Melanoma

Basics

Description

Melanoma is a malignancy arising from melanocytes, the melanin-producing cells found throughout the body. Although melanocytes are widely distributed, malignant transformation commonly occurs in the skin. Therefore, melanoma is classified into the following categories:
- Cutaneous melanoma: arises from melanocytes in the stratum basale of the epidermis
- Noncutaneous melanoma
  - Mucosal melanoma: originates from melanocytes in the mucosal membrane, most commonly in the head, neck, anorectal, and genitourinary regions
  - Uveal melanoma: originates from melanocytes in the uvea
  - Melanoma of unknown primary: likely originates from a less common site of melanocytes
Because cutaneous melanoma constitutes the vast majority of melanoma, this review focuses on cutaneous melanoma.
Major histologic subtypes
- Superficial spreading melanoma (70%): occurs on sun-exposed trunk/extremities, often from preexisting nevus; irregularly pigmented macule/plaques
- Nodular melanoma (15–30%): occurs on sun-exposed trunk/extremities; blue-black or pink nodules; smooth, ulcerate/bleed easily
- Lentigo maligna melanoma (<10%): occur on chronically sun-damaged face/forearms in elderly
- Acral lentiginous melanoma (<5%): occurs on palms, soles, nails; variegated macules; more common in darker-skinned or Asian patients
Uncommon subtypes
- Amelanotic melanoma (2–10%): mimics benign skin conditions (“great pretender”)
- Spitzoid melanoma: resembles Spitz tumors; amelanotic or blue-black papules/nodules
- Desmoplastic melanoma: occurs on sun-damaged skin in elderly; scar-like or mimics nonmelanoma cancers
- Pigment synthesizing (animal-type) melanoma: slow-growing blue-black nodules; usually on extremities

Epidemiology

Incidence

From 2018 to 2022, U.S. melanoma incidence was 21.9/100,000 men and women per year, with a median diagnosis age of 66 years.
Rates rose ~1.2% annually between 2013 and 2022.
Higher incidence in non-Hispanic White men >75 years of age

Prevalence

Melanoma is the 5th most common U.S. cancer.
In 2022, ~1.5 million people were living with melanoma.
2.2% lifetime risk of developing melanoma based on 2018–2021 data.

Etiology and Pathophysiology

Etiology: UV damage (sunburns, tanning beds, poor photoprotection), dysplastic/giant congenital nevi, and genetic mutations
Pathophysiology: genetic or UV injury drives uncontrolled melanocyte proliferation, progressing from radial to vertical growth with deeper invasion and metastasis

Genetics

Predisposing inherited skin conditions: familial atypical multiple mole melanoma syndrome, xeroderma pigmentosum
50% of melanomas harbor BRAF mutations (most often V600E).
CDKN2A mutations raise risk by 35 to 70 times.
BRCA2 mutation increases risk by 2.5%.

Risk Factors

Personal/family history of melanoma or other skin cancers
Fair skin, freckles, light eyes, red/blond hair
>50 melanocytic nevi or >5 cm congenital nevi
Indoor tanning (WHO class 1 carcinogen)
Chronic immunosuppression (leukemia, lymphoma, AIDS, posttransplant)
Occupational ionizing radiation exposure

General Prevention

Regular sunscreen (SPF 15 to 30+), protective clothing, sun avoidance
Avoid tanning beds.
For high-risk adults: periodic total-body skin exams
Biopsy suspicious lesions (narrow excision, 1 to 3 mm margins)

Commonly Associated Conditions

Other skin cancers: basal cell, squamous cell
Autoimmune diseases: rheumatoid arthritis, lichen planus, lupus, scleroderma
Parkinson disease

Diagnosis

History

Onset and changes in lesion (size, shape, color, bleeding, itching)
Personal/family history of skin cancer
Sunburns, tanning bed use, chronic sun exposure
Immunosuppression
Occupational exposures

Physical Exam

ABCDE: asymmetry, border irregularity with indistinct margins, color variegation, diameter ≥6 mm, evolution over time
Ugly duckling sign: lesion unlike patient’s other nevi
Bleeding, ulceration, sensory change/itch
Location: sun-exposed sites (White people); palms/soles/nails (African Americans)
Ocular exams (iris/retina)

Differential Diagnosis

Benign lesions: seborrheic keratosis, angiomas, dermatofibroma, irritated benign nevi, solar lentigo
Precancerous lesions: actinic keratosis, dysplastic nevi, Bowen disease
Other skin cancers: basal cell, squamous cell

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

Total body skin exam for suspicious lesions
Dermoscopy: first-line diagnostic tool; increases sensitivity and specificity of clinical diagnosis (1)
- Features: irregular pigment network, atypical dots/streaks, multiple asymmetric colors, blue-white veil, atypical vessels

Follow-Up Tests & Special Considerations

Excisional biopsy (preferred): full thickness with 1 to 3 mm margin
Incisional/partial biopsy: if complete excision is not feasible (face, palms/soles, nails, large lesions)

Diagnostic Procedures/Other

Sentinel lymph node biopsy (SLNB) (1)
- Indicated if ≥1 mm depth
- Consider if 0.8 to 1.0 mm or <0.8 mm with high-risk features (ulceration, high mitotic rate, positive margin, lymphovascular invasion, age <40 years)
Advanced workup if metastatic or positive SLNB
- Labs: CBC, CMP, LDH
- Imaging: CT/PET-CT chest, abdomen, pelvis, MRI brain, lymph node US, bone scan

Test Interpretation

Diagnosis is based on architectural and cytologic features; immunohistochemistry/molecular tests if results are unclear
- Poor prognosis features: increased Breslow depth, ulceration, high mitotic rate, microsatellitosis, positive margins, lymphovascular invasion
American Joint Committee on Cancer tumor-node-metastasis (TNM) criteria for staging: considers tumor thickness (mm) and ulceration, nodal involvement, and distant metastasis

Treatment

General Measures

Educate on self-skin exams, lymph node checks, photoprotection.
Counsel increased risk of melanoma in family members.

Medication

First Line

Primary treatment: full surgical excision; curative in most stage I to II cases
For high-risk (stage IIIB and C) melanoma: adjuvant nivolumab or pembrolizumab (anti-PD-1 monoclonal antibody) for 1 year
For unresectable or metastatic melanoma, regimens include either/both of the following (2):
- Immunotherapy combination therapy
  - Ipilimumab (anti-CTLA-3 monoclonal antibody) + nivolumab or pembrolizumab (anti-PD-1 monoclonal antibody)
  - Contraindications: severe asthma, unstable cardiovascular disease, prior anaphylaxis, autoimmune disease
  - Adverse effects: dermatitis, colitis, pneumonitis, endocrinopathies—managed with glucocorticoids
- Targeted combination therapy for BRAF-mutated melanoma (BRAF + MEK inhibitors)
  - Vemurafenib (BRAF inhibitor) + cobimetinib (MEK inhibitor)
    - Contraindications: known hypersensitivity reaction
    - Adverse effects: diarrhea, nausea, rash, arthralgia, cardiomyopathy, hepatotoxicity, ocular toxicity, severe cutaneous reactions
  - Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor)
    - Contraindications: known hypersensitivity reaction
    - Adverse effects: nausea, fatigue, hypertension, dermatologic reactions, fever, hemorrhage, thromboembolic events, pneumonitis, interstitial lung disease

Second Line

Nivolumab and relatlimab (Opdualag): combination anti-PD-1 and anti-LAG-3 inhibitor
- 18–20% overall response rate
- Contraindications: known hypersensitivity reaction
- Adverse effects: dermatitis, colitis, pneumonitis, endocrinopathies
High-dose interleukin-2:
- 10–15% durable response rate
- Contraindications: significant cardiovascular, pulmonary, renal, hepatic, or CNS disease; poor performance status
- Adverse effects: severe hemodynamic instability, renal/hepatic disease, infections
Chemotherapy: various agents (dacarbazine, cisplatin, carboplatin/paclitaxel, etc.)
- <20% overall response with median duration of 4 to 6 months
- Contraindications: severe bone marrow suppression, uncontrolled infection, poor performance status, pregnancy
- Adverse effects: myelosuppression, nausea/vomiting, alopecia, fatigue, neuropathy

Issues for Referral

Dermatology: lifelong follow-up for all patients
Oncology: referral for high-risk stage II and all stage III to IV melanomas

Additional Therapies

Talimogene laherparepvec (T-VEC): intralesional oncolytic HSV-1 expressing GM-CSF

Mechanism of action: direct tumor lysis + immune activation
Indication: unresectable, injectable cutaneous, subcutaneous, or nodal melanoma with limited visceral disease

Surgery/Other Procedures

Surgical excision (standard of care) (1)
- In situ: 0.5 cm margin
- ≤1 mm thickness: 1 cm margin
- 1.01 to 2.00 mm thickness: 1 to 2 cm margins
- 2.01 to 4.00 mm thickness: 2 cm margins
- ≥4 mm thickness: 2 cm margins
Mohs surgery: sometimes utilized for in situ, but not routine for melanoma
Radiation: palliative for localized disease, stereotactic radiosurgery for brain mets

Complementary & Alternative Medicine

Mind-body: Meditation, yoga, acupuncture improve quality of life, reduce stress, and manage side effects.
Psychosocial: support groups, counseling, and integrative care teams enhance coping

Admission, Inpatient, and Nursing Considerations

Most patients are managed outpatient, but admit if:
- Patient factors: advanced age, comorbidities, poor support, hospice needs
- Clinical instability: sepsis/bleeding, neurologic compromise, organ dysfunction
- Lab/radiology: severe hypercalcemia, cytopenias, liver failure, cord compression, brain edema/metastasis, malignant effusions
- Toxicity: severe immune-related or BRAF/MEK inhibitor adverse effects
- Perioperative: wide excisions, lymph node dissection, surgical complications
Inpatient care: stabilization, targeted medications (IV steroids if immunotherapy is used, antiepileptics, bisphosphonates, antibiotics, analgesics), imaging (brain MRI to evaluate for metastasis), procedures as needed
Nursing: Monitor vitals/neurologic status, manage symptoms, medications, and adherence.
Discharge: instructions on medications, follow-ups, red flag symptoms (dyspnea, diarrhea, fever, bleeding, neurologic changes)

Ongoing Care

Follow-up Recommendations

Patient Monitoring

Stage IA: skin/lymph node exam every 6 month × 2 years and then annually
Stage IB to IIA: exam every 4 to 6 months × 2 years and then annually
Stage IIB to IIIA: exam every 3 to 4 months × 2 to 3 years, then every 6 months up to 5 years, and then annually; CT scan of chest/abdomen/pelvis every 6 months × 3 years and then annually; nodal US if SLNB + without complete dissection
Stage IIC to IIID: exam every 3 months × 3 years and then every 6 months up to 5 years; CT scan of chest/abdomen/pelvis on same schedule; nodal US as above
Metastatic disease: surveillance tailored to treatment response

Diet

No melanoma-specific diet guidelines
For patients on immunotherapy: Mediterranean diet may improve response rates and progression-free survival.

Patient Education

Photoprotection: sunscreen, protective clothing, no tanning beds
Skin checks: regular full-body exams monitoring for lesions using ABCDE criteria

Prognosis

Older age and male sex are associated with worse outcomes.
Increased Breslow depth, higher number of positive lymph, elevated LDH predict poorer prognosis
5-year relative survival (2015 to 2021) in the United States: 94.7%
Median age at death: 72 years

Complications

Metastatic spread to lymph nodes, liver, lung, brain, and bone

Figures

Figure 22-25

Descriptive text is not available for this image

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

Ravjot Kaur Virdi, DO, MPH
Jon Richards, MD, PhD

References

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]
Seth R, Agarwala SS, Messersmith H, et al. Systemic therapy for melanoma: ASCO guideline update. J Clin Oncol. 2023;41(30):4794–4820. doi:10.1200/JCO.23.01136. [PMID:37579248]

Additional Reading

National Cancer Institute. Cancer Stat Facts: Melanoma of the Skin. Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/melan.html.

Codes

ICD-10

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

UV exposure and tanning beds are key modifiable risk factors. Use of sunscreen, protective clothing, and regular skin exams is proven preventive strategies.
Superficial spreading melanoma accounts for ~70% of cases. Nodular, acral lentiginous, and amelanotic subtypes present atypically (pink nodules, nail lesions, “scar-like” plaques).
In situ or thin (<1 mm) melanomas are often curable with surgical excision. Delayed diagnosis increases risk of nodal spread and mortality. Use ABCDE criteria for early identification.
SLNB is indicated for melanomas ≥1 mm thick, or thinner lesions (<0.8 to 1.0 mm) with high-risk features. Early detection of nodal involvement guides staging and adjuvant therapy.
Immunotherapy and BRAF/MEK inhibitors are frontline treatments that markedly improve survival but require vigilant monitoring for severe adverse effects.

Last Updated: 2027