Skin Cancers — Melanoma and Non-Melanoma

Mechanism 1 — UV-induced DNA damage (the dominant cause)

• UVB (290–320 nm): directly absorbed by DNA, producing cyclobutane pyrimidine dimers and 6-4 photoproducts; the resulting C→T and CC→TT "UV signature" transitions hit p53 in SCC/actinic keratosis and PTCH1 in BCC. Intense, intermittent sunburn (especially blistering burns in childhood) correlates best with melanoma; cumulative lifetime dose correlates best with SCC.
• UVA (320–400 nm): penetrates deeper, acts through reactive oxygen species and indirect base damage; the basis of tanning-bed risk. The FDA and AAD both counsel against indoor tanning, and use before age 35 carries the highest melanoma risk.
• Therapeutic UV: PUVA (psoralen + UVA) for psoriasis raises SCC risk dose-dependently.

Mechanism 2 — impaired immune surveillance

• Solid-organ transplant recipients: SCC risk rises dramatically and the normal BCC:SCC ratio reverses; azathioprine and calcineurin inhibitors are the usual culprits. Also seen in CLL, HIV, and chronic immunosuppression for autoimmune disease.
• HPV: β-HPV types in immunosuppressed skin; high-risk mucosal types (16, 18) in anogenital and periungual SCC.

Mechanism 3 — chronic inflammation, scarring, and chemical/radiation carcinogens

• Marjolin ulcer: SCC arising in a burn scar, chronic osteomyelitis sinus, or non-healing wound.
• Arsenic (well water, historic tonics) → SCC, BCC, and palmar/plantar keratoses; ionizing radiation and chronic occupational hydrocarbon exposure likewise.

Non-modifiable host factors examiners plant

• Fitzpatrick I–II skin, red hair, freckling, blue eyes (MC1R variants; pheomelanin is a poor UV filter).
• >50 nevi, dysplastic nevus syndrome, large congenital nevus; personal or first-degree-family melanoma history.
• Germline syndromes: CDKN2A/p16 familial melanoma; xeroderma pigmentosum (nucleotide excision repair defect, childhood cancers); Gorlin/basal cell nevus syndrome (PTCH1, jaw keratocysts, palmar pits); oculocutaneous albinism.

Melanoma

• BRAF and NRAS mutations (~50-70% of melanomas): constitutive activation of MAPK/ERK signaling pathway driving unchecked proliferation
• KIT mutations (15-20%): particularly in mucosal and acral melanomas; activate tyrosine kinase signaling
• NF1 loss (15-20%): loss of negative regulator of RAS signaling
• UV-induced DNA damage (UVA/UVB): causes thymine dimers and oxidative stress, leading to p53 mutations and impaired apoptosis in melanocytes
• Malignant transformation cascade: benign nevus → dysplastic nevus → radial growth phase (RGP) → vertical growth phase (VGP) with invasion into dermis and subcutis → lymphovascular invasion → metastasis
• Immune evasion: increased expression of PD-L1, reduced infiltrating lymphocytes, and production of immunosuppressive cytokines

Non-Melanoma Skin Cancers (NMSC)

• Basal Cell Carcinoma (BCC): Hedgehog pathway mutations (PTCH1, SMO) → uncontrolled basal cell proliferation; 90% causation by chronic UV exposure
• Squamous Cell Carcinoma (SCC): p53 mutations (50-90% of cases) and RAS mutations from UV exposure → loss of apoptosis and growth control; can arise from actinic keratosis (premalignant lesion)
• Field effect/field carcinization: widespread DNA damage from chronic sun exposure predisposes to multiple cancers over time

Melanoma (ABCDE Criteria)

• Asymmetry: one half does not mirror the other; key distinguishing feature from benign nevi
• Border irregularity: scalloped, notched, or poorly demarcated edges suggesting active growth
• Color variation: multiple colors (brown, black, red, white, blue) within single lesion; indicates heterogeneous cell populations
• Diameter >6 mm: though some melanomas are smaller; also consider "ugly duckling sign" (lesion that looks different from patient's other nevi)
• Evolution/Evolving: changing size, shape, or color over weeks to months; patient-reported change is highly suspicious
• Additional features: bleeding, oozing, itching, or pain may indicate advanced disease; nodular variants may lack some classic features

Melanoma Variants

• Superficial spreading melanoma (70%): most common; lateral spread before vertical invasion; variable pigmentation
• Nodular melanoma (15-20%): rapid growth; poor prognosis due to immediate vertical growth phase; often darker and more uniform
• Lentigo maligna melanoma (4-5%): arises on sun-exposed face/neck in elderly; preceded by extensive lentigo maligna (in-situ disease); better prognosis
• Acral lentiginous melanoma (5-10%): palms, soles, subungual; particularly common in darker-skinned individuals; worst prognosis

Non-Melanoma Skin Cancers

• BCC: pearly or translucent papule/nodule with rolled borders and central ulceration ("rodent ulcer"); may have telangiectasia; typically on head/neck; slow growth; rarely metastasizes
• SCC: scaly erythematous plaque on sun-exposed areas; may be ulcerated or hyperkeratotic; can arise from actinic keratosis; faster growth than BCC; higher metastatic potential
• Actinic keratosis (AK): precursor to SCC; rough, scaling patches on sun-exposed skin; often multiple; annual malignant transformation rate ~2.6%

• Dermoscopy/Dermoscopic criteria: handheld magnification tool revealing subsurface features; ABCDE of dermoscopy (Asymmetry of pattern, Blue-white veil, Color variegation, Differential structures, Eccentric growth) assists in melanoma identification; improves diagnostic accuracy to 90%+
• Excisional biopsy with narrow margins (1-3 mm) for suspicious lesions: gold standard; preserves architecture for staging; allows complete histopathologic assessment and margin status; recommended over punch or shave biopsy for suspected melanoma
• Histopathology assessment: Clark level (depth relative to skin layers I-V), Breslow thickness (millimeters of vertical depth; most important prognostic factor), mitotic rate, ulceration, lymphocytic infiltrate, angiolymphatic invasion
• Sentinel lymph node biopsy (SLNB): indicated for melanomas ≥1 mm thickness or with other high-risk features; staging tool and therapeutic benefit in node-positive disease; performed via radioisotope mapping and blue dye
• Imaging for staging: PET-CT, brain MRI, and chest imaging for stage III-IV disease to evaluate for metastases
• BRAF V600E/K mutation testing: prognostic and therapeutic; allows targeted therapy eligibility assessment
• Mismatch repair (MMR) deficiency testing: may indicate Lynch syndrome with increased skin cancer risk

Melanoma

• Stage I-II (localized disease; no nodal involvement): Surgical excision with appropriate margins (1 cm for <1 mm thickness, 1-2 cm for 1-2 mm, 2 cm for >2 mm); Mohs micrographic surgery option for head/neck lesions to preserve tissue while ensuring clear margins; sentinel lymph node biopsy for intermediate/high-risk features (Breslow >1 mm, Clark level IV-V, ulceration, high mitotic rate)
• Stage III (regional nodal disease): Complete lymph node dissection after positive SLNB; adjuvant immunotherapy with checkpoint inhibitors (pembrolizumab, nivolumab) or targeted therapy (dabrafenib/trametinib for BRAF-mutant tumors) for high-risk resected disease; significantly improves recurrence-free and overall survival
• Stage IV (metastatic disease):
• First-line immunotherapy combinations: nivolumab + ipilimumab (anti-PD-1 + anti-CTLA-4) shows superior response rates (~55-60%) vs monotherapy; significant toxicity (immune-related adverse events in 50%+)
• BRAF-mutant metastatic disease: dabrafenib/trametinib combination preferred over immunotherapy monotherapy; rapid response but shorter duration
• Palliative care and supportive treatment: radiation for brain metastases, chemotherapy (temozolomide, dacarbazine) reserved for select patients
• Adjuvant radiation therapy: considered for stage III disease with extranodal extension or multiple involved nodes

Non-Melanoma Skin Cancers

• BCC:
• Surgical excision (curative in >95%); Mohs micrographic surgery for high-risk locations (face, ears, nose) or recurrent tumors
• Topical agents: imiquimod (immune stimulant) or 5-fluorouracil for superficial BCC; cryotherapy for small lesions
• Hedgehog inhibitors (vismodegib, sonidegib): for advanced/metastatic disease or locally advanced unresectable BCC
• SCC:
• Surgical excision with adequate margins (4-6 mm); Mohs for high-risk features (perineural invasion, >4 mm depth, poor differentiation, recurrent)
• Topical therapy:

Disease-related

• Local destructive invasion (BCC): slow but relentless growth into cartilage, bone, and orbit — the rodent ulcer; periocular and nasal lesions can reach the orbital apex or dura. Signal: a long-standing "non-healing sore" with rolled borders that now distorts anatomy.
• Perineural invasion (SCC > BCC): tumor tracks along nerve sheaths. Signal: facial numbness, paresthesia, or a facial nerve palsy near a scalp/cheek tumor — mandates MRI and Mohs or multidisciplinary care per NCCN.
• Regional and distant metastasis: SCC spreads first to regional nodes (parotid/cervical for head-and-neck primaries); risk climbs with depth, poor differentiation, ear/lip site, recurrence, and immunosuppression. Melanoma metastasizes widely — brain, lung, liver, bone, and characteristically the small bowel (intussusception or obscure GI bleed in a patient with a remote melanoma excision).
• Emergencies: brain metastasis with hemorrhage or herniation (melanoma mets bleed), malignant spinal cord compression (back pain preceding weakness — dexamethasone and urgent MRI), and PTHrP-mediated hypercalcemia from bulky SCC (altered mental status, short QT).

Treatment-related

• Immune-related adverse events (checkpoint inhibitors): loss of peripheral tolerance. Colitis (perforation risk), hepatitis, pneumonitis, thyroiditis, hypophysitis with secondary adrenal insufficiency, and myocarditis — the last two are emergencies (adrenal crisis; fulminant myocarditis with troponin rise and heart block). ASCO/NCCN grading framework: grade 2 → hold the drug and consider corticosteroids; grade 3 → hold with high-dose corticosteroids; grade 4 (and any checkpoint-inhibitor myocarditis) → permanently discontinue. Endocrinopathies are managed with hormone replacement, not steroids alone.
• BRAF inhibitor monotherapy: paradoxical MAPK activation in RAS-mutant keratinocytes → keratoacanthomas and cutaneous SCC; adding a MEK inhibitor suppresses this. Dabrafenib/trametinib also causes pyrexia.
• Hedgehog inhibitors (vismodegib): muscle spasms, dysgeusia, alopecia; severely teratogenic — pregnancy prevention is mandatory.
• Surgical/nodal: completion lymph node dissection causes chronic lymphedema, seroma, and nerve injury — a major reason dissection has largely yielded to nodal surveillance.
• Topical 5-FU/imiquimod: brisk erosive inflammation is expected, not infection.

• Breslow thickness is the single most important prognostic factor in localized melanoma and drives both excision margin and SLNB decisions. Clark level is the classic distractor — it was dropped from AJCC 8th edition staging; T category is now defined by Breslow thickness (with the 0.8 mm cutoff) and ulceration. Mitotic rate remains an independently reported prognostic variable and informs the SLNB discussion, but it is no longer part of T staging.
• Best next step for any suspicious pigmented lesion is a full-thickness narrow-margin excisional biopsy. Shave biopsy risks transecting the base and losing depth; wide local excision before a tissue diagnosis is wrong; "observe and repeat in 6 months" is wrong when the lesion is changing.
• Nodular melanoma is the ABCDE escape artist — symmetric, uniformly dark or amelanotic, and it enters vertical growth immediately. A rapidly enlarging, bleeding dome-shaped nodule is melanoma until proven otherwise, and the ugly duckling sign outperforms ABCDE here.
• Acral lentiginous melanoma is the variant that presents in patients with darkly pigmented skin (its incidence is not UV-driven and is roughly equal across skin types); look for Hutchinson sign — pigment extending onto the proximal nail fold — to separate subungual melanoma from a hematoma, which migrates distally with nail growth.
• The transplant patient association: chronic immunosuppression flips the usual pattern so SCC outnumbers BCC and behaves aggressively. Similarly, SCC arising in a burn scar or chronic sinus tract is a Marjolin ulcer.
• Hypercalcemia + a large ulcerated skin lesion = PTHrP from SCC, not bone metastasis; BCC metastasizes very rarely (<1%) but is locally destructive — which is why advanced or truly metastatic BCC is the niche for hedgehog inhibitors.
• Melanoma is a classic cause of metastasis to the small bowel and to the brain, and brain metastases are prone to hemorrhage.
• Mohs micrographic surgery is the answer for high-risk facial/periorificial, recurrent, or poorly defined NMSC because it gives complete circumferential margin assessment with maximal tissue sparing (AAD/NCCN appropriate-use criteria) — cryotherapy or 5-FU on a nasal-ala BCC is the trap.