Nevus Spitz is a rare type of melanocytic nevi with special clinical and histological manifestations that can occur in childhood. The first report describing a rapidly developing melanocytic tumor on the nose of an 8-month-old boy was published by famous French dermatologists J. Darier and A. Civatte at the beginning of the 20^th century. The authors noted an unusual histological picture similar to skin melanoma and were unable to unambiguously assess the possible malignant potential of the tumor [1]. In subsequent publications the benign course of such formations in children is shown and the term «juvenile (pre-pubertal) melanoma» is proposed which differs from a «normal» tumor with a favorable prognosis [2]. A significant contribution to the description of this nosology and differential diagnosis with melanoma was made by the pathologist S. Spitz; so, in her memory the nevus got its name [3]. Soon, separate reports began to appear about the development of metastatic lesions and death in patients of different ages with Spitz nevus. Cases of such formations with variable histological manifestations and more pronounced structural or cytological atypia have been described [4]. This led to the additional identification of such nosology like «atypical Spitz nevus» and «melanoma with features of the Spitz nevus» [5]. The study of formations’ group with spitzoid characteristics is of great interest today since establishing an accurate diagnosis is a difficult task and diagnostic errors lead to the choice of the wrong treatment tactics and a worsening the prognosis for the patient's life.

A clinically typical Spitz nevus is represented by an asymptomatic single flat or hemispherical formation with clear boundaries [6]. By the nature of staining a «classic» non-pigmented pink nevus (Fig. 1) and pigmented varieties are distinguished. The possible color range varies from light brown to black and in some cases the Spitz nevus may be colored unevenly (Fig. 2) [7]. A number of authors distinguish intensely stained black formations into a separate nosology similar in clinical and histological characteristics — Reed's nevus (Fig. 3) [8]. Its typical localization is the skin of the face, neck and extremities, although it can be located on other areas of the skin [9]. The surface of the formation is smooth in most cases; less often it’s hyperkeratotic or warty. Distinctive features of this nevus are rapid growth within 2 — 3 months and a small size that rarely exceeding 6-8 mm. Nevus Spitz can appear at any age however in 32.8 — 75% of cases it occurs in the age of 20 years [10, 11]. In rare cases the Spitz nevus manifests itself as multiple formations or develops within the congenital melanocytic nevus [12, 13].

Fig. 1. A non-pigmented variety of Spitz nevus with symptoms of clinical atypia — the surface of the formation is ulcerated.

Fig. 2. A pigmented variety of Spitz nevus with an uneven coloration and slight hyperkeratosis on the surface.

Fig. 3. Reed’s nevus with intense and uneven coloration.

The wrong form of the formation is noted.

For a more accurate clinical assessment of melanocytic formations and differential diagnostics with skin melanoma, a non-invasive diagnostic method is used – dermatoscopy [14]. Known variants of the dermatoscopic picture of the Spitz nevus are presented in Table 1 and Fig. 4-7. Most often, there is radial radiance, globular and vascular models of the structure [15]. It is important to emphasize the possible presence in the Spitz nevus of shades of gray and blue that are unusual for melanocytic nevi. The complexity of dermatoscopic diagnostics is due to the described cases of skin melanoma with spitzoid manifestations that mimic the pigmented and non-pigmented variety of Spitz nevus [16, 17].

Table 1. Dermatoscopic variants of the Spitz nevus structure

Fig. 4. Vascular model of the Spitz nevus structure.

There is a uniform distribution of rounded telangiectasias in the form of dots and glomeruli throughout the entire area of formation.

Fig. 5. A homogeneous (structureless) model of the structure of Reed’s nevus, shown in Fig. 3.

On the periphery of the formation the pattern of the pigment network is noted.

Fig. 6. Gradual transformation of the globular structure model into radial radiance with the formation of a blue-white coloration in the central part of the formation.

Follow-up period is 21 months.

Fig. 7. Active growth of the Spitz nevus with a structure model according to the type of radial radiation accompanied by a change in the shape and coloration of the pathological site; the formation of a blue-white coloration in the central part.

Follow-up period is 3.5 months.

Clinical and dermatoscopic signs of Spitz nevus atypia include the nodal morphological element of the formation or its large size (more than 1 cm), the presence of ulceration, an atypical dermatoscopic model of the structure, pronounced vascular polymorphism, blue-white staining and a negative network [18].

On histological examination the classic Spitz nevus has a hemispherical silhouette and is most often a borderline (intra-epidermal) or mixed (epidermal-dermal) formation. In the thickened epidermis the neo-melanocytes are large, elongated or epithelioid in shape, form vertically oriented nests and separated from keratinocytes by light gaps — retraction artifacts (Fig. 8). Melanocyte nuclei can be moderately polymorphic with prominent centrally located eosinophilic nucleoli. The dermal component can be represented by small clusters of epithelioid cells located between collagen fibers or bundles and cords of fusiform cells. It’s typical the detection of nevus nests in the epithelium of the skin appendages, peri-neural growth of the formation and the phenomenon of maturation manifested by a decrease in the size of cells and their nuclei in the dermal component from the outside to the inside. It’s possible to detect the eosinophilic hyaline bodies of Kamino which are the material of basement membranes, pagetoid growth of individual cells or entire nests and mitotic activity in the epidermal and superficial dermal components of the Spitz nevus [19, 20]. Depending on the characteristics of the formation growth and the reaction of the stroma the variants of the Spitz nevus are additionally distinguished; it’s given in Table 2. The histological signs of atypia where differential diagnosis with melanoma is required including the large size of the formation, pronounced polymorphism of the nuclei and nucleoli, lack of maturation, solid structure of the dermal component, ulceration, multiple deep and atypical mitoses [21].

Fig. 8. Typical histological picture of Spitz nevus. The presence of nesting clusters of large melanocytes, separated from the surrounding tissue by retraction artifacts, is noted.

Hyperplasia of the epidermis and pagetoid growth are noteworthy.

Table 2. Rare histological variants of the Spitz nevus structure

In immune-histochemical study the markers cyclin D1, p53, HMB-45 are expressed in Spitz nevi with unequal frequency and usually zonal. The Ki-67 proliferation index should not exceed 15%; nuclear and cytoplasmic expression of the p16 protein in the dermal component is usually noted [22]. At the molecular genetic level the mutations of the HRAS oncogene are most often detected in Spitz nevi and BRAF or NRAS mutations but extremely rarely [23]. In a number of atypical Spitz nevi an additional detection of BAP1 gene mutations or translocation (fusion) of genes of various kinases is possible [24]. For differential diagnosis with skin melanoma in complex cases the method of fluorescence in situ hybridization (FISH) with myb1, CCND1, RREB1 probes and chromosome 6 centromere is recommended [25]. Increased copy numbers of 6p25 and 11q13 as well as homozygous loss of 9p21 are associated with a more aggressive course of atypical Spitz nevi [26].

The tactics of managing the spitzoid formations depends on the clinical manifestations of a particular pigmented lesion and the patient's age. A 2002 survey of 997 US dermatologists showed that the overwhelming majority of physicians (93%) recommend a diagnostic biopsy for Spitz nevus detection [27]. In a similar study the observation of a putative Spitz nevus in children of 7 years old was recommended by no more than 21% of doctors and at the age of 18 years — only 4% [28]. According to the results of a survey of 175 pediatric dermatologists the 49.3% of doctors would recommend dynamic observation of 3 years old children with a small non-pigmented nevus Spitz, 29.7% — for a pigmented nevus with a dermatoscopic model of the structure according to the type of radial radiation in 6-year-old children, only 13% — for a non-pigmented nevus with a diameter of 8 mm in a 16 years old person [29].

When dynamically observing Spitz's nevus it is necessary to remember about the continuing tendency to growth of the formations with a dermatoscopic model of the structure according to the type of radial radiation or with the presence of a peripheral globular component [30, 31]. After the completion of active growth the stabilization phase begins. Its feature is the replacement of the dermatoscopic model of the structure with a homogeneous or reticular one [32]. It has been shown that most formations gradually undergo spontaneous involution in the first two years from the beginning of observation [33]. Control examinations with photo documentation are carried out every 3-6 months depending on the determined dynamics.

All formations with clinical or dermatoscopic signs of atypia, atypical location (in the scalp, genitals, acral areas) as well as rare varieties of Spitz nevus (desmoplastic, verrucous, etc.) are the subject to complete surgical removal [34]. The identification of atypical signs in dynamic observation of a spitcoid formation or a long-term preservation of a tendency towards peripheral growth is considered as negative dynamics and an indication for a diagnostic biopsy. An additional indication for surgical treatment may be the age over 12 years. Despite the low (2 — 4.3%) detection rate of melanoma among spitzoid formations in children the probability of detecting a malignant tumor in patients over 12 years old is estimated at 9.2 — 13.3% [35, 36]. The optimal amount of surgical treatment is the removal of the formation and underlying tissues with an indent of 3—5 mm from the visible edge of the tumor. It has been shown that when removing with a smaller indent the development of relapse is noted in 20% of cases at least. [37].

In order to compare the literature data with the peculiarities of the clinical picture at the present stage we carried out a retrospective analysis of Spitz nevi cases in our practice for 2018–2019. In a general dermatological consultancy the frequency of Spitz nevus detection with a predominance of pigmented formations was 1.8% which coincides with the literature data on the relative rarity of this nosology [38]. During the observation period 27 patients were identified. Among them there were women — 63%, patients under 18 years old — 66.7%, from 18 to 35 — 22.2%, from 35 to 52 — 11.1%. The average age was 14.7 ± 14.5 years, the median was 7. The predominant localization was the skin of the extremities (74.1%); significantly less often Spitz nevi were located on the skin of the trunk (18.5%) and face (7.4%). Dermatoscopic models of the structure were distributed as follows: globular 40.8%, vascular 22.2%, homogeneous and radial radiance — 18.5% each. Detailed clinical and epidemiological characteristics of the identified formations are given in Table 3.

Table 3. Clinical and dermatoscopic characteristics of Spitz nevi from personal practice

The «Observation» group included 14 patients; 7 (50%) of them came for a second consultation. A change in the dermatoscopic model of the structure was observed in 4 out of 5 growing lesions which served as an indication for the removal of Spitz nevi in 2 children and 1 adult patient (see Fig. 6). In 2 cases a change in the staining of the formations to a lighter shade was noted that made it possible to speak of the beginning of a gradual involution of the Spitz nevus.

The «Removal» group includes 13 patients. In 7 (53.8%) cases the reason for removal immediately after the diagnosis was the older patients age, in 3 (23.1%) cases the parents were worried about the active growth of formations in children, in 2 (15.4%) cases the clinical dermatoscopic atypia were noted and in 1 (7.7%) case biopsy was recommended due to a family history of skin melanoma. Comparative characteristics of those taken under observation and removed formations are given in Table 4.

Table 4. Comparative characteristics of clinical and dermatoscopic manifestations of Spitz nevi, recommended for observation and removal at the initial consultation

Note. * — Differences are statistically significant at p<0.05 when comparing the mean values by Student's test (t-test).

Of particular interest are the results of comparing the selected management tactics with the results of existing algorithms for assessing the dermatoscopic picture [39]. The mean values of the dermatoscopic rule ABCD [40] did not have statistically significant differences in the comparison groups and only 3 (23.1%) lesions from the «Removal» group received a score ≥4.8 that allowed considering these lesions presumably malignant.

Taking into account the emergence of reports about the possible use of artificial intelligence for evaluating dermatoscopic images [41, 42] we additionally analyzed the images of Spitz nevi using the Moleanalyzer Pro artificial neural network in the Handyscope 3 application (Fotofinder Systems GmbH, Germany). The lesion was assessed as presumably malignant with a neural network-calculated value of ≥0.5. In the «Removal» group the algorithm also designated 3 (23.1%) formations as malignant, in one case it coincided with the ABCD rule and in 2 cases it marked other formations. Thus, when using the two algorithms together it turned out to be possible to determine the correct tactics for managing the Spitz nevus only in 38.5% of cases.

None of Spitz's non-pigmented nevi including atypical ones have prompted algorithms to speculate about skin melanoma. Taking into account the data on cases of spitzoid melanomas with false negative values of the ABCD rule [43] and the new data obtained, it can be concluded that the considered algorithms do not allow choosing the correct management tactics for patients with Spitz nevi in accordance with modern scientific concepts.

Thus, the Spitz nevus is a complex formation both for establishing a clinical diagnosis and for determining the correct treatment tactics. It must be remembered that the existing methods of clinical diagnostics do not allow an unambiguous differential diagnosis of these formations with skin melanoma. Before deciding to monitor Spitz's nevus it is necessary to discuss with the patient's parents the possibility of frequent visits and the expected changes in education. The peculiarity of dynamic observation of Spitz's nevi is due to the fact that during the initial examination the doctor cannot predict how quickly or how much the manifestations of the formation will change and whether there will be indications for surgical treatment. Our experience shows that the phenomena of clinical dermatoscopic atypia can develop in 3.5-21 months of observation (see Fig. 6, 7) and about 50% of patients do not appear for a follow-up examination. This may explain the frequent recommendations for the removal of the Spitz nevus since clinical diagnosis established.

Conclusion

Strict adherence to the existing protocols for the management of spitzoids and the use of modern molecular genetic studies can significantly facilitate the establishment of the final diagnosis. The task of developing new algorithms for the automated diagnosis of special groups of melanocytic neoplasms including those based on artificial neural networks remains urgent.

This work was supported by the Russian Science Foundation; project No. 19-11-00176.

The authors declare no conflict of interest.