clark nevus or common

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evus,
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evus or ommon
evus.
DYSPLASTIC NEVUS, CLARK NEVUS OR COMMON NEVUS? In 1978 Clark and his colleagues put forth a hypothesis that still provokes
controversy - the idea that a set of findings in nevi of members of families
with a tendency to develop melanoma was a clinicopathologic entity, repre­
senting an intermediate step between the "common nevus" and melanoma.
The dysplastic nevus is still a controversial entity with some specific clinical
and histological characteristics, but with "fuzzy" borders. The dividing line
between a "common nevus" at the lower end and melanoma in situ or superfi­
cially invasive melanoma at the upper end defies precise characterization,
similar to that in other "intermediate" lesions in pathology.
Clinically, the proposed lesion is best diagnosed if larger than a "common"
nevus (an objective finding), with irregular borders and an uneven distribution
of pigment (subjective ones). Histologically, either architectural disorder, scat­
tered cytologically atypical melanocytes or both are supposed to be present.
The combination of these clinical and histological traits make the dysplastic
nevus a frequent simulator of malignant melanoma. We have no doubt that the
presence of large, irregularly bordered nevi (especially if multiple) in a patient
with a history of melanoma is of great significance, we doubt that a single 2
millimeters nevus with bridging, fibroplasias, etc. is of great concern.
A counterproposal (Ackerman) is that the nevi that Clark described are just
one type of nevus among many, of no special significance. This does not seem
logical from the point of view of tumor biology, by which we now know that
NEVI most inherited tumor syndromes relate to the loss of a tumor suppressor gene, or to the activation of an oncogene leading to genetic instability. While increased numbers of benign neoplasms can occur in such syndromes, there is growing evidence that there are nosologically intermediate lesions as well, with some characteristics of malignancy, but not all of them. Our view is that "Clark nevus" is a nevus limited to the junction and papil­
lary dermis, usually clinically flat. Many have no special features, but a sub­
set (usually of larger and probably of older lesions) has the features that Clark outlined in his seminal papers. Some of these may prove to have special sig­
nificance, but much work remains in order to clarify this issue. Clinical features
. The clinical picture of "dysplastic" nevi is exemplified by the nevi found in
affected kindreds:
-large size (over 5 millimeters in diameter, but the larger the better);
color is uneven, with shades of pink (usually the rim), tan brown and
black; - borders are irregular; - smaller lesions can qualify if they are growing. Some of these features can best be appreciated on dermatoscopic examina­
tion. There is a risk of circular reasoning - if a patient has a history of melanoma, a clinician may be inclined to believe that small nevi on that patient's skin are "dysplastic". The risk of developing a melanoma seems to vary with the degree to which these traits are expressed, but can be strikingly increased. The compound form can resemble a "fried egg" appearance with a central papule surrounded by a brown macule (Barnes, Hofman). A mottled "veg­
etable pizza" appearance can also occur. The correspondence between the clinical and the histological diagnosis of the dysplastic nevus is poor in some studies (Black, Annessi); many lesions that clinically seem to be "dysplastic" are ordinary nevi (in our view "Clark nevi" with banal histological features). Other nevi that can develop some of the clinical traits noted above include congenital and Spitz nevi. Patients are usually young adults or adults (Sagebiel). The dysplastic nevus may occur in the first two decades of life, especially on the back, buttock, breast and scalp (Clemente). A rigorous pop­
ulation based study examining normal children with forcible biopsy of any unusual lesions has not been done, to our knowledge. Patients usually have only one or few "dysplastic" nevi and there is no per­
sonal or familial history of melanoma (Cooke, Cohen); in such a setting this entity is present in 5-20% of Caucasian population, and is called "sporadic". With a less rigorous definition, one can project a prevalence of about 80%, rendering the concept meaningless (Piepkom). It seems reasonable to us that the prevalence of a state (significantly large or unstable nevi) is more mean­
ingful than that of a histopathologically defined lesion. In time, genetic test­
ing may render nonsensical the entire controversy. Rarely, scores or hundreds of lesions occur in the so called dysplastic nevus syndrome, which is inherited in an autosomal dominant pattern (Greene). Subjects often have a personal or familial history of melanoma and are at increased risk of melanoma (Metcalf). The risk (Knoell) can be gradu­
ated as follows: 2-28 times the risk of the general population in patients with dysplastic nevus syndrome without personal and familial history of melanoma; j
,
- -
JSP as Ie
evus,
ar
evus or om
c.
- 148 times in patients with a family history of melanoma;
- 300-500 times in patients with both family and personal record of
melanoma;
- the patients with two or more relatives with melanoma seem to be
doomed to develop a melanoma in their lifetime.
The risk of melanoma seems roughly correlated to the number of nevi (but
is only threefold if the nevi are small, under 3 millimeters and stable).
To us, the overall risk of melanoma is best assessed by clinical phenotype
rather than by histopathologic scrutiny of a nevus. Many aspects of
histopathologic examination (such as size> 6 millimeters) are obvious clini­
cally and can be prejudicial. The main reason to biopsy a pigmented lesion
should be to rule out a developing melanoma, rather than to prove "dyspla­
sia". The degree of cytological atypia in a "Clark nevus" corresponds to pro­
gression in a neoplastic pathway and the risk of melanoma in the lesion or the
patient seems possible - but there are still significant problems with defining
the exact relationship.
Variants
Clinical variations on the theme of dysplastic nevus include:
- hyperpigmented dysplastic nevi. In these cases the lesion is rich in
melanin;
- combined forms. These have even more irregular clinical findings.
"Dysplastic nevi" can be present in combination with other lesions such as
the common nevus (Marchesi). Another very important combination is the
one with the Spitz nevus; sometimes there is a pattern of Clark nevus in
which there are distinct areas where cytologic findings are different (called
"side by side" combined nevus);
- achromic dysplastic nevus. A patient with hundreds of non pigmented
macules and discrete papules has been described by Knoell. Histologically,
the lesions were said to fulfill the criteria for the diagnosis of "dysplastic"
nevi.
Histological features
The criteria for the diagnosis of this entity have changed much during the past
years. Whether these nevi are common or rare depends in large part on the
restrictiveness of the criteria (Ackerman, de Wit, Barnhill, Murphy). The easi­
est task is to recognize a Clark nevus, which is flat or slightly mamillated, and
involves only the epidermis and papillary dermis (Fig. 15.1 15.4). There
seems to be progressively added significance to the following:
the lesion is larger than 6 millimeters clinically (5 millimeters histopatho­
logically, if the long axis is sampled this lesser number allows for shrinkage
due to fixation). Small Clark nevi are insignificant if cytologically bland and
few;
- obvious architectural disorder is present. This is exemplified by nests that
connect the bases of rete ridges ("bridging"); they may be more significant if
they are not uniform in size, shape or cellular composition (Balkau);
the nests are not only at the bases of the rete ridges, but are also along
their sides and above dermal papillae;
- scattered atypical melanocytes are present; either large and oval ("epithe­
lioid melanocytic dysplasia") with abundant pale cytoplasm, a large central
vesicular nucleus and a prominent nucleolus. Sometimes, atypical cells are
small with hyperchromatic, vertically oriented, almost pyknotic looking angu­
H!i_
NEVI lated nuclei with scant cytoplasm. Recognition of the latter type is less repro­
ducible due to differences in fixation, processing and staining. The majority
of melanocytes of the nevus remain small;
in some lesions, single cells predominate ("lentiginous melanocytic dys­
plasia" in Clark's papers). The "lower border" with a lentiginous junctional
nevus remains imprecisely defined;
- if single cells predominate, they should be evenly distributed along the
dermal-epidermal junction but may extend laterally beyond the last nests;
rete ridges are usually evenly elongated and of roughly equal width. If
not, greater scrutiny is warranted;
- a peculiar alteration of the papillary dermis is variably present and con­
sists of fibrosis in a parallel or curvilinear array ("lamellar fibroplasia" and
"concentric fibrosis"). In lamellar fibroplasia, there are clefts parallel to the
epidermal surface, beneath rete ridges bridged by horizontal nests of
melanocytes. In concentric fibroplasia, the collagen bundles are around the
bases of rete ridges. The extent to which these traits are defined by the plane
of section remains to be defined;
- a sparse inflammatory lymphocytic infiltrate is usually present in the der­
mis, along with a slight pigmentary incontinence;
- the intradermal component (if present) is restricted to the central part of
the lesion; consequently, the junctional component extends beyond the dermal
one forming "shoulders". The cells in the papillary dermis are usually small
round melanocytes, but are sometimes similar to those seen at the junction if
they are within marked fibroplasia.
All these traits are continuous variables subject to lack of reproducibility
between observers. It seems best to make a diagnosis of "Clark nevus", and
note if there are findings suggesting melanoma, or ones justifying re-excision.
"Clark nevi" with some cytologically atypical cells occur in special sites
(genitalia, umbilicus, the scalp of children, etc.) and do not need histological­
ly clear margins unless the atypia is overwhelming, or there are worrisome
findings not typical of these sites.
Variants
Histopathologic variants include:
- prevalence of large pale melanocytes with dusty melanin. These cells,
termed as "pagetoid melanocytes" by Ackerman are expected in nevi in the
scalp of children, breasts of women and vulva. The term "pagetoid
melanocytes" is best avoided as it invites confusion with pagetoid spread, a
more loaded phrase than other ambiguous ones such as "lentiginous" or
"lichenoid". Special caution is warranted if there is the least bit of single cell
scatter above the junction in such lesions, which can indicate melanoma in
situ;
- a dense lymphocytic infiltrate (a "halo reaction") can occur in "Clark
nevi", with or without the so called dysplastic features;
- Spitz nevus-like cells ("spitzoid Clark nevi", see below).
A dysplastic nevus can be ruled out in favor of melanoma when:
- cytologically atypical cells predominate (except when the cells are "spit­
zoid", e.g. large spindled melanocytes separated from each other by clefts);
- there is a striking pagetoid spread of melanocytes above the junction, in
the absence of explanatory factors;
_-
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eVllS,
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Fig.iS.i
Lentigo simplex or junctional
"dysplastic" nevus?
The diagnosis of "jentigo" or
nevus incipiens would probably
be enough for this lesion. A few
details, however, may induce one
to consider a "dysplastic" nevus:
- the lesion is larger than an
ordinary nevus;
- cells are unevenly distributed
along the junction, many of them
are also aligned in the basal
layer ofthe suprapapillary plate;
nests are irregularly shaped
and positioned.
The clinicopathologic diagnosis
of an early "dysplastic" nevus
would be plausible in an appro­
priate clinical context.
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-,
NEVI there are more than occasional mitotic figures;
rete ridges are variable (but on the back, one can see loss of rete ridges
and thinning of the epidermis in the raised center of a lesion), a finding that
taken out of the context simulates "nevoid" melanoma.
Despite the obvious clinical phenotype of the patients described in 1978, it
is actually (in our opinion) unusual to see an indisputable "dysplastic" or even
"Clark" nevus.iJ} I,lpposition to a melanoma or to a melanoma in situ. Some of
the studies claiming a high rate of this occurrence are marred by the claim of
"melanocytic dysplasia" in opposition to melanoma. The "melanocytic dys­
plasia" in question may represent a nested pattern of melanoma in situ at the
edge of the lesion. At the risk of underestimating the incidence of melanoma
in "dysplastic" or "Clark" nevi, we propose that the association is proven only
if the findings include small round melanocytes in the papillary dermis. In
lesions in which melanoma arises in such a nevus, it commences more often
at the edges of the lesion than in its center. A decisive difference in pattern is
often present, with a denser lymphocytic infiltrate beneath the melanomatous
focus, loss of the prevalent rete ridge pattern, and large irregular nests of
melanocytes or pagetoid scatter of them.
DIFFERENTIAL DIAGNOSIS
The distinction with melanoma is difficult, and can be subjective if the "dys­
plastic" findings are sufficiently developed (Hastrup). A "dysplastic form of
Clark nevus" has many features in common with melanoma, such as large
size, architectural disorder, cytologically atypical cells, mixture of nested and
single melanocytes, and fusion of nests. The fusion is different in Clark nevi
than in melanoma. In the former, nests bridge the bases of rete ridges, while
in the latter they can be directly apposed to the supraretial epidermis.
Both "Clark" and "dysplastic" nevi occur in older patients. Beware of such a
nevus in severely sun damaged skin (in which the dermis has a blue stain due
to severe elastosis)! This is especially relevant on the face, in which "Clark"
nevi of any type seldom occur. Such lesions are best completely excised, as
we have learned from experience.
The differential diagnosis obviously also is with other types of nevi.
The architectural features of "Clark nevus" are probably nearly obligatory
findings in radially expanding nevi (Piepkorn). Like the unusual traits of
human adolescent life, they are worrisome only if expressed in the wrong
context (in the nevic case, very large lesions, or rapid growth in previously
stable ones).
"Dysplastic" changes are also common in congenital nevi excised before
and during puberty, pregnancy and in children. Some cytological atypia, both
junctional and dermal is an expected finding in a halo nevus but greater
monomorphism is present. Many halo nevi have the architecture of "Clark"
nevi.
Toussaint described Spitz nevi with many traits of the dysplastic nevus
("shoulders", mesenchymal alterations, lymphocytic infiltrates, bridging of
nests and irregularly shaped nests). These nevi seem to be called "dysplastic
nevi with severe atypia" by some, dysplastic Spitz nevi by others and "spit­
zoid Clark nevi" by yet other observers (Ackerman, personal communication,
LeBoit). If the cytoplasm of the large melanocytes in such lesions is copious
r'
Fig. 15.2
"Clark" nevus,junctional
This lesion is a junctional nevus
which can be labeled as a
"Clark" nevus, with some inter­
esting findings. If the lesion had
a larger diameter and an irregu­
lar shape, the clinician would
label it a "dysplastic" nevus:
- melanocytes are arranged in
solitary units;
- some cells have large and
hyperchromic nuclei;
- rete ridges are elongated and
their bases are fused together;
- concentric fibroplasia is pre­
sent in the papillary dermis just
below the bases of rete ridges;
- a quite sparse inflammatory
infiltrate is present in the superfi­
cial dermis.
I
I
If changes such as these oc­
curred at the edges of a pre-exis­
tent congenital nevus, they would
correspond to an unstable lesion,
and if correlated clinically, could
signify an increased risk of
melanoma.
H
II Fig. 15.3
HClark" or H dysplastic" nevus
The lesion is a junctional nevus
with melanocytes singly and in
small nests, contributing to the
fusion of the bases of elongated
rete ridges. In the dermis there is
a sparse superficial lymphocytic
infiltrate without regression of
melanocytes.
The diagnosis of a dysplastic
nevus can be sustained because
of these details, although the
determination of cytologic atypia
in this lesion is in part subjec­
tive. Moreover there is absence
of a pagetoid spread of mel­
anocytes and they are evenly dis­
tributed along elongated rete
ridges; in most melanomas in
situ, there is variation in the
length and width ofrete ridges.
Fig. 15.4
"Clark" or " dysplastic" nevus
This compound nevus fulfils
many of the criteria for the diag­
nosis ofa "dysplastic" nevus:
- the nevus is limited to the junc­
tional zone, and to a thickened
papillary dermis (especially in
the center of the lesion);
- melanocytes· at the junction are
either in nests or in a lentiginous
pattern;
- nests bridge adjacent rete
ridges;
- melanocytes are occasionally
atypical with large hyperchromic
nuclei, atypical cells are also
present in the dermis;
- the intradermal component is
narrower than the junctional
one, which forms broad shoul­
ders;
a striking peculiar form of
fibrosis is present in the dermis
(delicate collagen fibers in par­
allel streaks, the so called lamel­
lar fibroplasia).
7
II Note that the fibrosis disrupts the
nests in the dermis which have a
disorderly distribution and are
irregularly shaped, and horizon­
tally oriented. Note the architec­
tural disorder of the intradermal
component of the nevus which
indeed simulates a melanoma.
This variant of "dysplastic"
nevus, in which the center is
raised and fibrotic, and has a
dermal component simulating
nevoid melanoma is a distinct
one, often found in the back. If
only the center is sampled by
punch biopsy, it may be impossi­
ble to distinguish the lesion from
a melanoma. The "shoulders" on
either side are symmetrical,
mostly nested and well circum­
scribed, unlike the case in
melanoma. Note also that
melanoma seldom arises "dead
center" in a nevus.
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l.
ie,
,~,
.
Fig. 15.5
"Clark" or " dysplastic" nevus
with some features of Spitz
nevus
Many different diagnoses can be given in this case, including melanoma. Hints of a dysplastic nevus are the prevalence of a lentiginous pattern at the junction, the con­
fluence of nests and the fibropla­
sia in.the papillary dermis. However, some cells are too large for a "dysplastic" nevus and their cytoplasm resembles ground glass, moreover, a couple of nests show the so called cap­
ping phenomena (a crescent shaped cleft between the nest and the epidermis) which are all indi­
cations of a Spitz nevus. Consequently the diagnosis of a dysplastic nevus with the features of a Spitz nevus (or of a com­
bined Spitz and Clark nevus), or "spitzoid" Clark nevus can be made. The diagnosis of an early melanoma (which could also be reasonably sustained) can be dis­
carded considering the uniform distribution of the cellular densi­
ty throughout the lesion, and the tendency of the melanocytes to form small uniform nests, at least in part of the lesion. Also, in most melanomas this broad, some upward scatter will be pre­
sent. If a lesion such as this one goes to the margins, re-excision should be considered. ('
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NEVI Summary
and eosinophilic, with distinct edges, clefts demarcating individual cells, and
the nuclei are monomorphous (allowing for variation in the plane of section­
ing of elongated nuclei) the diagnosis is benign, in our opinion, but the sub­
• The "Clark" or "dysplastic" ject clearly merits more study. The same consideration applies to the Reed
nevus is a lesion which is sup­
posed to be one of the prime nevus, which can have junctional "shoulders" (Fig. 15.5). If there is any
doubt about such lesions, complete excision is obligatory.
precursors of a malignant mel­
anoma; the incidence, the clini­
cal and histological settings of In conclusion, as stated by Toussaint "the histopathological changes described
this entity have always been in the dysplastic nevus may be found in any type of melanocytic nevus which
controversial. shows a junctional component" and almost all nevi contain one or more of
such findings (Barnhill). This explains the limits of inter-observer agreement
in this controversial entity, and emphasizes the need for clinical correlation in
• Histologically, the ('dysplastic" nevus is characterized by: assessing the risk of melanoma in a given patient.
- a flattish nevus limited to the References
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