Melanoma overview

# Overview
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.

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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.

# Causes
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).

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

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Screening
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.

# Natural History, Complications and Prognosis
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.

# Diagnosis

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

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

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

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

## Staging
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.

## Chest X Ray
There are no chest x-ray findings associated with melanoma.

## CT
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).

## MRI
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).

## Echocardiography or Ultrasound
There are no ultrasound findings associated with melanoma.

## Other Imaging Findings
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).

## Other Diagnostic Studies
No additional tests are recommended for the diagnosis of melanoma.

# Treatment

## Medical Therapy
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.

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

## Secondary Prevention
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.