Melanoma

Descriptive text is not available for this image BASICS

DESCRIPTION

  • Melanoma is a tumor arising from malignant transformation of pigment-containing cells called melanocytes, which are found in the stratum basale of the epidermis.
    • Most arise in the skin but may also present as a primary lesion in any tissue: ocular (uvea), GI, GU, lymph node, paranasal sinuses, nasal cavity, anorectal mucosa, and leptomeninges.
    • Extracutaneous sites have an adverse prognosis.
    • Metastatic spread to any site in the body
  • Types of invasive cutaneous melanomas include the following:
    • Superficial-spreading melanoma: ~70% of cases; occurs in sun-exposed areas (trunk, back, and extremities); most <1 mm thick at diagnosis; when seen in younger patients, presents as a flat, slow growing, irregularly bordered lesion
    • Nodular: 15–30% of cases; present older patients; tendency to ulcerate and hemorrhage; most commonly thick and pigmented; most common melanoma >2 mm
    • Lentigo maligna (subtype of melanoma in situ): slowest growing; older population; occurs in sun-exposed areas (head, neck, forearms); lentigo maligna melanoma (LMM) is its invasive counterpart seen in 10–15% of cases; it is most commonly seen in elderly patients most often in the head and neck regions.
    • Acral lentiginous: <5% of all melanomas; however, most common melanoma in black or Asian patients; found in palmar, plantar, and subungual areas; can mimic other skin abnormalities, including warts, calluses, tinea pedis, or ingrown toenails
      • An important subtype of acral lentiginous melanoma is a subungual melanoma; from the nail matrix, presents as dark stripe under the nail plate; Hutchinson nail sign: vertical brown or black pigment cuticle/proximal or lateral nail folds to nail edge
    • Amelanotic melanoma: <5% of cases; mimics benign skin conditions and thus is referred to as a “great pretender”
    • Desmoplastic melanoma: ~1% of cases; “neurotropic melanoma” or “spindled melanoma” with an abundance of fibrous tissue; demonstrates sarcoma-like tendencies with increased hematogenous spread; presents as a slow-growing lesion that is scar-like (no history of injury at the site is noted); often seen in the head and neck
  • System(s) affected: skin/exocrine

Geriatric Considerations
Lentigo maligna is most common in elderly patients. This type is usually found on the face, beginning as a circumscribed macular patch of mottled pigmentation showing shades of dark brown, tan, or black.Pediatric Considerations
Large congenital nevi (>5 cm) are risk factors and have a >2% lifetime risk of malignant conversion. Blistering sunburns in childhood significantly increase risk.Pregnancy Considerations
No increased risk of melanoma in pregnancy; wait 1 to 2 years after treatment for pregnancy as melanoma can spread to the placenta.

EPIDEMIOLOGY

Incidence

  • In 2023, new cases in Americans are 97,610, with ~7,990 deaths.
  • Predominant age: Median age at diagnosis is 66 years.
  • Predominant sex: male > female (1.5 times)
  • Melanoma is >20 times more common in whites than in African Americans.
  • Minority groups demonstrate increased rates of metastasis, advanced stages at diagnosis, thicker initial lesions, earlier age at diagnosis, and overall poorer outcomes.

Prevalence

  • Melanoma is the fifth most common type of cancer in the United States.
  • Lifetime risk: men: 1/28; female: 1/4
  • 1.2% of all cancer deaths

ETIOLOGY AND PATHOPHYSIOLOGY

  • DNA damage by UVA/UVB exposure
  • Tumor progression: initially confined to epidermis with lateral growth, vertical growth

Genetics

  • Dysplastic nevus syndrome is a risk factor for development of melanoma. Close surveillance is warranted.
  • 8–12% of patients with melanoma have a family history of disease.
  • Mutations in BRAF (V600E) implicated in 50–60% of cutaneous melanomas
  • Familial atypical mole malignant melanoma (FAMMM) syndrome characterized by >50 atypical moles, +FH of melanoma (1)

RISK FACTORS

  • Genetic predisposition, personal/family history of melanoma
  • UVA and UVB exposure
  • History of >5 sunburns during lifetime, blistering sunburns in childhood
  • Previous pigmented lesions (especially dysplastic melanocytic nevi)
  • Fair complexion, freckling, blue eyes, blond/red hair
  • Highest predictor of risk is increased number of nevi (>50).
  • Tanning bed use: 75% increased risk if first exposure before age 35 years
  • Changing nevus (see “ABCDE” criteria)
  • Large (>5 cm) congenital nevi
  • Chronic immunosuppression (chronic lymphocytic leukemia, non-Hodgkin lymphoma, AIDS, or posttransplant)
  • Living at high altitude (>700 meters or 2,300 feet above sea level)
  • Occupational exposure to ionizing radiation

GENERAL PREVENTION

  • Avoidance of sunburns, especially in childhood
  • Use of sunscreen with at least SPF 30 to all exposed skin; reapply regularly and after swimming.
  • Avoid tanning beds; class 1 carcinogen by World Health Organization (WHO)
  • Any suspicious lesions should be biopsied with a narrow excision with 1- to 3-mm margins that encompass the entire breadth plus sufficient depth of the lesion. Options include elliptical excisions, punch, or deep shave biopsies.

COMMONLY ASSOCIATED CONDITIONS

  • Dysplastic nevus syndrome
  • >50 nevi; high lifetime risk of melanoma because 30% of all melanoma arise in preexisting nevi.
  • Giant congenital nevus: 6% lifetime incidence of melanoma
  • Psoriasis after psoralen-UV-A (PUVA) therapy

Descriptive text is not available for this image DIAGNOSIS

HISTORY

  • Change in a pigmented lesion: either hypo- or hyperpigmentation, bleeding, scaling, ulceration, or changes in size or texture
  • Family history of skin cancer, occupation, sunbathing, tanning, and other sun exposure

PHYSICAL EXAM

  • ABCDE: Asymmetry, Border irregularity, Color variegation (especially red, white, black, blue), Diameter >6 mm, Evolution over time
  • Any new and/or changing nevus, bleeding/ulcerated
  • Location on Caucasians is primarily back and lower leg; on African Americans, it is the hands, feet, and nails.
  • May include mucosal surfaces (nasopharynx, conjunctiva)
  • Ocular exam to assess for presence of melanoma in the iris and retina

DIFFERENTIAL DIAGNOSIS

  • Cutaneous squamous cell carcinoma
  • Basal cell carcinoma
  • Dysplastic and blue nevi
  • Vascular skin tumor
  • Pigmented actinic keratosis
  • Traumatic hematoma
  • Pigmented basal cell carcinomas, seborrheic keratoses, other changing nevi
  • Common or atypical melanocytic nevi
  • Lentigo
  • Pyogenic granuloma

DIAGNOSTIC TESTS & INTERPRETATION

Lactate dehydrogenase (LDH), chest/abdomen/pelvic CT with or without PET/CT at baseline and in monitoring progression in metastatic disease (stage IV); brain MRI if any CNS symptoms or physical findings

Diagnostic Procedures/Other

  • Full-thickness excisional biopsy remains the gold standard for diagnosis. Any suspicious nevus should be excised, either by elliptical excision, punch biopsy, or a scoop shave (saucerization) biopsy.
  • Avoid superficial shave of suspicious lesion. Goal for full-thickness excision with 1- to 3-mm margins. Orient excisional biopsy to optimize future treatment.
  • Sentinel lymph node biopsy, a staging procedure, remains an important factor for prognosis.

Test Interpretation

  • Nodular melanoma is primarily vertical growth, whereas the other three types are horizontal.
  • Estimated that 1/10,000 dysplastic nevi become melanoma annually.
  • Staging is based on the tumor-node-metastasis (TNM) criteria by current American Joint Committee on Cancer (AJCC) criteria, including:
    • Thickness (mm) and ulceration; number of regional lymph nodes involved; distant metastases and serum LDH

Descriptive text is not available for this image TREATMENT

GENERAL MEASURES

Full surgical excision of melanoma is primary treatment for resectable/nonmetastatic melanomas.

  • For stages I to II, surgical excision is curative in most cases

MEDICATION

  • Treatment within the context of a clinical trial is always recommended.
  • FDA-approved first-line medication for unresectable or metastatic melanoma include the following:
    • Anti–PD-1 monotherapy
      • Pembrolizumab (Keytruda)
      • Nivolumab (Opdivo)
    • Anti–PD-1/anti–CTLA-4 therapy
      • Nivolumab with ipilimumab
        • Combo therapy demonstrated 61% response versus ipilimumab alone.
    • If BRAF V600–activating mutation is present, can opt for target therapy with BRAF/MEK inhibitors:
      • Dabrafenib/trametinib
      • Vemurafenib/cobimetinib + atezolizumab (new FDA-approved medications)
      • Encorafenib/binimetinib
  • Adjuvant medical therapy for certain high-risk patients after undergoing complete surgical excision with lymph node involvement or metastasis
    • Stage IIIA with sentinel lymph node metastases
      • Pembrolizumab (Keytruda)
      • Dabrafenib/trametinib for BRAF V600–activating mutation
    • Stage IIB/C and IV with nodal recurrence
      • Pembrolizumab (Keytruda)
      • Nivolumab (Opdivo)
      • Dabrafenib/trametinib for BRAF V600–activating mutation
    • Stage IV completely resected
      • Nivolumab (Opdivo)
    • Stage IV with nodal recurrence
      • Ipilimumab recommended only if prior exposure to anti–PD-1 therapy
  • Additional active regimens (e.g., dacarbazine [DTIC], temozolomide, paclitaxel, carmustine [BCNU], cisplatin, carboplatin, vinblastine) often limited to those who are not candidates to preferred regimens
  • Imatinib (Gleevec) in tumors with c-KIT mutation
  • Interferon-α as adjuvant therapy received FDA approval in 1995 (high dose) and 2011 (pegylated) to treat stage IIB to III melanoma; shown to improve 4-year relapse rate but no overall effect on survival; 1/3 of patients will discontinue due to toxicity (granulocytopenia, hepatotoxicity).

First Line

Anti–PD1 monotherapy, combination anti–PD-1/anti–CTLA-4 therapy, and BRAF/MEK inhibitors

ISSUES FOR REFERRAL

Oncology and surgical specialties may be required based on the extent of nodal and/or metastatic disease, if present.

ADDITIONAL THERAPIES

Local therapy for stage III in-transit disease when resection not possible, prior resection unsuccessful, or refusal of surgery, and seek conservative management including intralesional injections, topical imiquimod, laser ablation, and radiation therapy

  • Talimogene laherparepvec (T-VEC) intralesional injections is the recommended option for intralesional injection.
  • Other injections include IL-2, BCG, or IFN.

SURGERY/OTHER PROCEDURES

  • Standard of care for melanoma includes early surgical excision with the following recommended margins:
    • In situ tumors: 0.5- to 1.0-cm margin
    • Thickness of ≤1 mm (T1): 1-cm margin
    • Thickness of 1.01 to 2.00 mm (T2): 1- to 2-cm margins
    • Thickness of 2.01 to 4.00 mm (T3): 2-cm margins
    • Thickness of ≥4 mm (T4): 2-cm margins
  • Sentinel lymph node biopsy is indicated in patients with T1b-, T2-, T3-, and T4-staged melanomas.
    • Not recommended in melanoma in situ or T1a
  • Mohs micrographic surgery is being increasingly used for melanoma in situ, but in general, it is not considered a treatment modality for melanoma because it relies on frozen section technique.
  • Radiotherapy can be used to treat lentigo maligna in addition to certain head and neck lesions.
  • Palliative radiation therapy can be used with metastatic melanoma.
  • Stage IIIB/C—intralesional injections in certain cases if limited number of in-transit metastasis or not amenable to complete surgical excision

Descriptive text is not available for this image ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • Total body photography and dermoscopy should be used for surveillance of skin lesions, most commonly used for patients with >5 atypical nevi.
  • For patients with a history of cutaneous melanoma, consensus guidelines recommend screening every 3 to 12 months depending on recurrence risk, with annual examinations if there is no disease progression for 5 years.
  • Surveillance chest x-ray, CT, brain MRI, and/or PET/CT scan every 3 to 12 months for 3 to 5 years at discretion of physician
  • Lab and imaging tests after diagnosis and treatment of stage I to II melanoma are low yield, have high false-positive rates, and are not recommended.

PATIENT EDUCATION

Teach all patients to perform regular full-body skin examinations looking for ABCDE criteria.

PROGNOSIS

  • Breslow depth (thickness) in millimeters remains among strongest predictors of prognosis.
  • Median age at death is 70 years.
  • Highest survival seen in women <45 years of age at diagnosis
  • Metastatic melanoma has an average survival of 6 to 9 months; 15–20% 5-year survival with current treatment
  • Stages I and II, appropriately treated, have 20-year survival rates of 90% and 80%, respectively.

Figures

Figure 22-25

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In situ melanoma. Note jetblack coloration of the lesion. Compare with surrounding seborrheic keratoses.
Figure 22-26
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Acral lentiginous melanoma. Note the pronounced variegation pigmentation of this lesion. (Courtesy of Charles Miller, M.D., San Diego Naval Hospital.)
Figure 22-27
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Superficial spreading melanoma. Note the "ABCD" features: asymmetry, notched border, varied colors, and diameter of more than 6 mm.
Figure 22-28
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Superficial spreading melanoma. Note the central area (whitish gray) of regression.
Figure 22-31
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Nodular melanoma. This is a nodule with surrounding satellite lesions that represent local "in transit" metastases.
Figure 22-32
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Nodular amelanotic melanoma. This lesion arose de novo; it has a great probability of metastasizing.
Figure 22-33
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Lentigo maligna. Note the irregular color and irregular border of this malignant melanoma in situ.
Figure 22-34
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Lentigo maligna melanoma. Biopsy of this lesion demonstrated invasion into the dermis.
Figure 22-38
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Acral lentiginous melanoma. Hutchinson's sign shows uneven pigmentation spreading beyond the nail into surrounding skin.

Authors

Vaidehi K. Patel, MD, MS

REFERENCE

  1. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80(1):208–250.  [PMID:30392755]

Descriptive text is not available for this image CODES

ICD10

  • C43.9 Malignant melanoma of skin, unspecified
  • C43.30 Malignant melanoma of unspecified part of face
  • C43.4 Malignant melanoma of scalp and neck
  • C43.39 Malignant melanoma of other parts of face
  • C43.72 Malignant melanoma of left lower limb, including hip
  • C43.60 Malignant melanoma of unsp upper limb, including shoulder
  • C43.20 Malignant melanoma of unsp ear and external auricular canal
  • C43.52 Malignant melanoma of skin of breast
  • C43.51 Malignant melanoma of anal skin
  • C43.8 Malignant melanoma of overlapping sites of skin
  • C43.21 Malignant melanoma of right ear and external auricular canal
  • C43.61 Malignant melanoma of right upper limb, including shoulder
  • C43.71 Malignant melanoma of right lower limb, including hip
  • C43.70 Malignant melanoma of unspecified lower limb, including hip
  • C43.11 Malignant melanoma of right eyelid, including canthus
  • C43.62 Malignant melanoma of left upper limb, including shoulder
  • C43.10 Malignant melanoma of unspecified eyelid, including canthus
  • C43.59 Malignant melanoma of other part of trunk
  • C43.12 Malignant melanoma of left eyelid, including canthus
  • C43.31 Malignant melanoma of nose
  • C43.0 Malignant melanoma of lip
  • C43.22 Malignant melanoma of left ear and external auricular canal

SNOMED

  • 372244006 Malignant melanoma (disorder)
  • 93655004 malignant melanoma of skin (disorder)
  • 93225001 Malignant melanoma of skin of face
  • 188044004 Malignant melanoma of scalp and/or neck
  • 274087000 Malignant melanoma of eye (disorder)
  • 302837001 Lentigo maligna melanoma (disorder)
  • 269581007 Malignant melanoma of lower limb
  • 276751004 Amelanotic malignant melanoma of skin (disorder)
  • 93640008 Malignant melanoma of skin of lip
  • 423425006 malignant neoplasm of skin of eyelid (disorder)
  • 93651008 Malignant melanoma of skin of trunk
  • 93653006 Malignant melanoma of skin of upper limb
  • 403927001 Malignant melanoma of nail apparatus (disorder)
  • 403924008 Desmoplastic malignant melanoma (disorder)
  • 188032002 Malignant melanoma of ear and/or external auditory canal

CLINICAL PEARLS

  • Teach all patients to perform regular full-body skin examinations looking for ABCDE criteria.
  • Location on white people is primarily back and lower leg; on black people, it is the hands, feet, and nails.

Last Updated: 2026

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