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Book Title: Melanocytic and Dysplastic Nevi: Pathology, Potential Health
Effects and Preventive Measures. Nova Science Publishers, Inc. 2016 (In Press)
Chapter
ATYPICAL MELANOCYTIC NEVI:
GRADING AND CLASSIFICATION OF DYSPLASIA
AND DERMATOSCOPIC FINDINGS
Lucia Pozo-Garcia1 and Salvador J. Diaz-Cano2,*
1Dept of Dermatology, Lewisham and Greenwich NHS Trust, London UK
2Dept of Histopathology,
King’s College Hospital and King’s Health Partners, London, UK
ABSTRACT
The tumor progression in melanocytic lesions is assumed to follow a multistep
process where the genetic alterations and the morphological steps are closely related. In
general terms, this process is usually identified pathologically as dysplasia, intraepithelial
malignancy, and early neoplasm. However, melanocytic lesions with dysplasia are, on
one hand, controversial in its diagnostic criteria and, on the other hand, difficult to grade
and subcategorize due to its heterogeneity. The key condition is the atypical (dysplastic)
melanocytic nevus (AMN), which requires both architectural and cytological features to
be defined and always needs grading to provide a more accurate risk assessment for the
development of malignant melanoma. At this point, it is essential to identify reliably and
predict high-grade dysplasia/melanoma-in-situ (HGD-MIS) at clinical, dermatoscopic,
biological, and pathological levels within these highly heterogeneous lesions.
AMN-HGD and MIS share the same clinical and dermatoscopic features, which
makes extremely hard to differentiate between them at this level. They are clearly
different from atypical nevi with low-grade dysplasia, which usually present with soft
clinical and dermatoscopic findings. Key dermatoscopic features for the low-grade vs.
high-grade distinction are atypical pigment network, eccentric hyperpigmented blotches,
and peripheral globules. Histologically, HGD-MIS is mainly defined by junctional
asymmetry with both lentiginous and nested patterns, suprabasal melanocytes and at least
three nuclear abnormalities (mainly nuclear enlargement, anisokaryosis and
hyperchromatism as more predictive features). Biologically, these lesions reveal both cell
kinetics and topographic genetic heterogeneity, which are mostly driven by abnormal
* E-mail address: sjdiazcano@doctors.org.uk.
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
2
TP53, dissociated from cyclin-dependent kinase inhibitors (p21WAF1-CDKN1A and
p27KIP1-CDKN1B), especially for MIS. The differential diagnosis requires
distinguishing them from atypical but not dysplastic melanocytic lesions (particularly in
specific locations), and invasive malignant melanomas (mostly thin and non-tumorigenic
status). The implications are also different for lentiginous and epithelioid dysplastic
lesions, whose criteria are weighted in a slightly different way. Finally, the progression
pathway in dysplastic melanocytic lesions is unlikely linear at morphological and genetic
levels, and they show a distinct correlation with the molecular subtypes of malignant
melanomas.
Keywords: atypical melanocytic nevus, melanocytic dysplasia, melanoma in-situ, grading,
dermatoscopy, biologic progression
INTRODUCTION
Atypical melanocytic nevi (AMN) that exhibit histopathologic features of dysplasia were
initially described in the setting of familial melanoma. [1, 2] This distinctive syndrome was
characterized by multiple abnormal melanocytic nevi and revealed a high risk of melanoma
development and a family history of malignant melanoma [1, 3]. This condition was referred
to as “B-K mole syndrome” (the first letters of the surnames of the first 2 families studied),
[1] Familial Atypical Multiple Mole and Melanoma Syndrome “FAMMM,” a term that
describes the features of the syndrome, [3] and Familial atypical mole and melanoma
syndrome “FAM-M” as recommended by the consensus development conference of 1992. [4]
This syndrome is characterized by (a) occurrence of malignant melanoma in one or more first
or second-degree relatives; (b) large number of melanocytic nevi, often more than 50, some
are atypical and variable in size; and (c) a lifetime risk of melanoma development
approaching 100% occurring at a much younger age than control subjects who lack the
morphologic characteristics of the syndrome. [5] A similar clinical phenotype characterized
by multiple atypical nevi, high risk of melanoma development, but no history of familial
melanoma has been called “Dysplastic Nevus Syndrome” [6] or “Atypical Mole Syndrome.”
[7] A non-familial sporadic form of acquired dysplastic melanocytic nevi occurring in
individuals with no other skin abnormalities has also been reported. [8-10] The histological
features of both the familial and sporadic forms are indistinguishable. [11, 12] Since its
original description, dysplastic nevus or atypical melanocytic nevus has been surrounded by
controversy, confusion, ambiguity and disagreement even on its nomenclature. [13-16] These
lesions when clinically defined but not pathologically examined are classified as atypical
nevi, [17] and lesions characterized histologically by specific architectural and cytologic
features are called dysplastic nevi. [6] Histologic criteria for the diagnosis of atypical
(dysplastic) melanocytic nevus (AMN, term to be used in this work) have been described as
early as the 1950s, [18] and the concepts have been validated clinical and pathologically, [19]
conferring its presence a high risk of developing melanoma [20].
Atypical Melanocytic Nevi
3
DIAGNOSTIC CRITERIA
A robust stratification of melanoma risk associated with AMN must be based on a clearly
defined clinicopathological entity. It will, therefore, require both clinical and pathological
findings to fulfill. It has been demonstrated that clinically atypical nevi may show a non-
atypical histopathology. [19, 21] Reports concerning the correlation between the clinical and
histological diagnoses of AMN have given conflicting results ranging from very low (15%),
[22] to significantly high (75%). [23] However, the majority of reports reveal a poor
concordance between the clinical phenotype of AMN and the histological appearance. This
poor concordance is explained by the different criteria used clinically and histologically in
identifying AMN. Roush and colleagues examined biopsy specimens from 91 clinically
dysplastic nevi and found that only 23 of these were classifiable as histologically dysplastic.
[22] Also, histological features of AMN have been reported to be very common in clinically
bland looking nevi. [24, 25] The same observations were recorded by Annessi group, who
concluded that AMN can not be considered as a distinct clinicopathologic entity, based on the
lack of agreement between the clinical appearance and the histological picture. [26]
According to the different inclusion criteria applied by various authors for the clinical and
histological diagnosis of AMN, marked variability in the reported prevalence values of AMN
has resulted. [27] The prevalence of AMN has been estimated to range from 0.85% to 53%,
[9, 17, 24, 25, 28-31] with a low-frequency rate ranging from 0-1.5% in the pediatric age
group [32, 33].
Clinical requirements for the diagnosis of atypical nevus include a flat macule greater
than 6 mm, and at least two of the following features: variable pigmentation; irregular,
asymmetric outline; and indistinct borders (Figures 1-4). [34] The trunk is the commonest site
for AMN but when they occur in the context of dysplastic nevus syndrome they tend to
involve the buttocks, scalp, female breast, genital skin, and feet; sites where nevi are usually
absent or rare. [27] Skin surrounding AMN can show erythema, caused by reactive hyperemia
or sometimes an eczematous halo. [35] Atypical lesions in patients without familial
syndromes are more commonly found in sun-exposed areas.
The histological criteria of AMN should clearly distinguish them from common nevi and
malignant melanoma, [36-39] allowing a high degree of reproducibility and concordance
among pathologists; however, the situation is more problematic for grading. [40] An initial
publication of the National Institute of Health (NIH) consensus definition of AMN provided
several criteria for the diagnosis of AMN, recommending the discontinuation of the term
“dysplastic” and its replacement with “nevus with architectural disorder”; it added the degree
of melanocytic atypia as a comment, although it stated that atypia could be “absent.” [4] The
histological diagnosis of AMN depends on several features, including two major criteria
(basilar proliferation of atypical melanocytes, organized in a lentiginous or epithelioid-cell
pattern) and four minor criteria (dermal fibrosis, neovascularization, inflammation and rete
ridges fusion). It required the presence of both major criteria and at least two minor criteria
yielding a mean overall concordance of 92% among pathologists. [41] Nuclear atypia is a
mandatory requirement for the histologic diagnosis of AMN as the other features, whether
architectural disorder or host response, can occur individually in conventional nevi and,
therefore, are not specific features for the diagnosis of AMN. [25, 42] However, those
features have been found to correlate with nuclear atypia, leading to the recommendations
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
4
that the minimal essential histological criteria proposed for AMN must be based on both
nuclear atypia and associated architectural disorder. [12, 43, 44] Some pathologists reported
difficulties in reproducible assessment of nuclear atypia, whereas architectural atypia was
fairly reproducible. [45] Others reported the presence of variable degrees of nuclear atypia
together with other features of AMN in conventional nevi leading to the inseparability of both
lesions from each other with a continuous spectrum of melanocytic lesions observed, [46]
which has resulted in some variability in the incidence of these atypical melanocytic lesions.
[47, 48] The current consensus opinion for a robust histological diagnosis of AMN requires
the combination of architectural disorder, host response, and cytological atypia. [38, 41, 49,
50].
Figure 1. Epithelioid melanocytic dysplasia. A. Clinical image shows a small variegated pigmented
macule, this lesion was 5 mm in greatest diameter. B. Dermatoscopy reveals a dermoscopic island with
marked atypical pigment network (*). The presence of a dermoscopic island within a melanocytic
lesion has been associated with thin melanomas. C. Nested and continuous lentiginous growth and
numerous suprabasal atypical melanocytes characterize high-grade lesions. D. Epithelioid melanocytes
are normally large, with granular eosinophilic cytoplasm, and vesicular nuclei.
Architectural features: The majority of AMN are of the compound type, and a minor
proportion is of the junctional type, with no exclusively intradermal AMN recognized. [27]
The junctional component of AMN is usually made of variable sized and shaped melanocytic
nests associated with a lentiginous melanocytic proliferation along the sides of elongated rete
ridges. A bridging effect results from the fusion of melanocytic nests at the tips of adjacent
rete ridges. The shouldering phenomenon is the extension of single or nested junctional
Atypical Melanocytic Nevi
5
melanocytes beyond the dermal component in compound AMN. Limited suprabasal
migration of melanocytes may be seen, but obvious pagetoid spread with an extension of
melanocytes into the spinous layer is absent or quite rare in AMN, and if present, migrating
cells are usually small with dark nuclei and scanty cytoplasm (Figures 1-4). [27, 49, 51].
Figure 2. Lentiginous melanocytic dysplasia. A. Clinical image of a variegated pigmented macule. B.
Dermatoscopy reveals asymmetric follicular pigmentation (arrow) and dark homogeneous areas
obliterating the hair follicles opening (white arrow). C. Continuous lentiginous growth pattern with
single suprabasal melanocytes (highlighted by melan A immunostaining in the inset) in a background of
atrophic epidermis are common features associated with chronic sun-damage areas and lentigo maligna
appearances. D. Continuous lentiginous pattern and elongation of the rete ridges are more frequently
found in areas with no sun damage and mucosal atypical melanocytic lesions.
Host response: The host response in AMN is composed of a mononuclear inflammatory
infiltrate, dermal fibroplasia and prominent vascularity. The inflammatory infiltrate is mainly
made of lymphocytes with occasional macrophages and is of variable density. There are two
types of dermal fibroplasia associated with AMN. The commonest type is the concentric
fibroplasia, which consists of dense, refractile, concentric layers of collagen around junctional
melanocytic nests. The other kind is called lamellar fibroplasia, which is described as tree-
like branches of collagen extending laterally outward from junctional melanocytic nests [51-
54].
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
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Figure 3. AMN with low grade dysplasia (AMN-LGD). A. Clinical image shows an irregular
variegated pigmented macule larger than 6mm (meets three criteria from ABCD rule). B.
Dermatoscopy shows multifocal hyper and hypopigmentation with regular pigment network in keeping
with a low grade dysplastic lesion. C. Architectural disorder (lentiginous component, fusion of rete
ridges), lamellar fibroplasia, and minor nuclear abnormalities define low-grade melanocytic dysplasia.
D. Very focal suprabasal melanocytes with low nuclear grade and discontinuous lentiginous pattern are
frequent findings in AMN-LGD.
Cytological features: Nuclear atypia is a prerequisite for the histological diagnosis of
AMN. [42, 49] Features of nuclear atypia include larger nuclei than adjacent keratinocyte
nuclei, nuclear pleomorphism (anisokaryosis), hyperchromasia and prominent nucleoli. [49]
Cytologically atypical melanocytes are randomly distributed among a background of normal
melanocytes. When severely atypical melanocytes are present in a continuous manner, this
may be an indication of an intraepidermal malignancy (Figures 1-2) [42, 49].
SUBTYPES OF MELANOCYTIC DYSPLASIA
Dysplasia in neoplastic pathology refers to a preneoplastic/early neoplastic condition of
lesions arising in epithelia, where the basement membrane set a microanatomic landmark
during the neoplastic transformation. Morphologically, it is recognized by both cytological
(abnormal nuclear morphology) and architectural (disorganized growth pattern) alterations;
this is the concept incorporated by the consensus definition of dysplastic nevus. (41) By growth
pattern, two main types of melanocytic dysplasia can be recognized: epithelioid and
lentiginous [55].
Atypical Melanocytic Nevi
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Figure 4. AMN with high-grade dysplasia (AMN-HGD). A. A. Clinical image shows an irregular
variegated macule, 6x5 mm. B. Dermatoscopy highlights the presence of at least three colors and shows
a multicomponent pattern, a dermoscopic island (*), atypical pigment network (arrow) and atypical
globules (arrow head). Multicomponent pattern is commonly seen in melanomas. C. Nested and
lentiginous growth pattern with numerous suprabasal atypical melanocytes are features of high-grade
melanocytic dysplasia. The left hand side of the panel shows a coexistent melanocytic nevus. D.
Cytologically, these atypical melanocytes reveal high nuclear grade with irregularly distributed
chromatin, pleomorphism and frequently anisokaryosis.
In the epithelioid melanocytic dysplasia (Figure 1), there are large cells with ample
cytoplasm that have open oval nuclei with obvious nucleoli that are sometimes prominent and
contain dusty, coarse pigment granules. These cells almost fill the space in which they are
proliferating, and when nests form, fusion (bridging) is often observed. The cells may also
exhibit some evidence of pagetoid spread (Figure 1). Epidermal hyperplasia may or may not
be a prominent feature in this type of dysplasia. Related lesions have been reported as
pagetoid melanocytosis or pagetoid Spitz nevi, [56-58] which are characterized by junctional
proliferation of atypical epithelioid melanocytes with no tendency to nesting. The atypia is
not enough for melanoma-in-situ, and there are no dermal changes. These lesions are found
on the lower extremities of women and men and are associated with an atypical mole
phenotype and a personal and/or family history of melanoma, [58] dysplastic nevi and non-
melanoma skin cancer [56].
The second type is the lentiginous melanocytic dysplasia (Figure 2). This type is
associated with a very striking epidermal hyperplasia with elongation of the rete. Diffusely
scattered along the basilar region of the rete are pleomorphic cells that have a noticeable
shrinkage artifact so that the cells lie in obvious lacunae or spaces. The type of atypia that can
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
8
be observed in the lentiginous melanocytic dysplasia is variable; in high-grade (severe)
lentiginous dysplasia, the atypical cells are often present in the external root sheaths of the
hair follicle or even the eccrine ducts. Severely atypical dysplastic lesions are often tough to
differentiate from fully evolved intraepidermal melanomas, either acral lentiginous if the
epidermis is hyperplastic or lentigo malignant in the context of chronic sun damage and
atrophic epidermis.
GRADING DYSPLASIA IN AMN. CORRELATION
WITH CLINICAL AND DERMATOSCOPIC FINDINGS
The criteria used in grading dysplasia in AMN are less well defined and are associated
with an element of subjectivity, resulting in a low concordance and inter-observer
reproducibility. [37, 38, 45] A two-tier grading system of low and high grade has been
proposed to improve interobserver agreement and to correlate with the management of
individual cases. [51, 59] A critical analysis of more than 30 histological variables has
revealed that high-grade AMN (severe dysplasia) can be reliably distinguished from low-
grade AMN (mild-moderate dysplasia) based on the application of major features (three
nuclear and two architectural), being low-grade AMN significantly associated with histologic
regression (Figures 3-4). [12, 60] Anisokaryosis is a common finding to all AMN regardless
of the degree of dysplasia, and prominent nucleolus is more frequently associated with low-
grade AMN with regressive changes. [60] Therefore, the two most reliable nuclear changes
predicting high-grade dysplasia are pleomorphism and irregular chromatin distribution,
especially when they are present together. Mixed junctional pattern with confluent lentiginous
component and suprabasal atypical melanocytes are the most useful architectural
abnormalities in AMN-HGD (Figure 4). [12] The most reliable and clinically relevant
categorization includes grouping AMN-mild and AMN-moderate as AMN with low-grade
dysplasia (AMN-LGD, Figure 3), and AMN-severe as AMN with high-grade dysplasia
(AMN-HGD, Figure 4), based on the morphological similarities between the first two lesions
and the difficulty in separating them from each other with certainty. [12] Also, low-grade
AMNs frequently represent regressive rather than progressive lesions, according to cellular
kinetics, [60, 61] and correlate accurately with the clinical presentation. [23] The accuracy of
clinical diagnosis of moderate dysplasia has been reported low (20%); however, all cases of
severe dysplasia with or without melanoma in-situ are correctly diagnosed. An increasing
darkness and confluence of pigmentation in these dysplastic melanocytic nevi correlated with
increasing severity of dysplasia, [23] and severely dysplastic nevi are more often associated
with melanoma, and excision may be beneficial for melanoma detection or prevention [62].
Likewise, dermatoscopy is not reliable in distinguishing AMN-HGD and melanoma-in-
situ (MIS), but it is helpful as an aid technique to differentiate conventional melanocytic nevi
and AMN-LGD from high-grade intraepithelial melanocytic lesions (Figures 3-4).
Dermatoscopically, AMN-LGD reveal a predominantly reticular, globular, uniform pattern or
combinations of two of these patterns and variable distribution of pigmentation (central,
eccentric and multifocal hyper/hypopigmentation), [63, 64] which can be reliably
distinguished from AMN-HGD and intraepithelial melanomas. [65] The most frequent
dermatoscopic findings for AMN-HGD/MIS are the asymmetry in two axes and the presence
Atypical Melanocytic Nevi
9
of atypical pigment network; [65] in particular, a wider atypical network covering more than
half of the lesion and/or the presence of more tan one pigment network within a lesion are
more commonly seen in MIS than in AMN. [66] The presence of a mixture of globular,
reticular and homogeneous patterns within a given lesion and eccentric peripheral
hyperpigmentation have been described as useful findings to discriminate between benign and
malignant melanocytic lesions. Grey-blue regression is also more commonly found in MIS
lesions. [67, 68] The presence of at least two colours, peripheral globules/dots and
dermoscopic islands is also associated with thin melanomas. [69] The dermatoscopic features
of facial lentigo maligna are very characteristic and include the presence of grey granulation,
asymmetric follicular openings and dark rhomboidal areas. As the melanoma advances and
invades the hair follicles, some dark homogeneous areas appear obstructing the hair follicles
opening. [70, 71] The ugly duckling concept has also been postulated as an efficient way to
detect early melanoma in patients with multiple pigmented melanocytic nevi with regards to
the analytical approach of the ABCD rule. However, the detection of a mole, which differs
from other patient’s moles is not always a good discriminator of melanoma, especially in
patients who present with multiple atypical moles. [72] Atypical vessels, milky red areas or
blue-white veil are most commonly found discriminators for invasive melanomas [73].
CLINICAL AND BIOLOGICAL RELEVANCE
The majority of melanoma is sporadic, and in this setting, the role of atypical nevi has
become more clearly apparent. Atypical nevi among patients with sporadic melanoma are
clinically indistinguishable from those of patients with familial melanoma. Atypical nevi
occur in 2% to 7% of the white population and can be identified in 25% to 40% of patients
with melanoma, [6, 74] and they represent a significant risk factor for the development of
melanoma. [75] Their presence may indicate a general instability in melanocyte growth.
Estimating the risk incurred by the presence of atypical nevi has been difficult and ranged
widely in the literature. The risk of new primary melanoma among individuals with atypical
nevi was calculated according to the presence of a family or personal history of prior
melanoma by Kraemer et al. [74] This risk relates both to the presence of atypical nevi,
melanoma, or both in the balance of the family of a given individual. In cases in which
atypical nevi are isolated in an individual, the risk is lowest (27 times population risk). When
atypical nevi are found in multiple members of a family, or there is a history of melanoma in
additional members of the family, the risk rises. Those patients with multiple family members
exhibiting atypical nevi and a having a history of melanoma have the highest risk (148 times
population risk). [74, 76, 77] Unfortunately, the history of atypical nevi and of melanoma
itself is often difficult to elicit. Crijns et al. reported that more than one-half of patients
without an elicited history of melanoma or atypical nevi on first family history are later found
to have genetic patterns of atypical nevi, melanoma, or both. [78] Still the identification of
atypical nevi even among skilled clinicians and pathologists is problematic, and some find the
distinction from conventional nevi unconvincing [79].
There is a broad range of clinical and biologic data that support the validity of AMN as a
risk marker for malignant melanoma, especially for early malignant melanoma. The risk
incurred by the presence of atypical nevi has been difficult to establish accurately. In one
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
10
series, 716 patients with melanoma were compared with a group of matched controls. In the
absence of atypical nevi, increased numbers of small nevi were associated with an
approximately twofold elevated risk of melanoma, and increased numbers of both small and
large non-atypical nevi were associated with a fourfold greater risk. The presence of a single
clinically atypical nevus was associated with a twofold greater risk while ten or more
conferred a 12-fold greater risk of developing primary melanoma. [34] Another smaller series
suggested the danger of developing melanoma might be as high as 37 times greater in those
individuals who have atypical nevi. [80] These atypical nevi were also notable for their
location on the skin of the trunk that was not necessarily sun-exposed. The presence of
atypical nevi identifies patients with a high risk of melanoma among family members with
this syndrome. [81] The risk conferred by the presence of multiple atypical nevi in such
individuals approaches 100% by age 70. [18, 76, 81, 82] This risk is more complex than that
of a discrete precursor lesion that progresses stepwise into malignancy. Although many
melanomas have been identified to arise within atypical nevi, most occur in areas of skin that
show neither gross nor histologic evidence of a coexistent atypical nevus. This observation
suggests that removal of atypical lesions is not akin to the reduction in carcinoma risk after
resection of adenomatous polyps of the colon as most melanomas arise de novo. In patients
with familial melanomas, it is clear that atypical nevi may serve as non-obligate precursors
and markers of melanocyte dyscrasia.
Some lines of evidence favor the precursor melanoma concept, including the spatial co-
existence of both lesions clinically and histologically. Epidemiologically, AMN confers a
relative risk of melanoma development ranging from 1.0 to 12 with increasing likelihood of
melanoma as the number of AMN increases. [17, 22, 30, 34, 75, 83-89] The age-adjusted
incidence rate of melanoma is 413/100,000 patient-years in family members with AMN, but
without a history of melanoma, whereas the rate is 2779/100,000 patient-years in family
members with AMN and a history of melanoma, and melanoma family members with no
AMN did not develop MM. [90] The presence of AMN has been an independent risk factor
for melanoma irrespective of family history of melanoma; [91] however, the increased
number of nevi irrespective of being atypical or not has been found to be a strong risk factor
for melanoma development. [92] Although photographic follow-up of clinically atypical nevi
has been taken as a proof for their evolution into malignant melanoma, [93] new melanomas
can develop in patients having sporadic AMN as new lesions rather than from pre-existing
nevi; [84] only up to one third of cases of malignant melanoma reveals histological evidence
of AMN. [94-98] Thirty-nine percent of melanoma patients were found to have clinically
atypical nevi compared to 7% of the control group. [75] A recent study demonstrated that
melanoma risk correlated positively with the grade of atypia in AMN, [99] but a significant
correlation was not found in other studies. [100] All these observations were taken to support
AMN as a strong risk factor, a powerful predictor and even a direct precursor of melanoma
[101, 102].
The detection of dysplastic nevi also offers an opportunity to identify those
immunosuppressed patients who are at greatest risk of melanoma. [103-105] Sporadic cases
have also been related to immunosuppression, being the number of nevi higher and directly
correlated with the degree of immunosuppression. Such nevi are found most commonly on
the back and acral sites. [106] In normal adults, nevus counts increase in number, peaking in
the early 20s and then progressively decreasing with time. [107] The number of nevi less than
5 mm in diameter was found be greater in patients with human immunodeficiency virus than
Atypical Melanocytic Nevi
11
in the general population. Immunodeficiency may promote or permit the development of nevi
and raises the question of whether sun-induced immunosuppression plays a role in the
development of nevi. [108] The development of melanoma may relate directly to the
suppression of cellular immunity. Melanoma in immunosuppressed patients may evolve from
precursor nevi that are unable to elicit cellular immune recognition.
NATURAL HISTORY AND PROGRESSION MODEL
It has been argued that the decrease in counts of dysplastic nevi associated with
increasing age be only partly explained by the disappearance of nevi over time. [109] Clinical
and histologic studies have resulted in defining a multistep process during melanoma
development and progression, [101, 102] for which dysplastic melanocytic lesions represent
part of the intraepithelial/microinvasive non-tumorigenic step within the clonal origin and
evolution of neoplastic melanocytic lesions. [110, 111] The clonal origin is corroborated by
the lack of significant intratumor heterogeneity revealed for in-transit melanoma metastases
[112].
Figure 5. Linear model proposed for melanocytic lesions that can progress or regress depending on the
kinetic/genetic balance. Three classes and three transitions have been described from committed
melanocyte precursors to vertical growth phase melanomas. Inefficient cellular kinetics and not
consistent expression of cell cycle regulators make the initial progression from intraepithelial to
superficially invasive neoplasm unlikely. In this context, melanocytic dysplasia as direct precursor for
vertical growth phase and metastatic melanomas is not a likely event.
In this proposal, melanocytic lesions can be categorized into three classes: [101] Class I
represents precursor nevi; class II lesions are intermediates, confined to the epidermis or with
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
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microinvasion into the dermis and represented by in situ and microinvasive RGP (radial
growth phase) melanomas; class III are VGP (vertical growth phase) tumorigenic melanomas
(Figure 5). Within this context, AMN might be defined as a monoclonal and genetically
unstable, but limited melanocytic proliferation limited to the epidermis and superficial
dermis. [113] The AMN genetic instability is microsatellite independent and shows preserved
expression of mismatch repair protein. [114] As in any neoplastic system, individual
melanomas can skip steps in their development, appearing without identifiable intermediate
step lesions. It remains to be experimentally verified that melanoma cells can develop from a
precursor melanocyte, which seems to be present not only in murine but also in human skin.
Each stage progression is associated with specific biologic changes or transitions, as
demonstrated by experimental models and clinicopathological observations (Figure 5):
a) Transition 1 leads to nevus formation from committed melanocyte results from the
escape of the melanocyte from the regulatory control of keratinocytes, due to a
disruption of cell-cell crosstalk between melanocytes and keratinocytes. In the
absence of apparent chromosomal aberrations, nevi can develop not just through a
stimulatory event, but also through the loss of control of keratinocytes over
melanocytes.
b) Transition 2 would be responsible for irreversible changes leading to lesions of no-
to-low metastatic potential (dysplastic nevus or RGP melanoma), which does not
involve cell immortalization and increased telomerase activity. [115, 116] This
transition is defined by cytological and architectural atypia, no melanocyte apoptosis
away from the basement membrane zone, and demonstrable genetic aberrations.
Cells from RGP lesions have biologic properties in vitro that are intermediate
between benign and malignant, require several growth factors for proliferation, do
not grow anchorage independently in soft agar, and are nontumorigenic in mice. At
this time, a local immune response is observed, which could be critical for long-term
disease outcome. Specificity and nature of infiltrating lymphocytes in dysplastic nevi
or RGP melanoma have not yet been determined. Surgical excision of dysplastic nevi
and RGP melanomas leads to a cure for the disease. The histologic diagnosis of both
dysplastic nevi and RGP primary melanomas is still controversial because of a lack
of molecular markers. For example, in the diagnosis of 37 lesions by eight
pathologists, disagreements in diagnosis were noted in 40% of the cases [40].
c) Transition 3 determines to expand lesions with a tumorigenic/mitogenic activity that
invade deep into the dermis (VGP primary melanomas). These lesions show
increased blood vessel infiltration, a decreased host response, and approximately
35% of them have already disseminated at the time of surgical excision. Cultured
VGP melanoma cells grow independently of exogenous growth factors except IGF-1,
readily grow anchorage independently in soft agar, and all form tumors when
injected into immunodeficient mice. VGP primary melanomas are highly aneuploid,
which has hampered their cytogenetic and molecular genetic characterization.
Biologically, the cells are relatively plastic, and selective pressure over a few weeks
can render cells independent of all exogenous growth factors, [117] or they become
highly invasive. [118, 119] Some also acquire metastatic competence. Metastatic
cells also show a high level of phenotypic plasticity, depending on the environment
and any selective pressure placed on the cells.
Atypical Melanocytic Nevi
13
Their role as precursor lesions for melanoma is not their direct relationship to melanoma
because of the rarity of the transformation of any individual nevus to melanoma, [120]
questioning the linear progression (Figure 5). This progression becomes unlikely considering
the inefficient cellular kinetic and the lack of consistency in genetic abnormalities of cell
cycle regulators in the transition from low-grade lesions to high-grade dysplasia and RGP
melanomas (Figures 5-6). [61] Several studies have measured the DNA content of atypical
nevi, and many of them confirmed that it was normal. [121, 122] Others found it to be
increased compared to common nevi but with no aneuploidy, which was only detected in
MM. [123] The third group of investigators found aneuploid DNA content in AMN with
increasing percentage from moderate to severely dysplastic nevi. [124] Williams and
colleagues assessed DNA ploidy and nuclear morphometric features in AMN and suggested
that these characteristics overlapped with those of conventional nevi at one end and with
melanomas at the other. [125] Although there is still no single, universally agreed upon
histologic or clinical definition or even name for these nevi, dysplastic nevi should be
considered important because of their association with an increased risk for melanoma.
Figure 6. The alternative model proposes transformation from committed melanocyte precursors into
neoplastic melanocytic lesions that have progressed to a maximum level, but with unlikely interchange
between groups. In this context, progression from Class I or Class II lesions into Class III is not a
common event.
MOLECULAR SIGNATURE AND FUNCTIONAL SIGNIFICANCE
OF SPECIFIC GENE MUTATIONS DURING PROGRESSION
OF MELANOCYTIC LESIONS
Both AMN and melanomas are divisible into familial and sporadic subtypes. Our
understanding of the role of melanocytic precursor lesions in the genesis of melanoma has
been clarified over the past 30 years based on pioneering studies involving family clusters of
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
14
patients with melanoma, many of whom are observed to have nevi exhibiting atypical
features. [2, 81] In general, most tumor risk factors and true precancerous lesions (including
AMN) that are susceptible to screening programs are mainly associated with malignancies of
protracted natural history, which explains the unchanged incidence of high-grade neoplasms
in those organs. [48] In contrast, high-grade tumors normally develop de novo and show no
associated precancerous lesions, as expressed in thick melanomas that are frequently nodular
and mostly fast-growing tumors. Additionally, molecular genetic classification of
melanocytic lesions is currently being performed, often simultaneously with more traditional
histochemical and anatomic classification, during treatment. It is hoped that precise
knowledge of underlying genetics will lead to specific therapies suited to each patient. The
identification of inherited and somatic mutations involved in melanocytic lesions raises the
possibility of gene-based tests for cancer risk.
Figure 7. Molecular pathways implicated in the melanocyte neoplastic transformation. The key genetic
alterations are BRAF, NRAS, cell cycle regulatory mechanisms through cyclin-dependent kinase
inhibitors (CDKN, mainly CDKN2A and CDKN1B), and the complex CCND1 (cyclin D1) – CDK4.
along with Wnt (through b-catenin CCTNB1) and PTEN pathways. The regulation of RAS – MEK –
ERK signal transduction by NF1 and RTK is equally essential to maintain an appropriate BRAF
functional activity. Activating signals are presented by yellow arrows and the blocking signal by red
stop lines.
Although familial melanoma provides valuable insights into the disease, the number of
cases of familial AMN-melanoma is limited (10% of patients with melanoma). Among the
genetic loci, two proven tumor-suppressor proteins encoded by CDKN2A, p16, and p14 ARF
are involved in melanoma susceptibility (Figure 7). An enhanced incidence of melanoma is
associated with a single mutation in CDK4 as well as mutations in the CDKN2A and
CDKN2B genes. [126-130] There is a correlation between CDKN2A mutations in family
Atypical Melanocytic Nevi
15
members with atypical nevus syndromes. Clinical findings associated with this germ-line
mutation involve nevi in abnormal locations and odd numbers. These include nevi on the
buttocks, nevi on the feet, total nevi greater than 100, and two or more atypical nevi. [131]
Additional loci implicated as being inherited in a mutated form include PTEN, CDK4, and
CDK6, albeit in lower percentages (Figure 7). [5] Polymorphisms occurring in the
melanocyte-stimulating hormone receptor predict skin coloration, the risk of developing nevi,
and independently and synergistically with CDKN2A mutations, ultimately the development
of melanoma. The investigation of somatic alterations in primary lesions and cell lines has
permitted to focus the attention on defined regions in the genome. Somatic BRAF mutations
are implicated in approximately 60 percent of melanomas and nevi (both acquired and
congenital). One amino acid change in the BRAF protein (V600E) is by far the most
prominent genetic lesion and results in a constitutively active mitogen-activated protein
kinase (MAPK) pathway. Oncogenes such as those of the RAS gene family also have been
found to be mutated somatically, but their mutational spectrum differs from that observed in
other well-studied neoplasms. Several other loci, such as NOTCH, KIT, MITF, WNT5a, and
NEDD9, are also implicated in studies of progression. The main functional abnormalities in
AMN refer to genes involved in cell cycle regulation, β-catenin pathway, and PTEN
pathways (Figure 7) [61, 132, 133].
Cell-Cycle–Regulating Genes
The proliferation of melanocytes is tightly controlled in the late G1 phase of the cell
cycle through some checkpoint-modulating proteins. These include cyclins, [134] CDKs,
[135] CDK inhibitors, [130, 136] pocket proteins of the retinoblastoma (Rb) family, E2F
transcription factors, and other regulatory proteins (Figure 7). [137] A precise definition of
the restriction point in the cell cycle has enabled further characterization of each protein about
its effects on the cell cycle. This restriction point separates mitogenic signal-dependent pre–S
phase G1 cells from mitogenic signal-independent postmitotic G1 phase; growth factors such
as basic fibroblast growth factor (bFGF) and Insulin-like growth factor-1 (IGF-1) can
stimulate the cells to progress from the restriction point interface to the pre–S phase. Apart of
their ability to act as survival and maintenance factors, growth factors can stimulate the
expression of positive regulators such as cyclins and CDKs or suppress CDK inhibitors and
pocket proteins. Hemizygous deletions of CDK inhibitors (p16INK4a locus, missense and
intronic mutations) has been frequently reported in AMN (75%) with TP53 locus LOH in
60% (in particular for AMN-HGD, associated with missense mutations). [138] It has also
been demonstrated an increased incidence of TP53 mutations in dysplastic nevi in comparison
with conventional melanocytic nevi [139].
The cell cycle progression depends primarily from 1) an appropriate time expression of
cyclins, their kinases and inhibitory proteins around the RB1/TP53-regulated restriction point,
and 2) adequate response to external regulatory proteins through receptor tyrosine kinases
(RTK) (Figure 7). CDK4 behaves as a proto-oncogene; the mutant form is converted into an
overactive growth promotor, an oncogene. CDK4 only the second documented example of
germ-line melanoma mutations is a proto-oncogene (after RET proto-oncogene germline
mutations that predispose to the cancer-susceptibility syndrome multiple endocrine neoplasia
2A). [140] CDK4, p16, Rb, and D cyclins comprise part of a growth-control pathway that
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
16
operates in a variety of, and perhaps all, tissues. [132, 133] CDKN2A inhibits CDK4, which
has the consequence of preventing phosphorylation of Rb protein (Figure 7).
Hypophosphorylated Rb binds transcription factors such as members of the E2F family,
interfering with their ability to activate transcription of genes involved in DNA synthesis.
Sporadic tumors seldom contain mutations in more than one component of this pathway, an
observation that supports the mutually dependent function of the genes. [140-142] To date,
several known components of the pathway have been implicated in hereditary cancer
syndromes: CDK4, CDKN2A, and RB1. [140-142] Curiously, RB1 mutant gene carriers do
not suffer from excessive melanoma but rather from a particular childhood tumor of the eye,
retinoblastoma. [140-143] Why the phenotype of CDK4 and CDKN2A mutations differs from
the RB1 mutant phenotype is unclear, but it emphasizes the complexity of the growth-control
pathways that operate in cells. CDKN2A and CDK4 mutations are apparently mutually
exclusive (Figure 7).
RTKs (receptor tyrosine kinases such as EGFR and Xmrk) signaling pathway can, at least
experimentally, have profound impacts on melanocyte proliferation and survival and can
mediate survival through PI3-K activation of AKT, through the MAPK pathway, or by
activating a number of other proteins, including Stat5a and Stat3, both of which are
implicated in direct transcriptional regulation. [132, 133, 144-146] There is evidence that
active EGFR is necessary to confer the full oncogenic effects of mutant NRAS. [147] Other
RTKs that have been implicated include MET, ET (A)R, ET (B)R, and KIT. MET is expressed
on melanocytes, and its ligand is the so-called hepatocyte growth factor (HGF). HGF can
activate MET in a paracrine manner mediated by the MITF master transcriptional regulator.
[148, 149] Perhaps as important, CMET/HGF expression may be implicated in autocrine
expression patterning during progression. [150, 151] Experimentally, an elegant and powerful
series of mouse models have used HGF, which, in turn activates, CMET and such mice have
been shown to develop primary and metastatic melanomas after UV irradiation and/or
manipulation of the CDKN2A locus. The CKIT RTK has repeatedly been implicated in
melanocyte development, localization, and transformation. [132, 133] CKIT protein-coding
mutations have been discovered in a subset of melanoma patients, and such aberrant proteins
are implicated as an oncogenic signal leading toward melanoma. [152, 153] Although it also
has been proposed recently that such mutations may complement the more common BRAF
mutations, contributing to progression, [154, 155] activation of CKIT may also occur in the
absence of either NRAS or BRAF mutations. [152] Additionally, since CKIT and its ligand
SCF are developmentally implicated in the proper development, melanocyte motility, and
homing of melanocytes to the appropriate microenvironment [156, 157].
β-Catenin Pathway
β-Catenin is a multifunctional protein that is involved in cell-cell adhesion during tissue
morphogenesis and tumor growth, being its expression levels and subcellular localization
tightly regulated (Figure 7). [158, 159] In the absence of a Wnt signal or when not associated
with adherens junctions, β-catenin is present as a large multiprotein complex that consists of
glycogen synthase kinase 3β (GSK3β), adenomatous polyposis coli (APC), and axin.
Phosphorylation of this complex targets β-catenin for proteolytic degradation by the
ubiquitin-proteosome system. [160, 161] When the Wnt signaling pathway is activated via
Atypical Melanocytic Nevi
17
ligand binding to frizzled receptors, the GSK3β function is inhibited. β-Catenin then
accumulates, interacts with TCF/LEF-1 (T-cell factor/lymphoid enhancer factor-1)
transcription factors, and activates transcription of promoters of genes containing TCF/LEF-1
binding sites (Figure 7). [162] Posttranscriptionally, β-catenin’s fate is regulated by at least
two proteins that negatively control GSK3β: Akt/protein kinase B (PKB) and axin. Mutations
in the β-catenin gene would lead to an endogenous activation without degradation. [163]
Accumulating evidence suggests that Wnt/β-catenin signaling is subject to regulation by
cellular, temporal, and spatial contexts that make it difficult to generalize the end results of
pathway activation or inhibition. The context-specific nature of Wnt/β-catenin signaling may
preclude the development of universally applicable assays based on gene targets, but further
studies could identify context-specific readouts that could be used in melanocytic lesions to
validate the presence or absence of nuclear β-catenin and provide a robust indicator of
pathway activation in neoplasms [164].
Phosphatase and Tensin (PTEN) Homologue Deleted Pathway
PTEN has emerged as a major component in regulating survival of tumor cells through its
involvement in complex cascading pathways for growth and adhesion signaling (Figure 7).
Shc and Grb2 interactions are necessary for subsequent activation of the
RAS/RAF/MEK1/MAPK pathways, providing a central role for PTEN in controlling cellular
responses to growth factor– and integrin-mediated signaling. Both the growth factor and the
adhesion receptor (integrin) signaling pathways work in tandem, and signaling is initiated by
PI3 kinase, which acts as a relay station. [165] PI3 kinase activity is associated with the
transformation ability of oncoproteins and stimulation by growth factors. Akt/PKB binds to
phosphatidylinositol 3,4-diphosphate (PtdIns-3,4-P2), and phosphatidylinositol 3,4-
triphosphate (PtdIns-3,4,5-P3), and is then transported to the membrane where it activates PI3
kinase. PTEN dephosphorylates PtdIns phosphates, thereby depriving the PI3 kinase of its
substrate. Thus, a mutated PTEN can constitutively activate AKT/PKB to influence
downstream genes (Figure 7). Cells accumulate in the G1 phase of the cell cycle through up-
regulation of p27. However, it is unknown whether the phosphatase activity is involved in
this process and whether it is necessary for dephosphorylation of FAK leading to inhibition of
integrin-mediated signaling of cell spreading. It is not yet clear how the PTEN may signal to
regulate the RAS pathway [166, 167].
Genomic Approach
Careful molecular, genetic, and pathologic studies in patients with familial atypical mole-
melanoma syndrome may define the molecular basis of progression and identify markers for
adequate surveillance and primary disease prevention. [132, 144, 145] An integrative analysis
of cutaneous melanomas has recently established a framework for genomic classification into
four subtypes that can guide clinical decision-making for targeted therapies, [168]
corroborating previous similar results. [152] These genomic subtypes reveal a correlation
with classical subtypes, their potential association with precursor lesions, and the presence of
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
18
lymphocytic infiltrate and the stromal reaction. The primary genomic subtypes are named by
the key driver mutation: BRAF, RAS, NF1, and Triple-WT (wild-type). The multistep
tumorigenesis proposed for melanocytic lesions assumes an accumulation of genetic
alterations that would result in cellular expansion (BRAF mutation and MAPK pathway),
cytologic atypia (related with CDKN2A and PTEN pathways), and some level of decreased
differentiation (expressed by MIFT-regulated markers) for the level of high-grade dysplasia
(Figure 7). What is relevant is the accumulation of genetic alterations rather than their order,
which can be slightly different for epithelioid or lentiginous lesions. Biologically, these
lesions reveal both cell kinetics and topographic genetic heterogeneity, which are mainly
driven by abnormal TP53, dissociated from cyclin-dependent kinase inhibitors (p21WAF1-
CDKN1A and p27KIP1-CDKN1B), especially for high-grade dysplasia-MIS. [61] Classical
signaling pathway diagrams suggest that BRAF, RAS (N/H/K), and NF1 subtypes share
common downstream signaling (Figure 7). [132, 144, 145] Although CDKN2A/B alterations
are nearly evenly distributed across subtypes, CDK4 and CCND1 amplifications were more
frequent in Triple-WTs. RB1 mutations are detected in a higher fraction of NF1 subtype
tumors, all in UV signature samples. TP53 mutations cluster more frequently in BRAF, RAS,
and NF1 tumors and are mainly found in UV signature samples (93%). [168] PTEN mutations
and deletions are more frequent in BRAF-mutant melanomas than in the other subtypes,
whereas amplification and mRNA overexpression of AKT3 are significantly enriched in RAS
(N/H/K), NF1, and Triple-WT compared to the BRAF subtype. [168, 169] Not surprisingly,
components of the MAPK, PI (3)K, and apoptotic signaling pathways are differentially
activated by BRAF/ RAS (N/H/K)/NF1 driver mutations.
BRAF mutations, including V600E, are found in both congenital and acquired nevi that
can exist in the body for decades, remaining quiescent, [169, 170] perhaps representing a
primary event in the progression toward melanoma formation. Indeed, BRAF V600E
mutation can cause senescence in cells that are otherwise normal. However, as BRAF
mutations are found in a higher incidence of metastatic melanomas than in primary
melanomas, it may be indicative of disease progression. [171, 172] A high percentage of
BRAF somatic mutations (45 percent) has been reported in skin melanomas, although this rate
is lower than for nevi. This paradoxical situation has been the topic of considerable debate,
[173-176] but it is still very much unresolved.
The human RAS family of GTPases is encoded by four loci: HRAS, HRAS2 (also known
as ERAS), NRAS, and KRAS; NRAS is the most frequent mutated gene of this family; the
active (on)/inactive (off) forms of RAS is regulated by NF1 (Figure 7). NRAS mutations have
been documented in most congenital nevi, but they are rarely seen in dysplastic nevi,
suggesting that congenital nevi and dysplastic nevi may arise through activation of different
pathways in melanocytes. [177] Since NRAS activates the MAPK pathway and acts upstream
of BRAF, one would predict a mutually exclusive nature to mutations of these two genes.
[132, 133] NRAS can also be involved in signaling within the PI3K pathway (Figure 7)
leading to more potent oncogenic effects than mutant forms of BRAF, explaining the frequent
cosegregation of mutated NRAS with nodular melanomas. [152, 173, 174] Also, several
studies have indicated that within melanoma, NRAS and BRAF mutations may be mutually
exclusive events potentially indicating the sufficiency of NRAS and BRAF at activating the
same MAPK pathway. [173, 174] A high percentage (95%) of NRAS mutation rate has been
reported in a Swedish cohort of melanoma patients that have CDKN2A germline mutations.
[178] The same study found NRAS mutated in only 10 percent of sporadic melanomas.
Atypical Melanocytic Nevi
19
Furthermore, the authors discovered multiple activating NRAS mutations in tumor cells from
the same patient subset. Based on this suggestive study, [178] it may be possible that patients
with CDKN2A germline mutations may be predisposed to genomic instability and high
frequencies of NRAS mutations.
Melanocyte differentiation depends on genes such as tyrosinase, which confer
melanocytes with unique properties, are strictly regulated by MITF (MIcrophtalmia
Transcription Factor). MITF encodes a basic helix-loop-helix zipper transcription factor that
usually partners with other transcription factors; it is produced in several isoforms (MITF-M
isoform predominates in melanocytes), enabling the use of this transcript as a prognostic
marker. [179] MITF plays a profound role in the commitment and homeostasis of
melanocytes and their precursor cells, and the role of this locus in neural crest-derived cells
would greatly serve the understanding of melanocyte biology. [179] MITF is truly a master
regulator of melanocytes in that it not only turns on genes essential for the synthesis of
melanins but also regulates genes involved in cell-cycle regulation such as CDKN2A and
CDKN1A. [179, 180] It also transcriptionally regulates BCL2, which confers antiapoptotic
properties to cells, and activates CKIT expression. [149] Since MITF and its various
transcriptional binding partners are implicated in lineage commitment, differentiation, and the
inhibition of apoptosis, it is a very complex but important locus to understand. “MITF-low”
cluster samples had a higher percentage of BRAF-hotspot mutations (compared with “keratin”
and “immune” clusters. Also, a lower percentage of tumor samples that were classified as
“MITF-low” had no mutations in either BRAF, NRAS, and NF1 compared with “keratin” and
“immune” cluster. [168] Melanocyte differentiation and proliferation is also regulated by
epigenetic changes involving promoter methylation. A progressive epigenetic deregulation
has been reported during the progression of melanocytic lesions, AMN being affected by
promoter methylation of genes that are frequently methylated in melanoma but not in
common nevi. [181] In particular, CLDN11 promoter methylation was specific for melanoma,
as it occurred in 50% of primary melanomas but in only 3% of dysplastic nevi. A diagnostic
algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13 and
GNMT genes helps distinguish melanoma from the dysplastic nevus. [181] Hypomethylation
is also related with the MITF expression class, while the CIMP subtype reveals an apparent
association with the keratin expression subtype and miRNA subgroup; this cluster has a
relatively lower frequency of hot-spot BRAF mutations [168].
As predicted by copy-number analysis, Triple-WT tumors show the highest median KIT
protein abundance, in which MDM2 amplifications were more frequent. A low-copy-number
subgroup shows a normal-like methylation profile, and enrichment for tumors possessing the
immune mRNA expression signature, consistent with the presence of lymphocytic
infiltration.
Both the presence and subtype of dysplastic changes correlate with the genomic
subgroup, which depends on different levels of sun exposure (chronic sun-induced damage or
not), and location of the lesion (chronically exposed, such as head and neck, intermittently
exposed, like chest and back, and non-exposed areas, including acral skin and mucosae).
[152] Melanocytic lesions on skin without chronic sun-induced damage had mutations in
BRAF or NRAS, in contrast to mucosal and acral melanocytic lesions that reveal wild-type
BRAF/NRAS and increased number of copies of CDK4 and CCND1 (cyclin D1), both
downstream genes of the same pathway. CDKN2A, CDK4, and CCND1 function in a unique
pathway that affects the cell cycle; a mutation of CDKN2A has similar consequences as a
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
20
mutation of CCND1 or CDK4. [132, 144, 145] The default appearance during melanocytic
neoplastic transformation and progression is the epithelioid morphology, which results from
the common BRAF/NRAS mutations. The MEK pathway can be activated by a mutation in
either NRAS or BRAF, and an NRAS mutation can activate both the MEK and PTEN
pathways, segregating with nodular lesions without intraepithelial component most frequently
(dermal proliferative nodules in congenital nevi and nodular melanomas). Acral and mucosal
melanocytic lesions show predominantly lentiginous pattern, reveal a field change,
hyperchromatic spindle-shaped cellularity, and more frequently CCND1 or RTK such as KIT
or PDGFA [152-155].
PRACTICAL ASPECTS OF AMN/MELANOCYTIC DYSPLASIA
Melanocytic dysplastic lesions that share histologic criteria of both benign nevi and
melanomas fit in the gray zone of so-called “borderline” lesions that, as a rule, will defy
uniformity of diagnostic interpretation among experienced observers. That fact can easily be
illustrated with their independent examination by multiple observers; “blinded” interobserver
exercises of this nature will usually evoke a distressing divergence of interpretation as shown
by the grading of dysplasia. [38] A sensible differential diagnosis requires using strictly
standardized criteria and terminology for melanocytic lesions.
Table 1. Differential Diagnosis of Dysplastic Melanocytic Nevi
• Subtypes of acquired melanocytic nevus
o Halo melanocytic nevus
o Traumatized melanocytic nevus
o Melanocytic nevus from particular anatomic sites (acral, genital, flexural sites, scalp
region)
• Superficial atypical melanocytic proliferation of uncertain significance
• Congenital melanocytic nevus
o Dermal proliferative nodules
• Spitz tumor
o Atypical or ambiguous variants
• Blue nevus
o Atypical blue nevus or uncertain malignant potential
o Pigmented epithelioid melanocytoma
• Combined melanocytic nevus with phenotypic heterogeneity
o Deep penetrating nevus
o Combined nevus with spitzoid component
• Melanocytic tumor of uncertain malignant potential
From a practical standpoint, it would be advisable to acknowledge the complexity of this
problem, which leads to diagnostic and biologic uncertainty of a lesion; this aspect must be
incorporated through the use of terminology such as melanocytic neoplasm with
indeterminate biologic potential (or melanocytic tumor with uncertain malignant potential). In
this context, incisional, shave, or trephine biopsy has no place in the management of
dysplastic nevus. Because of the striking variations in cellular atypia in a given dysplastic
Atypical Melanocytic Nevi
21
nevus, it is recommended excisional biopsies for a complete evaluation. In any dysplastic
nevus, high-grade dysplasia may coexist side by side with a slightly-to-moderately atypical
lentiginous compound melanocytic nevus. An incisional biopsy of the clinically atypical
could miss the malignant melanoma and lead to a false reassurance of the patient and
physician.
The lesions to consider in the differential diagnosis of AMN and melanocytic dysplasia
appear in Table 1; only the general approach will be discussed below. General criteria for the
diagnosis of melanocytic lesions must first reliably differentiate benign from malignant
conditions, for which the most reliable predictive findings are symmetry and deep maturation.
Melanocytic lesions demonstrating both findings should be confidently classified as benign,
leaving the borderline category for those that deviate from this standard. The next step in the
assessment process has to consider some factors that will determine the baseline histologic
phenotype of melanocytic lesions, including age and programmed natural history; regional
microanatomy; genetic factors; physiologic, hormonal, and immunologic factors;
environmental factors such as sun exposure, trauma, and other insults. These factors can
explain the appearances in many cases deviating from the conventional benign or malignant
phenotype; both junctional and dermal components need careful evaluation. The junctional
component findings often requiring attention include: the pattern distribution (nested,
pagetoid, and lentiginous), size of junctional nests of melanocytes, irregularity of junctional
nesting with horizontal bridging or confluence of nests, hypercellular (crowded) junctional
nesting, large round or polygonal melanocytes in the junctional component, anisokaryosis of
melanocytes, and papillary dermal fibroplasia. [12, 60] These histological findings assess the
superficial cellular expansion and are essential features for the subcategorization of
superficial atypical melanocytic proliferations. The main diagnostic dilemma of the dermal
component is the presence of proliferative nodules mostly in congenital nevi; useful findings
in this context include a superficial location (the few melanomas that arise in congenital nevi
during infancy are generally deeply located, sarcoma-like, massively cellular tumors),
multiplicity (melanoma arising multiply is vanishingly rare), gradual transition/merging of the
atypical cells in the proliferative nodule with those of the surrounding nevus (rather than 2
distinct cell types in melanoma arising in congenital nevi), absence of an epidermal
component with pagetoid spread, absence of high-grade nuclear atypia and, mostly, necrosis.
[182, 183] The size of the lesion, deep dermal or subcutaneous extension and mitogenic or
dermal nodular pattern are features of diagnostically borderline lesions that biologically can
represent intermediate states during the neoplastic transformation or low-grade malignancies
(melanocytic tumors of uncertain malignant potential). Other characteristics including age of
the patient, ulceration, cytologic atypia, and ancillary studies such as assessment of mitotic
index, other biologic markers, and analysis of chromosomal aberrations may aid in this
evaluation.
Excised low-grade dysplastic nevi have been adequately treated when there is no clinical
evidence of residual nevi. It is not recommended re-excision for AMN-LGD when the
primary excision of the nevus has been multiply sectioned, and moderate atypia is the most
atypical grade. Concerning AMN-HGD, as long as the margins are less than 0.5 cm from the
actual atypical melanocytic proliferation in the original biopsy or excision specimen, a re-
excision with a 0.5 cm to 1.0 cm margin would be recommended. The margin excision would
depend on whether or not there is clinical evidence of residual nevus and whether or not the
lesions are present at the margin. [184] These recommendations presuppose the worst
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
22
scenario that dysplastic nevi do progress to malignant melanoma and that severely atypical
lesion should be treated in fact as if there is focal in situ malignant change. At a minimum,
complete resection of the primary lesion to achieve histologically clear margins is an obvious
management choice in the interest of patient safety, given the uncertainty of diagnosis;
whether the arbitrarily wide margins that have come to be customary for melanomas of
classical histologic phenotypes should be applied to them is a matter of differing perspective,
with no uniformity of opinion. In the instances of diagnostically indeterminate lesions that
ultimately prove by their natural histories to be malignant, there is no reason to presume that
patients’ chances of survival have been compromised by the application of narrower surgical
margins than are customary for melanomas of the common varieties. The only exception
would be the presence of local recurrences at the treatment sites have not occurred before
more distant metastases.
CONCLUSION AND CHECK LIST
Atypical (dysplastic) melanocytic nevi represent a risk marker for the development of
malignant melanoma, and it has been linked mainly to radial growth phase lesions. The
evaluation of these lesions must focus on:
• Strict clinical and histological criteria to fulfill.
• Pathologically, architectural changes, host response, and cytological abnormalities
are needed to define the lesion as truly dysplastic.
• Clinical, dermatoscopic and pathological correlations are reliable for high-grade
dysplastic lesions, which require more careful attention and management as
intraepithelial malignancies.
• Two subtypes of dysplastic patterns, lentiginous and epithelioid, are defined; these
patterns reflect a field change for the former and more localized process for the latter.
Chronic sun-induced damage and differential molecular pathways play a role in its
evolution.
• Grading is a paradigm and must identify the high-grade lesions, which are
characterized by a mixed junctional pattern with confluent lentiginous component,
suprabasal atypical melanocytes, high nuclear grade (at least three atypical features),
and host response.
• Although the linear progression can be observed in a minority of lesions, progression
in melanocytic is more likely to be direct from committed melanocyte precursors into
neoplastic lesions.
• Molecular signature and functional genetic abnormalities are emerging:
o Melanocytic lesions on skin without chronic sun-induced damage had mutations
in BRAF or NRAS, in contrast to mucosal and acral melanocytic lesions that
reveal wild-type BRAF/NRAS and increased number of copies of CDK4 and
CCND1 (cyclin D1), both downstream genes of the same pathway.
o The default appearance of melanocytic neoplastic transformation and
progression is the epithelioid morphology, which results from the common
BRAF/NRAS mutations.
Atypical Melanocytic Nevi
23
o The MEK pathway can be activated by a mutation in either NRAS or BRAF, and
an NRAS mutation can activate both the MEK and PTEN pathways, segregating
with nodular lesions without intraepithelial component most frequently (dermal
proliferative nodules in congenital nevi and nodular melanomas).
o Acral and mucosal melanocytic lesions show a predominantly lentiginous
pattern, reveal a field change, hyperchromatic spindle-shaped cellularity, and
more frequently CCND1 or RTK such as KIT or PDGFA.
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[151] Bastian BC, Kashani-Sabet M, Hamm H, Godfrey T, Moore DH, 2nd, Brocker EB, et
al. Gene amplifications characterize acral melanoma and permit the detection of occult
tumor cells in the surrounding skin. Cancer Res. 2000;60 (7):1968-73.
[152] Bastian BC, LeBoit PE, Hamm H, Brocker EB, Pinkel D. Chromosomal gains and
losses in primary cutaneous melanomas detected by comparative genomic
hybridization. Cancer Res. 1998;58 (10):2170-5.
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
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[153] Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct
sets of genetic alterations in melanoma. N Engl J Med. 2005;353 (20):2135-47.
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number in mutation-positive malignant melanoma. Hum Pathol. 2006;37 (5):520-7.
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detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting
analysis. Hum Pathol. 2005;36 (5):486-93.
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distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest
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[159] Arias AM, Brown AM, Brennan K. Wnt signalling: pathway or network? Curr Opin
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Top Dev Biol. 1999;43:153-90.
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other signals. Curr Opin Cell Biol. 1999;11 (2):233-40.
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tumorigenesis. Eur J Biochem. 1999;263 (3):605-11.
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formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad
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phosphatase. Trends Cell Biol. 1999;9 (4):125-8.
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2015;161 (7):1681-96.
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frequency of BRAF mutations in nevi. Nat Genet. 2003;33 (1):19-20.
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V599E mutation in growing melanocytic lesions. J Invest Dermatol. 2004;123 (4):733-
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Atypical Melanocytic Nevi
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mutations correlate with progression rather than initiation of human melanoma. Cancer
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CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an
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[183] Gonzalez-Campora R, Galera-Davidson H, Vazquez-Ramirez FJ, Diaz-Cano S. Blue
nevus: classical types and new related entities. A differential diagnostic review. Pathol
Res Pract. 1994;190 (6):627-35.
[184] Pozo L, Diaz-Cano SJ. Malignant deep sclerosing blue naevus presenting as a
subcutaneous soft tissue mass. Br J Dermatol. 2004;151 (2):508-11.
[185] Day CL, Jr., Mihm MC, Jr., Sober AJ, Fitzpatrick TB, Malt RA. Narrower margins for
clinical stage I malignant melanoma. N Engl J Med. 1982;306 (8):479-82.
BIOGRAPHICAL SKETCH
Lewisham and Greenwich NHS Trust
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
34
Dermatology
United Kingdom lpozo@doctors.org.uk
Lucia Pozo-Garcia, LMS, PhD
https://www.researchgate.net/profile/Lucia_Pozo-Garcia
Education
Sep 1999 – Jul 2015 Homerton University Hospital NHS Foundation Trust,
Dermatology, London, United Kingdom
Apr 1995 – Jul 1995 Hospital Infantil Universitario Niño Jesús, Madrid, Spain,
Fellowship on Paediatric Dermatology, Madrid, Spain
Sep 1993 – Jul 1996 Universidad de Sevilla, PhD, Eccrine Tumours, Sevilla, Spain
Jan 1992 – Dec 1995 Hospital Universitario Virgen Macarena, Sevilla, Spain, Board
Certification on Dermatology and Venereology , Certificate of Completion of Specialist
Training (CCST) in Dermatology (2005), Dermatology Training, Sevilla, Spain
Sep 1984 – Jun 1990 Universidad de Cádiz, LMS, Medicine, Cadiz, Spain
Research Experience
Sep 1999 – Jul 2015 Consultant Dermatologist, Homerton University Hospital NHS
Foundation Trust, Dermatology, London, United Kingdom
Sep 1999 – Jul 2015 Consultant Dermatologist, Homerton University Hospital NHS
Foundation Trust, Dermatology, London, United Kingdom
Statistics
RG Score 28
Publications 28
Total Impact Points 112.07
Reads 995
Citations 116
Awards and Grants
Skills and Activities
Skills Clinical Dermatology, Dermatology, Dermatopathology, Skin Care, p53,
Dermoscopy, Skin Cancer, Melanins, Apoptosis, Discriminant Analysis, Psoriasis,
Regression, Melanoma
Languages Spanish and English
Atypical Melanocytic Nevi
35
Scientific Memberships British Association of Dermatologists Royal Society of Medicine
International Dermoscopy Society UK Melanoma Focus Group Spanish Academy of
Dermatology (AEDV)
Interests
Journal Publications
Lucia Pozo-Garcia: Dermoscopy. Practical tips: Assessing lesions and learning aids.
S. Girgis, E. Ali, L. Cheng, G. Gillan, R. Qureshi, A. Qureshi, L. Pozo-Garcia, R. Agrawal:
An unusual case of severe pemphigus vulgaris in a Jamaican lady. International Journal
of Oral and Maxillofacial Surgery 10/2015; 44:e197. DOI:10.1016/j.ijom.2015.08.047
Sheena Ramyead, Salvador J. Diaz-Cano, Lucia Pozo-Garcia: Dermoscopy of clonal
seborrheic keratosis. Journal of the American Academy of Dermatology 08/2015; 73
(2):e47-49. DOI:10.1016/j.jaad.2015.04.013
A Blanes, L Pozo, SJ Diaz-Cano: Morphogenesis and Fibrogenesis Pathways for the
Distinction of Slerosing Melanocytic Nevus and Desmoplastic Malignant Melanoma.
Modern Pathology 02/2013; 26 (S2):111. DOI:10.1038/modpathol.2013.6
S. Siddiqui, T. Ashfiled, E. Ali, L. Pozo-Garcia, L. Cheng: Patient satisfaction after facial
skin cancer resection and reconstruction—a local survey. International Journal of Oral
and Maxillofacial Surgery 10/2011; 40 (10):1038. DOI:10.1016/j.ijom.2011.07.050
Ehab A Husain, Charles Mein, Lucia Pozo, Alfredo Blanes, Salvador J Diaz-Cano:
Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in
atypical (dysplastic) melanocytic nevi. Modern Pathology 02/2011; 24 (4):471-86.
DOI:10.1038/modpathol.2010.143
Lucia Pozo, Jonathan Bowling, Conal M Perrett, Richard Bull, Salvador J Diaz-Cano:
Dermoscopy of trichostasis spinulosa. Archives of dermatology 09/2008; 144 (8):1088.
DOI:10.1001/archderm.144.8.1088
L Pozo, S J Diaz-Cano: Trichilemmal carcinoma with neuroendocrine differentiation. Clinical
and Experimental Dermatology 04/2008; 33 (2):128-31. DOI:10.1111/j.1365-
2230.2007.02570.x
L Pozo, E Husein, A Blanes, S J Diaz-Cano: The correlation of regression with the grade of
dysplasia (atypia) in melanocytic naevi. Histopathology 03/2008; 52 (3):387-9.
DOI:10.1111/j.1365-2559.2007.02880.x
L Pozo, J J Sanchez-Carrillo, A Martinez, A Blanes, S J Diaz-Cano: Differential kinetic
features by tumor topography in cutaneous small cell neuroendocrine (Merkel cell)
carcinomas. Journal of the European Academy of Dermatology and Venereology
10/2007; 21 (9):1220-8. DOI:10.1111/j.1468-3083.2007.02236.x
Z Aly, L Pozo, S J Diaz-Cano: Colonization of epithelial pilar neoplasms by melanocytes.
Histopathology 02/2006; 48 (2):213-7. DOI:10.1111/j.1365-2559.2005.02213.x
Husain E, Pozo L, Blanes A, SJ Diaz-Cano: Deep VEGF up-regulation in atypical
melanocytic lesions: Differential correlation with apoptosis in Spitz tumors and atypical
melanocytic nevi. Modern Pathology 01/2006; 19 (3s):42.
DOI:10.6084/m9.figshare.100516
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
36
E Husain, L Pozo, A Blanes, SJ Diaz-Cano: Deep dermal up-regulation of HIF-1A is directly
correlated with apoptosis in Spitz tumors. Modern Pathology 01/2006; 19 (3s):42.
DOI:10.6084/m9.figshare.100506
L. Pozo-Garcia, E. Husain, A. Blanes, S.J. Diaz-Cano: Spitz tumours reveal distinctive
kinetics, VEGF-C and microvessel profiles by topographic compartments. British Journal
of Dermatology 01/2006; 155 (Suppl. 1):81.
L. Pozo-Garcia, A. Blanes, S.J. Diaz-Cano: Deep apoptosis down-regulation is the kinetic
hallmark of cutaneous Merkel cell carcinomas. British Journal of Dermatology 01/2006;
155 (Suppl. 1):80.
L Pozo, S J Diaz-Cano: Trichogerminoma: further evidence to support a specific follicular
neoplasm. Histopathology 02/2005; 46 (1):108-10. DOI:10.1111/j.1365-
2559.2005.01955.x
L Pozo, S.J. Diaz-Cano: Malignant deep sclerosing blue naevus presenting as a subcutaneous
soft tissue mass. British Journal of Dermatology 09/2004; 151 (2):508-11.
DOI:10.1111/j.1365-2133.2004.06114.x
Lucia Pozo-Garcia, Salvador J Diaz-Cano: Clonal origin and expansions in neoplasms:
Biologic and technical aspects must be considered together. American Journal Of
Pathology 02/2003; 162 (1):353-4; author reply 354-5. DOI:10.1016/S0002-9440
(10)63826-6
Lucia Pozo, Enrique Jorquera, Salvador J Diaz-Cano: Multilobated abdominal nodule.
Archives of Dermatology 12/2002; 138 (11):1509-14.
L. Pozo, E. Jorquera, S. J. Diaz-Cano: Multilobated abdominal nodule. Archives of
Dermatology 11/2002; 138 (11):1509-14.
E Husain, M de Miguel, A Blanes, R Cerio, L Pozo, SJ Diaz-Cano: Regressive Features
Define Spitz Tumors as Characterised by
Cell Kinetics, Cell Cycle Regulators, and Microvessel Density. The Journal of Pathology
01/2002; 198:56A. DOI:10.6084/m9.figshare.99888
Z Aly, R Cerio, L Pozo, S J Diaz-Cano: Melanocytes in epithelial nests: a diagnostic clue for
trichoepitheliomas-trichoblastomas. The Journal of Pathology 01/2002; 198:57A.
E Husain, M de Miguel, A Blanes, R Cerio, L Pozo, S J Diaz-Cano: ARE THE
INTRAEPIDERMAL HIGH-GRADE MELANOCYTIC LESIONS THE DIRECT
PRECURSORS OF INVASIVE MALIGNANT MELANOMAS?. The Journal of
Pathology 01/2002; 198:14A.
L Pozo, PhD Mahmoud Naase, R Cerio, A Blanes, S J Diaz-Cano: Critical Analysis of
Histologic Criteria for Grading Atypical (Dysplastic) Melanocytic Nevi. American
Journal of Clinical Pathology 03/2001; 115 (2):194-204. DOI:10.1309/KXJW-1UJE-
BPG6-AXBV
Lucia Pozo, Mahmoud Naase, Rino Cerio, Alfredo Blanes, Salvador J Diaz-Cano: Critical
Analysis of Histologic Criteria for Grading Atypical (Dysplastic) Melanocytic Nevi.
American Journal of Clinical Pathology 01/2001; 115:194-204.
Lucia Pozo, Francisco Camacho, Juan J. Rios-Martin, Salvador J. Diaz-Cano: Cell
proliferation in skin tumors with ductal differentiation: Patterns and diagnostic
applications. Journal of Cutaneous Pathology 08/2000; 27 (6):292-7.
DOI:10.1034/j.1600-0560.2000.027006292.x
L Pozo, S J Diaz-Cano: Tumor Screening and Biology in Malignant Melanomas. Archives of
Dermatology 08/2000; 136 (7):934-5. DOI:10.1001/archderm.136.7.934
Atypical Melanocytic Nevi
37
R Hergueta Lendínez, L Pozo García, A Alejo García, J Romero Cachza, J González
Hachero: Gianotti–Crosti syndrome due to a mixed infection produced by the mumps
virus and the parainfluenza virus type 2. Anales espanoles de pediatria 02/1996; 44
(1):65-6.
BIOGRAPHICAL SKETCH
King’s College London
Division of Cancer Studies
King’s College Hospital, Denmark Hill
London, [state] SE5 9RS
United Kingdom
sjdiazcano@me.com
Phone: 44 20 32993041
Mobile: [mobile]
Fax: 44 20 32993670
Website: http://scholar.google.co.uk/citations?user=b632u8sAAAAJ&hl=en
Salvador J Diaz-Cano, LMS, MD, PhD, FRCPath
https://www.researchgate.net/profile/Salvador_Diaz-Cano
Education
Jun 1994 – Jun 1997 Tufts Medical Center, Felowship in Anatomic Molecular Pathology,
Anatomic and Molecular Pathology, Boston, US
Jun 1994 – Jun 1998 Royal College of Pathologist, London, United Kingdom, Fellow of
the Royal College of Pathologist (FRCPath), Cytopathology and Histopathology, London,
England, United Kingdom
Jan 1990 – Dec 1993 Universidad de Sevilla, Specialist in Anatomic Pathology,
Anatomic Pathology, Sevilla, Spain
Jan 1988 – Dec 1989 Department of Science, Spain, MSc in Experimental Pathology,
Experimental Pathology, Malaga, Spain
Sep 1987 – Dec 1992 Universidad de Málaga, Ph.D., Oncologic Pathology, Malaga, Spain
Sep 1986 – Sep 1987 University of Malaga, M.D., Medicine and Surgery, Málaga, Spain
Sep 1981 – Jun 1987 Universidad de Málaga, LMS, School of Medicine, Malaga, Spain
Thesis
Salvador J Diaz-Cano: [Prognostic evaluation of muscle-invasive transitional cell
carcinomas of the urinary bladder. Histopathological, morphometric and DNA cytometric
analyses] [Spanish]. 04/1993, Degree: Ph.D. Oncopathology, Supervisor: Alfredo Matilla
Vicente, Alfred Blanes Berenguel.
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
38
Research Experience
Jan 2006 – present Molecular and kinetic evolution during the neoplastic
transformation. Analysis of topographic tumor heterogeneity with especial relevance to
functional genomics and DNA and gene expression profile of endocrine and skin neoplasms
King’s College London, Histopathology
London, United Kingdom
Jan 2006 – Dec 2012
King’s College Hospital London, Department of Dermatology
London, United Kingdom
Jun 2004 – present Consultant Physician Pathologist
King’s College Hospital NHS Foundation Trust, Endocrinology
London, United Kingdom
Jun 2004 – present Reader in Cellular and Molecular Pathology
King’s Health Partners, Pathology
London, United Kingdom
Jun 2004 – present Consultant Physician Pathologist
King’s College Hospital NHS Foundation Trust, Department of Pathology
London, United Kingdom
Jun 2004 – present Reader in Cellular and Molecular Pathology / Consultant Physician
Pathologist
King’s College London, Division of Cancer Studies
London, United Kingdom
Dec 2002 – present Professor (Full) of Anatomic and Molecular Pathology (non-active
post)
University of Malaga, Department of Histology and Pathological Anatomy
Málaga, Spain
Jan 2002 – Dec 2009 Visiting Professor
Universidad de Málaga, Department of Histology and Pathological Anatomy
Málaga, Spain
Jan 2001 – present Sequential Analysis of Gene Expression (SAGE)/Microaarray
studies in neoplasms
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London,
Jan 2000 – Dec 2006 Topographic analysis of cell kinetics, telomerase, E-cadherin and
angiogenesis in non-malignant atypical melanocytic proliferations of human cutaneous tissue
Queen Mary, University of London, The Blizard Institute of Cell and Molecular Science
London, United Kingdom
Supported by scholarship by Egyptian Government
Jun 1998 – present
National Health Service, Clinical Pathology Department
London, United Kingdom
Jun 1998 – May 2004 Reader In Cellular and Molecular Pathology
Barts and The London School of Medicine and Dentistry, The Blizard Institute of Cell
and Molecular Science
London, United Kingdom
Atypical Melanocytic Nevi
39
Jan 1996 – present Evaluation of tumor heterogeneity. Genetic and kinetic patterns by
tumor topographic compartments
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London.,
Jan 1996 – present Clonality and cell kinetics in the neoplastic progression
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London.,
Jan 1996 – present Contributions of microdissection to the analysis of tumor genetic
heterogeneity
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London,
Jan 1996 – present Relationship between microsatellite patterns and cell kinetics during
the neoplastic transformation and progression
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London.,
Jan 1996 – present Functional genomics and molecular profiles in tumors. Applications
to improve histological classification of neoplasms
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London,
Jan 1996 – present Anatomic Pathology (Histopathology and Cytopathology) with
especial interest in endocrine, skin, and bladder
New England Medical Center - Tufts University, GSF-Forschungszentrum, Queen Mary -
University of London, King’s College London School of Medicine - University of London,
Aug 1994 – Aug 1997
Tufts University, Department of Pathology
Boston, MA, USA
Aug 1994 – Aug 1997
Tufts Medical Center,
Boston, MA, USA
Jun 1994 – Jun 1997 Molecular Methods for Genotypic Detection of Malignant Cells in
Human Tissues
New England Medical Center - Tufts University., Dept of Pathology
Boston, MA, USA
Postdoctoral Research Grant, Spanish Department of Education and Science
Jan 1990 – Dec 1993 Resident in Anatomic Pathology
Hospital Universitario Virgen Macarena, Pathology
Sevilla, Spain
Statistics
RG Score 43.69
Publications 240
Total Impact Points 1086.78
Reads 8,671
Citations 1918
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
40
Awards and Grants
May 2014 Award: Honorary Member of the Alumni Association of the University of
Malaga
Jun 2013 Grant: Co-investigator of "Significance of PI3K/Akt/mTOR and
RAF/MEK/ERK signaling pathways analysed jointly with steroidogenesis in adrenocortical
cancer.” Cofinanced by Foundation for Polish Science, within ‘Brigde’ programme
(POMOST/2012-5/3) and European Union.
Jan 2002 Grant: Grant for the Consolidation of Research Teams. European Funds for
Regional Development, European Union
Jan 2000 Scholarship: Topographic analysis of cell kinetics, telomerase, E-cadherin
and angiogenesis in non-malignant atypical melanocytic proliferations of human cutaneous
tissue. Financed by Egyptian Government
Jun 1994 Grant: Spanish Department of Health - Molecular methods for genotypic
detection of malignant cells in human tissues
Jan 1994 Grant: Research Grant for the Programme of Personnel Formation and
Improvement and International Cooperation in Health Research and Development, 1994.
Spanish Department of Health. Title: “Molecular Methods for Genotypic Detection of
Malignant Cells in Human Tissues.”
Jun 1993 Award: Honours Degree, Ph.D. Degree
Jan 1993 Grant: Research Grant, Fondo de Investigaciones Sanitarias FIS 93/0569.
Spanish Department of Health - “Histologic grading of prostatic carcinomas by image
analysis.”
Jan 1991 Grant: Research Grant, Fondo de Investigaciones Sanitarias FIS 91/0605.
Spanish Department of Health. Title: “Application of image DNA cytometry in the
elaboration of prognostic indices for breast cancer“
Jan 1988 Grant: Predoctoral Grant for Professorship and Research Personnel Training.
Spanish Department of Education and Science. Title: “Establishment of Prognostic Indices in
Colorectal Carcinomas. Pathologic, Immunohistochemical, and Cytometric Studies in Human
and Wistar Rat Tissues.”
Jan 1988 Award: Honours Degree, LMS, M.D. Degree.
Skills and Activities
Skills Histopathology, Molecular Pathology, Immunohistochemistry, Anatomic
Pathology, Surgical Pathology, Cell Culture, Contributions of microdissection to the analysis
of tumor genetic heterogeneity, Clonality and cell kinetics in the neoplastic progression,
Evaluation of tumor heterogeneity; Genetic and kinetic patterns by tumor topographic
compartments, Relationship between microsatellite patterns and cell kinetics during the
neoplastic transformation and progression, Molecular methods for genotypic detection of
malignant cells in human tissues, Application of image DNA cytometry in the elaboration of
prognostic indices, Sequential Analysis of Gene Expression (SAGE)/Microaarray studies in
neoplasms, Functional Genomics, Next Generation Sequencing,
Pathologic/immunohistochemical/cytometric studies in human and Wistar rat tissues,
Prognostic indices in neoplasms, DNA, Histology, Gel Electrophoresis, PCR, Genetics,
Atypical Melanocytic Nevi
41
Electrophoresis, Cancer Biology, Adrenal Medulla, Molecular Biology, Cellular Biology,
Angiogenesis, Clonality, Bladder Cancer, Dermatopathology, Melanocytes, Cell Cycle,
Infection Biology, Virus, Granuloma, Endocrine System, Medullary Neoplasms,
Inflammation, Kinetics, Autoimmune Disorders, Pathology, Histopathological Techniques,
Endocrine Glands, Parathyroid Diseases, Cell Cycle Analysis, Flow Cytometry, Analytical
Techniques, Growth Kinetics, Genetic Disease, Cytokines, Adrenal Cortex Diseases,
Molecular Techniques, Molecular Biological Techniques, Oncology, Microscopy, Medical
Oncology, Endocrine, Dermatology, Anatomical Pathological Conditions, Cell Signaling,
Tumor Biology, Metastasis, Tumor Angiogenesis, Cell Cycle Regulation, Prognostic
Markers, Tumor Genetics, Cancer Biomarkers, Molecular Carcinogenesis, Molecular Cell
Biology, Gene Expression, Apoptosis, Tumor Microenvironment, Tumor Markers, Cancer
Cell Signaling, Cancer Diagnostics, Cancer Cell Biology, Medical Education, Pattern
Recognition, Diagnosis, Risk Assessment, Clinical Endocrinology, Infectious Diseases,
Endocrine System Diseases, Thyroid Gland, Clinical Pathology, Radiology, Genetic
Engineering, Imaging, Telomere, Electron Microscopy, Cell Biology, High Throughput
Sequencing, Molecular Cloning, Epigenetics, Tumors, Cloning, Anatomy, DNA Extraction,
Melanoma, Lymph Nodes, Cancer Research, Mutation
Languages English, English (fluent writing-reading-peaking), German (basic writing-
reding-speaking), Spanish; Castilian, Spanish (fluent writing-reading-speaking)
Scientific Memberships American Association for the Advancement of Science
American Society for Investigative Pathology Association for Molecular Pathology
Association of Clinical Pathologists UK European Society of Pathology International
Academy of Pathology Pathological Society of Great Britain and Ireland Royal College of
Pathologists United States and Canadian Academy of Pathology.
Publication Highlights
Salvador J Diaz-Cano: Tumor Heterogeneity: Mechanisms and Bases for a Reliable
Application of Molecular Marker Design. International Journal of Molecular Sciences
12/2012; 13 (2):1951-2011. DOI:10.3390/ijms13021951
Salvador J. Díaz-Cano, Manuel de Miguel, Alfredo Blanes, Robert Tashjian, Hugo Galera,
Hubert J. Wolfe: Clonality as Expression of Distinctive Cell Kinetics Patterns in Nodular
Hyperplasias and Adenomas of the Adrenal Cortex. American Journal Of Pathology
02/2000; 156 (1):311-9. DOI:10.1016/S0002-9440 (10)64732-3
S J Diaz-Cano: General morphological and biological features of neoplasms: Integration of
molecular findings. Histopathology 08/2008; 53 (1):1-19. DOI:10.1111/j.1365-
2559.2007.02937.x.
Books
Diaz-Cano SJ: [Teaching Program on Anatomic and Molecular Pathology] [Spanish]. 2nd
11/2002; University of Malaga.
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
42
Book Chapters
S J Diaz-Cano: Sentinel node in malignant melanoma – The pathologist’s point of view. Skin
and Environment - Perception and Protection., 10th EADV Congress edited by J Ring, S
Weidinger, U Darsow, 01/2001: chapter Sentinel node in malignant melanoma – The
pathologist’s point of view: pages 745-753; Monduzzi Editore S.p.A. - MEDIMOND
Inc.., ISBN: 88-323-1410-X. CD ISBN 88-323-1411-8
Salvador J. Diaz-Cano: Clonality assays in adrenal medullary and thyroid C-cell
proliferation. Surgical Pathology Update 2001, Edited by Hauptmann S, Dietel M,
Sobrinho-Simões M, 01/2001: chapter Clonality assays in adrenal medullary and thyroid
C-cell proliferation: pages 324-339; ABW Wissenschaftsverlag GmbH., ISBN: ISBN3-
936072-00-0.
Journal Publications for the Last Three Years
David Taylor, Lea Ghataore, Vincent RP, Roy Sherwood, Ben Whitelaw, Dorota
Dworakowska, Schulte KM, Salvadore Diaz-Cano, Dylan Lewis, Simon Aylwin, Norman
Taylor: Discrimination of adrenocortical carcinoma from other adrenal lesions: use of a
new 13 steroid serum panel based on LC–MS/MS. 11/2015;
DOI:10.1530/endoabs.38.P398.
S. Moshkelgosha, U. Berchner-Pfannschmidt, S. Diaz-Cano, B. Edelmann, G. Görtz, M.
Horstmann, A. Noble, W. Hansen, J. Banga, A. Eckstein: CONTRASTING DISEASE
SPECTRUM IN PRECLINICAL MODELS OF GRAVES’ ORBITOPATHY IN BALB/C
AND C57BL/6 MICE. Thyroid: official journal of the American Thyroid Association
10/2015; 25 (S1):P-1-A-337 (450).
U. Berchner-Pfannschmidt, S. Moshkelgosha, B. Edelmann, S. Diaz-Cano, G. Görtz, M.
Horstmann, A. Noble, W. Hansen, A. Eckstein, J. Banga: REPLICATION OF GRAVES’
ORBITOPATHY MOUSE MODEL IN TWO CENTRES REVEALS A LONG TERM T
CELL RESPONSE TO TSH-RECEPTOR ANTIGEN. Thyroid: official journal of the
American Thyroid Association 10/2015; 25 (S1):P-1-A-337.
DOI:10.1089/thy.2015.29004. abstracts.
Sheena Ramyead, Salvador J. Diaz-Cano, Lucia Pozo-Garcia: Dermoscopy of clonal
seborrheic keratosis. Journal of the American Academy of Dermatology 08/2015; 73
(2):e47-49. DOI:10.1016/j.jaad.2015.04.013.
V. Hogarth, Z. Laftah, S. Diaz-Cano, E. Higgins, T.T. Lew: Idiopathic vulval calcinosis in a
child - British Society for Paediatric Dermatology. British Journal of Dermatology
07/2015; 173 (Suppl S1):163. DOI:10.1111/ bjd.13819.
Sajad Moshkelgosha, Po-Wah So, Salvador Diaz-Cano, J. Paul Bang: Preclinical Models of
Graves’ Disease and Associated Secondary Complications. Current Pharmaceutical
Design 05/2015; 21 (18):2414-2421. DOI:10.2174/1381612821666150316121945.
Salvador J Diaz-Cano: Pathological Bases for a Robust Application of Cancer Molecular
Classification. International Journal of Molecular Sciences 04/2015; 16 (4):8655-8675.
DOI:10.3390/ijms16048655.
Michail Sideris, Katie Adams, Jane Moorhead, Salvador Diaz-Cano, Ingvar Bjarnason,
Savvas Papagrigoriadis: BRAF V600E Mutation in Colorectal Cancer Is Associated with
Atypical Melanocytic Nevi
43
Right-sided Tumours and Iron Deficiency Anaemia.. Anticancer research 04/2015; 35
(4):2345-50.
MICHAIL SIDERIS, KATIE ADAMS, JANE MOORHEAD, SALVADOR DIAZ-CANO,
INgVAR bJARNASON, SAVVAS PAPAgRIgORIADIS: BRAF V600E Mutation in
Colorectal Cancer Is Associated with Right-sided Tumours and Iron Deficiency Anaemia.
Anticancer research 04/2015; 35 (4):2345-2350.
Sajad Moshkelgosha, Po-Wah So, Salvador Diaz-Cano, J Paul Banga: Preclinical Models of
Graves’ Disease and Associated Secondary Complications.. Current pharmaceutical
design 03/2015; 21 (18).
Zani-Ruttenstock Elke, Zani Augusto, Paul Anu, Diaz-Cano Salvador, Ade-Ajayi Niyi:
Interstitial Cells of Cajal are Decreased in Patients with Gas- troschisis Associated
Intestinal Dysmotility. Journal of Pediatric Surgery 02/2015; 50 (5).
DOI:10.1016/j.jpedsurg.2015.02.029.
Salvador Diaz-Cano, Russel Sutherland, Alfredo Blanes, Jane Moorhead, Richard Dobson:
Functional Mutation Signatures of 5 Cancer Differentiation Subtypes and Epithelial
Tumor Grading: Utility of Exome Sequence Data and Random Forest Analysis. Modern
Pathology 02/2015; 28 (2 (Suppl 2)):456-457. DOI:10.1038/modpathol.2015.26.
Salvador Diaz-Cano, Pauline Szyszka, Gregory Weitsman, Dorota Dudka, Peter King, Marta
Korbonits, Ashley Grossman, Klaus-Martin Schulte, Gabrielle Galata, David Taylor,
Norman Taylor, Simon Aylwin, Krzysztof Sworczak, Stefan Bornstein, Tony Ng, Dorota
Dworakowska: Effect of Erlotinib on proliferation and steroidogenesis in primary
cultures of adrenocortical carcinoma. Modern Pathology 02/2015; 28 (2 (Suppl 2)):133.
DOI:10.1038/modpathol.2015.14.
Christina George, Sweta Rai, Salvador Diaz-Cano, Daniel Creamer: The Case of a Glomus
Tumour. BMJ British medical journal 01/2015; In Press.
M Sideris, K Adams, J Moorhead, S Diaz-Cano, S Papagrigoriadis: RIGHT-SIDED
TUMOURS AND RELATED UNEXPLAINED IRON-DEFICIENCY ANAEMIA (IDA)
ARE ASSOCIATED WITH BRAF V600E MUTATION IN COLORECTAL CANCER
PATIENTS. Anticancer research 10/2014; 34 (10):6167-8.
Newton Acs Wong, David Gonzalez, Manuel Salto-Tellez, Rachel Butler, Salvador J Diaz-
Cano, Mohammad Ilyas, William Newman, Emily Shaw, Philippe Taniere, Shaun V
Walsh: RAS testing of colorectal carcinoma-a guidance document from the Association
of Clinical Pathologists Molecular Pathology and Diagnostics Group. Journal of Clinical
Pathology 07/2014; 67 (9). DOI:10.1136/jclinpath-2014-202467.
Diggins B, Diaz-Cano SJ, Schulte KM: Campylobacter jejuni as a Cause of Acute Infectious
Thyroiditis, on a Background of SLE-related End Stage Renal Failure and CMV
Viraemia: A Case Report and Review of the Literature. Vaccine 05/2014; 5 (3).
DOI:10.4172/2157-7560.1000229.
Salvador J Diaz-Cano: Molecular Histology - Multicentric Papillary Thyroid Carcinoma:
Stratification for Treatment. Journal of Molecular Histology 04/2014; 45 (4).
DOI:10.6084/m9.figshare.1400471.
Victoria Perna, Norman F. Taylor, Dorota Dworakowska, Klaus-Martin Schulte, Simon
Aylwin, Fatima Al-Hashimi, Salvador J. Diaz-Cano: Adrenocortical Adenomas with
Regression and Myelolipomatous Changes: Urinary Steroid Profiling Supports a
Distinctive Benign Neoplasm. Clinical Endocrinology 04/2014; 81 (3). DOI:10.1111/
cen.12458.
Lucia Pozo-Garcia and Salvador J. Diaz-Cano
44
K M Schulte, N Talat, G Galata, J Gilbert, J Miell, L C Hofbauer, A Barthel, S Diaz-Cano, S
R Bornstein: Oncologic Resection Achieving R0 Margins Improves Disease-Free
Survival in Parathyroid Cancer. Annals of Surgical Oncology 02/2014; 21 (6).
DOI:10.1245/s10434-014-3530-z.
SJ Diaz-Cano, N Talat, A Blanes, K-M Schulte: Histological Risk Classification Predicts
Malignancy and Recurrence in Paragangliomas. Modern Pathology 02/2014; 27
(S2):152.
F Al-Hashimi, A Blanes, SJ Diaz-Cano: Two Main Subtypes of Aldosterone-Producing
Adrenocortical Adenomas by Morphological and Expression Phenotype. Modern
Pathology 02/2014; 27 (S2):150-151.
V Perna, N Taylor, D Dworakowska, K-M Schulte, A Blanes, SJ Diaz-Cano: Urinary Steroid
Profiling for the Preoperative Identification of Adrenocortical Adenomas with
Regression and Myelolipomatous Changes. Modern Pathology 01/2014; 27 (2):157-158.
R. M. Chakravartty, D. Ruiz, B. Corcoran, C. Hooker, E. Kalogianni, G. Galata, D. Gialvalis,
N. Mulholland, S. Diaz-Cano, K. M. Schulte, G. Vivian: Localising Ectopic Parathyroid
Adenomas: A Pictorial Review of 99mTc Sestamibi SPECT/CT. European journal of
nuclear medicine and molecular imaging 10/2013; 40 (Suppl 2):S486.
Sajad Moshkelgosha, Po-Wah So, Neil Deasy, Salvador Diaz-Cano, J Paul Banga: Cutting
Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a
Preclinical Female Mouse Model of Graves’ Orbitopathy Induced by Thyrotropin
Receptor Plasmid-in Vivo Electroporation. Endocrinology 07/2013; 154 (9).
DOI:10.1210/en.2013-1576.
J Fleming, A Fogo, S Haider, S Diaz-Cano, R Hay, S Bashir: Varicella zoster virus
brachioplexitis associated with granulomatous vasculopathy. Clinical and Experimental
Dermatology 06/2013; 38 (4):378-82. DOI:10.1111/ced.12096.
Claudio Lizarralde, Salvador J Diaz-Cano: Thyroid nodule with arteriovenous malformation:
Under-recognized cause of increased vascularity. Histology and histopathology 05/2013;
DOI:10.6084/m9.figshare.707349.
Omar Mustafa, Ben Whitelaw, Rebeka Jenkins, Tiana Kordbacheh, Paola Salaris, Chris
Manu, Norman Taylor, Roy Sherwood, Gill Vivian, Dylan Lewis, Klaus-Martin Schulte,
Salvador Cano Diaz, Jackie Gilbert, Alan McGregor, Simon Aylwin: Unusual
presentations of adrenocortical tumours. 03/2013; DOI:10.1530/endoabs.31.P107.
Benjamin Whitelaw, Omar Mustafa, Patsy Coskeran, Julia Prague, Tiana Kordbacheh, Dylan
Lewis, Salvador Cano Diaz: Initiation and maintenance of mitotane as adjuvant therapy
for adrenocortical cancer: a single centre experience. 03/2013;
DOI:10.1530/endoabs.31.P57.
T Ionnidis, J Moorhead, A Blanes, SJ Diaz-Cano: Morphological and stem cell-like features
predictive of stage in medullary thyroid carcinoma. Modern Pathology 02/2013; 26
(S2):133. DOI:10.1038/modpathol.2013.8.
J Moorhead, J Gonzalez, A Blanes, SJ Diaz-Cano: General Grading System of Malignancies:
High Grade Neoplasms Express Stem Cell-Like Phenotype. Modern Pathology 02/2013;
26 (S2):444. DOI:10.1038/modpathol. 2013.22.
A Blanes, L Pozo, SJ Diaz-Cano: Morphogenesis and Fibrogenesis Pathways for the
Distinction of Slerosing Melanocytic Nevus and Desmoplastic Malignant Melanoma.
Modern Pathology 02/2013; 26 (S2):111. DOI:10.1038/modpathol.2013.6.
Atypical Melanocytic Nevi
45
Gibran Yusuf, Maria E Sellars, Gordon G Kooiman, Salvador Diaz-Cano, Paul S Sidhu:
Global testicular infarction in the presence of epididymitis: clinical features,
appearances on grayscale, color Doppler, and contrast-enhanced sonography, and
histologic correlation. Journal of ultrasound in medicine: official journal of the American
Institute of Ultrasound in Medicine 01/2013; 32 (1):175-80.
DOI:10.6084/m9.figshare.105917.
Salvador J Diaz-Cano: Tumor Heterogeneity: Mechanisms and Bases for a Reliable
Application of Molecular Marker Design. International Journal of Molecular Sciences
12/2012; 13 (2):1951-2011. DOI:10.3390/ijms 13021951.
S Walsh, S Diaz-Cano, E Higgins, R Morris-Jones, S Bashir, W Bernal, D Creamer: Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS): Is cutaneous phenotype a
prognostic marker for outcome? A review of clinicopathological features of 27 cases..
British Journal of Dermatology 10/2012; 168 (2). DOI:10.1111/bjd.12081.
Salvador J Diaz-Cano: Pathology of fore and midgut neuroendocrine tumours. Histology and
histopathology 10/2012; 18 (10). DOI:10.1016/j.mpdhp. 2012.08.008.
Rachel E Roberts, Min Zhao, Ben C Whitelaw, John Ramage, Salvador Diaz-Cano, Carel W
le Roux, Alberto Quaglia, Guo Cai Huang, Simon J B Aylwin: GLP-1 and Glucagon
Secretion from a Pancreatic Neuroendocrine Tumor Causing Diabetes and
Hyperinsulinemic Hypoglycemia. The Journal of Clinical Endocrinology and Metabolism
07/2012; 97 (9):3039-45. DOI:10.1210/jc.2011-2005
H M Liew, R Morris-Jones, S Diaz-Cano, S Bashir: Pseudofolliculitis barbae induced by oral
minoxidil. Clinical and Experimental Dermatology 05/2012; 37 (7):800-1.
DOI:10.1111/j.1365-2230.2012.04376.x.
Klaus-Martin Schulte, Anthony J Gill, Marcin Barczynski, Elias Karakas, Akira Miyauchi, W
T Knoefel, Celestino Pio Lombardi, Nadia Talat, Salvador Diaz-Cano, Clive S Grant:
Classification of Parathyroid Cancer. Annals of Surgical Oncology 03/2012; 19
(8):2620-8. DOI:10.1245/s10434-012-2306-6.
Taylor NF, Diaz-Cano SJ, Schulte KM: Approaches to detection of adrenocortical
carcinoma. The Journal of Clinical Endocrinology and Metabolism 02/2012;
http://jcem.endojournals.org/content/96/12/3775. abstract/reply#content-block.
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