> Table of Contents > Melanoma
Melanoma
Carl Bryce, MD, Capt, USAF
Matthew J. Snyder, DO
image BASICS
DESCRIPTION
  • 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.
EPIDEMIOLOGY
Incidence
  • 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
Prevalence
  • 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).
ETIOLOGY AND PATHOPHYSIOLOGY
  • 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
Genetics
  • 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)
RISK FACTORS
  • 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
GENERAL PREVENTION
  • 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.
COMMONLY ASSOCIATED CONDITIONS
  • 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
image DIAGNOSIS
PHYSICAL EXAM
  • 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.
DIFFERENTIAL DIAGNOSIS
  • Dysplastic and blue nevi
  • Vascular skin tumor
  • Pigmented actinic keratosis
  • Traumatic hematoma
  • Pigmented squamous cell and basal cell carcinomas, seborrheic keratoses, other changing nevi
DIAGNOSTIC TESTS & INTERPRETATION
  • 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).
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image TREATMENT
GENERAL MEASURES
Full surgical excision of melanoma is the standard of care. See below for recommended surgical margins.
MEDICATION
  • 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].
ISSUES FOR REFERRAL
  • Consultation with oncologist for consideration of chemotherapeutic options
  • Plastic surgery sometimes needed after final excision
ADDITIONAL THERAPIES
Immunotherapy using various vaccine preparations has produced mixed results and remains an area for further research (7)[B].
SURGERY/OTHER PROCEDURES
  • 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.
COMPLEMENTARY & ALTERNATIVE MEDICINE
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].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Most treatments are done as outpatients with no stabilization needed.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
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].
DIET
No data to support specific dietary manipulations; general recommendations from American Cancer Society for cancer prevention
PATIENT EDUCATION
  • 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.
PROGNOSIS
  • 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.
REFERENCES
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
&NA;
  • 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
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Dysplastic Nevus Syndrome
Codes
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ICD10
  • 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
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  • 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.