Melanoma Molecular Maps Projects



1. Introduction

The ABCDE rule (asymmetry, irregular borders, multiple colors, diameter >6 mm, enlarging lesion) contains the main clinical criteria for naked-eye based diagnosis of suspected cutaneous malignant melanoma (CMM). The early phase of malignant melanoma is difficult to identify because CMM can share many clinical features with an atypical nevus. In fact several studies have described diagnostic accuracy rates ranging from 50-75% [1,2], indicating a need for additional diagnostic tools, in particular to detect the so-called small melanomas as well as melanoma regular in shape or color [3-5].
Over the last 20 years, dermoscopy (i.e. dermatoscopy, epiluminescence microscopy [ELM], surface microscopy) has opened a new dimension in the examination of pigmented skin lesions (PSL) and, especially, in the identification of the early phase of CMM [3-33].

Dermoscopy is a non-invasive method that allows the in vivo evaluation of colors and microstructures of the epidermis, the dermo-epidermal junction, and the papillary dermis not visible to the naked eye (FIGURE 1). These structures are specifically correlated to histological features [5,6].
The identification of specific diagnostic patterns related to the distribution of colors and dermoscopy structures can better suggest a malignant or benign PSL.
Based on the results of meta-analyses, dermoscopy is more accurate than clinical examination in the diagnosis of pigmented skin lesions [8,9]. However this technique must be considered as a valid support, but not a substitute, in the clinical diagnosis of melanoma [5,29-32].

FIGURE 1: Clinical (upper panel) and corresponding dermoscopic image (lower panel) of a melanocytic nevus. Dermoscopy shows symmetry in pigmentation and structures throughout the lesion with globules symmetrically distributed at periphery.

2. Technique

Dermoscopy involves the evaluation of the skin surface. During a dermoscopy assessment, the PSL is covered with a liquid (usually oil or alcohol) and examined under a specific optical system. Applying oil reduces the reflectivity of the skin and enhances the transparency of the stratum corneum. This allows visualization of specific structures related to the epidermis, the dermo-epidermal junction and the papillary dermis, and it also suggests the location and distribution of melanin (FIGURE 1).
Numerous instruments (FIGURE 2) are utilized for dermoscopic examination, such as conventional contact dermoscope, contact polarized light dermoscope, non-contact polarized light dermoscope, stereomicroscope, videodermoscope, digital camera. These instruments and the corresponding techniques can be equivalent and/or complementary and can influence the inter- and intra-observer reproducibility [10-15].

FIGURE 2: Dermoscopy instruments (in order of appearance, from top to bottom): dermatoscope; hand held stereomicroscope; stereomicroscope; digital epiluminescence by stereomicroscope; videomicroscope; digital camera.

2.1. Dermatoscope

The dermatoscope is the standard piece of equipment used to perform a dermoscopy examination (FIGURE 2). It is similar to an otoscope, is user friendly, and is inexpensive. These optical system's features include monocular observation, 10x magnification, and the use of an illumination system (3.5-V halogen lamp).
Recently the use of dermoscope with light-emitting diode (LED) lighting and polarizing filters for glare reduction eliminates the need for skin contact and the required liquids. Although these latter instruments are very useful for rapidly screening pigmented lesions in patients with multiple nevi, the clinical images can be different from those attained using conventional glass plate liquid-surface microscopes. For these reasons it has been suggested to use cross-polarized surface to rapid screening of pigmented lesions, with a final definitive diagnosis dependent on glass plate liquid instruments.
Furthermore digital epiluminescence microscopy system combined with a digital camera can capture a high quality, glare-free image (FIGURE 2).
Documenting lesions is simple for training, teledermoscopy, pre-surgical evaluation and mole mapping.

2.2. Stereomicroscope

Another optical instrument, the stereomicroscope, allows for an accurate binocular observation with different magnifications (6x-80x) (FIGURE 2).
The illumination system includes a halogen lamp (12 V/50 W).
From an empiric point of view, visualization is better than with the dermatoscope, but formal studies of the differences in diagnostic features and accuracy of the two instruments have never been published.

2.3. Videodermatoscope

Features of another optical system, the videodermatoscope, include a video probe that transmits images of the PSL to a color monitor (FIGURE 2).
The addition of a digital system to the stereomicroscope (also termed the digital epiluminescence microscope) or to the videodermatoscope has opened a new area in the field of skin cancer diagnosis with the advantages of computerized technology.
However, the technologic features (which are cost dependent) of the camera (single-chip video charge-coupled device, 3-chip charge-coupled device, or still digital), optical system, monitor, digitized board, and software significantly influence the resolution and quality of the images.

3. Color

Accurate evaluation of the PSL color, degree of pigmentation and distribution of the colors within the lesion are the most important elements of a dermoscopy examination.
The epidermis usually appears white, but acanthosis results in a grayish-brown or brownish-yellow color.
Melanin is the most important pigment in determining different structural and chromatic patterns. The PSL can have a different degree and distribution of pigmentation depending on the location of melanin in different layers of the skin.
Melanin location determines the color of the lesion according to the following schema (FIGURE 3):

- Epidermis ==> BLACK
- Dermo-epidermal junction ==> BROWN
- Dermis ==> BLUE

Other possible colors include various shades of white and red (FIGURE 4). White shades are related to regression and may be seen with melanomas, benign melanocytic nevi (halo nevus), and non-melanocytic lesions (lichenoid keratosis, scars). Red shades are related to increased angiogenesis in tumors, an increased number of capillary vessels, and bleeding within the lesion. If bleeding persists and crust develops, the color ranges from red-black to blue-black.
A good evaluation of colors and their relative distribution is essential for achieving the correct clinical diagnosis of a PSL.

FIGURE 3: Pigmented skin lesion (PSL) colors (in order of appearance, from top to bottom): black nevus (intraepidermal location); light-brown nevus (dermo-epidermal junction); dark-brown nevus (dermo-epidemal junction); blue nevus (dermis).

FIGURE 4: Pigmented skin lesion (PSL) colors (in order of appearance, from top to bottom): white (regression); milky red-white (regression + angiogenesis); red (angiogenesis); red-black (hemorrhage).

4. Dermoscopy features

Dermoscopy features (TABLE 1) can be divided into primary and secondary melanocytic and non-melanocytic structures, which show numerous different manifestations related to chromatic and geometric variables (e.g., distribution, width, and caliber).

4.1. Primary structures for melanocytic lesions

4.1.1. Pigment network

The most important epiluminescence microscopy (ELM) feature of melanocytic lesions is the pigment network (PN), which consists of pigmented network lines and hypopigmented holes.
This feature is correlated histologically to the length of the "rete ridges" and to the distribution of melanin within the keratinocytes of the epidermal "rete ridges". The network of hypopigmented holes corresponds to the suprapapillary plate, which is relatively thin and contains less melanin. The network lines correspond to the "rete ridges", which are thicker and have a greater quantity of melanin.
In normal melanocytic nevi, the PN is slightly pigmented. Light-brown network lines are thin and fade gradually at the periphery. Holes are regular and narrow (FIGURES 5-9). The distribution is symmetric and sometimes accentuated in the center of the lesion (FIGURES 10, 11).
In cutaneous malignant melanoma (CMM), the PN usually ends abruptly at the periphery and has irregular holes, thickened and darkened network lines, and tree-like branching at the periphery (FIGURES 12, 13). Moreover, in CMM the PN features change between different sectors of the PSL edge (border): some areas of malignant lesions manifest as a broad and prominent PN, while others have a discrete irregular PN; the PN may also be totally absent in some areas (FIGURES 12, 13).
Clinically atypical nevi (i.e., the nevi defined as dysplastic nevi at pathology evaluation) are often identified because they show areas of irregular and discrete PN distributed asymmetrically (FIGURES 14, 15).

FIGURE 5: Typical pigment network of melanocytic nevus: thin light-brown network lines with holes regular and narrow.

FIGURE 6: Typical pigment network of melanocytic nevus: brown network lines with holes regular and narrow. Color distribution is symmetric.

FIGURE 7: Typical pigment network of melanocytic nevus: thin light-brown network lines with holes regular and narrow. Perilesional skin shows subtle indefinite pigment network a swell as in sunburned fair skinned people.

FIGURE 8: Typical pigment network of melanocytic nevus: brown network lines with holes regular and narrow. The lines fade gradually at the periphery.

FIGURE 9: Typical pigment network of melanocytic nevus: dark-brown pigment network and symmetrical color distribution.

FIGURE 10: Typical pigment network of melanocytic nevus: brown pigment network with darker pigmentation at center of the lesion.

FIGURE 11: Typical pigment network of melanocytic nevus: dark-brown pigment network symmetrically distributed in a dark skinned patient.

FIGURE 12: In situ melanoma: asymmetrical color distribution, atypical pigment network, paracentral blotches suggest strongly a multicomponent pattern related to severe melanocytic atypia.

FIGURE 13: In situ melanoma: multicomponent pattern shows colors and pigment network asymmetrically distributed. Pigment dots (*) are randomly located and differ in size. These atypical structures are related to severe dysplasia at pathology assessment.

FIGURE 14: Atypical pigment network of dysplastic nevus: atypical dark-brown pigment network with prominent and thick lines focally.

FIGURE 15: Dysplastic nevus: this melanocytic lesion shows atypical pigment network branched streaks, peripheral pigment dots and white area (°).

4.1.2. Pseudopigmented network

ELM features of homogeneous pigmentation interrupted by hypopigmented hair follicles and hypopigmented sweat gland openings create a pseudopigmented network.
In benign lesions, this pseudonetwork tends to be uniform and symmetric in color and pattern (FIGURES 16, 17).
By contrast, in lentigo maligna and lentigo maligna melanoma (LMM) the pseudonetwork becomes non-uniform and asymmetric in color and pattern because of the increased number of atypical melanocytes extending along the hair follicles and adnexal structures (FIGURE 18). The meshes become broader, and the holes are larger.

FIGURE 16: Pseudopigmented network of a nevus located on the face. This structure is characterized by a homogeneous pigmentation interrupted by hypopigmented hair follicles.

FIGURE 17: Another example of typical pseudopigmented network of a nevus located on the face.

FIGURE 18: Malignant lentigo: naked eye (upper panel) and dermoscopy (lower panel) view. The atypical pseudopigmented network is asymmetric in color and pattern.

4.1.3. Radial streaming and pseudopods

Radial streaming and pseudopods are different morphologic expressions of malignant melanoma, specifically melanoma in the radial growth phase.
Radial streaming (FIGURE 19) is a linear extension of pigment at the periphery of a lesion, often appearing in groups of nearly parallel, radially arranged linear structures. Depth determines the colors, which are brown, dark brown, blue-gray, and black.
Pseudopods (FIGURE 20) are curved finger-like projections that are predominantly dark brown or black and are located at the periphery of a lesion. They occasionally have small knobs at their tips.
Radial streaming and pseudopods histologically correspond to confluent junctional nests of dysplastic melanocytes.

FIGURE 19: Microinvasive melanoma: multicomponent pattern with black color irregularly distributed. The pigmentation is associated to blue-whitish veil (*) and radial streaming/pseudopods at periphery (circled area): these structures are related to severe melanocytic dysplasia.

FIGURE 20: In situ melanoma: radial streaming at periphery (*) and pseudopods (circled area).

4.1.4. Globules

Pigmented globules are round or oval, dark brown or black, and larger than 1 mm in diameter.
They are uniform in normal PSL, whereas they vary in size, color, and shape in atypical nevi (FIGURE 21) and melanoma. When abundant, aggregated globules have a cobblestone pattern (FIGURE 22), which is typical of benign melanocytic lesions (FIGURES 23, 24).
In CMM, globules are dark or slate blue and are distributed irregularly (FIGURE 25).
Occasionally, isolated dark globules are seen at the margins of achromic lesions: in this case, a diagnosis of melanoma is suggested.
Pigmented globules correspond histologically to nests of pigmented melanocytes (nevus or melanoma) at the junction in the papillary dermis or, because of melanin storage, in melanophage clusters in the papillary dermis.
Milky-red globules can be seen in CMM, representing melanoma cell nests with increased vascularization.

FIGURE 21: Dysplastic nevus: melanocytic nevus with atypical pigment network and focal irregular distribution of globules at periphery.

FIGURE 22: Melanocytic nevus with typical globular pattern also called "cobblestone".

FIGURE 23: Melanocytic nevus with typical globular pattern.

FIGURE 24: Melanocytic nevus with homogeneous brown color at center and regular distribution of globules at periphery.

FIGURE 25: Invasive melanoma: peripheral globules and dots varied in size and colors and irregularly distributed.

4.2. Secondary structures

4.2.1. Dots

Pigmented dots are small, round or irregularly shaped pinpoint structures that are black or dark brown. They correspond to focal accumulations of free melanin or an increased number of highly pigmented melanocytes in the cornified layers of the epidermis.
The presence of melanophages and/or atypical melanocytes in the dermis correlates with blue-gray or slate blue dots and is typically found in pigmented melanocytic and non-melanocytic lesions undergoing regression.
Vertical capillaries found on apical dermal papillae appear as red dots on the palms and soles; sweat gland openings appear as white dots.
In benign melanocytic lesions, dots in the center of the lesion are homogeneous in color and are regular in size, shape, and distribution (FIGURE 26).
In CMM or in atypical lesions, dots may occur at the periphery of the lesion and are irregular in size, shape, and distribution (FIGURES 25, 27).

FIGURE 26: Melanocytic nevus: dark-brown dots (*) homogeneous in color and regular in size, shape and distribution.

FIGURE 27: Microinvasive melanoma: multicomponent pattern mainly characterized by regression phases (white and gray areas **). Other features include irregular vascular pattern (red arrow), pigmented dots (*) and globules (°) irregular in size and randomly located.

4.2.2. Blue-white veil

A blue-white veil is a ground-glass area of pigmentation that is blue-gray to blue-white in color.
This ELM feature is present in homogeneously pigmented black or dark brown lesions and is associated with thickening of the epidermis.
It is correlated histologically with compact orthokeratosis and hypergranulosis, with confluent nests of heavily pigmented melanocytes in the dermis.
A blue-white veil is often found in melanomas (FIGURE 28) and Spitz nevi (FIGURE 29).

FIGURE 28: Invasive melanoma: blue-whitish veil and gray blue areas with black dots ("peppering").

FIGURE 29: "Starburst" pattern in a Reed nevus with blue-whitish veil and radial streaming symmetrically oriented at periphery.

4.2.3. Blue-gray areas

Blue-gray areas are ELM features with coloration varying from gray-blue to deep gray.
Blue-gray or bluish areas may be either isolated disseminated granules or peppering and ill-defined spots with bizarre margins (FIGURES 28, 30).
They may be associated with melanoma regression and are correlated histologically with the presence of melanin and/or hemosiderin within melanocytes and melanophages, and blue-gray areas may be free in the papillary and middle dermis.

FIGURE 30: Regressive areas (blue-gray areas with gray granules [*]) in an atypical melanocytic nevus with histological regression.

4.2.4. Steel blue areas

Steel blue areas are structureless, gray-blue, and homogeneously diffuse.
They are found in blue nevi (FIGURE 31) and occasionally are associated with globules, dots, or both.

FIGURE 31: Blue nevus: homogeneous pattern with blue-steel areas.

4.2.5. Depigmentation

Depigmentation depends on a lack or reduction of pigment in the PSL.
With depigmentation, differentiation can occur in hypopigmented regions that correspond to pigmented areas lighter than other areas within the nevus (FIGURE 32). Differentiation also can occur in white areas that correspond to well-defined white (FIGURES 27, 30) or milky red-white areas related to regressive phase of melanocytic lesions (FIGURE 33).
In contrast to hypopigmented areas, depigmented areas completely lack pigment: histologically, they correspond to fibroplasia, telangiectasias, and loss of melanin.

FIGURE 32: Hypopigmented areas in a melanocytic nevus.

FIGURE 33: Regressive phase as milky red-white areas in invasive melanoma.

5. Main structures of non-melanocytic lesions

5.1. Milia-like cysts

Milia-like cysts are small, circular, whitish-yellow areas with sizes ranging from 0.1-1 mm (FIGURE 34).
They are important for the diagnosis of seborrheic keratosis but can also be found in papillary melanocytic nevi and melanoma, although in seborrheic keratosis, they are larger.
Histologically, milia-like cysts correspond to keratin-filled cysts.

FIGURE 34: Milia-like cysts (*) and comedo-like openings (°) in a seborrheic keratosis.

5.2. Comedo-like openings

Comedo-like openings are another typical diagnostic feature of seborrheic keratosis.
They are keratin-filled pore-like openings that communicate with the surface of the lesion, and are correlated histologically with keratin within the invaginations of the epidermis.
They appear yellow-brown, with a circular or oval shape and a light round halo (FIGURE 35).

FIGURE 35: Comedo-like openings (*) in a seborrheic keratosis.

5.3 Red-black lagoons

Red-black lagoons are the pathognomonic diagnostic criteria of hemangioma and angiokeratomas.
They are small, well-defined, oval or round areas that range from blue-red to blue-black (FIGURE 36).
Histologically, they correspond to large lagoons and thrombi within the vascular spaces of papillary dermis.
Subungual hemorrhages can have blue-red and/or red-black homogeneous pigmentation without vascular lagoons (FIGURE 37).

FIGURE 36: Angioma: red vascular lagoons. Naked-eye (upper panel) and dermoscopic (lower panel) view.

FIGURE 37: Subungueal hemorrhage: naked-eye (upper panel) and dermoscopic (lower panel) view.

5.4. Maple leaf-like pigmentation

Maple leaf-like pigmentation, an important diagnostic criterion for basal cell carcinoma (BCC), is gray-brown to gray-black with a shape similar to that of a maple leaf or to the fingers of a hand (FIGURE 38).
This appearance, combined with the presence of pigmented structures, may simulate CMM (FIGURE 38).
Histologically, they correspond to heavily pigmented basaloid cells within the nest of basal cell carcinoma.

FIGURE 38: Maple leaf-like pigmentation (*) in a basal cell carcinoma (BCC). Tree like vascular vessels are central located.

6. Vascular patterns

Vascular patterns are important markers for melanocytic and non-melanocytic lesions [17-33].
The vascular pattern can be evaluated more accurately using magnification higher than 10x.
Vascular pattern can present in the following ways:

- Tree-like vessels are described as thick, branching vessels; they are compatible with pigmented basal cell carcinoma of any type (FIGURES 38, 39).

- Corona vessels are thinner and less curved than treelike vessels. Generally, they surround a sebaceous gland hyperplasia (FIGURE 40).

- Comma-shaped vessels are parallel to the skin surface and appear as short, strong, curved vascular structures often visible in the dermal nevi (FIGURE 41).

- Dotted vessels are short capillary loops visible as pinpoint dots. They are commonly seen in all types of melanocytic tumors and superficial epithelial tumors (i.e., actinic keratosis (FIGURE 42); Bowen disease).

- Hairpin vessels are long capillary loops of thicker tumors and are related to angiogenesis of thick melanomas (at the border) but also squamous cell carcinoma, keratoacanthoma, and seborrheic keratosis.

A combined presence of linear and other types of vascular features (called linear irregular vessels) is often seen in melanoma (FIGURE 43).

FIGURE 39: Vascular pattern: tree-like vessels (basal cell carcinoma).

FIGURE 40: Vascular pattern: corona vessels (sebaceous hyperplasia).

FIGURE 41: Vascular pattern: comma-shaped vessels (dermal nevus).

FIGURE 42: Vascular pattern: dotted vessels (actinic keratosis).

FIGURE 43: Vascular pattern: dotted vessels (°) and linear irregular vessels (*) in a case of invasive melanoma.

TABLE 1: Dermoscopic features of skin lesions.

Dermoscopic feature


Clinical diagnosis

Regular pigment network

Network of brownish lines regularly meshed

Melanocytic nevus

Atypical pigment network

Black or gray network with irregular meshes and thick lines

Dysplastic nevus or melanoma

Regular dots & globules

Black, brown or gray round to oval variously sized structures regularly distributed within the lesion

Melanocytic nevus

Atypical dots & globules

Black, brown or gray round to oval variously sized structures irregularly distributed within the lesion

Dysplastic nevus or melanoma


Irregular linear structures not clearly combined with pigment network lines

Dysplastic nevus or melanoma

Blue whitish veil

Irregular confluent grey-blue pigmented areas

Dysplastic nevus or melanoma


White (scar-like) or blue (pepper-like) areas or their combination

Dysplastic nevus or melanoma

Milia-like cysts

White-yellowish dots

Seborrheic keratosis

Comedo-like openings

Brown-yellowish round to oval sharply circumscribed structures

Seborrheic keratosis

Leaf-like areas

Brown-gray to gray-black patches with leaf-like shape

Basal cell carcinoma

Vascular structures

Comma-like vessels

Melanocytic nevus

Arborizing vessels

Basal cell carcinoma

Hairpin vessels

Seborrheic keratosis

Dotted or irregular vessels

Dysplastic nevus or melanoma

7. Diagnostic procedures

Dermoscopy recognition of suggestive melanomas is based on the observation of multiple parameters, as none of these factors is pathognomonic for melanoma.
Many different systems have been proposed for dermoscopy-based classification/diagnosis of suspected PSL, the main aim being of providing clinicians with a practical tool to decide whether or not the PSL should be removed (and histologically evaluated) or just left in place (and followed up if needed).
The most widely used ELM procedures are Pattern Analysis [3], the ABCD Dermoscopy Rule [23], the Menzies score [22], the 7-Point Checklist [21], and the Stratification of Risk Level method (24).

8.1. Pattern analysis

Described by Pehamberger et al. [3] and then redefined by the Consensus Net Meeting on Dermoscopy (CNMD) [20], Pattern Analysis is the procedure most widely used by dermatologists.

Pattern Analysis uses a process of diagnostic framing that keeps control of the known analytic data of all the dermatoscopic parameters of PSL and of the prevalence of single variables: that is, it helps determine whether the PN is present or absent, and - should the PN is present - whether it is typical or atypical (according to the features above discussed).

The various types of PSL (with particular regard to the differentiation between benign and malignant melanocytic lesions) can be determined through Pattern Analysis of specific dermatoscopic features.
The two steps in the new process of Pattern Analysis are the following:
1) to decide whether the lesion is melanocytic or non-melanocytic;
2) to identify the melanocytic lesion, making a diagnosis, and planning relative management.

Pattern Analysis has been deemed superior to the other algorithms (i.e., ABCD Dermoscopy Rule, Menzies score, 7-Point Checklist) for diagnostic efficiency by experts from all over the world in the 2000 CNMD [20].

9.1.1. Pattern analysis: step-1

The first step (FIGURE 44) to identify a melanocytic lesion is to search for the presence of aggregated globules (FIGURE 23), pigment network (PN) (FIGURE 8), or branched streaks (i.e., fragmented irregular PN) (FIGURE 45).
If the above patterns are absent, other characteristics should be sought (substeps).
First, it should be noted that a typical marker for blue nevus is the presence of homogeneous steel blue areas (FIGURE 31).
Second, the lesion should be evaluated for the presence of moth-eaten borders, fingerprinting, comedo-like openings, and milia-like cysts: in this case, the lesion is suggestive of either a solar lentigo (FIGURE 46) or a seborrheic keratosis (FIGURE 34).
Third, if red or red-blue to black lagoons are present, the lesion should be considered a hemangioma (FIGURE 36) or an angiokeratoma.
Finally, the lesion should be evaluated for maple leaf-like structures, arborizing telangiectasias, spoke-wheel-like areas, and gray-blue ovoid nests: this appearance is compatible with a basal cell carcinoma (FIGURE 38).

All lesions should be reevaluated to determine if they have a melanocytic structure, even if they do not have the structures described above.

FIGURE 44: Pattern analysis.

FIGURE 45: Reticular pattern: presence of branched streaks (fragmented irregular pigment network) in an atypical melanocytic nevus.

FIGURE 46: Solar lentigo with moth-eaten borders.

9.1.2. Pattern analysis: step-2

The main goal for step-2 is to make an accurate differential diagnosis between benign melanocytic lesions and melanomas.
The important features in distinguishing these two groups are the overall general appearance of color, architectural order, symmetry of pattern, and homogeneity, also known by the acronym CASH [26].
Melanocytic nevi have few colors, a regular design, and symmetrical patterns (FIGURE 47). In contrast, malignant melanoma often has several colors, architectural disorder, asymmetrical patterns, and heterogeneity (FIGURE 48).

According to the CNMD [20], Pattern Analysis differentiates the general ELM characteristics as "global features" and the dermoscopy guidelines called "local features" are simplified and reduced.
The main global dermoscopic features of melanocytic nevi are characterized by a reticular or globular or cobblestone (globules symmetrically and evenly distributed in the lesion) or homogeneous pattern. The melanocytic lesion appears to have, in this case, a diffuse pigmentation, which might be brown, gray blue, gray-black, or reddish-black and no other dermoscopy structure is found.

The so-called starburst pattern is characterized by the presence of streaks, generally pseudopods visible at the periphery of the lesion radially distributed. In Reed nevi or Spitz nevi this pattern is commonly seen.

Due to the particular anatomy of the palms and soles, the parallel pattern is exclusively found there.
Multicomponent pattern is the combination of three or more distinctive dermoscopic structures (i.e., network, dots, globules and multifaceted areas of different degree of pigmentation) within a given lesion. This pattern strongly suggests a malignant melanoma but might also be seen in some cases of melanocytic nevi and congenital nevi.

FIGURE 47: Pattern analysis: presence of one color, a regular design and a symmetrical pattern in benign nevi.

FIGURE 48: Multicomponent pattern: presence of several colors, atypical pigment network, black dots varied in size, regression areas in melanoma. Architectural disorder, asymmetry of pattern and color are closely related to malignancy.

10. Diagnostic algorithms

The diagnostic algorithms described below can be utilized exclusively after the lesion has been diagnosed as a melanocytic lesion. Use of these algorithms is usually recommended for less expert operators and improves self-training in dermoscopy evaluation.
The CNMD has reported the usefulness and validity of the ABCD Dermoscopy Rule, Menzies Score and 7-Point Check List [20], which are below described.

10.1 ABCD dermoscopy rule

The ABCD Dermoscopy Rule (Stolz method) addresses quantitatively the issue of whether the selected melanocytic lesion is benign, suspicious (borderline) or malignant [23].
The criteria were defined by multivariate analysis and are related to the clinical ABCD rule for diagnosis of PSL (A = asymmetry, B = border, C = color, and D = different structures) (FIGURE 49).
A scoring system was developed using these criteria (FIGURE 50): it calculates the total dermoscopy score (TDS) using a linear equation. With the TDS, a grading of the lesions is possible with respect to their malignant potential (FIGURE 51).

It has been shown that relatively inexperienced operators can more accurately assess melanocytic lesions using this method.

A user-friendly calculator of the TDS is available in this website just by clicking the following link:

MMMP: Total Dermoscopy Score

Asymmetry (A):
For the asymmetry evaluation, the lesion is bisected by two perpendicular axes positioned to produce the lowest possible asymmetry score. Importantly, it is advisable to incorporate also color and structural asymmetry into this ELM parameter because most equivocal lesions have a symmetrical contour (FIGURE 52). Thus, asymmetry must be calculated according to the distribution of colors and structures on either side of each axis, and not solely based on contour, as in the clinical ABCD rule (i.e., during naked-eye evaluation).

Borders (B):
The emphasis is borders that brusquely interrupt at the periphery (FIGURE 52). The lesion is visually divided into 8 pie-shaped segments, and then the number of segments is counted in which an abrupt cut-off is present at the margins of the pigment pattern. The score can range from 0-8.

Colors (C):
The different colors of the lesion are evaluated (FIGURE 52). They include red, white, light and dark brown, blue-gray, and black. White should be counted only if it is lighter than the surrounding skin (white areas) and should not be confused with the hypopigmentation commonly seen in all types of melanocytic lesions. Each color is assigned one point, and the total score ranges from 1 to 6.

Different structural components (D):
The different structural components are examined (FIGURE 52). These components include the PN, branched streaks (thickened and branched PN anywhere in the lesion, not only at the borders), structureless or homogeneous areas (color, but no structures such as PN, branched streaks, dots, or globules), dots, and globules. In order to be counted, structureless or homogeneous areas must be larger than 10% of the lesion.

FIGURE 49: ABCD dermoscopy rule.

FIGURE 50: Total dermoscopy score (TDS).

FIGURE 51: TDS interpretation.

FIGURE 52: TDS examples: Clark nevus (upper panel) and cutaneous malignant melanoma (lower panel).

10.2. Menzies scoring method

Menzies scoring method is another effort to simplify the pattern analysis ELM system [22].
This classification identifies two negative aspects and nine positive aspects commonly used in the semeiotics of dermoscopy.
To make a diagnosis of melanoma, two negative aspects (negative features) must be absent from the lesion, and one or two positive aspects (among the nine positive features) must be present (FIGURE 53).

FIGURE 53: Menzies’ method.

10.2.1. Negative features

The symmetry of the pattern is related to the symmetry of the melanocytic lesion.
Homogeneity of color (i.e., a single color) is observed (FIGURE 54).

10.2.2. Positive features

A blue-white veil appears as irregular, confluent, structureless, blue pigmentation with an overlying ground-glass or hazy appearance (FIGURE 54).
Multiple brown dots appear as focal collections of multiple, dark brown dots, not to be confused with the dark brown globules that are larger and are commonly found in benign nevi.
Peripheral black dots and globules appear as black dots and/or globules found at or near the periphery of a lesion.
Radial streaming is observed.
Pseudopods can be considered variations of the fourth criterion. They are radially oriented or bulbous, fingerlike extensions of the PN at the periphery of a lesion. They should not be scored if they are seen regularly or symmetrically around the lesion.
Scar-like depigmentation (white scar-like area) appears white or milky-white and represents true scarring.
Multiple (5-6) colors are observed, including black, gray, blue, red, dark brown, and tan. White is not counted as a color.
Multiple blue or gray dots appear as foci of multiple "pepper-like" small, blue or gray dots. They are irregular in size and shape (not globules) in the regression areas.
A broadened network shows a localized, thickened, and irregular PN.

FIGURE 54: Examples of Menzies’ method application: melanocytic nevus (upper panel) and cutaneous melanoma (lower panel).

10.3. Seven points checklist

Developed by Argenziano and colleagues [20], the 7-Point Checklist is another variation of the qualitative pattern analysis system, but with a score system.
This method uses 7 criteria specific for melanoma. It includes 3 major criteria (2 points are attributed to each of them), and 4 minor criteria (1 point is attributed to each of them) (FIGURE 55).
This method has fewer criteria to be identified and analyzed as compared to the Pattern Analysis method.
A score of 3 or greater is associated with a high likelihood of melanoma diagnosis at pathology evaluation.

FIGURE 55: Seven-point checklist.

10.3.1. Major criteria

Atypical PN: Black, brown, or gray thickened and irregular line segments are observed anywhere in a lesion (FIGURE 56).
Blue-whitish veil: Irregular, confluent, gray-blue to whitish-blue diffuse pigmentation is observed that can be associated with PN alterations, dots/globules, or streaks. This differs from the Menzies definition, in which the blue color should be featureless.
Atypical vascular pattern: Linear-irregular and/or dotted red vessels are not seen in regression areas.

10.3.2. Minor criteria

Irregular streaks: pseudopods or radial streaming are irregularly arranged at the periphery of the lesion (FIGURE 56).
Irregular pigmentation: black, brown, or gray featureless areas with an irregular shape and/or distribution are observed.
Irregular dots/globules: black, brown, or gray; round to oval; variously sized structures are irregularly distributed in the lesion.
Regression structures: white scar-like areas and/or blue pepper-like areas are observed.

FIGURE 56: Examples of 7-Point checklist application: melanocytic nevus (upper panel) and cutaneous melanoma (lower panel).

10.4 Stratification of risk level

Described by Kenet and Fitzpatrick [24] in 1994 and recently revised by the Melanoma Cooperative Group [25], this method appears to provide very simple and standardized management of both the diagnosis and therapy of early melanomas and suggestive melanocytic lesions.
The stratification of risk level is the basis for the management of melanocytic pigmented lesions (FIGURE 57).
This classification system is based on a wide database of 61,000 examined cutaneous lesions, with 478 diagnosed as cutaneous melanomas (62% stage I, per the American Joint Committee on Cancer) [25].
It is characterized by five risk levels essentially correlated to the history (as described by the patient) and clinical course of the lesion, the presence or absence of a PN, the different variables of the PN associated with the lesion, and other ELM structures (FIGURE 58).

The stratification risk level includes the following three integrated steps [24,25]:

A) History and clinical evaluation: Genetic factors, including melanoma susceptibility, and a suggestive clinical history (i.e., lesion recently changed shape or dimension) should alert the clinician. After a full body evaluation of the skin, PSL are first classified by the clinical ABCDE rules (i.e., asymmetry, irregular border, different colors, diameter > 6 mm, evolution [significant changes over a short period of time, usually months]) as visible by the naked eye. After this first step, all PSL showing at least two ABCDE criteria and a suggestive family or clinical history should be evaluated using dermoscopy.

B) Dermoscopy evaluation, first analysis: A preliminary ELM evaluation should be performed to classify PSL as either non-melanocytic lesions or melanocytic lesions, using the same criteria according to previous guidelines. Melanocytic lesions must be further subclassified in order to plan the best diagnostic strategy.

C) ELM evaluation, second level evaluation for risk-related classification of melanocytic lesions: Melanocytic lesions are classified as very-low, low, medium, high, and very-high risk lesions on the basis of accurate assessment of structural and morphological parameters. The characteristics and classification of individual lesions is based on the presence or absence of dermoscopy melanocytic features.

• Type 1 is considered very high risk. These lesions are suspected of being melanoma because they demonstrate dermoscopy features typical for melanoma.

• Type 2 is considered high risk. These are atypical nevi or borderline lesions that, in most cases, present with an irregular network and other features, such as pseudopods or radial streaming.

• Type 3 is considered medium risk. These are lesions with a PN showing the subtle perturbations that may be present in atypical nevi and lesions with melanocytic hyperplasia. The detection of slight alterations can make diagnosis more difficult, lead to overestimation of the seriousness of a lesion, and result in unnecessary surgery. Clinical history and evaluation findings are important aids to avoid "overdiagnosis".

• Type 4 is considered low risk. These are PSL with benign-appearing networks.

• Type 5 is considered very low risk. These include lesions with a benign-appearing network and with a globular or other benign ELM pattern.

The Melanoma Cooperative Group emphasizes that anamnesis, clinical observation, and other additional parameters be integrated into dermoscopy evaluations for the stratification of risk level in order to standardize the management of melanocytic lesions.

FIGURE 57: Risk level stratification.

FIGURE 58: Examples of risk level stratification application: melanocytic nevus (upper panel) and cutaneous melanoma (lower panel).

11. Practical approach to the management of a PSL

The different dermoscopy classifications have their own worthy internal coherence; however, the use of the different diagnostic scores can be affected by inter-observer and intra-observer variability when only a single guideline is used for evaluation (i.e., limited qualitative and quantitative agreement). Furthermore, all of these classifications can prove to be very sensitive but not very specific: therefore, they do not lead to 100% accuracy.

Although very useful to detect intraepidermal lesions, dermoscopy is limited in regard to nodular lesions or clearly dermal lesions, lesions without pigmentation, very dark lesions in which the amount of pigment does not allow the observation of ELM signs, and faintly pigmented seborrheic warts.
A recent meta-analysis has provided more evidence that clinical examination with the use of dermoscopy is more accurate than naked eye examination alone for discriminating melanoma from non-melanoma in suspicious skin lesions for clinicians with at least minimal training in dermoscopy [9].

The adoption of dermoscopy in routine melanoma screening improves the malignant-benign ratio in excised lesions (from 1:18 to 1:4.3, P = 0.037). Furthermore dermoscopy may be cost saving, by reducing the false-positive diagnosis (and consequently the excision rate of benign lesions) [28].
However the efficiency of dermoscopy is closely related to an integrated diagnostic synopsis for trained clinicians [30,31].

The user must think in global diagnostic terms when considering the accuracy of dermoscopy findings, independent of the methods used; a broader aim is to include case histories and clinical assessment.
In fact, the first steps to be integrated by dermoscopic evaluation should be as follows:

1) Anamnesis (personal and family background)
2) Photo-type
3) Previous sunburn history
4) Complete analysis of the entire skin surface

Such a combination of the traditional clinical diagnostic procedures and dermoscopy allows better classification of melanocytic lesions [30,31].

12. Amelanotic melanoma

Amelanotic malignant melanoma is a subtype of cutaneous melanoma with little or no pigment at visual inspection [17,30,33]. Amelanotic melanomas represent 2-8% of all malignant melanomas; the precise incidence is difficult to calculate because the term amelanotic is often used to indicate melanomas only partially devoid of pigment.
Truly amelanotic melanomas are rare; often some pigmentation is present at the periphery of the lesion, and they may mimic benign and malignant variants of both melanocytic and non-melanocytic lesions.

According to the extent of the hypopigmentation, amelanotic melanoma can be classified as follows:
A) truly amelanotic melanoma, lacking any trace of melanin even if viewed under dermoscopy;
B) partially pigmented melanoma, with larger or smaller pigmented sections covering up to 30% of its total surface;
C) hypomelanotic melanoma, showing a faint brownish tan with little variation of its intensity, which can occupy more than 30% of its total surface and may cover the entire area.

Amelanotic malignant melanoma tends to occur in sun-exposed skin, especially in elderly persons with photodamage, and may appear as erythematous, sometimes scaly, macules or plaques with irregular borders, simulating benign inflammatory plaques, superficial basal cell carcinoma, actinic keratosis, Paget disease, or Bowen disease.
It may also manifest as translucent papules, thereby resembling basal cell carcinoma, or it may clinically resemble keratoacanthoma or Merkel cell carcinoma. Alternatively, it may manifest as an exophytic nodule, often eroded, simulating a pyogenic granuloma or hemangioma, or as a skin-colored dermal plaque/nodule known as desmoplastic malignant melanoma.

From a dermoscopic point of view, amelanotic melanoma lacks most of the dermoscopic criteria reflecting pigmentation, and the vascular structures are frequently the only clue for its diagnosis. The vascular patterns associated to amelanotic melanoma include milky-red globules/areas of dotted or linear irregular or polymorphous vessels (ie, a combination of dotted and linear irregular vessels (FIGURE 59). In addition, irregular hairpin-like or glomerular vessels can also be found in amelanotic melanoma, albeit less frequently.

Because dermoscopy uses criteria reflecting pigmentation and vascular patterns, it is a useful technique for pigmented melanoma and for amelanotic melanoma. However, the vascular patterns can suggest a diagnosis of melanoma when associated with other criteria found in melanocytic lesions, such as pigment network, irregular pigmentation, streaks, irregular dots/globules, regression structures, and a blue-whitish veil.
In truly amelanotic melanoma, vascular patterns alone may not be sufficient to diagnose melanoma because hairpin vessels, dotted areas, and even milky-red areas have also been found in seborrheic keratosis and common nevi, respectively, and in melanomas.

A combined approach of dermoscopic evaluation and clinical examination including clinical information such as age, sex, history of melanoma and/or of excessive sun exposure, number and sites of lesions, time of onset, and descriptions of any changes of the lesion over time must play an important role in the diagnosis of truly amelanotic melanoma and for the so-called "featureless" melanomas that lack specific surface microscopic features.

FIGURE 59: Amelanotic melanoma: vascular pattern associated to amelanotic melanoma: combination of dotted vessels (°) and linear irregular vessels (*).

13. Difficult diagnosis

The primary goal of melanoma detection is early tumor recognition and subsequent surgical treatment. The ABCD method for detecting cutaneous melanoma has been a useful tool in distinguishing benign lesions from melanoma. However, the clinical diagnosis of cutaneous melanoma may be difficult because some melanomas lack all or most of the features of the "ABCD" rule. In fact, some authors [29-31] have identified a subset of melanomas of unusual appearance, clinically indistinguishable from other pigmented and non-pigmented cutaneous lesions, that escape clinical recognition: the most common clinical diagnoses of these histopathologically confirmed melanomas were nevus, basal cell carcinoma, seborrheic keratosis, and lentigo, while the less common diagnoses included Bowen disease, verruca vulgaris, dermatofibroma, pyogenic granuloma, and hemangioma.

Dermoscopic diagnosis for melanoma also may be difficult because some cases lack specific features for melanoma. Some authors have demonstrated the limitations of dermoscopy in the detection of early melanomas that present with an uncharacteristic dermoscopic appearance. Some melanomas, the so-called "featureless melanomas," may lack specific dermoscopic features for melanoma diagnosis and dermoscopically may even appear as benign melanocytic lesions (nevus-like melanomas) or as atypical nevi, so that the diagnosis is impossible to make on dermoscopic grounds alone [22,30,31].
In fact, difficult melanomas present dermoscopic patterns indistinguishable from those of atypical nevi and common nevi. According some authors, melanomas that failed dermoscopic detection belong to the 3 following categories: melanomas showing criteria of melanocytic nevi, melanomas exhibiting criteria of non-melanocytic lesions, and melanomas lacking specific criteria of a melanocytic or non-melanocytic lesion (hypomelanotic/amelanotic melanoma) [22,30,31].
In addition, dermoscopy does not solve the dilemma of discriminating early, featureless melanoma from dysplastic nevi.
Only a meticulous comparative and interactive process based on an assessment of all the individual’s nevi ("ugly ducking" sign) and a knowledge about recent changes can lead to the recognition of melanomas that are difficult to diagnose [30].

14. References

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28. Carli P, De Giorgi V, Crocetti E et al. Improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997-2001. Br J Dermatol 2004; 150:687-692.

29. Carli P, De Giorgi V, Giannotti B. Dermoscopy as a second step in the diagnosis of doubtful pigmented skin lesions: how great is the risk of missing a melanoma. JEADV 2001; 15:24-26.

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31. Puig S, Argenziano G, Zalaudek I et al. Melanomas that failed dermoscopic detection: a combined clinicodermoscopic approach for not missing melanoma. Dermatol Surg 2007, 33:1262-73.

32. Pizzichetta MA, Talamini R, Stanganelli I et al. Amelanotic/hypomelanotic melanoma: clinical and dermoscopic features. Br J Dermatol 2004, 150:1117-24.

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Ignazio Stanganelli, MD - Skin Cancer Unit, IRST, Meldola, and Ospedale Niguarda, Milan, Italy.


October 2008

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