Spitz nevi are benign, acquired, melanocytic proliferations, which generally develop in children and adolescents, although it also occurs in adults. Spitz nevus was first described by Sophie Spitz in 1948, and it was regarded as a juvenile melanoma, with the implication of being a malignant lesion but noting that these lesions were less aggressive than the majority of adult melanomas [1]. Subsequently, to distinguish them from obviously malignant lesions, these lesions were designated as Spitz nevi. Since their description, the histologic diagnosis has been a cause for controversy because in some instances, it is not possible to render an unequivocal diagnosis of Spitz nevus versus melanoma and thus predict the biologic behavior. However, since currently there are no definitive immunohistochemical or molecular ancillary techniques that can reliably distinguish between the benign and malignant lesions, in our opinion the histopathologic evaluation continues to be the gold standard.

While there are certain histologic features that have been systematically evaluated to distinguish between Spitz nevi and spitzoid melanomas, experts’ opinions vary in defining the relative importance of the criteria to diagnose these tumors. As a matter of fact, we and others consider these entities to belong to a histologic spectrum suggesting stratifying those entities that fall in the gray zone between the two extremes [2]. This lack of objective criteria for predicting the biologic behavior of such lesions may result in a misdiagnosis with the potentially aggressive nature of an untreated spitzoid melanoma.

As mentioned above, Spitz nevus presents as an intraepidermal lesion, in which the dominant pattern of growth is single cells with pagetoid distribution [18]. Junctional Spitz nevi show symmetrical and sharply demarcated intraepidermal nests that are composed of spindle cells (in some cases, they may show an admixture of epithelioid cells) located mostly at the base of epidermis. The epidermis shows mild hyperplasia with elongated rete ridges, which characteristically stops at the edge of the lesion (clue to the diagnosis). The lateral borders of intraepidermal Spitz nevi often consist of a nest rather than of a gradual diminution of solitary melanocytes (demarcation). These epithelioid and/or spindle melanocytes are large in size with abundant eosinophilic cytoplasm, well-defined cytoplasmic borders, and vesicular nuclei with evenly distributed chromatin and prominent nucleoli. In some occasions, the cytoplasm might show light pigmentation. The intraepidermal nests tend to be vertically oriented and characteristically separated from the adjacent epidermis (“hanging bananas”), features also that helps in the diagnosis. The melanocytes are uniformly scattered throughout the lesion either singly or forming small nests within epidermis. In some cases, the melanocytes within the epidermis may show a lentiginous pattern of growth with focal pagetoid growth, in which the melanocytes are characteristically distributed along the sides of rete ridges, particularly near the center of the lesion and not at the periphery. In some cases, melanocytes display a dendritic morphology. Some examples of junctional Spitz nevi may show transepidermal elimination of nevus cell nests and can be associated with pagetoid upward spread of single melanocytes. This pagetoid upward spread of solitary melanocytes is generally focal and centrally located, and the number of ascending melanocytes is relatively small compared to the richly cellular junctional component. Pagetoid migration across the entire width of the lesion is not characteristic of Spitz nevi and its presence should raise the diagnosis of melanoma. These ascending melanocytes often diminish in size in Spitz nevi, whereas ascending melanoma cells often retain their original size and appearance [18].

An additional diagnostic clue of Spitz nevi is the presence of Kamino bodies, which are seen in most Spitz nevi. Kamino bodies are collections of amorphous, PAS-positive and diastase-resistant, eosinophilic globules and are found in about 60 % of Spitz nevi [19]. Although Kamino bodies resemble apoptotic cells, they are rather formed of basement membrane material, including collagens IV and VII, fibronectin, and laminin [20–22]. These bodies may be found at, or immediately subjacent to, the dermal-epidermal junction and sometimes within the nests; when they are numerous, they represent an important diagnostic clue in the diagnosis of Spitz nevi. Kamino bodies are more commonly seen in cases in which nests are well formed and the cellular density is high. Although more common in Spitz nevi, they can be seen in melanomas.

The differential diagnosis of junctional Spitz nevi, especially when dealing with a limited tissue sample, is with melanoma in situ. The presence of a small-sized lesion, lateral circumscription, and symmetry and the uniform distribution of melanocytes within epidermis are very important clues to the correct diagnosis. Also, the presence of “spitzoid” cell type (large, uniform nuclei with prominent, central nucleoli), the predominance of small nests surrounded by shrinkage artifacts, the relative paucity of pagetoid cells, and the absence of changes in cell type or lesional architecture from area to area are characteristic features of junctional Spitz nevi. In some cases, the distinction between junctional Spitz nevus and in situ melanoma may be impossible; however, this possible uncertainty has less of a clinical implication since both may be handled by simple, complete excision (a different situation from that of the distinction between a compound Spitz nevus and invasive melanoma). Particularly for this reason, complete excision is recommended when dealing with spitzoid lesions.

The vast majority of Spitz nevi are excised while in the compound stage when melanocytes are detected in the dermis. The majority of compound Spitz nevi are symmetric, well circumscribed with sharp lateral demarcation, and often wedge shaped; however, in some cases the architecture of Spitz nevi can exhibit a wide spectrum of appearances (such as a flat base or a dome, papillomatous or verrucous surface). In most cases, the epidermis exhibits distinctive epidermal changes including hyperplasia and elongated rete ridges including occasional frank pseudoepitheliomatous hyperplasia . It is not unusual to see expansion of the papillary dermis and vascular ectasia. In our experience, the presence of flattening of rete ridges (consumption of the epidermis) is considered a red flag, because it is much more commonly observed in spitzoid melanomas. The melanocytes within epidermis are arranged in nests that are relatively uniform in size and shape. The junctional nests are typically vertically oriented, and retraction artifact typically surrounds the junctional nests. Some of these nests show the “hanging-banana” pattern into papillary dermis, as the spindle cells run along the rete ridges perpendicular to the stratum corneum. As mentioned above, Kamino bodies can be seen in up to 60 % of Spitz nevi.

Pagetoid spread of melanocytes in the overlying epidermis can be seen either as single cells or forming small nests, although in most cases, it is limited to the central portion of the lesion and confined to the lower half of epidermis [23, 24]; however, in some rare occasions, they can even reach the stratum corneum. This phenomenon is more commonly seen in younger patients and suggests a diagnosis of melanoma in spitzoid lesions in adult. Since there is overlap in the amount of pagetoid migration in Spitz nevi and in melanoma, this is only one of many parameters that need to be assessed to make the diagnosis. In melanoma the pagetoid spread of melanocytes usually involves the entire epidermis (including the epidermis lateral to the dermal component). Also, it should be noted that pagetoid melanocytes can be seen not only in Spitz nevi but also acral nevi, congenital nevi, traumatized or recurrent nevi, etc. The presence of mitotic figures is uncommon in Spitz nevi and when encountered are more commonly observed in childhood cases and located in the junctional component and in mid- to upper dermis (very rarely grouped). Some authors suggest a cutoff number of up to two mitotic figures per lesion; however, we have rarely encountered lesions with more mitotic figures but located in the upper dermis, in some rapidly growing Spitz nevi as well as in recurrent or regressing lesions [25, 26]. The presence of atypical mitotic figures is exceedingly rare in these nevi and should definitely prompt for a search of other possible histologic features of melanoma.

As mentioned above, a very important histologic feature of Spitz nevi is their cytomorphology. Melanocytes are large, epithelioid, and spindle and have a variably enlarged vesicular nucleus, often with a central plump but regularly shaped monomorphous nucleolus (melanocytes). The color of the nucleoli may vary depending on stain of hematoxylin and eosin; in general most nucleoli will be blue/purple. The cytoplasm is generally ample and pale with a ground-glass appearance and distinct cell borders; the cells with the largest nucleus generally have the most abundant cytoplasm. Multinucleated epithelioid and giant melanocytes may be present and are numerous in some cases. Based on our experience, these multinucleated melanocytes are more commonly observed when the lesion is primarily composed of epithelioid melanocytes. Some lesions have large nuclei, but it is usually observed in the upper part of the lesion while the lower parts show cells with smaller nuclei (maturation). In some cases, there is shrinkage of melanocytes, resulting in irregular intercellular slit-like spaces, most prominent around the junctional nests. This is an important diagnostic clue, because melanomas tend to show much less cellular shrinkage. Melanin pigment is usually absent and if present the pigment is symmetrically distributed. The presence of melanin pigment is in fact a valuable diagnostic criterion for the distinction of Spitz nevi versus spitzoid melanoma, since the latter has irregularly distributed melanin and may be bottom heavy.

The dermal component of compound Spitz nevi varies as some cases are composed of just single cells in dermis, while some other lesions may extend deeply into the underlying subcutaneous fat. Melanocytes in dermis are mostly nested or arranged in fascicles. The dermal component of Spitz nevi shows gradual diminution of the cellularity, and nests decrease in size toward the base, which is associated with diminution in cell size and loss of proliferative activity (maturation). Lesions that show disproportionately large nests at the base should be carefully scrutinized. In general, the melanocytes in deep dermis infiltrate between collagen bundles; this is a very important diagnostic feature because spitzoid melanomas commonly show compact cell groups at the base, and these nests are horizontally arranged. Also, if melanocytes in Spitz nevus are large and pleomorphic at the base of the lesion, the degree of this enlargement and pleomorphism is similar throughout at any given level and is less pronounced than in the upper dermis. A superficial biopsy that does not contain the base of the lesion cannot be fully evaluated. For those lesions a possible diagnosis is that of spitzoid lesion and a complete excision is recommended. When the subcutaneous fat is involved, only the upper part is usually affected in the form of a nodule. If a spitzoid lesion involves the entire subcutaneous fat, this feature should be analyzed in conjunction with other histologic features as may represent a melanoma. Lymphocytic inflammatory infiltrate is often seen around perivascular spaces and at the base of deep compound lesions, but rarely intermixed with melanocytes. In thin or superficial compound Spitz nevi, the lymphocytic infiltrate can be distributed in a lichenoid fashion. The stroma of Spitz nevi in young patients has prominent edema and ectatic vessels in papillary dermis. In rare cases there may be lymphatic invasion or perineural invasion ; however, its presence should prompt the pathologist to carefully inspect the lesion. In addition, melanocytes can be seen within the adnexal epithelium especially within eccrine ducts. In some occasions, melanocytes can be observed within the arrector pili muscle, and its presence could be useful for its diagnosis since only rarely do melanomas show these features.

Intradermal Spitz nevi have a symmetrical architecture. The overlying epidermis can show epidermal hyperplasia but is not as common as that seen in compound Spitz nevi. This lack of epidermal changes is most likely due to the absence of a junctional component [27]. As opposed to cases of intraepidermal and compound Spitz nevi, Kamino bodies are only rarely observed [19, 27]. In some cases, one can find rare isolated melanocytes within the epidermis (these melanocytes show spitzoid features such as large epithelioid cells with well-defined cell borders). Also, deeper sections in such lesions may reveal rare junctional nests with the same cytomorphology as junctional or compound Spitz nevi. There may be a grenz zone right beneath the epidermis. The predominant cell in intradermal Spitz nevus is the epithelioid type; however, some cases may show a mixture of both epithelioid and spindle cell melanocytes or being purely composed of spindle cell melanocytes (rare) [27]. The melanocytes usually show mild hyperchromasia with irregular chromatin distribution and have prominent nucleoli. The cytoplasm of these melanocytes is abundant, eosinophilic, and devoid of pigment. Multinucleated giant melanocytes can be seen, especially in cases in which the epithelioid cell type predominates. In some cases there is a chronic inflammatory lymphocytic infiltrate, and the distribution of the infiltrate is perivascular and/or interstitial; rare examples show a dense, halo-like pattern. In intradermal Spitz nevi, the presence of melanin pigmentation is more commonly seen when lesions are composed primarily of epithelioid melanocytes. Marked pigmentation has been reported in Spitz nevi with epithelioid cell type, known as pigmented epithelioid Spitz nevus [28, 29]. Mitotic figures may be seen in intradermal Spitz nevus, up to 38 % of cases. These mitotic figures are located in the superficial portion of the lesion (superficial dermis) and are not seen in the deeper aspect of the lesions. Atypical mitotic figures are not identified in any of our cases. The presence of atypical mitotic figures, especially located at the base of the lesion, should be a red flag for melanoma.

Most Spitz nevi show maturation in the dermis; however, some lesions, usually in adults, lack this phenomenon. In our experience, the absence of maturation in intradermal Spitz nevi should not be used as a single criterion to establish a diagnosis of melanoma, especially if other histopathologic features are present such as symmetry, the absence of mitotic figures at the deep portion of the tumor, and lack of severe pleomorphism throughout the lesion.

The main differential diagnosis of Spitz nevi is with spitzoid melanoma . While it is fairly easy to distinguish conventional Spitz nevi from conventional melanomas, not all cases fall under this category. In our opinion, unified interpretation of histopathologic criteria for distinguishing such cases is lacking. On the other hand, to make a distinction between these entities is of crucial importance due to the marked difference in management and prognosis. Since most of the developed diagnostic criteria derive from conventional Spitz nevi and melanomas and not from the unusual variants of these neoplasms, it can be quite difficult to arrive to the correct diagnosis in some occasions. The tumors that deviate from the classic description can cause difficulties in diagnosis particularly since these lesions are relatively infrequently encountered. In addition, there are many factors such as age, trauma, pregnancy, and exposure to sunlight that are well known to alter the microscopic appearances of melanocytic lesions and may contribute to cause pitfalls in diagnosis.

Clinically, spitzoid melanomas occur rarely in younger patients and thus are more commonly seen in adults, whereas Spitz nevi are common in young patients. While we agree with many authors that Spitz nevi in adults are rare, we do not believe that all Spitz nevi in adults should be diagnosed as melanoma. Rather, all spitzoid lesions in adults should be carefully inspected and always keeping in mind the possibility of melanoma.

The clinical presentation of the lesion may be extremely important. Spitz nevi tend to have an initial brisk growth with further stabilization and are uniform in size and shape, whereas spitzoid melanomas tend to grow rapidly and keep increasing in size. Thus, when a lesion either in adults or children has been present for a long time without clinical change, it most likely represents a Spitz nevus (exceptions do exist). Size of the lesion is also an important consideration as only 10 % of Spitz nevi are larger than 1 cm in size; thus, larger lesions more likely represent melanoma (although spitzoid melanomas can be smaller than 1 cm in size). A recent study showed that the mean size of spitzoid melanoma cases was 7.27 mm [30]. The presence of ulceration in Spitz nevi is usually secondary to trauma; thus, not all lesions that show ulceration represent melanoma. The presence of severe, sun-damaged skin will favor the diagnosis of melanoma, especially if the lesion is junctional in nature (in general junctional nevi tend to appear at young age). In our experience, a diagnosis of unequivocal Spitz nevus in an elderly adult should only be made when the lesion shows the classic, conventional histologic features of Spitz nevus.

Histologically, Spitz nevi are symmetric and more often have either a wedge-shape or a flat-based dome shape. It is always very important to assess the lateral margins of the lesion. In Spitz nevi the nests at the junctional edges are similar in shape, size, and number, the lateral borders are clear-cut, and the junctional nests end abruptly. In some cases, especially in growing lesions and in lesions located in acral locations, the lateral borders may show single melanocytes rather than nests at the edges. On the other hand, in spitzoid melanoma the edges are asymmetric with single melanocytes extending beyond the last nest at the edge. These atypical melanocytes progressively decrease toward the periphery of the lesion and do not show the uniformity that one observes in Spitz nevi. Also, some cases of cutaneous metastatic melanoma may show spitzoid features with symmetric borders and thus can be exceedingly difficult to separate from intradermal Spitz nevus. When this problem arises, clinical history usually helps clarify the correct diagnosis.

Classic Spitz nevi display zonation with depth (uniformity of size, shape, and spacing of melanocytic nests and fascicles within the same horizontal plane); deeper cells should exhibit greater maturation as reflected in decreasing cellular density, progressively smaller nests with transition into single cells, and the infiltration of these individual melanocytes among collagen bundles. Therefore, marked lateral heterogeneity and persistence of deep nests of considerable size and a pushing deep border all represent red flags for the diagnosis of melanoma. While most Spitz nevi show a flat or a wedge-shaped base, in some occasions Spitz nevi can show irregular and infiltrative margins at the base of the lesion. In such cases, melanocytes tend to be arranged in an interstitial pattern, as linear clusters or isolated cells, and distributed among thickened collagen bundles. The presence of large nests of melanocytes or confluent fascicles in deep reticular dermis is a feature more characteristic of melanoma. Maturation is not always present in Spitz nevi and some melanomas may show “pseudo” maturation. Another important point to always assess is the depth of the lesion as Spitz nevi usually should not involve the deep subcutaneous fat (some cases may show superficial involvement of the subcutaneous tissue). Thus, the presence of a spitzoid lesion that involves the subcutis should be carefully scrutinized as probably it will represent melanoma.

The presence of Kamino bodies is a helpful clue. When Kamino bodies are confluent, numerous, and large, such finding is almost diagnostic of Spitz nevus; however, we seem to have melanomas with Kamino bodies developing metastasis. Unfortunately, Kamino bodies are more commonly seen in conventional Spitz nevi than in ambiguous, more challenging cases.

In Spitz nevi, the cells tend to be monomorphous despite the presence of cytologic atypia (“uniformly atypical”). Spitz nevi, especially in children, may display severe cytologic atypia, i.e., large cells with hyperchromatic nuclei and prominent eosinophilic nucleoli; however, such melanocytes tend to also show a large homogeneous cytoplasm. On the other hand, spitzoid melanomas tend to show cells with variable size and including large nuclei and prominent nucleoli with minimal or vacuolated cytoplasm. Also, the presence of prominent nucleoli is usually restricted to the epithelioid cells in the surface of the lesion in Spitz nevi. On the other hand, the presence of prominent eosinophilic nucleoli in the deep portion of the lesion, especially if a lesion is composed of primarily of spindle cells, is more indicative of melanoma. The melanocytes in Spitz nevi tend to show clear-cut borders, whereas in melanomas the cytoplasmic borders are blurred. Cellular density is a good discriminator between nevi and melanoma, as spitzoid melanoma tends to have a much higher cellular density, especially in cases in which the cells have minimal cytoplasm. Another important clue is the presence of expansile nodules, more commonly seen in melanomas. Spitz nevi can show a nodular appearance in dermis; however, the surrounding tissue is not compressed, whereas in melanomas the dermal nodules tend to have pushing, compressive margins.

Spitz nevi are well known to have mitotic figures , particularly in lesions that are growing. Mitotic figures in Spitz nevi range from 10 to 58 % [3, 27, 31–33]. They are scarce and typically located in the superficial areas of the neoplasm. When located in the deep aspect of the lesion (marginal mitotic figures), the likely diagnosis will be an atypical Spitz tumor or melanoma. In addition, if mitotic figures are arranged in clusters even if they are located in the surface of the lesion are features of melanoma. We consider this criterion very important in the differential diagnosis of Spitz nevus and spitzoid melanoma; thus, the presence of mitotic figures in the lower portion or many grouped in an area of a spitzoid lesion must be considered highly indicative of melanoma.

Pagetoid spread of melanocytes in the overlying epidermis or within epithelium of the intraepidermal portions of the adnexa (infundibula and acrosyringia) can be observed in Spitz nevi. Because both melanomas and Spitz nevi share this feature, there are certain points that need to be remembered when evaluating such tumors. In melanoma, the presence of pagetoid spread usually is seen beyond the dermal component (shouldering effect), since melanocytes are scattered throughout the entire lesional epidermis. Those melanocytes located in the adnexa are grouped as single melanocytes, and the epidermis lacks hyperplasia. In Spitz nevi, the pagetoid cells are usually located in the center of the lesion, the epidermis shows hyperplasia, the melanocytes in adnexal structures are arranged in nests, and the melanocytes are uniform and homogenous (similar to those observed in the junctional nests). In addition, one should keep in mind that irritated lesions (trauma) can induce pagetoid spread of melanocytes beyond the center of the lesion.

Epidermal hyperplasia is a feature seen in Spitz nevi. The epidermis shows rete ridges with pointed bases with uniform size and shape. In melanoma, the epidermis shows atrophic changes that alternate with irregular epidermal hyperplasia (in some cases there is even ulceration). In some cases of Spitz nevi, there is even pseudoepitheliomatous hyperplasia [19].

Atypical pigmented spindle cell nevus is a term used to raise clinical concern about the biological potential of a lesion consistent with a PSCN, but that demonstrates further atypical features [39] including some of the following: larger size (>6 mm), involvement of reticular dermis, loss of the benign silhouette, cytologic atypia with high cellularity, lack of symmetry with lentiginous growth at the periphery of the lesion, and large, epithelioid melanocytes with ample cytoplasm and prominent nucleoli. These atypical features warrant caution in the biological behavior of the lesion, and thus a diagnosis of atypical pigmented spindle cell nevus would be appropriate. In general, clinical follow-up of these cases has not suggested aggressive behavior in such lesions.