Case 1 History
The patient is a 40-year-old male with a 6-mm darkly pigmented right forearm macule, which is circumscribed and has been unchanging.
Microscopic Findings
Sections demonstrate slight epidermal acanthosis associated with a symmetric and laterally demarcated proliferation of single and nested conventional melanocytes ( Fig. 12.1 ). These cells populate the sides and tips of elongated rete ridges. Melanocytes have small dark nuclei and do not extend above the junction. Similar small melanocytes are present as nests and small clusters in the superficial dermis.
Diagnosis
Lentiginous Compound Melanocytic Nevus
Clinical Presentation
Compound melanocytic nevi typically present as pigmented macules and papules. Presentation can occur in childhood or adulthood. There may be clinical concern for the possibility of atypicality if pigmentation is dark or varied.
Histopathology
Melanocytic nevi are stratified into junctional, intradermal, and compound subtypes. Whereas the designation junctional refers to involvement limited to the epidermis, intradermal melanocytic nevi lack epidermal involvement. Compound melanocytic nevi involve both compartments. Lentiginous melanocytic nevi include many single melanocytes together with nests along the sides and tips of elongated rete ridges; however, bridging of nests across rete ridges or lamellar fibroplasia is typically not prominent. Horizontal symmetry is common, and pagetoid scatter (scatter above the junction) and confluence are uncommon. The dermal involvement in compound and intradermal melanocytic nevi typically exhibits a maturing configuration. That designation implies that both the size of melanocytes and the size of clusters of melanocytes tend to become smaller with progressive dermal depth. In melanocytic nevi with minimal dermal involvement, maturation can be inconspicuous.
Differential Diagnosis
The differential diagnosis includes lentigo simplex and lentiginous compound superficial congenital melanocytic nevus.
Lentigo Simplex
Lentigines represent small, pigmented macules. Lentigo simplex is typified by an increase in small single melanocytes, and actinic (solar) lentigo presents in sun-damaged skin and typically does not include an increase in melanocyte density.
Clinical Presentation
Lentigo simplex presents as a subcentimeter pigmented macule with sharp demarcation from adjacent uninvolved skin.
Histopathology
Conceptually, simple lentigines are often thought of as an early stage in melanocytic tumor development. There is an increase in single melanocytes distributed along the sides and tips of pigmented rete ( Fig. 12.2 ). Melanocytes have inconspicuous cytoplasm and tiny uniform nuclei. Nests are rarely present but can occasionally be found in level sections. The epidermis shows variable hyperplasia with elongated slender rete. Epidermal pigmentation may be prominent, and pigmentation of the stratum corneum may be seen.
Lentiginous Compound Superficial Congenital Melanocytic Nevus
Melanocytic nevi present at birth or during the first 2 years of life and commonly involve the reticular dermis in syncytial fashion. There may be periadnexal and perivascular involvement in the dermis as well. This distribution is referred to as a congenital pattern . Nevi with a similar histopathologic distribution may also present in an acquired fashion in adults.
Clinical Presentation
Congenital nevi are present at birth or develop early in life. Enlargement that is proportional to the growing child is to be expected. Involvement may be macular or papular, and papillomatous or verrucous exophytic morphology can develop over time. There may be enlarged terminal hair follicles within the melanocytic nevus. Congenital nevi may clinically mimic melanoma with changes in pigmentation, border irregularity, and asymmetrical enlargement.
Histopathology
Congenital melanocytic nevi are most commonly stratified into intradermal or compound types. Encountering pure junctional involvement in a congenital melanocytic nevus is a rarity. Whereas lentiginous compound superficial congenital melanocytic nevus includes a lentiginous junctional component with both single cells and nests, subjacent dermal involvement includes nests and syncytia in the reticular and adventitial (follicular or adnexal) dermis ( Fig. 12.3 ). Secondary changes, including neural differentiation and adipocytic metaplasia, can be found.
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Lentiginous compound melanocytic nevus
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Clinical: pigmented macule or papule
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Histopathology: small melanocytes distributed singly and in nests at the junction above similar maturing dermal melanocytes
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Lentigo simplex
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Clinical: flat, demarcated pigmented macule
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Histopathology: increase in single melanocytes with epidermal pigmentation and hyperplasia
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Lentiginous compound superficial congenital nevus
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Clinical: pigmented plaque with embedded terminal hair
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Histopathology: deep dermal or periadnexal involvement, entrapped terminal follicles, and deep neural differentiation
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Case 2 History
A 42-year-old female has a dark, blue-gray 5-mm flat lesion on her upper arm, which has been present since childhood.
Microscopic Findings
Sections reveal an intradermal proliferation of small spindled and dendritic melanocytes with pigmented cytoplasm situated in the superficial and mid-dermis with accompanying melanophages ( Fig. 12.4 ). There is accompanying sclerosis with compact collagen bundles.
Diagnosis
Blue Nevus
Clinical Presentation
Blue nevi often present with a distinctive blue-gray hue because of the Tyndall effect, which is an optical phenomenon triggered by deeply situated pigmentation. So-called common blue nevi are usually subcentimeter maculopapules involving the distal extremities, head, or buttock. Onset is often in late childhood. It is important to remember that blue nevi and conventional melanocytic nevi have distinct oncogenesis. Blue nevi are typically initiated by mutations in GNAQ and GNA11. By contrast, conventional melanocytic nevi are commonly initiated by mutations in BRAF or NRAS.
Histopathology
Blue nevi consist of uniform fusiform or dendritic melanocytes situated largely in the dermis (a compound distribution or subcutaneous involvement can also be found on occasion). The melanocytes are typically deeply pigmented and are often associated with melanophages. This confers a pigmented appearance at low power. Associated fibrosis or sclerosis is common. The triad of pigmented dendritic melanocytes, melanophages, and fibrosis is quite characteristic.
Differential Diagnosis
The differential diagnosis of blue nevi includes various subtypes of deeply pigmented melanocytic tumors. For purposes of this discussion, the differential diagnosis includes cellular blue nevus, deep penetrating melanocytoma, and pigmented epithelioid melanocytoma (PEM) ( Table 12.1 ).
| Common Blue Nevus | Cellular Blue Nevus | Deep Penetrating Melanocytoma | Pigmented Epithelioid Melanocytoma | |
|---|---|---|---|---|
| Melanocyte Cytology | Dendritic and pigmented | Hypercellular, fascicular, and variably pigmented | Epithelioid and finely pigmented; often combined | Enlarged with both fusiform and epithelioid cells; sometimes combined |
| Accompaniments | Melanophages and fibrosis | Melanophages and fibrosis | Melanophages | Melanophages and marked acanthosis |
| Architecture or silhouette | Incompletely circumscribed | Dumbbell or nodular | Domed or nodular with internal cords and nests (plexiform) | Domed with a wedge-shaped profile |
| Mutations | GNAQ/GNA11 | GNAQ/GNA11 | BRAF and CTNNB1 | BRAF and PRKAR1A |
Cellular Blue Nevus
Cellular blue nevi exhibit hypercellularity relative to common blue nevi. The arrangement is typically nodular and may include fascicles of melanocytes.
Clinical Presentation
Cellular blue nevi prototypically develop on the scalp, buttock, or sacrum as a deeply pigmented or blue plaque or nodule. The size may exceed 1 cm, and cellular blue nevi of 2 to 3 cm across are not rare. Because of their large size and prominent pigmentation, cellular blue nevi may trigger clinical concern for the possibility of melanoma.
Histopathology
Similar to common blue nevi, cellular blue nevi include pigmented melanocytes, melanophages, and associated sclerosis ( Fig. 12.5 ). Melanocytes are far more numerous in cellular blue nevi and aggregate in a nested or fascicular configuration with varying pigmentation. At scanning magnification, a dumbbell-shaped silhouette is not uncommon. Cells remain cytologically monomorphous. The mitotic index is typically low. Stromal degenerative changes, including edema, exaggerated sclerosis, hyalinization, and hypocellularity, are not uncommon.
Deep Penetrating (Wnt-Activated) Melanocytoma
Deep penetrating melanocytoma was previously known as deep penetrating nevus . , The clinical morphology is similar to blue nevus. Deep penetrating melanocytoma was originally interpreted as a subtype of blue nevus on the basis of shared deep pigmentation, but it is now known that the molecular oncogenesis of the two entities is distinct.
Clinical Presentation
Deep penetrating melanocytoma can present at any age or site. Involvement is typically asymptomatic.
Histopathology
Paradigmatically, deep penetrating melanocytoma represents an example of two-step oncogenesis. An initiating mutation (commonly involving BRAF V600E ) triggers the development of a melanocytic nevus and a subsequent activating mutation in CTNNB1 , which encodes the β-catenin protein, triggers Wnt pathway activation and eventuates in a secondary population of melanocytoma. Deep penetrating melanocytoma can present to the pathologist in pure or combined fashion. Per the paradigm discussed earlier in this paragraph, pure deep penetrating melanocytic melanocytoma presumably is associated with a focus of melanocytic nevus that falls out of the plane of section.
The histopathologic spectrum of deep penetrating melanocytoma is diverse. In pure deep penetrating melanocytoma, the distribution may be compound or wholly intradermal. The constituent melanocytes have ample pale pigmented morphology and may be arranged in nests or fascicles ( Fig. 12.6 ). Periadnexal extension and balloon cell change are common. Accompanying melanophages are typically conspicuous.
Combined deep penetrating melanocytoma is identical to pure deep penetrating melanocytoma with the additional finding of an explicit accompanying population of conventional melanocytic nevus. Because of the presence of two populations of melanocytes, combined deep penetrating melanocytoma may be asymmetrical.
Pigmented Epithelioid Melanocytoma
PEM was described on morphologic grounds before its molecular oncogenesis was defined, which created overlap with tumors categorized as epithelioid blue nevus or so-called animal-type melanoma. In short, early case series may have been nonhomogenous in nature. It has now been established that PEM follows two-step oncogenesis that is analogous to that of deep penetrating melanocytoma. An initiating mutation (such as mutation in BRAF V600E ) is followed by genetic inactivation (commonly of PRKAR1A ), which typically eventuates with a heavily pigmented fusiform tumor cell population. It is important to remember that PEM is commonly a misnomer, because many examples of PEM are composed of spindled melanocytes.
Clinical Presentation
PEM may present in the context of Carney complex or sporadically. (Carney complex is associated with PRKAR1A mutation.) The tumors present as deeply pigmented exophytic nodules or papules that are inherently concerning for melanoma. Clinical stigmata of Carney complex can be sought as a means to distinguish whether a given tumor is sporadic or germline in nature.
Histopathology
PEM presents to the pathologist as a deeply pigmented wedge-shaped compound or dermal proliferation composed of fusiform and epithelioid melanocytes ( Fig. 12.7 ). Associated acanthosis is almost universally present. A contiguous remnant of conventional melanocytic nevus may be found. Melanophages are typically abundant.
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Conventional (common) blue nevus
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Clinical: blue-gray macule on the distal extremity, head, or buttock
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Histopathology: pigmented dendritic melanocytes, melanophages, and sclerosis
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Cellular blue nevus
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Clinical: blue to brown plaque or nodule on the scalp or sacrum
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Histopathology: hypercellular with fascicles, stromal sclerosis, and variable pigmentation
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Deep penetrating melanocytoma
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Clinical: new or changing pigmented tumor
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Histopathology: may be pure or combined; includes epithelioid melanocytes with finely melanized cytoplasm arranged in nests and fascicles
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Pigmented epithelioid melanocytoma
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Clinical: deeply pigmented nodules that are sometimes associated with Carney complex
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Histopathology: may be pure or combined; acanthosis is typically present; melanocytes are enlarged and epithelioid or fusiform; melanophages are numerous
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