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
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.
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
0.21.7 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
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.
The Classical Compound Spitz Nevus
- 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.
- Binder SW, Asnong C, Paul E, Cochran AJ. The histology and differential diagnosis of Spitz nevus.
Semin Diagn Pathol 1993;10: 3646.
- 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: 156158, 1995
- 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: 2025.
- Darier J. Civatte A. Naevus ou naevo-carcinoma chez un nourisson. Bull Soc Fr Derm Syph 1910;21:
- Furukawa T, Chujoh T. A case of Spitz nevus. Rinsho Derma 1990;2: 315319.
- Harris MN, Hurwitz RM, Buckel LJ, Gray HR. Congenital Spitz nevus. Dermatol Surg 2000;26:931-935.
- Krakowski A, Tur E, Brenner S. Multiple agminated juvenile melanoma: a case with a sunburn history,
and a review. Dermatologica 1981;163: 270275.
- McGovern VJ, Caldwell RA, Duncan CA et al. Moles and malignant melanoma: terminology and
classification. Med J Aust 1967;1: 123125.
- Nogita T, Nagayama M, Kawashima M, Hidano A, Kasori J, Morishima T. Spitz naevus of the toe. Br J
Dermatol 1992;126: 520522.
- Pack GT, Persik SL, Scharfnagel IM. Treatment of malignant melanoma : report of 862 cases. Calif
Med 1947;66: 283287.
- Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's
nevus). Arch Dermatol 1978;114: 18111823.
- Spatz A, Barnhill RL. The Spitz tumor 50 years later: Revisiting a landmark contribution and
unresolved controversy. J Am Acad Dermatol 1999;40 (2Pt1): 223228.
- Spitz S. Melanomas of childhood. Am J Pathol 1948;24: 591610.
- 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): 21725.
- Weedon D. The Spitz nevus. Clin Oncol 1984;3: 493507.
- Weimar VM, Zuehlke RL. Multiple agminate spindle and epithelioid cell nevi in an adult. Arch
Dermatol 1978;114: 13834.
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
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 40micron 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
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.
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
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
"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.
Dermal Spitz Nevus
- Arbuckle S, Weedon D. Eosinophilic globules in the Spitz nevus. J Am Acad Dermatol 1982;7(3):
- 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.
- 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
- 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: 475478.
- 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: 17985.
- Crotty KA. Spitz nevus: histological features and distinction from malignant melanoma. Australas J
Dermatol 1997;38 Suppl 1:S49-53.
- Harvell JD, Meehan SA, LeBoit PE. Spitz's nevi with halo reaction: a histopathologic study of 17
cases. J Cutan Pathol 1997;24: 611619.
- 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): 13746.
- Howat AJ, Variend S. Lymphatic invasion in Spitz nevi. Am J Surg Pathol 1985;9:125128.
- 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: 319324.
- Kamino H, Jagirdar J. Fibronectin in eosinophilic globules in the Spitz nevus. Am J Dermatopathol
1984;6 (Suppl 1): 313316.
- McCarthy SW, Crotty KA, Palmer AA, Mg AB, McCarthy WH, Shaw HM. Cutaneous malignant melanoma in
teenagers. Histopathology 1994;24: 453461.
- 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): 866867.
- 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.
- 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:
- Toussaint S, Kamino H. Dysplastic changes in different types of melanocytic nevi. A unifying
concept. J Cutan Pathol 1999;26(2): 8490.
- Sprecher E, Bergman R, Meilick A, et al. Apoptosis, Fas and Fas-ligand expression in melanocytic
tumors. J Cutan Pathol 1999;26: 7277.
- 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.
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.
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
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 715 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
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.
Dermal Spitz Nevus and Its Nonmelanocytic Mimics
- Argenyi ZB, Kutzner H, Seaba MM. Ultrastructural spectrum of cutaneous nerve sheath myxoma/cellular
neurothekeoma. J Cutan Pathol 1995;22:137145.
- Barnhill RL, Mihm MC Jr. Cellular neurothekeoma. A distinctive variant of neurothekeoma mimicking
nevomelanocytic tumors. Am J Surg Pathol 1990;14:113120.
- 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:
- Gallagher RL, Helwig EB. Neurothekeoma : a benign cutaneous tumor of neural origin. Am J Clin
Pathol 1980;75: 759764.
- 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.
- Tomasini C, Aloi F, Pippione M. Cellular neurothekeoma. Dermatology 1996;192: 160163.
- Zelger BG, Steiner H, Kutzner H, Maier H, Zelger B. Cellular 'neurothekeoma': an epithelioid variant
of dermatofibroma? Histopathology 1009;32: 414422.
Epithelioid Cell Histiocytoma
- Glusac EJ, McNiff JM. Epithelioid cell histiocytoma: a simulant of vascular and melanocytic
neoplasms. Am J Dermatopathol 1999;21: 17.
- 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: 123129.
- Wilk M, Schmoeckel C, Nilles M, Krahl D, Eckert F, Kreysel HW. [Epithelioid cell histiocytoma].
Hautarzt 1996;47: 526529.
- Wilson-Jones E, Cerio R, Smith NP. Epithelioid cell histiocytoma: a new entity. Br J Dermatol
Plexiform Fibrohistiocytic Tumor
Sclerosing or Desmoplastic Spitz Nevus/desmoplastic Nevus
- 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: 350356.
- Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An
analysis of 65 cases. Am J Surg Pathol 1988;12:818826.
- Giard F, Bonneau R, Raymond GP. Plexiform fibrohistiocytic tumor. Dermatologica 1991;183: 290293.
- Redlich GC, Montgomery KD, Allgood GA, Joste NE. Plexiform fibrohistiocytic tumor with a clonal
cytogenetic anomaly. Cancer Genet Cytogenet 1999;108:141143.
- Remstein ED, Arndt CA, Nascimento AG. Plexiform fibrohistiocytic tumor: a clinicopathological
analysis of 22 cases. Am J Surg Pathol 1999;23: 662670.
- Salomao DR, Nascimento AG. Plexiform fibrohistiocytic tumor with systemic metastases: a case
report. Am J Surg Pathol 1997;21: 469476.
- Sass U, Andre J, Noel JC et al. [Plexiform fibrohistiocytic tumor]. Ann Dermatol Venereol 1994;121:
- Thomazy V, Nagy A, Gal I, Nemes Z. Plexiform fibrohistiocytic tumor with novel phenotypic features.
Histopathology 1994;25: 165169.
- 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: 235241.
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.
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).
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.
Pagetoid Spitz Nevus
- Barr RJ, Morales RV, Graham JH. Desmoplastic nevus: a distinct histologic variant of mixed spindle
cell and epithelioid cell nevus. Cancer 1980;46: 55764.
- 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
- 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.
- Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK. Hyalinizing Spitz nevus. J Dermatol 2000;27:273.
- Walsh NM , Roberts JT, Orr W, Simon GT. Desmoplastic malignant melanoma. A clinicopathologic study
of 14 cases. Arch Pathol Lab Med 1988;112: 922927.
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.
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).
As distinction of such lesions from high-grade de novo intraepidermal epithelioid melanocytic
dysplasia/malignant melanoma in situ is difficult, we advise re-excision.
Pigmented Spindle Cell Nevus of Reed
- Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid
spread. Am J Surg Pathol 1995;19:10611067.
- 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.
The pigmented spindle cell nevus presents as a black or dark brown (or rarely light gray or blue),
dome-shaped lesion, 26 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.
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: 0.221.90 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.
These lesions should be managed, in our opinion, by complete lesional excision.
Pigmented Spindle Cell Nevus
- Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline
melanomas. Semin Oncol 1975; 2: 119147.
- Sagebiel RW, Chinn EK, Egbert BM. Pigmented spindle cell nevus. Clinical and histologic review of
90 cases. Am J Surg Pathol 1984;8: 645653.
- Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of
ninety-five cases. J Am Acad Dermatol 1993;28: 565571.
- Requena L, Sanchez Yus E. Pigmented spindle cell naevus. Br J Dermatol 1990;123: 757763.
- Wistuba I, Gonzalez S. Eosinophilic globules in pigmented spindle cell nevus. Am J Dermatopathol.
Pigmented Epithelioid Cell Nevus
Plaque-Type Spitz Nevus
- Choi JH, Sung KJ, Koh JK. Pigmented epithelioid cell nevus: a variant of Spitz nevus?. J Am Acad
Dermatol 1993;28: 497498.
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.
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 68% 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
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.
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.
- 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: 51320.
- Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical Spitz tumors in
childhood. Cancer 1995;76: 18331845.
- Casso EM, Grin-Jorgensen CM, Grant-Kels JM. Spitz nevi. J Am Acad Dermatol 1992; 27(6 Pt 1):
- 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: 179185.
- McCarthy SW, Crotty KA, Palmer AA, Mg AB, McCarthy WH, Shaw HM. Cutaneous malignant melanoma in
teenagers. Histopathology 1994; 24:453461.
- Rapini RP. Spitz nevus or melanoma? Semin Cutan Med Surg 1993;18:5663.
- 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): 931939.
- 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;18:115122.
- Spatz A, Calonje E, Handfield-Jones S, Barnhill RL. Spitz tumors in children: a grading system for
risk stratification. Arch Dermatol 1999;135: 282285.