Nevus/Nevi

Definition and Classification

Definition

A nevus (plural nevi) is a benign 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. Structure and Function 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 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. Structure and Function of the 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 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. Structure and Function of the Skin; 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 (fat)
• Components or origin:
  • Melanocytic: composed of clusters of melanocytes (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
  • 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 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, 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 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” 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 Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. 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. Structure and Function of the 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
• 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 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.

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 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 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. Anatomy of the 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 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

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 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 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 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. 
  • 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.

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 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.
• 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 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 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 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 Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics: associated with activating NRAS or BRAF gene 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) 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
    • 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, 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

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 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
  • 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.

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. Structure and Function of the Skin examinations
• Encourage the use of broad-spectrum sunscreen.
• Excision of suspicious lesions
• Routine ophthalmologic examinations