IV.8 Melanoma of the Trunk and Limbs Including Superficial and Nodular Melanoma

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IV.8.1 Definition . . . .238

IV.8.2 Clinical Features . . . .238

IV.8.2.1 Clinical Symptoms . . . .237

IV.8.2.2 Clinical Signs . . . .238

IV.8.3 Superficial Spreading Melanoma . . . .239

IV.8.3.1 Borders in Superficial Spreading Melanoma . . . .240

IV.8.4 Nodular Melanoma . . . .243

IV.8.5 Dermoscopic Criteria . . . .243

IV.8.6 Methods for the Dermoscopic Diagnosis of Melanoma . . . .244

IV.8.7 Colors in Melanoma by Dermoscopy . . . .244

IV.8.8 Symmetry and Asymmetry in Melanoma by Dermoscopy . . . .244

IV.8.9 Global Patterns in SSM and Nodular Melanoma . . . .244

IV.8.10 Dermoscopic Findings in SSM . . . .244

IV.8.10.1 Pigment Network . . . .244

IV.8.10.2 Globules and Dots . . . .244

IV.8.10.3 Structureless (Homogeneous) Areas/Blotches . . . .245

IV.8.10.4 Blue-White Veil . . . .245

IV.8.10.5 Streaks . . . .245

IV.8.10.6 Negative Pigment Network . . . .245

IV.8.10.7 Regression Areas . . . .245

IV.8.10.8 Vascular Structures . . . .245

IV.8.11 Dermoscopic Findings in Nodular Melanoma . . . .245

IV.8.11.1 Additional Preoperative Information Obtained by Dermoscopy . . . .246

IV.8.12 Relevant Clinical Differential Diagnoses . . . .246

IV.8.13 Differential Diagnosis . . . .246

IV.8.13.1 Differential Diagnosis in SSM. . . .246

IV.8.13.1.1 Melanocytic Nevi . . . .246

IV.8.13.1.2 Pigmented Basal Cell Carcinoma . . . .246

IV.8.13.1.3 Pigmented Actinic Keratosis/ Bowen’s Disease . . . .246

IV.8.13.1.4 Seborrheic Keratosis . . . .247

IV.8.13.1.5 Dermatofibroma . . . .247

IV.8.13.2 Differential Diagnosis in Nodular Melanoma . . . .247

IV.8.13.2.1 Spitz Nevus . . . .247

IV.8.13.2.2 Blue Nevus . . . .247

IV.8.13.2.3 Basal Cell Carcinoma . . . .247

IV.8.13.2.4 Clear-Cell Acanthoma . . . .247

IV.8.13.2.5 Merkel Cell Carcinoma . . . .247

IV.8.13.2.6 Bednar Tumor . . . .247

IV.8.13.2.7 Atypical Fibroxantoma . . . .247

IV.8.13.2.8 Malignant Tumors of the Breast . . . . .248

IV.8.13.2.9 Hemangioma . . . .248

IV.8.13.2.10 Angiokeratoma . . . .248

IV.8.13.2.11 Dermatofibroma . . . .248

IV.8.13.2.12 Seborrheic Keratosis . . . .248

IV.8.13.2.13 Pyogenic Granuloma . . . .248

IV.8.14 Histopathology . . . .248

IV.8.14.1 Radial Growth Phase . . . .248

IV.8.14.2 Vertical Growth Phase . . . .249

IV.8.15 Management . . . .250

IV.8.15.1 Melanoma Screening and Identification of High-Risk Persons . . . .250

IV.8.15.2 Clinical History . . . .251

IV.8.15.3 Physical Examination . . . .251

IV.8.15.3.1 Examination of Lymph Nodes . . . .251

IV.8.16 Staging and Treatment of Primary Melanoma . . . .252

IV.8.16.1 Surgical Excision of the Tumor . . . . .252

IV.8.16.2 Sentinel Node Biopsy . . . .252

IV.8.17 Treatment of Distant Disease . . . .253

IV.8.18 Case Study . . . .254

References . . . .256

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IV.8.1 Definition

Superficial and nodular melanoma of the trunk and limbs are the most frequent melanoma subtypes in Caucasians, and are largely responsible for the increased incidence of melanoma noted over the past few decades [1, 2]. Superficial spreading melanoma (SSM) is defined as an invasive melanoma that has an in-situ component beyond three rete ridges of its invasive component at the dermal layer. The radial growth phase of SSM is characterized by invasion of tumor cells both singly and in nests upward within the epidermis (pagetoid spread). In the natural progression of the neoplasm the melanoma will progress from the radial growth phase to the vertical growth phase. The SSM may arise in a preexisting nevus or de novo, and although a predilection for the trunk (the back of men) and limbs in women is documented, SSM can cer- tainly develop at any site on the body [3, 4].

Nodular melanoma is the second most common type of melanoma. Epidemiologically it is most commonly seen in elderly men but can oc- cur at any age and in both sexes [1, 2]. By definition, nodular melanoma arises in normal skin or in a precursor lesion, but without an inter- vening radial growth phase. A widely accepted histopathological definition of nodular melanoma is a melanoma that lacks an in-situ component beyond three rete ridges of the invasive vertical growth phase; thus, nodular melanoma, even in its early stages, has the potential to metastasize [2–4]. While they represent only about 15% of invasive melanomas in Caucasian popu- lation, thick melanomas with a poor prognosis are predominantly nodular melanomas [2]. The classification of melanoma by subtype is based primarily on anatomical, epidemiological, and pattern of progression information; however, recent research has shown that there may also be molecular and genetic differences between melanoma subtypes [5, 6]. These differences may explain the difference in the natural evolution of melanoma subtypes. Furthermore, our understanding of this written message in the tumor cell’s DNA may play a principal roll in the therapeutic strategy and prognosis in the near future.

IV.8.2 Clinical Features IV.8.2.1 Clinical Symptoms

The mean age at diagnosis of SSM is 51 years, which is one or two decades earlier than that for lentigo maligna melanoma and acral lentiginous melanoma [2]. Patients with SSM often report a pre-existing, relatively stable pigmented lesion at the site which has been present for many years; however, this lesion then undergoes rapid change or develops symptoms, thus prompting the patient to seek medical advice. This pre-existing tumor may correspond to a pre-existing melanocytic nevus or early stages of superficial spreading melanoma. Some SSM can also be symptomatic producing symptoms of itching and pain; however, these symptoms are not specific for melanoma since many benign and malignant skin tumors can present with similar symptoms.

In contrast to SSM, nodular melanoma exhibits rapid vertical growth, making it difficult to detect during early phases of tumorigenesis.

By the time of presentation many nodular melanoma are deep and ulcerated tumors [7].

IV.8.2.2 Clinical Signs

Several mnemonics for the macroscopic findings of melanoma have been developed to help individuals recognize melanoma; these include the ABCD/ABCDE rules [8, 9] (Asymmetry:

one half of the lesion does not mirror the other half in shape or in color distribution; Border ir- regularity: the lesion tends to have an indented and jagged outline; Color variegation: the sur- face is multicolored and may include shades of tan, brown, blue-black, gray-white, and other variations; Diameter: generally greater than 6 mm, although some melanomas are smaller;

Enlargement–Evolution: the tumor changes in morphology and size), the three Cs (color, con- tour, change) [9], and the Glasgow 7-point checklist (change in size, irregular shape, irregular color, diameter at least 7 mm, inflammation, oozing/bleeding, sensation) [10, 11]. The features described in the above mnemonic apply mainly to superficial spreading melanoma but

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IV.8.3 Superficial Spreading Melanoma The fact that superficial spreading melanomas often manifest the ABCD features can be ex-

the lesions caused by lymphangitis or regression, respectively. It is important to note that amelanotic or hypomelanotic melanoma will have little or no distinguishing color. These lesions are often pink in color [14].

Fig. IV.8.1. Two faces of superficial spreading melano- ma. The lesions were detected in the first visit of a 27- year-old man consulting for atypical mole syndrome.

Clinical examination revealed multiple atypical melanocytic lesions on the trunk and extremities. Two lesions were considered for excision because of the suspicious appearance by clinical and dermoscopic examination (see also Fig. IV.8.2). The lesion on the right side (12¥8 mm) located on the back was slightly palpable with subtle erythema in the center and brown to grayish pigmentation.

The shape was rounded and discrete irregularity with indentation in the borders was found. The surface did not exhibit nodules or ulceration. Adnexal appendages were conserved. The histological analyses demonstrated a superficial spreading in-situ melanoma with marked regression. The lesion located on external side of the right

thigh was smaller (5 mm) and lightly palpable. The presence of erythema and subtle light brown pigmentation at the periphery with irregular borders that fade were observed. Histopathological examination revealed a superficial spreading melanoma, Clark II, Breslow thickness 0.9 mm, with severe regression. The thicker tumor was the smaller and less pigmented of the lesions. The recog- nition of “ugly duckling sign” (right lesion) and the “Red Riding Hood sign” (lesions on the left side) may be useful in patients with atypical mole syndrome. Nevertheless, the use of complementary tools, such as dermoscopy or the follow-up with total-body photography and digital dermoscopy (see Fig. IV.8.2), allows the identification of instability in atypical lesions that leads to early detection of melanoma in these patients.

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IV.8.3.1 Borders in Superficial Spreading Melanoma

Irregularity of outline is the second most common feature of superficial spreading melanomas. They, in contrast to benign nevi, tend to have an abrupt edge between lesional and surrounding normal skin. If a pre-existing nevus or regression are associated in SSM, then ill-defined borders may be noted. In some SSM, as a result of partial regression of the tumor, normal-appearing skin can be seen between islands of tumor. In these cases a detailed description of the tumor, and perhaps even the provision of drawings or images, will help both the pathologist and surgeon in determining the accurate pathological diagnosis and treatment options. It is important to distinguish regression areas resulting in tumor “islands” from satellitosis, since the prognosis for the latter is completely different. The Wood’s light can often help distinguish between regression and satellite metastasis.

Irregularity of the surface is another important sign in melanoma. The texture of the surface of the tumor and the skin marking, mostly in early tumors, may be similar to that of normal skin; however, in advanced melanoma the normal skin markings tend to disappear. Fur- thermore, the presence of hairs does not exclude melanoma, since in early SSM the follicles and adnexal appendages are still preserved. The characteristics of hair shafts may be similar to the adjacent skin or look like hamartomatous terminal hair seen in congenital nevi. In contrast, in deep tumors the hair follicles tend to be destroyed.

A characteristic feature of SSM is a “ground- glass” amorphous appearance to part of the lesion. Where the skin lines have been destroyed by the tumor, a shiny, glassy appearance is observed. Many melanomas also have small flakes of keratin on the surface, but it is extremely rare for the lesion to be extensively keratinized such as in the melanomas that resemble seborrheic keratosis.

Fig. IV.8.2. Dermoscopy of the lesions of Fig. IV.8.1. Left side: superficial spreading melanoma (Breslow 0.9 mm, Clark II with regression). Dermoscopy reveals asymmetry and remnants of light-brown pigment at the periphery (insets). Signs of melanocytic tumor with a typical pig- ment network and erythema and atypical vascularization

at the center are visible. Right side: superficial melanoma (in situ). Dermoscopy reveals an asymmetric tumor with multiple colors (dark and light brown, red and bluish to gray). Small grayish dots in a pepper-like pattern (inset) suggest intense regression with melanophagia.

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The surface of SSM can be macular or be macular with areas of elevated papules. In thick tumor, nodules can arise within relatively flat areas corresponding to the superficial spreading part of the tumor.

In rare instances SSM presents a verrucous surface, in which case differentiation from seborrheic keratosis may be difficult.

Ulceration is commonly seen when the SSM progresses to the vertical growth phase with nodules (Fig. IV.8.3, Fig. IV.8.4). Ulceration of the tumor, a well-recognized prognostic factor, can be seen in the clinical examination as a hemorrhagic crust or eroded area. This important finding is more frequently seen in nodular parts of SSM and this finding is rare in melanomas less that 1 mm of Breslow depth [80]. In tumors that are ulcerated the patient often reports a history of bleeding, although this is not a consistent finding. In addition, the absence of ulceration or bleeding by history or clinical examination does not predict its presence or absence under histopathology.

The phenomenon of regression is commonly seen in SSM and clinically it can be identified as a macule or slightly palpable plaque that shows a spectrum of pigmentation with light brown, pink, and shades of gray due to melanophages.

Some SSM can undergo complete regression and culminating in a white patch corresponding to fibrosis. In areas with prominent fibrosis a tone of pink coloration and small vessels may be visible due to the neoangiogenesis associated with regression. If the SSM regresses completely, it can be impossible to identify the site of the primary melanoma. This phenomenon explains, at least for some of the cases, the presence of metastatic melanoma without a known primary.

At the time of diagnosis most SSM have a diameter greater than 6 mm. However, it is not uncommon to encounter SSM that have a smaller diameter; thus, it is important to remember the “E” in the ABCDE mnemonic. Any melanocytic lesion, irrespective of its size, that is un- dergoing change should be viewed with cau- tion.

Fig. IV.8.3. Superficial spreading melanoma on the back of a 70-year-old patient with severe actinic damaged skin.

The tumor (6 mm) located on the upper trunk was slightly palpable with irregular borders and multiple colors: pink;

brownish; black; and bluish to whitish. The surface of the tumor was slightly palpable without nodulation, homogeneous in some parts with loss of skin marks, and some follicles were present. Ulceration was not observed. Dermos- copy revealed an asymmetric melanocytic tumor with multicomponent pattern exhibiting multiples colors: white;

grayish; blue; red/dark brown; and black. Atypical broadened network, irregular blotches, atypical dots and globules, and streaks (pseudopods) at the periphery were detected. In addition, marked regression is evidenced by homogeneous whitish areas with blue to grayish dots and subtle erythema in the flat part of the lesion.

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Fig. IV.8.4. Ulcerated superficial spreading melanoma arising on a congenital nevus (Clark IV, Breslow 2.8 mm) in a 34-year-old man. The lesion was located on the back of the patient. Dermoscopy of the tumor exhibits asymmetry, multiple colors, and two areas with radial growth phase and ulcerated nodule with blue-whitish veil and

atypical vessels. Regression structures (blue-gray dots) were distinguished in combination with atypical pigmented network, atypical dots/globules, and irregular blotches corresponding to the peripheral thinner part of the tumor.

Fig. IV.8.5. Two faces of nodular melanoma. Left side:

amelanotic ulcerated nodular melanoma (Breslow 10 mm, Clark V) on the right groin of a 44-year-old man.

The patient referred a rapid increase in size with bleeding of a tumor. On the inguinal fold lymph node multiple metastases were detected by palpation. The clinical examination revealed an ulcerated nodular tumor with

peripheral verrucous expansion (upper side). Right side:

pigmented nodular melanoma in a 55-year-old man (Breslow 3.31 mm, Clark IV) located on the trunk. Note the symmetry of the lesion with homogeneous pigmentation. The surface is polylobulated with some follicles.

At the periphery a bluish small lesion corresponding to satellite tumor is observed.

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IV.8.4 Nodular Melanoma

Nodular melanoma, by definition, arises without an apparent precursor radial growth phase.

Indeed, the clinical aspect of this type of melanoma is similar to the tumorigenic areas of other variants including SSM. Nodular melanoma starts with an expanding papule that increases in size quite rapidly and typically the ABCD criteria do not apply to the tumor nodule itself, which is commonly symmetrical with smooth borders [15, 16]. The color is often quite homogeneous compared with SSM and may be pink or reddish rather than black, bluish, or brown, and sometimes the surface of the tumor is shiny (Fig. IV.8.5, Fig. IV.8.6); however, nodular melanoma can be hypochromic or amelanotic. If the tumor is amelanotic, then striking vascularization is usually evident with a red or pink surface.

Diameter is usually smaller than SSM and it can be less than 6 mm even in thick tumors. For

all these reasons, diagnosis of nodular melanoma may be subtle and misdiagnosis or incorrect treatment at the first consultation is not infrequent. Lesional evolution or change has also been demonstrated to be a significant warning sign for nodular melanoma. In a study of 92 patients with nodular melanoma, 71% of patients noted evolution of their lesions [15].

IV.8.5 Dermoscopic Criteria

Dermoscopy constitutes a bridge between the clinical examination with naked eye and histopathology [17–22]. In cases in which melanoma is difficult to diagnose, the attention of the histopathologist should be directed to the areas of highestdiagnostic relevance based on dermoscopic findings [22–25]. Furthermore, sampling error can be minimized if the step-sectioning of the excised specimen is based on dermoscopic findings.

Fig. IV.8.6. Nodular melanoma with histological ulcer- ation on the trunk of a 62-year-old woman (Clark III, Breslow 2.01 mm). The patient reported progressive increase in size over a period of several months without bleeding. Examination revealed a 7-mm symmetric tumor with reddish, pink, and bluish coloration at the center. The surface of the tumor was slightly scaling without

adnexal structures. Dermoscopy exhibits an asymmetric tumor with multiple colors (red, pink, blue to grey, and white). A bluish and whitish veil, some remnants of brownish pigment in the center, and atypical vascularization with irregular polymorphous and irregular hairpin vessels are distinguished.

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IV.8.6 Methods for the Dermoscopic Diagnosis of Melanoma

In the dermoscopic evaluation of a skin tumor the algorithm of “The two-step method” is utilized [17]. The first step differentiates melanocytic from non-melanocytic tumors. The second step classifies melanocytic lesions into benign and malignant (see also Differential Di- agnosis). If a skin tumor is considered melanocytic, then different dermoscopic methods for the classification of benign, suspicious, and malignant tumors are used, including “pattern analyses” [17, 26, 27], “ABCD” [28], ABCDE rule” [29], “Menzies method” [30], “7-point checklist” [31], and ABC-point list [32]. Novice dermoscopists may find the ABCD rule, Men- zies method and 7-point checklist most helpful;

however, experienced dermoscopists usually rely on pattern recognition to help differentiate between benign nevi and melanoma [17].

For SSM and nodular melanoma we describe the main criteria under dermoscopy as global patterns and local features [17, 26].

IV.8.7 Colors in Melanoma by Dermoscopy

With dermoscopy colors are distinguished more accurately. Melanocytic tumors may display one or more of the following colors by dermoscopy:

light brown; dark brown; gray; black; red; white;

and blue.

IV.8.8 Symmetry and Asymmetry in Melanoma by Dermoscopy In contrast to the clinical definition of asymmetry, which includes the shape/silhouette of the lesion, in dermoscopy the symmetry is determined by the distribution of dermoscopic structures and colors within the lesion, and this is independent of the shape of the tumor. In general, benign lesions have dermoscopic structures and colors distributed symmetrically and melanomas have them distributed asymmetrically.

IV.8.9 Global Patterns in SSM and Nodular Melanoma

In superficial spreading melanoma different global patterns can be observed (see Chap. I.3):

reticular (a network of pigment); globular (aggregation of globules); and multicomponent (the combination of three or more dermoscopic structures such as pigment network, globules, structureless areas, and streaks, which are distributed asymmetrically). Some SSM may exhibit a “star- burst pattern” (multiple linear extensions in a radial arrangement at the periphery), but this is considered characteristic of spitzoid lesions [33].

In nodular melanoma reticulation is not seen because they lack an in-situ component. In this type of melanoma the dermoscopic patterns may be globular, homogeneous (structureless bluish to black homogeneous pigment covering the entire lesion), or multicomponent pattern [34].

If a tumor cannot be categorized with the above-mentioned patterns, then the “non-specific pattern” is considered and in this case a clear diagnosis cannot be made. A non-specific pattern can be found in melanoma, and therefore these lesions should be excised [17].

IV.8.10 Dermoscopic Findings in SSM IV.8.10.1 Pigment Network

A pigment network is present in over 50% of superficial melanomas. Pigment network tends to be atypical with irregular holes (wide and small), thick lines, and abrupt cut-off at the periphery.

The atypical pigment network is not totally specific of melanoma since it can also be seen in atypical nevi, and likewise some early melanomas may exhibit this feature at the beginning.

The term “branched streaks” corresponds to network fragments resulting from a broken-up pigment network.

IV.8.10.2 Globules and Dots

Globules and dots correspond to nests of melanoma cells with different depths. In melanoma globules tend to be irregular in size, color, and

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IV.8.10.3 Structureless (Homogeneous) Areas/Blotches

Structureless areas/blotches can be defined as regions devoid of structures and without signs of regression. These areas can be pigmented or hypopigmented; however, if the area is dark brown or black in color, it is called a “blotch.” In melanoma these homogeneous areas are irregularly distributed and variegated in shape and size. A blotch usually does not encompass the entire lesion. (It is noteworthy that all blotches are structureless, but not all structureless areas are blotches.)

IV.8.10.4 Blue-White Veil

Blue-white veil, an important feature, is a high- risk criterion for melanoma. It has been defined as an irregular, structureless area of confluent blue pigmentation with an overlying white

“ground-glass” film. The blue-white veil occu- pies the elevated parts of a nodular melanocytic lesion. Histopathologically this corresponds to compact orthokeratosis, acanthosis, and hyper- granulosis of the epidermis, and the presence of a compact aggregation of pigmented malignant cells in the papillary dermis. It is a specific criterion for melanoma; however, a blue-whitish veil can also be observed in Spitz nevi.

IV.8.10.5 Streaks

“Streaks” is an alternate term for radial streaming and/or pseudopods. When symmetrically arranged around the entire edge of the lesion,

hypomelanotic rete ridges. It is seen in many Spitz nevi; however, the negative pigment network is also a highly specific feature of invasive melanoma and can be seen in some dysplastic nevi [35].

IV.8.10.7 Regression Areas

Regression areas are white, scar-like depigmen- tation often combined with blue-gray color and/

or peppering (speckled blue-gray granules).

Peppering consists of tiny, blue-gray granules of melanin.

IV.8.10.8 Vascular Structures

Vascular structures are seen in melanoma because of the angiogenesis and regression. Some dermoscopic findings caused by vascularization have been described in melanoma such as milky red areas (red-pink whitish veil resulting from increased vascularity), irregular hairpin vessels, dotted vessels, and irregular polymorphous vessels [36, 37].

IV.8.11 Dermoscopic Findings in Nodular Melanoma

Dermoscopy of nodular melanoma is difficult since the asymmetry of pattern is less marked than in SSM [34]. Nevertheless, irregularity in colors is usually present in pigmented nodular melanoma.

In nodular melanoma many of the “classic”

dermoscopic features of SSM are observed much less commonly. Specifically those dermoscopic structures that correspond to the radial phase or

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flat parts of the SSM are absent in nodular melanoma: pseudopods; radial streaming; regression structures; and atypical brown dots (see above).

Pigment network is absent in nodular melanoma with the exception of the presence of contiguous melanocytic nevus or melanocytic hyperplasia; however, nodular melanomas often display dermoscopic findings associated with deep tumors such as multiple colors, blue-white veil, and atypical vessels due to angiogenesis. In the case of amelanotic or hypopigmented nodular melanoma the vascularization and remnants of pigment are the most important clues (see Chap. IV.3) [14].

IV.8.11.1 Additional Preoperative Information Obtained by Dermoscopy

Dermoscopy, due to the fact that it represents a bridge between the clinical examination and pathological examination, can aid in determining tumor thickness, thereby guiding surgery [38, 39]. The presence of pigment network corresponds to melanocytic hyperplasia and represents the radial growth phase. In contrast, blue- whitish veil or atypical vessels in a palpable area of the tumor corresponds to thick tumors with nests in dermis and neoangiogenesis, respectively. Algorithms based on dermoscopy, clinical observation, and/or sonography have been proposed for the preoperative evaluation of melanoma thickness [40]. If these methods are determined to be accurate, they could prove to be very useful in planning surgical treatment.

IV.8.12 Relevant Clinical Differential Diagnoses

Superficial spreading melanoma and nodular melanoma may be difficult to differentiate from other melanocytic tumors. During the early stages, SSM may be similar to benign atypical nevi. Moreover, when melanoma is atypical in appearance, even in nodular tumors such as in the case of amelanotic melanoma, the preoperative differential diagnosis can be extremely difficult or even impossible.

IV.8.13 Differential Diagnosis

A wide range of tumors may mimic melanoma, and vice versa [41–43].

IV.8.13.1 Differential Diagnosis in SSM IV.8.13.1.1 Melanocytic Nevi

Melanocytic nevi is the most important catego- ry since dysplastic nevi are the most important simulators of SSM. Melanocytic nevi may resemble SSM, because they may exhibit asymmetry, irregularity of borders, multiple colors, and a large diameter. In addition, these benign tumors may present some features seen in SSM such as multicomponent pattern, atypical network, regression, or atypical globules. In the case of banal melanocytic tumors, the presence of inflammation, regression, trauma, or surgical scar (recurrent nevus–pseudomelanoma) may modify the lesion and make it look like a melanoma.

IV.8.13.1.2 Pigmented Basal Cell Carcinoma

Pigmented basal cell carcinoma (BCC), due to the presence of melanin, can be pigmented with blue, brown, or black coloration. The intense vascularization and tendency to early ulceration are commonly seen. In these tumors the observation of specific dermoscopic criteria for BCC can help render the correct diagnosis (see Chap. V.1) [44].

IV.8.13.1.3 Pigmented Actinic Keratosis/

Bowen’s Disease

With regard to squamous cell carcinoma, in rare cases the clinical appearance can mimic melanoma. The dermoscopic presence of melanocytic criteria and specific features for melanoma are usually absent (see Chap. V.5) [45–

47].

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of melanomas present equivocal features by dermoscopy such as follicular openings, fissures and crypts, or intense hyperkeratosis . In these cases clinical clues, such as intense pigmentation, bluish coloration, or atypical evolution, may give the clue for the diagnosis (see Chap. V.7).

IV.8.13.1.5 Dermatofibroma

Clinically, some dermatofibroma may resemble SSM. The clinical history of the tumor, the presence of the “dimple sign” upon lateral compres- sion, and the observation of the typical dermoscopic central white patch and peripheral delicate reticulation may be useful in difficult cases (see Chap. V.2). Some recent studies have described the dermoscopic findings in atypical dermatofibromas, such as aneurysmatic variants, which can be a diagnostic challenge [52–

53].

IV.8.13.2 Differential Diagnosis in Nodular Melanoma IV.8.13.2.1 Spitz Nevus

Pigmented Spitz nevus can mimic nodular melanoma of the amelanotic type. In these cases the excision and histopathological examination of the lesion is mandatory (see Chap. III.16).

IV.8.13.2.2 Blue Nevus

Clinically and dermoscopically a blue nevus may be identical to nodular melanoma or meta-

the correct diagnosis (see Chap. V.1).

IV.8.13.2.4 Clear-Cell Acanthoma

This rare tumor may mimic hypopigmented nodular melanoma. In the case of clear-cell acanthoma, dermoscopy shows a characteristic vascular pattern with vessels arranged as a

“string of pearls” [54–56].

IV.8.13.2.5 Merkel Cell Carcinoma

Merkel cell carcinoma, a malignant tumor, is seen in elderly patients mainly on the head and neck. Its clinical evolution is similar to an amelanotic nodular melanoma with the rapid growth of a pink to reddish nodule [57].

IV.8.13.2.6 Bednar Tumor

The pigmented dermatofibrosarcoma protuber- ans is an unusual tumor that presents as a pigmented plaque with progressive development of nodules [58].

IV.8.13.2.7 Atypical Fibroxantoma

Atypical fibroxantoma is usually seen in exposed areas of the body, mainly in the head of elderly patients and less frequently in the trunk.

With its reddish to brownish coloration and nodular features the atypical fibroxantoma may mimic a thick melanoma [59].

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IV.8.13.2.8 Malignant Tumors of the Breast

A few cases of malignant tumors of the breast with skin involvement have been reported to mimic superficial melanoma [60–61].

IV.8.13.2.9 Hemangioma

Some hemangiomas, mainly when they are thrombosed, may mimic nodular melanoma.

Dermoscopy can readily differentiate between these tumors and correctly identify hemangiomas due to the absence of melanocytic structures and due to the presence of lacunas.

IV.8.13.2.10 Angiokeratoma

Similar to hemangiomas, angiokeratomas may mimic nodular melanoma by clinical examination with the naked eye. The dermoscopic examination is very specific for these tumors, reveal- ing the characteristic red and black lacunas [62].

IV.8.13.2.11 Dermatofibroma

In some nodular or atypical dermatofibromas the differential diagnosis may be very difficult and a biopsy has to be taken for histopathological diagnosis. The clinical history of the tumor with a long stable evolution in dermatofibroma helps in this discrimination, but in equivocal cases a biopsy is required for the correct diagnosis [41].

IV.8.13.2.12 Seborrheic Keratosis

Similar to SSM, some cases of acanthotic or clonal seborrheic keratosis may mimic nodular melanoma. Dermoscopy in these cases is very helpful, showing typical hairpin vessels associated with other criteria seen in these benign tumors [50–51]. Benign or malignant adnexal tumors may mimic melanoma. Biopsy is required for the correct diagnosis [41].

IV.8.13.2.13 Pyogenic Granuloma

Clinically and dermoscopically a pyogenic granuloma may be identical to the amelanotic variant of nodular melanoma; therefore, biopsy is recommended for these cases [41].

IV.8.14 Histopathology

The histopathology of superficial spreading and nodular melanoma can be explained by the

“three-step tumor progression model” [63–65]:

1. Radial growth phase exemplified by melanoma in situ when the tumor is confined above the epidermal basement membrane.

2. The microinvasive radial growth phase is when the melanoma penetrates the basement membrane and is present in the superficial papillary dermis.

3. Melanoma that has invaded into the dermis and has acquired the ability to metastasize, known as the vertical growth phase.

IV.8.14.1 Radial Growth Phase

Superficial spreading melanoma, by definition, must have a radial growth phase component.

The presence of the intraepidermal component, extending more than three rete ridges past the confines of the dermal component, has been proposed as the hallmark of SSM.

Initially, the radial growth phase is confined to the epidermis with an “in-situ” component.

The atypical melanocytes invade the epidermis from the basal layer, and these cells can be epithelioid or spindle-shaped and tend to manifest little cell-to-cell variability. Four basic patterns of intraepidermal growth have been described:

1. Pagetoid pattern with epithelioid melanoma cells. This is the most frequent form of intraepidermal growth and consists of melanoma cells with abundant quantities of eosinophilic or clear

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cytoplasm containing melanin granules of variable shape and sizes and round or oval nuclei with thick chromatinic rims and macronucleoli. The epidermis is usually hyperplastic and scattered mitotic figures are present.

2. Contiguous proliferation of single melanoma cells along the dermo- epidermal junction in a lentiginous pattern associated with obscuration of basal keratinocytes and effacement of rete ridges. In this pattern the tumoral cells exhibit angulated nuclei that exceed the size of adjacent nuclei of keratinocytes.

3. A pattern of confluent oblong nests of hyperchromatic spindle-shaped cells with variable melanization, distinct nuclear grooves, prominent nuclear chromatinic rims, and eosinophilic nucleoli.

4. The fourth pattern comprises the combination of the aforementioned presentations of intraepidermal invasion.

In the absence of regression, radial growth phase melanoma is almost never associated with metastases [66–69] (Fig. IV.8.7).

The concept of microinvasive phase has been introduced and widely used to define a interme- diate phase in the model of SSM tumor progression [70, 71]. In the microinvasive tumor one observes within the papillary dermis nested cells with a cytomorphology similar to that of the intraepidermal cells, albeit often with more abundant cytoplasm having an eosinophilic hue. Dermal-based mitosis should not be identified, and the size of the dermal nests should not exceed those found along the dermo-epidermal junction. Lymphocytic infiltration of the adjacent papillary dermis may herald the onset of incipient microinvasive melanoma.

Other malignant intraepidermal lesions exhibiting pagetoid spread may mimic melanoma in situ. These lesions include epidermotropic neuroendocrine carcinoma, Paget’s disease, or squamous cell carcinoma in situ. Immunohis- tochemistry can often help differentiate these tumors from each other [71].

IV.8.14.2 Vertical Growth Phase

Clark et al. [64] described the early vertical growth phase and distinguished it from the radial growth phase by criteria that included the presence of a dominant nest within the papil-

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lary dermis that is larger than any nest within the epidermis or surrounding dermis and forms a small expansible nodule of a shape distinctive from adjacent nests; it may be round or oblong, but it is typically oriented vertically (i.e., per- pendicularly to the long axis of the epidermis) w The atypical cells comprising the nodules are cytologically distinct from those of the intraepidermal component. Whereas the intraepidermal cells are usually epithelioid, those in the vertical growth phase may be spindle, small cell, or epitheloid, suggesting a different clonal proliferation. These cells often show greater cyto- plasmatic pigmentation than the intraepidermal cells. The cells in the tumorogenic dermal nests invariably show conspicuous nuclei, coarse chromatin, and irregularly thickened and/or notched nuclear membranes.

IV.8.15 Management

IV.8.15.1 Melanoma Screening and Identification of High-Risk Persons

A favorable prognosis from melanoma depends on early diagnosis. Efforts at improving early

diagnosis have focused on the identification of patients at high risk for developing this tumor [72, 73]. The genetic basis of melanoma risk have been partially elucidated with the identification of loci associated to the susceptibility to develop melanoma [75]. Furthermore, inherited mutations in the melanocortin-1 receptor gene have been linked to people with red hair, to photo- sensitivity, and to an increased risk of cutaneous melanoma. Having many melanocytic lesions of the common type or atypical moles is also associated with an increased risk of melanoma.

Atypical moles can be precursors to melanoma but are also markers that identify a subgroup at high risk for developing melanoma. Intermit- tent sun exposure and severe sunburns, especially during childhood, and use of tanning beds, have been associated with an increased risk for melanoma [76].

Patients with personal prior melanoma have an increased risk for developing a second primary melanoma [77, 78].

Patients with a strong family history of melanoma and multiple clinically atypical moles are at the greatest risk for cutaneous melanoma. In- herited mutations in the CDKN2A and CDK4 genes, which have been documented in families with hereditary melanoma and in patients with multiple primary melanoma, confer a 60–90%

Fig. IV.8.8. Histological view of non-ulcerated nodular melanoma (Clark III, Breslow 1.67 mm) on the trunk of a 49-year-old woman without personal/familial background of melanoma

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recognized by patients, it is strongly recommended that patients perform a monthly skin self-examination, in addition to periodic physi- cian-based examinations, to help detect any new or changing lesion. This is the best strategy for the early detection of melanoma in persons at high risk for developing melanoma such as patients with multiple moles [79].

IV.8.15.2 Clinical History

In the management of SSM and nodular melanoma patients a complete clinical history at the first visit prior to physical examination is always required. In the clinical history information of personal and familial risk factors for skin cancer, including sun exposure, should be documented. Personal background is also important to detect associated diseases that may impact the prognosis or treatment [72–74]. Examina- tion of the family members should be recommended especially if the patient has atypical mole syndrome or there is a familial history of melanoma [74]. Relevant information regarding the tumor should also be documented with spe- cial emphasis on any pre-existing lesion, time of evolution, time since the patient became suspicious, reason for the consultation, presence of pain, trauma, or bleeding. It is also useful if the patient can describe the colors, diameter, borders, presence of nodules, and other descriptors of the tumor at the time they first became aware of it.

atypical pigmented lesions or satellitosis), and symptoms such as itching or pain.

Dermoscopy of the primary tumor will be necessary to study the details of the tumor and detect areas with different components, regression, nodules with ulceration, associated tumors (precursor/collision tumor), and the ability to predict tumor thickness. Photographic docu- mentation is very helpful and should include an image with a perspective showing the tumor’s location followed by close-up images. Dermo- scopic photography, if possible, is recommended.Since it is not infrequent to detect a second malignant tumor including melanoma or skin carcinomas in patients with melanoma, a complete total-body examination should be performed at the time of the first consultation. The presence of lesions associated with photoaging or sunburns, skin type, number and characteristics of moles (common, atypical, congenital, etc.), or other lesions suggesting satellitosis or cutaneous metastasis (epidermotropic metastasis or palpable subcutaneous nodules) should be documented. Surgical scars, if prior biopsies were performed, should be examined to detect recurrent melanocytic lesions or recurrence of skin carcinomas. Examination should include clinical examination with the naked eye, palpation, and dermoscopy.

IV.8.15.3.1 Examination of Lymph Nodes Palpation of lymph nodes should be performed and, if possible, sonography of the regional lymph node basins may allow for the early detection of nodal metastasis.

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IV.8.16 Staging and Treatment of Primary Melanoma

Staging of the patient is conducted with information obtained from the primary tumor and the study of nodal status and distant metastasis [80].

IV.8.16.1 Surgical Excision of the Tumor The complete surgical excision of the tumor is preferable to partial incisional biopsies such as punch or shave biopsy [81]. Partial biopsies can be problematic for the pathologist and may not provide the clinician with enough information to make appropriate management decisions.

The first excised biopsy should be performed with a narrow excision margin (2–3 mm) and submitted for complete pathological examination. The use of complex closures, such as grafts or skin flaps, should be avoided. In most cases patients with SSM or nodular melanoma on the trunk and extremities can be effectively treated with a simple elliptical excision of the melanoma followed by primary closure. From a techni- cal standpoint, the long axis of the elliptical excision should be designed to maximally utilize the available local skin so as to achieve a relatively tension-free full-thickness primary closure, and the excision should be oriented toward the appropriate draining nodal basin whenever possible.

The final surgical margins depend on the tumor thickness. The rationale of the wide-excision margins is based on the risk of local recurrence including in-transit metastasis. Local failure is a function of both biology of the primary tumor and extent of the lesion. In thin melanomas the risk is low and narrower margins are safe. In contrast, thicker tumors and/or ulcerated melanomas are associated with higher rates of local recurrences due to the presence of clinically occult metastasis at the time of initial excision and which were not completely removed. Wide local excision of these high-risk tumors may completely remove these satellite metastases and thereby lower the risk of recurrence.

The most widely accepted surgical margins for melanoma are 1 cm for melanoma with Bre- slow thickness less than 1.01 mm, 2 cm in melanomas from 1.01 to 4.00 mm and 2–3 cm, in melanomas thicker than 4 mm.

IV.8.16.2 Sentinel Node Biopsy

The most accurate predictor of metastasis is the status of the regional lymph nodes [80, 82]. The current staging system of the AJCC is incorpo- rating the status of the sentinel node. In most centers sentinel node biopsy has been incorpo- rated into the staging protocols. If the sentinel node biopsy is positive, then the patients are of- fered complete lymph node dissection; however, impact of complete lymph node dissection on overall survival has not been conclusively proven. Sentinel-lymph-node biopsy, a technique developed in the early 1990s by Morton et al., samples selectively the first draining lymph node (or nodes) from a tumor site. A multidisci- plinary team is required to successfully perform the procedure including an experienced surgeon, a nuclear medicine radiologist, and a pathologist. In skilled hands, the sentinel node is identified in over 95% of cases [81]. The lymph node should be fixed and processed with both hematoxilin and eosin and inmunohisto- chemical staining (e.g., S-100, HMB-45, and MART-1). With this technique the detection of micrometastasis is possible. Some studies are investigating the impact of testing the sentinel lymph node biopsy by PCR analysis [83].

Since many retrospective studies have shown a strong negative impact on prognosis in the presence of melanoma in the sentinel node, the sentinel node biopsy is currently considered the most powerful technique for staging and prognosis. The proponents of the technique argue that accurate staging allows for the selection of patients that are candidates for further adjuvant treatments such as interferon alpha-2b; however, critics argue that sentinel node biopsy has no proven impact on survival and no adjuvant treatments have proved beneficial for patients with microscopic nodal disease. The Multi- center Selective Lymphadenectomy Trial and the Sunbelt Trial were designed to address these

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ing melanoma blood markers such as S-100, MIA, mRNA tirosinase), chest X-Ray, and imaging techniques (sonography, computed tomography, magnetic resonance imaging, posi- tron emission tomography) [79].

Although an optimal follow-up interval has not been determined, by consensus a minimum of an annual routine physical examination, including full skin assessment and palpation of lymph nodes, is proposed. It is reasonable to state that more frequent follow-up visits will be appropriate for patients with atypical mole syndrome, patients with high-risk tumors, and, of course, if adjuvant treatment is initiated [88]. In the case of patients with susceptibility to multiple melanomas, a short follow-up of 6 months and the use of imaging techniques as dermoscopy, total body photography and digital dermoscopy should be recommended to detect further primary melanomas at early stages [88–90].

Routine laboratory tests, including serum lactate dehydrogenase, albumin, and plasma he- moglobin measurements and chest radiography, have not been conclusively proven be beneficial in screening for recurrence in asymptomatic melanoma patients; therefore, these tests prob- ably should be reserved for patients at moderate to high risk for recurrence [91, 92].

IV.8.16.3 Adjuvant Therapy

The most important value of accurate staging of patients with melanoma is the identification of patients that may benefit from adjuvant therapy.

In more than 100 randomized, controlled trials attempts to reduce recurrent melanoma with adjuvant therapy have been studied [79]. Recent efforts have been focused on interferon alphal-

about the toxicity and the lack of consistent impact on overall survival. Since high-dose interferon alpha-2b has toxic effects and prevents recurrence and death in only a minority of patients at risk, it is not currently accepted worldwide and it is unevenly used in the United States and Europe [96–102]. Various efforts to reduce toxicity and improve the efficacy have included low-dosage regimens and the combination with vaccines, but at present such regimens have not provided an overall survival advantage, and therefore such regimens are not be routinely recommended worldwide [101, 103–105].

Since interferon alpha-2b is the only ap- proved therapy in many countries, it is reasonable to inform patients of this treatment. They should be informed of the potential risk and benefits and known adverse effects.

Many promising adjuvant regiments with vaccination are being studied in melanoma. Al- though vaccines are less toxic than some other treatments, their efficacy relative to that of interferon, and their ability to synergize with interferon, remain to be established.

IV.8.17 Treatment of Distant Disease For stage-IV patients, no single randomized, controlled trial has demonstrated an increase in overall median survival, including any combination of drugs and/or interleukin-2. Surgical resection of isolated metastatic foci can result in a 5-year survival rate of up to 25%. These results have been restricted to selected cases when few visceral metastasis could be completely removed [104]. High-dose bolus interleukin-2 was ap- proved by the FDA in 1998, and although tumor responses occurred in only 16% of cases, some cases had complete durable responses lasting for

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more than 30 months [106]. Unfortunately, this regimen is associated with many toxic effects, making it difficult to administer except in spe- cialized centers. Currently, among the cytotoxic agents, dacarbacine remains the key drug, since it produces responses in 15–20% of patients with a mean duration of the response of 4 months.

Recently, temozolamide has shown promising results [107].

The future directions in melanoma treatment focus on vaccine-based inmunotherapy and tar- geted-chemotherapy regimens. These approach- es will become ever more utilized as our knowl- edge of how the genetics, cellular regulatory pathways, tumor profile, and the immune system interact to allow for the growth of melanoma.

IV.8.18 Case Study Case Study 1

A 42-year-old woman without personal and familial background of melanoma consulted for a pigmented lesions on her left thigh, detected 18 months previously, with a progressive increase in size and changes in color. Discrete itching during the last months was reported, but bleeding was not detected.

Clinical examination revealed skin-type III without elevated number of moles but some lentigo solaris in exposed areas. The tumor was 16¥12 mm in maximal diameter and more palpable in the center. The colors were brown to gray to black and bluish. Signs of ulceration were not detected.

Dermoscopy showed a melanocytic tumor with a multicomponent pattern, light and dark

brown, bluish, withish, and black. The predomi- nant pattern was reticulated in the peripheral part with atypical network and brown dots. In the center homogeneous with bluish veil correlated with the papular area of the tumor. Irregu- lar black blotch was also seen.

Management

A surgical excision of the tumor with 0.5-cm margins with local anesthesia was performed to evaluate histologically the tumor. A superficial spreading melanoma, Breslow 1, 2 mm, Clark III without ulceration was reported (one mitosis per magnification ¥400 and mild lymphocyte inflammatory infiltrate).

Wide-margin excision with 1.5 cm around the scar (total 2-cm margins) and sentinel node biopsy revealed a negative sentinel node on the left groin without micrometastasis.

Staging of the patient was AJCC IB, and follow-up with clinical examination, including skin and lymph nodes every 6 months during 5 years, was recommended.

The patient is free of relapse after 2 years of follow-up.

Case Study 2

Woman of 32 years old with personal history of superficial spreading malignant melanoma (Stage IA) on the trunk excised 3 years before. Severe atypical mole syndrome with more that 200 lesions and multiple biopsies of dysplastic nevi.

The patient was included in a follow-up pro- gram of total-body photography and digital

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dermoscopy with 3 to 6 months of time between each visit.

At the time of the present visit the patient was not aware of any change in any of the lesions.

Clinical examination revealed a patient with high number of atypical lesions (Figure 1). Scar of the surgery of the primary melanoma and lymph node areas were normal.

lesions of the patient with a irregular brownish with grayish coloration.

Management

A surgical excision of the tumor with 0, 3 cm of margins with local anesthesia is performed to evaluate histologically the tumor. A superficial spreading malignant melanoma, Breslow 0,50 mm Clark II with severe regression is reported.

No signs of histological ulceration are observed.

Wide margins excision with 1 cm around the scar (total 1 cm margins)

The patient is free of relapse after 3 years follow-up including total body examination and digital follow-up.

C Core Messages

■ Superficial and nodular melanoma of the trunk and limbs are the most frequent melanoma subtypes in Caucasians.

■ A wide range of tumors may mimic melanoma, and vice versa.

■ Experienced dermoscopists usually rely on pattern recognition to help differentiate between benign nevi and melanoma.

■ The histopathology of superficial spreading and nodular melanoma can be explained by the “three-step tumor progression model.”

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