Skin & Subcutaneous Tissue

Melanoma: ABCDE, staging, and management

Clinical Overview and When to Suspect Melanoma

— Fair skin (Fitzpatrick I–II), red/blonde hair, blue eyes, freckling, inability to tan

— History of blistering sunburns, intermittent intense UV exposure, tanning bed use (especially before age 35)

— ≥50 common nevi or ≥5 atypical nevi; congenital nevi >20 cm

— Personal or family history of melanoma (CDKN2A, BAP1, MC1R variants)

— Immunosuppression (transplant, HIV), prior non-melanoma skin cancer, xeroderma pigmentosum

— Age >50, male sex (truncal lesions in men, lower extremity in women)

— A "changing mole" reported by patient or noticed during full-body skin exam

— New pigmented lesion in adulthood, especially after age 40

— Ulcerated, bleeding, or itching pigmented lesion

— Subungual pigmented streak (Hutchinson sign), pigmented oral/genital lesion

— Solitary enlarging lesion that looks different from the patient's other moles ("ugly duckling sign")

— USPSTF: insufficient evidence (I statement) for routine visual skin cancer screening in average-risk asymptomatic adults

— High-risk patients (FH of melanoma, dysplastic nevus syndrome, transplant, prior melanoma) — periodic full-body skin exam by dermatology, often with dermoscopy and total-body photography

Board pearl: On Step 3, any adult with a pigmented lesion that is new, changing, symptomatic, or different from the rest warrants excisional biopsy — not shave, not punch through the center, not "watch and reassure."

Definition: Malignant neoplasm of melanocytes, most commonly cutaneous but also mucosal, ocular (uveal), and acral. Accounts for ~1% of skin cancers but the majority of skin cancer deaths due to early metastatic potential.

Epidemiology and risk factors:

When to suspect on Step 3 stems:

Screening posture:

Why early detection matters: 5-year survival drops from >99% (localized, thin) to <35% (distant metastatic). Depth of invasion at diagnosis is the single most important modifiable prognostic factor.

Presentation Patterns and Key History

— Asymmetry: one half does not mirror the other

— Border irregularity: notched, scalloped, or poorly defined edges

— Color variegation: multiple shades of brown, black, red, white, blue

— Diameter >6 mm (pencil eraser); useful but melanomas can be smaller

— Evolution: change in size, shape, color, elevation, or new symptoms (itch, bleed) — most sensitive single feature

— Superficial spreading (~70%): trunk in men, legs in women; horizontal growth phase; classic ABCDE lesion

— Nodular (~15%): rapidly growing, often amelanotic, ulcerated or bleeding; vertical growth from onset → worse prognosis

— Lentigo maligna: sun-damaged face/scalp of elderly; slow-growing tan-brown macule with irregular borders

— Acral lentiginous: palms, soles, subungual — most common subtype in patients with darker skin (Black, Asian, Hispanic). Look for Hutchinson sign (pigment extending onto proximal nail fold) and longitudinal melanonychia >3 mm wide or changing

— Mucosal: oral, sinonasal, anogenital — often presents late

— Duration of lesion, recent change, symptoms (itch, pain, bleed, crust)

— UV exposure: sunburn history, tanning bed use, outdoor occupation, latitude of residence

— Personal/family history of melanoma or pancreatic cancer (CDKN2A), immunosuppression

— Constitutional symptoms (weight loss, bone pain, headache, vision change) suggesting metastatic disease

— Review of systems for in-transit nodules or palpable lymphadenopathy

Key distinction: Nodular melanoma frequently lacks classic ABCDE features. Use the EFG criteria (Elevated, Firm, Growing for >1 month) to avoid missing it — a stem describing a "rapidly enlarging dome-shaped pink nodule" is nodular melanoma until proven otherwise.

The ABCDE criteria — screening mnemonic for pigmented lesions:

"Ugly duckling" sign: a nevus that looks qualitatively different from the patient's other moles — often outperforms ABCDE in dermoscopy studies.

Subtype-specific clues:

Key history to elicit:

Physical Exam Findings and Lymph Node Assessment

— Patient fully undressed in gown; examine scalp, retroauricular areas, interdigital web spaces, palms/soles, nails, genitalia, perianal area, oral mucosa

— Use good lighting; dermoscopy improves sensitivity and specificity vs naked eye

— Document concerning lesions with measurement, photography, and anatomic mapping

— Asymmetry, irregular notched borders, ≥2 colors, diameter >6 mm

— Ulceration, bleeding, crusting, satellite pigmentation

— Loss of skin lines on dermoscopy; atypical pigment network, blue-white veil, irregular streaks/dots, regression areas

— Hutchinson sign: pigment on proximal/lateral nail fold from subungual melanoma

— Palpate draining basin based on lesion location: cervical/supraclavicular (head/neck), axillary (upper extremity, upper trunk), inguinal (lower extremity, lower trunk), epitrochlear, popliteal

— Note size, firmness, fixation, tenderness

— Examine skin between primary site and nodal basin for in-transit metastases (pigmented or pink papules along lymphatic pathway)

— Hepatomegaly (liver metastases), focal neuro deficits (brain metastases — melanoma has high CNS tropism)

— Bone tenderness, dyspnea (lung), abdominal mass

— Ocular exam in suspected uveal melanoma: leukocoria, visual field defects, asymmetric iris pigmentation

Step 3 management: If you palpate a clinically suspicious regional lymph node in a patient with melanoma, the next step is ultrasound-guided fine-needle aspiration (FNA) of the node — not sentinel lymph node biopsy. Confirmed nodal disease changes the patient from sentinel biopsy candidate to therapeutic completion lymphadenectomy or close nodal ultrasound surveillance + systemic therapy workup.

Full-body skin examination technique:

Lesion characteristics that raise suspicion:

Regional lymph node exam — mandatory in every suspected/confirmed melanoma:

Systemic exam for advanced disease:

Documentation pearl: record Breslow-relevant impression (flat vs raised), ulceration, dimensions in mm — pathology depth is the determinant but clinical features guide biopsy strategy.

Diagnostic Workup — Biopsy Technique and Initial Pathology

— Narrow margin (1–3 mm) of normal-appearing skin

— Includes subcutaneous fat to allow accurate Breslow depth measurement

— Orient excision along skin tension lines or future wide-excision/lymphatic drainage axis

— Full-thickness punch biopsy of the most atypical/thickest area

— Deep saucerization (broad shave) extending into reticular dermis — acceptable if depth is captured

— Avoid superficial shave biopsy — risk of transecting the base and underestimating Breslow depth, which alters staging and management

— Incisional partial sampling of small lesions

— Cryotherapy or electrodessication of a pigmented lesion without histology

— Re-excising before initial pathology is reviewed

— Breslow thickness in mm (granular layer to deepest tumor cell) — the single most important prognostic variable

— Ulceration (present/absent) — upstages tumor within each T category

— Mitotic rate (per mm²) — no longer formal staging criterion in AJCC 8 but still prognostic

— Margins (peripheral and deep), Clark level (largely historical), regression, lymphovascular invasion, neurotropism

— Histologic subtype, microsatellites

Board pearl: A stem showing a pigmented lesion managed by shave biopsy returning "melanoma, base involved" — the next step is wide local re-excision with sentinel lymph node biopsy planning, because Breslow depth is unreliable when the base is transected. Document this limitation in your reasoning.

Biopsy is the diagnostic gold standard. No imaging or lab can diagnose melanoma — tissue is required.

Preferred technique: full-thickness excisional biopsy

Acceptable alternatives when excisional is impractical (face, ear, palm, sole, large lesion):

Avoid:

Key pathology elements reported (AJCC 8th edition drivers):

Molecular testing (advanced/metastatic): BRAF V600 mutation status (≈50%), NRAS, c-KIT (acral/mucosal). Drives targeted therapy selection.

Diagnostic Workup — Staging Studies and AJCC Framework

— T (primary tumor): based on Breslow thickness and ulceration

– T1a: ≤0.8 mm, no ulceration; T1b: ≤0.8 mm with ulceration OR 0.8–1.0 mm

– T2: >1.0–2.0 mm; T3: >2.0–4.0 mm; T4: >4.0 mm (each subdivided a/b by ulceration)

— N: number of involved nodes, microscopic vs clinically detected, presence of in-transit/satellite/microsatellite disease

— M: distant metastases — M1a (skin/non-regional nodes), M1b (lung), M1c (other visceral), M1d (CNS); each subdivided by LDH (normal "0" vs elevated "1")

— Stage 0 (in situ) and Stage I (≤1 mm, no concerning features): no routine imaging or labs; history and exam only

— Stage IIB–IIC and beyond, or sentinel node positive: baseline cross-sectional imaging — CT chest/abdomen/pelvis with contrast and MRI brain with contrast (or PET/CT + brain MRI)

— Symptom-directed imaging at any stage for new neurologic, pulmonary, or bone complaints

— Discuss/offer for T1b–T2 (typically 0.8–1.0 mm with ulceration, or >1.0 mm) and higher

— Consider for T1a with high-risk features (high mitotic rate, young patient, deep margin involvement)

— Performed at the time of wide local excision

— Positive SLNB → no longer mandates completion lymphadenectomy (MSLT-II) — nodal ultrasound surveillance is now standard, plus consideration of adjuvant systemic therapy

Key distinction: Imaging in thin (Stage I/IIA) melanoma is not indicated — overuse leads to false positives and unnecessary biopsies. Reserve CT/MRI for ≥Stage IIB, node-positive disease, or symptom-driven workup.

AJCC 8th edition TNM staging (high-yield framework):

Imaging — stage-driven, not routine for thin melanomas:

Sentinel lymph node biopsy (SLNB) — staging tool, not therapeutic:

Labs: LDH for stage IV (independent prognostic factor in M designation); CBC/CMP as baseline before systemic therapy.

Risk Stratification and Management Logic by Stage

— Wide local excision with 0.5–1.0 cm margins

— No SLNB, no imaging

— Lentigo maligna on cosmetically sensitive areas: consider staged excision (Mohs with melanoma immunostains) or topical imiquimod if surgery contraindicated

— Wide local excision with 1 cm margins

— SLNB discussed for T1b; generally not for T1a unless high-risk features

— No adjuvant systemic therapy; no routine imaging

— Wide local excision margins: 1–2 cm for 1.01–2.0 mm; 2 cm for >2.0 mm (deeper margins do not improve survival beyond 2 cm)

— SLNB offered

— Stage IIB/IIC: adjuvant anti–PD-1 (pembrolizumab or nivolumab) now FDA-approved based on KEYNOTE-716; baseline staging imaging warranted

— Wide local excision + management of nodal basin (SLNB → nodal US surveillance, or therapeutic lymphadenectomy if clinically detected)

— Adjuvant systemic therapy standard: anti–PD-1 monotherapy (nivolumab, pembrolizumab) or dabrafenib + trametinib if BRAF V600-mutant

— Consider clinical trial enrollment

— Systemic therapy is primary modality (see chunk 7)

— Oligometastatic disease: consider metastasectomy, SRS for brain mets

— Palliative radiation for symptomatic lesions; supportive care integration

Step 3 management: For a 1.5 mm non-ulcerated melanoma with negative clinical nodes, the next steps are wide local excision with 1–2 cm margins + SLNB at the same operation. Do not delay surgery for staging CT in clinically node-negative Stage II.

Stage 0 (melanoma in situ):

Stage I (≤1.0 mm, T1a/T1b without nodal disease):

Stage II (>1.0 mm, node-negative):

Stage III (regional nodal or in-transit disease):

Stage IV (distant metastatic):

Decision drivers: Breslow depth, ulceration, nodal status, BRAF status, LDH, performance status, comorbidities, patient preferences.

Pharmacotherapy — Systemic Therapy for Advanced Melanoma

— Anti–PD-1 monotherapy: nivolumab or pembrolizumab — preferred for adjuvant Stage IIB/IIC/III and many Stage IV patients

— Combination ipilimumab (anti-CTLA-4) + nivolumab: higher response rate (~58%) and superior OS in metastatic disease, especially brain metastases and high LDH, but ~55% grade 3–4 immune-related adverse events

— Relatlimab (anti-LAG-3) + nivolumab: newer combination with better toxicity profile than ipi/nivo

— Dabrafenib + trametinib, encorafenib + binimetinib, or vemurafenib + cobimetinib

— Rapid responses, useful for symptomatic bulky disease; durability less than immunotherapy

— Adjuvant: dabrafenib + trametinib for Stage III BRAF-mutant

— Dermatitis, colitis (watery diarrhea → hold drug, rule out infection, start steroids if grade ≥2), hepatitis (transaminitis), pneumonitis (new dyspnea/cough → CT, hold drug, steroids)

— Endocrinopathies: hypophysitis, thyroiditis (transient hyperthyroidism → hypothyroidism), adrenal insufficiency, type 1 diabetes — often permanent, replace hormones

— Myocarditis (rare, high mortality — troponin/BNP/ECG for symptoms), nephritis, neuropathy

— Grade 1: continue with monitoring; Grade 2: hold, prednisone 0.5–1 mg/kg; Grade 3–4: hold/permanently discontinue, prednisone 1–2 mg/kg ± infliximab or MMF

Board pearl: A patient on pembrolizumab develops watery diarrhea 6× daily — stop the drug, check stool studies (rule out C. difficile and infectious causes), start IV methylprednisolone, and consult GI for possible colonoscopy. Do not simply give loperamide.

Immune checkpoint inhibitors (first-line for most metastatic and high-risk adjuvant disease):

BRAF/MEK targeted therapy (for BRAF V600-mutant tumors, ~50%):

Immune-related adverse events (irAEs) — Step 3 must-knows:

Targeted therapy toxicities: pyrexia (dabrafenib classic), rash, photosensitivity (vemurafenib), cutaneous SCC, retinopathy and decreased LVEF (MEK inhibitors), QT prolongation.

Surgical Management and Locoregional Therapies

— Margins based on Breslow depth (measured from biopsy):

– In situ: 0.5–1.0 cm

– ≤1.0 mm: 1 cm

– 1.01–2.0 mm: 1–2 cm

– >2.0 mm: 2 cm

— Excise down to but not including the deep muscular fascia

— Wider margins do not improve survival; aim for cosmetic/functional balance

— Performed at WLE using radiotracer (technetium) ± blue dye injected around primary site

— Identifies first-echelon node; pathology with immunostains (S100, SOX10, HMB-45, Melan-A)

— Positive SLNB → nodal basin ultrasound surveillance every 4 months × 2 years, then less frequently (MSLT-II showed no OS benefit to immediate completion lymphadenectomy)

— Adjuvant systemic therapy discussion triggered

— Reserved for clinically/radiographically detected nodal disease confirmed by FNA, bulky disease on surveillance US, or patient preference

— Higher lymphedema risk (especially inguinal), wound complications

— Surgical excision if limited

— Intralesional talimogene laherparepvec (T-VEC) — oncolytic HSV-1 injection

— Isolated limb perfusion/infusion with melphalan for extensive limb disease

— Radiation for unresectable disease

CCS pearl: After excisional biopsy returns 1.6 mm non-ulcerated melanoma, your CCS order set is: dermatology/surgical oncology consult, wide local excision with 1–2 cm margins + SLNB, baseline CMP/LDH, counsel on sun protection, schedule postop follow-up at 2 weeks.

Wide local excision (WLE) — definitive treatment of primary:

Sentinel lymph node biopsy (SLNB):

Completion lymph node dissection (CLND):

In-transit metastases:

Metastasectomy: consider for solitary or oligometastatic lung, GI, or soft tissue lesions in patients with good performance status and controlled extracranial disease.

Stereotactic radiosurgery (SRS): preferred for limited brain metastases; whole-brain radiation reserved for diffuse disease.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher melanoma incidence and worse stage-specific mortality — biology more aggressive, often thicker at presentation, more head/neck primaries

— Lentigo maligna melanoma disproportionately affects this group

— Decision-making for SLNB: weigh life expectancy, comorbidities, functional status; SLNB still appropriate in fit elderly patients but may be deferred if it would not change management

— Wide local excision tolerated well even in 80s/90s under local anesthesia for most lesions

— Geriatric assessment before systemic therapy (frailty, polypharmacy, falls)

— Anti–PD-1 monotherapy generally well tolerated and not dose-adjusted for age

— Avoid ipilimumab combinations when frailty or autoimmune disease present — irAE burden often unacceptable

— Monitor more closely for endocrine and colitis-related dehydration

— Checkpoint inhibitors: no dose adjustment for CKD; monitor for immune-related nephritis (rising creatinine, sterile pyuria) — hold drug, rule out other causes, steroids

— BRAF/MEK inhibitors: no formal renal adjustment but caution with severe impairment; monitor electrolytes

— Contrast imaging: weigh risk of contrast-associated AKI against staging benefit; use MRI without contrast or non-contrast CT when appropriate

— Vemurafenib, dabrafenib, encorafenib undergo hepatic metabolism — caution and monitoring with elevated LFTs; dose reductions per package insert in severe impairment

— Checkpoint inhibitors: baseline AST/ALT; immune-mediated hepatitis is a known irAE — grade 2+ → hold drug, steroids, hepatology if not resolving

— Avoid hepatotoxic adjuncts (acetaminophen >2 g/day, alcohol) during targeted therapy

Step 3 management: An 82-year-old with multiple comorbidities and a 1.2 mm melanoma — proceed with wide local excision under local anesthesia, and have a shared decision-making conversation about SLNB rather than reflexively skipping it; age alone is not a contraindication.

Elderly patients (>70 years):

Immunotherapy in elderly:

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Skin of Color

— Melanoma is among the most common malignancies diagnosed in pregnancy; pregnancy itself does not worsen prognosis stage-for-stage

— Excisional biopsy and wide local excision under local anesthesia are safe in all trimesters

— SLNB: technetium-99m sulfur colloid has minimal fetal radiation exposure and is generally considered safe; blue dye (isosulfan/methylene blue) should be avoided due to anaphylaxis risk and unclear fetal safety

— Staging imaging: MRI without gadolinium preferred; defer CT/PET when possible until postpartum

— Systemic therapy: immunotherapy and BRAF/MEK inhibitors are contraindicated in pregnancy — delay until postpartum or consider therapeutic termination discussion in advanced disease

— Counsel on transplacental metastasis (rare but possible with melanoma — placental and neonatal exam at delivery)

— Rare; often presents atypically — amelanotic, nodular, mimics warts or pyogenic granulomas

— Use modified ABCD criteria: Amelanotic, Bleeding/Bump, Color uniformity, De novo/any Diameter

— Spitz nevi can be diagnostically challenging — refer to pediatric dermatopathology

— Associated with xeroderma pigmentosum, giant congenital nevi, immunosuppression

— Treatment principles mirror adult disease; SLNB performed when indicated

— Lower overall incidence but higher mortality due to later-stage presentation

— Acral lentiginous melanoma is most common subtype — palms, soles, subungual, mucosal sites

— Examine these "hidden" sites carefully; longitudinal melanonychia >3 mm, dark, irregular, or with Hutchinson sign warrants biopsy

— Avoid the cognitive bias of "melanoma is a white-patient disease"

Board pearl: Pregnant patient with a suspicious mole — do the excisional biopsy now. Delaying biopsy until postpartum is a common wrong answer and can cost survival.

Pregnancy:

Pediatric melanoma:

Skin of color (Fitzpatrick IV–VI):

Complications and Adverse Outcomes

— Local recurrence at primary site — usually within 2–3 years; suggests inadequate margins or aggressive biology

— In-transit metastases — pigmented or pink nodules along lymphatic channels between primary and nodal basin

— Regional nodal recurrence — most common pattern of relapse after negative SLNB

— Distant metastases: lung (most common visceral), liver, brain (high CNS tropism — ~50% of metastatic patients develop brain mets), bone, GI tract (small bowel — can cause intussusception, obstruction, bleeding), skin/soft tissue

— Late recurrence (>10 years) is well documented in melanoma — long-term surveillance matters

— Surgical: wound infection, dehiscence, lymphedema (especially inguinal CLND — up to 30%), seroma, nerve injury, cosmetic deformity

— SLNB-specific: allergic reaction to blue dye, lymphedema (~5%), false-negative results

— Immunotherapy irAEs: see chunk 7 — colitis, pneumonitis, hepatitis, endocrinopathies (often permanent), myocarditis, nephritis, dermatitis (severe forms include SJS/TEN, bullous pemphigoid)

— BRAF/MEK toxicities: pyrexia syndrome (dabrafenib), cutaneous SCC and keratoacanthomas (vemurafenib monotherapy — reduced by adding MEK inhibitor), retinopathy, cardiomyopathy (MEK), QT prolongation

— Radiation: dermatitis, fatigue, brain necrosis (SRS to large lesions)

— Fear of recurrence, body image after large excisions, cost of long-term immunotherapy

— Increased risk of second primary melanoma (~5%) and other skin cancers — lifetime surveillance

Key distinction: New-onset vitiligo in a melanoma patient on pembrolizumab is not a drug adverse event requiring discontinuation — it correlates with improved tumor response and survival. Reassure and continue therapy.

Disease-related complications:

Treatment-related complications:

Psychosocial:

Paraneoplastic syndromes: rare — vitiligo-like leukoderma (actually favorable prognostic sign during immunotherapy), melanoma-associated retinopathy.

When to Escalate Care — Consults, Inpatient Triage, and ICU

— Any suspicious pigmented lesion when primary care lacks biopsy capability or dermoscopy expertise

— Multiple atypical nevi, familial melanoma syndromes, prior melanoma — establish longitudinal surveillance

— All biopsy-confirmed invasive melanomas for WLE ± SLNB planning

— Consider expedited referral (within 2–4 weeks of diagnosis) — delays >90 days associated with worse outcomes

— Stage III and IV disease for systemic therapy planning

— Stage IIB/IIC (adjuvant anti–PD-1 candidates)

— BRAF testing coordination

— Symptomatic brain metastases with edema/seizures — admit, dexamethasone, MRI, neurosurgery/rad onc consult

— Bowel obstruction or GI bleeding from metastases

— Severe irAEs: grade 3–4 colitis with dehydration, pneumonitis with hypoxia, hepatitis with coagulopathy, suspected myocarditis (chest pain, troponin elevation, new arrhythmia), adrenal crisis

— Febrile neutropenia (rare with immunotherapy/targeted, but possible)

— Tumor lysis (uncommon in melanoma but reported with rapid-response BRAF inhibitors in bulky disease)

— Immune-related myocarditis — telemetry/CCU; mortality ~40–50%; high-dose steroids ± infliximab, MMF, plasmapheresis

— Respiratory failure from grade 4 pneumonitis

— Status epilepticus from CNS metastases

— Severe colitis with perforation or sepsis

CCS pearl: Patient on ipilimumab/nivolumab returns with new dyspnea and hypoxia 4 weeks into therapy — CCS orders: room air SpO2, CXR → CT chest, ABG, CBC/BMP, blood/sputum cultures, hold immunotherapy, start IV methylprednisolone 1–2 mg/kg, pulmonology consult. Empiric antibiotics if infection cannot be excluded.

Dermatology referral (outpatient):

Surgical oncology referral:

Medical oncology referral:

Radiation oncology: brain metastases (SRS), bone metastases, unresectable in-transit disease, palliative.

Inpatient admission criteria:

ICU triage:

Multidisciplinary tumor board: stage III/IV, atypical sites (mucosal, ocular), pregnancy, pediatric cases.

Key Differentials — Other Pigmented and Melanocytic Lesions

— Symmetric, uniform color, well-defined borders, stable over time, <6 mm

— Junctional (flat, dark), compound, intradermal (raised, skin-colored to light brown)

— Reassure; biopsy if any ABCDE change

— Larger (often >5 mm), irregular borders, color variegation, "fried-egg" appearance

— Marker for increased melanoma risk (especially in dysplastic nevus syndrome) but most do not transform

— Biopsy if changing; routine prophylactic excision of all atypical nevi is not recommended

— "Stuck-on" waxy, warty, well-circumscribed plaques in older adults

— Horn cysts and milia-like cysts on dermoscopy

— Can be heavily pigmented and mimic melanoma — when in doubt, biopsy

— Sign of Leser-Trélat (sudden eruption) — paraneoplastic association with GI adenocarcinoma

— Flat, uniformly pigmented macules on sun-exposed skin (face, dorsal hands)

— Differs from lentigo maligna by uniformity and stability

— Solitary, dome-shaped, deeply pigmented (blue-black) due to dermal melanocytes

— Stable; biopsy if changing or atypical (cellular blue nevus can rarely transform)

— Pink-red dome-shaped lesion, often in children/young adults

— Histologically can mimic melanoma — refer to dermatopathology

— Risk of melanoma proportional to size; giant CMN (>20 cm projected adult size) carry meaningful lifetime risk and warrant surveillance ± excision discussion

Key distinction: Seborrheic keratosis vs melanoma — SK has a "stuck-on" appearance with horn cysts on dermoscopy and uniform surface keratin; melanoma shows atypical pigment network, blue-white veil, or irregular streaks. When unsure, biopsy wins over reassurance.

Benign melanocytic nevi (common moles):

Dysplastic (atypical) nevi:

Seborrheic keratosis:

Solar lentigo:

Blue nevus:

Spitz nevus:

Congenital melanocytic nevi:

Melanoacanthoma, pigmented basal cell carcinoma: pigmented variants that mimic melanoma — biopsy distinguishes.

Key Differentials — Non-Melanocytic Mimics

— Pearly, telangiectatic papule with brown-black pigment

— More common in skin of color than classic BCC

— Dermoscopy: leaf-like areas, blue-gray ovoid nests, spoke-wheel structures

— Treatment: excision or Mohs; not typically metastatic

— Rare; can resemble melanoma when heavily pigmented

— Usually on sun-damaged skin, scaly/crusted

— Firm, brown-pink papule, "dimple sign" (lateral compression causes central dimpling)

— Lower extremities common; benign, no excision needed unless symptomatic

— Rapidly growing, friable, bleeding red papule — often mistaken for amelanotic nodular melanoma

— History of recent trauma, pregnancy association

— Always send for pathology after excision — amelanotic melanoma can present identically

— Trauma history, distal location, moves distally with nail growth over weeks

— Subungual melanoma is proximal, doesn't migrate, may have Hutchinson sign

— When in doubt: nail plate avulsion and biopsy of nail matrix

Board pearl: A patient brings in an "amelanotic" pink nodule that has grown over weeks and bleeds easily. Do not anchor on "pyogenic granuloma" — excise and send for pathology, because nodular amelanotic melanoma is the classic missed diagnosis at this presentation.

Pigmented basal cell carcinoma:

Squamous cell carcinoma (pigmented variant):

Dermatofibroma:

Pyogenic granuloma:

Subungual hematoma:

Tinea nigra: superficial dematiaceous fungal infection of palms/soles — KOH prep distinguishes from acral melanoma

Talon noir (black heel): punctate hemorrhage from trauma in athletes; paring with a #15 blade reveals red-brown punctate hemorrhage, not pigment

Fixed drug eruption, post-inflammatory hyperpigmentation, café-au-lait macules: usually distinguishable by history and pattern.

Kaposi sarcoma: violaceous patches/plaques, immunocompromised patients (HIV, transplant) — biopsy reveals HHV-8.

Secondary Prevention, Survivorship, and Long-Term Plan

— Broad-spectrum sunscreen SPF ≥30, applied 15–30 min before exposure and reapplied every 2 hours or after swimming/sweating

— Protective clothing (UPF-rated), wide-brimmed hats, UV-blocking sunglasses

— Avoid peak UV hours (10 AM–4 PM); seek shade

— Strict avoidance of tanning beds — Class I carcinogen (IARC); discuss especially with adolescents and young women

— Vitamin D supplementation if sun avoidance leads to deficiency

— Monthly full-body self-exam using mirrors or partner assistance

— Mole-mapping apps and photographic baselines for high-risk patients

— Teach ABCDE and ugly-duckling concepts

— First-degree relatives at 2- to 8-fold increased risk — encourage dermatologic screening

— Genetic counseling/CDKN2A testing if 3+ melanomas in family, pancreatic cancer + melanoma, multiple primaries in one patient, or early-onset (<40) disease

— Patients with one melanoma have ~5% lifetime risk of a second; also increased risk of non-melanoma skin cancers

— Lifelong dermatologic surveillance

— Anti–PD-1 adjuvant courses typically 12 months

— Dabrafenib/trametinib adjuvant for 12 months in BRAF-mutant Stage III

— Document stage, treatment, surveillance schedule, late-effect risks

— Mental health screening — anxiety/depression and fear of recurrence are common

— Smoking cessation, exercise, healthy weight — improve outcomes in cancer survivors

Step 3 management: At every melanoma survivor visit, your counseling checklist includes sun protection, self-skin exam education, family screening recommendations, and second-primary surveillance — these are testable secondary prevention measures.

UV protection — cornerstone of secondary prevention:

Self-skin examination:

Family counseling:

Risk reduction for second primary:

Adjuvant therapy continuation:

Survivorship care plan:

Follow-Up, Monitoring, and Rehabilitation

— Stage 0 (in situ): annual full skin exam indefinitely; patient self-exam monthly

— Stage IA–IIA: history and full skin/lymph node exam every 6–12 months for 5 years, then annually

— Stage IIB–IV: every 3–6 months for 2 years, then every 6–12 months through year 5, then annually

— Lifetime annual skin exam for all melanoma survivors

— No routine imaging for Stage I–IIA in asymptomatic patients

— Stage IIB and higher: consider CT chest/abdomen/pelvis and brain MRI every 6–12 months for 2–3 years, then as clinically indicated (institutional variation)

— Nodal basin ultrasound every 4 months × 2 years for positive-SLNB patients on observation, then every 6 months × years 3–5

— LDH for metastatic disease (prognostic, treatment response)

— On immunotherapy: TSH, AM cortisol, CMP, CBC before each cycle for first 6 months, then less frequently

— On BRAF/MEK: LFTs, ECG (QT), echo for MEK (LVEF), ophthalmology for retinal monitoring

— Lymphedema therapy — early referral to certified lymphedema therapist after CLND or pelvic/axillary radiation; compression garments, manual lymph drainage

— Wound care for surgical sites; scar revision as needed

— Physical therapy after extremity surgery

— Neurocognitive rehabilitation after brain metastasis treatment

— Pregnancy planning — generally advised to wait 2–3 years after high-risk melanoma diagnosis (period of highest recurrence), though data limited

— Contraception during/after teratogenic therapies (BRAF/MEK; checkpoint inhibitors also avoided in pregnancy)

— Vaccination on immunotherapy: inactivated vaccines (flu, COVID) safe; avoid live vaccines

CCS pearl: A Stage IIIB melanoma patient at year 1 follow-up — order full skin and lymph node exam, nodal basin ultrasound, LDH, and review/symptom-driven CT C/A/P + brain MRI, plus continue anti–PD-1 adjuvant and counsel on irAE symptoms.

NCCN-aligned surveillance schedule (depth-stratified):

Imaging surveillance:

Laboratory monitoring:

Rehabilitation and supportive care:

Counseling:

Ethical, Legal, and Patient Safety Considerations

— Discuss diagnostic uncertainty, possible need for re-excision, scar, risks of bleeding/infection

— For SLNB: explain that it is a staging procedure without proven survival benefit but informs prognosis and therapy selection (per MSLT-II)

— Document shared decision-making for borderline indications (e.g., T1a with mitoses)

— Disclose risk of permanent endocrinopathies (lifelong hormone replacement), potentially fatal myocarditis/pneumonitis, autoimmune sequelae

— Cost discussion — checkpoint inhibitors and combinations can exceed $150,000/year; verify insurance coverage and copay assistance

— Discuss alternatives, observation in select adjuvant scenarios, and clinical trials

— Biopsy result communication: failure to communicate a positive melanoma pathology report is a leading malpractice claim. Establish closed-loop systems — patient notified within 1–2 weeks, documented in chart, referral made

— Handoff between dermatology → surgical oncology → medical oncology must include staging summary, pathology, BRAF status, and pending studies

— Discharge after irAE admission: clear instructions on steroid taper, signs of recurrence, follow-up timing, primary care notification

— Melanoma pathology has known inter-observer variability — request dermatopathology second opinion for ambiguous or atypical Spitz lesions, or when management hinges on borderline findings

— Melanoma is a reportable cancer to state cancer registries (HIPAA-permitted disclosure)

— Stage IV melanoma — early palliative care integration (improves QOL and possibly survival); document advance directives, surrogate decision-maker, code status, and goals of care before crisis

Board pearl: The single highest-yield safety item: a melanoma biopsy result that returns positive must be communicated to the patient and a specialist referral placed with documented closed-loop confirmation — this is the type of transition-of-care lapse Step 3 loves to test.

Informed consent for biopsy and surgery:

Informed consent for immunotherapy:

Transitions of care — high-risk Step 3 territory:

Pathology error and "second look":

Mandatory reporting:

Capacity and end-of-life planning:

Sun exposure counseling and adolescents: legal restrictions on tanning bed use for minors exist in most US states — reinforce in clinic.

High-Yield Associations and Rapid-Fire Clinical Facts

Key distinction: Melanoma's CNS tropism is exceptional — always include brain MRI in staging of intermediate-to-high-risk disease and have a low threshold for imaging with new neuro symptoms.

ABCDE = Asymmetry, Border, Color, Diameter >6 mm, Evolution; EFG for nodular = Elevated, Firm, Growing

Breslow depth is the most important prognostic factor; ulceration upstages within each T category

Most common subtype overall: superficial spreading; most common in skin of color: acral lentiginous

Hutchinson sign: pigment on proximal nail fold → subungual melanoma

Most common site: men → back/trunk; women → lower extremities

Tanning beds before age 35 → ~75% increased melanoma risk

CDKN2A mutation (p16) — familial melanoma + pancreatic adenocarcinoma syndrome

BAP1 mutation — uveal melanoma, mesothelioma, renal cell carcinoma

BRAF V600E mutation present in ~50% of cutaneous melanomas → eligible for BRAF/MEK inhibitor therapy

Uveal melanoma — liver is the dominant metastatic site (unique among melanomas due to hematogenous spread from choroid)

Surgical margins by depth: in situ 0.5–1 cm; ≤1 mm = 1 cm; 1–2 mm = 1–2 cm; >2 mm = 2 cm

SLNB threshold: generally offered when Breslow >0.8 mm or T1b

MSLT-II: completion lymphadenectomy after positive SLNB does not improve overall survival vs nodal ultrasound surveillance

Vitiligo on immunotherapy → favorable prognostic marker

Dabrafenib + trametinib pyrexia — classic early adverse effect, manage with antipyretics and dose interruption

Vemurafenib monotherapy → cutaneous SCC and keratoacanthomas (paradoxical MAPK activation in BRAF-wild-type keratinocytes); reduced by adding MEK inhibitor

Ipilimumab + nivolumab combination — highest response rate, highest toxicity, preferred for brain metastases

Adjuvant therapy in Stage III: anti–PD-1 or dabrafenib/trametinib (BRAF-mutant) for 12 months

Most common visceral metastasis: lung; CNS tropism distinguishes melanoma from many other solid tumors

Lentigo maligna — sun-damaged elderly skin; slow horizontal growth phase, can be treated with staged excision or topical imiquimod when surgery contraindicated

Pregnancy + melanoma — biopsy safely with local anesthesia; defer systemic therapy until postpartum

Board Question Stem Patterns

— 55-year-old with a 7 mm asymmetric, irregularly bordered, multicolored back lesion that has changed. Next step: excisional biopsy with narrow margins. Wrong answers: shave biopsy, cryotherapy, reassurance, photodynamic therapy.

— Pathology shows "melanoma, base involved." Next step: wide local excision + SLNB; depth is unreliable, so plan based on worst-case scenario.

— "Rapidly growing pink-red dome-shaped nodule that bleeds." Don't fall for pyogenic granuloma — excise and send for pathology.

— Black patient with a 4 mm dark longitudinal nail streak and pigment on the nail fold (Hutchinson sign). Next step: nail matrix biopsy.

— Stage IIIA after positive SLNB. Next step: nodal ultrasound surveillance + discuss adjuvant anti–PD-1 (or BRAF/MEK if mutant). Wrong answer: routine completion lymphadenectomy.

— Patient on pembrolizumab develops 8 watery stools/day, abdominal cramping. Next step: hold drug, stool studies (rule out C. difficile), start IV methylprednisolone, GI consult. Continued loperamide alone is wrong.

— Patient on ipi/nivo develops fatigue, hypotension, hyponatremia. Diagnosis: immune-mediated hypophysitis or adrenal insufficiency — check AM cortisol, ACTH, TSH, free T4; stress-dose hydrocortisone if crisis.

— 28-week pregnant patient with suspicious mole. Next step: excisional biopsy under local anesthesia now — do not delay.

— Stage IIA at year 2: history, full skin/LN exam every 6–12 months, no routine imaging in asymptomatic patient.

— Headache and focal deficit in known Stage IV melanoma. Next step: MRI brain with contrast, dexamethasone for edema, neurosurgery/radiation oncology consult for SRS.

Step 3 management: When stems mix derm exam, biopsy choice, irAE recognition, and surveillance cadence — the right answer almost always involves definitive tissue diagnosis first, stage-appropriate next step second, and recognition of immunotherapy toxicity patterns third.

Stem 1 — Classic ABCDE recognition:

Stem 2 — Shave biopsy underestimates depth:

Stem 3 — Nodular amelanotic melanoma:

Stem 4 — Acral lentiginous in skin of color:

Stem 5 — Sentinel node positive, what now:

Stem 6 — Immunotherapy adverse effect:

Stem 7 — Endocrinopathy:

Stem 8 — Pregnancy:

Stem 9 — Surveillance:

Stem 10 — Brain metastases:

One-Line Recap

Melanoma is a melanocyte-derived malignancy whose outcome hinges on early recognition via ABCDE/ugly-duckling assessment, accurate Breslow-depth diagnosis by excisional biopsy, stage-appropriate wide local excision ± sentinel lymph node biopsy, and integration of anti–PD-1 immunotherapy or BRAF/MEK-targeted therapy for advanced disease — all anchored in lifelong sun protection, surveillance, and vigilant management of immune-related adverse events.

Board pearl: If a Step 3 stem combines a "changing pigmented lesion" with any choice between shave, punch-through-center, or excisional biopsy — the answer is narrow-margin excisional biopsy, and from that single decision flows correct staging, correct surgery, and correct systemic therapy.

Diagnosis: Excisional (full-thickness) biopsy — never shave through a pigmented lesion suspicious for melanoma; Breslow depth and ulceration drive staging.

Surgery: Wide local excision margins scale with depth (in situ 0.5–1 cm; ≤1 mm = 1 cm; 1–2 mm = 1–2 cm; >2 mm = 2 cm); offer SLNB for T1b and above; post-MSLT-II, positive SLNB → nodal US surveillance, not routine completion dissection.

Systemic therapy: Adjuvant anti–PD-1 for Stage IIB/IIC/III; metastatic disease → checkpoint inhibitors (nivolumab, pembrolizumab, or ipi/nivo combination, particularly for brain mets) and BRAF/MEK inhibitors for V600-mutant tumors; recognize and manage irAEs with prompt drug hold and corticosteroids.

Surveillance and prevention: Stage-stratified follow-up (every 3–6 months for high-risk; every 6–12 months for low-risk), lifetime skin exams, sun protection, tanning bed avoidance, family screening for CDKN2A and high-risk pedigrees; ensure closed-loop communication of biopsy results — the highest-yield Step 3 safety lesson in melanoma care.