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Cutaneous Melanoma Clinical Presentation

  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Mar 28, 2016
 

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, 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.[16]

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,[17, 18] which are as follows:

  • Asymmetry: 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. More recent use of the "ugly duckling" warning sign, in which skin examination is focused on recognition of a pigmented or clinically amelanotic lesion that simply looks different from the rest, may assist with detection of lesions that lack the classic ABCDE criteria (eg, nodular, amelanotic, or desmoplastic melanomas).[19, 20]

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Physical

Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females. In African American, Hispanic, 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.[21, 22, 23] 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.[24]

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.[4] 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. Recent 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.[25, 26] 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 all in situ melanoma may not necessarily progress to invasive melanoma, complete removal is recommended to prevent invasion and result in cure.

Superficial spreading melanoma

It 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.

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.[27, 28]

It 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. It manifests as a dark brown-to-black papule or dome-shaped nodule, which may ulcerate and bleed with minor trauma; it may be clinically amelanotic (ie, not pigmented).

It 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.[29]  It is typically located on the head, neck, and arms (chronically sun-damaged skin) of fair-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).

It 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. Dermal invasion (progression to lentigo maligna melanoma) is characterized by the development of raised blue-black nodules within the in situ lesion.

Histologically, it is characterized by a predominantly junctional confluent proliferation of melanocytes and extension along adnexal structures, although dysplastic nevuslike features may be observed.[30] Solar elastosis is typically prominent.

Acral lentiginous melanoma

This is the least common subtype of melanoma in white persons (2-8% of melanoma cases). It is the most common subtype of melanoma in dark-skinned individuals (ie, African American, Asian, and Hispanic persons), representing 29-72% of melanoma cases and, because of delays in diagnosis, may be associated with a worse prognosis.[31, 32]

Acral lentiginous melanoma occurs on the palms, on the soles, or beneath the nail plate (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.

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,[33] (3) blue nevuslike 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 for 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.

It may occur in association with macular, lentigo maligna-type pigmentation, 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.[34]  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 extension and has a predilection for local recurrence. Wide excisional margins (≥2 cm) and adjuvant radiation therapy are frequently recommended 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 subtype 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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Causes

Melanoma shows an increased worldwide incidence in fair-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation. Most data support the hypothesis that melanoma development is related to intermittent, intense sun exposure, particularly in childhood or adolescence.[35, 36] In contrast, chronic sun exposure does not appear to confer increased risk, except for the more UV-related melanoma subtypes (lentigo maligna and lentigo maligna melanoma). The use of tanning beds has also increased the risk of melanoma in young patients.[37]

Primary risk factors and clinical warning signs for melanoma include the following:

  • Changing mole (most important clinical warning sign)
  • Presence of xeroderma pigmentosum or familial atypical mole melanoma syndrome: These genodermatoses confer a 500- to 1000-fold greater relative risk of developing melanoma.
  • Clinical atypical/dysplastic nevi in familial melanoma
  • Sporadic (nonfamilial) clinical atypical/dysplastic nevi (particularly >5-10)
  • Melanoma in first-degree relative(s) (especially multiple)
  • Large numbers of common nevi (>100)
  • Previous melanoma
  • Male sex
  • Age older than 50 years
  • Sun sensitivity/history of excessive sun exposure or sunburns
  • Large (giant) congenital nevi (>20 cm diameter in an adult)
  • Prior nonmelanoma skin cancer (basal cell and squamous cell carcinoma) [37]
  • Immunosuppression

A fair-skin phenotype (blue/green eyes, blond or red hair, light complexion, sun sensitivity) and the occurrence of blistering sunburn(s) in childhood and adolescence are universal risk factors for melanoma. Individuals with these traits have been the focus of preventive efforts worldwide.

Pregnancy or hormonal therapy with oral contraceptives or hormone replacement does not appear to be a risk factor for melanoma development.[38, 39, 40, 41, 42]

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Contributor Information and Disclosures
Author

Susan M Swetter, MD Director, Pigmented Lesion and Melanoma Program, Professor, Department of Dermatology, Stanford University Medical Center and Cancer Institute, Veterans Affairs Palo Alto Health Care System

Susan M Swetter, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, American Society of Clinical Oncology, Society for Melanoma Research, Eastern Cooperative Oncology Group, American Medical Association, Pacific Dermatologic Association, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

John G Albertini, MD Private Practice, The Skin Surgery Center; Clinical Associate Professor (Volunteer), Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine; President-Elect, American College of Mohs Surgery

John G Albertini, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery

Disclosure: Received grant/research funds from Genentech for investigator.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.

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Superficial spreading melanoma, left breast, 1.3-mm Breslow depth.
Lentigo maligna melanoma, right lower cheek. Centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ).
Acral lentiginous melanoma (1-mm Breslow depth), left sole. Diagnostic punch biopsy site is located superiorly.
Malignant melanoma. Courtesy of Hon Pak, MD.
Cutaneous melanoma with characteristic asymmetry, irregular borders, and color variation. Courtesy of Wendy Brick, MD.
Table. AJCC 2002 Revised Melanoma Staging
Stage TNM Classification Histologic/Clinical Features 5-Year Survival Rate, %
0 Tis N0 M0 Intraepithelial/in situ melanoma 100
IA T1a N0 M0 ≤1 mm without ulceration and mitotic rate < 1/mm2 97
IB T1b N0 M0



T2a N0 M0



≤1 mm with ulceration or mitotic rate ≥1/mm2



1.01-2 mm without ulceration



91-94
IIA T2b N0 M0



T3a N0 M0



1.01-2 mm with ulceration



2.01-4 mm without ulceration



79-82
IIB T3b N0 M0



T4a N0 M0



2.01-4 mm with ulceration



4 mm without ulceration



68-71
IIC T4b N0 M0 >4 mm with ulceration 53
IIIA T1-4a N1a M0



T1-4a N2a M0



Single regional nodal micrometastasis, nonulcerated primary



2-3 microscopic positive regional nodes, nonulcerated primary



78
IIIB T1-4b N1a M0



T1-4b N2a M0



T1-4a N1b M0



T1-4a N2b M0



T1-4a/b N2c M0



Single regional nodal micrometastasis, ulcerated primary



2-3 microscopic regional nodes, nonulcerated primary



Single regional nodal macrometastasis, nonulcerated primary



2-3 macroscopic regional nodes, no ulceration of primary



In-transit met(s)* and/or satellite lesion(s) without metastatic lymph nodes



54-59
IIIC T1-4b N2a M0



T1-4b N2b M0



Any T N3 M0



Single macroscopic regional node, ulcerated primary



2-3 macroscopic metastatic regional nodes, ulcerated primary



4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit met(s)/satellite lesion(s) and metastatic nodes



40
IV Any T any N M1a



Any T any N M1b



Any T any N M1c



Distant skin, subcutaneous, or nodal mets with normal LDH levels



Lung mets with normal LDH



All other visceral mets with normal LDH or any distant mets with elevated LDH



< 20
*Met is metastasis.
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