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Spitz Nevi
The diagnosis of Spitz nevi and their distinction from melanoma is one of the most difficult tasks in neoplastic dermatopathology. Before a group of melanocytic proliferations was accepted as benign and named Spitz's nevus, similar lesions in children had been reported as melanoma. Sophie Spitz, after whom this nevus variant was named, published a landmark case series on childhood melanoma in 1948. All but one of the 13 children of her study had an indolent clinical course. Sophia Spitz and Arthur Allen subsequently proposed the term “juvenile melanoma” to separate these lesions from adult melanomas. With time it became apparent that histopathologic criteria could be used to differentiate most Spitz nevi from melanoma and that these lesions also occur in adults. A spitzoid melanocytic neoplasm, for which no definitive distinction between nevus and melanoma can be made even by experts in melanocyte pathology, is generally referred to as “atypical Spitz tumor.”
Spitz nevi “tumors” and spitzoid melanomas represent a spectrum of melanocytic neoplasms that share distinctive features. Although pathologists commonly agree on a typical case, there is considerable interobserver variability regarding what set of microscopic findings is needed for a lesion to be designated as “spitzoid” and whether it is clearly benign, malignant, or indeterminate in its biologic potential. With the benefit of recent genomic aberrations, there is an opportunity to integrate molecular findings for the definition and classification of spitzoid melanocytic neoplasms along with light microscopic and dermoscopic findings.
Clinical Findings
Spitz nevi may occur at any age and any site but are most commonly found in children and young adults and preferentially affect the lower extremity and the face. In a recent study of 349 patients, the mean and median age at diagnosis was 21 years; 40% of Spitz nevi were diagnosed before the age of 15 years and 80% before the age of 30. In 1977 a study from Queensland, Australia, estimated an annual incidence of 1.4 cases per 100,000. Spitz nevi constitute approximately 1% of nevi removed during childhood. They can be found in individuals from all ethnic backgrounds.
Clinically the lesions usually manifest as dome-shaped papule or small plaque ( Figs. 4.1 and 4.2 ). The color may range from tan, pink, red to light or dark brown. The lesions tend to be symmetric and circumscribed. Most Spitz nevi measure less than 6 mm in diameter. Some have a polypoid and/or verrucous surface. Tumor ulceration is rare, but traumatic excoriation is not uncommon. Most nevi are solitary, but on occasion multiple lesions may be present at the same time—agminated (grouped) ( Fig. 4.3 ) or diffusely and randomly distributed (disseminated). A proliferative spitzoid nodule or multiple Spitz nevi may also develop in a background of a congenital melanocytic nevus.
Dermoscopic features of pigmented Spitz nevi include a starburst pattern with pseudopods symmetrically placed around the entire circumference of the lesion, or symmetric radial streaming all around the periphery of the lesion. Lesions may also display a granular, globular, or tiered globular pattern or a symmetric inverse pigment pattern. The latter is common in dome-shaped, grossly pink or erythematous papular Spitz nevi.
Histopathologic Findings
The silhouette of a Spitz nevus is fairly symmetric ( Fig. 4.4 ), often displaying an inverted wedge-shaped or superficial plaquelike appearance. The lesions tend to have sharp lateral borders ( Figs. 4.4 and 4.5 ). Associated epidermal hyperplasia is common. Junctional nests often show clefting (i.e., on routinely processed and stained tissue sections, there is a small empty space between the melanocyte nests and the adjacent epidermis) ( Figs. 4.5–4.7 ). The growth pattern is predominantly nested. The nests may be large and cellular. They often vary greatly in size and shape. Large elongated nests arranged parallel to hyperplastic rete ridges have been described as “raining down” or likened to “hanging bananas” ( Fig. 4.8 ).
A peculiar finding is the presence of eosinophilic globules (so-called Kamino bodies) ( Figs. 4.7, 4.9, and 4.10 ). They may be small or large. Although small eosinophilic globules can be seen in other nevi or even melanoma, large and/or numerous Kamino bodies are strongly associated with Spitz nevi.
Cytologically, Spitz nevi are composed of enlarged spindle and epithelioid melanocytes. The proportion of spindle versus epithelioid cells varies from lesion to lesion. In some nevi, spindle cells may dominate. Other lesions may be nearly exclusively composed of epithelioid melanocytes. Often there is a mixture of both cell types. The spindle cells tend to have polyangular contours ( Fig. 4.11 ). The cytoplasm, especially that of large epithelioid cells, tends to be abundant and opaque, with a “ground-glass” appearance. The nuclei are round to oval or fusiform. The nuclear chromatin pattern is typically finely dispersed. The nucleolus is usually small but distinct. However, in some lesions the nuclei may be hyperchromatic and/or contain pseudoinclusions. Multinucleated melanocytes are commonly found ( Fig. 4.12 ). Many lesions are amelanotic or paucimelanotic, but some are pigmented (pigmented Spitz nevus) ( Fig. 4.13 ).
Most Spitz nevi show evidence of maturation (i.e., the size of the melanocyte nests decreases from the superficial to deep dermis). At the bottom of a lesion, melanocytes are often displayed in a nondisruptive single cell infiltrative pattern. In some lesions, especially those limited to the superficial dermis, maturation may be limited or absent.
The mitotic rate is usually low (≤2 mitoses/mm 2 ). However, in young children a higher mitotic rate is still acceptable for a Spitz nevus. A mild inflammatory cell infiltrate is not uncommon. Lymphocytes are typically dispersed throughout the lesion. Some lesions may be heavily inflamed and/or associated with features of regression (e.g., “halo” Spitz nevi).
Histopathologic Variants of Spitz Nevi and Related Differential Diagnosis
The main histopathologic variants of Spitz nevus are shown in Table 4.1 and briefly described in alphabetical order:
TABLE 4.1
Variants of Spitz Nevus
| Morphologic Variant | Microscopic Findings |
|---|---|
| Angiomatoid Spitz Nevus | Spitz nevus associated with vascular proliferation with dilated vessels |
| Atypical Spitz Nevus | Spitz nevus with some asymmetry, architectural disorder, and cytologic atypia |
| Combined Spitz Nevus | Spitz nevus associated with another type of nevus (e.g., congenital or common nevus) |
| Desmoplastic Spitz Nevus | Spitz nevus associated with prominent stromal sclerosis |
| Epithelioid Spitz Nevus a | Spitz nevus characterized by the predominance of large epithelioid melanocytes with open nuclear chromatin pattern |
| Granulomatous Spitz Nevus | Spitz nevus with nodular aggregates simulating granulomas |
| Halo Spitz Nevus | Spitz nevus associated with dense inflammation and clinically a halo phenomenon |
| Hyalinizing Spitz Nevus | Spitz nevus with hyalinized stroma |
| Myxoid Spitz Nevus | Spitz nevus with myxoid stroma |
| Pagetoid Spitz Nevus | Spitz nevus (usually small diameter circumscribed lesion) with several suprabasilar melanocytes |
| Pigmented Spindle Cell Nevus | Sharply circumscribed pigmented lesion with densely cellular junctional nests of pigmented spindle cells; usually many dermal melanophages |
| Plexiform Spitz Nevus | Spitz nevus with plexiform growth: fascicles and nests grow along neurovascular bundles |
| Recurrent Spitz Nevus | Spitz nevus with features of a recurrent nevus |
| Regressing Spitz Nevus | Spitz nevus associated with fibrosis and loss of melanocytes |
| Spindle cell Spitz Nevus | Spitz nevus characterized by a predominant fusiform cytology |
| Tubular Spitz Nevus | Spitz nevus with tubular arrangement of cells |
| Verrucous Spitz Nevus | Spitz nevus with verrucous epidermal hyperplasia |
BAP1, BRCA1-associated protein-1.
a The large epithelioid cell nevus with loss of BAP1 is often listed as a variant of Spitz nevus. It has been argued that because of the frequent presence of BRAF mutations, this lesion is pathomechanistically not a Spitz nevus, but Spitz nevus-like (spitzoid).
Angiomatoid Spitz Nevus
Angiomatoid Spitz nevus is characterized by the association of usually paucicellular proliferation of spitzoid melanocytes with stromal fibrosis and an increased density of blood vessels of various sizes ( Fig. 4.14 ). At low magnification the findings may suggest an angioma. Sometimes the hypervascular stroma may lead to concerns about a regressed melanoma. The spitzoid cytology of the lesional melanocytes in conjunction with the clinical history, small size, and circumscription of the lesion should permit establishing the correct diagnosis of a nevus and avoid confusion with melanoma. Many lesions of angiomatoid Spitz nevus likely represent or may be regarded as a variant of desmoplastic Spitz nevus with stromal hypervascularity.
Desmoplastic Spitz Nevus
This variant of Spitz nevus is characterized by prominent stromal fibrosis ( Fig. 4.15 ). Lesions may be entirely intradermal or may be compound with a usually small junctional component. The silhouette of the nevus may be wedge shaped or broad plaque-like. Most lesions are amelanotic and relatively paucicellular, giving the lesion at low magnification a stroma-rich “pink” fibroma-like appearance. Within the dermal stroma the melanocytes may be arranged in small nests or short fascicles or be distributed as solitary units.
Clinically, this variant is more likely to occur in the head and neck region. It is also more likely found in individuals with sun damage compared with other Spitz nevus variants. It is clinically often confused with a fibroma and needs to be distinguished from desmoplastic melanoma.
For the distinction of desmoplastic Spitz nevus from desmoplastic melanoma, a number of architectural parameters and cytology features are helpful. In contrast to a desmoplastic melanoma, the silhouette of a desmoplastic Spitz nevus is usually symmetric—shaped like a wedge or as a superficial plaque, with sharp lateral circumscription. In desmoplastic Spitz nevus, nests of melanocytes are usually present and more prominent superficially than deep, thereby displaying zonation (aka “maturation”). The melanocytes in a desmoplastic Spitz nevus are usually plump and display a polygonal shape unlike the fibroblastic-like cells of desmoplastic melanoma. In the latter the nuclei are typically hyperchromatic. In desmoplastic Spitz nevus, the nuclei are round to oval or elongated but typically display a finely dispersed chromatin pattern. Both desmoplastic melanoma and desmoplastic Spitz nevi may be associated with lymphoid aggregates ( Fig. 4.16 ). Ancillary methods may help support the diagnosis of a desmoplastic Spitz nevus, such as documentation of HRAS expression by immunohistochemistry (IHC) or an isolated gain of 11p by cytogenetic methods. Expression of PReferentially expressed Antigen in MElanoma (PRAME) is only seen in desmoplastic melanoma (albeit with limited sensitivity) but not in desmoplastic Spitz nevus.
Epithelioid Spitz Nevus
Epithelioid Spitz nevus includes a spectrum of spitzoid melanocytic nevi with a predominantly epitheloid appearance characterized by enlarged melanocytes with abundant cytoplasm and enlarged round to oval nuclei, often with delicate open chromatin pattern (see Fig. 4.16 ). Some lesions are flat or form papules. Some may be polypoid ( Fig. 4.17 ). Multinucleation is common. A subset of epithelioid/spitzoid melanocytic nevi is associated with inactivation of BRCA1 -associated protein 1 (BAP1) (see later). The latter are often seen in association with a combined nevus and typically associated with a lymphocytic infiltrate.
Pagetoid Spitz Nevus
Small areas of suprabasilar intraepidermal melanocytes can be seen in various Spitz nevi, especially in association with trauma ( Fig. 4.18 ), in young children, or at acral sites. The term pagetoid Spitz nevus refers to a Spitz nevus characterized by prominent pagetoid growth of solitary units and/or nests of melanocytes in the spinous cell layer throughout most of the lesion ( Fig. 4.19 ). Caution is needed not to confuse a pagetoid Spitz nevus with superficial spreading melanoma in situ. The presence of spitzoid cytology, occurrence of the lesion in a young patient, small lesional diameter, and sharp circumscription are important parameters for accepting a lesion as a pagetoid Spitz nevus. Furthermore in a pagetoid Spitz nevus the distribution of suprabasilar melanocytes is usually relatively orderly and often confined to the lower half of the epidermis, whereas in melanoma in situ the distribution of melanocytes is more chaotic.
Pigmented Spindle Cell Nevus
This melanocytic nevus is characterized by the presence of spindle-shaped melanocytes with heavy melanization ( Figs. 4.5, 4.13, and 4.20 ). These lesions are mostly superficial (i.e. they are junctional nevi or compound nevi with often only a small superficial intradermal melanocyte population), but on occasion a pigmented spindle cell nevus may have a more substantial dermal component ( Fig. 4.21 ). The silhouette of this nevus is typically that of a thin cellular pigmented plaque composed of densely packed junctional nests of melanocytes with sharp lateral demarcation. Slight epidermal hyperplasia and clefting between the junctional nests and the adjacent epidermis are common. Lesional melanocytes contain fine cytoplasmic melanin granules. Melanin pigment is often present in adjacent and overlying keratinocytes and even the stratum corneum. A few solitary units of pigmented melanocytes may be present in the spinous cell later. The underlying dermis often displays a band or clusters of melanophages. Lymphocytes are also commonly present.
Features of pigmented spindle cell nevi, such as nests of pigmented spindle cells with clefts, can also be seen in association with some melanomas. However, melanoma is distinguished from pigmented spindle cell nevus by an asymmetric silhouette, usually broader growth (greater horizontal dimension), ill-defined borders, and more prominent and irregular pagetoid spread.
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