Melanoma – Symptoms, 11 Interesting Facts, Diagnosis, Treatment and Prognosis

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11 Interesting Facts of Melanoma

  1. Cutaneous melanoma is a malignancy that poses substantial metastatic risk when depth of invasion increases
  2. Melanoma is most commonly cutaneous, but it may rarely affect uveal tract of eye or mucous membranes of head and neck, gastrointestinal tract, and genital tract
  3. Risk factors include UV light exposure (especially a history of sporadic intense exposures leading to sunburn), tanning bed exposure, fair skin types (ie, light skin with little or no tanning ability), blond or red hair, blue eyes, family history of melanoma, dysplastic nevi, and congenital nevi. Melanoma may occur in either sun-exposed or non–sun-exposed skin or mucous membranes
  4. Melanoma may develop in a preexisting nevus or may arise de novo. Suspect the diagnosis when a pigmented lesion meets the ABCDE criteria (asymmetry, border irregularities, color variation, dimensions/diameter, evolution/change)
  5. Diagnosis is with excisional biopsy; depth of invasion (thickness) is the most important prognostic factor
  6. Cutaneous and mucosal melanomas initially spread via lymphatic channels to locoregional lymph nodes. Sentinel lymph node mapping and biopsy should be performed in patients with clinically node-negative disease when the melanoma is more than 1 mm thick, and in thinner melanomas when other adverse prognostic factors are present (eg, ulceration, high mitotic count)
  7. Initial management is with wide excision; early-stage disease less than 4 mm thick and node-negative does not require adjuvant therapy
  8. Locoregional lymph node involvement confers stage III status, and adjuvant systemic therapy is recommended based on extent of lymph node involvement; choices include high-dose interferon, immune checkpoint inhibitors, BRAF and MEK inhibitors, and biochemotherapy combinations
  9. For metastatic disease (beyond locoregional lymph nodes), limited, resectable disease may be treated with surgical excision followed by adjuvant immunotherapy. Disseminated unresectable disease is treated medically with immune checkpoint inhibitors or BRAF and MEK inhibitors (if a BRAF mutation has been identified)
  10. All patients should be monitored for at least 5 years after treatment, at intervals appropriate to disease stage, with continuing follow-up as clinically indicated 
  11. Survival depends on stage and extent of disease at presentation; 5-year survival is good in localized disease (about 98%), widely variable in node-positive disease (20%-70%, depending on number of involved nodes), and poor in disease with distant metastases (about 23%) 

Pitfalls

  • Although most melanoma occurs on sun-exposed cutaneous surfaces of face, trunk, arms, and legs, consider the diagnosis with melanocytic lesions on non–sun-exposed surfaces of soles and palms, as well as on mucosal surfaces and on conjunctiva and uveal tract of eye
  • Although most common in light-skinned people, melanoma can occur in a patient of any race or skin color. Acral melanomas are proportionally more common in patients of African descent
  • A high index of suspicion is needed for cutaneous melanoma in children and for nodular melanoma, both of which may be amelanotic in appearance
  • Diagnostic excisional biopsy of a suspected cutaneous melanoma must include 1- to 2-mm margin of normal skin and some subcutaneous fat. Large lesions may require incisional biopsy. Shallow shave biopsies, curettage, cryosurgery, laser, and electrodesiccation are contraindicated
  • Cutaneous melanoma is a malignancy that begins at the dermoepidermal junction in previously normal skin or at the site of a preexisting melanocytic nevus; vertical depth of invasion is an important prognostic factor for locoregional or distant metastatic disease
  • Melanoma may also develop at any noncutaneous site where melanocytes normally occur, including mucous membranes and uveal tract of eye, but these lesions are much less common than cutaneous melanomas

Classification

  • By organ/tissue affected
    • Cutaneous melanoma
      • Develops from preexisting dysplastic nevus or de novo
        • A dysplastic nevus is also commonly called an atypical nevus or a Clark nevus
    • Noncutaneous melanoma
      • Ocular
        • Arises from pigmented layer of eye and can occur in conjunctiva, iris, ciliary body, or choroid
        • Uveal melanoma is the most common intraocular malignancy of adults 
      • Mucosal epithelium
        • May involve gastrointestinal tract (including anal area), genitourinary tract, and nasal and nasopharyngeal mucosa
  • By histopathologic subtype of cutaneous melanoma
    • Superficial spreading melanoma
      • Accounts for 70% of all melanomas 
      • Can be located on any anatomic site
    • Nodular melanoma
      • Accounts for 15% to 30% of melanomas 
      • Rapidly enlarging elevated or polypoid lesion; coloration may be of 2 types
        • Blue or black (more common)
        • Amelanotic with a pink appearance (less common)
    • Lentigo maligna melanoma
      • Accounts for 4% to 10% of all melanomas 
      • More common in chronically sun-exposed skin in older patients (often on head and neck)
      • Macular lesion with varying degrees of color, usually brown
    • Acral lentiginous melanoma 
      • Flat to nodular lesion on palm, on sole, or beneath a nail (subungual)
      • Darkly pigmented
    • Desmoplastic melanoma 
      • Very rare
      • Characterized by malignant spindle cells
      • Desmoplastic cells may be a component of other melanomas (mixed melanoma). Pure desmoplastic tumors have a better prognosis than mixed or nondesmoplastic melanomas 
  • By stage, using TNM designations (tumor-node-metastasis) for cutaneous melanoma (mucosal and ocular melanomas are staged using a separate classification system) 
    • Clinical staging is conventionally performed after the biopsy (including microstaging of the primary melanoma and clinical or biopsy assessment of regional lymph nodes)
    • Pathologic staging uses microstaging information available from both the biopsy tissue and the wide reexcision, as well as biopsy assessment of regional lymph nodes
    • According to eighth edition of AJCC staging system (American Joint Committee on Cancer) 
      • T (primary tumor)
        • Based on vertical depth of invasion; ulceration status defines subcategory of a or b (a, unknown or unspecified ulceration status; b, with ulceration)
          • Tis (in situ): neoplastic melanocytes located only within epidermis and associated adnexal structures
          • T1: 1 mm or less
          • T2: more than 1 mm, up to 2 mm
          • T3: more than 2 mm, up to 4 mm
          • T4: more than 4 mm
      • N (regional lymph node involvement)
        • Based on number of tumor-involved regional lymph nodes; modified by subcategory (a, b, c) based on whether nodes were clinically occult and whether satellite, microsatellite, or in-transit metastases were detected
          • Pathologic N category not needed for T1 melanomas (classified as cN)
          • N0: no regional metastases
          • N1: 1 tumor-involved regional node or microsatellite metastasis with no tumor-involved nodes
          • N2: 2 to 3 tumor-involved regional nodes or 1 tumor-involved regional node with in-transit, satellite, or microsatellite metastases
          • N3: 4 or more tumor-involved regional nodes and/or 2 or more tumor-involved regional nodes with matting
      • M (presence of distant metastases)
        • Sites of metastases are subcategorized, with worsening prognosis at each subcategory
          • M0: no distant metastasis
          • M1a: skin, subcutaneous tissue, muscle, or distant lymph nodes
          • M1b: lung (with or without skin, subcutaneous, or distant lymph node metastases)
          • M1c: other visceral sites (excluding central nervous system)
          • M1d: central nervous system (irrespective of metastases to other sites)
      • TNM designations are used to determine stage, which informs treatment
        • Stages I and II indicate localized primary melanoma
          • All TNM classifications that are N0 and M0
        • Stage III indicates regional involvement (lymph nodes or in-transit metastases)
          • All TNM classifications that are N1 or more and M0 or more
        • Stage IV is metastatic disease beyond regional lymph nodes (eg, lung, liver, brain)
          • Any TNM classification that is M1

History

  • Exposure history, going back to childhood, often includes:
    • Episodic intense sunlight exposure, often recreational
    • Sunburns
    • Chronic sunlight exposure, either recreational or occupational (however, melanomas may also occur on sun-protected sites)
  • Family history may be significant
    • About 10% of patients have family history of melanoma, which may be related to any of several identified genetic variants, including BRCA2 mutation carrier status 
    • Family history of 3 or more invasive melanomas and/or a mix of melanoma, pancreatic cancer, and/or astrocytoma raises the possibility of a P16 (CDKN2A) mutation (and suggests the need for referral to genetic counselor) 
  • May report personal history of 1 or more atypical (dysplastic) nevi
  • Many patients report a preexisting mole at site of melanoma, with evolution (change in appearance over time)
    • Change in shape, color, or surface
    • Often described as a pigmented lesion that looks very different from any other skin lesion
    • Any melanocytic mole present at birth (congenital melanocytic nevus) is significant, because risk of malignant transformation is high 
      • Larger lesions (more than 40 cm) are more likely to become malignant during childhood
      • Smaller lesions (less than 40 cm) are more likely to become malignant during adulthood
  • Itching, burning, or pain in a pigmented lesion increases suspicion, although pain is unusual
  • Occasionally, patient notes regional adenopathy without noting a suspicious skin lesion (between 13% and 17% of melanoma diagnosed from lymph node biopsy has no identifiable primary site) 
  • Ocular melanoma may be asymptomatic when small and may be discovered incidentally during ophthalmologic examination. If it is symptomatic, symptoms vary with location of lesion 
    • Conjunctiva (extremely rare)
      • Usually asymptomatic
      • Patient notices an elevated pigmented lesion on conjunctiva
    • Iris
      • May be asymptomatic
      • Patient may notice an enlarging brown or yellow spot on iris
    • Ciliary body
      • Asymptomatic until large
      • Patient may notice a brown spot on episcleral surface (growth of melanoma through sclera)
      • Unilateral loss of vision or progressive unilateral astigmatism (patient describes need for frequent eyeglasses refractive change)
      • May produce symptoms of glaucoma if melanoma cells and debris shedding obstruct aqueous outflow from eye (Related: Angle-closure glaucoma )
    • Choroid
      • Asymptomatic until large
      • Visual loss, flashing lights, floaters, or visual field defects
  • Mucosal melanoma symptoms are nonspecific and vary depending on anatomic site of involved mucosa 
    • Mucosal melanoma most commonly presents as bleeding (eg, epistaxis, vaginal bleeding, blood with bowel movements that is misinterpreted by patient as hemorrhoidal bleeding)
    • In oral cavity, up to one-third of patients have a long history of mucosal pigmentation (melanosis) before diagnosis 
    • Sinonasal lesions may initially present with symptoms of nasal congestion and obstruction
  • All patients should be asked about symptoms of regional adenopathy and any symptoms related to the most common distant sites of metastases (ie, lung, liver, brain)

Physical examination

  • Examination focuses on complete inspection of skin and nails, with attention to locoregional lymph nodes draining suspicious lesions
    • Dermoscopy, when used by an experienced examiner, improves diagnosis compared with unaided eye 
    • Skin and nails
      • ABCDE rule is generally helpful for recognition of cutaneous melanoma; its components are as follows: 
        • Asymmetry
        • Border irregularity
        • Color variation
        • Diameter greater than 6 mm
        • Evolution (change in a skin lesion)
      • Color is most commonly a varying shade of brown, but lesions can be black, blue, or pink
        • Pediatric melanoma is more likely than adult melanoma to be amelanotic
      • Ugly duckling sign (a pigmented lesion that looks very different from any other skin lesion) is suggestive
      • Bleeding and ulceration are signs of a more advanced melanoma
      • Subtypes of cutaneous melanoma have specific physical characteristics
        • Superficial spreading melanoma
          • Located on any anatomic site, but most common on trunk and extremities
          • Macular
          • May arise de novo or may be associated with melanocytic nevus
        • Lentigo maligna melanoma
          • Most often located on chronically sun-exposed skin of head and neck
          • Macular
          • Color is usually shades of brown
          • Usually arises de novo; rarely associated with nevus
        • Nodular melanoma
          • Most commonly located on trunk and legs
          • Elevated or polypoid lesion
          • Often blue or black
          • May be amelanotic with a pink color
          • May arise de novo or in association with melanocytic nevus
          • Less likely to have classic ABCDE characteristics (asymmetry, border irregularities, color variation, dimensions/diameter, evolution/change)
        • Acral lentiginous melanoma
          • Acral melanoma has a variety of appearances and may appear anywhere on hands or feet, including non–sun-exposed areas
          • Subungual melanoma most commonly presents as melanonychia, a hyperpigmented longitudinal band on the nail; however, this can be a benign finding in darker-skinned persons if due to trauma
            • Presence of Hutchinson sign (ie, extension of pigmentation into proximal nail fold or periungual skin) suggests a malignant cause of melanonychia
            • Transverse melanonychia without Hutchinson sign suggests a benign cause
          • May arise de novo or in association with melanocytic nevi
        • Desmoplastic melanoma
          • Usually on sun-exposed skin
          • Typical appearance is a pigmented or skin-colored indurated patch, papule, or plaque 
    • Locoregional lymph nodes 
      • Primary tumors on extremities usually drain to predictable regions; these should be thoroughly examined by palpation
        • Upper extremities drain to axillary and/or epitrochlear basins
        • Lower extremities drain to inguinal and/or pelvic basins
      • Primary tumors on head, neck, and trunk may drain to a variety of regional basins
  • Ocular melanoma 
    • Iris melanoma
      • Most commonly in inferior portion of iris
      • May be nodular or diffuse
        • Nodular form appears as a thickened mass, often with dilated feeder vessels
        • Diffuse form appears without a definable mass but with growth of flat dark tissue over iris surface
    • Ciliary body melanoma
      • Sentinel vessels (dilated feeder vessels on episclera) suggest underlying pathology
      • After wide pupillary dilation, appears as nodular mass immediately behind lens
    • Choroidal melanoma
      • Can be seen with indirect ophthalmoscopy
      • Appears as mass deep to retina, brown or (less commonly) yellow
      • Typically there is secondary retinal detachment
  • Mucosal melanoma
    • Physical findings vary with anatomic location
      • Oral cavity
        • Typically hyperpigmented lesion that may be black, brown, gray, reddish, or white; may also be amelanotic
        • May be either nodular or macular; nodular lesions are typically exophytic in appearance
      • Sinonasal cavities
        • Visualized with nasal endoscopy; is typically a polypoid, fleshy, unilateral lesion
        • Variable degrees of pigmentation; completely amelanotic tumors are rare
        • Satellite lesions are frequently observed
      • Anorectal area
        • Difficult to diagnose visually and often mistaken for hemorrhoids, polyps, or anorectal cancer
      • Vulvovaginal area
        • Common locations include labia, vagina, urethra, and cervix
        • Appears as a pigmented mass

Causes and Risk Factors

Causes

  • Specific cause of malignant transformation of melanocytes is uncertain
  • UV light exposure, genetic susceptibility, and somatic mutations play a role in many patients 

Risk factors and/or associations

Age
  • May occur at any age, but risk increases with age 
  • Increasing incidence in children and adolescents younger than 18 years in the United States, especially in teenaged girls 
    • May be due to widespread use of artificial tanning, especially in teenaged girls
Sex
  • Lifetime risk is 1 in 34 for women and 1 in 54 for men 
Genetics
  • 10% of patients with melanoma have a positive family history 
    • Susceptibility genes include:
      • CDKN2A (also called P16; cyclin-dependent kinase inhibitor 2A) 
        • In melanoma-prone families, 25% to 40% have mutations in this gene 
        • Risk due to CDKN2A mutations is between 30% and 90% by age 80 years and varies by geographic location 
        • May be associated with other malignancies in family members (ie, pancreatic cancer, astrocytomas) 
      • Carriers of mutations in BRCA2 (a tumor suppressor gene whose loss of function increases risk of neoplasia) have an increased risk of cutaneous melanoma 
      • Variability in MC1R gene (melanocortin 1 receptor) plays a key role in pigmentation of skin and hair and more recently has been implicated in melanoma predisposition 
    • Somatic mutations/amplifications that may direct treatment include:
      • Activating mutation of BRAF (B-Raf proto-oncogene, serine/threonine kinase), which is present in about half of metastatic melanomas 
      • Mutation or amplification of KIT gene (also called c-KIT or CD117; KIT proto-oncogene receptor tyrosine kinase), which is commonly associated with acral and mucosal melanoma 
Ethnicity/race
  • Although most common in light-skinned people, melanoma can occur in a patient of any race or skin color. Lifetime risk of cutaneous melanoma is 1 in 52 across all populations; lifetime risk is less than 1 per 1000 in African Americans 
    • Darker-skinned ethnicities tend to have more advanced disease at initial diagnosis compared with white populations 
    • Darker-skinned ethnicities are diagnosed with proportionally more lower extremity disease and acral lentiginous subtype than are white populations 
  • Proportion of melanomas that are in mucosal locations differs by ethnicity/race 
    • 1% for non-Hispanic white people, 4% for Hispanic people, 9% for non-Hispanic black people, and 15% for Asian/Pacific Islanders
Other risk factors/associations
  • For cutaneous melanoma
    • Prior melanoma or nonmelanoma skin cancer 
    • Dysplastic nevi or an increased number of typical melanocytic nevi 
      • Dysplastic nevi are precursor lesions
      • 6% lifetime chance of developing melanoma with dysplastic nevi 
      • 80% lifetime chance in people who have dysplastic nevi and a strong family history of melanoma 
    • Congenital melanocytic nevi 
      • Risk of melanoma during childhood and adolescence has been controversial, but a systematic review has found that it was increased by 465-fold, especially for very large nevi 
    • Sun exposure 
      • Intermittent intense sun exposure may confer higher risk than chronic sun exposure
      • Sunlight is not thought to play a causative role in acral melanoma
    • Exposure to UV radiation in indoor tanning beds 
    • Light complexion, blond or red hair, blue eyes, freckles, and a tendency to burn rather than tan 
    • Xeroderma pigmentosum
    • Immunosuppressed states
  • For ocular melanoma 
    • Light eye color
    • Light skin color
    • Little or no ability to tan
    • Intermittent UV exposure from welding
    • Chronic occupational sun exposure (considered to be of borderline significance as a risk factor)
    • Congenital ocular melanocytosis (risk is 1 in 400 for development of uveal melanoma in white populations) 
    • Presence of uveal nevus (risk is 1 in 4800 to 1 in 8845 for development of uveal melanoma in white populations)
  • For mucosal melanoma
    • Oral cavity: smoking 
    • Sinonasal cavities: exposure to formaldehyde may be a risk factor 

How is this condition diagnosed?

  • Suspected cutaneous melanoma
    • Obtain biopsy of any suggestive lesion with complete excision; include 1- to 2-mm margin of normal skin and some subcutaneous fat 
      • An incisional biopsy may be necessary if lesion is too large for complete excision
      • Shallow shave biopsies, curettage, cryosurgery, laser, and electrodesiccation are contraindicated
      • Higher index of suspicion is needed for biopsy in children, as pediatric melanoma may not have easily recognizable features (eg, may be amelanotic) 
    • Consider sentinel lymph node mapping/biopsy for melanomas based on clinical stage and histopathologic findings from primary tumor biopsy (stages Ib and II) 
    • Perform imaging for staging in some patients 
      • In patients with high risk of metastatic disease (ie, primary melanoma more than 4 mm thick or node-positive), obtain CT of chest-abdomen-pelvis or full-body PET-CT scan 
      • Obtain brain imaging (CT or MRI) in all patients with known disseminated disease (beyond locoregional lymph nodes) and in anyone with even minimal central nervous system symptoms 
      • If disease is identified at distant site, biopsy confirmation is recommended to confirm stage IV status 
    • Laboratory testing is nondiagnostic but may be helpful in some patients
      • Liver enzyme tests may be performed at discretion of physician but generally have low diagnostic yield 
      • Lactate dehydrogenase level should be obtained in patients with stage IV disease as a prognostic factor 
  • Suspected ocular melanoma
    • If suspected by clinical presentation and examination, ocular imaging by a variety of imaging methods is performed by an ophthalmologist, with biopsy confirmation if diagnosis remains uncertain
    • Sentinel lymph node biopsy may have a role
      • Limited experience suggests that sentinel node biopsy can be performed and can identify micrometastatic disease within regional lymph nodes, although it is more difficult and complex than for cutaneous melanoma 
      • No role in management of choroidal melanoma (because most of the eye is not supplied with lymphatics) 
  • Suspected mucosal melanoma
    • Diagnostic work-up of mucosal melanoma of head and neck is outlined in the head and neck cancers guideline by the National Comprehensive Cancer Network 
      • Perform excisional biopsy 
      • Obtain CT of head and neck with contrast agent or MRI with contrast agent to evaluate potential local spread 
      • Consider PET-CT or CT of chest-abdomen-pelvis plus MRI of brain to rule out metastatic disease 
    • There are no specific guidelines for evaluation of mucosal melanoma in other locations

Lactate dehydrogenase level

  • Obtain in patients with distant metastasis (stage IV disease)
  • Degree of elevation, indicating amount of distant tissue damage, is a surrogate of tumor burden and is thus a prognostic factor for outcome 
  • For cutaneous melanoma:
    • CT of chest-abdomen-pelvis
      • Not indicated routinely in clinical stage I or II disease; findings are often nonspecific with poor diagnostic yield in these patients
      • Yield in detecting clinically occult metastatic disease is 0.5% to 3.7% in patients with positive result on sentinel lymph node biopsy 
    • PET-CT
      • Poor yield in detecting metastases in patients with clinically localized disease and therefore not routinely recommended 
      • Sensitivity of 68% to 87% and specificity of 92% to 98% for detecting metastatic disease (stages III and IV) 
    • CT or MRI of brain
      • Obtain for known stage IV disease and for any patient with even minimal central nervous system symptoms 

Procedures

Excisional biopsy
General explanation
  • For cutaneous melanoma, biopsy must include 1- to 2-mm margin of normal skin and some subcutaneous fat
Indication
  • All patients with suspected melanoma
Interpretation of results
  • Report describes the following: 
    • Deep and peripheral margin status
    • Breslow thickness, reported to nearest 0.1 mm
    • Ulceration status
    • Dermal mitotic rate
    • Microsatellitosis
  • For stage IV disease, presence or absence of BRAF and KIT mutations should be documented 
Sentinel lymph node mapping and biopsy
General explanation 
  • Technique that accurately evaluates whether there is microscopic melanoma involvement of regional lymph nodes
  • Performed by injecting the primary melanoma site with blue dye (isosulfan blue), radiolabeled colloid, or both
  • Biopsy of the identified sentinel node accurately determines whether melanoma cells have metastasized to that specific lymph node basin
  • Typically performed at same time as wide excision of primary tumor
Indication
  • National Comprehensive Cancer Network guidelines recommend the following, based on probability for identifying a positive sentinel node:
    • For lesions less than 0.8 mm thick with no ulceration: no biopsy is recommended (risk of positive sentinel lymph node is less than 5%) 
    • For clinical stage IB (T1a or T1b): discuss with patient and consider biopsy (risk of positive sentinel lymph node is 5%-10%) 
    • For stage IB (T2a) or stage II: offer to patient (risk of positive sentinel lymph node is more than 10%) 
Complications
  • Morbidity of sentinel lymph node biopsy is low 
Interpretation of results
  • When dye and radiolabeled colloid are used together, a sentinel node can be identified in 98% of patients 
  • If melanoma is detected in sentinel node: 
    • Valuable staging tool; confers stage III designation
    • Until recently, a complete regional lymph node dissection was performed if sentinel node biopsy result was positive 
    • Recent data suggest that complete lymph node dissections are unnecessary and that close observation with ultrasonographic monitoring is reasonable 

Differential Diagnosis

Most Common

How is this condition treated?

Treatment Goals

  • Stages I, II, and III are treated with curative intent
  • Stage IV is treated with a goal of long-term disease control

Recommendations for specialist referral

  • Refer to dermatologist for excisional biopsy and primary excision
    • Plastic surgeon may be appropriate surgical specialist in some cases
  • Refer to general surgeon or surgical oncologist for lymph node biopsy and dissection
  • Refer to ophthalmologist for evaluation and treatment of ocular melanoma
  • Refer to general surgeon, surgical oncologist, or surgical subspecialist for excision of mucosal melanoma
    • Anatomic site may determine the most appropriate subspecialist
  • Refer to medical oncologist for management of adjuvant therapies in locoregional and disseminated disease

Treatment Options

General overview

  • Primary melanoma
    • Surgical excision with wide margins (of remaining tumor or of biopsy site) is standard treatment for most patients, with the exception of disseminated, nonresectable stage IV disease 
    • For mucosal melanoma, treatment is surgical; wide excision is usually limited by anatomic considerations
      • For head and neck locations, postoperative radiotherapy is often recommended for stage III and limited stage IV disease, with systemic therapy for more advanced disease 
      • There are no specific guideline recommendations for mucosal melanoma in other anatomic locations 
    • Ocular melanoma may be treated surgically or with various other modalities
      • Treatment is surgical when complete removal is compatible with continued eyesight; if sight has already been lost, enucleation is usually performed 
      • Photocoagulation, thermotherapy, plaque radiotherapy, charged particle irradiation, chemotherapy, and immunotherapy may be appropriate depending on clinical circumstances 
    • Management of regional lymph nodes
      • If regional lymph nodes are clinically normal
        • For melanoma lesions more than 1 mm thick or for thinner lesions with adverse prognostic features (eg, ulceration, high mitotic count), sentinel lymph node mapping and biopsy should be performed 
          • If sentinel node is negative for melanoma, no further lymph node surgery is required 
          • If sentinel node is positive for melanoma, traditionally a complete lymph node dissection was performed, but based on recent data, this is no longer routinely recommended 
            • 2 large randomized controlled trials showed no increase in overall survival compared with active nodal surveillance 
      • If regional lymph nodes are clinically enlarged
        • Lymphadenectomy is the preferred treatment after pathologic confirmation of melanoma 
    • For node-positive disease and for melanomas 4 mm or more in thickness, consider postsurgical adjuvant therapy 
      • For resected node-positive (stage III) disease
        • Therapy is based on extent of lymph node involvement, with the following options: 
          • Observation only
          • Immunotherapy with immune checkpoint inhibitor
          • Molecularly targeted therapy based on somatic mutation profile 
            • For patients with BRAF mutations, selective kinase inhibitors of BRAF and of the MEK proteins MEK1 and MEK2 (ie, MAP2K1 and MAP2K2; mitogen-activated protein kinase kinases)
          • Interferon
          • Biochemotherapy (combination of chemotherapy and immunotherapy)
          • Participation in a clinical trial
      • For node-negative melanomas 4 mm or more in thickness:
        • Observation can be considered
        • Interferon alfa or pegylated interferon alfa 
    • For advanced melanoma (stage IV)
      • Limited, resectable disease may be treated with surgical excision followed by adjuvant immunotherapy
      • Disseminated unresectable disease is usually treated medically
        • Immunotherapy with immune checkpoint inhibitors (monotherapy or combination therapy) is often the initial treatment 
        • Molecularly targeted therapy based on somatic mutation profile may also be a reasonable first choice for selected patients 
          • For patients with BRAF V600 mutations, first line therapy consists of BRAF and MEK inhibitor combination therapy (dabrafenib-trametinib, vemurafenib-cobimetinib, or encorafenib-binimetinib) 
          • For patients with a contraindication to first line agents, monotherapy with dabrafenib or vemurafenib is appropriate 
        • Central nervous system metastases may be managed with radiotherapy before start of medical therapy
        • Additional options include intralesional immunotherapy injection (with talimogene laherparepvec) and palliative radiotherapy
      • Second line therapies include immune checkpoint inhibitors, BRAF and MEK inhibitors (if mutation is present and drugs were not previously used), imatinib (if KIT mutation is present), high-dose interleukin-2 (eg, aldesleukin), and cytotoxic chemotherapies

Rationale

  • Wide-margin surgical excision
    • Curative if disease is localized and completely removed
    • Recommended width of surgical margin is based on risk of local recurrence and metastatic disease
  • Lymphadenectomy 
    • Performed when there are clinically enlarged lymph nodes with the goal of long-term, disease-free survival and to reduce local morbidity of enlarged lymph nodes
  • Adjuvant therapy for resected node-positive (stage III) disease and for thick melanoma (more than 4 mm) 
    • These patients have high melanoma mortality risk with resection of primary tumor alone; therefore, adjuvant therapy is reasonable
  • Treatment regimens for stage IV disease 
    • Systemic therapy is the cornerstone when active (versus palliative) treatment is desired for disseminated disease; resection, intralesional injection, or localized radiotherapy may reduce localized disease burden and reduce associated symptoms (eg, pain)
    • With central nervous system lesions, depending on size and site of lesion and on presence of symptoms, radiotherapy may precede systemic therapies to reduce the risk of intratumoral hemorrhage, seizures, or neurologic dysfunction

Outcomes

  • Adjuvant therapy in stage III disease
    • A phase III trial (CheckMate 238) involving patients with resected stage III melanoma showed that nivolumab yielded higher recurrence-free survival and far fewer immunologic adverse effects compared with ipilimumab 
    • A phase III trial (COMBI-AD) evaluated the targeted therapies dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) in patients with node-positive melanoma with a BRAF mutation; 3-year relapse-free survival was 58% in the combination therapy arm and 39% in the placebo arm 
  • Systemic therapy in stage IV disease
    • Insufficient evidence is available to determine if immune checkpoint inhibitors or BRAF and MEK inhibitors result in better outcomes as first line therapy in patients with BRAF mutations 
    • Although combination therapy with ipilimumab-nivolumab has slightly better outcomes than monotherapy, toxicities are more severe with combination therapy; the patient’s overall health status and ability to tolerate adverse effects should be considered 
      • Median overall survival of patients with disseminated melanoma has increased from 9 months (before 2011) to at least 2 years (after advent of immune checkpoint inhibitor targeted therapies) 
    • BRAF inhibitor and MEK inhibitor combination therapy is associated with better outcomes and similar toxicities compared with BRAF inhibitor monotherapy 

Drug therapy

  • Immune checkpoint inhibitors
    • PD1 inhibitor (targets programmed cell death protein 1)
      • Nivolumab
      • Pembrolizumab
    • CTLA4 inhibitor (targets cytotoxic T-lymphocyte–associated protein 4)
      • Ipilimumab
  • BRAF inhibitor (targets B-Raf proto-oncogene, serine/threonine kinase)
    • Dabrafenib
    • Vemurafenib
    • Encorafenib
  • MEK inhibitor (targets mitogen-activated protein kinase kinases 1 and 2)
    • Trametinib
    • Cobimetinib
    • Binimetinib
  • Interferons
    • Interferon alfa
    • Pegylated interferon alfa

Nondrug and supportive care

Radiotherapy

  • May have a role in the following clinical scenarios: 
    • Definitive treatment for primary lesion in early-stage disease in medically inoperable patient
    • Primary excision with positive margins and not amenable to further surgical resection
    • Adjuvant therapy of primary tumor with close margins
    • Adjuvant therapy of head and neck mucosal melanoma
    • Adjuvant therapy of high-risk nodal disease (but no evidence of survival benefit)
    • Definitive or palliative therapy for unresectable nodes, microsatellites, or in-transit lesions
    • Palliative therapy for intracranial or extracranial metastatic disease
Procedures
Wide-margin surgical excision of cutaneous melanoma

General explanation

  • Excision of biopsy site (if excisional biopsy was performed) or excision of remaining portion of lesion (if incisional biopsy was done)
  • For cutaneous melanoma, extent of surgery depends on thickness of lesion measured from biopsy specimen
    • For melanoma in situ, excision with a 0.5-cm border of clinically normal skin is sufficient 
    • For melanomas less than 1 mm thick, a 1-cm margin is recommended 
    • If thickness is between 1 and 4 mm, a 1- to 2-cm margin is recommended 
    • For melanomas thicker than 2 mm, a 2-cm resection margin is sufficient 
    • In cosmetically sensitive areas (eg, face) or anatomically difficult areas (eg, ear, hand), it may be difficult to achieve the desired margin, but at least a 1-cm margin should be obtained whenever possible 

Indication

  • All patients with biopsy-proven cutaneous melanomas

Monitoring

  • Patients should receive regular follow-up for evidence of local or regional recurrence, distant metastasis, and a second primary melanoma
  • For cutaneous melanoma, frequency of surveillance (and extent of investigation) is based on risk for recurrence
    • Stages IA to IIA
      • Evaluation every 6 to 12 months for 5 years and then annually as clinically indicated 
      • Routine imaging is not recommended 
    • Stages IIB to IV
      • Evaluation every 3 to 6 months for 2 years, then every 3 to 12 months for 3 years, then annually, as clinically indicated 
      • For patients with positive result on sentinel lymph node biopsy who did not undergo complete lymph node dissection, ultrasonography of regional lymph nodes every 3 to 12 months for 2 to 3 years 
      • Imaging for recurrence every 3 to 6 months for 3 to 5 years 
        • CT of chest-abdomen-pelvis or whole-body PET-CT; consider brain MRI
  • Follow-up visits should include: 
    • Thorough skin examination
    • Examination of regional lymph nodes (obtain ultrasonography if findings are equivocal)
  • Routine blood tests are not recommended
  • All patients with history of melanoma should continue lifelong general skin examinations, especially if they have family history of melanoma or if they have dysplastic nevi 
  • Uveal melanoma should be monitored twice yearly with physical examination and liver function tests 
    • Annual liver imaging and chest radiograph are advised
  • There are no specific follow-up recommendations for mucosal melanoma as a category (ie, irrespective of site). For head and neck mucosal melanomas, recommendations are available in the head and neck cancer guidelines by the National Comprehensive Cancer Network 

Complications

  • Intracranial metastatic disease, resulting in intratumoral hemorrhage, seizures, and neurologic dysfunction
  • Extracranial metastasis, resulting in organ dysfunction
  • Death from progressive metastatic disease
  • Treatment complications include:
    • Scarring from wide excision of primary tumor and from lymph node dissection
    • Toxicities of immunotherapies and other targeted therapies 
      • Immune checkpoint inhibitors
        • Common: fatigue, rash, pruritus, cough, decreased appetite, diarrhea, constipation, and arthralgia
        • Less common but more severe: immune-mediated dermatitis, pneumonitis, hepatitis, colitis, nephritis, and endocrinopathies
      • Targeted kinase inhibitors of BRAF and MEK proteins 
        • Fever (most common with combined therapy)
        • Dermatologic toxicities (including squamous cell carcinoma)

Prognosis

  • Cutaneous melanoma
    • Survival depends on stage and extent of disease at presentation
      • 5-year survival is about 98% for localized disease 
      • Status of regional lymph nodes (ie, negative or positive and, if positive, number of affected nodes) is an important factor in survival
        • With regional lymph node involvement (stage III), 5-year survival rates range from 20% to 70%, depending on number of involved nodes 
        • Pediatric melanoma has a greater incidence of nodal metastasis compared with adult melanoma of the same thickness, but prognosis of stage III disease is better in children than in adults 
      • With distant metastases, 5-year survival is about 23% 
    • Prognostic factors related to primary tumor
      • Worse prognosis
        • Increasing thickness is associated with increased recurrence risk, regional lymph node involvement, and risk of melanoma-related death 
          • Depth of invasion (Breslow thickness, measured in millimeters from top of epidermis to underlying dermis)
            • Lesions less than 1 mm thick have about 80% to 90% 10-year survival rate 
            • Lesions more than 4 mm thick have about 40% to 50% 10-year survival rate 
        • Increasing level of peripheral invasion (Clark level) 
        • Presence of ulceration 
        • Presence of microscopic satellites 
        • High mitotic rate 
        • Serum lactate dehydrogenase level (biomarker of distant tissue damage in stage IV disease) 
      • Better prognosis
        • Site is on an extremity 
  • Ocular melanoma
    • Prognosis varies with location and size of tumor and with treatment method
    • Presents risk for metastasis to liver, lung, and skin but does not metastasize to lymph nodes because most of the eye is not supplied with lymphatics 
  • Mucosal melanoma
    • Has a less favorable prognosis compared with other melanoma subtypes
    • 5-year survival rates for head and neck mucosal melanoma are about 20% 

Screening

At-risk populations

  • All persons are at some risk of melanoma
  • Patients at higher risk are those with: 
    • Family history of melanoma
    • Dysplastic nevi
    • Increased numbers of common nevi (ie, typical, benign)
    • Fair skin types (ie, light skin with little or no tanning ability)
    • Light eye color
    • Intermittent intense sun exposure and long-term chronic exposure

Screening tests

  • Screening for skin cancer (including melanoma) in asymptomatic adults with no history of premalignant or malignant skin lesions is controversial 
    • Insufficient evidence exists to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults 
      • A single fair-quality ecologic study reported significant reduction in the risk of dying from melanoma after a public awareness program and 1-time visual screening examination 
    • Insufficient evidence exists to assess the balance of benefits and harms of counseling adults about skin self-examination 
  • Patients with a family history of melanoma or atypical nevi should have regular skin examinations every 6 to 12 months, with serial photography recommended 

Prevention

  • Behavioral interventions can increase sun protection behavior, but there is no consistent evidence that interventions are associated with reduction in frequency of sunburn in children or adults, and there is minimal evidence on skin cancer outcomes (including nonmelanoma skin cancers) 
    • Sun protection behaviors include:
      • Use sunscreen with a sun protection factor of 15 or more (UV-A plus UV-B), especially in childhood 
      • Wear sun-protective clothing (eg, broad-brimmed hat)
      • Avoid midday sun
      • Avoid sunburn
      • Avoid tanning parlors
  • Based on a systematic review, the US Preventive Services Task Force recommends the following to reduce risk of skin cancer: 
    • Counsel young adults, adolescents, children, and parents of young children about minimizing exposure to UV radiation for persons aged 6 months to 24 years with fair skin types (ie, light skin with little or no tanning ability) 
    • Selectively offer counseling to adults older than 24 years with fair skin types about minimizing their exposure to UV radiation 
  • In the same systematic review, it was found that current evidence is insufficient to assess the balance of benefits and harms of counseling adults (as a whole, without regard to skin type) about skin self-examination to prevent skin cancer 

Sources

National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 3.2018. NCCN website. Updated July 12, 2018. Accessed July 16, 2018. https://www.nccn.org/  Reference

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