Answer: A

René Théophile Hyacinthe Laennec first lectured on melanoma and coined the term “melanose,” meaning “black” in Greek, in 1804. Between 1829 and 1842, his colleague, Jean Cruveilhier, published articles on melanoma of the hand, foot, and vulva, as well as metastases to the heart.1 Melanoma is the most dangerous skin cancer, accounting for 80% to 90% of deaths from skin cancer, even though it represents only 4% of all dermatologic cancers.2-5 Like many dermatologic pathologies, this malignancy is thought to develop after repeated exposure to intense sunlight.2 Clinical appearance may vary, but the most common presentation is an asymmetric macule that may slowly develop into a papule, with an irregular border and variable pigmentation.2,3 Several other conditions mimic melanoma, including dysplastic nevi — a benign condition that may be a precursor to malignant melanoma.6,7 If diagnosed at an early stage, melanoma can be cured with resection, but cancers stage III and greater require treatment with adjunctive therapy, lymph node resection, and potentially chemotherapy and radiation.3,5

Incidence of melanoma ranges widely by region but is highest in New Zealand and Australia.5 Rates are also high in the European Union and North America, as the condition predominantly affects fair-skinned populations.3,5 Melanoma is in the top 10 most common malignancies for both men and women in the United States.5 It can occur anywhere on the body but is most common in sun-exposed areas, including the trunk, head, neck, face, and lower legs.3,8 Onset is dependent on the subtype of melanoma; superficial spreading is most common and diagnosed on average between the ages of 40 and 60 years.9 The elderly and men tend to have lower survival rates, but generally melanoma has a high 5-year survival rate of approximately 92% in the United States.5

Melanoma is a malignancy of melanocytes that develops from a series of mutations.2,9 The Clark model outlines a potential method of step-wise pathogenesis.2 First, melanocytes proliferate to form a nevus, which then continues via dysplasia and hyperplasia to form a dysplastic nevus, and then finally invades and undergoes metastasis in the form of malignant melanoma. Signaling pathways commonly mutated include MAPK (including BRAF) and PTEN (PI3K), which regulate growth and proliferation; WTN, which regulates differentiation; and MC1R-MITF, which is associated with a melanocyte-specific receptor.2,9 Additionally, the loss of E-cadherin and expression of N-cadherin marks the progression to vertical growth and thus increased Breslow depth.2,3 This transformation into melanoma is influenced by many factors, most notably exposure to ultraviolet (UV) radiation.2,5 Sun exposure induces genetic changes in the skin, forms DNA-damaging reactive oxygen species, and alters the local immune system and growth factors.2 The skin’s defense mechanism is to produce more melanin to absorb and dissipate damaging rays. With chronic, low-grade exposure the skin is able to shield itself against this process. This physiologic defense mechanism is overrun, however, with intermittent exposure to intense UV radiation, resulting in genetic damage and potential progression to skin cancer.2

Risk factors for the development of melanoma include a history of intermittent, intense sun exposure, frequent sun burns, personal or family history of melanoma, multiple benign or atypical nevi, fair skin, and immunosuppression.2,5,8 Despite identification of several genes associated with melanoma (eg, CDKN2A and MC1R), genetic testing has failed to show clinical benefit.2,5,9 Although the risk of transformation of a single benign or atypical nevus to melanoma is low, 1 in thousands and 1 in hundreds of individuals, respectively, with many nevi have been noted to have higher rates of melanoma.9 This is potentially because of increased sun exposure or an underlying condition such as dysplastic nevus-melanoma syndrome.9,10 Phenotypic characteristics including fair hair, eye, and skin colors and the tendency to freckle increase an individual’s susceptibility to UV-induced damage.3,9

Classic clinical characteristics of melanoma include asymmetry, irregular borders, color variability, and diameter >5 mm. This is easily remembered by the ABCD rule.8 The lesion may be itchy, tender, ulcerated, and/or bleeding. When the malignancy enters its rapid vertical growth phase, the original macule may transform into a papule or nodule.9 The main subtypes of melanoma include superficial spreading, lentigo maligna (malignant melanoma in situ), nodular, and acral-lentiginous.5,9 Superficial spreading is the most common variant; in women, it is found most commonly on the legs and in men, on the trunk.9 In the initial clinical evaluation, dermoscopy is useful in detection of melanoma. While this technique is user dependent, it is up to 90% effective.5 On histologic examination, markedly atypical melanocytes are seen in nests in the epidermis. These nests may be confluent and vary in size. Melanocytes may also be scattered above the dermal-epidermal junction and within the dermis.9

The differential diagnosis for melanoma is extremely broad. Various nevi — including dysplastic, combined, congenital, blue, black, and halo — can clinically mimic melanoma. Reticulated lentigo, seborrheic keratosis, dermatofibroma, and plantar warts are benign conditions on the differential. Malignant conditions to consider include pigmented basal cell carcinoma, pigmented actinic keratosis, and extramammary Paget disease.9 The first step in differentiating melanoma from similar-appearing conditions is dermoscopy to determine if the lesion is melanocytic in origin; various algorithms including the ABCD rule, Menzies method, and the 7-point checklist can then be used to decide if a biopsy should be performed.8,9

Diagnosis is made clinically and confirmed by excisional biopsy and histopathologic examination. Breslow thickness is the most important prognostic factor. Other prognostic factors include location, ulceration, gender, and mitotic activity.5 Classification is determined by tumor thickness (T stage; Breslow staging), involvement of lymph nodes (N stage), and presence of metastasis (M stage).3,5

After diagnosis is made, the lesion should be re-excised. Margins range from 0.5 cm for malignant melanoma in situ to 2 cm if the tumor is > 2 mm thick.5 As discussed previously, the tumor should be staged and lymph node involvement should be assessed. Lymph node biopsies are recommended if the tumor is >1 mm thick. Computed tomography or magnetic resonance imaging should be performed to determine if distant metastasis is present if evidence of metastasis is noted.5,9

For those with melanoma stage III and greater, adjunctive therapy is recommended, and chemotherapy may be needed to treat metastases.3,5,9 Immunotherapy such as PD-1 inhibitors and anti-CTLA-4 antibodies stimulates the patient’s immune system to more effectively attack the malignant cells. Ipilimumab, nivolumab, and pembrolizumab are  immunotherapy options approved to treat melanoma.3,4 BRAF gene mutations are the ones most commonly seen in melanoma and are found in 40% to 50% of tumors.4 Individuals with BRAF mutations can be treated with either a kinase inhibitor such as vemurafenib or dabrafenib, or the reversible MEK1 and MEK2 kinase inhibitor trametinib.4 These drugs can be given alone or in combination. The American Cancer Society lists many possible chemotherapy regimens including dacarbazine, temozolomide, nab-paclitaxel, paclitaxel, cisplatin, carboplatin, and vinblastine.11 The American Cancer Society also states that adding immunotherapy drugs (interferon-alfa and/or interleukin-2) to chemotherapy may be more effective than chemotherapy alone.

Follow-up is important to identify recurrence, but recommendations on the frequency of these visits vary depending on a patient’s particular case. Because 90% of all metastases occur within the first 5 years, it is recommended that more frequent visits occur during this time period.3 For individuals with melanoma stages I to II, screening every 3 months with the goal of detecting local recurrence is recommended.

Biopsy was performed on the lesion in this case, with pathologic evaluation revealing atypia and melanocyte nests. The patient was diagnosed with melanoma and returned for re-excision with 1-cm margins. Breslow thickness measured 0.6 mm; therefore, lymph node dissection was not recommended. The patient returned for regular screening and did not develop recurrence.

Click to the next page for Case 2.