III.16 Spitz Nevus and Its Variants

III.16.1 Definition

The eponymic designation “Spitz nevus” refers to a benign melanocytic proliferation, which was first described in 1948 by Sophie Spitz as

“melanoma of the childhood” [1]. Along with this original description, we presently consider as “classical” Spitz nevus a rapidly growing, pink or flesh-colored papule or nodule of the lower extremities or the face in childhood or early adulthood [2–6]. Its histopathological hallmark is the presence of large spindle and/or epithelioid cells, usually in the paucity or ab- sence of melanin.

“Reed nevus” is another eponymic designa- tion for a benign melanocytic lesion described by Reed et al. in 1975 as “pigmented spindle cell nevus” [7]. It is mostly found in young adults on the lower extremities as a rapidly growing brownish-black macule or papule [7]. Histo- pathologically, it is described as made up by in- terconnecting junctional fascicles of heavily pigmented spindle cells [4, 7]. The nosological

Chapter III.16

Spitz Nevus and Its Variants

Gerardo Ferrara, Elvira Moscarella, Caterina M. Giorgio,

Giuseppe Argenziano III.16

Contents

III.16.1 Definition . . . .151

III.16.2 Clinical Features . . . .152

III.16.3 Dermoscopic Criteria . . . .153

III.16.4 Relevant Clinical Differential Diagnosis . . . .158

III.16.5 Histopathology . . . .159

III.16.6 Management . . . .160

References . . . 161

autonomy of Reed nevus from Spitz nevus has been questioned since 1978, when Paniago- Pereira et al. [8] underlined the occurrence of cases of spindle and/or epithelioid cell nevi with heavy pigmentation, thereby ascribing Reed ne- vus to the morphological spectrum of Spitz ne- vus. At present, some authors still maintain that Reed nevus is an entity that can be clearly dif- ferentiated from pigmented spindle cell Spitz nevus [9–15]; however, a clinicopathological evaluation of a large case series has recently shown that the histopathological distinction be- tween these two diagnostic categories is often matter of great debate and has no clinical and dermoscopic relevance [16]. We can therefore refer to Spitz nevus by classifying it into two clinical variants, namely, the classical and the pigmented types (the latter also comprising Reed nevus).

Indisputably, some melanomas histopatho- logically resemble Spitz nevi to various extent [4]. When such similarities are striking from both an architectural and a cytological point of view the term “spitzoid melanoma” is justified [17]. A morphological spectrum of melanomas with “spitzoid” features probably exists, in which one end shows lesions with overtly atypi- cal histopathological features, i.e., lesions which are readily identified as malignant on histo- pathological examination At the opposite edge of this spectrum, one can conceivably find (rare) cases which can be diagnosed as malignant only retrospectively, i.e., after the development of metastases [17–19]. These lesions have been first referred to as “spindle cell and epithelioid cell nevi with atypia and metastasis” or “malignant (metastasizing) Spitz nevi” [19], and subse- quently as “atypical Spitz nevi/tumors” [18].

They could be considered as neoplasms with

152 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

“bland” histopathological features and meta- static potential limited to the regional lymph nodes [18–20]. The common (although not in- variable) absence of further dissemination be- yond the regional lymph nodes has even raised the question about the true malignant nature of the lymph node “implants” from spitzoid neo- plasms [21]. At present, however, we have no convincing scientific data which can allow to really challenge the dogma of the metastasis as an unequivocal sign of malignancy [22, 23].

The concept of an “intermediate” category of spitzoid lesions placed in between benignity and malignancy does not fit with the traditional di- chotomic (“benign vs malignant”) diagnostic approach to histopathology. According to this view, cases of “metastasizing nevi” are simply diagnostic errors, because the distinction be- tween Spitz nevi and melanoma, although sometimes difficult, can – and therefore must – be made [22, 24]. It is obvious, however, that such a “dual” diagnostic approach leads to lowering the diagnostic threshold for melano- ma – and therefore to overdiagnosing melano- ma – in order not to miss the histopathological recognition of metastasizing lesions with subtle histopathological clues to malignancy.

Ongoing molecular genetic studies on spit- zoid neoplasms seem to be a promising diagnos- tic tool. HRAS mutations/amplifications have been detected in 11.8% of Spitz nevi [25]. B-RAF and N-RAS mutations, which are frequently found in melanoma on skin without chronic sun damage [26], are consistently absent in Spitz nevi [27, 28] and probably expressed in a minor- ity of spitzoid melanomas [28]. These data sug- gest that spitzoid neoplasms probably have a different pathway to tumorigenesis than con- ventional types of nevi and melanomas.

III.16.2 Clinical Features

Spitz nevus is a solitary, round to oval, dome- shaped papule, measuring up to 1 cm in diame- ter. Its surface is smooth or keratotic/verrucous, and occasionally even papillomatous. Although initially described as a non-pigmented lesion [1], recent data underline that Spitz nevi are brown to black in 71.3–92.7% [16, 29] of histo- logically examined cases. Such a high frequency of pigmented variants in surgical series could be the result of a better clinical recognition due to dermoscopy (see below) coupled with a low ex- cision rate of classical “pink” Spitz nevi in chil- dren.

As a rule, a rapidly growing, pink or reddish lesion of the head/neck or (lower) limbs is the clinical presentation of classical Spitz nevus in children. A brown/black papule of the trunk or lower extremities is the common clinical picture of pigmented Spitz nevus in young adults [5, 30, 31]; transitional clinical features are also possi- ble. Large (>1 cm) nodular and/or ulcerated le- sions must be always regarded as worrisome even in childhood [32, 23].

Rare congenital cases have been reported [33, 34]. A halo phenomenon has also been described [35]. Multiple, and sometimes eruptive [36], Spitz nevi can present in a clustered (agminated) [37] or a disseminated pattern [38]. Agminated Spitz nevi can also occur within a background (diffuse) hyperpigmentation [39] or within a speckled lentiginous nevus [40].

Spitz nevi have a low recurrence rate, even

after incomplete excision [41]; however, some

cases of satellitosis [42] and giant nodule forma-

tion [43] have been reported following surgical

procedures. In our opinion, such unusual oc-

currences could be even in keeping with a low

(or very low) malignant potential of some of

these lesions.

Spitz Nevus and Its Variants Chapter III.16 153

III.16.3 Dermoscopic Criteria

Six main dermoscopic patterns can be ascribed to Spitz nevus, namely, vascular, globular, star- burst, reticular, atypical, and homogeneous [44].

Classical Spitz nevus (Fig. III.16.1) is an amelanotic or hypopigmented lesion with a vas- cular pattern composed of dotted vessels [45], which are responsible for its “definitional” pink color. Dotted vessels are monomorphic, regu- larly distributed throughout the lesion, often grouped and surrounded by regularly intersect- ing white lines, the so-called reticular depig- mentation (Fig. III.16.1). A slight pigmentation can be present as a diffuse brownish hue with

widely and regularly spaced gray-brown, small- to medium-sized globules.

In frankly pigmented lesions, globules are brown to black, large and regularly distributed at the periphery (Fig. III.16.2). In most cases of pigmented Spitz nevi, peripheral globules are fused with the central body of the lesion; these regular, “on focus” radial projections (so-called streaks) are responsible for a “starburst” appear- ance (Fig. III.16.3). In a minority of cases, a heavy pigmentation also gives rise to a regular black network, which rests above the lesion and can be removed by tape stripping (“superficial black network”; Fig. III.16.4) [46]. Several of these features can be simultaneously present and/or irregularly distributed within a given le-

Fig. III.16.1.  a A pink lesion located on the thigh of a 27-year-old woman. Dermoscopically there is a negative pigment network (reticular depigmentation) with dot- ted vessels especially visible at the periphery. b A large, sharply circumscribed, plaque-like melanocytic lesion.

c A striking epidermal hyperplasia with junctional mela-

nocytic nests demarcated by half-moon peripheral clefts

(“capping”). d At a higher magnification large Kamino

bodies are seen within the epidermis

154 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

Fig. III.16.2.  a A small pigmented plaque located on

the arm of a 23-year-old man. Dermoscopically this is a

symmetric lesion with striking brown to black globules

especially visible at the periphery and grayish pigmenta-

tion in the center. b A medium-sized, well-demarcated,

plaque-like melanocytic lesion. c An epidermal hyper-

plasia with “capping” of junctional nests. d Same features

at the opposite side of the lesion. e Periadnexal extension

of the melanocytic nests, a microscopic feature which

Spitz nevus shares with congenital nevus as well as with

melanoma

Spitz Nevus and Its Variants Chapter III.16 155

sion, thus giving an atypical or “melanoma-like”

pattern. Dermoscopic atypia can also be in- creased by virtue of the presence of a blue-whit- ish veil as a result of a deep dermal pigmenta- tion with an overlying epidermal hyperplasia (Fig. III.16.5).

The “starburst,” the “globular,” and the

“atypical” patterns are the most common der- moscopic findings in surgical series of Spitz ne- vus [16]; however, most of these different der- moscopic patterns simply correspond to different phases of the natural evolution of Spitz nevi. Pizzichetta et al. [47] clearly demonstrated

that a pigmented Spitz nevus can rapidly evolve from a globular pattern to a “starburst” pattern, and finally to a homogeneous pattern; the latter is characterized by a diffuse brown or dark brown color, which resembles a common der- mal nevus (Fig. III.16.6). Parenthetically, some

“dermal” nevi show that a homogeneous light- brown pattern could be the end phase of classi- cal Spitz nevi. On the other hand, the final stage in the natural evolution of Spitz nevi might also be represented by a complete involution of the lesion (personal observation).

Fig. III.16.3.  a A small hyperpigmented plaque located on the thigh of a 43-year-old man. A starburst pattern is clearly visible by dermoscopy. b A small- to medium- sized, sharply circumscribed, plaque-like melanocytic proliferation with a symmetric distribution of the mela-

nin pigment. c A slight epidermal hyperplasia with junc-

tional nests of melanocytes shows no sharp separation

from the nearby keratinocytes. d At a higher magnifica-

tion, the spindle morphology of junctional melanocytes

is evident

156 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

Fig. III.16.4.  a A small black macule dermoscopically typified by a starburst pattern with clearly visible super- ficial black network. b A small melanocytic proliferation with “skip” pigmented parakeratosis. c A slight epidermal hyperplasia with a “plug” of pigmented parakeratosis

above a junctional nest of melanocytes. d At a higher

magnification, junctional melanocytes appear spindle-

shaped. Some melanophages are intermingled within

nests, a microscopic feature which is often observed in

Reed nevus

Spitz Nevus and Its Variants Chapter III.16 157

Fig. III.16.5.  a Irregularly pigmented plaque located on

the thigh of a 12-year-old girl. Dermoscopically there

is asymmetry in color and structure, blue-white veil

in the center, and brown globules and dotted vessels at

the periphery. b A medium-sized, dome-shaped, and

symmetric melanocytic proliferation. c, d The lesion is

sharply demarcated at both its edges. e An epidermal

hyperplasia with junctional nests of spindle-shaped

melanocytes. Some focal “capping” is also evident

158 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

III.16.4 Relevant Clinical Differential Diagnosis

Classical Spitz nevus must be differentiated from viral wart, verrucous epidermal nevus, capillary hemangioma, pyogenic granuloma, angiolymphoid hyperplasia with eosinophilia, and lymphoid infiltration of the skin. It has been underlined that dotted vessels seen on der- moscopy are generally predictive for a melano- cytic lesion and are especially seen in Spitz ne- vus [45]. The uniform shape and distribution of dotted vessels can also help in differentiating classical Spitz nevus from amelanotic melano- ma. It must be emphasized, however, that no

dermoscopic criterion can allow such a differ- ential diagnosis with absolute reliability.

Differential diagnosis of pigmented Spitz ne- vus can include “globular” and “hypermelanot- ic” Clark nevus and melanoma. Brown globules of Clark nevus are usually smaller and regularly distributed throughout the entire surface of the lesion [48, 49]. Hypermelanotic (“black”) nevus is characterized by a central diffuse hyperpig- mentation (black lamella) and dark-brown net- work at the periphery of the lesion. Tape strip- ping removes the black lamella, but not the pigment network, as observed in rare cases of pigmented Spitz nevus [46]. Atypical pigment network, irregular dots and globules, irregular

Fig. III.16.6.  a A small black papule located on the arm of a 21-year-old woman. At dermoscopy a homogeneous pattern is seen, with brown to blue-gray structureless pigmentation. b A medium-sized, sharply circumscri bed, and symmetric melanocytic proliferation with dermal melanophages distributed in a band-like fashion.

c A moderate, regular epidermal hyperplasia with regu-

larly distributed junctional nests of melanocytes. d Me-

lanocytes within the junctional nests are spindle-shaped,

often with some dendritic processes, a feature which can

be observed in early Reed nevus

Spitz Nevus and Its Variants Chapter III.16 159

pigmentation, irregular streaks, and blue whit- ish veil are specific dermoscopic criteria of mel- anoma [48, 49]; however, the occurrence of an atypical dermoscopic pattern in Spitz nevus is well recognized [16], as is the occurrence of mel- anomas showing very few or no dermoscopic features suggestive of malignancy but exhibit- ing either the globular or the starburst pattern [50]. Remarkably, melanomas with “spitzoid”

dermoscopic features do not necessarily show

“spitzoid” histopathological features [16]. The substantial lack of reliable differential criteria from melanoma must always be taken into ac- count in the management of Spitz nevus (see below).

III.16.5 Histopathology

Spitz nevus is a neoplastic proliferation of mela- nocytes with large nuclei, prominent nucleoli, and abundant ground-glass cytoplasm with spindle and/or polygonal (epithelioid) outlines.

Its early intraepidermal growth phase is charac- terized by predominance of single melanocytes with some suprabasilar scatter, commonly con- fined to the lower layers of the epidermis (“pag- etoid” Spitz nevus [51] or “baby” Spitz nevus).

There can be a slight asymmetry, but some nest formation is evident even in small lesions.

Junctional, or predominantly junctional, Spitz nevus is a plaque-shaped, sharply demar- cated lesion composed mostly of sharply demar- cated melanocytic nests within a hyperplastic epidermis. Nests are equally sized, shaped, and spaced at the junction. Typically, some of them can undergo a transepidermal elimination. A periadnexal junctional component is very com- mon. Melanocytes are arranged perpendicular and parallel to the skin surface. They are highly cohesive and do not destroy the nearby kerati- nocytes; therefore, a semilunar cleavage is often evident around nests (“capping”) and even around the few single intraepidermal melano- cytes (“micro-capping”). Large and coalescent eosinophilic (Kamino) bodies may be found at the dermo-epidermal junction [52] and telangi- ectatic blood vessels can be seen in the superfi- cial dermis. Melanin pigment is common within spindle cells and dermal melanophages; howev-

er, even epithelioid melanocytes [53], as well as single intraepidermal dendritic melanocytes [54], can be pigmented. Finally, pigmented parakeratosis can be present in an ordered

“skip” fashion [46].

Neoplasms defined as Reed nevus are com- posed of heavily pigmented, monomorphic, small- to medium-sized spindle melanocytes, arranged mainly parallel to the skin surface.

Junctional nests typically show no sharp demar- cation from the overlying epidermis, with the latter showing only little hyperplasia. A band- like dermal infiltration of melanophages is a common ancillary finding [7–15].

Compound Spitz nevus is a dome-shaped le- sion with a dermal component composed of regularly spaced nests and cords of cells. Some maturation is at least focally seen and mitoses may be easily seen, but never as atypical figures and never close to the base of the lesion. Intra- vascular melanocytes can be detected and are not an ominous sign per se [4].

Dermal Spitz nevus is a dome-shaped or flat lesion which is often characterized by extensive desmoplasia encircling single melanocytes. Its overall picture can closely resemble dermatofi- broma [55]. The neoplasm described as “desmo- plastic nevus” [56] is probably related to desmo- plastic Spitz nevus. A plexiform arrangement of bundles and lobules of melanocytes has been described (plexiform Spitz nevus [4]). A promi- nent vasculature may also be seen (angiomatoid Spitz nevus [57]).

At present, an unequivocal and reproducible definition for “atypical Spitz nevus” and “atypi- cal Spitz(oid) tumor” is probably lacking [22, 24]. In general, these diagnostic categories can be used for lesions showing some distinctly ab- normal characteristics commonly absent in

“conventional spitzoid” lesions [17]. In a meta-

analysis based on 19 papers reporting 62 metas-

tasizing spitzoid neoplasms, an aggressive bio-

logical behavior was recorded even for lesions

showing only one of the following nine “atypi-

cal” features: (a) nodular dermal growth (solid

cellular sheets within the dermis); (b) deep ex-

tension with absent or impaired maturation; (c)

deep dermal mitoses; (d) marked nuclear/nucle-

olar pleomorphism; (e) heavy melanization in

depth; (f) asymmetry; (g) cellular necrosis; (h)

160 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

epithelioid epidermal melanocytes below para- keratosis and/or epidermal ulceration; and (i) neoplastic cells within the lymph vessels [58].

One can therefore conclude that even the pres- ence of one of the above-listed features is prob- ably enough for ascribing a given spitzoid lesion to an “intermediate” diagnostic category. We prefer to use the term “atypical spitzoid tumor”

for lesions which show a large nodular (“tumor- al”) dermal component, while leaving the term

“atypical Spitz nevus” to the remaining cases.

III.16.6 Management

The management of Spitz nevus must be decid- ed by considering the following issues:

1. Melanoma in childhood is exceedingly rare [59]; however, amelanotic melanoma surprisingly shows higher prevalence in children than in adults. Moreover, very large (>1 cm) and/or ulcerated spitzoid neoplasms of childhood can show sentinel lymph node metastases [23].

2. There are no reliable differential criteria between Spitz nevus and melanoma on dermoscopy [49, 50]. Actually, melano- mas showing Spitz nevus-like features on dermoscopy are not necessarily “spitzoid”

on histopathology [16].

Based on these considerations, a classical or pig- mented Spitz nevus appearing up to the age of 12 years [60] can be easily diagnosed and man- aged conservatively if it is relatively small (up to 1 cm) and shows no atypical clinical and der- moscopic features. Under these circumstances, a follow-up can be scheduled with controls ev- ery 6 months [60]. In the absence of dramatic changes in color, shape, or size, such a follow-up protocol can be held until the appearance of a homogeneous pattern. Afterward, a 1-year fol- low-up can be employed.

Large (>1 cm), ulcerated, rapidly changing, or otherwise atypical Spitz nevi of childhood must be excised. Surgical excision is also recom- mended when Spitz nevi appear in adulthood, regardless of the presence of atypical clinical/

dermoscopic features.

Every surgical excision must be carried out with a narrow (0.1 cm) margin. Diagnosis of atypical Spitz nevus/tumor requires further surgical procedures as suggested for melanoma [59].

Left: The lesion is mostly nested, mostly at the junction, with some irregular epidermal atrophy. Right: At the cen- ter of the lesion the epidermis is atrophic; the melanocyt- ic proliferation becomes more diffuse, with large sheets of cells separated by small amonts of collagen fibers

The lesion is a brownish, dome shaped papule with

smooth surface and regular borders. Dermoscopically

the lesion shows a central irregular grayish hyperpig-

mentation, and brown to black globules/dots irregularly

distributed throughout the lesion. Histopathogically, a

dome-shaped, sharply demarcated and symmetric mela-

nocytic proliferation is seen

Spitz Nevus and Its Variants Chapter III.16 161

C

Core Messages

■ Spitz nevus can clinically present either in the classical (reddish-pink) or in the pigmented (brownish-black) variant.

■ It can show six different dermoscopic patterns – i.e., vascular, globular, starburst, reticular, atypical, and homo- geneous – none of which is clearly distinguishable from melanoma.

■ Even histopathologically, a clear-cut differentiation between benign and ma- lignant spitzoid neoplasms is often difficult, so that an “intermediate”

diagnostic category is admitted, the so- called atypical Spitz nevus/atypical spitzoid tumor.

■ Because of these difficulties in both clinical and histopathological evalua- tion, surgical excision is recommended for clinically atypical (large, ulcerated, rapidly changing) spitzoid lesions of childhood and for all the spitzoid lesions of adulthood.

References

1. Spitz S. Melanomas of childhood. Am J Pathol 1948;24:591–609

2. Spatz A, Peterse S, Fletcher CDM, Barnhill RL.

Plexiform Spitz nevus. Am J Dermatopathol 1999;

21: 542–546

3. Gartman H, Ganser M. Der Spitz-Nevus, Spindelzel- len und/oder Epitheloidzellennevus: eine klinische analyse von 652 tumoren. Z Hautkr 1985;60:22–28 4. Kopf AW, Andrade R. Benign juvenile melanoma.

In: Kopf AW, Andrade R, eds. Year book of der- matology. Chicago: Year Book Medical Publisher, 1966;7–52

5. Weedon D. Lentigines, nevi and melanomas. In:

Weedon D (ed) Skin pathology, 2nd edn. Edin- burgh: Churchill Livingstone, 2002;803–858 6. Weedon D, Little JH. Spindle and epithelioid cell

nevi in children and adults: a review of 211 cases of the Spitz nevus. Cancer 1977;40:217–225

7. Reed RJ, Ichinose H, Clark WH, et al. Common and

uncommon melanocytic nevi and borderline mela-

nomas. Semin Oncol 1975;2:119–147

162 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

III.16

8. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cell (Spitz’s ne- vus). Arch Dermatol 1978;112:1811–1823

9. 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;22:53–58 10. Barnhill RL, Mihm MC Jr. Pigmented spindle cell

nevus and its variants distinction from melanoma.

Br J Dermatol 1989;121:717–726

11. Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell nevus: a distinctive variant of plexiform melanocytic nevus. Histopathology 1991;18:243–

12. Gartmann H. Der Pigmentierte Spindelzellentu- 247 mor. Z Hautkr. 1981;56:862–876

13. Grossin M. Reed’s nevus. Ann Dermatol Venereol 1992;119:145

14. Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of ninety- five cases. J Am Acad Dermatol. 1993;28:565–571 15. Smith NP. The pigmented spindle cell tumor of

Reed: an underdiagnosed lesion. Semin Diagn Pathol 1987;4:75–87

16. Ferrara G, Argenziano G, Soyer HP, et al. The spec- trum of Spitz nevi: a clinicopathologic study of 83 cases. Arch Dermatol 2005;141:1381–1387

17. Barnhill RL. The spitzoid lesion: the importance of atypical variants and risk assessment. Am J Derma- topathol 2006;28:75–83

18. Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumor: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999;30:513–520

10. Smith K, Skelton H, Lupton G, Graham J. Spindle cell and epithelioid cell nevi with atypia and me- tastasis (malignant Spitz nevus). Am J Surg Pathol 1989;13:931–939

20. Cerroni L. A new perspective for Spitz tumors? Am J Dermatopathol 2005;27:366–367

21. LeBoit PE. What do these cells mean? Am J Derma- topathol 25:355–356

22. Mones JM, Ackerman AB. “Atypical” Spitz’s ne- vus, “malignant” Spitz’s nevus, and “metastasizing”

Spitz’s nevus: a critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 2004;26:310–333

23. Urso C, Borgognoni L, Saieva C, Ferrara G, Tinacci G, Begliomini B, Reali UM. Sentinel lymph node biopsy in patients with atypical Spitz tumors. A re- port on 12 cases. Hum Pathol 37:816–823

24. Ackerman AB. Garble that derives from lack of defi- nition. Am J Dermatopathol 2005;27:369–370 25. Bastian BC, LeBoit PE, Pinkel D. Mutations and

copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 2000;157:967–972

26. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busan KJ, Kutzner H, Cho KH, Aiba S, Broecker EB, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135–2147

27. Gill M, Cohen J, Renwick N, et al. Genetic similari- ties between Spitz nevus and spitzoid melanoma in children. Cancer 2004;101:2636–2640

28. Palmedo G, Hantschke M, Ruetten A, Mentzel T, Huegel H, Flaig MJ, Yazdi AS, Sander CA, Kutzner H. The T1796A mutation of the BRAF gene is absent in Spitz nevi. J Cutan Pathol 2004;31:266

29. Dal Pozzo V, Benelli C, Restano L, Gianotti R, Cesa- na BM. Clinical review of 247 case records of Spitz nevus (epithelioid cell and/or spinale cell nevus).

Dermatology 1997;194:20–25

30. Casso EM, Grin-Jorgensen CM, Grant-Kels JM.

Continuating medical education: Spitz nevi. J Am Acad Dermatol 1992;27:901–913

31. Sagebiel RW, Chinn EK, Egbert BM. Pigmented spindle cell nevus: clinical and histologic review of 90 cases. Am J Surg Pathol 1984;8:645–653 32. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL.

Spitz nevus in children. A grading system for risk stratification. Arch Dermatol 199;135:282–285 33. Palazzo JP, Duray PH. Congenital agminated

Spitz nevi. Immunoreactivity with a melanoma- associated monoclonal antibody. J Cutan Pathol 1988;15:166–170

34. Zaenglein AL, Heintz P, Kamino H, Zisblatt M, Or- low SJ. Congenital Spitz nevus clinically mimicking melanoma. J Am Acad Dermatol 2002;47:441–444 35. Yasaka N, Furue M, Tamaki K. Histopathological

evaluation of halo phenomenon in Spitz nevus. Am J Dermatopathol 1995;17:484–486

36. Fass J, Grimwood RE, Kraus E, Hyman J. Adult on- set of eruptible widespread Spitz’s nevi. J Am Acad Dermatol 2002;46:S141–S143

37. Lancer HA, Muhlbauer JE, Sober AJ. Multiple agmi- nated spindle cell nevi. Unique clinical presentation and review. J Am Acad Dermatol 1983;8:707–711 38. Smith SA, Day CL. Eruptive widespread Spitz nevi.

J Am Acad Dermatol 1986;15:1155–1159

39. Renfro L, Grant-Kels JM, Brown SA. Multiple ag- minate Spitz nevi. Pediatr Dermatol 1989;6:114–117 40. Aloi F, Tomasini C, Pippione M. Agminated Spitz nevi occurring within a congenital speckled lentigi- nous nevus. Am J Dermatopathol 1995;17:594–598 41. Kaye VN, Dehner LP. Spindle and epithelioid cell

nevus (Spitz nevus). Natural history following bi- opsy. Arch Dermatol 1990;126:1581–1583

42. Gambini C, Rongioletti F. Recurrent Spitz nevus.

Case reoprt and review of the literature. Am J Der-

matopathol 1994;16:409–413

Spitz Nevus and Its Variants Chapter III.16 163 43. Krasovec M, Gianadda B, Hohl D. Giant recurrence

of an agminated Spitz nevus. J Am Acad Dermatol 1995;33:386–388

44. Peris K, Ferrari A, Argenziano G, et al. Dermoscop- ic classification of Spitz/Reed nevi. Clin Dermatol 2002;20:259–262

45. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G, Ruocco E, Hofmann-Wellenhof R, Soyer HP. Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485–

46. Argenziano G, Soyer HP, Ferrara G, et al. Superfi- 1489 cial black network: an additional dermoscopic clue for the diagnisis of spindle and/or epithelioid cell nevus. Dermatology 2001;203:333–335

47. Pizzichetta MA, Argenziano G, Grandi G, Giacomi C de, Trevisan G, Soyer HP. Morphologic changes of a pigmented Spitz nevus assesed by dermoscopy.

J Am Acad Dermatol.2002;47:137–139

48. Argenziano G, Soyer HP, Giorgi V de, et al. Inter- active atlas of dermoscopy (Book and CD-ROM).

Milan: Edra Medical Publishing and New Media, 49. Argenziano G, Soyer HP, Chimenti S, et al. Dermos- 2000

copy of pigmented skin lesion: results of a cosen- sus meeting via the Internet. J Am Acad Dermatol 2003;48:679–693

50. Argenziano G, Scalvenzi M, Staibano S, et al. Der- matoscopic pitfalls in differentiating pigmented Spitz nevi from cutaneous melanomas. Br J Derma- tol 1999;141:788–793

51. Busam KJ, Barnhill RL. Pagetoid Spitz nevus. In- traepidermal Spitz tumor with prominent pagetoid spread. Am J Surg Pathol 1995;19:1061–1067

52. Kamino H, Flotte TJ, Misheloff E. Eosinophilic globules in Spitz’s nevi. New findings and a diag- nostic sign. Am J Dermatopathol 1979;1:319–324 53. Choi JH, Sung KJ, Koh JK. Pigmented epithelioid

cell naevus: a variant of Spitz naevus? J Am Acad Dermatol 1993;28:497–498

54. Ferrara G, Crisman G, Soyer HP, Zalaudek I, Ar- genziano G. Intraepidermal dendritic melano- cytes in spitzoid neoplasms. Am J Dermatopathol 28:449–450

55. Maize JC, Ackerman AB (eds). Spitz’s nevus. In:

Pigmented lesion of the skin. Philadelphia, Lea and Febiger; 1987:228–242

56. Barr RJ, Morales RV, Graham JH. Desmoplastic ne- vus. A distinct histologic variant of mixed spindle cell and epithelioid cell nevus. Cancer 1980;46:557–

57. Diaz-Cascajo C, Borghi S, Weyers W. Angiomatoid 564 Spitz nevus. A distinct variant of desmoplastic Spitz nevus with prominent vasculature. Am J Dermato- pathol 2000;22:135–139

58. Urso C. A new perspective for Spitz tumors? Am J Dermatopathol 2005;27:364–365

59. Zalaudek I, Ferrara G, Argenziano G, Ruocco V, Soyer HP. Diagnosis and treatment of cutaneous melanoma: a practical guide. Skin Med 2003;2:20–

60. Brunetti B, Nino M, Sammarco E, Scalvenzi M. 31

Spitz naevus: a proposal for management. J Eur

Acad Dermatol Venereol 2005;19:391