Académique Documents
Professionnel Documents
Culture Documents
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
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
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.)
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.
View full drug information
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.
View full drug information
Vinblastine
Ipilimumab (Yervoy)
This agent alkylates and cross-links DNA strands, inhibiting cell proliferation. It is used
in the Dartmouth regimen.
View full drug information
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.
View full drug information
Trametinib (Mekinist)
Tamoxifen
Vemurafenib (Zelboraf)
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.