Melanoma

Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanomas usually present as pigmented skin lesions, but they can occur on mucosal surfaces, such as in the eyes, anal canal, and genital regions. Common findings may include Asymmetry of the lesion, irregular Border, varying Color, > 6 mm Diameter, and Evolving features (ABCDE). Definitive diagnosis is established with biopsy. Treatment relies primarily on surgical excision. The prognosis is very good for early-stage lesions but quite dismal for metastatic disease. Of all the skin malignancies, melanoma generally carries the worst prognosis.

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Overview

Definition

Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis.

Epidemiology

  • 5th most common malignancy in men and women in the United States
  • Average age at diagnosis: 57 years
  • Increasing incidence worldwide:
    • In Queensland, Australia (highest): 72 per 100,000
    • In the United States: 27 per 100,000
  • The deadliest skin cancer

Etiology

  • Excessive exposure to ultraviolet A (UVA) and B (UVB) radiation:
    • Exposure to sunlight (UVB more closely associated with melanoma)
    • Highest in equatorial areas (when adjusted for skin type), where UVB is more intense
    • Use of tanning beds (UVA)
    • ↑ number of blistering sunburns = ↑ risk
    • Exposure to psoralen and UVA radiation as treatment for psoriasis or other skin conditions
  • Role of sunscreen: 
    • Sunscreen users likely to have more sun exposure than the general public
    • Sunscreen protective mostly against UVB (increasing risk for UVA exposure)
  • Genetic predisposition and personal characteristics:
    • Positive family history in 5%–10% of cases
    • Fair skin, blue eyes, fair/red hair, freckles
    • Presence of > 40 melanocytic nevi (a marker for ↑ risk)
    • Genetic syndromes:
      • Familial atypical multiple mole melanoma (FAMMM) syndrome: an autosomal dominant genetic condition characterized by the presence of multiple atypical moles
      • Xeroderma pigmentosum: an autosomal recessive condition caused by a defect in DNA repair mechanisms that leads to ultraviolet light sensitivity (i.e., severe sunburns) and skin cancer development 
  • Immunosuppression:
    • Transplant patients
    • Hematologic malignancies

Anatomy

  • Melanomas most commonly arise from the skin.
  • Mucosal surfaces: about 1% of cases
    • Head and neck region: oral, nasal, and paranasal cavities
    • Anorectal region
    • Vulvovaginal region
  • Eyes: 
    • Uvea (95% of ocular melanomas)
    • Conjunctiva

Pathophysiology and Classification

Pathogenesis

  • Most melanomas arise in epidermis as slow-growing indolent tumors.
  • May arise in preexisting precursor lesion/nevus or de novo (from healthy skin).
  • Types of nevi considered precursors to melanoma:
    • Common acquired nevus
    • Dysplastic nevus
    • Congenital nevus
    • Cellular blue nevus
  • Commonly found mutations:
    • CDKN2A (most common specific mutation in familial melanoma)
    • BRAF (most common in superficial spreading melanoma)
    • KIT (most common in lentigo maligna melanoma and acral–lentiginous melanoma)
    • RAS
    • NF1
  • Phases of growth:
    • Horizontal growth (radial growth):
      • Along the dermal–epidermal junction
      • Most melanomas at this stage do not metastasize.
      • Microinvasion into the dermis may be present at this stage.
    • Vertical growth:
      • Clearly invasive deep into the dermis
      • Associated with metastatic potential

Morphologic types

Major types:

TypesFrequencyGrowthMorphologyCommon sites
Superficial spreading melanoma60%–75%
  • Horizontal or radial growth first (highly curable at 1 mm or less)
  • Eventual transition to vertical growth
  • Variable pigmentation with an irregular border
  • Flat or slightly elevated lesions
  • Torso (back)
  • Extremities
Nodular melanoma15%–30%
  • Vertical growth from the beginning
  • Most are diagnosed when lesion is 2 mm or more

  • Rapidly growing
  • Commonly ulcerated or crusted black nodule
Lentigo maligna melanoma10%
  • Horizontal growth early
  • Transition to vertical phase is slow (over years)
  • Brown-colored macule (freckle-like)
  • Flat lesions get darker.
  • Becomes palpable in vertical growth phase
  • Sun-exposed areas (e.g., face, head, neck)
Acral lentiginous melanoma< 5%; most common type in Asian and dark-skinned individuals
  • Horizontal growth predominates early
  • Black-brown pigmentation
  • Flat lesions
  • Hutchinson nail sign: extension of pigmentation to the nail folds (subungual melanoma)
  • Palms
  • Soles
  • Nail beds (subungual)

Uncommon variants:

  • Amelanotic melanoma:
    • Consists of poorly differentiated/dedifferentiated melanocytes
    • Present with lightly colored (pink/red) flat or raised lesions
    • Confused with benign lesions (e.g., melanocytic nevus), leading to delay in diagnosis (worse prognosis)
  • Spitzoid melanoma: 
    • Resembles Spitz tumors
    • Growing lesions: papules/nodules that may present with red, brown, black, or blue color
  • Desmoplastic melanoma: rare, slow-growing, pale plaques or nodules resembling a scar
  • Pigment-synthesizing melanoma (melanocytoma): 
    • Indolent type of blue-black nodules
    • Low risk of metastasis

Classification

Breslow depth:

  • A standardized method of melanoma depth measurement 
  • Use of an optical micrometer fitted to the microscope to measure from the top of the epidermal granular layer to the deepest tumor invasion
  • Utilized in the 8th edition of the American Joint Committee on Cancer tumor staging system (but tumor thickness recorded to the nearest 0.1 mm instead of the original 0.01 mm)
Breslow stageTumor sickness
Stage 1≤ 1 mm
Stage 21–2 mm
Stage 3> 2–4 mm
Stage 4> 4 mm

Clinical Presentation

Cutaneous melanomas (most common)

  • Majority present with new skin lesion (de novo):
    • Suspicious pigmented lesion
    • Pruritus or bleeding may be present. 
  • A preexisting nevus:
    •  Change in shape, size, or color
    • “Ugly duckling” sign: 1 different-looking mole among other moles that are predominantly of similar morphology

Other melanomas

  • Subungual:
    • Brown or black nail band
    • With or without nail dystrophy
    • Extension of the pigment onto the nailfold 
    • Most commonly affects great toe and thumb
  • Ocular:
    • Can be asymptomatic
    • Change in pupil shape
    • Pigmented spot on the iris
    • Vision changes
  • Anal: signs and symptoms similar to other anal cancers

Diagnosis

History

  • Sun exposure (occupational or recreational)
  • Family history
  • History of previous melanomas

Physical exam

  • Regular skin exam: should be thorough and comprehensive (entire body) and done under optimal lighting
  • Adjunctive techniques:
    • Dermoscopy
    • Reflectance confocal microscopy (allows visualization of cells of epidermis and papillary dermis)
    • Computer-assisted diagnosis
  • ABCDE criteria: 
    • Developed to differentiate benign melanocytic lesions from melanomas 
    • Further evaluation is warranted if the lesion meets ≥ 1 of the following criteria:
      • A (asymmetry): asymmetrical shape
      • B (border): irregular/indistinct border
      • C (color): varying pigmentation or irregularly distributed
      • D (diameter): > 6 mm
      • E (evolution): change in size, shape, or color; exceptional nevus different from other nevi

Biopsy

  • Excisional full-thickness biopsy (gold standard):
    • Complete excision of lesion with 1 to 3 mm margin of normal skin
    • Histopathologic diagnosis based on a combination of features, including:
      • Atypical melanocytes with large nuclei, prominent nucleoli
      • Architectural asymmetry
      • Poor circumscription (cells at the edge noted to be single, small instead of nested)
      • Lower epidermal and dermal cells vary in size and shape.
    • Immunohistochemistry (e.g., S-100, Sox10 proteins expressed by almost all melanomas)
    • Gives information about the Breslow stage and ulceration status (both needed for staging and prognostic assessment)
  • Incisional biopsy:
    • For large lesions
    • If lesion is in difficult or cosmetically sensitive area (e.g., facial, subungual)

Adjunctive studies

Adjunctive studies are used for evaluation of metastatic disease.

  • Laboratory studies:
    • CBC
    • Liver function tests
    • LDH
  • Imaging:
    • Chest X-ray: for lung metastases
    • Ultrasound: for lymphadenopathy
    • CT or PET: for distant metastases
Part of the ABCDs for detection of melanoma

Part of the ABCDs for detection of melanoma:
In the left column (top to bottom): melanomas showing (A) asymmetry; (B) a border that is uneven, ragged, or notched; (C) coloring of different shades of brown, black, or tan; and (D) diameter that has changed in size. In the right column (top to bottom): Normal moles do not have abnormal characteristics (all lesions have no asymmetry or change in diameter and have even border and color).

Image: “Melanoma vs normal mole ABCD rule NCI Visuals Online” by National Cancer Institute. License: Public Domain

Staging

Table: TNM description and substages
TNMDescriptionSubstages
Tumor (T)
  • Tis: in situ
  • T1: ≤ 1 mm
  • T2: >1–2 mm
  • T3: > 2–4 mm
  • T4: > 4 mm
  • Tis: NA
  • T1a: < 0.8 mm without ulceration*
  • T1b: < 0.8 mm with ulceration or 0.8 to 1 mm
  • T2-4a: without ulceration
  • T2-4b: with ulceration
Lymph node (N)
  • N0: 0 nodes
  • N1: 1 node
  • N2: 2–3 nodes
  • N3: 4+ nodes


  • N0: NA
  • N1a: 1 clinically occult node
  • N1b: 1 clinically detected node 
  • N1c: no node, + satellite, microsatellite, in-transit metastases 
  • N2a: 2–3 clinically occult nodes
  • N2b: 2–3 clinically detected nodes
  • N2c: 1 occult/clinically detected, + satellite, microsatellite, in-transit metastases
  • N3a: 4+ clinically occult nodes
  • N3b: 4+ clinically detected nodes or matted nodes
  • N3c: 2+ clinically occult or detected nodes, + satellite, microsatellite, in-transit metastases 
Metastases (M)
  • M0: no distant metastases
  • M1: with distant metastases
  • M0: no distant metastases
  • M1a: distant skin, soft tissue (muscle) and nonregional lymph node
  • M1b: lungs
  • M1c: other non-CNS visceral organs
  • M1d: CNS
  • M1a-d further classified by LDH level:
    • (0): LDH not elevated
    • (1): LDH elevated
* Ulceration: defined as no intact epithelium over the melanoma, and prognosis is worse (compared to a lesion with same thickness and without ulceration) if present
NA: not applicable
Table: American Joint Committee on Cancer staging based on TNM
StageTumor (T)Lymph node (N)Metastases (M)
0TisN0M0
IAT1aN0M0
IBT2a, T1bN0M0
IIAT2b, T3aN0M0
IIBT3b, T4aN0M0
IICT4bN0M0
IIIAny T≥ N1M0
IVAny TAny NM1

Management and Prognosis

Surgery

Wide local excision:

  • Mainstay of treatment
  • The recommended margins depend on lesion thickness.
  • Skin graft may be required for closure depending on size and location.
  • For acral/ subungual melanoma, digital amputation may be required.

Mohs micrographic surgery:

  • Specialized technique in removal of locally invasive skin cancers
  • Controversial in melanoma (as there are no clinical trials comparing it to wide local excision)
  • Used for in situ melanoma and lentigo maligna of the head and neck
  • Not for invasive melanoma
Table: Recommended resection margins
Invasion depthTumor stageMargins
Tis0.51 cm
1 mmT11 cm
> 1–2 mmT21–2 cm
> 2–4 mmT32 cm 
> 4 mmT4

Additional procedures

Sentinel lymph node biopsy (SLNB):

  • Sentinel lymph node (SLN): first draining lymph node in the lymphatic system of the tumor
  • Performed for clinically negative nodes (to detect occult metastasis) in:
    • Lesions > 0.8 mm thick 
    • Lesions of any thickness with ulceration

Regional lymph node dissection:

  • Completion lymph node dissection (CLND) (in those with positive SLNB), provided reduced regional lymph node recurrence.
  • However, there was no difference in survival in CLND versus observation.

Surgical metastasectomy:

  • Can be done for isolated distant metastases
  • Sometimes performed after good initial response to adjuvant therapy

Adjuvant therapies for advanced melanoma

  • Usually not recommended for stage IIC and lower
  • For stage III disease (lymph node involvement) and stage IV (metastatic disease)
  • Options:
    • Immunotherapy (combination of):
      • Nivolumab or pembrolizumab (anti–programmed cell death antibody)
      • Ipilimumab (monoclonal antibody to cytotoxic T lymphocyte–associated antigen 4)
    • Targeted therapy:
      • For BRAF V600E/K mutation: combination vemurafenib (BRAF kinase inhibitors) with cobimetinib (MEK inhibitor)
      • Other option for BRAF V600E/K mutation: dabrafenib + trametinib, encorafenib + binimetinib
      • For KIT mutation: imatinib (tyrosine kinase inhibitor)
    • Cytotoxic therapy:
      • Not very effective and does not improve overall survival
      • Limited to patients for whom other options have been exhausted
    • Radiotherapy: 
      • Mostly for palliation in locally advanced disease
      • Stereotactic radiosurgery has a role in brain metastasis.

Prognosis

Negative prognostic factors: 

  • Patient-related factors:
    • Advanced age
    • Men
  • Lesion-related factors:
    • Advanced tumor stage: tumor thickness, ulceration, lymph node involvement, and presence of distant metastasis
    • ↑ Mitotic rate
    • Nodular melanoma

5-year survival rate:

  • Stage I: > 90%
  • Stage II: 45%–77%
  • Stage III: 27%–70%
  • Stage IV: < 20%

Related videos

Differential Diagnosis

  • Atypical nevus: a benign melanocytic neoplasm that mimics melanoma in appearance, as it may be asymmetric and > 6 mm with color variegation. Thus, a biopsy is needed to exclude melanoma.
  • Seborrheic keratosis: a benign neoplasm consisting of immature keratinocytes occurring commonly in the elderly. A seborrheic keratosis usually presents as a sharply demarcated, round, exophytic, dark skin lesion.
  • Dermatofibroma: a benign proliferation of dermal fibroblasts that presents as a firm, indurated, mobile nodule measuring about 0.5–1 cm in size. Furthermore, a dimple-like depression in the overlying skin appears as a “buttonhole” sign upon lateral compression.
  • Other skin malignancies: squamous cell or basal cell carcinomas usually present as raised erythematous, scaly, or ulcerated lesions. The malignancies can resemble amelanotic melanomas. Diagnosis is established by biopsy.

References

  1. Buzaid A. C., Gershenwald J. E. (2019). Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/tumor-node-metastasis-tnm-staging-system-and-other-prognostic-factors-in-cutaneous-melanoma
  2. Curti B.D., & Leachman S, & Urba W.J. (2018). Cancer of the skin. Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
  3. Hassel J.C., & Enk A.H. (2019). Melanoma. Kang S, et al. (Ed.), Fitzpatrick’s Dermatology, 9th ed. McGraw-Hill.
  4. Heistein J.B., Acharya U. (2020). Malignant melanoma. https://www.ncbi.nlm.nih.gov/books/NBK470409/
  5. Liu V., Armstrong A.W., Mihm M.C. (2020). Pathologic characteristics of melanoma. UpToDate. Retrieved January 15, 2021, from https://www.uptodate.com/contents/pathologic-characteristics-of-melanoma
  6. Rastrelli M., Tropea S., Rossi C.R., Alaibac M. (2014). Melanoma: Epidemiology, Risk Factors, Pathogenesis, Diagnosis and Classification. https://iv.iiarjournals.org/content/28/6/1005.long
  7. Sosman J. A. (2020). Overview of the management of advanced cutaneous melanoma. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/overview-of-the-management-of-advanced-cutaneous-melanoma
  8. Stone M.D. (2020). Surgical management of primary cutaneous melanoma or melanoma at other unusual sites. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/surgical-management-of-primary-cutaneous-melanoma-or-melanoma-at-other-unusual-sites
  9. Swanson D.L. (2017). Nevi and melanoma. Soutor C, & Hordinsky M.K.(Eds.), Clinical Dermatology. McGraw-Hill.
  10. Swetter S., Geller A.C. (2020). Melanoma: Clinical features and diagnosis. UpToDate. Retrieved January 16, 2021, from https://www.uptodate.com/contents/melanoma-clinical-features-and-diagnosis
  11. Tan, W. (2020). Malignant Melanoma. Medscape. https://emedicine.medscape.com/article/280245-overview

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