Melanoma
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
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
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.
- Nivolumab with ipilimumab
- 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
- Anti–PD-1 monotherapy
- 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
- Stage IIIA with sentinel lymph node metastases
- 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
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
In situ melanoma. Note jetblack coloration of the lesion. Compare with surrounding seborrheic keratoses.
Figure 22-26
Acral lentiginous melanoma. Note the pronounced variegation pigmentation of this lesion. (Courtesy of Charles Miller, M.D., San Diego Naval Hospital.)
Figure 22-27
Superficial spreading melanoma. Note the "ABCD" features: asymmetry, notched border, varied colors, and diameter of more than 6 mm.
Figure 22-28
Superficial spreading melanoma. Note the central area (whitish gray) of regression.
Figure 22-31
Nodular melanoma. This is a nodule with surrounding satellite lesions that represent local "in transit" metastases.
Figure 22-32
Nodular amelanotic melanoma. This lesion arose de novo; it has a great probability of metastasizing.
Figure 22-33
Lentigo maligna. Note the irregular color and irregular border of this malignant melanoma in situ.
Figure 22-34
Lentigo maligna melanoma. Biopsy of this lesion demonstrated invasion into the dermis.
Figure 22-38
Acral lentiginous melanoma. Hutchinson's sign shows uneven pigmentation spreading beyond the nail into surrounding skin.
Authors
Vaidehi K. Patel, MD, MS
REFERENCE
- et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80(1):208–250. [PMID:30392755] , , ,
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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