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Melanoma is a tumor arising from malignant transformation of pigment-containing cells called melanocytes, which are found in the stratum basale of the epidermis.
Most arise in the skin but may also present as a primary lesion in any tissue: ocular (uvea), GI, GU, lymph node, paranasal sinuses, nasal cavity, anorectal mucosa, and leptomeninges.
Extracutaneous sites have an adverse prognosis.
Metastatic spread to any site in the body
Types of cutaneous melanoma include (1):
Superficial-spreading melanoma: 50–80% of cases; occurs in sun-exposed areas (trunk, back, and extremities); most ~6 mm diameter at diagnosis; when seen in younger patients, presents as a flat, slow growing, irregularly bordered lesion
Nodular: 20–30% of cases; present in older patients; tendency to ulcerate and hemorrhage; most commonly thick and pigmented
Lentigo maligna (subtype of melanoma in situ): slowest growing; older population; occurs in sun-exposed areas (head, neck, forearms). Lentigo maligna melanoma (LMM) is its invasive counterpart seen in (5–15% of cases); it is most commonly seen in elderly patients most often in the head and neck regions.
Amelanotic melanoma (<5%): can be missed and diagnosed at a later stage, as it can mimic benign skin conditions, and thus is referred to as a “great pretender”
Acral lentiginous: 2–8% of all melanomas; however, most common melanoma in black or Asian patients; found in palmar, plantar, and subungual areas
Subungual melanoma (0.7–3.5%): dark longitudinal stripe under the nail plate; Hutchinson nail sign is when brown or black pigment extends from the nail to the cuticle and proximal or lateral nail folds.
Desmoplastic melanoma (~1%): “neurotropic melanoma” or “spindled melanoma” with an abundance of fibrous tissue; demonstrates sarcoma-like tendencies with increased hematogenous spread; presents as a slow-growing lesion that is scar-like (no history of injury at the site is noted); often seen in the head and neck
System(s) affected: skin/exocrine
Lentigo maligna, slowly enlarging pigmented lesion, is most common in elderly patients. This type is usually found on the face, beginning as a circumscribed macular patch of mottled pigmentation showing shades of dark brown, tan, or black.
Large congenital nevi (>5 cm) are risk factors and have a >2% lifetime risk of malignant conversion. Blistering sunburns in childhood significantly increase risk.
No increased risk of melanoma in pregnancy. In the case of recent melanoma treatment, it is recommended to wait 1 to 2 years prior to becoming pregnant, as melanoma can spread to the placenta.
In 2017, an estimated 87,110 Americans were diagnosed with melanoma, with approximately 9,730 expected deaths (2).
Predominant age: median age: 62 and 54 years for men and women respectively; >50% of all individuals with melanoma are between 20 and 40 years of age.
Predominant sex: male > female (1.5 times)
Melanoma is more than 20 times more common in whites than in African Americans (2).
Minority groups demonstrate increased rates of metastasis, advanced stages at diagnosis, thicker initial lesions, earlier age at diagnosis, and overall poorer outcomes.
Low socioeconomic status associated with higher incidence of melanoma
Lifetime risk: men: 1/37; female: 1/56
Lifetime risk in whites is ~2.5% (1/40), 0.1% (1/1,000) in blacks, and 0.5% (1 in 200) in Hispanics) (2)
2% of all cancer deaths
The most common cancer affecting women 25 to 29 years of age and second only to breast cancer in women 30 to 34 years of age (1)
DNA damage by UVA/UVB exposure
Tumor progression: initially may be confined to epidermis with lateral growth, may then grow into dermis with vertical growth
Dysplastic nevus syndrome is a risk factor for development of melanoma. Close surveillance is warranted.
8–12% of patients with melanoma have a family history of disease.
Mutation in CDKN2A (p16) is found in 1/3 of patients with family incidence of melanoma.
Mutations in BRAF (V600E) implicated in 50–60% of cutaneous melanomas
Familial atypical mole malignant melanoma (FAMMM) syndrome characterized by >50 atypical moles, +FH of melanoma, clinical diagnosis (3)
Genetic predisposition, persona/family history of melanoma
UV-A and UV-B exposure
History of >5 sunburns during lifetime
History of intense intermittent sun exposure
Previous pigmented lesions (especially dysplastic melanocytic nevi)
Fair complexion, freckling, blue eyes, blond/red hair
Highest predictor of risk is increased number of nevi (>100).
Tanning bed use: 75% increased risk if first exposure before age 35 years
Changing nevus (see ABCDE criteria)
Large (>5 cm) congenital nevi
Chronic immunosuppression (chronic lymphocytic leukemia, non-Hodgkin lymphoma, AIDS, or posttransplant)
Blistering sunburns in childhood
Living at high altitude (>700 meters or 2,300 feet above sea level)
Occupational exposure to ionizing radiation
Avoidance of sunburns, especially in childhood
Use of sunscreen with at least SPF 30 to all skin exposed to sunlight, reapplying regularly and after toweling or swimming
Avoid tanning beds; class 1 carcinogen by World Health Organization (WHO)
Screening of high-risk individuals, especially males >50 years
Education for proper diagnosis plays a large factor in prevention.
Any suspicious lesions should be biopsied with a narrow excision encompassing the entire breadth plus sufficient depth of the lesion. Options include elliptical excisions, punch, or shave biopsies.
Dysplastic nevus syndrome
>50 nevi. These individuals have higher lifetime risk of melanoma than the general population, as 50% of all melanoma arise in preexisting nevi.
Giant congenital nevus: 6% lifetime incidence of melanoma
Xeroderma pigmentosum is a rare condition associated with an extremely high risk of skin cancers, including melanoma.
Psoriasis after psoralen-UV-A (PUVA) therapy
Change in a pigmented lesion: either hypo- or hyperpigmentation, bleeding, scaling, ulceration, or changes in size or texture
Obtain family and personal history of melanoma or nonmelanoma skin cancer.
Obtain social history including occupation, sunbathing, tanning, and other sun exposure.
ABCDE: Asymmetry, Border irregularity, Color variegation (especially red, white, black, blue), Diameter >6 mm, Evolution over time
Any new and/or changing nevus, bleeding/ulcerated
Location on Caucasians is primarily back and lower leg; on African Americans, it is the hands, feet, and nails.
May include mucosal surfaces (nasopharynx, conjunctiva)
Individuals at high risk for melanoma should have careful ocular exam to assess for presence of melanoma in the iris and retina.
Dysplastic and blue nevi
Vascular skin tumor
Pigmented actinic keratosis
Pigmented squamous cell and basal cell carcinomas, seborrheic keratoses, other changing nevi
Lactate dehydrogenase (LDH), chest/abdomen/pelvic CT, MRI, and/or PET CT at baseline and in monitoring progression in metastatic disease (stage IV) (4)
Imaging studies only helpful in detecting and evaluating for progression of metastatic disease
Dermoscopy allows for magnification of lesions, allowing for a decreased number of biopsies of benign skin lesions in addition to providing increased sensitivity in detecting melanoma and basal cell carcinoma (5)[B].
Surgical biopsy remains the standard of care. Any suspicious nevus should be excised, either by elliptical excision; a scoop shave (saucerization) technique may be appropriate, as long as a full-thickness can be achieved (1)[C].
Sentinel lymph node biopsy, a staging procedure, remains an important factor for prognosis (4)[A].
Nodular melanoma is primarily vertical growth, whereas the other three types are horizontal.
Estimated that 1/10,000 dysplastic nevi become melanoma annually.
Immunohistochemical testing increases sensitivity of lymph node biopsies.
Staging is based on the tumor-node-metastasis (TNM) criteria by current American Joint Committee on Cancer (AJCC) criteria, including:
(T) Thickness (mm) and ulceration
(N) Number of regional lymph nodes involved
(M) Distant metastases and serum LDH
See https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html for more information.
For stages I to III, surgical excision is curative in most cases; in patients with stage IV disease, systemic treatment with chemotherapy is recommended.
Preferred regimens (4)[A] include the following:
Ipilimumab (monoclonal antibody against CTLA-4) in combination with nivolumab (anti-PD-1 monoclonal antibody) demonstrated 61% response versus ipilimumab alone (6)[B].
In phase 3 of the randomized, open label study (KEYNOTE-006) comparing pembrolizumab to ipilimumab, pembrolizumab demonstrated superior progression-free survival for advanced, metastatic disease (6).
Vemurafenib (Zelboraf) or dabrafenib are BRAF inhibitors approved for metastatic, unresectable melanoma expressing BRAF V600E or V600K mutations.
High-dose interleukin-2 controversial (significant toxicity, 1–2% mortality related to treatment)
Referral for enrollment in clinical trials
Additional active regimens (e.g., dacarbazine [DTIC], temozolomide, paclitaxel, carmustine [BCNU], cisplatin, carboplatin, vinblastine); often limited to those who are not candidates to preferred regimens
Imatinib (Gleevec) in tumors with c-kit mutation
Interferon-α as adjuvant therapy received FDA approval in 1995 (high dose) and 2011 (pegylated) to treat stage IIB to III melanoma; shown to improve 4-year relapse rate but no overall effect on survival; 1/3 of patients will discontinue due to toxicity (granulocytopenia, hepatotoxicity) (4)[B].
Consultation with oncologist for consideration of chemotherapeutic options
Surgical specialties may be required based on the extent of nodal and/or metastatic disease, if present.
Standard of care for melanoma includes early surgical excision with the following recommended margins (4)[A]:
In situ tumors: 0.5 cm margin has been the standard of care but may be insufficient in lentigo maligna.
Thickness of 1.01 to 2.00 mm: 1 to 2 cm margins
Thickness of >2.00 mm: 2 cm margins
Sentinel lymph node biopsy is indicated in patients with T1b, T2-, T3-, and T4-staged melanomas.
Not recommended in melanoma in situ or T1a
Mohs micrographic surgery is being increasingly used for melanoma in situ, but in general, it is not considered a treatment modality for melanoma because it relies on frozen section technique.
Radiotherapy can be used to treat lentigo maligna in addition to certain head and neck lesions.
Palliative radiation therapy can be used with metastatic melanoma.
Routine screening clinical skin examination annually for all persons >40 years is controversial and without proven benefit.
Total body photography and dermoscopy should be used for surveillance of skin lesions, most commonly used for patients with >5 atypical nevi.
For patients with a history of cutaneous melanoma, NCCN guidelines recommend screening every 3 to 12 months depending on recurrence risk (4)[C], with annual examinations if there is no disease progression for 5 years.
Lab and imaging tests after diagnosis and treatment of stage I to II melanoma are low yield, have high false-positive rates, and are not recommended (4)[B].
Teach patients who are at risk, or have had melanoma, the principles of ABCDE examinations.
High-risk patients should perform monthly skin self-examinations and be taught to examine inaccessible areas. Educate patients on regular skin examinations.
Patients with a history of melanoma or dysplastic nevus syndrome should have regular total body examinations by a dermatologist.
Breslow depth (thickness) in millimeters remains among strongest predictors of prognosis.
Median age at death is 68 years.
Highest survival seen in women <45 years of age at diagnosis
Metastatic melanoma has an average survival of 6 to 9 months; 15–20% 5-year survival with current treatment
Stages I and II, appropriately treated, have 20-year survival rates of 90% and 80%, respectively.
Metastatic spread and subsequent death
Often referred to as the “great imitator,” given that metastatic disease may present in a variety of ways often confusing the clinician
Unsatisfactory cosmetic results following the primary surgery
The American Cancer Society (ACS) provides 5- and 10- year survival rates for melanoma based on stage: https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/survival-rates-for-melanoma-skin-cancer-by-stage.html
The American Joint Committee on Cancer (AJCC) offers an online calculator to predict survival outcome from initial diagnosis: http://www.melanomaprognosis.net/
Perkins A, Duffy RL. Atypical moles: diagnosis and management. Am Fam Physician. 2015;91(11):762–767. [View Abstract on OvidMedline]
C43.9 Malignant melanoma of skin, unspecified
C43.30 Malignant melanoma of unspecified part of face
C43.4 Malignant melanoma of scalp and neck
C43.39 Malignant melanoma of other parts of face
C43.72 Malignant melanoma of left lower limb, including hip
C43.60 Malignant melanoma of unsp upper limb, including shoulder
C43.20 Malignant melanoma of unsp ear and external auricular canal
C43.52 Malignant melanoma of skin of breast
C43.51 Malignant melanoma of anal skin
C43.8 Malignant melanoma of overlapping sites of skin
C43.21 Malignant melanoma of right ear and external auricular canal
C43.61 Malignant melanoma of right upper limb, including shoulder
C43.71 Malignant melanoma of right lower limb, including hip
C43.70 Malignant melanoma of unspecified lower limb, including hip
C43.11 Malignant melanoma of right eyelid, including canthus
C43.62 Malignant melanoma of left upper limb, including shoulder
C43.10 Malignant melanoma of unspecified eyelid, including canthus
C43.59 Malignant melanoma of other part of trunk
C43.12 Malignant melanoma of left eyelid, including canthus
C43.31 Malignant melanoma of nose
C43.0 Malignant melanoma of lip
C43.22 Malignant melanoma of left ear and external auricular canal
172.9 Melanoma of skin, site unspecified
172.3 Malignant melanoma of skin of other and unspecified parts of face
172.4 Malignant melanoma of skin of scalp and neck
172.8 Malignant melanoma of other specified sites of skin
172.5 Malignant melanoma of skin of trunk, except scrotum
172.1 Malignant melanoma of skin of eyelid, including canthus
172.6 Malignant melanoma of skin of upper limb, including shoulder
172.2 Malignant melanoma of skin of ear and external auditory canal
172.7 Malignant melanoma of skin of lower limb, including hip
172.0 Malignant melanoma of skin of lip
372244006 Malignant melanoma (disorder)
93655004 malignant melanoma of skin (disorder)
93225001 Malignant melanoma of skin of face
188044004 Malignant melanoma of scalp and/or neck
274087000 Malignant melanoma of eye (disorder)
302837001 Lentigo maligna melanoma (disorder)
269581007 Malignant melanoma of lower limb
276751004 Amelanotic malignant melanoma of skin (disorder)
93640008 Malignant melanoma of skin of lip
423425006 malignant neoplasm of skin of eyelid (disorder)
93651008 Malignant melanoma of skin of trunk
93653006 Malignant melanoma of skin of upper limb
403927001 Malignant melanoma of nail apparatus (disorder)
403924008 Desmoplastic malignant melanoma (disorder)
188032002 Malignant melanoma of ear and/or external auditory canal
Remember that amelanotic melanomas exist; pigmentation is not required.
80% of cutaneous melanomas arise in existing nevi. Any changing nevi should be biopsied, preferably utilizing an excisional method to ensure that complete margins are taken.
The prognosis is excellent with early detection and treatment.