CONTINUING

MEDICAL EDUCATION

How to diagnose nonpigmented skin tumors: A review of vascular structures seen with dermoscopy
Part I. Melanocytic skin tumors
Iris Zalaudek, MD,a Ju rgen Kreusch, MD, PhD,b Jason Giacomel, MBBS,c Gerardo Ferrara, MD,d `, MD,e and Giuseppe Argenziano, MD, PhDf Caterina Catricala beck, Germany; South Perth, Australia; and Benevento, Rome, and Naples, Italy Graz, Austria; Lu
Dermoscopy is a noninvasive tool that can be helpful in the diagnosis of nonpigmented skin tumors. This is because dermoscopy permits the visualization of key vascular structures that are usually not visible to the naked eye. Much work has concentrated on the identication of specic morphologic types of vessels that allow a classication into melanocytic versus nonmelanocytic and benign versus malignant nonpigmented skin tumors. Among a broad spectrum of different types of vascular patterns, six main morphologies can be identied. These are comma-like, dotted, linear-irregular, hairpin, glomerular, and arborizing vessels. With some exceptions, comma, dotted, and linear irregular vessels are associated with melanocytic tumors, while the latter three vascular types are generally indicative of keratinocytic tumors. Aside from vascular morphology, the architectural arrangement of vessels within the tumor and the presence of additional dermoscopic clues are equally important for the diagnosis. This article provides a general overview of the dermoscopic evaluation of nonpigmented skin tumors and is divided into two parts. Part I discusses the dermoscopic vascular patterns of benign and malignant melanocytic skin tumors. Part II discusses the dermoscopic vascular patterns of benign and malignant nonmelanocytic nonpigmented skin tumors. In each part, additional special management guidelines for melanocytic and nonmelanocytic nonpigmented skin tumors, respectively, will be discussed. ( J Am Acad Dermatol 2010;63:361-74.) Learning objectives: After completing this learning activity, participants should be able to categorize different vascular structures and the architectural arrangement of vessels within tumors and additional dermoscopic clues of nonpigmented skin tumors, recognize the diagnostic signicance of vessels associated with nevi and melanoma, and appropriately manage nonpigmented melanocytic skin tumors. Key words: amelanotic melanoma; Clark nevus; dermal nevus; dermoscopy; hypomelanotic melanoma; Spitz nevus; Spitz tumor; vessels.

ermoscopy is a noninvasive technique that has gained great popularity for the diagnosis of pigmented skin tumors (PSTs) because it improves diagnostic accuracy compared to examination with the naked eye.1-3 Dermatoscopes are modified magnifying devices that permit the visualization of pigmented structures or vessels in the epidermis and superficial dermis. Because most dermoscopic structures correspond to specific histopathologic correlates, dermoscopy can be regarded

as a link between clinical (macroscopic) and histopathologic (microscopic) morphology.4 In contrast to the traditional liquid or gelimmersion (contact) dermatoscopes, newer generations of handheld skin surface microscopes use cross-polarized light to visualize cutaneous structures.5 Both systems are commercially available and generally operate at 10-fold magnification.6 Polarized light dermatoscopes have the advantage that direct physical contact between the glass plate and the skin

From the Division of Dermatology,a Medical University of Graz; beck; Mends St Medical Centre,c South private practice,b Lu Perth; the Pathologic-Anatomy Unit,d Gaetano Rummo Hospital, Benevento; Department of Dermatologic Oncology,e Santa Maria and San Gallicano Dermatologic Institute, Rome; and the Department of Dermatology,f Second University of Naples. Dr Zalaudek is supported by the Elise Richter Program (V9-B05) of the Austrian Science Fund (FWF).

Conflicts of interest: The authors, editors, planners, and peer reviewers have no relevant financial relationships. Reprint requests: Iris Zalaudek, MD, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria. E-mail: iris.zalaudek@medunigraz.at. 0190-9622/$36.00 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.11.698

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is not required. Conversely, a disadvantage of nonreection, which can limit visualization of underlypolarized instruments is that contact of the optical ing vascular structures. In such cases, the application glass plate can exert pressure on the tumor surface, of liquids (water, alcohol, immersion oil, or ultracompressing surface capillaries and making them sound gel) onto the lesion often helps to diminish difficult to visualize. While this is of limited diagnostic this surface reection and improves the visualization disadvantage in the evaluation of PSTs, vessels may of vessels. be the only dermoscopic features observable in nonpigmented skin tumors A THREE-STEP (NPSTs) and they are thereDIAGNOSTIC CAPSULE SUMMARY fore a valuable key for ALGORITHM FOR THE diagnosis. DIAGNOSIS OF Dermoscopy improves the diagnosis of Given that NPSTs repreNONPIGMENTED SKIN nonpigmented skin tumors because it sent a diagnostic challenge TUMORS allows the visualization of vascular for the clinician, much work Key points patterns and residual pigmentation that has concentrated on the d Before beginning the are not visible to the naked eye. identication of vascular dermoscopic evaluation The dermoscopic diagnosis of a patterns that may aid their of a given nonpigmennonpigmented skin tumor is based on a correct recognition. 7-12 An ted skin lesion, it is three-step algorithm that considers overview of the dermoscopic necessary to establish vascular morphology, the architectural vascular patterns is provided whether the lesion is a arrangement of vessels, and additional in this article, and key points tumor or belongs to the clues. and diagnostic clues for the spectrum of inflammanagement of the most The predominant vascular pattern of matory or infectious common NPSTs are amelanotic/hypomelanotic melanoma skin diseases, because provided. strongly depends on the tumor the vascular pattern thickness. between these two cateBASIC ASPECTS TO gories may overlap Comma, dotted, and linear irregular VIEW VESSELS BY d The dermoscopic exvessels are suggestive of melanocytic DERMOSCOPY amination of a NPST skin tumors. The visualization of vasshould follow a stepwise Histopathologic diagnosis should always cular structures strongly algorithm assessing the be obtained for lesions displaying depends on the optical demorphology of the vasdotted, linear irregular, or polymorphous vice (contact or noncontact cular pattern, the architecvessels, milky red color or globules, or dermatoscope) and the tural arrangement of those that have a nonspecific technique of dermoscopic vessels in the tumor, and dermoscopic appearance. examination.6,7 When using the presence of additiocontact dermatoscopes, the nal dermoscopic criteria contact glass plate of these instruments must be set carefully on the tumoral surface, applying minimal The accurate diagnosis of NPST is clinically difdownward pressure. Liquids of low viscosity, such as cult given the wide spectrum of possible differential alcohol or immersion oil, are sometimes used as diagnoses, which vary from benign inammatory to contact media, but are best avoided in contact highly aggressive malignant skin tumors, such as dermoscopy. This is because they require excessive amelanotic melanoma or Merkel cell carcinoma. downward pressure to be exerted by the instrument Vascular patterns of NPSTs may overlap with onto the tumor in order to obtain complete optical those of inammatory skin disorders, so it is critical contact. In most dermatology offices, translucent to establish whether the lesion is a tumor or repreultrasound gel is an effective contact medium besents an inammatory or infectious process.12 When a nonpigmented skin lesion (NPSL) is clinically cause of its high viscosity. Moreover, a practical tip classified as a tumor (taking into consideration lesion for using contact dermoscopy in the examination of size, number, distribution, clinical features, and hisNPSTs is to apply a sufficiently generous dollop of tory), the dermoscopic examination should follow a ultrasound gel onto the lesion, which allows the stepwise algorithm assessing first the morphology of glass plate to be softly dipped into the gel. the vascular pattern, second the architectural arAlthough noncontact dermoscopy does not rerangement of vessels in the tumor and, third the quire a liquid interphase between the lens and the presence of additional dermoscopic criteria that skin, very dry or scaly lesions may cause signicant
d d d d d

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Abbreviations used: AHM: AK: BCC: BD: CCA: CMN: DM: IEC: KA: NPSL: NPST: PPV: PST: SCC: SH: SK: amelanotic/hypomelanotic melanoma actinic keratosis basal cell carcinoma Bowen disease clear cell acanthoma congenital melanocytic nevus desmoplastic melanoma intraepidermal carcinoma keratoacanthoma nonpigmented skin lesion nonpigmented skin tumor positive predictive value pigmented skin tumor squamous cell carcinoma sebaceous hyperplasia seborrheic keratosis

provide further clues for the diagnosis. Finally a diagnosisor at least an appropriate management plan based on several clues and rulescan be established.13

Step 1: Morphology of vascular patterns The most important chromophore in NPST is hemoglobin within the erythrocytes of the vascular lumen. Vessels located in the dermis generally appear pink and blurred because of the dispersion of light by dermal connective tissue bers, whereas vessels located more supercially (immediately below the epidermis) appear bright red and focused. Given that dermoscopy provides a horizontal view of the skin, vessels arranged parallel to the skin surface appear as lines, whereas vertically arranged vessels will be seen as dots or loops. Importantly, the prevailing vascular patterns strongly depend on tumor progression and volume.7 For example, clinically flat, superficial amelanotic/hypomelanotic melanoma (AHM) or basal cell carcinoma (BCC) show different vascular patterns compared to their thick, nodular counterparts. NPSTs are characterized by specic morphologic types of vessels that allow a further classication into melanocytic versus nonmelanocytic and benign versus malignant skin tumors. Among a broad spectrum of different types of vascular patterns that have been described in the literature, six main morphologic categories of vascular patterns can be identied. These are comma-like, dotted, linear irregular, hairpin, glomerular, and arborizing vessels (Fig 1, A-F ). In addition, three specific global features can be differentiatednamely, crown vessels surrounding a white center, strawberry pattern, and milky red areas/globules (Fig 1, G-I ).7,9,11,13 With some exceptions, comma, dotted, and linear irregular vessels are associated with melanocytic lesions (dermal nevi,

Spitz nevi, and AHM, respectively). Hairpin, glomerular, and arborizing vessels are generally indicative of the nonmelanocytic tumors seborrheic keratosis (SK) and squamous cell carcinoma (SCC), including keratoacanthoma (KA)-(hairpin), Bowen disease (BD) and intraepidermal carcinoma (IEC)-(glomerular), and basal cell carcinoma (BCC)-(arborizing).7,9,11 Crown vessels surrounding a white polylobular center are diagnostic for sebaceous hyperplasia (SH), while the strawberry pattern and milky red areas/globules are relatively specific features of facial actinic keratosis (AK) and thick AHM, respectively. Atypical linear vessels either alone or in combination with any other vascular pattern (ie, a polymorphous vascular pattern) should always raise the index of suspicion for malignant skin tumors.9,14 Kittler et al15 have proposed defining vessels using purely morphologic descriptive terminologies. According to this proposal, vessels can be classified into three main morphologic types: red dots (formerly dotted vessels), clods (formerly milky red globules), and linear vessels. With regard to the morphology of linear vessels, they can be further subdivided into linear straight (formerly linear irregular vessels), linear looped (formerly hairpin vessels), linear curved (formerly comma vessels), linear serpentine (formerly linear irregular, arborizing, crown, or short ne arborizing telangiectasias), linear helical (formerly corkscrew vessels), and linear coiled (formerly glomerular vessels). However, some of the newly introduced terms describe only barely the arrangement of vessels or their relation to tumor thickness. For example, in SH, the peripheral arrangement of vessels embracing the central tumoral area is included in the term crown vessels, but cannot be deduced from linear straight or linear serpentine.15 Whether this may decrease the diagnostic accuracy for some types of vascular patterns remains to be claried. Because no study to date has been performed comparing the inter- and intraobserver agreement for the traditional and new vessel terminologies, we have provided for convenience both the traditional and newly introduced (in parenthesis) terminologies of vascular patterns (Table I). Step 2: Architectural arrangement of vessels After the assessment of morphology, the recognition of the architectural arrangement of vascular structures is a critical step in the diagnosis of NPSTs. This is because different skin tumors may reveal similar types of vessels, but these can differ in their architectural arrangement. Figure 2 summarizes the

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Fig 1. Schematic drawing of the six most common morphologic types of vessels (A-F) and three specific global patterns (G-I) of nonpigmented skin tumors. A, Comma-like (linear curved) vessels, (B) dotted (red dots) vessels, (C) linear irregular (linear straight or linear helical) vessels, (D) hairpin (linear looped) vessels (from left to right: single stranded, double stranded, and twisted), (E) glomerular (linear coiled) vessels, (F) arborizing (linear serpentine) vessels, (G) crown (linear straight) vessels, (H) strawberry pattern, and (I) milky red globules (clods).

different distributions of vascular patterns in NPSTsnamely regular, string-like, clustered, radial, branched, and irregular.11,13,15 Step 3: Assessment of additional criteria The assessment of additional criteria provides further clues for the diagnosis, such as a white halo surrounding the vessels (as is typically seen in keratinizing tumors),7 residual pigmentation (in hypopigmented melanocytic tumors), hairs, central duct openings, surface scales, ulcerations, et cetera. Rules for an appropriate management Although several tumors, such as BD, SH, clear cell acanthoma (CCA), or nodular cystic BCC reveal highly specic patterns allowing a ready diagnosis in most cases; others, such as Spitz nevi, red Clark nevi, pyogenic granuloma, or AHM, may be difcult to differentiate.9 For this reason, general guidelines have been established to assist in

making the most appropriate management decision (Table II).11

VASCULAR PATTERNS OF MELANOCYTIC NEVI

Comma vessels (linear curved) in dermal nevi Key point d Dermal nevi are dermoscopically characterized by a regular distribution of comma vessels, which may be of various sizes The dermoscopic hallmark of dermal nevi are comma-like (linear curved) vessels, which show a positive predictive value (PPV) of 94%.8 These are coarse vessels that are slightly curved and barely branched (Fig 3) but can be highly variable in both size and caliber. Associated features such as terminal hairs, a few milia-like cysts or comedo-like openings, and residual brown-gray globules provide further clues for the diagnosis (Fig 3, A).11,16 Comma-like vessels (linear curved) have a fairly classical

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Table I. Standard and new terminology of different morphologic types of vessels and definitions of vascular structures seen by dermoscopy
Vascular morphology New terminology* Definition

Comma Dotted Glomerular

Linear curved Dots Linear coiled

Crown Hairpin

Linear serpentine Linear looped

Linear irregular Milky red globules/areas

Linear straight; linear serpentine Red clods

Corkscrew Arborizing

Linear helical Linear straight; linear serpentine (large caliber)

Fine short microarborizing Strawberry

Linear straight; linear serpentine (small caliber)

Polymorphous

Coarse vessels that are slightly curved and barely branching Tiny red dots densely aligned next to each other Variation on the theme of dotted vessels. They are tortuous capillaries often distributed in clusters mimicking the glomerular apparatus of the kidney Groups of orderly bending, scarcely branching vessels located along the border of the lesion Vascular loops sometimes twisted and bending, usually surrounded by a whitish halo when seen in keratinizing tumors Linear, irregularly shaped, sized, and distributed red structures Globules and/or larger areas of fuzzy or unfocused milky red color often corresponding to an elevated part of the lesion Linear vessels twisted along a central axis Stem vessels of large diameter branching irregularly into finest terminal capillaries. The vessels color is bright red, being sharply focused in dermoscopic images because of their location on the surface of the tumor (just below the epidermis) Irregularly shaped and distributed linear, elongated telangiectasias that are sharply focused. These vessels represent a variation of arborizing vessels Erythema forming a marked pink-to-red pseudonetwork around hair follicles of the face. Frequently intermingled with fine, linear-wavy vessels surrounding the hair follicles. Often hair follicle openings are filled with yellowish keratotic plugs that are surrounded by a white halo Any combination of two or more different types of vascular structures. The most frequent is linear irregular and dotted vessels

*According to Kittler et al.15

appearance in dermal nevi with a papillomatous surface (Unna type; Fig 3, A), while often being more polymorphic in dermal nevi of the Miescher type (Fig 3, B). Notably, the presence of comma-like vessels (linear curved) has been shown to represent a significant negative predictor for AHM (odds ratio, 0.10).17 Dotted vessels (red dots) in Spitz nevi Key points d Dotted vessels are highly predictive for melanocytic skin tumors in general d Regularly distributed dotted vessels over a pink (milky red) background associated with a reticular depigmentation are suggestive of nonpigmented Spitz nevus, but early amelanotic melanoma must be ruled out

Atypical, nodular Spitz nevi or Spitz tumors are dermoscopically indistinguishable from melanoma

Dotted vessels (red dots) are highly predictive for melanocytic skin tumors (PPV = 90%) in general, and are especially seen in Spitz nevi. In a study by our group, we found dotted vessels in 77.8% of Spitz nevi.9 These red dots correlate to the tips of vertically arranged vessels (capillaries) of small diameter that are located in the dermal papillae. In flat Spitz nevi, dotted vessels (red dots) appear as small red dots that are densely aligned in a very regular array (highly monomorphous appearance) and occur on a pink (milky red) background (Fig 4, A). Quite commonly, Spitz nevi exhibit reticular depigmentation (also called negative network), dermoscopically characterized by white lines which spare the red dot

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Fig 2. Schematic drawing of vascular arrangements. A, Regular, (B) in a string, (C) clustered, (D) radial, (E) irregularly branched, and (F) irregular.

vessels and intersect to form a white network structure (Fig 4, B).13,18 Less frequently, chrysalis-like structures can also be seen.19 The latter structure is a newly described morphologic criterion that is only visible when using polarized dermoscopy and consists of short, shiny white orthogonal lines, which probably correspond to altered papillary dermal collagen.20 In hypopigmented Spitz nevi, a residual starburst or globular pattern may facilitate the diagnosis.18 In our experience, nodular and atypical Spitz nevi differ from flat Spitz nevi in their vasculature as they often exhibit atypical vascular structures indistinguishable from those of thick AHM, including linear irregular vessels (linear straight), glomerular vessels (linear coiled), or milky red globules (red clods; Fig 4, C and D).9 Importantly, no single dermoscopic criterion has yet been described that allows for an accurate differentiation of flat, atypical, and nodular Spitz nevi from AHM. Therefore, excision of all Spitzoid lesions is generally recommended.21

Dotted vessels (red dots) and comma vessels (linear curved) in red Clark nevi Key point d It is important to evaluate all lesions in fair skinned individuals who have multiple red Clark nevi in order to verify similar vascular patterns and colors of these nevi Another type of melanocytic tumor frequently showing dotted vessels (red dots) is the red Clark nevus, as seen in fair skinned individuals (skin type I or II).22 In contrast to the dense arrangement of dotted vessels in Spitz nevi, vessels in red Clark nevi are more loosely arranged throughout the lesion and are often associated with a few comma-like (linear curved) vessels (Fig 5). The background color may provide a further criterion helpful in distinguishing red Clark nevi from Spitz nevi. The former commonly show a tan colored background, while Spitz nevi usually reveal a striking pink (milky red) color.

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Table II. Criteria and management recommendations for nonpigmented skin tumors
Step 1: Vessel morphology Step 2: Vessel arrangement Step 3: Additional criteria Diagnosis Management Level of evidence

Comma Dotted plus comma Dotted

Regular Regular

Residual brown globules, hairs Brownish pigmentation Reticular depigmentation; chrysalis structures; remnants of pigmentation White halo White halo, surface scales White halo; milia-like cysts; comedo-like openings White halo; central keratin crust Blue-gray ovoid nests/globules/ dots/blotches Multiple erosions; brown-gray, leaflike, or wheel spoke areas Red homogeneous pigmentation Chrysalis structures; remnants of whitepink-brown-gray pigmentation Multiple colors; milky red globules/areas White polylobular center

CMN or dermal nevus Red clark Nevus

No action If similar other nevi, follow-up; if single lesion: excision Excision

IIA* IIA*

Regular

Spitz nevus or thin AHM

IIA*

Dotted Dotted plus glomerular Hairpin

String-like Clustered Regular

CCA BD or IEC SK

No action Excision No action

IIIy IIA* IIBz

Radial or irregular Arborizing Large stem vessels; branching over lesion Fine microarborizing vessels scattered throughout lesion Central or irregular Central or irregular

SCC or KA Nodular cystic BCC

Excision Excision

IIBz IIA* IIBz

Superficial BCC

Excision

Linear irregular Linear irregular and dotted

PG or nodular AHM

Excision

IV IIBz

Thin or intermediate Excision thick AHM

Linear irregular and hairpin or corkscrew or arborizing Crown

Central or irregular

Thick AHM or melanoma metastases SH

Excision

IIA*

Radial

No action

IIIy

AHM, amelanotic/hypomelanotic melanoma; BCC, basal cell carcinoma; BD, Bowen disease; CCA, clear cell acanthoma; CMN, congenital melanocytic nevus; IEC, intraepidermal carcinoma; KA, keratoacanthoma; PG, pyogenic granuloma; SCC, squamous cell carcinoma; SH, sebaceous hyperplasia; SK, seborrheic keratosis. *Level IIAEvidence from at least one controlled study without randomization. z Level IIBEvidence from at least one other type of experimental study. y Level IIIEvidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case control studies. Level IVEvidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

Hypopigmented Clark nevi in fair skin individuals often reveal dotted (red dots) or comma-like vessels (linear curved) within an elevated hypopigmented center that is surrounded by a at peripheral light brown reticular or homogenous pigmentation.23 In fair skinned individuals with multiple red Clark nevi, it is critical to evaluate all lesions in order to detect deviation from the signature vascular patterns

and colors. This is particularly helpful for the diagnosis of nevi located on the legs of individuals suffering from chronic venous insufciency, acrocyanosis, and livedo reticularis (cutis marmorata), which frequently display dotted vessels.12 In such cases, comparison with neighboring nevi enables the recognition of similar vascular structures, which helps to reduce the suspicion of hypomelanotic melanoma.

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Fig 3. Dermoscopic images of dermal nevi: Unna (A) and Miescher (B) type. The nevus in part A reveals variably sized and shaped comma (linear curved) vessels, as well as some comedolike openings (arrows), hairs, and residual brown globules. The nevus in part B shows structureless brown pigmentation and elongated comma (linear curved) vessels.

VASCULAR PATTERNS OF AMELANOTIC AND HYPOMELANOTIC MELANOMA

The predominant vascular patterns of AHM and their arrangement strongly depend on the thickness of the tumor. The observed vascular patterns undergo time-related changes according to melanoma progression and should therefore always be correlated with the clinical palpability of a given lesion (ie, at, elevated, or nodular). Generally, in early (at) AHM, dotted vessels are seen, which appear homogeneous in shape and are arranged regularly. In contrast, vessels in advanced (raised) tumors are more irregularly distributed and appear longer, coarser, and more variable in shape. Hypopigmentation in melanoma requires a more precise denition. Tumors lacking any trace of melanin, even if viewed under the dermatoscope, are true amelanotic melanomas.17 Hypomelanotic tumors have some remnants of melanin pigmentation but are lighter overall than conventional pigmented melanoma. One subtype has faint brownish melanin pigment that may occupy the entire lesion area (light colored melanoma). Another has larger or smaller pigmented sections occupying less than 25% of the lesion, with the remaining part being amelanotic (partially pigmented melanoma).17 Finally, melanomas in advanced stages of regression are poorly pigmented or focally depigmented.24,25

Dotted vessels (red dots) in thin amelanotic melanoma (<1 mm thickness) Key point d The dermoscopic patterns of early amelanotic melanoma may be indistinguishable from those of nonpigmented Spitz nevus and vice versa The dermoscopic diagnosis of thin melanoma (\ 1 mm Breslow thickness) is suggested by dotted vessels (red dots) in a quite regular arrangement across the entire tumoral area.7,9,11,13,17,26-28 Dotted vessels (red dots) plus linear irregular vessels (linear straight) in intermediate thickness amelanotic melanoma (1-2 mm tumor thickness) Key point d The combination of dotted and linear irregular vessels over a milky red background with or without chrysalis-like structures or reticular depigmentation is highly suggestive for invasive melanoma Intermediate thickness AHMs reveal dotted vessels (red dots) either as the only dermoscopic vascular pattern or, more commonly, scattered in combination with hairpin (linear looped) or linear irregular (linear straight) vessels (ie, forming a

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Fig 4. Dermoscopic images of nonpigmented Spitz nevi. A, Regularly distributed small dotted vessels (red dots) over a milky red background are the most common finding in flat Spitz nevi. B, Example of a slightly pigmented Spitz nevus showing regularly distributed dotted vessels (red dots) and a reticular depigmentation appearing as white reticular lines. C, Nodular Spitz nevus showing vascular polymorphism composed of dotted (red dots) and glomerular (linear coiled) vessels along with reticular depigmentation. D, Atypical Spitz nevus showing predominantly milky red globules (red clods), in addition to a single linear telangiectasia (arrow) and remnants of brown pigmentation.

white), reticular depigmentation, or chrysalis-like structures can occur in both tumors, giving rise to the general rule that one should excise all lesions with a Spitzoid appearance under dermoscopy. Polymorphous vessels in thick amelanotic melanoma (>2 mm thickness) Key point d Thick melanoma exhibits irregularly distributed, elongated, and variably sized linear vessels including twisted and splintered hairpin vessels, corkscrew or arborizing vessels, and/or milky red globules
Fig 5. Dermoscopy of a red Clark nevus revealing loosely distributed dotted (red dots) and comma-like (linear curved) vessels on a light brownish background.

polymorphous vascular pattern). The latter vessels are often kinked and can be difcult to discern (PPV for melanoma = 67.6%; Fig 6).7,17,14,17,26,29-35 Although the vessels in melanoma tend to be more irregularly distributed than in Spitz nevi, it is undeniable that a proportion of AHMs are indistinguishable dermoscopically from Spitz nevi (Fig 7). In addition, a milky red color (shades of pink and

In contrast to the often subtle appearance of vessels in thin AHM, thick AHM exhibit irregularly distributed, elongated, and variably sized atypical linear vessels, including twisted and splintered hairpin loops (linear looped) and corkscrew vessels (linear helical).17,26,35-37 Of note, melanoma of more than approximately 3 mm thickness develops a different structure of vascular supply. Because vertical growth apparently cannot be maintained by further elongation of the capillary loops, vessels arising from the adjacent dermal plexus appear on the tumoral surface. These vessels resemble

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Fig 6. Clinical and dermoscopic images of true amelanotic melanoma (tumor thickness, 1.7 mm). Dermoscopy reveals a striking pink (milky red) color and predominant linear irregular (linear straight) vessels.

Fig 7. Side-by-side comparison of a partially pigmented spitzoid melanoma with a tumor thickness of 1.5 mm (A) and a Spitz nevus (B). Both tumors exhibit a striking asymmetry of colors and structures, a combination of peripheral dotted (red dots) and central linear irregular vessels (linear straight) and reticular depigmentation, making an accurate differentiation between the melanoma and nevus virtually impossible.

arborizing vessels of BCC; however, their winding and branching is less bizarre and irregular as compared to BCC. At this stage, dotted vessels (red dots) are rarely observed and, if present, are seen in a flat portion of the tumor. Less commonly seen, but quite suggestive of AHM (PPV = 77.8%) are milky red globules (red clods).9 These are large ovoid or polygonal structures of pink-white color that often show a central atypical linear vessel (Fig 8). Individual globules are usually separated from each other by blurred whitish lines.

Dermoscopic features of hypomelanotic melanoma Key point d Dermoscopy improves the diagnosis of hypomelanotic melanoma because it permits, besides vascular structures, the recognition of brown-gray-blue pigmentation patterns not discernible to the naked eye While true AHMs lacking any pigmentation still remain a diagnostic challenge, dermoscopy improves the diagnostic sensitivity (96%) and

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Fig 8. Clinical and dermoscopic images of hypomelanotic melanoma (tumor thickness, 2 mm). The central nodular part lacks any pigmentation and reveals milky red globules with linear irregular vessels (linear straight; arrows). In addition, chrysalis-like structures can be seen (square). The diagnosis of melanoma in this case is facilitated by the presence of melanoma-specific patterns in the flat area, such as an atypical network, residual homogeneous brown pigmentation, and large areas of white scar-like regression.

Fig 9. Clinical (insert) and dermoscopic images of hypopigmented melanoma (tumor thickness, 1.5 mm). Dermoscopy reveals predominantly dotted vessels (red dots) and a few linear irregular (linear straight) vessels, as well as structureless brown to bluish pigmentation. Although the lesion lacks pigmented patterns, such as a pigment network, globules, or streaks, the brown-blue pigmentation is suggestive for a melanocytic tumor.

specicity (88%) of hypopigmented melanoma compared with clinical examination alone (89% and 65%, respectively).17,26 This is because dermoscopy permits the visualization of vascular structures and the recognition of pigmentation patterns not discernible to the naked eye. The latter includes structureless brown, gray, or bluish blotches, features of regression, irregular globules, streaks, and residual areas of atypical pigment network (Figs 8 and 9). Recently, Menzies et al17 conducted a study investigating the predictive dermoscopic patterns of AHM in a series of benign and malignant, melanocytic, and NMSTs lacking significant pigmentation. In this study, comma-like (linear curved) vessels were a significant negative predictor for AHM, while the presence of remnants of pigment (including blue-white veil, scar-like depigmentation, multiple blue gray dots, irregular depigmentation, and irregular brown dots/ globules), multiple colors, and predominant central vessels were significantly associated with AHM. Based on their findings, a simple model for the diagnosis of nonmelanoma versus AHM was proposed. However, the latter model achieved only 70% sensitivity and 56% specificity in a test set. For this reason, the authors formulated an alternative model to distinguish between all malignant (including AHM, BCC, SCC, KA, and BD) and nonmalignant lesions lacking significant pigment. In an independent test, the diagnostic sensitivity for malignant lesions in the latter model increased to 96%. However, the rise in sensitivity of this model was attained at the expense of a very low specificity (37%).

RARE MELANOMA VARIANTS Key points

d

Nodular melanoma may lack significant vascular patterns Eczema-like melanoma should be considered in the differential diagnosis of solitary, scaly, eczematous patches or plaques that do not respond to topical treatment Dermoscopy may be helpful in the recognition of fully regressed melanoma or desmoplastic melanoma Cutaneous melanoma metastases reveal dotted or corkscrew vessels

Nodular melanoma commonly lacks any discernible vascular patterns. In such cases, polychromatism (shades of pink, white, red, blue, brown, or gray) may be the only clue for the correct diagnosis (Fig 10).17,26,35-39 Eczema-like melanoma is a rare variant of melanoma (to our knowledge, only six cases have been published to date) that can be extremely difcult to diagnose because of its similarity to a range of inammatory or infective processes, including nummular eczema, psoriasis, verrucous lichen planus, and tinea corporis. The clinical presentation is remarkable in that it typically presents as a solitary, scaly patch or plaque typically located on the extremities and is resistant to various topical treatments. However, dermoscopy may suggest the diagnosis by revealing vascular polymorphism including dotted (red dots), glomerular (linear coiled) or atypical linear (linear straight) vessels in association with residual brown to gray pigmentation.29,34,40

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tumors. The latter is characterized by poorly dened, large ovoid structures of homogeneous red-brown color.43

CLUES AND RULES FOR DIFFERENTIAL DIAGNOSIS AND MANAGEMENT REGARDING AMELANOTIC OR HYPOMELANOTIC MELANOMA
Four main points to avoid missing amelanotic melanoma First, a fair proportion of AHMs are nodular.36,37 In many instances, AHM presents as a clinically elevated tumor that is firm on palpation and may have been noted by the patient to have grown in recent weeks or months. These three characteristics are summarized in the clinical EFG rule, which can be used as a guide when dealing with melanomas lacking the classical ABCD clinical criteria.44-47 Second, the true prevalence of AHM is quite low. In most cases, melanomas lacking signicant pigmentation are of the hypomelanotic type. By using dermoscopy, residual pigmentation can be better visualized as small areas of blue, white-blue, or gray, involving a subsection of the tumor. Sometimes a residual pigment network and/or brown, gray, or black dots/globules may also be seen as a residual epidermal component at the periphery of an amelanotic proliferating nodule.17,26 Third, within the amelanotic area, vessels are easily visualized by dermoscopy. In many instances, melanoma is typied by atypical, polymorphic vessels (dened as having 2 or more vessel morphologic types). Dotted vessels may be seen in combination with linear irregular and/or hairpin vessels and are not surrounded by a whitish halo.9,14,17,26,31-35 Lastly, a fair proportion of AHMs show a typical pinkish background color, the so-called milky red color.9,10,17,26 This particular dermoscopic feature is not 100% specific for melanoma, because it may also be seen in BCC and pyogenic granuloma.47 However, milky red areas are very rare in benign tumors, such as intradermal nevi or seborrheic keratoses. Intradermal nevus versus thick amelanotic/hypomelanotic melanoma Thick AHM may be a great masquerader, mimicking the most banal lesions such as intradermal nevus. The diagnosis in such cases is facilitated by the correct recognition of vascular patterns associated with these tumors. In our experience, comma-like (linear curved) vessels often cause diagnostic difculties for beginners in dermoscopy, because of their striking variability in both size and caliber. It is therefore advisable for novice dermoscopists to

Fig 10. Clinically this nodular melanoma (tumor thickness, 4 mm) lacks asymmetry and border irregularity, but has subtle variegation in color. Dermoscopy highlights the polychromatism of the lesion, which is an important clue for the diagnosis of such challenging nodular melanoma (which often lack one or more criteria of the ABCD algorithm).

Dermoscopy has been also shown to aid the clinical detection of fully regressed melanomas.25 In a recent study, seven specific changes were associated with melanomas that underwent complete regression, including scar-like depigmentation, background pink coloration, linear irregular vessels, dotted vessels, remnants of pigmentation (structureless or pepper-like), and whitish transverse bands. The last feature was only observed with polarized light dermoscopy devices. Similar changes have also been recently described by Stante et al.41 Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma that is typically located on the chronically sun exposed areas of the head and neck. The diagnosis of DM is often delayed, because DM may mimic a variety of other less sinister skin lesions. In a recent study investigating the dermoscopic patterns of six cases of DM, the authors found criteria of a melanocytic tumor (ie, globules, network or streaks) in only half of the cases, whereas the remaining lesions lacked any specic criteria of either melanocytic or nonmelanocytic tumors.42 However, regression features were seen in all six cases, including white scar-like areas (6/6), gray peppering (3/6), multiple ([4) colors (5/6), and melanoma-related vascular patterns (5/6), such as linear irregular (linear straight) vessels (4/6) and milky red areas (2/6). Similar to primary melanoma, the prevailing vascular pattern in melanoma metastases depends on the vertical dimension of the lesion. As such, dotted vessels (red dots) prevail in thinner lesions, while corkscrew vessels (linear helical) or a saccular pattern is more commonly encountered in thicker

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practice observing banal dermal nevi so as to better recognize their repetitive morphology. This will assist in the recognition of lesions showing deviant vascular patterns. Apart from vascular morphology, a pink (milky red) background color provides a further important criterion in recognizing AHM, which contrasts to the tan background color of dermal nevi. Nonpigmented Spitz nevus or atypical Spitz tumor versus amelanotic/hypomelanotic melanoma Specic vascular criteria that differentiate nonpigmented or atypical Spitz tumors from AHM have not been identied; therefore, excision is recommended for all lesions with a Spitzoid appearance (Fig 7). Red Clark nevus versus nonpigmented Spitz nevus A helpful clue for differentiating Spitz nevus from red Clark nevi in fair skinned individuals is that the dotted (red dots) vessels in the former are usually densely arranged, while they are more scantily distributed in red Clark nevi. Furthermore, the diagnosis of Clark nevi is suggested if assessment of all neighboring lesions reveals similar dermoscopic patterns.

SUMMARY
Dermal nevi exhibit specic vascular patterns that facilitate their diagnosis and assist in the differentiation from melanoma. In contrast, no reliable criteria have yet been identied that allow the differentiation of Spitzoid neoplasms from AHM. Accordingly, lesions exhibiting dotted, linear irregular, and/or polymorphous vessels should always be excised in order to avoid missing AHM.
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