TINJAUAN PUSTAKA

2.1. Anatomi Palpebra

Palpebra superior dan inferior adalah modifikasi lipatan kulit yang dapat menutup dan
melindungi bola mata bagian anterior. Berkedip melindungi kornea dan konjungtiva dari
dehidrasi. Palpebra superior berakhir pada alis mata; palpebra inferior menyatu dengan pipi.13
Palpebra terdiri atas lima bidang jaringan utama. Dari superfisial ke dalam terdapat
lapiskulit, lapis otot rangka (orbikularis okuli), jaringan areolar, jaringan fibrosa (tarsus), dan
lapis membran mukosa (konjungtiva pelpebrae).13
1. Kulit
Kulit pada palpebra berbeda dari kulit bagian lain tubuh karena tipis, longgar, dan elastis,dengan
sedikit folikel rambut, tanpa lemak subkutan.
2. Muskulus Orbikularis okuli
Fungsi muskulus orbikularis okuli adalah menutup palpebra. Serat-serat ototnya mengelilingi
fissura palpebra secara konsentris dan meluas sedikit melewati tepian orbita. Sebagian serat
berjalan ke pipi dan dahi. Bagian otot yang terdapat di dalam palpebral dikenal sebagai bagian
pratarsal; bagian diatas septum orbitae adalah bagian praseptal. Segmen luar palpebra disebut
bagian orbita. Orbikularis okuli dipersarafi oleh nervus facialis.
3. Jaringan Areolar
Terdapat di bawah muskulus orbikularis okuli, berhubungan degan lapis subaponeurotik dari
kujlit kepala.
4. Tarsus
Struktur penyokong utama dari palpebra adalah lapis jaringan fibrosa padat yang disebuttarsus
superior dan inferior. Tarsus terdiri atas jaringan penyokong kelopak mata dengan kelenjar
Meibom.
5. Konjungtiva Palpebrae
Bagian posterior palpebrae dilapisi selapis membran mukosa, konjungtiva palpebra, yangmelekat
erat pada tarsus. Panjang tepian bebas palpebra adalah 25-30mm dan lebar 2 mm. Ia dipisahkan
oleh gariskelabu (batas mukokutan) menjadi tepian anterior dan posterior. Tepian anterior terdiri
dari bulumata, glandula Zeiss dan Moll.13
A. Tepian Anterior
Bulu mata muncul dari tepian palpebra dan tersusun tidak teratur. Bulu mata atas lebih
panjang dan lebih banyak dari yang di bawah dan melengkung ke atas; bulu mata bawah
melengkung ke bawah.
Glandula Zeiss adalah modifikasi kelenjar sebasea kecil yang bermuara dalam folikel rambut
pada dasar bulu mata.
Glandula Moll adalah modifikasi kelenjar keringat yang bermuara ke dalam satu baris dekat
bulu mata.13
B. Tepian palpebra posterior berkontak dengan bola mata, dan sepanjang tepian ini terdapatmuara-
muara kecil dari kelenjar sebasesa yang telah dimodifikasi (glandula Meibom atau tarsal).
C. Punktum lakrimalis terletak pada ujung medial dari tepian posterior palpebra, berupa elevasi
kecil dengan lubang kecil di pusat yang terlihat pada palpebra superior dan inferior. Punktum ini
berfungsi menghantarkan air mata ke bawah melalui kanalikulus terkait ke sakus lakrimalis.13
 Fisura palpebrae adalah ruang elips di antara kedua palpebra yang dibuka. Fisura ini berakhir di
kanthus medialis dan lateralis. Kanthus lateralis kira-kira 0,5 cm dari tepian lateral orbita dan
membentuk sudut tajam.13
Septum orbitale adalah fascia di belakang bagian muskularis orbikularis yang terletak di antara
tepian orbita dan tarsus dan berfungsi sebagai sawar antara palpebra orbita. Septum orbitale
superius menyatu dengan tendo dari levator palpebra superior dan tarsus superior; septum
orbitale inferius menyatu dengan tarsus inferior.13
Retraktor palpebrae berfungsi membuka palpebra. Di palpebra superior, bagian otot rangka
adalah levator palpebra superioris, yang berasal dari apeks orbita dan berjalan ke depan dan
bercabang menjadi sebuah aponeurosis dan bagian yang lebih dalam yang mengandung serat-
serat otot polos dari muskulus Muller (tarsalis superior). Di palpebra inferior, retractor utama
adalah muskulus rektus inferior, yang menjulurkan jaringan fibrosa untuk membungkus
meuskulus obliqus inferior dan berinsersio ke dalam batas bawah tarsus inferior dan orbicularis
okuli. Otot polos dari retraktor palpebrae disarafi oleh nervus simpatis. Levator dan muskulus
rektus inferior dipasok oleh nervus okulomotoris.13
Pembuluh darah yang memperdarahi palpebrae adalah a. Palpebra. Persarafan sensorik kelopak
mata atas didapatkan dari ramus frontal nervus V, sedang kelopak mata bawah oleh cabang
kedua nervus V. 13
TUMOR JINAK
1. HEMANGIOMA
Hemangioma kapiler merupakan tumor palpebra yang paling sering ditemukan pada anak.
Hemangioma kapiler atau hemangioma strawberry dapat mengenai kulit pada 10% bayi dan
tampaknya lebih sering pada bayi prematur dan anak kembar. Tumor ini biasanya muncul pada
waktu lahir atau segera sesudah lahir sebagai lesi yang berwarna merah terang, bertambah besar
dalam beberapa minggu hingga bulanan, dan mengalami involusi pada usia sekolah.1
Hemangioma merupakan pertumbuhan hamartomatous yang terdiri dari sel-sel endotel kapiler
yang berproliferasi. Hemangioma ditemukan pada fase awal pertumbuhan aktif pada bayi dengan
periode selanjutnya berupa regresi dan involusi.2
a. Klasifikasi
Secara histologik hemangioma dibedakan berdasarkan besarnya pembuluh darah yang terlibat,
menjadi 3 jenis, yaitu:3
1. Hemangioma kapiler yang terdiri atas:
1. hemangioma kapiler pada anak (nevus vasculosus, strawberry nevus)
2. granuloma piogenik
3. cherry-spot (ruby-spot), angioma senilis
2. Hemangioma kavernosum
1. hemangioma kavernosum (hemangioma matang)
2. hemangioma keratotik
3. hamartoma vaskular.
3. Telangiektasis
1. nevus flameus
2. angiokeratoma
 3. spider angioma
Dari segi praktisnya, umumnya para ahli memakai sistem pembagian sebagai berikut:3
1. Hemangioma kapiler
2. Hemangioma kavernosum
3. Hemangioma campuran
Perkembangan dalam karakteristik biologi dari lesi vaskuler telah merevisi klasifikasi dari
hemangioma. Klasifikasi lesi vaskuler yang digunakan saat ini mampu membedakan dengan
jelas gambaran klinis, histopatologi, dan prognosis antara hemangioma dan malformasi vaskuler.
Istilah lama hemangioma kapiler dan hemangioma strawberry diubah menjadi satu istilah saja
yaitu hemangioma. Sebaliknya, hemangioma kavernosa, port-wine stains, dan limfangioma
merupakan bagian dari malformasi vaskuler. Penamaan ini telah dimasukkan ke dalam literatur
kedokteran tetapi belum digunakan secara konsisten pada literature mata.2
b. Etiologi4
Sampai saat ini, patogenesis terjadinya hemangioma masih belum diketahui.
Meskipun growth factor, hormonal, dan pengaruh mekanik di perkirakan menjadi penyebab
proliferasi abnormal pada jaringan hemangioma, tapi penyebab utama yang menimbulkan defek
pada hemangiogenesis masih belum jelas. Dan belum terbukti sampai saat ini tentang pengaruh
genetik.
Vaskularisasi kulit mulai terbentuk pada hari ke-35 gestasi, yang berlanjut sampai
beberapa bulan setelah lahir. Maturasi sistem vaskular terjadi pada bulan ke-4 setelah lahir.
Faktor angiogenik kemungkinan mempunyai peranan penting pada fase proliferasi dan involusi
hemangioma. Pertumbuhan endotel yang cepat pada hemangioma mempunyai kemiripan dengan
proliferasi kapiler pada tumor.
Proliferasi endotel dipengaruhi oleh agen angiogenik. Angiogenik bekerja melalui dua cara:
1. Secara langsung mempengaruhi mitosis endotel pembuluh darah,
2. Secara tidak langsung mempengaruhi makrofag, mast cell, dan sel T helper.
Heparin yang dilepaskan makrofag menstimuli migrasi sel endotel dan pertumbuhan
kapiler. Di samping heparin sendiri berperan sebagai agen angiogenesis. Efek angiogenesis ini
dihambat oleh adanya protamin, kartilago, dan beberapa kortikosteroid. Konsep inhibisi
kortikosteroid ini diterapkan untuk terapi pada beberapa jenis hemangioma pada fase involusi.
Angioplastin, salah fragmen internal dari plasminogen merupakan inhibitor potent dan
spesifik untuk proliferasi endotel. Makrofag meghasilkan stimulator ataupun inhibitor
angiogenesis. Pada fase proliferasi, jaringan hemangioma di infiltrasi oleh makrofag dan mast
cell, sedangkan pada fase involusi terdapat infiltrasi monosit.
Diperkirakan infiltrasi makrofag dipengaruhi oleh Monocyte chemoattractant protein-1
(MCP-1), suatu glikoprotein yang berperan sebagai kemotaksis mediator. Zat ini dihasilkan oleh
sel otot polos pembuluh darah pada fase proliferasi, tetapi tidak dihasilkan oleh hemangioma
pada fase involusi ataupun malformasi vaskuler. Keberadaan MCP-1 dapat di-down-regulasi oleh
deksametason dan interferon alfa. Interferon alfa terbukti menghambat migrasi endotel yang
disebabkan oleh stimulus kemotaksis. Hal ini memberikan efek tambahan interferon alfa dalam
menurunkan jumlah dan aktifitas makrofag. Bukti-bukti di atas menjelaskan efek deksametason
dan interferon alfa pada hemangioma pada fase proliferasi.
c. Epidemiologi 4
 Prevalensi hemangioma infantil 1- 3% pada neonatus dan 10% pada bayi sampai
dengan umur 1 tahun. Lokasi tersering yaitu pada kepala dan leher (60%), dan faktor resiko yang
telah teridentifikasi, terutama neonatus dengan berat badan lahir di bawah 1500 gram. Rasio
kejadian perempuan disbanding laki-laki 3:1. Hemangioma infantil lebih sering terjadi di ras
kaukasia daripada ras di Afrika maupun Amerika.
Lesi hemangioma infantil tidak ada pada saat kelahiran. Seiring dengan bertambahnya
usia, resiko hemangioma infantil, pada usia 5 tahun meningkat 50%, pada usia 7 meningkatkan
70%, dan 90% pada usia 9 tahun. Mereka bermanifestasi pada bulan pertama kehidupan,
menunjukkan fase proliferasi yang cepat dan perlahan-lahan berinvolusi menuju bentuk lesi yang
sempurna.
d. Gambaran Klinis
Gambaran klinis hemangioma berbeda-beda sesuai dengan jenisnya. Hemangioma
kapiler tampak beberapa hari sesudah lahir. Strawberry nevusterlihat sebagai bercak merah yang
makin lama makin besar. Warnanya menjadi merah menyala, tegang dan berbentuk lobular,
berbatas tegas, dan keras pada perabaan. Ukuran dan dalamnya sangat bervariasi, ada yang
superfisial berwarna merah terang, dan ada yang subkutan berwarna kebiru-biruan. Involusi
spontan ditandai oleh memucatnya warna di daerah sentral, lesi menjadi kurang tegang dan lebih
mendatar.5
Hemangioma kavernosa tidak berbatas tegas, dapat berupa macula eritematosa atau
nodus yang berwarna merah sampai ungu. Biasanya merupakan tonjolan yang timbul dari
permukaan, bila ditekan mengempis dan pucat lalu akan cepat menggembung lagi apabila
dilepas dan kembali berwarna merah keunguan. Lesi terdiri atas elemen vaskular yang matang.
Lesi ini jarang mengadakan involusi spontan, kadang-kadang bersifat permanen.5
Gambaran klinis hemangioma campuran merupakan gabungan dari jenis kapiler dan jenis
kavernosum. Lesi berupa tumor yang lunak, berwarna merah kebiruan yang pada
perkembangannya dapat memberikan gambaran keratotik dan verukosa. Sebagian besar
ditemukan pada ekstremitas inferior dan biasanya unilateral.5
e. Pemeriksaan Penunjang
Ketersediaan alat-alat canggih saat ini memungkinkan pencitraan massa orbita untuk
dibedakan secara non-invasif dalam banyak kasus. Untuk evaluasi diagnostik pada orbita, CT-
Scan memiliki sensitivitas yang tinggi terhadap tulang, sedangkan MRI terutama untuk jaringan
lemak. Selain itu, di tangan yang berpengalaman, USG juga dapat memberikan informasi penting
dalam diagnosis massa orbita.2
Jika diagnosis hemangioma belum jelas secara klinis, MRI sangat berguna untuk
membedakan hemangioma dari neurofibroma pleksiformis, malformasi limfatik, dan
rhabdomiosarkoma, dimana masing-masing berhubungan dengan pertumbuhan dan proliferasi
yang cepat atau proptosis yang progresif. MRI atau USG Doppler dapat menggambarkan
perluasan tumor ke posterior apabila tidak dapat dipastikan secara klinis.2
Gambaran histopatologi tergantung dari stadium perkembangan hemangioma. Lesi awal
tampak banyak sel dengan sarang-sarang padat sel endotel dan selalu berhubungan dengan
pembentukan lumen vaskuler yang kecil. Lesi yang terbentuk secara khas menunjukkan saluran
kapiler yang berkembang dengan baik, rata, dan mengandung endotel dengan konfigurasi
lobuler. Lesi involusi menunjukkan peningkatan fibrosis dan hyalinisasi dinding kapiler dengan
oklusi lumen.2
f. Penatalaksanaan
Observasi dilakukan apabila hemangioma berukuran kecil dan tidak ada risiko terjadinya
ambliopia, baik akibat obstruksi aksis visual maupun astigmat terinduksi.2
Hemangioma yang belum mengalami komplikasi sebagian besar mendapat terapi konservatif,
baik hemangioma kapiler, kavernosa maupun campuran. Hal ini disebabkan lesi ini kebanyakan
akan mengalami involusi spontan. Pada banyak kasus hemangioma yang mendapatkan terapi
konservatif mempunyai hasil yang lebih baik daripada terapi pembedahan baik secara fungsional
maupun kosmetik. Terdapat dua cara pengobatan pada hemangioma, yaitu:3
Terapi konservatif
Pada perjalanan alamiahnya lesi hemangioma akan mengalami pembesaran dalam bulan-
bulan pertama, kemudian mencapai besar maksimum dan sesudah itu terjadi regresi spontan
sekitar umur 12 bulan, lesi terus mengadakan regresi sampai umur 5 tahun. Hemangioma
superfisial atau hemangioma strawberry sering tidak diterapi. Apabila hemangioma ini dibiarkan
hilang sendiri, hasilnya kulit terlihat normal.5
Terapi aktif
Hemangioma yang memerlukan terapi secara aktif, antara lain adalah hemangioma yang
tumbuh pada organ vital, seperti pada mata, telinga, dan tenggorokan; hemangioma yang
mengalami perdarahan; hemangioma yang mengalami ulserasi; hemangioma yang mengalami
infeksi; hemangioma yang mengalami pertumbuhan cepat dan terjadi deformitas jaringan.3
Terapi kompresi
Terdapat dua macam terapi kompresi yang dapat digunakan yaitu continous
compression dengan menggunakan bebat elastik dan intermittentpneumatic compression dengan
menggunakan pompa Wright Linear. Diduga dengan penekanan yang diberikan, akan terjadi
pengosongan pembuluh darah yang akan menyebabkan rusaknya sel-sel endothelial yang akan
menyebabkan involusi dini dari hemangioma.12
Terapi kortikosteroid
Steroid digunakan selama fase proliferatif tumor untuk menghentikan pertumbuhan dan
mempercepat involusi lesi. Steroid dapat digunakan secara topikal, intralesi, atau sistemik. Krim
clobetasol propionate 0,05% topikal dapat digunakan pada lesi superfisial yang kecil. Injeksi
intralesi kombinasi antara steroid kerja panjang dan kerja singkat sering digunakan pada
hemangioma periorbita terlokalisir (sebaiknya digunakan sediaan steroid yang terbukti dapat
digunakan untuk suntikan intralesi. Jika hemangioma difus atau meluas ke posterior orbita,
digunakan steroid sistemik dengan dosis anjuran prednison atau prednisolon 2-5 mg/kg BB/hari.
Terapi dengan kortikosteroid dalam dosis besar kadang-kadang akan menimbulkan regresi pada
lesi yang tumbuh cepat.2
Steroid dihubungkan dengan banyak komplikasi sehingga perlu dipertimbangkan keuntungan
dan kerugiannya. Supresi adrenal dan retardasi pertumbuhan dapat terjadi pada semua cara
penggunaan, termasuk krim topikal. Injeksi intralesi berisiko menyebabkan emboli arteri retinalis
bilateral, atrofi lemak subkutan linier, dan depigmentasi palpebra. Imunisasi perlu ditunda pada
anak-anak yang mendapat terapi steroid dosis tinggi. Dianjurkan untuk berkonsultasi dengan
dokter spesialis anak.2
Kriteria pengobatan dengan kortikosteroid ialah:
1. Apabila melibatkan salah satu struktur yang vital,
2. Tumbuh dengan cepat dan mengadakan destruksi kosmetik,
3. Secara mekanik mengadakan obstruksi salah satu orifisium,
4. Adanya banyak perdarahan dengan atau tanpa trombositopenia,
5. Menyebabkan dekompensasio kardiovaskular.7
Hemangioma kavernosum yang tumbuh pada kelopak mata dan mengganggu penglihatan
umumnya diobati dengan steroid injeksi untuk mengurangi ukuran lesi secara cepat, sehingga
penglihatan bisa pulih. Hemangioma kavernosum atau hemangioma campuran dapat diobati bila
steroid diberikan secara oral dan injeksi langsung pada hemangioma. Penggunaan kortikosteroid
peroral dalam waktu yang lama dapat meningkatkan infeksi sistemik, tekanan darah, diabetes,
iritasi lambung, serta pertumbuhan terhambat.7
Terapi pembedahan
Indikasi pembedahan tergantung dari ukuran dan lokasi hemangioma yang akan dieksisi.
Karena itu pemeriksaan radiologi dan penunjang lainnya sangat diperlukan untuk menegakkan
diagnosa secara akurat. Adapun indikasi dilakukannya terapi pembedahan pada hemangioma
adalah:
1. Terdapat tanda-tanda pertumbuhan yang terlalu cepat, misalnya dalam beberapa minggu lesi
menjadi 3-4 kali lebih besar,
2. Hemangioma raksasa dengan trombositopenia,
3. Tidak ada regresi spontan, misalnya tidak terjadi pengecilan sesudah 6-7 tahun.6
Eksisi hemangioma periorbita dapat dilakukan dengan mudah pada beberapa lesi yang
terlokalisir dengan baik. Pada kasus lain, pembedahan rekonstruksi dapat dilakukan bertahun-
tahun setelah terapi medis.2
Embolisasi sebelum pembedahan dapat sangat berguna apabila hemangioma yang akan
dieksisi mempunyai ukuran yang besar dan lokasi yang sulit dijangkau dengan pembedahan.
Embolisasi akan mengecilkan ukuran hemangioma dan mengurangi resiko perdarahan pada saat
pembedahan.6
Terapi radiasi
Pengobatan radiasi pada tahun-tahun terakhir ini sudah banyak ditinggalkan karena:
1. Penyinaran berakibat kurang baik pada anak-anak yang pertumbuhan tulangnya masih sangat
aktif,
2. Komplikasi berupa keganasan yang terjadi pada jangka panjang,
3. Menimbulkan fibrosis pada kulit yang masih sehat yang akan menyulitkan bila diperlukan
suatu tindakan.3
Terapi sklerotik
Terapi ini diberikan dengan cara menyuntikan bahan sklerotik pada lesi hemangioma,
misalnya dengan namor rhocate 50%, HCl kinin 20%, Na-salisilat 30%, atau larutan NaCl
hipertonik. Akan tetapi cara ini sering tidak disukai karena rasa nyeri dan menimbulkan
sikatriks.3
Terapi pembekuan
Aplikasi dingin dengan memakai nitrogen cair. Dianggap cukup efektif diberikan pada
hemangioma tipe superfisial, akan tetapi terapi ini jarang dilakukan karena dilaporkan
menyebakan sikatrik paska terapi.6
Terapi embolisasi
 Embolisasi merupakan tehnik memposisikan bahan yang bersifat trombus kedalam lumen
pembuluh darah melalui kateter arteri dengan panduan fluoroskopi. Embolisasi dilakukan apabila
modalitas terapi yang lain tidak dapat dilakukan atau sebagai persiapan pembedahan.
Pembuntuan pembuluh darah ini dapat bersifat permanen, semi permanen atau sementara,
tergantung jenis bahan yang digunakan. Banyak bahan embolisasi yang digunakan, antara lain
methacrylate spheres, balon kateter, cyanoacrylate, karet silicon, wol, katun, spon gelatin, spon
polyvinyl alcohol.6
Terapi laser
Penyinaran hemangioma dengan laser dapat dilakukan dengan menggunakanpulsed-dye laser
(PDL), dimana jenis laser ini dianggap efektif terutama untuk jenis Port-Wine stain. Pulsed-dye
laser dapat digunakan untuk mengobati hemangioma superfisial dengan beberapa komplikasi,
tetapi berefek kecil terhadap komponen tumor yang lebih dalam. Jenis laser ini memiliki
keuntungan bila dibandingkan dengan jenis laser lain karena efek keloid yang ditimbulkan
minimal.5
Kemoterapi
Vincristine merupakan alternatif yang dapat dipertimbangkan tetapi masih dalam penelitian.
Vinkristin merupakan terapi lini kedua lainnya yang dapat digunakan pada anak-anak yang tidak
berhasil diterapi dengan kortikosteroid dan juga dianggap efektif pada anak-anak yang menderita
Sindrom Kassabach-Merritt.Vinkristin diberikan secara intravena dengan angka keberhasilan
lebih dari 80%. Efek samping dari terapi ini adalah peripheral neuropathy, konstipasi dan
rambut rontok. Siklofosfamid jarang digunakan pada tumor vaskuler yang jinak karena
mempunyai efek toksisitas yang sangat besar.5
g. Komplikasi
Morbiditas hemangioma mata sangat bergantung dari seberapa besar ukurannya mengisi
rongga mata. Komplikasi yang paling sering dari hemangioma adalah ambliopia deprivasi pada
mata yang terkena jika lesi cukup besar untuk menghalangi aksis visual. Hal ini dapat ditemukan
pada 43-60% pasien dengan hemangioma palpebra. Jika lesi cukup besar untuk
menyebabkandistorsi kornea dan astigmat, maka ambliopia anisometrik dapat terjadi.1,2
Selain itu, perdarahan juga merupakan komplikasi yang paling sering terjadi.
Penyebabnya ialah trauma dari luar atau ruptur spontan dinding pembuluh darah karena tipisnya
kulit di atas permukaan hemangioma, sedangkan pembuluh darah di bawahnya terus tumbuh.6
Ulkus dapat menimbulkan rasa nyeri dan meningkatkan resiko infeksi, perdarahan dan
sikatrik. Ulkus merupakan hasil dari nekrosis. Ulkus dapat juga terjadi akibat ruptur.6
3.NEVUS
a. DEFINISI
Sel nevus berpigmen adalah pigmentasi tahi lalat yang umum terjadi pada kebanyakan orang.
Nevus berasal dari melanosit,yaitu sel yang memproduksi pigmen. Permukaan dari nevus bisa
halus ataupun berbenjol benjol tergantung pada jumlah keratin yang dikandungnya. Pada tahi
lalat bisa terdapat beberapa rambut dengan ukuran panjangnya yang bervariasi. Warna dari nevus
bervariasi mulai dari sewarna kulit hingga coklat dan hitam tergantung pada jumlah dan lokasi
dari melanin dan pigmen di dalam tumor. Nevus dengan warna yang lebih gelap memiliki
pigmen yang lebih dekat ke permukaan.11
b. Klasifikasi
 a. Junctional nevus
Junctional nevus biasanya datar dan berbatas tegas dengan warna coklat yang seragam.
Dinamakan junctional nevus karena sel sel nevus ini terletak pada perbatasan antara epidermis
dan dermis. Nevus ini memiliki potensi yang rendah untuk berubah menjadi suatu keganasan.
b. Intradermal nevus
Intradermal nevus umumnya meninggi di atas kulit dan merupakan jenis nevus yang paling
umum. Nevus ini biasanya berwarna coklat hingga hitam. Nevus intradermal sering terdapat
pada pinggir kelopak mata dan bulu mata pada kelopak mata yang ditumbuhi nevus tersebut
dapat tumbuh normal diatas nevus. Nevus ini juga bisa tumbuh pada alis mata dan bulu bulu
alis mata juga dapat tumbuh baik pada nevus. Oleh karena itu sebagian besar ahli berpendapat
bahwa nevus ini tidak memiliki potensi keganasan.
c. Compound nevus
Compound nevus adalah nevus yang berasal dari gabungan dari komponen jaringan pembatas
antara epidermis dan dermis dengan komponen jaringan dermis kulit. Nevus ini memiliki potensi
keganasan yang rendah.
d. Nevus biru
Nevus biru biasanya datar tetapi dapat pula berupa nodul yang berbatas tegas. Nevus ini dapat
berwarna biru, abu abu hingga hitam. Warna biru-hitam dari nevus ini dikarenakan karena
letaknya yang jauh lebih dalam dari kulit yang di atasnya.
e. Congenital oculodermal melanocytosis (nevus of Ota)
Adalah jenis dari nevus biru dari kulit di sekitar bola mata yang berhubungan dengan nevus biru
dari konjungtiva dan perluasan dari nevus di uvea. Nevus ini biasa mengenai ras kulit hitam dan
oriental dan jarang mengenai ras kaukasia. Nevus ini berpotensi untuk menjadi ganas khususnya
jika mengenai ras kaukasia.11
c. Tatalaksana
Walaupun dari tampilan klinis dan riwayat penyakit membantu dalam membuat diagnosis klinis,
biopsy biasanya diperlukan untuk mengkonfirmasi diagnosis nevus. Biopsi insisi bisa dilakukan
jika lesi berukuran besar dan untuk memastikan diagnosis. Biopsi eksisi juga dapat dilakukan
jika nevus ingin dihilangkan karena alasan kosmetik selain juga untuk konfirmasi diagnosis.
Nevus tidak sensitive terhadap radioterapi sehingga bedah eksisi adalah cara terbaik untuk
menghilangkan tumor ini.11
TUMOR GANAS
Klasifikasi Tumor Ganas Palpebra
Tumor ganas palpebra:13
1. Karsinoma
a. Karsinoma sel basal
b. Karsinoma sel skuamosa
c. Karsinoma kelenjar sebasea
2. Sarkoma
3. Melanoma
1. Karsinoma Sel Basal
a. Definisi dan Epidemiologi
 Karsinoma sel basal berasal dari lapisan basal epitel kulit atau dari lapis luar sel folikel
rambut. Berupa benjolan yang transparan, kadang dengan pinggir yang seperti mutiara. Bagian
sentral benjolan tersebut lalu mencekung dan halus, seakan-akan menyembuh. Tumbuhnya
lambat dengan ulserasi. Jenis ulkus rodiens tumbuh lebih cepat dan dapat menyebabkan
kerusakan hebat disekitarnya.17
Karsinoma sel basal merupakan tumor ganas paling banyak di kelopak mata dengan
frekuensi 90 95 % dari seluruh tumor ganas di kelopak mata. Karsinoma sel basal banyak
berlokasi di kelopak mata bawah bagian pinggir atau palpebra inferior (50 60 %) dan di daerah
kantus medial (25 30%). Selebihnya juga bisa tumbuh di kelopak mata atas atau palpebra
superior (15 %) dan di kantus lateral (5 %).14
b. Faktor Resiko
Pasien yang memiliki faktor resiko tinggi untuk terjadinya karsinoma sel basal adalah yang
memiliki corak kulit putih, mata biru, rambut pirang, usia pertengahan dan usia tua pada
keturunan Inggris, Irlandia, Skotlandia, dan Skandinavia. Pasien biasanya juga memiliki riwayat
terpapar sinar matahari dalam jangka waktu lama pada usia dekade dua kehidupan. Riwayat
merokok cerutu juga merupakan resiko unruk terjadinya karsinoma sel basal. Pasien dengan
karsinoma sel basal sebelumnya, memiliki kemungkinan lebih tinggi untuk berkembang menjadi
kanker kulit.14
Karsinoma sel basal terlihat meningkat frekuensinya pada pasien yang lebih muda dan
ditemukan lesi ganas di kelopak mata pada pasien ini atau mereka yang memiliki riwayat
keluarga dengan kelainan sistemik lain seperti basal cell nevus syndrome atau xeroderma
pigmentosum.Basal cell nevus syndrome (Gorlin syndrome) adalah kelainan autosomal dominan,
kerusakan multisitem yang ditandai dengan karsinoma sel basal nevoid yang multipel yang
muncul lebih awal dalam kehidupan yang diikuti dengan anomali skeletal khususnya pada
mandibula, maksila dan vertebra. Xeroderma pigmentosum merupakan kelainan resesif
autosomal yang ditandai dengan sangat sensitif terhadap paparan sinar matahari dan kerusakan
mekanisme repair terhadap sinar matahari sehingga merangsang kerusakan DNA pada sel
kulit.14
c. Gejala klinis
Tumor ini umumnya ditemukan di daerah berambut, bersifat invasif, jarang mempunyai
anak sebar atau bermetastasis. Dapat merusak jaringan di sekitarnya terumata bagian permukaan
bahkan dapat sampai ke tulang (bersifat lokal destruktif), serta cenderung untuk residif lebih bila
pengobatannya tidak adekuat. Ulserasi dapat terjadi yang menjalar dari samping maupun dari
arah dasar, sehingga dapat merusak bola mata sampai orbita.15
Karsinoma sel basal merupakan tumor yang bersifat radiosensitif dengan diagnosis pasti
dilihat dengan biopsi. Angka kematian untuk karsinoma sel basal adalah 2 3 % karena tumor
ini jarang bermetastasis.16
d. Klasifikasi
Secara klinis dan secara patologi, karsinoma sel basal di bagi menjadi empat tipe, yaitu :
1. Karsinoma sel basal tipe nodular merupakan manifestasi klinis terbanyak dari karsinoma sel
basal, keras, berbatas tegas, nodul seperti mutiara dan disertai dengan telangiectasia and sentral
ulkus. Secara histologi, tumor ini terbentuk dari sekumpulan sel basal yang asalnya dari lapisan
sel basal epitelium dan terlihat seperti pagar di bagian pinggir.14
 Pada tahap permulaan, sangat sulit ditentukan malah dapat berwarna seperti kulit normal atau
menyerupai kutil.Kumpulan sel atipik merusak permukaan epitel, nekrosis di tengah karena lebih
cekung dan timbul ulkus bila sudah berdiameter 0,5 cm yang pada pinggir tumor awalnya
berbentuk papular, meninggi, anular. Bila telah berkembang lebih lanjut, dapat melekat di
dasarnya. Dengan trauma ringan atau bila krustanya diangkat mudah terjadi perdarahan.15
2. Karsinoma sel basal tipe morphea merupakan jenis yang paling sedikit ditemukan, tetapi tumor
ini bersifat lebih agresif karena dapat berkembang lebih cepat daripada karsinoma sel basal tipe
nodular. Lesi tipe morphea bersifat keras, lebih datar dengan pinggir yang secara klinis susah
ditentukan. Secara histologi, lesi tidak terlihat seperti pagar di pinggirnya tetapi berbentuk seperti
kawat tipis yang menyebar di daerah pinggir. Di sekitar stroma terlihat proliferasi dari jaringan
penyambung menjadi pola fibrosis.14
Karsinoma sel basal mulai menstimulasi inflamasi kronis dari bagian pinggir kelopak mata dan
sering disertai dengan rontoknya bulu mata (madarosis).14
Invasi dari karsinoma sel basal ke orbita bisa terjadi karena pengobatan yang tidak adekuat,
klinis yang terlambat ditemukan serta karsinoma sel basal dengan tipe morphea.14
1. Karsinoma sel basal tipe ulserative16
2. Karsinoma sel basal tipe multisentrik atau superfisial terjadi akibat blefaritis kronis dan bisa
menyebar ke bagian pinggir kelopak mata tanpa di sadari.14
Ukurannya dapat berupa plakat dengan eritema, skuamasi halus dengan pinggir yang agak
keras seperti kawat dan agak meninggi. Warnanya dapat hitam berbintik-bintik atau homogen.15
e. Tatalaksana
Biopsi diperlukan untuk mengkonfirmasi kecurigaan secara klinis dari karsinoma sel basal.
Diagnosis yang sangat akurat bisa dijamin jika pada setiap biopsi insisional jaringan yang akan
diperiksa:
1. Mewakili keadaan lesi secara klinis
2. Ukuran yang tepat untuk pemeriksaan secara histopatologi
3. Tidak menambah trauma atau kerusakan
4. Mengikutsertakan jaringan normal di bagian pinggir sekitar daerah yang dicurigai
Biopsi insisi merupakan salah satu prosedur yang bisa digunakan untuk menkonfirmasi
kecurigaan terhadap tumor ganas. Area dari biopsi insisi seharusnya di potret atau di gambar
dengan pengukuran sehingga daerah asal tumor menjadi tidak sulit untuk ditemukan pada saat
prose pengangkatan tumor berikutnya.14
Biopsi eksisi bisa menjadi pertimbangan ketika lesi di kelopak mata kecil dan tidak terlibatnya
daerah di pinggir kelopak mata atau saat lesi di pinggir kelopak mata yang berlokasi di sentral
jauh dari kantus lateral atau pungtum lakrimal. Biopsi eksisi harus diarahkan secara vertikal
sehingga tidak terjadi traksi pada kelopak mata. Jika pinggir dari daerah kelopak mata yang di
eksisi positif terdapat sel tumor, maka area yang terlibat harus di reeksisi secara pembedahan
dengan teknikMohs micrographic untuk mengetahui batas bawah atau teknik frozen-
sectionuntuk mengetahui batas samping.14
Untuk menatalaksana karsinoma sel basal dapat ada beberapa pilihan terapi, diantaranya :
1. Bedah dilakukan dengan mengeksisi tumor sampai dengan benar-benar meninggalkan sisa.
Pilihan terapi bedah :
Eksisi dengan potong beku (frozen section)
Bedah mikrografi Mohs
 Bedah dengan laser CO2
Eksisi tanpa potong beku
Bedah merupakan pilihan terapi dari karsinoma sel basal di kelopak mata. Bedah eksisi
memberikan keuntungan dari diangkatnya tumor secara keseluruhan dengan batas areanya
dikontrol secara histologi. Tingkat kekambuhan tumor pada terapi bedah lebih sedikit dan lebih
jarang jika dibandingkan jika diterapi dengan modalitas terapi lain.14
Ketika karsinoma sel basal bertempat di daerah kantus medial, sistem aliran air mata juga
bisa terangkat jika dilakukan eradikasi tumor secara komplet. Jika sistem drainase air mata telah
terangkat setelah proses eradikasi tumor, rekonstruksi sistem aliran keluar air mata tidak bisa
dilakukan sampai pasien benar-benar bebas dari tumor. Beberapa tumor bisa menyebar ke daerah
subkutan dan tidak dapat diketahui sebelum operasi 14
Kambuhnya tumor yang sudah diangkat secara total, infiltrasi yang lebih dalam, atau tumor
tipe morphea dan tumor yang berada di kantus medial dikelola dengan cara bedah mikrografi
Mohs. Jaringan diangkat secara lapis demi lapis dan dibuat tipis yang dilengkapi dengan gambar
3 dimensi untuk mengangkat tumor. Reseksi tumor secara mikrografik Mohs paling sering
digunakan untuk mengeksisi karsinoma sel basal dan karsinoma sel skuamosa.14
Mikrografi eksisi bisa menjamin secara maksimal jumlah jaringan yang sehat untuk tidak
terlibat sehingga hanya area tumor yang terangkat secara komplet. Kekurangan dari bedah
mikrografi Mohs ini adalah dalam mengidentifikasi batas tumor ketika tumor sudah menginvasi
daerah orbita.14
Setelah dilakukan reseksi tumor, kelopak mata seharusnya direkonstruksi dengan prosedur
okuloplastik yang terstandar. Rekonstruksi ini penting walaupun bukan merupakan hal yang
mendesak, pembedahan awal bertujuan untuk melindungi secara maksimal bola mata lalu diikuti
dengan memperbaiki sisa kelopak mata yang masih baik. Jika rekonstruksi tidak bisa dilakukan
segera, kornea harus dilindungi dengan cara menempelkan atau sementara dengan cara menutup
kelopak mata. Jika defeknya kecil, maka granulasi jaringan secara spontan bisa menjadi alternatif
terapi.14
Untuk lesi yang nodular, angka kekambuhan jika diterapi dengancryotherapy lebih besar
daripada setelah diterapi secara pembedahan. Saat cryotherapy digunakan untuk
menangani diffuse sclerosing lesion, angka kekambuhan tinggi. Selain itu, secara histologi
pinggir area tidak bisa dievaluasi dengan cryotherapy. Akibatnya, modalitas terapi ini dihindari
untuk lesi yang kambuh, lesi dengan diameter lebih dari 1 cm, dan lesi tipe morphea.
Lagipula,cryotherapy menimbulkan depigmentasi dan atropi pada jaringan. Maka dari
itu, cryotherapy untuk karsinoma sel basal pada kelopak mata dijadikan cadangan terapi untuk
pasien yang intoleran terhadap pembedahan seperti pasien yang sangat tua yang aktifitasnya
terbatas di tempat tidur, atau pasien dengan kondisi medis yang serius yang kontraindikasi untuk
dilakukan intervensi bedah.14
Jika tumor terbatas pada adneksa dilakukan eksisi 3-5 mm dari batas makroskopis. Sedangkan
jika tumor sudah menginvasi orbita, maka ada dua pilihan terapi secara eksentrasi yaitu dengan
mengangkat seluruh bola mata disertai dengan adneksa mata dengan meninggalkan bagian tulang
saja, selain itu juga bisa dilakukan radioterapi. Jika sudah menginvasi intrakranial harus
dikonsultasikan ke bagian bedah saraf.16
2. Non bedah dilakukan jika lokasi cukup sulit untuk dilakukan pembedahan, respon dari terapi
non bedah cukup bagus tetapi memiliki efek samping yang cukup banyak. Pilihan terapi non
bedah yaitu :
Radioterapi
Kemoterapi
Interferon
Terapi radiasi juga bisa dipertimbangkan sebagai terapi paliatif tetapi untuk lesi periorbita
sebaiknya dihindari. Seperti cryotherapy, terapi radiasi juga tidak bisa digunakan untuk
memantau area pinggir tumor secara histologi. Angka kekambuhan jika diterapi dengan radiasi
juga lebih tinggi jika dibandingkan dengan terapi pembedahan. Ditambah lagi, kekambuhan
setelah radiasi sulit untuk dideteksi. Kekambuhan ini timbulnya lebih lama setelah terapi awal
dan lebih sulit untuk menangani secara pembedahan karena telah terjadi perubahan dari struktur
jaringan yang telah diradiasi sebelumnya.14
Komplikasi yang terjadi akibat terapi radiasi diantanya adalah timbulnya sikatrik pada
kelopak mata, pembentukan scar pada drainase air mata disertai dengan obstruksi, keratitis sica.
Radiasi juga merangsang timbulnya keganasan baru atau cedera pada bola mata yang timbul jika
bola mata tidak dilindungi selama terapi.14
2. Karsinoma sel skuamosa
1. Definisi
Karsinoma sel skuamosa adalah suatu jenis tumor ganas intra epitelial yang bermanifestasi
pada mata di saerah limbus dan margo palpebra,yaitu didaerah peralihan epitel(18). Margo
palpebra merupakan daerah peralihan epitel dari susunan sel gepeng berlapis epidermis menjadi
sel silindris konjungtiva tarsal,sedangkan pada daerah limbus terdapat peralihan berupa sel
mukosa konjungtiva bulbi menjadi epitel skuamosa kornea.Lesi-lesi yang berada di daerah
peralihan ini perlu di perhatikan karena cendrung dapat bersifat ganas(18,20,21)
2. Epidemiologi
Karsinoma sel skuamosa relatif jarang dijumpai pada kelopak mata dan konjungtiva,
frekuensinya kurang lebih 9,2% dari seluruh keganasan pada kelopak mata19. Meskipun
demikian kejadian karsinoma sel skuamosa yang telah menyerang orbita,tercatat sebanyak 36
pasien diantara 486bpasien tumor orbita di Rumah Sakit Cipto Mangunkusumo (RSCM) selama
tahun 1980-199019
Karsinoma sel skuamosa lebih banyak mengenai pria daripada wanita. Tumor ini sering terjadi
pada usia lanjut, walaupuin bdapat juga dijumpai pada dewasa muda. Tumor terutama didapat
pada daerah tropis dan sifat karsinoma sel skuamosa cendrung lebih invasif(18,21,22)
3. Etiologi
Penyebab karsinoma sel skuamosa ataupun tumor intraepitel belum diketahui,tetapi diduga
sebagai akibat terpapar oleh zat aktinik atau kimia,terapi radiasi, iritasi yang berlebihan, serta
virus yang akhir-akhir ini juga diduga sebagai penyebabnya,yaitu Virus papiloma humanum
4. Patofisiologi
Kelainan patologi karsinoma sel skuamosa dapat dijumpai dalam berbagai derajat keganansan
dimulai dari stadium awal pralesi displasia, karsinoma in situsampai dengan stadium lanjut
invasif.(18,20,22). Karsinoma sel skuamosa dapat didahului oleh berbagai macam tumor jinak
seperti lesi papiloma skuamosa atai diskeratosis sebelum berubah menjadi displasi. Pada
displasia stadium awal gambaran patologi belum menunjukan terjadi perubahab sel,yang terjadi
 hanya perubahan sel menjadi atipik,dimana secara histologis belum termasuk kriteria
keganasan.Displasia mempunyai gradasi dari sel atipik yang ringan sampai berat,bergantung
pada ketebalan perubahan sel epitel.Karsinoma in situ sering dimasukan dalam kategori kelainan
displasia berat oleh banyak peneliti. Apabila sel yang telah berubahs sifat tersebut ,menembus
membrana bsalis maka lesi tersebut merupakan karsinoma invasif .Karsinoma sel skuamosa
terjadi akibat progresivitas karsinoma in situ dan displasia berat
5 Diagnosis
1. Anamnesis
Ada riwayat perkembangan dari luka akibat paparan sinar matahari dan actinic keratosis
Ada riwayat kemoterapi dan transplantasi organ
Riwayat terpapar sinar matahari
Ada riwayat kekambuhan setelah pengobatan lesi kelopak mata
Perubahan kontur,ukuran,atau warna lesi seperti adanya ulserasi,luka,bintik merah dan
trikiasi.
2. Pemeriksaan fisik
Tumor ditemukan tumbuh lambat tanpa rasa sakit,berawal dari nodul hiperkeratotik yang dapat
berulkus dapat mengikis jaringan sekitar dan juga menyebar kelimfonodus regional melalui
sistem limfatik.
3. Pemeriksaan laboratorium
-Biopsi untuk memastikan tumor
-Tes fungsi hati atau CT scan jika terdapat metastasis
6. Tatalaksana
-Pembedahan dilaksanakan eksisi tumor
-Pembedahab radikal eksenterasi dengan atau tanpa kombinasi radiasi18,20
7. Prognosis
Rekurensi karsinoma sel skuamosa terjadi sebanyak 20-40 % dan dilaporkan umumnya terjafi
setelah penderita mengalami eksisi tidak lengkap pada karsinoma sel skuamosa tergantung
beberapa faktor,baik derajat keganasan secara patologis ataupun berdasarkan lokasi dan ukuran
masa20
2.3.4 Melanoma Maligna Palpebra
1. Epidemiologi
Melanoma adalah tumor palpebra berpigmen yang jarang yang harus dibedakan dari Nevi
dan karsinoma sel basal.26Terdapat peningkatan 4% kejadian melanoma maligna yang
didiagnosa setiap tahun. Ada 51.400 kasus baru melanoma didiagnosa pada tahun 2002 dengan
7.800 kematian. 25% pasien melanoma maligna dijumpai pada umur di bawah 40 tahun.27
Melanoma hanya ditemukan 1% dari keseluruhan lesi palpebra. Kenyataannya, walaupun
hanya 3% dari semua kanker kulit melanoma, ini sangat penting karena lebih dari dua pertiga
dari semua kematian akibat kanker kulit yang disebabkan melanoma maligna. Oleh karena itu,
penting untuk mengenali lesi jinak dan ganas kelopak mata, terutama ketika berpigmen.28
2. Faktor Risiko
Mereka yang paling berisiko untuk berkembangnya melanoma adalah kelompok yang
mempunyai riwayat melanoma dalam keluarga dan pasien dengan nevus displastik. Kelompok
berisiko tinggi adalah pasien dengan xeroderma pigmentosa, pasien dengan limfoma non-
Hodgkin, dan pasien dengan transplantasi organ atau AIDS. Pasien melanoma memiliki risiko
tinggi lima kali lipat untuk mengidap melanoma kedua.27
3. Diagnosis
Ciri khas dari melanoma maligna adalah pigmentasi variabel (yaitu sebuah lesi dengan
tingkat warna coklat, merah, putih, biru atau hitam gelap) batas tidak tegas, ulserasi dan
perdarahan. Melanoma palpebra yang melibatkan konjungtiva biasanya lebih agresif daripada
yang terbatas di kulit palpebra.27
Perubahan tampilan pada lesi berpigmen memerlukan biopsi eksisi pada lesi. Evaluasi
sistemik untuk metastasis regional atau jauh diperlukan bila didiagnosis melanoma.26
Clark dan Breslow membagi kedalaman invasi ke dalam lima tingkat anatomis:27
Tingkat 1 hanya terbatas pada epidermis (in situ).
Tingkat 2 menembus papiler dermis.
Tingkat 3 mengisi papiler dermis.
Tingkat 4 meluas ke reticular dermis.
Tingkat 5 tumor meluas ke dalam jaringan subkutan.

4. Penatalaksanaan
Terapi bedah dapat dilakukan untuk alasan kosmetik atau kecurigaan keganasan pada lesi
jinak berpigmen. Prosedur pilihan untuk pengobatan melanoma maligna kulit kelopak mata
adalah eksisi bedah lebar dengan 1 cm margin kulit dikonfirmasi oleh histologi. Pemotongan
kelenjar getah bening regional harus dilakukan untuk tumor yang lebih besar dari 1,5 mm secara
mendalam dan / atau untuk tumor yang menunjukkan bukti penyebaran vaskular atau limfatik.28
Laser dapat digunakan untuk lesi berpigmen kelopak mata tertentu, sebuah penelitian
terbaru telah menunjukkan kasus uveitis bilateral setelah terapi laser pada lesi kelopak mata
berpigmen.28

5. Prognosis
Tingkat 4 atau Tingkat 5 melanoma ganas kulit palpebra biasanya mempunyai prognosis buruk.
Breslow mengembangkan metode kuantitatif dengan mengukur kedalaman invasi dengan
milimeter. Pasien dengan tebal tumor kurang dari 0,75 mm memiliki prognosis sangat baik
dengan dapat bertahan hidup 5 tahun sebesar 100%. Pasien dengan lesi 0,75 mm sampai 1,5 mm
memiliki prognosis yang cukup baik, dan pasien dengan tumor lebih dari 1,5 mm memiliki
prognosis yang buruk dengan ketahanan hidup 5 tahun sebesar 50% sampai 60%.28
2.3.5 Sarkoma Palpebra
1. Epidemiologi
Sarkoma Kaposi merupakan salah satu manifestasi yang sering dijumpai pada penderita AIDS
(24%) dan 20% dari sarkoma dapat mengenai mata, yaitu palpebra atas/bawah menyerupai
hordeolum atau hemangioma dan pada konjuntiva forniks, dan bulbi bagian inferior (menyerupai
perdarahan subkonjuntiva granuloma atau hemangioma). Tumor ini bersifat agresif, multifokal
dan sering kambuh.29
 Pada tahun 1872, Kaposi melaporkan sarkoma multiple-pigmented dari kulit yang idiopatik.
Sarkoma Kaposi endemik lazim di Afrika Tengah, terutama mempengaruhi laki-laki muda
dengan lesi kulit yang agresif dan viseral.30
2. Etiologi
Penyebabnya belum diketahui pasti, tetapi beberapa faktor terlibat yang ditemui pada pasien
sarkoma Kaposi:30
Human herpesvirus-8 (HHV-8) DNA atau sarkoma Kaposi terkait virus herpes (KSHV) telah
ditemui pada pasien yang HIV-negatif dan HIV-positive.
Laki-laki homoseksual dengan HIV mempunyai risiko yang tinggi. Risiko ini meningkat
tajam dengan jumlah pasangan yang banyak.
Pasien yang sudah pernah transplantasi organ, dan menggunakan agen imunosupresif dan
steroid berisiko tinggi.
3. Patofisiologi
Sarkoma Kaposi kemungkinan besar disebabkan oleh beberapa faktor, termasuk ekspresi
deregulasi dari onkogen dan gen oncosuppressor oleh KSHV/HHV-8 dikombinasikan dengan
penurunan kekebalan tubuh dan pelepasan sitokin (interleukin [IL] -6) dan faktor pertumbuhan
dari HIV bertindak ke atas terjadinya infeksi sel. IL-6 menginduksi signal transducers
andactivators of transcription 3 (STAT3), sehingga menyebabkan ekspresi onkogen. Meskipun
mekanisme yang tepat tentang KSHV/HHV-8 bertindak sebagai perantara oncogenesis belum
sepenuhnya diketahui, banyak KSHV/HHV-8 onkogen virus yang telah dikatakan dapat
menyebabkan neoplasia.30
4. Diagnosis
Sarkoma Kaposi pada mata biasanya asimptomatik, kadang-kadang disertai iritasi ringan.
Tumor sarkoma Kaposi berwarna kemerah-merahan, padat, dengan gambaran proliferasi
vaskuler, sel-sel spindle dan serat-serat retikulin, diduga berasal dari endotel.29
Untuk mengidentifikasi faktor risiko pada sarkoma Kaposi, dokter harus anamnesa tentang
hal-hal berikut:30
Demografi
Status kekebalan
Lesi kulit Sebelumnya
Pengobatan sebelumnya untuk sarkoma Kaposi
Riwayat infeksi oportunistik
Penggunaan obat saat ini
Gejala sarkoma Kaposi adalah sebagai berikut:30
Sakit
Fotofobia
Mata merah atau perdarahan berulang
Iritasi dan sensasi benda asing
Epiphora
Kering mata
Keluarnya mukopurulen
Kelopak mata keras atau bengkak
Ketidakmampuan untuk menutup mata
Penglihatan kabur
 Pemeriksaan Fisik30
Pemeriksaan mata penuh harus mencakup sebagai berikut:
o Inspeksi dan eversi kelopak mata dan bulu mata.
o Lakukan slit lamp biomicroscopy.
o Periksa palpebral dan konjungtiva bulbi dan forniks dengan terperinci.
o Palpasi kelenjar lakrimal, dan pemeriksaan pada massa.
Lesi yang merah keunguan hingga merah terang dengan pembuluh telangiekstatik sekitarnya,
mungkin makula, seperti plak, atau nodular.
Dugel dkk menguraikan 3 tahapan klinis yang dapat membantu terapi langsung:
o Tahap I dan II, tumor merata dan datar. Lesi ini memiliki tinggi ketebalan kurang dari 3 mm
vertikal dan timbul kurang dari 4 bulan.
o Tahap III, tumor nodular dan kenaikan tinggi vertikal yang lebih besar dari 3 mm, cenderung
timbul lebih dari 4 bulan.
o Lesi sarkoma Kaposi oftalmik ditemukan di kelopak mata, konjungtiva, dan jarang ditemukan di
dalam orbital.
o Keterlibatan konjungtiva dapat disertai pendarahan subkonjunctiva, injeksi, dan kemosis.
Pemeriksaan Lab30
Pada pasien dengan sarkoma Kaposi diindikasikan:
HIV enzyme-linked immunosorbent assay
HIV Western blot
Berhubung dengan kulit atau konjungtiva, biopsi dari lesi mungkin diperlukan untuk
diagnosispasti.
5. Penatalaksanaan
Tidak ada pengobatan spesifik untuk sakoma Kaposi, hanya bersifat paliatif.
Radioterapiemberikan respon yang baik pada 93-100% penderita dengan sarkoma Kaposi.29
Tujuan terapi pada pasien dengan sarkoma Kaposi adalah untuk meringankan iritasi
mata,efek massa, dan kerusakannya. Sarkoma Kaposi cenderung untuk mempunyai respon
terhadap kemoterapi. Jika pasien memiliki keterlibatan sistemik yang membutuhkan kemoterapi,
lesi mataseringkali teratasi atau berkurang drastis setelah memulai terapi ini. Namun, biasanya
terjadikekambuhan berikut setelah penghentian kemoterapi.30
Pengobatan dengan Interferon hanya 10% memberikan respon baik, 20%
memberikanrespons partial sedangkan sebagian besar penderita tidak memberikan hasil yang
baik.29 Indikasiuntuk eksisi lokal mencakup lesi mengganggu secara kosmetik,
ketidaknyamanan, dan obstruksipenglihatan dari bagian terbesar tumor. Pertimbangan dalam
mengobati lesi untuk mencegahpembentukan entropion dengan trikiasis dan keratopati eksposur
dan ulkus kornea.30
6. Komplikasi
Keterlibatan pada kelopak mata dapat menyebabkan kerusakan dan disfungsi
kelopak.Lagofthalmos dan trikiasis dapat menyebabkan iritasi mendalam dan kekeringan,
infeksi, danjaringan parut pada kornea. Keterlibatan konjungtiva dapat mengakibatkan
pendarahansubkonjunctiva berulang. Pada akhirnya, penglihatan bisa hilang dari disfungsi
kelopak,perubahan permukaan kornea, atau obstruksi penglihatan.30
 LENTIGO

Background
A lentigo is a small, sharply circumscribed, pigmented macule surrounded by normal-
appearing skin. Histologic findings may include hyperplasia of the epidermis and
increased pigmentation of the basal layer. A variable number of melanocytes are
present; these melanocytes may be increased in number, but they do not form nests.
Lentigines may evolve slowly over years, or they may be eruptive and appear rather
suddenly. Pigmentation may be homogeneous or variegated, with a color ranging from
brown to black.
Multiple clinical and etiologic varieties exist. The distinction of a lentigo from other
melanocytic lesions (eg, melanocytic nevi, melanoma) and its role as a marker for
ultraviolet damage and systemic syndromes is of major significance.
A case-controlled study in France comparing 145 adults with multiple solar lentigines on
the upper back and 145 matched control subjects found that multiple solar lentigines on
the upper back and shoulders of adults may serve as clinical markers of past severe
sunburn and may be used to identify a population at higher risk of developing cutaneous
melanoma.[1]
Pathophysiology
Depending on the type of lentigo present, a solitary lesion or multiple lesions that can
occur anywhere on the body. Some lentigines have associated systemic manifestations
that accompany the skin lesions, such as the LEOPARD syndrome.
A Japanese microarray analysis evaluation of solar lentigo in 16 adults demonstrated
up-regulation of genes related to inflammation, fatty-acid metabolism, and melanocytes
and down-regulation of cornified envelope-related genes.[2] The researchers suggested
solar lentigo may be induced by the mutagenic effect of repeated past UV light
exposures, leading to characteristic enhancement of melanin production.
Little is known about the genetic basis of human solar lentigines, which were analyzed
for potential FGFR3 and PIK3CA mutations. FGFR3 mutations were detected in 5
(17%) of 30 solar lentigines, and PIK3CA mutations were detected in 2 (7%) of 28 solar
lentigines, suggesting that FGFR3 and PIK3CA mutations are involved in their
pathogenesis and further substantiating previous speculations that UV exposure may be
a causative factor for FGFR3 and PIK3CA mutations in human skin.[3] Lentigines, which
develop earlier and are more pronounced in Japanese than in German women, have
been found to correlate with variants in the SLC45A2 gene.[4]
The LEOPARD syndrome may be associated with a mutation in the PTPN11 gene at
Thr468Met.[5]
Epidemiology
Frequency
United States
In America, solar lentigines are observed in as many as 90% of whites older than 60
years and in 20% of whites younger than 35 years. Psoralen plus UVA (PUVA)
lentigines are noted in almost one half of individuals with psoriasis who receive PUVA
therapy for at least 5 years.
Lentigo simplex is the most common form of lentigo, but its frequency has yet to be
determined. Alper and Holmes[6] noted multiple lentigines in 91 (18.5%) of 492 black
newborns and 1 (0.04%) of 2682 white newborns; however, histologic confirmation of
these lesions was lacking.
International
Lentigines are observed worldwide. The incidence depends on the type of lesion.
Seborrheic keratosis and lentigo solaris were found to be increased on the driver side of
the face in an evaluation of truck drivers in Turkey assessing the effects of UV light.[7]
Mortality/Morbidity
Lentigines are benign by nature. However, some lentigines are associated with
systemic abnormalities, in addition to the dermatologic manifestations.
Race
Solar lentigines are more abundant in fair-skinned whites than in dark-skinned
individuals, in whom the disease is distinctly uncommon because they have a greater
amount of natural pigment that provides some degree of photoprotection. Lentigines,
prominent skin signs of aging, develop earlier and are more pronounced in Japanese
than in German women.[4]
Inherited patterned lentiginosis can occur in blacks, particularly those with mixed
American Indian heritage and those with relatives with red hair.[8]
Ephelides, PUVA lentigines, tanning-bed lentigines, vulvar lentigines, ink-spot
lentigines,[9] oral and labial melanotic macules, and Laugier-Hunziker syndrome are also
more common in people with light skin than in those with dark skin. Ink-spot lentigo
occurs in patients of Celtic ancestry.
Acral lentigines are more common in dark-skinned individuals, but they may also be
present in light-skinned individuals.
Sex
PUVA lentigines are more common in men than in women. Tanning-bed lentigines and
oral and labial melanotic macules are more common in women than in men.
Age
Lentigines can appear in both children and adults; however, children are more likely to
have genetically associated lesions such as those of Peutz-Jeghers syndrome.
 Adults are more likely to acquire lesions due to chronic exposures, which cause solar
lentigo for example.
History
The initial appearance of lentigines varies widely and depends on the following:
Race
History of exposures
Genetic predisposition
Other factors, depending on the type of lentigo
Physical
The physical appearance and morphology of lentigines depend on the type of lesion.
Lentigo simplex
Lentigo simplex (eg, simple lentigo, juvenile lentigo) is the most common form of lentigo.
Lentigo simplex is not induced by sun exposure, and it is not associated with systemic
disease. Clinically, the lesions are round or oval asymptomatic macules that are 3-15
mm in diameter. Their margins can be either jagged or smooth. Pigmentation is evenly
distributed, with a color ranging from brown to black. The lesions are few in number and
may occur anywhere on the skin or mucous membranes. The lesions usually appear
first in early childhood, but they can also be present at birth or develop later.
Multiple dysplastic nevi and lentigines were reduced in number in a patient with familial
gastrointestinal stromal tumors syndrome after treatment with imatinib mesylate.[10] The
effect of effect of imatinib on pigmentation is not well understood.
Solar lentigo
Solar lentigo (eg, actinic lentigo, senile lentigo, sun spot, liver spot) is the most common
benign sun-induced lesion that occurs in sun-exposed areas. Solar lentigo most
commonly appears on the face, arms, dorsa of the hands, and upper part of the trunk.
The spots initially are smaller than 5 mm in diameter. The surface of the lesions is either
flat or depressed, and it may be split by fine wrinkles.
The lesions are usually brown, but the color may range from yellow-tan to black. Older
lesions are often dark brown or brownish black. Solar lentigines slowly increase in
number and in size. Many lesions eventually coalesce to form larger patches. Although
these lesions are most common in individuals aged 30-50 years, they are now seen in
younger individuals because of their increased exposure to sun tanning and the use of
artificial sources of UV light. Although they are often called liver spots, they are not a
manifestation of systemic disease.
In vivo reflectance confocal microscopy may show solar lentigines having increased
melanin and hemoglobin levels and a higher rate of epidermal proliferation. Deformation
and the number of the hyperrefractive dermal papillary rings may increase significantly
over the 5-year time span, with the lentigo size enhanced and color darkened.[11]
Ink-spot lentigo
Ink-spot lentigo (ie, reticulated black solar lentigo) can be distinguished by a wiry or
beaded, markedly irregular outline; these lesions occur in patients of Celtic ancestry.
The benign lesions have a reticulated pattern, and most lesions resemble a spot of ink.
The distribution is limited to sun-exposed areas of the body, similar to that of solar
lentigo; however, in contrast to solar lentigines, patients usually have only 1 ink-spot
lentigo. The most common presentation includes 1 ink-spot lentigo among an extensive
number of solar lentigines.
These lesions can also be distinguished from the darkly pigmented PUVA lentigo by
their more reticulated or beaded pattern and multiple central and peripheral skip areas.
Ink-spot lentigines can initially suggest melanoma because of their dark color, irregular
border, and limited number; however, further investigation, which may include biopsy,
reveals the characteristic features of these benign lesions.
PUVA lentigo
PUVA lentigo is a persistent, pale brown macule appearing 6 months or longer after the
start of PUVA therapy for psoriasis. The lesions resemble solar lentigines, but they often
have more irregular borders and may mimic ephelides. The occurrence of lesions is
closely associated with greater cumulative doses of PUVA, and the lesions may occur
on all treatment sites. The most common areas include the upper part of the chest and
back, groin, buttocks, glans penis, and penile shaft. The axillae, palms, soles, and
gluteal cleft are spared. The lesions vary from 3-8 mm in diameter, but stellate lesions
can be as large as 3 cm in diameter. The lentigines may persist for 3-6 months after
therapy is discontinued. In contrast, stellate lesions can persist longer than 2 years.
Radiation lentigo
Radiation lentigo resembles UV-induced lentigo, but it often includes other
histopathologic signs of long-term cutaneous radiation damage such as epidermal
atrophy, subcutaneous fibrosis, keratosis, and telangiectasias. The presence of a
radiation lentigo is considered an indicator of a prior cutaneous exposure to a large
single dose of ionizing radiation (eg, exposure during the Chernobyl nuclear accident).
These lesions have not been shown to occur after local fractionated radiation therapy.
Radiation lentigines are persistent and typically occur 4 months or longer after the initial
exposure. The malignant potential of the lesions is unknown; however, the induction of
melanoma by ionizing radiation has never been proven.
Tanning-bed lentigines
Tanning-bed lentigines[12, 13, 14] usually occur in women with a history of tanning-bed use.
Tanning-bed lentigines are similar to PUVA lentigines, except psoralens are not
involved. The site of tanning-bed lentigines is primarily acral despite whole-body
exposure. The most common areas include the anterior aspects of the arms and legs,
but they can also occur on the neck and chest. The size of the lesions varies. The
lesions are usually 2-5 mm in diameter, with color ranging from dark brown to black.
Some lentigines may coalesce and enlarge. Pigmentation of the lesions may be
uneven, with irregular or stellate shapes. The lesions can appear abruptly after intense
tanning, or they can appear after prolonged (eg, 1 y) regular use of tanning beds. The
malignant potential of the lesions is unknown.
Oral and labial melanotic macules
Oral and labial melanotic macules are similar to each other. Labial lesions almost
always occur on the vermilion of the lower lip, and their color ranges from brown to blue
to blue-black. Occasionally, variegated pigmentation occurs. The lesions are usually
solitary, symmetric, and asymptomatic. Oral lesions can appear on the gingiva, buccal
mucosa, palate, and tongue. Usually, oral and labial lesions have a diameter smaller
than 4 mm. The individual's age at onset ranges from 25-71 years.
The differential diagnosis should include Laugier-Hunziker syndrome and Peutz-
Jeghers syndrome. The absence of systemic features and involvement at other sites
should assist in differentiating oral and labial melanotic macules from these syndromes.
Both oral and labial melanotic macules are benign; however, lesions suggestive of
malignancy should be examined at biopsy.
Vulvar and penile lentigo
Vulvar and penile lentigo are benign lesions similar to labial melanotic macules. In men,
the most common sites are the glans penis, corona, corona sulcus, and penile shaft.
The lesions vary in color from tan to brown to dark brown, and they have irregular
borders and skip areas. Individual lesions may have a diameter as large as 15 mm. In
women, the lesions appear anywhere on the genital mucosa as a mottled, pigmented
patch with skip areas. The diameter can be 5-15 mm or larger. The lesions may also
occur in episiotomy scars after childbirth. Lentigines involving the external genitalia are
also reported in LAMB syndrome.
Lentigines profusa
Lentigines profusa (ie, generalized lentigines) is characterized by numerous lentigines
without signs of associated abnormalities or triggering factors. The clinical appearance
of lentigines profusa resembles that of ephelides, but its distribution is widespread.
Usual areas of involvement include the extremities, trunk, palms, and genitalia. Mucosal
surfaces such as the conjunctiva can also be affected, but the buccal mucosa may be
spared. The macules vary from 1 mm to 2 cm in diameter. The color of the macules
ranges from dark brown to black.
Lentigines profusa appears similar to the cutaneous manifestations of LEOPARD,
LAMB, and NAME syndromes; however, a notable exception is the absence of the
variety of the physical anomalies and defects associated with these syndromes.
Agminated lentiginosis
Agminated (segmental, unilateral, partial unilateral) lentiginosis is characterized by
numerous lentigines confined to a body segment, with a sharp demarcation at the
midline. The distribution frequently corresponds to one or more dermatomes. Less
commonly, the lesions can be distributed unilaterally, bilaterally, in a checkerboard
pattern, or in midline clusters. Usually, the disease appears in early childhood, although
the lentigines may also be noted at birth. These lesions have been associated with
numerous diseases. Clinically, the lesions appear as circumscribed, tan or dark brown
macules on healthy background skin.
Xeroderma pigmentosum
Xeroderma pigmentosum (XP) is an autosomal-recessive condition involving
abnormalities that stem from an inability of cells to repair DNA damage induced by
exposure to UV light and certain chemicals. Clinically, patients have skin atrophy and
progressive pigmentary changes. Subsequently, neoplastic changes occur on the skin,
often in childhood; squamous cell and basal cell carcinomas are the most common
malignancies. Other cancers, such as melanoma, may appear as well. All of these
neoplastic changes evolve on sun-exposed areas, particularly the head, neck, and face.
XP is diagnosed in young children, who are typically healthy. Children should avoid sun
exposure because the acceleration of skin changes leads to the formation of
neoplasms. Ocular and neurologic defects are also associated with XP. See the image
below.
LEOPARD syndrome
LEOPARD syndrome (lentigines, electrocardiographic conduction defects, ocular
hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and
deafness syndrome) (ie, multiple lentigines syndrome) is a complex dysmorphogenetic
disorder that is transmitted as an autosomal-dominant trait with variable penetrance. A
mutation of the PTPN11 gene may be documented.[15] The diagnosis can be difficult
because most patients have only 3-5 of the criteria. Lentigines are the most common
feature of the syndrome, although they do not have to be present to diagnose
LEOPARD syndrome.
In the absence of lentigines, the diagnosis can be made if the patient has 3 features of
the disease and an immediate relative with the disease. Lentigines are present at birth
and increase in number until puberty. The intensity of the pigmentation varies. The
lesions are numerous on the neck and trunk, but they can also be widespread and
involve the genitalia, palms, soles, and scalp. Lentigines spare some parts of the face
and may be limited to one side of the body in some cases.
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome is an autosomal-dominant condition with a high degree of
penetrance and is characterized by gastrointestinal polyps and pigmented macules. The
polyps are benign hamartomas that can affect the entire bowel, most characteristically
the jejunum. These polyps result in recurrent perirectal bleeding and abdominal pain.
Patients are often first seen with bleeding or with intussusception that manifests as an
obstruction, abdominal pain, rectal prolapse, vomiting, and/or currant jellylike stool.
Lentigines are brown-to-black-to-blue macules that usually arise in early childhood.
Their size ranges from 1-12 mm in diameter. Hyperpigmented macules occur in more
than 95% of patients, and they have a characteristic distribution around the mouth, on
the lips, and on the buccal mucous membranes; they can also be scattered around the
nose and face. Additionally, lesions appear on the fingers and toes on both the palmar
and volar surfaces. Lesions are characteristically absent on the flexor and extensor
surfaces of the rest of the body. The buccal mucosal macules are important because
they persist, whereas the other macules may fade with age. A relationship between the
extent of melanosis and the extent of polyposis has not been found.
Almost all women have unusual sex cord tumors that are small, bilateral, asymptomatic,
and multifocal. Gonadal tumors are also noted in men. Women have an increased risk
of breast cancer, either unilateral or bilateral in presentation.
Laugier-Hunziker syndrome
Laugier-Hunziker syndrome is characterized by a variable number of pigmented
macules that most commonly appear on the lower lip; buccal mucosa; hard palate; and,
occasionally, tips of the fingers. Other locations include the labial commissure, tongue,
gums, floor of the mouth, neck, thorax, abdomen, nails, and soles. The lentigines may
be numerous and confluent, but they rarely occur in a linear pattern. The lesions mostly
occur on the nails. Their borders are smooth and well defined. The color of the lesions
can vary from gray to brown, blue, or black. Although the syndrome has a chronic
course without remission, individuals are generally asymptomatic.
This syndrome differs from Peutz-Jeghers syndrome because of the absence of
intestinal polyps. Laugier-Hunziker syndrome occurs in individuals aged 20-50 years
and in both sexes, whereas isolated labial melanotic macules affect younger patients
and are usually solitary. Pigmentation of the oral mucosa and nails is reported to occur
in patients taking the antiretroviral medication zidovudine. The clinical and drug histories
are important in differentiating this phenomenon from Laugier-Hunziker disease.
Myxoma syndrome
The myxoma syndrome is associated with mucocutaneous lentigines along with various
additional abnormalities. Some constellations of abnormalities have been given specific
names. They may all be part of a spectrum of manifestations of the same disorder.
LAMB syndrome
LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome
is one of the myxoma syndromes. The lentigines most commonly occur on the lips,
face, sclera, and vulva. The lesions are brown and can be as large as 1 cm in diameter.
The mucocutaneous myxomas appear as papules or dermal nodules at various sites on
the body, including the breasts, shoulders, oral mucosa, and tongue. Cardiac myxomas
are rare in children and usually occur in the form of atrial myxomas, which are clinically
evident as intermittent embolic episodes and valvular obstructions. An association with
benign thyroid nodules is noted.
NAME syndrome
NAME (nevi, atrial myxoma, myxoid neurofibroma, and ephelides) syndrome is another
myxoma syndrome. This possible variant of LAMB syndrome involves multiple, flat,
 pigmented macules. The lesions begin at birth and are accentuated in the summer. The
color of the lesions varies from pale to dark brown. The most commonly involved areas
are the neck, trunk, and thighs. The palms and soles are sometimes affected.
Carney syndrome
Carney syndrome is an autosomal dominant multiple neoplasia syndrome involving
cardiac, cutaneous, and mammary myxomatous masses; lentigines; blue nevi;
endocrine disorders; and testicular tumors.[16] Often, multicentric and bilateral organ
involvement is present; this usually occurs in young patients. The cutaneous myxomas
are often observed on the eyelids and other sites such as the nipples, scalp, face, oral
mucosa, ears, neck, trunk, limbs, and perineum. Cardiac myxomas are either single or
multiple and often result in fibrosis or calcification.
Two types of pigmented macules exist: blue nevi and lentigines. Lentigines are brown to
black and 0.2-2 mm in diameter; they have irregularly shaped, jagged margins. They
are widespread throughout the body and may coalesce to form brown patches. The
lesions can be found on the face, eyelids, ears, vermilion borders of the lips,
conjunctiva, vulva, extremities, and glans penis. Unlike Peutz-Jeghers syndrome,
Carney syndrome infrequently involves buccal lesions. Endocrine involvement includes
calcifying pigmented neuroectodermal tumors, pituitary adenomas with acromegaly and
gigantism, and adrenocortical disease leading to Cushing syndrome.
Testicular tumors feature Sertoli cell tumors, Leydig cell tumors, and adrenocortical rest
tumors. Mammary involvement includes gynecomastia and myxomatous enlargement of
the stroma.
Inherited patterned lentiginosis
Inherited patterned lentiginosis can occur in blacks. This form is characterized by
hyperpigmented macules on the face and lips. At times, additional lesions are seen on
the elbows, knees, buttocks, and palmoplantar surfaces. Lesions are not present on the
oral mucosa, and they are not associated with organ involvement or an apparent risk of
cancer. The inheritance pattern appears to be autosomal dominant. Light-skinned
African American families, some of whom have a mixed American Indian heritage and
those with relatives with red hair, are particularly affected. See the image below.
Nevus spilus
The nevus spilus is a both a lentigo and melanocytic nevus, a unique neoplasm that has
only a slight potential to develop into melanoma.[17] It is evident as multiple pigmented
macules or papules within a congenital or acquired pigmented patch.
Causes
The cause of lentigo formation depends on the type of lesion, as follows:
The cause of lentigo simplex is unknown. Case reports have described simple
lentigines developing in children after use of topical tacrolimus for atopic dermatitis.[18]
Solar lentigo and ink-spot lentigo are associated with sun exposure in fair-skinned
people.
 PUVA lentigines[19, 20, 21] are associated with PUVA therapy in patients with psoriasis.
Radiation lentigo is caused by local high-dose irradiation.[22]
Genetic factors may be involved in other forms of lentigines, including XP, LEOPARD
syndrome, Peutz-Jeghers syndrome, and inherited patterned lentiginosis.
Differential Diagnoses
Actinic Keratosis
Ephelides (Freckles)
Seborrheic Keratosis
Other Tests
Dermoscopic evaluation of a few lichenoid regressing solar lentigines showed a pattern
similar to that of lichenoid regressing seborrheic keratosis.[24]
Histologic Findings
Lentigo simplex is characterized by a slight-to-moderate elongation of the rete ridges
with melanocyte proliferation in the basal layer, increased melanin in both the
melanocytes and the basal keratinocytes, and the presence of melanophages in the
upper dermis. Lentigines profusa and agminated lentigo are similar in appearance.
Solar lentigines have elongated rete ridges and a proliferation of pigmented basaloid
cells, which form buds and strands. Ink-spot lentigines are also similar to solar
lentigines, except the rete ridges in ink-spot lentigines appear less blunted and more
tortuous. No atypia of the melanocytes is present. The solar lentigo has an increased
number of melanophages compared with unaffected skin from the same
subject.[25] These melanophages were demonstrated to be factor XIIIa-positive dermal
dendrocytes.
The melanocytes of PUVA lentigines are increased in number and hypertrophic; they
frequently demonstrate cellular atypia. Elongation of the rete ridges and increased
pigmentation in the basal cell region is present with transepidermal pigment cell
excretion.
Radiation lentigines show increased melanin deposition in basal keratinocytes, cellular
or nuclear atypia, increased number of melanocytes, and reduction of rete ridges.
Oral and labial melanotic macules show epithelial hyperplasia with somewhat irregular
widening and elongation of the rete ridges. Melanin is increased in the melanocytes and
keratinocytes of the basal layer and in the melanophages in the dermal papillae; this
increase in melanin indicates pigment incontinence. Vulvar and penile lentigines have
similar histologic features except for a slight increase in dendritic melanocytes along the
basal layer of the epidermis.
Tanning-bed lentigines resemble PUVA lentigines with the increased density of
melanocytes, some of which show mild nuclear atypia. Ultrastructurally, these lesions
are similar to those of other forms of lentigo.
Ephelides have an increase in pigment content in the basal cell layer, with neither
elongated rete ridges nor increased number of melanocytes.
 The myxoma syndromes (ie, LAMB, NAME, and Carney syndromes) show basal layer
and, sometimes, spinous layer hyperpigmentation with or without elongation of the rete
ridges and melanocytic hyperplasia. Melanocytes may have large dendritic processes,
and melanophages may be observed in the upper dermis.
In Peutz-Jeghers syndrome, the lentigines also show marked hyperpigmentation of the
basal layer. LEOPARD syndrome involves increased pigment content of the epidermis
with an increased number of melanocytes. The melanocytes are filled with
melanosomes and are distributed singly or in the form of micronests.
Medical Care
Noninvasive topical creams are also used. After several months of application, tretinoin
cream and hydroquinone cream can lighten lentigines.
The efficacy and safety of cryotherapy and trichloroacetic acid (TCA) were compared for
the treatment of solar lentigo.[26] Cryotherapy was more effective than TCA 33% solution
in the treatment of solar lentigines of the back of the hands, particularly in lighter-
complexioned individuals. For darker-complexioned people, TCA 33% may be
preferred, although postinflammatory hyperpigmentation remains a risk for both
modalities.
The effect of a bleaching solution containing 2% mequinol (4-hydroxyanisole, 4HA) and
0.01% tretinoin (Solag) applied twice daily for 3 months on solar lentigines present on
the back of one hand demonstrated a significant lightening effect after 2 months of
treatment and was maintained at least 2 months after stopping treatment. [27]
Skin-lightening products commercially available target natural melanin production, many
as competitive inhibitors of tyrosinase.[28]
A selection of related clinical trials is as follows:
Combination Therapy With Imiquimod Cream 5% and Tazarotene Cream 0.1% for the
Treatment of Lentigo Maligna
Solar Lentigines Treatment With the Triple Combination Cream
Side Effects of Q-Switched Ruby Laser for the Treatment of Lentigines in Light and
Dark Skin Types
Also see the clinical guideline summary from the Australian Cancer Network,Lentigo
maligna. In: Clinical practice guidelines for the management of melanoma in Australia
and New Zealand.
Surgical Care
Treatment of solar lentigines with a focal medium-depth chemical peel may be clinically
superior to treatment with cryosurgery, owing to the paucity of adverse effects (eg,
hypopigmentation, pain) associated with chemical peels.[29]
Cryosurgery[30] is a simple treatment for isolated lentigines. Many consider the first-line
therapy for solar lentigines to be ablative therapy with cryotherapy. [31]This procedure is
often successful because of the susceptibility of melanocytes to freezing with liquid
nitrogen. Squamous cells resist injury at -20C, whereas melanocytes freeze at -4 to -
7C.
Lasers are effective in the treatment of various lentigines. The recent development of
short-pulsed, pigment-specific lasers to selectively destroy the pigment within the solar
lentigo has led to significant clinical improvement, a low risk of adverse effects, and high
patient acceptance.[32] The frequency-doubled, Q-switched Nd:YAG laser,[33] the HGM
K1 krypton laser, and the 532-nm diode-pumped vanadate laser are all used with
success.[34] Use of a low-fluence 1,064-nm Q-switched neodymium-doped yttrium
aluminum garnet (QS Nd:YAG) laser is another choice.[35]
Intense pulsed-light (IPL) treatment is another option.[36]
Medication Summary
The goal of pharmacotherapy is to reduce morbidity and prevent complications.
Retinoids
Class Summary
Retinoids decrease the cohesiveness of abnormal hyperproliferative keratinocytes and
may reduce the potential for malignant degeneration. These agents modulate
keratinocyte differentiation. They have been shown to reduce the risk of skin cancer in
patients who have undergone renal transplantation.
View full drug information

Tretinoin 0.025 to 0.1% (Retin-A, Avita)

Keratolytic agent. Acts by increasing epidermal cell mitosis and turnover while
suppressing keratin synthesis. Important side effect of interest is hypopigmentation,
which reduces the appearance of lentigines.
Bleaching creams
Class Summary
These agents lighten hyperpigmented skin by inhibiting enzymatic oxidation of tyrosine
and by suppressing other melanocyte metabolic processes, thereby further inhibiting
melanin production.
View full drug information

Hydroquinone (Eldopaque-Forte, Solaquin Forte, Lustra)

Suppresses melanocyte metabolic processes, especially enzymatic oxidation of tyrosine

to 3,4-dihydroxyphenylamine. Exposure to sun reverses effects and causes
repigmentation.
Deterrence/Prevention
The application of sunscreen helps decrease the rate of appearance and the darkening
of solar lentigines.
Limiting one's exposure to sun tanning and the use of artificial sources of UV light may
help prevent solar lentigines.
Individuals of Celtic ancestry might limit their exposure to the sun to help prevent ink-
spot lentigines.
The avoidance of a large single dose of ionizing radiation may prevent radiation
lentigines.
Children with XP should avoid sun exposure because the acceleration of skin changes
leads to the formation of neoplasms.
The avoidance of the intense or prolonged, regular use of tanning beds may help in
preventing tanning-bed lentigines.
Complications
Some lentigines have associated systemic manifestations that accompany the skin
lesions (see Physical).
Prognosis
Lentigines are benign by nature.
In patients in whom lentigines are associated with systemic abnormalities or
complications, the prognosis may depend on the severity of the associated conditions.
Treatments with cryosurgery, lasers, and/or topical creams have been successful (see
Medical Care).
Patient Education
Patients should be advised about the risks of sun exposure and the use of tanning
beds.
 MELANOMA MALIGNA

Practice Essentials
Malignant melanoma is a neoplasm of melanocytes or a neoplasm of the cells that
develop from melanocytes. Although it was once considered uncommon, the annual
incidence has increased dramatically over the past few decades. Surgery is the
definitive treatment for early-stage melanoma, with medical management generally
reserved for adjuvant treatment of advanced melanoma.
Essential update: FDA approves trametinib/dabrafenib combo for treating
advanced melanoma in patients with BRAF mutations
The FDA has approved a combination of trametinib (Mekinist), a MEK inhibitor, and
dabrafenib (Tafinlar), a BRAF inhibitor, for the treatment of patients with unresectable or
metastatic melanoma and BRAF V600E or V600K mutations. Accelerated approval was
granted based on response rate and duration in a randomized, phase 2, open-label
study, in which patients who received combination treatment had an overall response
rate of 76%, compared with 54% for those who received only dabrafenib. Median
duration of response was longer with combination treatment (10.5 vs 5.6 months).
These results, reported by the investigators, were superior to those reported by a
blinded independent radiologic review committee.[3, 4]
Signs and symptoms
The history should address the following:
Family history of melanoma or skin cancer
Family history of irregular, prominent moles
Family history of pancreatic cancer or astrocytoma
Previous melanoma (sometimes multiple; patients have reported as many as 8 or
more primary melanomas)
Previous sun exposure
Changes noted in moles (eg, size, color, symmetry, bleeding, or ulceration)
History or family history of multiple nevus syndrome
Physical examination includes the following:
Total-body skin examination, to be performed on initial evaluation and during all
subsequent visits
Serial photography, epiluminescence microscopy, and computerized image analysis,
to be considered as adjuncts
Skin examination involves assessing the number of nevi present and distinguishing
between typical and atypical lesions. (The images below depict examples of
melanomas.) Early melanomas may be differentiated from benign nevi by the ABCDs,
as follows:
A - Asymmetry
B - Border irregularity
 C - Color that tends to be very dark black or blue and variable
D - Diameter 6 mm
If a patient is diagnosed with a melanoma, examine all lymph node groups.
See Clinical Presentation for more detail.
Diagnosis
The following laboratory studies are indicated:
Complete blood count
Complete chemistry panel (including alkaline phosphatase, hepatic transaminases,
total protein, and albumin)
Lactate dehydrogenase
The following imaging modalities may be considered:
Chest radiography
Magnetic resonance imaging of the brain
Ultrasonography (possibly the best imaging study for diagnosing lymph node
involvement)
Computed tomography of the chest, abdomen, or pelvis
Positron emission tomography (PET; PET-CT may be the best imaging study for
identifying other sites of metastasis)
Procedures to be considered in the workup include the following:
Complete excisional biopsy of a suggestive lesion
Surgical excision or reexcision after biopsy
Elective lymph node dissection (ELND) for patients with clinically enlarged nodes and
no evidence of distant disease
Sentinel lymph node biopsy (SLNB; see Sentinel Lymph Node Biopsy in Patients With
Melanoma)
Characteristic histologic findings include the following:
Cytologic atypia, with enlarged cells containing large, pleomorphic, hyperchromic
nuclei with prominent nucleoli
Numerous mitotic figures
Pagetoid growth pattern with upward growth of the melanocytes
See Workup for more detail.
Management
Surgery (eg, wide local excision with SLNB, ELND, or both) is the definitive treatment
for early-stage melanoma. Medical management is reserved for adjuvant therapy of
patients with advanced melanoma.
Agents used in adjuvant therapy include the following:
Interferon alfa
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
BRAF inhibitors (vemafurenib and dabrafenib)
 Agents that may be considered for treatment of advanced-stage (stage IV) melanoma
include the following:
Dacarbazine
Temozolomide (currently used as the first-line drug for melanoma by most oncologists)
Interleukin-2
Cisplatin, vinblastine, and dacarbazine (CVD)
Cisplatin, dacarbazine, carmustine, and tamoxifen (Dartmouth regimen)
Imatinib mesylate[5]
Carboplatin and paclitaxel (sometimes combined with sorafenib)
Thymosin alpha 1
Melanoma vaccines and gene therapy
Ipilimumab
Peginterferon alfa-2b[6]
The following procedures may be used to treat brain metastases:
Stereotactic radiosurgery (for patients with a limited number of metastases)
External-beam radiation
See Treatment and Medication for more detail.
Background
Malignant melanoma is a neoplasm of melanocytes or of the cells that develop from
melanocytes. Although melanoma was once considered an uncommon disease, the
annual incidence has increased dramatically over the over the past few decades, as
have deaths from melanoma. (See the images of malignant melanoma below.) (See
Etiology and Epidemiology.)
Growth
Melanomas have 2 growth phases, radial and vertical. During the radial growth phase,
malignant cells grow in a radial fashion in the epidermis. With time, most melanomas
progress to the vertical growth phase, in which the malignant cells invade the dermis
and develop the ability to metastasize. (See Etiology and Workup.)
Clinically, lesions are classified as thin if they are 1 mm or less in depth; moderate if
they are 1-4 mm in depth; and thick if they are greater than 4 mm in depth.
Histologic types of melanoma
There are 5 different forms, or histologic types, of melanoma:
Superficial spreading melanomas
Nodular melanomas
Lentigo maligna melanomas
Acral lentiginous melanomas
Mucosal lentiginous melanomas
Superficial spreading melanomas
Approximately 70% of cutaneous malignant melanomas are the superficial spreading
melanoma (SSM) type. Many SSMs arise from a pigmented dysplastic nevus, often one
that has long been stable. Typical changes include ulceration, enlargement, or color
changes. An SSM may be found on any body surface, especially the head, neck, and
trunk of males and the lower extremities of females.
Nodular melanomas
Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also
are found commonly on all body surfaces, especially the trunk of males. These lesions
are the most symmetrical and uniform of the melanomas and are dark brown or black.
The radial growth phase may not be evident in NMs; however, if this phase is evident, it
is short-lived, because the tumor advances rapidly to the vertical growth phase, thus
making the NM a high-risk lesion. Approximately 5% of all NMs are amelanotic
melanomas.
Lentigo maligna melanomas
Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They
typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of
hypopigmentation and often are quite large. LMMs arise from a lentigo maligna
precursor lesion. (See the image of lentigo maligna melanoma below.)

Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal
frequency among blacks and whites. They occur on the palms, soles, and subungual
areas. Subungual melanomas often are mistaken for subungual hematomas (splinter
hemorrhages). Like NM, ALM is extremely aggressive, with rapid progression from the
radial to vertical growth phase.
Mucosal lentiginous melanomas
Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines
the respiratory, gastrointestinal, and genitourinary tracts. These lesions account for
approximately 3% of the melanomas diagnosed annually and may occur on any
mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female
urethra, penis, and anus. Noncutaneous melanomas commonly are diagnosed in
patients of advanced age. MLMs appear to have a more aggressive course than
cutaneous melanomas, although this may be because they commonly are diagnosed at
a later stage of disease than the more readily apparent cutaneous melanomas.
Sites other than the skin
The majority of melanomas are in the skin, but other sites include the eyes, mucosa,
gastrointestinal tract, genitourinary tract, and leptomeninges. Metastatic melanoma with
an unknown primary site may be found in lymph nodes only.
Staging
Clark staging is as follows:
 level I - All tumor cells above basement membrane (in situ)
level II - Tumor extends into papillary dermis
level III - Tumor extends to interface between papillary and reticular dermis
level IV - Tumor extends between bundles of collagen of reticular dermis (extends into
reticular dermis)
level V - Tumor invasion of subcutaneous tissue
Breslow classification (thickness) is as follows:
Less than or equal to 0.75 mm
0.76-1.5 mm
1.51-4 mm
Greater than or equal to 4 mm
The staging system for cutaneous melanoma was revised by the American Joint
Committee on Cancer (AJCC) in early 2002.[1, 2] AJCC groupings based on TNM
classification are as follows:
Stage 0 - Tis, N0, M0
Stage IA - T1a, N0, M0
Stage IB - T1b, N0, M0; T2b, N0, M0
Stage IIA - T2b, N0, M0; T3a, N0, M0
Stage IIB - T3b, N0, M0; T4a, N0, M0
Stage IIC - T4b, N0, M0
Stage III - Any T, N 1-3, M0
Stage IIIA - pT1-4a, N1a, M0; pT1-4a, N2a, M0
Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0;
pT1-4a/b, N2c, M0
Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0
Stage IV - Any T, Any N, Any M
T classification (thickness) is as follows:
TX - Primary tumor cannot be assessed (shave biopsy, regressed primary)
Tis - Melanoma in situ
T1 - 1.0 mm (a: without ulceration, b: with ulceration)
T2 - 1.01-2.0 mm (a: without ulceration, b: with ulceration)
T3 - 2.01-4.0 mm (a: without ulceration, b: with ulceration)
T4 - < 4.0 mm (a: without ulceration, b: with ulceration)
N classification is as follows:
N1 - 1 lymph node; a: micrometastasis (clinically occult), b: macrometastasis (clinically
apparent)
N2 - 2-3 lymph nodes; a: micrometastasis, b: macrometastasis, c: in transit met(s),
satellite(s), without metastatic lymph nodes (N2a: 2-3 nodes positive for
micrometastasis; N2b: 2-3 nodes positive for macrometastasis; N2c: In transit met(s)
or satellite(s) without metastatic nodes)
N3 - 4 or more metastatic nodes or matted nodes or in-transit metastases or
satellite(s) with metastatic node(s)
Note that micrometastases are diagnosed after elective or sentinel lymphadenectomy.
Macrometastases are defined as clinically detectable nodal metastases confirmed by
 therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular
extension.
M classification is as follows:
M1a - Distant skin, subcutaneous, or nodal metastases, normal lactate dehydrogenase
(LDH) level
M1b - Lung metastases, normal LDH level
M1c - All other visceral metastases or any distant metastases with an elevated LDH
level
Also see Malignant Melanoma Staging.
Etiology
Melanomas originate from melanocytes, which arise from the neural crest and migrate
to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which
reside in the skin and produce a protective melanin, are contained within the basal layer
of the epidermis, at the junction of the dermis and epidermis.
Melanomas may develop in or near a previously existing precursor lesion or in healthy-
appearing skin. A malignant melanoma developing in healthy skin is said to arise de
novo, without evidence of a precursor lesion. Many of these melanomas are induced by
solar irradiation. Melanoma also may occur in unexposed areas of the skin, including
the palms, soles, and perineum.
Certain lesions are considered to be precursor lesions of melanoma. These include the
following nevi:
Common acquired nevus
Dysplastic nevus
Dongenital nevus
Cellular blue nevus
Genetics
Many genes are implicated in the development of melanoma, including CDKN2A (p16),
CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras. CDKN2A (p16)appears to be
especially important in both sporadic and hereditary melanomas. This tumor suppressor
gene is located on band 9p21, and its mutation plays a role in various cancers.
Ultraviolet radiation
Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most
melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-
320 nm, potentially are carcinogenic and actually may work in concert to induce a
melanoma.
UVR appears to be an effective inducer of melanoma through many mechanisms,
including suppression of the immune system of the skin, induction of melanocyte cell
division, free radical production, and damage of melanocyte DNA.
 Interestingly, melanoma does not have a direct relationship with the amount of sun
exposure because it is more common in white-collar workers than in those who work
outdoors.
Sunburn
Acute, intense, and intermittent blistering sunburns, especially on areas of the body that
only occasionally receive sun exposure, are the greatest risk factor for the development
of sun exposureinduced melanoma. This sun-associated risk factor is different than
that for squamous and basal cell skin cancers, which are associated with prolonged,
long-term sun exposure.
LMM is an exception to this rule, because it frequently appears on the head and neck of
older individuals who have a history of long-term sun exposure.
Additional risk factors
Importantly, other factors exist that may predispose an individual to melanoma;
chemicals and viruses are 2 etiologic agents that also have been implicated in the
development of melanoma.
Greatly elevated risk factors for cutaneous melanoma include the following:
Changing mole
Dysplastic nevi in familial melanoma
More than 50 nevi, 2 mm or greater in diameter
Moderately elevated risk factors for cutaneous melanoma include the following:
One family member with melanoma
Previous history of melanoma
Sporadic dysplastic nevi
Congenital nevus
Slightly elevated risk factors for cutaneous melanoma include the following:
Immunosuppression
Sun sensitivity
History of acute, severe, blistering sunburns
Freckling
Epidemiology
Occurrence in the United States
The American Cancer Society estimates that 76,100 cases of cutaneous melanoma will
be diagnosed in the United States in 201443,890 in men and 32,210 in women.[7] The
incidence of melanoma increases by 5-7% yearly, an annual increase second only to
lung cancer in women. While the lifetime risk of developing melanoma in 1935 was only
1 per 1500, the lifetime risk in 2000 was estimated at 1 per 75.
Although melanoma accounts for only approximately 5% of skin cancers, it is
responsible for 3 times as many deaths each year as nonmelanoma skin cancers. The
American Cancer Society estimates that 9,710 people in the US (6,470 men and 3,240
women) will die of melanoma in 2014.[7]
International statistics
The incidence of malignant melanoma is increasing rapidly worldwide, and this increase
is occurring at a faster rate than that of any other cancer except lung cancer in
women.Queensland, Australia, has the highest incidence of melanoma in the world,
approximately 57 cases per 100,000 people per year. Israel also has one of the highest
incidences, approximately 40 cases per 100,000 people annually.
Racial demographics
Melanoma is more common in whites than in blacks and Asians. The rate of melanoma
in blacks is estimated to be one twentieth that of whites. White people with dark skin
also have a much lower risk of developing melanoma than do those with light skin. The
typical patient with melanoma has fair skin and a tendency to sunburn rather than tan.
White people with blond or red hair and profuse freckling appear to be most prone to
melanomas. In Hawaii and the southwestern United States, whites have the highest
incidence, approximately 20-30 cases per 100,000 people per year.
Sex demographics
Melanoma is slightly more common in men than in women (1.2:1). Melanoma is the fifth
most common malignancy in men and the sixth most common malignancy in women,
accounting for 5% and 4% of all new cancer cases, respectively.[7] Women tend to have
lesions that are nonulcerated and thinner than those in men.
Age demographics
Melanoma may occur at any age, although children younger than age 10 years rarely
develop a de novo melanoma.
The average age at diagnosis is 57 years, and up to 75% of patients are younger than
70 years.
Melanoma is the most common malignancy in women aged 25-29 years and accounts
for more than 7000 deaths annually.
Melanoma is notorious for affecting young and middle-aged people, unlike other solid
tumors, which mainly affect older adults. It is commonly found in patients younger than
55 years, and it accounts for the third highest number of lives lost across all cancers.
Prognosis
If detected early, melanoma can be cured with surgical excision.
Superficial spreading and nodular types of melanoma are the 2 most common fatal
melanomas, based on a review of data from the original 9 registries of the Surveillance,
Epidemiology, and End Results Program from 1978-2007.[8] This confirms prior studies.
Factors predicting the likelihood of response to treatment include the following:
 Good performance status
Soft-tissue disease or only a few visceral metastases
Age younger than 65 years
No prior chemotherapy
Normal hepatic and renal function
Normal complete blood count (CBC)
Absence of central nervous system (CNS) metastases
The prognosis of a melanoma lesion can be predicted based on the following: the depth
of invasion, the presence or absence of ulceration, and the nodal status at diagnosis.
Important factors that also affect melanoma-specific survival include age, lymph node
involvement, and extranodal extension.[9]
Malignant melanomas usually present at 2 extremes: at one end of the spectrum are
patients with small skin lesions that are easily curable by surgical resection, and at the
other are patients with widely metastatic disease, in whom the therapeutic options are
limited and the prognosis is nil, with a median survival of only 6-9 months. For this
reason, physicians must be aware of the clinical characteristics of melanoma to make
an early diagnosis. Prognosis also is related to the type of melanoma.
In a review of 3,872 cases of lymph node positive melanoma, the proportion of
examined lymph nodes found to be positive (the lymph node ratio) independently
predicted disease-specific survival. These researchers concluded that the lymph node
ratio consistently improved the prognostic accuracy of the TNM system.[10]
A study of patients who developed melanoma after solid organ transplantation found
that their overall survival was worse than the rate reported in a national sample of
patients with melanoma. Among transplant recipients with thicker melanomas, disease-
specific survival was significantly poorer than in patients without a prior history of
transplantation.[11]
In patients with mucosal melanoma, a multivariable analysis determined that anatomic
primary site was an independent predictor of overall survival and disease-specific
survival. Tumors in the nasal cavity and oral cavity were associated with survival
superior compared with tumors in the nasopharynx and paranasal sinuses. Age older
than 70 years, tumor size, nodal status, and distant metastasis status were also
predictive of outcome.[12]
Stage and prognosis
Prognosis depends on the disease stage at diagnosis, as follows:
Patents with stage I disease - 5-year survival rate of greater than 90%
Patients with stage II disease - 5-year survival rate ranging from 45-77%
Patients with stage III disease - 5-year survival rate ranging from 27-70%
Patients with metastatic disease have a grim prognosis, with a 5-year survival rate of
less than 20%.
Stage IA
Lesions less than or equal to 1 mm thick with no evidence of ulceration or metastases
(T1aN0M0) are associated with a 5-year survival rate of 95%.
Stage IB
Lesions less than or equal to 1 mm thick with ulceration noted but without lymph node
involvement (T1bN0M0) or lesions 1.01-2 mm thick without ulceration or lymph node
involvement (T2aN0M0) are associated with a 5-year survival rate of approximately
91%.
Stage IIA
Melanomas greater than 1 mm but less than 2.01 mm in thickness with no evidence of
metastases but with evidence of ulceration (T2bN0M0) or lesions 2.01-4.0 mm without
ulceration or lymph node involvement (T3aN0M0) are associated with an overall 5-year
survival rate of 77-79%.
Stage IIB
Melanomas 2.01-4 mm thick with ulceration but no lymph node involvement (T3bN0M0)
or lesions greater than 4 mm without ulceration or lymph node involvement (T4aN0M0)
are associated with a 5-year survival rate of 63-67%.
Stage IIC
Lesions greater than 4 mm with ulceration but no lymph node involvement (T4bN0M0)
are associated with a 5-year survival rate of 45%.
Stage IIIA
Patients with any depth lesion, no ulceration and 1 positive (micrometastatic) lymph
node (T1-4a,N1a,M0) have a 5-year survival rate of 70%. T1-4a,N2a,M0 lesions (any
depth lesion, no ulceration but 2-3 nodes positive for micrometastasis) are associated
with a 5-year survival rate of 63%.
Stage IIIB
Patients with any depth lesion, positive ulceration, and 1 lymph node positive for
micrometastasis (T1-4b,N1a,M0) or 2-3 nodes positive for micrometastasis (T1-
4b,N2a,M0) have a 5-year survival rate of 50-53%. Patients with any depth lesion, no
ulceration, and 1 lymph node positive for macrometastasis (T1-4a,N1b,M0) or 2-3
nodes positive for macrometastasis (T1-4a,N2b,M0) have a 5-year survival rate of 46-
59%.
Stage IIIC
Patients with any depth lesion, positive ulceration, and 1 lymph node positive for
macrometastasis (T1-4b,N1b,M0) or 2-3 nodes positive for macrometastasis (T1-
4b,N2b,M0) or 4 or more metastatic lymph nodes, matted lymph nodes, or in transit
met(s)/satellite(s) have a 5-year survival rate of 24-29%.
Stage IV
Melanoma metastatic to skin, subcutaneous tissue, or lymph nodes with normal LDH
(M1a) is associated with a 5-year survival rate of 19%. M1b disease (metastatic disease
to lungs with normal LDH) has a 5-year survival rate of 7%. M1c disease (metastatic
disease to all other visceral organs and normal LDH or any distant disease with
elevated LDH) is associated with a 5-year survival rate of 10%.
Also see Malignant Melanoma Staging.
Patient Education
The focus of melanoma prevention and patient education is avoidance of sun exposure.
For patient education information, see the Cancer Center, as well as Skin Cancer,Skin
Biopsy, and Mole Removal.
History
Family history
Carefully obtain any family history of melanoma or skin cancer. Also, a family history of
irregular, prominent moles is important. Approximately 10% of all patients with
melanoma have a family history of melanoma. These patients typically develop
melanoma at an earlier age and tend to have multiple dysplastic nevi. These patients
also are more likely to have multiple primaries.
Presence of a familial melanoma syndrome should be considered in patients with a
family history of pancreatic cancer or astrocytoma. Mutations in the CDKN2Atumor
suppressor gene (also known as p16) are the most common genetic abnormalities
found in these families.
Patient history
Any previous history of melanoma must be elicited from patients, because those
patients are at increased risk of developing a second melanoma. Patients have reported
as many as 8 or more primary melanomas. Multiple primaries especially are prevalent in
patients with multiple dysplastic nevi. The term familial atypical mole or melanoma
(FAMM) syndrome is used to describe this hereditary tendency to develop multiple
dysplastic nevi and melanomas.
Sun exposure
Question the patient extensively about previous sun exposure, including severe
sunburns in childhood. The capacity to tan is also important, because individuals who
tan easily are less likely to develop a melanoma than those who burn easily.
Moles
Question the patient about any changes noted in moles. Any history of change in size,
color, or symmetry, as well as knowledge of bleeding or ulceration of the lesion must be
obtained. Also elicit any history or family history of multiple nevus syndrome.
 Physical Examination
Total body examination
A total-body skin examination is crucial when evaluating a patient with an atypical nevus
or a melanoma. The skin examination should be performed on initial evaluation of the
patient and during all subsequent visits. A study from a general dermatology practice
found that most melanomas diagnosed during a 3-year period were not the presenting
complaint but were discovered only because a dermatologist performed a total-body
skin examination; moreover, these incidentally discovered melanomas were more likely
to be thinner or in-situ lesions.[13]
Crucial to a good skin examination is a well-lit examining room and a completely
disrobed patient.
Serial photography and new techniques, such as epiluminescence microscopy and
computerized image analysis, are useful adjuncts. Epiluminescence microscopy uses a
magnifying lens to examine a lesion that has had oil applied. Computerized image
analysis stores images of the lesions and makes them available for comparison over
time.
Skin examination
During a skin examination, assess the total number of nevi present on the patient's skin.
Attempt to differentiate between typical and atypical lesions. (The images below depict
examples of melanomas.) The ABCDs for differentiating early melanomas from benign
nevi include the following:
A - Asymmetry (melanoma lesion more likely to be asymmetrical)
B - Border irregularity (melanoma more likely to have irregular borders)
C - Color (melanoma more likely to be very dark black or blue and to have variation in
color than would a benign mole, which more often is uniform in color and light tan or
brown)
D - Diameter (mole < 6 mm in diameter usually benign)
Lymph node examination
If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma
may disseminate through the lymphatics, leading to the involvement of regional lymph
nodes, and hematogenously, leading to the involvement of any node basin in the body.
Diagnostic Considerations
Differentials to consider in the diagnosis of malignant melanoma include the following
conditions:
Benign melanocytic lesions
Dysplastic nevus
Squamous cell carcinoma
Metastatic tumors to the skin
Blue nevus
Epithelioid (Spitz) tumor
 Pigmented spindle cell tumor
Halo nevus
Atypical fibroxanthoma
Pigmented actinic keratosis
Sebaceous carcinoma
Histiocytoid hemangioma
Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck
Mucosal Melanomas.
Differential Diagnoses
Basal Cell Carcinoma
Lentigo Maligna Melanoma
Mycosis Fungoides
Histologic Findings
Although no single histologic feature is pathognomonic for melanoma, many
characteristic features exist. Cytologic atypia virtually always is noted, with enlarged
cells containing large, pleomorphic, hyperchromic nuclei with prominent nucleoli.
Numerous mitotic figures often are noted.
A pagetoid growth pattern with upward growth of the melanocytes, so they are no longer
confined to the basal layer, is considered pathognomonic for melanoma by some
pathologists.
Although immunohistochemical stains usually are not necessary for diagnosis, they are
generally performed for completeness. Both S-100 and homatropine methylbromide
(HMB45) stains are positive in melanoma. The S-100 is highly sensitive, although not
specific, for melanoma, while the HMB45 is highly specific and moderately sensitive for
melanoma. The 2 stains, in concert, can be useful in diagnosing poorly differentiated
melanomas.
Approach Considerations
The diagnosis of melanoma is confirmed by excisional biopsy. Patients with clinically
enlarged lymph nodes and no evidence of distant disease should undergo a complete
regional lymph node dissection. Sentinel lymph node biopsy is appropriate in selected
patients.
Laboratory studies that are indicated include the following:
Complete blood cell count (CBC)
Comprehensive serum chemistry panel
Lactate dehydrogenase (LDH) level
Imaging studies are often obtained in patients with newly diagnosed melanoma, to rule
out clinically occult distant disease. Nevertheless, available evidence suggests that
preoperative imaging studies have significant costs and offer minimal benefit in most
patients with melanoma.[14] One meta-analysis of diagnostic tests used in staging
melanoma has shown that ultrasonography is the best imaging study to diagnose lymph
node involvement and that positron emission tomography computed tomography
scanning (PET/CT) is the best imaging study to look for other sites of metastasis. [15]
Complete Chemistry Panel
The chemistry panel may give a clue to possible metastatic disease. For example, an
elevated alkaline phosphatase level may signal metastasis to the bone or liver, while
elevated levels on liver function tests (aspartate aminotransferase [AST], alanine
aminotransferase [ALT]) may represent metastasis to the liver.
Total protein and albumin provide information concerning the overall health and
nutritional status of the patient and may afford prognostic information.
Many chemotherapy regimens may be toxic to the kidneys; therefore, a creatinine level
is necessary prior to initiation of any treatment.
Lactate Dehydrogenase Study
The LDH level is elevated in many conditions, including many malignancies. Although
LDH is not specific for melanoma, it may be useful at diagnosis and also in the follow-up
care of patients with melanoma. A markedly elevated LDH at diagnosis or at a follow-up
visit may indicate distant metastases, especially in the lung and liver.
Although the specificity and sensitivity of this test are low, multiple studies show an
elevated LDH level to be an independent predictive factor for poor prognosis. LDH level
now is considered part of the staging system for melanoma.
Chest Radiography
For patients with stage I or II disease, a chest radiograph is often obtained, although its
result will likely be negative. To date, no studies support obtaining a radiograph in these
patients, but a normal chest radiograph finding at diagnosis provides a baseline for
future comparison.
Patients with stage III disease, in-transit disease, or local recurrence should have a
chest radiograph or CT scan of the chest because the lungs often are the first site of
metastatic disease.
MRI
Magnetic resonance imaging (MRI) of the brain should be obtained during the workup of
a patient with known distant metastases to detect additional asymptomatic metastatic
disease. This is especially true for patients being considered for high-dose interleukin-2
treatment.
MRI of the brain in patients without known metastatic disease should be reserved for
those patients who are symptomatic.
CT Scanning
Chest CT scan
A chest CT scan should be included in the staging workup of a patient with stage IV
disease (ie, the patient with known distant metastases) to detect asymptomatic
metastatic lesions.
 In patients with stage I, II, or III disease, a chest CT scan should be performed only if
clinically indicated.
CT scan of the abdomen
A CT scan of the abdomen often is obtained when evaluating a patient with stage III,
locally recurrent, or in transit disease. Although the yield is low, a negative CT scan
provides a baseline study for future comparison.
CT scan of the pelvis
This study is indicated only if a patient has local regional recurrence below the waist, is
symptomatic, or has known metastatic disease with a history of primary tumors below
the waist.
Positron Emission Tomography
PET scans are not indicated in early-stage disease (Stage I or II), but a PET scan may
aid in staging patients with known node involvement or in-transit or satellite lesions.
Many studies report that PET scans have greater sensitivity than conventional
radiographic studies for the detection of metastatic disease.
One meta-analysis found PET CT scanning to be the best imaging study to utilize for
finding other sites of metastasis.[15] In particular, fluorodeoxyglucose (FDG) PET/CT
scans are a valuable tool for detecting additional metastasis as part of the preoperative
evaluation of patients with advanced and metastatic melanoma. [16]Finally, PET scans
often are useful in evaluating the response of metastatic disease to therapy.
Biopsy of a Suggestive Lesion
A complete excisional biopsy is preferred. The sample should have a 1-2 mm margin of
healthy skin and should include all layers of skin and some subcutaneous fat. Although
sparing of the deep fascia is not standard in biopsies for suspected melanoma,
investigators at the Mayo Clinic recommend this practice in some patients.[17]
If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional
or punch biopsy may be appropriate. The incisional biopsy specimen should be taken
from the most abnormal area of the lesion.
Because all layers of the skin must be included in the biopsy, a shave biopsy is
contraindicated. In some cases where a shave biopsy was done on a lesion, a complete
excisional biopsy should be performed if possible to determine the depth and extent of
the lesion.
Surgical Excision or Reexcision After Biopsy
Because failure to perform a reexcision after biopsy of a melanoma is associated with a
local recurrence rate of as high as 40%, a reexcision must be performed.
Current recommendations for margins of excision are as follows:
Lesions less than 1 mm in thickness - 1 cm margin
Lesions 1-4 mm in thickness - 2 cm margin
 Lesions greater than 4 mm in thickness - at least 2 cm margin
A study by Gillgren et al determined that a 2-cm excision provided a safe and reliant
resection margin to treat lesions thicker than 2 mm.[18]
Elective Lymph Node Dissection
Patients with clinically enlarged lymph nodes and no evidence of distant disease should
undergo a complete regional lymph node dissection (LND).
For years, patients without clinically enlarged nodes underwent LND. However, studies
show that in patients with melanomas that are 1-4 mm thick, LND may not yield a
significant survival advantage.
The only patients who seem to benefit from LND are those with lesions 1.12 mm thick
and who are younger than 60 years. Patients with lesions greater than 4 mm in
thickness are widely considered not to benefit from removal of clinically negative nodes.
Sentinel Lymph Node Dissection
Lymphatics from any given region on the skin drain to a single lymph node. This node is
called the sentinel lymph node and almost always is the first site of nodal involvement
when melanoma spreads to regional nodes.
To determine which node is the sentinel node, the following 2 techniques, often in
combination, are used. The combination of the 2 techniques allows detection of the
sentinel node in as many as 98% of cases.
The first technique involves injecting a blue dye at the site of the primary and, through a
small incision over the nodal basin, determining the location of the sentinel node. The
node is then removed for pathologic evaluation.
The second technique involves a radiolabeled solution injected into the site of the
primary and the use of a hand-held gamma detector to determine the location of the
sentinel node.
Sentinel node biopsy is now known to offer important prognostic, diagnostic, and
therapeutic information.[19]
Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that it is
reasonable to offer sentinel lymph node biopsy to patients with thick melanoma (4 mm
or greater) in whom the probability of a positive sentinel node is 30-40% and in whom
sentinel lymph node status is a strong independent predictor of outcome. [20] Sentinel
node biopsy may be offered either as standard care or in the context of a clinical trial.
The NCCN does not recommend sentinel lymph node biopsy for patients with in situ
melanoma (stage 0) or stage IA melanoma that is 1 mm or less with no adverse
features. Although there appears to be a subset of patients with thin melanoma who are
at sufficient risk for a positive sentinel lymph node to justify a biopsy, there is not yet
clear consensus regarding which factors best predict this risk; possible factors include
thickness over 0.75 mm, high mitotic rate, and young patient age; other possible factors
include positive deep margins and lymphovascular invasion.[21]
Joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of
Surgical Oncology (SSO) recommend sentinel lymph node biopsy for patients with
intermediate-thickness melanomas (Breslow thickness 14 mm) of any anatomic site.
There is less evidence for patients with thick melanomas (T4; Breslow thickness >4
mm), but sentinel lymph node biopsy is recommended for staging and facilitating
regional disease control. Evidence supporting routine sentinel lymph node biopsy for
patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking, but it may be
an option in selected patients with high-risk features in whom the benefits of staging
outweigh the risks of the procedure.
The guidelines recommend completion lymph node dissection (CLND) for all patients
with a positive sentinel lymph node biopsy; CLND achieves good regional disease
control. Whether CLND improves survival after a positive sentinel lymph node biopsy is
being examined in the ongoingMulticenter Selective Lymphadenectomy Trial II.[22]
Although current standards of practice suggest CLND for patients with a positive result
on sentinel lymph node biopsy, Cadili et al reported that the likelihood of nonsentinel
lymph node metastasis can be predicted on the basis of total metastasis within the
sentinel lymph node. Patients with 5 mm of metastasis have a 30% risk of metastasis.
In contrast, those with less than 2 mm of total sentinel lymph node metastasis are
unlikely (< 3.67% likelihood) to harbor metastasis in non-sentinel nodes, and those
patients may not benefit from additional nodal dissection.[23]
Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information
on this topic.
Approach Considerations
Surgery is the definitive treatment for early-stage melanoma. Wide local excision with
sentinel lymph node biopsy and/or elective lymph node dissection (LND) is considered
the mainstay of treatment for patients with primary melanoma. In patients with solitary or
acutely symptomatic brain metastases, surgical management may alleviate symptoms
and provide local control of disease.[24]
Because the definitive treatment of cutaneous melanoma is surgery, medical
management is reserved for adjuvant therapy of patients with advanced melanoma.
Less than one half of patients with deep primaries (>4 mm) or regional lymph node
involvement have long-term disease-free survival; consequently, these patients are
classified as high risk and should be considered for adjuvant therapy.
Interferon alfa is approved for adjuvant treatment after excision in patients who are free
of disease but are at high risk for recurrence. Currently, there are no standard systemic
therapeutic regimens that offer significant prolongation of survival for most patients with
metastatic melanoma without significant risk of toxicities.
Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck
Mucosal Melanomas.
Adjuvant Therapy
 Gould Rothberg et al developed and validated a multimarker prognostic assay for
determining survival in stage II melanoma, which these researchers suggest might be
beneficial in improving the selection of patients for adjuvant therapy. [25] Multiple
iterations of a genetic algorithm using the automated quantitative analysis (AQUA)
method for immunofluorescence-based immunohistochemistry on 246 serial primary
melanomas yielded a consistent 5-marker solution. A favorable prognosis was predicted
by the following criteria:
ATF2 ln(non-nuclear/nuclear AQUA score ratio) greater than -0.052
p21(WAF1) nuclear compartment AQUA score greater than 12.98
p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) -0.083 or less
Beta-catenin total AQUA score greater than 38.68
Fibronectin total AQUA score 57.93 or less
Primary tumors that met at least 4 of these 5 conditions were considered low risk.
Validation of the score showed that tumors in the high-risk group (those that met 3 or
fewer conditions) were associated with significantly reduced survival (hazard ratio, 2.72;
95% confidence interval, 1.12-6.58; P = .027).
Interferon alfa
A large multicenter study, Eastern Cooperative Group (ECOG) 1684, showed
improvement in disease-free survival using high-dose interferon alfa-2b (IFN) and
survival benefit (time to progression improvement of 8 months, with a 1-year survival
benefit).[26] On the basis of ECOG-1684, the US Food and Drug Administration (FDA)
approved IFN as adjuvant treatment after excision in patients who are free of disease
but are at high risk for recurrence.
A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials
showed a significant increase in relapse-free survival (P = .006) but not overall survival
(P = .42).[27]
Concerns about toxicity associated with high-dose adjuvant interferon alfa have
prompted several investigators to test lower doses of the drug. Lower-dose adjuvant
interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less
efficacy in delaying progression, with no survival advantage.
To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with
its incorporation of an induction phase of maximally tolerated dosages of IFN given
intravenously for the initial 4 weeks, Pectasides et al conducted a prospective,
randomized study in 364 patients with stage IIB, IIC, or III melanoma who had
undergone curative surgery. Patients were randomly assigned to receive IFN-alpha-2b
IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed
by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At
a median follow-up of 63 months, there were no significant differences in overall survival
and relapse-free survival between the 2 arms, and patients in arm B had more grade 1
to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. [28]
On the other hand, Hauschild et al found that the addition of a 4-week modified high-
dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment
schedule did not improve the clinical outcome. In their prospective, randomized,
multicenter trial in 674 lymph nodenegative patients with resected primary malignant
melanoma of more than 1.5-mm tumor thickness, there was no significant difference in
5-year relapse-free survival and overall survival between patients who received an
induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly
subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and
patients who received low-dose subcutaneous treatment 3 times a week for 24
months.[29]
Hauschild et al also studied optimal duration of treatment of malignant melanoma with
low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-
dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with
intermediate- and high-risk primary melanoma. Patients with resected cutaneous
melanoma of at least 1.5 mm tumor thickness and lymph node negative were included
in this prospective, randomized, multicenter trial (n=850). Patients were randomly
assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median
follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did
not differ between the 2 groups.[30]
Meta-analysis data shows that ulceration and tumor stage are important predictors of
response to interferon alfa/pegylated-interferon.[31]
Granulocyte-macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the
adjuvant setting to treat high-risk melanoma. Spitler et al treated 46 patients with
resected stage III or IV melanoma with a subcutaneous dose of 125 mg/m 2for 2 weeks
on and 2 weeks off for a year and found that the improvement in progression-free
survival over historical controls was 37 vs 12 months.[32] Based on this promising result,
a trial was done to test the efficacy of this regimen compared with placebo and a
vaccine (ECOG-4697). The results of the trial are still pending at this time.
Treatment of Advanced-Stage Melanoma (Stage IV)
Treatment of patients with advanced-stage melanoma (stage IV) has not improved
significantly in recent years.
Currently, there are no standard systemic therapeutic regimens that offer significant
prolongation of survival for most patients with metastatic melanoma without significant
risk of toxicities.
At this time, no combination chemotherapy regimen has proven to be significantly better
than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate.[33]
Two combination regimens commonly are used in the treatment of patients with
advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC
(CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which
is a combination of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-
analysis found that the strength of evidence does not support the addition of tamoxifen
to combined chemotherapy regimens.[34]
Biologic therapies now are being used alone and with chemotherapy regimens in the
treatment of patients with advanced-stage melanoma. To date, studies do not show that
IFN and interleukin-2 added to DTIC is better than DTIC alone.
Dacarbazine
DTIC was the first drug approved for the treatment of metastatic melanoma. In the initial
studies with dacarbazine, the overall response rate was 22%, with no impact on
survival. In a phase 3 study of dacarbazine compared with temozolomide, the response
rate was 12% versus 13%.[39] On the basis of this trial, and the greater ease of
administration of temozolomide versus dacarbazine (oral versus intravenous), most
oncologists currently use temozolomide as their first-line drug for melanoma.
Interleukin 2
The second drug approved by the Food and Drug administration (FDA) was interleukin
2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell
derived growth factor and used as a lymphokine-activated cell killer therapy.
A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000
units/kg administered every 8 hours for 5 days) resulted in an objective response rate of
16% (complete response of 6%) with the best response in patient with soft tissue and
lung metastases. The overall median survival was 11.4 months.[40]
The treatment was quite toxic, with some patients requiring intensive care unit support.
The more common toxicities included hypotension (45%), vomiting (37%), diarrhea
(32%), and oliguria (39%). Consequently, this therapy is offered only in centers that
have adequately trained staff and facilities. To qualify for this type of treatment, patients
must have normal results on pulmonary function testing, brain MRI, and cardiac stress
testing, plus adequate renal and hepatic function.
Carboplatin and paclitaxel
Carboplatin and paclitaxel have been tested in 2 small phase 2 studies, and when used
in combination with sorafenib, the response rate was 11-17%. This sometimes is being
used by clinicians in clinical practice because of lesser toxicity than dacarbazine and
also as a second- or third-line regimen.
However, a randomized, placebo-controlled phase 3 study by Hauschild et al found that
the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in
patients with unresectable stage III or IV melanoma; these investigators recommend
against this combination in the second-line setting for patients with advanced
melanoma.[41, 42]
Thymosin alpha 1
Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances
effector T-cell responses.
Maio et al evaluated the efficacy and safety of Talpha1 when combined with DTIC and
IFN alfa in a randomized study of 488 patients with metastatic melanoma. Their results
suggested that Talpha1 has activity in these patients. Tumor responses were higher in
the groups who received Talpha1 (in a dose of 3.2 mg) with DTIC and IFN (10
responses) or with DTIC (12 responses) than in the DTIC/IFN control group (4
responses).[43]
Treatment of melanoma with BRAF mutations
BRAF mutations are present in 40-60% of melanomas. When detected, this mutation
can help to guide treatment. In a multicenter, phase 1, dose-escalation trial, 32 patients
with metastatic melanoma who had a BRAF mutation were treated with vemurafenib
(PLX4032).[44] Two patients had a complete response, and 24 had a partial response.
Vemurafenib (Zelboraf) was approved by the US Food and Drug Administration (FDA)
in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine
kinase, including BRAF -V600E. The drug is indicated for the treatment of unresectable
or metastatic melanoma with BRAF -V600 mutation as detected by the cobas
4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been
studied with wild-type BRAF melanoma.
In May 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same
class as vemurafenib, for patients with unresectable or metastatic melanoma
withBRAF V600E mutation confirmed by the THxID BRAF mutation test.[45] In a
multicenter, open-label, phase 3 randomized controlled trial, treatment with dabrafenib
significantly improved progression-free survival in patients with BRAF-mutated
metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[46]
Phase 3 trial results for the investigational BRAF inhibitor vemurafenib included a 63%
relative reduction in the risk of death as well as a 74% relative reduction in the risk of
tumor progression in patients with previously untreated metastatic melanoma with
the BRAF V600E mutation compared with dacarbazine, the only chemotherapeutic drug
currently approved by the US Food and Drug Administration (FDA) for this disease.[47]
In addition, the overall survival rate at 6 months in the vemurafenib group was 84%
relative to 64% in the dacarbazine group.[47] Despite the short follow-up period, these
results have significant clinical implications, as, of the previously mentioned 40-60% of
cutaneous melanomas with BRAF mutations, about 90% involve theBRAF V600E
mutation. Moreover, a response to vemurafenib in 4 of 10 patients with
the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to
vemurafenib.[47]
Vemurafenib was generally well tolerated, with cutaneous events (squamous cell
carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia,
fatigue, and photosensitivity the most common adverse events; such events led to dose
modification or interruption in 38% of patients.[47] Adverse events seen with dacarbazine
were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification
or interruption in 16% of patients.
Dabrafenib was shown to significantly improve progression-free survival compared with
dacarbazine (5.1 vs 2.7 mo) in patients with BRAF -mutated metastatic melanoma in a
multicenter, open-label, phase 3 randomized controlled trial.[48]
Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK)
inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic
melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF
mutation test.[45] Approval was based on a phase 3 open-label trial that compared
trametinib to either dacarbazine or paclitaxel. Median progression-free survival was 4.8
months in the trametinib group and 1.5 months in the chemotherapy group. At 6
months, the rate of overall survival was 81% in the trametinib group and 67% in the
chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to
0.92).[49]
In January 2014, the FDA approved trametinib for use in combination with dabrafenib
for treating patients with unresectable or metastatic melanoma with BRAF V600E or
V600K mutations. Approval was based on the demonstration of response rate and
median duration of response in a phase 1/2 study. Median progression-free survival in
the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8
months in the dabrafenib monotherapy group (hazard ratio for progression or death,
0.39; 95% confidence interval, 0.25 to 0.62). The rate of complete or partial response
with combination therapy was 76% compared with 54% with monotherapy.
Improvement in disease-related symptoms or overall survival has not been
demonstrated for this combination.[50]
Vaccines
Melanoma vaccines and gene therapy are 2 additional treatment options that may
become available.[51]
A 2007 review found no clear evidence that the addition of immunotherapy to
chemotherapy increases survival in metastatic melanoma and recommended that
combined immunotherapy and chemotherapy be limited to clinical trials. [52]Because
numerous protocols for patients with advanced-stage melanoma exist, eligible patients
should be referred to an oncology center participating in these studies. Vaccines have
not been successful as a treatment for metastatic melanoma but are still a reasonable
area of research in the adjuvant setting.
External-beam radiation
The brain is a common site of metastasis in malignant melanoma. Brain metastases are
associated with a poor prognosis. Management of brain metastases can be difficult due
to rapid progression of disease and resistance to conventional therapies. Stereotactic
radiosurgery is used increasingly in patients with a limited number of metastases; it is
less invasive than craniotomy. External-beam radiation alone appears effective in
palliating symptoms. Chemotherapy alone is relatively ineffective, although the
combination of chemotherapy with external-beam radiation is being investigated.[24]
Future therapies
In a multicenter phase 2 trial, targeted therapy with imatinib was an effective treatment
option in patients with advanced melanoma harboring mutations or amplification of the
KIT proto-oncogene.[35, 36, 37] Of 50 patients with melanomas arising from acral, mucosal,
or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT-
mutant (n = 8), KIT-amplified melanoma (n = 11), or both (n = 5) were treated with
imatinib. Of these 24 patients, 7 achieved a partial response to therapy, with 5 patients'
responses confirmed on subsequent imaging studies, for an overall confirmed response
rate of 21%.[35, 36]
These findings reinforce similar findings in 2 earlier studies.[5, 38]
Ipilimumab
Anticytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody
directed at a down-regulatory receptor on activated T-cells.[53] The proposed mechanism
of action is inhibition of T-cell inactivation, allowing expansion of naturally developed
melanoma-specific cytotoxic T-cells.
Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with
metastatic melanoma. Clinical trials for monotherapy and in combination with other
immunotherapies and vaccines have been concluded or are currently under
way.[54] Ipilimumab was approved by the FDA in March 2011 for unresectable or
metastatic melanoma.
Hodi et al reported improved survival with ipilimumab in patients with metastatic
melanoma. Ipilimumab blocks CTLA-4 to a potentiate T-cell response. In a phase 3
study, 676 patients with HLA2-positive patients with unresectable stage III or IV
melanoma who disease progressed while receiving therapy for metastatic disease were
randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100, ipilimumab, or gp100
alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without
gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive
reinduction therapy. The median overall survival was 10 months among patients
receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100
alone. There was no difference in survival in the other ipilimumab arm compared with
the ipilimumab-plus-gp100 arm. Because of these findings, ipilimumab has been
approved as a treatment for metastatic melanoma.[54]
In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and
placebo, survival among patients with metastatic melanoma was improved by 2 months
(11 mo vs 9 mo) in the ipilimumab arm; however, they had more grade 3 and 4
toxicity.[55]
In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in
676 patients previously treated for metastatic melanoma who were randomly assigned
to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus
glycoprotein 100 melanoma antigen vaccine (gp100); (2) ipilimumab plus placebo; or (3)
gp100 plus placebo.[56, 57] Most of the immune-related AEs developed within 12 weeks of
initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any
ipilimumab treatment experienced an immune-related AE more than 70 days after their
last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related
AEs, even grade 3/4 events, were readily managed with monitoring and early
corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all
5 subsequently improved.[56, 57]
Peginterferon Alfa-2b
Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and
lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy
following definitive surgical resection, including complete lymphadenectomy.
The drugs approval was based on a 5-year, open-label, multicenter trial in which cancer
recurrence was delayed about 9 months longer in patients who took peginterferon alfa-
2b than it was in patients who did not take the drug.[6]
Talimogene laherparepvec
Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapeutic vaccine
engineered through the genetic alteration of the herpes simplex type I virus. In this
process, the gene ICP 34.5 is deleted and replaced with the coding sequence for
granulocyte-macrophage colony-stimulating factor (GM-CSF). T-VEC promoted
shrinkage in 64% of patients with advanced melanoma. A phase 3 study, OPTIM,
compared T-VEC with GM-CSF in stages IIIB, IIIC and 4 melanoma. T-VEC was
administered at < 4 ml x 106 pfu/ml for 3 weeks followed by the same dose every 2
weeks and GM-CSF was administered at 125 g/m2 for 14 days every 28 days. T-VEC
produced a durable response rate in 16.3% compared with 2.1% in patients treated with
GM-CSF. Response rate (RR) was 26.4% and complete response (CR) was 10.8% with
T-VEC compared with an RR of 5.7% and CR of 0.7% for GM-CSF.[62]
Prevention of Malignant Melanoma
The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially
those individuals at high risk of developing a melanoma, should wear protective
clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation,
avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least
15. This last recommendation is considered somewhat controversial, because no study
has shown sunscreen to reduce the incidence of melanoma.[58] Moreover, a systematic
review found that sunscreen use leads to longer duration of intentional sun exposure,
and sunburns tend to be more frequent among sunscreen users.[59]
First-degree relatives of a patient diagnosed with familial melanoma should be
encouraged to have annual skin examinations.
Consultations
A patient with a suggestive lesion should be referred to a dermatologist or surgical
oncologist for excisional biopsy.
If the diagnosis of melanoma is made, the patient should be referred to an oncologist
after definitive surgery is performed.
 Long-Term Monitoring
Follow-up care of a patient with melanoma is based on the stage of the primary. The
follow-up examination should be performed with the knowledge that the patient has an
increased risk for a second primary and that, of all solitary sites of visceral recurrence,
the lungs are the most frequent.
Follow-up guidelines from the National Comprehensive Cancer Network are listed
below.[20]
Follow-up for stage 0 in situ is as follows:
At least annual skin examination for life
Educate patient in monthly self-examination of skin
Follow-up for stage IA is as follows:
History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12
mo for 5 y, then annually as clinically indicated
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:
H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2
y, then annually as clinically indicated
Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count
(CBC) every 6-12 mo (optional)
Routine imaging is not recommended for stage IB or IIA disease
CT scans to follow up for specific signs and symptoms
Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
Medication Summary
High-dose interferon (IFN) alfa-2b is the only adjuvant therapy approved by the US
Food and Drug Administration (FDA) for high-risk resected melanoma, defined as deep
primaries greater than 4 mm in Breslow depth (AJCC stage IIB) and regional lymph
node metastasis (stage III). Various trials of low-dose IFN have shown no benefit in
disease-free relapse or overall survival (OS) rates.[60]
Similarly, multiple melanoma vaccine trials are in progress, predominantly for stage III
and IV disease, but they have not demonstrated an OS advantage to date.
Ipilimumab, a CTLA-4 blocker, enhances the T-cell response in HLA2-positive patients
and demonstrates remarkable promise in patients with metastatic melanoma. It is being
studied by itself and in combination with other immunotherapies and vaccines.[54]
Antineoplastic Agents
Class Summary
These agents inhibit cell growth and differentiation. Chemotherapeutic agents used to
treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.
 View full drug information

Dacarbazine

Although the mechanism of action for dacarbazine is unknown, possible actions include
alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result
is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.
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Cisplatin

Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by
causing DNA cross-links and denaturation of the double helix.
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Vinblastine

Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic

spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD
regimen.
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Ipilimumab (Yervoy)

Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that

overcomes CTLA-4-mediated T-cell suppression to enhance the immune response
against tumors. The marker CTLA-4 is associated with promoting a regulatory response
by the immune system. This regulatory response has a dampening effect on the
immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows
the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is
the first new agent to be approved for melanoma in over a decade.
Ipilimumab has demonstrated remarkable promise in patients with metastatic
melanoma. Clinical trials for monotherapy and in combination with other
immunotherapies and vaccines have been concluded or are currently underway.
Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic
melanoma.
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Carmustine (BiCNU)

This agent alkylates and cross-links DNA strands, inhibiting cell proliferation. It is used
in the Dartmouth regimen.
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Dabrafenib (Tafinlar)

Dabrafenib inhibits some mutated forms of BRAF kinases with in vitro IC50 values of
0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes,
respectively. It is indicated for unresectable or metastatic melanoma with BRAF V600 E
mutation confirmed by with the THxID BRAF mutation test.
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Trametinib (Mekinist)

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated

kinase 1 (MEK1) and MEK2 activation, and of MEK1 and MEK2 kinase activity. It is
approved for unresectable or metastatic melanoma with BRAF V600E or V600K
mutations confirmed by with the THxID BRAF mutation test.
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Tamoxifen

Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex

that decreases DNA synthesis and inhibits estrogen effects. It is used in the Dartmouth
regimen to possibly abrogate the multidrug resistance phenotype.
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Vemurafenib (Zelboraf)

Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E.

The drug is indicated for unresectable or metastatic melanoma with BRAF-V600
mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular
Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.
Biological Response Modulators
Class Summary
Immunotherapy (biotherapy) currently used to treat patients with melanoma includes
IFN and interleukin (IL)-2. An oncologist should administer these treatments.
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Interferon alfa 2b (Intron A)

IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The

mechanism of antitumor activity is not clearly understood; however, direct
antiproliferative effects against malignant cells and modulation of host immune
response may play important roles. It is the drug of choice for adjuvant therapy in
patients with high-risk melanoma. Its immunomodulatory effects include suppression of
tumor cell proliferation, enhancement of macrophage phagocytic activity, and
augmentation of lymphocyte cytotoxicity.
IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by
medical oncologists.
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Peginterferon alfa 2b (Sylatron)

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and

lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors,
which, once activated, are known to inhibit cellular growth, alter the state of cellular
differentiation, interfere with oncogene expression, alter cell surface antigen expression,
increase the phagocytic activity of macrophages, and enhance the cytotoxicity of
lymphocytes for target cells.
A covalent attachment of polyethylene glycol polymer chains to interferon molecules
(known as PEGylation) can significantly increase the time the drug remains in the
bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce
the severity and frequency of adverse effects.
It was approved by the FDA in March 2011 as adjuvant therapy following definitive
surgical resection, including complete lymphadenectomy. It is the first therapy approved
for the adjuvant treatment of melanoma in 15 years.
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Interleukin 2 (Proleukin)
IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells
and amplifies their responses. It enhances natural killer cell antitumor activity.