Clinical History:
A 17 year old girl presented to her dermatologist's office with a "mole" in her genital area.
Physical examination showed a 0.8 x 0.6 cm tan-colored, slighted elevated lesion on her right mons
pubis. A shave biopsy was performed. Light microscopy showed nests of melanocytes at the
dermo-epidermal junction that manifested multinucleated giant cells with pale cytoplasms and
variably-sized pigment granules. The melanocyte nuclei were similar in size to those of adjacent
keratinocytes and showed discrete nucleoli. There was prominent homogeneous stromal collagen
superficially. The junctional component extended past the lateral confines of a banal dermal melanocytic
populace in a symmetrical fashion. There were no mitoses in the melanocytes.
Pathologic Diagnosis: Compound Nevus of Milk Line Type
Case 2 - Figure A - Low power shows an asymmetric junctional extension of melanocytes with foci of central confluent growth, bridging between rete ridges and aberrant disposition of junctional nests along the shoulders of rete ridges and in the inter-rete epidermal bridge. There is a nested dermal nevomelanocytic component.
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Case 2 - Figure B - Higher power magnification shows multi-nucleated giant melanocytes along the dermoepidermal junction. There is no appreciable lymphocytic inflammation in the dermis. An eosinophilic stromal condensation is present around rete ridges.
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Case 2 - Figure C - High power showing the multi-nucleated giant melanocyte. The individual melanocytic nuclei are not atypical. The cytoplasms, however, are irregularly melanized with prominent pigment granules. The stromal fibrosing pattern is not one of lamellar fibroplasia as one associates with a dysplastic nevus.
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Introduction
The main melanocytic lesions in the genital area include the mucosal lentigo, the common acquired
nevus, the dysplastic nevus, melanoma, and a distinctive form of nevus termed "atypical melanocytic nevus
of the genital type" by Wallace Clark et al (1999). The latter is clinically and
histologically distinctive from the dysplastic nevus, and frequently shows clinical changes reflecting
alterations in hormone levels such as during pregnancy. Identical lesions are seen throughout the
anatomical milk line: the axillae, the breasts, the peri-umbilical region, the groins and the genital
areas of men and women (Crowson et al., 2001). Thus, we prefer the term "nevus of milk-line type".
These nevi manifest distinctive histologic features that may prove problematic with respect to their
distinction from dysplastic nevi. The incidence of dysplastic nevi is no higher on the vulva than other
sites; vulvar dysplastic nevi were seen in 3 of 500 unselected patients who underwent a gynecologic
examination; 2 of whom had dysplastic nevus syndrome. The case presented is an "atypical" melanocytic
nevus of the genital or milk-line type. In the vulva, these lesions present at a median age of 25 years
(Christenson et al., 1987; Clark et al., 1998), and are typically located on either the mucosal surface
or glabrous skin of the labia, clitoris, or mons pubis. The clinical morphology ranges from a polypoid
evenly pigmented lesion to a flat one with variable pigmentation. Lesions range in size from 2 mm to 2
cm. More challenging is the occurrence of a nevus in the setting of vulvar lichen sclerosis, where flat
pigmented lesions usually no greater than 56 mm but often only 23 mm in size contrast with a
white-colored, depigmented background reflecting the lichen sclerosis component; the histologic and
clinical concern is invariably regressed melanoma (Carlson et al., 2002).
Histology
The "atypical" melanocytic nevus of milk-line type manifests an intraepidermal component comprising
epithelioid nevomelanocytes arranged in both a lentiginous and a dominantly nested fashion. An admixture
of giant melanocytes and pigmented dendritic melanocytes is typical. The nuclei range in size from 8 to
12 μm and manifest open chromatin patterns distinct from those of adjacent nonlesional vulvar
melanocytes, which are smaller with uniformly dense chromatin. The nested epithelioid cells assume an
aberrant disposition along the sides of the rete ridges and in apposition to suprapapillary plates
(Blickstein et al., 1991). Some lesions show oval nests of spindle cell tracking obliquely along the
junction of the epidermis and the retia. These nests may extend into the superficial dermis and are of
variable size, sometimes showing dyshesion and retraction artifact. The melanin granules are typically
large and coarse, thus being distinct from the dustlike melanin granules in the cytoplasms of
intraepidermal melanoma cells. The junctional nests sometimes form a confluent plaque-like array and/or
extend along the basal layer of adnexae in a single-cell and a nested fashion. Pagetoid spread of intact
nests and/or single melanocytes is seen in roughly 80% of cases. Such cells have a nuclear morphology
identical to those of the junctional and superficial dermal components; permeation into the granular cell
layer has been said to be unusual (Haupt + Stern, 1995), but may be seen, particularly over the areas of
maximal junctional proliferation. Lentiginous growth may extend on either side of the nested junctional
proliferation but does not necessarily indicate dysplasia. Despite the nest irregularity and the often
high-density of the intraepidermal proliferation, the epidermis generally has the hyperplastic,
papillomatous character that typifies a benign nevus. The pagetoid growth pattern is invariably focal,
never represents the dominant intraepidermal pattern, and is rarely present at the lateral borders.
There is typically sharp lateral circumscription, with termination as cohesive junctional and dermal
nests. These lesions are symmetrical in profile. The aforesaid are clues to a diagnosis of "atypical"
genital or milk-line nevus over that of melanoma or dysplastic nevus.
The fibrotic dermal reaction characteristic of milk-line nevi comprises broad, amorphous collagen in
the papillary and reticular dermis in which dermal nevus cells are embedded. The collagen does not
resemble the organized periretal stromal response that typifies dysplastic nevi or the desmoplastic
response seen with some invasive melanomas. The nevus cells are smaller than those cells situated in the
overlying epidermis but are nonetheless larger than the cells of a common acquired nevus.
Nevomelanocytic maturation is seen as cells grow smaller in the depths of the lesion.
Differential diagnosis
In addition to dysplastic nevus and melanoma, the differential diagnosis includes the Spitz nevus.
The cells of the Spitz nevus are larger with more prominent nucleolation. The characteristic
ganglion-like cells of the Spitz nevus are not seen in milk line nevi. Inflammation is typical for a
dysplastic nevus but is uncommon in milk line nevi. The dermal component of the dysplastic nevus is
usually banal in contrast with the large oval nuclei that may be seen in the superficial component of the
milk line nevus. The dominantly nested intra-epidermal proliferation of the milk line nevus contrasts
with the single-cell lentiginous change in the dysplastic nevus. One would consider a diagnosis of
malignant melanoma if one saw: 1) fully transformed cytologic criteria for malignancy in melanocytes
infiltrating the epidermis in a single-cell pagetoid fashion; 2) asymmetry with poor lateral
circumscription; 3) a dominant pagetoid growth pattern; 4) irregular dermal nests that exceeded the size
of those nests at the dermoepidermal junction; 5) delicate linear fibroplasia with regression comprising
absence of lesional nevomelanocytes both in the dermal and epidermal compartments; 6) effacement of the
epidermal architecture; 7) a bandlike lymphocytic infiltrate; 8) lack of maturation in the depths of the
lesion; and 9) dermal mitoses.
References
- Clark WH Jr, Hood AF, Tucker MA, Jampel RM. Atypical melanocytic nevi of the genital type with a
discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia. Hum Pathol 29 (1
Suppl 1): S1- A24, 1998 Jan
- Crowson AN, Magro CM, Mihm MC, Jr. Dysplastic nevi, de novo intraepidermal epithelioid and
lentiginous melanocytic dysplasias, and nevi at specific anatomic sites. In: Crowson AN, Magro CM, Mihm
MC, Jr. The melanocytic proliferations : a comprehensive textbook of pigmented lesions. New York :
John Wiley and sons, 2001:225-280.
- Blickstein I, Feldberg E, Dgani R, Ben-Hur H, Czernobilsky B. Dysplastic vulvar nevi. Obstet Gynecol 78(5 Pt 2): 968970, 1991 Nov
- Christensen WN, Friedman KJ, Woodruff JD, Hood AJ. Histologic characteristics of vulvar
nevomelanocytic nevi. J Cutan Pathol 14(2): 8791, 1987 Apr
- Carlson JA, Mu XC, Slominski A, Weismann K, Crowson AN, Malfetano J, Mihm MC Jr.
Melanocytic proliferations associated with lichen sclerosus. Arch Dermatol 2002;138:77-87.
THE PRECURSORS OF MALIGNANT MELANOMA
Recent Results Cancer Res 2002;160:75-84.
A. Neil Crowson, MD; Cynthia M. Magro, MD; Ignacio Sanchez-Carpintero, MD, PhD;
Martin C. Mihm Jr, MD
Introduction
In recent decades the systematic study of patients with malignant melanoma has revealed the presence
in a significant number of patients of precursor lesions which appear to place patients at an increased
risk for the development of malignant melanoma. We intend to elucidate recent advances in our
understanding of those precursor lesions from the standpoint of the biological events and the histologic
clues which help to predict malignant transformation. These precursor lesions include, but are not
restricted to : the dysplastic nevus, lentigo maligna, the congenital nevus, mucosal melanocytoses of
conjunctival, nasopharyngeal, penile, vulvar and gastrointestinal tract mucosa, and the atypical Spitz
tumor(1). Only the first three of these lesional categories will be considered here.
The dysplastic melanocytic nevus and the dysplastic nevus syndrome
In 1978, Lynch and co-workers(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 and co-workers(3) characterized the dysplastic nevus
as a defining element of this syndrome. The National Institutes of
Health (NIH) consensus conference recommended supplanting the term dysplastic nevus with the appellation
"nevus with architectural disorder and cytologic atypia" in 1992(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 genital sites) manifest architectural disorder
and cytologic atypia but have no association with subsequent malignant melanoma. The confusing NIH
terminology, which also does not encompass grading which we believe is integral to assessment of any
dysplastic nevus, has largely been abandoned. The incidence of dysplastic nevi is likely in the 510%
range in Cauacasians(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 precursors for up to 18% of all nonfamilial melanomas(6). Roughly 95% of malignant
melanomas arising in dysplastic nevi are of superficial spreading type.
Patients with two or more dysplastic nevi are said to suffer from the dysplastic nevus syndrome, which
may occur sporadically or in a familial complex with an autosomal dominant pattern of inheritance, 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
development of melanoma of 100%(8). A patient with sporadic dysplastic nevus syndrome may resemble a
person with familial dysplastic nevus syndrome by virtue of numerous large, atypical nevi that may appear
at puberty and continue to do so throughout life. Such patients appear either to have expressed a
spontaneous genetic event or to have family members with the syndrome who were never identified. Most
patients with sporadic dysplastic nevus syndrome present in the 4th-5th decades of
life with only a few atypical moles on sun-exposed areas; UV radiation may play a role in the development
of sporadic dysplastic nevui.
Mutations and loss of heterozygosity of p16 and p53 genes have been detected in blood lymphocytes from
members of kindreds with hereditary cutaneous malignant melanoma, most of the mutations being of the C ฎT
transitional type known to be a signature for UV light-induced point mutation. One study showed areas of
chromosomal loss at regions encoding for p16 (9p2122) 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 kinase 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 covered areas (breasts of women and the bathing trunk area
of men and women), and lower legs. Banal acquired nevi usually spare the scalp, the doubly covered
areas, and the legs. Dysplastic nevi have characteristic features: unlike common acquired nevi, they
are larger than 6 mm in diameter, have irregular 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 numerous 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 response, 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 regression 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 illumination. Nevi only a few millimeters in diameter removed from patients with
familial dysplastic nevus syndrome may manifest the classic dysplastic nevus histology. Patients with
multiple primary melanomas with or without familial dysplastic nevus syndrome may show a diffuse pattern
of irregular pigmentation resembling freckling, but with an histology comprising intraepidermal
lentiginous melanocytic dysplasia.
Epiluminescence microscopy of dysplastic nevi reveals a pattern of patchy interruptions in the pigment
network (the "broken network"), which is distinctive from common banal nevi and melanoma. We have
established that the use of near infrared spectroscopy to probe molecular vibration of chemical bonds and
so to assay tissue biochemistry non-destructively can be applied in-vivo to distinguish dysplastic nevi
from banal nevi and from lentigines with a high degree of accuracy(12). There is no doubt that
dysplastic nevi differ from banal nevi from all of clinical, histological, biochemical and molecular
standpoints.
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 magnification as it requires assessment of cytology which can only be assessed at
ื40 or higher magnification. The constellation of histological findings in the dysplastic nevus
encompasses two broad components: architecture and cytology(13).
Major Criteria for Diagnosis of a Dysplastic Nevus
- Asymmetric basilar proliferation of
nevomelanocytes along the dermoepidermal junction extending laterally beyond the confines of a
preexisting dermal component if present.
- Cells have 1 or both of 2
characteristic cytological and architectural intraepidermal patterns:
- Lentiginous dysplasia: randomly disposed single cells are located along
and between elongate rete with nests of varying sizes; nuclei are hyperchromatic, angulated and are
similar in size to or larger than adjacent keratinocytes.
- Epithelioid dysplasia: epithelioid melanocytes are disposed in variably
sized junctional nests as well as in a single-cell array along the dermoepidermal 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 amelanotic to coarsely melanized with giant melanosomes.
Minor Criteria for Diagnosis of a Dysplastic Nevus
- 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 presumptive neural crest-derived facultative
fibroblasts laying collagen along the tips of hyperplastic retia in parallel arrays.
- Lymphocytic infiltrates in the papillary dermis.
- Telangiectasia and/or vascular proliferation.
- 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 appended
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
dysplastia may be seen in other subtypes of nevi including 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
elongated with an irregular shape and fusion. There is increased vascularity, a sparse lymphocytic
infiltrate and scattered dermal melanophages. Broad laminated 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 melanocytic dysplasia. Studies have
shown that criteria can be learned and reproducibly applied by pathologists with a consistency that is
maintained in both the three tier grading system which we employ, namely, mild, moderate and severe, or a
two tier system, namely low and high grade dysplasia(4,13,15). Some observers have found reasonable
concordance in grading of architectural, 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 cytologic grades of atypia tend to correlate. A
recent study found significant 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 suspicious lesion should be removed. It is our practice
that excisional biopsy with a few millimeters margin is appropriate. If a partial biopsy has been
performed, we advise removal of any clinically apparent residuum with a few millimeter margin. If slight
atypia is present at a histologic margin without a clinically-evident residuum, we do not advise
reexcision. If moderate atypia is present at a margin, we advise conservative reexcision with a few
millimeter margin. 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 dependent on the number of lesions and the degree of clinical or histological atypia. Photographic
documentation is desirable.
LENTIGO MALIGNA
Clinical features
Lentigo maligna (LM) occurs on sun-exposed skin of Caucasians and predominantly affects the face, the
head and neck and, less often, other sun-exposed 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. Lentigo maligna 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 (LMM) 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 rearrangement of chromosome 10 at the 10q2426 region(20),
use of estrogen, progesterone, and hair dyes(1). Four15% of all melanomas and 1026% of all head
and neck melanomas represent 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 4th decade of life or, rarely, earlier. There is a slight
female predominance. From its initial small size it gradually evolves, sometimes to a size of 1520 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 invasion evidenced by palpable
nodularity. The fully evolved lesion is strikingly variegated, exhibiting colors of tan, brown, dark
brown, and sometimes black admixed with gray or blue-black. As the lesion progresses, it may extend into
the conjunctiva, oral mucosa, or external auditory canal. The characteristic 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 versus 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 epidermis in a discontiguous ashion and
extending along the eccrine ducts and the outer root sheath epithelium of hair follicles. Also
characteristic 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
multinucleation of melanocytes as a sequel of photoactivation, in which case nuclei 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
dermal collagen; telangiectasia and melanophages complete the picture(18). As the lesion progresses,
continuity of single-cell basilar melanocytic proliferation is observed, followed by variably sized
dyshesive junctional th่ques along the dermo-epidermal 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 invasion.
Transition to microinvasive melanoma is accompanied by a lichenoid infiltrate 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 circumstances 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. Histologic 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 th่que within the epidermis. The cells in vertical growth phase
melanoma often assume a spindled morphology with a variable stromal response. At times prominent
desmoplasia may be observed, warranting the designation of desmoplastic melanoma; neurotropism is a
frequent concomitant. 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. Invasion 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 discernible; then, the measurement should to the point of
infiltration of the adventitial dermis from the innermost layer of the outer root sheath epithelium.
Problematic is deciding whether a low-density proliferation of singly disposed atypical melanocytes in
sun-damaged skin represents LM or photoactivation. Critical in this determination are the clinical
circumstances. When in doubt, additional biopsies or complete removal of the lesion may be necessary.
Novel application of topical biological response modifiers such as Imiquimod may make this distinction
less crucial in the near future.
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 resembling 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 associated 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 3 patients who
developed melanomas did so in 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 101(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 2nd occurring from puberty into adulthood.
Small congenital nevi, on the other hand, are not reported to undergo malignant transformation during the
first 2 decades of life, but the risk of malignancy appears during late adolescence 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 47%.
Small- and intermediate-sized congenital nevi do not require excision, at least for the first 2 decades
of life, because there appears to be no significant risk of developing malignant melanoma during this
time period. Congenital nevi covering 4% or less of the body surface may not be at 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 associated 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 histological evaluation to exclude
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).
TREATMENT
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 consistent with overt melanoma. Nevi up to 5 cm in size can be
excised in a 1stage procedure, but larger lesions may mandate use of a tissue expander, 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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- Lynch HT, Frichot B, Lynch JF. Familial atypical multi-mole melanoma syndrome. J Med Genet 1978;15:352356.
- Clark WH, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas
from heritable melanocytic lesions. "The B-K mole syndrome." Arch Dermatol
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- Shea CR, Vollmer RT, Prieto VG. Correlating architectural disorder and cytologic atypia in Clark
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in patients with melanoma and comparison subjects. Cancer Res
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- Grob JJ, Andrac L, Romano MH, et al. Dysplastic naevus in non-familial melanoma. A
clinicopathological study of 101 cases. Br J Dermatol 1988;118:745752.
- Cannon-Albright LA, Meyer LJ, Lewis CM et al. Penetrance and expressivity of the chromosome 9p
melanoma susceptibility locus (MLM). Cancer Res 1994;54: 60416044.
- Greene MH, Clark WH, Tucker MA, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in
melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:
458465.
- Park WS, Vortmeyer AO, Pack S, et al. Allelic deletion at chromosome 9p21(p16) and 17p13(p53) in
microdissected sporadic dysplastic nevus. Hum Pathol 1998;29:127130.
- Birindelli S, Tragni G, Bartoli C et al. Detection of microsatellite alterations in the spectrum of
melanocytic nevi in patients with or without individual or family history of melanoma. Int J Cancer 2000;86:255-261.
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cancer in families associated with a specific 19 bp deletion of p16 (p16-Leiden). Int J Cancer 2000;87:809-811.
- McIntosh LM, Summers R, Jackson M et al. Towards non-invasive screening of skin lesions by
near-infrared spectroscopy. J Invest Dermatol 2001;116:175-181.
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