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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Dermatology

      Cutaneous Melanoma Clinical Presentation

      Updated: Mar 22, 2022
      • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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      Presentation

      History

      A new or changing mole or blemish is the most common warning sign for melanoma. Variation in color and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by the majority of patients with melanoma at the time of diagnosis. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common but warrant an evaluation. Again, because the majority of cutaneous melanoma arises de novo (ie, on normal-appearing skin and not in association with a precursor nevus), routine sampling or mass removal of stable-appearing melanocytic nevi is not warranted for melanoma prevention. However, individuals with numerous moles (common or atypical/dysplastic) or a family history of melanoma are at increased risk of developing melanoma and should be educated regarding the importance of skin self-examination for early detection.

      A total-body skin examination is critical when evaluating a patient at risk for melanoma, particularly those with increased mole count, presence of clinical atypical nevi, prior nonmelanoma skin cancer (i.e., keratinocyte carcinoma), and/or strong family history of melanoma. Multiple studies have demonstrated that thinner melanomas are associated with physician detection during routine skin or physical examinations, compared with patient detection of melanoma when a lesion changes or becomes symptomatic. [41]

      Clinician and patient education regarding the warning signs of early melanoma (particularly the superficial spreading subtype) has been achieved successfully through the use of the ABCDE criteria for a changing mole, [42, 43] which are as follows:

      • Asymmetry: Onw half the lesion does not match the other half.

      • Border irregularity: The edges are ragged, notched, or blurred.

      • Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration is of particular concern.

      • Diameter: A diameter greater than 6 mm is characteristic, although some melanomas may be smaller in size; any growth in a nevus warrants an evaluation.

      • Evolving: Changes in the lesion over time are characteristic; this factor is critical for nodular or amelanotic (nonpigmented) melanoma, which may not exhibit the ABCD criteria above.

      The ABCDEs have the greatest diagnostic accuracy when used in combination. Lesions exhibiting these features should be considered potential melanoma, although severely atypical/dysplastic nevi may be difficult to distinguish clinically. The "ugly duckling" warning sign, in which skin examination is focused on recognition of a pigmented or clinically amelanotic “outlier” lesion that looks different from the rest, may assist with detection of lesions that lack the classic ABCDE criteria (eg, nodular, amelanotic, or desmoplastic melanomas). [44, 45]

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      Physical Examination

      Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females. In African American, Hispanic/Latinx, and Asian persons, the most common site is the plantar foot, followed by subungual, palmar, and mucosal sites. Melanoma can occur on any skin or mucosal surface, although a history of cutaneous melanoma does not appear to increase the risk of developing primary intraocular, oral, or other mucosal melanoma.

      Four major clinicopathologic subtypes of primary cutaneous melanoma have been identified, although newer classifications of melanoma include location on chronically sun-exposed versus intermittently or non‒sun-exposed skin and incorporate the presence of driver mutations in BRAF, NRAS, NF-1, and other oncogenes. Classic histopathologic melanoma subtypes include superficial spreading, nodular, lentigo maligna, and acral lentiginous. Distinction among these subtypes is based on histologic growth pattern (predominantly junctional in lentiginous types vs pagetoid in superficial spreading and predominantly dermal in nodular), anatomic site, and degree of sun damage. The pattern of sun exposure varies between the types (chronic in lentigo maligna vs intermittent in superficial spreading and nodular subtypes vs noncontributory in acral lentiginous and mucosal subtypes).

      Whether the melanoma subtype affects the overall prognosis remains controversial. However, molecular analysis has demonstrated different patterns of cell death; oncogene expression; gene amplification; and BRAF, NRAS, and KIT mutation frequency among the four main histogenetic types. [46, 47, 48] Differing microRNA signatures between superficial spreading melanoma and nodular melanoma have also been described, which supports the concept of molecular classification of superficial spreading melanoma and nodular melanoma as two distinct phenotypes. [49]

      A pooled analysis of more than 30 studies from 1989-2010 concludes that the incidence of BRAF and NRAS mutations differ based on histologic subtype and anatomic site. [8] BRAF mutations are more commonly detected in superficial spreading melanomas and melanomas that arise on nonchronically sun-damaged skin. NRAS mutations are more common in patients with nodular melanomas and melanomas arising on chronically sun-damaged skin. Some, but not all data have shown that NRAS mutations may be associated with thicker tumors (>1 mm) and higher mitotic rate (>1/mm2) compared with mutations in BRAF, and that NRAS mutation status may be associated with worse clinical outcomes, including shorter melanoma specific survival. [50, 51] These studies suggest that further molecular classification of melanoma may assist in the development of more effective targeted therapies.

      With the exception of nodular melanoma, the growth patterns of the other subtypes are characterized by a preceding in situ (radial growth) phase that lacks the biologic potential to metastasize and may last from months to years before dermal invasion occurs. While in situ melanomas may not necessarily progress to invasive melanoma, complete removal is recommended to prevent invasion and result in cure.

      Superficial spreading melanoma

      Superficial spreading melanoma accounts for nearly 70% of cutaneous melanoma and is the most common subtype in individuals aged 30-50 years, as well as those with clinical atypical/dysplastic nevi. It is most common on the trunk in men and women and on the legs in women. See the image below.

      Superficial spreading melanoma, left breast, 1.3-m Superficial spreading melanoma, left breast, 1.3-mm Breslow depth.
      View Media Gallery

      Superficial spreading melanoma commonly displays the ABCD warning signs. It manifests as a flat or slightly elevated brown lesion with variegate pigmentation (ie, black, blue, pink, or white discoloration). It is generally greater than 6 mm in diameter. Irregular asymmetric borders are characteristic.

      Histologically, it is characterized by buckshot (pagetoid) scatter of atypical melanocytes within the epidermis.

      Nodular melanoma

      This subtype occurs in 15-30% of patients. It is seen most commonly on the legs and trunk in men and women. Rapid growth occurs over weeks to months; this subtype is responsible for most thick melanomas. [52, 53]

      Nodular melanoma may be clinically amelanotic (ie, not pigmented); thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical evaluation. Nodular melanoma typically manifests as a dark brown-to-black papule or dome-shaped nodule, which may ulcerate and bleed with minor trauma; however, it may also be clinically amelanotic (ie, not pigmented).

      Nodular melanoma tends to lack the typical ABCDE melanoma warning signs and, thus, may elude early detection. More commonly, it exhibits elevation, ulceration with bleeding, or both at presentation.

      Histologically, it is believed to lack a preceding radial or in situ growth phase.

      Lentigo maligna melanoma

      The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States. [54]  It is typically located on the head, neck, and arms (chronically sun-damaged skin) of lighter-skinned older individuals (average age 65 y). See the image below.

      Lentigo maligna melanoma, right lower cheek. Centr Lentigo maligna melanoma, right lower cheek. Centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ).
      View Media Gallery

      This subtype grows slowly over 5-20 years. The in situ precursor lesion (termed lentigo maligna) is usually large (>1-3 cm in diameter), present for a minimum of 10-15 years, and demonstrates macular (flat) pigmentation ranging from dark brown to black, although hypopigmented (white) areas are common within lentigo maligna. Progression to dermal invasion (i.e., lentigo maligna melanoma) is believed to be an uncommon event for most melanomas in situ/lentigo maligna type but is clinically characterized by the development of raised blue-black nodules within the in situ lesion.

      Histologically, lentigo maligna melanoma  is characterized by a predominantly junctional confluent proliferation of melanocytes and extension along adnexal structures, although dysplastic nevus-like features may be observed. [55] Solar elastosis is typically prominent, and this subtype is now commonly referred to as high cumulative sun damage (CSD) melanoma [56] .

      Acral lentiginous melanoma

      Acral melanoma is the least common subtype of melanoma in white persons (2-8% of melanoma cases).However, is the most common melanoma subtype in individuals with darker skin tones (ie, African American, Asian, and Hispanic/Latinx persons - who are at lower risk of UVR-related melanomas), representing 29-72% of melanoma cases. Because of delays in diagnosis, acral melanoma may be associated with a worse prognosis. [57, 58, 19]

      Acral lentiginous melanoma occurs on the palms, on the soles, or beneath the nail plate of the fingernails or toenails (subungual variant). See the image below.

      Acral lentiginous melanoma (1-mm Breslow depth), l Acral lentiginous melanoma (1-mm Breslow depth), left sole. Diagnostic punch biopsy site is located superiorly.
      View Media Gallery

      Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band (melanonychia striata) within the nail plate. It must be differentiated from a benign junctional melanocytic nevus of the nail bed, which has a similar appearance. Pigment spread to the proximal or lateral nail folds is termed the Hutchinson sign, which is a hallmark for subungual melanoma. Subungual melanoma may be mistaken for a subungual hematoma, which is usually due to trauma and resolves with time.

      Fungal infection of the nail (onychomycosis) can also be confused with subungual melanoma, particularly in the setting of nail dystrophy without suspicious pigmentation. Nonresponsiveness to antifungal agents should prompt more thorough evaluation, including potential biopsy.

      Rare variants

      Rare melanoma variants (< 5% of melanomas) include (1) desmoplastic/neurotropic melanoma, (2) mucosal (lentiginous) melanoma, [59] (3) blue nevus-like melanoma, (4) melanoma arising in a giant/large congenital nevus, and (5) melanoma of soft parts (clear cell sarcoma).

      Desmoplastic melanoma

      Desmoplastic melanoma is a less common but important melanoma subtype, given its predilection in older-age individuals, clinical features similar to nonmelanoma (keratinocytic) skin cancer, and potential indication for adjuvant radiation therapy for improved local control following wide excision.

      Desmoplastic melanoma may occur in association with macular, lentigo maligna-type pigmentation and show high-CSD features histologically, or it may present de novo as a firm, amelanotic nodule or scar. It occurs most often on sun-exposed areas of the head and neck, with a mean age of 60-65 years. [60]  Lack of pigmentation and clinical features more suggestive of keratinocytic (“nonmelanoma”) skin cancer may result in delay in detection and thicker tumors at diagnosis.

      Desmoplastic melanoma frequently exhibits perineural invasion/neurotropism, which confers an increased risk for local recurrence. Wide excision  (based on Breslow thickness) and adjuvant radiation therapy may be necessary for improved local control of this uncommon melanoma subtype.

      Amelanotic melanoma

      Amelanotic melanoma (< 5% of melanomas) can occur with any subtype. This type is nonpigmented and, clinically appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma, dermatofibroma, or a ruptured hair follicle. It occurs most commonly in the setting of the nodular or desmoplastic melanoma subtypes or melanoma metastasis to the skin, presumably because of the inability of these poorly differentiated cancer cells to synthesize melanin pigment.

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      Complications

      Metastasis may occur locally (within or around the primary cutaneous site), in the regional lymph node basins, or distally in the following sites:

      • Remote skin (away from the melanoma scar)

      • Remote lymph node(s)

      • Viscera

      • Skeletal

      • CNS sites

      Disease relapse is seen most commonly in the skin, subcutaneous tissue, and lymph nodes.

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