Malignant melanoma accounts for just 5% of all skin cancer cases, but it causes more deaths than any other skin condition.¹ In 2011, for example, an estimated 70,230 melanoma cases were diagnosed in the United States, and an estimated 8,790 people died from the condition.^1,2

Overall incidence rates have been increasing in the United States for at least 30 years.¹ From 2004 to 2008, the age-adjusted incidence rate was 20.8 per 100,000 men and women per year.^2,3 And while the U.S. malignant melanoma death rate has been decreasing since the 1990s among people younger than 50, it has been stable or increasing in people older than 50.¹ The age-adjusted death rate from 2004 to 2008 was 2.7 per 100,000 men and women per year.^2,3

Risk Factors

Among all risk factors for developing melanoma, repeated excessive exposure to ultraviolet (UV) radiation emitted by the sun is the most responsible culprit. The two main types of radiation produced by the sun are ultraviolet A (UVA) and ultraviolet B (UVB).

UVB is approximately 1,000 times more likely to cause sunburn than is UVA. Repeated overexposure to UVB rays eventually can lead to changes in the DNA of the skin's melanocytes. If UVB radiation causes oncogene and tumor suppressor gene mutations in melanocytes, the cells begin to multiply uncontrollably, producing a malignant melanoma.⁴

UVA is more effective in the production of immediate and persistent skin darkening. It has twice the bandwidth of UVB and comprises 90% to 95% of the total UV energy produced by the sun. The longer wavelengths of solar UVA rays facilitate the passage of UVA through most glass windows; UVB rays do not significantly penetrate glass. This property of UVA also allows for deeper penetration into the skin directly to the level of the melanocytes, potentially leading to melanoma.

UVA radiation also can damage the DNA of healthy cells by creating single-strand breaks, mutations, sister chromatid exchanges and chromosomal aberrations that result in cytotoxicity and carcinogenesis. Psoralen-plus-UVA therapy units, tanning beds and other indoor artificial tanning devices also produce UVA; moreover, most sunscreens contain chemicals that help block UVB but not UVA.⁴

In addition to UV radiation exposure, being older than 65 is a significant melanoma risk factor.⁵ Other melanoma risk factors include but are not limited to fair skin, light eyes, many freckles and more than 50 moles on the skin; severe, blistering sunburns as a child or adult; a family history of melanoma, previous melanoma or noncancerous, unusual looking moles (dysplastic nevi); exposure to UV radiation from tanning salons and tanning beds; and having a weakened immune system.⁶

Contrary to popular belief, smoking tobacco likely is unrelated to the predisposition for developing malignant melanoma.⁷

History and Physical

Items elicited from a patient's history that increase the suspicion of melanoma include a personal past history of melanoma, a family history of melanoma (first-degree relative), a history of sunburns and sun exposure, and the inability to tan.⁸

Other important items to obtain from a history are immune system status and any history of artificial tanning exposure.⁶ A history of itching, burning and/or pain associated with a lesion also is important to note,⁸ as well any recent changes in the lesion's appearance.⁹

The ABCDs of melanoma apply for healthcare providers in the clinical setting as well as for patient self-evaluation at home. Thoroughly examine any mole for asymmetry, irregular borders, multiple colors (which might indicate melanoma) and diameter greater than 6 mm.⁹ The American Academy of Dermatology has added "E," for evolving behavior of a suspicious mole or lesion, such as recent bleeding, itching or changes in size, shape or color.¹⁰

Typical Workup

As with any diagnosis, a careful history, a pertinent review of systems and a meticulous physical examination are standard in the initial workup of patients suspected of having malignant melanoma.⁸

Melanomas are more likely to develop in new or changing moles, and from 20% to 40% of melanomas arise from an atypical mole.¹⁰ For this reason, atypical or changing moles most likely warrant a biopsy. Other warning signs that raise the suspicion of melanoma are as follows:¹⁰

• A change in a mole's appearance, such as the spreading of pigment from the border to the surrounding skin
• A mole that looks scaly, oozes or bleeds
• Itching, tenderness or pain in a mole or lesion
• A brown or black streak that appears underneath a nail or around the nail
• A bruise on the foot that does not heal.

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Baseline laboratory and imaging studies are unnecessary in the initial melanoma workup, unless the patient shows signs and symptoms of metastasis. If metastases are suspected, a sentinel lymph node biopsy (SLNB) should be performed to help determine whether the melanoma has metastasized, and if so, how far. Combined with lymphatic mapping, SLNB helps a clinician decide whether regional lymphadenectomy is indicated. The thicker the cutaneous melanoma, the higher the probability that SLNB will be positive. This procedure should be considered in patients whose lesion is 1 mm or thicker, even in the absence of clinical or radiographic evidence of regional lymph node or distant metastases.⁸

No further nodal investigation is necessary with a negative SLNB. However, if the SLNB is positive, elective lymph node dissection (ELND) may be performed in the near future. ELND generally is not recommended in patients whose melanoma is 1 mm or less in thickness unless palpable lymph nodes are present. While it was once thought that prophylactic dissection of lymph nodes in patients with cutaneous melanoma measuring 1 to 4 mm in thickness increased survival rates, recent research has proven that there is no benefit to this procedure.⁸

Other Diagnostic Tests

Genetic testing is not part of the typical melanoma workup but might be useful in its diagnosis and prognosis. The genes cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) are high-risk melanoma susceptibility genes; both exhibit autosomal dominance.¹¹

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Serum lactate dehydrogenase (LDH) is another biologic marker used nonspecifically to detect melanoma. High levels of serum LDH are found in patients with late-stage malignant melanoma. In patients with stage IV melanoma, LDH is the strongest independent prognostic factor and has been included in the current American Joint Committee on Cancer staging system for cutaneous melanoma.^12,13

Treatment and Follow-up

Surgical excision with clear margins is the gold standard of treatment for localized cutaneous melanoma.¹⁴ The thickness or depth to which the lesion invades the skin determines the size of the excisional margins.¹⁵ The Breslow measurement system is used to determine tumor thickness and how far the excisional margins should extend (Table 1).

Nonsurgical treatments for advanced-stage malignant melanoma include radiation with chemotherapy to prevent further metastases and induce remission.⁸ Immunotherapy drugs also are used.¹⁶ Among the primary chemotherapeutic and immunologic agents available are interleukin-2,¹⁶ temozolomide,¹⁷ ipilimumab,¹⁸ and dacarbazine.¹⁹

No matter the stage of the melanoma, long-term management and follow-up are essential. Patients who have had melanoma should have follow-up visits every 3 months for the first 2 years and annually thereafter.⁸ The entire cutaneous surface and lymph nodes should be examined at each visit, and patients with invasive disease require an annual chest radiograph, complete blood count and liver function tests.⁸

Prognosis

The Breslow system also is used to determine prognosis by correlating different tumor thicknesses with 5-year survival rates. Thinner tumors have a better 5-year survival rate and a better prognosis compared with thicker tumors, which are associated with a poorer outcome.⁷ The thickness of the lesion is measured from the deepest malignant cell under the skin's surface to the top of the lesion extending above the skin.

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Melanomas measuring 0.75 mm or less have the best 5-year survival rate of 98% to 99%. Lesions measuring greater than 3 mm thick have a 5-year survival rate of less than 50%. It also is important to note that distant and nodal metastasis is more likely to occur with melanomas measuring greater than 4 mm in thickness (Table 2).⁸

The Clark level is another tool used in gauging the prognosis of patients with melanoma (Table 3).⁸ Higher-grade (deeper) lesions have worse outcomes. Other prognostic tools include sentinel lymph node status, gender (men have a worse prognosis than women), age (prognosis worsens as age increases), the presence of ulceration and regional or distant metastases.⁸

References

1. Melanoma skin cancer. American Cancer Society. http://http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-skin-cancer-key-statistics. Updated Aug. 17, 2011. Accessed Dec. 12, 2011.

2. Howlader N, et al, eds. SEER Cancer Statistics Review, 1975-2008. Bethesda, MD: National Cancer Institute. http://http://seer.cancer.gov/csr/1975_2008/. Accessed Dec. 12, 2011.

3. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://http://seer.cancer.gov/statfacts/html/melan.html. Accessed Dec. 12, 2011.

4. Wang SQ, et al. Ultraviolet A and melanoma: a review. J Am Acad Dermatol. 2001;44(5):837-846.

5. Gershenwald JE, Hwu P. Melanoma. In: Hong WK, et al., eds. Holland-Frei Cancer Medicine. Shelton, CT: People's Medical Publishing House; 2010:1459-1486.

6. Gordon RM, Skin cancer: more than skin deep. Adv Skin Wound Care. 2009;22(12):574-580.

7. Merimsky O, Inbar M. Cigarette smoking and skin cancer. Clin Dermatol. 1998;16(5):585-588.

8. Premalignant and malignant skin neoplasms. In: Goodheart HP, ed. Goodheart's Photoguide to Common Skin Disorders: Diagnosis and Management. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:405-427.

9. Berger TG. Dermatologic disorders. In: McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment 2009. 48th ed. New York, NY: McGraw-Hill; 2009:90-146.

10. Melanoma: what it looks like. American Academy of Dermatology SkinCancerNet. http://http://www.skincarephysicians.com/skincancernet/melanoma.html. Accessed Dec. 12, 2011.

11. Gerstenblith MR, et al. Genetic testing for melanoma predisposition: current challenges. Cancer Nurs. 2007;30(6):452-463.

12. Mouawad R, et al. Old and new serological biomarkers in melanoma: where are we in 2009. Melanoma Res. 2010;20(2):67-76.

13. Balch CM, et al. Melanoma of the skin. In: Edge SE, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009:325-344. http://http://www.cancerstaging.org/staging/PDFs/gershenwald-melanoma.pdf. Accessed Dec. 12, 2011.

14. Minton TJ. Contemporary Mohs surgery applications. Curr Opin Otolaryngol Head Neck Surg. 2008;16(4):376-380.

15. Sladden MJ, et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD004835.

16. Tarhini AA, Agarwala SS. Cutaneous melanoma: available therapy for metastatic disease. Dermatol Ther. 2006;19(1):19-25.

17. Quirt I, et al. Temozolomide for the treatment of metastatic melanoma: a systematic review. Oncologist. 2007;12(9):1114-1123.

18. Sarnaik AA, Weber JS. Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J. 2009;15(3):169-173.

19. Crosby T, et al. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev. 2000;(2):CD001215.

Micah H. Lancaster is a physician assistant at Dublin Area Dermatology & Skin Cancer Center in Dublin, Ga. Sara Haddow-Liebel is an instructor and the education director at the Georgia Health Sciences University physician assistant program in Augusta, Ga. They have completed disclosure statements and report no relationships related to this article.