Dysplastic nevus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

A dysplastic nevus, is an atypical mole; a mole whose appearance is different from that of common moles. Dysplastic nevi are generally larger than ordinary moles and have irregular and indistinct borders. Their color frequently is not uniform and ranges from pink to dark brown; they usually are flat, but parts may be raised above the skin surface. Dysplastic nevus can be found anywhere, but are most common on the trunk in men, and on the calves in women.

Dysplastic nevus is a type of melanocytic lesion.

Depending on cytologic atypia, melanocytic lesions range from dysplastic nevus to melanoma.

Dysplastic nevus should be differentiated from common moles and melanoma.

Males are more commonly affected by dysplastic nevus compared to females.

Sunlight exposure is the most important risk factor for the development of dysplastic nevus.

Patients with dysplastic nevus should undergo regular screening to prevent progression to melanoma.

Dysplastic nevus can progress to melanoma if it is not treated adequately. Complications of dysplastic nevi include melanoma and metastasis.

The only way to diagnose dysplastic nevus is to remove tissue and check it for dysplasia.

When an atypical mole has been identified, a biopsy takes place in order to best diagnose it. Local anesthetic is used to numb the area, then the mole is biopsied. The biopsy material is then sent to a laboratory to be evaluated by a Pathologist.

Surgery is the mainstay of treatment for dysplastic nevus.

Everyone should protect their skin from the sun and stay away from sunlamps and tanning booths, but for people who have dysplastic nevi, it is even more important to protect the skin and avoid getting a suntan or sunburn.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: :

Dysplastic nevus is a type of melanocytic lesion. Depending on the degree of cytologic atypia it can be classified into mild, moderate or severe.

Most dermatologists and dermatopathologists use a system devised by the National Institutes of Health (NIH) for classifying melanocytic lesions. In this classification, a nevus can be defined as benign, having atypia, or being a melanoma.

• A benign nevus is read as (or understood as) having no cytologic or architectural atypia.
• An atypical mole is read as having architectural atypia, and having (mild, moderate, or severe) cytologic (melanocytic) atypia.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Depending on cytologic atypia, melanocytic lesions range from dysplastic nevus to melanoma. The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene. It is thought that the progression to melanoma requires multiple genetic mutations, where activation of the oncogene alone does not lead to the development of melanoma, and additional mutations (multiple hits), such as loss-of-function mutation of P53 tumor suppressor gene (or less commonly P16/CDKN2A or PTEN in familial cases) is required for the development of melanoma. The development of melanoma may arise de novo or from pre-existing nevi. In both cases, mutations result in dysplasia and cytologic atypia that predispose to the malignant potential of the cells. As more genes are mutated and the tumor grows, changes include the overexpression of N-cadherin, αVβ3 integrin, MMP2, MSH, cAMP, and survivin, and the loss of E-cadherin and TRMP1 proteins.

• The development of melanoma begins with the disruption of nevus growth control.^[1]
• The progression to melanoma usually involves the serine-threonine kinases of the MAPK/ERK pathway (mitogen-activated protein kinase) following mutation of either the N-RAS or BRAF oncogene.
• It is thought that the progression to melanoma requires multiple genetic mutations, where activation of the oncogene alone does not lead to the development of melanoma, and additional mutations (multiple hits), such as loss-of-function mutation of P53 tumor suppressor gene (or less commonly P16/CDKN2A or PTEN in familial cases) is required for the development of melanoma.^[1]
• The development of melanoma may arise de novo or from pre-existing nevi. In both cases, mutations result in dysplasia and cytologic atypia that predispose to the malignant potential of the cells.
• As more genes are mutated and the tumor grows, changes include the overexpression of N-cadherin, αVβ3 integrin, MMP2, MSH, cAMP, and survivin, and the loss of E-cadherin and TRMP1 proteins.^[1]
• The following genes are involved in the pathogenesis of melanoma:^[1]

• Tumor-suppressor genes:

• P53
• P16/CDK2NA
• PTEN
• RB
• ARF

• Proto-oncogenes:

• N-RAS
• BRAF
• CCND1

• Most dermatologists and dermatopathologists use a system devised by the NIH for classifying melanocytic lesions.
• In this classification, a nevus can be defined as benign, having atypia, or being a melanoma.
• A benign nevus is read as (or understood as) having no cytologic or architectural atypia.
• An atypical mole is read as having architectural atypia, and having (mild, moderate, or severe) cytologic (melanocytic) atypia.^[2]
• Usually, cytologic atypia is of more important clinical concern than architectural atypia.
• Usually, moderate to severe cytologic atypia will require further excision to make sure that the surgical margin is completely clear of the lesion.\
• The most important aspect of the biopsy report is that the pathologist indicates if the margin is clear (negative or free of melanocytic nevus), or if further tissue (a second surgery) is required.
• If this is not mentioned, usually a dermatologist or clinician will require further surgery if moderate to severe cytologic atypia is present – and if residual nevus is present at the surgical margin.

• Atypical Mole syndrome
  • A hereditary condition which causes the person to have a large quantity of moles (often 100 or more) with some dysplastic nevi.
  • This often leads to a higher risk of melanoma, a serious skin cancer.^[3]
  • A slight majority of melanomas do not form in an existing mole, but rather create a new growth on the skin.
  • Nevertheless, those with more dysplastic nevi are at a higher risk for this type of melanoma occurrence.^[4][5]
  • Such persons need to be checked regularly for any changes in their moles and to note any new ones.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Dysplastic nevus arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photo-protective properties). Melanoma may be caused by sporadic genetic (e.g. BRAF and/or N-RAS) or may be part of familial syndromes (e.g. familial atypical multiple mole melanoma syndrome).

Dysplastic nevus arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). Melanoma may be caused by sporadic genetic mutations (e.g. BRAF and/or N-RAS) or may be part of familial syndromes.^[1]

• The majority (90%) of the cases of melanoma are due to sporadic genetic mutations.
• More than one genetic mutation (multiple hits) is usually the requirement for the development of melanoma.
• The most common mutations that result in the development of melanoma are BRAF (approximately 50% of melanomas) and N-RAS (approximately 15% of melanomas).^[1][2][3][4]

Melanoma may be caused by hereditary diseases (10%) and is associated with mutations of the P16/CDKN2A gene:

• Familial atypical multiple mole melanoma syndrome (FAMMM syndrome)^[5][6]
• Melanoma–astrocytoma syndrome^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Dysplastic nevus should be differentiated from common moles and melanoma.

Dysplastic should be differentiated from:

• Common moles
• Melanoma

Biopsy is the only way to differentiate above mentioned conditions from dysplastic nevus.

Oral melanoma must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Denture users Poorly controlled diabetes As a side effect of medication, most commonly having taken antibiotics. Inhaled corticosteroids for the treatment of lung conditions (e.g, asthma or COPD) may also result in oral candidiasis which may be reduced by regularly rinsing the mouth with water after taking the medication. People with poor nutrition, specifically vitamin A, iron and folate deficiencies. People with an immune deficiency (e.g. as a result of AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female sex	Physical examination Viral culture Tzanck smear	Orofacial Infection Anogenital Infection Ocular Infection Herpes Encephalitis Neonatal Herpes Herpetic Whitlow Herpes Gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Being a female Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	Self-limiting , Pain decreases in 7 to 10 days, with complete healing in 1 to 3 weeks
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Atypical Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive sub type with multiple lesions and higher conversion to warts or carcinoma[5]
Melanoma	A lesion with ABCD Asymmetry Border irregularity Color variation Diameter changes Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	ABCD characteristics Bleeding or ulceration may show malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for them primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is low in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical exam Types Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic
Diseases involving oral cavity and other organ systems
Behcet’s disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance, disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Over active immune system	Physical examination	Mouth Genitals GIT Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels
Crohn’s disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibodies (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications[6] Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro litre Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types Drug-induced Malignant Autoimmune
Syphilis[7]	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Men who have sex with men Residence in highly prevalent areas HIV infection Presence of other STIs Previous history of STIs Intravenous drug use	Darkfield microscopy Non treponemal tests like VDRL and RPR test) Treponemal testsFTA-ABS tests, (TP-PA) assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh =1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals[8][9] Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Dysplatstic nevi are very commonly seen in white people. The prevalence of any atypical nevi in white-skinned populations ranges from 2 to 10 percent. Acquired dysplastic nevi are more common in childhood and adolescence and reach a maximum number in early adulthood.

• The prevalence of any atypical nevi in white-skinned populations ranges from 2 to 10 percent.^[1]
• Some of the prevalence variation is explained by differences in the diagnostic criteria used.
• In patients with a personal history of melanoma, the estimated prevalence is 30 to 60 percent.  

• Acquired dysplastic nevi are more common in childhood and adolescence and reach a maximum number in early adulthood.^[1]

• Melanocytic nevi are reported to be less common in Asian and black people.^[1]

• Males are more commonly affected by dysplastic nevus compared to females.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [2]

Sunlight exposure is the most important risk factor for the development of dysplastic nevus.

Common risk factors for the development of dysplastic nevi are:^{[1][2][3][4][5][6]}

• Old age^[7]
• Male gender
• Family history of melanoma^[8][9][10]
• Multiple benign or atypical nevi^[10]
• Personal history of melanoma
• Administration of immunosuppressive therapy
• Sun sensitivity
• Therapeutic agents such as
  • Psoralen^[11]
  • Ultraviolet A light therapy^[12]
  • Neonatal blue light phototherapy
• Exposure to environmental chemicals such as:
  • Polyvinyl chloride
  • Heavy metals
  • Pesticides
• Hereditary diseases including:
  • Giant congenital pigmented nevus syndrome
  • Melanocortin 1 receptor mutation^[13]
  • Dysplastic nevus syndrome
  • Retinoblastoma^[14]
  • Xeroderma pigmentosum^[15]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Patients with dysplastic nevus should undergo regular screening to prevent progression to melanoma. According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for skin tumors, including dysplastic nevus or melanoma.

According to the National Cancer Institute, physicians believe that dysplastic nevi are more likely than ordinary moles to develop into a type of skin cancer called melanoma. Because of this, moles should be checked regularly by a physician or nurse specialist, especially if they look unusual; grow larger; or change in color, or outline; or if any changes occur. According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for skin tumors, including dysplasytic nevus and melanoma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

If left untreated, dysplastic nevus progression occurs horizontally (radial growth plate) and vertically (vertical growth plate) and is then followed by dermal invasion and distant metastasis. Dysplastic nevus is an aggressive tumor characterized by early metastasis. Common sites of metastasis include bones, brain, kidneys, lungs, liver and skin (secondary distant site). Complications of dysplastic nevus are usually related to the site of metastasis. The 5-year relative survival of patients with dysplastic nevus is approximately 93%. Features associated with worse prognosis are tumor thickness (Breslow thickness), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, location of lesion, presence of satellite lesions, and the presence of regional or distant metastasis.

• If left untreated, melanocytes first proliferate randomly with an aberrant growth within an existing nevus.
• More advanced stages are characterized by a radial growth phase with intraepidermal growth and penetration into the papillary dermis.
• Final stages demonstrate a vertical growth phase with dermal invasion and widening of the papillary dermis before cancerous cells finally metastasize to other parts of the skin and other organs.

Complications of Dysplastic nevus are usually due to distant metastasis. Common sites of metastasis are shown below:

• Bone
• Brain
• Liver
• Kidney
• Skin (secondary distant site)
• Lungs^[1]

• Features that affect prognosis include:^[2]

• Tumor thickness in millimeters (Breslow’s depth)
• Depth related to skin structures (Clark level)
• Type of melanoma
• Presence of ulceration
• Presence of lymphatic/perineural invasion
• Presence of tumor infiltrating lymphocytes (if present, prognosis is better)
• Location of lesion
• Presence of satellite lesions
• Presence of regional or distant metastasis

• Extent of malignancy within a node is also important; micro-metastases in which malignancy is only microscopic have a more favorable prognosis than macro-metastases.
• In some cases, micro-metastases may only be detected by special staining, and if malignancy is only detectable polymerase chain reaction (PCR), the prognosis is better.
• Macro-metastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extra-capsular extension, the prognosis is still worse.

• Between 2004 and 2010, the 5-year relative survival of patients with melanoma was 92.9%.^[3]

• When stratified by age, the 5-year relative survival of patients with melanoma was 92.7% and 88.2% for patients <65 and ≥ 65 years of age respectively.^[3]

• When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.^[4]

• The survival of patients with melanoma varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of melanoma:^[3]

• Shown below is an image depicting the 5-year conditional relative survival (probability of surviving in the next 5-years given the cohort has already survived 0, 1, 3 years) between 1998 and 2010 of melanoma by stage at diagnosis according to SEER. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[3]

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