> Table of Contents > Melanoma
Carl Bryce, MD, Capt, USAF
Matthew J. Snyder, DO
image BASICS
  • Melanoma is a tumor arising from malignant transformation of cells from the melanocytic system.
  • Most arise in the skin but may also present as a primary lesion in any tissue: ocular, GI, GU, lymph node, and leptomeninges.
    • Metastatic spread to any site in the body
  • Main types of cutaneous melanoma include the following (1):
    • Superficial-spreading melanoma: 50-80% 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%, present in older patients, often 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.
    • Amelanotic melanoma (<5%): can be missed and diagnosed at a later stage, as it can mimic benign skin conditions
    • 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 band in nail bed; Hutchinson sign when proximal nail fold involved
    • Desmoplastic melanoma (˜1%): sarcoma-like tendencies with increased hematogenous spread
  • System(s) affected: skin/exocrine
Geriatric Considerations
Lentigo maligna, slowly enlarging pigmented lesion, is most common in elderly patients. This type is usually found on face, beginning as a circumscribed macular patch of mottled pigmentation showing shades of dark brown, tan, or black.
Pediatric Considerations
Large congenital nevi (>5 cm) are risk factors and have a >2% lifetime risk of malignant conversion. Blistering sunburns in childhood significantly increase risk.
Pregnancy Considerations
No increased risk of melanoma in pregnancy. However, it is suggested waiting 1 to 2 years if further pregnancy is desired in case of recent melanoma. Melanoma can spread to the placenta.
  • In 2015, an estimated 73,870 Americans were diagnosed with melanoma, with 9,940 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)
  • Incidence among whites greater than that among minority groups; ˜20 times higher than blacks (1)
  • 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
  • 2% of all cancer deaths
  • The most common cancer affecting women age 25 to 29 years of age and second only to breast cancer in women 30 to 34 years of age (1).
  • DNA damage by UV-A/UV-B 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
  • 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, and blond/red hair
  • Highest predictor of risk is increased number of nevi (>100).
  • Family/personal history of melanoma
  • Tanning bed use: 75% increased risk if 1st exposure before age 35 years
  • Changing nevus
  • Large (>5 cm) congenital nevi
  • Other skin cancers
  • 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
  • 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 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
  • Traumatic hematoma
  • 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) (5)
  • Imaging studies only helpful in detecting and evaluating for progression of metastatic disease
Diagnostic Procedures/Other
  • 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 (4)[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 fullthickness can be achieved (1)[C].
  • Sentinel lymph node biopsy, a staging procedure, remains an important factor for prognosis (5)[A].
Test Interpretation
  • 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 2010 American Joint Committee on Cancer (AJCC) criteria (5).

Full surgical excision of melanoma is the standard of care. See below for recommended surgical margins.
  • 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 (5)[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)[A].
    • 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-&agr; 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). Biochemotherapy is advocated by some (i.e., chemo + immunotherapy combination), although optimal regimen remains uncertain given disease heterogeneity (5)[B].
  • Consultation with oncologist for consideration of chemotherapeutic options
  • Plastic surgery sometimes needed after final excision
Immunotherapy using various vaccine preparations has produced mixed results and remains an area for further research (7)[B].
  • Standard of care for melanoma includes early surgical excision with the following recommended margins (5)[A]:
    • In situ tumors: 0.5 cm margin has been the standard of care but may be insufficient in lentigo maligna (8)[B].
    • 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 T2-, T3-, and T4-staged melanomas.
    • Selected patients with stage T1b melanoma should also be considered for sentinel lymph node biopsy.
    • Not recommended in melanoma in situ or T1a
  • Mohs surgery is often used for lesions with ill-defined borders or lesions of head and neck.
  • 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.
Molecular and mouse tumor model studies support role of topical silymarin (milk thistle derivative) in decreasing UV radiation-induced inflammation, oxidative stress, and carcinogenesis (8)[B].
Admission Criteria/Initial Stabilization
Most treatments are done as outpatients with no stabilization needed.
After diagnosis and treatment, close follow-up and skin protection (i.e., sunblock, UV protective clothing) are highly advised.
Patient Monitoring
  • 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, specialty guidelines suggest every 3 to 12 months depending on recurrence risk (5)[C], general agreement to plan annual examinations after 5 years stable (9)[A].
  • 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 (5)[B].
No data to support specific dietary manipulations; general recommendations from American Cancer Society for cancer prevention
  • Teach patients who are at risk, or have had melanoma, the principles of ABCDE examinations.
  • High-risk patients should perform monthly skin selfexaminations and be taught to examine inaccessible areas.
  • Patients with a history of melanoma or dysplastic nevus syndrome should have regular total body examinations.
  • Breslow depth (thickness) in millimeters remains among strongest predictors of prognosis.
  • Median age at death 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.
1. Shenenberger D. Cutaneous malignant melanoma: a primary care perspective. Am Fam Physician. 2012;85(2):161-168.
2. American Cancer Society. What are the key cancer statistics about melanoma skin cancer? http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Accessed June 2015.
3. Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2011;65(5):1032-1047.
4. Marghoob AA, Usatine RP, Jaimes N. Dermoscopy for the family physician. Am Fam Physician. 2013;88(7):441-450.
5. Coit DG, Andtbacka R, Anker CJ, et al. Melanoma, version 2.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013;11(4):395-407.
6. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. New Engl J Med. 2015;372(21):2006-2017.
7. Ozao-Choy J, Lee DJ, Faries MB. Melanoma vaccines: mixed past, promising future. Surg Clin North Am. 2014;94(5):1017-1030.
8. Erickson C, Miller SJ. Treatment options in melanoma in situ: topical and radiation therapy, excision and Mohs surgery. Int J Dermatol. 2010;49(5):482-491.
9. Cromwell K, Ross MI, Xing Y, et al. Variability in melanoma post-treatment surveillance practices by country and physician specialty: a systematic review. Melanoma Res. 2012;22(5):376-385.
Additional Reading
  • American Joint Committee on Cancer offers an online calculator to predict survival outcome from initial diagnosis. http://melanomaprognosis.org
  • Perkins A, Duffy RL. Atypical moles: diagnosis and management. Am Fam Physician. 2015;(91):762-767.
  • Tuong W, Cheng LS, Armstrong AW. Melanoma: epidemiology, diagnosis, treatment, and outcomes. Dermatol Clin. 2012;30(1):113-124.
See Also
Dysplastic Nevus Syndrome
  • C43.9 Malignant melanoma of skin, unspecified
  • C43.30 Malignant melanoma of unspecified part of face
  • C43.4 Malignant melanoma of scalp and neck
Clinical Pearls
  • Remember that amelanotic melanomas exist; pigmentation is not required.
  • 80% of cutaneous melanomas arise in existing nevi. Any changing nevi should be considered for full-thickness biopsy.
  • Excellent prognosis in early detection and treatment, as well as being a common cancer affecting young adult women, require a high clinical suspicion and low threshold for thorough evaluation.