Nevus/Nevi

Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Additionally, nevi can be found within different depths of the layers of the skin and originate from various types of cells (e.g., melanocytic, connective tissue, vascular). Nevi also have a wide variety of characteristic forms, which must be well understood in order to differentiate nevi from malignant melanoma. In this concept page, we will cover the basic classifications and most common types of nevi as well as the clinical criteria used to assess them.

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Definition and Classification

Definition

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.

Classification

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
  • Pigmentation:
    • 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
Classification of Specific Melanocytic Lesions

From left to right: reticular, starburst, and globular types of nevi

Image: “Clark nevus” by the Department of Automatics and Biomedical Engineering, AGH University of Science and Technology, Aleja Mickiewicza 30, 30-059 Krakow, Poland. License: CC BY 4.0.

Common Congenital Nevi

Congenital melanocytic nevus

  • Epidemiology: occurs in 1%–3% of newborn infants
  • Appearance: 
    • 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 melanocytic nevus

Congenital melanocytic nevus: a brown well-circumscribed papule on the nose that developed shortly after birth

Image: “Congenital melanocytic nevus” by M. Sand et al. License: CC BY 2.0.

Congenital dermal melanocytosis

  • Previously called “Mongolian spots”
  • Epidemiology: more common in Native Americans, African Americans, and people of Asian and Latin descent
  • Appearance: 
    • 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.
Mongolian spots

Mongolian spot or congenital dermal melanocytosis over the lumbar and gluteal regions

Image: “Enorme tache mongoloïde” by Service de Pédiatrie, Hôpital Militaire d’Instruction Mohamed V, Université Med V, Souissi, Maroc. License: CC BY 2.0.

Nevus of Ito

  • Epidemiology: more common in Asians and African Americans
  • Appearance:
    • 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 Ito

Congenital nevus of Ito: blue-gray macule, representing a benign dermal melanocytosis that preferentially affects areas innervated by the posterior supraclavicular nerves

Image: “Nevus of Ito” by the U.S. National Library of Medicine. License: CC BY 4.0.

Nevus of Ota

  • Epidemiology:
    • More common in Asians and African Americans
    • Women are nearly 5 times more affected than men.
  • Appearance:
    • 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
Nevus eye

Congenital nevus of Ota: benign dermal melanocytosis that preferentially affects areas innervated by the 1st and 2nd division of the trigeminal nerve. A congenital nevus of Ota often affects the sclerae.

Image: “Nevus” by Luninsky. License: CC BY 3.0.

Common Acquired Nevi

Epidemiology

  • 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.

Etiology

  • 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.

Histopathology

  • 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.
  • 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:  
    1. Junction nevus = 1st stage of growth
    2. Compound nevus = 2nd stage of growth
    3. 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.
Table: Acquired nevi
TypeDescriptionPresentation
Junctional nevi
  • Nevus cells found at the dermo-epidermal junction
  • Large cells that produce melanin
  • Most common mole in children
  • Well-demarcated, brownish macules that are minimally raised
  • Uniformly pigmented, tan to brown/black
  • Usually ≤ 5 mm
Compound neviNevus cells found at the dermo-epidermal junction and intradermally, smaller cells that produce less melanin
  • Pigmented papules
  • Smooth, dome shaped
  • Similar to junctional nevi but with elevation and lighter color
Intradermal neviNevus cells found intradermally, small cells that produce little to no melanin
  • Most common mole in adults
  • Skin-colored to tan
  • Similar to compound nevi
  • Dome shaped or papillomatous
  • May present with terminal hair, fibrotic texture, speckled appearance
Non-Melanoma

Natural history of acquired melanocytic nevi

Common nevi (“moles”) begin as uniformly tan or brown macules, 1 to 2 mm in diameter (a), expand to a larger macule (b), progress to a pigmented papule that may be minimally (c) or obviously (d) elevated above the surface of the skin, and terminate as a pink or flesh-colored papule (e).
Acquired melanocytic nevi are junctional (a, b), compound (c, d), and dermal (e) nevi, respectively. Note their smooth borders, uniform coloring, and clear demarcation from the surrounding skin with smooth borders.
Acquired melanocytic nevi are usually < 5 mm in diameter.

Image: “Non-melanoma” by Visualsonline.cancer.gov. License: Public domain.

Diagnosis

Based on clinical appearance, a typical benign nevus should have the following characteristics: 

  • Symmetric
  • < 5 mm in diameter
  • Smooth border
  • Uniform, unchanging color
  • Slow growth history

Management

  • 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

Definition

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:
    • Asymmetry
    • 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

Diagnosis

  • 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.
Table: ABCDE criteria to differentiate nevi and melanoma
Common (benign) neviAtypical neviMelanoma (m.)
Asymmetry (A)Symmetric (a straight line drawn through the center of the lesion gives 2 mirror images)
  • Asymmetric
  • May have both macular and papular components
  • Asymmetric
  • May have both macular and papular components
Border (B)Smooth, well-defined borderIrregular margin with ill-defined borderIrregular margin with ill-defined border
Color (C)Uniform color or regular color pattern (e.g., speckled or starburst)Variegated color or varying shades of colorVariegated color or varying shades of color
Diameter (D)< 5 mmOften ≥ 5 mm> 6 mm
Evolution (E)Stable or slow growth
  • Not present at birth
  • Generally remain stable
  • Depends on type
  • Varies from rapid growth (e.g., nodular m.) to slow growth (lentigo maligna m.)
Location (not part of criteria, but an important factor)Concentrated on sun-exposed sites
  • Sun-exposed areas and in unusual sites (scalp, buttocks, breast)
  • In familial forms:
    • The back is more affected in both males and females.
    • The extremities are more affected in females.
Depends on type:
  • Trunk and extremities in superficial spreading and nodular m.
  • Sun-exposed areas in superficial spreading m.
  • Palms, soles, and under nail plate, in acral-lentiginous m.

Management and follow-up

  • Annual skin examinations
  • Encourage the use of broad-spectrum sunscreen.
  • Excision of suspicious lesions
  • Routine ophthalmologic examinations

Differential Diagnosis

  • 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.

References

  1. 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.
  2. Dinulos, J.G.H. (2020). In Habif’s Clinical Dermatology (7th ed. pp. 863-875). Elsevier, Inc.
  3. 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
  4. 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
  5. Rammel, K. (2017). Classification of Melanocytic Nevi. Medical University of Graz.

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