20 Chapter 116 :: Melanoma
:: Jessica C. Hassel & Alexander H. Enk
AT-A-GLANCE
■ Rising incidence worldwide in countries with
white inhabitants, with highest incidence rates
in Australia (35 new cases per year per 100,000
population), followed by North America (21.8 new
cases per 100,000 population) and Europe (13.5
Part 20
new cases per 100,000 population).
■ Risk factors include history of sunburns and/or
heavy sun exposure, blue or green eyes, blonde or
::
red hair, fair complexion, >100 typical nevi, any
Neoplasia
atypical nevi, prior personal or family history of
melanoma, or p16 mutation.
■ Mean age of diagnosis is 63 years, with 15% being
younger than 45 years.
■ Most common location is the back for men, and
lower extremities followed by trunk for women,
but can occur anywhere on the skin surface.
■ Features used for melanoma recognition: A
(asymmetry), B (border), C (color), D (diameter,
>5 mm in most common use), and E (evolution).
■ Follows a highly variable course and represents
a heterogeneous disorder; surgically curable
if diagnosed and treated in early phase, but
potentially lethal with increased risk when
diagnosed and treated late.
■ In the last decades, completely new and effective
treatment options for metastatic melanoma
approved with immunotherapies such as the
immune checkpoint blockade (anti-CTLA4,
anti-PD-1 antibodies) and targeted therapies like
BRAF/MEK inhibitors leading to a median overall
survival of 2 years in stage IV melanoma and the
chance for a long-term tumor control.
INTRODUCTION
DEFINITIONS
Melanoma (a word derived from the greek melas
[dark] and oma [tumor]) is a malignant tumor aris-
ing from melanocytic cells and hence can occur any-
where where these cells are found. The most frequent
type is cutaneous melanoma but melanomas develop
also at the mucosal, the uveal, or even the meningeal
membrane. Ten percent of melanomas are detected
by lymph node metastases with so-called “unknown
primary” and are likely to develop in the lymph node
from preexisting nodal nevi.1
Kang_CH116_p1982-2017.indd 1982
HISTORICAL PERSPECTIVE
Cancer is a disease that probably accompanied human
life from the very beginning. The earliest physical
evidence of melanoma comes from diffuse melanotic
metastases found in skeletons of Pre-Colombian mum-
mies from Chancay and Chingas in Peru, dated to be
about 2400 years old (radiocarbon). However, the first
descriptions of the disease can be found in the writings
of Hippocrates of Cos in the 5th century BC.2
Until a few years ago, the only cure was by surgery
in the early stages. The first documented operation of
a melanoma was done by the Scottish surgeon John
Hunter in 1787. The preserved tumor is still housed
in the Hunterian Museum at Lincolns Inn Fields in
London.2 Until recently, in the unresectable meta-
static setting, no treatment was available that could
prolong patients’ survival. This was revolutionized
in the last decade by the approval of immunothera-
pies, the so-called immune checkpoint blockers, and
targeted treatments to the frequently found BRAF
mutations.
EPIDEMIOLOGY
The incidence of melanoma has increased signifi-
cantly worldwide over the last several decades. It is
mainly a tumor of people with fair skin from more
developed regions. There is a low annual incidence
in the whole world population of 3.0 new cases per
100,000 population—thus, it is not one of the top 10
cancers worldwide.3 The highest incidence of mela-
noma is reported for Australia/New Zealand with
about 35 new cases per year and 100,000 popula-
tion, followed by Northern Europe and Northern
America (Fig. 116-1). In the year 2016, an estimated
76,380 new cases of melanoma will be diagnosed in
the United States of America translating to an annual
incidence of 21.8 new cases per 100,000 population.4
In Europe, incidence rates are lower, with an annual
incidence of 13.5 new cases per 100,000 population
and large differences between European countries,
with the highest incidence in Switzerland for men
and in Denmark for women.5 Central and Eastern
European countries have the lowest reported inci-
dence rates in Europe. In the United States, incidence
rises about 2.6% per year, leading to an increase of
33% for men and 23% for women between 2002 and
2006.6 Across all cancers, melanoma incidence is the
most rapidly increasing in men and is only second to
lung cancer in women. Invasive melanoma of the skin
is the fourth most frequent site for cancer to occur
in men and the sixth most frequent site in women.
08/12/18 12:40 pm
 Estimated cancer incidence for melanoma world map
20
Incidence ASR
Both sexes

Melanoma of skin

Chapter 116 :: Melanoma

4.2+
1.6-4.2
0.89-1.6
0.48-0.89
<0.48
No Data

Source: GLOBOCAN 2012 (IARC)

Figure 116-1 Estimated cancer incidence for melanoma world map. ASR = age-standardized rate. (Reproduced with per-
mission from Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:
IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://
globocan.iarc.fr, accessed 13 September 2016.)

By 2015, it is estimated that 1 in 50 Americans will SUPERFICIAL SPREADING

develop melanoma in their lifetime.6
The median age for a melanoma diagnosis is
63 years with 15% being younger than 45 years. Incidence
rises with age to a maximum between 55 and 74 years.
Mortality data parallel incidence data, with a median
age at death of 69 years.4 Even though melanoma
accounts for only 4% of all skin cancer diagnoses each
year in the United States, it is responsible for 75% of
skin cancer deaths. Currently, one US citizen dies from
a melanoma every hour. However, even though mela-
noma incidence is rising rapidly with a tripling from
1980 to 2003, it is not associated with a corresponding
increase in melanoma deaths. This is probably based
on earlier detection and hence better prognosis of the
melanoma.6
CLINICAL FEATURES
CUTANEOUS FINDINGS
The different subtypes of cutaneous melanoma can
be distinguished clinically. However, these subtypes
are not of prognostic significance itself, for example, a
nodular or amelanotic melanoma might have a poorer
prognosis compared to a superficial spreading mela-
noma but this is most likely based on a higher tumor
thickness because of a later diagnosis.7 However, clini-
cal heterogeneity of melanomas might be explained by
genetically distinct types of melanoma with different
susceptibility to ultraviolet light.8
MELANOMA (SSM)
SSM is the most common subtype, accounting for
approximately 70% of all cutaneous melanomas. It
is diagnosed most commonly on intermittently sun-
exposed areas, most frequently the lower extremity of
women, and the upper back of men. Its classic clinical
appearance best fits into the ABCD criteria (see sec-
tion “Making a Diagnosis”), with irregular borders
and irregular pigmentation, but it may present subtly
as a discrete focal area of darkening within a preexist-
ing nevus. The range of appearance of SSM is broad
(Figs. 116-2A,B, and Fig. 116-3). Although varying
shades of brown typify most melanocytic lesions, strik-
ing aspects of dark brown to black, blue-gray, red, and
gray-white (which may represent regression) may be
found in melanoma. SSM is the subtype of melanoma
most commonly associated with preexisting nevi. The
history of SSM is often of a lesion slowly changing over
months to years. It may be mistaken for an atypical
nevus or seborrheic keratosis.
NODULAR MELANOMA (NM)
NM is the second most common melanoma sub-
type and accounts for approximately 15% to 30% of
all melanomas. The trunk is the most common site.
NM is remarkable for rapid evolution, often arising
over several weeks to months. NM more often lacks 1983
an apparent radial growth phase. It is more common

Kang_CH116_p1982-2017.indd 1983 08/12/18 12:40 pm

20 Part 20
::

A B
Neoplasia

C D

E F

Figure 116-2 Clinical subtypes of melanoma: A, B, Superficial spreading melanoma, in A with extensive signs of regres-
sion (whole center of the lesion); C, ulcerated amelanotic nodular melanoma; D, pigmented nodular melanoma; E, lentigo
1984 maligna melanoma; F, acral lentiginous melanoma; G, subungual melanoma with melanonychia striata; H, ulcerated des-
moplastic melanoma.

Kang_CH116_p1982-2017.indd 1984 08/12/18 12:40 pm

 20

Chapter 116 :: Melanoma

G H

Figure 116-2 (Continued)

for NM to begin de novo than to arise in a preexist- LENTIGO MALIGNA (LM)

ing nevus. NM typically appears as a uniformly dark
blue-black or bluish-red raised lesion, but 5% are
amelanotic (Fig. 116-2C,D). Early lesions often lack
asymmetry, have regular borders, and are a uniform
color. Amelanotic lesions may be mistaken for basal
cell carcinoma, pyogenic granuloma, or hemangioma,
whereas pigmented lesions may be mistaken for blue
nevi or pigmented basal cell carcinomas. SSM and
NM have the highest rate of mutations in the BRAF
gene, with up to 56% of the melanomas harboring this
alteration.8 There is also an association with multiple
melanocytic nevi.
AND LENTIGO MALIGNA
MELANOMA (LMM)
LM is a melanoma in situ with a prolonged radial
growth phase that eventually becomes invasive and is
then called LMM. LMM constitutes 10% to 15% of cuta-
neous melanomas. LM and LMM are diagnosed most
commonly in the seventh to eighth decades in an older
population than other types of melanoma—uncommon
before the age 40. The most common location is on
the chronically sun-exposed face, on the cheeks and

A H&E Melan-a

B H&E Melan-a
1985
Figure 116-3 Clinical, dermoscopic and histologic presentation of 2 superficial spreading melanomas (A, B).

Kang_CH116_p1982-2017.indd 1985 08/12/18 12:41 pm

20 nose in particular; the neck, scalp, and ears in men.
Its pathogenesis is thought to be related to cumula-
tive sun exposure rather than intermittent exposure.
Clinical appearance is an initially flat, slowly enlarg-
ing, brown, frecklelike macule with irregular shape
and differing shades of brown and tan, usually arising
in a background of photodamage (Fig. 116-2E). Both
LM and LMM often have clinically ill-defined borders,
which may be obscured by background actinic damage
consisting of lentigines, pigmented actinic keratoses,
or ephelides. LM and LMM are associated with sig-
nificantly higher rates of extensive subclinical lateral
growth, resulting in higher recurrence rates with stan-
dard recommended margins and failure to completely
Part 20
excise the lesion. LM and LMM have the least common
association with nevi, at 3% of cases, but the highest
rate of association with desmoplastic melanoma (DM,
see below). Molecularly, melanomas occurring in sun-
::
damaged skin carry c-KIT aberrations (mutations and
Neoplasia
copy number changes) more frequently than BRAF
mutations, with up to 28% versus 6%.9
ACRAL LENTIGINOUS
MELANOMA (ALM)
ALM is a subtype of melanoma with distinct differ-
ences in frequencies seen between ethnic groups.
ALM constitutes only 2% to 8% of melanomas in
whites but represents the most common form in
darker-pigmented individuals (60% to 72% in African
Americans and 29% to 46% in Asians). Although the
proportion of ALM seen in darker-pigmented individ-
uals is higher, the incidence of ALM is similar between
whites and other ethnicities. ALM is diagnosed more
often in an older population, with the median age
of onset of 65. The most common site for ALM is the
sole, with the palm and subungual locations following
(Fig. 116-2F). The clinical appearance of ALM is mainly
brown to black, but red with variegations in color and
irregular borders can occur. Often ALM are misdiag-
nosed first as a plantar wart or hematoma, leading to a
more advanced lesion upon diagnosis associated with
poorer outcomes. ALM is not thought to be associated
with sun exposure.
Subungual melanoma, considered a variant of ALM,
generally arises from the nail matrix, most commonly
on the great toe or thumb (Fig. 116-2G). It appears as
a brown to black discoloration or growth in the nail
bed (Table 116-1). A widening, dark, or irregularly
pigmented longitudinal nail streak (melanonychia
striata) with or without nail dystrophy and nail plate
elevation may be seen. Hutchinson sign, the finding of
pigmentation on the proximal nail fold, may be noted
with subungual melanoma. Benign lesions that mimic
subungual melanoma include benign longitudinal
melanonychia, subungual hematoma, pyogenic gran-
uloma, or even onychomycosis with pigmentation or
hemorrhage.
In acral melanoma, the most frequent targetable
1986 mutation is the BRAF mutation (21%), followed by a
c-KIT mutation (13%)10—c-KIT aberrations including
Kang_CH116_p1982-2017.indd 1986
TABLE 116-1
When to Consider Malignancy in Pigmented
Nail Lesions
■ Lesion is isolated on a single digit
■ Occurrence in the fourth to sixth decade
■ Abrupt pigmentation in a previously normal nail plate
■ Pigmentation appears darker, larger, or blurred towards the nail
matrix (proximally)
■ Acquired pigmentation of the thumb, index finger, or large toe
■ Pigmentation occurring after a history of trauma, after ruling out
subungual hematoma
■ Individual with a history of melanoma
■ Pigmentation associated with nail dystrophy, or absence of nail
plate
■ Pigmentation extending to the periungual skin (Hutchinson sign)
Braun R, Baran R, Frederique A, et al. Diagnosis and management of nail
pigmentations. J Am Acad Dermatol. 2007;56(5):835-847.
copy number changes are higher, with up to 36% but
with questionable clinical significance.9
DESMOPLASTIC MELANOMA (DM)
DM most commonly develops in the sixth or seventh
decade on sun-exposed head and neck regions. The
lesions typically have a firm, sclerotic, or indurated
quality, and one-half are amelanotic (Fig. 116-2H).
Approximately half of the lesions arise in association
with the LM histologic subtype. Although often deeply
invasive at the time of diagnosis with a tendency to
perineural growth, DM is associated with higher local
recurrence but lower nodal metastatic rates than other
subtypes of melanoma when matched for depth of
invasion. Results from a small study that involved
10 samples that investigated gene expression profil-
ing demonstrated a molecular distinction between
DM and nondesmoplastic melanoma.11 DMs reveal
a high mutation burden most likely induced by UV
radiation. BRAF and NRAS mutations are not found;
instead, other genetic alteration known to activate the
MAPK signaling cascade were identified, for example,
mutations in neurofibromin (NF1) in more than 90%
of cases.12,13
MUCOSAL MELANOMA
Melanoma can infrequently (1.3% of melanomas) arise
on mucosal surfaces on the head and neck (conjuncti-
val, intranasal, sinus, and oral cavities), genital, ano-
rectal, or even urethral mucosa (Fig. 116-4).14 With the
exception of the conjunctiva, patients present most
often with delayed detection and a deeply pigmented,
irregular lesion, often tumorous with signs of bleed-
ing. As most of these lesions present initially with a
radial growth phase manifesting a macular pigmenta-
tion, any suspicious area in these sites should be biop-
sied. Lesions of the conjunctiva are visible and appear
increased in patients with atypical nevi.15 Mucosal
melanomas are more frequent in women, especially
08/12/18 12:41 pm
 20

Chapter 116 :: Melanoma

B

E F

Figure 116-4 Mucosal melanomas: A, Introitus vaginae; B, gingiva; C, intranasal; D, conjunctiva; E, F uveal melanoma.
(A-C, With friendly permission to publish from J. Thierauf, Department of ENT, University Hospital Heidelberg; D-F, Permis-
sion to publish from A. Scheuerle, Department of Ophthalmology, University Hospital Heidelberg.)

based on the genital tract melanomas. Melanomas on mucosal melanomas. Anorectal melanomas account
vulva and vagina account for about 50% of the mucosal for only 16.5% of mucosal melanomas.14
melanomas among women. In both genders, the nasal Mucosal melanoma differs from cutaneous mela- 1987
cavity was otherwise the most frequent location for noma on the molecular level. Besides NF1, the most

Kang_CH116_p1982-2017.indd 1987 08/12/18 12:41 pm

20 frequently occurring driver mutations are RAS altera-
tions, consisting of NRAS and KRAS mutations with
a frequency between 5% and 30% that lead to an acti-
vation of the MAPK pathway similar to BRAF muta-
tions. Less than 10% of mucosal melanomas harbor
BRAF mutations.16-18 Only in mucosal melanomas of
vulvovaginal origin, the mutation frequency is higher,
with up to 26% for BRAF and lower for RAS.19 More
frequent than in cutaneous melanoma, mutations of
the receptor tyrosine kinase c-kit can be found with
varying frequencies in between 5% and 20% of muco-
sal melanomas.9,16,17 Here, frequency again seems to be
higher in tumors of vulvovaginal or anorectal origin,
compared with other sites.19,20 This mutation is targe-
Part 20
table with multi-kinase inhibitors such as imatinib21;
however, the mutation status of the tumors showed no
association with patients’ survival outcomes.17
::
NEVOID MELANOMA
Neoplasia
Nevoid melanoma describes a heterogeneous group of
rare lesions that histologically resemble benign nevi by
their symmetry and apparent maturation with descent
in the dermis, thus with greater potential for misdi-
agnosis. Clues to their histologic diagnosis include
marked hyperchromasia of the nuclei of the tumor
cells, the presence of mitoses, and expansive growth
of the dermal cells. Clinically, this may correspond to
a tan papule or nodule, more often >1 cm in diameter
on a young adult.22
SPITZOID MELANOMA
Spitzoid melanoma is a subtype of melanoma that clin-
ically and histologically resembles a Spitz nevus, but
tends to be larger and have asymmetry and irregular
coloration. Features that favor the diagnosis of a Spitzoid
melanoma over a benign Spitz nevus are large size
(greater than 1 cm in greatest dimension); lesions with
a thick invasive component (>2 mm Breslow thick-
ness); lesions with numerous mitoses (especially any
atypical forms), many cytologically atypical cells, and
lesions that have a clinically concerning course such
as very rapid growth in size or satellitosis. Clinical
and histologic distinction between the two is often
extremely difficult, and tumors with overlapping
features of Spitz nevi and melanoma are classified as
atypical Spitz tumors of uncertain biologic behavior
(AST).23
Whereas common acquired nevi and melanoma
often harbor BRAF mutations, NRAS mutations, or
inactivation of NF1, Spitz tumors show HRAS muta-
tions, inactivation of BAP1, or genomic rearrange-
ments involving kinases like ALK, ROS1 and others.
Additional genomic aberrations may abrogate various
tumor-suppressive mechanisms and lead to atypia
and malignant transformation. Comparative genomic
hybridization (CGH) is generally able to differentiate
Spitz tumors of benign or malignant behavior and may
1988 help classify the histologically ambiguous tumors, that
is, the AST.24
Kang_CH116_p1982-2017.indd 1988
OTHER RARE TYPES
Several other rare and unusual types of melanoma
are beyond the scope of this chapter, but previously
reported in a comprehensive review, which include
metaplastic melanoma, balloon cell melanoma, signet-
ring cell melanoma, myxoid melanoma, rhabdoid mel-
anoma, animal-type melanoma, and malignant blue
nevus.22,25
NONCUTANEOUS FINDINGS
Although most melanomas develop on the skin, there
are rarer types of noncutaneous melanomas arising
from extracutaneous melanocytes, for example, in
the choroidea. In addition, mucosal melanomas (see
before) are defined as noncutaneous melanomas as
they can occur at mucosa of the ear, nose, and throat
(ENT) region, intestine, or urinary tract. Melanomas of
unknown primary that most often are diagnosed with
lymph node metastases might develop from nodal
nevi.1 As nodal nevi only occur in skin draining lymph
nodes, the precursor lesion here might be nevus cells
that escaped from melanocytic nevi of the skin.26,27
UVEAL MELANOMAS
Uveal melanomas account for about 5% of all melano-
mas and develop mainly in the choroid, followed by
ciliary body and iris of the eye.28 Nevertheless, uveal
melanoma is the most common primary intraocular
malignancy. The median age at diagnosis is 58 years.
Risk factors include the presence of a choroidal nevus,
a nevus of Ota, and dysplastic nevus syndrome. There
is an 8 times higher incidence rate in whites as com-
pared to the black population, leading to the hypoth-
esis that UV exposure increases the risk for uveal
melanoma, but this has not been definitely proven.14
Clinically most patients present with painless loss
or distortion of vision or the tumor is diagnosed in
asymptomatic patients in routine ophthalmic screen-
ing. The risk of metastases could be linked to chromo-
somal aberrations. Patients with monosomy 3 (about
50% of patients) had a much poorer clinical outcome,
with a disease-specific mortality of 75.1% for patients
with monosomy 3 and 13.2% for patients with disomy
3 after 5 years, respectively.29 Patients usually die from
liver metastases, the primary metastatic site in uveal
melanoma probably based on the microenvironment
in the liver that seems to support growth of the metas-
tases there, for example, by secretion of the hepatocyte
growth factor (HGF).30
COMPLICATIONS
If complications occur with melanoma, they are usu-
ally based on metastatic disease within organs lead-
ing to symptoms associated with the affected organ.
08/12/18 12:41 pm
 These include pain (any metastases), convulsion (brain
metastases), instabilities (bone metastases), etc and
later on all the symptoms associated with progression
of the disease and death in the palliative setting.
Relatively frequent cutaneous changes associated with
melanoma are localized or diffuse hypo- or hyperpig-
mentation. The development of a melanoma-associated
vitiligo as an accompanying autoimmune disease
against melanocytes is reported to occur in up to 4%
of patients and is associated with a better prognosis.31
Vitiligo has become especially frequent in patients
treated with immune checkpoint blockers, and is also
correlated with a better treatment response.32 In highly
advanced patients, a diffuse cutaneous melanosis can
occur that is characterized by a slate-grey pigmentation
over the entire skin surface, mucosal membranes, and
internal organs, with accentuation in photo-exposed
areas. Such cases are often associated with melanuria,
a darkening of the urine. Histopathologically, melanin
deposits in the connective tissue and within macro-
phages in a perivascular distribution can be found.
These most likely come from ischemic metastases dis-
tributed through the body via the blood.31
Rare complications based on paraneoplastic mecha-
nisms described like dermatomyositis (Chap. 62)31 and
autoimmune retinopathies also occur.33 Melanoma-
associated retinopathies (MAR) present after the mela-
noma has been diagnosed as metastatic and are more
frequent in men. Patients may develop vision problems
years later, leading to latency from melanoma diagno-
sis to recognition of MAR on average after 3.6 years.
Pathophysiologically, antiretinal antibodies against
different structures like the bipolar cells, transducing,
rhodopsin, and others can be found.
ETIOLOGY AND
PATHOGENESIS
There are several risk factors for melanoma, with sun
exposure and genetics being the 2 most important
ones. Risk prediction models reveal in detail that the
number of nevi, presence of freckles, history of sun-
burn, hair color, and skin color are the best measures to
estimate melanoma risk.34,35 All these factors are influ-
enced by the genetic background leading to a certain
photosensitivity.
SUN EXPOSURE
There is clear convincing evidence that sun exposure,
and more specifically ultraviolet (UV) exposure, is a
major environmental cause of melanoma, especially
in high-risk populations. However, certainly not
all melanomas are sun related. Bastian and others
suggested a molecular classification for melanoma
based on the hypothesis that clinical heterogeneity is
explained by genetically distinct types of melanoma
with different susceptibility to ultraviolet light.8
Kang_CH116_p1982-2017.indd 1989
Epidemiologic studies suggest that periodic, intense
sun exposure (particularly during the critical time
20
period of childhood and adolescence) rather than
long, continued, heavy sun exposure is most impor-
tant in melanoma causation, termed the intermittent
exposure hypothesis. Sunburn history, notably blister-
ing and peeling burns, serves as a surrogate measure
of intermittent intense sun exposure. In most mela-
noma risk prediction models, the history of sunburns
is an important risk factor, not just in childhood,34-36
that is, the more sunburns in a lifetime, the higher the
melanoma risk. One blistering sunburn in childhood
more than doubles a person’s chances of developing
melanoma later in life.37
Chapter 116 :: Melanoma
The anatomic distribution of melanoma by body
site demonstrates that intermittently exposed skin
areas have the highest rates of developing melanoma.
In men, the trunk, particularly the upper back, is
the most common site for melanoma. In women, the
lower legs, followed by the trunk, are the most com-
mon sites.38 These intermittently exposed areas are the
most common areas to develop melanoma in younger
persons. In older persons, there is a greater incidence
of melanomas located on chronically exposed areas
with maximal cumulative sun exposure. The face is the
most common location for melanoma in older persons,
with the addition of the neck, scalp, and ears as well,
in older men.39
Several forms of artificial light have been associ-
ated with the development of melanoma, particu-
larly psoralen and UVA light (PUVA) and UVB as
well as tanning booths. The so-called PUVA Follow-
up Study demonstrated increased rates of melanoma
after PUVA exposure, with an incidence rate ratio of
9.3 approximately 20 years after PUVA therapy; these
rates increase over time and are higher in patients
exposed to high cumulative doses of PUVA.40 How-
ever, in 2 European cohorts of PUVA-treated patients,
there was no increased risk for melanoma detected in
contrast to nonmelanoma skin cancers such as squa-
mous and basal cell carcinomas.41 There is also rising
concern over tanning beds and melanoma risk, espe-
cially because exposure to the artificial UV radiation
is intermittent in nature. Any exposure to artificial
tanning devices significantly increases the risk of
cutaneous melanoma, and longer duration of bed use,
younger age at first exposure, and higher frequency
of use are associated with a significantly elevated risk
(odds ratio 1.69).42 Moreover, indoor tanning also has
been associated with accelerated skin aging and ocular
melanoma.43
Pathophysiologically, DNA-damaging, carcinogenic,
inflammatory, and immunosuppressive properties
of UV radiation contribute to initiation, progression,
and metastasis of primary melanoma.37,44 UV-A (320 to
400 nm) and UV-B (280 to 320 nm) have a significant
impact, with UV-B directly damaging the DNA and
UV-A mainly by the production of reactive oxygen spe-
cies (ROS). The final proof of the carcinogenic property
of UV on melanoma development was given by a large
Australian clinical trial. In 1992, a total of 1621 ran- 1989
domly selected residents from Queensland between
08/12/18 12:41 pm
20 25 and 75 years of age were randomly assigned to daily
or discretionary sunscreen use to head and arms until
2006. Ten years after trial cessation, the rate of primary
melanomas was halved in the daily sunscreen group,
with 11 new primary melanomas instead of 22 in the
discretionary sunscreen group.45
SKIN PHENOTYPE
Light skin pigmentation, blond or red hair, blue or green
eyes, prominent freckling tendency, and tendency to
sunburn with Fitzpatrick skin phototype I–II are phe-
Part 20
notypic features associated with an increased risk of
melanoma of 2- to 3-fold.34,46 Melanoma occurs much
less frequently in Type V–VI skin, suggesting that skin
pigment plays a protective role. This is explained of
::
course by different photosensitivity and ability to tan.
Neoplasia
MELANOCYTIC NEVI
There is an increased risk of melanoma associated with
nevi, both in a quantitative (ie, number of nevi) and
qualitative (ie, typical vs atypical nevi) manner.34,47
Adults with more than 100 clinically typical-appearing
nevi, children with more than 50 typical-appearing
nevi, and any patient with atypical nevi are at risk. The
presence of a solitary dysplastic nevus doubles the risk
of melanoma, while having 10 or more atypical nevi is
associated with a 12-fold elevation of risk.48 Nevi more
often serve as a genetic marker of increased risk rather
than a premalignant lesion, as most melanomas arise
de novo. In a study of 1606 patients with melanoma,
only 26% of the melanomas were histologically associ-
ated with nevi (43% of these atypical nevi, 57% other
nevi).49 However, sun exposure plays an important
role to acquire melanocytic nevi, particularly in early
childhood. Hence, the amount of melanocytic nevi as a
risk factor for melanoma development is influenced by
genetic as well as environmental factors.47
There is a recognized risk of melanoma develop-
ment in large congenital nevi, which varies depending
on the size of the lesion.50,51 Many series define large
congenital nevi as greater than 20 cm in diameter in
adulthood, and lifetime risks for developing mela-
noma are generally accepted to be in the 2% to 10%
range. In a large review of more than 2500 patients
with a large congenital melanocytic nevus, 2% devel-
oped a melanoma at a median age of 12.6 years (range
birth to 58 years). In 74% of patients, the melanocytic
nevus was greater than 40 cm in diameter, and 94%
had satellite nevi.51 Patients with large congenital nevi
located on the posterior axis (paraspinal, head, and
neck regions) or in conjunction with multiple satellite
lesions are at risk for neurocutaneous melanosis, with
an increased risk of developing melanoma in the CNS.
Melanomas developing on large congenital nevi are
1990 usually detected late and hence have a bad prognosis,
with more than 50% of them being fatal.51 For small- to
Kang_CH116_p1982-2017.indd 1990
TABLE 116-2
Genes Associated with Melanoma
CDKN2A
p16
CDK4
POT1
TERT
BAP1
BRAF
NRAS
HRAS
NF1
c-KIT
medium-sized congenital nevi, the melanoma risk is
similar to any other area of skin.50 Thus, prophylactic
excision of small- and medium-sized congenital nevi is
usually unwarranted.
FAMILY HISTORY
Patients with familial melanoma are estimated to
account for approximately 5% to 12% of all patients
with melanoma.46 Having one first-degree relative
with melanoma doubles the risk of melanoma, whereas
having 3 or more first-degree relatives with melanoma
increases the risk 35- to 70-fold.52 Some of this risk may
be attributed to shared risk factors such as skin pheno-
type, multiple nevi, and excessive sun exposure. The
association between familial melanoma and multiple
atypical nevi has historically been given various
names, including B-K mole∗ syndrome, familial atypical
multiple mole-melanoma syndrome, and dysplastic nevus
syndrome. Patients with familial melanoma typically
have earlier-onset melanoma and multiple primaries
as well as atypical nevi. In addition, patients with
familial melanoma have an increased risk of internal
cancers, such as pancreatic cancer or CNS tumors.46
Different genes are responsible for the development
of inherited melanoma (Table 116-2) and genetic altera-
tions typically increase cancer risk via 3 major mecha-
nisms: the activation of oncogenes, the loss of tumor
suppressor genes, or increased chromosomal instabil-
ity. Inherited mutations in CDKN2A, CDK4, POT1, and
TERT confer a 60% to 90% lifetime risk of melanoma.
CDKN2A-CDK4-TP53
PATHWAY MUTATIONS
Germline mutations in the chromosome 9p21 tumor
suppressor gene, cyclin-dependent kinase inhibitor 2A
(CDKN2A), account for approximately 40% of heredi-
tary melanoma cases (≥3 melanomas in one lineage). In
countries with high levels of UV exposure, the lifetime
melanoma risk in carriers of the CDKN2A mutation
∗B-K=initials of the first 2 described related patients.
08/12/18 12:41 pm
 is 76% (United States) and 91% (Australia), whereas
the risk is lower in countries with low levels of UV
exposure (58%, United Kingdom).46 Individuals with
germline CDKN2A mutations also exhibit a higher risk
of pancreatic cancer; an estimated 15% of individuals
with a mutant allele will develop pancreatic cancer in
their lifetime.53 Bona fide deleterious point mutations
in CDKN2A are relatively uncommon in primary mela-
noma tumors although homozygous deletions of this
gene may obscure the true rate of somatic loss in mela-
noma. CDKN2A encodes 2 gene products: p16 (also
known as INK4a, inhibitor of kinase 4a) and p14ARF
(alternative reading frame). p16 is a cell-cycle regula-
tor that binds and inhibits cyclin-dependent kinases
The p14ARF protein from CDKN2A inhibits a cellular
oncogene Hdm2, which in turn accelerates the destruc-
20
tion of the p53 tumor-suppressor gene.54 Complete loss
of CDKN2A also leads to abrogation of p14ARF and loss
of p53 function. Thus, this single locus can inactivate
both the retinoblastoma protein and p53 pathways and
probably explains the low rate of direct TP53 mutagen-
esis in melanoma.
GENES INVOLVED IN TELOMERE
MAINTENANCE
POT1 and TERT mutations are prevalent in 9% of
patients with hereditary melanoma and, when nor-

Chapter 116 :: Melanoma

Cdk4 or Cdk6, thereby inhibiting progression of cells
through the G1 phase of the cell cycle (Fig. 116-5). If
p16 function is absent or inactivated by mutation,
unrestrained Cdk4 activity phosphorylates the retino-
blastoma protein, thereby releasing the transcription
factor E2-F and inducing S-phase entry. This sequence
culminates in enhanced cellular proliferation, which,
in the absence of checkpoint regulation, results in
unrestrained growth and neoplasia.
The binding partner of the p16 protein is Cdk4.
Only a handful of families worldwide thus far have
been reported to carry hereditary mutations in CDK4,
while somatic mutations in this gene also have been
detected in some melanoma cell lines. Functional
studies suggest that mutations in Cdk4 render the
cyclin-dependent protein kinase resistant to p16 inhi-
bition, resulting in a phenotype identical to that from
p16 loss.
mally functioning, contribute to protection of exposed
chromosomal ends.46 Increased TERT activity may
allow unlimited cell division and subsequently pro-
mote cancer progression.
DIAGNOSIS
Early detection is the key to improving prognosis in
melanoma, as the risk of metastases increases with
infiltration depth of the primary. Although melanoma
may have a characteristic appearance, there is no sin-
gle clinical feature that ensures or excludes a diagno-
sis of melanoma. Change in color and increase in size
(or a new lesion) are the 2 most common early char-
acteristics noticed by patients that may be useful in
discriminating between melanoma and other benign
lesions.55

CDKN2A-CDK4-TP53 pathway

CDKN2A CDKN2A

P16INK4A
P27kip1
RB P P P21cip1 P14ARF
CDK4/6 RB
E2F
cyclinD
CDK2 Hdm2
cyclinE DNA damage
se
ha Restriction
-P

point
S-
G1

Pha
se

E2F p53
se
ha

M
-P -P
h ase G2

Figure 116-5 Mutations in the tumor suppressor gene CDKN2A account for approximately 40% of hereditary melanoma 1991
cases and lead to a loss of cell cycle control (A) and antiapoptosis (B).

Kang_CH116_p1982-2017.indd 1991 08/12/18 12:41 pm

20 PHYSICAL EXAMINATION
The skin examination should be conducted under
optimal lighting and encompass the entire skin integu-
ment, including the scalp, external ocular/conjunctivae,
oral mucosa, groin, buttocks, and palms/soles/web
spaces. Melanomas in hidden anatomic sites are associ-
ated with thicker tumors at diagnosis, often as a result
of later detection.56 Clinical diagnosis of melanoma can
be made in about 80% to 90% of cases. The well-known
ABCDE acronym for melanoma detection continues to
be a useful tool for the lay public and physicians.57,58
A stands for asymmetry (one half is not identical to
Part 20
the other half), B for border (irregular, notched, scal-
loped, ragged, or poorly defined borders as opposed to
smooth and straight edges), C for color (having vary-
ing shades from one area to another), D for diameter
::
(ie, greater than 5 mm), and E for evolution (changes
Neoplasia
in the lesion over time). Lesions having these charac-
teristics may potentially represent melanoma. Stud-
ies have found the sensitivity of the ABCDE checklist
(Table 116-3) to be very high, but the specificity much
lower.59
Another diagnostic aid that is useful in detecting
melanoma is the “ugly duckling” sign.60 A pigmented
lesion that is different from other pigmented lesions on
a particular individual should be approached with a
high index of suspicion. This is based on the premise
that within an individual, nevi should globally share
a common appearance or family resemblance. Even
in an individual with multiple atypical nevi, the nevi
should be morphologically similar.
DERMOSCOPY
Dermoscopy (also known as epiluminescence micros-
copy, dermatoscopy, incident light microscopy, and sur-
face microscopy) is a noninvasive technique in which a
handheld device is used to examine a lesion through a
film of liquid (eg, immersion oil), using nonpolarized
light (contact dermoscopy), or the lesion is examined
under polarized light without a contact medium (non-
contact dermoscopy). In experienced hands, it may
improve both the sensitivity and specificity for the
clinical diagnosis of melanoma and other pigmented
and nonpigmented lesions.61,62 Morphologic features
(Table 116-4) that are otherwise not visible to the naked
TABLE 116-3
ABCDE Checklista
■ A = Asymmetry
■ B = Border
■ C = Color
■ D = Diameter
■ E = Evolution
1992
a
Does not apply to nodular or desmoplastic melanoma.
Kang_CH116_p1982-2017.indd 1992
TABLE 116-4
Dermoscopic Features of Melanoma
■ Atypical pigment network
■ Negative network
■ Atypical dots or globules
■ Irregular streaks
■ Regression structures
■ Blue-white veil
■ Shiny white lines
■ Atypical blotch
■ Polymorphous vessels
Data from Wolner Z, Yelamos O, Liopyris K, et al. Enhancing skin cancer
diagnosis with dermoscopy. Dermatol Clin. 2017;35(4):417-37.
eye are observed using this technique that allows
visualization of microstructures of the epidermis, the
dermoepidermal junction, and the papillary dermis
(Fig.116-3).
Different diagnostic algorithms using dermoscopic
findings have been developed for melanoma, including
the ABCD rule, the 7-point checklist, pattern analysis,
Menzies method, modified ABC-point list, and CASH
(color, architecture, symmetry, and homogeneity).63-66
Several studies have compared these methods to deter-
mine the most effective method for dermoscopic detec-
tion of melanoma.63,64 Pattern analysis, which provides
an overall impression of multiple dermoscopic pat-
terns without rigid rules, based primarily on a subjec-
tive, simultaneous evaluation of a number of different
criteria, is the most widely used method among expe-
rienced users of dermoscopy for evaluating pigmented
lesions.67
Digital dermoscopy or digital epiluminescent micros-
copy permits computerized digital dermoscopic
images to be retrieved and examined at a later
date so that comparisons can be made and changes
detected over time. There are also a number of com-
mercially available automated computer image analy-
sis programs, devices that incorporate image analysis
algorithms to digital dermoscopic images, provid-
ing objective measurement of changes over time.
Sequential digital dermoscopy was shown to improve
early diagnosis of melanoma compared to standard
dermoscopy.68,69
The use of body or lesional photography can help
to monitor minor changes in melanocytic lesions,
particularly in patients with many nevi. Finally, con-
focal scanning laser microscopy and multispectral
digital dermoscopy are among a number of new imag-
ing techniques being evaluated for early detection of
melanomas.70,71
HISTOLOGY
Patients with lesions clinically suspicious for mela-
noma should, whenever possible, undergo prompt
excisional biopsy with narrow margins. A wider mar-
gin should be avoided to permit the most accurate
08/12/18 12:41 pm
 subsequent SLNB if indicated.72 However, if the lesion
is large and/or located on anatomic areas such as the
palm/sole, digit, face, or ear, an incisional skin biopsy
may be performed in the most elevated or darkest
area of the lesion, with a strong appreciation that the
clinically most suspicious area may not always cor-
relate with the thickest portion of the lesion. There is
no evidence that biopsy or incision of a primary mela-
noma leads to “seeding” of tissue and adversely affects
survival.73 Excisional biopsy performed after incisional
biopsy of melanoma with ≥50% of the lesion remain-
ing resulted in significant upstaging in 21% of patients,
and change in SLNB consideration in 10% of patients
in one large study.74 Hence, a wider margin should be
taken after complete excision with narrow margins
and histologic evaluation of the whole lesion.
Excisional biopsy, if possible, is important because
symmetry of the whole lesion is one major criterion
in differentiating a benign melanocytic nevus from
melanoma. The histologic diagnosis of melanoma is
based on the assessment of a constellation of findings,
including both architectural and cytologic features.
No single feature is diagnostic. The major architec-
tural features of melanoma include asymmetry, poor
Superficial spreading melanoma
Penetrates Spreads along
basement membrane epidermis
Nodular melanoma
Primarily deep
B invasion
Lentigo maligna melanoma
Site of invasion Multifocal atypical
into dermis melanocytes
Malignant
C cells in dermis
Figure 116-6 Histologic appearance (schematic, histopathologic overview, and close-up) of superficial spreading mela-
noma (A), nodular melanoma (B), and lentigo maligna melanoma (C).
Kang_CH116_p1982-2017.indd 1993
circumscription (cells at the edge of the lesion tend
to be small, single, and scattered rather than nested),
20
and large size (>5 to 6 mm). Nests of melanocytes in
the lower epidermis and dermis tend to vary in size
and shape, and to become confluent. There is a lack of
maturation of nests with descent into the dermis. In
addition, single melanocytes dominate over nests and
show an aberrant distribution (Fig. 116-3).75 The pres-
ence of melanocytes above the basal layer (pagetoid
spread), usually considered diagnostic of melanoma
in situ, should be assessed cautiously in the context
of other findings, as pagetoid spread may be seen in
benign lesions including Spitz nevi and nevi in special
anatomic regions (vulvar nevi, acral nevi). The differ-
Chapter 116 :: Melanoma
ent subtypes of melanoma may also have histopatho-
logic differences (Fig. 116-6), especially DM, which is
composed of strands of elongated, spindle-shaped cells
that often infiltrate deeply in a sarcomatoid pattern.
Immunohistochemistry may be useful for the diag-
nosis of melanoma, especially in poorly differentiated
neoplasms with little or no pigment (ie, amelanotic
melanomas), spindle cell tumors, or tumors with paget-
oid spread that are not obviously melanoma. S100 and
Sox10 proteins are expressed by almost all melanomas,
1993
08/12/18 12:41 pm
20 but also by melanocytic nevi, and other tumor types,
including cutaneous neural tumors. HMB-45 is a mono-
clonal antibody with high specificity for melanoma cells.
Melan-A and MART-1 (melanoma antigen recognized
by T cells) are the names given independently to the
same gene encoding a melanocytic differentiation anti-
gen expressed in the skin and retina. Melan-A is broadly
expressed in benign and malignant melanocytic lesions.
It is more sensitive than HMB-45 and more specific than
S100 for melanoma. Search for the microphthalmia-
associated transcription factor (MiTF) may be useful,
especially in amelanotic melanomas, as it is a marker
in the nucleus, whereas all other markers are mainly
intracytoplasmic.76 Immunohistochemically, DMs com-
Part 20
monly express only S100 and Sox1077 and lack other
melanocytic markers like HMB-45, Melan-A, and MiTF.
In nevoid melanomas staining for the prolifera-
tion rate, for example, with Ki-67, might be helpful to
::
uncover malignancy.
Neoplasia
In addition to diagnosis, histology gives fur-
ther clinically important information on the infil-
tration depth (Breslow thickness) and ulceration
status—features needed for AJCC (American Acad-
emy of Dermatology) classification and prognostic
evaluation.78 Further diagnostic investigations are
stage dependent as the risk to metastasize increases
with tumor stage.78
LABORATORY TESTING
As early as in 1954, increased levels of lactate dehydro-
genase (LDH) were detected in the serum of melanoma
patients.79 Ever since, the value of LDH as a tumor
marker for melanoma has been discussed. S100B in the
serum is a bit more specific than LDH but lacks sensi-
tivity. For that reason, S100B can be detected and moni-
tored in clinical followup as an additional marker to
detect progression of the disease.80 Hence, blood inves-
tigations to measure for tumor markers play a minor
role in the diagnosis of melanoma, but are mainly used
to monitor the clinical course. Testing of the nonspe-
cific tumor marker LDH is indicated only for patients
with distant metastatic disease as it is needed for AJCC
classification and prognostic evaluation.78,81
Other tumor markers like melanoma-inhibiting
activity (MIA), tumor-associated antigen 90 immune
complex (TA90IC), and YKL-40 are under investiga-
tion and not used in routine clinical practice. It is not
clear as of this writing if they add a benefit to S100B
and LDH.79
IMAGING
REGIONAL SKIN AND LYMPH
NODE ULTRASOUND
1994 Patients should be evaluated for regional spread by
careful palpation of lymph nodes first, particularly
Kang_CH116_p1982-2017.indd 1994
the primary echelon nodal basin(s). The concepts of
aberrant lymphatic drainage pathways to unexpected
nodal basins and interval nodes located between the
primary site and the expected regional nodal basin
have taught physicians to search for clinically detect-
able nodal disease in unexpected locations.82 Skin and
lymph node ultrasonography is perhaps the most
sensitive noninvasive method to detect small nodal
metastases and is much more sensitive than clinical
examination.83 Lymph node metastases are character-
ized by a ballooned shape, loss of central echo, and
peripheral perfusion.84 If a lymph node or a dermal/
subcutaneous nodule in the regional area of the pri-
mary is found, an excisional biopsy should be per-
formed if possible.
TOMOGRAPHY
Routine imaging and hematologic tests in asymptom-
atic patients rarely identifies occult systemic disease.85
Tomographic investigations like computed tomog-
raphy (CT), magnet resonance imaging (MRI) and
positron emission tomography (PET) are generally not
recommended at the stage of primary melanoma.86,87
The rate of false positive findings is far too high
(8%-15%), for example, unspecific lung lesions,88 which
leads to additional cost of followup studies and possi-
bly invasive procedures, as well as increased patient
anxiety. Unfortunately, there are no data demonstrat-
ing improved survival rates if metastases are detected
when clinically asymptomatic versus early symptom-
atic stage IV disease. However, especially in high-risk
melanomas (>4 mm Breslow thickness), the risk for
hematologic spread increases, and tomographic imag-
ing can be justified. Distant metastases are more likely
in patients with regional metastases. However, in a
retrospective analysis of 185 patients with a positive
sentinel lymph node (SLN), only 1 patient (0.5%) had
detectable metastatic disease on the imaging. Hence,
imaging with CT, MRI, or PET is indicated only in
high-risk and known metastatic melanoma and rec-
ommended to be performed as clinically indicated.
This further emphasizes the importance of a thorough
melanoma-focused review of systems and physical
examination.
SENTINEL LYMPH NODE
BIOPSY (SLNB)
The SLN is per definition the first draining lymph
node in the lymphatic draining system of the primary
tumor. SLNB is a powerful staging and prognostic
tool which may be used to detect occult micrometas-
tases in regional lymph nodes,89 and represents the
best baseline staging test for detection of occult nodal
metastasis in the subset of melanoma patients where it
is indicated. SLNB is far more sensitive and accurate
at detecting microscopic metastases than PET scan,
CT scans, or ultrasonographic imaging combined with
08/12/18 12:41 pm
 lymph node fine-needle aspiration.85 In a meta-analysis
of 34 studies, a Breslow thickness of <1 mm was associ-
Diagnostic algorithm
20
ated with a positive SLN in 5.6% of patients.90 This rate
was higher (19.5%) in patients younger than 40 years Clinical evaluation
and a tumor with 0.75 to 1 mm thickness as well as
in ulcerated primary melanomas and melanomas with
detectable mitoses.91-93 For patients with lesions of a
Breslow thickness between 1 and 4 mm Breslow, 25.2%
had a positive SLN, whereas those with lesions >4 mm
in thickness had a 50% likelihood of SLN positivity.92,94
Excisional biospy
Based on this risk stratification, SLNB is recom-
mended in patients with a melanoma ≥1 mm Breslow
thickness.89,90 In addition, it can be offered for patients
with thinner melanomas (0.8-1 mm) or even <0.8 mm

Chapter 116 :: Melanoma

if additional risk factors such as high mitotic index or Staging
lymphovascular invasion exists, especially in the set-
ting of young age.91
In current practice, technetium-99–labeled radio-
colloid solution, often complemented with vital blue
dye, allows for detection of the SLN >98% of the time
in skilled hands.95 Ideally, the procedure should be per-
formed at the same time as wide local excision (WLE)
of the primary melanoma for greatest accuracy. SLNB
may not be accurate if performed after WLE in areas SLNB Treatment according
of ambiguous or surgically altered lymphatic drain- to melanoma stage
age or following a local skin flap due to radiocolloid
and dye injection location away from the true primary
site.96 Once removed, the SLN(s) must be assessed with
serial sectioning, using standard hematoxylin and
eosin (H&E) techniques often combined with immu-
nohistochemical stains such as S100, HMB-45, and/or
Melan-A. The use of immunostains increases sensitiv- Figure 116-7 Diagnostic algorithm.
ity for melanoma and has resulted in the upstaging of
up to 10% to 20% of patients.97 In melanoma, even sin-
gle melanoma cells in the immunostains of the sentinel
define the lymph node as sentinel positive (N1a). In
2006, Morton et al published the third interim analy- DIAGNOSTIC ALGORITHM
sis of the multicenter sentinel lymphadenectomy trial
(MSLT)–I, the first prospective randomized controlled See Fig. 116-7.
clinical trial of SLNB in melanoma.98 In this analysis,
1269 clinically node-negative patients with newly
diagnosed melanoma 1.2 to 3.5 mm in depth were ran- DIFFERENTIAL DIAGNOSIS
domized to wide excision and nodal basin observation
See Table 116-5.
versus wide excision and SLNB. Patients with a posi-
tive SLN received an immediate complete lymph node
dissection (CLND), and patients in the observation
arm also received CLND if they developed regional
lymph node metastasis. SLN status was demonstrated TABLE 116-5
to be a powerful predictor of survival, as those with a Differential Diagnosis of Melanoma
negative SLN had a 5-year survival of 90.2%, versus
■ Atypical nevus: ABCD criteria help to differentiate
72.3% 5-year survival for those with a positive SLN.
■ Seborrheic keratosis: no pigment net in dermoscopy
Recently, results of the DECOG-SLT trial have been
■ Basal cell carcinoma, especially if pigmented: more black than
published. In this German trial, almost 500 patients brown, prominent vasculature
with a positive SLN with an at least 1-mm metasta- ■ Hemangioma: can be difficult to distinguish from amelanotic
sis were randomized to obtain CLND or observation. melanoma
This led to an improvement in local recurrence rate ■ Pyogenic granuloma: especially difficult to distinguish from amela-
but did not lead to a survival benefit.99 Final analysis notic acral melanoma
of both trials confirm these results with no significant ■ Solar lentigo, pigmented actinic keratosis, flat seborrheic keratosis:
benefit of an immediate CLND. Hence, this procedure can mimic lentigo maligna melanoma
is not recommended any more in patients with only ■ Plantar wart: might be hard to distinguish from acral melanoma
■ Hematoma: especially acral or subungual hematoma
microscopic nodal disease. However, Sentinel positive 1995
■ Longitudinal melanonychia: look for Hutchinson sign
patients might be selected for adjuvant therapy.

Kang_CH116_p1982-2017.indd 1995 08/12/18 12:41 pm

20 CLINICAL COURSE AND
PROGNOSIS
Melanoma can progress to different stages of the dis-
ease, starting with the primary (stage I/II), regional
metastases (stage III) and distant metastases (stage IV)
(Fig. 116-8). In general, prognosis and survival rates
worsen with increasing stage. At initial presentation,
approximately 85% of patients have localized disease,
10% have regional metastatic disease, and 5% have dis-
tant metastatic disease already.78

A
Part 20

STAGES I AND II
MELANOMA
::

In general, the 5- to 10-year survival for patients with

Neoplasia

localized thin primary melanoma <1 mm in Breslow

depth is more than 90%. Melanoma typically recurs in
a predictable fashion, first in a local and regional dis-
tribution, then to distant sites. It is also recognized that
melanoma may bypass the regional nodes with direct
hematogenous dissemination. The majority of recur-
rences manifest in the first 5 years after diagnosis and
treatment, depending on tumor thickness and other
prognostic features of the primary lesion. However,
melanoma can recur at any time, and the incidence of
late recurrence 10 or more years after initial diagnosis
is approximately 1% to 5%.100
B

STAGE III MELANOMA

Stage III melanoma represents a broad range of
patients with a diverse clinical outcome, from patients
with microscopic nodal disease (IIIA) to patients with
bulky clinical nodes or in-transit metastases (IIIC)
(Fig. 116-8). The general overall 5-year survival range
of 38% to 78% is wide, primarily related to several
variables such as the number of positive lymph nodes
(most important); tumor burden within a lymph node
(microscopic vs macroscopic); age; and ulceration status
as well as Breslow thickness of the primary melanoma
(Table 116-6).78 There is a significant decline in survival
in melanoma patients who present with clinically evi-
dent macroscopic nodal disease versus those with
microscopic nodal disease identified via SLNB.

STAGE IV MELANOMA
Melanoma is known for its propensity to metas- C
tasize to virtually any organ and also for its highly
Figure 116-8 A, Patient with stage III disease (primary
variable clinical course. Melanoma metastasizes to
melanoma with bulky lymph node metastases). B, Patient
nonvisceral sites: distant skin/subcutaneous tissue with in-transit metastases. C, Patient with stage IV disease
1996 and distant lymph nodes in approximately half of and extensive cutaneous metastases.
the stage IV cases (42% to 57%) (Fig. 116-8). The most

Kang_CH116_p1982-2017.indd 1996 08/12/18 12:41 pm

 TABLE 116-6
common visceral sites are the lungs (18%-36%), liver
(14%-20%), brain (12%-20%), bone (11%-17%), and GI
20
Melanoma TNM Classifications (AJCC 2017) tract (1%-7%). Once metastases to distant sites have
been detected, median survival without any treat-
T ment is approximately 6 to 9 months. With the help of
CLASSIFICATION THICKNESS (mm) ULCERATION STATUS
targeted and immunotherapies this can be increased
T1 ≤1.0 a: <0.8 mm without to 2 years, and even long-term tumor control can be
ulceration achieved.101,102
b: <0.8 mm with
ulceration or 0.8-1 mm
(with or without
ulceration) METASTATIC MELANOMA
T2 1.01-2.0 a: without ulceration
b: with ulceration OF UNKNOWN
PRIMARY (MUP)

Chapter 116 :: Melanoma

T3 2.01-4.0 a: without ulceration
b: with ulceration
T4 >4.0 a: without ulceration Metastatic melanoma of unknown primary (MUP) is
b: with ulceration defined as the presence of histologically confirmed
N NUMBER OF melanoma in a lymph node, visceral site, or dis-
CLASSIFICATION METASTATIC NODES NODAL METASTATIC MASS tant skin/subcutaneous tissues without a history or
n1 1 a: clinically occult evidence of a primary cutaneous, mucosal, or ocu-
    b: clinically apparent lar melanoma. This situation occurs in 2% to 5% of
c: pure in-transit all cases of melanoma. Approximately 60% of these
met(s)/satellite(s) involve the lymph nodes and might have developed
without metastatic nodes from nodal nevi.1 The remaining involve distant sites,
N2 2-3 a: only occult metastases typically skin/subcutaneous tissue, and less com-
b: at least one clinically monly lung, brain, or GI tract. MUP has similar sur-
apparent metastasis vival rates compared to equivalently staged cutaneous
c: in-transit met(s)/
melanomas of known primary origin. MUP metastatic
satellite(s) with
to lymph nodes had 5- and 10-year survival rates of
1 metastatic node (clini-
cally occult or apparent)
46% and 41%, which is comparable to the equivalent
stage III melanoma of known primary.103 Melanoma of
N3 ≥4 a: only clinically occult
unknown primary metastatic to viscera had a median
metastases
b: at least one clinically
survival of 6 months.104
apparent metastasis Evaluation of melanoma of unknown primary
c: in-transit met(s)/ should involve a complete skin examination look-
satellite(s) with at least ing for a primary site. Wood lamp may be used to
2 metastatic nodes identify subclinical hypopigmented areas, which
(clinically occult or may suggest a regressed primary lesion. In mela-
apparent) noma of unknown primary metastatic to a lymph
M SERUM LACTATE node, particular attention should be focused on the
CLASSIFICATION SITE DEHYDROGENASE skin areas that drain to the nodal basin involved. A
m1a Distant skin or soft M1a(0): Normal complete history of previously excised skin lesions
tissue including M1a(1): Elevated should be reviewed. The patient should be referred
muscles, or nodal for proctoscopic, gynecologic, ocular, and nasal
metastases mucosal examinations, when warranted. However,
M1b Lung metasta- M1b(0): Normal only rarely a primary tumor is detectable, and hence
ses (with or M1b(1): Elevated more invasive procedures like gastroscopy/colonos-
without M1a copy should be avoided without any clinical hints
involvement) for a melanoma at these locations. Staging workup
M1c All other visceral M1c(0): Normal and treatment should be performed as for the equiv-
metastases M1c(1): Elevated alent clinical stage of known primary.
without CNS
metastases
(with or without
M1a or M1b
involvement)
THE AJCC CLASSIFICATION
M1d CNS metastasis M1d(0): Normal Accurate staging forms the basis for prognosis and
(with or without M1d(1): Elevated treatment, which is invaluable for the majority of
M1a, M1b, or M1c
patients in their informed decision-making process.
involvement
The American Joint Committee on Cancer (AJCC) pub- 1997
lished a revised staging system for melanoma in 2017

Kang_CH116_p1982-2017.indd 1997 08/12/18 12:41 pm

20 TABLE 116-7
metastases. Table 116-6 presents the TNM categories,
and Table 116-7 lists the Stage groupings.
Stage Groupings for Cutaneous Melanoma
CLINICAL STAGINGa PATHOLOGIC STAGINGb
T N M T N M CLINICAL PROGNOSTIC
0
IA
Tis
T1a
N0
N0
M0
M0
Tis
T1a/b
N0
N0
M0
M0
FACTORS
IB T1b N0 M0 T2a N0 M0
  T2a N0 M0       GENDER AND AGE
IIA T2b N0 M0 T2b N0 M0 A large number of studies have reported that women
  T3a N0 M0 T3a N0 M0 have better survival rates than men, even after adjust-
IIB T3b N0 M0 T3b N0 M0 ment for tumor thickness and anatomic site.107 In addi-
Part 20

  T4a N0 M0 T4a N0 M0 tion, increasing patient age portends a worse prognosis

IIC T4b N0 M0 T4b N0 M0 with respect to overall survival rates. Males more than
IIIc Any T N1 M0       60 years of age have the highest mortality rates from
    N2         melanoma. Older patients have thicker primaries and
::

    N3         a higher proportion of ulcerated melanomas, but even

Neoplasia

IIIA       T1a/b– N1a or M0 after adjusting for these factors, age appears to be an
N2a independent prognostic factor.108,109 It has been postu-
        T2a N1a or M0 lated that age may serve as a surrogate for declining
N2a host immune defense mechanisms.
IIIB       T0 N1b/c M0
        T1a/ N1b/c or M0
        b–T2a N2b
        T2b/T3a N1a-N2b M0 PROGNOSTIC FACTORS OF
IIIC       T0 N2b/c or
N3b/c
M0
THE PRIMARY MELANOMA
        T1a–T3a N2c or M0

        T3b/T4a
N3a/b/c
Any N M0
TUMOR THICKNESS
T4b N1a-N2c M0 (BRESLOW INDEX)
IIID       T4b N3a/b/c M0
The single most important prognostic factor for sur-
IV Any T Any N Any Any T Any N Any vival and clinical management in localized stage I
M1 M1 and II cutaneous melanoma is tumor thickness.78 As
a
Clinical staging includes microstaging of the primary melanoma and originally described by Breslow, thickness is mea-
clinical/radiologic evaluation for metastases. By convention, it should sured from the top of the granular layer of the epider-
be used after complete excision of the primary melanoma with clinical mis to the greatest depth of tumor invasion using an
assessment for regional and distant metastases. ocular micrometer measured in millimeters. Survival
b
Pathologic staging includes microstaging of the primary melanoma and decreases with increasing Breslow thickness. Clark
pathologic information about the regional lymph nodes after partial or level is an alternate, less accurate method of measur-
complete lymphadenectomy. Pathologic stage 0 or stage IA patients are
ing tumor thickness by the anatomic level of invasion.
the exception; they do not require pathologic evaluation of their lymph
Clark level of invasion is no longer used in routine
nodes.
c
There are no stage III subgroups for clinical staging.
staging of melanoma.
M, metastasis classification; N, node status; T, tumor size.
From Amin MB et al. AJCC Cancer Staging Manual, 8th ed. 2016.
ULCERATION
Ulceration correlates with tumor thickness; it occurs
infrequently in thin melanomas (6% for melanomas
(Tables 116-6 and 116-7).78,105,106 The 2017 melanoma <1 mm) and frequently in thick melanomas (63% for
staging system was obtained from a data set of >46,000 melanomas >4 mm). However, patients with an ulcer-
melanoma patients from 10 centers worldwide. This ated melanoma do much worse than patients with
represents the largest body of AJCC melanoma data a non-ulcerated melanoma with the same Breslow
analyzed in an evidence-based approach and incor- thickness.110 Ulceration is an independent prognos-
porates many patients more accurately staged using tic factor for localized melanoma.78 The presence of
SLNB. The tumor size, node status, metastasis clas- ulceration in the primary confers a higher risk of
sification (TNM) system continues to form the back- developing advanced disease and lower survival rate
bone of the staging system, in which T describes the and upstages all patients with localized and regional
1998 extent or thickness of the primary tumor, N the extent disease (ie, stages I to III [Table 116-6]). The worse
of lymph node metastases, and M the extent of distant prognosis of ulcerated melanoma might be due to the

Kang_CH116_p1982-2017.indd 1998 08/12/18 12:41 pm

 fact that ulceration may be indicative of a melanoma
with different biologic potential.111 Ulcerated melano-
mas tend to have increased vascularity and lymphatic
and angiogenic metastatic rates, immunosuppressive
features, and a gene profile that differs from nonul-
cerated melanoma. In 2 large European Organization
for Research and Treatment of Cancer (EORTC) tri-
als with adjuvant interferon, ulceration was found to
be an independent predictive factor for the beneficial
effect of the immunotherapy.111-113 The same was seen
for ipilimumab adjuvant in stage III disease.111
MITOTIC RATE
Several studies reported the importance of tumor
mitotic rate as an independent predictor of survival,
with an increasing mitotic rate correlating with
decreasing survival.114 Among patients with clini-
cally localized melanoma, a mitotic rate of 1/mm2 or
greater was described as the second most powerful
predictor of survival, after tumor thickness.78 In the
2009 revised AJCC staging system, the mitotic rate
had replaced Clark level of invasion in defining T1b
melanomas because when ulceration, tumor thick-
ness, and mitotic rate are accounted for, Clark level
was no longer an independent predictor of survival.
Mitotic rate may also correlate with SLNB positivity,
especially in younger patients.115 However, in the new
classification system based on >46,000 patients the
mitotic rate was not an independent prognostic factor
any more and hence, does not define clinical staging
(Tables 116-6 and 116-7).
ANGIOLYMPHATIC INVASION
Vascular involvement denotes the invasion of tumor
cells into the microvasculature in the dermis. Some
reports note that vascular invasion significantly
increases the risk of relapse, lymph node involvement,
distant metastases, and death.108,115
MICROSCOPIC SATELLITES
The presence of microscopic satellitosis, in particu-
lar, has been consistently reported to correlate with
a poorer outcome, and this has been retained in the
current AJCC melanoma staging system (Tables 116-6
and 116-7).78,105 Patients with any satellite metastases,
including microsatellite metastases, are considered
to have stage III disease even in the absence of nodal
metastases (N1c, satellite metastases without nodal
metastases).
TUMOR INFILTRATING
LYMPHOCYTES (TILs)
TILs in primary melanomas are thought to repre-
sent the host antitumor immune response. In the
radial growth phase, a brisk host response is com-
monly present, and this feature may be associated
Kang_CH116_p1982-2017.indd 1999
with the appearance of areas of partial regression
(Fig. 116-2A).116 However, signs of regression itself
20
play no role for the risk of nodal involvement nor
in survival of patients with melanoma.107 In contrast
to this, TIL in the vertical growth phase of the mel-
anoma are less frequent and might be relevant for
prognosis of the patient. They have been character-
ized as brisk (a dense band of lymphocytes among
tumor cells across the entire base or throughout the
tumor), nonbrisk, or absent, and a direct relation-
ship between the TIL grade and prolonged survival
was observed.116 In 2 large studies, up to 3330 and
1241 primary melanomas were investigated for TIL
infiltration. TILs were classified as absent in 21%
Chapter 116 :: Melanoma
and 31%, nonbrisk in 64% and 27%, and brisk in 15%
and 42%, respectively.117,118 Patients with a higher
TIL grade of the primary melanoma were associated
with a lower risk of melanoma-specific death, inde-
pendent of tumor characteristics by AJCC tumor
stage.117 Patients with brisk TIL had improved recur-
rence-free and overall survival compared to patients
with non-brisk and absent TILs.118
PROGNOSTIC FACTORS IN
REGIONAL METASTASES
The status of the regional lymph nodes is the most pow-
erful prognostic factor for survival in melanoma, with
regional lymph node metastasis portending a worse
prognosis. The number of lymph nodes involved (inde-
pendent of tumor deposit size) is the most significant
risk factor in patients with stage III melanoma.78 The
second most important risk factor is tumor burden,
stratified into micro-metastatic disease (determined
by SLNB) or macro-metastatic disease (clinically pal-
pable nodes). In clinically node-negative stage I or II
patients, SLN status is the most significant prognostic
factor with respect to disease-free and disease-specific
survival.98,119 As such, consideration of SLNB to search
for micro-metastatic disease has become the standard
of care for most clinically node-negative patients with
melanomas 1 mm and greater in thickness, and for a
subset of thinner melanomas, with additional risk
factors such as high mitotic rate and lymphovascular
invasion, especially in younger patients. SLNB is a
powerful tool for accurately staging clinically node-
negative patients and as such, use of this technique
continues to play a central role in the AJCC staging
classification system for melanoma.78 Ulceration of the
primary lesion indicates a worse prognosis in regional
stage III disease. Mitotic rate of the primary lesion
strongly correlates with a worse prognosis for micro-
scopic regional stage III disease. Satellite metastases,
both clinical and microscopic, around a primary mela-
noma and in-transit metastases between the primary
and its nodal basin represent intra-lymphatic disease
(N1c, N2c, N3c) and portend the worst prognosis
for regional metastases (stage IIIB/C disease) with a 1999
5-year survival rate less than 50%.78
08/12/18 12:41 pm
20 PROGNOSTIC FACTORS IN
DISTANT METASTASES
The presence of distant metastases is associated with
the worst prognosis, with mean survival rates mea-
sured in months rather than years—at least till a
few years ago. Site of metastasis continues to be an
important prognostic factor in the AJCC melanoma
staging; with visceral metastases having a relatively
poorer prognosis than nonvisceral (skin, subcutane-
ous tissue, and distant lymph nodes) sites.78 Other
variables of prognostic significance are the number
of metastatic sites and surgical resectability. Solitary
Part 20
metastases resected after radiologic demonstration of
stability over 3 to 6 months have been associated with
prolonged survival in some patients, but no strong evi-
::
dence exists that asymptomatic detection is associated
with significant overall survival as of this writing.120
Neoplasia
Elevated serum LDH levels are associated with a
worse prognosis, regardless of the site of metastatic
disease (Table 116-6).
MANAGEMENT
SURGICAL TREATMENT OF
PRIMARY MELANOMA
The standard of therapy for primary cutaneous
melanoma is wide local excision (WLE). The pur-
pose of the wider excision is to prevent local recur-
rence due to subclinical persistent disease—whether
there is a minor influence on overall survival is not
clear as of this writing.121,122 The risk of satellite
metastases is directly related to primary melanoma
thickness.123 Hence, current recommendations on
the clinical margins differ depending on the Bre-
slow thickness of the primary and are based on
several large randomized trials comparing differ-
ent-sized margins.121 For melanoma in situ, a 0.5- to
1-cm margin, for melanoma <1 mm Breslow depth a
1-cm margin, for melanoma 1 to 2 mm thick a 1- to
2-cm margin, and for melanoma >2 mm thick a 2-cm
margin is recommended. Wider excisions with up
to 5-cm margins have not shown a benefit for local
recurrence rate.124
Ultimately, each patient should be evaluated indi-
vidually, taking into account current surgical guide-
lines as well as anatomic site (ie, location near a vital
structure), the possibility of primary closure ver-
sus need for skin graft, and the presence or lack of
adverse prognostic factors from micro-staging. Mela-
noma excision at special sites, such as the digits, soles,
ears, vagina, or anus, also requires separate surgical
and functional considerations. When anatomically
in a difficult location, for example, lentigo maligna
on the face or acral melanoma on the hands/feet, an
2000 excision with histopathologically confirmed free mar-
gins can be done instead after informed consent of the
Kang_CH116_p1982-2017.indd 2000
patient.125 Still, the fundamental oncologic principle
should always be tumor clearance first, reconstruc-
tion second.
SURGICAL TREATMENT OF
REGIONAL METASTASES
MICROSCOPIC NODAL DISEASE
Elective lymph node dissection (ELND) is the removal
of regional lymph nodes draining the site of a primary
cutaneous melanoma in the absence of any palpable
or clinically evident metastatic disease. Historically,
before the advent of SLNB, ELND was advocated for
melanomas at higher risk of regional spread to eradi-
cate occult micro-metastases in a potentially curative
manner. Multiple prospective randomized controlled
trials failed to demonstrate a significant benefit from
ELND for melanoma.126 Thus, there is no role for ELND
today, especially in light of the development and avail-
ability of SLNB.
As mentioned previously, the SLNB procedure is a
powerful staging tool that identifies micro-metastatic
nodal disease.127 After positive SLNB, up to 15% to
20% of patients have evidence of non-SLN metasta-
ses found during CLND.128-130 For the entire group,
patients in the randomized MSLT-I trial who received
an SLNB did not have an improved melanoma spe-
cific survival when compared to patients who did not
receive an SLNB, and thus SLNB cannot be classified
as therapeutic as of this writing based on interim data.
Importantly, the study is underpowered to answer
that question, with approximately 80% of subjects not
harboring nodal deposits. Nevertheless, in the group
of patients with melanoma metastatic to the lymph
nodes, the 5-year survival was significantly higher
among patients with a positive SLNB and immediate
CLND compared to patients in the observation fol-
lowed by CLND for clinical nodal disease arm (72%
vs 52%).98 Critics accurately point to the fact that this
trial component was not randomized and data are not
mature.
In the DECOG-SLT trial where patients with a
positive SLN were randomized to CLND or observa-
tion (followed by CLND in the case of local recur-
rence) no benefit in overall survival was found for
the CLND group.99 Three-year overall survival was
81.2% in the CLND group and 81.7% in the obser-
vation group (hazard ratio [HR] 0.96; P = .87). The
only difference detected between the groups was
the rate in regional lymph node recurrences, with
8.3% in the CLND arm and 14.6% in the observation
arm (P = .029). This finding did not translate into
a benefit in recurrence-free survival, with a 3-year
recurrence-free survival of 66.8% in the CLND arm
and 67.4% in the observation arm (P = .75). Hence,
CLND is not recommended any more for patients
with a positive Sentinel node. Recent data from the
MSLT-II trial with a similar scientific objective of
08/12/18 12:41 pm
 assessing the impact of SLNB on survival support
this recommendation.
MACROSCOPIC NODAL DISEASE
The current standard of therapy for macroscopic
(stage IIIB or IIIC) melanoma in lymph nodes is CLND
of the involved regional basin. Uncontrolled nodal dis-
ease is a cause of melanoma-related morbidity with
a significant high negative impact on quality of life.
CLND for regional metastatic melanoma has been
associated with long-term survival in a proportion of
patients.131
ADJUVANT TREATMENT
Adjuvant therapy is treatment for patients with surgi-
cally resected disease who are at high risk for relapse,
such as those with thick primary melanomas or nodal
disease. For decades, treatment with interferon-α was
the only adjuvant option outside clinical trials for
these patients. Recently, the immune checkpoint block-
ers used to treat stage IV disease like the anticytotoxic
T-lymphocyte–associated protein 4 (CTLA-4) antibody
ipilimumab and the anti-PD-1 antibodies nivolumab
and pembrolizumab have been studied in the adjuvant
setting for stage III disease, leading to FDA approval of
ipilimumab and nivolumab already.111
INTERFERON-α
Interferons (IFNs) are cytokines that are usually
released by cells in response to the presence of sev-
eral pathogens such as viruses, bacteria, parasites, and
also tumor cells. Typically, IFNs lead to a protection of
neighboring cells from virus infection. But they have
various other functions like the activation of natural
killer cells and macrophages and enhancing immune
recognition by upregulation of MHC class I and II
molecules. In addition, IFN-α has direct antineoplastic
activity leading to the inhibition of tumor cell prolifer-
ation likely via activation of STAT1132-134 and a possible
antimetastatic effect.135 However, in the treatment of
melanoma, IFN-α only has moderate activity and the
survival advantage associated with this treatment is
unclear. Two different dosage regimens were routinely
used: high-dose (HDI) and low-dose interferon (LDI)
treatment. The high-dose regimen consists of 20 mil-
lion units per square meter of body surface area per day
given intravenously 5 days a week for 4 weeks (induc-
tion phase), followed by 10 million units per square
meter per day given subcutaneously 3 times a week for
48 weeks (maintenance phase). The low-dose regimen
uses 3 million units 3 times a week given subcutane-
ously for 1.5 years. In a Cochrane data review, 18 ran-
domized controlled trials were included, with a total of
10,499 patients.136 This analysis showed that adjuvant
interferon was associated with significantly improved
disease-free survival (HR 0.83; P < .00001) and overall
Kang_CH116_p1982-2017.indd 2001
survival (OS) (HR 0.91; P = .003). The authors state that
considering a 5-year OS rate for TNM stage II to III is
20
60%, the number needed to treat to prevent 1 death
is 35. However, the patients treated with IFN have
very different prognoses worsening from stage I to
III. Unfortunately, even though so many patients were
included, subgroup analysis failed to answer the ques-
tion of whether some treatment features like dosage or
treatment duration might have an impact on interferon
efficacy or whether subgroups (eg, stage II vs stage III)
might benefit.
In another meta-analyses of more than 6000 patients,
survival benefit was 7% for progression-free survival
(PFS) and 3% for OS after 5 years with no signifi-
Chapter 116 :: Melanoma
cant differences between HDI and LDI treatment.137
A subgroup analysis of 2 EORTC trials revealed that
patients with an ulcerated primary melanoma and/
or a positive SLN might benefit more from IFN.112 The
effect on ulcerated primary melanoma is currently
being validated by another prospective EORTC trial
(NCT01502696) in SLN-negative melanoma patients.
For patients with a positive SLN, the Sunbelt
Melanoma Trial showed that they do not benefit from
HDI treatment after CLND.138 However, patient num-
bers were too small to answer this question.
There are significant toxicities associated with IFN
treatment, the most frequent being flulike symptoms
in almost all patients (ie, fatigue, anorexia, weight loss,
myalgias, fever, nausea, and headache). Other side
effects include depression, hepatotoxicity (elevated
transaminases), and myelosuppression.132 The toxici-
ties may require dose modification, especially in HDI
treatment, and if the patient makes it through the first
3 months of therapy, most are able to complete at least
80% of the scheduled dosing and are able to finish
treatment.139 Interestingly, the appearance of autoanti-
bodies or clinical manifestations of autoimmunity such
as vitiligo during treatment with IFN may be associ-
ated with a significant improvement in relapse-free
survival and overall survival in melanoma patients
undergoing adjuvant IFN.140
Importantly, HDI treatment is not recommended any
more as more effective treatments are now approved
for stage III disease.
IMMUNE CHECKPOINT BLOCKERS
For patients with stage III disease in the USA, treat-
ment with the anti-CTLA-4 antibody ipilimumab
is FDA approved. CTLA-4 (or CD152) is a so-called
immune checkpoint molecule that is expressed on the
surface of activated T cells and leads to their deacti-
vation on binding to CD80 or CD86 on the surface of
antigen-presenting cells. This mechanism seems to be
in place to downregulate an immune response after
activation and thereby prevent autoimmunity. In a ran-
domized double-blind phase 3 trial, 951 stage III mela-
noma patients were included after complete resection
of nodal metastases of at least 1 mm diameter to
receive either 10 mg/kg ipilimumab or placebo every 2001
3 weeks for 4 doses and then every 3 months for up to
08/12/18 12:41 pm
20 3 years.111 Ipilimumab treatment led to an improvement
of the median recurrence-free survival by 9 months
from 17.1 months in the placebo group to 26.1 months
in the ipilimumab group. Three-year recurrence-free
survival was 34.8% in the placebo group and 46.5% in
the ipilimumab group. Whether this approach leads
to a benefit in overall survival is still under analysis.
In addition, the ipilimumab treatment is also being
compared to HDI in clinical trials to assess relative
effectivity.
Side effects with ipilimumab are mainly of autoim-
mune nature and can be severe but are manageable (see
below). However, treatment with less toxic immune
checkpoint blockers nivolumab or pembrolizumab
Part 20
directed against programmed cell death protein 1
(PD-1) have just been reported to be even more effec-
tive with a better tolerability -reducing the relative risk
for recurrence by half (Checkmate 238, Keynote-054).
::
Neoplasia
ADJUVANT RADIOTHERAPY
Adjuvant radiotherapy after CLND can help to control
metastases in the nodal basin of stage III melanoma
patients. Recommendations are based on retrospec-
tive analyses focusing on the likelihood of nodal
recurrence as a function of different risk factors.141-143
These investigations revealed 3 main risk factors for
relapse: ≥3 lymph node metastases, lymph nodes
with extracapsular spread, or lymph nodes >3 cm in
diameter. In addition, adjuvant radiotherapy should
be considered in the case of nodal recurrence. A small
randomized controlled trial with patients at high risk
for lymph node relapse judged on these criteria con-
firmed data from the retrospective analyses and dem-
onstrated a significantly higher loco-regional control
rate for patients with adjuvant radiotherapy but no
effect on relapse-free or overall survival.144 If this stays
right under adjuvant immunotherapies with immune
checkpoint blockers needs to be verified.
MANAGEMENT OF
SATELLITE OR IN-TRANSIT
METASTASES
In general, regional in-transit or satellite disease
should be surgically excised whenever possible with
curative intent. However, if multiple lesions make
surgery unreasonable, other treatment options should
be considered. In locally limited disease, radiation
can be a good option, especially in multiple small
metastases.145 Additional application of hyperthermia
can increase the ratio for complete responses.146 Small
and superficial metastases respond very well to intra-
lesional interleukin-2. For bigger metastases, intral-
esional injections with the oncolytic virus Talimogene
Laherparepvec (T-VEC) or electrochemotherapy (ECT)
2002 are therapeutic options. In a meta-analysis, 47 trials on
skin-directed treatment approaches were compared.147
Kang_CH116_p1982-2017.indd 2002
In these trials, 915 patients with 4313 metastases
received different treatments such as ECT, photody-
namic therapy, radiotherapy, intralesional, or topical
treatments. Patients showed an overall response rate
of 60.2%, a complete remission rate of 35.5%, and a
recurrence rate of 9.2%. If local treatments do not lead
to local control, patients with extensive disease in the
extremities can benefit from locally applied chemo-
therapy by isolated limb perfusion. All systemic treat-
ment options are also available for nonresectable stage
III disease.
INTRALESIONAL INTERLEUKIN-2
This is a very effective approach especially for small
and superficial metastases, with a response rate of
more than 80% if applied 2 to 3 times a week over
multiple weeks (Fig. 116-9). Unexpectedly long sur-
vival times and good responses to subsequent che-
motherapies were noted in a retrospective analysis,
suggesting that a systemic effect may accompany such
intralesional administration.148 In a systemic review,
140 patients with 2182 metastases from 6 publications
were evaluated and showed a complete response rate
of 50%.149 Treatment is tolerated well, with local pain
and swelling and mild flu-like symptoms as main side
effects.
TALIMOGENE LAHERPAREPVEC
(T-VEC)
Intralesional application of an oncolytic virus is a new
treatment option for patients with unresectable stage III
or stage IV M1a disease. T-VEC is a transgenic her-
pes virus (Type 1) that is selectively replicated in
the tumor and produces granulocyte macrophage
colony-stimulating factor (GM-CSF) to augment local
and potentially distant immune responses. In a ran-
domized phase 3 trial versus GM-CSF monotherapy,
the best durable response with T-VEC was found in
patients with stage IIIB/C or M1a disease without sys-
temic pretreatment.150 Also, this treatment is tolerated
relatively well, with fatigue and fever being the most
frequent side effects.
ELECTROCHEMOTHERAPY (ECT)
ECT is an effective and tolerable treatment option for
patients with in-transit metastases, but needs spe-
cial technical equipment. ECT is a combination of a
local or systemic chemotherapy (usually bleomycin
or cisplatin) with intralesionally applied electrical
pulses. As these lead to painful muscle contractions
the procedure should be done in general anaesthesia
or local anaesthesia with sedation and is hence usu-
ally done in the operating room. Theoretically, the
electric pulses increase the permeability of the tumor
cell membranes (electroporation) and thereby sensi-
tize them to the chemotherapy. In a systematic review
and meta-analysis, data from 44 trials with altogether
08/12/18 12:41 pm
 20

Chapter 116 :: Melanoma

A B

C D

Figure 116-9 Treatment of satellite metastases with intralesional interleukin-2: A, before treatment; B, after 6 weeks of
treatment; C, 4 weeks later without any further treatment; D, 2 years later without any further treatment.

431 patients and 1894 metastases were pooled.151 were associated with a higher response rate com-
The response rate of single metastases was 80.6%, pared to systemic chemotherapy, because of practical
complete remissions were observed in 56.8%. Even reasons systemic chemotherapy is preferred in rou- 2003
though intralesional injections of the chemotherapy tine clinical practice.

Kang_CH116_p1982-2017.indd 2003 08/12/18 12:42 pm

20 ISOLATED LIMB PERFUSION (ILP)
Isolated limb perfusion (ILP) may be considered for
loco-regional disease control limited to an extremity. ILP
is a form of regional chemotherapy that delivers higher
doses of chemotherapeutic agents to the limb with less
systemic toxicities. The technique involves perfusing an
isolated extremity under hyperthermic conditions with
cytotoxic agents, conventionally melphalan. ILP with
melphalan is an effective form of regional therapy in
some cases with an associated considerable morbidity,
producing partial or complete regional responses in up
to 80%.152 The benefit is aimed at loco-regional control,
not overall survival. The ILP procedure may be associ-
Part 20
ated with serious local morbidities, including signifi-
cant tissue damage or compartment syndrome. Elderly
age and serious medical comorbidities are generally
considered exclusion criteria. Isolated limb infusion
::
(ILI) is a, simpler, less-invasive technique. Early studies
Neoplasia
of ILI with melphalan and actinomycin D demonstrate
efficacy comparable to that of ILP with melphalan.153 ILI
may be considered for patients ineligible for ILP.
LOCAL HEPATIC THERAPY
FOR UVEAL MELANOMA
WITH LIVER METASTASES
As uveal melanomas metastasize preferentially into
the liver, local treatments to the liver can be a treatment
option. Different procedures have been established
from surgery or ablation of isolated metastases to che-
moperfusion/embolization or radio-embolization. In a
phase 3 trial, hepatic intraarterial infusion of fotemus-
tine was compared with fotemustine applied intrave-
nously. The trial was stopped early, as interim analysis
revealed that the local application of fotemustine did
not improve overall survival compared to the IV arm
despite having a better response rate and better PFS.154
In another randomized phase 3 trial of percutaneous
hepatic perfusion with melphalan (chemosaturation)
versus best available care, a highly significant difference
was found concerning hepatic PFS (7.0 vs 1.6 months;
P < .0001) and overall PFS (5.4 vs 1.6 months; P < .0001).
However, overall survival again was not significantly
different—though this might be influenced by the cross-
over design of the trial.155 All procedures can achieve
responses but have not been shown to prolong survival
of the patients. Additionally, the procedure is laborious
and has a significant risk of complications. As such, ran-
domized controlled trials are rarely performed.
TREATMENT OF
UNRESECTABLE
METASTATIC DISEASE
2004 Until a few years ago, treatment of stage IV melanoma
was purely palliative with the intention to potentially
Kang_CH116_p1982-2017.indd 2004
increase length of survival and palliation of symp-
toms. Recently, significant progress was achieved and
treatment modalities are available now that substan-
tially improve patient survival from a median of 6 to
9 months to 2 years with the chance to achieve long-
term tumor control.101,102,156
SURGERY AND RADIOTHERAPY
Even though hematologic spread should be defined as
unresectable in general, surgical excision of isolated
visceral metastases (ie, metastasectomy) can be consid-
ered and may be performed with long-term disease-
free intervals in some patients. In addition, surgery also
may be palliative, for example, to treat isolated brain
metastases or relieve obstruction from GI metastases.
Surgical excision of skin/subcutis or distant lymph
node metastases may result in improved loco-regional
control and decreased morbidity.157 Radiotherapy is an
option and preferably used to treat brain metastases,
especially using stereotactic radiation for limited brain
disease. Palliative radiation may be indicated for spi-
nal cord compression and painful bone metastases.
IMMUNOTHERAPIES
The importance of the immune system in cancer control
was nicely shown in a mouse experiment where sarco-
mas can be induced by chemical carcinogenesis with
3′-methylcholanthrene (MCA).158 Mice with clinically
stable tumors were either injected with depleting anti-
bodies against T cells (CD4/CD8/IFN-γ) or a control
antibody. Mice receiving the control antibody remained
stable but mice with a T-cell depletion developed grow-
ing sarcomas in 60% of cases. Hence, tumors can be con-
trolled by the immune system. This is suggested to work
via the so-called Cancer-Immunity-Cycle159 where the
release of cancer cell antigens by cancer cell death leads
to presentation of the antigens by dendritic cells. These
prime and activate T cells in the lymph nodes, which
then traffic through the blood vessels to the tumor and
infiltrate it. Finally, recognition of cancer cells by these
T cells lead to cancer killing and elimination.
A known phenomenon in primary melanomas is the
tendency for regression (Fig. 116-2). When observed
in melanoma metastases it is often associated with a
favorable outcome.160 This has been linked to an effec-
tive immune defense, and the number of TILs in the
primary melanoma could be correlated with patients’
survival.117,118 In addition, it is well known that immu-
nosuppressed patients, for example, transplant recipi-
ents have an increased risk for developing melanoma
and show an aggressive clinical course of the disease.161
Hence, treatments that stimulate the immune response
and aim to overcome immune escape mechanisms of
the tumor have a potential to effectively fight cancer.
Historically, several approaches have been studied
starting with William Coley, an American surgeon,
who tried to elicit a therapeutic immune response
through injection of bacterial broth (later called Coley
toxin) into soft-tissue tumors. In the following decades
08/12/18 12:42 pm
 cytokines like interleukin-2 and interferon-α have
been used in the clinic. In addition, multiple attempts
have been made to develop a therapeutic vaccine—all
with limited success.162 The scientific turning point for
cancer immunotherapy came with the understanding
that T-cell immune responses are controlled through
on and off switches, the so-called immune checkpoints
that protect the body from possibly damaging immune
responses.
Immune Checkpoint Blockade: T-cell acti-
vation relies on 2 stimulating signals mediated via
several surface receptors: one is the T-cell receptor
(TCR) recognition of antigens associated with MHC
antigen–presenting molecules, the second is binding
of a costimulatory molecule like CD28, CD27, GITR,
OX40, or ICOS. On activation, T cells express coin-
hibitory receptors like CTLA-4, PD-1, TIM-3, and
LAG-3, the so-called immune checkpoints that lead
to downregulation of the T-cell response and T-cell
anergy. Ipilimumab is a monoclonal blocking anti-
body against CTLA-4 and hence stops inhibition of the
T-cell response (Fig. 116-10). Ipilimumab is particularly
remarkable because it was the first drug to show a sig-
nificant benefit for OS in patients with stage IV mela-
noma.163 In addition, despite a response rate of only
about 10%, more than 20% of patients reach a long-
term tumor control of more than 3 years.156
These results were improved even further by the
use of blocking antibodies against PD-1, namely,
nivolumab and pembrolizumab. PD-1 on the surface
of activated T cells binds to PD-L1 and PD-L2, which
Diverse roles
oles of different immune checkpoints
Lymph node
Priming
phase
Dendritic T cell
cell
MHC TCR
Activation
signals
B7 CD28
Inhibitory
nhibitory
ory
r y signals
B7
CTLA-4
Antibody
Figure 116-10 Mechanism of action of immune checkpoint blockage: The anti-CTLA-4 antibodies block the downregula-
tion of T cells in their priming phase in the lymph nodes whereas the anti-PD-1 antibodies block the downregulation of
activated T cells in their effector phase in the tumor microenvironment.
Kang_CH116_p1982-2017.indd 2005
are expressed in peripheral tissues and different cancer
types, including melanoma. The PD-1/PD-L1 pathway
20
plays a critical role in tumor escape as binding leads to
downregulation of tumor-associated T cells. In some
tumors, surface expression of PD-L1 has been reported
to be an independent predictor of adverse clinical
outcome,164 although it appears to be a positive prog-
nostic feature in patients with melanoma.165-167
In melanoma, PD-1 blockage leads to signifi-
cant tumor reduction in 30% to 40% of patients and
was shown to prolong PFS and OS with a 2-year OS
of roughly 60%.102,168 Patients with a PD-L1 tumor
expression of at least 5% might have a better objective
response to the treatment (odds ratio 2.52) ranging
Chapter 116 :: Melanoma
from 46% for PD-L1-positive and 27% for PD-L1-
negative tumors.164 Two-year OS rates differ too, with
57.2% of patients alive with a PD-L1-positive tumor and
32.6% with a PD-L1-negative tumor in the Keynote 001
trial.169 Hence, patients with a PD-L1-negative tumor
can still respond to treatment. This might be partly
based on the fact that PD-L1 expression is focal and
dynamic, leading to potential sampling error on
smaller biopsies. Additionally, numerous immunohis-
tochemical assays with potentially different scoring
systems of positivity as well as sensitivity for PD-L1
detection are currently being used to test specimens.
For patients with melanoma, testing for PD-L1 expres-
sion is not required for anti-PD-1 administration, as it
is for some other tumor types.
The combination of both ipilimumab and nivolumab
lead to remarkable responses in melanoma in the
Checkmate 067 trial. Response rates of 58% and
Peripheral tissue
Effector
phase
T cell Cancer
cell
TCR MHC
N
Ne
Negative
t e
regulation
PD-1 PD-L1
Antibodies
2005
08/12/18 12:42 pm
20 a median PFS of 11.5 months were seen with the
combination compared to a 19.0% response rate
and a median PFS of 2.9 months with ipilimumab
monotherapy.170 In addition, responses to the combina-
tion immunotherapy seem to occur faster, including
potentially in patients with highly advanced disease.
Concerning OS, median OS had not been reached yet
for the ipilimumab plus nivolumab combination at a
minimum followup of 36 months, it was 37.5 months
in the nivolumab and 19.9 months in the ipilimumab
monotherapy group. The overall survival rate at 3
years was 58% for ipilimumab plus nivolumab, 52%
for nivolumab, and 34% for ipilimumab.171 Unfortu-
nately, in the treatment of metastasized ocular mela-
Part 20
noma immunotherapies have been of limited success
with no responses and a median OS of 6.8 months in a
Phase II trial.172 Responses to PD-1 directed treatment
are rarely observed. Reported response rates range
::
from 3% to 30% and may be higher in patients with
Neoplasia
extrahepatic disease.173-175
Side effects from these treatments can be severe
to life-threatening. These consist of mainly autoim-
mune effects, so-called immune-related adverse events
(irAEs), against different organs secondary to immune
stimulation. The most frequent side effects affect the
skin, the liver, the GI tract, and the endocrine system
(hypophysis, thyroid) (Table 116-8).176 The dermatitis is
typically mild in degree. IrAEs affecting other organ
systems such as colitis, however, can be severe and
require high-dose immunosuppressant treatment to
prevent complications like bowel perforations.
Even though the character of these side effects is simi-
lar between the anti-CTLA-4 antibodies, the PD-1 anti-
bodies, and a combination of both, the frequency differs
considerably. Side effects can be nicely compared within
the CheckMate 067 trial.170 Here, severe side effects
(grade 3 or higher according to the common toxicity cri-
teria for adverse events [CTC-AE]) occurred in only 16%
of patients receiving treatment with nivolumab, 27% in
TABLE 116-8
Common Side Effects from Immune Checkpoint Blocker Treatment (Treatment-Related Adverse Events
from CheckMate 067 Trial)
IMMUNE CHECKPOINT BLOCKER IPILIMUMAB
SEVERITY (CTC-AE) OF EVENT ANY 3 OR 4
All treatment-related events (in %) 86 27
GI (lower tract: Diarrhea, Colitis) 37 12
GI (upper tract: Nausea, decreased appetite) 29 1 24
Dermatologic (Rash, Pruritus) 55 3 44
Hepatic (elevated transaminases) 7 2
Endocrine (Hypo-/hyperthyroidism) 12 3 16
Pulmonary (Pneumonitis) 2 <1
Renal (elevated creatinine) 3 <1
Fatigue 28 1 34
2006 Arthralgia 6 0
Kang_CH116_p1982-2017.indd 2006
those receiving ipilimumab, and 55% of those receiving
nivolumab plus ipilimumab. In addition to experienc-
ing a higher frequency of side effects with combina-
tion therapy, patients receiving combination treatment
tended to have several organs affected, for example, one
patient experiencing colitis, hepatitis, thyroiditis, and
pancreatitis. An increasing familiarity with this new
class of side effects led to the development of special
treatment algorithms that can be used to effectively treat
patients experiencing irAEs (see Fig. 116-11). In general,
side effects should be treated quickly, with the choice
of the immunosuppressive treatment dependent on the
severity of symptoms. The relationship between the
side effects and response to therapy is still under discus-
sion, though a number of reports have suggested that
there might be a relationship with an improved clinical
outcome.32,177-181
Adoptive T-Cell Therapy: Adoptive T-cell
therapy (ACT), in particular, autologous in vitro
expanded TIL therapy, is another promising approach
in immunotherapy of cancer but is only established in
a few cancer centers worldwide. TILs from melanoma
metastases are expanded under GMP conditions and
reinfused into the patient after lymphoablative chemo-
therapy followed by high-dose interleukin-2 treatment.
Several clinical trials demonstrated durable clinical
responses for more than 50% of patients.182,183 However,
not much is known on the nature of expanded T cells.
Recent findings suggest that a crucial component of the
therapeutic T-cell response targets patient- and tumor-
specific neoantigens resulting from somatic mutations
and that only a minority of TILs respond to defined
melanoma-associated antigens like differentiation
(MART-a, gp100, tyrosinase) or cancer/testis antigens
(MAGE, NY-Eso).184 Newer approaches attempt to
genetically modify the T cells with expression of TCRs
or chimeric antigen receptors (CARs) against known
antigens before re-infusion.
NIVOLUMAB IPILIMUMAB + NIVOLUMAB
ANY 3 OR 4 ANY 3 OR 4
82 16 96 55
22 3 48 15
0 44 3.5
2 60 6
7 3 32 20
2 32 6
2 <1 7 1
1 <1 6 2
1 35 4
8 0 11 <1
08/12/18 12:42 pm
 Algorithm to treat side effects from immune checkpoint blockers
Severity Examinations
Monitor clinical course
Monitor clinical course
Hospital admission
Figure 116-11 Algorithm to treat side effects from immune checkpoint blockers.
High-Dose Interleukin-2 (IL-2): Before the
era of immune checkpoint inhibition, high-dose bolus
IL-2 was the only FDA-approved immunologic treat-
ment for metastatic melanoma that was recognized to
produce rare but durable complete responses. It has
been shown as a single agent to induce a 16% overall
response rate with durable response in up to 5% to 8%
of patients.185 High-dose IL-2 is associated with signifi-
cant toxicity, for example, a capillary-leak syndrome.
Following FDA approval of immune checkpoint block-
ing agents, IL-2 is generally not used systemically in
routine clinical use.
TARGETED THERAPIES
Melanoma is characterized by a high genetic instabil-
ity that leads to a high mutation rate and molecular
heterogeneity attributed to the mutagenic effects of
UV irradiation. In a 2002 genomewide screen, BRAF
point mutations were discovered at high frequency
in melanomas relative to other cancers such as those
of the thyroid and colon.186 Most oncogenic BRAF
mutations cause valine-to-glutamic acid substitutions
at codon 600 (V600E) that constitutively activate the
kinase domain and thereby the mitogen-activated
protein kinase (MAPK) signaling pathway. Further
sequencing studies identified numerous novel mela-
noma genes involved in regulation of the MAPK and
other signaling pathways. BRAF and NRAS muta-
tions are found in two-thirds of melanomas (other
genetic alterations include amplification of AKT3
and loss of PTEN), leading to an activation of the
Kang_CH116_p1982-2017.indd 2007
20
Management
Symptomatic treatment
Oral corticosteroid treatment
Chapter 116 :: Melanoma
IV corticosteroid treatment
phosphatidylinositol 3-kinase (PI3K) pathway. In
addition, these pathways can be hyperactivated by
overexpression or mutation of growth factor receptors
such as c-Kit, Met and EGF-R or inactivating mutation
in neurofibromin 1 (NF1).187
BRAF/MEK Inhibition: The BRAF V600 muta-
tion is most common in melanomas of sun-exposed
skin8 and can be detected in about 50% of melanomas.
The first BRAF inhibitor used was sorafenib which
is an orally available unspecific RAF inhibitor that
inhibits B-raf and C-raf in addition to other kinases.
Sorafenib demonstrated little activity in patients with
unresectable stage III or stage IV melanoma.187,188 The
observed clinical benefit was substantially different
with the development of the selective BRAF inhibi-
tors such as vemurafenib and dabrafenib (Fig. 116-12),
both of which are FDA approved. Approximately
50% of patients with a BRAF V600-mutated mela-
noma respond, and those who do tend to demonstrate
incredibly fast responses.189,190 Treatment prolongs sur-
vival, with a median PFS of 7 to 8 months and a median
OS of 16 to 18 months.101,191 Because patients do tend to
respond quickly, these agents can specifically benefit
those with a high tumor load (Fig. 116-13) and provide
symptom relief. Unfortunately, most patients develop
later resistance to the treatment.192 Mutational analysis
of resistant metastases revealed several genes known
to reactivate the MAPK pathway by bypassing BRAF.
These include somatic mutations in NRAS, amplifica-
tions of BRAF and mutation in MAP2K1/K2, MITF, and
NF1. Additional alterations with less clear of a relation- 2007
ship to resistance were observed in the PI3K pathway,
08/12/18 12:42 pm
20 MAPK pathway

GF
GF Cell membrane
receptor

P P Grb2 SOS RasGTP P

Kinases
P P Raf-1 eg, Src, PAK
GDP P
P PP2A P Vemurafenib
P Dabrafenib
Cobimetinib
MEK Encorafenib
Trametinib P
Binimetinib ERK P Substrate in cytosol
and cytoskeleton
Part 20

ERK
ERK ERK ERK
::

Substrates
P
in nucleus
Neoplasia

P
Nucleus SRF Elk-1 Gene transcription

Figure 116-12 The BRAF and MEK inhibitors block the activity of the respective kinases in the MAPK signaling pathway
and hence block cell proliferation and facilitate apoptosis.

Graph showing drop of tumor marker serum

lactate dehydrogenase
Lactate dehydrogenase (LDH)
U/I
803.2

342.0

159.8
0105 0105 0107 0108 0109 0110 0111 01

B C Start CobiVem

Figure 116-13 A 62-year-old patient with a superficial spreading melanoma on the left shoulder that metastasized to the
regional lymph nodes already and was unresectable at the time of diagnosis (A). As a BRAF V600E mutation was detected,
he received a combination treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. After 2 months
2008 of treatment, the lymph node conglomerates decreased in size significantly (B), accompanied by a drop of the tumor
marker serum lactate dehydrogenase (C).

Kang_CH116_p1982-2017.indd 2008 08/12/18 12:42 pm

 including PIK3CA/R1, PTEN, and HOXD8 or RAC1.
Reactivation of the MAPK pathway is the most fre-
quent mechanism of acquired therapeutic resistance;
thus, BRAF inhibitors have been combined with MEK
inhibitors such as trametinib and cobimetinib. Combi-
nation treatment leads to even higher response rates
of up to 70%, a median PFS of 10 to 11 months, and a
median OS of about 2 years. Hence, combination treat-
ment with a BRAF and a MEK inhibitor is standard of
care for patients with BRAF mutant melanoma in addi-
tion to the immunotherapeutic options.
Treatment is generally well tolerated, with fatigue,
nausea, diarrhea, arthralgia, and skin side effects as
most common.101 Skin side effects include exanthe-
mas, hyperkeratosis, verrucous lesions, and secondary
malignancies (cutaneous squamous cell carcinoma and
even melanoma). The squamous lesions are explained
by a paradoxical activation of MAPK signaling dur-
ing treatment with BRAF inhibitors in BRAF wildtype
keratinocytes. In most of the lesions, an RAS mutation
can be found.193,194 Such lesions are less frequent in the
combination of BRAF and MEK inhibition.
Some side effects are not class but substance specific
such as photosensitivity by vemurafenib and fever by
dabrafenib. MEK inhibitors can worsen a preexisting
heart insufficiency and lead to eye side effects like reti-
nal vein occlusions and retinopathies. Hence, patients
need surveillance by a cardiologist and an ophthalmol-
ogist under treatment.
In patients with NRAS mutations, the MEK inhibi-
tor binimetinib was tested in a phase 3 trial against
dacarbazine. It revealed limited efficacy, with an
overall response rate of 15% and a median PFS of
2.8  months,195 and hence will at best be a treatment
after failure of immunotherapy.
c-KIT Inhibition: Melanomas from acral and
mucosal sites are genetically distinct from other
melanomas.8 Most melanomas from acral and muco-
sal sites do not demonstrate mutations in BRAF, but a
subset has activating mutations or amplification of the
tyrosine kinase receptor KIT. These oncogenic lesions
occur mostly in the juxtamembrane domain (KIT exons
11, 13, and 17)—a region that is frequently targeted in
other cancers, including GI stromal tumors. Early stud-
ies with the tyrosine kinase inhibitor imatinib have
demonstrated significant responses in patients with
metastatic melanoma harboring activating mutations in
c-KIT.196,197 In several Phase II trials, imatinib and other
KIT inhibitors such as nilotinib were tested in patients
with KIT mutations and amplifications. Responses were
observed in 16% to 23% of patients.198,199 In both studies,
certain mutations in exon 11 and 13 of c-KIT (particu-
larly L576P mutation in exon 11) were associated with
the highest response rate. Thus, sensitivity to KIT inhi-
bition exists in metastatic melanoma but it is confined to
a subset of this already small subpopulation of patients.
CHEMOTHERAPIES
The alkylating agent dacarbazine (DTIC) is the
only FDA-approved chemotherapy for metastatic
Kang_CH116_p1982-2017.indd 2009
melanoma and is generally tolerated very well. How-
ever, response rates are only in the 10% range, with a
20
median response duration of 4 to 6 months.200 There
is no difference in terms of response rates and dura-
tion of response between the various dosing schedules
used. The major side effects are nausea and vomiting,
which can be controlled by antiemetics. Temozolomide
(TMZ) is an alkylating agent with the same active
metabolite as DTIC, but it is absorbed orally and can be
taken as a capsule. TMZ has been shown in a random-
ized Phase III study to have efficacy equal to DTIC.201
Combination chemotherapies, for example, carboplatin/
paclitaxel, might reveal higher response rates but
have no survival benefit compared with monochemo-
Chapter 116 :: Melanoma
therapy.187,202 Toxicity is generally remarkably higher.
With the approval of immune checkpoint blocker
and BRAF/MEK inhibitors, the use of chemotherapies
has faded into the background. They might be used in
a later line though it is important to keep in mind that
an advantage in patient survival has not been shown.
No randomized clinical trial exists where chemother-
apy was compared to best supportive care.
TREATMENT ALGORITHM
See Fig. 116-14.
FUTURE DIRECTIONS
First results are available for the combination of tar-
geted therapies with immune checkpoint blockade.
The combination is enticing as the fast response to tar-
geted therapies might be combined with a higher rate
of long-term remissions, especially in patients with
highly advanced disease. Combination of vemurafenib
and ipilimumab demonstrated apparent success in a
case series.203 However, a significant hepatotoxicity
was seen in a Phase I trial testing this combination.204
Combination of BRAF/MEK inhibitors with PD-1/
PD-L1–directed therapy seems to be less toxic.205 Ran-
domized phase 3 trials are recruiting patients, and data
are pending.
Other combination strategies combine different
immunotherapeutic approaches, for example, the com-
bination of the PD-1 antibody pembrolizumab with the
oncolytic virus T-VEC (Masterkey-265; NCT02263508)206
or the indolamin-2,3-dioxygenase (IDO) inhibitor
indoximod (NCT02073123) (Table 116-9). IDO is a
negative immune modulator that may be expressed
by antigen-presenting cells in the tumor microenvi-
ronment. Other inhibitory checkpoint molecules that
could be targeted to modulate the immune response
include LAG-3 and TIM-3, both of which are being tar-
geted in early clinical trials for a number of indications.
In addition, costimulatory TCR signals could be elic-
ited, eg, by targeting CD137, OX40, CD27 or GITR. The
complexity of the immune system and tumor microen- 2009
vironment gives an idea of possible future treatment
08/12/18 12:42 pm
20 Treatment algorithm

Surgery Systemic treatment

Wide local excision Consider adjuvant treatment

Stage I/II

Complete lymph-node dissection Adjuvant treatment

Stage III (CLND)
Part 20

Consider metastasectomy Immune checkpoint blocker

Stage IV
::

Targeted Therapy
Neoplasia

Figure 116-14 Treatment algorithm.

strategies and the challenge will be to find the best characteristics like the mutational load (number of
suitable targets and combinations. mutations) correlates with response to treatment with
The best treatment option might differ considerably immune checkpoint blockers.207,208 This is probably
between patients eg, it is known already that tumor based on an increased chance for the immune system

TABLE 116-9
New Developments in Immunotherapy of Stage IV Melanoma
SUBSTANCE TARGET CLINICAL TRIALS NCT NUMBER

Epacadostat IDO inhibitor Phase 3, in combination with pembrolizumab NCT02752074

Indoximod IDO inhibitor Phase I/2 in combination with either ipilimumab, NCT02073123
nivolumab or pembrolizumab
Immune Checkpoint Blockers
IMP321 LAG-3Ig Fusion Protein Phase I, in combination with pembrolizumab NCT02676869
Costimulatory TCR Signals
BMS-663513 CD137 (4-1BB) antibody Phase II, monotherapy NCT00612664
Varlilumab CD27 antibody Phase I/2, in combination with ipilimumab +/- CDX-1401 NCT02413827
(NY-ESO vaccine)
TRX518-001 GITR antibody Phase I, monotherapy NCT01239134
Other Costimulatory Signals
APX005M CD40 antibody Phase I/2 in combination with pembrolizumab NCT02706353
Vaccinations
Lipo-Merit RNA vaccine encoding for 4 shared Phase I, first in human NCT02410733
tumor antigens
IVAC Mutanome Individual RNA vaccine encoding Phase I, first in human NCT02035956
neoantigens
Other Mechanisms
RFT-5-dgA Immunotoxin against CD25+ T cells Phase II, monotherapy NCT00314093
IMCgp100 Bispecific soluble gp100-specific TCR Phase1b/2 monotherapy and combination with either NCT02535078
fused to anti-CD3protein durvalumab (PD-L1 Ab) or tremilimumab (CTLA-4 Ab)
2010 Phase I in uveal melanoma NCT02570308

Kang_CH116_p1982-2017.indd 2010 08/12/18 12:42 pm

 to detect neo-antigens of the tumor by specific T-cell
clones and hence a cancer-specific immune attack. In
addition, other patient characteristics such as compo-
sition and responsiveness of the immune system are
likely to influence treatment efficacy. Hence, it is very
likely that several individual patient characteristics
beyond the BRAF status will direct treatment choice
to an individualized treatment in the near future—
including analysis of tumor mutations, expression of
immunoactive proteins such as PD-L1, and studies
on the composition and geography of tumor-infiltrat-
ing immune cells. The understanding of the tumor
immune defense can lead to new therapeutic strategies,
for example, vaccination approaches not only against
tumor-associated antigens209 but individualized vac-
cines targeting the tumor mutanome of the patient.
In addition to combination with other systemic
treatments, combination of immune checkpoint block-
ers with radiotherapy likely enhances tumor immune
response by release of tumor antigens and proinflam-
matory cytokines as well as enhanced antigen presen-
tation by upregulation of MHC molecule expression.210
After radiation of single metastases, responses have
been seen in metastases outside the radiation field, so-
called abscopal responses.211 Clinical trials will be nec-
essary to evaluate fully the efficacy of this combination.
PREVENTION/SCREENING
Public awareness and knowledge of melanoma and
UV exposure is improving, but still a substantial gap
exists between knowledge and behavior. Primary pre-
vention strategy should focus on safe sun exposure,
including limited UV exposure and sunburn preven-
tion, especially in childhood and adolescence when the
risk is greatest. Avoidance of peak sunlight hours and
use of wide-brimmed hats, clothing, and sunscreen are
recommended. In addition, early detection by regular
self-skin examinations, skin awareness, and know-
ledge of the early signs and symptoms of melanomas
should also be emphasized to patient, partners, and
family members. The goal of secondary prevention
is early diagnosis, which greatly reduces melanoma-
related morbidity and mortality.
FOLLOWUP
Patients with melanoma are at risk for local, regional,
and distant recurrence, with the level of risk dependent
on the stage at initial diagnosis and workup. Followup
visits are an opportunity to review how to perform
monthly skin and lymph node self-examinations,
address any psychosocial emotional distress issues,
obtain a melanoma-focused review of systems, and
provide continuing patient education regarding early
detection signs and symptoms and sun-protection/
prevention strategies. Regular followup is indicated
for all patients with melanoma. Current NCCN and
Kang_CH116_p1982-2017.indd 2011
national melanoma center guidelines call for at least
annual followup visits for life, with followup inter-
20
vals generally ranging from every 3 to 6 months for
1 to 3  years after diagnosis and annually thereafter,
depending primarily on stage of disease.212 Patients
with other risk factors, such as a positive family history
of melanoma, numerous nevi, or difficulty with self-
examination, may require more frequent followup. A
referral to a genetics counselor is warranted if there is a
strong family history of melanoma, or a family history
of pancreatic cancer.
The followup visit should consist of a thorough com-
plete skin examination for additional primary lesions
and cutaneous/subcutaneous metastases, particularly
Chapter 116 :: Melanoma
in the regional distribution of the primary, palpation of
lymph nodes preferably accompanied by lymph node
ultrasound with particular attention to the regional nodal
basin, and thorough history taking. The review of sys-
tems is the foundation for detecting symptomatology
possibly attributable to melanoma, and directs additional
testing or imaging. The yield and value of routine imag-
ing to restage asymptomatic patients as part of standard
melanoma followup are low and, thus, internationally
recommendation concerning followup procedures based
on imaging and hematologic tests differ substantially.
ACKNOWLEGDMENTS
This chapter was revised and updated from the for-
mer version, composed by Evans C. Bailey, Arthur J.
Sober, Hensin Tsao, Martin C. Mihm Jr, and Timothy
M. Johnson, and we thank them for their contribution.
We thank Nina Reuter, Media Center, University
Hospital Heidelberg for photograph search.
REFERENCES
1. Shain AH, Bastian BC. From melanocytes to melano-
mas. Nat Rev Cancer. 2016;16(6):345-358.
2. Rebecca VW, Sondak VK, Smalley KSM. A brief history
of melanoma: from mummies to mutations. Mela-
noma Res. 2012;22(2):114-122.
3. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN
2012 v1.0, Cancer Incidence and Mortality World-
wide: IARC CancerBase No. 11 [Internet]. Lyon,
France: International Agency for Research on Cancer;
2013. http://globocan.iarc.fr. Accessed day/month/
year.
4. Howlader N, Noone AM, Krapcho M, et al. SEER
Cancer Statistics Review, 1975-2013, National Cancer
Institute. Bethesda, MD, http://seer.cancer.gov/
csr/1975_2013/, based on November 2015 SEER data
submission, posted to the SEER web site, April 2016.
5. Svedman FC, Pillas D, Taylor A, et al. Stage-specific
survival and recurrence in patients with cutaneous
malignant melanoma in Europe—a systematic review
of the literature. Clin Epidemiol. 2016;8:109-122.
6. Arrangoiz R, Dorantes J, Cordera F, et al. Melanoma
review: epidemiology, risk factors, diagnosis and
staging. J Cancer Treat Res. 2016;4(1):1-15.
7. Thomas NE, Kricker A, Waxweiler WT, et al; Genes, 2011
Environment, and Melanoma (GEM) Study Group.
08/12/18 12:42 pm
20 Comparison of clinicopathologic features and sur-
vival of histopathologically amelanotic and pig-
mented melanomas: a population-based study.
JAMA Dermatol. 2014;150(12):1306-1314.
8. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets
of genetic alterations in melanoma. N Engl J Med.
2005;353(20):2135-2147.
9. Curtin JA, Busam K, Pinkel D, et al. Somatic activation
of KIT in distinct subtypes of melanoma. J Clin Oncol.
2006;24(26):4340-4346.
10. Torres-Cabala CA, Wang WL, Trent J, et al. Correla-
tion between KIT expression and KIT mutation in
melanoma: a study of 173 cases with emphasis on
the acral-lentiginous/mucosal type. Mod Pathol.
2009;22(11):1446-1456.
11. Busam KJ, Zhao H, Coit DG, et al. Distinction of des-
Part 20
moplastic melanoma from non-desmoplastic mela-
noma by gene expression profiling. J Invest Dermatol.
2005;124(2):412-418.
12. Shain AH, Garrido M, Botton T, et al. Exome sequencing
::
of desmoplastic melanoma identifies recurrent NFK-
Neoplasia
BIE promoter mutations and diverse activating muta-
tions in the MAPK pathway. Nat Genet. 2015;47(10):
1194-1199.
13. Wiesner T, Kiuru M, Scott SN, et al. NF1 Mutations
are common in desmoplastic melanoma. Am J Surg
Pathol. 2015;39(10):1357-1362.
14. McLaughlin CC, Wu XC, Jemal A, et al. Incidence
of noncutaneous melanomas in the U.S. Cancer.
2005;103(5):1000-1007.
15. Rodriguez-Sains RS. Pigmented conjunctival neo-
plasms. Orbit. 2002;21(3):231-238.
16. Cosgarea I, Ugurel S, Sucker A, et al. Targeted next
generation sequencing of mucosal melanomas iden-
tifies frequent NF1 and RAS mutations. Oncotarget.
2017;8(25):40683-40692.
17. Amit M, Tam S, Abdelmeguid AS, et al. Mutation
status among patients with sinonasal mucosal
melanoma and its impact on survival. Br J Cancer.
2017;116(12):1564-1571.
18. Öztürk Sari Ş, Yilmaz İ, Taşkin OÇ, et al. BRAF, NRAS,
KIT, TERT, GNAQ/GNA11 mutation profile analysis of
head and neck mucosal melanomas: a study of 42
cases. Pathology. 2017;49(1):55-61.
19. Hou JY, Baptiste C, Hombalegowda RB, et al. Vulvar
and vaginal melanoma: a unique subclass of muco-
sal melanoma based on a comprehensive molecu-
lar analysis of 51 cases compared with 2253 cases
of nongynecologic melanoma. Cancer. 2017;123(8):
1333-1344.
20. Yang HM, Hsiao SJ, Schaeffer DF, et al. Identification
of recurrent mutational events in anorectal mela-
noma. Mod Pathol. 2017;30(2):286-296.
21. Kim KB, Alrwas A. Treatment of KIT-mutated metastatic
mucosal melanoma. Chin Clin Oncol. 2014;3(3):35.
22. Magro CM, Crowson AN, Mihm MC. Unusual vari-
ants of malignant melanoma. Mod Pathol. 2006;
19(suppl 2):S41-S70.
23. Ludgate MW, Fullen DR, Lee J, et al. The atypical Spitz
tumor of uncertain biologic potential: a series of 67
patients from a single institution. Cancer. 2009;115(3):
631-641.
24. Wiesner T, Kutzner H, Cerroni L, et al. Genomic aber-
rations in spitzoid melanocytic tumours and their
implications for diagnosis, prognosis and therapy.
Pathology. 2016;48(2):113-131.
2012 25. Ludgate MW, Fullen DR, Lee J, et al. Animal-type
melanoma: a clinical and histopathological study
Kang_CH116_p1982-2017.indd 2012
of 22 cases from a single institution. Br J Dermatol.
2010;162(1):129-136.
26. Dutton-Regester K, Kakavand H, Aoude LG, et al. Mel-
anomas of unknown primary have a mutation profile
consistent with cutaneous sun-exposed melanoma.
Pigment Cell Melanoma Res. 2013;26(6):852-860.
27. Carson KF, Wen DR, Li PX, et al. Nodal nevi and cuta-
neous melanomas. Am J Surg Pathol. 1996;20(7):
834-840.
28. Chattopadhyay C, Kim DW, Gombos DS, et al. Uveal
melanoma: from diagnosis to treatment and the sci-
ence in between. Cancer. 2016;122(15):2299-2312.
29. Thomas S, Pütter C, Weber S, et al. Prognostic sig-
nificance of chromosome 3 alterations determined
by microsatellite analysis in uveal melanoma: a
long-term follow-up study. Br J Cancer. 2012;106(6):
1171-1176.
30. Woodward JK, Elshaw SR, Murray AK, et al. Stimula-
tion and inhibition of uveal melanoma invasion by
HGF, GRO, IL-1alpha and TGF-beta. Invest Ophthalmol
Vis Sci. 2002;43(10):3144-3152.
31. Vyas R, Selph J, Gerstenblith MR. Cutaneous mani-
festations associated with melanoma. Semin Oncol.
2016;43(3):384-389.
32. Hua C, Boussemart L, Mateus C, et al. Association of
vitiligo with tumor response in patients with meta-
static melanoma treated with pembrolizumab. JAMA
Dermatol. 2016;152(1):45-51.
33. Grewal DS, Fishman GA, Jampol LM. Autoimmune
retinopathy and antiretinal antibodies: a review. Ret-
ina. 2014;34(5):827-845.
34. Usher-Smith JA, Emery J, Kassianos AP, et al. Risk
prediction models for melanoma: a systematic
review. Cancer Epidemiol Biomarkers Prev. 2014;23(8):
1450-1463.
35. Vuong K, McGeechan K, Armstrong BK, et al. Risk
prediction models for incident primary cutaneous
melanoma: a systematic review. JAMA Dermatol.
2014;150(4):434-444.
36. Elwood JM, Jopson J. Melanoma and sun expo-
sure: an overview of published studies. Int J Cancer.
1997;73(2):198-203.
37. Volkovova K, Bilanicova D, Bartonova A, et al. Asso-
ciations between environmental factors and inci-
dence of cutaneous melanoma. Environ Health. 2012;
11(suppl 1):S12.
38. Gillgren P, Brattström G, Djureen Mårtensson E,
et al. A new computerized methodology to analyse
tumour site in relation to phenotypic traits and epi-
demiological characteristics of cutaneous malignant
melanoma. Br J Dermatol. 2002;146(6):1023-1030.
39. Elwood JM, Gallagher RP. Body site distribution of
cutaneous malignant melanoma in relationship to
patterns of sun exposure. Int J Cancer. 1998;78(3):
276-280.
40. Stern RS. The risk of melanoma in association with
long-term exposure to PUVA. J Am Acad Dermatol.
2001;44(5):755-761.
41. Pouplard C, Brenaut E, Horreau C, et al. Risk of cancer
in psoriasis: a systematic review and meta-analysis of
epidemiological studies. J Eur Acad Dermatol Vene-
reol. 2013;27(suppl 3):36-46.
42. Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sun-
lamps, and risk of cutaneous malignant melanoma.
Cancer Epidemiol Biomarkers Prev. 2005;14(3):562-566.
43. Le Clair MZ, Cockburn MG. Tanning bed use and mel-
anoma: establishing risk and improving prevention
interventions. Prev Med Rep. 2016;3:139-144.
08/12/18 12:42 pm
 44. Bald T, Quast T, Landsberg J, et al. Ultraviolet-
radiation-induced inflammation promotes angiot-
ropism and metastasis in melanoma. Nature. 2014;
507(7490):109-113.
45. Green AC, Williams GM, Logan V, et al. Reduced mela-
noma after regular sunscreen use: randomized trial
follow-up. J Clin Oncol. 2011;29(3):257-263.
46. Ransohoff KJ, Jaju PD, Tang JY, et al. Familial skin
cancer syndromes: increased melanoma risk. J Am
Acad Dermatol. 2016;74(3):423-434.
47. Bauer J, Garbe C. Acquired melanocytic nevi as risk
factor for melanoma development. A comprehen-
sive review of epidemiological data. Pigment Cell Res.
2003;16(3):297-306.
48. Tucker MA, Halpern A, Holly EA, et al. Clinically recog-
nized dysplastic nevi. A central risk factor for cutane-
ous melanoma. JAMA. 1997;277(18):1439-1444.
49. Bevona C, Goggins W, Quinn T, et al. Cutaneous
melanomas associated with nevi. Arch Dermatol.
2003;139(12):1620-1624.
50. Tromberg J, Bauer B, Benvenuto-Andrade C, et al.
Congenital melanocytic nevi needing treatment.
Dermatol Ther. 2005;18(2):136-150.
51. Vourc’h-Jourdain M, Martin L, Barbarot S, et al. Large
congenital melanocytic nevi: therapeutic manage-
ment and melanoma risk: a systematic review. J Am
Acad Dermatol. 2013;68(3):493-498,e1-e14.
52. Niendorf KB, Tsao H. Cutaneous melanoma: family
screening and genetic testing. Dermatol Ther. 2006;
19(1):1-8.
53. Hansen CB, Wadge LM, Lowstuter K, et al. Clini-
cal germline genetic testing for melanoma. Lancet
Oncol. 2004;5(5):314-319.
54. Sharpless E, Chin L. The INK4a/ARF locus and mela-
noma. Oncogene. 2003;22(20):3092-3098.
55. Liu W, Hill D, Gibbs AF, et al. What features do patients
notice that help to distinguish between benign pig-
mented lesions and melanomas? The ABCD(E) rule
versus the seven-point checklist. Melanoma Res.
2005;15(6):549-554.
56. Nagore E, Oliver V, Moreno-Picot S, et al. Primary
cutaneous melanoma in hidden sites is associated
with thicker tumours—A study of 829 patients. Eur J
Cancer. 2001;37(1):79-82.
57. Friedman RJ, Rigel DS, Kopf AW. Early detection of
malignant melanoma: the role of physician examina-
tion and self-examination of the skin. CA Cancer J Clin.
1985;35(3):130-151.
58. Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis
of cutaneous melanoma: revisiting the ABCD criteria.
JAMA. 2004;292(22):2771-2776.
59. Whited JD, Grichnik JM. The rational clinical examina-
tion. Does this patient have a mole or a melanoma?
JAMA. 1998;279(9):696-701.
60. Gachon J, Beaulieu P, Sei JF, et al. First prospec-
tive study of the recognition process of mela-
noma in dermatological practice. Arch Dermatol.
2005;141(4):434-438.
61. Vestergaard ME, Macaskill P, Holt PE, et al. Dermos-
copy compared with naked eye examination for the
diagnosis of primary melanoma: a meta-analysis of
studies performed in a clinical setting. Br J Dermatol.
2008;159(3):669-676.
62. Bafounta ML, Beauchet A, Aegerter P, et al. Is dermos-
copy (epiluminescence microscopy) useful for the
diagnosis of melanoma? Results of a meta-analysis
using techniques adapted to the evaluation of diag-
nostic tests. Arch Dermatol. 2001;137(10):1343-1350.
Kang_CH116_p1982-2017.indd 2013
63. Annessi G, Bono R, Sampogna F, et al. Sensitivity,
specificity, and diagnostic accuracy of three der-
20
moscopic algorithmic methods in the diagnosis of
doubtful melanocytic lesions: the importance of light
brown structureless areas in differentiating atypical
melanocytic nevi from thin melanomas. J Am Acad
Dermatol. 2007;56(5):759-767.
64. Dolianitis C, Kelly J, Wolfe R, et al. Comparative per-
formance of 4 dermoscopic algorithms by nonex-
perts for the diagnosis of melanocytic lesions. Arch
Dermatol. 2005;141(8):1008-1014.
65. Blum A, Rassner G, Garbe C. Modified ABC-point
list of dermoscopy: a simplified and highly accurate
dermoscopic algorithm for the diagnosis of cuta-
neous melanocytic lesions. J Am Acad Dermatol.
2003;48(5):672-678.
Chapter 116 :: Melanoma
66. Henning JS, Dusza SW, Wang SQ, et al. The CASH
(color, architecture, symmetry, and homogene-
ity) algorithm for dermoscopy. J Am Acad Dermatol.
2007;56(1):45-52.
67. Noor O 2nd, Nanda A, Rao BK. A dermoscopy survey
to assess who is using it and why it is or is not being
used. Int J Dermatol. 2009;48(9):951-952.
68. Haenssle HA, Krueger U, Vente C, et al. Results from
an observational trial: digital epiluminescence
microscopy follow-up of atypical nevi increases the
sensitivity and the chance of success of conventional
dermoscopy in detecting melanoma. J Invest Dermatol.
2006;126(5):980-985.
69. Kittler H, Guitera P, Riedl E, et al. Identification of clini-
cally featureless incipient melanoma using sequen-
tial dermoscopy imaging. Arch Dermatol. 2006;142(9):
1113-1139.
70. Goodson AG, Grossman D. Strategies for early mela-
noma detection: approaches to the patient with nevi.
J Am Acad Dermatol. 2009;60(5):719-735.
71. Lien MH, Sondak VK. Diagnostic techniques for pri-
mary cutaneous melanoma [review]. G Ital Dermatol
Venereol. 2009;144(2):187-194.
72. Tran KT, Wright NA, Cockerell CJ. Biopsy of the pig-
mented lesion—when and how. J Am Acad Dermatol.
2008;59(5):852-871.
73. Martin RC 2nd, Scoggins CR, Ross MI, et al. Is inci-
sional biopsy of melanoma harmful? Am J Surg.
2005;190(6):913-917.
74. Karimipour DJ, Schwartz JL, Wang TS, et al. Micro-
staging accuracy after subtotal incisional biopsy of
cutaneous melanoma. J Am Acad Dermatol. 2005;
52(5):798-802.
75. Smoller BR. Histologic criteria for diagnosing pri-
mary cutaneous malignant melanoma. Mod Pathol.
2006;19(suppl 2):S34-S40.
76. Davis IJ, Kim JJ, Ozsolak F. Oncogenic MITF dysregula-
tion in clear cell sarcoma: defining the MiT family of
human cancers. Cancer Cell. 2006;9(6):473-484.
77. Ramos-Herberth FI, Karamchandani J, Kim J, et al.
SOX10 immunostaining distinguishes desmoplas-
tic melanoma from excision scar. J Cutan Pathol.
2010;37(9):944-952.
78. Balch CM, Gershenwald JE, Soong SJ, et al. Final ver-
sion of 2009 AJCC melanoma staging and classifica-
tion. J Clin Oncol. 2009;27(36):6199-6206.
79. Gogas H, Eggermont AM, Hauschild A, et al. Bio-
markers in melanoma. Ann Oncol. 2009;20(suppl
6):vi8-vi13.
80. Mocellin S, Zavagno G, Nitti D. The prognostic value of
serum S100B in patients with cutaneous melanoma: 2013
a meta-analysis. Int J Cancer. 2008;123(10):2370-2376.
08/12/18 12:42 pm
20 81. Wang TS, Johnson TM, Cascade PN, et al. Evalua-
tion of staging chest radiographs and serum lactate
dehydrogenase for localized melanoma. J Am Acad
Dermatol. 2004;51(3):399-405.
82. Uren RF, Howman-Giles R, Thompson JF. Patterns of
lymphatic drainage from the skin in patients with
melanoma. J Nucl Med. 2003;44(4):570-582.
83. Bafounta ML, Beauchet A, Chagnon S, et al. Ultra-
sonography or palpation for detection of mela-
noma nodal invasion: a meta-analysis. Lancet Oncol.
2004;5(11):673-680.
84. Voit C, Van Akkooi AC, Schäfer-Hesterberg G, et al.
Ultrasound morphology criteria predict metastatic
disease of the sentinel nodes in patients with mela-
noma. J Clin Oncol. 2010;28(5):847-852.
85. Sabel MS, Wong SL. Review of evidence-based sup-
Part 20
port for pretreatment imaging in melanoma. J Natl
Compr Canc Netw. 2009;7(3):281-289.
86. Sawyer A, McGoldrick RB, Mackey SP, et al. Does stag-
ing computed tomography change management in
::
thick malignant melanoma? J Plast Reconstr Aesthet
Neoplasia
Surg. 2009;62(4):453-456.
87. Vereecken P, Laporte M, Petein M, et al. Evaluation of
extensive initial staging procedure in intermediate/
high-risk melanoma patients. J Eur Acad Dermatol
Venereol. 2005;19(1):66-73.
88. Johnson TM, Bradford CR, Gruber SB, et al. Staging
workup, sentinel node biopsy, and follow-up tests for
melanoma: update of current concepts. Arch Dermatol.
2004;140(1):107-113.
89. Valsecchi ME, Silbermins D, de Rosa N, et al. Lym-
phatic mapping and sentinel lymph node biopsy
in patients with melanoma: a meta-analysis. J Clin
Oncol. 2011;29(11):1479-1487.
90. Warycha M, Zakrzewski J, Ni Q, et al. Metaanalysis
of sentinel lymph node positivity in thin melanoma
(≤1 mm). Cancer. 2009;115(4):869-879.
91. Kretschmer L, Starz H, Thoms KM, et al. Age as
a key factor influencing metastasizing patterns
and disease-specific survival after sentinel lymph
node biopsy for cutaneous melanoma. Int J Cancer.
2011;129(6):1435-1442.
92. Kunte C, Geimer T, Baumert J, et al. Prognostic fac-
tors associated with sentinel lymph node positivity
and effect of sentinel status on survival: an analysis of
1049 patients with cutaneous melanoma. Melanoma
Res. 2010;20(4):330-337.
93. McMasters KM, Reintgen DS, Ross MI, et al. Factors
that predict the presence of sentinel lymph node
metastasis in patients with melanoma. Surgery. 2001;
130(2):151-156.
94. Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph
node status is the most important prognostic factor
for thick (> or = 4 mm) melanomas. J Dtsch Dermatol
Ges. 2008;6(3):198-203.
95. Morton DL, Wen DR, Wong JH, et al. Technical details
of intraoperative lymphatic mapping for early stage
melanoma. Arch Surg. 1992;127(4):392-399.
96. McCready DR, Ghazarian DM, Hershkop MS, et al.
Sentinel lymph-node biopsy after previous wide
local excision for melanoma. Can J Surg. 2001;44(6):
432-434.
97. Thompson JF, Shaw HM, Hersey P, et al. The his-
tory and future of melanoma staging. J Surg Oncol.
2004;86(4):224-235.
98. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-
2014 node biopsy or nodal observation in melanoma.
N Engl J Med. 2006;355(13):1307-1317.
Kang_CH116_p1982-2017.indd 2014
99. Leiter U, Stadler R, Mauch C, et al. German Dermato-
logic Cooperative Oncology Group (DeCOG): com-
plete lymph node dissection versus no dissection in
patients with sentinel lymph node biopsy positive
melanoma (DeCOG-SLT): a multicentre, randomised,
phase 3 trial. Lancet Oncol. 2016;17(6):757-767.
100. Crowley NJ, Seigler HF. Late recurrence of malig-
nant melanoma. Analysis of 168 patients. Ann Surg.
1990;212(2):173-177.
101. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib
and trametinib versus dabrafenib and placebo for
Val600 BRAF-mutant melanoma: a multicentre, double-
blind, phase 3 randomised controlled trial. Lancet.
2015;386(9992):444-451.
102. Robert C, Ribas A, Hamid O, et al. Three-year over-
all survival for patients with advanced melanoma
treated with pembrolizumab in Keynote-001 [abstract
9503]. J Clin Oncol. 2016;34(suppl).
103. Chang P, Knapper WH. Metastatic melanoma of
unknown primary. Cancer. 1982;49(6):1106-1111.
104. Schlagenhauff B, Stroebel W, Ellwanger U, et al. Meta-
static melanoma of unknown primary origin shows
prognostic similarities to regional metastatic mela-
noma: recommendations for initial staging examina-
tions. Cancer. 1997;80(1):60-65.
105. Edge SB, Compton CC. The American Joint Committee
on Cancer: the 7th edition of the AJCC cancer stag-
ing manual and the future of TNM. Ann Surg Oncol.
2010;17(6):1471-1474.
106. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma
staging: evidence-based changes in the American
Joint Committee on Cancer eighth edition cancer
staging manual. CA Cancer J Clin. 2017;67(6):472-492.
107. Tas F, Erturk K. Presence of histological regression as
a prognostic factor in cutaneous melanoma patients.
Melanoma Res. 2016;26(5):492-496.
108. Stucky CC, Gray RJ, Dueck AC, et al. Risk factors asso-
ciated with local and in-transit recurrence of cutane-
ous melanoma. Am J Surg. 2010;200(6):770-774.
109. Homsi J, Kashani-Sabet M, Messina JL, et al. Cutane-
ous melanoma: prognostic factors. Cancer Control.
2005;12(4):223-229.
110. Balch CM, Soong SJ, Gershenwald JE, et al. Prognos-
tic factors analysis of 17,600 melanoma patients:
validation of the American Joint Committee on
Cancer melanoma staging system. J Clin Oncol.
2001;19(16):3622-3634.
111. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.
Adjuvant ipilimumab versus placebo after complete
resection of high-risk stage III melanoma (EORTC
18071): a randomised, double-blind, phase 3 trial.
Lancet Oncol. 2015;16(5):522-530.
112. Eggermont AM, Suciu S, Rutkowski P, et al. EORTC
Melanoma group: long term follow up of the EORTC
18952 trial of adjuvant therapy in resected stage
IIB-III cutaneous melanoma patients comparing inter-
mediate doses of interferon-alpha-2b (IFN) with
observation: ulceration of primary is key determinant
for IFN-sensitivity. Eur J Cancer. 2016;55:111-121.
113. Eggermont AM, Spatz A, Lazar V, et al. Is ulceration in
cutaneous melanoma just a prognostic and predic-
tive factor or is ulcerated melanoma a distinct bio-
logic entity? Curr Opin Oncol. 2012;24(2):137-140.
114. Azzola MF, Shaw HM, Thompson JF, et al. Tumor
mitotic rate is a more powerful prognostic indicator
than ulceration in patients with primary cutaneous
melanoma: an analysis of 3661 patients from a single
center. Cancer. 2003;97(6):1488-1498.
08/12/18 12:42 pm
 115. Paek SC, Griffith KA, Johnson TM, et al. The impact
of factors beyond Breslow depth on predicting sen-
tinel lymph node positivity in melanoma. Cancer.
2007;109(1):100-108.
116. Elder DE, Gimotty PA, Guerry D. Cutaneous mela-
noma: estimating survival and recurrence risk based
on histopathologic features. Dermatol Ther. 2005;
18(5):369-385.
117. Thomas NE, Busam KJ, From L, et al. Tumor-infiltrating
lymphocyte grade in primary melanomas is indepen-
dently associated with melanoma-specific survival in
the population-based genes, environment and mela-
noma study. J Clin Oncol. 2013;31(33):4252-4259.
118. Weiss SA, Han SW, Lui K, et al. Immunologic heteroge-
neity of tumor infiltrating lymphocyte composition
in primary melanoma. Hum Pathol. 2016;57:116-125.
119. Gershenwald JE, Thompson W, Mansfield PF, et al.
Multi-institutional melanoma lymphatic mapping
experience: the prognostic value of sentinel lymph
node status in 612 stage I or II melanoma patients.
J Clin Oncol. 1999;17(3):976-983.
120. Tsao H, Feldman M, Fullerton JE, et al. Early detection
of asymptomatic pulmonary melanoma metastases
by routine chest radiographs is not associated with
improved survival. Arch Dermatol. 2004;140(1):67-70.
121. Sladden MJ, Balch C, Barzilai DA, et al. Surgical exci-
sion margins for primary cutaneous melanoma.
Cochrane Database Syst Rev. 2009;(4):CD004835.
122. Hayes AJ, Maynard L, Coombes G, et al; UK Melanoma
Study Group; British Association of Plastic, Recon-
structive and Aesthetic Surgeons; Scottish Cancer
Therapy Network: wide versus narrow excision mar-
gins for high-risk, primary cutaneous melanomas:
long-term follow-up of survival in a randomised trial.
Lancet Oncol. 2016;17(2):184-192.
123. Veronesi U, Cascinelli N. Narrow excision (1-cm mar-
gin). A safe procedure for thin cutaneous melanoma.
Arch Surg. 1991;126(4):438-441.
124. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.
Long term results of a randomized study by the
Swedish Melanoma Study Group on 2-cm versus
5-cm resection margins for patients with cutaneous
melanoma with a tumor thickness of 0.8-2.0 mm.
Cancer. 2000;89(7):1495-1501.
125. McLeod M, Choudhary S, Giannakakis G, et al. Surgical
treatments for lentigo maligna: a review. Dermatol Surg.
2011;37(9):1210-1228.
126. Lens MB, Dawes M, Goodacre T, et al. Elective lymph
node dissection in patients with melanoma: system-
atic review and meta-analysis of randomized con-
trolled trials. Arch Surg. 2002;137(4):458-461.
127. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel
node biopsy for early-stage melanoma: accuracy and
morbidity in MSLT-I, an international multicenter
trial. Ann Surg. 2005;242(3):302-311.
128. Sabel MS, Griffith K, Sondak VK, et al. Predictors of
nonsentinel lymph node positivity in patients with a
positive sentinel node for melanoma. J Am Coll Surg.
2005;201(1):37- 47.
129. Ghaferi AA, Wong SL, Johnson TM, et al. Prognos-
tic significance of a positive nonsentinel lymph
node in cutaneous melanoma. Ann Surg Oncol.
2009;16(11):2978-2984.
130. Sabel MS, Griffith KA, Arora A, et al. Inguinal node
dissection for melanoma in the era of sentinel lymph
node biopsy. Surgery. 2007;141(6):728-735.
131. Young SE, Martinez SR, Faries MB, et al. Can sur-
gical therapy alone achieve long-term cure of
Kang_CH116_p1982-2017.indd 2015
melanoma metastatic to regional nodes? Cancer J.
2006;12(3):207-211.
20
132. Bender C, Hassel JC, Enk A. Immunotherapy of mela-
noma. Oncol Res Treat. 2016;39(6):369-376.
133. Hassel JC, Winnemöller D, Schartl M, et al. STAT5 con-
tributes to antiapoptosis in melanoma. Melanoma
Res. 2008;18(6):378-385.
134. Wellbrock C, Weisser C, Hassel JC, et al. STAT5 contrib-
utes to interferon resistance of melanoma cells. Curr
Biol. 2005;15(18):1629-1639.
135. Ortiz A, Fuchs SY. Anti-metastatic functions of type 1
interferons: Foundation for the Adjuvant Therapy of
Cancer. Cytokine. 2016;S1043-4666(16)30010-2.
136. Mocellin S, Lens MB, Pasquali S, et al. Interferon alpha
for the adjuvant treatment of cutaneous melanoma.
Cochrane Database Syst Rev. 2013;18(6):CD008955.
Chapter 116 :: Melanoma
137. Wheatley K, Ives N, Eggermont A, et al. Interferon-
alpha as adjuvant therapy for melanoma: an individ-
ual patient data meta-analysis of randomized trials
[abstract 8526]. J Clin Oncol. 2007;25(suppl).
138. McMasters KM, Egger ME, Edwards MJ, et al. Final
results of the sunbelt melanoma trial: a multi-
institutional prospective randomized phase III study
evaluating the role of adjuvant high-dose interferon
alfa-2b and completion lymph node dissection for
patients staged by sentinel lymph node biopsy. J Clin
Oncol. 2016;34(10):1079-1086.
139. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and
low-dose interferon alfa-2b in high-risk melanoma:
first analysis of intergroup trial E1690/S9111/C9190.
J Clin Oncol. 2000;18(12):2444-2458.
140. Gogas H, Ioannovich J, Dafni U, et al. Prognostic signifi-
cance of autoimmunity during treatment of melanoma
with interferon. N Engl J Med. 2006;354(7):709-718.
141. Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The
benefits of adjuvant radiation therapy after thera-
peutic lymphadenectomy for clinically advanced,
high-risk, lymph node-metastatic melanoma. Cancer.
2009;115(24):5836-5844.
142. Bibault JE, Dewas S, Mirabel X, et al. Adjuvant radia-
tion therapy in metastatic lymph nodes from mela-
noma. Radiat Oncol. 2011;6(Web Page):12.
143. Strojan P, Jancar B, Cemazar M, et al. Melanoma metas-
tases to the neck nodes: role of adjuvant irradiation.
Int J Radiat Oncol Biol Phys. 2010;77(4):1039-1045.
144. Burmeister BH, Henderson MA, Ainslie J, et al. Adju-
vant radiotherapy versus observation alone for
patients at risk of lymph-node field relapse after
therapeutic lymphadenectomy for melanoma: a ran-
domised trial. Lancet Oncol. 2012;13(6):589-597.
145. Chadha M, Hilaris B, Nori D, et al. Role of brachyther-
apy in malignant melanoma: a preliminary report.
J Surg Oncol. 1990;43(4):223-227.
146. Overgaard J, Gonzalez Gonzalez D, Hulshof MC, et al.
Hyperthermia as an adjuvant to radiation therapy of
recurrent or metastatic malignant melanoma. A mul-
ticentre randomized trial by the European Society for
Hyperthermic Oncology. Int J Hyperthermia. 2009;
25(Web Page):323-334.
147. Spratt DE, Gordon Spratt EA, Wu S, et al. Efficacy of
skin-directed therapy for cutaneous metastases
from advanced cancer: a meta-analysis. J Clin Oncol.
2014;32(28):3144-3155.
148. Weide B, Eigentler TK, Pflugfelder A, et al. Survival
after intratumoral interleukin-2 treatment of 72
melanoma patients and response upon the first
chemotherapy during follow-up. Cancer Immunol 2015
Immunother. 2011;60(4):487-493.
08/12/18 12:42 pm
20 149. Byers BA, Temple-Oberle CF, Hurdle V, et al. Treat-
ment of in-transit melanoma with intra-lesional
interleukin-2: a systematic review. J Surg Oncol.
2014;110(6):770-775.
150. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimo-
gene laherparepvec improves durable response rate
in patients with advanced melanoma. J Clin Oncol.
2015;33(25):2780-2788.
151. Mali B, Jarm T, Snoj M, et al. Antitumor effectiveness
of electrochemotherapy: a systematic review and
meta-analysis. Eur J Surg Oncol. 2013;39(1):4-16.
152. Grunhagen DJ, de Wilt JH, van Geel AN, et al. Isolated
limb perfusion for melanoma patients—a review of
its indications and the role of tumour necrosis factor-
alpha. Eur J Surg Oncol. 2006;32(4):371-380.
153. Thompson JF, Kam PC. Isolated limb infusion for mel-
Part 20
anoma: a simple but effective alternative to isolated
limb perfusion. J Surg Oncol. 2004;88(1):1-3.
154. Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic
intra-arterial versus intravenous fotemustine in
::
patients with liver metastases from uveal melanoma
Neoplasia
(EORTC 18021): a multicentric randomized trial. Ann
Oncol. 2014;25(3):742-746.
155. Hughes MS, Zager J, Faries M, et al. Results of a ran-
domized controlled multicenter phase III trial of
percutaneous hepatic perfusion compared with
best available care for patients with melanoma liver
metastases. Ann Surg Oncol. 2016;23(4):1309-1319.
156. Schadendorf D, Hodi FS, Robert C, et al. Pooled
analysis of long-term survival data from phase II and
phase III trials of ipilimumab in unresectable or meta-
static melanoma. J Clin Oncol. 2015;33(17):1889-1894.
157. Tagawa ST, Cheung E, Banta W, et al. Survival analy-
sis after resection of metastatic disease followed
by peptide vaccines in patients with Stage IV mela-
noma. Cancer. 2006;106(6):1353-1357.
158. Koebel CM, Vermi W, Swann JB, et al. Adaptive immu-
nity maintains occult cancer in an equilibrium state.
Nature. 2007;450(7171):903-907.
159. Chen DS, Mellman I. Oncology meets immunology:
the cancer-immunity cycle. Immunity. 2013;39(1):
1-10.
160. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous
regression of metastases from melanoma: review of
the literature. Melanoma Res. 2009;19(5):275-282.
161. Robbins HA, Clarke CA, Arron ST, et al. Melanoma
risk and survival among organ transplant recipients.
J Invest Dermatol. 2015;135(11):2657-2665.
162. Hoos A. Development of immuno-oncology drugs-
from CTLA4 to PD1 to the next generations. Nat Rev
Drug Discov. 2016;15(4):235-247.
163. Hodi FS, O’Day SJ, McDermott DF, et al. Improved
survival with ipilimumab in patients with metastatic
melanoma. N Engl J Med. 2010;363(8):711-723.
164. Gandini S, Massi D, Mandalà M. PD-L1 expression in
cancer patients receiving anti PD-1/PD-L1 antibod-
ies: a systematic review and meta-analysis. Crit Rev
Oncol Hematol. 2016;100:88-98.
165. Taube JM, Anders RA, Young GD, et al. Colocalization
of inflammatory response with B7-h1 expression in
human melanocytic lesions supports an adaptive
resistance mechanism of immune escape. Sci Transl
Med. 2012;4(127):127ra37.
166. Obeid JM, Erdag G, Smolkin ME, et al. PD-L1, PD-L2
and PD-1 expression in metastatic melanoma: cor-
relation with tumor-infiltrating immune cells and
2016 clinical outcome. Oncoimmunology. 2016;5(11):
e1235107.
Kang_CH116_p1982-2017.indd 2016
167. Danilova L, Wang H, Sunshine J, et al. Association
of PD-1/PD-L axis expression with cytolytic activ-
ity, mutational load, and prognosis in melanoma
and other solid tumors. Proc Natl Acad Sci U S A.
2016;113(48):e7769-e7777.
168. Robert C, Long GV, Brady B, et al. Nivolumab in previ-
ously untreated melanoma without BRAF mutation.
N Engl J Med. 2015;372(4):320-330.
169. Daud A, Hamid O, Robert C, et al. Relationship
between PD-L1 expression and efficacy in 655
patients with melanoma treated with pembroli-
zumab (MK-3475). Society for Melanoma Research
Annual Meeting; San Francisco, CA; November 18-21,
2015.
170. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Com-
bined nivolumab and ipilimumab or monotherapy
in untreated melanoma. N Engl J Med. 2015;373(13):
1270-1271.
171. Wolchok JD, Rollin L, Larkin J. Nivolumab and ipi-
limumab in advanced melanoma. N Engl J Med.
2017;377(25):2503-2504.
172. Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-
study of ipilimumab in pretreated and treatment-
naïve patients with metastatic uveal melanoma. PLoS
One. 2015;10(3):e0118564.
173. Algazi AP, Tsai KK, Shoushtari AN, et al. Clini-
cal outcomes in metastatic uveal melanoma
treated with PD-1 and PD-L1 antibodies. Cancer.
2016;122(21):3344-3353.
174. Karydis I, Chan PY, Wheater M, et al. Clinical activity
and safety of pembrolizumab in ipilimumab pre-treated
patients with uveal melanoma. Oncoimmunology.
2016;5(5):e1143997.
175. Kottschade LA, McWilliams RR, Markovic SN, et al.
The use of pembrolizumab for the treatment of
metastatic uveal melanoma. Melanoma Res. 2016;
26(3):300-303.
176. Hassel JC, Heinzerling L, Aberle J, et al. Combined
immune checkpoint blockade (anti-PD-1/anti-CTLA-4):
evaluation and management of adverse drug reac-
tions. Cancer Treat Rev. 2017;57:36-49.
177. Sanlorenzo M, Vujic I, Daud A, et al. Pembroli-
zumab cutaneous adverse events and their asso-
ciation with disease progression. JAMA Dermatol.
2015;151(11):1206-1212.
178. Weber JS, Hodi FS, Wolchok JD, et al. Safety pro-
file of nivolumab monotherapy: a pooled analysis
of patients with advanced melanoma. J Clin Oncol.
2017;35(7):785-792.
179. Dick J, Lang N, Slynko A, et al. Use of LDH and
autoimmune side effects to predict response to
ipilimumab treatment. Immunotherapy. 2016;8(9):
1033-1044.
180. Buder-Bakhaya K, Benesova K, Schulz C, et al. Char-
acterization of arthralgia induced by PD-1 antibody
treatment in patients with metastasized cutaneous
malignancies. Cancer Immunol Immunother. 2017;
41(10):1381-1389.
181. Kaunitz GJ, Loss M, Rizvi H, et al. Cutaneous erup-
tions in patients receiving immune checkpoint
blockade: clinicopathologic analysis of the nonli-
chenoid histologic pattern. Am J Surg Pathol. 2017;
41(10):1381-1389.
182. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell
therapy for patients with metastatic melanoma:
evaluation of intensive myeloablative chemoradia-
tion preparative regimens. J Clin Oncol. 2008;26(32):
5233-5239.
08/12/18 12:42 pm
 183. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Clini-
cal responses in a phase II study using adoptive
transfer of short-term cultured tumor infiltration
lymphocytes in metastatic melanoma patients. Clin
Cancer Res. 2010;16(9):2646-2655.
184. Lu YC, Yao X, Crystal JS, et al. Efficient identification of
mutated cancer antigens recognized by T cells asso-
ciated with durable tumor regressions. Clin Cancer
Res. 2014;20(13):3401-3410.
185. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose
recombinant interleukin 2 therapy for patients
with metastatic melanoma: analysis of 270 patients
treated between 1985 and 1993. J Clin Oncol.
1999;17(7):2105-2116.
186. Lo JA, Fisher DE. The melanoma revolution: from UV
carcinogenesis to a new era in therapeutics. Science.
2014;346(6212):945-949.
187. Hauschild A, Agarwala SS, Trefzer U, et al. Results of
a phase III, randomized, placebo-controlled study of
sorafenib in combination with carboplatin and pacli-
taxel as second-line treatment in patients with unre-
sectable stage III or stage IV melanoma. J Clin Oncol.
2009;27(17):2823-2830.
188. Egberts F, Gutzmer R, Ugurel S, et al. Sorafenib and
pegylated interferon-α2b in advanced metastatic
melanoma: a multicenter phase II DeCOG trial. Ann
Oncol. 2011;22(7):1667-1674.
189. Chapman PB, Hauschild A, Robert C, et al. BRIM-3
Study Group: improved survival with vemurafenib in
melanoma with BRAF V600E mutation. N Engl J Med.
2011;364(26):2507-2516.
190. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in
BRAF-mutated metastatic melanoma: a multicentre,
open-label, phase 3 randomised controlled trial.
Lancet. 2012;380(9839):358-365.
191. Sosman JA, Kim KB, Schuchter L, et al. Survival in
BRAF V600-mutant advanced melanoma treated
with vemurafenib. N Engl J Med. 2012;366:707-714.
192. Van Allen EM, Wagle N, Sucker A, et al. Dermatologic
Cooperative Oncology Group of Germany (DeCOG):
the genetic landscape of clinical resistance to RAF
inhibition in metastatic melanoma. Cancer Discov.
2014;4(1):94-109.
193. Su F, Viros A, Milagre C, et al. RAS mutations in
cutaneous squamous-cell carcinomas in patients
treated with BRAF inhibitors. N Engl J Med. 2012;
366(3):207-215.
194. Hassel JC, Groesser L, Herschberger E, et al. RAS
mutations in benign epithelial tumors associated
with BRAF inhibitor treatment of melanoma. J Invest
Dermatol. 2015;135(2):636-639.
195. Dummer R, Schadendorf D, Ascierto PA, et al. Results
of NEMO: a phase II trial of binimetinib vs dacarba-
zine in NRAS-mutant cutaneous melanoma [abstract
9500]. J Clin Oncol. 2016;34(suppl).
196. Lutzky J, Bauer J, Bastian BC. Dose-dependent, com-
plete response to imatinib of a metastatic mucosal
melanoma with a K642E KIT mutation. Pigment Cell
Melanoma Res. 2008;21(4):492-493.
Kang_CH116_p1982-2017.indd 2017
197. Hodi FS, Friedlander P, Corless CL, et al. Major
response to imatinib mesylate in KIT-mutated mela-
20
noma. J Clin Oncol. 2008;26(12):2046-2051.
198. Guo J, Si L, Kong Y. Phase II, open-label, single-arm
trial of imatinib mesylate in patients with metastatic
melanoma harboring c-Kit mutation or amplification.
J Clin Oncol. 2011;29(21):2904-2909.
199. Lee SJ, Kim TM, Kim YJ, et al. Phase II trial of nilotinib
in patients with metastatic malignant melanoma
harboring KIT gene aberration: a multicenter trial of
Korean Cancer Study Group (UN10-06). Oncologist.
2015;20(11):1312-1319.
200. Tarhini AA, Agarwala SS. Cutaneous melanoma: avail-
able therapy for metastatic disease. Dermatol Ther.
2006;19(1):19-25.
201. Middleton MR, Grob JJ, Aaronson N, et al. Random-
Chapter 116 :: Melanoma
ized phase III study of temozolomide versus dacar-
bazine in the treatment of patients with advanced
metastatic malignant melanoma. J Clin Oncol. 2000;
18(1):158-166.
202. Eigentler TK, Caroli UM, Radny P, et al. Palliative ther-
apy of disseminated malignant melanoma: a system-
atic review of 41 randomised clinical trials. Lancet
Oncol. 2003;4(12):748-759.
203. Hassel JC, Lee SB, Meiss F, et al. Vemurafenib and ipi-
limumab: a promising combination? Results of a case
series. Oncoimmunology. 2015;5(4):e1101207.
204. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity
with combination of vemurafenib and ipilimumab.
N Engl J Med. 2013;368(14):1365-1366.
205. Ribas A, Hodi FS, Lawrence DP, et al. Pembrolizumab
(pembro) in combination with dabrafenib (D) and
trametinib (T) for BRAF-mutant advanced mela-
noma: phase 1 KEYNOTE-022 study [abstract 3014].
J Clin Oncol. 2016;34(suppl).
206. Ribas A, Dummer R, Puzanov I, et al. Oncolytic
virotherapy promotes intratumoral T cell infiltra-
tion and improves anti-PD-1 immunotherapy. Cell.
2017;170(6):1109.e10-1119.e10.
207. Van Allen EM, Miao D, Schilling B, et al. Genomic cor-
relates of response to CTLA-4 blockade in metastatic
melanoma. Science. 2015;350(6257):207-211.
208. Snyder A, Makarov V, Merghoub T, et al. Genetic basis
for clinical response to CTLA-4 blockade in mela-
noma. N Engl J Med. 2014;371(23):2189-2199.
209. Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery
to dendritic cells exploits antiviral defence for cancer
immunotherapy. Nature. 2016;534(7607):396-401.
210. Shahabi V, Postow MA, Tuck D, et al. Immune-priming
of the tumor microenvironment by radiotherapy:
rationale for combination with immunotherapy to
improve anticancer efficacy. Am J Clin Oncol. 2015;
38(1):90-97.
211. Postow MA, Callahan MK, Barker CA, et al. Immuno-
logic correlates of the abscopal effect in a patient
with melanoma. N Engl J Med. 2012;366(10):925-931.
212. Coit DG, Andtbacka R, Bichakjian CK, et al. Melanoma.
J Natl Compr Canc Netw. 2009;7(3):250-275.
2017
08/12/18 12:42 pm