Benign Melanocytic Lesions Mimicking Melanoma James W. Patterson, M.D. Atypical (“Dysplastic”) Melanocytic Nevi • Terminology • “Dysplastic nevus” intended to be a clinical term, referring generally to a familial or sporadic syndrome of multiple atypical moles • We use: architectural disorder, with or without degrees of cytologic atypia Dysplastic Nevi – Cinical Features • A macular component in at least one area • At least 3 of the following: – Border not well defined – Size > 5 mm – Color variation – Uneven peripheral contour – Erythema Dysplastic Nevi – Microscopic • Single cells between junctional nests (often) • Entirely junctional, or ‘shoulders’ adjacent to dermal component • Bridging of nests • Subtle suprabasal melanocyte scatter • Concentric and/or lamellar fibroplasia • Patchy lymphocytic infiltrate Not a Dysplastic Nevus Formerly ‘mild dysplasia’: • Nuclear size the same as resting basal cells • Sometimes hyperchromatic • Minimal variation in nuclear size & shape • Nucleoli small or absent Low-Grade Dysplasia Formerly ‘moderate dysplasia’: • Nuclear size up to 1.5x that of resting basal cells • Hyperchromatic or dispersed chromatin • Prominent variation in nuclear size & shape in small minority of cells • Nucleoli small or absent High-Grade Dysplasia Formerly ‘severe dysplasia’: • Nuclear size > 1.5x that of resting basal cells • Hyperchromatic, coarse granular chromatin or peripheral condensation • Prominent variation in nuclear size & shape in a larger minority of cells • Nucleoli prominent, often lavender Architectural Features of High-Grade Dysplasia • Pagetoid scatter above basal layer (usually not above the middle third of epidermis and focal, confined to an area < 0.5 mm2 • Focal continuous basal proliferation • Intraepidermal mitoses (any dermal mitosis, or anything more than a rare mitosis, should raise concern for melanoma) Dysplastic Nevi – Microscopic • ‘Stratification’ of dermal component with HMB45 staining • Ki -67 index < 5% in dermal ‘hotspot’ • Ki -67 can also be used to evaluate junctional component – Most cells unlabeled in DN; can be >30% in melanoma in situ • P16 tumor suppressor staining can r/o homozygous loss of CDKN2A (but + staining does not r/o melanoma; inactivation of p16 can occur by mechanisms other than deletion) Atypical (“Dysplastic”) Nevi • Changes favoring melanoma over nevus: – Lack of preservation of rete ridges – Extensive pagetoid proliferation of melanocytes – Confluence of junctional melanocytes sufficient to fill an entire high power field – Lack of maturation descent into the dermis Risks for Melanoma in Patients with Dysplastic Nevi • > 5 dysplastic nevi = relative risk of 6.4 • Moderate-severe atypia • Size alone (> 4.4 mm) Special Site Nevi • Defined as nevi developing in specific anatomic sites: breast, axilla and other flexures, scalp, ear, umbilicus, genitalia, and acral skin • These have atypical or unusual features that can make distinction from melanoma difficult Special Site Nevi • Cause unknown – Embryological – Hormonal (e.g. estrogens) – Physical • UV • Trauma (e.g. friction) • Clinically ordinary; large, irregular borders • Distinct entities vs a spectrum of microscopic changes Special Site Nevi • Asymmetry • Irregular nesting • Cytologic atypia • Pagetoid spread • Fibroplasia • Lymphocytic infiltrate Genital Nevus • Junctional melanocytes, singly or in round/fusiform nests with retraction and dyscohesion • Mushroom-like • Focal, central pagetoid spread • Nests haphazard along rete ridges • Dermal cytologic atypia, but maturation • Rare, only superficial mitoses • Dense lymphocytic infiltrate; lichen sclerosis Breast Nevus • Nesting irregularities (“garland-like” arrangement of junctional nests) • Prominent intraepidermal melanocytes (mild pagetoid spread) • Melanocyte atypia • Dermal fibroplasia Flexural Nevus • Sometimes “mushroom” pattern • Variably sized nests along sides and tips of rete ridges • Mild cytologic junctional atypia • Another pattern resembles nevi from breast • Another pattern nested and dyscohesive Scalp Nevus • Lentiginous growth • Large, bizarrely-shaped nests arranged in a disorderly manner; dyshesion among nested melanocytes • Random melanocytes with large nuclei and abundant pale cytoplasm • Nests along lateral sides of rete ridges • Follicular involvement • Rare suprabasal melanocytes • Superficial fibroplasia Ear Nevus • Poor lateral circumscription • Suprabasilar melanocytes • Elongation of rete ridges • Some cytologic atypia • Shares many features with other “special site” nevi Acral Nevus • Relatively small and circumscribed (compared to melanoma) • Junctional nevus cells singly and in variably sized nests; bridging between rete ridges • Pagetoid scatter (“MANIAC”) • Random cytologic atypia • When compound, is maturation with descent • Stromal fibroplasia • Role of dermatoglyphics (symmetry, circumscription, organization of intraepidermal melanocytes & pigment in furrows when sections are oriented perpendicular to skin markings) Conjunctival Nevus • Lack of strong desmosomes; as a result, may have horizontal extension of junctional component far beyond subepithelial component, large, irregularly shaped nests, pagetoid growth, confluence of melanocytes along epithelial-subepithelial junction • Combined clonal epithelioid and deep penetrating components can occur • Can involve skeletal muscle • Limited or “reverse” maturation • Pseudoglandular spaces Halo Nevus • Incidence of halo nevus in general population 1% • Average age at presentation 15 years • “Immunologic rejection” of a nevus • Possibility of melanoma should be considered when solitary lesions occur in older adults Halo Nevus The halo phenomenon may also involve these types of lesions: • Dysplastic nevi • Spitz nevi • Congenital nevi • Melanomas Halo Nevus - Microscopic • Circumscribed lesion • Side-to-side symmetry, maturation with descent • Lymphocytic infiltrate partly or completely obscures the nevus cells • Nevus cells gradually disappear with time, leaving behind a lichenoid infiltrate • Little or no melanocytic abnormality at shoulder • May be nuclear hyperchromasia, cytologic atypia Halo Nevus – Distinction from Melanoma Melanoma is suggested by • Separate population of cells with expansile growth pattern • Severe, uniform cytologic atypia • Frequent mitoses • Ulceration • Necrosis Meyerson’s Nevus • Eczematous changes superimposed upon a melanocytic nevus • Young adults, equal sex distribution • Trunk, proximal extremities • May be triggered by factors within the nevus • Other causes: UV exposure, chermotherapy, IF alpha-2b • Multiple nevi may be involved ` Meyerson’s Nevus - Microscopic • Parakeratosis and serous transudation • Acanthosis and spongiosis • Superficial perivascular infiltrate; lymphocytes and sometimes eosinophils • The infiltrate may obscure the nevus, which can be acquired or congenital Meyerson’s Nevus – Differential Diagnosis • Halo nevi lack the spongiotic features of Meyerson’s nevi • Halo nevus infiltrates are predominantly CD8+; those of Meyerson’s nevi are predominantly CD4+ Persistent/Recurrent Melanocytic Nevus • A nevus that returns after incomplete excision, biopsy or trauma • More than ½ arise within 6 months of biopsy • Most commonly compound or intradermal nevi • Most frequent in lesions > 1 cm, positive margins, back, removed by shave excision • Morphology can vary, raise concerns for melanoma Persistent/Recurrent Nevus - Microscopic • Dermal scar (parallel fibroblasts, sclerotic collagen, vertically oriented vessels) • Attenuation of the overlying epidermal rete ridge pattern • Trizonal configuration is classic • Single and/or nested junctional melanocytes, occasionally pagetoid; sometimes a few atypical melanocytes in the superficial portion of the scar • Atypia independent of the original type of nevus Persistent/Recurrent Nevi vs Melanoma Recurrent nevi: • Atypical changes overlie the dermal scar • Remnant nevomelanocytes may be present in the dermis • Persistent benign junctional nevus may extend beyond the scar • Differential also includes traumatized nevus, sclerosing nevus, dysplastic nevus with florid fibroplasia, melanoma with regression Deep Penetrating Nevus • Reported by Seab, Graham and Helwig in 1989 • Hyperpigmented nodule, bluish brown to black, sometimes variegated color, usually < 5 mm in diameter • Face, upper trunk and proximal extremities in young persons, especially women > 40 years • May be related to plexiform spindle cell nevus, congenital nevus, blue nevus, and “clonal” nevus Plexiform Spindle Cell Nevus • In WHO, discussed with pigmented spindle cell nevus and atypical pigmented spindle cell tumor • Both sexes, shoulders and back • Slightly raised, blue or darkly pigmented Deep Penetrating Nevus - Microscopic • Well -circumscribed, symmetrical, dermal based • Enlarged, pigmented spindle and epithelioid cells • Distinctive wedge-shaped configuration • Cellular, superficial dermal component, transitioning to fascicles of large pigmented cells extending into deep reticular dermis or subcutis • Associated with adnexal or neurovascular structures – sometimes with bulbous contours • Moderate nuclear pleomorphism, mitoses absent to rare (1- 2/mm2) • Express most melanocytic markers; diffusely HMB45+ Plexiform Spindle Cell Nevus- Microscopic • Small diameter, sharp circumscription, symmetry • Fascicular (candelabra-like) architecture corresponding to neurovascular plexus, not necessarily deep or wedge- shaped • May have nevus components, low grade cytologic atypia, sparse mitoses • Diminished HMB45 gradient