Approach

Early melanoma may be asymptomatic. History regarding a new or changing pigmented lesion should be obtained.

History

Questions should focus on when the lesion was first noted, although approximately 25% to 42% of melanomas arise from a pre-existing melanocytic nevus that may not be suspicious.[19][20][21]

Another useful inquiry regards the change in size, shape, coloration, or ulceration of the lesion. If the lesion is pruritic or has bled, suspicion should be high.[50]

Growths with no history of a pigmented lesion are described as nodular, amelanotic, or desmoplastic melanoma.

Certain markers help identify patients at higher risk:[15][17][33][35][36][39][40][41]​​[42][44][45][46][47][51]

  • Personal or family history of melanoma

  • Personal history of skin cancer (including actinic damage)

  • Fitzpatrick skin type I or II (white skin)

  • Light eye color

  • High freckle density

  • Red or blond hair

  • Prior sun bed use

  • Childhood history of sunburns

  • Large number of melanocytic nevi

  • Presence of atypical melanocytic nevi (previously called dysplastic nevi)

  • Presence of large (>20 cm) congenital melanocytic nevi

  • Genetic syndromes with skin cancer predisposition (e.g., xeroderma pigmentosum)

  • Immunosuppression (i.e., immunosuppressive medications, history of extensive psoralen and ultraviolet A [PUVA] therapy, or HIV).

Constitutional symptoms such as cough, weight loss, fatigue, night sweats, and headache may be symptoms of systemic metastasis in a patient with a history of melanoma.

[Figure caption and citation for the preceding image starts]: Fitzpatrick skin typeCreated by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@7a5dad52

Physical examination

Patients should receive a complete physical examination of the entire surface of the skin, including the scalp and mucous membranes.

The American Cancer Society ABCD signs of melanoma mnemonic is useful for both physicians and patients in the early detection of melanoma.[52] The addition of evolving (letter E added to the ABCD mnemonic) has been proposed to increase the sensitivity and specificity of diagnosis using the ABCD rule.[50]

  • Asymmetry of the lesion

  • Border irregularity

  • Color variability

  • Diameter >6 mm

  • Evolution.

A specificity of 0.88 and a sensitivity of 0.73 for melanoma have been reported if 2 out of 3 of the following characteristics are noted: irregular outline, diameter >6 mm, and color variegation.[52]

In addition to the ABCDEs of melanoma, any melanocytic lesion that is atypical in appearance with respect to the patient's surrounding moles should raise suspicion. This finding has been termed the "ugly duckling sign."[50][53]

Early melanoma lesions, especially those involving sun-exposed and acral sites, may be completely macular.[Figure caption and citation for the preceding image starts]: Superficial spreading melanomaFrom the personal collection of Dr Hobart Walling and Dr Brian Swick. [Citation ends].com.bmj.content.model.Caption@90564a5 However, with progression they usually develop a papular or nodular component.[Figure caption and citation for the preceding image starts]: Nodular melanomaFrom the personal collection of Dr Hobart Walling and Dr Brian Swick. [Citation ends].com.bmj.content.model.Caption@7480a480

Melanomas with atypical features, such as those lacking pigment (amelanotic melanomas) or those resembling seborrheic keratoses, can be difficult to diagnose without a high index of suspicion.

Nodular melanomas tend to grow rapidly and often do not have any ABCD criteria.[54]

In the setting of pigmented bands in the nail bed and matrix (melanonychia striata), extension of pigment into the proximal or lateral nail fold is known as Hutchinson sign and is concerning for melanoma.[55][Figure caption and citation for the preceding image starts]: Subungual melanoma in situFrom the personal collection of Dr Hobart Walling and Dr Brian Swick. [Citation ends].com.bmj.content.model.Caption@1520ac9b

Subcutaneous masses between the skin lesion and the draining lymph node basin should raise clinical suspicion of in-transit (intralymphatic) metastases. Fixed lymphadenopathy is concerning for regional nodal metastasis.

Dermoscopy

In the UK, it is recommended that any lesion that is suspected for melanoma on physical examination should be further evaluated with dermoscopy.​[56][57][58][59]​ In the US, skin biopsy is the preferred method of further evaluation of suspicious lesions.[14]

In dermoscopic evaluation, the skin lesion is usually covered with an immersion fluid. The skin lesion is then inspected using a handheld magnifying lens attached to a light source. Dermoscopes with a polarized light source do not require an immersion liquid.

The most important application of dermoscopy is distinguishing melanoma from benign melanocytic lesions. However, the technique is also useful in distinguishing melanocytic lesions from nonmelanocytic pigmented lesions such as seborrheic keratoses, pigmented basal cell carcinomas, and vascular lesions.

[Figure caption and citation for the preceding image starts]: Dermoscopy: the most important application of dermoscopy is distinguishing melanoma from benign melanocytic lesions© DermNet New Zealand; used with permission [Citation ends].com.bmj.content.model.Caption@1331f7fd

The use of dermoscopy by trained individuals results in increased diagnostic accuracy compared with naked-eye exam alone.[60] Utilizing dermoscopy, the nonabsolute sensitivity for diagnosing melanoma increased by 19% (83.2% with dermoscopy versus 69.6% without dermoscopy).[61]

[Figure caption and citation for the preceding image starts]: Key dermoscopic features of melanoma: (A) Melanoma presenting with atypical globules and dots of different sizes and shapes (yellow arrows), patches of atypical network (blue arrowhead) and a blue-white veil (blue arrow). (B) Melanoma with diffuse polymorphous vasculature, consisting of serpentine, dotted, and glomerular vessels, can be found throughout the lesion (yellow arrowheads); in addition, patches of atypical network (blue arrowheads) are seen. (C) Superficial spreading melanoma with pseudopods distributed asymmetrically around the lesion (black arrowheads). (D) Melanoma with the regression structure blue-gray peppering (black star); shiny white lines are also seen throughout the entire lesion (red arrows) along with a central blue-white veil (red arrowhead)Wolner ZJ et al. Enhancing skin cancer diagnosis with dermoscopy. Dermatol Clin. 2017 Oct;35(4):417-37; used with permission [Citation ends].com.bmj.content.model.Caption@eabf59

Skin biopsy

Histopathologic analysis of a new or changing atypical pigmented lesion is essential in the diagnosis. Any suspicious lesion should be biopsied. The excision of a pigmented lesion enables the dermatopathologist to accurately diagnose melanoma, and influences prognosis and the extent of further surgery or other treatment.[14]

The ideal management is a complete full-thickness excision of the lesion with a 1-3 mm margin.[14][62]​​ Full-thickness incisional or punch biopsy of clinically thickest or most atypical portion of lesion is acceptable and may be preferred in certain anatomic areas (e.g., palm/sole, digit, face, ear) or for very large lesions. Multiple "scouting" biopsies may help guide management for very large lesions.[14]

Skin biopsy confirms the diagnosis of melanoma and provides prognostic information. Prognostic indicators include tumor thickness measured as Breslow thickness (depth of invasion measured in millimeters from the top of the granular cell layer to the point of deepest tumor penetration in the dermis or subcutis), ulceration, mitotic count, lymphovascular invasion, and microscopic satellites.[14][63] An unfavorable prognosis is associated with greater depth of invasion, ulceration, increased mitotic count, vascular invasion, regression, and the presence of microscopic satellites.[14]

Immunohistochemistry

Immunohistochemistry is increasingly used to interpret biopsies that are not easily classified based on histopathologic features.[64][65] It can help to distinguish melanocytic lesions from tumors with different origin, and benign from malignant melanocytic lesions.[66]

Melanocytic markers that can be used in the immunohistochemical analysis include Melan-A/MART-1, S-100, MITF, tyrosinase, HMB45, SOX10, and PRAME.[14][64][67][68]​​

Genomic analysis of melanoma

Serves to identify common genetic mutations associated with melanoma. Increasingly, gene panels are performed to test for mutations of interest.

BRAF mutational analysis

Approximately 40% of melanomas contain an activating mutation in the BRAF gene, most commonly at position V600. Valine to glutamate (V600E) accounts for 75% to 90% of BRAF mutations within melanoma. Other less common mutations include valine to lysine (V600K) in 10% to 30% of BRAF mutations, and valine to arginine (V600R) in 1% to 3%. These mutations lead to constitutive activation of the mitogen-activated protein kinase signaling pathway.[26][27][28]

Recommendations for BRAF mutational analysis vary by country. It is generally performed in patients who will require systemic therapy, and in those at high risk of recurrence for whom future BRAF-directed therapy may be appropriate.[14][56]​ 

In the UK, immunohistochemistry is recommended as the initial test for BRAF V600E if available.[56] This is rapid, with high sensitivity and specificity for BRAF V600E.[69] If immunohistochemistry is inconclusive or negative, a different BRAF genetic test should be tried.[56]

An automated molecular assay to identify BRAF mutations at position V600 is available, but it only readily detects the V600E mutation.[70] Several other platforms, including pyrosequencing, next generation sequencing, and Sanger sequencing, detect all known V600 mutations.

All patients who test positive for any BRAF V600 mutation are suitable for BRAF/MEK inhibitor therapy.

NRAS mutation analysis

NRAS mutations activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, thereby promoting tumor proliferation and survival, are found in approximately 15% to 25% of melanomas and are associated with rapidly progressing disease.[25][71]

More than 80% of NRAS mutations involve a point mutation leading to the substitution of glutamine to leucine at position 61, and in melanoma are generally mutually exclusive to BRAF mutations.

Detection methods include post-polymerase chain reaction high resolution melt analysis.

CDKN2A mutation analysis

  • Mutations in the CDKN2A gene on chromosome 9 have been found in families with the atypical nevus syndrome and in 39% of melanoma-prone families.[18][38]

  • Next generation sequencing or single gene assays may be used for molecular testing in the research setting.

If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[14][72]

Clinical staging of melanoma: American Joint Committee on Cancer TNM staging system (8th Edition)

The American Joint Committee on Cancer (AJCC) staging system describes the extent of disease based on the following anatomic factors: size and extent of the primary tumor (T); regional lymph node involvement (N); and presence or absence of distant metastases (M).[62] Nonanatomic prognostic factors (e.g., tumor grade, biomarkers) may be used to supplement the staging of certain cancers.

In general, cutaneous melanoma is categorized as:[14]

  • Localized disease (no evidence of metastases, stage I-II)

  • Regional disease (stage III)

  • Distant metastatic disease (stage IV).

Imaging

Ultrasound of the lymph node basin may be performed before sentinel lymph node biopsy, if the physical examination of the lymph nodes is equivocal. Ultrasound is not needed for clinically suspicious lymph nodes, because biopsy is indicated. Any suspicious lymph nodes identified on ultrasound should be biopsied.[14]

Baseline cross-sectional imaging

Guideline recommendations for use of baseline cross-sectional imaging differ.

In the US, baseline cross-sectional staging imaging should be considered for patients with stage IIIa melanoma (sentinel lymph node positive), and is indicated for all patients with stage IIIb, IIIc, IIId, and IV melanoma. Imaging studies should include the chest, abdomen, and pelvis, plus the neck if clinically indicated. CT or fluorodeoxyglucose positron emission tomography/computed tomography (FDG-CT/PET) may be used.[14] FDG-CT/PET has the highest specificity, sensitivity, and diagnostic odds ratio for distant metastases.[73]​ For stages IIIb, IIIc, and IIId brain imaging for baseline staging may be indicated prior to initiation of therapy, and is recommended for all patients with stage IV melanoma.[14]

Imaging should also be performed to evaluate any symptoms or signs suggestive of possible metastases (e.g., headache) if present, at any stage of disease.[14]

In the UK, whole-body and brain contrast-enhanced computed tomography (CE-CT) should be considered for people with stage IIB melanoma.[56] Staging with CE-CT should be offered to all patients with IIC to IV melanoma. If available, a brain magnetic resonance imaging (MRI) can be used instead of a brain CE-CT.[56]

A whole-body and brain MRI, instead of CE-CT should be offered to:[56]

  • Children and young adults (from birth to 24 years) with stage IIB and IV melanoma

  • Women with stage IIB to IV melanoma who are pregnant.

For people with stage IIIC to IV melanoma and one of the following risk factors, a staging brain MRI, instead of a CE-CT can be considered:[56]

  • Mitotic index of 5 or more

  • Primary melanoma on the scalp.

If adjuvant treatment is begun longer than 8 weeks after initial staging, a repeat staging scan should be considered before starting adjuvant treatment.[56]

Routine imaging is not recommended for people with stage IA melanoma, and should not be considered before sentinel lymph node biopsy (SLNB) unless lymph node or distant metastases are suspected.[56]

One European guideline recommends baseline brain imaging with magnetic resonance imaging (MRI) with intravenous contrast or CT should be considered for patients with stage IIC melanoma with a poor prognosis, and is indicated for all patients with stage III to IV melanoma.​​[67]​ MRI with intravenous contrast is the preferred method for brain imaging, as it is better at detecting brain metastases than CT scan.[67]

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) is based on the concept that a tumor will drain to a particular first lymph node within a lymph node basin. There may be multiple draining lymph node basins and multiple sentinel nodes, depending on individual lymphatic drainage patterns.

A radiotracer or a blue dye is injected intradermally at the site of the primary lesion (before wide local excision [WLE]) to identify the sentinel node.[14]

SLNB may be performed for selected patients with stage I and stage II melanoma. It permits accurate staging of patients with no clinical or radiologic evidence of nodal metastases, and provides prognostic information.[14]

NCCN guidelines advise that SLNB should be discussed with patients with stage IB or II disease with the following considerations:[14]

  • Tumor thickness <0.8 mm with ulceration

  • Tumor thickness 0.8 to 1.0 mm with or without ulceration

  • Tumor thickness >0.5 mm who have additional adverse prognostic features (e.g., age ≤42 years, head/neck location, lymphovascular invasion, and/ or mitotic index ≥2/mm²)

The probability of a positive SLNB is 5% to 10% for these patients, with an increased risk for patients with multiple adverse prognostic features.[14]

SLNB is not generally recommended for patients with tumors <0.8 mm thick without ulceration or adverse prognostic features, unless there is significant uncertainty about the adequacy of microstaging (e.g., positive deep margins or limited sampling of a larger lesion). The risk of positive SLNB in these patients is <5%.[14]

UK guidelines recommend considering SLNB as a staging (rather than therapeutic) procedure for patients with a Breslow thickness of 0.8 to 1.0 mm, with at least one of following features:[56]

  • Ulceration

  • Lymphovascular invasion

  • A mitotic index of 2 or more.

For people without adverse prognostic features, SLNB should be considered with a Breslow thickness of greater than 1.0 mm.[56] Consider delaying SLNB for pregnant women until postpartum.

One phase 3 trial reported that SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 mm and 3.5 mm in thickness.[74] [ Cochrane Clinical Answers logo ] ​​​ However, subsequent evidence from a systematic review demonstrated that SLNB is associated with improved overall survival in patients with head and neck cutaneous melanoma.[75]

Laboratory tests

Serum lactate dehydrogenase (LDH) has prognostic value in patients with stage IV melanoma and has been incorporated into the AJCC staging system for melanoma.[14][62][76]​ Patients with distant metastases and elevated LDH are in the highest risk category.[14]

Some evidence suggests that LDH may serve as a potential biomarker to identify patients who would benefit from anti-PD 1/PD-L1 treatment.[77]

No blood work is usually necessary in patients with other stages of melanoma unless they have systemic symptoms.

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