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Melanoma

Melanoma is a malignant tumor Tumor Inflammation arising from 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, the melanin-producing cells 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. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanomas usually present as 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 lesions, but they can occur on mucosal surfaces, such as in the eyes, anal canal, and genital regions. Common findings may include Asymmetry of the lesion, irregular Border, varying Color, > 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 Diameter, and Evolving features (ABCDE). Definitive diagnosis is established with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment relies primarily on surgical excision. The prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is very good for early-stage lesions but quite dismal for metastatic disease. Of all 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 malignancies, melanoma generally carries the worst prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.

Last updated: Sep 13, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Melanoma is a malignant tumor Tumor Inflammation arising from 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, the melanin-producing cells 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.

Epidemiology

  • 5th most common malignancy Malignancy Hemothorax in men and women in the United States
  • Average age at diagnosis: 57 years
  • Increasing 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 worldwide:
    • In Queensland, Australia (highest): 72 per 100,000
    • In the United States: 27 per 100,000
  • The deadliest 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

Etiology

  • Excessive exposure to ultraviolet A (UVA) and B (UVB) radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma:
    • Exposure to sunlight (UVB more closely associated with melanoma)
    • Highest in equatorial areas (when adjusted for 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 type), where UVB is more intense
    • Use of tanning beds (UVA)
    • ↑ number of blistering sunburns = ↑ risk
    • Exposure to psoralen and UVA radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma as treatment for psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis or other 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 conditions
  • Role of sunscreen: 
    • Sunscreen users likely to have more sun exposure than the general public
    • Sunscreen protective mostly against UVB (increasing risk for UVA exposure)
  • Genetic predisposition and personal characteristics:
    • Positive family history Family History Adult Health Maintenance in 5%–10% of cases
    • Fair 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, blue eyes, fair/red hair, freckles Freckles Primary Skin Lesions
    • Presence of > 40 melanocytic nevi Nevi Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi (a marker for ↑ risk)
    • Genetic syndromes:
      • Familial atypical multiple mole melanoma Familial atypical multiple mole melanoma 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 ( 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: an 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 genetic condition characterized by the presence of multiple atypical moles Moles Primary Skin Lesions
      • Xeroderma pigmentosum Xeroderma pigmentosum A rare, pigmentary, and atrophic autosomal recessive disease. It is manifested as an extreme photosensitivity to ultraviolet rays as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. Lentigo Maligna: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance condition caused by a defect in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair mechanisms that leads to ultraviolet light Ultraviolet light That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-uv or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-uv or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. Bullous Pemphigoid and Pemphigus Vulgaris sensitivity (i.e., severe sunburns) and 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 development 
  • Immunosuppression:
    • Transplant patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Hematologic malignancies

Anatomy

  • Melanomas most commonly arise from 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.
  • Mucosal surfaces: about 1% of cases
    • Head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess region: oral, nasal, and paranasal cavities
    • Anorectal region
    • Vulvovaginal region
  • Eyes: 
    • Uvea Uvea The pigmented vascular coat of the eyeball, consisting of the choroid; ciliary body; and iris, which are continuous with each other. Eye: Anatomy (95% of ocular melanomas)
    • Conjunctiva Conjunctiva The mucous membrane that covers the posterior surface of the eyelids and the anterior pericorneal surface of the eyeball. Eye: Anatomy

Pathophysiology and Classification

Pathogenesis

  • Most melanomas arise in 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 slow-growing indolent tumors.
  • May arise in preexisting precursor lesion/ nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi or de novo (from healthy 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).
  • Types of nevi Nevi Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi considered precursors to melanoma:
    • Common acquired nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
    • Dysplastic nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
    • Congenital Congenital Chorioretinitis nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
    • Cellular blue nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
  • Commonly found mutations:
    • CDKN2A (most common specific 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 in familial melanoma)
    • BRAF (most common in superficial spreading melanoma)
    • KIT (most common in 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 melanoma and acral–lentiginous melanoma)
    • RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
    • NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1
  • Phases of growth:
    • Horizontal growth (radial growth):
    • Vertical growth:
      • Clearly invasive deep into 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
      • Associated with metastatic potential

Morphologic types

Major types:

Types Frequency Growth Morphology Common sites
Superficial spreading melanoma 60%–75%
  • Horizontal or radial growth first (highly curable at 1 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 or less)
  • Eventual transition to vertical growth
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables pigmentation with an irregular border
  • Flat or slightly elevated lesions
  • Torso (back)
  • Extremities
Nodular melanoma 15%–30%
  • Vertical growth from the beginning
  • Most are diagnosed when lesion is 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 or more

  • Rapidly growing
  • Commonly ulcerated or crusted black nodule Nodule Chalazion
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 melanoma 10%
  • Horizontal growth early
  • Transition to vertical phase is slow (over years)
  • Sun-exposed areas (e.g., face, head, neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess)
Acral lentiginous melanoma < 5%; most common type in Asian and dark-skinned individuals
  • Horizontal growth predominates early
  • Palms
  • Soles
  • Nail beds (subungual)

Uncommon variants:

  • Amelanotic melanoma:
    • Consists of poorly differentiated/dedifferentiated 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
    • Present with lightly colored (pink/red) flat or raised lesions
    • Confused with benign Benign Fibroadenoma lesions (e.g., melanocytic nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi), leading to delay in diagnosis (worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas)
  • Spitzoid melanoma: 
    • Resembles Spitz tumors
    • Growing lesions: papules/nodules that may present with red, brown, black, or blue color
  • Desmoplastic melanoma: rare, slow-growing, pale plaques or nodules resembling a scar Scar Dermatologic Examination
  • Pigment-synthesizing melanoma (melanocytoma): 

Classification

Breslow depth:

  • A standardized method of melanoma depth measurement 
  • Use of an optical micrometer fitted to the microscope to measure from the top of the epidermal granular layer to the deepest tumor Tumor Inflammation invasion
  • Utilized in the 8th edition of the American Joint Committee on Cancer tumor Tumor Inflammation staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis system (but tumor Tumor Inflammation thickness recorded to the nearest 0.1 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 instead of the original 0.01 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)
Breslow stage Tumor Tumor Inflammation sickness
Stage 1 Stage 1 Trypanosoma brucei/African trypanosomiasis ≤ 1 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
Stage 2 1–2 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
Stage 3 > 2–4 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
Stage 4 > 4 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

Clinical Presentation

Cutaneous melanomas (most common)

  • Majority present with new 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 (de novo):
    • Suspicious pigmented lesion
    • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema) or bleeding may be present. 
  • A preexisting nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi:
    •  Change in shape, size, or color
    • “Ugly duckling” sign: 1 different-looking mole Mole Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi among other moles Moles Primary Skin Lesions that are predominantly of similar morphology

Other melanomas

  • Subungual:
  • Ocular:
    • Can be asymptomatic
    • Change in pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities shape
    • Pigmented spot on the iris
    • Vision Vision Ophthalmic Exam changes
  • Anal: signs and symptoms similar to other anal cancers

Diagnosis

History

Physical exam

  • Regular Regular Insulin 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 exam: should be thorough and comprehensive (entire body) and done under optimal lighting
  • Adjunctive techniques:
    • Dermoscopy Dermoscopy A noninvasive technique that enables direct microscopic examination of the surface and architecture of the skin. Seborrheic Keratosis
    • Reflectance confocal microscopy (allows visualization of cells of 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 and papillary 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)
    • Computer-assisted diagnosis
  • ABCDE criteria ABCDE criteria Nevus/Nevi: 
    • Developed to differentiate benign Benign Fibroadenoma melanocytic lesions from melanomas 
    • Further evaluation is warranted if the lesion meets ≥ 1 of the following criteria:
      • A ( asymmetry Asymmetry Examination of the Upper Limbs): asymmetrical shape
      • B (border): irregular/indistinct border
      • C (color): varying pigmentation or irregularly distributed
      • D (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
      • E (evolution): change in size, shape, or color; exceptional nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi different from other nevi Nevi Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

  • Excisional full-thickness biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (gold standard):
    • Complete excision of lesion with 1 to 3 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 margin of normal 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
    • Histopathologic diagnosis based on a combination of features, including:
      • Atypical 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 with large nuclei, prominent nucleoli
      • Architectural asymmetry Asymmetry Examination of the Upper Limbs
      • Poor circumscription (cells at the edge noted to be single, small instead of nested)
      • Lower epidermal and dermal cells vary in size and shape.
    • Immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency (e.g., S-100, Sox10 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis expressed by almost all melanomas)
    • Gives information about the Breslow stage and ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers status (both needed for staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis and prognostic assessment)
  • Incisional biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • For large lesions
    • If lesion is in difficult or cosmetically sensitive area (e.g., facial, subungual)

Adjunctive studies

Adjunctive studies are used for evaluation of metastatic disease.

  • Laboratory studies:
    • CBC
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function tests
    • LDH LDH Osteosarcoma
  • Imaging:
    • Chest X-ray Chest X-ray X-ray visualization of the chest and organs of the thoracic cavity. It is not restricted to visualization of the lungs. Pulmonary Function Tests: for lung metastases
    • Ultrasound: for lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • CT or PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging: for distant metastases
Part of the abcds for detection of melanoma

Part of the ABCDs for detection of melanoma:
In the left column (top to bottom): melanomas showing (A) asymmetry Asymmetry Examination of the Upper Limbs; (B) a border that is uneven, ragged, or notched; (C) coloring of different shades of brown, black, or tan; and (D) diameter that has changed in size. In the right column (top to bottom): Normal moles Moles Primary Skin Lesions do not have abnormal characteristics (all lesions have no asymmetry Asymmetry Examination of the Upper Limbs or change in diameter and have even border and color).

Image: “Melanoma vs normal mole Mole Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi ABCD rule NCI Visuals Online” by National Cancer Institute. License: Public Domain

Staging

Table: TNM description and substages
TNM Description Substages
Tumor Tumor Inflammation (T)
  • Tis: in situ
  • T1: ≤ 1 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
  • T2: >1–2 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
  • T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones: > 2–4 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
  • T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones: > 4 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
Lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node (N)
  • N0: 0 nodes
  • N1: 1 node
  • N2: 2–3 nodes
  • N3: 4+ nodes


  • N0: NA
  • N1a: 1 clinically occult node
  • N1b: 1 clinically detected node 
  • N1c: no node, + satellite, microsatellite, in-transit metastases 
  • N2a: 2–3 clinically occult nodes
  • N2b: 2–3 clinically detected nodes
  • N2c: 1 occult/clinically detected, + satellite, microsatellite, in-transit metastases
  • N3a: 4+ clinically occult nodes
  • N3b: 4+ clinically detected nodes or matted nodes
  • N3c: 2+ clinically occult or detected nodes, + satellite, microsatellite, in-transit metastases 
Metastases (M)
  • M0: no distant metastases
  • M1: with distant metastases
  • M0: no distant metastases
  • M1a: distant 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, soft tissue Soft Tissue Soft Tissue Abscess (muscle) and nonregional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node
  • M1b: lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
  • M1c: other non-CNS visceral organs
  • M1d: CNS
  • M1a-d further classified by LDH LDH Osteosarcoma level:
* Ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers: defined as no intact epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology over the melanoma, and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is worse (compared to a lesion with same thickness and without ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers) if present
NA: not applicable
Table: American Joint Committee on Cancer staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis based on TNM
Stage Tumor Tumor Inflammation (T) Lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node (N) Metastases (M)
0 Tis N0 M0
IA T1a N0 M0
IB T2a, T1b N0 M0
IIA T2b, T3a N0 M0
IIB T3b, T4a N0 M0
IIC T4b N0 M0
III Any T ≥ N1 M0
IV Any T Any N M1

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Management and Prognosis

Surgery

Wide local excision:

  • Mainstay of treatment
  • The recommended margins depend on lesion thickness.
  • 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 graft Graft A piece of living tissue that is surgically transplanted Organ Transplantation may be required for closure depending on size and location.
  • For acral/ subungual melanoma, digital amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation may be required.

Mohs micrographic surgery:

  • Specialized technique in removal of locally invasive 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
  • Controversial in melanoma (as there are no clinical trials comparing it to wide local excision)
  • Used for in situ melanoma and 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 of the head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess
  • Not for invasive melanoma
Table: Recommended resection margins
Invasion depth Tumor Tumor Inflammation stage Margins
Tis 0.51 cm
1 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 T1 1 cm
> 1–2 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 T2 1–2 cm
> 2–4 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 T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones 2 cm 
> 4 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 T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones

Additional procedures

Sentinel lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (SLNB):

Regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node dissection:

  • Completion lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node dissection (CLND) (in those with positive SLNB), provided reduced regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node recurrence.
  • However, there was no difference in survival in CLND versus observation.

Surgical metastasectomy Metastasectomy Surgery to remove one or more neoplasm metastases. Hepatocellular Carcinoma (HCC) and Liver Metastases:

  • Can be done for isolated distant metastases
  • Sometimes performed after good initial response to adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy

Adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapies for advanced melanoma

  • Usually not recommended for stage IIC and lower
  • For stage III disease ( lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement) and stage IV (metastatic disease)
  • Options:
    • Immunotherapy (combination of):
      • Nivolumab or pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) (anti–programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death antibody)
      • Ipilimumab (monoclonal antibody to cytotoxic Cytotoxic Parvovirus B19 T lymphocyte–associated antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 4)
    • Targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy:
    • Cytotoxic Cytotoxic Parvovirus B19 therapy:
      • Not very effective and does not improve overall survival
      • Limited to patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship for whom other options have been exhausted
    • Radiotherapy: 
      • Mostly for palliation in locally advanced disease
      • Stereotactic radiosurgery has a role in brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Negative prognostic factors: 

5-year survival rate:

  • Stage I: > 90%
  • Stage II: 45%–77%
  • Stage III: 27%–70%
  • Stage IV: < 20%

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Differential Diagnosis

  • Atypical nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi: a benign Benign Fibroadenoma melanocytic neoplasm that mimics melanoma in appearance, as it may be asymmetric and > 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 with color variegation. Thus, a biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is needed to exclude melanoma.
  • 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: a 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 occurring commonly in the elderly. A 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 usually presents as a sharply demarcated, round, exophytic Exophytic Retinoblastoma, dark 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.
  • Dermatofibroma: a benign Benign Fibroadenoma proliferation of dermal fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis that presents as a firm, indurated, mobile nodule Nodule Chalazion measuring about 0.5–1 cm in size. Furthermore, a dimple-like depression 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 appears as a “buttonhole” sign upon lateral compression Compression Blunt Chest Trauma.
  • Other 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 malignancies: squamous cell or basal cell Basal Cell Erythema Multiforme carcinomas usually present as raised erythematous, scaly, or ulcerated lesions. The malignancies can resemble amelanotic melanomas. Diagnosis is established by biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.

References

  1. Buzaid A. C., Gershenwald J. E. (2019). Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/tumor-node-metastasis-tnm-staging-system-and-other-prognostic-factors-in-cutaneous-melanoma
  2. Curti B.D., & Leachman S, & Urba W.J. (2018). Cancer of the skin. Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
  3. Hassel J.C., & Enk A.H. (2019). Melanoma. Kang S, et al. (Ed.), Fitzpatrick’s Dermatology, 9th ed. McGraw-Hill.
  4. Heistein J.B., Acharya U. (2020). Malignant melanoma. https://www.ncbi.nlm.nih.gov/books/NBK470409/
  5. Liu V., Armstrong A.W., Mihm M.C. (2020). Pathologic characteristics of melanoma. UpToDate. Retrieved January 15, 2021, from https://www.uptodate.com/contents/pathologic-characteristics-of-melanoma
  6. Rastrelli M., Tropea S., Rossi C.R., Alaibac M. (2014). Melanoma: Epidemiology, Risk Factors, Pathogenesis, Diagnosis and Classification. https://iv.iiarjournals.org/content/28/6/1005.long
  7. Sosman J. A. (2020). Overview of the management of advanced cutaneous melanoma. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/overview-of-the-management-of-advanced-cutaneous-melanoma
  8. Stone M.D. (2020). Surgical management of primary cutaneous melanoma or melanoma at other unusual sites. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/surgical-management-of-primary-cutaneous-melanoma-or-melanoma-at-other-unusual-sites
  9. Swanson D.L. (2017). Nevi and melanoma. Soutor C, & Hordinsky M.K.(Eds.), Clinical Dermatology. McGraw-Hill.
  10. Swetter S., Geller A.C. (2020). Melanoma: Clinical features and diagnosis. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/melanoma-clinical-features-and-diagnosis
  11. Tan, W. (2020). Malignant Melanoma. Medscape. https://emedicine.medscape.com/article/280245-overview

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