International Scholarly Research Network
Volume 2011, Article ID 813513, 3 pages
Nevogenesis:A BenignMetastatic Process?
AndrewL.Ross,1MargaretI.Sanchez,1andJames M. Grichnik1,2,3
1Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2Melanoma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
3Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Correspondence should be addressed to James M. Grichnik, firstname.lastname@example.org
Received 13 February 2011; Accepted 8 March 2011
Academic Editors: F. M. Camacho, A. Firooz, and J. F. Val Bernal
Copyright © 2011 Andrew L. Ross et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
It is generally accepted that cutaneous nevogenesis is a localized event that occurs exclusively in the dermis and/or epidermis.
However, the discovery of nevocytes circulating in the peripheral blood suggests that other, more systemic, benign metastatic
nevus progenitor cells in the development of nodal nevi and eruptive melanocytic nevi will be reviewed.
The process of nevogenesis is generally thought to be the
result of a localized dermal and/or epidermal event. In the
localized model, a single nevus progenitor cell located in
the skin undergoes a transforming event that leads to local
migration and proliferation creating a single nevus in the
vicinity of where the progenitor cell was transformed.
Though more controversial, it is also possible that nevo-
genesis occurs through a more systemic, benign metastatic
process. In the systemic model, a single transformed imma-
ture nevus progenitor cell gives rise to multiple systemic nevi
through lymphatic and hematogenous dissemination. This
model provides an alternative explanation for the develop-
ment of both simultaneous eruptive nevi and nodal nevi.
2.Model for Benign Metastasis
In the systemic model, a melanocytic stem cell residing in
event that primes the cell to proliferate excessively (see
Figure 1). This nevus progenitor cell would remain quiescent
in the dermis until environmental conditions prompted the
cell to either (1) undergo localized proliferation to form
a nevus at that site, or (2) enter into systemic circulation
through a lymphatic or hematogenous route. Lymphatic
entry seems most plausible because the loosely adherent
nature of melanocytic stem cells may predispose them to
be swept into lymphatic channels in the dermis . The
initiating event that transforms a melanocytic precursor cell
into a nevus progenitor cell may facilitate this process (i.e.,
inflammation after a sunburn). Direct hematogenous entry
is lesslikely given thatit does not readily explain thepresence
of nodal nevi.
Upon entering the lymph node, the nevus progenitor
cell could follow one of two paths. First, it could implant
in the node. Upon implantation, the cell could either
remain quiescent or migrate into the capsule where it would
proliferate into a nevus. Second, its loosely adherent nature
could allow it to pass through without being sequestered
by the node . The nevus progenitor cells that failed to
implant in the node would continue on to enter into the
circulatory system. At some point in this process, the nevus
progenitor cell would begin to undergo limited division.
This could take place in the tissue where the initiating event
occurred, within the lymph node, or upon entry into the
circulation. The resultant cells would continue to circulate
for an indeterminate period of time.
In the course of their travel, the circulating cells
would eventually be exposed to a microenvironment that
encourages diapedesis and implantation. Depending on
the signaling molecules present in the extracellular milieu,
Figure 1: Model of benign metastasis. In this model, a melanocytic
stem cell (1) undergoes an initiating event that transforms it into
an immature nevus progenitor cell (2). This cell (2) may remain
into a nevus (3). Alternatively, this loosely adherent cell could enter
the lymphatic system (4). Upon encountering a lymph node, the
progenitor cell could either implant in the node and proliferate into
a nodal nevus (5) or pass through without being sequestered (6)
to eventually reach the circulatory system (7). The progenitor cell
would continue to circulate (8) until a transforming event, like a
mutation, or environmental conditions signals the cell to implant
in the skin (9). The implanted nevus progenitor cell would remain
quiescent in the skin until local environmental factors stimulate it
to proliferate into a nevus (10).
the implanted cells could immediately begin to proliferate
or remain quiescent until recruited by a change in local
One of the most important facts that supports this theory
is the existence of nodal nevi. Benign nevocyte aggregates in
lymph nodes were first described by Stewart and Copeland
in 1931. Since then, their existence has been confirmed
in multiple reports [3–9]. Although the existence of nodal
nevi could be explained by arrested melanocyte precursor
migration during embryogenesis, Patterson has put forth
a compelling argument in favor of mechanical transport
. It has been suggested that mechanical transport is
initiated when a melanoma arises in a preformed nevus
and displaces benign nevocytes into the lymphatic system
[6, 10]. This hypothesis is supported by the fact that benign
nevocytes reported in the literature frequently colocalize
with malignant melanocytes in lymph nodes . However,
this observation is likely secondary to selection bias, as
few healthy individuals commonly undergo lymph node
sampling. Additionally, nodal nevi have been described in
individuals with other malignancies and individuals with
no comorbidities [3, 4]. If nodal nevi are derived from
nevocytes displaced from preformed nevi, then it would
be expected that all corresponding dermatomes drained by
lymph nodes containing nevocyte aggregates should possess
a parent nevus. Although Holt et al. did demonstrate that 6
of 8 nodal nevi had an associated cutaneous nevus, this was
their report could be accounted for by the systemic model in
which cells may pass from tissue and through nodes without
requiring the development of a nevus at the cutaneous site.
Another important finding that supports the aforemen-
tioned theory is that benign nevocytes have been isolated in
the peripheral blood . Direct hematogenous invasion by
nevocytes is unlikely given the cells’ benign nature. As such,
it is probable that hematogenously disseminated nevocytes
entered into systemic circulation through the lymphatic
system. This implies that loosely adherent nevus progenitor
lymph nodes. Consequently, there is evidence to support the
notion that upon entering a lymph node, nevus progenitor
cells can either implant in or pass through the node to enter
the peripheral blood stream.
There is currently no direct evidence that supports
the hypothesis that benign nevus progenitor cells in the
peripheral blood stream are able to exit the circulation and
implant in the skin. However, the phenomenon of epider-
motropic metastatic melanoma does suggest that circulating
melanocytes, albeit malignant ones, can demonstrate a
propensity to implant in either the dermis and/or epidermis
. Given the fact that malignant melanoma and benign
nevi possess similar growth promoting mutations, it is not
unreasonable to propose that they also share the ability to
hematogenously disseminate and implant in the skin. This
shared ability to metastasize does not necessarily imply that
these two very different cells will behave similarly upon
implantation. It is likely that additional mutations in senes-
cence pathways permit malignant melanocytes to undergo
uncontrolled proliferation , while nevus progenitor cells
with intact senescence pathways eventually undergo growth
The phenomenon of eruptive nevi is characterized by the
sudden systemic development of multiple nevi over a short
conditions , and cytokines . It thus appears that the
systemic eruption of nevi is triggered by a discrete systemic
event that causes transformed, quiescent nevus progenitor
cells located throughout the skin to proliferate. The existence
of this susceptible nevus progenitor cell is supported by
the fact that not all individuals exposed to these stimuli
develop eruptive nevi and that patients who do undergo this
phenomenon develop discrete lesions as opposed to general
hyperpigmentation. It remains plausible that this systemic
population of susceptible nevus progenitor cells was derived
from a single cell. Supporting evidence includes a recent
case report by Sekulic et al. that demonstrated a BRAF
V600E mutation in 17 of 20 eruptive nevi removed from a
single patient who was being treated with 6-Mercaptopurine
. Although the authors interpreted their results to imply
that treatment with this immunosuppressive agent increases
mutational frequency, it is also possible that most of these
nevi share a monoclonal origin. In the latter scenario, the
mutation would have occurred in a progenitor cell whose
progeny disseminated systemically.
In summary, given the phenomena of epidermotrophic
metastatic melanoma in which tumor cells can focally prolif-
consider the possibility that nevogenesis occurs by a benign
The benign metastasis model is unproven and there exist
a number of questions that remain to be answered. One
of these questions is if benign nevus progenitor cells do
metastasize, then why are nevi not frequently found in other
internal organs like the lungs and brain? While it could
be argued that these organs do not support implantation
and growth of circulating benign nevocytes, this is difficult
to reconcile with malignant melanocytes’ proclivity for
these tissues. Nevertheless, it remains possible that benign
melanocytes possess intrinsic characteristics that prevent
them from implanting or growing in these tissues. If this
is true, the recognition of these characteristics and the
discovery of their control mechanisms could have potential
The systemic dissemination of nevus progenitor cells
through lymphatic and hematogenous routes could play a
role in nevogenesis.
DigitalDerm, Inc-Major Shareholder, Spectral Image, Inc-
past grants and consulting, Electro Optical Sciences, Inc-
past grants and consulting, Genentech-consultant, Archives
of Dermatology, skINsight section editor.
 J. M. Grichnik, “Melanoma, nevogenesis, and stem cell
biology,” Journal of Investigative Dermatology, vol. 128, no. 10,
pp. 2365–2380, 2008.
 J. M. Grichnik, “Hypothesis letter: the reason sentinel and
lymph node dissections do not improve melanoma mortality,”
Journal of Investigative Dermatology, vol. 129, no. 3, pp. 779–
 D. A. Biddle, H. L. Evans, B. L. Kemp et al., “Intraparenchymal
nevus cell aggregates in lymph nodes: a possible diagnostic
pitfall with malignant melanoma and carcinoma,” American
Journal of Surgical Pathology, vol. 27, no. 5, pp. 673–681, 2003.
 S. Andreola and C. Clemente, “Nevus cells in axillary
lymph nodes from radical mastectomy specimens,” Pathology
Research and Practice, vol. 179, no. 6, pp. 616–618, 1985.
 N. C. Bautista, S. Cohen, and K. H. Anders, “Benign
melanocytic nevus cells in axillary lymph nodes: a prospective
incidence and immunohistochemical study with literature
review,” American Journal of Clinical Pathology, vol. 102, no.
1, pp. 102–108, 1994.
 K. F. Carson, D. R. Wen, P. X. Li et al., “Nodal nevi
and cutaneous melanomas,” American Journal of Surgical
Pathology, vol. 20, no. 7, pp. 834–840, 1996.
 D. Fontaine, W. Parkhill, W. Greer, and N. Walsh, “Nevus
 J. B. Holt, O. P. Sangueza, E. A. Levine et al., “Nodal
melanocytic nevi in sentinel lymph nodes. Correlation with
melanoma-associated cutaneous nevi,” American Journal of
Clinical Pathology, vol. 121, no. 1, pp. 58–63, 2004.
 B. G. Howell, J. E. Lipa, and D. M. Ghazarian, “Intracapsular
melanoma: a new pitfall for sentinel lymph node biopsy,”
Journal of Clinical Pathology, vol. 59, no. 8, pp. 891–892, 2006.
 J. W. Patterson, “Nevus cell aggregates in lymph nodes,”
American Journal of Clinical Pathology, vol. 121, no. 1, pp. 13–
 G. Argenziano, H. P. Soyer, S. Chimenti et al., “Dermoscopy
of pigmented skin lesions: results of a consensus meeting via
vol. 48, no. 5, pp. 679–693, 2003.
 J. L. Abernethy, H. P. Soyer, H. Kerl, J. L. Jorizzo, and W.
L. White, “Epidermotropic metastatic malignant melanoma
simulating melanoma in situ: a report of 10 examples from
two patients,” American Journal of Surgical Pathology, vol. 18,
no. 11, pp. 1140–1149, 1994.
 O. Straume, L. Sviland, and L. A. Akslen, “Loss of nuclear
p16 protein expression correlates with increased tumor cell
proliferation (Ki-67) and poor prognosis in patients with
vertical growth phase melanoma,” Clinical Cancer Research,
vol. 6, no. 5, pp. 1845–1853, 2000.
 I. Betlloch, C. Amador, E. Chiner, F. Pasquau, J. L. Calpe, and
A. Vilar, “Eruptive melanocytic nevi in human immunodefi-
ciency virus infection,” International Journal of Dermatology,
vol. 30, no. 4, p. 303, 1991.
 V. L´ opez, I. Molina, J. M. Mart´ ın, N. Santonja, M. J. Forner,
A for psoriasis treatment,” Archives of Dermatology, vol. 146,
no. 7, pp. 802–804, 2010.
 H. J. Bovenschen, M. Tjioe, H. Vermaat et al., “Induction of
eruptive benign melanocytic naevi by immune suppressive
agents, including biologicals,” British Journal of Dermatology,
vol. 154, no. 5, pp. 880–884, 2006.
 J. N. W. N. Barker and D. M. MacDonald, “Eruptive dysplastic
naevi following renal transplantation,” Clinical and Experi-
mental Dermatology, vol. 13, no. 2, pp. 123–125, 1988.
 N. Onsun, S. Saracoglu, C. Demirkesen, Y. B. Kural, and U.
Atilganoglu, “Eruptive widespread spitz nevi: can pregnancy
be a stimulating factor?” Journal of the American Academy of
Dermatology, vol. 40, no. 5, part 2, pp. 866–867, 1999.
 C. M. Lanschuetzer, M. Emberger, R. Hametner et al.,
Dermato-Venereologica, vol. 83, no. 5, pp. 332–337, 2003.
hormone-Induced eruptive nevi,” Archives of Dermatology,
vol. 145, no. 4, pp. 441–444, 2009.
 A. Sekulic, M. B. Colgan, M. D. P. Davis, D. J. DiCaudo,
and M. R. Pittelkow, “Activating BRAF mutations in eruptive
melanocytic naevi,” British Journal of Dermatology, vol. 163,
no. 5, pp. 1095–1098, 2010.