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Actas
Dermosifiliogr.
2013;
104(9)
:757---775
REVIEW
Lentigo
Maligna

E.
Samaniego,
a
,
P.
Redondo
b
a
Servicio
de
Dermatología,
Complejo
Asistencial
Universitario
de
León,
León,
Spain
b
Departamento
de
Dermatología,
Clínica
Universitaria
de
Navarra,
Pamplona,
Spain
Received
25
November
2011;
accepted
19
May
2012
Available
online
6
October
2013
KEYWORDS
Lentigo
maligna;
Diagnosis;
Treatment
Abstract
Lentigo
maligna
is
a
type
of
in
situ
melanoma.
It
develops
mainly
in
middle-aged
and
elderly
individuals
on
areas
of
the
skin
chronically
exposed
to
sunlight.
It
progresses
to
its
invasive
form,
lentigo
maligna
melanoma,
in
5%
to
50%
of
cases.
Management
of
lentigo
maligna
is
open
to
debate,
with
a
notable
lack
of
randomized
trials
and
specific
guidelines
and
protocols.
Early
diagnosis
and
treatment
is
necessary
to
achieve
cure
if
possible
and
prevent
progression
to
invasive
melanoma
with
the
corresponding
risk
of
metastasis.
The
treatment
of
choice
for
lentigo
maligna
is
surgery.
When
surgery
is
not
possible,
other
alternatives
are
available
although
outcomes
and
rates
of
recurrence
are
variable.
The
objective
of
this
study
was
to
review
the
diagnostic
methods
and
criteria
for
lentigo
maligna,
as
well
as
the
different
surgical
options
and
alternatives
to
surgery,
in
order
to
provide
information
on
the
best
approach
in
each
case.
©
2011
Elsevier
España,
S.L.
and
AEDV.
All
rights
reserved.
PALABRAS
CLAVE
Lentigo
maligno;
Diagnóstico;
Tratamiento
Lentigo
maligno
Resumen
El
lentigo
maligno
(LM)
es
una
variante
de
melanoma
in
situ
que
se
desarrolla
prin-
cipalmente
en
áreas
de
exposición
solar
crónica
en
pacientes
de
edad
media-avanzada.
Puede
evolucionar
a
su
forma
invasiva
lentigo
maligno
melanoma
(LMM)
en
el
5-50%
de
los
casos.
Su
manejo
en
ocasiones
en
controvertido,
destacando
la
ausencia
de
estudios
prospectivos
alea-
torizados
y
de
guías
específicas
o
protocolos.
Es
necesario
realizar
un
diagnóstico
y
tratamiento
precoces
para
obtener
la
curación,
si
es
posible,
y
evitar
la
evolución
a
melanoma
invasivo
con
el
consiguiente
riesgo
metastásico.
El
tratamiento
de
elección
del
LM
es
la
cirugía.
Cuando
esta
no
es
posible
pueden
utilizarse
otras
alternativas
con
resultados
y
tasas
de
recidiva
variables.
El
objetivo
del
presente
trabajo
es
realizar
una
revisión
de
los
métodos
y
criterios
diagnósticos
de
LM,
así
como
de
las
diferentes
modalidades
de
tratamiento
quirúrgico
y
las
alternativas
al
mismo,
que
favorezca
el
mejor
enfoque
en
cada
caso.
©
2011
Elsevier
España,
S.L.
y
AEDV.
Todos
los
derechos
reservados.

Please
cite
this
article
as:
Samaniego
E,
Redondo
P.
Lentigo
maligno.
Actas
Dermosifiliogr.
2013;104:757---775.
Corresponding
author.
E-mail
addresses:
eliasamaniego@yahoo.es
,
esamagon@gmail.com
(E.
Samaniego).
1578-2190/$
see
front
matter
©
2011
Elsevier
España,
S.L.
and
AEDV.
All
rights
reserved.
758
E.
Samaniego,
P.
Redondo
Introduction
Lentigo
maligna
(LM)
is
a
variant
of
melanoma
in
situ
that
mainly
affects
chronically
sun-exposed
parts
of
the
body
in
older
patients.
1
This
type
accounts
for
between
79%
and
83%
of
all
cases
of
melanoma
in
situ
2
and
can
run
a
very
slow
course
(up
to
decades)
before
progressing
to
its
inva-
sive
form,
lentigo
maligna
melanoma
(LMM).
Four
to
15%
of
all
melanomas
are
LMs
or
LMMs,
3
and
most
affect
the
head
and
neck
(86%
of
all
cases).
4
The
incidence
of
LM
is
rising,
and
while
most
cases
are
described
in
patients
aged
between
65
and
80
years,
there
have
been
reports
of
LM
in
patients
aged
20
to
30
years;
in
some
large
series
10%
of
the
patients
were
younger
than
40
years.
1,5
No
specific
protocols
have
been
published
for
the
treat-
ment
of
LM,
and
because
of
its
special
features,
its
management
is
still
debated.
LM
generally
occurs
in
elderly
patients,
affects
parts
of
the
body
that
have
been
dam-
aged
by
the
sun
or
carry
a
risk
of
cosmetic
or
functional
defects,
has
poorly
defined
clinical
and
histologic
margins,
and
recurs
frequently
following
treatment.
6
We
review
the
diagnosis
of
LM,
including
methods
and
criteria,
and
provide
an
overview
of
the
different
treatment
modalities
available,
with
a
description
of
the
advantages
and
disadvantages
of
each
in
order
to
guide
clinical
decision
making.
Methods
We
performed
a
literature
search
using
the
Cochrane
and
MEDLINE
databases.
The
search
terms
entered
in
PubMed
were
Hutchin-
son
melanotic
freckle
,
lentigo
maligna
,
diagnosis
,
therapy
,
surgery
,
and
radiotherapy
.
Preference
was
given
to
reviews
and
articles
published
in
English
or
Spanish.
We
also
reviewed
the
main
clinical
management
guidelines
for
melanoma.
Diagnosis
of
LM
LM
presents
clinically
as
a
slow-growing,
asymmetric
macule
with
irregular,
poorly
defined
borders
and
varied
pigmenta-
tion
(dark
gray,
light
brown,
dark
brown,
black,
and
white
[areas
of
regression]).
3,7
Albeit
rarely,
primary
or
recurrent
LM
can
present
clinically
and
histologically
as
an
amelanotic
lesion.
8,9
Histology
remains
the
diagnostic
method
of
choice
in
LM.
10
Characteristic
histologic
findings
are
the
proliferation
of
atypical
melanocytes
along
the
dermal-epidermal
junc-
tion;
cells
are
often
oriented
perpendicular
to
the
surface,
and
involvement
of
the
periadnexal
structures
of
the
epithe-
lium
is
a
common
finding.
In
more
advanced
lesions,
nests
of
cells
at
the
dermal-epidermal
junction
and
multinucle-
ated
giant
cells
may
be
observed.
Occasionally,
there
may
be
pagetoid
spread,
epidermal
atrophy,
and
solar
elastosis
in
the
dermis.
The
papillary
dermis
may
contain
melanophages
and
a
chronic
inflammatory
infiltrate.
8
It
is
sometimes
difficult
to
distinguish
atypical
melanocytes
from
the
atypical
junctional
melanocytic
hyperplasia
seen
in
actinically
damaged
skin.
A
useful
approach
is
to
take
a
control
biopsy
from
the
contralateral
side
of
the
face.
11
In
general,
biopsy
of
suspicious
or
changing
pigmented
lesions
on
the
face
is
recommended.
12
Excisional
biopsy
is
the
most
accurate
diagnostic
method
in
LM,
but
because
lesions
are
often
large
and
located
in
cosmetically
sensitive
areas,
punch
biopsy
is
the
most
widely
used
procedure,
13
despite
the
problem
of
sampling
error.
14
Based
on
observa-
tional
studies
by
Stevens
and
Cocherell,
15
deep
incisional
biopsy
extending
as
far
as
the
subcutaneous
tissue
with
a
punch
of
at
least
5
mm
can
minimize
this
source
of
error.
For
large
lesions,
mapping
and
taking
multiple
punch
biop-
sies
of
the
most
representative
sites
(darker
or
palpable
areas
suspicious
for
invasion)
offers
a
possible
approach.
The
use
of
complementary
techniques
such
as
dermoscopy
and
confocal
reflectance
microscopy
(CRM)
is
also
useful.
Some
facial
lesions
that
are
clinically
insignificant,
i.e.,
that
do
not
meet
the
ABCD
criteria
(Asymmetry;
Borders,
uneven;
Color,
multiple;
Diameter,
>
6
mm),
are
histolog-
ically
malignant.
16,17
Routine
dermoscopy
is
therefore
a
useful
complementary
tool
that
can
help
to
identify
such
lesions
early
so
that
even
lesions
that
appear
clinically
benign
can
be
excised.
Schiffner
and
Stoltz
18
reported
that
dermoscopy
has
a
sensitivity
of
89%
and
a
specificity
of
96%
for
the
early
diagnosis
of
LM
when
several
dermoscopic
fea-
tures
are
detected
and
that
the
presence
of
a
single
feature
is
not
diagnostically
useful.
Main
Dermoscopic
Criteria
for
LM
The
most
characteristic
dermoscopic
finding
in
facial
LM
lesions
is
a
pigmented
pseudonetwork,
which
is
an
area
of
homogeneous
pigmentation
disrupted
by
follicular
or
adnexal
openings
on
the
face.
19
Other
dermoscopic
criteria
for
LM/LMM
are
asymmetric
pigmented
follicular
openings
(corresponding
to
follic-
ular
invasion
by
tumor
melanocytes);
dark
rhomboidal
structures
(proliferation
of
melanocytes
around
the
interfol-
licular
spaces);
slate-gray
dots
and
globules
(melanin-laden
macrophages
in
the
superficial
dermis
that
may
form
gran-
ular,
ring-like
images
in
several
areas);
dark
streaks
(rows
of
melanoma
cells
in
the
epidermis
or
superficial
der-
mis);
homogeneous
areas
(complete
obliteration
of
follicular
openings
by
invading
melanoma
cells);
and
isobar
structures
(concentric
pigmented
circles
around
the
follicular
open-
ings).
Another
recently
described
pattern
is
a
series
of
brown
or
blue-gray
dots
in
lines
that
form
a
zigzag.
20
Dermoscopy
is
also
useful
for
selecting
biopsy
sites,
dis-
tinguishing
LM
from
other
pigmented
lesions
on
the
face,
18,19
delineating
surgical
margins,
and
assessing
and
monitoring
treatment
response.
Dermoscopy
as
a
Guide
for
Punch
Biopsy/Mapping/Incisional
Biopsy
Biopsy
sites
should
contain
rhomboidal
structures
or
homo-
geneous
areas,
and
sites
with
regression
or
melanophages
should
be
avoided.
If
histology
is
negative
and
suspicion
is
still
high,
a
second
biopsy
should
be
performed
or
the
entire
lesion
excised
if
possible.
Because
lesions
can
contain
Lentigo
Maligna
759
Figure
1
A,
Lentigo
maligna.
Macule
with
irregular
light
and
dark
brown
pigmentation.
B,
Dermoscopic
image
of
the
same
lesion
showing
dermoscopic
features
of
early-phase
lentigo
maligna:
follicular
openings
with
asymmetric
pigmentation
and
rhomboidal
structures.
both
benign
and
malignant
features,
areas
with
benign
fea-
tures,
such
as
light
brown
fingerprint-like
structures
(solar
lentigines),
comedo-like
openings
(seborrheic
keratosis),
or
opaque
yellowish
areas
(seborrheic
keratosis)
should
not
be
sampled.
20
Early
Diagnosis:
The
Schiffner
Dermoscopic
Progression
Model
Rapid
recognition
of
the
first
dermoscopic
signs
of
primary
or
recurrent
LM
is
important
during
follow-up.
Schiffner
and
colleagues
18,21
designed
a
progression
model
for
LM
that
shows
the
characteristic
dermoscopic
structures
of
LM
lesions
from
the
earliest
to
the
latest
phases
in
the
following
order:
dots
around
the
hair
follicle,
short
streaks,
rhom-
boidal
structures,
follicular
openings,
and
homogeneous
areas-obliteration
of
follicular
openings
(
Figs.
1
and
2
).
Differential
Diagnosis
of
Pigmented
Facial
Lesions
It
can
be
difficult
to
distinguish
LM
from
other
pigmented
lesions
(solar
lentigines,
pigmented
actinic
keratosis,
sebor-
rheic
keratosis,
benign
lichenoid
keratosis)
by
simple
visual
examination.
Furthermore,
dermoscopy
alone
may
not
be
sufficient
as
LM
shares
several
dermoscopic
features
with
other
lesions.
22,23
The
most
useful
noninvasive
diagnostic
approach
is
the
correlation
of
dermoscopic
and
clinical
findings.
Table
1
summarizes
several
key
dermoscopic
features
for
distin-
guishing
between
pigmented
lesions
on
the
face.
LM
and
pigmented
actinic
keratosis
are
known
to
be
clinically
similar,
but
there
are
cases
in
which
histologic
distinction
can
be
difficult.
In
such
cases,
immunohisto-
chemical
staining
with
human
melanoma
black
45
and
Melan-A
may
be
useful;
these
markers
can
be
combined
with
Giemsa
staining,
whereby
melanin
deposits
acquire
a
green-
ish
color,
allowing
melanocytes
to
be
distinguished
from
melanophages.
Almost
all
of
the
dermoscopic
features
of
LM
are
also
found
in
pigmented
actinic
keratosis,
with
the
exception
of
homogeneous
areas,
which
are
highly
specific
for
LM/LMM.
10
In
summary,
the
most
specific
dermoscopic
structures
seen
in
pigmented
actinic
keratosis
are
multiple
brown-
grayish
dots
and
globules
with
a
similar
size
and
color
and
a
perifollicular
arrangement
(more
regular
than
in
LM),
rhom-
boidal
structures,
and
an
annular
granular
pattern.
These
first
3
structures
are
the
most
common
(
Fig.
3
).
Other
pat-
terns
are
a
brown
to
gray
pseudonetwork,
a
superficial
fragmented
pseudonetwork,
and
follicular
openings
with
yellowish
keratotic
material
surrounded
by
a
whitish
halo
giving
a
target-like
appearance.
10,24
Delineating
Margins
Margins
are
clinically
difficult
to
define
in
LM,
as
these
lesions
occur
in
areas
of
chronic
sun
damage.
While
margins
can
be
seen
more
clearly
under
Wood’s
light,
as
Robinson
25
showed,
greater
accuracy
can
be
achieved
if
Wood’s
light
is
used
in
combination
with
dermoscopy
as
there
is
a
correla-
tion
between
dermoscopic
and
histologic
findings.
Robinson
showed
that
margins
excised
with
Mohs
micrographic
surgery
were
larger
(and
more
accurate)
than
those
determined
by
dermoscopy,
but
that
the
margins
determined
by
der-
moscopy
were
in
turn
more
accurate
than
those
determined
using
Wood’s
light.
CRM
is
a
noninvasive
technique
that
permits
the
visual-
ization
of
skin
cells
and
structures
in
real
time.
The
images
this
in
vivo
diagnostic
tool
provides
have
very
similar
reso-
lution
to
those
assessed
in
conventional
histology.
CRM
also
shows
a
depth
of
250
to
350

m,
which
is
sufficient
to
visual-
ize
the
epidermis,
the
papillary
dermis,
and
the
superficial
reticular
dermis
in
horizontal
sections.
This
tool
serves
as
a
bridge
between
dermoscopy
and
histology.
Uses
of
CRM
in
LM
1.
As
a
diagnostic
tool
for
equivocal
cases
following
der-
moscopy
CRM
is
particularly
useful
in
hypopigmented
or
760
E.
Samaniego,
P.
Redondo
Figure
2
A,
Dermoscopic
image
of
early-phase
lentigo
maligna
showing
irregularly
distributed
slate-gray
dots
and
globules
(red
arrows),
short
dark
streaks,
early
rhomboidal
structures
(black
arrow),
and
asymmetric
perifollicular
pigmentation
(asterisks).
B,
Dermoscopic
image
of
lentigo
maligna
showing
follicular
openings
with
asymmetric
pigmentation,
some
of
which
have
signs
of
early
obliteration
(red
arrows).
C,
Image
showing
isobar
structures
(asterisk),
rhomboidal
structures
(red
arrow),
and
follicular
openings
with
asymmetric
pigmentation.
D,
Image
of
histologically
confirmed
lentigo
maligna
melanoma
following
biopsy
taken
of
area
marked
by
the
asterisk,
showing
homogeneous
areas
with
obliterated
follicular
openings.
Table
1
Differential
Diagnosis
of
Pigmented
Facial
Lesions
by
Dermoscopy.
Lentigo
Maligna
Pigmented
Actinic
Keratosis
Solar
Lentig-
ines/Seborrheic
Keratosis
Benign
Lichenoid
Keratosis
Pseudonetwork
+
+
+
+
Homogeneous
areas
+
Rhomboidal
structures
+
+
+/
Annular
granular
pattern
+
+
+
Grayish-brown
granules
Irregular
distribution
and
size
Similar
color,
size,
and
distribution
(predominantly
perifollicular)
Diffuse
or
localized
distribution
Asymmetric
perifollicular
pigmentation
+
+/
-
Moth-eaten
border
+/
+
Fingerprint-like
structures
+
Lentigo
Maligna
761
Figure
3
A,
Dermoscopic
image
of
lentigo
maligna
(rhomboidal
structures
asymmetric
perifollicular
pigmentation,
and
granular
pattern
with
asymmetrically
distributed
irregular
globules).
B,
Dermoscopic
image
of
pigmented
actinic
keratosis
(multiple
similarly
shaped
and
colored
brown-gray
dots
with
a
predominantly
perifollicular
distribution,
and
rhomboidal
structures).
C,
Histologic
image
(hematoxylin-eosin,
original
magnification
×
100)
of
the
lesion
in
Figure
3
A,
showing
proliferation
of
atypical
melanocytes
along
the
dermal-epidermal
junction
with
involvement
of
the
perifollicular
epithelium.
Melanophages
and
solar
elastosis
can
also
be
observed
in
the
dermis.
D,
Histologic
image
(hematoxylin-eosin
original
magnification
×
100)
of
the
lesion
in
Figure
3
B,
showing
atypical
pigmented
keratinocytes
at
the
dermal-epidermal
junction
and
solar
elastosis
in
the
dermis.
amelanotic
lesions,
as
it
reflects
even
small
traces
of
melanin.
26,27
2.
To
guide
the
selection
of
biopsy
sites
so
that
common
sampling
errors
are
avoided.
3.
To
complement
Wood’s
light
examination
and
der-
moscopy
for
identifying
poorly
defined
margins
prior
to
surgery.
28
4.
Tool
for
monitoring
treatment
response.
For
detecting
subclinical
recurrence
or
recurrence
in
which
dermo-
scopic
features
are
not
visible
due
to
scarring
or
lack
of
pigment
29---31
(
Fig.
4
).
The
following
CRM
patterns
have
been
described
for
LM:
a)
epidermal
disarray
(areas
with
complete
or
partial
loss
of
honeycomb
pattern)
and
loss
of
definition
of
keratinocyte
borders;
b)
pagetoid
spread
of
atypical
melanocytes
(iso-
lated
round
or
dendritic
cells
in
the
superficial
layers
of
the
epidermis);
c)
atypical
melanocytes
in
the
superfi-
cial
dermis;
d)
melanophages
in
the
superficial
dermis;
e)
focal
increase
of
atypical
melanocytes
and
nests
around
the
adnexal
openings
(corresponding
to
the
dots
around
the
follicular
openings
seen
in
dermoscopy);
f)
confluence
of
atypical
dendritic
melanocytes
between
the
adnexal
openings
or
obliterating
them
(corresponding
to
the
rhom-
boidal
or
rhomboidal
and
homogeneous
structures
seen
in
dermoscopy);
g)
crests
in
a
cordlike
arrangement
at
the
dermal-epidermal
junction
(reduced
number
of
crests
and
flattening
of
dermal-epidermal
junction,
seen
as
branched,
tube-like
structures
with
a
heterogeneous
reflectance)
and
poorly
visible
dermal
papillae
with
an
undefined
pattern;
and
h)
infiltration
of
adnexal
structures
(round
to
dendritic
nucleated
cells
along
the
adnexal
structures).
25,26,32
CRM
has
certain
limitations
as
the
depth
of
analysis
is
limited
to
the
superficial
reticular
dermis;
when
it
is
sus-
pected
that
a
palpable
lesion
is
a
recurrence,
it
should
be
biopsied,
regardless
of
the
CRM
results.
This
technique
is
also
not
valid
for
palmoplantar
or
crusted
lesions.
Additional
disadvantages
are
that
trained
staff
must
be
available
to
interpret
the
findings
and
that
the
procedure
is
laborious
and
very
time
consuming.
It
is
also
not
widely
used.
Prognosis
of
LM
The
exact
percentage
of
cases
of
LM
that
progress
to
LMM
is
unknown,
but
based
on
studies
published
to
date,
progres-
sion
rates
would
appear
to
be
highly
variable,
ranging
from
5%
to
50%.
3,33,34
No
clinical,
histologic,
or
biologic
predictors
of
malignant
transformation
have
been
identified.
An
invasive
component
has
been
histologically
demonstrated
in
22%
of
fully
excised
LMs
following
diagnosis
by
incisional
biopsy.
2,7
The
risk
of
LMM
may
be
proportional
to
lesion
size,
as
foci
of
inva-
sive
melanoma
are
seen
more
frequently
in
large
lesions.
762
E.
Samaniego,
P.
Redondo
Figure
4
Seventy-year-old
man
with
recurrent
lentigo
maligna
in
a
cryotherapy
scar
on
the
left
cheek;
no
previous
biopsy.
Confocal
reflectance
microscopy
(CRM)
showing
the
presence
of
atypical
cells,
compatible
with
the
diagnosis
of
lentigo
maligna,
confirmed
by
biopsy.
A,
A
hypochromatic
scar
lesion,
possibly
due
to
cryotherapy,
with
slight,
nonspecific
light
brown
pigmentation.
Visualization
of
the
positive
margins
provides
a
guide
for
treatment.
B,
Dermoscopic
image
of
a
lesion
with
a
homogeneous
pigmented
pattern
without
signs
of
malignancy.
The
lesion
has
a
scar
that
distorts
the
structure
of
the
skin
in
the
area
and
erases
the
typical
pseudonet-
work
pattern;
the
image
is
therefore
not
informative.
C,
CRM
in
vivo
(VivaScope
1500).
Mosaic
in
the
stratum
spinosum
showing
typical
honeycomb
pattern
and
abundant
hyperrefractile
linear
structures
at
low
magnification
consistent
with
the
characteristic
dendritic
melanocytic
of
lentigo
maligna
melanoma.
D,
Image
of
the
spinous
stratum,
showing
an
area
500

m
×
500

m
with
atyp-
ical
hyperrefractile
dendritic
cells.
E,
Image
of
the
stratum
granulosum,
showing
an
area
500

m
×
500

m
with
atypical
dendritic
cells
consistent
with
pagetoid
melanocytes.
(Images
were
kindly
provided
by
Dr
Josep
Malvehy
of
Hospital
Clínic
de
Barcelona.)
The
period
of
latency
between
the
development
of
LM
and
progression
to
LMM
can
be
long
(10-50
years),
but
rapid
pro-
gression
(6
months)
has
also
been
reported.
LMM
should
be
managed
like
other
invasive
melanomas
since
prognosis
for
all
these
tumors
is
similar.
35---38
Recurrence
rates
vary
from
3%
to
50%,
depending
on
treatment.
Rates
of
3%
have
been
associated
with
microscopically
controlled
excision,
while
rates
of
50%
(and
even
100%)
have
been
seen
in
LMs
managed
nonsurgically.
Most
recurrences
present
as
in
situ
lesions,
3
but
invasive
forms,
which
have
a
poorer
prognosis
due
to
the
risk
of
metastasis,
have
been
described.
1,39,40
Treatment
There
is
a
notorious
lack
of
prospective,
randomized
studies
and
specific
guidelines
and
protocols
on
the
management
of
LM.
Nevertheless,
the
main
guidelines
on
the
management
of
melanoma
11,12,41,42
address
LM
and
should
be
consulted.
The
aim
of
treatment
is
to
achieve
cure
and
thereby
pre-
vent
progression
to
invasive
melanoma
(LMM),
which
carries
a
risk
of
regional
and
distant
metastasis.
1
Treatment
should
be
effective
and
initiated
as
early
as
possible;
the
treatment
of
choice
is
surgical
excision
whenever
possible,
especially
in
younger
patients.
5
The
following
factors
should
be
taken
into
account
when
deciding
on
the
best
treatment
modality:
the
patient’s
age
and
general
state
of
health,
comorbidity,
life
expectancy,
size
of
lesion,
location
in
cosmetically
or
functionally
sensitive
areas,
accessibility
and
convenience
of
treatment,
and
patient
preferences.
43
Both
patients
and
their
relatives
should
be
informed
about
the
advantages
and
disadvantages
of
each
treatment
option.
The
levels
of
evidence
and
grades
of
recommendation
associated
with
the
different
treatment
options
are
shown
in
Table
2
.
(See
Appendices
A
and
B
for
the
meaning
of
these
classifications.)
Surgery
Surgery
is
the
mainstay
of
treatment,
with
a
safety
mar-
gin
depending
on
Breslow
thickness.
A
margin
of
0.5
cm
is
recommended
for
melanoma
in
situ
and
LM,
but
in
certain
cases
this
may
be
insufficient
to
remove
all
affected
tissue
and
might
lead
to
recurrence.
Zalla
et
al.
44
reported
on
a
series
of
46
LMs
in
which
margins
of
6
mm
achieved
full
exci-
sion
in
only
50%
of
cases.
In
another
study
of
92
LMs,
58%
of
lesions
required
safety
margins
of
over
5
mm
to
achieve
complete
clearance.
45
These
data
confirm
that
the
margins
recommended
by
the
National
Institutes
of
Health
for
the
treatment
of
LM
46
may
be
insufficient.
The
best
surgical
procedure
for
the
treatment
of
LM
and
LMM
in
terms
of
ensuring
complete
excision
involves
the
3-dimensional
study
of
the
excised
tumor
before
any
type
of
reconstruction
using
Mohs
micrographic
surgery
or
microscopically
controlled
surgery
with
frozen
or
paraffin-
embedded
sections.
One
group
of
authors
reported
a
97%
cure
rate
with
the
frozen-section
technique
in
patients
with
Lentigo
Maligna
763
Table
2
Levels
of
Evidence
and
Grades
of
Recommendation
for
the
Treatments
of
Lentigo
Maligna.
Treatment
Level
of
Evidence
Grades
of
Recommendation
Surgery
IIb
A
Cryotherapy
III
C
Radiation
therapy
III
C
Imiquimod
III
C
Azelaic
acid
IV
C
Laser
IV
C
Intralesional
interferon
IV
C
5-Fluorouracil
IV
C
Retinoids
IV
D
LM
and
LMM.
47
Mohs
micrographic
surgery
was
introduced
in
1941
by
Frederic
Edward
Mohs,
48,49
although
the
tech-
nique
and
name
have
changed
over
the
years.
In
all
the
variations,
the
entire
excised
tumor
is
histologically
exam-
ined
using
horizontal
and
vertical
sections
or
a
section
that
includes
the
peripheral
and
deep
margins
after
the
tissue
is
flattened
with
a
cryostat.
Variations
of
histographic
surgery
that
do
not
involve
the
flattening
of
peripheral
margins
but
rather
study
peripheral
and
deep
margins
separately
using
vertical
and
horizontal
sections
are
perfectly
applicable
in
LM
and
are
technically
less
complex
than
the
conventional
Mohs
procedure.
Following
a
review
of
the
literature
on
the
treatment
of
LM
and
LMM,
McLeod
et
al.
50
showed
that
recurrence
rates
were
lower
after
Mohs
micrographic
surgery
and
its
variations
than
after
conventional
surgical
excision
with
safety
margins.
This
finding
is
consistent
with
what
we
have
discussed
here
because
the
radial
growth
of
atypical
melanocytes
may
not
be
uniform,
meaning
that
subclinical
disease
may
exist
beyond
one
of
the
resection
margins,
even
in
the
case
of
wide
excision.
LM
and
LMM
are
mainly
located
on
the
face,
and
therefore
better
cosmetic
and
functional
outcomes
are
achieved
when
the
operator
uses
healthy
tissue---sparing
approaches,
which
are
not
incom-
patible
with
oncologic
control.
This
principle
is
particularly
relevant
in
recurrent
LM,
where
lesions
are
less
well
defined
and
the
chances
of
treatment
success
are
lower.
Staged
excision
is
a
simple,
acceptable
alternative
for
treating
LM
and
LMM
and
offers
comparable
results
to
those
seen
in
Mohs
micrographic
surgery
(
Tables
3
and
4
,
Fig.
5
).
One
recent
study
found
that
staged
excision
was
associated
with
a
significantly
lower
recurrence
rate
than
Mohs,
and
there
were
no
differences
in
the
final
size
of
the
surgical
defect.
51
This
technique,
which
was
first
referred
to
as
the
square
procedure,
consists
of
enclosing
the
target
lesion
and
safety
margins
within
a
geometric
figure
(in
this
case
a
square)
and
histologically
examining
the
peripheral
margins
using
paraffin-embedded
sections.
52,53
More
recent
alternatives
are
the
perimeter
technique
54
and
the
spaghetti
technique,
68
which
involve
the
same
basic
principle----evaluation
of
all
peripheral
margins
before
reconstruction----but
differ
from
the
previously
described
excision
methodologies.
The
main
obstacle
to
the
successful
treatment
of
LM
is
the
difficulty
of
distinguishing
between
atypical
or
dys-
plastic
melanocytes
and
normal
melanocytes
in
chronically
sun
exposed
parts
of
the
body.
Failure
to
make
this
dis-
tinction
can
complicate
diagnosis
and
lead
to
slow
tumor
recurrence.
69
Paraffin-embedded
sections
are
preferable
to
frozen
sections,
in
which
it
is
difficult
to
identify
dysplastic
melanocytes.
In
some
cases,
immunohistochemical
staining
may
be
needed
to
reach
a
definitive
diagnosis.
Nonetheless,
several
recent
articles
describing
the
use
of
immunohisto-
chemical
stains
on
Mohs
frozen
sections
have
reported
rapid
Table
3
Studies
on
the
Treatment
of
Lentigo
Maligna
Using
Staged
Surgical
Excision.
Authors
(Year)
No.
of
Patients
Technique
Recurrence
Follow-up
Duration
a
Johnson
et
al.
52
(1997)
35
Square
procedure
0
-
Hill
and
Gramp
55
(1999)
38
Vertical
sections
1
(2.6%)
25
mo;
10-48
mo
Anderson
et
al.
53
(2001)
150
Square
procedure
1
(0.67%)
-
Agarwal-Antal
et
al.
45
(2002)
93
Similar
technique
to
the
square
procedure;
longitudinal
sections
(perimeter
margins)
Bread-loaf
sections
(central
portion)
-
Malhotra
et
al.
56
(2003)
109
Vertical
sections
4
(3.7%)
32
(26)
mo
Bub
et
al.
57
(2004)
55
Radial
sections
2
(3.6%)
57
mo;
9-139
mo
Huilgol
et
al.
58
(2004)
125
Vertical
sections
2
(1.6%)
38
(25)
mo
Mahoney
et
al.
54
(2005)
11
Perimeter
technique
0
4.7
mo
(1-13
mo)
Jejurikar
et
al.
59
(2007)
48
Square
procedure
0
31
mo
(15-45
mo)
Walling
et
al.
51
(2007)
41
Vertical
sections
3
(7.3%)
60-240
mo
Lee
and
Ryman
60
(2008)
31
Study
of
total
circumference
margin
using
vertical
and
horizontal
permanent
sections
3
(9.7%)
42
mo
Bosbous
et
al.
61
(2009)
49
Vertical
permanent
sections
(central
portion)
and
horizontal
permanent
sections
(peripheral
margins)
1
2.2
y;
0-10.29
y
Adapted
from
McLeod
et
al.
50
a
Expressed
as
mean
(SD)
and/or
range.
764
E.
Samaniego,
P.
Redondo
Table
4
Studies
on
Treatment
of
Lentigo
Maligna
Using
Mohs
Micrographic
Surgery
(MMS).
Authors
(Year)
No.
of
Patients
Technique
Recurrence
Follow-up
Duration
Dhawan
et
al.
62
(1990)
1
MMS
with
horizontal
permanent
sections
0
1
y
Robinson
46
(1994)
16
Conventional
MMS
with
frozen
and
permanent
sections
and
IHQ
with
S-100
protein
and
HMB-45
1
(6.3%)
5-9
y
Cohen
et
al.
47
(1998)
26
Frozen
sections
followed
by
permanent
sections
0
58
mo
Clayton
et
al.
63
(2000)
81
Permanent
sections
1
(1.2%)
22
mo
Bienert
et
al.
64
(2003)
67
0
33
mo
Temple
and
Arlette
65
(2006) 119
0
29.8
mo
Bhardwaj
et
al.
66
(2006)
158
Frozen
sections,
Mel-5
1
(0.67%)
38.4
mo
Walling
et
al.
51
(2007)
18
6
(33%)
117.5
(27.4)
mo
Bene
67
(2008)
116
Frozen
and
permanent
sections
without
IHQ
1
(0.87%)
63
mo
(median)
Adapted
from
McLeod
et
al.
50
Abbreviations:
HMB-45,
human
melanoma
black;
IHQ,
immunohistochemistry.
a
Expressed
as
mean
(SD)
unless
otherwise
specified.
staining
protocols
(19
and
20
minutes
for
MART-1
and
35
minutes
for
MITF)
that
give
results
similar
to
those
seen
in
paraffin-embedded
sections.
60,70---72
These
results,
however,
need
to
be
confirmed
in
larger
series
or
controlled
studies.
Nonsurgical
Treatment
Because
LM
frequently
affects
older
patients
with
comor-
bidities
and
involves
large
lesions
requiring
wide
excision
margins
in
cosmetically
or
functionally
sensitive
areas,
nonsurgical
treatments
are
sometimes
required.
These
treatments
are
also
necessary
for
patients
who
decline
to
undergo
surgery.
While
the
main
advantages
of
nonsurgi-
cal
treatments
are
good
cosmetic
results
and
low
morbidity,
these
modalities
are
unfortunately
associated
with
higher
recurrence
rates.
In
a
study
of
melanoma
in
situ,
Zalaudek
et
al.
73
reported
a
mean
(SD)
5-year
recurrence
of
6.8%
(1.3%)
for
surgical
excision
and
of
11.3%
±
8.5%
for
non-
surgical
alternatives
as
a
whole.
The
authors
concluded
Figure
5
Sixty-five-year-old
man
with
lentigo
maligna.
A,
The
lesion
on
the
nasal
dorsum.
B,
Under
Wood’s
light
the
margins
are
more
clearly
defined.
Note
the
ulcer
on
the
bridge
of
the
nose,
caused
by
the
use
of
continuous
positive
airway
pressure.
C,
Inking
of
margins
guided
by
Wood’s
light
examination
after
biopsy
confirmation
of
the
diagnosis.
D,
Surgical
defect
after
2
steps
of
Mohs
micrographic
surgery
using
paraffin-embedded
sections;
all
margins
were
positive.
E,
Final
defect
with
clear
margins
after
3
steps.
Lentigo
Maligna
765
that
radiation
therapy,
which
has
similar
recurrence
rates
to
surgery,
was
the
best
alternative.
73
Based
on
a
sur-
vey
conducted
among
British
dermatologists
in
2001,
the
most
common
nonsurgical
treatments
were
cryotherapy
and
radiation
therapy.
74
The
general
limitations
of
nonsurgical
treatments
are
summarized
below.
1.
Recurrence
rates
are
higher
because
the
whole
tumor
is
not
evaluated
histologically
and
so
invasive
areas
may
be
missed
(sampling
error).
2
It
is
also
difficult
to
treat
deep
periadnexal
melanocytes,
which
explains
why
any
treat-
ment
must
reach
a
depth
of
at
least
3
to
5
mm,
regardless
of
treatment
modality.
2.
Residual
hypopigmentation
following
certain
treatments
may
lead
to
delayed
detection
of
recurrence
during
follow-up.
3.
The
efficacy
of
nonsurgical
treatments
has
not
yet
been
well
established
due
to
the
lack
of
randomized
controlled
studies.
Regardless
of
the
treatment
modality
employed,
long-
term
follow-up
is
essential.
In
the
following
sections,
we
review
the
main
nonsurgical
treatments
used
in
LM.
Cryotherapy
Cryotherapy
is
one
of
the
most
common
treatment
alternatives
for
LM
in
clinical
practice.
As
melanocytes
are
very
sensitive
to
damage
induced
by
freezing,
cryotherapy
selectively
destroys
melanocytes
but
not
keratinocytes
at
temperatures
of
--- 4
C
to
--- 7
C,
although
there
is
no
evidence
that
it
also
destroys
neoplastic
melanocytes.
The
fall
in
tem-
perature
must
penetrate
to
at
least
3
mm
so
that
atypical
melanocytes
extending
into
normal
skin
and
down
to
the
hair
follicles
are
also
destroyed.
75
Some
authors
have
pro-
posed
monitoring
the
temperature
at
the
base
of
the
tumor
to
ensure
adequate
penetration
depth,
but
there
does
not
appear
to
be
any
correlation
between
this
temperature
and
cure
rates.
72
No
cryotherapy
protocols
have
been
estab-
lished
for
LM
and
the
technique
varies
from
one
center
to
the
next.
The
treatment
should
generally
be
aggressive,
with
double
freeze-thaw
cycles
and
a
spray
distance
of
2
to
3
cm
to
achieve
a
temperature
of
---40
C
to
---50
C
at
the
base
of
the
tumor.
Freezing
duration
depends
on
the
size
of
the
lesion,
with
periods
of
45
to
60
seconds
required
to
freeze
a
lateral
margin
of
apparently
healthy
skin
of
1
cm
(minimum
5
mm).
This
cycle
is
then
repeated
after
a
thaw
period
of
2
to
3
minutes.
3,76
Treating
large
lesions
in
several
sessions
ensures
adequate
treatment
of
lateral
margins
with
fewer
complications.
Treatment
duration
depends
on
the
size
of
the
lesion.
Response
is
variable,
with
reported
rates
varying
according
to
technique,
histologic
evaluation,
duration
of
follow-up,
etc.
Over
200
cases
of
LM
treated
with
cryother-
apy
have
been
described
since
1979;
the
overall
recurrence
rates
are
under
9%,
but
specific
studies
have
reported
rates
of
0%,
8%
to
10%,
and
even
50%.
1,75---79
There
have
also
been
reports
of
lesions
recurring
7
to
9
years
after
treatment
(
Table
5
).
The
advantages
of
cryotherapy
are
that
it
is
fast
and
easy
to
apply
and
the
good
cosmetic
outcome.
Retreatment
can
be
effective.
Disadvantages
are
the
general
limitations
of
nonsurgical
treatment
as
well
as
long
healing
times
(up
to
3
months,
which
is
even
longer
than
with
surgery)
and
a
risk
of
hypertrophic
scarring.
Radiation
Therapy
Radiation
therapy
is
the
most
effective
nonsurgical
treat-
ment
for
LM.
2,86,87
It
has
been
used
mainly
in
older
patients
with
large
lesions
located
in
anatomically
sensitive
areas,
as
it
is
generally
associated
with
minimal
morbidity
and
good
cosmetic
results.
88
Reports
of
good
results
after
con-
ventional
orthovoltage
irradiation
in
LM
and
LMM
have
been
published
in
the
United
States,
89,90
with
all
authors
stressing
that
conventional
fractionated
radiation
therapy
is
highly
effective
because
the
doses
administered
in
the
subcuta-
neous
tissue
(50%
of
the
dose
between
6
mm
and
4
cm)
prevent
subepidermal
recurrences.
The
disadvantage
of
using
high-energy
x-rays
is
that
they
can
reach
underlying
tissues,
especially
bone
tissue,
in
the
treated
area
and
cause
radiation
necrosis.
91
This
adverse
effect
can
be
significantly
minimized
with
the
Miescher
technique,
which
has
been
used
in
Europe
as
a
primary
treatment
or
adjuvant
to
surgery
since
it
was
first
described
in
the
1950s
92
and
involves
the
application
of
high
doses
of
Grenz
rays
or
superficial
x-rays
with
a
very
low
voltage
(12-50
kV)
and
a
maximum
penetra-
tion
depth
of
2
to
3
mm.
In
the
Miescher
technique
and
its
variations,
the
technician
uses
an
X-ray
tube
with
a
beryl-
lium
window
of
12
kV,
15
MAamp
at
a
distance
of
20
cm
to
administer
50%
of
the
dose
at
1
to
1.3
mm.
Because
only
the
epidermis
and
the
superficial
dermis
are
affected,
the
treat-
ment
induces
acute
radiodermatitis,
but
less
atrophy.
93
A
very
common
and
well-tolerated
regimen
is
a
total
fraction-
ated
dose
of
100
Gy
administered
over
10
sessions
(5
sessions
a
week
for
2
weeks).
The
treatment
must
be
carefully
planned
to
ensure
inclu-
sion
of
the
entire
tumor
with
a
sufficiently
wide
margin:
1
cm
for
lesions
smaller
than
2
cm
and
2
cm
for
larger
lesions.
In
practice,
both
superficial
x-rays
(100-200
kV)
and
high-
energy
electrons
(6-9
MeV)
are
adequate.
Doses
of
45
to
50
Gy
in
15
to
25
fractions
are
sufficient
to
achieve
dis-
ease
control
in
the
majority
of
patients.
The
recommended
dose
per
fraction
is
2
to
3.5
Gy
depending
on
the
size
and
thickness
of
the
tumor
and
the
treatment
regimen
used.
Postoperative
radiation
therapy
is
useful
for
recurrent
lesions,
large
lesions
with
insufficient
surgical
margins,
and
lesions
with
a
lentiginous
part
that
cannot
be
fully
excised
due
to
the
risk
of
considerable
morbidity.
Cure
rates
of
86%
to
95%
have
been
reported
for
radi-
ation
therapy
with
Grenz
rays
or
superficial
x-rays
using
the
Miescher
technique,
but
they
are
from
small
series
with
short
follow-up
times
(2-5
years)
2
(
Table
6
).
Clinical
regres-
sion
has
been
observed
2
to
8
months
after
treatment.
91
In
2002,
Farshad
et
al.
93
published
a
retrospective
study
of
150
patients
(93
patients
with
LM,
54
with
LMM,
and
3
with
LM
and
LMM)
in
which
the
overall
recurrence
rate
was
7%
(5.2%
in
LMs).
Radiation
therapy
appears
to
be
less
effective
in
LMM
than
in
LM.
In
many
cases,
it
is
used
as
adjuvant
therapy
after
the
surgical
excision
of
the
nodular
part
of
the
lesion.
88,91
766
E.
Samaniego,
P.
Redondo
Table
5
Main
Studies
on
Lentigo
Maligna
Treated
With
Cryotherapy.
Authors
(Year)
No.
of
Patients
Regimen
Recurrence
Follow-up
Duration
a
Dawber
and
Wilkinson
78
(1979)
14
6
patients
treated
with
cotton-wool
swab;
8
with
spray
0
7.5-30
mo
Pitman
et
al.
77
(1979)
4
2
(50%)
3.5
y
Coleman
et
al.
79
(1980)
2
1
(50%)
3
y;
1-12
y;
Kuflik
80
(1980)
4
Spray
with
single-double
cycles
---25
C
---30
C;
measurement
of
temperature
at
base
of
lesion;
1-cm
margin
0
1-3
y
Zacarian
76
(1982)
20
Double
freeze-thaw
cycle
at
---50
C
2
(10%)
42.6
mo
Lorenz
81
(1983)
33
0
2-5
y
Burge
and
Dawber
82
(1984)
14
6
patients
treated
with
cotton-wool
swab;
8
with
spray;
single
cycles
1
(7.1%)
>
5
y;
recurrence
at
6
y;
free
of
disease
6
mo
after
retreatment
Collins
et
al.
83
(1991)
10
3
patients
treated
with
cotton-wool
swab;
8
with
spray
Once
every
6
wk
6
times
or
until
clearance
4
(40%)
4
y
Böhler-
Sommeregger
et
al.
84
(1992)
20
Double
freeze-thaw
cycle
at
---30
C
to
---40
C;
5-mm
margin
3
(15%)
7-80
mo
Kuflik
and
Gage
75
(1994)
30
Double
cycle
at
---40
C
to
---50
C,
beyond
margin
2
(6.7%)
3
y
Machado
et
al.
85
(2007)
18
Two
1-min
freeze
cycles
separated
by
2-min
thaw
period
0
75.5
mo;
53-98
mo
a
Expressed
as
mean
(SD)
and/or
range.
Adverse
Effects
In
most
cases,
radiation
therapy
causes
erythema,
scal-
ing,
and
local
hair
loss
from
the
second
week
of
treatment
onwards.
Late
complications
include
atrophy,
flattening
of
the
epidermis,
fibrosis,
telangiectasis,
pigmentary
changes
(hyperpigmentation
or
hypopigmentation),
and
an
increased
risk
of
squamous
cell
carcinoma.
The
advantages
of
radiation
therapy
are
good
tolerance
and
cosmetic
results
and
shorter
treatment
periods
than
with
topical
treatments.
Cure
rates
are
similar
to
those
observed
with
conservative
surgery.
Because
the
skin
in
exposed
areas
of
the
head
and
neck
is
very
thin
in
older
patients,
a
penetration
depth
of
1.1
mm
is
sufficient
to
reach
a
considerable
portion
of
the
dermis.
91
The
disadvantages
of
radiation
therapy
are
the
limited
penetration
of
x-rays
(which
explains
why
the
Miescher
technique
can
fail
in
cases
where
melanocytes
extend
below
the
adnexal
structures
91
),
the
need
for
multiple
ses-
sions
(generally
done
only
in
urban
areas
with
adequate
infrastructure
93
),
and
the
difficulty
of
detecting
recurrence
due
to
treatment-induced
pigmentary
changes.
Imiquimod
Imiquimod,
a
synthetic
imidazoquinoline
amine,
is
a
topical
immune
response
modifier
that
exerts
its
effect
through
the
stimulation
of
both
innate
and
acquired
immunity.
It
has
also
been
shown
to
induce
apoptosis
99
and
exert
antiangiogenic
effects.
100
After
the
first
reported
case
of
imiquimod-treated
LM
was
published
in
2000,
101
by
2006
there
were
descriptions
of
68
cases
treated
in
this
way
according
to
a
review
of
15
reports
in
the
English-language
literaure.
102
The
authors
of
the
review
concluded
that,
because
of
the
risk
of
leaving
invasive
or
residual
disease,
‘‘without
controlled
evidence
and
prolonged
follow
up,
the
use
of
imiquimod
for
LM
must
still
be
considered
experimental.’’
102
The
literature
now
contains
reports
of
the
use
of
imiquimod
in
234
patients
with
LM,
all
from
uncontrolled
studies.
A
recent
review
evaluated
161
of
these
cases.
2
However,
the
authors
included
highly
variable
types
of
studies
(
Table
7
):
case
series,
individual
case
reports,
and
open-label
studies.
There
were
also
differ-
ences
in
lesion
size
and
type
(primary
or
recurrent),
previous
treatment,
treatment
regimens
(from
twice-weekly
to
daily
applications)
and
duration
(8
days-9
months),
margin
width,
confirmation
of
treatment
response
(not
always
by
biopsy),
and
follow-up
times
(shorter
than
the
standard
5-year
period
used
in
oncology).
Many
of
the
studies
had
a
follow-up
time
of
less
than
a
year.
Imiquimod
is
generally
not
recommended
in
invasive
tumors
or
in
young
patients
due
to
the
risk
of
progression
to
invasive
disease,
or
in
patients
who
cannot
be
closely
monitored.
103,104
Response
and
Response-Related
Factors
Imiquimod
applied
5
times
a
week
for
at
least
12
weeks
has
been
proposed
as
the
most
effective
treatment
reg-
imen.
Response
rates
vary
from
series
to
series.
104
While
Lentigo
Maligna
767
Table
6
Main
Studies
on
the
Treatment
of
Lentigo
Maligna
Using
Radiation
Therapy
(RT).
Authors
(Year)
No.
of
Patients
Regimen
Recurrence
Follow-up
Duration
a
Arma-Szachcic
et
al.
94,95
(1970)
61
Miescher
technique
2
(28.4%)
Kopf
et
al.
96
(1976)
16
Miescher
technique
8
(50%)
10
mo-9.5
y
Pitman
et
al.
77
(1979)
8
Miescher
technique
3
(38%)
3.5
y
Dancuart
et
al.
89
(1980)
8
Conventional
orthovoltage
RT,
dose
2000-5000
rad
in
1-20
fractions;
100-280
kV
1
(12.5%)
1-4.5
y;
1
patient
free
of
disease
11
years
after
reirradiation
Harwood
90
(1983)
20
Conventional
orthovoltage
RT;
100-280
kV,
35-50
Gy
2
(10%)
5
mo-8
y
(median,
26
mo)
Panizzon
(1997)
104
Miescher
technique
1
7.3
y
Tsang
et
al.
98
(1994)
36
Superficial
x-rays;
30-50
Gy,
100-250
kV;
margins
of
0.5-1
cm
4
(11%)
1-12
y
6
y
Schmid-Wendtner
et
al.
91
(2000)
42
Modified
Miescher
technique;
margins
of
0.5-2
cm
0
Short
follow-up:
15
mo,
1-96
mo
Farshad
et
al.
93
(2002)
96
Grenz
rays;
12
kV,
100-120
Gy;
margins
of
7-10
mm
5
(5.2%)
Majority
>
2
y;
mean,
8
y
Hedblad
and
Mallbris
97
(2011)
593
(215
LMs);
188
RT
only;
26
partial
excision
+
RT
Grenz
rays;
twice
weekly
for
3
wk;
100-160
Gy
27/188
for
RT
only;
3/26
for
partial
excision
+
RT
425
for
at
least
2
y;
241
for
5
y
Adapted
from
Stevenson
et
al.
1
a
Expressed
as
mean
and/or
range
unless
otherwise
specified.
an
85%
clinical
response
rate
with
histologic
confirmation
has
been
reported,
91
in
most
cases
evaluation
was
done
by
punch
biopsy
of
a
previously
positive
area.
2
In
3
studies,
after
initial
imiquimod
treatment
full
tumor
excision
was
achieved,
with
histologic
clearance
rates
of
75%,
63%,
and
53%.
105---108
Progression
to
LMM
was
reported
during
treat-
ment
in
3
patients.
5,109,110
Because
of
variations
in
study
design,
it
is
not
possible
to
identify
optimal
parameters
or
predictors
of
treatment
failure
or
absence
of
response.
110,111
Imiquimod
has
been
associated
with
a
hypothetical
risk
of
favoring
tumor
progression.
103,112
One
study
showed
that
treatment
efficacy
was
significantly
related
only
to
a
moderate
to
severe
clinical
inflammatory
response.
113
Different
strategies
have
been
used
to
improve
inflamma-
tory
response,
including
increasing
frequency
of
application
(twice
a
day)
or
using
occlusion,
cryotherapy,
or
tazarotene
0.1%
in
gel.
110,114,115
Clinical
response
should
not
be
used
on
its
own
to
evaluate
treatment
response,
as
clinical
and
his-
tologic
findings
may
not
match
(
Fig.
6
).
All
lesions
should
be
biopsied
after
treatment.
116
In
some
cases,
at
least
3
months
should
be
left
before
biopsy
unless
an
inflammatory
response
is
absent
or
abnormal
pigmentation
persists.
Biop-
sies
performed
too
soon
are
difficult
to
interpret
because
of
the
frequent
presence
of
florid
interface
dermatitis.
Sev-
eral
authors
have
proposed
performing
a
second
biopsy
1
or
3
years
after
treatment,
as
late
recurrences
have
been
described.
110
As
mentioned
earlier,
dermoscopy
and
CRM
may
be
useful
for
monitoring
response.
The
adverse
effects
associated
with
imiquimod
treat-
ment
are
postinflammatory
dyschromia,
frequent
erythema
and
edema,
erosions,
telangiectasia,
110
superinfection,
and
reversible
punctate
keratopathy
with
reduced
visual
acuity
in
periocular
lesions.
117
Systemic
effects
include
cytokine
release
syndrome
(headache,
gastrointestinal
discomfort,
fever,
and
general
malaise).
There
have
also
been
reports
of
vitiligo,
110
herpes
simplex
infection,
and
elevated
liver
enzymes.
118
The
advantages
of
imiquimod
are
the
same
as
those
asso-
ciated
with
other
nonsurgical
treatment
modalities.
Disadvantages
include
the
lack
of
standardized
proto-
cols
and
regimens
and
of
clinical
and
histologic
response
criteria.
111
Furthermore,
residual
hyperpigmentation
fol-
lowing
treatment
may
be
confused
with
recurrence.
119
In
conclusion,
the
use
of
imiquimod
should
be
reserved
for
cases
in
which
surgery
and
other
nonsurgical
treatments
such
as
radiation
therapy
are
contraindicated,
at
least
until
further
evidence
is
available
on
its
efficacy
and
safety.
7
Imiquimod
can
be
used
as
adjuvant
therapy
before
surgery
to
reduce
tumor
size
108,113
or
after
surgery
to
treat
extensive
melanoma
in
situ
around
the
lesion
excised.
120
Some
authors
have
recommended
its
use
in
recurrent
LM
768
E.
Samaniego,
P.
Redondo
Table
7
Main
Studies
on
Lentigo
Maligna
(LM)
Treated
Using
Imiquimod
(IMQ).
Authors
(Year)
No.
of
Patients
Regimen
Margin
Response
Histologic
Confirmation
Follow-up
Duration
b
Other
Ahmed
and
Berth-Jones
101
(2000)
1
3
times
a
wk
for
4
wk;
daily
for
2
wk
Alternating
days
for
7
mo
NR
CR
Yes
9
mo
Ormond
et
al.
124
(2002)
5
Daily
for
6-12
mo
NR
CR
and
PR
Only
1
case
Up
to
6
mo
Chapman
et
al.
114
(2003)
1
Once/twice
daily
NR
CR
Yes
3
mo
Epstein
125
(2003)
1
Alternating
days
NR
CR
NR
18
mo
Fisher
and
Lang
109
(2003)
1
Test:
Alternating
days
for
3
mo;
rest:
3
times
a
week
for
14
wk
NR
PR.
Developed
amelanotic
LM
with
satellite
lesions
Yes
Free
of
disease
17
mo
after
MMS
and
IMQ
Naylor
et
al.
5
(2003)
30
Daily
for
12
wk
2
cm
26/28
Yes
12
mo
1
case
resolved
in
8
d
Powell
et
al.
126
(2004)
11
3
times
a
wk
for
4-20
wk
2
cm
6
CR,
4
PR
Yes
9
mo
Powell
and
Jones
9
(2004)
2
3
times
a
wk
for
12
and
20
wk
NR
CR
Yes,
3
mo
posttreatment
9
y
18
mo
Treated
2
amelanotic
LMs
Kupfer
et
al.
127
(2004)
2
3
times
a
wk
for
3
mo
3
times
a
wk
for
4
mo
NR
CR
Yes,
3
mo
posttreatment
14
and
13
mo
Flemming
et
al.
106
(2004)
6
Daily
for
6
wk
1
cm
4/6
Yes
(standard
excision
with
5-mm
margin
after
treatment)
First
study
with
complete
excision
Michapoulos
et
al.
128
(2004)
1
5
times
a
wk
for
2
wk
3
times
a
wk
for
16
wk
NR
CR
Yes
9
mo
Study
of
inflammatory
infiltrate
Mu
̃
noz
et
al.
129
(2004)
1
Daily
for
1
wk
2-3
times
a
wk
for
16
wk
NR
CR
Yes
4
mo
Kamin
et
al.
130
(2005)
1
5
times
a
wk
for
6
wk
Second
3-mo
period
after
1
mo
NR
CR
Yes
12
mo
Wolf
et
al.
131
(2005)
6
Daily
for
5-13
wk
0.5-1
cm
5/6
Yes
3-18
mo
Response
in
1
amelanotic
LM
Noel
and
Kunzle
132
(2005)
1
Twice
a
week
for
12
wk
NR
CR
Yes
12
mo
Ray
et
al.
133
(2005)
3
3
times
a
wk
for
6-12
wk
0.5-1
cm
CR
Yes
7-12
mo
Van
Meurs
et
al.
111
(2007)
10
3
times
a
wk/d
depending
on
inflammation
6-13
wk
(minimum
of
3
mo
proposed)
2
cm
9/10
One
biopsy
after
4
wk
and
second
one
after
1
y
31
mo
4
recurrences
including
1
case
of
histologic
confirmation
without
clinical
evidence
Spenny
et
al.
121
(2007)
12
2-7
times
a
wk
for
7-44
wk
NR
CR
Four
unconfirmed
18.3
mo
Mahoney
et
al.
118
(2008)
7
Variable
depending
on
inflammation
Mean,
12.4
wk
0.5-1
cm
6/7
Yes
19.1
mo
1
case
of
herpes
simplex
infection
and
elevated
liver
enzymes
Troya-Martin
et
al.
119
(2008)
2
5
times
a
wk
for
16
wk
and
12
wk
NR
CR
Yes
3
y
Lentigo
Maligna
769
Buetticker
et
al.
110
(2008)
34
1-2
times
daily
with/without
occlusion
2-20
wk
No
margin CR
Yes
(not
all)
17.2
mo
Vitiligo
recurrence
after
30
mo
in
a
patient
with
B-cell
lymphoma
Cotter
et
al.
105
(2008)
40
5
times
daily
for
3
mo
2
cm
Clinical,
83%;
histologic,
75%
2
mo
after
staged
excision
with
2-mm
margin
18
mo;
12-34
mo
6
cases
with
different
clinical
and
histologic
findings
Powell
et
al.
113
(2009)
48
a
3
times
a
wk/d
for
6-12
wk
2
cm
37/48
Yes,
4
mo
after
treatment
25-72
mo
Follow-up
of
>5
y
without
recurrence
Ventura
et
al.
134
(2009)
1
Daily
for
4
mo
NR
CR
Yes,
3
mo
after
treatment
1
y
LMM
Nodules
excised
and
rest
treated
with
IMQ
Woodmansee
and
McCall
123
(2009)
1
Daily
for
6-8
wk;
alternating
days
for
5
wk
1
cm
CR
but
recurrence
Cure
at
4
mo,
but
recurrence
as
LMM
24
mo
before
recurrence
Free
of
disease
for
11
mo
after
MMS
Ramsdell
and
Zeitouni
135
(2009)
1
3
times
a
week
for
up
to
1
y
depending
on
area
NR
CR
after
treatment
and
at
3
y
3
y
10-cm
lesion
(largest
treated)
Ly
et
al.
107
(2011)
43
5
times
a
wk
for
12
wk
1
cm
20/38
Complete
excision
after
treatment
Abbreviations:
CR,
complete
response;
LMM,
lentigo
maligna
melanoma;
MMS,
Mohs
micrographic
surgery;
NR,
not
reported,
PR,
partial
response.
a
In
this
article,
37
patients
were
added
to
the
cases
reported
in
another
article
126
by
the
same
author.
b
Expressed
as
mean
and/or
range.
770
E.
Samaniego,
P.
Redondo
Figure
6
A,
Lentigo
maligna
melanoma
(0.125-mm
Breslow
depth
after
diagnostic
biopsy)
on
the
forehead
of
a
94-year-old
woman.
B,
Marked
inflammatory
response
after
2
months
of
treatment.
C,
Residual
grayish
hyperpigmentation
between
the
eyebrows
after
3
months
of
treatment.
Tumor
persistence
ruled
out
by
histology.
following
conventional
excision
or
Mohs
micrographic
surgery,
in
cases
with
positive
margins
(as
adjuvant
therapy),
or
to
prevent
recurrence.
37,100,121,122
Other
Nonsurgical
Treatments
Azelaic
Acid
Azelaic
acid
(C9
dicarboxylic
acid)
20%
in
cream
or
15%
to
35%
in
ointment
has
been
used
to
treat
LM
since
the
1970s.
This
agent
is
selectively
cytotoxic
for
abnormal
melanocytes
due
to
the
reversible
inhibition
of
tyrosinase
and
the
inhibi-
tion
of
mitochondrial
enzymes.
136
It
is
applied
twice
a
day
for
2
to
12
weeks,
depending
on
response.
1
Treatment
results
have
been
highly
variable,
137---139
and
there
is
insufficient
evi-
dence
to
recommend
its
use
over
other
modalities
in
clinical
practice.
Laser
Several
types
of
lasers
are
capable
of
destroying
melanocytes,
and
argon,
carbon
dioxide,
ruby,
and
Q-
switched
Nd:YAG
lasers
have
all
been
used
to
treat
LM
140,141
(
Table
8
).
While
promising
results
have
been
reported,
there
is
still
insufficient
evidence
to
recommend
laser
therapy
over
other
alternatives.
1
Finally,
atypical
melanocytes
that
have
lost
their
pigment-forming
capacity
may
be
resistant
to
laser
therapy
(
Table
9
).
Curettage
and
Electrocoagulation
Very
few
studies
have
analyzed
the
use
of
curettage
and
electrocoagulation
in
the
treatment
of
LM
since
the
first
cases
were
published
over
20
years
ago
79
(mean
recurrence
of
27%
for
11
patients
mentioned
in
a
review
1
discussing
that
and
another
study).
This
treat-
ment
modality
cannot
currently
be
recommended
over
others
due
to
a
lack
of
evidence.
Furthermore,
the
histologic
sample
obtained
is
generally
inadequate
for
con-
firming
complete
excision/destruction,
and
melanocytes
extending
beyond
the
adnexal
structures
may
remain
untreated.
1,77,79
Intralesional
Interferon
Although
a
group
of
authors
reported
the
clearance
of
11
lesions
in
10
patients
treated
with
intralesional
interferon,
only
4
cases
were
confirmed
histologically.
148
A
report
of
6
LMs
successfully
treated
in
a
patient
with
xeroderma
pig-
mentosum
has
also
been
published.
149
The
follow-up
periods
reported
have
been
very
short
and
there
is
little
evidence
to
support
the
use
of
intralesional
interferon
in
LM.
,
1
5-Fluorouracil
The
mechanism
of
action
of
5-fluorouracil
is
related
to
the
inhibition
of
DNA
synthesis.
Litwin
et
al.
150
used
it
for
the
first
time
in
1975
to
treat
3
patients
with
twice-daily
appli-
cation
regimens
of
6,
9,
and
13
months.
The
treatment
was
successful
in
all
3
cases,
although
1
patient
required
retreatment
for
recurrence.
There
have
also
been
reports
of
clearance
followed
by
recurrence
in
an
additional
3
patients.
79
Little
evidence
supports
the
use
of
5-fluorouracil
to
treat
LM
in
clinical
practice.
1,79,150
Lentigo
Maligna
771
Table
8
Main
Studies
on
Lentigo
Maligna
Treated
With
Laser.
Authors
(Year)
No.
of
Patients
Regimen
Recurrence
Follow-up
Duration
a
Arndt
et
al.
145
(1984)
1
Argon
laser,
5-cm
distance;
1-mm
spot,
3.8
W,
50
ms
No
8
mo
Arndt
140
(1986)
3
Argon
laser
(as
above)
33%
(1/3)
75
wk
Kopera
141
(1995)
4
10
600-nm
carbon
dioxide
laser,
12
W,
1-mm
spot,
2
passes
0%
(0/4)
15
mo
Thissen
and
Westerhof
142
(1997)
1
694-nm
Q-switched
ruby
laser
0
12
mo
Orten
et
al.
143
(1999)
1
Q-switched
Nd:YAG
laser
4
-11
J/cm
2
,
532
and/or
1064
nm,
10-20
ns,
2-
to
3-mm
spot,
10
Hz
37.8%
(3/8)
8
mo-3.5
y
Iyer
and
Goldman
144
(2003)
1
Q-switched
alexandrite
laser;
5
different
treatments
1/1
3.5
y
Niiyama
et
al.
146
(2007)
1
Q-switched
ruby
laser
5
J/cm
2
,
4-mm
spot
1/1
2
y
Madan
and
August
147
(2009)
22
532-nm-switched
Nd:YAG
laser,
6
J/cm
2
,
2-mm
spot,
5
ns;
755-nm
alexandrite
laser,
12
J/cm
2
,
2-mm
spot,
50
ns
23%
(5/22)
2-5
y
Adapted
from
McLeod
et
al.
50
a
Expressed
as
mean
or
range.
Table
9
Summary
of
Key
Diagnostic
and
Therapeutic
Issues
in
Lentigo
Maligna
(LM).
-
Histology
is
the
method
of
choice
for
the
diagnosis
of
LM.
10
Excisional
biopsy
has
the
highest
diagnostic
accuracy.
Imaging
techniques
such
as
dermoscopy
or
confocal
reflectance
microscopy
(CRM)
can
help
to
select
biopsy
areas.
Dermoscopy
is
a
useful
complementary
tool
in
clinical
practice
for
the
early
diagnosis
of
LM.
CRM
is
useful
as
a
follow-up
to
dermoscopy
for
the
diagnosis
of
equivocal
cases,
particularly
in
hypopigmented
and
amelanotic
lesions.
-
The
treatment
of
choice
is
surgery.
Mohs
micrographic
surgery
(MMS)
and
its
variants
are
associated
with
a
lower
recurrence
rate
than
conventional
surgery
with
safety
margins.
MMS
is
particularly
indicated
in
large
or
recurrent
lesions,
lesions
with
poorly
defined
clinical
borders,
and
lesions
in
anatomically
sensitive
areas.
Wood’s
light
examination,
dermoscopy,
and
CRM
can
help
to
define
margins
prior
to
surgery.
-
In
cases
where
surgical
treatment
is
not
possible:
-
Radiation
therapy
is
considered
to
be
the
most
effective
nonsurgical
treatment
for
patients
whose
general
health
and
life
expectancy
are
good.
-
Alternatives
such
as
imiquimod
or
cryotherapy
can
be
used
in
patients
with
a
poor
state
of
health,
a
short
life
expectancy,
or
who
do
not
wish
to
undergo
other
treatments.
These
alternatives
are
not
currently
supported
by
scientific
evidence;
reliable,
noninvasive
methods
are
needed
to
completely
rule
out
an
underlying
invasive
component.
-
Long-term
monitoring
is
essential.
Dermoscopy
and
CRM
are
useful
monitoring
tools.
Posttreatment
biopsy
is
advisable
when
recurrence
is
suspected
and
is
necessary
after
topical
treatment.
Retinoids
Retinoids
have
been
used
to
treat
LM
due
to
their
ability
to
inhibit
the
proliferation
and
induce
the
differentiation
of
murine
melanocytes
in
cultures.
A
recent
article
reported
the
resolution
of
LM
in
2
elderly
patients
following
treat-
ment
with
tazarotene
0.1%
gel,
with
no
signs
of
recurrence
at
18
and
30
months.
151
There
are
currently
no
data
to
support
the
use
of
retinoic
acid
or
topical
tretinoin
in
the
treatment
of
LM,
although
these
retinoids
have
been
used
in
combination
with
other
treatments,
such
as
imiquimod,
to
enhance
inflammatory
response.
110
More
studies
are
needed.
1
Table
9
summarizes
key
points
related
to
the
diagnosis
and
treatment
of
LM.
Conflicts
of
Interest
The
authors
declare
that
they
have
no
conflicts
of
interest.
Acknowledgments
Dr
Estefanía
Palacios
of
the
Radiotherapy
Oncology
Depart-
ment
at
the
Complejo
Asistencial
Universitario
de
León
for
her
assistance
with
radiation
therapy
section.
Dr
Malvehy
of
772
E.
Samaniego,
P.
Redondo
the
Dermatology
Department
of
Hospital
Clínic
de
Barcelona
for
providing
the
CRM
images.
Appendix
A.
Levels
of
Evidence
Ia
Evidence
obtained
from
meta-analysis
of
randomized
clinical
trials
Ib
Evidence
obtained
from
at
least
1
randomized
clinical
trial
IIa
Evidence
obtained
from
at
least
one
well
designed
controlled
study
without
randomization
IIb
Evidence
obtained
from
at
least
1
type
of
well
designed
quasi-experimental
study
III
Evidence
obtained
from
nonexperimental
descriptive
studies
IV
Evidence
obtained
from
expert
opinion
or
clinical
experience
Adapted
from
Stevenson
et
al.
1
Appendix
B.
Grades
of
Recommendation
A
There
is
good
evidence
to
support
use
of
the
procedure
B
There
is
fair
evidence
to
support
use
of
the
procedure
C
There
is
poor
evidence
to
support
use
of
the
procedure
D
There
is
fair
evidence
to
support
rejection
of
use
of
the
procedure
E
There
is
good
evidence
to
support
rejection
of
use
of
the
procedure
From
Stevenson
et
al.
1
References
1.
Stevenson
O,
Ahmed
I.
Lentigo
maligna:
prognosis
and
treat-
ment
options.
Am
J
Clin
Dermatol.
2005;6:151---64.
2.
Erickson
C,
Miller
SJ.
Treatment
options
in
melanoma
in
situ:
topical
and
radiation
therapy,
excision
and
Mohs
surgery.
Int
J
Dermatol.
2010;49:482---91.
3.
Mc
Kenna
J,
Florell
S,
Goldman
G,
Bowen
G.
Lentigo
maligna/lentigo
maligna
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Surg.
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Nagore
E,
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R,
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S,
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C,
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JM.
Clinicopathological
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Naylor
MF,
Crowson
N,
Kuwahara
R,
Teague
K,
Garcia
C,
Mackinnis,
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Treatment
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