Spitz Nevus and Its Variants Gerardo Ferrara, Elvira Moscarella, Caterina M

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Chapter III.16 Spitz Nevus and Its Variants Gerardo Ferrara, Elvira Moscarella, Caterina M. Giorgio, III.16 Giuseppe Argenziano

Contents autonomy of Reed nevus from Spitz nevus has been questioned since 1978, when Paniago- III.16.1 Definition ...... 151 Pereira et al. [8] underlined the occurrence of III.16.2 Clinical Features ...... 152 cases of spindle and/or epithelioid cell nevi with III.16.3 Dermoscopic Criteria...... 153 heavy pigmentation, thereby ascribing Reed nevus to the morphological spectrum of Spitz ne- III.16.4 Relevant Clinical Differential vus. At present, some authors still maintain that Diagnosis...... 158 Reed nevus is an entity that can be clearly dif- III.16.5 Histopathology...... 159 ferentiated from pigmented spindle cell Spitz nevus [9–15]; however, a clinicopathological III.16.6 Management...... 160 evaluation of a large case series has recently References...... 161 shown that the histopathological distinction between 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 III.16.1 Definition clinical variants, namely, the classical and the pigmented types (the latter also comprising Reed The eponymic designation “Spitz nevus” refers nevus). to a benign melanocytic proliferation, which Indisputably, some melanomas histopatho- was first described in 1948 by Sophie Spitz as logically resemble Spitz nevi to various extent “melanoma of the childhood” [1]. Along with [4]. When such similarities are striking from this original description, we presently consider both an architectural and a cytological point of as “classical” Spitz nevus a rapidly growing, view the term “spitzoid melanoma” is justified pink or flesh-colored papule or nodule of the [17]. A morphological spectrum of melanomas lower extremities or the face in childhood or with “spitzoid” features probably exists, in early adulthood [2–6]. Its histopathological which one end shows lesions with overtly atypi- hallmark is the presence of large spindle and/or cal histopathological features, i.e., lesions which epithelioid cells, usually in the paucity or ab- are readily identified as malignant on histo- sence of melanin. pathological examination At the opposite edge “Reed nevus” is another eponymic designa- of this spectrum, one can conceivably find (rare) tion for a benign melanocytic lesion described cases which can be diagnosed as malignant only by Reed et al. in 1975 as “pigmented spindle cell retrospectively, i.e., after the development of nevus” [7]. It is mostly found in young adults on metastases [17–19]. These lesions have been first the lower extremities as a rapidly growing referred to as “spindle cell and epithelioid cell brownish-black macule or papule [7]. Histo- nevi with atypia and metastasis” or “malignant pathologically, it is described as made up by in- (metastasizing) Spitz nevi” [19], and subse- terconnecting junctional fascicles of heavily quently as “atypical Spitz nevi/tumors” [18]. pigmented spindle cells [4, 7]. The nosological They could be considered as neoplasms with 152 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

“bland” histopathological features and meta- III.16.2 Clinical Features static potential limited to the regional lymph nodes [18–20]. The common (although not in- Spitz nevus is a solitary, round to oval, dome- III.16 variable) absence of further dissemination be- shaped papule, measuring up to 1 cm in diame- yond the regional lymph nodes has even raised ter. Its surface is smooth or keratotic/verrucous, the question about the true malignant nature of and occasionally even papillomatous. Although the lymph node “implants” from spitzoid neo- initially described as a non-pigmented lesion plasms [21]. At present, however, we have no [1], recent data underline that Spitz nevi are convincing scientific data which can allow to brown to black in 71.3–92.7% [16, 29] of histo- really challenge the dogma of the metastasis as logically examined cases. Such a high frequency an unequivocal sign of malignancy [22, 23]. of pigmented variants in surgical series could be The concept of an “intermediate” category of the result of a better clinical recognition due to spitzoid lesions placed in between benignity and dermoscopy (see below) coupled with a low ex- malignancy does not fit with the traditional di- cision rate of classical “pink” Spitz nevi in chil- chotomic (“benign vs malignant”) diagnostic dren. approach to histopathology. According to this As a rule, a rapidly growing, pink or reddish view, cases of “metastasizing nevi” are simply lesion of the head/neck or (lower) limbs is the diagnostic errors, because the distinction be- clinical presentation of classical Spitz nevus in tween Spitz nevi and melanoma, although children. A brown/black papule of the trunk or sometimes difficult, can – and therefore lower extremities is the common clinical picture must – be made [22, 24]. It is obvious, however, of pigmented Spitz nevus in young adults [5, 30, that such a “dual” diagnostic approach leads to 31]; transitional clinical features are also possi- lowering the diagnostic threshold for melano- ble. Large (>1 cm) nodular and/or ulcerated le- ma – and therefore to overdiagnosing melano- sions must be always regarded as worrisome ma – in order not to miss the histopathological even in childhood [32, 23]. recognition of metastasizing lesions with subtle Rare congenital cases have been reported [33, histopathological clues to malignancy. 34]. A halo phenomenon has also been described Ongoing molecular genetic studies on spit- [35]. Multiple, and sometimes eruptive [36], zoid neoplasms seem to be a promising diagnos- Spitz nevi can present in a clustered (agminated) tic tool. HRAS mutations/amplifications have [37] or a disseminated pattern [38]. Agminated been detected in 11.8% of Spitz nevi [25]. B-RAF Spitz nevi can also occur within a background and N-RAS mutations, which are frequently (diffuse) hyperpigmentation [39] or within a found in melanoma on skin without chronic speckled lentiginous nevus [40]. sun damage [26], are consistently absent in Spitz Spitz nevi have a low recurrence rate, even nevi [27, 28] and probably expressed in a minor- after incomplete excision [41]; however, some ity of spitzoid melanomas [28]. These data sug- cases of satellitosis [42] and giant nodule forma- gest that spitzoid neoplasms probably have a tion [43] have been reported following surgical different pathway to tumorigenesis than con- procedures. In our opinion, such unusual oc- ventional types of nevi and melanomas. 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

Fig. III.16.1. a A pink lesion located on the thigh of a c A striking epidermal hyperplasia with junctional mela- 27-year-old woman. Dermoscopically there is a negative nocytic nests demarcated by half-moon peripheral clefts pigment network (reticular depigmentation) with dot- (“capping”). d At a higher magnification large Kamino ted vessels especially visible at the periphery. b A large, bodies are seen within the epidermis sharply circumscribed, plaque-like melanocytic lesion.

III.16.3 Dermoscopic Criteria widely and regularly spaced gray-brown, small- to medium-sized globules. Six main dermoscopic patterns can be ascribed In frankly pigmented lesions, globules are to Spitz nevus, namely, vascular, globular, star- brown to black, large and regularly distributed burst, reticular, atypical, and homogeneous at the periphery (Fig. III.16.2). In most cases of [44]. pigmented Spitz nevi, peripheral globules are Classical Spitz nevus (Fig. III.16.1) is an fused with the central body of the lesion; these amelanotic or hypopigmented lesion with a vas- regular, “on focus” radial projections (so-called cular pattern composed of dotted vessels [45], streaks) are responsible for a “starburst” appear- which are responsible for its “definitional” pink ance (Fig. III.16.3). In a minority of cases, a color. Dotted vessels are monomorphic, regu- heavy pigmentation also gives rise to a regular larly distributed throughout the lesion, often black network, which rests above the lesion and grouped and surrounded by regularly intersect- can be removed by tape stripping (“superficial ing white lines, the so-called reticular depig- black network”; Fig. III.16.4) [46]. Several of mentation (Fig. III.16.1). A slight pigmentation these features can be simultaneously present can be present as a diffuse brownish hue with and/or irregularly distributed within a given le- 154 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

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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 pigmentation in the center. b A medium-sized, well-demarcated, plaque-like melanocytic lesion. c An epidermal hyperplasia 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

Fig. III.16.3. a A small hyperpigmented plaque located nin pigment. c A slight epidermal hyperplasia with junc- on the thigh of a 43-year-old man. A starburst pattern tional nests of melanocytes shows no sharp separation is clearly visible by dermoscopy. b A small- to medium- from the nearby keratinocytes. d At a higher magnifica- sized, sharply circumscribed, plaque-like melanocytic tion, the spindle morphology of junctional melanocytes proliferation with a symmetric distribution of the mela- is evident

sion, thus giving an atypical or “melanoma-like” that a pigmented Spitz nevus can rapidly evolve pattern. Dermoscopic atypia can also be in- from a globular pattern to a “starburst” pattern, creased by virtue of the presence of a blue-whit- and finally to a homogeneous pattern; the latter ish veil as a result of a deep dermal pigmenta- is characterized by a diffuse brown or dark tion with an overlying epidermal hyperplasia brown color, which resembles a common der- (Fig. III.16.5). mal nevus (Fig. III.16.6). Parenthetically, some The “starburst,” the “globular,” and the “dermal” nevi show that a homogeneous light- “atypical” patterns are the most common der- brown pattern could be the end phase of classi- moscopic findings in surgical series of Spitz ne- cal Spitz nevi. On the other hand, the final stage vus [16]; however, most of these different der- in the natural evolution of Spitz nevi might also moscopic patterns simply correspond to be represented by a complete involution of the different phases of the natural evolution of Spitz lesion (personal observation). nevi. Pizzichetta et al. [47] clearly demonstrated 156 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

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Fig. III.16.4. a A small black macule dermoscopically above a junctional nest of melanocytes. d At a higher typified by a starburst pattern with clearly visible super- magnification, junctional melanocytes appear spindle- ficial black network. b A small melanocytic proliferation shaped. Some melanophages are intermingled within with “skip” pigmented parakeratosis. c A slight epidermal nests, a microscopic feature which is often observed in hyperplasia with a “plug” of pigmented parakeratosis 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.

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Fig. III.16.6. a A small black papule located on the arm c A moderate, regular epidermal hyperplasia with regu- of a 21-year-old woman. At dermoscopy a homogeneous larly distributed junctional nests of melanocytes. d Me- pattern is seen, with brown to blue-gray structureless lanocytes within the junctional nests are spindle-shaped, pigmentation. b A medium-sized, sharply circumscri often with some dendritic processes, a feature which can bed, and symmetric melanocytic proliferation with be observed in early Reed nevus dermal melanophages distributed in a band-like fashion.

III.16.4 Relevant Clinical Differential dermoscopic criterion can allow such a differ- Diagnosis ential diagnosis with absolute reliability. Differential diagnosis of pigmented Spitz ne- Classical Spitz nevus must be differentiated vus can include “globular” and “hypermelanot- from viral wart, verrucous epidermal nevus, ic” Clark nevus and melanoma. Brown globules capillary hemangioma, pyogenic granuloma, of Clark nevus are usually smaller and regularly angiolymphoid hyperplasia with eosinophilia, distributed throughout the entire surface of the and lymphoid infiltration of the skin. It has lesion [48, 49]. Hypermelanotic (“black”) nevus been underlined that dotted vessels seen on der- is characterized by a central diffuse hyperpig- moscopy are generally predictive for a melano- mentation (black lamella) and dark-brown net- cytic lesion and are especially seen in Spitz ne- work at the periphery of the lesion. Tape strip- vus [45]. The uniform shape and distribution of ping removes the black lamella, but not the dotted vessels can also help in differentiating pigment network, as observed in rare cases of classical Spitz nevus from amelanotic melano- pigmented Spitz nevus [46]. Atypical pigment ma. It must be emphasized, however, that no network, irregular dots and globules, irregular Spitz Nevus and Its Variants Chapter III.16 159 pigmentation, irregular streaks, and blue whit- er, even epithelioid melanocytes [53], as well as ish veil are specific dermoscopic criteria of mel- single intraepidermal dendritic melanocytes anoma [48, 49]; however, the occurrence of an [54], can be pigmented. Finally, pigmented atypical dermoscopic pattern in Spitz nevus is parakeratosis can be present in an ordered well recognized [16], as is the occurrence of mel- “skip” fashion [46]. anomas showing very few or no dermoscopic Neoplasms defined as Reed nevus are com- features suggestive of malignancy but exhibit- posed of heavily pigmented, monomorphic, ing either the globular or the starburst pattern small- to medium-sized spindle melanocytes, [50]. Remarkably, melanomas with “spitzoid” arranged mainly parallel to the skin surface. dermoscopic features do not necessarily show Junctional nests typically show no sharp demar- “spitzoid” histopathological features [16]. The cation from the overlying epidermis, with the substantial lack of reliable differential criteria latter showing only little hyperplasia. A band- from melanoma must always be taken into ac- like dermal infiltration of melanophages is a count in the management of Spitz nevus (see common ancillary finding [7–15]. below). Compound Spitz nevus is a dome-shaped lesion with a dermal component composed of regularly spaced nests and cords of cells. Some III.16.5 Histopathology maturation is at least focally seen and mitoses may be easily seen, but never as atypical figures Spitz nevus is a neoplastic proliferation of mela- and never close to the base of the lesion. Intra- nocytes with large nuclei, prominent nucleoli, vascular melanocytes can be detected and are and abundant ground-glass cytoplasm with not an ominous sign per se [4]. spindle and/or polygonal (epithelioid) outlines. Dermal Spitz nevus is a dome-shaped or flat Its early intraepidermal growth phase is charac- lesion which is often characterized by extensive terized by predominance of single melanocytes desmoplasia encircling single melanocytes. Its with some suprabasilar scatter, commonly con- overall picture can closely resemble dermatofi- fined to the lower layers of the epidermis (“pag- broma [55]. The neoplasm described as “desmo- etoid” Spitz nevus [51] or “baby” Spitz nevus). plastic nevus” [56] is probably related to desmo- There can be a slight asymmetry, but some nest plastic Spitz nevus. A plexiform arrangement of formation is evident even in small lesions. bundles and lobules of melanocytes has been Junctional, or predominantly junctional, described (plexiform Spitz nevus [4]). A promi- Spitz nevus is a plaque-shaped, sharply demar- nent vasculature may also be seen (angiomatoid cated lesion composed mostly of sharply demar- Spitz nevus [57]). cated melanocytic nests within a hyperplastic At present, an unequivocal and reproducible epidermis. Nests are equally sized, shaped, and definition for “atypical Spitz nevus” and “atypi- spaced at the junction. Typically, some of them cal Spitz(oid) tumor” is probably lacking [22, can undergo a transepidermal elimination. A 24]. In general, these diagnostic categories can periadnexal junctional component is very com- be used for lesions showing some distinctly ab- mon. Melanocytes are arranged perpendicular normal characteristics commonly absent in and parallel to the skin surface. They are highly “conventional spitzoid” lesions [17]. In a meta- cohesive and do not destroy the nearby kerati- analysis based on 19 papers reporting 62 metas- nocytes; therefore, a semilunar cleavage is often tasizing spitzoid neoplasms, an aggressive bio- evident around nests (“capping”) and even logical behavior was recorded even for lesions around the few single intraepidermal melano- showing only one of the following nine “atypi- cytes (“micro-capping”). Large and coalescent cal” features: (a) nodular dermal growth (solid eosinophilic (Kamino) bodies may be found at cellular sheets within the dermis); (b) deep ex- the dermo-epidermal junction [52] and telangi- tension with absent or impaired maturation; (c) ectatic blood vessels can be seen in the superfi- deep dermal mitoses; (d) marked nuclear/nucle- cial dermis. Melanin pigment is common within olar pleomorphism; (e) heavy melanization in spindle cells and dermal melanophages; howev- depth; (f) asymmetry; (g) cellular necrosis; (h) 160 G. Ferrara, E. Moscarella, C.M. Giorgio et al.

epithelioid epidermal melanocytes below para- Every surgical excision must be carried out keratosis and/or epidermal ulceration; and (i) with a narrow (0.1 cm) margin. Diagnosis of neoplastic cells within the lymph vessels [58]. atypical Spitz nevus/tumor requires further III.16 One can therefore conclude that even the pres- surgical procedures as suggested for melanoma ence of one of the above-listed features is prob- [59]. 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 Left: The lesion is mostly nested, mostly at the junction, with some irregular epidermal atrophy. Right: At the cen- surprisingly shows higher prevalence in ter of the lesion the epidermis is atrophic; the melanocyt- children than in adults. Moreover, very ic proliferation becomes more diffuse, with large sheets of large (>1 cm) and/or ulcerated spitzoid cells separated by small amonts of collagen fibers 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, melanomas showing Spitz nevus-like features on dermoscopy are not necessarily “spitzoid” on histopathology [16].

Based on these considerations, a classical or pigmented 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 dermoscopic features. Under these circumstances, a follow-up can be scheduled with controls every 6 months [60]. In the absence of dramatic The lesion is a brownish, dome shaped papule with changes in color, shape, or size, such a follow-up smooth surface and regular borders. Dermoscopically protocol can be held until the appearance of a the lesion shows a central irregular grayish hyperpig- homogeneous pattern. Afterward, a 1-year fol- mentation, and brown to black globules/dots irregularly low-up can be employed. distributed throughout the lesion. Histopathogically, a dome-shaped, sharply demarcated and symmetric mela- Large (>1 cm), ulcerated, rapidly changing, nocytic proliferation is seen or otherwise atypical Spitz nevi of childhood must be excised. Surgical excision is also recommended when Spitz nevi appear in adulthood, regardless of the presence of atypical clinical/ dermoscopic features. 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 homogeneous – none of which is clearly distinguishable from melanoma. ■ Even histopathologically, a clear-cut differentiation between benign and malignant 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 evaluation, surgical excision is recommended for clinically atypical (large, ulcerated, rapidly changing) spitzoid lesions of childhood and for all the spitzoid lesions of adulthood.

References

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