Definition and Classification
A nevus (plural nevi) is a benign neoplasm of the skin:
- Commonly known as “mole,” “beauty mark,” or “birthmark”
- Nevus/nevi is a non-specific medical term because it encompasses several types of lesions (e.g., congenital and acquired, hyper- and hypopigmented, raised or flat).
- Usually used to refer to a hyperpigmented, slightly raised lesion (melanocytic nevi)
- Some sources refer to nevi as benign neoplasms composed of nevus cells, which are variants of melanocytes found at the dermo-epidermal junction or in the dermis.
- Melanocytes: melanin-producing cells derived from the neural crest, located in the stratum basale of the epidermis, as well as other places in the body
- This definition only refers to melanocytic nevi.
Nevi can be classified in various ways, according to several factors that are not mutually exclusive:
- Clinical history:
- Congenital: present at birth or develop within the 1st 4 weeks of life, though some sources include nevi that appear up to 2 years after birth
- Acquired: present later in life
- Location or depth of lesion:
- Epidermal: located in the epidermis (outermost layer of skin); usually comprises keratinocytes or adnexal structures (oil and sweat glands)
- Junction: located at the tips of the rete ridges in the dermal-epidermal junction; usually comprises melanocytes
- Compound: located both at the dermal-epidermal junction and in the dermis; usually comprises melanocytes
- Dermal: located only in the dermis; usually comprises melanocytes
- Subcutaneous: located under the skin; usually comprises adipose tissue (fat)
- Components or origin:
- Melanocytic: composed of clusters of melanocytes (most common)
- Vascular: composed of abnormal blood vessels, including capillaries
- Connective tissue: composed of abnormal clusters of dermal extracellular matrix (e.g., collagen, elastic fibers, fibroblasts)
- Morphology or distribution:
- Globular: presents a pattern of brown globules throughout the lesion but especially at the periphery, usually congenital
- Reticular: presents a patchy pigment network with or without areas of hypopigmentation or structureless brown-black coloration; usually acquired
- Starburst (Spitz/Reed): presents in a starburst pattern, meaning multiple streaks and/or globules of pigmentation arranged in a radiating pattern
- Hyperpigmented: either due to clusters of melanocytes or capillaries, can be blue-black, brown, pink, or red in color
- Hypopigmented: due to lack of melanin or constricted blood vessels, usually white in color
- Characteristics or associated risk of melanoma:
- Typical: has the common characteristics expected of a nevus
- Atypical or dysplastic: has an appearance that differs from common nevi/“moles” based on the ABCDE criteria (asymmetry, border irregularity, color variegation, diameter ≥ 6 mm, and evolution)
- Other classifications:
- Site-related nevi
- Nevi with special features (e.g., halo nevi)
- Unclassifiable nevi
Common Congenital Nevi
Congenital melanocytic nevus
- Epidemiology: occurs in 1%–3% of newborn infants
- Tan or light brown to black lesions
- May occur in any area of the body that is covered in skin
- Have somewhat irregular but defined borders
- Usually begin flat but may become raised over time
- May present with terminal hair growing within the lesion, sometimes associated with hypertrichosis (excessive hair growth)
- Increase in size proportionately to the lifetime growth of the individual
- Classification by size:
- Small: < 1.5 cm
- Medium: 1.5–19.9 cm
- Large: ≥ 20 cm
- Malignant potential: associated with the size of the nevus:
- Risk for small and medium-sized nevi: < 1%
- Risk for giant congenital nevi: 5%–10%
Congenital dermal melanocytosis
- Previously called “Mongolian spots”
- Epidemiology: more common in Native Americans, African Americans, and people of Asian and Latin descent
- Appear as blue-grey patches with indefinite borders
- The blue-black color is due to the entrapment of melanocytes in the dermis, instead of the epidermis.
- Usually in the lumbosacral or gluteal area
- Are always flat (macula)
- Normally disappear 2–3 years after birth and almost always by puberty
- Malignant potential: There are no case reports of melanoma developing from congenital dermal melanocytosis.
Nevus of Ito
- Epidemiology: more common in Asians and African Americans
- Blue, gray, or brown lesion
- Preferentially affects areas innervated by the posterior supraclavicular nerves, such as the shoulder, upper chest, and side of the neck
- Usually unilateral
- Malignant potential: Melanoma very rarely develops from a nevus of Ito.
Nevus of Ota
- More common in Asians and African Americans
- Women are nearly 5 times more affected than men.
- Bluish or brownish flat hyperpigmentation (macula)
- Preferentially affects areas innervated by the 1st and 2nd division of the trigeminal nerve (e.g., forehead, nose, cheek, periorbital region, and temple)
- Often affects the sclerae
- Malignant potential:
- Melanoma very rarely develops from a nevus of Ota.
- Requires yearly ophthalmologic examinations because of the rare risk of glaucoma
Common Acquired Nevi
- Present in almost everyone; 55% of adults have 10–45 nevi greater than 2 mm.
- Increase in incidence that peaks around the 4th decade, diminishing in number with advancing age
- Risk/triggering factors for the development of nevi:
- Family history
- Fair complexion
- Prolonged or excessive sun exposure
- The higher the number of nevi, the higher the risk for developing melanoma.
- Benign neoplasms of nevus cells that usually arise after 6 months of age:
- Nevus cells are a variant of melanocytes, derived from the neural crest.
- Typically form as a result of BRAF-V600E–activating mutations:
- Despite having the mutation, most nevi do not progress to melanoma because common acquired nevi are growth-arrested neoplasms.
- 33% of melanomas arise from a pre-existing nevus.
- 2 cardinal histopathologic features of nevi are nesting and maturation:
- Nesting: the tendency of nevus cells to form small clusters of cells within a tissue:
- Nevus cells can also aggregate in a non-nested pattern at the dermo-epidermal junction.
- Maturation: Nevi in the dermis show a gradual and progressive change (from superficial to deep) in nest architecture and cytology.
- Nesting: the tendency of nevus cells to form small clusters of cells within a tissue:
- No, or only rare, mitotic figures are seen in a nevus.
- Acquired melanocytic nevi are classified into 3 types depending on their depth, which represents the different stages of a continuous progression of growth:
- Junction nevus = 1st stage of growth
- Compound nevus = 2nd stage of growth
- Dermal or intradermal nevus = 3rd stage of growth
- As the cells migrate deeper, common acquired nevi develop a neural or Schwannian-type morphology before undergoing complete regression or atrophy, ultimately replaced by fat and fibrotic tissue.
|Compound nevi||Nevus cells found at the dermo-epidermal junction and intradermally, smaller cells that produce less melanin|
|Intradermal nevi||Nevus cells found intradermally, small cells that produce little to no melanin|
Based on clinical appearance, a typical benign nevus should have the following characteristics:
- < 5 mm in diameter
- Smooth border
- Uniform, unchanging color
- Slow growth history
- Skin surveillance including regular photos to follow the evolution of moles for patients at higher risk for melanoma
- Any lesion suspicious for melanoma must be biopsied or referred for biopsy.
- A nevus with small dark spots within (“hyperpigmented foci”) may signify melanoma arising in a previously benign mole.
Dysplastic or Atypical Nevi
A dysplastic or atypical nevus is a benign melanocytic nevus with an appearance that differs from common nevi or “moles” based on the ABCDE criteria (asymmetry, border irregularity, color variation, diameter ≥ 6 mm, and evolution):
- Some sources refer to dysplastic nevi as premalignant or precancerous lesions.
- Some sources refer to dysplastic nevi as a term for “diagnostic uncertainty,” where the lesion is either benign or malignant but has not yet been confirmed via biopsy.
Etiology and Epidemiology
- Often appear during puberty
- Prevalence in White populations: 2%–10%
- Share some of the clinical features of melanomas:
- Color variegation
- Irregular borders
- Diameter > 5 mm
- Development is primarily due to genetics: associated with activating NRAS or BRAF gene mutations, among others
- Associated with a 3–20–fold higher risk of melanoma
- Risk factors for developing atypical nevi:
- Fair complexion
- Prolonged or excessive sun exposure, but can occur on non-exposed surfaces
- Family/personal history of melanoma
- Familial atypical multiple mole and melanoma (FAMMM) syndrome:
- Autosomal dominant
- 40% of cases have mutations in CDKN2A, a tumor-suppressor gene
- Increased risk for malignancies, especially of the pancreas, breast, and esophagus
- Can be made on a clinical basis and may be assisted by dermoscopy, but the lesions must be biopsied for confirmation and to rule out melanoma
- Histologically characterized by:
- Architectural and cytologic atypia
- Enlargement of nevus cells
- Nests that often coalesce with adjacent nests
- The ABCDE criteria/mnemonic can help differentiate a nevus from melanoma.
|Common (benign) nevi||Atypical nevi||Melanoma (m.)|
|Asymmetry (A)||Symmetric (a straight line drawn through the center of the lesion gives 2 mirror images)|
|Border (B)||Smooth, well-defined border||Irregular margin with ill-defined border||Irregular margin with ill-defined border|
|Color (C)||Uniform color or regular color pattern (e.g., speckled or starburst)||Variegated color or varying shades of color||Variegated color or varying shades of color|
|Diameter (D)||< 5 mm||Often ≥ 5 mm||> 6 mm|
|Evolution (E)||Stable or slow growth|
|Location (not part of criteria, but an important factor)||Concentrated on sun-exposed sites||Depends on type:|
Management and follow-up
- Annual skin examinations
- Encourage the use of broad-spectrum sunscreen.
- Excision of suspicious lesions
- Routine ophthalmologic examinations
- Melanoma: the most deadly of all skin cancers. Clinical features that differ from atypical or dysplastic nevi are shades of blue-gray ugly duckling sign (distinct nevi differing from nevi pattern). Two-thirds arise de novo and ⅓ arise from pre-existing nevi.
- Basal cell carcinoma: the most common type of skin cancer. Arises from the basal cell layer of the epidermis. Most patients present with a slowly growing pearly nodular skin lesion with telangiectatic vessels on the surface.
- Seborrheic keratosis: benign neoplasm consisting of immature keratinocytes. Occurs most commonly in the elderly. Seborrheic keratosis is well-demarcated, waxy, and has a “stuck-on” appearance.
- Actinic keratosis: precancerous lesion affecting sun-exposed areas (e.g., scalp and hands) in elderly people and appears as a scaly, slightly elevated lesion that should be removed to prevent invasive squamous cell carcinoma development.
- Dermatofibroma: mesenchymal growth of the skin where skin fibroblasts are the major constituents. Appears as a firm, indurated, mobile nodule measuring 0.5–1 cm in size. Presents with a “buttonhole” sign with lateral compression. A dimple-like depression occurs in the overlying skin.
- Café-au-lait macule: flat, pigmented skin lesion. May be associated with type 1 neurofibromatosis and McCune-Albright syndrome.
- Lazar, A.L. (2020). The Skin. In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.), Robbins & Cotran Pathologic Basis of Disease. (10 ed. pp. 1135-1141). Elsevier, Inc.
- Dinulos, J.G.H. (2020). In Habif’s Clinical Dermatology (7th ed. pp. 863-875). Elsevier, Inc.
- Damsky, W. E., & Bosenberg, M. (2017). Melanocytic nevi and melanoma: unraveling a complex relationship. Oncogene, 36(42), 5771–5792. https://doi.org/10.1038/onc.2017.189
- Braun, R.P., Deinlein, T., & Salaudek, I. (2020). Classification of Nevi / Benign Nevus Pattern – Dermoscopedia. Dermoscopedia.Org. https://dermoscopedia.org/Classification_of_nevi_/_benign_nevus_pattern
- Rammel, K. (2017). Classification of Melanocytic Nevi. Medical University of Graz.