and Victor G. Prieto2
Division of Dermatopathology, Miraca Life Sciences, Dallas, TX, USA
MD Anderson Cancer Center, University of Texas, Houston, TX, USA
Common Acquired Melanocytic Nevi
Melanocytic nevi are defined as benign hamartomatous lesions composed of melanocytes. Melanocytes are derived from the neural crest and migrate during embryogenesis to selected ectodermal sites, primarily the skin and the central nervous system, including the eyes and the ears; however, ectopic melanocytes have been found in other organs such as multiple locations of the gastrointestinal tract. Acquired melanocytic nevi commonly form during early childhood and their onset is believed, at least in some cases, to be a response to sun exposure. However genetic factors are also involved in the development of some types of acquired nevi. Melanocytic nevi are biologically stable, benign lesions but in some occasions they can be associated with melanoma. The frequency of transformation of a melanocytic nevus into melanoma varies widely in the literature, with some data suggesting that up to 40 % of melanomas are associated with a precursor nevus.
Melanocytic nevi are more common lesions in patients with light skin. As mentioned above, some melanocytic nevi are likely stimulated by exposure to sunlight; thus, individuals with dark skin might have fewer nevi because of the protective properties of melanin. There is no clear sex predilection for the development of nevi; however, melanocytes have shown to exhibit some degree of sex hormone responsiveness and the fact that nevi may enlarge and darken during pregnancy supports this relationship with gender.
Common acquired nevi are usually smaller than 1 cm in diameter and evenly pigmented. They are most commonly tan to brown, but coloration can be variable, ranging from skin colored to black. It is believed that some acquired nevi tend to follow an orderly process of progression from junctional to compound nevus and then intradermal nevus and gradual involution. Nonetheless, at any of these stages, the nevus may arrest its growth.
Junctional nevi tend to be macular and uniformly pigmented, dark brown to black, but minor degrees of color variegation are not uncommon, especially if they have a lentiginous component. Junctional nevi are typical in young patients but can be seen at any age; however, they clearly decrease with age and thus, in old patients, melanoma should always be considered in the differential diagnosis of junctional melanocytic lesions. Compound nevi are elevated relative to the surrounding uninvolved skin. Compound nevi are often lighter in color than junctional nevi, but those that have been recently irritated may show areas of dark pigmentation. Intradermal nevi are often elevated and since they lose most of their pigmentation, they usually appear as skin-colored papules. Nonetheless, it should be emphasized that there is clinical overlap among these three categories of nevi. Additionally, the development of a new area of hyperpigmentation within a long-standing compound or intradermal melanocytic nevus should be taken as a red flag for the possibility of development of melanoma. Although these hyperpigmented areas could be due to incidental inflammation or recent trauma, the possibility of melanoma should be always considered.
Histologic Features of Melanocytes in Common Acquired Melanocytic Nevi
Nevi have three types of melanocytes: type A, type B, and type C. Type A melanocytes tend to show an epithelioid configuration with uniformly dispersed chromatin with a ground-glass basophilic appearance and delicate nuclear membranes. Nucleoli can be noted, however, as usually small in size. Some of these type A melanocytes can be pigmented, and when present the pigment is evenly distributed in the cytoplasm. Type B melanocytes tend to be arranged in compact cords and small nests. These melanocytes are round and nonpigmented, with a round nucleus and inconspicuous nucleoli. The cytoplasm is small and the histomorphology of these melanocytes is reminiscent of lymphocytes. Type C melanocytes have spindle cell configuration begriff with fibrillary elongate cytoplasmic processes that are reminiscent of a Schwann cell. These melanocytes lack nuclear pleomorphism and show only small, inconspicuous nucleoli. Melanocytes in the dermis show maturation; this implies a change of morphology from the epidermis to the deeper dermis, i.e., diminished size of those melanocytes in deeper aspects of the lesion and change from epithelioid to spindle, i.e., A to C. This change has been identified as similar to the changes from neurons to Schwann cells (“schwannian metaplasia”). However, one needs to be aware of the fact that schwannian maturation is not only seen in benign lesions but can also be present in melanoma, so-called pseudo-maturation .
Histology of Junctional Melanocytic Nevi
This type of nevus refers to restriction of melanocytes almost exclusively located within the epidermis. These intraepidermal melanocytes are present in single cells or forming nests. The proliferation of single junctional melanocytes is present at the basal layer of the epidermis, usually at the tips of rete ridges. The junctional nests aggregate more frequently in the tips and the basilar region of the rete ridges. These nests are uniform in size and evenly distributed with variable degrees of pigmentation (when present the pigment is fine and uniformly distributed in the cytoplasm). Within the nests, melanocytes are cohesive, homogeneous, and surrounded by a clear space. The cells tend to have ample cytoplasm with small dendrites and round nucleus, with delicate nuclear margins and small amphophilic nucleoli. Melanocytes within the nests have similar size and shape and tend to have either type A or B morphologies . The dermal stroma underneath a junctional nevus may show scattered melanophages, but it is usually identical to that seen in the uninvolved skin.
Histology of Compound Melanocytic Nevi
Compound melanocytic nevi contain melanocytes in both the epidermis and dermis. The proliferation of melanocytes in the junctional component in compound nevi is the same as seen in junctional nevi; thus, melanocytes are distributed either in nests or single cells. The junctional component usually does not extend at the lateral edges beyond the nested component; however, some nevi with lentiginous pattern (i.e., single cells along the rete ridges) may extend beyond the nested component. The intradermal component in the papillary and reticular dermis has nests and cords of melanocytes, sometimes arranged in a coalescent, band-like pattern. Nonetheless, these nests are equidistant rather than forming expansile nodules; thus, when large and confluent nests are seen in the dermis, this finding should raise suspicion for melanoma, similarly if nests at the deep aspect of the lesion are larger than the ones superficially. The majority of acquired compound nevi do not extend beyond the papillary-reticular dermis junction. The exception is nevi on the head and neck, since they commonly extend around hair follicles and in reticular dermis mimicking the pattern seen in congenital nevi. As mentioned above there is a change in morphology with depth. The melanocytes in superficial dermis show a similar morphology as those seen in the junctional component, i.e., epithelioid cells with round nuclei and abundant cytoplasm with variable pigmentation; single nucleoli can be seen in the center of the nuclei (type A melanocytes). The melanocytes deeper in the lesion are smaller and with minimal cytoplasm (type B melanocytes) or can be spindle with schwannian differentiation (type C melanocytes).
The stroma in the dermis is composed of collagen fibers arranged among single melanocytes and small nests. Large, irregular, and confluent sheets of melanocytes in the dermis without the presence of interposed collagen in between them are not a characteristic feature of a common nevus and should raise suspicion for melanoma. As described above, most nevi show maturation as characterized by the presence of progressive reduction of the size of melanocytes as well as by the decrease in size of the intradermal nests in the deeper aspects of the lesion. Also, the cells adopt spindle cell morphology and there is decreased pigmentation at the base of the lesion.
Histology of Intradermal Melanocytic Nevi
In this type of nevus, the melanocytes are almost exclusively confined to the dermis, as there are no or very few melanocytes in the overlying epidermis. The dermal component of a compound nevus is identical to the dermal component seen in an intradermal nevus (see above). Thus, these lesions show the normal maturation pattern as described above.
The diagnosis of a junctional nevus is most of the times straightforward; however, there are some occasions in which the single-cell component (lentiginous growth) predominates, and the distinction with melanoma in situ can be a difficult one, especially in limited tissue samples. There are certain histologic features that will favor a diagnosis of melanoma such as the presence of irregularly distributed nests, large size, and irregular distribution of melanin pigment. The presence of pagetoid upward migration should be carefully inspected and only accepted when nevi are localized in special sites (genital areas, acral sites) or when there has been previous trauma. Furthermore, melanoma pagetoid upward migration, if present, is usually seen beyond the dermal nests at the periphery of the lesion. In small biopsies, sometimes immunohistochemical studies may be helpful to highlight the degree of single-cell proliferation above the basal layer and beyond the dermal component. We prefer MITF-1 over MART-1, since the former provides a nuclear pattern. Also, MART-1 may label some pigmented keratinocytes, thus giving a false-positive reaction. In general, mitotic figures seen in the junctional component are not a criterion for a diagnosis of melanoma; however, if these mitotic figures are atypical or numerous, such finding should be considered a red flag. The age of the patient is also very important to take into account as melanoma in situ in young patients is exceedingly rare. Junctional nevi in older patients with severe actinic damage should always be carefully inspected as may represent part of a melanoma in situ.
Junctional nevus. Note the symmetrical elongation of rete ridges and the similar size of nests located in the epidermis (a). There is no evident dermal component, fibrosis, inflammation, or vascular proliferation (features of dysplastic nevi). Uniformly sized intraepidermal nests (b).Fig. 3.1 (continued) Only rare melanophages in the dermis without significant fibrosis (main difference with dysplastic nevus) and lack of pagetoid upward migration (c)
Hypermelanotic lentiginous junctional nevus. This example is irritated and pigmented. Note the symmetry and the small size of the lesion, as well as the marked pigmentation of the epidermis (especially the stratum corneum) (a). Higher magnification showing single cells melanocytes located lower in the epidermis with minimal pagetoid upward migration. The marked amount of melanin in the stratum corneum is consistent with a prior trauma (b)
Compound nevus. The lesion is symmetric and with normal maturation (decrease in size of nests with depth in the dermis) (a). Higher magnification showing small nests of melanocytes lacking cytologic atypia (b)
Lentiginous compound nevus: Note symmetry of the lesion with regular elongation of rete ridges
Compound nevus. Wedge-shaped lesion with uniform elongation of the rete ridges (a). Maturation pattern with decreased pigmentation and size of nests with depth (b)
Intradermal nevus. Note the lack of a visible junctional component and the large intradermal component extending well into the reticular dermis (a). Higher magnification showing small, uniform melanocytes with delicate, intervening stroma (b)
Intradermal nevus. Note the melanocytes surrounding the adnexal structures, consistent with a congenital onset (a). There are signs of chronic irritation such as the presence of fibrosis in superficial dermis (arrow) (b). The cells are epithelioid (type A melanocytes) and with uniform nuclei without cytologic atypia (c)
Nevus with congenital features. This is an intradermal nevus with a congenital pattern that includes melanocytes surrounding the adnexal structures and arrector pili muscle (a). Upper portion with nests of small melanocytes (b).Fig. 3.8 (continued) Involvement of the arrector pili muscles (c). Periadnexal arrangement of melanocytes (d)
Melanocytic Nevi Variants
Unna Melanocytic Nevi
These nevi are more commonly seen on the neck, extremities, and trunk, with some predisposition in the flexural areas, thus similar to skin tags [2, 3]. These nevi have a characteristic exophytic and pedunculated architecture and present as a dark papule that sometimes shows an umbilicated appearance. Unna nevus is a predominantly intradermal melanocytic nevus that is mainly exophytic and wholly adventitial; thus, all melanocytes are located within an expanded papillary dermis and frequently within perifollicular adventitial dermis. Histologically, these nevi can be either compound or intradermal. The overlying epidermis tends to be flat; however, in some occasions it is papillated simulating a seborrheic keratosis. The melanocytes in dermis mostly occupy the papillary dermis and tend to wrap the perifollicular adventitial dermis while sparing the reticular dermis. The nevus cells aggregate in dermis to form radial nests, resembling the sticks of a fan . This configuration is more frequently noted on the periphery of the lesion. Another characteristic feature of Unna nevi is the presence of pseudovascular spaces lined by nevus cells. The melanocytes mature following the pattern above described showing lymphocyte-like melanocytes in the reticular dermis (type B) and spindle cell melanocytes toward the deeper portion of the lesion (type C). Mitotic figures in the Unna nevus are very rare, and when seen they are isolated. Although exceptional there may be a rare, deeply located mitotic figure. The junctional component when present is sparse; however, in some cases the junctional component can show asymmetric growth mimicking a melanoma. However, it should not extend beyond the dermal component. Rare cases of melanoma have arisen in the junctional component of an Unna nevus.
Miescher Melanocytic Nevi
Miescher nevus presents clinically as a dome-shaped papule with light brown color mostly found on the face and neck [2, 3]. Histologically, Miescher nevus is a predominantly intradermal melanocytic lesion with a smooth, slightly convex to semispherical surface and intradermal nevus cells infiltrating diffusely both the adventitial and the reticular dermis in a V-shaped (wedge) pattern. These nevi are mostly intradermal (few nests can be seen in epidermis). The melanocytes in the dermis form small nests in the upper part of the lesion and toward the base form cords separated by collagen bundles. In Miescher nevi, nevus cells almost never aggregate in radial nests, and pseudovascular spaces are present only exceptionally, as opposed to Unna nevi. Multinucleated melanocytes and adipocytes in between nevus cells are frequent and much more commonly seen than in Unna nevi. Cytologically melanocytes in dermis are banal appearing; however, some cases may show mild cytologic atypia possibly related to senescence or to actinic damage. As long as there is no expansile growth in the dermis, these changes should not be interpreted as nevoid melanoma. Also, melanocytes in Miescher nevus have an indistinct nucleoli as opposed to nevoid melanoma in which melanocytes have prominent nucleoli (sometime can show multiple nucleoli). Dermal mitotic figures are exceedingly rare. Large, dilated follicular structures and/or follicular cysts are not an uncommon finding in this type of nevus. In some cases, these follicular cysts can rupture and develop a granulomatous reaction. When the junctional component is noted, it is usually mildly cellular with a lentiginous pattern and only rare small nests; however, in some cases these junctional melanocytes can be asymmetrically arranged and melanocytes can have a large in size with epithelioid morphology. These large, isolated melanocytes in the epidermal basal layer are more commonly seen in Miescher nevi than Unna nevi. In such cases, this atypical junctional component does not extend lateral to the dermal component. It is important to be aware of this possible finding so it is not misinterpreted as melanoma in situ.
Meyerson Melanocytic Nevi
Meyerson nevus is generally caused by an eczematization of the center and/or the periphery of a melanocytic nevus [4–7]. This nevus is mostly found in male young adults (only rarely seen in children) and is more commonly located on the trunk or proximal extremities, although it can present on virtually any location of the skin. Clinically, it presents as a symmetrical area of erythema encircling a central melanocytic nevus. The phenomenon spontaneously resolves in months, although the nevus usually persists. Sometimes, Meyerson nevus can progress to a standard halo nevus or vice versa [8, 9]. In most cases, Meyerson nevi represent an isolated event; however, in some cases they can be associated with atopic dermatitis . Meyerson phenomenon has been associated with congenital or acquired nevi, dysplastic nevi, and other cutaneous non-melanocytic lesions, such as seborrheic keratoses, basal cell carcinomas, squamous cell carcinomas, etc. [11–13]. Histologically, beyond the standard nevus, the adjacent epidermis shows spongiosis, acanthosis, and parakeratosis, and depending on the stage of the eczematous component, there may be frank vesiculation (acute phase). In the dermis, there is a superficial perivascular lymphohistiocytic infiltrate, and in some cases, there is eosinophilia. Of note, the lymphocytic infiltrate in Meyerson nevi is mainly CD4+ T cells, with a small population of CD8+ T cells, as opposed to the inflammatory reaction seen in halo nevi, which are predominantly CD8+ T cells [13, 14].
Cockarde Melanocytic Nevi
Cockarde nevus , also known as speckled lentiginous nevus, is a rare, benign, acquired targetoid nevus characterized by a distinct variegated pattern of pigmentation (compound nevus bordered by a junctional nevus) [7, 15–17]. Cockarde nevus is most commonly seen in children and young adults and the most common location is the trunk. Clinically, it presents as a central, dark papule with an intervening, nonpigmented zone and peripheral stippled pigmented papules arranged in a circle . Histologically, the central area is usually a junctional or compound nevus, and the periphery is composed of junctional theques with variable pigmentation. The periphery of the lesion may show pigmented melanophages in the superficial dermis.
Spilus Melanocytic Nevi
Nevus spilus it is a benign, large, lightly brown, pigmented macular lesion that usually presents at birth or in infancy, although it can appear at any age. This nevus commonly appears as a solitary lesion made of multiple pigmented macules, or papules, within a lightly pigmented macular background [7, 19]. It commonly progresses to more noticeable red-brown macules and papules over the years. This nevus can occur anywhere on the body, although it is more common on the trunk and extremities. The risk of melanoma seems to be higher in congenital cases and in cases where the lesions have a large diameter [20, 21]. Histologically, the background of the lesion shows mild pigmentation of the basal layer similar to a lentigo simplex, but in some cases, there may be slightly increased melanocytes or even frank nests. The darker speckled areas show either a junctional or a compound nevus. There are cases of nevus spilus with a blue or Spitz nevus component [22–24].
Inverted Type A Melanocytic Nevi (Clonal Nevi)
Inverted type A nevus is a variant of melanocytic nevus that histologically exhibits a localized proliferation of pigmented, epithelioid, dermal melanocytes within an otherwise ordinary nevus [25, 26]. It most commonly affects young adults and is more commonly located on the head and neck but can be seen at any anatomic site. This type of nevus can be either dermal or compound and shows no cytologic atypia or architectural changes. The pattern is that of a banal nevus admixed with the “clonal” cells. These clonal cells are located near the horizontal center of the nevus, arranged in nests, strands, and cords. Characteristically, these cells are large epithelioid pigmented melanocytes that are associated with occasional melanophages [27, 28]. The nuclei are usually small or slightly enlarged (severe cytologic atypia is not a feature). Mitotic figures are rarely present.
“Ancient” Melanocytic Nevi
This term was coined by Kerl et al. to describe a simulator of melanoma [7, 29, 30]. The designation “ancient” was chosen because of histopathologic similarities with ancient schwannoma. Recently, the term “pleomorphic melanocytic nevus with degenerative changes” has been used to delineate these nevi. Ancient nevi are found most commonly on the face, especially the cheek or ear, in middle-aged and older patients. Other sites include the trunk and extremities. These nevi are usually dome shaped, either skin-colored or reddish-brown papule.
Histologically, ancient nevi are well circumscribed, are exoendophytic, and involve most or all of the dermis. These lesions tend to lack a junctional component. In the dermis there are two populations of melanocytes, one with large pleomorphic nuclei and the other with small monomorphous ones. The large melanocytes are epithelioid or spindled and tend to be arranged in nests and sheets, cytologically reminiscent of the cells of a Spitz nevus; their nuclei are pleomorphic and hyperchromatic with sometimes prominent nucleoli; their cytoplasm tends to be abundant. The smaller melanocytes may be arranged in a congenital pattern and are situated above, underneath, or at the lateral margins of where the larger melanocytes are situated. These smaller melanocytes have scant cytoplasm. If any mitotic figure is identified, they usually are in the superficial portion of the large cell component. In addition, there are other senescent changes that include degenerative stromal changes, including thrombi, hemorrhage, pseudoangiomatous spaces, perivascular rims of sclerosis (hyaline rings), edema, and mucin .
Differential Diagnosis: Ancient nevus can be misdiagnosed as dermal melanoma. The distinction from melanoma should be based on the presence of only rare atypical melanocytes restricted to one area of the lesion. Also, the architecture in ancient nevus is not affected by the presence of these atypical melanocytes, which do not conglomerate in solid nests, pushing outward the small cell population, as happens in melanomas arising in nevi. Also, melanoma lacks the presence of degenerative stromal changes, which is a clue to the diagnosis of ancient nevus. In summary, dermal melanoma shows marked cytologic atypia of melanocytes, frequent mitotic figures, absence of degenerative changes (only the presence of necrosis), and large nodules and sheets of atypical melanocytes. It is unknown the relationship between ancient nevi and BAP1-deficient nevi (see also below).
Ancient melanocytic nevi vs. dermal melanoma
• Degenerative stromal changes, such as the presence of a vascular component, are a diagnostic clue of ancient nevus. Melanoma usually does not display degenerative changes
• Two populations of melanocytes are characteristically observed in ancient nevus (large- and small-sized melanocytes)
• In melanoma, the atypical melanocytes are arranged in expansile, large nodules and sheets
• Rare mitotic figures in dermis in ancient nevus. Melanoma usually shows frequent mitotic figures
Balloon Cell Melanocytic Nevi
Balloon cell nevus is a rare variant that is characterized histologically by a predominance or complete occurrence of large, vesicular, clear cells, known as balloon cells [31, 32]. The most common site appears to be the head and neck area, followed by the trunk and extremities, and most commonly under the age of 30. Clinically, these nevi do not have any specific features but are generally asymptomatic, are brown in color, and may appear as a smooth papule [31, 33–35]. Histologically, they can be either compound or intradermal. By definition, the balloon cell component involves more than 50 % of the lesion in balloon cell nevi; however, focal balloon cell change (balloon cell melanocytes in <50 % of the lesion) can be seen in any benign and malignant melanocytic lesions [32, 36–39]. The classic pattern is that of balloon cells admixed with ordinary melanocytes. Balloon cell nevus is composed of melanocytes that have ample cytoplasm which is finely vacuolated and have small hyperchromatic wrinkled nuclei with scalloped contour. Sometimes these balloon cell melanocytes can have scarce melanin pigment. While the majority of these balloon melanocytes are seen in the intradermal component, in some occasions they may be seen in the dermal-epidermal junction. Within the dermal component, these balloon cell melanocytes merge with the type A, type B, and type C melanocytes . In only rare occasions, balloon cell nevi are composed solely of balloon cell melanocytes without the presence of more typical melanocytes. Multinucleated melanocytes with balloon cell change may be seen. Maturation is seen as in ordinary acquired nevi.
Differential Diagnosis: The main differential diagnosis of balloon cell nevus is with balloon cell melanoma. Balloon cell melanoma displays melanocytes with nuclear pleomorphism (irregular distributed chromatin) and prominent nucleoli throughout the neoplasm . In balloon cell nevi, the melanocytes appear rather small and monomorphous. Also, mitotic figures are virtually absent in balloon cell nevus, thus any mitotic figure should alert the possibility of melanoma. Clinically, balloon cell nevus is usually seen in younger patients, whereas melanomas are more common in older patients.
Neurotized Melanocytic Nevi
Neurotized nevus refers to a nevus which histologically is composed of spindle-shaped melanocytes arranged in cords or fascicles resembling neuroid structures in the dermis which reportedly represent the end of development of an intradermal nevus [41–43]. The predominant melanocytic type in neurotized nevus is the type C, which in some occasions may organize into neuroidal structures resembling Meissner corpuscles. Schwannian and perineurial differentiation may be identified. This nevus in some occasions may look very similar to a neurofibroma, although it usually preserves a few nests of melanocytes in the papillary dermis. Neurotization can also be observed at the base of many other melanocytic neoplasms including Unna nevus, congenital nevus , and even melanomas (especially desmoplastic type).
Melanocytic Nevi with Adipose Metaplasia
Nevus with mature adipose tissue is a common histologic change related to senescence. The etiology is likely to be multifactorial. In addition to advancing age, the degree of body fat may contribute to the pathogenesis of these lesions. Clinically, these nevi are most commonly located in the head and neck area and resemble a skin tag [42, 44, 45]. It may occur in all age groups; however, they are observed most commonly in middle-aged persons (>50 years of age). Histologically, nearly 90 % are intradermal nevi.
Melanocytic Nevi with Pseudovascular Spaces
Melanocytic nevus may be histologically associated with clefts or slits of nests, resembling lymphatic or vascular spaces (pseudovascular spaces). This unique histologic feature might be due to an artifact during tissue processing or perhaps it is an involutional event [46–48]. The pseudovascular spaces may resemble lymphatic invasion of melanoma; however, one can easily make a distinction by identifying the regular contour and the presence of flattened endothelial cells in real vascular spaces, while the cells lining the pseudovascular spaces are similar in morphology to the adjacent melanocytes. Most nevi with pseudovascular spaces are intradermal or congenital; this phenomenon has not been identified in cases of dysplastic nevi, Spitz nevi, or melanoma. An important point to remember is that melanocytes can be identified within the dermal lymphatics in a nevus, and this should not be interpreted as melanoma.
Melanocytic Nevi with Dermal Mitotic Figures
The presence of dermal mitotic figures is an important diagnostic criterion for differentiating melanoma from melanocytic nevi. However, mitotic activity can be identified in some examples of benign intradermal or compound melanocytic nevi [48–52]. While the presence of dermal mitotic figures in a nevus should alert the pathologist to the possibility of melanoma, it is important to be aware that they can be identified in histologically and clinically banal-appearing nevi . In these nevi the cytology and the architecture of the lesion are identical to standard melanocytic nevi, and there are no changes that indicate the histologic diagnosis of melanoma.
In a recent study, authors revealed that up to 8 % of benign melanocytic nevi had one or more mitotic figures. In this study the great majority of mitotically active nevi contained a single mitotic figure (>80 % of cases); however, some cases contained more than one mitotic figure, highlighting the potential for multiple mitotic figures in otherwise banal lesions . An important point to remember is that nevi exhibiting mitotic figures are significantly more frequent in the youngest age group (0–20 years) than in patients older than 50 years . Polypoid or verrucous configuration of the nevus and signs of traumatization are associated with higher mitotic activity [49, 54, 55]. When mitotic figures are present, they are located usually in superficial dermis, but in cases where multiple mitotic figures are seen within a single nevus, they are usually distributed far from one another and in some cases even distributed in the deeper parts of the lesion but never forming clusters [49–52]. The most common nevus type that is more commonly to show mitotic activity cases is a compound nevus. Some studies have found the highest incidence in special sites, including the genitals, perineum, groin, and acral regions. Some other studies have shown that most nevi with mitotic activity are located on the head and neck . In addition, exposure to ultraviolet radiation has been shown to increase proliferative activity in nevi, which may explain the increased incidence of mitotic figures in sun-exposed areas, such as the head and neck . Nevi in pregnancy may show an increase number of mitotic figures and modest ki-67 proliferation index .
It is very important to identify where the mitotic figures are located, as some of them may actually correspond to inflammatory cells. Some studies had recommended to try to separate those proliferating cells by using immunohistochemistry studies, including dual anti-Ki-67/MART-1 or mitotic markers phosphohistone H3 (PHH3) and MPM2 [49, 59]. This particular study  identified that mitotic figures in inflammatory cells were present in 35.4 % of the PHH3 and 42.2 % of the MPM2-stained sections, respectively. Mitotic figures were more frequently identified in heavily inflamed lesions in which proliferative active melanocytes and inflammatory cells were intermixed and could hardly be distinguished from each other concluding that the number of mitotic figures in melanocytes may be overestimated by the application of immunohistochemistry. In our experience, immunohistochemistry studies to detect mitotic figures are usually not needed for the diagnosis of banal melanocytic nevi; however, mitotic markers may be a very helpful ancillary tool for the evaluation of suspected nevoid melanomas, spitzoid melanocytic neoplasms, and cellular blue nevi as they give an overall impression of the distribution and the degree of proliferation and approximate number of mitotic figures at a low magnification. In heavily pigmented melanocytic lesions, mitotic figures can be easily overlooked on H&E stain but are well identifiable by immunohistochemistry.
Melanocytic nevi with mitotic figures vs. melanoma
• Melanocytic nevi with mitotic figures are more commonly seen in young patients
• Polypoid or verrucous architecture and signs of trauma are associated with higher mitotic activity
• Mitotic figures in banal melanocytic nevi are never atypical or clustered together; this finding is very supportive of a diagnosis of melanoma
• The distribution of dermal mitotic figures in melanoma is highly heterogeneous. In nevi, mitotic figures are evenly distributed
Traumatized Melanocytic Nevi
Melanocytic nevi when they are traumatized undergo changes in their clinical appearance and can clinically mimic atypical melanocytic lesions and in some cases even melanoma. This phenomenon causes clinical concern because a small percentage of nevi with such clinical features (e.g., ulceration or bleeding) show an associated melanoma.
Although one of the most useful histologic features in making a diagnosis of melanoma is the presence of pagetoid upward migration of melanocytic cells, such phenomenon is not specific to melanoma and can be seen in Spitz nevi, congenital nevi, recurrent nevi, acral nevi, and genital nevi [60, 61]. In traumatized nevi, the melanocytes underneath the ulcer can show pagetoid upward migration, mild cytologic atypia, and focal confluent growth pattern. In fact, one study found that up to 20 % of nonsurgical traumatized nevi can show pagetoid upward migration , but that should be limited to the area of trauma (parakeratosis, irregular flattening of the epidermis). The presence of ulceration is another histologic feature that is commonly seen in traumatized nevi and can easily raise concern for malignancy.
Histologically, traumatized nevi show evidence of trauma including ulceration, parakeratosis, presence of melanin within the stratum corneum, hemorrhage, dermal inflammation, granulation tissue in the dermis, and, depending on the stage of the lesion, dermal fibrosis. Pagetoid upward migration can be observed and is usually limited to the site of trauma. In addition, traumatized nevi with pagetoid spread can be separated from melanoma based on the cytologic features of the cells and knowledge of the clinical scenario including age and anatomic site. The presence of dermal mitotic figures can be identified in traumatized nevi, but the presence of more than one or two mitotic figures in the entire lesion should be a red flag for melanoma . Atypical melanocytes are usually absent but when noted are located in superficial dermis and are entrapped in the fibrotic dermis. Thus, in our opinion, caution should be used when purported traumatized nevi display significant cytologic atypia, marked pagetoid spread (lateral to the traumatized epidermis), or atypical dermal mitotic figures.
One study showed that while aberrant HMB-45 labeling (i.e., absence of maturation) is observed in the region of trauma in cases of late traumatized nevi, the overall assessment of the lesions shows both histologic and immunohistochemical maturation . In this same study, authors showed that low MIB-1 labeling (<5 %) in traumatized nevi is an additional reassuring finding as higher MIB-1 immunoreactivity is usually seen in melanoma.
Traumatized melanocytic nevi vs. melanoma
• In ulcerated melanocytic lesions, it is always advised to inspect the adjacent non-ulcerated epidermis for signs of melanoma
• Pagetoid spread in traumatized nevi is usually seen underneath the area of trauma; pagetoid spread seen lateral to the area of trauma is usually indicative of melanoma
• In traumatized nevi, dermal mitotic figures are not uncommonly identified. These dermal mitotic figures are not clustered or atypical
• In traumatized nevi, melanocytic atypia when seen is usually mild
Predominantly intradermal exophytic nevus (Unna nevus). Note the exophytic and pedunculated architecture of this nevus
Unna nevus. Another classic example showing polypoid architecture (a). Note the interstitial disposition of the small melanocytes leaving collagen fibers among them (maturation) (b)
Predominantly intradermal endophytic (Miescher) nevus: note the V-shaped infiltrate of melanocytes in dermis (a). Miescher nevus: note the small melanocytic nests in the upper part of the lesion (b)
Predominantly intradermal endophytic (Miescher) nevus: another example showing the wedge-shaped arrangement in the dermis
Inflamed (Meyerson) compound nevus. Note this compound nevus with marked epidermal spongiosis along with perivascular lymphohistiocytic infiltrate (a). The associated lymphocytic infiltrate may result in focal, mild cytologic atypia (hyperchromasia and pleomorphism of melanocytes) (b).Fig. 3.13 (continued) Lymphocytic infiltrate and focal cytologic atypia of melanocytes. Note the absence of significant pagetoid migration (c). Lymphocytic infiltrate and focal cytologic atypia of melanocytes (d)
Compound nevus (Speckled/spilus). Note a few intradermal nests alternating with areas of hyperpigmentation in the epidermis (a). Elongation and hyperpigmentation of some of the rete ridges. Scattered, small dermal nests (b).Fig. 3.14 (continued) Small intradermal nests with minimal junctional component (c). Subtle junctional component with small melanocytes in a lentiginous pattern (d).Fig. 3.14 (continued) Small junctional melanocytes, mostly as single cells but with occasional nests (e)
“Ancient” nevus. Large intradermal lesion with two distinct areas. Top with small nests of melanocytes (standard intradermal nevus) and a large area in the center with hyper- and hypocellular areas and small clusters of melanin (a).Fig. 3.15 (continued) Standard intradermal nevus on the top (arrow) and ancient area (arrow head) underneath (b). Standard intradermal nevus in the upper dermis (c).Fig. 3.15 (continued) Area with edematous stroma, dilated vessels, and epithelioid melanocytes with focal melanin pigment (d)
Another example of “Ancient nevus”. Predominantly intradermal nevus with a congenital pattern (deep infiltration with arrangement around skin adnexa) (a). Note the standard intradermal nevus with small melanocytes to the right and the dermal nodule to the left with a few dilated vessels (b).Fig. 3.16 (continued) Note the contrast between the standard nevus cells (to the right) and the large, epithelioid cells in the nodule to the left with a few thick vessels (c). Large, epithelioid cells in the nodular area. Although they are cytologically atypia, the type of nuclei resembles those seen in “ancient” schwannomas. Mitotic figures are not evident (d).Fig. 3.16 (continued) A double immunostudy with anti-MART1 (red) and anti-Ki67 (brown) shows minimal proliferation in the dermis, supporting the diagnosis of nevus (e)
Nevus with bone metaplasia. Note the ruptured follicle with adjacent mature bone formation (a–c)
Nevus with bone metaplasia. This particular case also shows a congenital nevus
Balloon cell nevus. Intradermal melanocytic lesion composed of melanocytes that have ample cytoplasm (a). Melanocytes with ample cytoplasm admixed with pigmented melanophages (b).Fig. 3.19 (continued) Deeply located dermal melanocytes with interspersed melanin pigment (c). Junctional component with vacuolated melanocytes (corresponding to markedly dilated melanosomes) (d)
Nevus with ruptured folliculitis. Such situation may be interpreted as a “changing” nevus and thus may raise the clinical suspicion of melanoma arising in a nevus
Nevus with ruptured folliculitis. Note the nevus cells surrounding the inflamed hair follicle. The patient possibly pulled a hair from the nevus (a). Higher power view of the distorted hair follicle (b)
Neurotized nevus. Intradermal nevus with neuroid-like structures (a). Note the type C melanocytes arranged in neuroidal structures (b).Fig. 3.22 (continued) High power of the neuroidal structures (c). Meissner-like corpuscles (d)
Nevus with lipomatous metaplasia (a). Note the adipocytes arranged within the lesion (b)
Nevus with lipomatous metaplasia. This is the face of a 32-year-old male with an intradermal nevus with congenital pattern. Note the numerous adipocytes at all levels of the lesion (a, b)
Intradermal nevus with pseudovascular spaces (a). Clefts within the melanocytic nests, resembling vascular spaces (pseudovascular spaces) (b)
Melanocytic nevus with pseudovascular spaces. These spaces are lined by melanocytes and not by endothelial cells (hence the term “pseudovascular”) (a, b)
Predominantly intradermal nevus with mitotic figures. This otherwise standard nevus shows rare mitotic figures in the upper half of the lesion (a). Some of these patients may have hormonal changes (e.g., pregnancy) resulting in this histologic feature (b). High-power view of the mitotic figures (c)
Combined Melanocytic Nevi
Combined melanocytic nevi are composed of two or more distinct melanocytic populations in a single lesion. The constituent components may include any combination of benign acquired nevi (with or without dysplasia) or congenital nevi with blue nevus, cellular blue nevus, or Spitz nevus [64, 65]. It is not clear whether combined nevi represent the coexistence of two discrete nevus cell populations or whether they reflect divergent terminal differentiation of a single-cell population. Combined nevi may occur at any age but are most commonly observed in children and young adults and slightly more common in women than in men . The most common type of combined nevus is a blue nevus and a nevus with an intradermal component which is histologically readily identified as a standard benign nevus. In contrast, those tumors with deeply pigmented or Spitz nevus elements often have atypical features; thus, it is very important to distinguish these lesions from melanoma.
Clinically, combined nevi present as small, dark, papules with regular, well-circumscribed borders but with focal variegation in pigmentation. While it is the presence of the latter feature that may provide a clinical clue to the diagnosis, it may also raise the clinical suspicion of malignancy and thus usually prompts surgical excision. Also, some patients have a history of rapid growth or change in a long-standing lesion, which may cause alarm to expert dermatologists. Combined nevi with blue nevus component are more commonly located in the face, back, and shoulders. Combined nevi including a Spitz nevus component are more commonly located in the extremities.
Histologic Features of Combined Nevus
As discussed above combined nevi may potentially display the entire spectrum of melanocytic nevi. When two distinct melanocytic cell populations are identified histologically within a nevus, the differential diagnosis is between a combined melanocytic nevus and a melanoma arising in association with a nevus. A combined nevus could be misdiagnosed as melanoma if it is not recognized that the dual cell populations identified are benign [67, 68]. The difficulty for the pathologist relies if one of the melanocytic cell populations shows an infiltrative growth pattern, has large atypical melanocytes, displays occasional dermal mitotic figures, or is associated with a lymphocytic response. Unfortunately, all of these histologic features can be seen in both nevi and melanomas, and thus careful inspection is necessary when these features are encountered. In particular, it is the Spitz nevus component that is most likely to be responsible for a misdiagnosis of melanoma because the histologic features may include large epithelioid cells and dermal mitotic figures . Below we highlight the most common combinations seen in combined nevi.
Blue and Common Intradermal Nevus: This is the most common combination seen in combined nevi. In the majority of cases, the ordinary nevus overlies or is adjacent to the blue nevus component. The blue nevus consists of a dermal proliferation of dendritic, evenly pigmented melanocytes with small, round-to-oval nuclei. Some cases show scattered melanin-laden macrophages and variable fibrosis. The ordinary melanocytic population is usually a common intradermal nevus; however, it can be a compound nevus or a dysplastic nevus (junctional or compound). In cases with atypia, those atypical features most often represent cytologic atypia of the intraepidermal component of a dysplastic nevus. The presence of mitotic figures in this type of combined nevus is exceedingly rare, if ever identified. The histopathology of this type of combined nevus is benign appearing; thus, the differential diagnosis of melanoma is usually not a consideration.
Spitz and Common Nevus: This combination is unusual and is more commonly seen in female adults. Histologically, combined nevi with Spitz elements usually display a characteristic dermal proliferation of large epithelioid cells that is usually more nested in the superficial dermis and extends as individual cells among the deep reticular dermal collagen bundles, alongside an ordinary intradermal or compound nevus, dysplastic nevus, or blue nevus. Cytologically the spitzoid cells show similar features to that observed in ordinary Spitz nevi, i.e., epithelioid cells with large monomorphous and vesicular nuclei with prominent nucleoli. As mentioned above, the combination of Spitz and common nevus type is the one that most often displays atypical features. In one study it was found that significant atypical features were seen in nearly half of the cases of combined nevi that had Spitzoid elements . Atypical features in this type of combined nevi usually manifest as lack of symmetry and presence of hypercellularity, cytologic atypia, and increased numbers of mitotic figures. In addition, combined nevi with Spitz elements may display dermal sclerosis, which may contribute to a diagnostic consideration of melanoma. In order to differentiate them from melanoma, the most important feature in combined nevi is the almost universal absence of deep dermal mitotic figures.
Spitz and Blue Nevus: This variant of combined nevus is rare and some authors have used the term “BLITZ” (blue + Spitz) for such neoplasms . Histologically, they usually show a clear component of Spitz and blue nevus, and in some cases on low magnification, they can be confused with pigmented epithelioid melanocytoma or epithelioid blue nevus. Most cases show a symmetrical lesion in dermis with wedge-shaped architecture. The overlying epidermis usually shows acanthosis and hyperplasia and there may be a focal junctional component. The Spitz component shows epithelioid and spindle cell melanocytes with large vesicular nuclei, prominent nucleoli, and variable pigmented cytoplasm. Intranuclear cytoplasmic inclusions are commonly seen. These lesions are associated with scattered, heavily pigmented, dendritic melanocytes and melanophages and, at times, slight fibroplasia, in a pattern similar to a blue nevus. These lesions are essentially indistinguishable from an intradermal Spitz nevus.
Traumatized nevus. Note the ulcerated epidermis (arrow) (a). Melanocytes located in the dermis display small nuclei and appear to mature with depth (b)
Traumatized nevus. Note the scar in the upper dermis (arrows) above the dermal nests of melanocytes (a). Irregular junctional component with large nests (arrow) and single melanocytes. Melanocytes mature normally toward the base of the lesion (b)
Combined melanocytic nevi (intradermal + blue). Note the epithelioid melanocytes admixed with a subtle dermal proliferation of dendritic pigmented melanocytes (a, b).Fig. 3.30 (continued) High power showing the mixture of both standard intradermal and dendritic, pigmented melanocytes (c, d)
Combined nevus (intradermal and Spitz). A 17-year-old male, back, with recent change in color. The low power of the lesion shows a conventional intradermal nevus with epithelioid melanocytes located in the center of the lesion (a). The melanocytes in the central region are epithelioid, have an ample dusky cytoplasm, and abundant melanin pigment (b).Fig. 3.31 (continued) Note the central cells with ample cytoplasm and melanin pigment (Spitz cells) surrounded by standard intradermal melanocytes (c). The cells in the center lack mitotic figures (d)
Halo nevus, also known as Sutton nevus or leukoderma acquisitum centrifugum, is a benign melanocytic nevus that is surrounded by a halo of depigmentation. This halo of depigmentation is represented histologically in most cases by a dense inflammatory infiltrate; however, the relationship between the area of depigmentation (halo) and the inflammatory infiltrate is inconsistent as some nevi that display an inflammatory infiltrate do not show clinically this area of depigmentation or vice versa [71–73]. This phenomenon usually indicates the beginning of involution and subsequent regression of a melanocytic nevus, a process that extends over a period of several months. Some authors prefer to use the term “halo nevus” only for melanocytic nevi that clinically show a depigmented area (halo). We, as others, use the term “nevus with halo phenomenon” when we identify a dense lymphocytic infiltrate within the lesion, in those cases in which there is no clear clinical description of a halo.