Angiomatoid Spitz Nevus David E. Elder University of Pennsylvania, Philadelphia

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Clinical History: Female, 33, Right posterior thigh. "Elevated, purple dome-like skin lesion". Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Scanning magnification shows a dome-shaped lesion in the skin . Figure 2 At low magnification, thickened collagen bundles and increased cellularity can be appreciated. Figure 3 The lesion extends through much of the thickness of the reticular dermis. Figure 4 The lesion is comprised of uniform cells placed among thickened collagen bundles. Figure 5 The lesional cells are plump spindle cells. A prominent vascular stroma is also appreciated. Figure 6 At higher magnification prominent relatively thick walled vessels are present in association with the infiltrating spindle cells and the thickened collagen bundles. Figure 7 Plump spindle cells infiltrating among thick collagen fibers at the base of the lesion. Figure 8 In another area near the base, lesional cells infiltrate as single cells among more normal collagen fiber bundles. In the upper left, one of the thick walled vessels with plump endothelial cells is appreciated. Figure 9 - S-100 An S100 stain demonstrates strong and diffuse uniform positivity throughout the lesion. Figure 10 - S-100 The plump spindle cells are uniformly and strongly S100 positive. Figure 11 - HMB45 An HMB45 stain demonstrates a rare group of positive cells in the superficial portion of the lesion. Figure 12 - HMB45 The positive cells are strongly stained. A few cells containing pigment, mostly melanophages, are also present along with a sprinkling of lymphocytes. Figure 13 - Actin An actin stain highlights the vessels which are present throughout the profile of the tumor. Contrast this increased vascularity with the normal vascularity of the adjacent uninvolved reticular dermis. Figure 14 - Actin The actin strongly stains vessel walls, indicating the presence of pericytes. Figure 15 - FVIIIRAg A stain for factor VIII highlights the thickened endothelial cells. Diagnosis: Angiomatoid Spitz Nevus The Spitz nevus was first described by Sophie Spitz in 1948 and was characterized at that time as a "juvenile melanoma," a term intended to capture its important clinicopathologic distinctions from obvious benign nevi in children and malignant melanomas in adults [1]. Synonyms for the Spitz nevus include benign juvenile melanoma and nevus of large spindle and/or epithelioid cells, the latter being useful because it underscores the critical histopathologic feature which distinguishes this nevus. The defining feature of Spitz lesion is the presence of large spindle and/or epithelioid cells, a feature that can give rise to concern for melanoma. Although the vast majority of Spitz lesions are benign and differ cytogenetically from melanomas [2], there may be biological overlap and there certainly is diagnostic overlap with melanoma, such that it may be best to separate these lesions from routine nevi by the use of the term "Spitz tumor" or "Spitz nevus/tumor" [3], however for the usual benign Spitz lesions, the term "nevus" is still the most commonly used. Clinically, Spitz nevi occur most commonly in the first two decades of life but may be seen in adults of almost any age though they are quite rare after the fourth decade. They commonly present as smooth, round or dome-shaped nodules with a pink, red or tan color and are typically non-ulcerated. Common sites of involvement include the head and neck and the legs—the former particularly in children and the latter especially in adolescent and adult females [1, 4, 5, 6]. The lesions may be solitary or multiple, and multiple lesions can occur either as an agminated focal grouping or as an eruptive-disseminated process [4, 7, 8]. Distinct histopathological variants of the Spitz nevus have been described and include halo Spitz nevus [9] , tubular Spitz nevus [10, 11], plexiform Spitz nevus [12], myxoid Spitz nevus [13], polypoid Spitz nevus [14], desmoplastic Spitz nevus [5, 15] and angiomatoid Spitz nevus [16, 17, 18]. The angiomatoid Spitz nevus was originally described as a histopathologic variant of desmoplastic Spitz nevus, and to date, 6 cases have been characterized in the literature [16, 17], with 6 additional cases in a manuscript presently submitted [18] (Table 1). The lesions typically present as solitary papules on the extremities of young women, and are characterized by a distinctive dermal fibrous and highly vascular stroma. Because of this vascularity, angiomatoid Spitz nevus can commonly be diagnosed clinically as an angioma. Table 1. Demographics of classic angiomatoid Spitz nevi from current and published studies. Case and Reference Age Gender Site Type ASN-01; current study 35 F L shin Compound ASN-02; current study 27 F R forearm Compound ASN-03; current study 36 F Dorsum of hand Compound ASN-04; current study 10 F L medial calf Compound ASN-05; current study 22 M Neck Compound ASN-06; current study 33 F R thigh Dermal Diaz-Cascajo -1 [16] 22 F Upper arm Dermal Diaz-Cascajo -2 [16] 28 F Lower leg Dermal Diaz-Cascajo -3 [16] 25 F Buttock Dermal Diaz-Cascajo -4 [16] 28 F Heel Dermal Diaz-Cascajo -5 [16] 19 F Lower leg Dermal Fabrizi [17] 35 F Leg Compound As indicated in Table 1, the 12 reported cases are from patients ranging in age from 10 to 36 years, (mean 27.5, median 27.6 years). Only one lesion came from a male patient. The lesions in females have been mostly located on the extremities, (3 on the upper and 8 on the lower extremities, with one on the buttock). In most cases, the clinical impression was that of a nevus or a benign nodule. In addition to findings typical of Spitz tumors, reviewed below and constituting primarily the presence of large spindle and/or epithelioid cells in the dermis, the striking finding in these cases is the presence of an increased number of mature, thick-walled small vessels within the tumors, and of thickened collagen bundles imparting a desmoplastic appearance to the stroma. Examination at scanning magnification generally reveals symmetrical, well-circumscribed lesions. Most are compound lesions, and when a junctional component is present the diagnosis of a melanocytic compared to another spindle cell tumor is more obvious. The density of lesional cells in the dermis varies from relatively few to moderate to focally numerous melanocytes. In more subtle lesions, single cells or discrete clusters of a few cells in the dermis are the predominant finding, while other lesions contain more obvious lesional cells in the dermis. These cells in all cases are large cells with a "spindle and/or epithelioid" morphology. The epithelioid Spitz nevus cell morphology tended to predominate in our experience of six cases. These large epithelioid cells are characterized by voluminous pale eosinophilic to amphophilic cytoplasm, enlarged oval nuclei with evenly distributed pale chromatin and a prominent centrally placed nucleolus. They tend to be arranged in small clusters and to disperse singly, especially at the base. Intranuclear cytoplasmic pseudo-inclusions are often identifiable. Melanin pigment is not prominent, although there may be scattered pigmented cells. Mitoses are exceedingly rare in these lesions and completely absent in most. Giant mononucleated cells and multi-nucleated cells are often present. Focal pagetoid extension of the lesional cells was identified in only one of our six lesions, and was limited to the stratum spinosum. With the exception of mild epidermal melanosis in three of the lesions, there was no prominent epidermal change (hyperplasia, parakeratosis, ulceration or crusting) in any of the lesions. Kamino bodies are occasionally present. Immunohistochemical stains for S100 have revealed diffuse positivity in the cells throughout the lesions, while immunohistochemical stains for HMB-45 tend to be focally positive in superficially located lesional cells. The cells are similarly positive for MART, generally in a more diffuse pattern than in the HMB-45 stains. The distinctive feature of these lesions compared to other Spitz tumors is the presence of a prominent vasculature in the papillary and reticular dermis. These vessels have a patent, round lumen with a variably thickened wall lined by plump, rounded endothelial cells with oval-shaped conspicuous nuclei, which extend into the round lumens of the vessels. Immunohistochemical stains for smooth muscle actin (SMA) and Factor VIII (FVIII) demonstrate small to medium-sized vessels scattered uniformly throughout the lesion, in a pattern that is confined entirely to and defined by the boundaries of the lesion itself. The SMA stains reveal these vessels to be mature, with pericytes present in their thick mural matrix. Finally, FVIII or CD31 immunohistochemistry decorates a hyperplastic endothelium lining the luminal surface of these vessels. In addition to the prominent vessels, a striking feature of these lesions is dense dermal fibrosis, characterized by thick bands of collagen throughout the dermis in all of the lesions. There was also mild to moderate papillary dermal edema noted in all of our specimens. A variably prominent perivascular lymphoplasmacytic infiltrate is often noted in association with the prominent vessels; in some cases the infiltrate is more diffuse. Differential Diagnosis Important differential diagnostic considerations include primary vascular lesions and melanocytic and other spindle cell lesions. The most important distinction is from regressing or desmoplastic malignant melanoma. Many features of angiomatoid Spitz resemble a regressing melanoma, most notably the presence of a prominent vasculature throughout the papillary and reticular dermis, with an associated lymphocytic infiltrate (albeit perivascular) in a background of diffuse fibroplasia, and the melanocytic constituents of the lesion can be arranged in such a manner as to appear focally asymmetric. The melanocytes in a Spitz nevus have historically been described as difficult to differentiate from those of malignant melanoma given the degree of cytologic atypia and superficial mitoses (albeit rare in our series) they can typically exhibit. However, the Spitz tumors in the current as well as the published series can be differentiated from regressed melanoma based upon a constellation of reliable features. The clinical presentation of a relatively stable lesion appearing on the extremities of young patients without frank evidence of sun damage favors a benign diagnosis. Histologically, the lesions described here are symmetric, consisting of uniform, large epithelioid melanocytes distributed throughout the lesion as single cells or in small clusters. The melanocytes of an individual characteristic angiomatoid Spitz lesion are essentially devoid of pleomorphism—instead, they are composed of relatively monotonous cells, uniform from side to side at each level of the dermis, and maturation is evident from superficial to deep, typically with dispersion of single cells into the reticular dermis collagen at the base. There is similarly no evidence of a rapid growth rate: mitoses are exceedingly rare to absent, and expanding nodules in the form of large clusters of dermal melanocytes are absent. Furthermore, the inflammatory infiltrate in the majority of the lesions (8/12) was almost exclusively perivascular, rather than the asymmetric, band-like type of inflammatory infiltrate directed towards the melanocytes that would be expected in a regressed melanoma. Finally, the dermal fibrosis within a regressed melanoma is composed of fine, thin bands of collagen, whereas the dermal collagen in angiomatoid Spitz tumors assimilates into large thickened bands in the papillary and reticular dermis. Table 2. Comparison of salient features differentiating regressed melanoma from angiomatoid Spitz nevus Features favoring regressed melanoma Features favoring angiomatoid Spitz nevus Residual melanocytes exhibit significant cytologic atypia and tend to cluster Single/few nevus cells with maturation and devoid of significant pleomorphism Mitoses frequent in residual melanocytes Mitoses rare and when present, superficial Delicate dermal fibroplasia Thick bands of collagen Prominent dermal vasculature and inflammation with marked pigment incontinence and melanophages Prominent thick-walled vasculature is mature and inflammation is peri-vascular, not band-like Unstable, asymmetrical lesion Stable symmetrical lesion on the extremities of young women The pattern of desmoplasia also differs from that in a desmoplastic melanoma, where there are delicate collagen fibers between individual lesional spindle cells, except in more epithelial areas of "combined" (epithelial and spindle cell) tumors [19]. The lesional cells also tend to be different, having narrow elongated cytoplasm and a suggestion of schwannian differentiation (wavy fiber bundles, serpentine nuclei), rather than the plump spindle cells of a Spitz tumor. The reactivity of the spindle cells with Melan A/Mart and HMB-45 would also be unusual, and most desmoplastic melanomas will have an atypical junctional component, usually that of lentigo maligna melanoma in sun-damaged skin of an elderly subject. In cases with subtle lesional spindle cells, the differential diagnosis includes angiomas. The prominent endothelial cells could perhaps give rise to suspicion of angiosarcoma however the vessels in angiomatoid Spitz nevus are mature as discussed above. The presentation as a purple nodule could give rise to suspicion of Kaposi's sarcoma, and in the latter case a negative HHV-8 stain could be reassuring though rarely necessary. In cases with prominent spindle cells and lacking a diagnostic junctional component or pigment, the differential diagnosis is that of dermal spindle cell tumors. A diagnosis of dermatofibroma could be supported by a Factor 13a study, of leiomyoma by SMA and desmin reactivity, or a spindle cell carcinoma by keratin reactivity of the lesional cells. However, any of these diagnoses would be ruled out if the melanocytic markers discussed above are positive. These lesions do not demonstrate schwannian differentiation that might lead to consideration of a neurofibroma. The degree of atypia does not usually suggest an atypical fibroxanthoma. We have also seen at least two lesions, composed almost entirely of usual type nevus cells, which exhibited dermal changes reminiscent of angiomatoid Spitz tumors. Angiomatoid changes similar to those described here are therefore not unique to the angiomatoid Spitz nevus. The polypoid Spitz nevus [14] also demonstrates neovascularization and may overlap morphologically with the angiomatoid Spitz nevus. Other studies have described "angiomatoid" changes in a variant of cellular blue nevus [20], typified by ectatic vessels containing a prominent constituent of red blood cells, and lined by flattened endothelium. These lesions give rise to the notion that angiomatoid changes classically described in angiomatoid Spitz nevus can also be a focal feature of other benign melanocytic processes and in isolation, should not necessarily prompt confusion with either an angiomatoid Spitz tumor or a more aggressive lesion. The mechanism of development of the angiomatoid change has not been studied. One may speculate that the lesional cells, at least during the period of the lesions' initial development, have synthesized angiogenic factors such as Vascular Endothelial Growth Factor (VEGF), Endothelins [21], Fibroblast Growth Factor (bFGF) and IL-8 [22, 23], all known to be overexpressed in melanocytic tumors at least in the context of melanoma. Since these and other like factors may also be responsible for desmoplasia as well as vascular hyperplasia, the constellation of features in these lesions could be explained by this hypothesis, which however would be impossible to rule out completely since early diagnosis of an evolving angiomatoid Spitz tumor is not possible. Acknowledgements to Michael Zsymanski MD for contributing the case used in this presentation, and to Michael Tetzlaff MD PhD for collection of additional cases and literature review. Take Home Messages Participants should be able to discuss: Methods of assessment spindle cell proliferations in the skin Criteria for diagnosis of dermal spindle cell tumors Significance of vascular and desmoplastic stromal responses in a dermal spindle cell tumor References: Spitz S: Melanomas of childhood. Am J Pathol 1948, 24: 591-609 Bastian BC, Olshen AB, LeBoit PE, and Pinkel D: Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol 2003, 163: 1765-1770 Barnhill RL: The Spitzoid lesion: rethinking Spitz tumors, atypical variants, 'Spitzoid melanoma' and risk assessment. Mod Pathol 2006, 19 Suppl 2: S21-S33 Casso EM, Grin-Jorgensen CM, and Grant-Kels JM: Spitz nevi. J Am Acad Dermatol 1992, 27: 901-913 Paniago-Pereira C, Maize JC, and Ackerman AB: Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch Dermatol 1978, 114: 1811-1823 Weedon D and Little JH: Spindle and epithelioid cell nevi in children and adults. 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