Blue Nevus Gerardo Ferrara and Giuseppe Argenziano III.4

Chapter III.4 Blue Nevus Gerardo Ferrara and Giuseppe Argenziano III.4

Contents sole or the main components of several other melanocytic lesions named “dermal dendritic III.4.1 Definition ...... 78 melanocytic proliferations” [40]. Three catego- III.4.2 Clinical Features ...... 80 ries of dermal dendritic melanocytic prolifera- III.4.3 Dermoscopic Criteria...... 80 tions have been identified in the classical der- matopathology literature: (a) hamartomatous III.4.4 Relevant Clinical Differential dermal melanocytoses (Mongolian spot, nevus Diagnosis...... 82 of Ota, and is nevus of Ito); (b) classic and cel- III.4.5 Histopathology...... 82 lular blue nevus; and (c) malignant blue nevus [40]. In addition, “combined” lesions made up III.4.5 Management...... 84 of dermal dendritic melanocytic proliferations III.4.5 Case Study...... 84 admixed with any other benign melanocytic References...... 85 proliferation (congenital non-blue, common acquired, dysplastic/Clark, and Spitz nevi) were III.4 considered as well (see also Chap. III.6) [1, 4, 11, III.4.1 Definition 12, 23, 24, 29, 37]. In recent years, a number of additional histo- According to the original description by Tieche pathological variants of dermal dendritic me [33], to which little can be added, blue nevus is a lanocytic proliferations have been described dermal-based, benign melanocytic lesion histo- [1, 6, 8–11, 13, 14, 16, 17, 18, 21, 23, 27–30, 35, pathologically made up by variable proportions 38–40]. A comprehensive histopathological of oval/spindle and bipolar, usually heavily pig- classification of these entities is given in Ta- mented dendritic cells (G. Ferrara et al., submit- ble III.4.1, which groups together several dermal ted) [37, 40]. The aggregation of oval/spindle dendritic melanocytic proliferations into a melanocytes with pale cytoplasm into discrete group of non-hamartomatous benign mela expansile nodules features a “cellular” blue ne- nocytic lesions which we also refer to as “the vus [23, 37]. blue nevus family.” Such a taxonomic approach The definitional color of this lesion is proba- implies that each entity merges within another bly due to the Tyndall effect, which involves se- along a spectrum of morphological changes, as lective absorption of long-wavelength light by suggested by the well-documented occurrence deep dermal melanin and reflection of the short- of “mixed” types of nevi, e.g., common and cel- wavelength blue light from the skin surface. lular [23], sclerotic and mucinous [28], and scle- The cell components of blue nevus consist of rotic and hypo-amelanotic (G. Ferrara et al., arrested embryonal melanocytes migrating submitted). from the neural crest into the epidermis during Within the benign lesions of the blue nevus embryonic development [40]. Immunohisto- family we can also include “atypical” variants chemically, they usually express melanoma-as- [3, 5, 34, 40]. These are defined as blue nevi, sociated antigen HMB45, together with S100 most often of the cellular type, in which histo- protein and Melan A/Mart-1. These cells are the pathology shows one or several atypical features, Chapter III.4 Blue Nevus Chapter III.4 79 Blue Nevus Table III.4.1. A classification of dermal dendritic melanocytic proliferations Benign Borderline Malignant Gerardo Ferrara and Giuseppe Argenziano III.4 Hamartomatous Non-hamartomatous Large infiltrative Melanoma arising (“blue nevus family”) cellular blue nevus in blue nevus Mongolian spot Common blue nevus Of the scalp Blue nevus-like (dendritic cell) primary melanoma Nevus of Ota Cellular blue nevus At other sites Blue nevus-like metastatic melanoma Nevus of Ito Classical Cutaneous neurocristic hamartoma⁄malignant neurocristic tumor Angiomatoid Pigmented epithelioid melanocytomab With schwannian differentiation (Masson neuronevus) With prominent vascular network (paraganglioma-like dermal melanocytic tumor) “Hypochromic” (white) blue nevus/ cellular blue nevus Myxoid (cystic) Desmoplastic/sclerotic Hypomelanotic Amelanotic Deep penetrating (polychromous) nevus Compound (black) blue (Kamino) is nevus Combined (brown) blue nevus Atypical blue nevus/ cellular blue nevusa a If strict morphological criteria are used, atypical blue nevus and atypical cellular blue nevus have a completely favorable clinical outcome b Cases of epithelioid blue nevus in Carney complex did not metastasize to date; however, they cannot be morphologically distinguished from cases of metastasizing epithelioid blue nevus and from animal-type melanoma, thereby justifying their inclusion into a unique rubric designated “pigmented epithelioid melanocytoma”

including mitoses (not atypical and up to 3–4/ The clinicopathological spectrum of dermal mm2), ulceration, large size/deep extension, nu- dendritic melanocytic proliferations also en- clear pleomorphism, focal necrosis. This con- compasses some entities whose nosology and cept has been criticized in the name of a “dual” prognosis still remain controversial (large infil- (benign vs malignant) concept of nosology [25]. trative cellular blue nevus, cutaneous neurocris- Indeed, if defined according to strict morpho- tic hamartoma, pigmented epithelioid mela logical criteria, atypical blue nevi have a com- nocytoma) [9, 17, 22, 23, 27, 38, 40]. The pletely benign biological behavior [40]. clinicopathological features of such exceptional 80 G. Ferrara, G. Argenziano

neoplasms have been recently revisited [40]: sions (lentigines and myxoid neurofibromas) in their illustration is beyond the scope of this the clinical context of a Carney (myxoma) syn- book. Finally, some dermal dendritic melano- drome [9]. This is an autosomal-dominant dis- cytic proliferations are overtly malignant [3, 7, order typified by the triad: cutaneous lesions; 37], but the term “malignant” or “metastasiz- cardiac myxomas; and hormonal hyperfunction ing” blue nevus is an oxymoron and should be (adrenal hyperplasia, pituitary adenomas, tes- therefore avoided. Melanoma can seldom arise ticular tumors). These alterations are summa- in the context of a cellular blue nevus: prelimi- rized into the acronyms LAMB (Lentigines, nary molecular data suggest that it has a differ- Atrial myxomas, Mucocutaneous myxomas, ent pathway to tumorigenesis than that of con- Blue nevi) and NAME (Nevi, Atrial myxomas, ventional melanoma [3]. Myxoid neurofibromas, Ephelides).

III.4.2 Clinical Features III.4.3 Dermoscopic Criteria Common or classic blue nevus is a small (<1 cm), The dermoscopic features of common blue nevi gray-blue or blue-black macule, papule, or are considered to be peculiar enough as to help plaque usually located on the head, neck, presa- their clinical recognition [2, 31]. In fact, they are cral region, or distal extremities [2, 14, 32, 37, described as showing a homogeneous pattern 40]. Exceptional extracutaneous locations have with a characteristic steel-blue pigmenta- also been described [15, 20, 26]. It is almost in- tion – either in a diffuse “structureless” or, less variably acquired during the second decade of commonly, in a “dotted-globular” pattern [31]. life; most patients belong to phototypes III–IV When pressing with the lens plate, a skin fold- [37]. The cellular variant is a much larger blue- ing above the peripheral area of the lesion often black nodular lesion whose typical location is appears as a circular whitish line (Fig. III.4.1). the gluteal region [23, 37]. The scalp and the ex- Both arborizing vessels and peripheral streak- III.4 tremities are less commonly affected. like extensions are sometimes discernible as Unusual clinical features of blue nevi include typically out-of-focus structures. congenital, familial, eruptive, plaque-like, target- Indeed, the “blue nevus family” is composed oid, and linear forms [4, 22, 24, 36, 37, 40]. The by lesions which are not always “blue” on der- term “agminated blue nevus” has been used for moscopy. Large, often ovoid areas of discolor- multiple blue nevi sometimes arising within a ation due to loss of melanin and/or to stromal Mongolian spot (see also Chap. III.3) [36, 37, 40]. response are definitional for “white” blue nevi. Most lesions belonging to the blue nevus These lesions represented 46.8% of all excised family show demographic and clinical features blue nevi in a recent series (G. Ferrara et al., which are similar to those of common and cel- submitted) . lular blue nevi. In particular, “hypochromic” Much less commonly, a black lamella – name- variants of blue nevi (see Table III.4.1) do not ly, a homogeneous, black, disc-like area which seem to be “ancient” blue nevi because of the can be removed by tape stripping – covers most young age of most of the patients (G. Ferrara et of the surface of blue nevi, thus featuring “black” al., submitted) [6, 10, 40]. Remarkably, these blue nevi (G. Ferrara et al., submitted) [14]. variants of blue nevus are rarely recognized as Finally, a minority of these nevi are either tan such on clinical grounds: in fact, the paucity of (“brown” blue nevi) or variegated (“polychro- melanin often imparts a grayish or even a gray- mous” blue nevi) in their dermoscopic color ish-brown color [6, 10, 16, 40]. (G. Ferrara et al., submitted) [12]. Interestingly, Epithelioid blue nevus also resembles blue deep penetrating nevus, an unusual melanocyt- nevus from a clinical point of view, but is histo- ic neoplasm belonging to the blue nevus family, pathologically distinctive [9, 17]. The majority has been recently described as a polychromous of epithelioid blue nevi are detected as multiple lesion which can undergo rapid dermoscopic elements associated with other cutaneous le- changes (G. Ferrara et al., submitted) [18]. Blue Nevus Chapter III.4 81

Fig. III.4.1. a A nodular lesion located on the dorsum of dense sclerotic collagen. e The deep portion of the lesion, the foot of a 34-year-old woman. b In dermoscopy only made by densely packed melanocytes with heavily pig- homogeneous bluish pigmentation is visible. Note the mented dendritic processes. f At a higher magnification, network-like structures corresponding to unusual skin there is intimate relationship among the dendritic mela- markings on the lesion surface. c A V-shaped, dermal- nocytes and the sclerotic collagen of the dermis, which based pigmented lesion. d The superficial portion of the features the classical “dendritic–sclerotic” histotype of lesion, made by sparse dendritic melanocytes within a blue nevus 82 G. Ferrara, G. Argenziano

III.4.4 Relevant Clinical Differential III.4.5 Histopathology Diagnosis The histopathological pattern of common blue The clinical recognition of a blue nevus is com- nevus is defined as dendritic–sclerotic [19]: this monly not problematic. A dermoscopic diagno- is typified by the presence of elongated, finely sis of nodular pigmented basal cell carcinoma branched, heavily pigmented dendritic melano- can be sometimes evoked because of the pres- cytes interspersed with some melanophages ence of arborizing vessels. In blue nevus, how- among thickened bundles of collagen in the mid ever, these vessels are typically out of focus. and the upper dermis. A thick grenz zone usu- Some adnexal neoplasms (e.g., trichoblasto- ally separates the lesion from the unaffected ma, pigmented intradermal poroma) are char- epidermis (Fig. III.4.2). acterized by a diffuse bluish pigmentation. As a Not uncommonly, some areas of otherwise rule, patients report the onset of these lesions as typical blue nevi are composed of oval, often more recent than that expected for a blue nevus. plump, melanocytes almost devoid of any pig- Apocrine hydrocystoma is an adnexal lesion ment. When the pigment loss is sizable, but in- which is typically located in the periocular area. volves less that 95% of the lesion, the term “hy- Its consistency is floating or elastic; not uncom- pomelanotic” blue nevus seems to be appropriate monly, patients report its sudden onset. (G. Ferrara et al., submitted). Cases in which “Hypochromic” variants of blue nevi can be pigment loss involves at least 95% of the lesion clinically hard to differentiate from dermal nevi can be labeled as “amelanotic” [6]. A minority of or dermatofibromas [6, 10]. Dermoscopy can blue nevi show a marked degree of fibrosis (scle- help their recognition by showing foci of steel- rosing blue nevi; G. Ferrara et al., submitted) blue pigmentation which could not be discerned [16, 40] and/or myxoid changes of the stroma by the naked eye (G. Ferrara et al., submitted) (G. Ferrara et al., submitted) [28, 40]. We have [16]. noticed that transition types between hypo- Pigmented Spitz/Reed nevus must be differ- amelanotic and sclerosing blue nevi also exist III.4 entiated from deep penetrating nevus clinically (G. Ferrara et al., submitted) These lesions can [11, 30] and from common blue nevus dermo- therefore be grouped together into “hypochro- scopically [2, 31]; however, when present, pe- mic” blue nevi. On dermoscopy most “hypo- ripheral extensions of blue nevus are different chromic” lesions appear as “white” blue nevi from true radial streaks/pseudopods of pig- (G. Ferrara et al., submitted) [16]. mented Spitz/Reed nevus because they are typi- In rare instances, blue nevus is located super- cally grayish-blue in color and out of focus. ficially and some dendritic melanocytes are ar- The most important differential diagnosis ranged in single units within the epidermis: must be made between blue nevus and melano- these cases have been labeled as “compound ma. Dermoscopy can aid the recognition of blue nevi” [21] or “blue nevi, superficial type, nodular melanoma by showing subtle differen- with prominent intraepidermal dendritic mela- tiating features (vascular pattern, remnants of nocytes” [1] or, simply, “Kamino nevi” [14]. On pigment network, blue-whitish veil) [2]. Excep- dermoscopy, these lesions often appear as “black” tional cases of metastatic melanoma can strictly blue nevi (G. Ferrara et al., submitted) [14]. mimic the clinical and dermoscopic features of A nevus of another kind is occasionally as- blue nevus. Anamnestic data are relevant, but sociated with a blue nevus: such a lesion is not always clear-cut. A peripheral halo of ery- termed “combined blue nevus” (G. Ferrara et thema in metastatic melanoma is quite charac- al., submitted) [1, 2, 11, 12 31, 37]. The present teristic but inconstant [2, 31]. In these cases, the authors and others [12] have noticed that com- “golden rule” is to not schedule any follow-up bined blue nevi are often “brown” blue nevi on for a nodular lesion and to excise it. dermoscopy. The histological pattern of “cellular” blue nevus is defined as spindle/fascicular [19]. It is composed by dendritic melanocytes together Blue Nevus Chapter III.4 83

Fig. III.4.2. a A bluish papule located on the arm of a cells embedded within a sclerotic and somewhat myxoid 54-year-old woman. b Dermoscopically the lesion is typi- stroma. e Oval to spindle melanocytes within a sclerotic fied by homogeneous pattern made of bluish to white- stroma. A few melanocytes with pigmented dendritic blue structureless pigmentation. c A papular lesion with processes are still evident. f Same features as described in a slight epidermal hyperplasia and little pigment depo- a at a higher magnification sition within the dermis. d A dermal proliferation of with islands of epithelioid and plump spindle with a typical clapper-like silhouette [23, 37, 40]. cells with abundant pale cytoplasm and usually Stromal desmoplasia and balloon-cell changes little pigment. Melanophages are found between are rare occurrences [23, 40]. the cellular islands. The tumor often bulges into A peculiar lesion which places somewhat in the subcutaneous fat as a nodular downgrowth between combined cellular blue and Spitz (Blitz) 84 G. Ferrara, G. Argenziano

nevus [17, 37] and epithelioid blue nevus [9, 17, 37] is deep penetrating nevus [11, 30, 37]. It is a dermal V-shaped lesion that bulges into the sub- cutis; typically dendritic and spindle melanocytes are its main components, with some interspersed epithelioid (spitzoid) cells whose morphological hallmark is a finely vacuolated (sebocyte-like) cytoplasm. The dermoscopic appearance of this lesion is often “polychromous” (G. Ferrara et al., submitted).

III.4.5 Management Case Study III.4.1. Neither surgical procedures nor further clinical controls are needed for most cases of blue nevi, because their clinical recognition is obvious. In the presence of atypical features (e.g., recent onset and/or recent changes, peripheral halo of in- flammation, unusual dermoscopic features) surgical excision is mandatory.

III.4.5 Case Study A 59-year-old man with a previous history of III.4 melanoma of the dorsum (Breslow’s thickness: 1.30 mm) came to our outpatient service because of a 4-mm nodular lesion of the left arm. According to the patient’s report, the le- Case Study III.4.2. sion had slightly enlarged during the last few months. Dermoscopic examination disclosed a structureless pattern with a homogeneous steel- blue pigmentation consistent with blue nevus (Case Study III.4.1); however, in consideration of both the history of melanoma and the recent enlargement of the lesion a surgical excision was performed. Histological examination disclosed an over- all architecture of a blue nevus with heavily pigmented dendritic and spindle dermal melanocytes (Case Study III.4.2). Spindle melanocytes, however, showed slightly pleomorphic and enlarged nuclei with a dispersed chromatin pattern and small but evident nucleoli (Case Study III.4.3). A few mitotic figures (up to 2/mm2) were also detected (Case Study III.4.4). Necro- Case Study III.4.3. sis, ulceration, and lymphocyte infiltration were not present. A diagnosis of atypical blue nevus was thus rendered. Blue Nevus Chapter III.4 85

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