# Melanocytic Lesions: Benign, Atypical, and Malignant

## Overview

The spectrum of melanocytic lesions ranges from benign nevi through dysplastic nevi to melanoma. The histologic distinction between severely dysplastic nevi and early melanoma stands as one of the most challenging and consequential diagnoses in surgical pathology, carrying significant interobserver variability and medicolegal implications.

## Benign Melanocytic Nevi

### Common Acquired Nevi

Junctional nevi consist of nests of melanocytes confined to the dermoepidermal junction (DEJ) and are clinically flat. Compound nevi have nests at both the DEJ and within the dermis, producing a raised center with a flat periphery. Intradermal nevi contain nests entirely within the dermis and appear papillomatous or dome-shaped. The key histologic feature of benign nevi is maturation: nests become smaller and melanocytes become more dispersed with increasing depth, creating a maturation gradient. Nuclear features remain small, uniform, and bland without prominent nucleoli.

### Special Nevus Variants

#### Spitz Nevus

Spitz nevi occur predominantly in children and young adults, presenting clinically as a dome-shaped pink papule. Morphologically, they consist of large spindle and/or epithelioid melanocytes in vertically oriented nests with sharp lateral borders, epidermal hyperplasia, and Kamino bodies (eosinophilic globules at the DEJ). Mitotic figures may be present superficially, but deep mitoses are concerning for malignancy. By immunohistochemistry, PRAME is typically negative, p16 is retained (homogeneous), and Ki-67 is low. Molecularly, HRAS mutations occur in approximately 20 percent of classic Spitz nevi, while ALK, ROS1, NTRK1/3, BRAF, and MET fusions characterize "spitzoid" tumors.

#### Blue Nevus

Blue nevi consist of deep dermal collections of dendritic melanocytes laden with melanin. The common blue nevus is well-circumscribed with bland spindle melanocytes in the dermis. The cellular blue nevus is larger and more cellular, often dumbbell-shaped, and can be confused with melanoma. GNAQ or GNA11 mutations are characteristic of these lesions.

#### Congenital Melanocytic Nevus

These nevi are present at birth or appear within the first weeks of life. Large or giant congenital nevi (exceeding 20 cm) carry a risk of neurocutaneous melanocytosis and malignant transformation. Histologically, they are distinguished by melanocytes permeating adnexal structures (hair follicles, vessels, nerves) and extending into the deep reticular dermis and subcutis.

#### Halo Nevus (Sutton Nevus)

A halo nevus shows a dense lymphocytic infiltrate surrounding and destroying a nevus, producing clinical depigmentation around a central lesion. The key distinction from regressing melanoma is that the underlying lesion should be a symmetric, maturing nevus.

#### Recurrent/Persistent Nevus

When a nevus is incompletely removed, the melanocytic proliferation that regrows at the scar site can show alarming features including junctional confluence, pagetoid spread, and lack of maturation. The critical point is that these changes are confined to the scar area. Comparing with the original biopsy is essential and always reveals a benign nevus.

## Dysplastic Nevus (Clark Nevus)

### Histologic Features

Dysplastic nevi show lentiginous junctional melanocytic hyperplasia extending beyond the dermal component (the "shoulder phenomenon"), bridging of rete ridges by melanocytic nests, lamellar or concentric fibroplasia of the papillary dermis, cytologic atypia (nuclear enlargement, hyperchromasia, irregular contours, dusty melanin), and a random or disordered nesting pattern with variation in nest size and shape.

### Grading of Dysplasia

Mild dysplasia shows minimal cytologic atypia with limited architectural disorder. Moderate dysplasia has intermediate features. Severe dysplasia shows significant cytologic atypia approaching melanoma in situ, with limited pagetoid scatter and confluence of melanocytes. The distinction between severe dysplasia and melanoma in situ is one of the most controversial areas in dermatopathology, with poor interobserver agreement (kappa approximately 0.3 to 0.5). Some institutions use the term "MELTUMP" (melanocytic tumor of uncertain malignant potential) for truly borderline cases.

### Management Based on Dysplasia Grade

Mild or moderate dysplasia with clear margins generally requires no re-excision. Severe dysplasia warrants re-excision with clear margins, and many institutions treat it similarly to melanoma in situ. Positive margins for mild dysplasia can be managed with clinical follow-up alone.

## Melanoma

### Melanoma In Situ

Melanoma in situ consists of malignant melanocytes confined entirely to the epidermis without dermal invasion. Key features include pagetoid spread (melanocytes scattered upward through the epidermis), confluence of melanocytes along the DEJ, poor maturation, and cytologic atypia. Lentigo maligna is melanoma in situ occurring on sun-damaged skin with an atrophic epidermis, showing atypical melanocytes along the DEJ extending down adnexal structures. Management requires excision with 5 mm margins or wider for lentigo maligna.

### Invasive Melanoma

#### Morphologic Features of Malignancy

The features that distinguish invasive melanoma from benign melanocytic lesions include asymmetry (irregular silhouette), poor circumscription (lack of sharp lateral borders), pagetoid spread (melanocytes scattered throughout the epidermis in a "buckshot" pattern), confluence (continuous sheets of melanocytes at the DEJ without intervening keratinocytes), lack of maturation (melanocytes remaining large and atypical with depth rather than diminishing in size), deep mitoses, cytologic atypia (large nuclei with prominent eosinophilic nucleoli and irregular nuclear membranes), ulceration (loss of overlying epidermis), and regression (fibrosis, melanophages, and lymphocytic infiltrate replacing tumor).

#### Histologic Subtypes

Superficial spreading melanoma is the most common subtype at approximately 70 percent. It shows a radial growth phase with pagetoid spread, extending laterally before developing a vertical growth component. Nodular melanoma displays vertical growth phase from onset without a significant radial growth component, grows rapidly, and carries a worse prognosis stage-for-stage. Lentigo maligna melanoma is an invasive component arising within a lentigo maligna on sun-damaged skin, typically in elderly patients on the head and neck. Acral lentiginous melanoma occurs on palms, soles, and subungual sites, is the most common melanoma in darker-skinned populations, and shows lentiginous growth with pagetoid spread. Desmoplastic melanoma features spindle cell morphology with a fibrotic stroma and common perineural invasion; it is S100-positive but often HMB-45 and Melan-A negative, with SOX10 being positive. It is locally aggressive but has a lower metastatic rate.

### Prognostic Factors and Staging

#### Breslow Thickness

Breslow thickness is the single most important prognostic factor in melanoma. It is measured from the granular layer of the epidermis (or the base of ulceration if ulcerated) to the deepest point of invasion. Lesions under 1 mm carry excellent prognosis (greater than 95 percent 10-year survival), 1 to 2 mm is intermediate risk, 2 to 4 mm is higher risk, and greater than 4 mm carries the highest risk (approximately 50 to 60 percent 10-year survival).

#### Ulceration

Ulceration is the second most important prognostic factor. It upstages within each T category (distinguishing T2a from T2b, for example) and is defined as full-thickness loss of epidermis overlying the melanoma, not processing artifact.

#### Mitotic Rate

While mitotic rate (1 or more per mm2) was previously used for T1 substaging in the AJCC 7th edition and was removed from staging in the 8th edition, it remains prognostically relevant. A high mitotic rate is associated with sentinel lymph node positivity and worse survival.

#### Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy is recommended for melanomas exceeding 0.8 mm Breslow thickness, or for thinner melanomas with ulceration or high mitotic rate. A positive sentinel lymph node is the strongest predictor of recurrence. Histologic assessment includes H&E and immunohistochemistry (S100, HMB-45, Melan-A) on multiple sections. Micrometastases are classified using the Dewar system (subcapsular, combined, multifocal, extensive, or focal nodal involvement).

### Immunohistochemistry for Melanocytic Lesions

S100 is the most sensitive marker and is positive in nearly all melanomas, though it lacks specificity (also staining nerve, cartilage, and dendritic cells). HMB-45 is positive in junctional melanocytes and melanoma but negative in intradermal nevus cells, making it a useful maturation marker. Melan-A (MART-1) is sensitive for melanoma but can overestimate melanocyte density on sun-damaged skin by highlighting dendritic processes. SOX10 is a nuclear transcription factor that is both sensitive and specific for melanocytic lineage, particularly useful in desmoplastic melanoma. PRAME shows diffuse nuclear positivity in melanoma and is emerging as an important adjunct for distinguishing melanoma from nevi. Loss of p16 expression (reflecting homozygous CDKN2A deletion) supports melanoma, while retained expression favors benign nevi and Spitz nevi. Ki-67 shows higher proliferation index in melanoma compared to nevi and serves as a useful adjunct though not a standalone marker.

| Marker | Melanoma | Benign Nevus | Notes |
|---|---|---|---|
| S100 | + (most sensitive) | + | Lacks specificity |
| HMB-45 | + (diffuse, including deep) | + superficial only (maturation) | Loss with depth = benign |
| Melan-A | + | + | Overstains sun-damaged skin |
| SOX10 | + | + | Best for desmoplastic melanoma |
| PRAME | + (diffuse, >75%) | - or patchy | Emerging key adjunct |
| p16 | Lost (null) | Retained (strong +) | Loss = CDKN2A deletion |
| Ki-67 | High (>10%, deep labeling) | Low (<5%, superficial only) | Adjunct, not standalone |

<image>A medical illustration showing the histologic features distinguishing benign nevi, dysplastic nevi, and melanoma. Panel A (Compound nevus): Symmetric, well-circumscribed lesion with orderly junctional nests that mature and become smaller with depth into the dermis, bland cytology, and no pagetoid spread. Panel B (Dysplastic nevus with severe dysplasia): Asymmetric, with a shoulder of junctional melanocytic hyperplasia extending beyond the dermal component, bridging of rete ridges, lamellar fibroplasia, cytologic atypia with enlarged hyperchromatic nuclei, and limited pagetoid scatter. Panel C (Invasive melanoma, superficial spreading type): Asymmetric with poor circumscription, extensive pagetoid spread through all layers of the epidermis (buckshot pattern), confluence of melanocytes at the DEJ, lack of maturation with depth (large atypical cells with prominent nucleoli remaining in the deep component), and deep mitotic figures (arrow). Breslow thickness measurement line shown from granular layer to deepest invasive cell.</image>

<image>A medical illustration demonstrating the immunohistochemistry panel used to distinguish melanoma from nevus. Left column (Melanoma): HMB-45 showing diffuse positivity including deep component (no maturation loss), Ki-67 showing elevated proliferation index (>10%) with labeling in the deep component, PRAME showing diffuse strong nuclear positivity, and p16 showing loss of expression (negative). Right column (Nevus): HMB-45 showing positivity in superficial junctional component with loss in deep dermal component (maturation), Ki-67 showing low proliferation index (<5%) limited to superficial cells, PRAME negative, and p16 showing retained strong expression. A summary comparison table with expected staining patterns is included below.</image>

## Clinical Pearls

HMB-45 maturation (loss of staining with depth) is a hallmark of benign nevi; when HMB-45 positivity persists in the deep component, melanoma is favored. PRAME is an increasingly important adjunct marker: diffuse nuclear positivity in more than 75 percent of lesional cells supports melanoma, while negativity or patchy staining favors a benign nevus, though it is not 100 percent specific and must be interpreted in context.

Melan-A immunohistochemistry on sun-damaged skin can dramatically overestimate melanocyte density because it highlights dendritic processes. For accurate melanocyte counting at margins, SOX10 (a nuclear stain) provides superior results. Recurrent or persistent nevi can display alarming histologic features (pagetoid spread, confluence) confined to the scar, so the original biopsy must always be requested and reviewed before diagnosing recurrent melanoma.

Desmoplastic melanoma is frequently misdiagnosed as scar or fibromatosis because HMB-45 and Melan-A are often negative; SOX10 and S100 are essential for making the diagnosis. Breslow thickness is measured to the nearest 0.1 mm from the granular layer of the overlying epidermis (or the base of ulceration if ulcerated) to the deepest invasive melanoma cell. When genuine uncertainty exists between severely dysplastic nevus and melanoma in situ, seeking an expert second opinion is appropriate given the significant management and medicolegal implications.

## References
- Elder DE, et al. *WHO Classification of Skin Tumours*. 4th ed. IARC; 2018.
- Gershenwald JE, et al. Melanoma staging: Evidence-based changes in the AJCC Cancer Staging Manual, Eighth Edition. *CA Cancer J Clin*. 2017;67(6):472-492.
- Elmore JG, et al. Pathologists' diagnosis of invasive melanoma and melanocytic proliferations: Observer accuracy and reproducibility study. *BMJ*. 2017;357:j2813.
- Lezcano C, et al. PRAME expression in melanocytic tumors. *Am J Surg Pathol*. 2018;42(11):1456-1465.
- Barnhill RL, et al. *Pathology of Melanocytic Nevi and Melanoma*. 3rd ed. Springer; 2014.