hypercy-
tokinemic patients should be conducted with the
surgical and wound fixation techniques described
above, followed by close monitoring.
Genetic
As mentioned, keloids are often strongly under-
pinned by genetic factors, including ethnic14 and
familial genes: multiple cases of keloid-susceptible
families have been reported.38,39 Moreover, several
single-nucleotide polymorphisms associate with
keloids40–42: four promote keloidogenesis40 and
one associates with severe keloids.41
Several genetic diseases associate with keloido-
genesis, including Rubinstein-Taybi syndrome43,44:
a cross-sectional study44 reported that 24 per-
cent of such patients had spontaneously growing
keloids. Multiple hereditary exostoses also associ-
ate with keloidogenesis.45
These risk factors cannot be obviated. Thus,
patients with familial history and genetic diseases
should be treated carefully during and after sur-
gery. The relatively low frequency of keloid-associ-
ated single-nucleotide polymorphisms means that
testing for them is impractical.
Lifestyle
Several lifestyle factors could exacerbate
surgery-induced wound and scar inflammation,
including strenuous wound-stretching physical
activity. Athletes and manual laborers should rest
their wounds. Certain diets and hot baths could
aggravate surgery-induced inflammation46: my
experience with thousands of patients suggests
they often experience itch and pain after consum-
ing hot and spicy foods or taking hot baths.
EARLY DETECTION AND FIRST-LINE
HYPERTROPHIC SCAR AND KELOID
TREATMENT
Hypertrophic scars and keloids should be
detected early because they may respond well
to conservative therapy. As discussed later, the
first-line conservative therapy for hypertrophic
scars and keloids in the 2019 Japanese guide-
line5 is long-term/continuous steroid tape or
plaster application. Strong steroid (deprodone
propionate) plaster effectively extinguishes early
hypertrophic scars and keloids5,31,47,48 but is only
available in Japan.47 Nevertheless, if applied very
early and continuously, even weaker fludroxycor-
tide tape can extinguish early hypertrophic scars
and keloids.5
HYPERTROPHIC SCAR TREATMENT
Hypertrophic scars are detected several weeks
after injury (Fig. 1). They grow for 3 to 6 months;
if risk factors are minor, they then plateau and
regress spontaneously. This process can be accel-
erated by the following conservative therapies,
which reduce hypertrophic scar volume and sup-
press pain and itch. Hypertrophic scars rarely
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 Plastic and Reconstructive Surgery • January 2022
require surgery unless they contract and cause
joint dysfunction49,50; in this case, reconstructive
surgery is indicated.
Compression Therapy
A recent meta-analysis (12 randomized con-
trolled trials) showed that 15- to 25-mmHg
compression therapy improves burn and hyper-
trophic scar thickness, erythema, and hardness.30
Compression therapy may promote wound heal-
ing by means of local vasoconstriction that limits
burn-induced inflammation.
Gel Sheets
Gel sheets are soft and self-adhesive. A meta-
analysis (20 trials)27 reported that continuous
gel sheeting improves hypertrophic scar matura-
tion. A new meta-analysis51 on this question is cur-
rently underway: it will be of interest to learn their
findings.
The type of material may not matter: a ran-
domized controlled trial52 showed that silicone
and hydrocolloid matrix gel sheets reduce
hypertrophic scar dimensions equally well. More
important may be patient education: a random-
ized controlled trial53 on burn and hypertrophic
scar patients suggests that instructional handouts
and videotapes increase gel sheet effectiveness.
Computer analysis suggests that gel sheets may
prevent hypertrophic scar formation and promote
hypertrophic scar maturation by limiting wound
and scar tension.54
Scar Massage
Randomized controlled trials on burn reha-
bilitation massage have conflicting results, and
a meta-analysis of 10 randomized controlled tri-
als concluded that the supporting evidence is
weak.55 I advise caution regarding massage ther-
apy. Wound healing associates with initial inflam-
mation that normally slowly wanes. At this point,
massage may promote mature scarring. However,
in patients with risk factors, inflammation rises
rather than subsides. Because massage stretches
the scar, it could induce and worsen hypertrophic
scars and keloids. Thus, scar massage in high-risk
patients should be avoided.
Corticosteroid Injection
Recent meta-analyses of four to 14 trials,28,56,57
a network meta-analysis of 23 trials,58 a systematic
review of 11 studies,59 comprehensive reviews,60,61
and several new randomized controlled trials62,63
show that intralesional corticosteroid can induce
84e
50 to 100 percent regression of both hypertro-
phic scars and keloids. An international expert
panel recommends triamcinolone acetonide at
doses of 2.5 to 40 mg/site.64 The injections prob-
ably act by decreasing inflammatory cytokine
production.65 However, disadvantages include
injection-induced pain, systemic side effects
(e.g., menstrual dysfunction, adrenocortical
suppression,66 and cataracts and glaucoma),
and local side effects (e.g., skin thinning and
atrophy, steroid acne, capillary dilatation, and
hypopigmentation).
Corticosteroid Tape and Plaster
Corticosteroid tape and plaster is a painless
alternative to corticosteroid injections. When
60 hypertrophic scar and keloid patients were
treated with fludroxycortide (weak steroid) tape,
20 percent of the 30 adults and 80 percent of the
30 children exhibited improved scar elevation
and erythema and pruritus after 12 months. The
strong pediatric response may reflect thinner skin.
When the 24 nonresponsive adults were switched
to deprodone propionate (stronger steroid) plas-
ter, 70.8 percent demonstrated improved scar
features after 6 months.47,67 Other observational
studies and good clinical experiences with ste-
roid tape and plaster have caused it to become
a mainstay of scar-management protocols.31
Consequently, a Japanese guideline5 recently
recommended that corticosteroid tape and plas-
ter should be the first-line hypertrophic scar and
keloid therapy. Figure 3 depicts a deprodone pro-
pionate plaster–treated hypertrophic scar. Tape
and plaster should be used continuously as early
as possible5 for at least 3 months. If unsuccessful,
it should be replaced with stronger treatments.
Corticosteroid Ointment and Cream
Randomized controlled trials on corticoste-
roid ointment and cream are lacking, but a case
series study68 showed that triamcinolone aceton-
ide injections of hypertrophic scar and keloid-
excision sites combined with twice-daily 6-month
corticosteroid ointment application yielded
keloid and hypertrophic scar recurrence rates
of 14.3 percent and 16.7 percent, respectively.
These outcomes and good clinical experiences
recently led several Japanese burn and scar societ-
ies5,69 to recommend corticosteroid ointment and
cream materials for superficial dermal burns70
and hypertrophic scar prevention and treat-
ment.5 However, since corticosteroid ointment
and cream should be applied four times daily to
Volume 149, Number 1 • Hypertrophic Scars and Keloids

Fig. 3. Treatment of hypertrophic scars with deprodone propionate plaster. (Left)

Pretreatment view. (Right) Three years after starting deprodone propionate plaster. A
50-year-old woman had several hypertrophic scars as a result of cesarean delivery. She was
provided with deprodone propionate plaster and told to apply it 24 hours per day until fur-
ther notice. She was instructed to peel it off while taking a bath and then reapply it. When
the plaster lost its adhesiveness, it was replaced by a new plaster. After 6 months, the scar
became soft. After 3 years, the scar became completely flat and its tone was close to that
of the surrounding skin.

generate steroid tape and plaster effects,67 patient
education is necessary.
Laser
Two reviews70,71 and a meta-analysis72 showed
that pulsed-dye laser significantly reduces hyper-
trophic scar erythema and pruritus73–77 because its
wavelength (585 to 595  nm) reaches the hyper-
trophic scar angiogenic region: its heat reduces
hypertrophic scar blood flow and therefore
inflammation. Neodymium:yttrium-aluminum-
garnet laser (532/1064 nm) has similar effects, as
shown by a review,71 a meta-analysis,72 case-series
studies,48,78 and a randomized controlled trial.79
Randomized controlled trials showed that nonab-
lative/ablative carbon dioxide fractional lasers
have no beneficial effects.80,81 Fully ablative laser
therapy is not recommended for pathologic scars
because of high recurrence.82,83
dysfunction. Such scar contractures should be
released surgically. This also accelerates matura-
tion of surrounding hypertrophic scars. Small and
linear hypertrophic scars can be treated by com-
plete resection. All hypertrophic scar operations
should involve tension-releasing techniques,5
including Z-plasty,84 W-plasty,85 and local flaps.86–89
Figure  4 shows a Z-plasty–treated hypertrophic
scar contracture.
One randomized controlled trial suggests that
absorbable/nonabsorbable sutures do not differ
in hypertrophic scar risk,90 but another91 showed
that nonabsorbable sutures reduce hypertrophic
scar frequency. The suturing method is probably
more important than the material: clinical expe-
rience92 suggests that tensile-reduction sutures
reduce hypertrophic scar and keloid scarring
and recurrence because they decrease dermal
tension.6,92,93

Surgery Other Hypertrophic Scar Therapies

When hypertrophic scars occur near or Other therapies have been proposed for
on a joint, their contraction can induce joint hypertrophic scars. Some may also be suitable for

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 Plastic and Reconstructive Surgery • January 2022

Fig. 4. Treatment of a traumatic scar contracture between the finger and palm by using Z-plasty. (Left) Preoperative view. (Center)
Immediately after surgery. (Right) Eighteen months after surgery. A 10-year-old boy sustained trauma to his left ring finger and
palm. A hypertrophic scar with mild scar contracture developed. Because the width of the scar was narrow, the scar could be
removed completely. Thereafter, Z-plasties were placed over the joints and the main crease in the palm. After surgery, the inflam-
mation decreased uneventfully. The scar became mature over the next year.

keloids. The evidence level is generally low. One is
adipose tissue transplantation by using lipotrans-
fer and lipoinjection techniques. A recent review94
noted that adipose-derived stem cells can secrete
trophic factors that alter fibrotic and remodeling
mediator expression. The evidence is too limited
to justify changes in clinical practice. A recent
review95 of case series studies showed that cryo-
therapy is safe and achieves good scar reduction,
albeit with some adverse effects (depigmentation,
recurrence, pain).
Recent meta-analyses and reviews28 show that
5-fluorouracil injections are effective as a mono-
therapy but reduce hypertrophic scar and keloid
elevation and erythema better when combined with
triamcinolone acetonide injections. Intralesional
botulinum toxin type A (Botox; Allergan, Inc.,
Dublin, Ireland) injections may improve and pre-
vent hypertrophic scars and keloids by suppress-
ing scar tension and fibroblast activities.96 Recent
randomized controlled trials97,98 show that post-
surgical Botox injections prevent hypertrophic
scar development. A meta-analysis of 14 studies57
showed that, compared to placebo, Botox injec-
tions significantly improved hypertrophic scar and
keloid appearance and width.
A meta-analysis99 of five trials showed that
bleomycin injections improved hypertrophic
scars and keloids more effectively than triamcino-
lone acetonide and/or 5-fluorouracil injections.
A 14-study review on topical onion extract gel
(a nonsteroidal antiinflammatory drug) reported
that 11 detected beneficial effects on hypertro-
phic scars and keloids.100
Oral tranilast (an antiallergic drug) improves
inflammatory diseases with few adverse effects. It
has long been used in Japan to treat hypertrophic
scars and keloids.5,101–103 Randomized controlled
trials showed that tranilast improved hypertrophic
scars and keloids and reduced the redness of new
postsurgical hypertrophic scars.104
KELOID TREATMENT
Keloid treatment starts with determining the
keloid number and size (Fig.  2): this indicates
the strength of the patient’s keloid risk factors.1
If there is one keloid or the keloids are small,
skin tension is probably the cause. However, if
there are multiple or large keloids, genetic and
systemic factors should be considered, especially
when keloids are on different body regions. Single
or small keloids can be treated with conservative
therapy. Thick, large, multiple keloids should be
assessed for surgery plus adjuvant therapy because
they respond poorly to topical drugs. Physicians
must carefully discuss therapeutic options with
the patient and establish treatment goals.
Keloid inflammation generally worsens over
time. Because scar massage, ablative lasers, and
surgical monotherapy provoke inflammation and
worsen keloids, they should be avoided.

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Volume 149, Number 1 • Hypertrophic Scars and Keloids

Gel Sheets to good effects on existing keloids105 and reduced

The meta-analysis of O’Brien and Jones27 recurrence to 14.3 percent when applied postop-
showed that silicone gel sheets alone can reduce eratively.68 However, a limitation is that the cream
keloid thickness and erythema. is easily rubbed off.

Corticosteroid Injection Cryotherapy

Many studies show that intralesional cortico-
steroid injections induce keloid regression.58–63
However, combining corticosteroid injections
with 5-fluorouracil, pulsed-dye laster, or cryother-
apy has better outcomes than corticosteroid injec-
tions alone.70
Corticosteroid Tape and Plaster
As with hypertrophic scars, corticosteroid
tape and plaster is the first-line keloid therapy in
the 2019 Japanese guideline.5 Its long-term, con-
tinuous application softens and then flattens the
mass. It also reduces pruritus and erythema.47,67
Figure  5 shows a steroid plaster–treated keloid.
However, in my experience, rapidly growing
keloids cannot be stopped by steroid tape and
plaster alone, and this therapy must be com-
bined with triamcinolone acetonide injections
or other methods. The greatest advantages of
steroid tape and plaster are its painlessness and
few side effects. Strong steroid (deprodone pro-
pionate) plaster, which is available only in Japan,
is more effective than fludroxycortide tape. It
should become available worldwide for treating
pathologic scars.
Corticosteroid Ointment and Cream
Case series studies showed that multiple daily
corticosteroid cream applications had excellent
Recent reviews56,106 showed that cryotherapy
(monotherapy or with triamcinolone aceton-
ide injection) effectively reduces keloid size.
Cryotherapy methods include direct contact,107
sprays,107–109 and intralesional needles. 109,110
However, supporting evidence is limited to case
series studies.106
Antitumor and Immunosuppressive Agents
Recent meta-analyses, reviews, and new ran-
domized controlled trials58–60 show that intral-
esional 5-fluorouracil injection is an effective
keloid monotherapy and reduces postoperative
recurrence.58–60 They also show that 5-fluorouracil
effectively reduces keloid elevation and erythema
when combined with triamcinolone acetonide
injections.58–60 A meta-analysis99 reported that
bleomycin injections improve keloids more effec-
tively than triamcinolone acetonide and/or 5-flu-
orouracil injections.
Surgery
Small keloids can be radically resected. Large
and multiple keloids may be suitable for partial
and core excision that reduces the thick, hard
areas or the number of keloids. Radical resec-
tion should always be combined with adjuvant
therapies (e.g., radiation therapy) because sur-
gery alone results in 45 to 100 percent recurrence

Fig. 5. Treatment of keloids using deprodone propionate plaster. (Left) Pretreatment view. (Right)
Three years after starting deprodone propionate plaster. A 40-year-old woman developed a
keloid on her left shoulder as a result of folliculitis. She was treated with deprodone propionate
plaster for 24 hours/day. The patient changed the tape every day and continued to use it for 3
years. Six months after starting this therapy, the scar became soft. In the ensuing 3 years, the scar
became almost flat.

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 Plastic and Reconstructive Surgery • January 2022

rates.64 Surgery should involve tension-reducing
techniques, namely, subcutaneous and deep fas-
cial tensile-reduction sutures,31,92,93 Z-plasties,111–113
and local-flap transfer.114
Tensile-reduction sutures elevate the wound
edges smoothly and relieve dermal tension.31,92,93
Our clinical experience112 suggests that they help
reduce recurrence rates.
Regarding Z-plasty, case series studies of ante-
rior chest wall keloids111 and upper-arm keloids113
showed that excision, tension-reduction suturing,
Z-plasty, and radiotherapy led to respective recur-
rence rates of 10.6 and 5.3 percent, at 24 months.
All recurrences were readily extinguished by ste-
roid plaster and injections. Figure  6 depicts a
Z-plasty–treated chest wall acne keloid.
Flap choice depends on the affected region.
A case series study showed that none of 10 huge
anterior chest wall keloids recurred after par-
tial or total resection and flap reconstruction.114
Flaps are superior to skin grafts: the latter do not
expand postoperatively and can yield pathologic
scars encircling the skin graft. When using flaps,
the donor-site must undergo multimodal therapy
to prevent new keloids.114 Figure 7 shows a hatchet
flap–treated scapular keloid.
A special region is the ear. Wedge excision is
recommended for earlobe keloids.5 A case series
study112,115 of earlobe keloids showed that wedge
excision and radiotherapy yielded 4.7 percent
recurrence at 18 months. Core excision is recom-
mended for auricular cartilage keloids.5 A case
series study116 showed that core excision of ear-
lobe and auricular keloids plus steroid injections
yielded 9.5 percent recurrence rate at 22 months.
Similarly, another case series study117 showed that

Fig. 6. Treatment of a chest wall acne keloid by using Z-plasty and postoperative radiotherapy.
(Above, left) Preoperative view. (Above, right) Immediately after total keloid excision. (Below, left)
Immediately after surgery. (Below, right) Two years after surgery. A 60-year-old man developed a
chest-wall keloid as a result of acne. It was excised completely and the wound was closed with
Z-plasties to release the tension on the scar. The surgery was followed with electron beam radio-
therapy (18 Gy, in three fractions, over 3 days). The inflammation dropped uneventfully and the
scar became mature over 18 months.

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Volume 149, Number 1 • Hypertrophic Scars and Keloids

Fig. 7. Treatment of a scapular folliculitis keloid by using a hatchet flap and postoperative
radiotherapy. (Above, left) Preoperative view. (Above, right) Immediately after total keloid
excision and flap design. (Below, left) Immediately after surgery. (Below, right) Two years after
surgery. A 70-year-old man developed scapular keloids. They were excised completely and
reconstructed by using a hatchet flap. After surgery, the scar was irradiated (18 Gy, in three
fractions, over 3 days). The inflammation fell uneventfully and the scar became mature over
18 months.

total and core excision led to 8.1 and 0 percent
recurrence, respectively. Figure  8 depicts a core
excision–treated auricular keloid.
Radiation Therapy
Radiotherapy effectively treats or prevents
keloids by suppressing angiogenesis and there-
fore inflammation.118 Radiation monotherapy
should be reserved for older patients or those
with huge keloids because large radiation doses
are needed. It immediately reduces pain and itch
and slowly ameliorates scar color and thickness in
the next year.31
Radiotherapy is particularly effective as a sur-
gery adjunct. Recent meta-analysis of 72 studies119
showed that surgery plus radiotherapy is associated
with fewer recurrences (22 percent) than radiation
monotherapy (37 percent). Notably, this surgery
plus radiotherapy rate is higher than the rate in
our center (<10 percent).112 This may reflect the
fact that the meta-analysis examined studies pub-
lished from 1957 to 2014.112 Refinements in surgery,
radiotherapy, and postoperative care techniques
probably all contribute to our low recurrence rate.
Superficial or orthovoltage x-rays (photons)
were once used,120,121 but many institutions now

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 Plastic and Reconstructive Surgery • January 2022

Fig. 8. Treatment of an auricular keloid by using the core excision method and postoperative radiotherapy. (Left) Preoperative
view. (Center) The flap made on the keloid after the core was removed. (Right) Two years after surgery. A 20-year-old woman devel-
oped auricular keloids. A flap was designed on the anterior side of the keloid and the core was removed. The flap was sutured
using 6-0 polypropylene sutures. After surgery, the site was irradiated (15 Gy, in two fractions, over 2 days). The inflammation
dropped uneventfully and the scar became mature over 18 months.

prefer electron beam (β-ray) instruments because LONG-TERM POSTTREATMENT

of fewer internal organ side effects.122–124 High-
dose-rate brachytherapy (mainly γ-rays) is increas-
ingly used,125,126 but its safety for internal organs
should be studied further.
The maximal biologically effective dose for
keloids is 30 Gy.127–129 Doses exceeding this have
no gains in efficacy and only increase the second-
ary carcinogenesis risk. Given that body sites vary
in recurrence susceptibility, a 30-Gy biologically
effective dose is not always necessary. Our facility
exploits this to further decrease the secondary car-
cinogenesis risk: we apply body site–specific post-
operative irradiation for keloids, namely, 18 Gy in
three fractions over 3 days (biologically effective
dose, approximately 30 Gy) to high-recurrence
sites, 8 Gy in one fraction over 1 day to earlobes,
and 15 Gy in two fractions over 2 days to other
body sites.112
Over 70 years, there has been a small handful
of case reports of malignant carcinogenesis after
keloid radiotherapy.129–134 Mostly, it is unclear
whether these are true secondary carcinogenesis
cases. Moreover, a survey135 of radiation oncolo-
gists worldwide showed that greater than 90
percent considered keloids to be an acceptable
radiotherapy indication. Thus, before exclud-
ing the possibility of keloid radiotherapy, sur-
geons should discuss the issue with radiation
oncologists.129
FOLLOW-UP OF HYPERTROPHIC SCARS
AND KELOIDS
Treated hypertrophic scar and keloid patients
should be educated about scar management and
followed-up over the long-term. Close follow-
up allows early detection and treatment of small
recurrences that respond well to steroid tape,
plaster, or injection. Thus, patients should be
followed up for greater than 18 to 24 months.
Follow-up can stop when the scar is flat and soft.
Hypertrophic scar and keloid patients often
experience psychological stress that may aggra-
vate their scars. They may benefit from makeup or
camouflage therapies136–139 because they improve
cosmetic appearance and promote beneficial
physiologic changes.
CONCLUSIONS
In the past decade, many high-quality studies
have been conducted, and the level of evidence
for many treatment or prevention regimens has
strengthened. As reflected in my reprised review
here, these changes have led to pathologic scar
management strategies that now effectively and
safely prevent, eliminate, or ameliorate these
pernicious scars. However, given ethnic differ-
ences in pathologic scar propensity, prevention
and treatment algorithms should be optimized

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Volume 149, Number 1 • Hypertrophic Scars and Keloids
for each human race by means of international
collaboration.
Rei Ogawa, M.D., Ph.D.
Department of Plastic, Reconstructive,
and Aesthetic Surgery
Nippon Medical School
1-1-5 Sendagi Bunkyo-ku
Tokyo 113-8603, Japan
r.ogawa@nms.ac.jp
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 PEMBAHASAN

Keloid adalah tumor jinak kulit, tumor ini berbatas tegas dan merupakan

pertumbuhan yang berlebihan dari jaringan fibrosa yang melampaui defek aslinya,

disebabkan oleh adanya ketidakseimbangannya antara deposisi dan penghancuran

komponen matriks ekstraselular pada kolagen dermis bisa akibat adanya luka atau

trauma pada kulit, namun bisa juga tanpa didahului oleh adanya trauma, memiliki

karakteristik tegas, agak lunak dan lebih sering terdapat pada bahu, dada, leher,

lengan atas dan pipi walaupun merupakan tumor jinak, keloid bisa menyerang kulit

normal sekitarnya (Samuel et al, 2021).

Etiologi keloid masih belum diketahui sepenuhnya.

Keloid lebih sering dialami oleh orang kulit hitam. Perbedaan jenis kelamin tidak

terbukti sebagai faktor predisposisi keloid. Diduga ada faktor genetik yang berperan

(Trace et al., 2016).

Individu berkulit gelap keturunan Afrika, Asia, dan Hispanik memiliki

tingkat kejadian keloid yang lebih tinggi dibandingkan dengan Kaukasia. Insiden

pada populasi berpigmen lebih gelap ini berkisar antara 4,5% hingga 16%. Insiden

ini terutama lebih tinggi selama kehamilan dan pubertas. Riwayat keluarga yang

positif meningkatkan risiko perkembangan keloid meskipun tidak ada gen spesifik

yang diidentifikasi. Sindrom genetik yang langka juga dapat meningkatkan risiko

perkembangan keloid termasuk sindrom Rubinstein-Taybi dan Goeminne (Samuel

et al, 2021).
 Keloid cenderung terjadi pada lokasi tubuh dengan ketegangan kulit yang

tinggi dan adanya mekanik dan inflamasi berulang serta adanya predisposisi

genetik. Keloid berkembang sejak 3 bulan hingga 1 tahun setelah trauma dan fase

terakhir penyembuhan luka adalah fase maturasi dimana fase ini dimulai pada

minggu ketiga setelah luka lalu berakhir kurang lebih 12 bulan. Keloid bisa terjadi

setelah operasi, trauma atau berkembang secara spontan (Ogawa et al, 2021).

Akibat ketidakseimbangan sintesis kolagen dan degradasinya, skar normal

digantikan oleh jaringan fibrotik patologis yang mengandung molekul matriks

ekstraseluler yang kaya akan produksi kolagen tipe I dan III, bronektin, dan laminin,

dan miskin akan kandungan asam hialuronat dan decorin I (Trace et al., 2016).

Kemerahan, gatal, nyeri, rasa terbakar, dan penonjolan reguler maupun

ireguler merupakan gejala yang dapat menyertai keloid, walaupun alasan utama

pasien berobat adalah gangguan kosmetik. Keloid muncul di area pasca trauma.

Tempat predileksi tersering adalah cuping telinga, dada, bahu, dan perut (Trace et

al., 2016).

Diagnosis keloid sering didasarkan pada gambaran klinis saja. Biopsi tidak

diperlukan kecuali diagnosis curiga kearah keganasan. Dalam hal ini, biopsi adalah

alat diagnostic penunjang. Tidak diperlukan pemeriksaan lebih lanjut (Ogawa,

2022).

Menghindari terjadinya luka berlebihan tetap merupakan solusi terbaik.

Semua terapi dapat dilakukan pada keloid.. Angka keberhasilan lebih tinggi bila

dilakukan terapi kombinasi. Keterlambatan proses epitelisasi hingga 10-14 hari

meningkatkan angka kejadian keloid. Lokasi, ukuran, kedalaman luka, usia pasien,
dan keberhasilan terapi sebelumnya merupakan pertimbangan klinisi untuk

menentukan terapi (Linda, 2018).

Terapi Tekan. Efektivitasnya masih kontroversial. Mekanisme kerja yang

diharapkan adalah dengan pemberian tekanan, maka sintesis kolagen menurun

karena terbatasnya suplai darah dan oksigen, serta nutrisi ke jaringan scar dan

apoptosis diharapkan meningkat. Tekanan kontinu (15-40 mmHg) diberikan

minimal 23 jam dan/atau 1 hari selama minimal 6 bulan atau selama scar masih

aktif. Terapi ini terbatas karena sering menyebabkan maserasi, eksema, ataupun bau

tidak sedap karena penggunaan bahan kain. Terapi tekan biasanya berhasil lebih

baik pada anak-anak (Gauglitz et al, 2011).

Injeksi Kortikosteroid. Kortikosteroid bekerja mensupresi proses inflamasi

luka. Selain itu, kortikosteroid mampu mengurangi sintesis kolagen dan

glikosaminoglikan, menghambat pertumbuhan fibroblas, dan meningkatkan

degradasi kolagen dan fibroblas. Injeksi intralesi menggunakan triamcinolon

acetonide (TAC) 10-40 mg/mL diulang setiap 3-4 minggu dapat dilakukan hingga

6 bulan memberikan hasil yang cukup baik, pada kasus tertentu terkadang

dibutuhkan tambahan sesi. Pada terapi tunggal, hasil maksimal hingga rata

sepenuhnya didapatkan pada scar yang masih baru. Untuk scar lama, hasil yang

dicapai hanya lesi menjadi lebih kecil dan membantu mengurangi gejala. Efek

samping yang sering muncul adalah atrofi kulit, telangiektasis, dan rasa nyeri di

area penyuntikan (Gauglitz et al, 2011).

Revisi Scar. Sebelum tindakan bedah, harus dipastikan perbedaan antara

scar hipertrofi dan keloid. Keloid memiliki angka rekuren 45-100% pasca-tindakan
bedah. Tindakan eksisi sering menyebabkan scar yang lebih besar. Tindakan bedah

sebaiknya dikombinasi dengan injeksi triamcinolone acetonide dan terapi tekan di

area tindakan untuk hasil yang lebih baik (Gauglitz et al, 2011).

Radioterapi. Superficial x-rays, electron-beam therapy, dan brachytherapy

dosis rendah atau tinggi memberikan hasil yang cukup baik. Radioterapi

menghambat neovaskular dan proliferasi fibroblas, sehingga produksi kolagen

menurun. Terapi sebaiknya dimulai sejak 24-48 jam pasca-tindakan eksisi dengan

dosis total 40 Gy untuk mencegah efek samping seperti hipo- atau hiperpigmentasi,

eritema, telangiektasis, dan atrofi (Gauglitz et al, 2011).

Secara umum scar dibedakan menjadi dua bentuk, yaitu scar hipertrofik dan

scar keloid. Gambaran klinis kedua jenis ini dapat sulit dibedakan, salah identifikasi

dapat menyebabkan manajemen yang tidak tepat dan sering menghasilkan

keputusan operasi yang salah (Ogawa, 2022).

Scar hipertrofik terbentuk mulai minggu ke-4 hingga ke-6 setelah luka dan

tumbuh cepat hingga 6 bulan. Setelah itu akan mengalami regresi hingga terbentuk

jaringan normal. Sedangkan pada keloid scar terus bertumbuh dan cenderung

menetap. Scar hipertrofik biasanya didahului trauma dan luas scar tidak melebihi

luas luka. Keloid dapat didahului trauma dan kadang dapat terjadi spontan tanpa

didahului luka. Scar pada keloid dapat lebih luas dari area lukanya. Pada scar

hipertrofik, tindakan pembedahan dapat menjadi pilihan penanganan yang baik,

tetapi pada scar keloid, tindakan pembedahan sering menyebabkan scar menjadi

lebih besar akibat luka operasi (Gauglitz et al, 2011).

 Fase inflamasi yang memanjang diduga merupakan salah satu penyebab

timbulnya scar hipertrofik atau keloid. Meningkatnya jumlah sel-sel imun pada

keloid meningkatkan aktivitas fibroblas dan terus terjadi pembentukan matriks

ekstraseluler. Hal ini juga yang diduga menyebabkan scar timbul melebihi margin

atau batas luka pada keloid. Pada scar hipertrofik, infiltrasi sel imun akan menurun

sehingga mungkin terjadi regresi (Gauglitz et al, 2011).

Pada fase awal terbentuknya scar hipertrofik, terjadi hiperseluler, dan pada

fase remodelling sel fibroblas berkurang dan perlahan-lahan menjadi scar normal

melalui proses apoptosis. Proses ini mulai terjadi sejak hari ke-12 pasca-luka.

Penelitian pada scar hipertrofik akibat luka bakar derajat tinggi menemukan

keterlambatan proses apoptosis, yaitu pada bulan ke-19-30 pasca-luka (Gauglitz et

al, 2011).

Algoritma pengobatan untuk bekas luka hipertrofik (HSs): Bekas luka

pertama-tama harus dinilai untuk tingkat kontraktur bekas luka. Jika kontrakturnya

parah, operasi yang menghilangkan kontraktur adalah pilihan pertama. Jika

kontrakturnya ringan, bekas luka dapat direseksi seluruhnya; namun, terapi

multimodal non-bedah juga merupakan pilihan (Ogawa, 2022).

Metode pengobatan yang dipilih untuk keloid tergantung pada apakah

keloid itu kecil tunggal atau besar dan multipel. Keloid kecil dan tunggal dapat

diobati secara radikal dengan pembedahan dengan terapi adjuvant (termasuk terapi

radiasi); sebagai alternatif, mereka dapat diobati dengan terapi multimodal non-

bedah. Untuk keloid besar dan multipel, operasi pengurangan volume dan jumlah

adalah pilihan (Ogawa, 2022).

 DAFTAR PUSTAKA

1. Ekstein, S. F., Wyles, S. P., Moran, S. L., & Meves, A. (2021). Keloids: a

review of therapeutic management. International journal of

dermatology, 60(6), 661- 671.

2. Gauglitz, G. G., Korting, H. C., Pavicic, T., Ruzicka, T., & Jeschke, M. G.

(2011). Hypertrophic scarring and keloids: pathomechanisms and current

and emerging treatment strategies. Molecular medicine, 17(1), 113-125.

3. Ogawa, R., Dohi, T., Tosa, M., Aoki, M., & Akaishi, S. (2021). The latest

strategy for keloid and hypertrophic scar prevention and treatment: the

Nippon Medical School (NMS) protocol. Journal of Nippon Medical

School, 88(1), 2-9.

4. Ogawa, R. (2022). The most current algorithms for the treatment and

prevention of hypertrophic scars and keloids: a 2020 update of the

algorithms published 10 years ago. Plastic and reconstructive

surgery, 149(1), 79.

5. Sinto, L. (2018). Scar hipertrofik dan keloid: patofisiologi dan

penatalaksanaan. Cermin Dunia Kedokteran, 45(1), 29-32.

6. Trace, A. P., Enos, C. W., Mantel, A., & Harvey, V. M. (2016). Keloids and

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clinical dermatology, 17(3), 201-223.

The Most Current Algorithms for the Treatment
and Prevention of Hypertrophic Scars and
Keloids: A 2020 Update of the Algorithms
Published 10 Years Ago
Pembimbing:
dr. Rahimah, Sp. KK.

Oleh:
JOURNAL READING Fladinish Sinta Aurora Pambudi
202120401011093

KSM ILMU KULIT DAN KELAMIN RSU HAJI SURABYA

FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH MALANG
 Abstrak
● Latar Belakang: Pada tahun 2010, Jurnal ini menerbitkan tinjauan komprehensif pada literatur bekas luka hipertrofik dan
keloid. Dalam artikel tersebut, dipresentasikan algoritma berbasis bukti ilmiah untuk pencegahan dan pengobatan
bekas luka patologis yang refrakter.. Pada dekade selanjutnya, kemajuan substansial telah dibuat di lapangan, termasuk
banyak uji acak terkendali baru. Makadari itu, tinjauan ini telah diperbarui.
● Metode: Semua studi dievaluasi untuk kualitas metodologis. Karakteristik dasar pasien diekstraksi bersama dengan
intervensi dan keluaran. Telaah sistematis, meta-analisis, dan tinjauan komprehensif disertakan jika tersedia.
● Hasil: Faktor risiko yang memicu hypertropic scar dan pertumbuhan keloid meliputi, faktor lokal (tekanan pada
luka/bekas luka), faktor sistemik (mis., hipertensi), faktor genetik (mis., polimorfisme nukleotida tunggal) , dan faktor gaya
hidup.
Pengobatan bekas luka hipertrofik tergantung pada keparahan kontraktur jaringan parut: jika parah, pembedahan adalah
pilihan pertama. Jika tidak, maka terapi konservatif diindikasikan. Perawatan keloid bergantung pada ukurannya, apakah
kecil dan tunggal atau besar dan multipel. Keloid kecil dan tunggal dapat diobati secara radikal dengan pembebedahan
dengan terapi adjuvant (misalnya radioterapi) atau terapi konservatif multimodal. Untuk keloid besar dan multiple,
operasi pengurangan volume dan jumlah adalah pilihan. Terlepas dari pengobatannya, pasien harus ditindaklanjuti
dalam jangka panjang. Terapi konservatif, termasuk lembaran gel, fiksasi pita, agen eksternal topical dan injeksi, agen
oral, dan terapi rias, harus diberikan berdasarkan kasus per kasus.
● Kesimpulan: Uji acak terkendal pada manajemen bekas luka patologis telah meningkat tajam selama decade terakhir.
Meskipun penelitian mengalami beberapa keterbatasan, penelitian tersebut telah sangat meningkatkan manajemen
bekas luka hipertrofik dan keloid. Uji coba berkualitas tinggi di masa depan kemungkinan akan meningkatkan algoritme
perawatan keloid dan bekas luka hipertrofik saat ini lebih lanjut.
 PERKEMBANGAN BARU SELAMA DEKADE TERAKHIR

● Inflamasi kronis pada dermis retikuler → hypertropic scar & keloid

● Pencegahan dan pengobatan
● Plester deprodone propionate (steroid kuat)
● Metode pembedahan
● Protokol radioterapi pasca operasi
 Hypertropic Scar & Keloid Diagnosis
Differential Diagnosis
Hypertropic scar dan keloid merupakan kelainan fibroproliferative pada lapisan dermis letikular: menunjukkan
inflamasi yang berlangsung terus menerus, angiogenesis yang berlebihan, dan terdapat akumulasi kolagen.

Hypertropic Scar Keloid

Luasnya menyebar sesuai dengan
01 batas luka 01 Menyebar secara agresif

02 Dapat sembuh spontan 02 Jarang sembuh secara spontan

03 Hanya memiliki nodul 03 Mengandung kolagen keloid

 Hypertropic Scar & Keloid Diagnosis
International Differences in Hypertropic scar and Keloid Diagnosis

Asia <0,1%

Afrika
0,1%-1%

Eropa
5%-10%
 Hypertropic Scar & Keloid Diagnosis
Differential Diagnosis of Hypertropic Scar & Keloid from Similarly Appearing Disease

Hypertropic scar dan keloid sering didiagnosis berdasarkan tampilan klinis saja.
Namun, tumor ganas seperti dermatofibrosarcoma protuberans dan giant-cell
fibroblastoma dapat salah didiagnosis secara klinis sebagai keloid. Maka dari itu,
biopsy diperlukan jika curiga suatu keganasan.
 Prevention of Postsurgical hypertropic scars & keloid

Faktor Risiko

Lokal

o Muncul pada area tubuh yang sering teregang oleh Gerakan tubuh sehari-hari :
sendi, dada anterior, scapula, dan perut bagian bawah.
o Jarang terjadi pada kulit kepala dan tungkai bawah anterior → tegangan
regangan rendah
o Regangan luka memperpanjang dan memperburuk inflamasi, sehingga memicu
pembentukan hypertropic scar dan keloid
 Prevention of Postsurgical hypertropic scars & keloid

Faktor Risiko

Sistemik

o Pada wanita: hormone estrogen

o Estrogen menginduksi vasodilatasi → memperparah inflamasi luka dan bekas
luka
o Pada wanita hamil, rentan terjadi hypertropic scar dan keloid
o Hipertensi dan penyakit hipersitokinemi juga merupakan factor risiko sistemik
pada pembentukan hypertropic scar dan keloid
 Prevention of Postsurgical hypertropic scars & keloid

Faktor Risiko

Genetik

o Keloid kerap kali dipengaruhi oleh faktor genetik; termasuk etnis dan gen
familial
o Beberapa penyakit genetik berhubungan dengan genesis keloid, termasuk
sindrom Rubinstein-Taybi
 Prevention of Postsurgical hypertropic scars & keloid

Faktor Risiko

Gaya Hidup

o Aktivitas fisik yang berat, mandi dengan air panas dapat memperburuk
peradangan luka dan bekas luka pasca pembedahan.
 Early Detection & First Line Hypertropic Scar and Keloid Treatment

o Terapi konservatif lini pertama : pengaplikasian plester steroid jangka Panjang

o Ex: Deprodone propionate → steroid kuat
o Hanya tersedia di Jepang
o Alternatif: fludroxycortide tape
 Hypertropic Scar Treatment

Bekas luka hipertrofik dapat dideteksi dalam beberapa minggu setelah cedera,
tumbuh dalam waktu 3-6 bulan. Jika memiliki faktor risiko minor, maka luka akan
memasuki fase plateu dan memudar secara spontan. Proses ini dapat dipercepat
dengan beberapa terapi konservatif → mengurangi volume, rasa sakit serta gatal
pada luka.

Hypertropic scar jarang meemrlukan terapi pembedahan, kecuali melibatkan

disfungsi pada sendi serta kontraktur maka dapat dilakukan pembedahan
rekontruksi.
 Hypertropic Scar Treatment

Terapi Kompresi

o Diberikan tekanan 15mmHg-20mmHg pada luka

o Terjadi vasokontriksi → inflamasi berkurang
 Hypertropic Scar Treatment

Gel Sheets

o Ex: silicon dan hydrocolloid matrix gel

o Dapat mengurangi luas bekas luka dengan cara mempercepat maturase
hypertropic scar.
 Hypertropic Scar Treatment

Pijat Bekas Luka/Scar massage

o Evidance based lemah

o Pijatan dapat meningkatkan maturase luka
o Pada pasien dengan factor risiko, dapat meningkatkan inflamasi: pijatan dapat
meregangkan luka → menginduksi hypertropic scar.
o Hindari pada pasien dengan factor risiko tinggi.
 Hypertropic Scar Treatment

Injeksi Kortikosteroid

o Triamcinolone acetonide 2,5mg-40mg/area.

o Mengurangi sitokin inflamasi
o Terbukti hypertropic scar dan keloid mengalami regresi sebanyak 50%-100%
pada beberapa penelitian.
o Kekurangan: sakit akibat suntikan, efek sistemik steroid ( disfungsi menstruasi,
supresi adrenocortical, katarak, dan glaucoma), efek samping local (penipisan
kulit dan atrofi, steroid acne, dilatasi pembuluh darah kapiler, dan
hipopigmentasi)
 Hypertropic Scar Treatment

Plaster kortikosteroid

• Merupakan lini pertama terapi hypertropic scar dan keloid

• Diberikan sedini mungkin selama minimal 3 bulan.
• Dapat menggunakan steroid lemah hingga kuat
• Hasil terlihat pada penggunaan hingga 12 bulan (steroid lemah) dan 6 bulan
(steroid kuat)
• Ex: fludroxycortide (weak steroid) tape, deprodone propionate (stronger steroid)
 Hypertropic Scar Treatment

Salep dan Krim Kortikosteroid

o Dikombinasikan dengan pemberian injeksi kortikosteroid: salep diaplikasikan 2-4

kali sehari selama 6 bulan setelah injeksi.
o Diperlukan edukasi penggunaan kepada pasien
Plaster kortikosteroid
 Hypertropic Scar Treatment

Laser

o Pulsed-dye Laser dengan Panjang gelombang 585 – 595nm mencapai area

angigenik pada hypertropic scar→ panas yang dihasilkan oleh laser mengurangi
aliran darah/blood flow
o Neodymium:yttrium-aluminumgarnet laser (532/1064 nm) memiliki efek yang
sama.
o Laser fraksional karbon dioksida nonablatif/abalatif tidak memiliki efek yang
menguntungkan
o Terapi laser ablatif penuh tidak di rekomendasikan karena angka kekambuhan
yang tinggi.
 Hypertropic Scar Treatment

Pembedahan/Surgery

o Indikasi: bekas luka berada di dekat atau pada sendi → kontraksinya dapat
menyebabkan disfungsi pada sendi.
o Z-plasty, W-plasty, local flaps → merupakan tehnik pembedahan tension-
release
Z-plasty surgery
 Hypertropic Scar Treatment

Terapi lainnya

o Transplantasi jaringan adiposa : menggunakan tehnik lipotransfer dan

lipoinjection
o Cryotherapy
o Injeksi 5-fluorouracil dikombinasikan dengan injeksi triamcinolone acetonide.
o Injeksi botox (type A) → dapat mencegah bekas luka dengan mengurangi
tekanan pada bekas luka dan aktivitas fibroblast.
o Injeksi bleomycin (antibiotic)→ lebih efektif daripada injeksi steroid dan atau
injeksi 5-fluorouracil
o Topical ekstrak gel bawang merah
o Tranilast oral (obat anti alergi)
 Keloid Treatment

o Gel sheets
o Injeksi kortikosteroid (dapat dikombinasi dengan 5-fluorouracil, pulsed-dye
laser, atau cryotherapy untuk hasil yang lebih baik)
o Plaster kortikosteroid (terapi lini pertama)
o Krim kortikosteroid → kekurangan: mudah terhapus
o Cryotherapy
o Antitumor dan agen imunosupresif
o Pembedahan
o Radioterapi
 Kesimpulan

Uji acak terkendal pada manajemen bekas luka patologis telah

meningkat tajam selama satu dekade terakhir. Meski penelitian
mengalami beberapa keterbatasan, penelitian tersebut telah sangat
meningkatkan manajemen bekas hypertropic scar dan keloid. Uji
coba berkualitas tinggi di masa depan kemungkinan akan
meningkatkan algoritme perawatan keloid dan hypertropic scar saat
ini lebih lanjut.
TERIMA KASIH
 HHS Public Access
Author manuscript
Int J Dermatol. Author manuscript; available in PMC 2022 June 01.
Author Manuscript

Published in final edited form as:

Int J Dermatol. 2021 June ; 60(6): 661–671. doi:10.1111/ijd.15159.

Keloids: A Review of Therapeutic Management

Samuel F. Ekstein, B.S.1, Saranya Wyles, M.D., Ph.D.2, Steven Moran, M.D.3,4, Alexander
Meves, M.D., FAAD2
1Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN
2Department of Dermatology, Mayo Clinic, Rochester, MN
3Division of Plastic Surgery, Mayo Clinic, Rochester, MN
Author Manuscript

4Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN

Abstract
Keloid scar formation arises from a disorganized fibro-proliferative collagen response that extends
beyond the original wound margins due to excessive production of extracellular matrix. Despite
treatment options for keloid scars including medical and surgical therapies such as intralesional
steroid injection and surgical excision, the recurrence rate remains high. Herein we consolidate
recently published narrative reviews, systematic reviews, and meta-analyses to provide an
overview of updated treatment recommendations for keloidal scar formation. PubMed access to
the MEDLINE database was used to investigate updates regarding keloid incidence and treatment.
More than 100 articles were reviewed. Keloid management remains a multimodal approach. There
Author Manuscript

continues to be no gold standard of treatment that provides a consistently low recurrence rate;
however the increasing number of available treatments and synergistic combinations of these
treatments (i.e., laser-based devices in combination with intralesional steroids, or 5-fluorouracil in
combination with steroid therapy) is showing favorable results. Future studies could target the
efficacy of novel treatment modalities (i.e., autologous fat grafting or stem cell-based therapies)
for keloid management. This review article provides updated treatment guidelines for keloids and
discusses insight into management to assist patient-focused, evidence-based clinical decision-
making.

Introduction
Keloid, meaning “crab’s claw,” was derived from Greek to describe its characteristic clinical
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presentation.1–3 Historically, the earliest-known keloid scarring was reported around 1700
CE Egypt in the Smith Papyrus.4 The term was first introduced into modern medical
literature in 1814.5 Later that century, a medical textbook published, “In regards to
treatment, we are almost helpless. It is pretty certain to reappear after excision, even though
the incisions be carried far into the healthy skin”.6 Today, despite various treatment options,

Address correspondence to Alexander Meves, M.D., Mayo Clinic, 200 First Street S.W., Rochester, MN 55905,
meves.alexander@mayo.edu, Phone: 507-284-2555.
Disclosures: The authors do not have any conflicts of interest and/or relevant financial relationships relevant to the work presented in
this article.
 Ekstein et al. Page 2

keloid scarring continues to escape the normal process of wound healing and remains
recalcitrant.7,8
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From a clinical perspective, keloids appear as elevated, firm bosselated papules and ill-
defined plaques accompanied by variation in color, including erythematous, violaceous, or
brown pigmentation.9 In contrast to normal and hypertrophic scarring, keloids extend
beyond the borders of original injury and fail to regress.8,9 Given their composition of
haphazardly branched and septal disorganized type I and III collagen bundles, keloids are
often symptomatic with accompanying pain and pruritus.10 Following disruption of skin
integrity resulting from superficial and deep injuries, keloids can form within months to
years later,9 causing cosmetic deformation, functional impairment, psychological distress,
and poor quality of life.10,11 A variety of epidermal to dermal insults are implicated
including iatrogenic surgical incisions, burns, trauma wounds, body piercings, insect bites,
folliculitis, chickenpox, herpes zoster infection, vaccinations, and acne.3 Keloid formation
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has also been observed following facial dermabrasion in patients on isotretinoin therapy.12
Indeed, apart from the hairless tissue of palms and soles, keloid scar distribution occurs
without topographic discrimination, including on the cornea.13

Due to the complexity and mechanical forces at work during the wound healing process, the
exact pathophysiology of keloid formation is still undetermined. Risk factors include
personal or family history of keloids, skin of color ethnic groups, pregnancy, puberty and
skin injuries overlying osteogenic surfaces.14 The incidence of keloid scaring in the
Hispanic and African American population is 4.5 to 16%.15 In African Americans, there is a
significant association between keloid scars, obesity, and hypertension.16,17 In a study
examining systemic medical conditions and keloid formation, obesity was present in 28.57%
of the keloid population as compared to 10.98% for the general population (P < 0.001).17
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Hypertension was present in 44.29% of the keloid population as compared to 15.75% of the
general population (P < 0.001).2

Despite a firm understanding of the risk factors for keloid formation, the lack of animal
models limits investigational studies into the precise mechanism of keloid formation.18 The
wound healing process that leads to tissue repair and regeneration proceeds in four time
sensitive phases: (1) hemostasis, (2) inflammation, (3) proliferation, and (4) remodeling.19
The early phase of wound healing leads to the recruitment of inflammatory cells, epithelial
cells and fibroblasts, which relocate into the wound matrix and contribute to scar
remodeling. Specifically, fibroblasts and myofibroblasts create a collagen-containing
extracellular matrix (ECM) that is in a delicate balance of synthesis and degradation.20 An
imbalance associated with collagen production and ECM degradation therefore contributes
to scar formation.20 A pro-inflammatory microenvironment triggered by dysregulated levels
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of three TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3) and other cytokines secreted by the
type 2 T-helper cell (Th2) immune response (IL-4, IL-5, IL-10, IL-13) has been postulated
to play a role in keloid formation.10,21 Furthermore, increased elastin and fibrillin-1
expression has been noted in scar elasticity.22 Recent studies suggest that keloid fibroblasts
displayed different actin filament stiffness and force generation as compared to normal
fibroblasts, which may delineate keloid extension beyond original wound margin.2,23 Keloid
fibroblasts also produce excess ECM when grown on a stiff substrate,2 partly informing the

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 Ekstein et al. Page 3

increased risk of keloid formation in high-tension body surfaces, such as chest and upper
back.2
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Despite the fact that keloid formation is classified as a benign dermal growth, it can behave
like a malignant tumor in regards to invasion and hyper-proliferation. In contrast to a keloid,
a hypertrophic scar behaves differently and contains mainly type III collagen arranged
parallel to an epidermal surface. Studies suggest a greater genetic predisposition in keloids
compared to hypertrophic scars.24 Four single-nucleotide polymorphisms (SNPs) across
three loci on chromosome bands 1q41, 3q22.3–23, and 15q21.3 associated with keloid
pathogenesis have been identified, although the mechanisms by which these SNPs contribute
to keloid formation is poorly understood.25 MicroRNA-21 signaling pathways also
contribute to keloid formation.24 Furthermore, epigenetic signaling involving histone
modification, regulatory RNA alterations, and DNA methylation are also implicated in
keloid pathogenesis.26
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Keloidal pathophysiology therefore remains multimodal and complex. There are a wide
range of therapies used in treating keloids with various degrees of success graded by time to
recurrence. Keloid treatment can be classified into medical and surgical interventions as well
as a combination including topical agents, intralesional injections, radiation and laser
therapy.27, 28 Numerous clinical trials have reported the effectiveness of various treatments
on keloid scarring. Yet variability in quality and other limitations render it difficult to
ascertain intra-trial comparison. To date, the gold standard of treatment continues to vary
across academic institutions and independent private practitioners.7 Herein, we consolidate
recently published narrative reviews, systematic reviews, and meta-analyses to provide an
overview of updated treatment recommendations for keloidal scar formation.
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Methods
This review explores current therapies available to treat keloids. The PubMed search engine
was used to access the MEDLINE database in order to search for studies pertaining to
keloids. The following search phrases were used to refine results: “Keloid/drug therapy” OR
“Keloid/therapy” OR “keloid”. The article type was limited to review, publication dates were
limited to January 1, 2016, to January 1, 2019, and species was limited to human. A total of
60 articles were identified with the above search criteria. Screening based on English
language (n=4) and relevance (n=16) excluded 20 articles (Figure 1).

Results
I. Medical Therapies
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Triamcinolone acetonide—Triamcinolone acetonide (TAC; Kenalog), an intralesional

corticosteroid injection, remains the most commonly used, first-line choice treatment for
keloid scarring.29 Corticosteroids affect multiple key pathways in the formation of keloids
by decreasing inflammation during the wound healing process.29 It also suppresses collagen
and glycosaminoglycan synthesis, reduces fibroblast development and augments collagen
degradation.29 This treatment can be used as a monotherapy on a mature keloid or as an
adjuvant to surgical excision or laser therapy. Response to TAC injections varies widely with

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 Ekstein et al. Page 4

a reported 50% to 100% regression.30 One year post- treatment, the recurrence rate is an
estimated 33%.30 After 5 years, the recurrence rate increases to 50%.30 TAC is injected at a
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dosage of 10 to 40 mg/ml into the mid-dermis every 4 to 6 weeks until the scar has resolved.
29 Side effects include skin atrophy and hypopigmentation.

Triamcinolone acetonide in combination with 5-Fluorouracil—The addition of 5-

fluorouracil (5-FU) to TAC is postulated to lower the side effect profile due to a decreased
dose requirement of each agent. Several studies have reported on this combination treatment,
however, the number of reported cases is low.31 Ren et al. report the effectiveness of
intralesional TAC alone compared to TAC in combination with 5-FU in a systematic review
and meta-analysis.31 While hypertrophic scars were not analyzed separately from keloid
scars, the combination of TAC and 5-FU was more effective than TAC alone. Effectiveness
was measured in terms of patient assessment after treatment (odds ratio (OR), 2.92; 95% CI,
1.63 to 5.22, P<0.001), observer assessment following treatment (OR, 4.03; 95% CI, 1.40 to
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11.61; P<0.01), scar height after treatment (mean differences (MD), −0.14; 95% CI, −0.23 to
–0.05; P<0.01), and erythema score (MD, −0.20; 95% CI, −0.34 to –0.06; P<0.01).31 Data
from Alexandrescu et al. support these findings.32

Mitomycin C—Mitomycin C (MMC), a derivative of Streptomyces caespitosus, is an

antibiotic agent with anti-neoplastic and anti-proliferative activities, which has been used as
a topical agent following keloid surgical excision. By inhibiting DNA, RNA and protein
synthesis, MMC prevents cell division and fibroblast proliferation.27 In a meta-analysis,
Shin and colleagues determined the recurrence rate for topical MMC to be 16.5% (95% CI,
7.9 to 31.1). Treatment consisted of 1 mg/mL MMC applied to the surgical wound for 3–5
minutes every 3 weeks.27 No adverse effects at the 1 mg/mL dose were noted.
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Bleomycin—Bleomycin is a cytotoxic agent that induces sclerosis and is commonly used

in the treatment of various malignancies.33 The first reported use of this intralesional
treatment for keloids was in 1996 and achieved a 47% remission rate.30 Illustrating the
difficulty of assessing treatment efficacy, subsequent studies report widely varying degrees
of recurrence. The lowest recurrence rate noted for this treatment is 0% at a mean duration
of 19 months follow up.34 However, another group reported recurrence rates in a Vietnamese
population of 3.8%, 15.4%, 45.5% and 50% at 6, 12, 15 and 18 months follow-up,
respectively.35 The wide range of recurrence rates based on follow-up time is also seen in
intralesional TAC treatment as discussed previously. In a study comparing intralesional
bleomycin to TAC in patients with Fitzpatrick skin types III to V, both treatments were
comparable with no significant difference in efficacy between the two groups.36 However,
there was a high rate of bleomycin induced hyperpigmentation (71.4%).36 A meta-analysis
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to standardize the efficacy of intralesional bleomycin is warranted.

Imiquimod—Imiquimod 5% cream (Aldara) is a topical immunomodulatory treatment,

which increases expression of tissue necrotic factor alpha (TNF-α), gamma and alpha
interferons (IFN-γ and α), and interleukin 1, 6, 8, 12. It also acts as a Toll-like receptor
(TLR) agonist. A meta-analysis of topical 5% imiquimod cream applied for 6–8 weeks post-

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 Ekstein et al. Page 5

keloid excision showed that the rate of recurrence was 24.7% (95% CI, 3.2 to 76.4); variable
outcomes were reported.27
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Botulinum A—Use of botulinum toxin-A (BoNT-A) in keloid treatment is based on its

ability to reduce muscle tension and thereby wound tension.37 BoNT-A has been reported to
decrease TGF-β expression, reduce fibroblast proliferation and alter collagen activity during
pathologic scar formation.38 A meta-analysis of treating keloids with BoNT-A remains to be
conducted, however, Schlessinger and colleagues reviewed several small studies that have
been performed to date.39 Efficacy of BoNT-A in keloid treatment is not definitive with
studies showing mixed results.39 Interestingly, a meta-analysis of randomized controlled
trials has been conducted on hypertrophic scars in the maxillofacial area and neck, which
showed a statistically significant difference in scar width, patient satisfaction and visual
analysis scores in the treatment of hypertrophic scars.40 While BoNT-A has been reported to
be effective in hypertrophic scar prevention, its use in keloid treatment remains uncertain.
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Interferons—Immune-response modifiers, interferon alpha and gamma (IFN-α and IFN-

γ), are observed at decreased concentrations in keloids.41 Interferons exert anti-viral, anti-
proliferative and anti-fibrotic properties.42 Indeed, IFN-γ and IFN-α antagonize TGF-β
stimulated collagen metabolism in vitro.43 Treating keloids with intralesional interferon
injections have had varying levels of success with adverse reactions, including systemic flu-
like symptoms, pain at the injection site, edema and erythema reported.42,44 IFN-α−2b did
not demonstrate efficacy in treating keloids.45 Al-Khawajah et al. reported that cases that
withdrew due to local pain (n=7 out of 22 patients) during injection and due to severe
systemic symptoms following the first injection (n=2 out of 22 patients).45 Other studies
demonstrate more favorable results. Berman et al. found that intralesional IFN-α−2b
injections into a keloid resulted in a 41% reduction in area.46 In a larger study (n=124) on
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interferon injections following keloid excision, IFN-α−2b demonstrated a lower recurrence

rate (18.7%) compared to TAC (58.5%) and excision alone (51.2%).47

Onion extract (Allium cepa)—Onion extract (Allium cepa) has been shown to
significantly improve dermal collagen organization in animal model scars.48 Additionally,
the derivative of Allium cepa, quercetin, displays anti-proliferative and anti-histamine
effects.48 The majority of trials to date tested this treatment on non-keloidal scars. In a study
by Wananukul and colleagues, 10% onion extract in silicone derivative gel significantly
decreased the incidence of hypertrophic scar formation from median sternotomy.49 However,
no significant difference in keloid incidence between treatment and placebo groups was
observed.49 The use of onion extract may be better suited for combination therapy. When
intralesional TAC alone was compared to TAC with onion extract to treat keloid and
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hypertrophic scars, the TAC with onion extract group demonstrated a statistically significant
improvement in pain-sensitiveness, pruritus, and elevation at week 20.50 Although, no
significant difference in erythema or induration was seen between treatment groups.50 An
additional study examining keloid and hypertrophic scars compared the following three
treatment arms: onion extract alone, silicone gel sheet alone, and combination onion extract
and silicon sheet.51 While onion extract alone was more effective in improving scar color,

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 Ekstein et al. Page 6

the silicone gel sheet was more effective in reducing scar height.51 The combination of these
treatments provided the best response.51
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Laser-based devices—Forbat and colleagues reviewed the effectiveness of light-, laser-,

and energy-based devices in the management of keloid scars.28 Laser-based devices can be
divided into ablative and non-ablative categories. Ablative lasers remove the epidermal layer
and include erbium-doped yttrium aluminium garnet (Er: YAG) and carbon dioxide (CO2)
lasers. Non-ablative lasers target the dermis and include potassium titanyl phosphate (KTP),
pulsed dye (PDL) and neodymium-doped yttrium garnet (Nd:YAG) lasers.28,52 For CO2
laser treatments, keloid recurrence was noted between 2 weeks and 3 years post-laser.
Treatment with the Er:YAG laser resulted in a 22% recurrence rate at 8 months post-laser.
Nd:YAG laser exhibited recurrence rates that differed based on keloid site at 6 months post-
laser; 52.9% recurrence for anterior chest, 35.7% recurrence for upper arms and 25% for
scapula keloids. While this data is promising for the use of multiple laser sub-categories,
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additional randomized controlled trials are warranted to determine the effectiveness. Khansa
et al. reported a similar conclusion that laser-based devices produced variable results.53
Higher Fitzpatrick skin types are at a greater risk of adverse effects from laser therapy, and
thus the efficacy of laser-based devices to treat keloids in skin of color ethnic groups is not
widely studied.28 In one study evaluating the 1064 nm Nd:YAG laser on patients with
Fitzpatrick skin types I to VI, post-inflammatory pigmentation changes were not observed.54
The Nd:YAG laser may therefore be an acceptable option for patients with darker skin types
IV to VI.54

Laser-based devices in combination with TAC—Pulsed-dye laser (PDL) is a non-

ablative laser that can attenuate keloidal pain and pruritus53 but is limited in its ability to
decrease scar size. PDL alone appears to downregulate TGF-β1 expression with no impact
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on type I collagen formation.53,55 Therefore, PDL in combination with TAC may provide a
synergistic effect as corticosteroids also contribute to reducing collagen synthesis and
increasing collagen degradation.29,53 Combination of these modalities yielded a 60%
improvement in height, 40% improvement in erythema and 75% improvement in pruritus;
however the sample size was small (n=7).56

Improved results with the CO2 and Nd:YAG lasers in combination with TAC have also been
noted.30 Specifically, Stucker et al. demonstrated that intralesional TAC halts early
recurrences of keloids treated with the CO2 laser.57 Another study using CO2 laser with
intralesional TAC over 6 months noted a significant increase in recurrence of keloids in
patients who did not follow-up regularly for TAC injections.58 Kumar et al. noted an additive
effect of TAC and Nd:YAG laser; keloids that persisted following Nd:YAG laser therapy
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were subsequently treated with intralesional TAC, resulting in complete resolution over 18
months to 5 years of follow-up.59

Cryotherapy—Traditional cryotherapy involves using freeze-thaw cycles to damage scar

tissue. Consequent damage to the surrounding skin surface gave rise to a more targeted
approach of intralesional cryotherapy in which a specialized needle probe freezes the scar
from the inside.60,61 A comprehensive review of eight studies found this approach favorable
in reducing scar volume, pain, and pruritis.62 However, persistent hypopigmentation in

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Fitzpatrick 4–6 skin types was observed and recurrence rates varied widely between 0% to
24%.62
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II. Surgical Therapy

Excision—Excising keloids without secondary intervention generally results in a poor
outcome. Excision alone results in a recurrence rate of greater than 50%.63 While certain
wound closure techniques reduce tension at the wound site, no data supports whether a
specific wound closure technique reduces the likelihood of keloid recurrence. However, a
tensionless closure following excision is considered important in reducing scar hypertrophy
and scar widening.64

III. Combined Medical and Surgical Therapies

Triamcinolone acetonide following excision—A recent meta-analysis reported
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whether triamcinolone intralesional injection following surgical excision prevented the

recurrence of keloids.65 Researchers analyzed 4 studies comprising 254 patients and found
that surgery combined with TAC was not effective in lowering the rate of keloid recurrence
with a pooled risk difference of 0.06 (95% CI, −0.16 to 0.28; P, not significant).65 However,
the location of the keloid may be associated with the success of TAC following excision. Ear
keloids exhibited increased responsiveness to TAC following excision.66 In a meta-analysis
examining the use of TAC following excision of ear keloids, the recurrence rate was 15.4%
(95% CI, 9.4 to 24.1%; P<0.001) proving to have similar efficacy as radiotherapy following
excision.66

5-Fluorouracil following excision—5-Fluorouracil (5-FU) is an anti-neoplastic

pyrimidine analog that has an inhibitory effect on fibroblasts.65 Shin and Kim conducted a
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meta-analysis on whether 5-FU prevents keloid recurrence following surgical excision.65

Following analysis of 2 studies with 107 total patients, keloid recurrence was statistically
lower in patients treated with 5-FU (risk ratio, 0.18; 95% CI, 0.04 to 0.75; P=0.02).65 Most
studies injected 50 to 150 mg of 5-FU to the excision border and wound bed following
keloid removal.65

Radiotherapy following excision—Use of radiotherapy for keloid treatment was first

described in 1906.5 Radiotherapy disrupts the normal wound healing process and can
therefore be administered directly to a mature keloid or following surgical excision to
prevent keloid re-formation. Mankowski and colleagues conducted a meta-analysis
systematic review on radiation-based treatments involving 72 studies and 9048 keloids.63
Their data demonstrated that post-excisional radiotherapy was more effective in preventing
recurrence than radiotherapy alone (22% and 37% recurrence rate, respectively, p=0.005).63
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However, radiation as a monotherapy may be recommended when treating elderly patients

for whom surgical removal may not be a viable option due to location or size. Additionally,
radiotherapy applied to mature keloid has been reported to reduce pain and pruritus.67 In
comparing radiation modalities, post-operative brachytherapy had the lowest recurrence rate
of 15%, compared to a 23% recurrence rate for x-ray and 23% recurrence rate for electron
beam radiation.63 In a separate meta-analysis examining ear keloids, radiotherapy following

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 Ekstein et al. Page 8

surgical excision proved to be effective with a recurrence rate of 14.0% (95% CI, 9.6 to
19.9%; P < 0.001).66
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Furthermore, several studies have reported that excision followed by radiation is safe and
practical.1,63 The most common side effect reported for radiotherapy treatment was
alterations in skin pigmentation including erythema, transient hyperpigmentation,
hyperpigmentation, hypopigmentation, and unspecified pigmentation changes with a total
occurrence of 32.5%.63 Mankowski and colleagues also found that chest keloids have the
highest recurrence rate.63

Pressure therapy following excision—Pressure therapy involves the use of specialized

garments or devices, such as Zimmer splints or magnets to apply a prolonged state of
pressure to the skin.68,69 It is hypothesized that the added pressure modifies wound tension
and causes localized hypoxia.68,70 A meta-analysis examining trials using pressure garments
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to prevent scar formation in burn patients did not report a difference in global scar
assessment between pressure garment treated scars and non-pressure treated scars.71
However, several observational studies using pressure therapy following surgical excision
for ear keloids demonstrate favorable results with recurrence rate of 6.7% to 10.6%.68,69,72
One trial reported a 0% recurrence rate, however, a corticosteroid injection was combined
with pressure therapy following surgical excision, and the study population was small (n=7).
73

Topical silicone following excision—Silicone for prevention of keloids is a pragmatic

form of at-home treatment. Its exact mechanism of action is yet to be elucidated; however
postulated explanations include decreased skin stretching, occlusion, and hydration.7,74
While early studies of silicone gel sheeting suggested high success rates in treating keloids
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and hypertrophic scars, meta-analyses conclude silicone is not an effective treatment

modality for the prevention of keloids.30,75,76 Hsu and colleagues reviewed the effectiveness
of silicone for prevention of keloid scarring in patients with new wounds by evaluating 10
trials that were designed with a treatment and placebo arm.74 Topical silicone did not
provide a significant difference in the prevention of keloids in patients who have a history of
abnormal scarring.74 Furthermore, Cochrane systematic review analyzing 20 clinical trials
concluded that there is weak evidence supporting the use of silicone gel sheeting as a means
of prevention of abnormal scarring, however improvements in scar color and thickness were
observed.77 Silicone can be applied to the skin in the form of a silicone gel sheet or a topical
silicone gel for 12–24 hours per day with twice daily washing for a minimum of 1 month.78

IV. New therapeutic developments

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Verapamil, a calcium channel blocker, which alters fibroblast gene expression resulting in
reduced collagen synthesis and increased collagenase, has been utilized in keloidal
treatment.4 Studies using intralesional verapamil following surgical excision or alone
reported a wide efficacy range from 1.4 to 48% recurrence.79 Its efficacy has been reported
similar to TAC injections; high-quality trials are needed to define the role of verapamil in
keloid treatment.80

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Ultraviolet A1 (UV-A1) phototherapy in the spectral range of 340–400 nm induces increased

collagenase activity.4 Evidence supports its use for fibrosing disorders, including localized
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scleroderma, lichen sclerosus et atrophicus and graft-versus-host disease.81 Only few studies
to date have tested UV-A1 phototherapy in treating keloids in a total of 6 patients with
mixed results.82–84

Other agents that may have a potential role in keloid treatment include tamoxifen and
calmodulin inhibitors. Tamoxifen citrate is a non-steroidal anti-estrogen that downregulates
TFG-β, fibroblast and collagen expression.85 Similarly, calmodulin inhibitors may also
result in scar degradation and warrant further study.4

Angiotensin-converting enzyme inhibitors (ACEIs) affects wound healing by reducing

collagen synthesis, TGF-β1 expression, and fibroblast proliferation.86 Topical enalapril
significantly reduced the mean size of hypertrophic scars in a double-blinded clinical trial.87
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One case report observed improvement in keloid scarring following oral enalapril.88 Topical
captopril used in a separate case report on a post-burn keloid demonstrated improvement in
the lesion and reduced redness, scaling, and itchiness.89

A new alternative to topical silicone is a combination of silicone oil with hypochlorous acid
(HOCL); it is a gel or spray that can be applied twice daily.90 HOCL has an antimicrobial,
antipruritic and anti-inflammatory role by increasing oxygenation and disrupting biofilm
formation.90 Anecdotal reports suggest that HOCL gel performed better than 100% silicone
gel in the management of keloid and hypertrophic scars.90

Apligraf® is a living, human, bi-layered skin substitute that promotes wound healing.91
FDA approved its use for venous leg ulcers and diabetic foot ulcers.91 The potential of using
neodermal products for restructuring keloids continues to be an area of exploration with few
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case reports available in the literature and a pilot study with a small number of participants.
92

Mammalian target of rapamycin (mTOR) is a potential therapeutic target for keloids.93

Research suggests mTOR plays a role in the regulation of collagen expression and decreases
ECM deposition when inhibited.93 It is therefore postulated targeting mTOR with rapamycin
therapy may block excess fibroproliferation leading to abnormal scarring.94 Indeed,
rapamycin treatment of human fibroblasts in vitro blocks collagen synthesis pathways that
are significantly increased in keloid scarring.94

TGF-β1, TGF-β2 and TGF-β3 isoforms appear to have interrelated roles in keloid
pathogenesis.95 The TGF-β3 isoform in particular has been studied in clinical trials.95
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Intradermal avotermin (recombinant TGF-β3) was administered prophylactically to improve

scarring in three double-blind, placebo-controlled, phase I/II studies.96 However, it appears
the phase 3 clinical trial in 2011 did not accomplish its endpoints leading the company to
conclude avotermin may not provide significant benefit for scar revision.97 Efficacy of
targeting other TGF-β isoforms remains to be further investigated.95

miRNAs (microRNA) are non-coding RNAs that silence genes at the post-transcriptional
level.98 The expression of miRNAs in keloidal fibroblasts are expressed at different

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 Ekstein et al. Page 10

concentrations compared to normal fibroblasts.99 A growing body of research suggests

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specific miRNAs, such as miRNA-29 and miRNA-21–5p, appear to play key roles in keloid
development providing additional targets for novel therapeutics.100,101

Discussion
Understanding fibro-proliferative process of keloid pathogenesis and achieving scar
resolution through treatment modalities has behooved clinical investigators for decades.
Herein we have categorized treatment options into medical, surgical or combination
therapies. In this review, excision alone was the least effective method of treatment (Table
1). While TAC is a current mainstay of keloid management, it is not effective in lowering the
rate of recurrence when administered following excision.65 However, effectiveness may
depend on the location of the keloid as excision followed by TAC was effective for ear
keloids.66 Anatomical location also influences the responsiveness to laser-based devices and
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pressure therapy. TAC appears to be effective in the management of mature keloids,

however, repeated injections may be needed as the recurrence rate increased 27% from year
1 post-treatment to year 5 post-treatment30.

Chemotherapeutics and immunomodulatory agents, 5-fluorouracil, mitomycin C,

imiquimod, and bleomycin are each effective for keloid management (Table 1). Yet long
term follow-up to 5 years post-treatment is lacking. Mitomycin C may reduce recurrence
rates compared to imiquimod. In the meta-analysis conducted comparing mitomycin C to
imiquimod, mitomycin C proved to have greater efficacy in terms of recurrence rates.27
Furthermore, TAC in combination with 5-fluorouracil was more effective in reducing
hypertrophic and keloid scar recurrence compared to TAC alone.31,32 One mechanism could
involve 5-fluorouracil inhibiting the expression of type I collagen gene that is induced by
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TGF-β; thereby inhibiting excess collagen synthesis similar to corticosteroids.102

Laser-based devices and forms of radiotherapy have also been effective in the treatment of
keloids (Table 1). Efficacy varied by laser type. CO2 laser is least effective, while the
Er:YAG laser resulted in a 22% keloid recurrence rate.28 The Nd:YAG laser shows varying
results based on keloid location with a recurrence rate ranging from 25% for scapular
keloids to 52.9% for keloids located on the anterior chest.28 Radiotherapy showed promising
results following excision. Recurrence rates varied based on radiation type with electron
beam and x-ray resulting in a 23% recurrence rate and brachytherapy resulting in a 15%
recurrence rate.1,63,67 (Table 1)

Future areas of interest include the use of stem cells in preventing keloid formation. Certain
stem cell types such as mesenchymal stem cells and umbilical cord blood stem cells can
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provide antioxidant effects and reduce inflammation during the wound healing process.103
However, their translation into clinical application continues to be limited due to unresolved
concerns related to safety, potential tumorigenicity and effects on fibroblasts.103 Autologous
fat grafting is another method that is being tested due to the lack of adequate results with the
current treatments available.104 Silva and colleagues reviewed the studies of this treatment
for hypertrophic scars and keloids.104 Due to the limited number of studies and hypertrophic

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scars being grouped with keloids, more data is needed to determine the efficacy of this
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therapy.

Conclusion
As keloid pathogenesis becomes better understood, additional mechanistic targets will be
elucidated paving the way for more effective treatments. Further research into tumor growth
and metastasis may provide further insight into keloid pathogenesis. Similarities between
keloid scar formation, tumor growth, and metastasis have been observed, including over-
expression of collagen triple helix repeat containing-1 (CTHRC1), fibroblast activation
protein alpha (FAP-α), and dipeptidyl peptidase IV (DPPIV).105,106 For now, keloid
management remains a multimodal approach. There continues to be no single treatment
available that provides a consistently low recurrence rate. An increasing number of studies
are examining the combination of existing treatments for a synergistic effect. This includes
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laser-based devices in combination with TAC, and 5-FU in combination with TAC. These
combinations are providing favorable outcomes when compared to monotherapy.

Based on the most recent evidence, brachytherapy following excision provides the lowest
rate of recurrence. For ear keloids, specifically, pressure therapy following excision is the
most efficacious based on observational studies. However, in clinical practice, the patient
and physician may opt to a minimally invasive, cost-effective treatment initially. In these
circumstances, multiple TAC injections may be first line, followed by combination therapies
if adequate results with TAC alone are not achieved. Treatment option may be limited to
physician preference and resources available. Radiotherapy is limited to larger, well-funded
medical establishments. Low cost and minimally invasive TAC injections may explain why
TAC, while less effective than other modalities, is the most common form of treatment
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today.

There continues to be a need for randomized studies with larger sample sizes and longer
follow-up time. Robust keloid patient registries could help assess additional risk factors,
systemic medical conditions associated with keloid formation and effectiveness of various
treatments. As discoveries in keloid pathogenesis unfold, targeted treatment can be designed
to halt mechanistic checkpoints implicated in this type of scar formation. Keloids continue to
have no gold standard of treatment; however the increasing number of treatments available
and synergistic combinations of these treatments is showing favorable results. Future studies
could target the efficacy of novel treatment modalities and the use of combination therapies
for the management of keloids.

1. The following is true about keloids:

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a. Keloids are benign fibroproliferative skin tumors growing beyond the

site of original dermal injury

b. Keloids are malignant fibroproliferative skin tumors growing beyond

the site of original dermal injury

c. Keloids are benign fibroproliferative skin tumors limited to the site of

original dermal injury with high rates of recurrence

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 Ekstein et al. Page 12

d. Keloids are benign fibroproliferative skin tumors limited to the site of

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original dermal injury with low rates of recurrence

2. True or false: Given their composition of haphazardly branched and septal

disorganized type I and III collagen bundles, keloids are often symptomatic with
accompanying pain and pruritus.

3. Which of the following is considered to be a risk factor associated with keloids?

a. Personal or family history of keloids

b. Skin of color ethnic groups

c. Pregnancy

d. Puberty
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e. Skin injuries overlying osteogenic surfaces

f. All of the above

4. True or false: Pro-inflammatory microenvironment triggered by excess TGF-β

and elevated production of certain cytokines has been postulated to play a role in
keloid formation.

5. What is the correct order of four time sensitive wound healing phases?

a. (1) Inflammation (2) Hemostasis (3) Proliferation (4) Remodeling

b. (1) Inflammation (2) Hemostasis (3) Remodeling (4) Proliferation

c. (1) Hemostasis (2) Inflammation (3) Proliferation (4) Remodeling

d. (1) Hemostasis (2) Inflammation (3) Remodeling (4) Proliferation

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6. How do corticosteroids (i.e. intralesional triamcinolone) affect keloid formation?

a. Decrease inflammation during would healing process

b. Increases collagen and glycosaminoglycan synthesis

c. Reduces fibroblast development

d. Augments collagen degradation

e. A, C and D are correct

f. A, B and C are correct

7. Which of the following lasers is a potential option for keloid treatment in

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patients with darker skin types (Fitzpatrick IV to VI)?

a. Ablative erbium-doped yttrium aluminium garnet laser (Er:YAG)

b. Ablative yttrium-scandium-gallium-garnet laser (YSGG)

c. Ablative carbon dioxide laser (CO2)

d. Non-ablative neodymium-doped yttrium garnet laser (Nd:YAG)

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8. True or false: Excising keloids without secondary intervention generally results

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in a good outcome with minimal recurrence rate.

9. Recent studies have proposed that mesenchymal stem cells and umbilical cord
blood stem cells affect wound healing and reduce scar formation. What is the
proposed mechanism?

a. Reduces antioxidant and anti-inflammatory effects during wound

healing

b. Improves antioxidant and anti-inflammatory effects during wound

healing

c. It is unknown

10. True or false: There continues to be no gold standard of keloid treatment that
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provides a consistently low recurrence rate.

Answers

1. A 6. E

2. True 7. D

3. F 8. False

4. True 9. B

5. C 10. True
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Acknowledgments
Funding: This work was supported by the National Cancer Institute; grant CA215105.

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Figure 1.
Flowchart of study identification in literature review.
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 Ekstein et al. Page 21

Table 1.

Efficacy of medical and surgical treatments on keloid scars

Author Manuscript

Mean Recurrence Mean Follow-up

Category Treatment References
Rate (%) (months)

33 12 Morelli Coppola et al, 2018 30

Triamcinolone acetonide
50 60 Morelli Coppola et al, 2018 30

Er:YAG laser 22 8 Forbat et al, 2017 28

Nd:YAG laser 25 to 52.9 6 Rossi et al, 2013 42

Shin et al, 2017 27

Medical Mitomycin C 16.5 ≥6
Rossi et al, 2013 42

Imiquimod 24.7 ≥6 Shin et al, 2017 27

Morelli Coppola et al, 2018 30

Bleomycin 0 to 50 6 to 19 Saray et al, 2005 34
Hu et al, 2019 35
Author Manuscript

Intralesional cryotherapy 0 to 24 6 to 21.5 van Leeuwen et al, 2015 51

Surgical Excision >50 6 to 12 Mankowski et al, 2017 52

Triamcinolone acetonide after

excision
15.4 12 to 35 Shin et al, 2016 54, 55

Brachytherapy after excision 15 14.4 Mankowski et al, 2017 52

Combined (Medical X-ray after excision 23 14.4 Mankowski et al, 2017 52
and Surgical)
Electron beam after excision 23 14.4 Mankowski et al, 2017 52

Pressure therapy after Park et al, 2011 57

6.7 to 10.6 18
excision Park et al, 2013 61

Er:YAG, erbium-doped yttrium aluminium garnet; Nd:YAG, neodymium-doped yttrium garnet

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Hypertrophic Scarring and Keloids: Pathomechanisms and
Current and Emerging Treatment Strategies

Gerd G Gauglitz,1,2 Hans C Korting,1 Tatiana Pavicic,1 Thomas Ruzicka,1 and Marc G Jeschke2,3,4,5
1
Department of Dermatology and Allergology, Ludwig Maximilians University, Munich, Germany; 2Shriners Hospitals for Children,
Department of Surgery, University Texas Medical Branch, Galveston, Texas, United States of America; 3Ross Tilley Burn Centre and
4
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; and 5Department of Surgery, Division
of Plastic Surgery, University of Toronto, Toronto, Ontario, Canada

Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any insult to the deep der-
mis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient’s quality of life, both physically
and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led
to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches
remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of
scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid
and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.
© 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org
Online address: http://www.molmed.org
doi: 10.2119/molmed.2009.00153

INTRODUCTION the initial site of injury, keloids typically fection, wound closure with excess ten-
A total of 100 million patients develop project beyond the original wound mar- sion or other traumatic skin injury (7), has
scars in the developed world alone each gins (3,4). Nevertheless, clinical differenti- a rapid growth phase for up to 6 months,
year as a result of 55 million elective op- ation between hypertrophic scars and and then gradually regresses over a pe-
erations and 25 million operations after keloids can be problematic. Incorrect riod of a few years, eventually leading to
trauma (1). Excessive scars form as a re- identification of scar type may result in flat scars with no further symptoms (8,9).
sult of aberrations of physiologic wound inappropriate management of pathologic Keloids, in contrast, may develop up to
healing and may develop following any scar formation, and occasionally con- several years after minor injuries and may
insult to the deep dermis, including burn tribute to inappropriate decision making even form spontaneously on the midchest
injury, lacerations, abrasions, surgery, related to elective or cosmetic surgery (5). in the absence of any known injury.
piercings and vaccinations. By causing Although there are clinical similari- Keloids also persist, usually for long peri-
pruritus, pain and contractures, excessive ties between hypertrophic scars and ods of time, and do not regress sponta-
scarring can dramatically affect a pa- keloids, there are some clinical, histo- neously (10). Keloids appear as firm,
tient’s quality of life, both physically and logical and epidemiological differences mildly tender, bosselated tumors with a
psychologically. (Table 1 and Figure 1) that indicate that shiny surface and sometimes telangiecta-
Excessive scarring was first described these entities may be distinct from one sia. The epithelium is thinned and there
in the Smith papyrus about 1700 BC (2). another (5,6). may be focal areas of ulceration. The color
Many years later Mancini (in 1962) and is pink to purple and may be accompa-
Peacock (in 1970) differentiated excessive HYPERTROPHIC SCARS VERSUS KELOIDS nied by hyperpigmentation (11). The bor-
scarring into hypertrophic and keloid ders of the tumor are well demarcated but
scar formation. Per their definition, both Clinical Characteristics irregular in outline. A hypertrophic scar
scar types rise above skin level, but while Hypertrophic scarring usually occurs has a similar appearance, but is usually
hypertrophic scars do not extend beyond within 4 to 8 weeks following wound in- linear, if following a surgical scar, or
papular or nodular, following inflamma-
tory and ulcerating lesions (12). Both le-
Address correspondence and reprint requests to Marc Jeschke, Sunnybrook Research sions are commonly pruritic, but keloids
Institute, Rm D704, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: may even be the source of significant pain
416-480-6703; Fax: 416-480-6763; E-mail: marc.jeschke@sunnybrook.ca. and hyperesthesia (7,9).
Submitted October 22, 2009; Accepted for publication October 4, 2010; Epub In the majority of cases, hypertrophic
(www.molmed.org) ahead of print October 5, 2010. scarring develops in wounds at anatomic

M O L M E D 1 7 ( 1 - 2 ) 1 1 3 - 1 2 5 , J A N U A R Y- F E B R U A R Y 2 0 1 1 | G A U G L I T Z E T A L . | 1 1 3
HYPER TR OPHIC SCARS AND KELOIDS

Table 1. Hypertrophic scars and keloids: epidemiological, clinical and histological differences.

Hypertrophic scarring Keloids

Incidence 40% to 70% following surgery, up to 91% following 6% to 16% In African populations
burn injury
Equal in sex distribution with highest incidence in the second to third decade

Predilection sites Shoulders, neck, presternum, knees and ankles Anterior chest, shoulders, earlobes, upper arms and
cheeks
Less affected: eyelids, cornea, palms, mucous membranes, genitalia and soles

Time course Within 4 to 8 weeks following wounding, rapid
growth phase for up to 6 months, then regression
over a period of a few years
Low recurrence rates after excision of the original
hypertrophic scar
Within years after minor injuries or spontaneous
formation on the midchest in the absence of any
known injury. Persistence for long periods of time.
No spontaneous regression
High recurrence rates following excision

Appearance Do not extend beyond the initial site of injury Projects beyond the original wound margins

Histological characteristics
Primarily fine, well-organized, wavy type III collagen
bundles oriented parallel to epidermis surface with
abundant nodules containing myofibroblasts and
plentiful acidic mucopolysaccharide. Proliferating
cell nuclear antigen (PCNA)/p53-level/ATP
expression low
Disorganized, large, thick, type I and III hypocellular
collagen bundles with no nodules or excess
myofibroblasts. Poor vascularization with widely
scattered dilated blood vessels. PCNA/p53-level/ATP
expression high

locations with high tension, such as
shoulders, neck, presternum, knees and
ankles (9,12,13), whereas anterior chest,
shoulders, earlobes, upper arms and
Figure 1. Clinical appearance of hyper-
trophic scars and keloids. Development of
hypertrophic scars after a scald burn (A);
hypertrophic scar on lower leg 4 months
after surgical procedure (B); keloid on
chest after two minor operations (C); keloid
on right ear, no history of trauma (D).
cheeks have a higher predilection for
keloid formation. Eyelids, cornea, palms,
mucous membranes, genitalia and soles
are generally less affected (14). Keloids
tend to recur following excision, whereas
new hypertrophic scar formation is rare
after excision of the original hyper-
trophic scar (13,15).
Histology
Histologically, both hypertrophic scars
and keloids contain an overabundance of
dermal collagen. Hypertrophic scars con-
tain primarily type III collagen oriented
parallel to the epidermal surface with
abundant nodules containing myofibrob-
lasts, large extracellular collagen filaments
and plentiful acidic mucopolysaccharides
(6). Keloid tissue, in contrast, is mostly
composed of disorganized type I and III
collagen, containing pale-staining hypocel-
lular collagen bundles with no nodules or
excess myofibroblasts (Table 1) (6,16). Both
scar types demonstrate overproduction of
multiple fibroblast proteins, including fi-
bronectin, suggesting either pathological
persistence of wound healing signals or a
failure of the appropriate downregulation
of wound-healing cells (16).
Epidemiology
The occurrence of keloids and hyper-
trophic scars has equal sex distribution
and the highest incidence in the second to
third decade (17,18). Incidence rates of hy-
pertrophic scarring vary from 40% to 70%
following surgery to up to 91% following
burn injury, depending on the depth of
the wound (19,20). Keloid formation is
seen in individuals of all races, except al-
binos, but dark-skinned individuals have
been found to be more susceptible to
keloid formation, with an incidence of 6%
to 16% in African populations (14,21). The
concept of a genetic predisposition to
keloids has long been suggested, because
patients with keloids often report a posi-
tive family history, unlike patients suffer-
ing from hypertrophic scarring. Bayat and
colleagues (22) compared the profiles of
patients of Afro-Caribbean origin with
keloid scars at single versus multiple
anatomical site and found the latter to be
more common in younger age groups and
in females. An important finding was that
more than 50% of all keloid patients had a
positive family history of keloid scarring,
and family history was strongly associ-
ated with the formation of keloid scars in

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 REVIEW ARTICLE

multiple sites as opposed to a single

anatomical site. Marneros and colleagues
(23) studied two families with an autoso-
mal-dominant inheritance pattern of
keloids and identified linkage to chromo-
some 7p11 and chromosome 2q23 for the
African and Japanese family, respectively.
Brown and colleagues (24) found a ge-
netic association between HLA-DRB1*15
status and the risk of developing keloid
scarring in white individuals. Also, carri-
ers of HLA-DQA1*0104, DQB1*0501 and
DQB1*0503 have been reported to be have
an increased risk of developing keloid
scarring (24). Keloid growth may also be
stimulated by various hormones, as indi-
cated by some studies in which results
have suggested a higher incidence of
keloid formation during puberty and
pregnancy, with a decrease in size after
menopause (18,25,26). Also, immunologic
associations of keloids have been pro-
posed. A study by Placik and Lewis (27)
revealed a direct correlation between the Figure 2. Differences between normal wound healing and excessive scar formation over
time. Processes of wound repair follow a specific time sequence and can be temporally
incidence of keloid formation and levels
grouped into three distinct phases: inflammation (I), proliferation (II) and remodeling (III).
of serum immunoglobulin E, and Smith et
Platelet degranulation is responsible for the release and activation of an array of potent
al. (28) found a higher incidence of aller- cytokines, which serve as chemotactic agents for the recruitment of, for example,
gic symptoms in keloid-afflicted patients macrophages, neutrophils, epithelial cells and fibroblasts. In normal wounds, a balance is
compared with individuals with hyper- achieved between new tissue biosynthesis and degradation mediated by apoptosis and
trophic scars, suggesting a possible role of remodeling of ECM (A). During excessive scar formation, a dysfunction of the underlying
mast cells in the pathophysiology of regulatory mechanisms may lead to persistent inflammation, excessive collagen synthesis
keloid formation. Other investigators or deficient matrix degradation and remodeling (B).
have reported an association between the
formation of keloids and blood type A factor (IGF-I), platelet-derived growth the wound is closed, the immature scar
(14,29). factor (PDGF) and transforming growth can transition into the final maturation
factor β (TGF-β), which serve as chemo- phase, which may last several months.
PATHOPHYSIOLOGY OF EXCESSIVE tactic agents for the recruitment of neu- The abundant ECM is then degraded and
SCAR FORMATION trophils, macrophages, epithelial cells, the immature type III collagen of the
The physiologic response to wound- mast cells, endothelial cells and fibrob- early wound can be modified into mature
ing in adult tissue is the formation of a lasts (14,30). Within 48 to 72 hours after type I collagen (6).
scar, a process that can be temporally the initial event, the healing process tran- The transformation of a wound clot
grouped into three distinct phases (Fig- sitions into the proliferation phase, which into granulation tissue thus requires a
ure 2): inflammation, proliferation and may last for up to 3 to 6 weeks (6). Re- delicate balance between ECM protein
remodeling (14). cruited fibroblasts synthesize a scaffold of deposition and degradation, and when
Immediately following wounding, reparative tissue, the so-called extracellu- this process is disrupted, abnormalities
platelet degranulation and activation of lar matrix (ECM). This granulation tissue in scarring appear, resulting in either
the complement and clotting cascades is made of procollagen, elastin, proteogly- keloid or hypertrophic scar formation.
form a fibrin clot for hemostasis, which cans and hyaluronic acid and forms a Both lesions represent aberrations in
acts as a scaffold for wound repair (30). structural repair framework to bridge the the fundamental processes of wound
Platelet degranulation is responsible for wound and allow vascular ingrowth (6). healing, in which there is an obvious im-
the release and activation of an array of Modified fibroblasts, so-called myofi- balance between the anabolic and cata-
potent cytokines, such as epidermal broblasts, which contain actin filaments, bolic phases; however, keloids seem to
growth factor (EGF), insulinlike growth help to initiate wound contraction. Once be a more sustained and aggressive fi-

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HYPER TR OPHIC SCARS AND KELOIDS
brotic disorder than hypertrophic scars
(31). Evidence to date strongly suggests a
more prolonged inflammatory period,
with immune cell infiltrate present in the
scar tissue of keloids, the consequence of
which may contribute to increased fi-
broblast activity with greater and more
sustained ECM deposition (31). The elu-
cidation of this process may help to ex-
plain why keloid scars spread beyond
the margins of the original wound, while
hypertrophic scars, in which the immune
cell infiltrate decreases over time, remain
within the original wound margins and
often regress over time. However, only a
few published studies on the pathophys-
iology of keloid and hypertrophic scar
formation have included direct compari-
son of the two entities.
Inflammation
Recent evidence suggests that it is not
simply the severity of inflammation that
predisposes individuals to hypertrophic
and keloid scarring, but also the type of
immune response (31). T-helper (Th)
CD41 cells have been implicated as
major immunoregulators in wound heal-
ing. The characteristic cytokine expres-
sion profile of the CD41 T cells repre-
sents the basis for describing either a
predominantly Th1 or Th2 response to a
specific or unspecific stimulus (32).
While the development of a Th2 re-
sponse (with production of interleukin
[IL]-4, IL-5, IL-10 and IL-13) has been
strongly linked to fibrogenesis, a pre-
dominance of Th1 CD41 cells has been
shown to almost completely attenuate
the formation of tissue fibrosis via pro-
duction of interferon-γ (IFN-γ) and IL-12
(33,34).
Secretion and activation of these medi-
ators during the inflammatory phase of
healing are prerequisites for subsequent
processes, such as angiogenesis, reepithe-
lialization, recruitment and proliferation
of fibroblasts and matrix deposition (30).
Angiogenesis is stimulated by endothe-
lial chemoattractants and mitogens such
as heparin, fibroblast growth factor
(FGF)-β, IL-8 and IGF-I. Wound reepithe-
lialization occurs following the migration
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of epithelial cells from the wound mar-
gin and epidermal appendages within
the wound bed and has been shown to
be enhanced by EGF, TGF-α and IGF-I
(30). Fibroblast recruitment and prolifera-
tion, and production of ECM, as well as
inhibition of production of proteases re-
quired to maintain the balance between
production and degradation, are influ-
enced predominantly by the fibrogenic
growth factors PDGF, IGF-I and FGF-β,
as well as TGF-β (14).
Fibrogenic Response
Inflammation is not the only critical
step in the development of the fibrotic
response. One reason for this hypothesis
is the failure of current antiinflammatory
therapies, even in combination with po-
tent immunosuppressives, to improve
outcomes in fibroproliferative diseases
such as pulmonary fibrosis (35). Current
research thus focuses on direct inhibition
of specific fibrogenic events such as cy-
tokine elaboration, fibroblast prolifera-
tion and ECM deposition (36). Central to
the formation of hypertrophic scar and
keloid scar tissue is an alteration of the
fibroblast phenotype (36,37). Indeed,
when compared with normal fibroblasts,
keloid fibroblasts show increased num-
bers of growth-factor receptors and re-
spond more briskly to growth factors
like PDGF and TGF-β, which may up-
regulate these abnormal cells from the
beginning of wound healing (38,39).
Using Affymetrix-chip analysis to iden-
tify pathways critical to keloid patho-
genesis, Smith and colleagues found
increased expression of several IGF-
binding and IGF-binding–related pro-
teins and decreased expression of a sub-
set of Wnt-pathway inhibitors and
multiple IL-1–inducible genes, providing
preliminary evidence for epigenetic si-
lencing of a subset of genes in the al-
tered program of keloid fibroblasts (40).
TGF-β. Many of the biologic actions of
TGF-β contribute to the normal wound-
healing process and have been impli-
cated in a wide variety of fibrotic disor-
ders. Early after injury, high levels of
TGF-β are being released from degranu-
lating platelets at the site of injury, where
they act as chemoattractants for lympho-
cytes, fibroblasts, monocytes and neu-
trophils (41).
The TGF-β family consists of at least
five highly conserved polypeptides, with
TGF-β1, -β2 and -β3 being the principal
mammalian forms. TGF-β1 and -β2 are
among the most important stimulators of
collagen and proteoglycan synthesis, and
they affect the ECM not only by stimulat-
ing collagen synthesis but also by pre-
venting its breakdown (42,43). In con-
trast, TGF-β3, which is predominantly
induced in the later stages of wound
healing, has been found to reduce con-
nective tissue deposition (44). TGF-β has
been linked to hypertrophic scar and
keloid formation in a number of ways.
Strong and persistent expression of TGF-β
and its receptors has been shown in
fibroblasts of post-burn hypertrophic
scars (45). Also, overexpression of TGF-β1
and -β2 has been found in keloid and
keloid-derived fibroblasts, with signifi-
cantly lower TGF-β3 mRNA expression
(46,47). Comparing the expression pro-
files of TGF-β1, -β2 and -β3 and their re-
ceptors in keloids, hypertrophic scar and
normal skin derived fibroblasts, Bock
and colleagues found significantly lower
TGF-β2 mRNA expression in hyper-
trophic scar fibroblasts compared with
fibroblasts derived from keloids and nor-
mal skin, while TGF-β3 mRNA expres-
sion was significantly lower in keloid fi-
broblasts in comparison with fibroblasts
derived from hypertrophic scar and nor-
mal skin (44). Thus, specifically, beyond
1 week, differential expression of TGF-β
isoforms, receptors and activity modula-
tors, rather than the mere presence or ab-
sence of TGF-β, may have a major role in
the development of both keloids and hy-
pertrophic scarring (48).
Indeed, antisense phosphorothioate
oligonucleotides against TGF-β1 and -β2
have been used in vivo to significantly re-
duce postoperative scarring in rabbit and
mouse models of glaucoma surgery (49).
In two studies, Shah and colleagues
(50,51) found that dermal wounds of
adult rats healed without scar-tissue for-

mation after injection of a neutralizing
antibody to TGF-β1 and -β2 into the
wound margins, compared with controls.
The SMAD signal-transduction
pathway as a downstream mediator of
TGF-β action. The SMADs are a family
of intracellular regulatory proteins that
act downstream of the TGF-β type I re-
ceptor in the cell’s response to a specific
TGF-β (Figure 3). Once these SMADs are
phosphorylated, they form a complex
with the common mediator Co-SMAD 4.
This SMAD complex translocates to the
nucleus, where it is recruited to DNA by
site-specific inhibitors, activators or coac-
tivators to regulate the transcription of
specific genes (52).
SMAD intracellular signaling proteins
can be categorized into receptor-regulated
SMADs (R-SMADs), common-mediator
SMADs, and inhibitory SMADs (53).
R-SMADs 3 and 4 have been identified as
the predominant mediators of autocrine
stimulation by TGF-β in hypertrophic-
scar–derived fibroblasts (54). The poten-
tial importance of SMAD3 and its rela-
tionship with TGF-β in keloid etiology
has been demonstrated by Wang et al.,
who showed that downregulation of
SMAD3 expression can significantly de-
crease procollagen gene expression and
reduce ECM deposition by keloid fibrob-
lasts (55). Inhibitory SMAD 7 prevents
phosphorylation of R-SMADs by forming
stable associations with activated type I
TGF-β receptors and thus provides nega-
tive feedback to the actions of TGF-β (56).
Indeed, a potential therapeutic benefit of
SMAD 7 overexpression has already been
shown in bleomycin-induced lung fibro-
sis, postobstructive renal fibrosis and ex-
cessive cutaneous scar formation (57–59).
SMAD 3 inhibition and SMAD 7 overex-
pression may thus be potential therapeu-
tic targets to improve excessive scarring.
Interactions between keratinocytes
and fibroblasts. Keratinocytes have been
shown to mediate the behavior of fibrob-
lasts during wound healing through
their secretion, activation or inhibition of
growth factors such as TGF-β (32). In
particular, the release of IL-1 from ker-
atinocytes at the wound site seems to
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REVIEW ARTICLE
Figure 3. The SMAD signal-transduction pathway as a downstream mediator of TGF-β ac-
tion. The TGF-β receptor consists of type I and type II subunits that are serine-threonine ki-
nases that signal through the SMAD family of proteins. Binding of TGF-β to its cell-surface
receptor type II causes phosphorylation of the type I receptor by type II. The type I recep-
tor is then able to phosphorylate and activate the R-SMAD proteins. Once these SMADs
are phosphorylated, they form a complex with the common mediator Co-SMAD 4. This
SMAD complex translocates to the nucleus, where the activated SMAD complex recruits
other transcription factors (TF) that together activate the expression of target genes me-
diating the biological effects of TGF-β. Inhibitory SMAD 7 is able to prevent phosphoryla-
tion of R-SMADs by forming stable associations with activated type I TGF-β receptors and
thus provides negative feedback to the actions of TGF-β.
represent the initial trigger for the in- ent in the skin, and they are an important
flammatory reaction and serves as an au- source of a variety of proinflammatory
tocrine signal to fibroblasts and endothe- mediators that can promote inflammation
lial cells, resulting in a pleiotropic effect and vascular changes (63). Mediated by
on them (60,61). Greater thickness of the release of soluble mediators such as
neodermis production was seen in fi- histamine, heparin and cytokines, mast
broblast-seeded skin models when ker- cells have been shown to promote fibrob-
atinocytes from hypertrophic scars were last proliferation (64). Increased numbers
added in culture (32). Similar results of mast cells have been reported during
were detected with coculturing of keloid- the active period of hypertrophic and
derived keratinocytes and fibroblasts keloid scar formation (28,65). Clinically,
(62), suggesting that keratinocytes might the release of histamine by these cells
have an important role in keloid and hy- likely contributes to the common patient
pertrophic scar pathogenesis by produc- complaint of itchiness. In addition, the
ing signals that stimulate the fibroblasts vasodilatory effect of histamine may pro-
in the underlying dermis to proliferate or mote erythema and leakage of plasma
produce more ECM. The basis for an in- proteins into the regional tissues (30).
herent abnormality among hypertrophic
scar and keloid-derived keratinocytes re- Matrix Remodeling/Maturation Phase
mains elusive, however. Matrix metalloproteinases (MMPs).
Mast cells. Our understanding of the The major effectors of ECM degradation
role of the mast cell in scar formation is and remodeling belong to a family of
expanding with new discoveries regard- structurally related enzymes called
ing cell–cell communication. Mast cells MMPs. The MMP family consists of
are an additional leukocyte subset pres- about 25 zinc-dependent and calcium-
HYPER TR OPHIC SCARS AND KELOIDS
dependent proteinases in the mammalian
system (66). The levels of MMP expres-
sion in normal cells are low and allow
healthy connective tissue remodeling. An
imbalance in expression of MMPs has
been implicated in a number of patholog-
ical conditions such as dermal fibrosis
(67) and tumor invasion and metastasis
(68). In both conditions, cell interactions
between either fibroblasts and ker-
atinocytes or fibroblasts and tumor cells
result in increased MMP production. In
particular, secreted cytokines and growth
factors, including IL-1β, PDGF, EGF and
TNF-α, seem to play important roles in
controlling the signal mechanism in-
volved in regulation of MMP expression
in fibroblasts (69). Several MMPs have
been shown to mediate the breakdown of
type I and III collagen, the most abun-
dant types of collagen in the skin ECM
(66). Specifically, MMP-2 and MMP-9 ac-
tivity persists after wound closure and
seems to play a potent role in the remod-
eling process (70). Interestingly, hyper-
trophic scars and keloids were found to
have high levels of MMP-2 and low lev-
els of MMP-9 (71). MMP-2 was shown to
have major effects on matrix remodeling
later in wound healing via degrading de-
natured collagen, and MMP-9 was found
to be typically involved in early wound
repair by degrading native types IV and
V collagen, elastin and fibronectin (72,73).
Also, recent in vitro data suggested that
MMPs may downregulate inflammation
via cleavage of chemokines, which then
act as antagonists (74,75).
Decorin. Decorin, a small proteoglycan
with one dermatan sulfate sugar chain, is
normally prevalent in the dermal ECM.
Decorin regulates collagen fibril, fiber
and fiber-bundle organization and has
been shown to be decreased by about
75% in hypertrophic scars (76). Decorin is
able to bind and neutralize TGF-β, thus
minimizing the stimulatory effects of this
cytokine on collagen, fibronectin and gly-
cosaminoglycan production (32). The low
levels of decorin found in hypertrophic
scarring may thus account for their irreg-
ular collagen organization, as well as in-
creased ECM production (77). Zhang and
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colleagues (78) showed similar results,
with decorin inhibiting both the basal
and TGF-β1–enhanced contraction of col-
lagen gel by both normal and hyper-
trophic scar fibroblasts, suggesting that
decorin may have therapeutic potential
for excessive skin contraction as observed
in hypertrophic scarring. Mukhopadhyay
and colleagues (79) examined the role of
decorin in keloid tissue and found that
decorin was able to decrease extracellular
matrix proteins, highlighting its impor-
tance as an antifibrotic agent.
Apoptosis. Recently, apoptosis has
been shown to play a critical role in the
transition from granulation tissue into
scar formation after tissue injury (43). As
described by Amour and others (32),
wound epithelialization and scar colla-
gen formation are accompanied by a
gradual decrease in cellularity on cross-
sectional histology. Early immature hy-
pertrophic scars are hypercellular; and
during the process of remodeling and
maturing, fibroblast cell density reduces
to resemble normal skin, partly due to
induction of apoptosis. In particular,
apoptosis of myofibroblasts can be de-
tected 12 days after wounding, and is be-
lieved to peak on day 20 in normal scar
formation (32). In hypertrophic scar tis-
sue of severely burned patients, however,
the authors found that maximal apopto-
sis occurred much later (19–30 months
following injury). The percentage of my-
ofibroblasts was also higher in hyper-
trophic scars compared with normal
scars or in normal skin, and was found
to correlate with the size of the original
burn (80).
Scar maturation. Scar maturation is
the least recognized phase in the process
of wound healing, and this process is rel-
atively underresearched in regard to the
alterations in the clinical and histologic
appearance of a scar over time. In a
study of incisional scars in patients with-
out any history of excessive scarring,
Bond and colleagues (81) found progres-
sive changes in relation to the dermal
structure but persistent fibroblastic den-
sity at 4 months, indicating the existence
of a continuing high-turnover state simi-
lar to the proliferative phase, with sub-
jects younger than 30 years displaying a
prolonged longitudinal progression of
scar maturation compared with subjects
older than 55 years (82). In another study
in which they examined the natural his-
tory of scar redness and maturation in
incisional and excisional wounds, the
same authors found that the majority of
scars fade at approximately 7 months.
These investigators also showed that a
considerable proportion of scars dis-
played persistent redness at 12 months,
in the absence of features suggestive of
hypertrophic or keloid scarring, and they
advocated the term “rubor perseverans”
to describe the physiologic redness of a
normal scar as it matures beyond the
first month (82).
CURRENT AND EMERGING TREATMENT
STRATEGIES
Multiple studies on hypertrophic scar
and keloid formation have led to a
plethora of therapeutic strategies to pre-
vent or attenuate keloid and hyper-
trophic scar formation. In 2002, Mustoe
et al. published the “international clinical
recommendations on scar management,”
which serve as an outline for most of the
currently published reviews (83). In a re-
cently published work, Durani and
Bayat (84) evaluated for the first time
primary clinical studies on keloid dis-
ease therapy over the last 25 years and
levels of evidence for the treatment
modalities assigned. These authors con-
cluded that high-quality research in
evaluating keloid therapy is still lacking.
Within this review we critically discuss
the techniques currently used to
avoid/treat keloid and hypertrophic scar
formation based on our experience from
a dermatological and surgical perspec-
tive (Table 2).
It is critical to note that generally most
of the therapeutic approaches we men-
tion may be used for both hypertrophic
scarring and keloids. Nevertheless, clini-
cal differentiation between hypertrophic
and keloid scars is of central importance
before the initiation of any treatment,
particularly before starting any surgical
 REVIEW ARTICLE

Table 2. Hypertrophic scars and keloids: current therapeutic strategies.

Treatment Use Indications, efficiency and comments

Prophylaxis

Pressure therapy Continuous pressure (15–40 mmHg) for at least •Prophylaxis of hypertrophic burn scars, ear keloids
23 h/d ≥6 months of scar healing (postexcision)
•Controversial success
•Reduced compliance due to frequent patient
discomfort
Silicone gel sheeting ≥12 h/d for ≥2 months beginning 2 weeks after wound •Prophylaxis for the development of hypertrophic scars
healing and keloids
•No effects on mature keloids and hypertrophic scars
Silicone gel Twice daily for 2 months beginning 2 weeks after
wound closure
Flavonoids For example, Contractubex gel (Merz Pharma, •Limited to prophylaxis of hypertrophic scar and keloid
Frankfurt, Germany), Mederma Skin Care Gel (Merz, development
Pharmaceuticals, Greensboro, NC, USA). Twice daily for
4 to 6 months beginning 2 weeks after wound closure

Current therapies

Corticosteroids Intralesional injections of TAC (10–40 mg/mL), several
treatments once or twice a month
Cryotherapy Contact/spray freezing with liquid nitrogen using
10–20 s freeze-thaw cycles
Scar revision Excision with linear, tension-free closure, split- or
full-thickness skin grafting, z-plasty, w-plasty
Radiotherapy Superficial x-rays, dosages 15–20 Gy, overall limit 40 Gy.
Over 5-6 sessions in the early postoperative period
Laser therapy Short-pulsed dye laser (585-nm PDL) with doses ranging
from 6.0 to 7.5 J/cm2 (7-mm spot) or from 4.5 to
5.5 J/cm2 (10-mm spot), 2 to 6 treatments every
2 to 6 weeks
•First-line therapy for keloids, second-line therapy for
hypertrophic scars
•Combination with surgery, PDL and cryotherapy
•Common adverse effects: skin and subcutaneous
fat atrophy, telangiectasias
•Overall effective for hypertrophic scars, for keloids
combination with triamcinolone acetonide injections
recommended
•Limited to management of smaller scars
•Common adverse effects: blistering and pain
•Efficacious for therapy of hypertrophic scarring
•Recurrence rates of 45-100% after keloid excision
without adjuvant therapy
•Overall good efficiency rates of adjuvant radiotherapy
after keloid excision
•Common adverse effects: potential risk of malignant
change/carcinogenesis
•Excellent therapeutic option for the treatment of
primarily keloids and younger hypertrophic scars
•High recurrence rates with other (ablative) laser
techniques for the treatment of keloids

Emerging Therapies

Interferon Intralesional injection of INF-α2b (1.5–2 × 106 IU) •Clinical studies report overall effectiveness
twice daily over 4 days •Common adverse effects: flu-like symptoms on
injection
5-FU Intralesional injection of 5-FU 50 mg/mL •Overall effective for the treatment of keloids and
hypertrophic scars
•Common adverse effects: anemia, leucopenia,
thrombocytopenia; blood-count monitoring is needed
No therapy in pregnant women or patients with bone
marrow suppression

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HYPER TR OPHIC SCARS AND KELOIDS
or laser related manipulations as speci-
fied below.
Prophylaxis
Prevention of pathologic scarring is
undoubtedly more effective than treat-
ment. Thus, avoiding all unnecessary
wounds in any patient, whether or not
the patient is prone to keloid/hyper-
trophic scars, remains an obvious but im-
perfect solution (6). Because delayed ep-
ithelialization beyond 10 to 14 days
increases the incidence of hypertrophic
scarring dramatically (83), achievement
of rapid epithelialization is mandatory
for avoiding excessive scar formation. In
particular, wounds subjected to tension
due to motion, body location or loss of
tissue are at increased risk of scar hyper-
trophy and spreading (85). Thus, in case
of cutaneous injury, the importance of
rapid primary closure of wounds under
little to no tension cannot be overstated.
It is also crucial to adequately debride
contaminated wounds, obtain good he-
mostasis, handle tissues gently and limit
foreign bodies in the form of debris and
braided polyfilamentous suture material,
such as polyglactin or silk (6).
Pressure therapy. Pressure therapy
has been the preferred conservative
management for both the prophylaxis
and treatment of hypertrophic scars and
keloids since the 1970s. Currently, pres-
sure garments are predominantly used
for the prophylaxis of hypertrophic burn
scar formation, despite controversial
data regarding their value in reducing
excessive scarring and little scientific ev-
idence supporting their use (5). The
mechanism of action of pressure therapy
remains poorly understood; however,
possible mechanisms are decreased col-
lagen synthesis attributable to limiting
of the supply of blood, oxygen and nu-
trients to the scar tissue (86–88) and in-
creased apoptosis (89).
Recommendations for the amount of
pressure and the duration of the therapy
are based merely on empirical observa-
tions and advocate continuous pressure
of 15–40 mmHg for at least 23 hours
and/or 1 day for more than 6 months
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while the scar is still active (87,90). How-
ever, compression therapy is ultimately
limited by inability to adequately fit the
garment to the wounded area and by pa-
tient discomfort, which frequently re-
duces compliance.
Silicone gel sheeting. Topical silicone
gel sheeting has been a well-established
treatment for management of scars since
its introduction in the early 1980s, and its
therapeutic effects on predominantly hy-
pertrophic scars have been well docu-
mented in the literature (91,92). Current
opinion suggests that occlusion and hy-
dration are likely the mechanisms of the
therapeutic action of silicone gel sheeting
rather than an inherent antiscarring
property of silicone (93). Silicone sheets
are recommended to be worn for
≥12 hours and/or 1 day for at least
2 months beginning 2 weeks after wound
healing. Silicone gel is favored for areas
of consistent movement, where sheeting
will not conform, and should be applied
twice daily (6).
Flavonoids. Flavonoids (quercetin and
kaempferol) are found in well-known top-
ical scar creams, such as Mederma skin
care gel (Merz Pharmaceuticals, Greens-
boro, NC, USA) and Contractubex gel
(Merz Pharma, Frankfurt, Germany). So
far, efficacy studies testing the ultimate
benefit of these flavonoid-containing topi-
cal scar creams have provided controver-
sial data (94–98). Interestingly however,
quercetin, a dietary bioflavonoid, has
been recently shown to inhibit fibroblast
proliferation, collagen production and
contraction of keloid and hypertrophic
scar-derived fibroblasts. A study by Phan
and others (94) suggested that these in-
hibitory effects may be mediated through
inhibition of the above discussed SMAD
2, 3, and 4 expression by quercetin.
Emerging Prophylactic Approaches
Imiquimod 5% cream. Imiquimod
5% cream, a topical immune-response
modifier, is approved for the treatment
of genital warts, basal cell carcinoma
and actinic keratoses (99). Imiquimod
stimulates interferon, a proinflammatory
cytokine, which increases collagen break-
down. In addition, imiquimod alters the
expression of apoptosis-associated
genes (100). Therefore, it has been used
in an attempt to reduce keloid recur-
rence after excision and was reported to
have positive effects on the recurrence
rate of keloids after postoperative appli-
cation (101). However, in a prospective,
double-blind, placebo-controlled pilot
study in which imiquimod 5% cream
was applied nightly for 2 weeks before
being given 3 times/week under occlu-
sion for 1 month postoperatively, no sig-
nificant difference in keloid recurrence
rates between groups could be detected
(102). The role of imiquimod in the pre-
vention of postsurgical keloid recur-
rence thus remains questionable. In a
preliminary, small, randomized, pro-
spective clinical trial, imiquimod was
shown to improve hypertrophic scar
quality after surgery (103), but addi-
tional studies with a larger sample size
and longer follow-up are necessary to
determine the role of imiquimod 5%
cream in hypertrophic scar therapy.
Recombinant TGF-β3 and mannose-6-
phosphate. A recently published mile-
stone study by Ferguson and colleagues
(104) on the prophylactic effects of
TGF-β3 on skin scarring has further in-
creased the current interest in the TGF-β
family. In three double-blind, placebo-
controlled studies, intradermal avoter-
min (recombinant, active human TGF-β3
at concentrations ranging from 0.25 to
500 ng/100 μL per linear centimeter
wound margin) was administered to
both margins of 1-cm, full-thickness skin
incisions before wounding and 24 hours
later, in healthy subjects. In both young
and old participants, only one dose regi-
men, 50 ng per 100 μL per linear cen-
timeter, achieved more than 10% scar im-
provement in nearly two-thirds of
wounds. However, in the final phase II
study, each of three doses was judged to
be effective by lay observers and by clini-
cians (105). Although the investigators
acknowledged their commercial interests
in TGF-β3, adherence to established stan-
dards in this translational investigation
and the rigorous nature of the statistical

analysis in a well-powered series of stud-
ies provided strong evidence for the ben-
efits of avotermin in this setting.
In March 2009, the company Renovo
reported the results of a double-blind,
placebo-controlled, randomized phase 2
efficacy trial in 195 male and female sub-
jects to investigate the safety and efficacy
of inhibition by TGF-β1 and -β2 using
two dose levels of mannose-6-phosphate
(Juvidex®, 300 mmol/L and 600 mmol/L)
via two routes of administration (intra-
dermal and topical in combination and
topical alone) in the acceleration of heal-
ing of split-thickness skin-graft donor
sites. Although the trial did not meet its
primary endpoint, which was demon-
stration of a statistically significant dif-
ference in the time to complete wound
closure at the skin-graft site as assessed
by the investigating physician, it did
meet some of the specified secondary
endpoints with statistical significance.
These included a between-patient com-
parison performed by an external panel
of clinical experts who assessed photo-
graphs of the donor sites, where the
300 mmol/L Juvidex topical-alone appli-
cation versus standard care showed a
statistically significant acceleration of
healing in favor of Juvidex.
Current Treatment Strategies
Intralesional corticosteroid injections.
Since the mid-1960s intralesional steroid
injections have gained popularity as one
of the most common approaches to atten-
uate hypertrophic scar and keloid forma-
tion (106), while topical administration of
corticosteroid-containing creams has been
used with only varying success. Most of
the known effects of corticosteroids are
thought to result primarily from its sup-
pressive effects on the inflammatory
process in the wound (93), and secondar-
ily from diminished collagen and gly-
cosaminoglycan synthesis, inhibition of
fibroblast growth (107) and enhanced col-
lagen and fibroblast degeneration (108).
Two or three injections of triamcinolone
acetonide (TAC, 10 to 40 mg/mL) are
usually sufficient, although occasionally
injections are continued for 6 months or
M O L M E D 1 7 ( 1 - 2 ) 1 1 3 - 1 2 5 , J A N U A R Y- F E B R U A R Y 2 0 1 1 | G A U G L I T Z E T A L . | 1 2 1
more (106). Response rates have been
highly variable, with figures ranging
from 50% to 100%, and a recurrence rate
of 9% to 50% (109). An important finding
was that intralesional corticosteroid injec-
tions, when used alone, have the most ef-
fect on younger keloids, which can be-
come completely flattened. In older scars
and keloids, corticosteroids can soften
and flatten the scars only to some extent
and can provide symptomatic relief (5).
Injections may be used alone or com-
bined with other therapies (10), of which
the combination with cryotherapy or sur-
gery are the most widely used modalities
in clinical practice (110). Side effects in-
clude dermal atrophy, telangiectasia and
pain at the site of injection. The latter can
be averted by topical anesthesia and/or
regional injections of local anesthetic
around the scars to be injected (30). De-
spite relatively few randomized, prospec-
tive studies, TAC remains a first-line ther-
apy for the treatment of early keloids and
a second-line therapy for the treatment of
early hypertrophic scars if other easier
treatments have not been efficacious (83).
Cryotherapy. Cryotherapy has been
used as monotherapy and in conjunction
with other forms of treatment for exces-
sive scars. In particular, the combination
of cryotherapy with intralesional TAC in-
jections seems to yield marked improve-
ment of hypertrophic scars and keloids
(111–113). We recommend cryotherapy
directly before the administration of in-
tralesional TAC injections, because suc-
cess rates seem to be increased with this
sequence.
Cryotherapy is believed to induce vas-
cular damage that may lead to anoxia
and ultimately tissue necrosis (114). Suc-
cess rates in studies in which contact or
spray cryosurgery with liquid nitrogen
was used varied between 32% and 74%
after two or more sessions, with higher
response rates of hypertrophic scars com-
pared with keloids (83,115,116). The use-
fulness of cryotherapy, however, is lim-
ited to the management of small scars. A
delay of several weeks between sessions
is usually required for postoperative
healing, and the commonly occurring
REVIEW ARTICLE
side effects, including permanent hypo-
and hyperpigmentation, moderate skin
atrophy, blistering and postoperative
pain, are major handicaps (5,116). Re-
cently, the intralesional-needle cryoprobe
method has been assessed in the treat-
ment of hypertrophic scars and keloids
(117), and has been demonstrated to have
increased efficacy compared with that ob-
tained with contact/spray probes and
shorter reepithelialization periods (117).
Surgical manipulation. Surgical exci-
sion remains the traditional treatment for
keloids and hypertrophic scars (6). How-
ever, it is imperative to clearly differenti-
ate between hypertrophic scars and
keloids before starting any surgical ma-
nipulations.
In case of hypertrophic scars, timing of
surgical treatment is an important con-
sideration in the treatment protocol of
strategies for scar revision. Scars mature
during a period of at least 1 year and can
show decreased contractures along with
flattening, softening, and repigmentation
without any physical manipulation (93).
Surgical excision thus might not be
needed, even though postexcisional re-
currence rates of the original hyper-
trophic scar are usually low (13,15).
Recurrence rates of keloids after exci-
sion, in contrast, range between 45% and
100% (83). Given this high recurrence
rate, surgical intervention without adju-
vant therapy, such as postexcisional cor-
ticosteroid injections or radiation, should
be considered with caution. Excision
may frequently result in a longer scar
than the original keloid, and recurrence
in this new area of trauma may lead to
an even larger keloid (109,118). Surgical
repair (core excision with low-tension
wound closure, or shave excision) of ear-
lobe keloids with corticosteroid injections
and postoperative pressure on the inci-
sion site, however, usually provides
good cosmetic results (119).
Radiotherapy. Superficial x-rays,
electron-beam therapy and low- or high-
dose–rate brachytherapy have been used
with good results in scar reduction pro-
tocols, primarily as adjuncts to surgical
removal of keloids (120). The effects of
HYPER TR OPHIC SCARS AND KELOIDS
radiation on keloids are thought to be
mediated through inhibition of neovas-
cular buds and proliferating fibroblasts,
which result in decreased collagen pro-
duction (93). Electron beam irradiation is
usually started 24 to 48 h after keloid ex-
cision, and the total dose is limited to 40
Gy over the course of several administra-
tions to prevent side effects such as
hypo- and hyperpigmentation, erythema,
telangiectasia and atrophy (121). How-
ever, because radiation entails a risk of
carcinogenesis, particularly in areas such
as the breast and thyroid, its use should
be handled with caution (5,15).
Laser therapy. Since the introduction
of laser treatment for keloids in the
mid-1980s (122), the therapeutic use of
more and more lasers with different
wavelengths has been investigated, and
success has varied. Until today, the
most encouraging results have been ob-
tained with the 585-nm pulsed-dye
laser (PDL), which has been recognized
as an excellent therapeutic option for
the treatment of younger hypertrophic
scars and primarily keloids (123).
Nonoverlapping laser pulses at fluences
ranging from 6.0 to 7.5 J/cm2 (7-mm
spot) or from 4.5 to 5.5 J/cm2 (10-mm
spot) have been recommended for the
treatment of hypertrophic scars and
keloids (124). Two to six treatments
may be necessary to successfully im-
prove scar resolution, including scar
color, height, pliability and texture
(123). By causing local ischemia via de-
stroying blood vessels, 585-nm PDL
therapy is believed to induce neocolla-
genesis, collagen-fiber heating with dis-
sociation of disulfide bonds and subse-
quent collagen-fiber realignment, and
decreased fibroblast proliferation as
well as release of histamine and other
factors that influence fibroblast activity
(125–127). Adverse effects include tran-
sient hyper- or hypopigmentation and
blistering (125,128). Hyperpigmentation
has been reported with a frequency of
1–24% (129,130). The most common ad-
verse side effect of 585-nm PDL treat-
ment is postoperative purpura, which
can persist for 7–10 days.
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Emerging Therapies
IFN injections. IFN therapy, which
has potential therapeutic benefit in the
treatment of abnormal scars, is based on
the effect of IFN in decreasing the syn-
thesis of collagen types I and III
(15,131). Specifically, IFN-α2b has been
proposed to have antiproliferative prop-
erties, and it may improve the patho-
logic features of dermal fibrosis directly
or by antagonizing the effects of TGF-β
and histamine (132). In vivo, systemic
administration of IFN-α2b in severely
burned patients resulted in improved
clinical appearance of the hypertrophic
scars and a lower Vancouver Burn Scar
Assessment score (133). IFN-α2b admin-
istered intralesionally (1.5 × 106 IU,
given twice daily over 4 days) was
found to result in a 50% reduction of
keloid size by 9 days and thus was
much more effective than intralesionally
injected corticosteroid (132). Hyper-
trophic scars injected three times weekly
with IFN-α2b showed significant mean
rates of improvement and sustained re-
duced serum TGF-β levels (134). Unfor-
tunately, adverse effects are common
with IFN treatment and include flu-like
symptoms and pain on injection (15).
Although IFN is an expensive form of
therapy, it remains a promising thera-
peutic approach in the management of
excessive scars.
Bleomycin. Bleomycin sulfate, an-
other antineoplastic agent that was
found to directly inhibit collagen syn-
thesis via decreased stimulation by
TGF-β1 (135), was first investigated in
the mid-1990s as a scar-reducing agent
(136). After administering three to five
intralesional injections of bleomycin
within a 1-month period, the authors
observed complete regression in 69.4%
of the keloids. Subsequent studies re-
vealed similar results, with significant
improvement in hypertrophic scar and
keloid height and pliability as well as
reduction in erythema, pruritus and
pain (135,137,138). Occasionally, devel-
opment of hyperpigmentation and der-
mal atrophy may occur with bleomycin
treatment. Because of bleomycin’s toxic-
ity, clinicians are encouraged to be
aware of associated potential problems.
However, systemic toxic effects of in-
tralesionally administered bleomycin
seem to be uncommon (15). Bleomycin
may thus be a promising agent for the
therapy of keloids and hypertrophic
scars; however, further investigation
and efficacy trials are needed before this
agent is included in future treatment
protocols.
5-Fluorouracil (5-FU). 5-FU is a
pyrimidine analog that is used as an an-
timetabolite in cancer chemotherapy
(109). 5-FU is converted intracellularly
to its active version, which was sug-
gested to directly increase fibroblast
apoptosis via inhibiting DNA synthesis
preferentially in rapidly proliferating
and metabolizing cells (58,139). In 1999,
Fitzpatrick (140) was the first to report
the use of 5-FU to effectively reduce
scars during his 9-year experience, in
which he administered more than 5000
injections to more than 1000 patients.
Ever since, the use of intralesional 5-FU
in combination or as a sole agent for
treatment of keloids has been shown to
be effective. In a prospective, random-
ized trial including 28 consecutive pa-
tients with keloids of varying size and
duration, weekly intralesional 5-FU in-
jections (50 mg/mL) for 12 weeks re-
sulted in reduction in scar size of at
least 50% in the majority of the patients,
with no patient showing failure to re-
spond to therapy or recurrence of symp-
toms within the follow-up period of 24
months (141). Adverse side effects in-
cluded pain, ulceration and burning
sensations. Intralesional 5-FU treatment
has also been used for the treatment of
inflamed hypertrophic scars and seems
to be both effective and safe (140).
CONCLUSIONS
Scarring following surgery or injury is
difficult to predict, and both physicians
and their patients are highly concerned
with minimizing scar appearance and
value as clinically meaningful even small
improvements in scarring. Despite a
plethora of various in vivo and in vitro

studies, to date only limited information
is available on the exact cause of hyper-
trophic scar and keloid formation.
Knowledge of the cellular and molecular
mechanisms implicated in the develop-
ment of these fibroproliferative disorders
remains relatively poor because of the
lack of representative and well-
recognized animal models of human
hypertrophic scar formation. Instead,
scar tissue for study is usually obtained
from humans undergoing scar revision—
usually months after the scar first devel-
oped. Therefore, early alterations in
wound repair mechanisms that likely de-
termine the development of hypertrophic
scars may be missed.
Existing prophylactic and therapeutic
strategies include pressure therapy, sili-
cone gel sheeting, intralesional TAC,
cryosurgery, radiation, laser therapy, INF,
5-FU and surgical excision as well as a
multitude of extracts and topical agents.
Many of these treatments have been
proven to be effective through extensive
use, but few have been supported by
well-designed prospective studies with
adequate control groups.
Emerging therapies for patients prone
to excessive scars support earlier interven-
tions aimed at modulating single cell
types, inflammatory metabolites, cy-
tokines or signaling receptors. Encourag-
ing results obtained with the use of recom-
binant human TGF-β3 and anti–TGF-β1
and -β2 support substantial optimism re-
garding the future discovery of new solu-
tions to difficult fibrotic disorders.
DISCLOSURE
The authors declare that they have no
competing interests as defined by Molecu-
lar Medicine, or other interests that might
be perceived to influence the results and
discussion reported in this paper.
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 ―Review―

The Latest Strategy for Keloid and Hypertrophic Scar Prevention and
Treatment: The Nippon Medical School (NMS) Protocol

Rei Ogawa, Teruyuki Dohi, Mamiko Tosa,

Masayo Aoki and Satoshi Akaishi

Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School Hospital, Tokyo, Japan

In 2006, we established a scar/keloid-specialized unit in the Department of Plastic, Reconstructive, and

Aesthetic Surgery at Nippon Medical School (NMS) in Tokyo, Japan. In the ensuing 15 years, we treated
approximately 2,000 new scar/keloid patients annually. This extensive experience has greatly improved
the efficacy of the treatments we offer. Therefore, we discuss here the latest NMS protocol for prevent-
ing and treating keloids and hypertrophic scars. While this protocol was optimized for Japanese pa-
tients, our experience with a growing body of non-Japanese patients suggests that it is also effective in
other ethnicities. The extensive evidence-based experience underlying the NMS protocol suggests that it
may be suitable as the foundation of a standard international prevention/treatment algorithm for
pathological scars. (J Nippon Med Sch 2021; 88: 2―9)

Key words: keloid, hypertrophic scar, wound

Introduction tation, including trauma, burn, surgery, vaccination, skin

In 2006, we established a scar/keloid-specialized unit in
the Department of Plastic, Reconstructive, and Aesthetic
Surgery at Nippon Medical School (NMS) in Tokyo, Ja-
pan. In the following 15 years, we treated approximately
2,000 new scar/keloid patients annually. This vast experi-
ence has greatly improved the efficacy of the treatments
we offer. Therefore, we discuss here the latest NMS algo-
rithm for preventing and treating keloids and hy-
pertrophic scars (HSs). While this algorithm has been op-
timized for Japanese patients, our experiences with a
growing body of international patients suggest that it is
also effective in other ethnicities and could therefore
serve as the starting point in the development of an in-
ternational prevention/treatment algorithm.
Pathomechanisms of Keloids/HSs
To effectively prevent and treat keloids/HSs, it is neces-
sary to understand the pathomechanisms that drive their
formation and progression. The abnormal growth of
these scars is powered by chronic inflammation in the re-
1
ticular dermis that is triggered by dermal injury or irri-
piercing, acne, and herpes zoster. In general, the scars
that spontaneously lose this dermal inflammation over
time are defined as HSs, whereas the scars with enduring
inflammation are defined as keloids. This difference in
inflammation durability explains the disparate growth
habits of HSs and keloids. Thus, the temporary, waning
inflammation in HSs means that they do not grow over
the borders of the original wound. By contrast, the con-
tinuous, escalating inflammation of keloids causes them
to grow into the adjacent normal skin.
In terms of histopathology, the inflammation and the
resulting accumulation of extracellular matrix causes der-
mal nodules and thick eosinophilic (hyalinizing) collagen
bundles called “keloidal collagen” to form over time2. If
the dermal nodule is the main histological finding, it is
diagnosed as an HS. This suggests that keloids/HSs are
manifestations of the same inflammatory fibroprolifera-
tive condition and simply differ in the intensity and du-
ration of inflammation.
Multiple lines of evidence suggest that the intensity/
duration of dermal inflammation in keloids/HSs is dic-

Correspondence to Rei Ogawa, MD, PhD, FACS, Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical
School, 1―1―5 Sendagi, Bunkyo-ku, Tokyo 113―8603, Japan
E-mail: r.ogawa@nms.ac.jp
https://doi.org/10.1272/jnms.JNMS.2021_88-106
Journal Website (https://www.nms.ac.jp/sh/jnms/)

2 J Nippon Med Sch 2021; 88 (1)

 Keloid & Hypertrophic Scar NMA Protocol
tated by genetic, systemic, local, and lifestyle risk fac-
tors1. Genetic causes include single nucleotide polymor-
3,4
phisms and genetic diseases such as Rubinstein-Taybi
5,6
syndrome . There are probably many other, as yet un-
identified, genetic factors. Systemic factors include preg-
7 8
nancy , hypertension , high circulating concentrations of
inflammatory cytokines9, and possibly female sex10.
The key local risk factor is mechanical force on the
wound/scar: considerable evidence shows that this
strongly influences inflammation-driven pathological
11―13 13
scarring . Indeed, our finite-element analysis suggests
that keloid shape is largely determined by the direction
of the tension on the skin around the wound/scar site.
We also showed that keloids are particularly prevalent
on body regions with strong skin-stretching force due to
body movements, such as the joints, anterior neck, chest
wall, scapula/upper-arm, and suprapubic region. Re-
peated dermal injury and infection is also a local risk fac-
tor.
Lifestyle risk factors include strong/continuous body
movements (e.g. those of athletes/manual workers) that
stretch the wounds/scars. Other factors are excessive
consumption of hot/spicy foods and alcohol and over-
long bathing in hot water, which may augment wound/
scar inflammation. Obesity may also be a risk factor.
Prevention of Keloids/HSs
Because traumatic, surgical, and burn wounds and
wounds caused by infectious agents, can turn into patho-
logical scars, it is important to assess the pathological
scarring risk of patients with such wounds. If the patient
or his/her family has a history of keloid and/or the
wound is on a high-risk zone, the patient should be con-
sidered to be high risk and treated appropriately, as de-
scribed below.
Trauma and Burn Wounds with a Raw Surface
In general, the longer wounds take to epithelialize, the
greater the risk that keloids/HSs develop. Therefore,
trauma/burn wounds should undergo primary suturing
or skin grafting/flap transfer as soon as possible. How-
ever, if surgery cannot be planned, the raw surface must
be encouraged to epithelialize rapidly by applying con-
servative therapies that limit infection and inflammation
and accelerate granulation-tissue formation. These thera-
pies, which should be applied on a case-by-case basis, in-
clude negative-pressure wound therapy, appropriate
wound dressing materials, topical drugs (e.g. basic fibro-
blast growth factor spray), antibiotics, and anti-
inflammatory agents. The wound should also be stabi-
J Nippon Med Sch 2021; 88 (1)
lized by placing bandages or garments over the dressing.
In normal wound healing, once epithelialization is
completed, the inflammation in the dermis/dermal-like
granulation tissues under the epidermis starts to subside
spontaneously and the dermal tissues begin maturing.
However, if strong/repetitive mechanical forces are ex-
erted on the immature scar, they can prolong the inflam-
mation, thereby fomenting pathological scarring. One of
the keys to preventing such scarring is to understand
that the healing rates of the epidermis and dermis differ
completely. In the case of sutured wounds, the epidermis
can regenerate within 7-10 days, leading both the patient
and the physician to believe that the wound has healed
completely. In fact, it can take 3 months before the der-
mis regains 90% of its normal strength14. This lengthy
vulnerability to inflammation-triggering mechanical
forces means that it is essential to provide the immature
scar with protracted external mechanical support (i.e. scar
stabilization) until maturity has been attained (i.e. the
scar becomes soft, pliable, and flat).
Therefore, all immature scars should be fixed continu-
ously with tape. Silicone tape is the best choice. The tape
is retained until it detaches naturally. Alternatively,
silicone-gel sheets or cheaper paper tapes can be used on
a case-by-case basis.
When an individual is at high risk of keloid formation
and/or the scars are located on keloid-prone regions,
scar stabilization should be prolonged for at least 6-12
months after maturation. It should also be combined
with first steroid ointment and then tape/plaster admini-
stration. In Japan, two types of steroid tapes are avail-
able15: the strong deprodone-propionate plaster (EclarⓇ
plaster; Hisamitsu Pharmaceutical Co., Inc., Tokyo, Ja-
pan) should be used for adults while the weak fludroxy-
cortide tape (DrenisonⓇ tape; Teikoku Seiyaku Co., Inc.,
Kagawa, Japan) is suitable for children. The steroid oint-
ment should be applied for the first 2-3 weeks after epi-
thelialization because the epidermis is still immature (full
epithelialization takes 4 weeks) and could be injured by
daily steroid tape/plaster changes. Once steroid tape/
plaster replaces the ointment, it is continued until the
scar is soft and flat. Scar redness should be ignored: con-
tinuing steroid tape/plaster just because of redness ele-
vates the risk of telangiectasia because the steroid thins
the structures supporting the blood vessels. Once steroid
tape/plaster is discontinued, a non-steroidal ointment/
cream such as heparinoid ointment/lotion/spray (Hiru-
doidⓇ; Maruho Co., Inc., Osaka, Japan) or an NSAID
ointment/cream (Ibuprofen piconol: StadermⓇ; Torii
3
 R. Ogawa, et al
Pharmaceutical Co., Ltd., Tokyo, Japan) should be ap-
plied to keep scar surface moist and inhibit inflamma-
tion.
In the case of low-risk individuals and/or wounded
regions (e.g. the face, lower leg), wound stabilization is
sufficient to prevent pathological scarring.
Primarily Closed Wounds
Sutured wounds should be cleaned daily with tap
water/saline or disinfectant and covered with non-
adhesive materials until the sutures can be removed. This
prevents infections and wound stretching, thereby block-
ing excessive inflammation. After suture removal, wound
stabilization with silicone tape/gel-sheets should be
started. For high-risk individuals and/or regions,
silicone-tape fixation should be replaced 2-3 weeks later
with steroid tape/plaster that continues until scar matu-
ration. For low-risk individuals and/or regions, silicone-
tape fixation is sufficient.
Inflammatory Skin Diseases
Inflammation associated with skin diseases such as
acne, folliculitis, and herpes zoster can strongly provoke
pathological scarring if it spreads into the dermis. To pre-
vent this, the lesions caused by these diseases should be
treated topically with ointments/creams that contain
anti-infection agents until the exudation stops. The anti-
inflammatory preventive measures described above
should then be started. Thus, high-risk individuals and/
or regions should be treated with silicone tape-mediated
wound stabilization plus 2-3-week steroid ointment treat-
ment that is then replaced by steroid tape/plaster.
Wound stabilization alone is sufficient for low-risk indi-
viduals and/or regions.
Early Detection of Keloids/HSs
The earlier pathological scarring is detected, the easier
it is to treat it. Therefore, at follow-up after epithelializa-
tion, scars should be palpated. Any stiffness/hardness,
even in a small part of the scar, indicates continued in-
flammation that has led to collagen accumulation. In this
case, silicone-tape fixation should be changed immedi-
ately to steroid tape/plaster. If it is ineffective in the next
1-3 months, steroid injections should be started/added. If
the scar remains refractory, surgery and adjuvant therapy
is indicated.
In general, keloids/HSs form 1-3 months after injury/
surgery. Therefore, patients should be instructed to touch
their scar daily for at least 3 months to check for stiff-
ness.
4 J Nippon Med Sch 2021; 88 (1)
Treatment of Hypertrophic Scars and Keloids
Diagnosis of Keloid/HS Risk
The Japan Scar Workshop (JSW) scar scale (JSS)16 helps
to differentially diagnose HS/keloid-like lesions. It also
has indicators that suggest the scar may be or become in-
tractable:
1. The patient has multiple keloid/HS-like lesions on
the body
2. The keloid/HS-like lesion is large, even if it is soli-
tary
3. Age at pathological-scar onset is <20 years
4. The patient is a female around 10-30 years of age (i.
e. of reproductive age)
5. The patient is pregnant
6. The patient has hypertension
7. The patient is a physical laborer/professional athlete
8. The lesion is on a mobile body area (e.g. major
joints, anterior chest/neck)
If the patient is judged to have low risk, his/her lesion
resembles an HS and conservative therapy is the primary
choice. However, if contracture is observed, especially on
a joint, contracture-releasing surgery may be indicated.
After surgery, recurrence can be prevented by steroid
tape/plaster.
If the patient is judged to have high risk, his/her le-
sion resembles a keloid and multimodal therapy should
be planned. If surgery is selected, postoperative radio-
therapy must be performed to prevent recurrence.
Steroid Tape/plaster
Steroid tape/plaster15 is the first-line therapy for
keloids/HSs in the NMS protocol (Fig. 1). Most pediatric
and older patients can be treated by steroid tape/plaster
alone because they have much thinner skin, which easily
absorbs the steroid. However, thick keloids are difficult
to treat by steroid tape/plaster alone and require the ad-
dition of corticosteroid injections (KenacortⓇ; Bristol-
Myers Squibb K.K., Tokyo, Japan). These injections cause
the keloids/HSs to soften, thereby enhancing the absorp-
tion of steroid from the tape/plaster.
Steroid tape/plaster also serves to prevent keloid/HS
recurrence after excision. The same protocol used to pre-
vent keloids/HSs after skin injury/infection is used:
thus, steroid tape/plaster is started with daily changes 2-
3 weeks after suture removal; scar stiffness is checked
during follow-up; steroid injection is added if the scar is
refractory to the tape/plaster; and tape/plaster therapy
is continued until the scar softens and flattens. Treatment
concludes with non-steroidal ointment/cream applica-
tion.
 Keloid & Hypertrophic Scar NMA Protocol

a b
Fig. 1 The left scapular keloid of a woman in her 30s was treated by deprodone-propionate
plaster.
(a) Pretreatment.
(b) Twenty-four months after starting treatment.
The tape was placed on the keloid 24 hours a day and changed daily. After 24 months,
the inflammation had completely resolved and the subjective and objective symptoms
improved.

a b
Fig. 2 The right shoulder keloid of a woman in her 50s was treated by triamcinolone acetonide
steroid injections.
(a) Pretreatment.
(b) Twenty-four months after starting treatment.
The keloid underwent steroid injection (5 mg triamcinolone diluted with 1.5 mL xylo-
caine 1% with epinephrine) every 2–3 months. After 24 months, the subjective and objec-
tive symptoms improved.

Steroid Injection
Triamcinolone acetonide is a powerful tool because it
rapidly reduces inflammation (Fig. 2). Each injection
should comprise 5-10 mg mixed with a local anesthetic
16
such as xylocaine 1% with epinephrine . Women may ex-
perience fewer menstrual irregularities if the dose does
not exceed 5 mg. We use thin needles such as 30 G and
27 G along with syringes with locks. The initial target of
the injection should not be the center of the mass: its
hardness means the injection fluid will not disperse suffi-
ciently throughout the tissue. The consequent local pres-
sure may also cause pain. Rather, the target should be
the scar border where it meets the normal skin: the nee-
dle should penetrate either shallowly to target the heav-
ily inflamed leading edge of the scar or deeply towards
the center (the scar tissue along this deep plane is softer
than the upper central core). Once one or more injections
have softened the scar, the needle can be injected straight
into the core. Smaller keloids/HSs can improve markedly
after just 1-2 injections. If these improvements can be

J Nippon Med Sch 2021; 88 (1) 5

 R. Ogawa, et al

a b c d e
Fig. 3 The left upper-arm keloid of a woman in her 30s was treated by z-plasty and postoperative radiotherapy.
(a) Before surgery.
(b) After keloid excision.
(c) Z-plasty design.
(d) Immediately after surgery.
(e) Two years after surgery.
The keloid developed from BCG vaccination. It was excised, tension was released by fascial sutures, and z-plasties were performed.
Postoperative radiotherapy (18 Gy/3 fr/3days) was then conducted. No recurrence was observed 2 years after surgery.

continued/maintained with steroid tape/plaster, further
injections are unnecessary. If patients are afraid of
injection-induced pain, we recommend steroid tape/plas-
ter until the scar has softened. Injections can then be
added because the risk of pain is much reduced.
Surgery
Surgical monotherapy associates with an atrocious rate
of keloid/HS recurrence. Therefore, surgical techniques
that abrogate dermal tension, namely, subcutaneous/fas-
cial tensile-reduction sutures, z-plasties, and local flap
transfer17,18, should be used in combination with postop-
erative radiation (described below) and steroid tape/
plaster.
Placing sutures on the superficial/deep fascia below
the dermis causes the wound edges to juxtapose natu-
rally. This allows dermal sutures to be placed with very
little tension, after which superficial sutures can be
added. It is essential to realize that without the deep su-
tures, dermal sutures not only fail to reduce the dermal
tension, they may in fact exacerbate it.
Zig-zag sutures, including z-plasties, are good for re-
leasing linear scar contractures and tension (Fig. 3). An-
other advantage is that segmented scars mature faster
than long linear scars. Zig-zag incision/suturing is par-
ticularly indicated if scars cross a joint.
Local flaps are also useful for releasing scar contrac-
tures (Fig. 4): they expand naturally after surgery and are
therefore not prone to postsurgical contractures, unlike
skin grafts, which often form pathological scars around
the graft. Compared to island flaps, skin-pedicled flaps
are superior because they extend more postsurgically and
therefore release contractures more effectively19. Flap sur-
gery is especially suitable for severe keloids; however,
multimodal therapy should be applied to both the exci-
sion and donor sites to prevent recurrent and new le-
sions from forming.
Radiation
Post-excision keloid/HS recurrence can be effectively
controlled by adjuvant radiation. Radiation protocols are
constantly improving. In the past, orthovoltage or super-
ficial or soft X-rays were used. However, the safety and
efficacy of radiotherapy protocols have improved mark-
edly recently; therefore, we now routinely use postopera-
tive electron-beam irradiation after keloid/HS resection.
This, when combined with the surgical and steroid tape/
plaster modalities described above, markedly reduces the
recurrence rate: the keloid-recurrence rate after surgery is
now less than 10% in our hospital18. Moreover, 15 years
of close monitoring and long-term follow-up has shown
that this protocol has no major side effects (Fig. 3, 4)18.
Another, increasingly popular, radiation modality for
keloids is high-dose rate-superficial brachytherapy. De-
pending on the shape of the surgical scar, an applicator
can be used to ensure the evenness and localization of
the radiation to the wound surface. However, we prefer
electron beams because they reach the reticular dermis

6 J Nippon Med Sch 2021; 88 (1)

 Keloid & Hypertrophic Scar NMA Protocol

a b c d
Fig. 4 The chest and abdominal keloids of a man in his 70s were treated by flap surgery, z-plasties, and postoperative radiothera-
py.
(a) Before surgery.
(b) Intraoperative view of the first operation, during which the chest keloid was excised and reconstructed with a flap.
(c) Intraoperative view of the second operation, during which the abdominal keloid was removed and closed with z-plas-
ties.
(d) Two years after the second operation.
The keloids were removed in two operations. The donor and recipient sites were irradiated. The post-treatment course was
uneventful. After 2 years, recurrence was not observed and the remaining pathological scars had matured.

a b
Fig. 5 The chest-wall keloid of a woman in her 70s was treated by radiation monotherapy.
(a) Before treatment.
(b) Eighteen months after treatment.
This mild chest-wall keloid was treated by high-dose rate-superficial brachytherapy (25 Gy/5
fr/5days). The inflammation resolved completely. Six months later, the subjective and objective
symptoms improved dramatically. Eighteen months later, the pathological scars matured.

more selectively; moreover, the beam attenuates after
passing through the skin and thus has little effect on the
internal organs.
To further improve the safety of our adjuvant radio-
therapy protocol, we optimized them in 2013 such that
fewer fractions are now used18. As a result, high-
recurrence keloid-excision sites are now treated with 18
Gy/3 fr/3days while low-recurrence sites (e.g. earlobe)
and other body sites are now treated with 8 Gy/1 fr/1
day and 15 Gy/2 fr/2days, respectively.
We also occasionally employ radiation monotherapy to
treat older patients or patients with huge keloids (Fig.
5)1. However, since the total radiation dose needed is
higher than the postoperative radiation doses, the radia-
tion should be delivered carefully to avoid secondary ra-
diation carcinogenesis. It is also essential to secure in-
formed consent. However, the risks of primary radiother-
apy should be measured against its immense benefits: it
rapidly decreases subjective symptoms such as pain and
itch and, over the following year, progressively normal-
izes scar color and thickness.
Laser Therapy
In our institution, a 1,064-nm long-pulsed Nd:YAG la-
ser is used for flattish keloids/HSs that have low levels
of inflammation20,21. It is mainly used to decrease the red-
ness/telangiectacia caused by steroid therapy. Flat

J Nippon Med Sch 2021; 88 (1) 7

 R. Ogawa, et al
keloids/HSs are particularly suitable for laser therapy
because the laser beam can reach the blood vessels in the
dermis.
Once scar inflammation has been completely quelled
by other methods, fractional abrative lasers can be used
for low-risk individuals. This induces a wound healing
response that increases collagen III production, thereby
encouraging scar remodeling. Note: it is important to
cool the skin when conducting laser therapy to prevent
superficial injury.
However, these lasers have only limited efficacy with
thick, highly inflamed keloids/HSs.
Make-up Therapy
Medical make-up techniques such as “Rehabilitation
Make-upⓇ” are recommended if the scars are on exposed
areas (e.g. the face, neck, and upper limbs). These tech-
niques can be learned and self-applied by the patients.
Since our cosmetics are water-proof, they are not affected
by humid/wet conditions. These techniques associate
with improved mental health, acceptance of the scar ap-
pearance, and more positive attitudes to scar treatment.
Since it is difficult to improve the aesthetics of highly
elevated scars with make-up therapy, scar thickness
should be reduced with steroid plaster/injection before
commencing make-up therapy.
Slightly rough scars can be covered by thin tapes prior
to applying the foundation.
Follow-up of Keloids/HSs
Keloid/HS patients who receive multimodal therapy
should undergo prolonged follow-up and be taught how
to manage their scar and any new wounds. Patient edu-
cation is a hugely important factor that dictates the suc-
cess of our protocol.
Conclusions
Multimodal therapy, particularly surgery, radiation, and
steroid tape/plaster, successfully manages keloids/HSs.
Our extensive experience, including with international
patients, suggests that the NMS protocol may be suitable
as a foundation for a standard international prevention/
treatment algorithm for pathological scars. It should be
noted that the NMS protocol relies on close, prolonged
follow-up, which is only feasible if keloid/HS treatments
are covered by a national universal insurance system (as
it is in Japan)22. We expect that treatments will improve
significantly as our understanding of scar biology grows,
more good-quality institutional trials are conducted, and
new agents are found.
8 J Nippon Med Sch 2021; 88 (1)
Conflict of Interest: The authors declare no conflicts of inter-
est.
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Journal of Nippon Medical School has adopted the Creative Com-
mons Attribution-NonCommercial-NoDerivatives 4.0 International
License (https://creativecommons.org/licenses/by-nc-nd/4.0/) for
this article. The Medical Association of Nippon Medical School re-
mains the copyright holder of all articles. Anyone may download,
reuse, copy, reprint, or distribute articles for non-profit purposes
under this license, on condition that the authors of the articles are
properly credited.
9
 TINJAUAN PUSTAKA

Scar Hipertrofik dan Keloid:

Patofisiologi dan Penatalaksanaan
Linda Sinto
Klinik Gracia, Cileungsi, Bogor, Indonesia

ABSTRAK
Angka terjadinya kelainan fibrotik yang sering muncul pasca-luka terus meningkat, baik luka karena operasi elektif maupun luka yang disebabkan
oleh trauma lainnya. Seringkali disertai dengan keluhan lain seperti kontraktur, gatal hingga nyeri, sehingga mengganggu kualitas hidup
seseorang baik secara fisik maupun psikologis. Secara umum kelainan fibrotik ini dibedakan atas scar hipertrofik dan keloid. Scar hipertrofik
lambat laun dapat terjadi regresi secara sempurna, sedangkan keloid jarang sekali terjadi regresi. Gambaran klinis keduanya seringkali serupa.
Oleh karena itu, sangat penting untuk menegakkan diagnosis yang tepat antara kedua jenis kelainan fibrotik ini sebelum mengambil keputusan
untuk terapi. Saat ini sudah ada beberapa macam terapi yang ada, tetapi terapi ini pun masih terus berkembang. Melalui artikel ini akan dibahas
mengenai perbedaan mendasar antara kedua jenis kelainan fibrotik ini dan pilihan kombinasi terapi yang baik untuk penanganannya.

Kata kunci: Keloid, luka, scar hipertrofik

ABSTRACT
Excessive scars form following in wound healing from elective surgery and other traumatic may keep arise. Mostly it causes contractures, pruritus,
pain, and its affect the patient’s quality of life both physically and also physicology. Excessive scaring identified in two types: hypertrophic scar
and keloid. Sometimes hypertrophic scar generally regressing spontaneously but in keloid they do not regress with time. Clinically both of them
most similar but incorrect identification of scar type may bring clinician to inappropriate management. Nowdays there are many choices for
treat this excessive scar but still need more studies to find satisfied result. This review will summarize the different between hypertrophic scar
and keloid, management using therapeutic combination for excessive scar. Linda Sinto. Scar Hypertrophic and Keloid : Pathophysiology and
Management.

Keywords: Hypertrophic scar, keloid, wound

PENDAHULUAN
Angka penderita scar pasca-luka terus
meningkat baik karena luka penyembuhan
operasi elektif maupun luka karena luka
bakar, laserasi, tato, akne, abses, dan injeksi.1
Karena sering disertai gatal hingga nyeri juga
kontraktur, scar sering menurunkan kualitas
hidup.1
Secara umum scar dibedakan menjadi
dua bentuk, yaitu scar hipertrofik dan scar
keloid. Gambaran klinis kedua jenis ini dapat
sulit dibedakan, salah identifikasi dapat
menyebabkan manajemen yang tidak tepat
dan sering menghasilkan keputusan operasi
yang salah.2
EPIDEMIOLOGI
Faktor risiko keloid diduga berkaitan dengan
beberapa hal. Riwayat keloid pada keluarga
akan meningkatkan insidens keloid.8 Gen
yang diduga memiliki peran terjadinya keloid
adalah HLA-B14, HLA-B21, HLA-BW16, HLA-
BW35, HLA-DR5, dan HLA-DQW3.8
Keloid dapat terjadi pada semua ras, kecuali
albino, dan ras kulit hitam memiliki risiko
hingga 15 kali lebih besar.1,8 Angka kejadian
keloid lebih tinggi pada saat masa pubertas
dan kehamilan, dan menurun pada masa
menopause. Hormon juga diduga menjadi
penyebab. Diduga ada peranan sel mast pada
terjadinya keloid.1,5,8
PATOFISIOLOGI
Ada 3 fase penyembuhan luka, yaitu fase
inflamasi, fase proliferasi, dan fase remodelling.
Fase Inflamasi
Fase ini dimulai saat terjadi luka dan
berlangsung selama 2 hingga 3 hari. Diawali
dengan vasokonstriksi untuk mencapai
hemostasis. Pada fase ini keping darah
melepaskan growth factor seperti platelet-
derived growth factor (PDGF) dan transforming
growth factor β (TGF-β). Neutrofil mencapai
area luka dan memenuhi rongga perlukaan.
Neutrofil akan memfagosit jaringan mati dan
mencegah infeksi. Selanjutnya monosit akan
memasuki area luka. Makrofag memfagosit
debris dan bakteri serta berperan pada
produksi growth factor yang dibutuhkan
untuk pembuatan matriks ekstraseluler
oleh fibroblas dan pembuluh darah baru
untuk penyembuhan luka. Oleh karena
itu, ketidakhadiran monosit atau makrofag
akan menghambat fase penyembuhan
luka. Terakhir, sel limfosit dan sel mast akan
berdatangan ke area luka, tetapi peranannya
masih belum diketahui pasti.1,3,4

Alamat Korespondensi email: linda_sinto@yahoo.com

CDK-260/ vol. 45 no. 1 th. 2018 29

 TINJAUAN PUSTAKA
Fase Proliferasi
Fase ini dimulai pada hari ke-4 hingga minggu
ke-3 setelah luka. Makrofag terus memproduksi
growth factor seperti PDGF dan TNF-β1 yang
membuat fibroblas dapat terus berproliferasi
dan migrasi membentuk jaringan matriks
ekstraseluler. Selain itu, juga menstimulasi sel
endotel untuk membentuk pembuluh darah
baru. Kolagen tipe III juga mulai terbentuk
yang nantinya akan digantikan oleh kolagen
tipe I pada fase remodelling. Yang penting
pada fase ini adalah saat mulai terjadi
pengisian rongga luka dengan kolagen maka
fibroblas harus sudah berkurang dan proses
angiogenesis juga harus mulai melambat agar
didapatkan scar normal.1,3,4
Fase Remodelling
Fase terpanjang dalam fase penyembuhan
luka, berlangsung mulai minggu ke-3 hingga 1
tahun. Fase ini ditandai dengan kontraksi luka
dan remodelling kolagen. Kolagen tipe I mulai
menggantikan kolagen tipe III. Kekuatan luka
terus meningkat sejalan dengan reorganisasi
kolagen.1,4,6
Fase inflamasi yang memanjang diduga
merupakan salah satu penyebab timbulnya
scar hipertrofik atau keloid. Meningkatnya
jumlah sel-sel imun pada keloid meningkatkan
aktivitas fibroblas dan terus terjadi
pembentukan matriks ekstraseluler. Hal ini
juga yang diduga menyebabkan scar timbul
melebihi margin atau batas luka pada keloid.
Pada scar hipertrofik, infiltrasi sel imun akan
menurun sehingga mungkin terjadi regresi.
Teori lain menyatakan bahwa TGF-β
memainkan peranan sangat penting dalam
terjadinya kelainan jaringan fibrotik ini. TGF-β1
dan TGF-β2 merupakan stimulan penting
sintesis kolagen dan proteoglikan serta
mempengaruhi matriks ekstraseluler yang
tidak hanya meningkatkan sintesis kolagen
tetapi juga menghambat pemecahannya.
Sedangkan TGF-β3 yang ditemukan lebih
dominan pada fase akhir penyembuhan
luka memiliki fungsi sebaliknya. Decorin
merupakan proteoglikan yang memiliki
kemampuan mengikat dan menetralisir
TGF-β serta menurunkan protein matriks
ekstraseluler. Kadar decorin yang rendah
dapat memicu terjadinya kelainan fibrotik.1,6
Akhir-akhir ini dinyatakan bahwa apoptosis
juga menjadi penyebab kelainan fibrosis.1
30
Pada fase awal terbentuknya scar hipertrofik, epitelisasi hingga 10-14 hari meningkatkan
terjadi hiperseluler, dan pada fase remodelling angka kejadian scar hipertrofik/keloid. Lokasi,
sel fibroblas berkurang dan perlahan-lahan ukuran, kedalaman luka, usia pasien, dan
menjadi scar normal melalui proses apoptosis. keberhasilan terapi sebelumnya merupakan
Proses ini mulai terjadi sejak hari ke-12 pertimbangan klinisi untuk menentukan
pasca-luka. Penelitian pada scar hipertrofik terapi.
akibat luka bakar derajat tinggi menemukan
keterlambatan proses apoptosis, yaitu pada Terapi Tekan
bulan ke-19-30 pasca-luka.1 Efektivitasnya masih kontroversial. Mekanisme
kerja yang diharapkan adalah dengan
KLINIS pemberian tekanan, maka sintesis kolagen
Scar hipertrofik terbentuk mulai minggu ke-4 menurun karena terbatasnya suplai darah
hingga ke-6 setelah luka dan tumbuh cepat dan oksigen, serta nutrisi ke jaringan scar dan
hingga 6 bulan. Setelah itu akan mengalami apoptosis diharapkan meningkat. Tekanan
regresi hingga terbentuk jaringan normal. kontinu (15-40 mmHg) diberikan minimal 23
Sedangkan pada keloid scar terus bertumbuh jam dan/atau 1 hari selama minimal 6 bulan
dan cenderung menetap.1 atau selama scar masih aktif. Terapi ini terbatas
karena sering menyebabkan maserasi, eksema,
Scar hipertrofik biasanya didahului trauma ataupun bau tidak sedap karena penggunaan
dan luas scar tidak melebihi luas luka. Keloid bahan kain. Terapi tekan biasanya berhasil
dapat didahului trauma dan kadang dapat lebih baik pada anak-anak.1
terjadi spontan tanpa didahului luka. Scar
pada keloid dapat lebih luas dari area lukanya. Silicone Gel Sheeting
Pada scar hipertrofik, tindakan pembedahan Silicone gel sheeting bekerja dengan
dapat menjadi pilihan penanganan yang baik, cara meningkatkan temperatur parut
tetapi pada scar keloid, tindakan pembedahan 1-2 derajat dari suhu tubuh, keadaan ini
sering menyebabkan scar menjadi lebih besar akan meningkatkan aktivitas kolagenase.9
akibat luka operasi (Tabel 1).1,2 Penggunaan dianjurkan ≥12 jam dan/
atau 1 hari dimulai sejak 2 minggu pasca-
PENATALAKSANAAN penyembuhan luka. Penggunaan silicone
Menghindari terjadinya luka berlebihan tetap sheet ini lebih disukai pada area yang sering
merupakan solusi terbaik. Semua terapi dapat bergerak.1,7
dilakukan pada scar hipertrofik ataupun keloid.
Walaupun demikian, pembedaan klinis antara Extractum Cepae
keduanya tetap perlu terutama sebelum Extractum cepae dengan turunan spesifiknya
tindakan pembedahan dan laser. adalah quercetin memiliki efek anti-inflamasi,
anti-bakterial, dan fibrinolitik, sehingga
Angka keberhasilan lebih tinggi bila dilakukan mampu menghambat proliferasi fibroblas
terapi kombinasi. Keterlambatan proses dan produksi kolagen pada keloid dan scar
Tabel 1. Perbandingan epidemiologi, gambaran klinis, dan histologi antara scar hipertrofik dan keloid.1
Scar Hipertrofik Scar Keloid
Insidens 40-70% terjadi pasca-operasi dan >90% pasca- 6-16% terjadi pada ras Afrika
luka bakar
Tidak ada perbedaan antara laki-laki dan perempuan, insidens tertinggi pada usia 20 hingga 30 tahun.
Area Predileksi Bahu, leher, sekitar sternum, lutut, pergelangan Dada depan, pundak, telinga, lengan atas, dan
kaki pipi
Area paling jarang terkena: kelopak mata, kornea, telapak tangan, genitalia, dan telapak kaki
Onset 4-8 minggu setelah luka, pertumbuhan cepat Beberapa tahun setelah terjadinya luka atau
terjadi hingga 6 bulan kemudian mengalami spontan tanpa didahului luka di area dada tengah.
regresi Cenderung menetap, jarang regresi spontan.
Jarang berulang setelah eksisi scar awal Sering berulang setelah eksisi scar awal
Gambaran Klinis Jarang meluas melebihi area luka Luas melebihi area luka
G a m b a r a n Terorganisir. Tidak terorganisir, luas, tebal. Kolagen tipe I&III
Histopatologis Kolagen tipe III yang paralel epidermis, terdapat tanpa nodul atau miofibroblas. Vaskularisasi
nodul mengandung miofibroblas dan banyak sangat buruk. Ekspresi ATP tinggi.
mengandung asam mukopolisakarida. Ekspresi
ATP rendah.
CDK-260/ vol. 45 no. 1 th. 2018
 TINJAUAN PUSTAKA

hipertrofik.1,7 Zat ini banyak ditemukan di
bawang, apel, anggur merah, dan teh hitam.2
Quercetin mampu menghambat TGF-β1
dan TGF-β2.7 Penggunaan topikal diberikan
pasca-tindakan laser untuk menghilangkan
tattoo dan sering digunakan sebagai terapi
pencegahan terutama pasca-tindakan bedah.7
Injeksi Kortikosteroid
Kortikosteroid bekerja mensupresi proses
inflamasi luka. Selain itu, kortikosteroid
mampu mengurangi sintesis kolagen
dan glikosaminoglikan, menghambat
pertumbuhan fibroblas, dan meningkatkan
degradasi kolagen dan fibroblas. Injeksi
intralesi menggunakan triamcinolon acetonide
(TAC) 10-40 mg/mL diulang setiap 3-4 minggu
dapat dilakukan hingga 6 bulan memberikan
hasil yang cukup baik, pada kasus tertentu
terkadang dibutuhkan tambahan sesi.7
Pada terapi tunggal, hasil maksimal hingga
rata sepenuhnya didapatkan pada scar yang
masih baru. Untuk scar lama, hasil yang dicapai
hanya lesi menjadi lebih kecil dan membantu
mengurangi gejala.1 Efek samping yang sering
muncul adalah atrofi kulit, telangiektasis, dan
rasa nyeri di area penyuntikan.1,2,7
Cryotherapy
Dapat digunakan sebagai terapi tunggal
ataupun kombinasi dengan terapi injeksi
kortikosteroid untuk hasil lebih maksimal.
Untuk kombinasi terapi, disarankan
cryotheraphy terlebih dahulu kemudian
dilanjutkan dengan injeksi triamcinolon
acetonide. Cryotherapy menyebabkan
kerusakan vaskular, sehingga terjadi anoksia
dan nekrosis jaringan.1,2,7
Revisi Scar
Sebelum tindakan bedah, harus dipastikan
perbedaan antara scar hipertrofi dan keloid.
Pada penanganan scar hipertrofi, scar <1
tahun masih dapat menunjukkan perbaikan
tanpa manipulasi. Kemungkinan rekuren
setelah tindakan bedah lebih kecil pada scar
hipertrofik. Keloid memiliki angka rekuren
45-100% pasca-tindakan bedah. Tindakan
eksisi sering menyebabkan scar yang lebih
besar. Tindakan bedah sebaiknya dikombinasi
dengan injeksi triamcinolone acetonide dan
terapi tekan di area tindakan untuk hasil yang
lebih baik.1,7

Tabel 2. Penatalaksanaan scar hipertrofi dan keloid1,7 Radioterapi

Superficial x-rays, electron-beam therapy,
Terapi Penggunaan Indikasi dan Efisiensi
dan brachytherapy dosis rendah atau
Profilaksis tinggi memberikan hasil yang cukup baik.1
Terapi Tekan Tekanan kontinu (15-40 mmHg) Profilaksis scar hipertrofik akibat luka bakar, keloid di Radioterapi menghambat neovaskular dan
minimal 23 jam dan/atau 1 hari hingga area telinga (post-eksisi)
6 bulan. Keberhasilan masih kontroversial
proliferasi fibroblas, sehingga produksi
Pasien sering merasa tidak nyaman kolagen menurun. Terapi sebaiknya dimulai
Silicone Gel Sheeting ≥12 jam dan/atau 1 hari dimulai sejak Profilaksis scar hipertrofik dan keloid sejak 24-48 jam pasca-tindakan eksisi dengan
2 minggu pasca-penyembuhan luka Kurang bermanfaat pada scar hipertrofik dan keloid
yang sudah matur
dosis total 40 Gy untuk mencegah efek
Silicone Gel Dioles 2 x sehari sejak 2 minggu pasca-penyembuhan luka hingga 2 bulan samping seperti hipo- atau hiperpigmentasi,
eritema, telangiektasis, dan atrofi.1
Flavonoids Dioles 2 x sehari sejak 2 minggu pasca- Hanya sebagai terapi profilaksis scar hipertrofik dan
penyembuhan luka hingga 4-6 bulan keloid
Terapi Penyembuhan Laser
Kortikosteroid Injeksi intralesi triamcinolon acetonide Terapi utama untuk keloid dan pilihan kedua untuk Terapi 585-nm pulse dye laser (PDL)
(10-40 mg/mL), diulang 1-2x per bulan scar hipertrofi
memberikan hasil yang cukup baik. Tanpa
Kombinasi dengan pembedahan, pulse dye laser,
dan cryotherapy overlap, dengan fluence 6,0-7,5 J/cm2 (7 mm
Efek samping yang sering: atrofi kulit dan jaringan spot) atau 4,5-5,5 J/cm2 (10 mm spot) sangat
lemak subkutan, telangiektasis
dianjurkan untuk terapi scar hipertrofik
Cryotherapy Pembekuan jaringan dengan Efektif untuk scar hipertrofik, sedangkan untuk
menggunakan nitrogen cair keloid dianjurkan kombinasi dengan injeksi ataupun keloid. Untuk hasil maksimal,
triamcinolone acetonide sebaiknya terapi diulang hingga 2-6 kali.
Terbatas hanya untuk scar kecil
Efek samping yang sering muncul: rasa nyeri dan Dengan panas yang merusak kolagen, terapi
blister 585 nm PDL dipercaya dapat membentuk
Revisi Scar Eksisi dengan linear, tension-free Efektif untuk scar hipertrofi. Angka kejadian kolagenesis baru. Hati-hati dengan efek
closure, split or full thickness skin grafting, berulang 45-100% pada eksisi keloid bila tidak diberi
z-plasty, w-plasty terapi tambahan samping hipo- atau hiperpigmentasi serta
Radioterapi X-rays superfisial 15-20 Gy hingga 40 Efisiensi hasil sangat baik sebagai terapi tambahan blister. Sering terjadi purpura pasca-terapi
Gy 5-6 sesi pada fase awal post-operasi. setelah eksisi keloid yang bertahan hingga 7-10 hari.1
Faktor risiko keganasan jaringan
Terapi Laser Short pulse dye laser (585 nm) 6,0-7,5 J/ Terapi pilihan untuk lesi keloid primer dan scar
cm2 (7 mm spot) atau 4,5-5,5 J/cm2 (10 hipertrofik Terapi 1064-nm Neodym: YAG Laser
mm spot), 2-6 sesi setiap 2-6 minggu. Terapi pilihan untuk keloid yang lebih dalam juga memberikan hasil yang cukup baik.
1064-nm Neodym: YAG Laser, 5-10 kali
dengan interval 1-2 minggu Mekanisme kerjanya serupa dengan PDL,
Terapi Terkini tetapi Nd:YAG mampu menembus jaringan
Interferon Injeksi intralesi INF-α2b (1.5-2x106IU) 2 Cukup efektif lebih dalam, sehingga sangat baik untuk
x sehari hingga 4 hari Efek samping yang sering: flu like symptoms terapi keloid yang tebal. Ditemukan perbaikan
5-FU Injeksi intralesi 5-FU 50 mg/mL atau Cukup efektif untuk terapi keloid dan scar hipertrofi pigmentasi, vaskularisasi, dan ukuran scar
Kombinasi TCA 10-40 mg/mL dan Efek samping: anemia, leukopenia, trombositopenia.
5-FU 50 mg/mL (1:9) Dibutuhkan hitung darah. Kontraindikasi untuk setelah 5-10 terapi dengan interval 1-2
wanita hamil atau pasien dengan supresi sumsum minggu menggunakan fluence rendah.7
tulang.

CDK-260/ vol. 45 no. 1 th. 2018 31

 TINJAUAN PUSTAKA

Injeksi Interferon (IFN) meningkatkan proses fibrinase.2 (1:9).7

Merupakan terapi yang cukup potensial
karena IFN mampu mengurangi sintesis
kolagen tipe I dan III. Secara spesifik INF-α2b
memiliki efek antagonis terhadap TGF-β
dan histamin. INF-α2b disuntikkan intralesi
(1,5x106 IU, 2 kali sehari selama 4 hari) mampu
mereduksi ukuran scar hingga 50% di hari ke-
9. Efek samping yang sering muncul adalah flu
like symptoms dan nyeri di area penyuntikan.1,2
Injeksi Doxorubicin
Doxorubicin dapat menghambat sintesis
kolagen melalui mekanisme penghambatan
enzim prolidase yang merupakan enzim kunci
dalam proses resintesis kolagen. Doxycycline,
daunorubicin, gentamicin, netilmicin, dan
anthracycline juga memiliki kemampuan
menghambat enzim prolidase.2
Injeksi Verapamil
Verapamil termasuk dalam golongan calcium
channel blocker yang bekerja menghambat
sintesis dari matriks ekstraseluler dan
Bleomycin Sulfate
Bleomycin sulfate bekerja menghambat
langsung sintesis kolagen melalui mekanisme
penghambatan terhadap stimulasi TGF-β1.
Penyuntikan intralesi sebanyak 3-5 kali dalam
1 bulan telah terbukti menurunkan 69,4%
keloid. Efek samping hiperpigmentasi dan
atrofi dermal. Walaupun cukup menjanjikan
tetapi masih dibutuhkan penelitian lebih
lanjut.2,7
5-Fluorouracil (5-FU)
Zat kemoterapi kanker ini bekerja dengan
cara meningkatkan apoptosis fibroblas. Injeksi
5-FU intralesi (50 mg/mL) setiap minggu
selama 12 minggu berhasil mengurangi
ukuran scar hingga 50% pada rata-rata pasien
tanpa kegagalan dan rekuren dalam 24 bulan
kemudian.1 Efek samping yang mungkin
muncul adalah nyeri, ulserasi, dan sensasi
terbakar. Pernah dilakukan terapi kombinasi
TAC 10-40 mg/mL dengan 5-FU 50 mg/mL
Botulinum Toxin A (BTA)
BTA mampu menghambat mobilisasi otot dan
mengurangi tegangan kulit, sehingga dapat
mengurangi mikrotrauma dan inflamasi.
Uji coba injeksi 15 U BTA di sepanjang garis
operasi dengan jarak setiap 2 cm pada 24 jam
pasca-penutupan luka berhasil cukup baik.7
Posisi anatomi harus menjadi perhatian karena
risiko asimetri terutama pada injeksi otot
tertentu dengan jumlah besar hanya pada
satu sisi, misalnya risiko asimetri alis. Masih
dibutuhkan penelitian lanjutan efektivitas BTA
dan pertimbangan lain termasuk biaya terapi.7
SIMPULAN
Scar pasca-operasi ataupun trauma sulit
diprediksi. Terapi pencegahan hingga terapi
penanganan meliputi terapi tekan, silicone gel
sheeting, injeksi TAC, cryotherapy, radioterapi,
laser, INF, 5-FU hingga pembedahan.

DAFTAR PUSTAKA
1. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol
Med 2011;17(1-2):113-25. Available from: http://dupuytrens.org/DupPDFs/2011_Gauglitz.pdf
2. Maghrabi IA, Kabel AM. Management of keloid and hyperthropic scars: Role of nutrition, drugs, cryotherapy and phototherapy. World J Nutr Health 2014;2(2):28-32.
Available from: http://pubs.sciepub.com/jnh/2/2/4/
3. Sudjatmiko G. Petunjuk praktis ilmu bedah plastik rekonstruksi. 1st ed. Indonesia: Yayasan Khasanah Kebajikan; 2007
4. Thorne CH, Chung KC, Gosain AK, editors. Grabb and Smith’s plastic surgery. 7th ed. Philadelphia: Lippincott Williams&Wilkins; 2014. p. 14-9.
5. Atiyeh BS. Nonsurgical management of hypertrophic scars: Evidence-based therapies, standard practices, and emerging methods. Aesthetic Plas Surgery.
2007;31(5):468-92.
6. Huang C, Murphy GF, Akaishi S, Ogawa R. Keloids and hypertrophic scar: Update and future directions [Internet]. 2013. Available from: https://dash.harvard.edu/
bitstream/handle/1/13347635/4173836.pdf?sequence=1.
7. Gauglitz GG. Management of keloid and hypertrophic scars: Current and emerging options [Internet]. 2013. Available from: http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3639020/
8. Jansen D. Keloid [Internet]. 2016. Available from: http://emedicine.medscape.com/article/1298013-overview#a1
9. Perdanakusuma DS, Noer MS. Penanganan parut hipertrofi dan keloid. Surabaya: Airlangga University Press; 2006.

32 CDK-260/ vol. 45 no. 1 th. 2018

Am J Clin Dermatol
DOI 10.1007/s40257-016-0175-7

REVIEW ARTICLE

Keloids and Hypertrophic Scars: A Spectrum of Clinical

Challenges
Anthony P. Trace1 • Clinton W. Enos2 • Alon Mantel3 • Valerie M. Harvey3,4

Ó Springer International Publishing Switzerland 2016

Abstract Since their earliest description, keloids and

hypertrophic scars have beleaguered patients and clinicians
alike. These scars can be aesthetically disfiguring, func-
tionally debilitating, emotionally distressing, and psycho-
logically damaging, culminating in a significant burden for
patients. Our current understanding of keloid pathophysi-
ology has grown and continues to advance while molecular
biology, genetics, and technology provide ever-deepening
insight into the nature of wound healing and the pathologic
perturbations thereof. Greater understanding will lead to
the development and application of refined therapeutic
modalities. This article provides an overview of our current
understanding of keloids, highlighting clinical character-
istics and diagnostic criteria while providing a compre-
hensive summary of the many therapeutic modalities
available. The proposed mechanism, application, adverse
events, and reported efficacy of each modality is evaluated,
and current recommendations are summarized.
A. P. Trace and C. W. Enos contributed equally in the generation of
this manuscript.
& Valerie M. Harvey
harveyvm@evms.edu
1
Department of Radiology, Eastern Virginia Medical School,
Norfolk, VA, USA
2
The School of Medicine, Eastern Virginia Medical School,
Norfolk, VA, USA
3
Hampton University Skin of Color Research Institute,
Hampton University, Hampton, VA, USA
4
Department of Dermatology, Eastern Virginia Medical
School, 721 Fairfax Ave., Norfolk, VA 23507, USA
Key Points
Pathologic scarring is difficult to predict, prevent,
and treat although certain patient populations are at
higher risk than others.
Few large-scale clinical trials exist and there is no
clinical consensus or therapeutic algorithm. The
strongest clinical data support the use of silicone gel
sheeting and intralesional steroids.
Emerging therapies aim to interrupt key aspects of
the complex pathophysiology of pathologic scarring.
1 Introduction
Wound healing is a complex and progressive process that
involves intricate communication and regulation between
multiple cellular populations. Wound healing has been
described as taking place in three main phases: inflamma-
tion, proliferation, and remodeling [1]. Clinically, the
outcomes of the remodeling phase are most important.
During remodeling, collagen deposition occurs in an
organized fashion, ideally resulting in an inconspicuous,
normotrophic scar [1]. Perturbations in this process can
lead to excess collagen synthesis and deposition that results
in a hypertrophic scar or keloid.
Keloids are benign dermal fibroproliferative growths,
unique to humans, that occur in predisposed individuals
and are associated with aberrant wound healing following
an injury [2, 3]. Hypertrophic scars can be difficult to
differentiate from keloids [4]. Both can be firm, raised,
pruritic, and painful; however, hypertrophic scars remain

within the borders of the inciting wound and tend to regress
over time [5, 6]. Importantly, both keloids and hypertrophic
scars may cause cosmetic disfigurement and physical
impairment, ultimately leading to psychological stress and
decreased quality of life [7, 8].
The management of excessive scarring remains a chal-
lenge. A complex etiology, lack of a reliable model system
for study, and a limited amount of data from well-designed,
prospective, randomized, controlled clinical trials has
resulted in less than optimal therapeutic regimens such that
a universally effective treatment plan does not exist [7, 9].
This review is a concise clinical review of keloids and
hypertrophic scars. We describe the histologic and clinical
characteristics that define keloids and hypertrophic scars,
review the molecular mechanisms supporting the currently
available pathogenic theories, and provide a summary of
currently available therapeutic modalities.
2 Clinical Characteristics
The appearance of a keloid (Fig. 1) is characterized by a
dense fibrous growth, most often at a site of previous
trauma. On examination, these elevated, firm, protuberant
nodules or plaques extend beyond the boundaries of an
inciting injury, causing disfigurement [2, 10]. Keloids
range from erythematous to violaceous to brown and may
exhibit telangiectasia or even ulceration [4, 10]. Unlike
keloids, hypertrophic scars remain confined within the
borders of the injury, may elevate (typically \4 mm)
within 4–8 weeks of the inciting event, and finitely grow
over several months prior to regressing [4, 10–13]. Keloids
develop months to years following injury and rarely regress
[7, 14–17].
The reported incidence of keloid scars ranges between
4.5 and 16 % [4, 17, 18]; however, these data are drawn
primarily from retrospective case series and likely do not
reflect the true burden of disease. While keloids can occur
at any age, they show a peak incidence in patients aged
between 15 and 24 years [19, 20] and have a predilection
for specific areas of the body: the earlobe (piercing) [21],
sternum (sternotomy) [22], shoulders, upper arms (vacci-
nations) [23, 24], and cheeks (acne) [13, 25]. A 20-year
retrospective study noted that the two highest risk areas,
the trunk (chest and abdominal area) and the face, together
account for about half of all keloids, 39.57 and 10.65 %,
respectively [20]. Cutaneous infections, surgical trauma,
ulcerative lesions, and burns are the most frequent inciting
events [20]. With regards to hypertrophic scarring, inci-
dence rates have been reported as high as 91 % following
extensive trauma, such as a deep burn injury, suggesting a
role for the extent of trauma in their development [4, 7].
However, among patients undergoing standard surgical
A. P. Trace et al.
procedures, a significant group (34–36 %) develop hyper-
trophic scarring, supporting a genetic predisposition in
certain individuals [7, 26, 27].
The most commonly reported symptom, pruritus, fre-
quently occurs at the edges of lesions, while the second
most common, pain, primarily occurs in the central aspects
of the lesion [28]. Hyperemia, dysesthesia, growth,
restriction of movement or other functional impairment,
and cosmetic disfigurement are also important sequelae
[20]. The psychosocial impact of skin disorders is well
documented [29–33], and pathologic scarring is no
exception [8, 34].
3 Histopathology
Butler et al. [35] describe four histologic features uniquely
associated with keloids: (1) the presence of large, brightly
eosinophilic collagen in a haphazard arrangement; (2)
‘‘tongue-like’’ advancing edge beneath normal-appearing
epidermis and papillary dermis; (3) horizontal cellular
fibrous bands in the upper reticular dermis; and (4)
prominent fascia-like fibrous bands [35] (Fig. 2). Histo-
logic features of hypertrophic scars include flattening of the
epidermis as well as papillary and reticular scarring, with
notable vertically oriented blood vessels. The collagen
bundles in hypertrophic scars are arranged parallel to the
upper dermis [10, 36, 37]. The collagen in keloids and
hypertrophic scars is cellular, with varying reports on the
presence of alpha-smooth muscle actin (a-SMA) ? stain-
ing myofibroblasts [36–39]. There is a moderate degree of
inflammation composed of cluster of differentiation (CD)-
3?, CD4?, and CD45RO lymphocytes and CD1a?,
CD36?, human leukocyte antigen–antigen D-related
(HLA-DR?), and intercellular adhesion molecule-1
(ICAM-1?) dendritic cells. An increase has been observed
in the number of macrophages and epidermal Langerhans
cells, as well as scattered mast cells [4, 37, 40].
4 Pathogenesis
4.1 Genetics
The etiology of keloids and hypertrophic scars is not
completely understood. Keloids are 15 times more likely to
occur in darker-skinned individuals, the highest prevalence
noted among people of African, Hispanic, and Asian des-
cent. In the majority of studies, no predilection for sex has
been identified [41]. The increased prevalence in certain
ethnic groups suggests a genetic predisposition. As such,
multiple familial-based studies have delved into the
hereditary nature of keloids. Omo-Dare [42] examined 34
Clinical Review of Keloid and Hypertrophic Scars
Fig. 1 Common locations for
pathologic scar development. a,
b Periauricular, c shoulder, d,
e anterior chest, and f abdomen
families in a Nigerian population and concluded an auto-
somal-recessive mode of inheritance. Four other studies
have confirmed the autosomal nature of inheritance, but
one found an autosomal-dominant pattern, while three
suggested incomplete penetrance [43–46]. Taken together,
these studies support a genetic basis for predisposition to
keloid formation; however, the precise mode of inheritance
has yet to be clearly defined.
In the last 20 years, our understanding of the genetic
causes for human disease has been significantly accelerated
by the completion of the genome project and the identifi-
cation of genetic and epigenetic changes through genome-
wide association studies (GWAS). In contrast, the search
for genes responsible for excessive scarring have only
generated a few strong candidates. Studies have found the
involvement of several HLA alleles (HLA-DRB1*15,
HLA-DQA1*0104, DQ-B1*0501, and DQB1*0503) as
well as up to 25 dysregulated genes reported in multiple
microarray analyses, including major pathways associated
with apoptosis, mitogen-activated protein kinase (MAPK),
transforming growth factor (TGF)-b, interleukin (IL)-6,
and plasminogen activator inhibitor (PAI)-1 [41].
A GWAS study in Japan of 824 patients with keloids
versus 3205 healthy controls identified four single-nu-
cleotide polymorphisms in three chromosomal regions
(1q41, 3q22.3-23, 15q21.3) [47]. The 1q41 and 15q21.3
loci were later confirmed by GWAS in the Chinese Han
population, suggesting a common genetic factor underlying
the observed predisposition to keloid formation [48].
4.2 Dysregulation and Growth Factors
In both keloids and hypertrophic scars, aberrancies disrupt
the sequential events and cellular responses required to
complete the wound healing process. For example, an
imbalance in the synthesis and degradation of the

Fig. 2 Histopathology of a keloid scar using hematoxylin and eosin
(H&E) staining. a Normal scar from a biopsy site for comparison,
b low power view of a keloid scar demonstrating the tongue-like
advancing edge (black arrow) and the presence of horizontal cellular
extracellular matrix (ECM), dysregulated cytokines,
inflammation, persistent proliferation, and/or resistance to
apoptosis in fibroblasts and myofibroblasts [49, 50] could
significantly alter the healing process, resulting in patho-
logical scarring (Fig. 3). The proliferative nature of
fibroblasts in keloids and hypertrophic scars has been
shown to be increased, and thus abnormal, as compared
with normal skin, with keloid fibroblasts showing the most
proliferative activity [51]. This is supported by reports that
keloid fibroblasts have a decreased rate of apoptosis as well
as downregulation of apoptotic-associated genes and
under-expressed levels of p53 [52–54]. Possessing a
tumorigenic-like phenotype, when implanted into athymic
mice, human keloid fibroblasts continue to proliferate and
deposit collagen haphazardly [55]. The dysregulated nature
of keloid fibroblasts is further accentuated by an elevated
expression of cytokines and growth factors such as vascular
endothelial growth factor (VEGF), TGF-b1/b2, connective
tissue growth factor (CTGF), and platelet-derived growth
factor (PDGF)-a [3, 56–58]. These factors can act in a
A. P. Trace et al.
fibrous bands (white arrow) in the upper reticular dermis. Note the
flattening of the epidermis in regions of this section. c, d Medium and
high power views demonstrating the haphazardly arranged, strongly
eosinophilic, dense collagen
positive feedback loop to further promote cell growth and
proliferation of abnormal fibroblasts and myofibroblasts.
TGF-b is considered as one of the most potent stimu-
lators of collagen synthesis and has the ability to stimulate
fibroblast chemotaxis and proliferation [1]. Schmid et al.
[59] found increased expression levels of TGF-b1 and
TGF-b2 receptors in granulation tissue fibroblasts, but such
levels decrease during granulation tissue remodeling in
normal-healing excisional wounds. In post-burn pathologic
scars, overexpression of TGF-b1/b2 receptors persisted for
20 months after injury. The failure to diminish the popu-
lation of TGF-b receptors overexpressing fibroblasts during
normal wound healing can lead to a persistent autocrine,
positive feedback loop, resulting in excess production of
ECM proteins and subsequent fibrosis [59]. Similarly, an
earlier study of TGF-b1 noted that high expression from
both fibroblasts and neovascular endothelial cells resulted
in activation of adjacent fibroblasts and increased expres-
sion of type I and VI collagen genes [60]. This increased
TGF-b expression likely influences the local differentiation
Clinical Review of Keloid and Hypertrophic Scars
Fig. 3 Schematic overview of keloid scar formation. (1) Stimulus
(wound/burn or other trauma). (2) Blood platelets secrete TGF-b1 and
promote angiogenesis via VEGF secretion. (3) Increased TGF-b is a
key mediator of fibroblast proliferation and differentiation, EMT and
EndoMT, all of which result in increased myofibroblast count (all
these processes are described in the shaded frame, emphasizing the
role of TGF-b). (4) Genetic susceptibility results in keloid myofi-
broblast. (5) These cells then: (a) produce growth factors to further
stimulate proliferation; (b) increase NFjB activity, resulting in
increased synthesis of pro-inflammatory cytokines, which promote
further survival and cause chronic inflammation; (c) secrete TGF-b1,
further contributing to the TGF-b1 milieu; (d) secrete VEGF to
of fibroblasts to myofibroblasts, the transition of ker-
atinocytes to myofibroblasts (epithelial to mesenchymal
transition), and the transition of endothelial cells to
myofibroblasts, an endothelial to mesenchymal transition
(EndoMT) [50, 61, 62]. The presence of increased numbers
of myofibroblasts results in overproduction of ECM pro-
teins as well as local tissue remodeling via chronic scar
contraction [50].
The unique regenerative capacity of fetal wound
healing, or scarless healing, also offers support for a
further promote angiogenesis; (e) contract the scar; (f) secrete an
excessive amount of ECM while downregulating ECM-degrading
components. (6) The final outcome is the formation of an abnormal
hyperfibrotic scar that expands and contracts. CTGF connective tissue
growth factor, ECM extracellular matrix, EGF epidermal growth
factor, EMT epithelial mesenchymal transition, EndoMT endothelial
mesenchymal transition, IL interleukin, MMP matrix metallopro-
teinase, NFkB nuclear factor kappa B, PAI plasminogen activator
inhibitor, PDGFa platelet-derived growth factor alpha, TGF tumor
growth factor, TNF tumor necrosis factor, VEGF vascular endothelial
growth factor
central role of TGF-b signaling. The expression profiles
of the three TGF-b isoforms as well as several key
modulators of the canonical TGF-b signaling pathway
were recently described in an elegant analysis comparing
human fetal versus adult skin [63]. Dramatic differences
were observed in gene expression and protein localization
(epidermal vs. dermal); notably, fetal skin showed an
increased expression of TGF-b2 and TGF-b3 [63]. Fetal
skin also showed lower immunohistochemical levels of
TGF-b1 in the dermis [63].

In cell culture, keloid keratinocytes express more TGF-
b1, -b3, and TGF-b receptor 1 than normal keratinocytes.
Co-culture of keloid fibroblasts with keloid keratinocytes
exhibits increased gene expression of TGF-b1, -b2, TGF-b
receptor 1, and Smad2, further indicating a role for both
increased TGF-b and subsequent TGF-b-induced genes in
keloid formation [64]. For example, CTGF messenger
RNA (mRNA) expression in fibroblasts has been shown to
be strongly increased upon activation with TGF-b [65].
CTGF plays a role in the pathogenesis of keloids by further
promoting collagen synthesis and deposition as well as
having chemotactic effects on fibroblasts [58].
Expression of PAI-1, a member of the serine protease
inhibitor gene family, is regulated in part by TGF-b via SMAD
and MAPK signaling [66, 67]. PAI-1 is a major inhibitor of
urokinase-type (uPA) and tissue-type (tPA) plasminogen
activators, primary proteases in fibrinolysis that have roles in
the breakdown of glycoproteins and ECM, the activation of
matrix metalloproteinases (MMP), as well as the release of
TGF-b from its latency-associated protein [68]. Tuan et al.
[68] utilized PAI-1-expressing adenovirus to overexpress the
protein in normal fibroblasts. The results suggest a causal
relationship between increased PAI-1 expression and collagen
accumulation [69]. As such, keloid fibroblasts have been
found to have increased levels of PAI-1 expression both
in vitro and in vivo, correlating with increased accumulation
of predominantly type I collagen [68]. The combination of
increased expression of PAI-1, TGF-b, and other growth
factors such as CTGF potentiates a cyclic process that could
begin to explain the progressive, self-perpetuating nature of
keloids. However, the disinhibited signaling that promotes
this environment is still incompletely understood. Lu et al.
[70] noted decreased levels of connexin 43 protein in fibrob-
lasts derived from both hypertrophic scar and keloids as
compared with fibroblasts from normal skin. This correlates
with decreased gap junction intercellular communication,
suggesting a potential contributing factor for the impaired
balance of proliferation and apoptosis [70].
Manipulation of the TGF-b isoform dynamics is an
attractive target for therapeutic intervention and is the
proposed pharmacologic mechanism behind the use of
tamoxifen, a nonsteroidal anti-estrogen that has been
shown to inhibit scar contraction in a dose- and time-de-
pendent manner [71]. While tamoxifen uniformly down-
regulates all three TGF-b isoforms [72], the anti-estrogen
effects appear to inhibit the activation of myofibroblasts
through the effects of TGF-b on the extracellular signal-
regulated kinases (ERK) pathway [73].
4.3 Inflammation
The theme of altered communication also extends to the
role of inflammation in wound repair and scar formation.
A. P. Trace et al.
The nature of the immune/inflammatory response early in
the process of wound healing likely plays a role in the final
quality of the scar, such that a prolonged or abnormal
immune response may lead to excessive scarring [7].
Fibroblasts play a central role in the process of wound
healing as both target and effector cells, aiding the complex
parade of immune cells traversing the wound microenvi-
ronment. An atypical phenotype of keloid fibroblasts cells
has been linked, in part, to constitutive nuclear factor (NF)-
jB signaling. This results in the up-regulation of proin-
flammatory mediators, such as IL-1a, IL-1b, IL-6, and
tumor necrosis factor (TNF)-a, which in turn promote
survival [49, 74]. Makino et al. [75] showed that inhibition
of NFjB activation with dehydroxymethyle-
poxyquinomicin reduced keloid fibroblast proliferation and
type I collagen accumulation in vitro, highlighting the role
of inflammation in keloid formation. Beyond persistent
inflammation, experimental models have shown that
fibrosis is also linked to the phenotype of the developing T
helper (TH) cell response. TH2 CD4? cells have a cytokine
profile (IL-4, IL-5, and IL-13) strongly linked to fibroge-
nesis. In the scope of keloid proliferation, increased levels
of IL-4 and IL-13 combined with elevated TGF-b shifts the
balance of collagen synthesis and catabolism, resulting in
net collagen accumulation. Interestingly, the TH1 response,
mainly via IFN-c, attenuates tissue fibrosis [76]. Further
evidence of the direct impact of the T cell subset on the
fibrotic process has been shown when keloid fibroblasts are
co-cultured with regulatory CD4? T cells (which modulate
immune responses and suppress other effector CD4? T
cells); the result is reduced collagen synthesis [77]. Despite
this complex understanding, many questions remain about
the multifaceted pathophysiology of excessive scarring.
5 Treatment Modalities
A multitude of therapeutic modalities (in series or in
combination) have been described, each demonstrating
varying degrees of effectiveness [78]. Available treatment
options and their associated adverse events, costs, and
efficacy should be thoroughly reviewed with the patient in
order to develop realistic expectations [79, 80]. Table 1
summarizes recent studies, highlighting treatment modal-
ity, efficacy, and adverse effects; Table 2 includes less
common treatment options for keloids and hypertrophic
scars.
5.1 Intralesional Steroid Injection
In addition to being anti-inflammatory, corticosteroids
impair fibroblast growth and inhibit a2-macroglobulin,
thereby increasing collagen degradation [81]. Intralesional
Clinical Review of Keloid and Hypertrophic Scars

Table 1 Review of common treatment modalities for keloids and hypertrophic scars and their efficacy and adverse effects [82, 86, 89, 90, 92,
97, 115, 122, 123, 127, 139, 177, 192, 197, 210, 213, 215, 216, 232–242]
Study design Scar type Treatment Response Length of Adverse events References
and follow-up
sample
size

Bleomycin
Pro cohort 14 pts Bleomycin 0.1 ml (1.5 IU/ Complete flattening reported 19 months Hyperpigmentation, [216]
with 15 ml) delivered to each lesion in *73 % of cases. skin atrophy
KD or by dermojet injections, Significant improvements
HS repeated monthly (range in scar pliability, erythema,
2–6 sessions) pain and pruritus. No
reported recurrences
Pro, sb, ran, 26 pts Group A received ILT No significant differences 12 weeks Hyperpigmentation [214]
contr with (10 mg/ml) monthly for between test groups.
KD or 3 months, Group B Recurrence rates NR
HS received intralesional
bleomycin (1 mg/ml)
monthly for 3 months
Pilot 20 pts Electrochemotherapy 87 % median reduction in 18 months No AEs reported [217]
with 35 (intralesional bleomycin volume. Significant
KD or followed by electrical improvement in pain
HS pulses). Doses were reported. One recurrence
adjusted to the size of the reported
scar
Pilot 50 pts Bleomycin (1.5 IU/ml) via 44 % reported complete 18 months 16 % ulceration, [211]
with multiple superficial flattening. 22 % reported 14 %
KD or puncture technique (40 significant flattening. 89 % hyperpigmentation
HS punctures/cm2) described decreased
pruritus. 7 recurrences
reported
Cryotherapy
RCT 21 pts Liquid nitrogen cryotherapy [85 % of KD showed 18 months Temporary [90]
with 60 alone (Group A) vs. [50 % flattening in Group dysesthesias,
KD combined liquid nitrogen B vs. only 70 % of lesions hyperpigmentation,
cryotherapy ? ILT (Group in Group A. Group A hypopigmentation
B). Each intervention was reported 5 recurrences and
given monthly up to Group B reported 1
6 months
Ret 21 pts Scar volume reduction was ILC and combination therapy 12 months Hypopigmentation [123]
with 32 assessed comparing pts (ILC ? silicone gel
KD treated with ILC alone or sheeting) both resulted in
ILC in combination with significant reduction in KD
silicone gel therapy volume but were not
significantly different from
one another
Pilot 28 pts ILC followed by ILT at 93.5 % volume reduction. 7 months Hyperpigmentation, [92]
with 35 month 1; ILT was repeated Decreased subjective hypopigmentation
KD or every 3 months for 4 complaints. Significant
HS sessions, and then every softening, decreased height
6 months for 4 sessions and redness. 12 %
recurrence
5-Fluorouracil
Case series 24 pts Intralesional injections of About half of the pts saw 3–6 months Pain (100 %), [198]
with 50–150 mg 5-FU per week [50 % flattening; a third hyperpigmentation
KD for maximum of 16 showed [75 % flattening. (100 %), rarely
injections Improved response was erosion or
noted in lesions \5 years ulceration
duration
 A. P. Trace et al.

Table 1 continued
Study design Scar type Treatment Response Length of Adverse events References
and follow-up
sample
size

Pro, ran, 28 pts Intralesional 5-FU (50 mg/ [50 % improvement 24 weeks Pain at the injection [233]
uncontrolled with ml) was administered reported in the majority of site, burning,
KD weekly for a maximum of pts. No recurrence ulceration
12 weeks
Db, ran, contr 40 pts Group 1 received ILT Greater improvement in 44 weeks No side effects [234]
with (20 mg/cm2), Group 2 erythema, pruritus, height, reported
KD received 5-FU (50 mg/ml) surface, and induration
tattooing. Treated every (p \ 0.05) seen in Group 2
4 weeks for 12 weeks
Db, RCT 40 pts Group 1 received ILT 10 mg Combination of 5-FU and 8 and Combination group [86]
with weekly for 8 weeks; Group ILT produced results 12 weeks experienced no
KD or 2 received ILT 4 mg ? superior to ILT alone; adverse textural or
HS 5-FU 45 mg weekly for notable decrease in skin pigmentary
8 weeks atrophy and telangiectasias alterations
RCT 150 pts Group A received ILT 68 % of Group A reported 4, 8, and Skin atrophy, [89]
with (10 mg) weekly for good to excellent results vs. 12 weeks telangiectasia
KD or 8 weeks. Group B received 84 % in Group B. Group B
HS 4 mg ILT ? 5-FU 45 mg also reported fewer
weekly for 8 weeks complications
Db, RCT 50 pts Control group received In the trial group 75 % were 12 months Pain at injection site, [235]
with surgical excision and KD free vs. 43 % in control burning, ulceration
KD silicone gel sheeting. The group. Trial group reported
trial group received 4 % recurrence vs. 22 %
adjuvant intralesional 5-FU for controls
(50 mg/ml); dose depended
on size of the keloid
Laser
Uncontrolled, 86 pts 8 sessions of IPL 88 % pt satisfaction and NR Telangiectasia, [236]
clinical with (450–1200 nm filter, 89 % clinical hyperpigmentation,
KD Fluence 30–40 J/cm2, pulse improvement. 72.1 % had atrophy
duration of 2.1–10 ms and full recovery
pulsed delay 10–40 ms)
combined with
intralesional corticosteroids
(dose NR); 3-week therapy
interval
Ret cohort 102 cases Long-pulsed 1064 nm Greater success noted in HS 6 months Pain [139]
with Nd:YAG laser used in pts. 1 HS recurrence and 27
KD or contact mode every KD recurrences reported
HS 3–4 weeks for 1 year.
Evaluated by Japan Scar
Workshop scale
Ret case series 99 pts Comparison of PDL tx vs. 76 % reported moderate to 6 months Redness, discomfort, [237]
with rotational PDL and ILT excellent result from pruritus
KD (10 mg/ml) combination therapy.
Recurrence rates were not
assessed
Case series 22 pts Long-pulsed 1064 nm 36 % of pts reported Not NR [238]
with 16 Nd:YAG laser in non- reduction in size by 90 % assessed
KD, 6 contact mode every after tx. Recurrence and
HS 3–4 weeks (average 14.05 extended follow-up not
tx) assessed
Clinical Review of Keloid and Hypertrophic Scars
Table 1 continued
Study design Scar type Treatment
and
sample
size
Pilot 12 pts Combination of 578 nm
with copper bromide laser and
KD or intralesional corticosteroids
HS (10 mg/ml). Six tx at
4-week intervals
Ret 23 pts Combination of ablative
with erbium laser in fractional
KD mode with topical high-
potency corticosteroid
cream. Tx every other
week (average 9) until
resolution or lack of
clinical improvement
Open-label, 15 pts Three CO2 fractional laser
contr, clinical with 4 sessions every 4–6 weeks
KD, 11 on half of scar
HS
Pressure therapy
MA 6 trials, RCT results were pooled to
316 pts yield weighted mean
differences or standardized
mean difference and
reported using 95 % CIs
Silicone-gel therapy
Ran, pc, db, 50 pts Sternal wounds were divided
pro clinical with HS into upper and lower halves
(100 (treated and untreated).
wounds) One of two coded tubes,
prepared by an independent
pharmacist, was used on
either half. Application of
tube contents began
2 weeks following
procedure and concluded at
3 months
Pro 30 pts Pts with bilateral scars were
with included in this study (1
KD or treated and 1 left untreated
HS as a control). Group 1
applied silicone gel to scar
twice daily. Group 2
applied silicone gel
sheeting daily. Group 3
applied silicone gel in the
morning and silicone gel
sheeting at night
Response Length of Adverse events References
follow-up
42 % reported [75 % 4 weeks Mild to moderate [239]
improvement based on the pain, transient
physicians’ global erythema, edema,
assessment at follow-up. hyperpigmentation
Recurrence NR at time of
follow-up
50 % reported improvement. 8 months Hypochromia, [157]
Two pts reported eczematiform
worsening symptoms. reaction, folliculitis
22 % reported recurrence
at time of follow-up
Improvement in texture of 3 months Tolerable pain, [155]
HS as well as decreased hyperpigmentation,
Vancouver, POSAS transient erythema,
observer, and pt scores for mild swelling
HS. Histopathology
showed decreased scar
thickness in HS only.
Decrease in collagen
bundle thickness and
density in upper dermis of
HS and KD
Failed to demonstrate Pt discomfort [177]
effectiveness of pressure
garment therapy in the
prevention or tx of
pathologic scarring after
burn injury
At 3 months, treated HS 3 months No side effects [242]
showed improvement in all reported
areas based on Vancouver
Scar Scale. Statistically
significant improvements
in pigmentation,
vascularity, pliability,
height, pain, and itchiness
were reported
All treated scars showed 90 days No AEs reported [243]
improvement vs. untreated
controls. Silicone gel alone
and in combination with
silicone gel sheeting
showed decreased scar
height and erythema. Pts
found silicone gel easier to
use vs. silicone gel sheeting
 A. P. Trace et al.

Table 1 continued
Study design Scar type Treatment Response Length of Adverse events References
and follow-up
sample
size

Cochrane 20 trials, RCTs comparing silicone gel Statistically significant Local irritation [193]
review 873 pts sheeting for prevention or reduction in scar elasticity,
with tx of HS or KD with any thickness, and color.
KD or other nonsurgical tx, no tx Reduced the incidence of
HS or PL were compiled HS in pts prone to scarring.
Overall, weak evidence is
available for the benefit of
silicone gel sheeting as a
means for preventing
abnormal scarring
Intralesional corticosteroids
Pro 12 pts ILT (0.5–4 ml depending on Majority of pts showed 8 weeks No AEs reported [82]
with size) monthly. All pts [50 % reduction in scar
KD treated for a minimum of volume over 8-week study
8 weeks. Assessment using
3D camera system
Pro, open, non- 12 pts ILT (40 mg/ml) given 10 of 12 pts reported 90 days No AEs reported [97]
comparative, with HS 15 days following surgery complete regression
single-center to nasal area. Optional day-
45 injection
Pilot 18 pts 3–4 sessions of Mean volume reduction was 5 years No AEs reported [240]
with radiofrequency tx followed 95.4 %. Small scar
KD by ILT (10 mg/ml) recurrence reported in
10 %
Surgical excision
Pro 43 pts Excision followed by post- Symptomatic improvement 33 months Both [115]
with 67 operative radiation and 56.7 % reduction in hyperpigmentation
KD (2 9 6 Gy) at 4 h and a scar surface. Recurrence and
second dose at 24 h rate of 3.1 % hypopigmentation
reported in 21.4 %
Non-ran, pro, 26 pts Surgical excision with Complete remission in 19 months Hypopigmentation, [241]
clinical with 76 immediate post-operative 70.4 % (Group A) vs. ulceration, necrosis,
KD radiation (12 Gy) (Group 68.8 % (Group B). Failure telangiectasia
A) vs. cryotherapy with rate: 18.2 % (Group A),
repeated ILT (10 mg/ml, 28.1 % (Group B)
max dose 40 mg) (Group
B) sessions every 20 days
3D three-dimensional, 5-FU 5-fluorouracil, AE adverse event, CI confidence interval, contr controlled, db double-blind, Gy SI unit of absorbed
radiation, HS hypertrophic scar, ILC intralesional cryotherapy, ILT intralesional triamcinolone, IPL intense pulsed light, KD keloid, MA meta-
analysis, Nd:YAG neodymium:yttrium–aluminum-garnet, NR not reported, pc placebo-controlled, PDL pulse dye laser, PL placebo, POSAS
Patient and Observer Scar Assessment Scale, pro prospective, pt(s) patient(s), ran randomized, RCT randomized controlled trial, ret retro-
spective, sb single-blind, tx treatment

triamcinolone (ILT) injection is effective in reducing the
volume of lesions in a majority of patients, with response
rates reported of 50–100 % [13, 82, 83]. Enhanced results
have been reported when ILT injections are combined with
other modalities. Intralesional steroid injections in con-
junction with silicone gel or sheeting has been recom-
mended as first-line therapy for the treatment of small
keloids (focally raised) [9, 78, 84]. In large keloids (raised
[0.5 cm), monthly ILT (0.1 ml of 40 mg/ml), with or
without adjuvant cryotherapy, is considered first line [85].
If little improvement is seen by 3–4 months with ILT
monotherapy, it is recommended to add intralesional
5-fluorouracil (5-FU) (0.9 ml of 50 mg/ml) [9]. Several
studies have shown the combination of 5-FU and ILT to
produce results superior to ILT alone, with a notable de-
crease in skin atrophy and telangiectasia [22, 86–89]. One
study showed that the addition of 5-FU produced a sig-
nificant 92 % reduction in lesion size compared with only
Clinical Review of Keloid and Hypertrophic Scars
Table 2 Less common treatment modalities for keloids and hyper-
trophic scars [109, 110, 201–209, 221, 243–307]
Treatment References
IFN-a2b [244–251]
Mitomycin C [252–256]
Onion extract [257–261]
Radiotherapy [262–280]
Vitamins A and E [281–288]
Verapamil [289–293]
Polyurethane dressing [222, 294–300]
Botox [301–303]
Photodynamic therapy [304–308]
IFN interferon
73 % reduction in those treated with ILT alone [87].
Multiple studies have shown similar improvements when
ILT injections accompany topical cryotherapy [90, 91],
intralesional cryotherapy [92], lasers [93], or surgical
excision [94–97]. Postoperative ILT effectively prevents
recurrence of keloids following their surgical excision and
is considered the optimal therapy for recalcitrant lesions
that have failed previous modalities [78, 98, 99]. Amici
[97] demonstrated the effectiveness of early ILT (40 mg/
ml) in early hypertrophic scars following surgery for basal
cell carcinoma of the nasal region [97].
Serial ILT (dosage depends on size and bulk of the
lesion; common concentrations used include 10–20 mg/ml
or 40 mg/ml) spaced 3–4 weeks apart is continued until an
acceptable therapeutic or cosmetic outcome is achieved or
the side effects become problematic [15, 78, 82, 100].
Common side effects include pain and bleeding, both of
which are usually attenuated with the addition of lidocaine
[100]. Stucker et al. [101] suggested the addition of hya-
luronidase to help disperse the injection and further atten-
uate the discomfort associated with these injections. More
serious side effects include atrophy, telangiectasia,
hypopigmentation, and, although a systemic response is
rare, adrenal insufficiency [78, 84, 102]. The use of low
doses may help minimize these [85].
5.2 Surgery
A multitude of techniques have addressed lesions in vari-
ous locations [103–110], with the goal to debulk and
remove any fibrogenic stimuli or sources of residual
inflammation (trapped hair follicles, epithelial cysts, and
sinus tracts) [111]. Scars disposed to tension may benefit
from the additional physical support of intradermal sutures
[84, 112]. As a monotherapy, recurrence rates range from
45 to 100 % [94, 95, 99, 113]. Current evidence suggests
that surgical therapy may be an effective therapeutic option
when used in combination with other modalities [78, 84,
114, 115]. Combined with intralesional corticosteroid
injections, recurrence drops to less than 50 %; combined
with perioperative radiation it drops to less than 10 % [84,
94, 111]. A prospective study by van Leeuwen et al. [115]
showed that surgical excision followed by post-operative
radiation resulted in low rates of recurrence (3.1 %) at a
follow-up of 33 months. Aside from the risks associated
with surgery and expected postoperative pain, the risk of
generating new keloids should always be discussed with
the patient.
5.3 Cryotherapy
Cryotherapy is a minimally invasive dermatologic main-
stay with relatively few contraindications. The low tem-
perature creates ice crystals that compromise the cellular
integrity and ultimately lead to tissue destruction [116,
117]. Clinically, this manifests as edema, pain, blistering,
and erythema. The reported efficacy of cryotherapy to treat
keloids ranges from 51 to 74 % [116, 118, 119]. However,
only partial scar eradication has been achieved with this
modality, and scar recurrence ranges from 0 to 24 % [120].
In a head-to-head comparison treating small, highly vas-
cular keloids, cryotherapy was superior to ILT injections
[121]. In regards to location, cryotherapy has been shown
most effective as a monotherapy for earlobe keloids [122,
123]. The addition of intralesional corticosteroid injections
improves outcomes beyond either modality alone [90,
124]. In refractory keloids, Stromps et al. [123] suggested
the use of intralesional cryotherapy followed by silicone
gel sheeting; however, reductions in volume did not sig-
nificantly differ from the use of intralesional cryotherapy
alone [125]. Temporary dysesthesias and hyperpigmenta-
tion can occur; alopecia, atrophy, cartilage necrosis, and
hypopigmentation have also been reported and may be
permanent, so caution, especially in dark-skinned individ-
uals, is always required [117, 126, 127].
5.4 Lasers
The efficacy of laser therapy has evolved alongside tech-
nologic advancements. The argon laser initially reduced
symptoms associated with keloids; however, this effect was
temporary and ultimately failed to demonstrate significant
clinical utility/effectiveness [128, 129]. In fact, the non-
specific thermal destruction of tissue associated with this
therapy is associated with higher levels of recurrence [84,
130]. The initial success of carbon dioxide (CO2) lasers as
a primary modality was plagued by similar problems after
subsequent larger-scale studies demonstrated a failure to
suppress keloid growth and recurrence [131, 132]. As
monotherapy, recurrence rates as high as 90 % have been

reported [131, 132]. Refinements of this technology led to
the development of several new types of CO2 lasers: high-
energy, short-pulsed lasers [133], scanned continuous wave
CO2 lasers [134], and fractional CO2 lasers [135]. Despite
improved safety and efficacy, CO2 lasers are no more
effective than other modalities for the treatment of patho-
logic scars [17, 78, 84].
Wavelength-specific lasers induce local ischemia by
selectively ablating blood vessels. The neodymium:yt-
trium-aluminum-garnet (Nd:YAG) 1064 nm continuous
wave lasers electively inhibit collagen metabolism [136].
Response rates vary between 36 and 58 %, and studies
have shown that Nd:YAG laser treatments can produce
significant reductions in size, improvements in pliability,
and normalization of lesion color [136–140].
Employing the principle of selective photothermolysis,
the 585-nm pulsed dye laser (PDL) targets the vascular
component of scars [141]. Additionally, it has been
hypothesized that superheating collagen fibers may result
in perturbations of disulfide bonds [142]. Data also sup-
port PDL-induced down-regulation of TGF-b1 leading to
increased collagen degradation [143] and perturbations in
the ERK and p38 signaling cascade, triggering increased
fibroblast apoptosis [144]. The 585-nm PDL is the stan-
dard for vascular lesions (port wine stains, hemangiomas,
and telangiectasias) and is also effective for keloids and
hypertrophic scars, with response rates reportedly ranging
between 57 and 83 % [145]. In addition to significant
symptomatic relief, multiple studies demonstrate that
serial PDL treatments significantly reduce or completely
eliminate erythema, objectively improving the appearance
and surface texture of hypertrophic scars while simulta-
neously flattening hypertrophic portions [146–148]. Fur-
ther, the combination of intralesional corticosteroid
injections with PDL treatments appears to have a syner-
gistic effect and may prove especially effective in previ-
ously resistant keloids [22, 149]. Despite similar
symptomatic improvements, a randomized controlled
series conducted by Chan et al. [150] failed to show
significant objective clinical improvements using PDL for
the prevention and treatment of hypertrophic scars,
although this study was conducted exclusively in a Chi-
nese patient population.
Similar conflicting reports exist for the flashlamp-
pumped pulsed dye laser (FLPDL). Several studies report
significant improvements, touting FLPDL as a useful
adjuvant in the treatment of erythematous, hypertrophic
scars [151, 152]. However, a single-blind, randomized,
controlled study found no benefit over less invasive
modalities [153]. As data continue to emerge, the current
recommendation suggests early initiation of laser therapy
may prevent or arrest scar proliferation and may prove
beneficial in erythematous lesions [78, 84, 111].
A. P. Trace et al.
Fractional laser therapy has also been explored in the
treatment of hypertrophic scars and keloids. Fractional
laser therapy produces a repeating injury pattern in the skin
with skip areas that, depending on the type of fractional
laser, can involve the epidermis and dermis, with the
desired effect of improved tone and texture to the skin as a
result of the healing process [154]. A recent open-label
controlled clinical and histopathological study showed
promise for the use of CO2 fractional laser in the treatment
of post-burn hypertrophic scars: patients reported improved
skin texture and decreased scar thickness as opposed to the
enrolled keloid patients [155]. Likewise, Makboul et al.
[156] also showed normalization of dermal collagen as
well as decreased TGF-b1 expression following laser
treatment of hypertrophic scars. Fractional laser therapy
has also been used in drug delivery in the treatment of
keloids, taking advantage of the vertical channels, or
microthermal zones, it produces in the skin. This allows
patients to avoid painful ILT injections, and offers com-
bination therapy for keloids recalcitrant to ILT or laser
treatment alone [157, 158].
Erythema and blistering occur in virtually all patients
(persisting between 7 and 24 weeks). Transient hyper- and
hypo-pigmentation are also commonly noted following
laser therapy [150, 159].
5.5 Pressure Therapy
Pressure therapy is one of the older and most well studied
modalities in the treatment of keloid and hypertrophic
scarring [160]. It is generally accepted as the standard non-
invasive modality for preventing and controlling patho-
logic scarring following burn and other thermal injuries.
While the precise mechanism of action of pressure therapy
remains elusive, several hypotheses, encompassing the
molecular to the mechanical, have been proposed: altered
blood flow leads to decreased a2-macroglobulin and
chondroitin4-sulfate, leading to increased collagenase-me-
diated degradation of fibrotic tissue [161–163]; hypoxia-
induced apoptosis of a-SMA-expressing myofibroblasts
[164]; reduction of the proteolytic enzyme epilysin (MMP-
28) [165]; attenuated cytokine expression (TNF-a and IL-
1b) [166]; early scar maturation [163, 167, 168]; and
simple reduction of tension at the scar [169]. When applied
pressure exceeds capillary pressure (*24 mmHg), the
induced hypoxia may lead to fibroblast destruction and
collagen degradation. This theory is supported by histo-
logic evidence of decreased cell numbers and looser col-
lagen bundles with increased interstitial space [170]. The
true mechanism is likely multifaceted and may involve
aspects of several of these proposed theories.
Multiple devices have been developed to address the
challenges posed by each lesion’s unique parameters and
Clinical Review of Keloid and Hypertrophic Scars
location on the body, although pressure therapy seems
optimally suited as a non-invasive treatment of earlobe
keloids. Empiric recommendations advocate commence-
ment of pressure therapy upon re-epithelialization of the
wound with 15–40 mmHg pressure applied for 8–24 h a
day for 6–12 months [4, 17, 78, 84], although some evi-
dence suggests a loss of efficacy after 6 months of treat-
ment [163]. This therapy is understandably limited by
adequate anatomic fit and consistent application of pres-
sure, which may lead to patient discomfort and noncom-
pliance [171, 172]. This remains an important issue, as
duration of pressure appears directly related to efficacy
[171–173]. In addition, the application of pressure is often
subjective and not uniform among studies, even in trials
utilizing similar devices [174].
A variety of materials and devices to apply the neces-
sary pressure have been developed, from custom-made
elastic compression garments to adhesive plaster molds,
pressure earrings, and custom-fitted splints. Studies have
indicated that pressure therapy as monotherapy is effective
for the prevention of hypertrophic burn scars and alleviates
the pain and pruritus associated with keloids [167, 175].
However, a large prospective randomized study found no
significant difference in wound maturation or length of
hospital stay among those receiving pressure garment
therapy and those not receiving pressure garment therapy
[176]. A meta-analysis of six independent studies (316
patients total) failed to demonstrate the effectiveness of
pressure garment therapy to prevent or treat abnormal
scarring [177]. The role of pressure garment therapy in the
treatment of established scars may be better relegated to a
second-line option when used in combination with other
modalities like surgical excision [169].
5.6 Silicone Gel Therapy
Silicone gel sheeting is a soft, flexible, self-adhesive, semi-
occlusive dressing composed of polydimethylsiloxone
polymer that easily molds to the contours of the body.
Studies have shown that silicone sheets do not significantly
alter mechanical pressure, temperature, or oxygen tension
at the site of the wound [178, 179]. Instead, these dressings
create a hydrated, occlusive environment that impairs
capillary activity and subsequent perpetuation of patho-
logic regeneration signaling [179, 180]. Hydration is also
believed to lead to the stabilization of mast cells, thus
inhibiting inflammation [111]. Interestingly, one study
comparing silicone cream alone with the same cream under
occlusion found a striking disparity in response rates (22
vs. 82 %, respectively) [180]. Another study found non-
silicone gel dressing as effective as silicone gel dressing,
suggesting that occlusion is a significant aspect of its
effectiveness [181].
Since the introduction of silicone products in the 1980s,
multiple case series and other uncontrolled studies have
reported they provide both symptomatic and objective
improvement in pathologic scarring [182–186]. Many
valid, well-designed, controlled studies support the efficacy
of silicone products in preventing and treating keloids [181,
187–189]. Not only has the use of silicone sheeting been
shown to decrease the pain, pruritus, and hyperemia asso-
ciated with scarring, it has also been shown to minimize
fibroblast production of collagen, increasing pliability and
promoting flattening [184]. As a prophylactic measure,
silicone sheeting has effectively minimized new scarring,
especially in patients with a previous history of pathologic
scarring [26, 184, 190].
Evidence from at least eight randomized controlled tri-
als and a Cochrane Review of over 15 trials supports the
efficacy of silicone sheeting, especially as an adjuvant with
other modalities [84, 191–193]. Given its ease of use and
mild adverse event profile, which is limited to local irri-
tation that resolves with discontinuation of therapy, this
noninvasive modality is ideal for children and patients
unable to tolerate other modalities. Silicone sheeting
effectively prevents the development of new scars, mini-
mizes the severity of existing scars, and promotes remis-
sion/resolution of existing/established scars. For more,
please see the review by Mustoe [194] on the many forms
of silicone gel products, their proposed mechanisms of
action, and the supporting evidence behind their use.
Similar results have been demonstrated with silicone gel
cream. A randomized controlled trial of 110 patients who
underwent dermatologic surgery showed a significant
reduction in keloid (0 vs. 11 %) and hypertrophic scar (9
vs. 22 %) formation at the 8-month follow-up appointment
in patients prescribed silicone gel cream to be applied
twice daily for 60 days after the removal of stitches versus
controls [195]. Another more detailed study of the effects
of silicone gel on scar characteristics showed similar rates
of reduced pathologic scarring and significantly improved
scar characteristics, as assessed by the Modified Vancouver
Scar Scale (MVSS) among those treated with silicone gel
cream versus non-treated controls [196].
5.7 5-Fluorouracil
An intracellular enzymatic reaction converts 5-fluorouracil
(5-FU) to its active form as a pyrimidine analog capable of
inhibiting DNA synthesis, therefore targeting rapidly pro-
liferating cells [88, 98]. Intralesional 5-FU as a
monotherapy was first reported by Fitzpatrick [197] to be
effective in the treatment of keloids and hypertrophic scars.
Alone, 5-FU is effective in treating hypertrophic scars and
small more recently developed keloids [197, 198]. As an
adjunct to surgical excision, Haurani et al. [199]

demonstrated that 5-FU is effective in treating recalcitrant
keloids (those that failed to respond to ILT injections) with
19 % recurring after 1 year. Employing 5-FU in combi-
nation with ILT as an adjunct to 585-nm FLPDL treatments
was shown to improve patient comfort and cosmetic sat-
isfaction [200].
Adverse events are common. Pain (100 %) and hyper-
pigmentation (100 %) are universal; rarely, erosions or
ulceration can occur. Due to the risk of systemic effects,
including anemia, leukopenia, and thrombocytopenia,
5-FU is contraindicated in pregnant women and immuno-
suppressed patients [198, 201].
5.8 Imiquimod 5 % Cream
As an immune modulator, imiquimod stimulates activated
T cells, enhancing the local production of inflammatory
cytokines (ILs, IFNs, and TNF-a), which alters the
expression of apoptosis-associated genes as well as
decreases the production of collagen and glycosaminogly-
cans [202, 203]. Its efficacy in the treatment of keloids
appears to be site dependent. Several studies report that the
postsurgical use of imiquimod 5 % cream effectively
reduces the recurrence of earlobe keloids [109, 110, 204,
205], while other studies have shown no lasting effect in
the recurrence of excised keloids elsewhere on the body:
pre-sternal [206] and trunk [207]. It is important to note
that a majority of these data are drawn from relatively
small case series. From this, the prevailing recommenda-
tion currently states that imiquimod 5 % cream is a safe
and effective modality with few side effects (hyperpig-
mentation [63.6 %] and rarely mild pain, irritation, or
superficial erosion that fully resolved with temporary dis-
continuation of treatment) that may be optimally employed
as an adjunct to excision of keloids in low tension areas
such as the pinna [204, 206, 208–210].
5.9 Bleomycin
Bleomycin, an anti-neoplastic antibiotic capable of
inhibiting DNA, RNA, and protein synthesis, is cytotoxic
to keratinocytes and eccrine epithelium [211, 212]. Bodokh
and Brun [213] reported that 86 % (25/36) of patients
treated three to five times with intralesional bleomycin over
a 1-month period showed significant lesion regression and
subsequent reduction in functional impairment [213].
However, a recent study by Payapvipapong et al. [214]
reported no statistical difference when comparing intrale-
sional bleomycin (1 mg/ml) versus ILT (10 mg/ml) in the
treatment of keloids and hypertrophic scars [214]. In
treating large, bulky lesions, bleomycin alone was shown
to be superior to combination therapy (cryosurgery with
ILT) [215]. One study demonstrated encouraging results in
A. P. Trace et al.
the treatment of recalcitrant lesions, as 73.3 % of patients
showed complete flattening of their scars with significant
improvements in scar pliability, erythema, pain, and pru-
ritus. There were no reported recurrences after 19 months
of follow-up [216]. In a prospective observational study,
Manca et al. [217] investigated the efficacy of elec-
trochemotherapy in patients with treatment-resistant
keloids or hypertrophic scars. Bleomycin was administered
intralesionally, and the lesion site was subjected to elec-
trical pulses. The authors reported an 87 % median
reduction in volume and a 94 % reduction in pain; there
was one observed recurrence at 18 months of follow-up
[217].
Multiple routes of administration have been described:
intralesional injection [213, 218], multiple puncture
deposits [219], Dermojet injection [216], and tattooing
[215]. To date, no studies have demonstrated the superi-
ority of one method over another. Of note, the risk of
serious systemic adverse effects (pulmonary fibrosis and
hepatotoxicity) are negligible at the doses used in the
treatment of keloids [220]. Overall, cutaneous application
of bleomycin is generally well tolerated, with common side
effects being local hyperpigmentation and atrophy [211,
213, 216, 221].
6 Prevention
Physicians should inquire about a patient’s disposition to
abnormal scarring, particularly in preparation for surgical
procedures. Proper atraumatic surgical technique and
handling of tissues is critical, along with efficient home-
ostasis, adequate wound debridement, and limitation of
foreign bodies (polyfilamentous suture material) [84].
Wounds should be closed under minimal tension, with
efforts made to promote healing, as delayed epithelializa-
tion increases the incidence of keloid formation [4, 84,
222–224]. For individuals considered high risk (i.e., those
with a history of keloid or hypertrophic scar, positive
family history, or surgery involving an at-risk area), sili-
cone-based products are recommended as a preventive
measure [9]. Other considerations include limiting scar
exposure to direct sunlight [225]. Ultimately, prevention,
while optimal, may not always be practical.
7 Conclusion
Pathologic scarring remains tremendously difficult to pre-
dict, prevent, and treat.
The earliest record of pathologic scarring, the Edwin
Smith Papyrus (1500 BCE), describes keloids as ball-like
tumors on a chest [226, 227]. Interestingly, when
Clinical Review of Keloid and Hypertrophic Scars
translated, the recommended treatment on the papyrus was
to do nothing. Even so, keloids and hypertrophic scars are a
clinical challenge to treat and manage. They are multi-
faceted pathologic processes, or series of interrelated pro-
cesses, initiated by an environmental insult to a susceptible
anatomic location on the background of complex genetic
predisposition. Several emerging therapies have shown
promise. Topical and intradermal immune modulators
exert an anti-inflammatory effect capable of suppressing
fibroblast activity and potentiating apoptosis [228]. Anti-
bodies against TGF-b effectively reduced the scar height
and collagen contraction in experimental animal models
[229]. Building on our understanding of complex metabolic
signaling, modalities such as micro RNA (miRNA) and
small interfering RNA (siRNA) are being employed to
modulate expression of key factors believed to be involved
in keloid development and progression, including a recent
clinical trial evaluating CTGF siRNA [69, 230–232].
While progress continues to be made into the under-
standing of the molecular physiology of wound healing,
much remains to be translated into clinical application.
This review provides an overview of our current under-
standing of keloids, highlighting clinical characteristics and
diagnostic criteria while providing a comprehensive sum-
mary of the many therapeutic modalities currently avail-
able. Our hopes are that clinicians will gain insight into the
management of these pathologic scars despite the lack of a
universally effective treatment and, further, that they rec-
ognize the need for further research.
Acknowledgments The authors would like to thank Antoinette F.
Hood, MD, for the histopathology slides and Donald Glass, MD, for
the clinical pictures of keloids. The authors would also like to
acknowledge Meena Katdare, PhD, for her guidance throughout the
writing process.
Compliance with Ethical Standards
Funding No funding was received for this review.
Conflicts of interest Anthony Paul Trace, Clinton Enos, Alon
Mantel, and Valerie Harvey report no conflicts of interest.
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