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A new concept of melanocytic neoplasia pathogenesis based on the phenotype of common acquired nevi
Medical Hypotheses (2007) 69, 1334–1339
http://intl.elsevierhealth.com/journals/mehy
A new concept of melanocytic neoplasia pathogenesis based on the phenotype of common acquired nevi Anna Batistatou a,*, Aikaterini Zioga a, John Panelos a, Daniela Massi b, Niki J. Agnantis a, Konstantinos Charalabopoulos c a
Department of Pathology, University of Ioannina Medical School, University Campus, P.O. Box 1186, 451 10 Ioannina, Greece b Department of Human Pathology and Oncology, University of Florence, Florence, Italy c Department of Physiology, Clinical Unit, University of Ioannina Medical School, Ioannina, Greece Received 27 February 2007; accepted 1 March 2007
Summary Common melanocytic nevi are ubiquitous lesions which in some cases constitute a risk factor for the development of melanoma. To date, despite long term research there are no known molecular hallmarks for nevus development. We have observed that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance and in the immunohistochemical expression of E-cadherin. Based on these observations, we hypothesize that all melanocytes are genetically similar in the same individual and changes predisposing to neoplasia are a global melanocytic event characteristic for each person and propose a microgenomics/ proteomics approach to test this hypothesis. c 2007 Elsevier Ltd. All rights reserved.
Introduction Common acquired melanocytic nevi are benign neoplasms of melanocytes that arise from Schwann cells or the perineurium of the nerve sheath, the latter developing from the neural crest [1]. Today, although we no longer believe in Unna’s theory, published in 1893, that melanocytes originate in the epidermis and drop off into the dermis (abtrop* Corresponding author. Tel.: +30 26510 97574; fax: +30 26510 97850. E-mail address: [email protected] (A. Batistatou).
fung), we know that at least some types of nevi, like compound melanocytic nevi, develop in childhood or adolescence, remain stable for decades and subsequently evolve into dermal nevi [2]. Acquired nevi are ubiquitous lesions which constitute a risk factor for development of melanoma when they appear in excessive numbers, or are atypical [3]. Recent studies have suggested that nevi and melanoma may share, at least in part, a common pathogenesis [4–6]. Indeed, nevus development, as well as melanoma, is associated with ultraviolet (UV) exposure. To date, despite long term research there are no known molecular hallmarks for nevus
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.03.004
A new concept of melanocytic neoplasia pathogenesis based on the phenotype Table 1 Patient
1335
Detailed morphological characteristics of all nevi examined Age
Sex
Site
Size (max diameter, cm)
Nevus morphological characteristics
1
25
$
Trunk Trunk Trunk Trunk
(back) (back) (back) (back)
0.5 0.4 0.4 0.5
N N N N
C D D C
U U U U
Multinuclear Multinuclear Multinuclear Multinuclear
2
39
$
Trunk (back) Trunk (back) Trunk (back) Neck
1 1 0.9 0.7
N N N N
C D D D
U U U U
Cavernous spaces Cavernous spaces Cavernous spaces NR
3
19
#
Shoulder Arm Shoulder Shoulder
0.5 0.4 0.3 0.5
N N N N
C C C C
M M M M
Type Type Type Type
4
23
$
Neck Neck Trunk (abdomen)
0.9 0.3 0.6
N N N
C C C
U U U
Intranuclear inclusions Intranuclear inclusions Intranuclear inclusions
5
48
$
Trunk (abdomen) Trunk (abdomen) Trunk (abdomen)
0.8 0.6 0.7
N N N
C C C
U U U
NR Dysplastic nevus NR
6
49
$
Face Face Face
0.5 0.6 0.6
N N N
D D D
U U U
Ancient changes Ancient changes Ancient changes
7
46
$
Face Face Face
0.8 0.4 0.5
N N N
D D C
U U U
NR NR NR
8
24
$
Trunk (sternum) Trunk (sternum) Trunk (sternum)
0.7 0.4 0.9
N N N
C C C
U U U
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
9
16
$
Axilla Arm Hand
0.3 0.5 0.4
N N N
C D D
M M M
Neurotization Neurotization Neurotization
10
38
$
Face Face Face
0.6 0.3 0.3
N N N
D D D
M M M
NR NR NR
11
45
$
Neck Face Face
0.6 0.8 0.4
N N N
D D D
M M M
Many type C cells Many type C cells Many type C cells
12
58
$
Face Face Face
0.6 0.4 0.5
N N N
D D D
M M M
‘‘Ancient’’ changes ‘‘Ancient’’ changes ‘‘Ancient’’ changes
13
27
$
Trunk (back) Trunk (back) Trunk (back)
0.7 1 0.8
N N N
C C C
U U U
Type A and B cells mostly Type A and B cells mostly Type A and B cells mostly
14
58
$
Face Face Face
0.6 0.4 0.7
N N N
D D D
M M M
Neurotization Neurotization Neurotization
15
37
$
Trunk (back) Trunk (back) Trunk (back)
0.7 0.8 0.5
N N N
D D D
M M M
NR ‘‘Ancient’’ changes ‘‘Ancient’’ changes
16
23
$
Trunk (back) Trunk (back) Trunk (abdomen)
1 0.6 0.7
N N F
C D D
M M –
NR Irriation NR
17
17
#
Shoulder Shoulder Shoulder
0.8 0.5 0.8
N N N
C C C
M M M
Types B cells mostly Types B cells mostly Types B cells mostly (continued on next page)
A A A A
and and and and
cells cells cells cells
B B B B
cells cells cells cells
only only only only
1336
Batistatou et al.
Table 1 (continued) Patient
Age
Sex
Site
Size (max diameter, cm)
Nevus morphological characteristics
18
26
$
Neck Neck Neck
0.4 0.6 1
N N N
D D D
M M M
Multinuclear cells Multinuclear cells Multinuclear cells
19
28
$
Shoulder Trunk (back) Trunk (back)
0.4 0.4 0.4
F F F
C C C
– – –
NR NR NR
20
32
#
Trunk (abdomen) Trunk (abdomen)
0.7 0.6
N N
C C
U –
NR NR
21
16
#
Foot Foot
1 0.6
F F
C C
– –
NR NR
22
25
$
Trunk (abdomen) Trunk (abdomen)
0.9 1
N N
C C
U U
Fatty metaplasia Fatty metaplasia
23
30
$
Trunk (abdomen) Trunk (back)
0.6 0.4
N N
C C
U U
Cavernous spaces Cavernous spaces
24
37
$
Face Face
0.5 0.7
N N
D D
M M
Folliculitis Folliculitis
25
18
$
Trunk (back) Trunk (back)
0.5 0.7
F F
C C
– –
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
26
21
$
Toe Toe
0.5 0.5
F F
C C
– –
NR NR
27
23
$
Trunk (back) Trunk (abdomen)
1 0.5
N N
C C
M M
Fatty metaplasia Fatty metaplasia
28
17
#
Neck Face
0.9 0.4
N F
D D
U –
NR NR
29
24
$
Face Face
0.7 0.6
N N
D D
U U
Many type B cells Many type B cells
30
39
$
Face Face
0.3 1.2
F N
D D
– U
NR NR
31
32
$
Face Trunk (back)
0.3 0.5
N N
D D
M M
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
N = nodular, F = flat, D = dermal, C = compound, U = Unna’s nevus, M = Meischer’s nevus, ‘‘active nevus’’ is characterized by plump epithelioid nevus cells, with increased cytoplasm and melanin pigments, NR = not remarkable.
development; efforts to detect molecular changes are hindered partly because benign nevi are not a homogeneous entity on the basis of clinical, dermoscopic and histopathological examination [7]. Despite the fact that their pathogenesis is still under investigation, much progress has been made on the classification of melanocytic nevi. For example, common acquired nevi are classified into junctional, compound and dermal, based on the topography of nevus cells. Clinically, junctional nevi are small, flat and impalpable. Compound and dermal nevi display considerable variation in size, elevation and surface texture. Accordingly, their morphological variations are microscopically well appreciated. Two eponyms have been suggested by Ackerman,
one attributed to Unna, for an exophytic, papillomatous, acrochordon-like nevus and the other one attributed to Miescher and von Albertini, for a dome-shaped endophytic nevus in which melanocytes show a wedge-shaped permeation of the reticular dermis [8,9]. In the dermis, nevus cells are arranged in nests, anastomosing cords or single units (in deepest areas) and on the basis of their ‘‘maturation’’ they are designated as type A (small, round, pigmented), type B (smaller, round, nonpigmented) and type C (spindle shaped). In the dermal component, particularly in old lesions, several features may be observed, such as formation of cavernous spaces among the nevus cells, ‘‘neurotization’’ with formation of Schwannian structures, fatty metaplasia, multinu-
A new concept of melanocytic neoplasia pathogenesis based on the phenotype
1337
Figure 1 Nevi stained with haematoxylin-eosin (magnification ·100, unless otherwise specified). A–D: Two nevi from patient No. 13 (A,B: first nevus; C,D: second nevus). In higher magnifications (B and D, ·400), the presence of nests with type A cells is obvious. E–F: Two nevi from patient No. 27. Both nevi exhibit fatty metaplasia. G–H: Two nevi from patient No. 4. In both nevi there are conspicuous intranuclear inclusions.
clear nevus cells and ‘‘ancient cytological changes’’ (nuclear enlargement and hyperchromasia). Despite these morphological variations,
it is generally thought that most common acquired nevi are composed of a single cell type [2].
1338
Batistatou et al.
Figure 2 Nevi from patient No. 29 stained immunohistochemically for E-cadherin (DAB, ·400). Note similar reduction/aberrant expression of E-cadherin.
The hypothesis Our interest was stimulated by the observation that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance, including cytological features, fat metaplasia and secondary changes. In order to further investigate and substantiate this observation we retrieved from our files (Department of Pathology, University Hospital of Ioannina, Ioannina, Greece) all the reports on excised nevi during the period 8/2005-8/2006. From these we selected only those that were more than one per patient and were diagnosed as common acquired nevi, compound or dermal. In total, our material consisted of 84 nevi from 31 individuals (female:male = 25:6, mean age 31 years). Three patients had four excised nevi, 16 had three and 12 had two excised nevi. Two experienced pathologists (AB and AZ) reviewed the histological slides and recorded all phenotypical characteristics. As shown in Table 1 multiple nevi from the same individual share similar morphology, including secondary changes, some of which are not common (Fig. 1). To get further insight into this phenomenon, we evaluated the immunohistochemical expression of E-cadherin (E-cad), a cell–cell adhesion molecule in these lesions. The cadherin superfamily is a group of calcium-dependent cell–cell adhesion molecules, acting in a homophilic fashion, which are essential for the induction and maintenance of tissue structures and architecture [10,11]. Cadherins are known to link to the actin cytoskeleton through catenins and besides regulating adhesion they produce forces to generate changes in cell shape [10]. We have examined the immunohistochemical expression of E-cadherin, as described previously [12], in these nevi and found similar changes in expression in nevi of each individual (Fig. 2).
On the basis of these observations, we hypothesize that melanocytes of the whole body, although dispersed in the entire epidermis, are all genetically similar in the same individual and changes predisposing to neoplasia are possibly a global melanocytic event characteristic for each person. In order to test this hypothesis, recently developed highly sophisticated molecular methods need to be used. Laser-assisted microdissection will allow to obtain pure nevus cell populations or to isolate non-neoplastic epidermal melanocytes from the same patient by means of exact separation under microscopic control. Subsequently, microgenomics will allow identification of new molecular patterns, profiles and signatures of normal and neval melanocytes [13]. This genomic-based approach can be complemented or even substituted by a proteomics-based approach which will examine the proteins’ expression [14]. Emphasis should be given to adhesion molecules focused mainly to E-cadherin. This analysis will complement studies on genetic susceptibility for melanocytic neoplasia and will prove or disprove the hypothesis that all melanocytes in the body have similar changes that predispose them to the development of melanocytic neoplasia. Nevi are the most suitable melanocytic lesions to test this hypothesis since melanoma is a notorious malignancy that has several molecular alterations.
References [1] Worret W-I, Burgdorf W. Which direction do nevus cells move? Abtropfung reexamined. Am J Dermatopathol 1998;20:135–9. [2] Elder DE, Murphy GF. Melanocytic tumors of the skin. AFIP; 1991. [3] Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005;365:687–701. [4] Rivers JK. Is there more than one road to melanoma? Lancet 2004;363:728–30.
A new concept of melanocytic neoplasia pathogenesis based on the phenotype [5] Rampen FHJ. Naevocytic naevi as an atavism; Their relationship to melanoma risk. Med Hypotheses 1988;27: 71–5. [6] Yun AJ. Environmental discontinuity hypothesis: buffer dysfunctions as a source of human disease. Med Hypotheses 2007;68:434–8. [7] Nicholls EM. Genetic susceptibility and somatic mutation in the production of freckles, birthmarks and moles. Lancet 1968;13:71–3. [8] Unna PG. The histopathology of the diseases of the skin. Edinbourgh: Clay; 1986. p. 1129–44. [9] Miescher C, von Albertini A. Histologie de 100 cas de nevi pigmentaires d’apres les methods de Masson. Bull Soc Franc Dermatol Syph 1935;42:1265–73.
1339
[10] Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci 2003;94:575–81. [11] Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev 2005;6:622–34. [12] Batistatou A, Charalabopoulos AK, Scopa C, et al. Expression patterns of dysadherin and E-cadherin in lymph node metastases in colorectal carcinoma. Virchows Arch 1996;448:763–7. [13] Talor TB, Nambiar PR, Raja R, Cheung E, Rosenberg DW, Anderegg B. Microgenomics: identification of new expression profiles via small and single-cell sample analyses. Cytometry 2004;59A:254–61. [14] Banks RE, Dunn MJ, Hochstrasser DF, et al. Proteomics: new perspectives, new biomedical opportunities. Lancet 2000;356:1749–56.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
A new concept of melanocytic neoplasia pathogenesis based on the phenotype of common acquired nevi Anna Batistatou a,*, Aikaterini Zioga a, John Panelos a, Daniela Massi b, Niki J. Agnantis a, Konstantinos Charalabopoulos c a
Department of Pathology, University of Ioannina Medical School, University Campus, P.O. Box 1186, 451 10 Ioannina, Greece b Department of Human Pathology and Oncology, University of Florence, Florence, Italy c Department of Physiology, Clinical Unit, University of Ioannina Medical School, Ioannina, Greece Received 27 February 2007; accepted 1 March 2007
Summary Common melanocytic nevi are ubiquitous lesions which in some cases constitute a risk factor for the development of melanoma. To date, despite long term research there are no known molecular hallmarks for nevus development. We have observed that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance and in the immunohistochemical expression of E-cadherin. Based on these observations, we hypothesize that all melanocytes are genetically similar in the same individual and changes predisposing to neoplasia are a global melanocytic event characteristic for each person and propose a microgenomics/ proteomics approach to test this hypothesis. c 2007 Elsevier Ltd. All rights reserved.
Introduction Common acquired melanocytic nevi are benign neoplasms of melanocytes that arise from Schwann cells or the perineurium of the nerve sheath, the latter developing from the neural crest [1]. Today, although we no longer believe in Unna’s theory, published in 1893, that melanocytes originate in the epidermis and drop off into the dermis (abtrop* Corresponding author. Tel.: +30 26510 97574; fax: +30 26510 97850. E-mail address: [email protected] (A. Batistatou).
fung), we know that at least some types of nevi, like compound melanocytic nevi, develop in childhood or adolescence, remain stable for decades and subsequently evolve into dermal nevi [2]. Acquired nevi are ubiquitous lesions which constitute a risk factor for development of melanoma when they appear in excessive numbers, or are atypical [3]. Recent studies have suggested that nevi and melanoma may share, at least in part, a common pathogenesis [4–6]. Indeed, nevus development, as well as melanoma, is associated with ultraviolet (UV) exposure. To date, despite long term research there are no known molecular hallmarks for nevus
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.03.004
A new concept of melanocytic neoplasia pathogenesis based on the phenotype Table 1 Patient
1335
Detailed morphological characteristics of all nevi examined Age
Sex
Site
Size (max diameter, cm)
Nevus morphological characteristics
1
25
$
Trunk Trunk Trunk Trunk
(back) (back) (back) (back)
0.5 0.4 0.4 0.5
N N N N
C D D C
U U U U
Multinuclear Multinuclear Multinuclear Multinuclear
2
39
$
Trunk (back) Trunk (back) Trunk (back) Neck
1 1 0.9 0.7
N N N N
C D D D
U U U U
Cavernous spaces Cavernous spaces Cavernous spaces NR
3
19
#
Shoulder Arm Shoulder Shoulder
0.5 0.4 0.3 0.5
N N N N
C C C C
M M M M
Type Type Type Type
4
23
$
Neck Neck Trunk (abdomen)
0.9 0.3 0.6
N N N
C C C
U U U
Intranuclear inclusions Intranuclear inclusions Intranuclear inclusions
5
48
$
Trunk (abdomen) Trunk (abdomen) Trunk (abdomen)
0.8 0.6 0.7
N N N
C C C
U U U
NR Dysplastic nevus NR
6
49
$
Face Face Face
0.5 0.6 0.6
N N N
D D D
U U U
Ancient changes Ancient changes Ancient changes
7
46
$
Face Face Face
0.8 0.4 0.5
N N N
D D C
U U U
NR NR NR
8
24
$
Trunk (sternum) Trunk (sternum) Trunk (sternum)
0.7 0.4 0.9
N N N
C C C
U U U
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
9
16
$
Axilla Arm Hand
0.3 0.5 0.4
N N N
C D D
M M M
Neurotization Neurotization Neurotization
10
38
$
Face Face Face
0.6 0.3 0.3
N N N
D D D
M M M
NR NR NR
11
45
$
Neck Face Face
0.6 0.8 0.4
N N N
D D D
M M M
Many type C cells Many type C cells Many type C cells
12
58
$
Face Face Face
0.6 0.4 0.5
N N N
D D D
M M M
‘‘Ancient’’ changes ‘‘Ancient’’ changes ‘‘Ancient’’ changes
13
27
$
Trunk (back) Trunk (back) Trunk (back)
0.7 1 0.8
N N N
C C C
U U U
Type A and B cells mostly Type A and B cells mostly Type A and B cells mostly
14
58
$
Face Face Face
0.6 0.4 0.7
N N N
D D D
M M M
Neurotization Neurotization Neurotization
15
37
$
Trunk (back) Trunk (back) Trunk (back)
0.7 0.8 0.5
N N N
D D D
M M M
NR ‘‘Ancient’’ changes ‘‘Ancient’’ changes
16
23
$
Trunk (back) Trunk (back) Trunk (abdomen)
1 0.6 0.7
N N F
C D D
M M –
NR Irriation NR
17
17
#
Shoulder Shoulder Shoulder
0.8 0.5 0.8
N N N
C C C
M M M
Types B cells mostly Types B cells mostly Types B cells mostly (continued on next page)
A A A A
and and and and
cells cells cells cells
B B B B
cells cells cells cells
only only only only
1336
Batistatou et al.
Table 1 (continued) Patient
Age
Sex
Site
Size (max diameter, cm)
Nevus morphological characteristics
18
26
$
Neck Neck Neck
0.4 0.6 1
N N N
D D D
M M M
Multinuclear cells Multinuclear cells Multinuclear cells
19
28
$
Shoulder Trunk (back) Trunk (back)
0.4 0.4 0.4
F F F
C C C
– – –
NR NR NR
20
32
#
Trunk (abdomen) Trunk (abdomen)
0.7 0.6
N N
C C
U –
NR NR
21
16
#
Foot Foot
1 0.6
F F
C C
– –
NR NR
22
25
$
Trunk (abdomen) Trunk (abdomen)
0.9 1
N N
C C
U U
Fatty metaplasia Fatty metaplasia
23
30
$
Trunk (abdomen) Trunk (back)
0.6 0.4
N N
C C
U U
Cavernous spaces Cavernous spaces
24
37
$
Face Face
0.5 0.7
N N
D D
M M
Folliculitis Folliculitis
25
18
$
Trunk (back) Trunk (back)
0.5 0.7
F F
C C
– –
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
26
21
$
Toe Toe
0.5 0.5
F F
C C
– –
NR NR
27
23
$
Trunk (back) Trunk (abdomen)
1 0.5
N N
C C
M M
Fatty metaplasia Fatty metaplasia
28
17
#
Neck Face
0.9 0.4
N F
D D
U –
NR NR
29
24
$
Face Face
0.7 0.6
N N
D D
U U
Many type B cells Many type B cells
30
39
$
Face Face
0.3 1.2
F N
D D
– U
NR NR
31
32
$
Face Trunk (back)
0.3 0.5
N N
D D
M M
‘‘Active’’ nevus cells ‘‘Active’’ nevus cells
N = nodular, F = flat, D = dermal, C = compound, U = Unna’s nevus, M = Meischer’s nevus, ‘‘active nevus’’ is characterized by plump epithelioid nevus cells, with increased cytoplasm and melanin pigments, NR = not remarkable.
development; efforts to detect molecular changes are hindered partly because benign nevi are not a homogeneous entity on the basis of clinical, dermoscopic and histopathological examination [7]. Despite the fact that their pathogenesis is still under investigation, much progress has been made on the classification of melanocytic nevi. For example, common acquired nevi are classified into junctional, compound and dermal, based on the topography of nevus cells. Clinically, junctional nevi are small, flat and impalpable. Compound and dermal nevi display considerable variation in size, elevation and surface texture. Accordingly, their morphological variations are microscopically well appreciated. Two eponyms have been suggested by Ackerman,
one attributed to Unna, for an exophytic, papillomatous, acrochordon-like nevus and the other one attributed to Miescher and von Albertini, for a dome-shaped endophytic nevus in which melanocytes show a wedge-shaped permeation of the reticular dermis [8,9]. In the dermis, nevus cells are arranged in nests, anastomosing cords or single units (in deepest areas) and on the basis of their ‘‘maturation’’ they are designated as type A (small, round, pigmented), type B (smaller, round, nonpigmented) and type C (spindle shaped). In the dermal component, particularly in old lesions, several features may be observed, such as formation of cavernous spaces among the nevus cells, ‘‘neurotization’’ with formation of Schwannian structures, fatty metaplasia, multinu-
A new concept of melanocytic neoplasia pathogenesis based on the phenotype
1337
Figure 1 Nevi stained with haematoxylin-eosin (magnification ·100, unless otherwise specified). A–D: Two nevi from patient No. 13 (A,B: first nevus; C,D: second nevus). In higher magnifications (B and D, ·400), the presence of nests with type A cells is obvious. E–F: Two nevi from patient No. 27. Both nevi exhibit fatty metaplasia. G–H: Two nevi from patient No. 4. In both nevi there are conspicuous intranuclear inclusions.
clear nevus cells and ‘‘ancient cytological changes’’ (nuclear enlargement and hyperchromasia). Despite these morphological variations,
it is generally thought that most common acquired nevi are composed of a single cell type [2].
1338
Batistatou et al.
Figure 2 Nevi from patient No. 29 stained immunohistochemically for E-cadherin (DAB, ·400). Note similar reduction/aberrant expression of E-cadherin.
The hypothesis Our interest was stimulated by the observation that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance, including cytological features, fat metaplasia and secondary changes. In order to further investigate and substantiate this observation we retrieved from our files (Department of Pathology, University Hospital of Ioannina, Ioannina, Greece) all the reports on excised nevi during the period 8/2005-8/2006. From these we selected only those that were more than one per patient and were diagnosed as common acquired nevi, compound or dermal. In total, our material consisted of 84 nevi from 31 individuals (female:male = 25:6, mean age 31 years). Three patients had four excised nevi, 16 had three and 12 had two excised nevi. Two experienced pathologists (AB and AZ) reviewed the histological slides and recorded all phenotypical characteristics. As shown in Table 1 multiple nevi from the same individual share similar morphology, including secondary changes, some of which are not common (Fig. 1). To get further insight into this phenomenon, we evaluated the immunohistochemical expression of E-cadherin (E-cad), a cell–cell adhesion molecule in these lesions. The cadherin superfamily is a group of calcium-dependent cell–cell adhesion molecules, acting in a homophilic fashion, which are essential for the induction and maintenance of tissue structures and architecture [10,11]. Cadherins are known to link to the actin cytoskeleton through catenins and besides regulating adhesion they produce forces to generate changes in cell shape [10]. We have examined the immunohistochemical expression of E-cadherin, as described previously [12], in these nevi and found similar changes in expression in nevi of each individual (Fig. 2).
On the basis of these observations, we hypothesize that melanocytes of the whole body, although dispersed in the entire epidermis, are all genetically similar in the same individual and changes predisposing to neoplasia are possibly a global melanocytic event characteristic for each person. In order to test this hypothesis, recently developed highly sophisticated molecular methods need to be used. Laser-assisted microdissection will allow to obtain pure nevus cell populations or to isolate non-neoplastic epidermal melanocytes from the same patient by means of exact separation under microscopic control. Subsequently, microgenomics will allow identification of new molecular patterns, profiles and signatures of normal and neval melanocytes [13]. This genomic-based approach can be complemented or even substituted by a proteomics-based approach which will examine the proteins’ expression [14]. Emphasis should be given to adhesion molecules focused mainly to E-cadherin. This analysis will complement studies on genetic susceptibility for melanocytic neoplasia and will prove or disprove the hypothesis that all melanocytes in the body have similar changes that predispose them to the development of melanocytic neoplasia. Nevi are the most suitable melanocytic lesions to test this hypothesis since melanoma is a notorious malignancy that has several molecular alterations.
References [1] Worret W-I, Burgdorf W. Which direction do nevus cells move? Abtropfung reexamined. Am J Dermatopathol 1998;20:135–9. [2] Elder DE, Murphy GF. Melanocytic tumors of the skin. AFIP; 1991. [3] Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005;365:687–701. [4] Rivers JK. Is there more than one road to melanoma? Lancet 2004;363:728–30.
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