—  SHORT COURSE #31  —

Precursors To Melanoma And The Problematic Nevomelanocytic Proliferation

Section 4 - Spitz Nevus and Variants

Neil Crowson, MD
Cynthia M. Magro, MD
Martin C. Mihm, Jr., MD


Case # 3 Spitz Nevus

Introduction
Darier and Civatte first noted that certain pigmented lesions of childhood with a morphology similar to that of melanoma behaved in an indolent fashion (Darier and Civatte, 1910). It was thought that melanoma behaved better in children due to endocrine factors (Pack and Anglem, 1939; Pack et al., 1947). Despite the absence of metastases in the vast majority of these prepubertal or juvenile "melanomas", the prevalent approach was to widely excise them before puberty to avoid risk (Spatz and Barnhill, 1999). Sophie Spitz, in her classic 1948 article, made the observation that

"…[D]ifferentiation histologically between … juvenile and adult melanomas could not be made with certainty in most cases. The one feature, found in almost one-half of the cases of juvenile melanoma, was the presence of giant cells. In view of the survival of patients having this type of tumor, these have been regarded as an indication that the lesion is benign. This is so, despite the fact that, except for the giant cells, such lesions have all the histologic criteria for the diagnosis of malignant melanoma." (Spitz, 1948).

Dr. Spitz proposed a criterion to distinguish aggressive melanocytic proliferations of childhood from their indolent but histologically similar counterparts. The latter are now called "Spitz nevi," a designation first used by McGovern (McGovern et al., 1967). The term "Spitz tumor", as opposed to "Spitz nevus," is applied in certain restricted circumstances that will be discussed presently.

Clinical Features
Spitz nevi are seen most frequently in prepubertal children and are sometimes present at birth (Harris et al., 2000), but 25% of lesions are biopsied or excised from patients older than 25 years of age and even up to the seventh decade. The classical Spitz nevus presents as a flesh-colored, dome-shaped, hairless papule on the trunk (39%), lower (25%) or upper (12%) extremity, or head and neck area (24%) (Weedon and Little, 1977). There is one report of a Spitz nevus on the lateral aspect of the toe in a Caucasian patient (Nogita et al., 1992), and we have seen a Spitz nevus in the conjunctiva of a 14-year-old boy.

A recent study of clinical features of Spitz nevi removed from 247 patients (Dal Pozzo et al., 1997) showed most lesions to be pigmented (71.7%) and extremity based (43.3%) and to occur most often in the first decade of life (55.8%) in females (57.9%). Morphologically, pigmented spindle cells predominated in the flat pigmented variants, whereas dome-shaped lesions usually comprised both spindle and epithelioid cells (Dal Pozzo et al., 1997). The average size is 6.0 mm in diameter, with a range of 0.2–1.7 cm; less than 5% of lesions are greater than 1.0 cm in diameter. Occasionally, a compound Spitz nevus will present as a variegated plaque with mottled brown or tan pigmentation mimicking melanoma, ie, the "plaque-type Spitz nevus." Rare clinical variants are the agminated Spitz nevus, comprising multiple pigmented or flesh-colored papules localized to a discrete area (Akyurek et al., 1999), and the disseminated or eruptive variant (Bullen et al., 1995). The former presentation may occur after attempts at complete surgical excision of a solitary Spitz nevus (Paties et al., 1987). Implicated in the etiology of disseminated and agminated Spitz nevi include trauma, sunburn exposure (Krakowski et al., 1981), pregnancy (Onsun et al., 1999), and radiotherapy (Weimar and Zuehlke, 1978). Clinical differential diagnostic considerations include juvenile xanthogranuloma, mastocytoma, hemangioma and, in the case of the sclerosing Spitz nevus, dermatofibroma. Ulceration, pruritus, and pain are described (Weedon, 1984).

Spitz nevi may be junctional, compound, or intradermal. Compound nevi account for two thirds and junctional Spitz nevi for 10% of lesions; purely dermal lesions are seen mainly in adults and represent the balance (Binder et al., 1993). With respect to cytology, spindle cells predominate in 45% of cases and epithelioid cells in 20%. An admixture of spindle and epithelioid cells is seen in the remainder (Weedon and Little, 1977). Some authors suggest that certain histologic features are more common in childhood than in adult Spitz nevi, namely, papillomatosis, dermal edema and telangiectasia, and a dominant epithelioid cytomorphology.

References
  1. Akyurek M, Kayikcioglu A, Ozkan O, Guler G, Mavili E, Erk Y. Multiple agminaated Spitz nevi of the scalp. Ann Plast Surg 199;43: 459- 460.

  2. Binder SW, Asnong C, Paul E, Cochran AJ. The histology and differential diagnosis of Spitz nevus. Semin Diagn Pathol 1993;10: 36–46.

  3. Bullen R, Snow SN, Larson PO, Kircik LH, Nychay S, Briggs P. Multiple agminated Spitz nevi: report of two cases and review of the literature. Pediatr Dermatol 1995;12: 156–158, 1995

  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: 20–25.

  5. Darier J. Civatte A. Naevus ou naevo-carcinoma chez un nourisson. Bull Soc Fr Derm Syph 1910;21: 61–63.

  6. Furukawa T, Chujoh T. A case of Spitz nevus. Rinsho Derma 1990;2: 315–319.

  7. Harris MN, Hurwitz RM, Buckel LJ, Gray HR. Congenital Spitz nevus. Dermatol Surg 2000;26:931-935.

  8. Krakowski A, Tur E, Brenner S. Multiple agminated juvenile melanoma: a case with a sunburn history, and a review. Dermatologica 1981;163: 270–275.

  9. McGovern VJ, Caldwell RA, Duncan CA et al. Moles and malignant melanoma: terminology and classification. Med J Aust 1967;1: 123–125.

  10. Nogita T, Nagayama M, Kawashima M, Hidano A, Kasori J, Morishima T. Spitz naevus of the toe. Br J Dermatol 1992;126: 520–522.

  11. Pack GT, Persik SL, Scharfnagel IM. Treatment of malignant melanoma : report of 862 cases. Calif Med 1947;66: 283–287.

  12. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol 1978;114: 1811–1823.

  13. Spatz A, Barnhill RL. The Spitz tumor 50 years later: Revisiting a landmark contribution and unresolved controversy. J Am Acad Dermatol 1999;40 (2Pt1): 223–228.

  14. Spitz S. Melanomas of childhood. Am J Pathol 1948;24: 591–610.

  15. 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(1): 217–25.

  16. Weedon D. The Spitz nevus. Clin Oncol 1984;3: 493–507.

  17. Weimar VM, Zuehlke RL. Multiple agminate spindle and epithelioid cell nevi in an adult. Arch Dermatol 1978;114: 1383–4.

The Classical Compound Spitz Nevus

Clinical Features
The compound Spitz nevus most commonly occurs on the face of children but may appear at any age and any anatomic site including the oral cavity. Most manifest sudden onset and rapid growth, being dome shaped with a pink-tan to brown appearance; some are red and resemble hemangiomata or verrucae, while others are plaquelike or agminate. A standard clinical test, diascopy, involves compressing the lesion with a glass slide, which causes the pink Spitz nevus to turn brown. Epiluminescence microscopy can also be used to improve clinical diagnostic accuracy. Spitz nevi have two characteristic patterns large globules in a light tan background in 22%, or radial streaming in a starburst pattern, seen in 53% of cases respectively (Argenziano et al, 1999). An overlap between pigmented Spitz nevi and melanoma can prompt misdiagnosis if epiluminescence is used in isolation from other clinical features (Argenziano et al, 1999).

Histology
The compound Spitz nevus manifests a sharply circumscribed dermal and epidermal proliferation that assumes the architecture of an inverted cone with its base oriented parallel to the dermoepidermal junction and its apex pointing toward the subcutis. Large thθques of nevomelanocytes at the dermoepidermal junction are separated by cleftlike spaces from the adjacent epidermis and are accompanied by acanthosis that may be pseudoepitheliomatous with overlying hyperkeratosis and hypergranulosis. The papillary dermis appears edematous, and there is vascular ectasia with junctional nests seeming to "rain down" as spindle cells orient themselves parallel to elongated retia. The nests may manifest dyshesion and eosinophilic hyaline bodies in the 30– to 40–micron size range, termed "Kamino bodies," seen in 60% of all cases. Kamino bodies comprise bundles of extracellular filaments (Arbuckle and Weedon, 1982) with basement membrane components including types IV and VII collagen and laminin (Havenith et al., 1989) and fibronectin (Kamino and Jagirdar, 1984). Kamino bodies are present in both benign and malignant nevomelanocytic proliferations, but are considered by some observers to be an important diagnostic aid because they are smaller and tend to coalesce in cases of melanoma (Weedon, 1984). We speculate that their likely origin is the cytosolic shell, inclusive of its surrounding basement membrane, which derives from the apoptotic melanocyte; the finding of greater apoptosis in Spitz nevi vs melanoma (Sprecher et al., 1999), reflective of greater Fas expression, could explain the greater frequency of Kamino bodies in Spitz nevi. The larger size of the Kamino body in the Spitz nevus may be a reflection of an inherent characteristic of the cells which comprise the epithelioid component of the Spitz nevus, namely, large cells with an abundance of cytoplasm. The compound Spitz nevus typically comprises a variable admixture of epithelioid and spindled nevomelanocytes (Weedon, 1984). The former manifest prominent nuclei with evenly dispersed chromatin, uniform nuclear margins that may be fine or thick, and prominent, centrally located nucleoli. Cytoplasms are generally abundant with undulating rather than spherical cytoplasmic margins and are eosinophilic with variable deposition of melanin pigment; N/C ratios are low. The spindled component, manifests banal nuclear characteristics, but with fusiform shapes and cytoplasms ranging from clear to heavily pigmented. Cell variability is inherent between epithelioid and spindled cell types, but between cells of the same type is minimal, as is most apparent when comparing the cytological features of adjacent cells in a given nest. In Spitz nevi, melanocytes are 2-3X the size of the small cuboidal nevomelanocyte that typifies the common acquired nevus. Also characteristic of Spitz nevi are bizarre, "ganglion-like" mononuclear cells or bi- and multinucleated melanocytes. Such cells show striking cell-to-cell variability and are disposed singly within the dermis amidst a background population of bland spindle and/or epithelioid cells.

Some degree of pagetoid spread either singly or as nests is seen in most Spitz nevi with an epidermal component and is most obvious in childhood; it is generally confined to the central portion of the lesion and is in close proximity to junctional nests. In acral Spitz nevi the pagetoid spread is also confined to the area over the junctional nested component but lesions tend to be broader, hence the areas of pagetoid spread is more extensive and may be confluent. A single-cell pattern of epidermal growth is the most common pattern although it is reassuring when the pagetoid component is predominantly in a nested array. Invasion of eccrine ducts, hair follicles, and nerve twigs is routine and does not necessarily imply congenital onset. Intravascular nevus cells are identified in 14% of all Spitz nevi in children (Howatt and Variend, 1985). Mitoses are identified in roughly 20% of Spitz nevi (Binder et al., 1993), mainly in the junctional and superficial dermal components. Any mitotic activity at the base of a Spitz nevus should (ie "marginal mitoses") prompt concern with respect to malignancy; marginal mitoses are those seen within 0.25 mm of the lesional edge (Crotty et al., 1992; Crotty, 1997). McCarthy and co-workers also found that features favoring malignancy over Spitz nevus in epithelioid melanocytic proliferations in adolescents include thickness, fine, dusty cytoplasmic melanization, atypical mitoses, epithelioid intraepidermal melanocytes beneath mounds of parakeratin, the mitotic rate in the papillary dermis, and dermal nests larger than overlying junctional nests (McCarthy et al., 1994). Features favoring a Spitz nevus included Kamino bodies, especially if numerous or clustered, diffuse maturation, spindle cells, and spindled nuclei (McCarthy et al., 1994). Maintaining a uniform and benign cytologic character, the cells of a Spitz nevus diminish in size away from the epidermal surface; the cells superficially are disposed in nests and fascicles that become progressively smaller and break up into single cells in the mid- and lower reticular dermis. The aforesaid features define maturation characteristic of the Spitz nevus (Binder et al., 1993) which we consider an important criterion that augers well when present. In some Spitz nevi, particularly the superficial tumors, maturation may be absent. Computer-assisted image analysis confirms our impression that this phenomenon is a real one. In contrast to the foregoing, atypical Spitz tumors do not show a decrease in nest and/or fascicle size or a single-cell pattern of dispersal but remain cohesive at the lesional margin to produce a pushing, nodular, or expansile border. By electron microscopy, melanocytes in Spitz nevi are typically smaller than those of nodular melanoma (roughly 500 vs. 775 cubic microns) and diminish in volume in the lesional base; nuclear volume actually increases in the base of nodular melanoma (Steiner et al., 1994). This ultrastructural evidence underscores the contribution of cytology to the histologic assessment of melanocytic neoplasia. Variations in the low-power morphologic features of a lesion, namely, one that lacks the architecture of an inverted cone, fails to mature, or manifests marginal mitoses or large fascicles or expansile nodules in the depths of the lesion should prompt concern that the lesion may represent an atypical Spitz tumor whose biological behavior is uncertain or a melanoma. The observation of these changes requires close scrutiny and the evaluation of deeper sections. When in doubt, consultation is advisable.

A distinctive variant of the compound Spitz nevus resembles a lichenoid and granulomatous dermatitis with lymphocytes admixed with coalescing nodules of epithelioid cells that resemble epithelioid granulomata but are actually melanocytic in nature, a clue to which is the identification of a junctional nevus component. The authors who described this variant used the appellation granulomatous Spitz nevus (Paniago-Pereira and Maize, 1978). A single case of tubular Spitz nevus is described (Burg et al., 1998); this morphologic finding is not restricted to Spitz nevi (Soyer et al., 1999). There May be architectural features associated with dysplastia such as an asymmetrical shoulder that extends on either side of the dermal-based component and organized periretal fibroplasia. Up to 3% of all dysplastic nevi may manifest a cytology compatible with a Spitz nevus (Toussaint and Kamino, 1999). A lymphocytic host response may be observed in Spitz nevi; it is uniform throughout the lesion, imparts a symmetrical wedge-shaped morphology and varies from a pandermal patchy perivascular infiltrate to a dense one obscuring the nevus (Harvell et al., 1997). The host reaction in Spitz nevi, as in other benign halo nevi, constitutes an oligoclonal expansion of T lymphocytes (Birck et al., 1997), usually dominated by CD8-positive cytotoxic/suppressor T cells that elaborate perforin and are capable of inducing individual cell pattern of necrosis that may contribute to the generation of Kamino bodies.

We recommend a conservative reexcision of all Spitz nevi that have not been completely excised or of those cases with atypical light microscopic features if narrowly excised. These recommendations derive from the fact that one must examine an entire lesion microscopically to arrive at a correct diagnosis. In a partially removed lesion one might miss an expansile nodular component at the base or the edge of the lesion. Atypical lesions may recur and in their recurrence the histology may appear even more atypical; persistent recurrence of any pigmented lesion is always an ominous sign. Further excision at the outset will obviate these problems.

Differential Diagnosis
Criteria to distinguish Spitz nevi from melanomas with a Spitz-like cytology include Kamino bodies, a lower mitotic rate, absent mitoses close to the lesional base, absent abnormal mitoses, symmetry, and uniformity of nests from side to side (Walsh et al., 1998). We emphasize the following differentiating points:

Melanoma does not show sharp lateral circumscription or symmetry. The former refers to an intraepidermal component that terminates abruptly as a nest rather than a trailing off in the horizontal axis as singly disposed cells in a lentiginous and pagetoid array. Symmetry is the side-to-side mirror-image identity of the two halves of a profile folded down the middle.

Pagetoid spread mimicking melanoma is seen in compound Spitz nevi, the upwardly migrating cells manifest an identical cytology to that of the banal cells in the junctional nests. Single-cell pagetoid spread at the lateral edge is unusual in the compound Spitz nevus.

The epidermal component may extend laterally past the dermal component, especially in congenital Spitz nevi, but mirror-image symmetry is present.

Spitz nevi often exhibit epidermal hyperplasia; epidermal effacement typifies vertical growth phase melanoma.

"Raining down" fascicles are not observed in melanoma. In Spitz nevi, the nests are sharply demarcated by a cleft and are dominantly localized to the tips of retia. In contrast, the nests in melanoma have an infiltrative pattern, are poorly circumscribed, coalesce, and are variably disposed within the epidermis, often assuming a parallel disposition to the epidermis. Considerable variation in the size of the nests in melanoma contrasts with uniform nest size in Spitz nevi. The dermal component of a vertical growth phase melanoma similarly exhibits variability in nest sizes at the same depth.

The confluent, sheetlike growth of a vertical growth phase melanoma is unlike the Spitz nevus, where individual melanocytes are separated by fine strands of dermal collagen.

Dermal cells in Spitz nevi show greater pleomorphism than in most melanomas; malignant autonomous nodules, although showing high-grade dysplasia, manifest monotony reflective of clonality. In contrast, when comparing cells side-by-side within the intradermal component, there is very little variation in cell morphology in the Spitz nevus, whereas there is marked variation in cells of melanoma.

Maturation (ie reduction in nuclear size) does not occur in most melanomas, and mitoses, including atypical forms, are often present at the base.

Despite pagetoid growth and pleomorphism, the Spitz nevus still has the background banal spindled and/or epithelioid melanocytic populace.

The Spitz nevus almost invariably lacks a precursor lesion, such as a dysplastic or common acquired nevus; a precursor nevomelanocytic proliferation is identified in 30% of melanomas.

The inflammatory host response in Spitz nevi is predominantly perivascular and is diffusely distributed throughout the dermal portion; in melanoma the infiltrate is often dense, tends to include plasma cells, and is nonuniform.

References
  1. Arbuckle S, Weedon D. Eosinophilic globules in the Spitz nevus. J Am Acad Dermatol 1982;7(3): 324–327.

  2. Argenziano G, Scalvenzi M, Staibano S et al. Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous melanomas. Br J Dermatol 1999;141:788-793.

  3. Birck A, Thor Straten P, Li L, Hou-Jensen K, Sugar J, Zeuthen J. Analysis of T cell receptor AV and BV chain gene expression by infiltrating lymphocytes in Spitz nevi and in halo nevi. Melanoma Res 1997;7: 49–57.

  4. Burg G, Kempf W, Hochli M, Huwyler T, Panizzon RG. 'Tubular' epithelioid cell nevus: a new variant of Spitz's nevus. J Cutan Pathol 1978;25: 475–478.

  5. Crotty KA, McCarthy SW, Palmer AA et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg 1992;16: 179–85.

  6. Crotty KA. Spitz nevus: histological features and distinction from malignant melanoma. Australas J Dermatol 1997;38 Suppl 1:S49-53.

  7. Harvell JD, Meehan SA, LeBoit PE. Spitz's nevi with halo reaction: a histopathologic study of 17 cases. J Cutan Pathol 1997;24: 611–619.

  8. Havenith MG, van Zandvoort EH, Cleutjens JP, Bosman FT. Basement membrane deposition in benign and malignant naevomelanocytic lesions: an immunohistochemical study with antibodies to type IV collagen and laminin. Histopathology 1989;15(2): 137–46.

  9. Howat AJ, Variend S. Lymphatic invasion in Spitz nevi. Am J Surg Pathol 1985;9:125–128.

  10. Kamino H, Flotte TJ, Misheloff E, Greco MA, Ackerman AB. Eosinophilic globules in Spitz's nevi. New findings and a diagnostic sign. Am J Dermatopathol 1979;1: 319–324.

  11. Kamino H, Jagirdar J. Fibronectin in eosinophilic globules in the Spitz nevus. Am J Dermatopathol 1984;6 (Suppl 1): 313–316.

  12. McCarthy SW, Crotty KA, Palmer AA, Mg AB, McCarthy WH, Shaw HM. Cutaneous malignant melanoma in teenagers. Histopathology 1994;24: 453–461.

  13. Onsun N, Saracoglu S, Demirkesen C, Kural YB, Atilganoglu U. Eruptive widespread Spitz nevi : can pregnancy be a stimulating factor? J Am Acad Dermatol 1990;40(5 pt 2): 866–867.

  14. Soyer HP, Breier F, Cerroni L, Kerl H. 'Tubular' structures within melanocytic proliferations: a distinctive morphologic finding not restricted to Spitz nevi. J Cutan Pathol 1999;26:315-7.

  15. Steiner A, Binder M, Mossbacher U, Wolff K, Pehamberger H. Estimation of the volume-weighted mean nuclear volume discriminates Spitz's nevi from nodular malignant melanomas. Lab Invest 1994;70: 381–385.

  16. Toussaint S, Kamino H. Dysplastic changes in different types of melanocytic nevi. A unifying concept. J Cutan Pathol 1999;26(2): 84–90.

  17. Sprecher E, Bergman R, Meilick A, et al. Apoptosis, Fas and Fas-ligand expression in melanocytic tumors. J Cutan Pathol 1999;26: 72–77.

  18. Walsh N, Crotty K, Palmer A, McCarthy S. Spitz nevi versus Spitzoid malignant melanoma : An evaluation of the current distinguishing histopathologic criteria. Hum Pathol 1009;29: 1105-1112.

Dermal Spitz Nevus

Clinical Features
The dermal Spitz nevus usually presents in adulthood as a firm nodule on the upper extremities, the shoulder, or the proximal thighs up to a size of 1.0 cm. Lesions are flesh colored, tan-brown, or blue-gray and are often mistaken for dermatofibromas or blue nevi or, when flesh colored, for epidermal inclusion cysts or appendage tumors. At a light microscopic level, the dermal Spitz nevus calls into question a differential diagnosis that includes not only other melanocytic tumors, including malignant melanoma, but also a variety of obscure, lesions of nonmelanocytic histogenesis.

Histology
Scanning magnification reveals a symmetrical inverted triangular architecture while the epidermis shows hyperplasia with variable hypermelanosis. There is dissipation of cellularity in the depths of a lesion that terminates as small nests or as single cells dispersed between collagen bundles and along adnexal structures, the latter phenomenon most apparent centrally. The dominant cell of the dermal Spitz nevus is usually epithelioid, but admixed spindle cells may be observed and an amelanotic spindle cell form may occur. The cells show mild hyperchromasia with irregular chromatin distribution; cytoplasms are usually devoid of pigment. Variable numbers of giant cells are present; in some cases, there are none. A delicate reactive fibrosis surrounds individual nevus cells, but is not prominent as seen in the desmoplastic Spitz nevus and is in sharp contrast to the fibroplasia provoked by melanoma, where tumor cell invasion disrupts the preexisting collagen network and, in lesions of desmoplastic melanoma, is associated with fibroplasia. The melanocytes become smaller toward the base of the lesion. Mitotic figures are seldom observed but, when present, are found only in the superficial portions of the lesion.

Differential Diagnosis of Dermal Spitz Nevus

Cellular Neurothekeoma
The neurothekeoma presents as a nondescript papule or nodule in the head and neck area of a young adult, raising consideration to a nevus, appendage tumor, cyst, or neurofibroma. The classic neurothekeoma/nerve sheath myxoma manifests nests and cords of large epithelioid or spindled cells in a myxomatous matrix with a close histologic relationship with peripheral nerve elements; this is not likely to be confused with a Spitz nevus (Gallager and Helwig, 1980). The cellular neurothekeoma, in contrast, occurs in the 4th decade on the upper and lower limbs and the back (Laskin et al., 2000) and lacks myxomatous areas. It instead comprises cellular dermal lobules and fascicles of spindle cells with eosinophilic or pale-staining cytoplasms showing mild cytologic atypia and scattered mitoses. Mitoses may be evident and multinucleated giant cells are seen in most cases. Expanded endoneurial- and perineurial-like structures resembling nerve fascicles may be seen and may mimic the changes seen in amputation neuromata and plexiform neurofibromata. Dilated lymphatic spaces in the papillary dermis overlying the dermal tumor nodule are a helpful clue. Immunohistochemical markers including antibodies to S100 protein, myelin basic protein, epithelial membrane antigen, and histiocytic markers are characteristically negative in cellular neurothekeoma.

There is controversy as to the cell of origin of these tumors. While the classical neurothekeoma/nerve sheath myxoma has features of schwannian differentiation with myelinoid figures (Argenyi et al, 1995), the cellular neurothekeoma is mainly composed of undifferentiated cells with partial features of schwannian differentiation admixed with fibroblasts and myofibroblasts (Argenyi at al, 1995). The expression of factor XIIIa in the cellular neurothekeoma has been variably held to confirm perineural differentiation (Tomasini et al, 1996) or to indicate an epithelioid variant of dermatofibroma (Zelger et al, 1998). Actin expression has prompted others to suggest that the lesion is, in fact, an epithelioid form of piloleiomyoma (Calonje et al, 1992). The uniform expression of S100 protein in neurothekeoma, and its absence in the cellular variant (Barnhill and Mihm, 1990, Zelger et al., 1998; Laskin et al., 2000), substantiates the ultrastructural evidence of derivation from a Schwann cell in the former instance and from a pleiotropic mesenchymal cell in the latter. So, too, does the presence of epithelial membrane antigen (EMA) in the classical neurothekeoma and its absence in the cellular variant; EMA is expressed in normal perineural cells (Laskin et al, 2000).

Epithelioid Cell Histiocytoma
The epithelioid cell histiocytoma is an unusual benign histiocytoma (Wilson-Jones et al., 1989) that presents on lower or upper extremities of adults (age range 7-80 years (Singh Gomez et al., 1994) as a nonpedunculated dome-shaped or polypoid flesh-colored nodule 7–15 mm in diameter. The histology comprises a proliferation of polygonal or rounded epithelioid cells with abundant eosinophilic cytoplasm; some cells are bi- or trinucleated but multinucleated giant cells are absent. Nuclei are smooth contoured with open chromatin and discrete nucleoli. The histiocytic proliferation may lie in close apposition to the epidermis and there may be an epidermal collarette. There is a variable inflammatory cell infiltrate. Individual cells are surrounded by hyalinized collagen bundles and a vascular stroma with a sparse lymphocytic infiltrate. Most observers, however, have found the critical cells to express vimentin and α1-antitrypsin but not to react with histiocytic markers such as KP1/MAC387 (Wilk et al., 1996) or with antibodies to S100 protein or to gp100 protein. Expression of factor XIIIa suggests derivation from the dermal dendrocyte and is an important adjunct to diagnosis (Glusac and McNiff, 1999).

Plexiform Fibrohistiocytic Tumor
The plexiform fibrohistiocytic tumor is an uncommon cutaneous soft tissue neoplasm of children and young adults typically seen in females aged 14-17 years (Enzinger and Zhang, 1989; Remstein et al., 1999). Lesions are slow-growing, poorly demarcated dermal and/or subcutaneous masses with a mean diameter of 2.5 cm (but up to 8 cm or more) and occasionally extend into skeletal muscle (Remstein et al, 1999). Most are seen on the upper extremity although lesions occur virtually anywhere. One-third recur and a small minority are associated with regional lymph node metastases; systemic metastases are uncommon, with the lung being the most common distant metastatic site (Salomao and Nacimento, 1997). In one series of 22 cases, 3 patients manifested pulmonary metastases, only 1 of whom died of disease (Remstein et al, 1999).

These are histologically poorly defined neoplasms and occupy the lower two-thirds of the dermis with extension into subcutis along the interlobular septae in a multinodular, plexiform array of epithelioid cells and/or fascicles of spindle cells, the latter growing as ramifying trabeculae generating a reticulated pattern with interposed osteoclast-like giant cells (Zelger et al, 1997). The dominant cell is usually a mononuclear cell with a smooth, round or oval nuclear contour containing evenly distributed chromatin and a small nucleolus. Cytoplasms are moderately abundant and pale staining. Transition forms between the osteoclast-like and mononuclear cells are sometimes seen. A "fibroblastic variant" represents the mononuclear cells cut longitudinally, whereas a "fibrohistiocytic variant" may represent fascicles of the same cells cut en face; both cell "types" express EBM/11 and tissue transglutaminase (Thomzy et al, 1994). Some cases show a proliferation of thin-walled vessels, hemosiderin deposition (August et al, 1994) and/or vascular invasion. There are mitoses in most cases; some manifest numerous division figures (up to 2 per Χ40 HPF) including atypical forms. Nonuniform karyotypic anomalies are reported (Redlich et al., 1999). Immunohistochemical studies demonstrate reactivity of the cells for vimentin, actin, α1-antitrypsin, and α1-antichymotrypsin (Angervall et al., 1992). Tumor cells do not express factor XIIIa (Giard et al, 1991). Ultrastructure suggests myofibroblastic derivation (Hollowood et al, 1991).

Complete excision of the primary lesion is considered mandatory (Sass et al., 1994) and is likely curative in most cases.

References

Dermal Spitz Nevus and Its Nonmelanocytic Mimics

Neurothekeoma
  1. Argenyi ZB, Kutzner H, Seaba MM. Ultrastructural spectrum of cutaneous nerve sheath myxoma/cellular neurothekeoma. J Cutan Pathol 1995;22:137–145.

  2. Barnhill RL, Mihm MC Jr. Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking nevomelanocytic tumors. Am J Surg Pathol 1990;14:113–120.

  3. Calonje E, Wilson-Jones E, Smith NP, Fletcher CD. Cellular 'neurothekeoma': an epithelioid variant of pilar leiomyoma? Morphological and immunohistochemical analysis of a series. Histopathology 1002;20: 397–404.

  4. Gallagher RL, Helwig EB. Neurothekeoma : a benign cutaneous tumor of neural origin. Am J Clin Pathol 1980;75: 759–764.

  5. Laskin WB, Fetsch JF, Miettinen M. The "neurothekeoma": immunohistochemical analysis distinguishes the true nerve sheath myxoma from its mimics. Hum Pathol 2000;31: 1230-1241.

  6. Tomasini C, Aloi F, Pippione M. Cellular neurothekeoma. Dermatology 1996;192: 160–163.

  7. Zelger BG, Steiner H, Kutzner H, Maier H, Zelger B. Cellular 'neurothekeoma': an epithelioid variant of dermatofibroma? Histopathology 1009;32: 414–422.

Epithelioid Cell Histiocytoma
  1. Glusac EJ, McNiff JM. Epithelioid cell histiocytoma: a simulant of vascular and melanocytic neoplasms. Am J Dermatopathol 1999;21: 1–7.

  2. Singh Gomez C, Calonje E, Fletcher CD. Epithelioid benign fibrous histiocytoma of skin: clinicopathological analysis of 20 cases of a poorly known variant. Histopathology 1994;24: 123–129.

  3. Wilk M, Schmoeckel C, Nilles M, Krahl D, Eckert F, Kreysel HW. [Epithelioid cell histiocytoma]. Hautarzt 1996;47: 526–529.

  4. Wilson-Jones E, Cerio R, Smith NP. Epithelioid cell histiocytoma: a new entity. Br J Dermatol 1989;120: 185–195.

Plexiform Fibrohistiocytic Tumor
  1. Angervall L, Kindblom LG, Lindholm K, Eriksson S. Plexiform fibrohistiocytic tumor. Report of a case involving preoperative aspiration cytology and immunohistochemical and ultrastructural analysis of surgical specimens. Pathol Res Pract 1992;188: 350–356.

  2. Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol 1988;12:818–826.

  3. Giard F, Bonneau R, Raymond GP. Plexiform fibrohistiocytic tumor. Dermatologica 1991;183: 290–293.

  4. Redlich GC, Montgomery KD, Allgood GA, Joste NE. Plexiform fibrohistiocytic tumor with a clonal cytogenetic anomaly. Cancer Genet Cytogenet 1999;108:141–143.

  5. Remstein ED, Arndt CA, Nascimento AG. Plexiform fibrohistiocytic tumor: a clinicopathological analysis of 22 cases. Am J Surg Pathol 1999;23: 662–670.

  6. Salomao DR, Nascimento AG. Plexiform fibrohistiocytic tumor with systemic metastases: a case report. Am J Surg Pathol 1997;21: 469–476.

  7. Sass U, Andre J, Noel JC et al. [Plexiform fibrohistiocytic tumor]. Ann Dermatol Venereol 1994;121: 109–112.

  8. Thomazy V, Nagy A, Gal I, Nemes Z. Plexiform fibrohistiocytic tumor with novel phenotypic features. Histopathology 1994;25: 165–169.

  9. Zelger B, Weinlich G, Steiner H, Zelger BG, Egarter-Vigl E. Dermal and subcutaneous variants of plexiform fibrohistiocytic tumor. Am J Surg Pathol 1997;21: 235–241.

Sclerosing or Desmoplastic Spitz Nevus/desmoplastic Nevus

Clinical Features
The sclerosing or desmoplastic Spitz nevus is a variant of the dermal Spitz nevus (Lee et al., 2000). Stromal desmoplasia can accompany virtually any type of benign dermal melanocytic nevus (Magro et al., 2001). Although Maize and Foster attributed the desmoplasia to an age-related change (Maize and Foster, 1979), we have encountered sclerosing nevi in patients from the second to the seventh decades of life and so do not subscribe to this construction. The average duration of the lesion before biopsy or excision is 3.7 years (Barr et al., 1980). Desmoplastic nevi are located preferentially on the extremities and trunk and spare the palms and soles.

Histology
The low-power architecture is that of a poorly circumscribed fibrotic plaque without sharp lateral or vertical margins. In contrast, desmoplastic melanoma has a diffuse pattern of growth. The epidermis shows hyperkeratosis, minimal parakeratosis, irregular acanthosis, and mild pigmentation (Barr et al., 1980), recapitulating the changes overlying a dermatofibroma. Lesional melanocytes are usually in a wholly intradermal location, although small junctional nests may be present. Higher-power examination reveals an interpolation of bizarre cells between sclerotic collagen bundles in a low-density proliferation. Inflammation is minimal to absent. There is cell-to-cell variability with little cytoplasmic pigment deposition. The cells can have either a large polygonal ganglion-like morphology with multinucleated forms having a ringlike arrangement of nuclei resembling a Touton giant cell, but lacking peripheral cytoplasmic lipid vacuoles. Intranuclear vacuoles are freqeuent; nucleolation may be observed but mitoses are absent or rare (i.e., no more than 1 in 20 high-power fields). The cells are primarily singly disposed, although a few small clusters of cells may be observed. Maturation is observed in only a minority of cases. An "angiomatoid desmoplastic Spitz nevus" has a richly vascular stroma with plump endothelia (Diaz-Cascajo et al., 2000).

Differential Diagnosis
Desmoplastic melanoma, the most important diagnostic mimick (Walsh et al., 1988), tends to occur on sun-exposed areas, particularly the head and neck region. The desmoplastic melanoma shows: 1) An attenuated epidermis, within which an intraepidermal atypical melanocytic proliferation is often observed overlying sun-damaged collagen; 2) Haphazard fascicles of spindle cells extending into the deep dermis and distorting the normal dermal architecture; 3) Fusiform cells with irregular shapes and hyperchromatic nuclei containing amorphous chromatin without admixed epithelioid cells; 4) An asymmetrical inflammatory host response with mucinosis; 5) Neurotropism; 6) Necrosis; and 7) Atypical mitoses.

Metastatic carcinoma of breast ductal primary derivation may enter into the differential diagnosis because of the pleomorphic epithelioid quality of the cells and the desmoplastic nature of the stroma. Immunohistochemistry should enable this distinction.

References
  1. Barr RJ, Morales RV, Graham JH. Desmoplastic nevus: a distinct histologic variant of mixed spindle cell and epithelioid cell nevus. Cancer 1980;46: 557–64.

  2. Magro CM, Crowson AN, Mihm MC Jr. Spitz Nevus. In: Crowson AN, Magro CM, Mihm MC, Jr. The melanocytic proliferations : a comprehensive textbook of pigmented lesions. New York : John Wiley and sons, 2001:121-181.

  3. Diaz-Cascajo C, Borghi S, Weyers W. Angiomatoid Spitz nevus: a distinctive variant of desmoplastic Spitz nevus with prominent vasculature. Am J Dermatopathol 2000;22: 135-139.

  4. Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK. Hyalinizing Spitz nevus. J Dermatol 2000;27:273.

  5. Walsh NM , Roberts JT, Orr W, Simon GT. Desmoplastic malignant melanoma. A clinicopathologic study of 14 cases. Arch Pathol Lab Med 1988;112: 922–927.

Pagetoid Spitz Nevus

Clinical Features
This entity appears clinically as a small pigmented macule in a young patient, typically less than 0.4 cm in diameter (Busam and Barnhill, 1995). Although clinically innocuous, the microscopic appearance can raise concern with respect to radial growth phase confined superficial spreading melanoma.

Histology
The dominant pattern of growth is as single cells in a pagetoid array with variable nest formation. The lesion appears symmetrical with sharp lateral circumscription and the cytology is typical of the epithelioid cell component of the common Spitz nevus; the nuclei are round or oval and do not exhibit the aberrant, folded or angulated contours encountered in the cells of high-grade melanocytic dysplasia. Cytoplasms are abundant with an eosinophilic or lightly pigmented staining quality and heterogeneity of melanization is not a feature (Han et al., 2000).

Differential Diagnosis
As distinction of such lesions from high-grade de novo intraepidermal epithelioid melanocytic dysplasia/malignant melanoma in situ is difficult, we advise re-excision.

References
  1. Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread. Am J Surg Pathol 1995;19:1061–1067.

  2. Han MH, Koh KJ, Choi JH, Sung KJ, Moon KC, Koh JK. Pagetoid Spitz nevus: a variant of Spitz nevus. Int J Dermatol 2000;39: 555-557.

Pigmented Spindle Cell Nevus of Reed

Clinical Features
The pigmented spindle cell nevus presents as a black or dark brown (or rarely light gray or blue), dome-shaped lesion, 2–6 mm in diameter (average 2.8 mm), on the proximal extremities, back, or abdomen of a young woman (Reed et al., 1975). A minority have an irregular border (Sau et al., 1993). Preferential involvement of the elbows and knees has been noted in childhood, whereas 50% of lesions in young women are located on the thigh or arm (Sagebiel et al., 1984). There is a mean age of 25 years at presentation and a female predominance of 2:1.

Histology
This is a variant of the Spitz nevus dominated by spindle cells showing prominent melaninogenesis, accompanied by a variable admixture of epithelioid cells. Such lesions are either purely intraepidermal or else have only a superficial dermal contribution. The lower border often abuts the papillary-reticular dermal interface as a broad horizontal shelf distinct from the wedge-shaped architecture of the classic spindle and epithelioid cell (Spitz's) nevus; the average thickness is 0.67 mm (range: 0.22–1.90 mm) (Sau et al., 1984). Three-quarters of lesions showed sharp lateral circumscription, with only 2% showing an ill-defined edge and roughly one-quarter showing sharp lateral demarcation at one margin and gradual diminution of junctional activity at the opposite margin (Sagebiel et al., 1984). Some spindle cell nevi show recent change such as rapid growth, peripheral erythema, or a halo effect after intense sun exposure, suggesting that at least some have clinical, as well as histologic, overlap with dysplastic nevi. The epidermis is of variable thickness, with one series reporting epidermal hyperplasia in 14 of 22 cases and atrophy in 3 (Requena et al., 1990). Pagetoid growth is seen in most cases, being maximal overlying areas of prominent nested junctional activity (Requena et al., 1990). In our experience, a nested pattern of upward migration often predominates over a single-cell pattern.

The cytology resembles of the spindle cell component of the classical Spitz nevus. There is often transepidermal elimination of melanin pigment to the cornified layer and melanophages n the superficial dermis (Requena et al., 1990). The cells in the epidermis are disposed in a nested, lentiginous and/or pagetoid array, with a nested pattern predominating. The nests lie within slightly elongated retia that may fuse; cells are often vertically oriented at the tips of retia or horizontally oriented when associated with fusion of retia. Careful attention to the banal cytology will prevent false-positive diagnoses when pagetoid spread is prominent, as it may be over nested areas of prominent junctional activity. Mitoses may be observed but are always typical. Transepidermal elimination of pigment and of entire nevomelanocytic nests may be seen. Vertical arrays of papillary dermal collagen may be seen, but lamellar fibroplasias is uncommon. Maturation is invariably present. Perivascular dermal inflammation is frequent, although regressive stromal changes are uncommon. Kamino bodies are a very frequent finding, being identified in over 80% of cases (Witsuba and Gonzalez, 1990).

Pigmented Epithelioid Cell Nevus

The pigmented epithelioid cell nevus manifests the same clinical features as the pigmented spindle cell nevus with an identical histology save that the constituent cell has a cytology typical of the epithelioid cell component of the Spitz nevus (Choi et al, 1993).

Differential Diagnosis of spindle or epithelioid cell nevus
The differential diagnosis of the spindle cell nevus includes dysplastic nevus and spindle cell melanomas such as acral lentiginous or lentigo maligna melanoma, while the pigmented epithelioid cell nevus raises consideration of melanoma with prominent pigmented synthesis (i.e., "animal type melanoma") and its mimics. The patternless fibrosis in the pigmented spindle cell nevus deviates from the concentric eosinophilic fibrosis associated with dysplastic nevi, while a lymphocytic host reaction and pigment incontinence may be seen in either. In dysplastic nevi, pagetoid spread is not seen, unless a severely atypical melanocytic proliferation has arisen in a dysplastic nevus; the upwardly-migrating melanocytes have atypical nuclei, unlike the banal pagetoid cells in the Spitz nevus. The intraepidermal component is not often spindles in dysplastic nevi.

Acral lentiginous and lentigo maligna melanoma manifest parallel stromal fibrosis with or without telangiectasia, melanophages, and partial regression. Other distinguishing features from melanoma include sharp lateral circumscription, ganglion-like cells within the dermis and Kamino bodies in the epidermis. Some pigmented spindle cell nevi show dermal-based proliferation centers, in which the expansile nodule has a cytology identical to the intraepidermal cells, in contrast to vertical growth phase melanoma, in which the nevomelanocytes of the dermal nodule show distinctive malignant cytology.

Management
These lesions should be managed, in our opinion, by complete lesional excision.

References

Pigmented Spindle Cell Nevus
  1. Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975; 2: 119–147.

  2. 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.

  3. 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.

  4. Requena L, Sanchez Yus E. Pigmented spindle cell naevus. Br J Dermatol 1990;123: 757–763.

  5. Wistuba I, Gonzalez S. Eosinophilic globules in pigmented spindle cell nevus. Am J Dermatopathol. 1990;12: 268–271.

Pigmented Epithelioid Cell Nevus
  1. Choi JH, Sung KJ, Koh JK. Pigmented epithelioid cell nevus: a variant of Spitz nevus?. J Am Acad Dermatol 1993;28: 497–498.

Plaque-Type Spitz Nevus

This lesion is clinically held to be a dermatofibroma or scar but manifests features of a junctional or compound Spitz nevus. Stromal changes reminiscent of regression, in concert with asymmetry and epithelioid cell atypia, might cause confusion with a partially regressed melanoma; critical to the diagnosis is recognition of the characteristic cytology: plump epithelioid melanocytes typical of a Spitz nevus. The epidermis does not show attenuation typical of regression.

Atypical Spitz Tumor

Introduction and Clinical Features
This is a subset of Spitz nevi that will have clinically and pathologically disturbing features (Barnhill et al., 1999). We believe that such lesions are likely indolent; although metastatic disease may occur, it tends to remain localized to regional lymph nodes despite the identification of cytogenetic abnormalities similar to those reported in lymph node deposits of metastatic melanoma (Smith et al., 1989; Smith et al., 1998). Unfortunately, lethal Spitz-like melanomas are also described (Barnhill et al., 1995). We feel that the atypical Spitz tumor has histologic features at variance with Spitz-like melanoma, and that such lesions have a clinical appearance similar to the subtypes of Spitz nevi described above; however, they are often larger, reaching sizes of 2.0 cm or more, and may have a history of recent change.

Histology
The atypical Spitz tumor manifests a failure of maturation; the cells do not diminish in size toward the base and may even appear larger than their superficial counterparts. Mitotic figures may be seen in this deep-seated component, as may one or more expansile, dermal nodules. A grading system for risk stratification of atypical Spitz tumors in children and adolescents has been proposed in an attempt to identify lesions at greater risk for aggressive behavior. Among the parameters studied, only diagnosis at age greater than 10 years, lesional diameter greater than 10 mm, presence of ulceration, involvement of the subcutaneous fat, and mitotic activity of at least six per square millimeter carried a significant likelihood of metastatic behavior (Spatz et al., 1999). Patient age, sharp demarcation, symmetry, maturation of melanocytes at the base, and epithelial hyperplasia were all indicative of benignity (Spatz et al., 1999). Of particular significance as discussed above, are marginal mitoses within 0.25 mm of the lesional edge (Crotty et al., 1992; McCarthy et al., 1994) [see histology of spitz nevi above]. In some 6–8% of cases, confident distinction of Spitz nevi from malignant melanoma cannot be made (Rapini, 1999), another fact that prompts us to advise complete excision of all Spitz nevi and atypical Spitz tumors irrespective of histology or patient age. That said, the atypical Spitz tumor, in our view, merits a more aggressive therapeutic strategy.

Differential Diagnosis
The separation from vertical growth phase malignant melanoma hinges upon recognition of a background population of epithelioid and spindled cells typical of the classical Spitz nevus, including in the context of a junctional Spitz nevus component. The cells within the cellular, nodular, and fascicular aggregates have a cytology characteristic of a Spitz nevus and the effacement of dermal architecture seen with vertical growth phase melanoma is absent, as is an overlying melanoma in situ. The cells within the dermis exhibit fully evolved cytologic criteria of malignancy with high N/C ratios, an increased and irregularly-distributed chromatin, and heterogeneity of melanization. The question arises as to what separates the atypical Spitz tumor from a minimal-deviation melanoma of spitzian type. The distinction is based on the spitzian melanoma having larger deforming nodules with minimal intervening stroma between individual tumor cells, and greater numbers of mitoses including atypical forms. A background population of the more banal-appearing component of the Spitz nevus may not be present; in contrast, pleomorphism is striking throughout the lesion.

Management
We advise a re-excision of atypical Spitz tumors to obtain a 1.0-cm margin. For lesions with marked atypia, i.e., those with a deep-seated, expansile nodular growth pattern or with deep-seated mitoses, we recommend reexcision with a 1.5-cm margin down to but not including the fascia. If a tumor is over 1.0 mm in depth, a sentinel lymph node biopsy is typically advised as well. These recommendations are empirically based and without statistical validation.

References
  1. Barnhill RL, Argenyi ZB, From L et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 1999;30: 513–20.

  2. Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer 1995;76: 1833–1845.

  3. Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol 1992; 27(6 Pt 1): 901–913.

  4. Crotty KA, McCarthy SW, Palmer AA et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg 1992;16: 179–185.

  5. McCarthy SW, Crotty KA, Palmer AA, Mg AB, McCarthy WH, Shaw HM. Cutaneous malignant melanoma in teenagers. Histopathology 1994; 24:453–461.

  6. Rapini RP. Spitz nevus or melanoma? Semin Cutan Med Surg 1993;18:56–63.

  7. Smith KJ, Barrett TL, Skelton HG 3d, Lupton GP, Graham JH. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol 1989;13(11): 931–939.

  8. Smith NM, Evans MJ, Pearce A, Wallace WH. Cytogenetics of an atypical Spitz nevus metastatic to a single lymph node. Pediatr Pathol Lab Med 1998;18:115–122.

  9. Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for risk stratification. Arch Dermatol 1999;135: 282–285.