Melanoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.; Sara Mohsin, M.D.[2]

Malignant melanoma is the most common fatal skin cancer that arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). The prevalence of melanoma is approximately 150 – 200 per 100,000 individuals. It may be caused by sporadic genetic mutations (e.g. BRAF and/or N-RAS) or may be part of familial syndromes (e.g. familial atypical multiple mole melanoma syndrome). Melanoma may be classified into either cutaneous or non-cutaneous melanomas. The most common 4 subtypes of cutaneous melanoma include superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Development of melanoma is the result of multiple genetic mutations (multiple hits). 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. On gross pathology, the majority of melanomas appear as hyperkeratotic, black-brown, asymmetric nodules with irregular borders, but the morphology of the lesion mostly depends on the subtype of melanoma and amelanotic (no pigmentation) melanomas are not uncommon. On microscopic histopathological analysis, each subtype of melanoma has unique characteristic features. The two most potent risk factors in the development of melanoma are light-colored skin and exposure to ultraviolet radiation. If left untreated, melanoma progression occurs both horizontally (radial growth plate) and vertically (vertical growth plate) and is then followed by dermal invasion and distant metastasis. Common sites of metastasis include bones, brain, kidneys, lungs, liver, and skin (distant site). The 5-year relative survival of patients with melanoma is highly dependent on the stage at diagnosis. Staging is based on the 2010 AJCC TNM Classification and is divided into stage 0 or melanoma in situ, stage I or invasive melanoma with good prognosis, stage II or high-risk melanoma, stage III or melanoma with regional lymph node metastasis, and stage IV or melanoma with distant metastasis. The predominant treatment for primary melanoma is wide excision of the lesion margins. The choice of clinical margins is based on the tumor thickness. When lymph nodes are involved, complete dissection of the nodal basin is recommended. Chemotherapy is indicated for high risk melanomas (stages IIB-IV) as adjuvant therapy and for metastatic disease as first-line therapy. Once diagnosed, follow-up at regular intervals is recommended.

Melanoma was first described by Hippocrates in the 5th century BC. It was often described as the fatal black tumor. In 1838, the term melanoma was first proposed by Sir Robert Carswell, a British pathologist. In 1956, Henry Lancaster, an Australian mathematician, was the first to discover the association between UV radiation exposure and development of melanoma. In 2003, BRAF mutations were first identified in the pathogenesis of melanoma.

Melanoma may be classified into either cutaneous or non-cutaneous melanomas. The most common 4 subtypes of cutaneous melanoma include superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Less common subtypes of melanoma include desmoplastic/spindle cell melanoma, nevoid melanoma, spitzoid melanocytic melanoma, angiotropic melanoma, blue nevus-like melanoma, and composite melanoma.

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). Development of melanoma is the result of multiple genetic mutations. 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. On gross pathology, the majority of melanomas appear as hyperkeratotic, black-brown, asymmetric nodules with irregular borders, but the morphology of the lesion mostly depends on the subtype of melanoma. On microscopic histopathological analysis, each subtype of melanoma has unique characteristic features. All patients with suspected melanoma require biopsy. Findings on biopsy may distinguish the subtype and the stage of melanoma.

Melanoma may be caused by sporadic genetic mutations (e.g. BRAF and/or N-RAS) or may be part of familial syndromes (e.g. familial atypical multiple mole melanoma syndrome).

Melanoma must be differentiated from other causes of skin lesions, such as other skin cancers, premalignant skin tumors, and benign skin lesions.

The prevalence of melanoma is approximately 150 – 200 per 100,000 individuals. The majority of patients are diagnosed after the age of 65 years. Melanoma is more common among males and individuals of Caucasian race.

The two most potent risk factors in the development of melanoma are light-colored skin and exposure to ultraviolet radiation. Other risk factors include old age, male gender, family history of melanoma, personal history of skin cancers, immunodeficiency, and certain hereditary disorders.

The 1992-1994 free American Academy of Dermatology’s National Skin Cancer Early Detection and Screening Program provided broad skin cancer educationalinformation to general public and enabled thousands of free expert skin cancer examinations. The 2001-2005 American Academy of Dermatology National Melanoma/Skin Cancer Screening Program emphasized on the use of HARMM criteria to identify the higher-risk subgroup of skin cancer screening population via assessment of multiple risk factors for MM hence, both reducing the cost & increasing the yields for suspected MM in future mass screening initiatives. MelanomaGenetics Program identifies the genetic causes of skin cancer, and provides genetic counseling to the individuals with strong family history of melanoma. Dermoscopy usage improves the ability of primary care physicians to triage lesions suggestive of skin cancer, thus saving from unnecessary expert consultations. Combination of dermoscopy and short-term sequential digital dermoscopy imaging (SDDI) in a primary care setting doubles the sensitivity for melanoma diagnosisand leads to >50% chance of reduction in excision or referral of benign pigmented lesions.

If left untreated, melanoma progression occurs horizontally (radial growth plate) and vertically (vertical growth plate) and is then followed by dermal invasion and distant metastasis. Melanoma is an aggressive tumor characterized by early metastasis. Common sites of metastasis include bones, brain, kidneys, lungs, liver, and skin (distant site). Complications of melanoma are usually related to the site of metastasis. The 5-year relative survival of patients with melanoma 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 presence of regional or distant metastasis.

Symptoms of melanoma include a rapidly growing existing nevus, non-healing skin ulcers, pruritus, or bone pain.

Physical examination findings suggestive of malignant melanoma include ABCDE: Asymmetry of lesion, Border irregularity, Color change, large Diameter, and Evolution over time.

There are no laboratory findings associated with the diagnosis of melanoma. Serum lactate dehydrogenase (LDH) may be elevated among patients with metastasis.

All patients with suspected melanoma require biopsy. Findings on biopsy may distinguish the subtype and the stage of melanoma.

Staging of melanoma is essential to determine the prognosis. Staging is based on the 2010 AJCC TNM Classification and is divided into stage 0 or melanoma in situ, stage I or invasive melanoma with good prognosis, stage II or high-risk melanoma, stage III or melanoma with regional lymph node metastasis, and stage IV or melanoma with distant metastasis.

There are no chest x-ray findings associated with melanoma.

There are no CT scan findings associated with melanoma. Chest CT scan is recommended for diagnosis of metastatic lesions among patients who have been diagnosed with stage IA-IV melanoma and for secondary prevention of melanoma among patients who were previously diagnosed with stage IIB-IV melanoma (annually for 5 years).

There are no MRI scan findings associated with melanoma. Brain MRI may be considered for diagnosis of metastatic lesions among patients who have been diagnosed with stage IA-IV melanoma and for secondary prevention of melanoma among patients who were previously diagnosed with stage IIB-IV melanoma (annually for 5 years).

There are no ultrasound findings associated with melanoma.

There are no PET scan findings associated with melanoma. Chest PET scan may be considered for diagnosis of metastatic lesions among patients who have been diagnosed with stage IA-IV melanoma and for secondary prevention of melanoma among patients who were previously diagnosed with stage IIB-IV melanoma (annually for 5 years).

No additional tests are recommended for the diagnosis of melanoma.

Chemotherapy is indicated for high risk melanomas (stages IIB-IV) as adjuvant therapy and for metastatic disease as first-line therapy. Several single agent and combination regimens have been studied, all with modest impact on survival. All current guidelines still recommend enrollment in clinical trials over current available regimens for patients with metastatic disease. Interferon therapy is the only regimen recommended as adjuvant therapy.

The predominant treatment for primary melanoma is wide excision of the lesion margins. The choice of clinical margins is based on the tumor thickness. When lymph nodes are involved, complete dissection of the nodal basin is recommended.

Primary prevention of melanoma includes avoidance of sunlight/ultraviolet radiation exposure.

The choice of work-up for secondary prevention of melanoma is based on the stage of melanoma at diagnosis. Secondary prevention includes monthly self-exams, routine dermatologic evaluations, and chest and brain imaging.

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

Melanoma was first described by Hippocrates in the 5th century BC. It was often described as the fatal black tumor. In 1838, the term melanoma was first proposed by Sir Robert Carswell, a British pathologist. In 1956, Henry Lancaster, an Australian mathematician, was the first to discover the association between UV radiation exposure and development of melanoma. In 2003, BRAF mutations were first identified in the pathogenesis of melanoma.

• Melanoma was first described by Hippocrates in the 5th century BC. It was often described as the fatal black tumor.^[1][2]
• Initially, melanoma was thought to be associated with black carbon deposits in patients with lung cancer. It was not until 1804 that René Laennec, a French physician and inventor of the stethoscope, distinguished melanoma (referred to as melanose) as a unique disease.
• In 1838, the term melanoma was first proposed by Sir Robert Carswell, a British pathologist.^[1]
• The association between hereditary diseases and melanoma was first made by William Norris, a British general practitioner.^[3]
• In 1853, Sir James Paget, a British surgeon, described the characteristic radial and vertical growth phases of melanoma.^[4]
• In 1905, the surgical management using “excision and dissection in continuity” was first suggested by William Handley, a British researcher. This surgical approach remained the predominant therapeutic approach for the management of melanoma until the mid-20th century.^[4]
• In 1956, Henry Lancaster, an Australian mathematician, was the first to discover the association between UV radiation exposure and development of melanoma.^[4][5]
• In 1970, Alexander Breslow evaluated factors that alter the prognosis of melanoma, including tumor size, depth of invasion, and tumor thickness. The total vertical depth was later referred to as Breslow’s depth.
• In 2003, BRAF mutations were first identified in the pathogenesis of melanoma.^[4][6][7]

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

Melanoma may be classified into either cutaneous or non-cutaneous melanomas. The most common 4 sub-types of cutaneous melanoma include superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Less common sub-types of melanoma include desmoplastic/spindle cell melanoma, nevoid melanoma, spitzoid melanocytic melanoma, angiotropic melanoma, blue nevus-like melanoma, and composite melanoma.

Shown below is a table that demonstrates the various sub-classes of melanoma:^[1][2]

Subtype	Frequency	Clinical Features
Common Subtypes
Superficial spreading melanoma	70%	Most common sub-type Usually affects sun exposed sites among both men and women aged 50-70 years Characterized by the presence of abundant junctional intra-epidermal spread of malignant melanocytes
Nodular melanoma	15-25%	Second most common subtype Usually affects sun exposed sites among both men and women aged 50-70 years Characterized by the absence of junctional intra-epidermal spread of malignant melanocytes
Acral lentiginous melanoma	5%	Not associated with chronic ultraviolet exposure Affects the extremities of individuals of all races Common among the elderly Caucasian and non-Caucasian individuals
Lentigo maligna melanoma	1-5%	Preceded by lentigo maligna Common among the elderly Caucasian patients Usually appears as a flat, non-palpable lesion that affects sun exposed sites, especially the head and neck (lesions on extremities are less common)
Non-cutaneous melanoma	5%	Melanoma that does not affect the skin Usually affects the eye (ocular melanoma) or the mucus membranes (mucosal melanoma)
Less Common Subtypes
Desmoplastic/Spindle cell melanoma	Rare	Lesion typically amelanotic and has a morphology similar to a scar tissue Appears indolent but is highly infiltrative Characterized by local recurrence and perineural spread Usually affects males aged 60-70 years in sun exposed sites May be de novo or can be associated with a pre-existing melanoma Has several subtypes: Pure: paucicellular Desmoplastic-neurotropic melanoma: characterized by neurotropism Pure neurotropic melanoma: no desmoplasia with spindle cell melanoma of neurotropic phenotype Mixed/Combined: epithelial and spindle cells
Nevoid melanoma	Rare	Lesion has features of both melanoma and melanocytic nevus on histopathological analysis Clinical features resemble those of a typical melanoma
Spitzoid melanocytic neoplasm	Rare	Lesion has features of both melanoma and Spitz (epithelioid) tumor Typically affects sun exposed sites among children and young adults, but adults with Spitz tumors are more often diagnosed with Spitzoid melanoma Compared to benign Spitz tumors, Spitzoid melanomas are usually large (>5 mm)
Angiotropic melanoma	Rare	Lesion characterized by angiotropism, whereby the melanoma grows in proximity (within 1-2 mm) to blood and/or lymphatic tissue but no tumor within the vascular lamina itself The tumor may originally be another sub-type of melanoma Clinical features similar to typical melanoma
Blue nevus-like melanoma	Rare	Melanoma that develops from a pre-existing blue nevus One of the rarest forms of melanoma Appears as a blue nevus that has recently been rapidly expanding with irregular contours Typically affects middle-aged men
Composite melanoma	Rare	Melanoma that develops in the proximity of other pre-existing epithelial malignancies (e.g. basal/squamous cell carcinoma) May be characterized by one of the following: Collision tumor: Collision of melanoma and another nearby malignant tumor Colonization: Colonization of melanocytes in a tumor Combined: Two distinct tumors appear to have mixed features of the melanoma and the other tumor Biphenotypic: One tumor that has features of melanoma and another epithelial malignancy

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

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). Development of melanoma is the result of multiple genetic mutations. 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. On gross pathology, the majority of melanomas appear as hyperkeratotic, black-brown, asymmetric nodules with irregular borders, but the morphology of the lesion mostly depends on the sub-type of melanoma. On microscopic histopathological analysis, each sub-type of melanoma has unique characteristic features.

Malignant melanoma arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties).

• 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

• Characteristic features on gross pathology and microscopic analysis are variable depending on the melanoma sub-type.
• The following table illustrates the findings on gross pathology and microscopic analysis of the sub-types of melanoma:^[2][3]

Melanoma Subtype	Features on Gross Pathology	Features on Histopathological Microscopic Analysis
Superficial spreading melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Presence of intraepidermal lateral spread (most characteristic feature) Dermal invasion Desmoplasia Epidermal hyperplasia Appearance of epithelioid cells with occasional spindle cells
Nodular melanoma	Tan/reddish brown color Sharp borders Well-demarcated, dome-shaped papular/verrucous lesion	Sharp border differentiating malignant vs. normal tissue due to absence of intraepidermal lateral spread / no radial growth plate (most characteristic feature) Appearance of epithelioid cells with occasional spindle cells Melanocytes may have absent/minimal pigmentation
Acral lentiginous melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal acanthosis and hyperkeratosis (most characteristic feature) Malignant melanocytes spread along the basal layer Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction May be any of round, epithelioid, spindle, or oval cells May have perineural or endoneural invasion
Lentigo maligna melanoma	Brown/black color, but may include reddish brown or white Hyperkeratotic, diffused borders with no distinct demarcation Irregular and elevated	Epidermal atrophy and flattening and prominent dermal invasion (most charactersitic feature) Large, pleomorphic cells Cells arranged in lentiginous and dyscohesive pattern along the dermoepidermal junction Preservation of retiform epidermis May be any of round, epithelioid, spindle, or oval cells Evidence of actinic damage of the dermal matrix May have perineural or endoneural invasion Positivity for CD133+ and CD34+
Non-cutaneous melanoma	Variable morphology depending on location of melanoma	Histopathologically similar to other sub-types of melanoma
Desmoplastic/Spindle cell melanoma	Skin colored and morphologically resembles scar tissue	Dermal, fibrotic nodule Ill-defined, variable spindle cells with irregular contours and stromal desmoplasia Highly infiltrative pattern Appearance of sclerotic collagen fibers Nuclear hyperchromasia Appearance of lymphoid aggregates Solar elastosis Involvement of endoneurium and perineurium (neurotropism) Possibly evidence of other melanoma sub-types (co-existing tumors, especially lentiginous melanoma)
Nevoid melanoma	Morphologically similar to a melanocytic nevus	Dermal mitosis Hypercellular and monomorphous-appearing dermal melanocytes that have a characteristic sheet-like appearance Evidence of cytologic atypia (nuclear enlargement, pleomorphism, irregular nuclear membrane, hyperchromasia) Irregular basal infiltration Evidence of angiotropism
Spitzoid melanocytic neoplasm	Morphologically similar to a Spitz nevus	Appearance of melanocytic proliferation along with features of Spitz tumors (small diameter, well-demarcated, symmetric lesion with no ulceration, epidermal effacement, dermal mitosis, or involvement of the subcutaneous fat) May have features that are not typically characteristic of Spitz tumors (ulceration, poor demarcation) Vertically oriented spindled melanocytes Clefts between junctional melanocytes
Angiotropic melanoma	No gross morphological features that distinguish angiotropic melanoma from other sub-types of melanoma	Melanoma cells in close proximity to abluminal surfaces of blood and/or lymphatic channels No invasion within the vascular lamina itself
Blue nevus-like melanoma	Morphologically similar to a blue nevus	Asymmetric nodular/multinodular appearance Aggregates of melaninized, atypical spindle cells
Composite melanoma	Features of more than one sub-type on gross pathology	Features of more than one sub-type on microscopic analysis May be characterized by one of the following: Collision tumor: Collision of melanoma and another nearby malignant tumor Colonization: Colonization of melanocytes in a tumor Combined: Two distinct tumors appear to have mixed features of the melanoma and the other tumor Biphenotypic: One tumor that simultaneously has features of melanoma and another epithelial malignancy

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

Malignant melanoma 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).

Malignant melanoma 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]

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

Melanoma must be differentiated from other causes of skin lesions, such as other skin cancers, premalignant skin tumors, and benign skin lesions.

Melanoma must be differentiated from other causes of skin lesions, such as:

• Angiokeratoma^[1]
• Atypical fibroxanthoma^[2]
• Basal cell carcinoma of the skin
• Dermatofibroma^[3]
• Dermatofibroma protuberans
• Dysplastic nevus^[4]
• Epithelioid (Spitz) tumors
• Halo nevus
• Histiocytoid hemangioma^[5]
• Keratoacanthoma^[6]
• Lentigo^[7]
• Lentigo maligna
• Metastasis of other primary tumors
• Mycosis fungoides^[8]
• Oral candidiasis^[9]
• Peripheral nerve sheath tumor
• Pigmented actinic keratosis^[10]
• Scar tissue or keloid
• Sclerosing angioma^[11]
• Sclerosing blue nevus^[12][13]
• Sarcoma
• Sebaceous carcinoma^[14]
• Seborrheic keratosis^[15][16]
• Spindle cell squamous cell carcinoma^[17]
• Squamous cell carcinoma of the skin^[18]
• Traumatic hematoma^[19][20]
• Melanocytic nevus and other benign melanocytic lesions^[21]
• Traumatized nevus
• Venous lake
• Vitiligo^[22]

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

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]; Yazan Daaboul, M.D.; Serge Korjian M.D.; Anum Ijaz M.B.B.S., M.D.[3]

The prevalence of melanoma is approximately 150-200 per 100,000 individuals. The majority of patients are diagnosed after the age of 65 years. Melanoma is more common among males and individuals of the Caucasian race. In 2025, cutaneous melanoma is the fifth most common cancer in the U.S.^[1], and by 2040, it is expected to become the second most common. ^[2]

• In the United States, the age-adjusted prevalence of melanoma was 187 per 100,000 individuals in 2011.^[3]

• The delay-adjusted incidence of melanoma in 2011 was estimated to be 23.21 per 100,000 persons in the United States.^[3]

• In 2011, the age-adjusted incidence of melanoma was 22.74 per 100,000 persons in the United States.^[3]

• In 2025, an estimated 104,960 new cases of cutaneous melanoma are expected in the U.S., comprising 60,550 in males and 44,410 in females.^[1]

• While the overall age-adjusted incidence of melanoma in the United States between 2007 and 2011 is 21.3 per 100,000, the age-adjusted incidence of melanoma by age category is:^[3]
  • Under 65 years: 12.6 per 100,000
  • 65 and over: 81.1 per 100,000

• Shown below is an image that demonstrates the delay-adjusted incidence and observed incidence of melanoma by age and gender in the United States between 1975 and 2011. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[3]

• There is a slight male preponderance to the development of melanoma.
• The male to female ratio is approximately 1.2-1.6 to 1.
• Between 1999 and 2021, melanoma incidence rose by 57.5% in females and 47.4% in males based on age-adjusted rates.
• The image below shows trends in melanoma incidence by gender from 1999 to 2021.^[4]

• There is a racial preponderance to the development of melanoma, where Caucasian individuals are at a significantly increased risk compared to dark-skinned individuals.
• Shown below is a table that demonstrates the age-adjusted prevalence of melanoma by race in 2011 in the United States.^[3]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	187 per 100,000	234.5 per 100,000	7.5 per 100,000	11.1 per 100,000	37.9 per 100,000

• Shown below is a table that demonstrates the annual age-adjusted incidence of melanoma by race in 2024 in the United States.^[2]

Race	Asian	Black	Hispanic	Native American	Hispanic
Age-adjusted incidence	1.3 per 100,000	1.0 per 100,000	4.8 per 100,000	10.3 per 100,000	30.6 per 100,000

• Shown below is an image depicting the trends for incidence of melanoma by race in the United States between 1999 and 2021.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]; Yazan Daaboul, M.D.; Serge Korjian M.D.

The two most potent risk factors in the development of melanoma are light-colored skin and exposure to ultraviolet radiation. Other risk factors include old age, male gender, family history of melanoma, personal history of skin cancers, immunodeficiency, and certain hereditary disorders.

• The two most potent risk factors in the development of melanoma are light-colored skin and exposure to ultraviolet radiation.^[1][2]
• Other risk factors for the development of melanoma are mentioned in the table below:

Risk Factors
Heritable	Lighter skin pigmentation that burns easily (*Fitzpatrick phototype 1 and 2).[3] Eye pigmentation (blue, green, hazel, gray).[3] Family history of melanoma in a first-degree relative (18-24). [1] Hereditary diseases including: Giant congenital pigmented nevus syndrome Melanocortin 1 receptor mutation[4] Dysplastic nevus syndrome Retinoblastoma[5] Xeroderma pigmentosum[6]
Modifiable	Sunburn Tanning bed use immunosuppression:[3] Kidney transplant recipient. Solid organ transplant recipient. Administration of immunosuppressive therapy. Therapeutic agents such as: Psoralen[7] Ultraviolet A light therapy[1] Neonatal blue light phototherapy Exposure to environmental chemicals such as: Polyvinyl chloride Heavy metals Pesticides Multiple benign or atypical nevi[8] Personal history of melanoma
Non-modifiable Risk Factors	Old age.[3] Male gender.[3]

* Fitzpack Patrick phototypes: Ⅰ( always burns, never tans), Ⅱ ( usually burns, tans less than average), Ⅲ ( sometimes mild burns, tans about average), and IV( rarely burns, tans more than average).^[9]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D. Anum Ijaz M.B.B.S., M.D.[2]

The 1992-1994 free American Academy of Dermatology’s National Skin Cancer Early Detection and Screening Program provided broad skin cancer educational information to general public and enabled thousands of free expert skin cancer examinations. The 2001-2005 American Academy of Dermatology National Melanoma/Skin Cancer Screening Program emphasized on the use of HARMM criteria to identify the higher-risk subgroup of skin cancer screening population via assessment of multiple risk factors for MM hence, both reducing the cost & increasing the yields for suspected MM in future mass screening initiatives. Melanoma Genetics Program identifies the genetic causes of skin cancer, and provides genetic counseling to the individuals with strong family history of melanoma. Dermoscopy usage improves the ability of primary care physicians to triage lesions suggestive of skin cancer, thus saving from unnecessary expert consultations. Combination of dermoscopy and short-term sequential digital dermoscopy imaging (SDDI) in a primary care setting doubles the sensitivity for melanoma diagnosis and leads to >50% chance of reduction in excision or referral of benign pigmented lesions.

According to different studies going on for so many years, following data is available regarding the different methods/tools and their effectiveness for skin cancer screening:

• From 1992 to 1994, free American Academy of Dermatology’s National Skin Cancer Early Detection and Screening Program was launched which provided broad skin cancer educational information to general public and enabled almost 750,000 free expert skin cancer examinations which mostly found out thin, localized stage 1 melanomas with high projected 5-year survival rate^[1][2]
• From 2001 to 2005, American Academy of Dermatology National Melanoma/Skin Cancer Screening Program was launched which led to the conclusion that HARMM criteria can be used to identify the higher-risk subgroup of skin cancer screening population via assessment of multiple risk factors for MM , which will not only reduce the cost but will also increase the yields for suspected MM in future mass screening initiatives^[3]
• Melanoma Genetics Program identifies the genetic causes of skin cancer, and also provides genetic counseling to the individuals having a strong family history of melanoma^{[4][5][6][1][7][8][9]}
• Dermoscopy usage improves the ability of primary care physicians to triage lesions which are suggestive of skin cancer and saves from unnecessary expert consultations^[10]
• Combination of dermoscopy and short-term sequential digital dermoscopy imaging (SDDI) in a primary care setting doubles the sensitivity for melanoma diagnosis and also leads to >50% chance of reduction in excision or referral of benign pigmented lesions^{[11][12][13][14][15]}
• In 2023, the US Preventive Services Task Force (USPSTF) reported insufficient evidence to support routine visual skin examination for melanoma screening in asymptomatic individuals. Screening is instead recommended for high-risk patients, such as those with significant UV exposure, fair skin that burns easily (Fitzpatrick I-II) , personal or family history of skin cancer, numerous or atypical moles, or immunosuppression.^[16],^[17]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.; Anum Ijaz M.B.B.S., M.D.[2]

If left untreated, melanoma progression occurs horizontally (radial growth plate) and vertically (vertical growth plate) and is then followed by dermal invasion and distant metastasis. Melanoma 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 melanoma are usually related to the site of metastasis. The 5-year relative survival of patients with melanoma 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 melanoma 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

• The TNM staging classification summarizes most of the above mentioned findings. Using the TNM classification, prognosis can be determined based on the stage of the disease as follows:

• Stage 0: Melanoma in situ, 100% Survival
• Stage I: Invasive Melanoma, 85-95% Survival
• Stage II: High Risk Melanoma, 40-85% Survival
• Stage III: Regional Metastasis, 25-60% Survival
• Stage IV: Distant Metastasis, 9-15% Survival

Please check the staging page for more details about the staging scheme and the TNM classification.

• The Breslow’s depth is independent of other features of the tumor and has been demonstrated to be associated with 5-year survival:

Breslow’s Depth	5-year survival
< 0.76 mm	95% to 100%
0.76-1.5 mm	80% to 96%
1.5-4 mm	60% to 75%
> 4 mm	37% to 50%

• 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]

Stage	5-year relative survival (%), 2004-2010
All stages	91.3%
Localized	98.1%
Regional	62.6%
Distant	16.1%
Unstaged	78.4%

• 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]

• The 5-year relative survival rate for melanoma of the skin for diagnoses during 2014-2020 was 94% for all races and ethnicities, including White individuals.^[5]
• For Black individuals, the 5-year relative survival rate for melanoma of the skin during 2014-2020 was 70%. ^[5]

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