The Precursors of Malignant Melanoma

A. Neil Crowson, Cynthia M. Magro, Ignacio Sanchez-Carpintero,

and Martin C. Mihm Jr

Abstract

The precursors to melanoma are generally considered to be related to nevi of

different types. Here we emphasize the dysplastic nevus, the congenital
nevus, and lentigo maligna as specific lesions. The dysplastic nevus is
discussed not only as a formal precursor but also as a marker of cutaneous
melanoma. The clinical and histologic characteristics are outlined, as well as
evidence of progression in dysplastic nevi. The congenital nevus is briefly
reviewed and emphasis is placed upon clues to malignant degeneration. The
concept of lentigo maligna as a precursor as distinct from an in situ phase is
detailed.

Introduction

In recent decades the systematic study of patients with malignant melanoma

has revealed the presence in a significant number of patients of precursor le-
sions which appear to place patients at an increased risk for the development
of malignant melanoma. We intend to elucidate recent advances in our un-
derstanding of those precursor lesions from the standpoint of the biologic
events and the histologic clues which help to predict malignant transforma-
tion. These precursor lesions include, but are not restricted to: the dysplastic
nevus, lentigo maligna, the congenital nevus, mucosal melanocytoses of con-
junctival, nasopharyngeal, penile, vulvar and gastrointestinal tract mucosa,
and the atypical Spitz tumor [1]. Only the first three of these lesional catego-
ries are considered here.

Recent Results in Cancer Research, Vol. 160

© Springer-Verlag Berlin Heidelberg 2002
76 A. N. Crowson et al.

The Dysplastic Melanocytic Nevus and the Dysplastic Nevus Syndrome

In 1978, Lynch et al. [2] coined the term "familial mUltiple atypical mole
melanoma syndrome" for a symptom complex of multiple atypical nevi
which placed family members at increased risk for developing melanoma.
Clark et al. [3] characterized the dysplastic nevus as a defining element of
this syndrome. In 1992 the National Institutes of Health (NIH) Consensus
Conference recommended supplanting the term dysplastic nevus with the ap-
pellation "nevus with architectural disorder and cytologic atypia" [4]. We
use the original term "dysplastic nevus" with which clinicians are familiar, as
subgroups of congenital and acquired nevi (such as those in acral and geni-
tal sites) manifest architectural disorder and cytologic atypia but have no as-
sociation with subsequent malignant melanoma. The confusing NIH termi-
nology, which also does not encompass grading that we believe is integral to
assessment of any dysplastic nevus, has largely been abandoned.
The incidence of dysplastic nevi is likely in the 5-10% range in Cauca-
sians [5]. The concern raised by the dysplastic nevus relates to the inherent
risk of transformation to malignant melanoma and to its being a marker for
the development of melanoma at other sites. Melanoma patients with two or
more dysplastic nevi may also be at increased risk for a second primary. The
risk of progression of a dysplastic nevus to melanoma is unknown. Up to
92% of melanomas occurring in patients with dysplastic nevus syndrome
have evidence of a dysplastic nevus precursor, while dysplastic nevi are pre-
cursors for up to 18% of all nonfamilial melanomas [6]. Roughly 95% of ma-
lignant melanomas arising in dysplastic nevi are of superficial spreading
type.
Patients with two or more dysplastic nevi greater than 8 mm in size are
said to suffer from the dysplastic nevus syndrome, which may occur sporadi-
cally or in a familial complex with an autosomal dominant pattern of inheri-
tance, the latter most commonly encoded by a gene found on chromosome
9 at 9p21 [7]. Dysplastic nevus patients with a family history of dysplastic
nevi and melanoma are held to have a cumulative lifetime risk for the devel-
opment of melanoma of 100% [8]. The features of sporadic dysplastic nevus
syndrome may resemble those of familial dysplastic nevus syndrome by vir-
tue of numerous large, atypical nevi that may appear at puberty and con-
tinue to appear throughout life. Such patients appear either to have ex-
pressed a spontaneous genetic event or to have family members with the syn-
drome who were never identified. Most patients with sporadic dysplastic ne-
vus syndrome present in the fourth to fifth decades of life with only a few
atypical moles on sun-exposed areas; UV radiation may playa role in the de-
velopment of sporadic dysplastic nevi.
Mutations and loss of heterozygosity of p16 and p53 genes have been de-
tected in blood lymphocytes from members of kindreds with hereditary cu-
taneous malignant melanoma, most of the mutations being of the C -+ T
transitional type known to be a signature for UV light-induced point muta-
tion. One study has shown areas of chromosomal loss at regions encoding
 The Precursors of Malignant Melanoma 77

for p16 (9p21-22) and p53 (17p13) in 78% of dysplastic nevi, with no loss of
heterozygosity in benign intradermal nevi [9]. Loss of heterozygosity at 9p21
appears to be restricted to melanoma and to dysplastic, as opposed to banal
nevi [10]. The CDKN2A gene responsible for melanoma susceptibility in
most families with melanoma linked to 9p encodes a cyclin-dependent ki-
nase inhibitor, the dysfunction of which is also implicated in several sporadic
cancers. The second most frequent cancer in such kindreds linked to
CDKN2A gene mutations is pancreatic carcinoma, which occurs in up to 17%
of patients [11].

Clinical Features

Patients with familial dysplastic nevi develop multiple large atypical moles
distributed everywhere on the body surface including the scalp, doubly cov-
ered areas (breasts of women and the bathing trunk area of men and wom-
en), and lower legs. Banal acquired nevi usually spare the scalp, the doubly
covered areas, and the legs. Dysplastic nevi have characteristic features: un-
like common acquired nevi, they are more than 6 mm in diameter, have ir-
regular borders and a variegated pattern of pigmentation with shades of tan,
dark-brown, and black and even, rarely, hypopigmented macules. The great
heterogeneity among lesions in a given patient contrasts with the less-numer-
ous and more-homogeneous common acquired nevi, the latter having
smooth borders, uniform pigmentation, and a diameter less than 6 mm. The
presence of erythema often correlates with a brisk inflammatory host re-
sponse, sometimes associated with the clinical halo phenomenon. Although
this pattern of inflammation may herald progression to malignant melanoma,
it is also seen as part of the host response to a dysplastic nevus. When re-
gression occurs, a lesion may acquire zones of depigmentation.
Although dysplastic nevi may be flat or slightly raised, in our experience,
most have a pebbled surface best appreciated with oblique or side illumina-
tion. Nevi only a few millimeters in diameter removed from patients with fa-
milial dysplastic nevus syndrome may manifest the classic dysplastic nevus
histology. Patients with multiple primary melanomas with or without famil-
ial dysplastic nevus syndrome may show a diffuse pattern of irregular pig-
mentation resembling freckling, but with a histology comprising intraepider-
mal lentiginous melanocytic dysplasia.
Epiluminescence microscopy of dysplastic nevi reveals a pattern of patchy
interruptions in the pigment network (the "broken network"), which is dis-
tinctive from common banal nevi and melanoma. We have established that
the use of near-infrared spectroscopy to probe molecular vibration of chemi-
cal bonds and so to assay tissue biochemistry nondestructively can be ap-
plied in vivo to distinguish dysplastic nevi from banal nevi and from lenti-
gines with a high degree of accuracy [12]. There is no doubt that dysplastic
nevi differ from banal nevi from all of clinical, histologic, biochemical and
molecular standpoints.
78 A. N. Crowson et al.

Histology

The histology of the dysplastic nevus is so reproducible that a diagnosis can

usually be rendered on scanning magnification. Interobserver variability lies
in the area of grading of atypia, which should not be done at scanning mag-
nification as it requires assessment of cytology which can only be assessed at
400 x or higher magnification. The constellation of histologic findings in the
dysplastic nevus encompasses two broad components: architecture and cytol-
ogy [13].

Major Criteria for Diagnosis of a Dysplastic Nevus

1. Asymmetric basilar proliferation of nevomelanocytes along the dermoepi-

dermal junction extending laterally beyond the confines of a preexisting
dermal component if present.
2. Cells have one or both of two characteristic cytologic and architectural in-
traepidermal patterns:
a) Lentiginous dysplasia: randomly disposed single cells are located along
and between elongate rete ridges with nests of varying sizes; nuclei are
hyperchromatic, angulated and are similar in size to or larger than ad-
jacent keratinocytes.
b) Epithelioid dysplasia: epithelioid melanocytes are disposed in variably
sized junctional nests as well as in a single-cell array along the dermo-
epidermal junction of an often normal or hyperplastic epidermis. The
cells have round to oval nuclei with delicate chromatin, nucleoli, thick
membranes, and diameters greater than those of adjacent keratinocytes.
Rounded cytoplasmic contours encompass cytosols ranging from ame-
lanotic to coarsely melanized with giant melanosomes.

Minor Criteria for Diagnosis of a Dysplastic Nevus

1. Papillary dermal collagen shows concentric eosinophilic fibrosis in which

a dense zone of hypocellular collagen envelops rete ridges and/or lamellar
fibroplasia in which delicate layers of collagen are interspersed with pre-
sumptive neural crest-derived facultative fibroblasts laying collagen along
the tips of hyperplastic retia in parallel arrays.
2. Lymphocytic infiltrates in the papillary dermis.
3. Telangiectasia and/or vascular proliferation.
4. Fusion of retia by confluent growth between adjacent melanocytic nests.

A diagnosis of dysplastic nevus is made when both major and at least two
minor criteria are met. If a lesion exhibits cytologic without architectural
atypia, or if all architectural features are present without cytologic atypia,
the diagnosis rendered is junctional or compound nevus and a note is ap-
 The Precursors of Malignant Melanoma 79

pended to the report to state that, in the absence of an adequate constellation

of criteria, a diagnosis of dysplastic nevus cannot be rendered. Such lesions
need not be reexcised.
Histologic features of dysplasia may be seen in other subtypes of nevi in-
cluding congenital nevi, Spitz nevi, and neurotized nevi [14]. A variant of
dysplastic nevus characterized by an exclusively lentiginous proliferation of
atypical nevomelanocytes in concert with periretal stromal fibrosis is termed
"de novo melanocytic dysplasia". A similar form of "lentiginous" dysplasia
characterizes lentigo maligna and atypical mucosal melanocytic hyperplasias
but, unlike these forms of preinvasive melanocytic proliferations, there is no
upward migration of melanocytes or conspicuous nest formation in de novo
dysplasia. Further, there is no retiform effacement, the retia appearing elon-
gated with an irregular shape and fusion. There is increased vascularity, a
sparse lymphocytic infiltrate and scattered dermal melanophages. Broad lam-
inated superficial dermal fibroplasia as seen in the classic dysplastic nevus
and lichenoid inflammation are absent.
We grade atypia as mild, moderate and severe for all forms of melanocy-
tic dysplasia. Studies have shown that criteria can be learned and reproduci-
bly applied by pathologists with a consistency that is maintained in both the
three-tier grading system which we employ, namely mild, moderate and se-
vere, or a two-tier system, namely low- and high-grade dysplasia [4, 13, 15].
Some observers have found reasonable concordance in grading of architec-
tural, but not cytologic, features implying that the interpretation of cytology
is more challenging [16]. We grade atypia on the basis of both architecture
and cytology, which are assessed separately, although architectural and cyto-
logic grades of atypia tend to correlate. A recent study has found a signifi-
cant correlation, but by no means perfect concordance, between the degree
of architectural and nuclear atypia [4]. For a comprehensive treatment of our
grading criteria we refer the reader elsewhere [1].

Management

At the first patient visit, we recommend that a clinically atypical nevus be

excised to confirm the impression of dysplastic nevus. Any changing or sus-
picious lesion should be removed. It is our practice that excisional biopsy
with a margin of a few millimeters is appropriate. If a partial biopsy has
been performed, we advise removal of any clinically apparent residuum with
a margin of a few millimeters. If slight atypia is present at a histologic mar-
gin without a clinically evident residuum, we do not advise reexcision. If
moderate atypia is present at a margin, we advise conservative reexcision
with a margin of a few millimeters. If severe dysplasia is present at a margin,
or if a margin is only clear by a millimeter or two, we advise reexcision to
obtain a 5-mm margin of normal skin. Follow-up of any patient is depen-
dent on the number of lesions and the degree of clinical or histologic atypia.
Photographic documentation is desirable.
80 A. N. Crowson et al.

Lentigo Maligna

Clinical Features

Lentigo maligna (LM) occurs on sun-exposed skin of Caucasians and pre-

dominantly affects the face, the head and neck and, less often, other sun-ex-
posed areas of the body [17]. Extrafacial lentigo maligna melanoma (LMM)
constitutes 18% of all cases and preferentially involves the trunk in men and
lower legs in women, and presents at a thinner depth relative to LMM of the
head and neck. LM has been designated a form of malignant melanoma in
situ, although distinction between LM as a melanoma precursor and an in
situ form of the disease has been proposed [18]. The term "lentigo maligna
melanoma" is used when the tumor assumes invasive properties. The lifetime
risk for developing LMM in a lesion of LM is estimated to be 5% [19]. Long-
term exposure to UV irradiation is the greatest risk factor, and, in fact, the
diagnosis of LM or LMM is not made if the lesion occurs on sun-protected
skin or in the absence of solar elastosis. Other risk factors include rearrange-
ment of chromosome 10 at the 10q24-26 region [20], use of estrogen, proges-
terone, and hair dyes [1]. Of all melanomas, 4-15% are LMM, and of all
head and neck melanomas, 10-26% are LMM [1,21].
The LM presents as a pigmented macule with a variegated tan to brown
color and irregular borders. The initial presentation may be in the fourth de-
cade of life or, rarely, earlier. There is a slight female predominance. From its
initial small size it gradually evolves, sometimes to a size of 15-20 cm. One
aspect of its evolution is partial regression evidenced by areas of light gray
or blue-gray discoloration. The in situ lesion is nonpalpable, with areas of in-
vasion evidenced by palpable nodularity. The fully evolved lesion is strik-
ingly variegated, exhibiting colors of tan, brown, dark brown, and sometimes
black admixed with gray or blue-black. As the lesion progresses, it may ex-
tend into the conjunctiva, oral mucosa, or external auditory canal. The char-
acteristic evolution of this lesion takes anywhere from 10 to 50 years before
invasion supervenes, at which time the average size is 6.0 cm. Controlled for
level of invasion and thickness, there is no difference in survival in compari-
son with other subtypes of melanoma [21].

Histology

The histology of LM is one of polygonal melanocytes with hyperchromatic,

angulated nuclei dispersed as individual units, initially confined to the basal
layer of the epidermis in a discontiguous fashion and extending along the ec-
crine ducts and the outer root sheath epithelium of hair follicles. Also char-
acteristic is the multinucleated giant melanocyte set along the basal layer of
the epidermis; termed "star-burst giant cells", these may contain more than
30 fully malignant nuclei and have been identified in up to 85% of cases
[22]. Sun-damaged skin of the head and neck of the elderly may show multi-
 The Precursors of Malignant Melanoma 81

nucleation of melanocytes as a sequel of photoactivation, in which case nu-

clei of the multinucleated giant cells show only mild hyperchromasia with
regular nuclear contours. The epidermis in LM is characteristically atrophic,
manifesting thinning and loss of the retiform pattern overlying elastotic der-
mal collagen; telangiectasia and melanophages complete the picture [18]. As
the lesion progresses, continuity of single-cell basilar melanocytic prolifera-
tion is observed, followed by variably sized dyshesive junctional theques
along the dermoepidermal junction which assume a parallel disposition to
the long axis of the epidermis and are referred to as "the swallow's nest
sign". Foci of prominent pagetoid infiltration attend lesional progression.
Nesting, confluence of melanocytes along the basal layer and pagetoid spread
of neoplastic melanocytes, which we designate as melanoma in situ [18], are
the harbingers of the next phase of lesional evolution, namely, dermal inva-
sion.
Transition to microinvasive melanoma is accompanied by a lichenoid infil-
trate with admixed melanophages in a sclerotic papillary dermis, findings
which warrant careful scrutiny for singly disposed neoplastic melanocytes
with a cytomorphology identical to those within the epidermis. These are
typically epithelioid with abundant, variably pigmented cytoplasms. Their
distinction from activated melanophages may be difficult. Under such cir-
cumstances we employ an HMB-45 or Melan-A preparation, preferably with a
red as opposed to a brown chromagen. An S100 preparation is less desirable
as many antigen-presenting dendritic cells stain positively in the dermis. His-
tologic features that define the progression of LMM to vertical growth phase
include the formation of a nodule or fascicle within the dermis that exceeds
the size of any theque within the epidermis. The cells in vertical growth
phase melanoma often assume a spindled morphology with a variable stro-
mal response. At times prominent desmoplasia may be observed, warranting
the designation of desmoplastic melanoma; neurotropism is a frequent con-
comitant.
Assessment of level and depth of invasion in LMM can be difficult, as the
dermis is usually thin and contains sparse collagen with abundant elastotic
material complicating the distinction of papillary from reticular dermis. In-
vasion of the adventitial dermis of a follicle situated in the reticular dermis
may be misinterpreted as level IV melanoma if the follicular epithelium is
not apparent in the sections examined. The maximum depth should not be
based on adventitial dermal involvement unless that is the only invasion dis-
cernible; then, the measurement should be to the point of infiltration of the
adventitial dermis from the innermost layer of the outer root sheath epithe-
lium.
Problematic is deciding whether a low-density proliferation of singly dis-
posed atypical melanocytes in sun-damaged skin represents LM or photoacti-
vation. Critical in this determination are the clinical circumstances. When in
doubt, additional biopsies or complete removal of the lesion may be neces-
sary. Novel application of topical biologic response modifiers such as Imiqui-
mod may make this distinction less crucial in the near future.
82 A. N. Crowson et al.

Congenital Nevi and the Risk of Malignant Transformation

Congenital nevi are identified in approximately 1% of newborn infants. This

definition encompasses a broad category of lesions whose size varies from a
few millimeters to many centimeters, sometimes extending over much or all
of the body surface. The congenital nevus undergoes an evolutionary change
with age. Some affect subcutaneous structures such as muscle, bone, lymph
nodes and, in rare scalp lesions, the brain. Giant congenital nevi have been
variously described as those covering a large area of the body, those resem-
bling a garment covering a limb or the trunk, or those greater than 20 cm in
diameter. Lesions located in the region of the head and neck may be asso-
ciated with melanocytic proliferations of the meninges with rare extension
into the cisterna magni causing secondary hydrocephalus. This phenomenon,
termed neurocutaneous melanocytosis, may be associated with intracranial
melanoma.
In one prospective series of 160 patients with large congenital nevi, all
three patients who developed melanomas did so at extracutaneous sites: two
in the central nervous system and one in the retroperitoneum [23]. The 5-
year cumulative risk for developing melanoma was 2.3% and the relative risk
was lOl [23]. The giant congenital nevus has a bimodal peak of incidence of
melanoma, the first occurring in the first 5 years of life and the second oc-
curring from puberty into adulthood. Small congenital nevi, on the other
hand, are not reported to undergo malignant transformation during the first
two decades of life, but the risk of malignancy appears during late adoles-
cence, and the incidence then progressively rises in adult life. Epidemiologic
studies impute an incidence of malignant transformation in small congenital
nevi of approximately 1% and in giant congenital nevi of roughly 4-7%.
Small- and intermediate-sized congenital nevi do not require excision, at
least for the first two decades of life, because there appears to be no signifi-
cant risk of developing malignant melanoma during this period. Congenital
nevi covering 4% or less of the body surface may not be associated with a
significant risk for malignant transformation [24].
The morphology of the congenital nevus changes with age, irrespective of
the nevus size. There is darkening within the first 5-6 years of life and then
again at puberty. The lesion is flat at birth and becomes progressively more
palpable with age, gradually acquiring terminal hairs. As the patient ages,
these lesions usually develop areas of hyperkeratosis, "doughy" alterations as-
sociated with mucinous degeneration, and the formation of neurofibromata.
The appearance of firm nodules in congenital nevi is always of concern and
any nodular proliferation should be excised for histologic evaluation to ex-
clude malignant transformation. One diagnostic consideration in this setting
is the development of proliferative nodules. Up to 5 mm in diameter with
smooth or sometimes ulcerated surfaces, these are held to reflect self-limited,
slowly growing and often spontaneously regressing proliferations [25].
 The Precursors of Malignant Melanoma 83

Treatment

We believe that no lesion should be prophylactically removed in its entirety.

Each patient is carefully followed and evaluated with gross inspection and
palpation for subcutaneous nodules, changes in lesional consistency, surface
topography or coloration. Should any such change occur, an excision of this
area with a margin of the nevus is recommended. We recommend complete
excision or partial extensive excision of a giant congenital nevus in a patient
in whom biopsy shows foci worrisome for evolution into melanoma or con-
sistent with overt melanoma. Nevi up to 5 cm in size can be excised in a
one-stage procedure, but larger lesions may mandate the use of a tissue ex-
pander, sometimes with staged therapy using full- or intermediate-thickness
grafts following superficial partial removal of the nevus, with the proviso
that no histologic evidence of atypia is identified.

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