Spitz nevi: In vivo confocal microscopic features, dermatoscopic aspects, histopathologic correlates, and diagnostic significance

Spitz nevi: In vivo confocal microscopic features, dermatoscopic aspects, histopathologic correlates, and diagnostic significance Giovanni Pellacani, MD,a Caterina Longo, MD,a Gerardo Ferrara, MD,c Anna Maria Cesinaro, MD,b Sara Bassoli, MD,a Pascale Guitera, MD,d Scott W. Menzies, MB BS, PhD,d and Stefania Seidenari, MDa Modena and Benevento, Italy; and Sydney, Australia Background: Spitz nevi are benign melanocytic tumors, sometimes misdiagnosed as malignant melanoma (MM). Objective: We sought identification of characteristic in vivo microscopic features of Spitz nevi, their histopathologic correlates, and diagnostic usefulness. Methods: Forty Spitz nevi were studied by in vivo confocal microscopy and dermatoscopy, evaluating histopathologic correlates, and compared with 40 MMs and 40 Clark nevi. Results: Some histologic aspects characteristic for Spitz nevus diagnosis were correlated with confocal features, comprising some that can be useful for atypical Spitz nevus classification. The most striking features for differentiating Spitz nevi from MMs were the presence of sharp border cut-off, junctional nests, and melanophages. Limitations: No correlates were found for other aspects, such as Kamino bodies, hyperkeratosis, acanthosis, mitoses, and maturation with depth. The impossibility of exploring deeper aspects hampered an accurate distinction from MMs in some cases. Conclusion: Confocal and dermatoscopic examination enabled the identification of different Spitz categories with different histologic substrates. ( J Am Acad Dermatol 2009;60:236-47.)

E

pithelioid and/or spindle cell melanocytic nevus, including the lesions first described by Spitz1 and Reed et al,2 is an acquired benign melanocytic tumor, sometimes leading to diagnostic confusion with malignant melanoma (MM) because of its alarming clinical presentation.3,4

From the Departments of Dermatologya and Pathology,b University of Modena and Reggio Emilia; Department of Pathology, Pathologic Anatomy Unit, Gaetano Rummo General Hospital, Beneventoc; and Sydney Melanoma Diagnostic Centre, Sydney Cancer Centre and Dermatology Department, Royal Prince Alfred Hospital, Faculty of Medicine, University of Sydney.d Supported in part by a grant of the Fondazione Cassa di Risparmio di Modena. Conflicts of interest: None declared. Accepted for publication July 14, 2008. Reprint requests: Giovanni Pellacani, MD, Department of Dermatology, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy. E-mail: pellacani.giovanni@ unimore.it. Published online December 17, 2008. 0190-9622/$36.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.07.061

236

Histologically, these nevi are defined by a set of characteristic features,5-8 although sometimes they cannot be differentiated from MMs with certainty.8-10 The introduction of dermatoscopy enabled the identification of characteristic dermatoscopy features of Spitz nevi11-13 and a classification into 3 different subgroups on the basis of the predominant dermatoscopic pattern, corresponding to the starburst, globular, and aspecific types.14 However, lack of characteristic features in approximately one third of pigmented Spitz nevi, diagnostic difficulties approaching the nonpigmented variety,15 or the presence of MMs showing a starburst or a globular pattern mimicking Spitz nevi, lead to surgical excision with a provisional diagnosis of Spitz nevus.16,17 Moreover, more than half of Spitz nevi showing an atypical and/or multicomponent dermatoscopic pattern were found to be histopathologically atypical.18 In vivo reflectance confocal microscopy (RCM) is a novel imaging technique enabling the visualization of epidermal and papillary dermal structures at a nearly histologic resolution, which improves diagnostic accuracy for different skin tumors19 and for

J AM ACAD DERMATOL

Pellacani et al 237

VOLUME 60, NUMBER 2

MM.20 Although globular Spitz nevi showed characteristic RCM aspects,21 they still remain indistinguishable from MMs in the majority of cases because of the frequent presence of cytologic and/or architectural atypia.20 The purpose of this study was to identify RCM and histologic correlates for characteristic Spitz nevus features, and to evaluate their usefulness in the distinction between MMs and nevi.

METHODS The study has been approved by our institutional review board, and the Declaration of Helsinki protocols were followed. Participants gave their written informed consent. Study population This study sample included 40 consecutive Spitz nevi from as many patients, recorded by means of RCM at our university department of dermatology. As a control population, 40 consecutive MMs (median Breslow thickness 0.63; interquartile range 0.37-1.04) and 40 Clark nevi, equivocal on clinical and/or dermatoscopic evaluation, and excised to rule out MM, were also acquired by dermatoscopy and RCM. Lesions were equally distributed on the trunk and limbs (46.6% and 53.4%, respectively), with a slight prevalence of Spitz nevi on the lower limbs (57.5%). No lesion of the face, palm, or sole was included in the study because of the peculiarity of dermatoscopic and RCM patterns at these sites, as a result of the accentuated (palm/sole) or effaced (face) rete ridge patterns. Instruments and acquisition procedure Before biopsy, dermatoscopy and RCM images were acquired respectively by means of a videodermatoscope (FotoFinder, TeachScreen Software GmbH, Bad Birnbach, Germany) and near-infrared reflectance confocal laser scanning microscopes (Vivascope 1000 and 1500, Lucid Inc, Henrietta, NY), which use an 830-nm laser beam with a maximum power of 35 mW. Instrument and acquisition procedures are described elsewhere.22 Each image corresponds to a horizontal section at a selected depth with a lateral resolution of 1.0 m and axial resolution of 3 to 5 m.22 A sequence of montage images (block image) was acquired for each lesion at the level of the dermoepidermal junction and superficial (granulosum/spinosum) epidermal layers obtaining 4- 3 4-mm mosaics of the imaged area. For large lesions, not completely comprised within the field of view, the device was repositioned and a new acquisition performed to examine the majority of the lesion surface. Confocal sections, beginning at the stratum corneum and ending inside the papillary

dermis, were recorded at areas of interest. More than 100 capture images per lesion were recorded. Feature description Dermatoscopic and confocal features were separately described by two expert observers (G. P. and C. L.), different from the one who performed the acquisition of the images, on the whole population blinded from information other than lesion location. Dermatoscopic aspects were described according to the standard terminology23 and dermatoscopy diagnosis was made at the time of the first consultation using a hand-held immersion-mode dermatoscope (Heine Delta 20, Heine Optotechnik, Herrsching, Germany) before RCM examination by the Modena, Italy, expert (G. P.) using pattern analysis. All study lesions were categorized according to the main dermatoscopic pattern into 4 groups: (1) typical Spitzoid pattern, such as starburst or globular, characterized only by a starburst pattern or globules, any combinations belonging to the multicomponent category; (2) peculiar Spitzoid aspects, such as negative network or superficial black network; (3) reticular, homogeneous, complex, or multicomponent pattern; and (4) nonspecific pattern. For RCM evaluation, a series of 37 features, corresponding to previous observations24 and new parameters, were considered. Lesion symmetry, sharp border cut-off (considering the presence of a rim of nests at the periphery and/or for the presence of a marked change in brightness with a clearly outlined edge between the normal-appearing skin features and the lesion), and regularity of the papillary contour were evaluated on 4- 3 4-mm mosaics acquired in all cases at dermoepidermal junction. Mosaics acquired at superficial epidermal layers were considered for the evaluation of the distribution of pagetoid infiltration. Moreover, atypical cells in the epidermis were described, considering the shape as spindled, roundish/polygonal, or dendritic. Cells clustered into nests with ovoid bulging, resembling dense nests fused in one structure, were described as ‘‘confluent nests.’’ Histopathologic evaluation In each case, the detailed histopathologic description was based on hematoxylin-eosinestained slides. The microscopic slides were contemporary reviewed by two pathologists (G. F. and A. M. C.) and two lesions with no diagnostic agreement were excluded from the study, both interpreted as MM by one of the two reviewing pathologists. Single histologic features were described filling in an appropriate digital form subdivided in 4 sections: (1) general architectural overview: asymmetry, sharp

238 Pellacani et al

J AM ACAD DERMATOL FEBRUARY 2009

lateral demarcation, rete-ridge contours, and contours of growth at the deep margin; (2) cytologic aspects: cell type (spindled and/or epithelioid), pagetoid infiltration, cellular atypia, pigmentation, mitoses, and reticular dermal mitotic figures; (3) epidermal features: hyperkeratosis, acanthosis, parakeratosis, transepidermal melanin dispersion, ulceration, and Kamino bodies; and (4) dermal features: melanocytic nests aspects (regular, irregular discrete, and nondiscrete), size, and location (junction, papillary dermis, and/or reticular dermis); confluence of nests; clefting; sheets of melanocytes; prominent dermal cellularity; loss of cellular cohesion; lack of maturation in the dermis; extensive involvement of the subcutis; regression, desmoplasia and solar elastosis; inflammatory infiltrate type (leucocytes/melanophages); and distribution. Moreover, a lesion not fulfilling the histopathologic criteria for MM was classified as atypical Spitz nevus when showing at least one of the following histopathologic features: asymmetry, poor lateral demarcation, ulceration, prominent dermal cellularity, presence of dermal sheets of melanocytes, lack of maturation in the dermis, evidence of reticular nonmarginal dermal mitotic figures, or extensive involvement of the subcutis.18 In presence of atypical histologic features, a third opinion was asked and the case was excluded in case of discordant diagnosis. Statistics Statistical evaluation was carried out using software (SPSS statistical package, release 12.0.0, SPSS Inc, Chicago, IL). Absolute and relative frequencies of the observations in Spitz nevi were obtained for each RCM and histologic feature. Correlation between RCM and histologic features in Spitz nevi was performed by means of Cohen kappa calculation. Absolute and relative frequencies of RCM features were also obtained for MMs and Clark nevi. Significant differences among Spitz nevi, MMs, and Clark nevi were evaluated by means of the x2 test of independence (Fisher exact test was applied if any expected cell value in the 2 3 2 table was less than 5). The total RCM score was calculated for each lesion evaluating the presence of two major features (nonedged papillae and cellular atypia at dermoepidermal junction), each scored 2 points, and 4 minor ones (roundish pagetoid cells, widespread pagetoid infiltration, cerebriform nests, nucleated cells within the dermal papillae), each scored 1 point, considering as threshold for malignancy a score equal or greater than 3.20,25 RCM feature frequencies were also clustered according to the different dermatoscopic subgroups. For multivariate analysis, discriminant analysis was performed for the identification of the

independently significant features in distinguishing Spitz nevi from MMs. Stepwise forward selection was used to choose the features for the prediction models. Wilk lambda was used to determine whether the model adequately described the data. At each step, the predictor with the largest F to Enter value that exceeds the entry criteria (by default, 3.84) was added to the model. Variables with F to Enter values smaller than 3.84 were left out the model. For each included parameter, a coefficient was calculated. A linear equation was generated and a total score was obtained for each lesion. Receiver operating characteristic analysis was performed to investigate sensitivity and specificity of this method. The area under the curve, which represents an index of the overall discriminant power, was calculated by the nonparametric trapezoidal method. Sensitivity, specificity, diagnostic accuracy, odds ratio, and 95% confidence interval were calculated for each score value. The leave-one-out method was applied to evaluate the stability of the model. A P value less than .05 was considered significant.

RESULTS Confocal characteristics of Spitz nevi RCM pattern analysis for Spitz nevi, compared with MMs and Clark nevi, is reported in Table I. Spitz nevi differed from MMs and Clark nevi in many aspects. Discriminant analysis enabled the identification of RCM features useful for distinguishing between Spitz nevi and MMs. Broadened honeycombed pattern, disarranged epidermal pattern, and presence of small pagetoid cells were more likely correlated with MM diagnosis, whereas junctional nests, sharp border cut-offs, and plump bright cells were more characteristic for Spitz nevi. Evaluating single features in detail in Spitz nevi, some features suggestive of malignancy, such as pagetoid infiltration, nonedged papillae, and nucleated cells within papillary dermis, showed intermediate frequencies between MMs and Clark nevi. Spitz nevi were often characterized by the presence of a few scattered large atypical cells, predominantly spindled and/or roundish/polygonal in shape, showing numerous markedly atypical cells throughout the dermoepidermal junction in only 6 cases. On the other hand, MMs predominantly showed numerous atypical and pleomorphic cells, also frequently presenting dendritic aspects, whereas nevi showed atypical cells in less than one third of cases. Junctional and dermal nests were present in the majority of Spitz nevi, usually seen as regular dense nests, sometimes in combination with dishomogeneous and sparse cell nests, whereas cerebriform clusters were observed in only two cases. Spitz nevi

Pellacani et al 239

J AM ACAD DERMATOL VOLUME 60, NUMBER 2

Table I. Frequency of confocal features in Spitz nevi compared with melanomas and Clark nevi Features

Honeycombed Atypical Broadened Cobblestone Atypical Nucleated cells Disarrangement Pagetoid cells Roundish Dendritic Small Large Cell pleomorphism Edge papillae Nonedge papillae Nonvisible papillary contour Atypical cells Spindled Round/polygonal Dendritic Junctional nests Junctional clusters Junctional thickening Sheetlike structures Nests Dense regular Dishomogeneous Sparse cell Cerebriform Confluence of nests Rim of nests at periphery Sharp border cut-off Nucleated cells in dermis Bright spots in dermis Plump bright cells in dermis Plump cells extent # 25% Plump cells extent [ 25%

Spitz nevi 40 (%)

12 5 2 20 14 11 8 21 10 18 11 15 11 14 19 8 29 20 20 7 33 27 24 3 25 18 8 5 2 10 18 29 7 16 35 13 22

(30) (12.5) (5) (50) (35) (27.5) (20) (52.5) (25) (45) (27.5) (37.5) (27.5) (35) (47.5) (20) (72.5) (50) (50) (17.5) (82.5) (67.5) (60) (7.5) (62.5) (45) (20) (12.5) (5) (25) (45) (72.5) (17.5) (40) (87.5) (32.5) (55)

MMs 40 (%)

14 13* 12* 5* 4* 3* 26* 31* 24* 26* 26* 12 9 10 37* 2 28 12 14 18* 15* 3* 12* 2 13* 5* 5 5 2* 2* 3* 13 11 24* 6 18

(35) (32.5) (30) (12.5) (10) (7.5) (65) (77.5) (60) (65) (65) (30) (22.5) (25) (92.5) (5) (70) (30) (35) (45) (37.5) (7.5) (30) (5) (32.5) (12.5) (12.5) (12.5) 0 (5) (5) (7.5) (32.5) (27.5) (60) (15) (45)

Clark nevi 40 (%)

12 11 11 18 3* 3* 9 9* 2* 9* 8 6* 2* 32* 13

(30) (2.5) (2.5) (45) (7.5) (7.5) (22.5) (22.5) (5) (22.5) (20) (15) (5) (80) (32.5) 0* 10* (25) 2* (5) 7* (17.5) 5 (12.5) 25* (62.5) 15* (37.5) 23 (57.5) 0 16* (40) 15 (37.5) 2 (5) 0 0 7 (17.5) 8* (20) 12* (30) 0* 5* (12.5) 20* (50) 7 (17.5) 13 (32.5)

Discriminant analysis coefficients

1.546

1.180

0.720

1.063

0.856

1.331

0.782

MM, Malignant melanoma. *Significant in respect of Spitz nevi (P \ .05).

were frequently characterized by sharp borders, constituted by a rim of dense clusters at the periphery of the lesions or by a clearly outlined contour between the skin and the lesion, whereas the majority of MMs and Clark nevi showed ill-defined skin-lesion outline. Large plump bright melanophages were present in the majority of Spitz nevi, although they were also frequently observed in MMs and Clark nevi.

Dermatoscopy and RCM correlates of Spitz nevi Dermatoscopic general patterns of Spitz nevi and their main confocal substrates are reported in Table II.

A typical Spitzoid pattern was observed in less than half of Spitz nevi (9 starburst and 9 globular). Spitz nevi showing starburst or globular pattern were characterized by numerous dense regular nests at the dermoepidermal junction and within the papillary dermis, and by sharp borders constituted predominantly by a peripheral rim of dense nests (Fig 1). Moreover, epidermis showed honeycombed or cobblestone pattern, and roundish pagetoid cells were rarely observable. On the other hand, nonedged papillae, along with atypical spindled or polygonal cells, and numerous melanophages, extended over 25% of the lesion, were frequently present in basal layer and papillary dermis, respectively. Histologically, no

240 Pellacani et al

J AM ACAD DERMATOL FEBRUARY 2009

Table II. Dermatoscopic general pattern in Spitz nevi and confocal microscopic correlates Dermatoscopic pattern

No. of cases (%)

RCM correlate

Starburst Globular

9 (22.5) 9 (22.5)

Numerous dense regular nests at dermoepidermal junction and within the papillary dermis. Sharp borders constituted by a peripheral rim of dense nests. Typical epidermis, sometimes showing a few pagetoid cells. Non edged papillae, atypical spindled or polygonal cells, and numerous melanophages in basal layer and dermis.

Inverse network Superficial black network

4 (10) 2 (5)

Thickened, frequently acanthotic epidermis, with a honeycombed pattern in coincidence with inverse network and a cobblestone pattern in the latter. Papillary contours often not clearly distinguishable.

Reticular/homogeneous/complex Multicomponent

6 (15) 7 (17.5)

Nonedged papillae and atypical cells at dermoepidermal junction. Nests lacking of homogeneity and with loss of cell cohesion (sparse-cell nests).

Nonspecific

3 (7.5)

Disarranged or broadened honeycombed epidermal pattern, few roundish pagetoid cells. No visible papillary contours. Numerous large atypical cells, sometimes forming sheetlike structures, at dermoepidermal junction. Sparse cell and cerebriform clusters in dermis.

RCM, Reflectance confocal microscopy.

Fig 1. A, Dermatoscopy (350) of globular Spitz nevus. B, Confocal mosaic at dermoepidermal junction showing dense nests and sharp border cut-off. White bar = 500 m. C, Highmagnification confocal microscopy showing dense regular nests at dermoepidermal junction. White bar = 50 m. D, Corresponding histology presenting discrete melanocytic nests. (D, Hematoxylin-eosin stain; original magnification: 3200.)

feature suggestive of atypia was observed in these subgroups. Negative network and superficial black network characterized 4 and two cases, respectively. At RCM

examination, these lesions showed similar features, presenting a thickened, frequently acanthotic epidermis, with a honeycombed pattern coinciding with inverse network and a cobblestone pattern in the

J AM ACAD DERMATOL

Pellacani et al 241

VOLUME 60, NUMBER 2

Fig 2. A, Dermatoscopy (330) of negative network Spitz nevus. B, Confocal mosaic at basal layer showing epidermal honeycombed structures and rarely thin, not well-distinguishable, dermal papillae. White bar = 500 m. C, High-magnification confocal detail showing concentric honeycombed structures centered by thin dermal papillae (white asterisks). White bar = 50 m. D, Corresponding histology presenting acanthotic epidermis with elongated cristae separated by thin papillae and hypopigmented melanocytes predominantly clustered in small nests at tip of epidermal cristae. (D, Hematoxylin-eosin stain; original magnification: 3100.)

latter. In half of the cases, papillary contour was not clearly distinguishable (Fig 2). All lesions were typical Spitz nevi, but one case demonstrated asymmetric silhouette on histologic examination. Reticular, homogeneous, complex, or multicomponent patterns were observed in 13 cases, 7 of which strongly mimicked MM. They were frequently characterized by nonedged papillae and atypical cells at dermoepidermal junction, with sharp border cut-offs in less than half of the cases (Fig 3). Nests were frequently observable, showing lack of homogeneity and loss of cell cohesion (sparse-cell nests) in 5 of 13 cases. Nucleated cells were also reported in the papillary dermis in 3 cases. Histologically, 9 of 13 cases showed asymmetry and/or poor lateral demarcation. The remaining 3 cases were palpable to nodular lesions showing a nonspecific dermatoscopic pattern. They presented a disarranged epidermal pattern in two cases and broadened honeycombed in one, with few roundish pagetoid cells. No papillary contour was distinguishable at the dermoepidermal junction, but numerous large atypical cells, roundish to polygonal in shape, were reported in all cases. Two of these formed

sheetlike structures, sparse cell nests, and cerebriform clusters in the dermis, corresponding with the observation of sheets of melanocytes and increased cellularity on histologic examination. Histologic aspects and RCM correlates of Spitz nevi Histologically, 18 cases were junctional, 21 were compound, and one was intradermal. RCM and histologic significant correlates are listed in Table III. General architectural overview. Symmetric silhouette and sharp lateral margins were frequently present and correlated with the corresponding RCM features. Irregular rete-ridge contours, observed in approximately half of the cases, showed a high concordance with RCM, whereas irregular contour of growth at deep margin was not seen at all. Cytologic aspects. At histology, 13 cases predominantly constituted spindled cells, 14 by epithelioid ones, whereas the remaining 13 had both cell types. Spindled cells found an RCM correspondence (Fig 4), whereas no correlation was observed for epithelioid cells. Pagetoid infiltration strongly

242 Pellacani et al

J AM ACAD DERMATOL FEBRUARY 2009

Fig 3. A, Dermatoscopy (330) of multicomponent Spitz nevus. B, Confocal mosaic showing marked asymmetry with brighter area, irregular nonedged papillae and poor border demarcation (white line outlines lesion contour). White bar = 500 m. C, Nonedged papillae and atypical cells (white arrowheads) at basal layer and plump bright cells (white arrow) within papillary dermis. White bar = 50 m. D, Irregular rete-ridge contour, large epithelioid cells in basal layer, and inflammatory infiltrate rich in melanophages in papillary dermis at histology. (D, Hematoxylin-eosin stain; original magnification: 3200.)

correlated with roundish cells in superficial epidermal layers on RCM, whereas mitoses did not correlate with RCM cell figures. Presence and aspects of melanocytic nests found correspondence with RCM features, except for the confluence of nests (Fig 5). Prominent dermal cellularity and deep tumor extension, observed in two cases, showed a strong correlation with the presence of sheetlike structures and/or cerebriform nests at RCM (Fig 6). No RCM correlate was found for clefting, and loss of cellular cohesion was never observed. Epidermal features. Hyperkeratosis, acanthosis, and Kamino bodies were not correlated to any RCM feature. Pigmented parakeratosis was associated with a cobblestone pattern at RCM. Dermal features. Regression and desmoplasia, rarely present, were not significantly correlated with RCM collagen features. Inflammatory infiltrate, reported in almost all cases, correlated with the presence of plump bright cells within the papillary dermis at RCM. On the whole, 13 of 40 Spitz nevi had at least one feature suggestive of atypia, in 11 cases

corresponding to asymmetry and/or poor lateral demarcation, whereas the remaining two were characterized by the presence of large dermal sheets of melanocytes, evidence of reticular nonmarginal dermal mitotic figures, and increased cellularity.

Diagnostic impact of dermatoscopy and RCM Discriminant analysis identified RCM features useful for distinction between Spitz nevi and MMs (Table I). Modeling the equation for discriminating between Spitz and MMs, 92.5% sensitivity and specificity were obtained, with a corresponding receiver operating characteristic curve area of 0.975 (95% confidence interval = 0.945-1.000). At dermatoscopy, 23 (57.5%) Spitz nevi (all the starburst, globular, and superficial black network type, and 3 of 4 reticular depigmentation type) were diagnosed as such on dermatoscopy, whereas 6 were diagnosed as Clark nevi and 11 as MMs. RCM algorithm score equal or greater than 3, suggestive of malignancy, was calculated in 70% of Spitz nevi, with no substantial differences in the dermatoscopic subgroups.

Pellacani et al 243

J AM ACAD DERMATOL VOLUME 60, NUMBER 2

Table III. Confocal findings correlating with characteristic histologic features for Spitz nevus diagnosis Concordant evaluations Histologic features

Sharp lateral demarcation Irregular rete-ridge contour Spindled cells Pagetoid infiltration Discrete regular nests Discrete irregular nests Irregular nondiscrete nests Confluence of nests Increased cellularity and reticular dermal extension Transepidermal melanin dispersion Melanophages

RCM correlate

Percent*

Presencey

Rim of nests at periphery and/or abrupt border cut-off Irregular papillary contour Spindled cells Roundish pagetoid cells Dense nests Dishomogeneous nests Sparse cell nests

77.5%

25

6

0.419

80%

19

13

0.592

70% 87.5% 72.5% 87.5% 92.5%

17 27 17 4 4

11 8 12 31 33

0.400 0.677 0.469 0.545 0.684

72.5% 95%

7 2

22 36

0.371 0.643

65%

17

9

0.300

85%

31

3

0.415

Confluence of nests Sheetlike structures and/or cerebriform nests Cobblestone pattern Plump bright cells

Absencey

Cohen kappa

RCM, Reflectance confocal microscopy. *Overall proportion of concordant evaluations (of 40) for examined feature. y Absolute No. of histologic and confocal concordant evaluations for presence or absence of evaluated feature.

Fig 4. A, Confocal aspect of spindled cells (white arrows) in superficial and basal cell layer, showing up as fusiform cells with bipolar elongations or dendrites. White bar = 50 m. B, Corresponding histology showing typical spindled melanocytes (white arrows). (B, Hematoxylin-eosin stain; original magnification: 3400.)

On the other hand, 37 (92.5%) MMs, predominantly characterized by multicomponent pattern, were correctly classified on dermatoscopy, with the exception of two lesions showing a complex pattern and interpreted as Clark nevi, and one with starburst pattern classified as Spitz nevus. Similarly, the RCM algorithm score positively classified the 92.5% of MMs, although the misclassified MMs were different using the two techniques (Table IV). Only 14 of 40 (35%) Clark nevi, all showing homogeneous reticular or complex patterns, were correctly diagnosed by dermatoscopy. All the remaining lesions were classified as MMs but

two, considered Spitz nevi because of the presence of a globular pattern and a peripheral rim of globules. The RCM algorithm score showed a greater specificity (67.5%) compared with dermatoscopy, classifying as MMs only 13 (32.5%) of 40 cases (Table IV).

DISCUSSION Spitz nevi seem to represent a type of melanocytic neoplasm distinct from conventional melanocytic nevi and MM. Owing to the peculiar nature of Spitzoid lesions, classification is still under debate, especially for tumors with one or more atypical

244 Pellacani et al

J AM ACAD DERMATOL FEBRUARY 2009

Fig 5. A, Confocal presentation of confluent nests, characterized by cells clustered into nests with ovoid bulging, resembling dense nests each fused in unique structure. White bar = 50 m. B, Corresponding confluence of melanocytic nests on histology. (B, Hematoxylin-eosin stain; original magnification: 3200.)

Fig 6. A, Sheetlike structures corresponding to discrete irregular clusters of tightly packed cells associated to loss of dermal papillae regular contour. White bar = 50 m. B, Prominent dermal cellularity at histology. (B, Hematoxylin-eosin stain; original magnification: 3200.)

features (atypical Spitz tumor), characterized by indeterminate biological potential.8-10 The most typical Spitz tumors can be identified by characteristic histologic criteria with shared features with conventional acquired melanocytic nevi. However, the problem is with lesions not fulfilling the histopathologic criteria of MM or of typical Spitz nevi. Thus, terms such as ‘‘Spitz-like tumor’’ and ‘‘atypical Spitz nevus’’ have been generated to identify an intermediate category that is difficult to classify as clearly benign or malignant.10,26,27 Dermatoscopy enabled the identification of some characteristic features in Spitz nevi, improving diagnostic accuracy compared with naked-eye examination.11 Starburst and globular patterns were designated as characteristic of Spitz nevi, and they also seemed to represent different phases of progression of the same lesion.28 Further dermatoscopic clues, such as negative network and superficial black network, although having a low sensitivity for the diagnosis of Spitz nevi, appeared to be specific.12,13 On the other hand, the nonspecific type

frequently simulated melanocytic or nonmelanocytic lesions.15,18 Whereas lesions showing a multicomponent pattern were usually misclassified as atypical nevi or superficial spreading MMs, diagnostic difficulty increased when approaching nonpigmented lesions or nodular tumors. The latter were frequently misclassified not only with hypomelanotic or nodular MMs but also with other skin cancer or inflammatory lesions.15 Recently, Ferrara et al18 described a series of Spitz nevi by histopathology and dermatoscopy, relating the histopathologic findings with the dermatoscopic features. A great variability was observed in the dermatoscopic appearance of Spitz nevi, and histopathological atypia were frequently found in dermatoscopically atypical and/or multicomponent lesions, although lacking tight histologic-dermatoscopic correlation. A potential source of the dermatoscopic overestimation was found in the presence of bandlike melanophage infiltration, appearing as suspicious bluish structures. In recent reports, RCM, together with the possibility of improving diagnostic accuracy in skin cancer

Pellacani et al 245

J AM ACAD DERMATOL VOLUME 60, NUMBER 2

Table IV. Diagnostic impact of dermatoscopy and reflectance confocal microscopy in different dermatoscopicconfocal subgroups Dermatoscopy Subgroups

Starburst/globular pattern Spitz nevi MMs Clark nevi Inverse network/superficial black network Spitz nevi MMs Clark nevi Reticular, homogeneous, complex, multicomponent pattern Spitz nevi MMs Clark nevi Nonspecific pattern Spitz nevi MMs Clark nevi

Confocal microscopy

No. of cases

Suggestive of benign lesion

Suggestive of melanoma

RCM score \ 3

RCM score $ 3

21 18 1 2 7

21 18 1 2 5

0 0 0 0 2

8 6 0 2 3

13 12 1 0 4

6 1 0 85

5 0 e 19

1 1 e 66

2 1 e 29

4 0 e 56

13 34 38 7 3 4 0

5 2 12 1 1 0 e

8 32 26 6 2 4 e

4 0 25 2 0 2 e

9 34 13 5 3 2 e

MM, Malignant melanoma; RCM, reflectance confocal microscopy.

and melanocytic lesions,20,29 enabled exploration of the cytologic substrates of numerous dermatoscopic features. For example, it was useful in distinguishing the different nature of the atypical network, globules and dots, pigment blotches, and blue structures in MMs and nevi.30-33 Nevertheless, Spitz nevi were not distinguishable from MMs in many cases because it was impossible to explore the lesion in significant vertical depth.20 These data were confirmed by the application in this case series of the previously proposed RCM score,25 which accurately differentiated between atypical nevi and MMs, with sensitivity and specificity comparable with previous literature data,20,25 but misclassified in 70% of Spitz cases. In this study, we first aimed to identify characteristic RCM features of Spitz nevi, evaluating previously reported and new features, and their histopathologic correlates. A good correlation was found for some histologic aspects and RCM features, some of which were considered to be characteristic of Spitz nevi, such as sharp lateral demarcation and presence of spindled cells. There were other useful but not very specific features, such as pagetoid infiltration, junctional and dermal nests, parakeratosis and transepidermal melanin dispersion, and inflammatory infiltrate rich in melanophages. However, no correlates were found for other characteristic histologic aspects, such as Kamino bodies, hyperkeratosis, acanthosis, mitoses, and maturation with depth.

Interestingly, 4 of the 8 histologic features considered for the atypical Spitz nevus classification demonstrated a high correlation with RCM features. Specifically, lesion asymmetry corresponded with histology. The limited field of view (4 3 4 mm) required, in some cases, more than one acquisition session but this seems to be overcome in the most recent version of the near-infrared reflectance confocal laser scanning microscopes, enabling the visualization of a 10 -3 10-mm field of view. Poor lateral demarcation correlated with fading-off margins and absence of peripheral nests. The presence of prominent dermal cellularity and of dermal sheets of melanocytes were associated with sheetlike structures and cerebriform nests with RCM. No lesion showed ulceration, whereas in-depth aspects (eg, lack of maturation in the dermis, reticular dermal mitotic figures, and extensive involvement of the subcutis) did not correlate with RCM features. This could probably be a result of the limited laser-light penetration 300 m below the surface. As a secondary aim, diagnostic usefulness of RCM features in distinguishing Spitz nevi from both MMs and Clark nevi was tested on a corresponding population of consecutively excised lesions, with sharp border cut-off, junctional nests, and presence of melanophages being among some of the most striking features for differentiating Spitz nevi from MMs. Although discriminant analysis equation

246 Pellacani et al

J AM ACAD DERMATOL FEBRUARY 2009

significantly distinguished between Spitz nevi and MMs, the frequent presence of features suggestive of malignancy in Spitz nevi hamper a reliable application of the algorithm in clinical practice. Such features include pagetoid and atypical cells, nonedged papillae and dishomogeneous nests, and the impossibility of exploring in-depth aspects that are requisite to rule out pathologic diagnosis. However, because characteristic RCM patterns correlated with different dermatoscopic subgroups, we suggest a classification of Spitz nevi based on their dermatoscopic and RCM aspects, to enable discernment among different subtypes in vivo, which are more likely to correlate with histologic atypia. From our cases, starburst and globular lesions were predominantly characterized by dense nests. These lacked RCM or histologic atypical features, thus confirming their common origin28 and suggesting the possibility of observation of these lesions. Furthermore, in spite of their very different dermatoscopic presentation, lesions characterized by negative and superficial black network showed similar RCM and histologic substrates, usually lacking atypical features. However, in these cases excision needs to be considered because the hyperkeratotic and acanthotic epidermis frequently prevented a clear RCM distinction of the dermoepidermal junction and papillary dermis to be made, thereby possibly concealing features suggestive of malignancy when using this technique. On the other hand, reticular, homogeneous, complex, and multicomponent lesions should be excised because of the presence of RCM features suggestive of malignancy in 9 of 13 cases of our series, and histologic atypical aspects in the same 9 cases. Moreover, all the 3 lesions presenting a dermatoscopic nonspecific pattern showed atypical RCM and histologic features. Two of these lesions were clinically nodular, and presented reticular dermal mitoses and lacked maturation in the dermis. Once further instrumentation refinements, such as deeper light penetration and increased resolution, become available, a noninvasive reliable diagnosis of Spitz nevi should be achievable; meanwhile combined RCM and dermatoscopic examination can satisfactorily identify different Spitz categories. Spitz nevi should be studied as constituted by different populations to improve our understanding of the different biological origin and invasive potential of these lesions. REFERENCES 1. Spitz S. Melanoma of childhood. Am J Pathol 1948;24:591-609. 2. Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975;2:119-47.

3. Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol 1992;27:901-13. 4. Dal Pozzo V, Benelli C, Restano L, Gianotti R, Cesana BM. Clinical review of 247 case records of Spitz nevus (epithelioid cell and/or spindle cell nevus). Dermatology 1997;194:20-5. 5. Ackerman AB, Magana-Garcia M. Naming acquired melanocytic nevi. Am J Dermatopathol 1990;12:193-209. 6. Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of ninety-five cases. J Am Acad Dermatol 1993;28:565-71. 7. Piepkorn M. On the nature of histologic observations: the case of the Spitz nevus. J Am Acad Dermatol 1995;32:248-54. 8. Barnhill RL, Barnhill MA, Berwick M, Mihm MC Jr. The histologic spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. Hum Pathol 1991;22:52-8. 9. Mones JM, Ackerman AB. ‘‘Atypical’’ Spitz’s nevus, ‘‘malignant’’ Spitz’s nevus, and ‘‘metastasizing’’ Spitz’s nevus: a critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 2004;26:310-33. 10. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol 2006;19(Suppl):S21-33. 11. Steiner A, Pehamberger H, Binder M, Wolff K. Pigmented Spitz nevi: improvement of the diagnostic accuracy by epiluminescence microscopy. J Am Acad Dermatol 1992;27:697-701. 12. Stolz W, Braun-Falco O, Bilek P, Landthaler M, Cognetta AB. Pigmented spindle-cell nevus and Spitz nevus. In: Stolz W, Braun-Falco O, Bilek P, Landthaler M, Cognetta AB, editors. Color atlas of dermatoscopy. Oxford (United Kingdom): Blackwell Science Ltd; 1994. pp. 66-70. 13. Argenziano G, Soyer HP, Ferrara G, Piccolo D, HofmannWellenhof R, Peris K, et al. Superficial black network: an additional dermoscopic clue for the diagnosis of spindle and/or epithelioid cell nevus. Dermatology 2001;203:333-5. 14. Argenziano G, Scalvenzi M, Staibano S, Brunetti B, Piccolo D, Delfino M, et al. Dermatoscopic pitfalls in differentiating pigmented Spitz nevi from cutaneous melanomas. Br J Dermatol 1999;141:788-93. 15. Pellacani G, Cesinaro AM, Seidenari S. Morphological features of Spitz nevus as observed by digital videomicroscopy. Acta Derm Venereol 2000;80:117-21. 16. Peris K, Ferrari A, Argenziano G, Soyer HP, Chimenti S. Dermoscopic classification of Spitz/Reed nevi. Clin Dermatol 2002;20:59-62. 17. Brunetti B, Nino M, Sammarco E, Scalvenzi M. Spitz nevus: a proposal for management. J Eur Acad Dermatol Venereol 2005;19:391-3. 18. Ferrara G, Argenziano G, Soyer HP, Chimenti S, Di Blasi A, Pellacani G, et al. The spectrum of Spitz nevi: a clinicopathologic study of 83 cases. Arch Dermatol 2005;141:1381-7. 19. Gonza´lez S, Gilaberte-Calzada Y, Gonza´lez-Rodrı´guez A, Torres A, Mihm MC Jr. In vivo reflectance-mode confocal scanning laser microscopy in dermatology. Adv Dermatol 2004;20:371-87. 20. Pellacani G, Guitera P, Longo C, Avramidis M, Seidenari S, Menzies S. The impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. J Invest Dermatol 2007;127:2759-65. 21. Pellacani G, Cesinaro AM, Grana C, Seidenari S. In vivo confocal scanning laser microscopy of pigmented Spitz nevi: comparison of in vivo confocal images with dermoscopy and routine histopathology. J Am Acad Dermatol 2004;51:371-6. 22. Rajadhyaksha M, Gonzalez S, Zavislan JM, Anderson RR, Webb RH. In vivo confocal scanning laser microscopy of human skin II: advances in instrumentation and comparison with histology. J Invest Dermatol 1999;113:293-303.

Pellacani et al 247

J AM ACAD DERMATOL VOLUME 60, NUMBER 2

23. Argenziano G, Soyer HP, Chimenti S, Talamini R, Corona R, Sera F, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 2003;48:679-93. 24. Scope A, Benvenuto-Andrade C, Agero AL, Malvehy J, Puig S, Rajadhyaksha M, et al. In vivo reflectance confocal microscopy imaging of melanocytic skin lesions: consensus terminology glossary and illustrative images. J Am Acad Dermatol 2007;57: 644-58. 25. Pellacani G, Cesinaro AM, Seidenari S. Reflectance-mode confocal microscopy of pigmented skin lesions-improvement in melanoma diagnostic specificity. J Am Acad Dermatol 2005; 53:979-85. 26. Barnhill RL, Argenyi ZB, From L, Glass LF, Maize JC, Mihm MC Jr, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction outcome. Hum Pathol 1999;30:513-20. 27. Urso C. Melanocytic lesions, Spitz tumors, and Don Ferrante’s logic. Am J Dermatopathol 2007;29:491-4. 28. Pizzichetta MA, Argenziano G, Grandi G, de Giacomi C, Trevisan G, Soyer HP. Morphologic changes of a pigmented

29.

30.

31.

32.

33.

Spitz nevus assessed by dermoscopy. J Am Acad Dermatol 2002;47:137-9. Gerger A, Koller S, Weger W, Richtig E, Kerl H, Samonigg H, et al. Sensitivity and specificity of confocal laser-scanning microscopy for in vivo diagnosis of malignant skin tumors. Cancer 2006;107:193-200. Pellacani G, Cesinaro AM, Longo C, Grana C, Seidenari S. Microscopic in vivo description of cellular architecture of dermoscopic pigment network in nevi and melanomas. Arch Dermatol 2005;141:147-54. Scope A, Benvenuto-Andrade C, Agero AL, Halpern AC, Gonzalez S, Marghoob AA. Correlation of dermoscopic structures of melanocytic lesions to reflectance confocal microscopy. Arch Dermatol 2007;143:176-85. Pellacani G, Bassoli S, Longo C, Cesinaro AM, Seidenari S. Diving into the blue: in vivo microscopic characterization of the dermoscopic blue hue. J Am Acad Dermatol 2007;57:96-104. Pellacani G, Longo C, Malvehy J, Puig S, Carrera C, Segura S, et al. In vivo confocal microscopic and histopathologic correlations of dermoscopic features in 202 melanocytic lesions. Arch Dermatol. In press.