Combined Melanocytic Nevi

Combined melanocytic nevi are benign melanocytic proliferations with two (or more) histopathologic nevus phenotypes in the same clinical lesion. Their clinical importance lies in the diagnostic pitfall they pose—their possible confusion with melanoma. Knowledge of the clinical and histopathologic spectrum of features that occur in combined nevi is useful to enable the pathologist to avoid an erroneous diagnosis of melanoma associated with a preexisting nevus. Combined nevi have also been referred to as melanocytic nevi with phenotypic heterogeneity . They are regularly encountered in high-volume dermatopathology laboratories but are uncommon, accounting for fewer than 1% of biopsied melanocytic nevi and probably for a smaller proportion of all nevi in the general community (because combined nevi typically have a variegated appearance and are more frequently biopsied than common nevi).

Clinical Findings

Combined nevi may occur at any age. They are most often found in children and young adults but may also affect the elderly and can occur at any anatomic site. They display a spectrum of clinical findings. Most combined nevi present as circumscribed papules measuring up to 5 mm in diameter. There is often an associated clinical history of change, such as the appearance of a darker area in a preexisting macule or papule ( Figs. 9.1 and 9.2 ) and/or recent growth, raising concerns about a possible melanoma developing in association with a nevus. Combined nevi are often asymmetric because of the presence of two or more colors, ranging from skin-colored, red, blue, and brown to black. Asymmetry may also be related to the presence of both flat and raised tumor components within the same lesion.

Fig. 9.1, (A) Clinical appearance of a combined deep penetrating nevus. There is a bluish-black area eccentrically located in association with a light brown macule. (B) Dermoscopic features. The lesion is circumscribed, but the two colors create asymmetry, leading to clinical concerns.

Fig. 9.2, Clinical Appearance of a Combined Deep Penetrating Nevus.

The clinical phenotype of a combined nevus reflects the histopathologic findings. Conventional small acquired or congenital melanocytic nevi combined with a blue nevus, deep penetrating nevus (DPN), or pigmented large epithelioid melanocyte component usually manifest as a dark brown or bluish-black area in a more lightly colored lesional background (see Fig. 9.1 ). Combined melanocytic nevi with a Spitz nevus or BRCA1 Associated Protein 1 (BAP1)-deficient epithelioid melanocyte population (also known as “BAP1-inactivated melanocytic nevi” or “Wiesner nevi”) usually present as skin-colored to reddish dome-shaped papules ( Fig. 9.3 ). They may be associated with a clinically visible flat nevus remnant.

Fig. 9.3, Clinical Appearance of a Combined BAP1-inactivated Nevus.

Histopathologic Findings

In principle, any cytologic features of melanocytes and related nevus phenotype can occur in the same clinical lesion to form a combined nevus. Frequent combinations include those of a conventional acquired or small congenital nevus together with a blue nevus, DPN, Spitz nevus, or nevus of large pigmented epithelioid melanocytes ( Box 9.1 ). The conventional nevus is usually composed of small, plump, round to oval melanocytes with bland nuclear features (“type B” melanocytes). It is typically amelanotic or paucimelanotic whereas the second population—except for spitsoid, desmoplastic, or neurotized tumors—is often pigmented. Various nevus phenotypes may also be combined with a Clark or “dysplastic” nevus or with each other (e.g., blue and Spitz nevi). As can occur with other melanocytic nevi, combined melanocytic nevi may become inflamed or may be associated with features of trauma or partial regression.

Box 9.1

Variants of Combined Nevi

Combined conventional ^a

a The conventional nevus may be a common acquired, congenital, or “dysplastic”/Clark nevus.

and blue nevus

Combined conventional ^a and deep penetrating nevus

Combined conventional ^a and inverted type A nevus

Combined conventional ^a and Spitz nevus ^b

b The spectrum of Spitz nevi includes the BAP1-inactivated combined nevus.

Combined conventional ^a and desmoplastic nevus

Combined conventional ^a and balloon cell nevus

Combined conventional ^a nevus and pigmented epithelioid melanocytoma

Combined blue and Spitz nevus

Conventional Nevus Combined With a Blue Nevus

In combined nevi with a blue nevus component, the pigmented fusiform and dendritic melanocytes along with melanophages may be admixed with a conventional nevus, or each component may have its own territory and dominate a distinct area within one clinical lesion ( Figs. 9.4–9.6 ). The blue nevus component may be adjacent to or located under the conventional nevus cell population, or it may surround the latter.

Fig. 9.4, Combined Conventional and Blue Nevus.

Fig. 9.5, Congenital nevus, in which a blue nevus cell population is located adjacent to ordinary epithelioid melanocytes.

Fig. 9.6, Combined Conventional and Blue Nevus.

The blue nevus cell population in a combined nevus usually displays features of a common blue nevus, but on occasion it may also display epithelioid cell or sclerosing features. In the context of a large congenital nevus, it may have features of cellular blue nevus. The blue nevus cell population is usually pigmented, but the phenotype of an amelanotic blue nevus can also be found in combination with a conventional nevus.

Conventional Nevus Combined With a Deep Penetrating Nevus

In conventional nevi combined with a DPN, the latter nevus population usually dominates the histopathologic picture; that is, it is usually larger than the conventional nevus remnant ( Figs. 9.7 and 9.8 ). However, sometimes it constitutes a minor cell population of a nevus ( Figs. 9.9 and 9.10 ). The DPN population shows characteristically large, oval or polygonal, lightly pigmented cells with vacuolated cytoplasm admixed with melanophages. There may also be hyperchromatic and large nuclei with nuclear pseudoinclusions. The DPN cells typically grow in a plexiform fashion, often following neurovascular or appendiceal structures. In some combined lesions, the DPN component is rather superficial. In others it may extend deep into the subcutis, and cell aggregates may be found a significant distance beyond the conventional nevus. There are many variations in the cytologic composition of deep penetrating nevi, from mixed spindle and epithelioid to predominantly fusiform or predominantly epithelioid.

Fig. 9.8, Congenital compound melanocytic nevus combined with a deep penetrating nevus. There is a broad plaque lesion of a superficial conventional nevus overlying a deep penetrating nevus, which occupies the middle and deep dermis.

Fig. 9.9, Congenital melanocytic nevus combined with a minor subpopulation of pigmented spindle and epithelioid melanocytes with melanophages in the middle of the conventional nevus.

Fig. 9.10, Congenital Melanocytic Nevus Combined With a Deep Penetrating Nevus (DPN).

Incompletely removed combined nevi with a DPN component may persist and clinically recur ( Fig. 9.11 ). If the DPN component was prominent and present at the base of the prior biopsy, the clinical recurrence may display a pure DPN phenotype.

Fig. 9.11, Persistent/Recurrent Combined Deep Penetrating Nevus.

Conventional Nevus Combined With a Proliferation of Large Epithelioid Melanocytes

In this variant of a combined nevus, there is a proliferation of large, variably pigmented epithelioid melanocytes associated with a conventional (acquired or small congenital) nevus. The large pigmented melanocytes may form small aggregates within an otherwise undisturbed nevus or form more densely cellular aggregates, in middle or near the base of a lesion ( Figs. 9.12–9.14 ). Mitotic figures may be seen, but they are usually rare (≤2 mitoses/mm ² ). Melanocytic nevi with a subpopulation of large pigmented epithelioid melanocytes have also been termed clonal or inverted type A nevi, or they may be reported descriptively as melanocytic nevus with a focal atypical epithelioid cell component . Many lesions classified as clonal or inverted type A nevus could also be regarded as epithelioid variants of DPN if activating mutations of beta-catenin were found that would support such an interpretation. However, in some combined lesions the pigmented epithelioid melanocytes look cytologically different from the pigmented melanocytes of DPN ( Fig. 9.15 ). It is therefore possible that there is some heterogeneity in the associated molecular pathways of this group of combined lesions.