III.4
III.4.1 Definition
According to the original description by Tieche [33], to which little can be added, blue nevus is a dermal-based, benign melanocytic lesion histo- pathologically made up by variable proportions of oval/spindle and bipolar, usually heavily pig- mented dendritic cells (G. Ferrara et al., submit- ted) [37, 40]. The aggregation of oval/spindle melanocytes with pale cytoplasm into discrete expansile nodules features a “cellular” blue ne- vus [23, 37].
The definitional color of this lesion is proba- bly due to the Tyndall effect, which involves se- lective absorption of long-wavelength light by deep dermal melanin and reflection of the short- wavelength blue light from the skin surface.
The cell components of blue nevus consist of arrested embryonal melanocytes migrating from the neural crest into the epidermis during embryonic development [40]. Immunohisto- chemically, they usually express melanoma-as- sociated antigen HMB45, together with S100 protein and Melan A/Mart-1. These cells are the
Chapter III.4
Blue Nevus
Gerardo Ferrara and Giuseppe Argenziano III.4
Contents
III.4.1 Definition . . . .78
III.4.2 Clinical Features . . . .80
III.4.3 Dermoscopic Criteria . . . .80
III.4.4 Relevant Clinical Differential Diagnosis . . . .82
III.4.5 Histopathology . . . .82
III.4.5 Management . . . .84
III.4.5 Case Study . . . .84
References . . . .85
sole or the main components of several other melanocytic lesions named “dermal dendritic melanocytic proliferations” [40]. Three catego- ries of dermal dendritic melanocytic prolifera- tions have been identified in the classical der- matopathology literature: (a) hamartomatous dermal melanocytoses (Mongolian spot, nevus of Ota, and is nevus of Ito); (b) classic and cel- lular blue nevus; and (c) malignant blue nevus [40]. In addition, “combined” lesions made up of dermal dendritic melanocytic proliferations admixed with any other benign melanocytic proliferation (congenital non-blue, common ac- quired, dysplastic/Clark, and Spitz nevi) were considered as well (see also Chap. III.6) [1, 4, 11, 12, 23, 24, 29, 37].
In recent years, a number of additional histo- pathological variants of dermal dendritic me- lanocytic proliferations have been described [1, 6, 8–11, 13, 14, 16, 17, 18, 21, 23, 27–30, 35, 38–40]. A comprehensive histopathological classification of these entities is given in Ta- ble III.4.1, which groups together several dermal dendritic melanocytic proliferations into a group of non-hamartomatous benign mela- nocytic lesions which we also refer to as “the blue nevus family.” Such a taxonomic approach implies that each entity merges within another along a spectrum of morphological changes, as suggested by the well-documented occurrence of “mixed” types of nevi, e.g., common and cel- lular [23], sclerotic and mucinous [28], and scle- rotic and hypo-amelanotic (G. Ferrara et al., submitted).
Within the benign lesions of the blue nevus
family we can also include “atypical” variants
[3, 5, 34, 40]. These are defined as blue nevi,
most often of the cellular type, in which histo-
pathology shows one or several atypical features,
Blue Nevus
Gerardo Ferrara and Giuseppe Argenziano III.4
including mitoses (not atypical and up to 3–4/
mm 2 ), ulceration, large size/deep extension, nu- clear pleomorphism, focal necrosis. This con- cept has been criticized in the name of a “dual”
(benign vs malignant) concept of nosology [25].
Indeed, if defined according to strict morpho- logical criteria, atypical blue nevi have a com- pletely benign biological behavior [40].
The clinicopathological spectrum of dermal dendritic melanocytic proliferations also en- compasses some entities whose nosology and prognosis still remain controversial (large infil- trative cellular blue nevus, cutaneous neurocris- tic hamartoma, pigmented epithelioid mela- nocytoma) [9, 17, 22, 23, 27, 38, 40]. The clinicopathological features of such exceptional
Table III.4.1. A classification of dermal dendritic melanocytic proliferations
Benign Borderline Malignant
Hamartomatous Non-hamartomatous
(“blue nevus family”) Large infiltrative
cellular blue nevus Melanoma arising 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
melanocytoma b 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 nevus a
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 mor-
phologically distinguished from cases of metastasizing epithelioid blue nevus and from animal-type melano-
ma, thereby justifying their inclusion into a unique rubric designated “pigmented epithelioid melanocytoma”
80 G. Ferrara, G. Argenziano
III.4
neoplasms have been recently revisited [40]:
their illustration is beyond the scope of this book. Finally, some dermal dendritic melano- cytic proliferations are overtly malignant [3, 7, 37], but the term “malignant” or “metastasiz- ing” blue nevus is an oxymoron and should be therefore avoided. Melanoma can seldom arise in the context of a cellular blue nevus: prelimi- nary molecular data suggest that it has a differ- ent pathway to tumorigenesis than that of con- ventional melanoma [3].
III.4.2 Clinical Features
Common or classic blue nevus is a small (<1 cm), gray-blue or blue-black macule, papule, or plaque usually located on the head, neck, presa- cral region, or distal extremities [2, 14, 32, 37, 40]. Exceptional extracutaneous locations have also been described [15, 20, 26]. It is almost in- variably acquired during the second decade of life; most patients belong to phototypes III–IV [37]. The cellular variant is a much larger blue- black nodular lesion whose typical location is the gluteal region [23, 37]. The scalp and the ex- tremities are less commonly affected.
Unusual clinical features of blue nevi include congenital, familial, eruptive, plaque-like, target- oid, and linear forms [4, 22, 24, 36, 37, 40]. The term “agminated blue nevus” has been used for multiple blue nevi sometimes arising within a Mongolian spot (see also Chap. III.3) [36, 37, 40].
Most lesions belonging to the blue nevus family show demographic and clinical features which are similar to those of common and cel- lular blue nevi. In particular, “hypochromic”
variants of blue nevi (see Table III.4.1) do not seem to be “ancient” blue nevi because of the young age of most of the patients (G. Ferrara et al., submitted) [6, 10, 40]. Remarkably, these variants of blue nevus are rarely recognized as such on clinical grounds: in fact, the paucity of melanin often imparts a grayish or even a gray- ish-brown color [6, 10, 16, 40].
Epithelioid blue nevus also resembles blue nevus from a clinical point of view, but is histo- pathologically distinctive [9, 17]. The majority of epithelioid blue nevi are detected as multiple elements associated with other cutaneous le-
sions (lentigines and myxoid neurofibromas) in the clinical context of a Carney (myxoma) syn- drome [9]. This is an autosomal-dominant dis- order typified by the triad: cutaneous lesions;
cardiac myxomas; and hormonal hyperfunction (adrenal hyperplasia, pituitary adenomas, tes- ticular tumors). These alterations are summa- rized into the acronyms LAMB (Lentigines, Atrial myxomas, Mucocutaneous myxomas, Blue nevi) and NAME (Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides).
III.4.3 Dermoscopic Criteria
The dermoscopic features of common blue nevi are considered to be peculiar enough as to help their clinical recognition [2, 31]. In fact, they are described as showing a homogeneous pattern with a characteristic steel-blue pigmenta- tion – either in a diffuse “structureless” or, less commonly, in a “dotted-globular” pattern [31].
When pressing with the lens plate, a skin fold- ing above the peripheral area of the lesion often appears as a circular whitish line (Fig. III.4.1).
Both arborizing vessels and peripheral streak- like extensions are sometimes discernible as typically out-of-focus structures.
Indeed, the “blue nevus family” is composed by lesions which are not always “blue” on der- moscopy. Large, often ovoid areas of discolor- ation due to loss of melanin and/or to stromal response are definitional for “white” blue nevi.
These lesions represented 46.8% of all excised blue nevi in a recent series (G. Ferrara et al., submitted) .
Much less commonly, a black lamella – name- ly, a homogeneous, black, disc-like area which can be removed by tape stripping – covers most of the surface of blue nevi, thus featuring “black”
blue nevi (G. Ferrara et al., submitted) [14].
Finally, a minority of these nevi are either tan
(“brown” blue nevi) or variegated (“polychro-
mous” blue nevi) in their dermoscopic color
(G. Ferrara et al., submitted) [12]. Interestingly,
deep penetrating nevus, an unusual melanocyt-
ic neoplasm belonging to the blue nevus family,
has been recently described as a polychromous
lesion which can undergo rapid dermoscopic
changes (G. Ferrara et al., submitted) [18].
Fig. III.4.1. a A nodular lesion located on the dorsum of the foot of a 34-year-old woman. b In dermoscopy only homogeneous bluish pigmentation is visible. Note the network-like structures corresponding to unusual skin markings on the lesion surface. c A V-shaped, dermal- based pigmented lesion. d The superficial portion of the lesion, made by sparse dendritic melanocytes within a
dense sclerotic collagen. e The deep portion of the lesion,
made by densely packed melanocytes with heavily pig-
mented dendritic processes. f At a higher magnification,
there is intimate relationship among the dendritic mela-
nocytes and the sclerotic collagen of the dermis, which
features the classical “dendritic–sclerotic” histotype of
blue nevus
82 G. Ferrara, G. Argenziano
III.4
III.4.4 Relevant Clinical Differential Diagnosis
The clinical recognition of a blue nevus is com- monly not problematic. A dermoscopic diagno- sis of nodular pigmented basal cell carcinoma can be sometimes evoked because of the pres- ence of arborizing vessels. In blue nevus, how- ever, these vessels are typically out of focus.
Some adnexal neoplasms (e.g., trichoblasto- ma, pigmented intradermal poroma) are char- acterized by a diffuse bluish pigmentation. As a rule, patients report the onset of these lesions as more recent than that expected for a blue nevus.
Apocrine hydrocystoma is an adnexal lesion which is typically located in the periocular area.
Its consistency is floating or elastic; not uncom- monly, patients report its sudden onset.
“Hypochromic” variants of blue nevi can be clinically hard to differentiate from dermal nevi or dermatofibromas [6, 10]. Dermoscopy can help their recognition by showing foci of steel- blue pigmentation which could not be discerned by the naked eye (G. Ferrara et al., submitted) [16].
Pigmented Spitz/Reed nevus must be differ- entiated from deep penetrating nevus clinically [11, 30] and from common blue nevus dermo- scopically [2, 31]; however, when present, pe- ripheral extensions of blue nevus are different from true radial streaks/pseudopods of pig- mented Spitz/Reed nevus because they are typi- cally grayish-blue in color and out of focus.
The most important differential diagnosis must be made between blue nevus and melano- ma. Dermoscopy can aid the recognition of nodular melanoma by showing subtle differen- tiating features (vascular pattern, remnants of pigment network, blue-whitish veil) [2]. Excep- tional cases of metastatic melanoma can strictly mimic the clinical and dermoscopic features of blue nevus. Anamnestic data are relevant, but not always clear-cut. A peripheral halo of ery- thema in metastatic melanoma is quite charac- teristic but inconstant [2, 31]. In these cases, the
“golden rule” is to not schedule any follow-up for a nodular lesion and to excise it.
III.4.5 Histopathology
The histopathological pattern of common blue nevus is defined as dendritic–sclerotic [19]: this is typified by the presence of elongated, finely branched, heavily pigmented dendritic melano- cytes interspersed with some melanophages among thickened bundles of collagen in the mid and the upper dermis. A thick grenz zone usu- ally separates the lesion from the unaffected epidermis (Fig. III.4.2).
Not uncommonly, some areas of otherwise typical blue nevi are composed of oval, often plump, melanocytes almost devoid of any pig- ment. When the pigment loss is sizable, but in- volves less that 95% of the lesion, the term “hy- pomelanotic” blue nevus seems to be appropriate (G. Ferrara et al., submitted). Cases in which pigment loss involves at least 95% of the lesion can be labeled as “amelanotic” [6]. A minority of blue nevi show a marked degree of fibrosis (scle- rosing blue nevi; G. Ferrara et al., submitted) [16, 40] and/or myxoid changes of the stroma (G. Ferrara et al., submitted) [28, 40]. We have noticed that transition types between hypo- amelanotic and sclerosing blue nevi also exist (G. Ferrara et al., submitted) These lesions can therefore be grouped together into “hypochro- mic” blue nevi. On dermoscopy most “hypo- chromic” lesions appear as “white” blue nevi (G. Ferrara et al., submitted) [16].
In rare instances, blue nevus is located super- ficially and some dendritic melanocytes are ar- ranged in single units within the epidermis:
these cases have been labeled as “compound blue nevi” [21] or “blue nevi, superficial type, with prominent intraepidermal dendritic mela- nocytes” [1] or, simply, “Kamino nevi” [14]. On dermoscopy, these lesions often appear as “black”
blue nevi (G. Ferrara et al., submitted) [14].
A nevus of another kind is occasionally as- sociated with a blue nevus: such a lesion is termed “combined blue nevus” (G. Ferrara et al., submitted) [1, 2, 11, 12 31, 37]. The present authors and others [12] have noticed that com- bined blue nevi are often “brown” blue nevi on dermoscopy.
The histological pattern of “cellular” blue ne-
vus is defined as spindle/fascicular [19]. It is
composed by dendritic melanocytes together
with islands of epithelioid and plump spindle cells with abundant pale cytoplasm and usually little pigment. Melanophages are found between the cellular islands. The tumor often bulges into the subcutaneous fat as a nodular downgrowth
with a typical clapper-like silhouette [23, 37, 40].
Stromal desmoplasia and balloon-cell changes are rare occurrences [23, 40].
A peculiar lesion which places somewhat in between combined cellular blue and Spitz (Blitz)
Fig. III.4.2. a A bluish papule located on the arm of a 54-year-old woman. b Dermoscopically the lesion is typi- fied by homogeneous pattern made of bluish to white- blue structureless pigmentation. c A papular lesion with a slight epidermal hyperplasia and little pigment depo- sition within the dermis. d A dermal proliferation of
cells embedded within a sclerotic and somewhat myxoid
stroma. e Oval to spindle melanocytes within a sclerotic
stroma. A few melanocytes with pigmented dendritic
processes are still evident. f Same features as described in
a at a higher magnification
84 G. Ferrara, G. Argenziano
III.4
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 melano- cytes are its main components, with some inter- spersed epithelioid (spitzoid) cells whose morphological hallmark is a finely vacuolated (sebocyte-like) cytoplasm. The dermoscopic ap- pearance of this lesion is often “polychromous”
(G. Ferrara et al., submitted).
III.4.5 Management
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 on- set 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 melanoma of the dorsum (Breslow’s thickness:
1.30 mm) came to our outpatient service be- cause of a 4-mm nodular lesion of the left arm. According to the patient’s report, the le- 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 pig- mented dendritic and spindle dermal melano- cytes (Case Study III.4.2). Spindle melanocytes, however, showed slightly pleomorphic and en- larged nuclei with a dispersed chromatin pat- tern and small but evident nucleoli (Case Study III.4.3). A few mitotic figures (up to 2/mm 2 ) were also detected (Case Study III.4.4). Necro- sis, ulceration, and lymphocyte infiltration were not present. A diagnosis of atypical blue nevus was thus rendered.
Case Study III.4.1.
Case Study III.4.2.
Case Study III.4.3.
This case is an example of a nodular lesion promptly excised (and not scheduled for follow- up protocols) because of its recent enlargement in the presence of a positive anamnesis for mel- anoma. A histopathological diagnosis of atypi- cal blue nevus was made because of a mild cyto- logical atypia and some mitotic figures within the dermal spindle melanocytes. The histopath- ological features of atypia shown in this case cannot be detected by means of dermoscopy. In current practice, however, this is not a problem because strictly defined atypical blue nevi be- have in a completely benign fashion [4].
C
