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Nevus/Nevi

Nevi (singular nevus), also known as “ moles Moles Primary Skin Lesions,” are benign Benign Fibroadenoma neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions. Nevus is a non-specific medical term because it encompasses both congenital Congenital Chorioretinitis 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and originate from various types of cells (e.g., melanocytic, connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology, vascular). Nevi also have a wide variety of characteristic forms, which must be well understood in order to differentiate nevi from malignant melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. 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.

Last updated: Sep 8, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Definition and Classification

Definition

A nevus (plural nevi) is a benign Benign Fibroadenoma neoplasm of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:

  • 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 Congenital Chorioretinitis 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 Benign Fibroadenoma neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors composed of nevus cells, which are variants of melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions found at the dermo-epidermal junction or in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions
    • Melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions: melanin-producing cells derived from the neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease, located in the stratum basale Stratum basale Skin: Structure and Functions of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions, 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 Congenital Chorioretinitis: 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 Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions (outermost layer of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions); usually comprises keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions or adnexal structures (oil and sweat glands Sweat glands Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. Soft Tissue Abscess)
    • Junction: located at the tips of the rete ridges Rete Ridges Lentigo Maligna in the dermal-epidermal junction; usually comprises melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions
    • Compound: located both at the dermal-epidermal junction and in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions; usually comprises melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions
    • Dermal: located only in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions; usually comprises melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions
    • Subcutaneous: located under the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions; usually comprises adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology (fat)
  • Components or origin:
    • Melanocytic: composed of clusters of melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions (most common)
    • Vascular: composed of abnormal blood vessels, including capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology
    • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology: composed of abnormal clusters of dermal extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars (e.g., collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology, elastic Elastic Connective Tissue: Histology fibers, fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis)
  • Morphology or distribution:
    • Globular: presents a pattern of brown globules throughout the lesion but especially at the periphery, usually congenital Congenital Chorioretinitis
    • Reticular: presents a patchy pigment network with or without areas of hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi 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 Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions or capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology, can be blue-black, brown, pink, or red in color
    • Hypopigmented: due to lack of melanin Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis or constricted blood vessels, usually white in color
  • Characteristics or associated risk of melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma:
    • Typical: has the common characteristics expected of a nevus
    • Atypical or dysplastic: has an appearance that differs from common nevi/“ moles Moles Primary Skin Lesions” based on the ABCDE criteria ( asymmetry Asymmetry Examination of the Upper Limbs, border irregularity, color variegation, diameter ≥ 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma, 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 Congenital Chorioretinitis melanocytic nevus

  • Epidemiology: occurs in 1%–3% of newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn infants
  • Appearance: 
    • Tan or light brown to black lesions
    • May occur in any area of the body that is covered in skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
    • 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:
Congenital melanocytic nevus

Congenital Congenital Chorioretinitis melanocytic nevus: a brown well-circumscribed papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes on the nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose and Nasal Cavity: Anatomy that developed shortly after birth

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

Congenital dermal melanocytosis Congenital Dermal Melanocytosis Physical Examination of the Newborn

  • Previously called “ Mongolian spots Mongolian Spots Physical Examination of the Newborn
  • Epidemiology: more common in Native Americans, African Americans, and people of Asian and Latin descent
  • Appearance: 
    • Appear as blue-grey patches Patches Vitiligo with indefinite borders
    • The blue-black color is due to the entrapment of melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions, instead of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions.
    • Usually in the lumbosacral or gluteal area
    • Are always flat ( macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy)
    • Normally disappear 2–3 years after birth and almost always by puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
  • Malignant potential: There are no case reports of melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma developing from congenital dermal melanocytosis Congenital Dermal Melanocytosis Physical Examination of the Newborn.
Mongolian spots

Mongolian spot or congenital dermal melanocytosis Congenital Dermal Melanocytosis Physical Examination of the Newborn 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 Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess
    • Usually unilateral
  • Malignant potential: Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma very rarely develops from a nevus of Ito.
Nevus of ito

Congenital Congenital Chorioretinitis nevus of Ito: blue-gray macule Macule Nonpalpable lesion < 1 cm in diameter Generalized and Localized Rashes, representing a benign Benign Fibroadenoma 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 Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi ( macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy)
    • Preferentially affects areas innervated by the 1st and 2nd division of the trigeminal nerve Trigeminal nerve The 5th and largest cranial nerve. The trigeminal nerve is a mixed motor and sensory nerve. The larger sensory part forms the ophthalmic, mandibular, and maxillary nerves which carry afferents sensitive to external or internal stimuli from the skin, muscles, and joints of the face and mouth and from the teeth. Most of these fibers originate from cells of the trigeminal ganglion and project to the trigeminal nucleus of the brain stem. The smaller motor part arises from the brain stem trigeminal motor nucleus and innervates the muscles of mastication. The 12 Cranial Nerves: Overview and Functions (e.g., forehead Forehead The part of the face above the eyes. Melasma, nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose and Nasal Cavity: Anatomy, cheek, periorbital Periorbital Orbital and Preseptal Cellulitis region, and temple)
    • Often affects the sclerae 
  • Malignant potential: 
    • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma very rarely develops from a nevus of Ota.
    • Requires yearly ophthalmologic examinations because of the rare risk of glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
Nevus eye

Congenital Congenital Chorioretinitis nevus of Ota: benign Benign Fibroadenoma dermal melanocytosis that preferentially affects areas innervated by the 1st and 2nd division of the trigeminal nerve Trigeminal nerve The 5th and largest cranial nerve. The trigeminal nerve is a mixed motor and sensory nerve. The larger sensory part forms the ophthalmic, mandibular, and maxillary nerves which carry afferents sensitive to external or internal stimuli from the skin, muscles, and joints of the face and mouth and from the teeth. Most of these fibers originate from cells of the trigeminal ganglion and project to the trigeminal nucleus of the brain stem. The smaller motor part arises from the brain stem trigeminal motor nucleus and innervates the muscles of mastication. The 12 Cranial Nerves: Overview and Functions. A congenital Congenital Chorioretinitis 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 MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma.
  • Increase in incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency that peaks around the 4th decade, diminishing in number with advancing age
  • Risk/triggering factors for the development of nevi:
    • Family history Family History Adult Health Maintenance
    • Fair complexion 
    • Prolonged or excessive sun exposure 
    • The higher the number of nevi, the higher the risk for developing melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma.

Etiology

  • Benign Benign Fibroadenoma neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors of nevus cells that usually arise after 6 months of age:
    • Nevus cells are a variant of melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions, derived from the neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease.
  • Typically form as a result of BRAF-V600E–activating mutations: 
    • Despite having the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, most nevi do not progress to melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma because common acquired nevi are growth-arrested neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
    • 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 Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions 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 Regression Corneal Abrasions, Erosion, and Ulcers or atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation, ultimately replaced by fat and fibrotic tissue.
Table: Acquired nevi
Type Description Presentation
Junctional nevi
  • Nevus cells found at the dermo-epidermal junction
  • Large cells that produce melanin Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis
  • Most common mole in children
  • Well-demarcated, brownish macules that are minimally raised
  • Uniformly pigmented, tan to brown/black
  • Usually ≤ 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
Compound nevi Nevus cells found at the dermo-epidermal junction and intradermally, smaller cells that produce less melanin Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis
  • Pigmented papules
  • Smooth, dome shaped
  • Similar to junctional nevi but with elevation and lighter color
Intradermal nevi Nevus cells found intradermally, small cells that produce little to no melanin Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis
  • Most common mole in adults
  • Skin-colored to tan
  • Similar to compound nevi
  • Dome shaped or papillomatous
  • May present with terminal hair, fibrotic texture Texture Dermatologic Examination, speckled appearance
Non-melanoma

Natural history of acquired melanocytic nevi

Common nevi (“ moles Moles Primary Skin Lesions”) begin as uniformly tan or brown macules, 1 to 2 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in diameter (a), expand to a larger macule Macule Nonpalpable lesion < 1 cm in diameter Generalized and Localized Rashes (b), progress to a pigmented papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes that may be minimally (c) or obviously (d) elevated above the surface of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, and terminate as a pink or flesh-colored papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes (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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions with smooth borders.
Acquired melanocytic nevi are usually < 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in diameter.

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

Diagnosis

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

  • Symmetric
  • < 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in diameter
  • Smooth border
  • Uniform, unchanging color
  • Slow growth history

Management

  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions surveillance Surveillance Developmental Milestones and Normal Growth including regular Regular Insulin photos to follow the evolution of moles Moles Primary Skin Lesions for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship at higher risk for melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • Any lesion suspicious for melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma must be biopsied or referred for biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.
  • A nevus with small dark spots within (“hyperpigmented foci”) may signify melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma arising in a previously benign Benign Fibroadenoma 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 Moles Primary Skin Lesions” based on the ABCDE criteria ( asymmetry Asymmetry Examination of the Upper Limbs, border irregularity, color variation, diameter ≥ 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma, and evolution):

  • Some sources refer to dysplastic nevi as premalignant or precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett’s Esophagus lesions.
  • Some sources refer to dysplastic nevi as a term for “diagnostic uncertainty,” where the lesion is either benign Benign Fibroadenoma or malignant but has not yet been confirmed via biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.

Etiology and Epidemiology

  • Often appear during puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
  • Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency in White populations: 2%–10%
  • Share some of the clinical features of melanomas:
    • Asymmetry Asymmetry Examination of the Upper Limbs
    • Color variegation
    • Irregular borders
    • Diameter > 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Development is primarily due to genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics: associated with activating NRAS or BRAF gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations, among others
  • Associated with a 3–20–fold higher risk of melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. 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 Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma 
    • Familial atypical multiple mole and melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma ( FAMMM FAMMM Clinically atypical nevi (usually exceeding 5 mm in diameter and having variable pigmentation and ill defined borders) with an increased risk for development of non-familial cutaneous malignant melanoma. Biopsies show melanocytic dysplasia. Nevi are clinically and histologically identical to the precursor lesions for melanoma in the B-K mole syndrome. Exocrine Pancreatic Cancer) syndrome:
      • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
      • 40% of cases have mutations in CDKN2A, a tumor-suppressor gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
      • Increased risk for malignancies, especially of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy, breast, and esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: Anatomy

Diagnosis

  • Can be made on a clinical basis and may be assisted by dermoscopy Dermoscopy A noninvasive technique that enables direct microscopic examination of the surface and architecture of the skin. Seborrheic Keratosis, but the lesions must be biopsied for confirmation and to rule out melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma 
  • Histologically characterized by:
    • Architectural and cytologic atypia Atypia Fibrocystic Change
    • Enlargement of nevus cells
    • Nests that often coalesce with adjacent nests
  • The ABCDE criteria/mnemonic can help differentiate a nevus from melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma.
Table: ABCDE criteria to differentiate nevi and melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
Common ( benign Benign Fibroadenoma) nevi Atypical nevi Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma (m.)
Asymmetry Asymmetry Examination of the Upper Limbs (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 border Irregular margin with ill-defined border Irregular margin with ill-defined border
Color (C) Uniform color or regular Regular Insulin 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 MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma Often ≥ 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma > 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
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 Lentigo Maligna Lentigo maligna is melanoma in situ, a precancerous lesion that may progress to an invasive melanoma (specifically lentigo maligna melanoma subtype). This condition typically occurs in sun-damaged areas (e.g., face and neck) of elderly patients. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions examinations
  • Encourage the use of broad-spectrum Broad-Spectrum Fluoroquinolones sunscreen Sunscreen Chemical or physical agents that protect the skin from sunburn and erythema by absorbing or blocking ultraviolet radiation. Melanoma.
  • Excision of suspicious lesions
  • Routine ophthalmologic examinations

Differential Diagnosis

  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma: the most deadly of all skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions 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 Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma (BCC): the most common type of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions cancer. Arises from the basal cell Basal Cell Erythema Multiforme layer of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions. Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with a slowly growing pearly nodular skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion with telangiectatic vessels on the surface.
  • Seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a “stuck-on” appearance. Seborrheic Keratosis: benign Benign Fibroadenoma neoplasm consisting of immature keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions. Occurs most commonly in the elderly. Seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a “stuck-on” appearance. Seborrheic Keratosis is well-demarcated, waxy, and has a “stuck-on” appearance. 
  • Actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis: precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett’s Esophagus 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 Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma (SCC) development.
  • Dermatofibroma: mesenchymal growth of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions where skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis are the major constituents. Appears as a firm, indurated, mobile nodule Nodule Chalazion measuring 0.5–1 cm in size. Presents with a “buttonhole” sign with lateral compression Compression Blunt Chest Trauma. A dimple-like depression occurs in the overlying skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions.
  • Café-au-lait macule Macule Nonpalpable lesion < 1 cm in diameter Generalized and Localized Rashes: flat, pigmented skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion. May be associated with type 1 Type 1 Spinal Muscular Atrophy neurofibromatosis and McCune-Albright syndrome Mccune-Albright Syndrome Cushing 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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