Combined Nevi

Abstract

Combined nevi (CN) are clinically defined as melanocytic lesions comprising two or more distinct melanocytic nevus components, and from the cytological point of view, CN are determined by the presence of two or more different nevus cell types in one biopsy specimen. They are very uncommon and represent less than 1% of all biopsied melanocytic nevi. CN comprise any melanocytic nevi, but the most prevalent combination is CN that consist of blue nevus associated with common melanocytic nevus. CN owe their diversity to combination of different nevi, that are variously combined. Consequently, they can have variable clinical aspects and dermatoscopic features. Because of the presence of at least two distinct subtypes of nevomelanocytes, dermatoscopically CN can show multicomponent, unspecific, and peculiar patterns. Therefore, CN can mimic melanomas, their most important differential clinical, dermatoscopical and histopathological diagnosis.

1. Introduction

Combined nevi (CN) are specific, uncommon type of melanocytic nevi, and they represent less than 1% of all biopsied melanocytic nevi [1, 2]. Clinically, they are defined as melanocytic lesions comprising two or more distinct melanocytic nevus components [3]. From a histopathologic point of view, combined nevi are determined by the presence of two or more different nevus cell types in one biopsy specimen [4]. Based on their clinical and histopathological features, CN represent a subcategory of so-called collision or compound tumors, which are defined by the occurrence of two distinctive neoplastic skin lesions, that collide concurrently within the same specimen [5].

Combined nevi can be comprised by any melanocytic nevi. Although any collision is possible, it is most likely that CN present a combined variant of blue nevus, acquired nevus (Clark nevus), superficial congenital nevus, Spitz nevus or deep penetrating nevus [1]. The most frequent combination that is seen in practice is that of blue nevus associated with common melanocytic nevus and Spitz nevus [4].

2. Clinical features

Combined nevi are mainly congenital, although they are not always visible at birth, but later in life [6]. Although CN could be seen in childhood, as well as at an old age, they are most frequent in young adults (median age reported from 29 to 47) [1, 4, 7, 8]. In early studies of CN, a slight predominance in females was reported [1, 4, 8], with the female: male ratio 1.1:1 [1]. Newer study with larger number of observed CN, has shifted that ratio towards male predominance 0.6:1 [7].

In the view of distribution, the predilection site has not been officially established, but literature data show that this nevus type does most frequently appear on the trunk [1, 4, 7, 8, 9] and head and neck region [7], and it is less common on the extremities [7].

Since CN are composed of distinct nevi, their clinical appearance could be very diverse. In practice, CN are usually small, flat, or minimally raised lesions [1, 7], often characterized by a small blue or black spot (corresponding to the blue nevus component) in the context of a larger area of brown color (corresponding to the common nevus) surrounding the blue nevus part [10] (Figure 1). The latter is known as the targetoid combined blue nevus type [11].

Figure 1.

Combined nevus clinical presentation: Slightly raised, round lesion; small black spot in the center, surrounded by brown area (Targetoid combined blue nevus type).

3. Dermatoscopic features

Since CN are composed of at least two different nevus types in various combinations, their dermatoscopic features are characterized by mostly multicomponent, unspecific, and random patterns. Typically, multicomponent structure of CN exhibit reasonably symmetrical appearance [3, 7] (Figure 2), which is consistent with already established findings that benign nevi tend to exhibit symmetry [12]. This is one of the most distinguishing features when differentiating CN from melanomas, as chaos (asymmetry of structure or colors) is principally imperative of a malignant neoplasm [6, 13].

Figure 2.

Combined nevus dermatoscopy: A. well defined structureless blue area in the center of the lesion, pigmented globules at the periphery; B. ill-defined structureless blue area in the center of the lesion, brown reticular lines at the periphery.

Looking at the color, simultaneous occurrence of different colors (primarily brown and blue, rarely black, and white) is common appearance in CN, where the pigmentation originates from both junctional and dermal portion of the skin [6]. Since blue nevus is the most common component of CN, structureless blue part of the lesion is frequently presented [7], usually covering about 30% of the lesion (Figure 2A and B). Being such a regular finding, structureless blue area is an important element in the dermatoscopic analysis of this nevus type [7], even reported as a hallmark of CN [14]. Both well and ill-defined structureless blue areas (Figure 2A and B) are presented in CN. It is important to remember that the presence of ill-defined structureless blue area in any lesion must always raise suspicion, since it may resemble the “blue veil”, common characteristic of melanomas with the blue part [7].

Regarding the position of the structureless blue areas and their proximity to the edge of the lesion, in the majority of observed cases, these areas do not touch the edge of the lesions (Figure 2A and B) [7]. Diffuse and patchy type of structureless blue areas distribution appears in only less then 10% CN and cannot be considered as a specific feature for this nevus type (Figure 3A and B). Structureless blue area could be presented either eccentrically (Figure 4) or in the central part of CN, whereas central distribution is more common (Figure 2A and B) [7, 9], distinctive for benign lesions and reflects benign nature of these nevi. If located centrally, blue structureless area is surrounded by another pattern, mostly brown clods (Figure 2A), or reticular pattern (Figure 2B), which was previously stated as the stereotypical appearance of CN [15]. Within and around the structureless blue area of CN brown dots may be present [14, 16]. Yet, this cannot be considered as a dermatoscopic clue specific for CN, since it could be found in melanomas as well.

Figure 3.

Combined nevus dermatoscopy: A. diffuse distribution of structureless blue area, structureless brown at the periphery; B. patchy distribution of structureless blue area.

Figure 4.

Combined nevus dermatoscopy: Eccentric structureless blue area, at the edge of the lesion.

Curved lines at the periphery of the lesion can be contemplated as additional specific dermatoscopic features of CN [9, 14]. The other dermatoscopic features like radial circumferential or segmental lines, branched lines, as well as blue and gray clods and dots are not specific for CN [7, 17]. In some cases, when blue nevus is associated with a dermal nevus, gray-blue pigmentation could be distributed irregularly [9].

In cases where CN exhibit chaotic appearance, featuring eccentric structureless, particularly blue area (Figure 4), CN lack clues such as white lines, gray structures, pseudopods/radial lines, thick reticular lines, ulcerations, and polygons which are typical for melanomas [7]. Lesions with multicomponent pattern and eccentric, particularly structureless blue area, lacking specific dermatoscopic features of melanoma do not require excision.

4. Differential diagnosis

Due to their variable nature and different nevus types combined in variety of patterns, clinical and dermoscopic determination of CN could be challenging. For that reason, differential diagnoses may include several benign or malignant neoplasms. Combined nevus may resemble blue nevus, common nevus, Spitz nevus (pigmented type), pigmented spindle cell nevus, plexiform spindle cell nevus, benign vascular tumors, hemosiderotic variant of dermatofibroma, pigmented basal cell carcinoma, cutaneous metastases [6, 9, 18, 19]. Despite this broad similarity to the various skin lesions, CN usually simulate melanoma, which is the most common differential diagnosis. Due to their inconsistent, atypical and irregular clinical and dermatoscopic appearance, CN are frequently misdiagnosed as melanomas [1] and careful histologic examination to exclude melanoma is occasionally required.

5. Histopathology

The term “combined” can be both used in cytological and dermatoscopic context. Histopathological features of CN depend on nevi that are combined within the lesion, and vary depending on the nevi types present.

Histopathologically, there are several types of CN, characterized by the combination of any morphological expression of congenital and/or acquired nevi. Superficial congenital nevus combined with blue nevus, either common or cellular type are most common combination seen in practice. Less frequent are Spitz nevus combined with Clark nevus (“SPARK”), superficial congenital nevi combined with deep penetrating nevus, and blue nevus combined with Spitz nevus (“BLITZ”) [7].

The most common histopathological finding in diagnosis of CN is a compound or dermal nevus with a dermal population of enlarged nevus cells (Figure 5A), either admixed with or overlie pigmented epithelioid and/or spindled melanocytes component in association with melanophages [19] (Figure 5B and C).

Figure 5.

Combined nevus histopathological findings: A. epidermal and dermal nests of common melanocytic nevus, no signs of atypia or mitotic activity: B, C. slender spindle cells and melanophages in the center of the lesion.

In the case of blue nevus, dendritic, cellular blue or deep penetrating nevus are present, with melanin in the deeper dermal portions [1]. Common blue nevus is characterized by elongated, often slightly wavy melanocytes with long, branching dendrites, either grouped together or in bundles in the upper and mid dermis, parallel to the epidermis, with variable numbers of macrophages and increase amount of collagen [1]. Melanocytes could extend into the subcutaneous tissue or approach the epidermis, but they never alter the epidermis structure [1, 19]. In case of cellular blue nevus, deeply pigmented dendritic melanocytes are visible in addition to nests and fascicles of spindle-shaped cells with abundant pale cytoplasm containing little or no melanin. These melanocytes also frequently penetrate the subcutaneous tissue. Some of the cells may appear atypical, with nuclear pleomorphism accompanied by multinucleated giant cells, rare mitoses, and inflammatory infiltrates. In addition to this, overlapping features of common and cellular blue nevi could be seen in some lesions [19].

If Spitz nevus is present, nests of large epithelioid cells, spindle cells or both can be seen, usually extending from the epidermis into the reticular dermis, within hyperplastic epidermis and mononuclear and multinucleate giant epithelioid cells infiltrating dermal collagen. In some observed cases, necrotic cells, mitotic figures and intraepidermal eosinophilic globules were found [19].

6. Management

Better and more uniformed description of clinical and dermatoscopic features of CN, together with improvement in routine differentiation between CN and melanomas can significantly reduce the number of excisions and biopsies performed. Biopsy should still be considered for any suspicious lesion. If distinction from melanoma cannot be clearly made, complete surgical excision is recommended.