Skin & Subcutaneous Tissue

Squamous cell carcinoma: recognition and management

Clinical Overview and When to Suspect Cutaneous SCC

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

— Age >50, male sex, outdoor occupation, tanning bed use

— Chronic immunosuppression: solid organ transplant recipients (SOTRs) have 65–100× risk; HIV, CLL, long-term azathioprine/voriconazole

— Prior actinic keratoses (AKs) — ~1–10% transformation risk per lesion over years; field cancerization concept

— HPV (especially types 16/18) in anogenital and periungual SCC

— Chronic wounds/scars (Marjolin ulcer in burn scars, osteomyelitis sinuses)

— Arsenic exposure, ionizing radiation, PUVA therapy

— Genodermatoses: xeroderma pigmentosum, epidermolysis bullosa, oculocutaneous albinism

— Any non-healing scaly papule, plaque, or ulcer on sun-exposed skin (face, ears, scalp, dorsal hands, lower lip) lasting >4–6 weeks

— Rapidly enlarging hyperkeratotic nodule, especially tender or bleeding

— New lesion arising within an AK, scar, or chronic ulcer

— Lower lip lesion in a smoker (actinic cheilitis → SCC)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer after basal cell carcinoma, with ~1 million US cases annually and rising incidence in older adults.

Arises from keratinocytes of the epidermis; driven primarily by cumulative UV exposure (UVB > UVA) causing TP53 mutations.

Key risk factors to flag in any primary care visit:

When to suspect at the family medicine visit:

Board pearl: The single highest-yield Step 3 trigger for cSCC is a non-healing, indurated, hyperkeratotic lesion on the ear, lip, or dorsal hand of an older fair-skinned patient or a transplant recipient on tacrolimus/MMF. These locations carry higher metastatic risk.

Step 3 management: Do not "watch and rewick" suspicious lesions — perform or refer for biopsy at the index visit rather than empirically treating as eczema or wart. Documenting size, location, and photos supports continuity and medicolegal protection.

Presentation Patterns and Key History

— Actinic keratosis (AK): rough, sandpaper-like, erythematous macule/papule; often "felt before seen"; sun-exposed sites

— SCC in situ (Bowen disease): well-demarcated, scaly erythematous patch or plaque, often mistaken for eczema/psoriasis; can occur on non-sun-exposed skin

— Invasive cSCC: firm, indurated, hyperkeratotic papule/nodule, often ulcerated with rolled borders and a central keratin plug

— Keratoacanthoma: rapidly growing dome-shaped nodule with central keratin crater; considered a well-differentiated SCC variant — treat as SCC

— Verrucous SCC: cauliflower-like, slow-growing (oral, plantar “epithelioma cuniculatum,” anogenital)

— Marjolin ulcer: SCC arising in a chronic wound, burn scar, or sinus tract — aggressive

— Duration, growth rate, bleeding, pain, paresthesias (perineural invasion clue)

— Prior skin cancers (single biggest predictor of next one — ~50% 5-yr recurrence-of-any-NMSC rate)

— Immunosuppression: transplant date, regimen (voriconazole, azathioprine ↑ risk), HIV CD4, chemotherapy

— Occupational/recreational UV; tanning bed history; radiation therapy decades earlier

— HPV risk factors for genital/periungual lesions

— Family history (XP, albinism); arsenic in well water

cSCC has a clinical spectrum from precursor to invasive disease — recognizing the continuum is high-yield:

History elements to elicit:

Key distinction: BCC vs SCC — BCC is pearly, telangiectatic, slow-growing, rarely metastasizes; SCC is scaly, hyperkeratotic, tender, faster-growing, and can metastasize (especially ear, lip, scar, immunosuppressed).

Board pearl: A transplant recipient with multiple eruptive hyperkeratotic papules on dorsal hands/forearms has cSCC until proven otherwise — these patients develop SCC at 2–3× the rate of BCC (reverse of the general population).

Step 3 management: Document lesion mapping in the chart for high-risk patients; this guides surveillance intervals and supports referral justification.

Physical Exam Findings

— Depth and fixation to underlying tissue

— Tenderness (often present in SCC, rare in BCC)

— Surrounding satellite lesions or in-transit nodules

— Erythematous base + adherent hyperkeratotic scale

— Central ulceration with rolled, indurated borders

— Keratin horn or crusted plug

— Bleeding with minor trauma

— Cervical, preauricular, postauricular, occipital, submandibular for head/neck lesions

— Axillary for upper extremity; inguinal for lower extremity/genital

— Document size, mobility, tenderness

Inspection of the entire skin surface, scalp, ears (including post-auricular), vermilion lip, oral mucosa, dorsal hands, and nails — full-body skin exam (FBSE) is the standard high-risk approach.

Palpation is critical — SCC is typically indurated and firm, unlike the soft surface scale of eczema or seborrheic keratosis. Palpate for:

Classic morphology checklist:

High-risk anatomic "mask areas" (NCCN high-risk zones): central face, eyelids, eyebrows, periorbital, nose, lips, chin, mandible, preauricular/postauricular, temple, ear, genitalia, hands, feet.

Regional lymph node exam is mandatory for any biopsy-proven or strongly suspected invasive cSCC:

Neurologic exam if perineural symptoms (numbness, tingling, facial weakness, diplopia) — assess CN V and VII function for facial lesions.

Functional/cosmetic assessment: proximity to eyelid margin, lip vermilion, nasal ala, ear cartilage — affects surgical approach and need for Mohs.

Board pearl: Paresthesia, anesthesia, or motor weakness near a facial SCC = perineural invasion until proven otherwise → MRI with contrast and Mohs/multidisciplinary referral.

Key distinction: A palpable, fixed regional node in a patient with a head/neck SCC upstages disease to at least N1 and triggers FNA/core biopsy + cross-sectional imaging — do not aspirate-and-wait.

Step 3 management: In the ambulatory note, explicitly document size in mm, location, induration, ulceration, and node exam — these elements feed directly into AJCC/BWH staging and risk stratification.

Diagnostic Workup — Initial Evaluation and Biopsy

— Shave (tangential) biopsy: appropriate for most superficial/elevated lesions; quick, low-cost, adequate for diagnosis

— Punch biopsy (3–4 mm): for flat or pigmented lesions, or when depth assessment matters

— Excisional biopsy: small lesions in non-cosmetic areas; less common as initial step

— Incisional/wedge biopsy: large tumors — sample the thickest, most indurated area, not just the crusted edge

— CBC, BMP, LFTs if considering systemic therapy or in advanced disease

— HIV testing in unusual presentations or eruptive SCCs

— Tumor >2 cm, deep invasion, fixation to underlying structures

— Clinical or pathologic perineural invasion (especially named nerves)

— Palpable or suspected regional lymphadenopathy

— Recurrent disease or high-risk anatomic site (lip, ear, temple)

— CT neck with contrast — bony invasion, nodal disease, head/neck primaries

— MRI with contrast — perineural spread along V2/V3 or facial nerve; soft tissue depth

— PET-CT — selectively for advanced/metastatic staging

— Ultrasound + FNA of suspicious nodes

Skin biopsy is the diagnostic gold standard — no lab or imaging substitutes for tissue.

Biopsy technique selection:

Avoid superficial shaves that miss depth — pathology should report Breslow-like depth, differentiation, perineural invasion (PNI), and lymphovascular invasion (LVI).

Routine labs are not required for localized, low-risk cSCC. Order selectively:

Imaging is NOT routine for low-risk primary cSCC. Order cross-sectional imaging when:

Preferred imaging:

Board pearl: Pathology report must specify depth (>6 mm or invasion beyond subcutaneous fat) and PNI of nerves ≥0.1 mm — these are Brigham and Women's (BWH) high-risk staging criteria that predict nodal metastasis and recurrence.

CCS pearl: In the simulated case, order "skin biopsy, punch" of any non-healing >4-week scaly indurated lesion before prescribing topical steroids — the wrong move is empiric "triamcinolone" for "eczema."

Diagnostic Workup — Staging and Advanced Studies

— AJCC 8th edition (head and neck only): T1 ≤2 cm; T2 2–4 cm; T3 >4 cm or minor bone erosion or PNI or deep invasion (>6 mm or beyond subcutis); T4a gross cortical bone/marrow; T4b skull base/foramen

— Brigham and Women's (BWH) system: stratifies by 4 risk factors — tumor ≥2 cm, poorly differentiated, PNI of nerve ≥0.1 mm, invasion beyond subcutaneous fat (excluding bone, which is automatic T3). T2b (2–3 factors) carries ~20% nodal metastasis and ~30% recurrence risk

— Not standard in cSCC, unlike melanoma

— Consider for BWH T2b/T3 or AJCC T3/T4 high-risk tumors in multidisciplinary settings; evidence evolving

— FNA or core biopsy of palpable node

— CT neck with contrast is first-line imaging for H&N cSCC with adenopathy

— Multidisciplinary tumor board for advanced/regional disease

— Not routine; gene expression profiling (e.g., 40-GEP) is emerging but not yet a Step 3 standard

— Consider germline workup in young patients or multiple SCCs without UV exposure (xeroderma pigmentosum, Fanconi anemia)

— Anogenital/penile SCC — HPV testing, exam of cervix/anus, HIV screening

— Oral/lip SCC — full head and neck exam, ENT referral, panoramic dental imaging if bone concern

Two complementary staging systems for cSCC of head/neck — know both for Step 3:

Sentinel lymph node biopsy (SLNB):

Workup of suspected nodal disease:

Genetic/molecular testing:

Special workups:

Key distinction: High-risk cSCC features (any one): location on ear/lip/scar; size >2 cm on trunk/extremity or >1 cm on cheek/forehead/scalp/neck/pretibia or >0.6 cm on mask areas; depth >6 mm or beyond fat; PNI; poorly differentiated; recurrent; immunosuppressed host. One or more of these triggers Mohs and consideration of imaging.

Board pearl: Compared with AJCC, the BWH system more accurately predicts nodal metastasis and disease-specific death — high-yield trivia and increasingly cited in NCCN.

Risk Stratification and Management Logic

Low-risk cSCC features (all must be present):

— Trunk/extremity tumor <2 cm (or area-specific size cutoffs)

— Well-defined borders, primary (non-recurrent)

— Immunocompetent host, no PNI, no prior radiation field

— Well or moderately differentiated, depth ≤6 mm and confined to dermis

High-risk cSCC features (any one):

— Size above area-specific threshold

— Mask-area, ear, lip, genital location

— Recurrent, poorly defined, prior radiation

— Immunosuppressed (especially SOTR, CLL)

— Perineural, lymphovascular, or deep invasion (>6 mm or beyond fat)

— Poorly differentiated histology

Very high-risk: ≥2 high-risk features, BWH T2b/T3, gross bone invasion.

— AK (precursor): cryotherapy (single lesions), field therapy with 5-FU, imiquimod, tirbanibulin, PDT for multiple lesions

— SCC in situ: topical 5-FU/imiquimod, cryotherapy, electrodessication and curettage (ED&C) in non-hair-bearing sites, or excision

— Low-risk invasive cSCC: standard excision with 4–6 mm margins to subcutaneous fat; ED&C acceptable in select non-terminal-hair sites

— High-risk cSCC: Mohs micrographic surgery (MMS) is first-line — superior margin control, tissue conservation, lowest recurrence

— Advanced/unresectable: radiation ± systemic therapy; multidisciplinary referral

Treatment algorithm hinges on low-risk vs high-risk classification (NCCN):

Management mapping:

Step 3 management: Refer to dermatology/Mohs surgery for any high-risk cSCC, lesions on face/ears/lips/hands/genitalia, recurrent lesions, or transplant patients — do not attempt cryo or ED&C on invasive SCC at these sites.

Board pearl: Mohs > standard excision for high-risk cSCC due to 100% margin assessment and ~3% 5-year recurrence vs ~8% with standard excision.

Key distinction: AKs are treated with field therapy; invasive SCC requires surgical excision — never substitute topical 5-FU for biopsy-proven invasive disease.

Pharmacotherapy — Topical, Adjuvant, and Systemic

— 5-fluorouracil 5% cream BID × 2–4 weeks (face/scalp); expect brisk erythema, crusting — counsel patients this is the desired response, not a "reaction"

— Imiquimod 5% 5 nights/week × 6 weeks — TLR-7 agonist; induces inflammation, flu-like symptoms

— Tirbanibulin 1% ointment once daily × 5 days — newer microtubule inhibitor for facial/scalp AKs

— Diclofenac 3% gel BID × 60–90 days — gentler, slower

— Photodynamic therapy (PDT) with aminolevulinic acid + blue light — field treatment with excellent cosmesis

— Nicotinamide (vitamin B3) 500 mg PO BID — RCT evidence (ONTRAC): ~23% reduction in new NMSCs; well-tolerated

— Oral retinoids (acitretin 10–25 mg/day) — for transplant recipients with high tumor burden; teratogenic, hyperlipidemia, hepatotoxicity, mucocutaneous side effects; rebound on discontinuation

— First-line: anti-PD-1 immune checkpoint inhibitors

– Cemiplimab — FDA-approved for locally advanced or metastatic cSCC; ~45% response rate

– Pembrolizumab — alternative

— Second-line: EGFR inhibitors (cetuximab), platinum-based chemotherapy (cisplatin ± 5-FU), or clinical trial

— Avoid or use with hematology/transplant input in solid organ transplant recipients — high rejection risk

— Monitor for immune-related adverse events (irAEs): thyroiditis, hepatitis, colitis, pneumonitis, hypophysitis

Topical/field therapy for AK and SCC in situ:

Chemoprevention in high-risk patients (especially SOTRs and prior multiple SCCs):

Systemic therapy for advanced/metastatic/unresectable cSCC:

Cautions with checkpoint inhibitors:

Board pearl: Cemiplimab is the cSCC analog of pembrolizumab for melanoma — high-yield for advanced disease vignettes.

Step 3 management: When prescribing 5-FU or imiquimod, document expected inflammatory reaction, instruct sun protection, and schedule a 4–8 week follow-up to assess response and rule out persistent invasive disease.

Procedures — Surgical and Radiation Management

— 4–6 mm clinical margins to depth of mid-subcutaneous fat

— Larger margins (≥6 mm) for tumors >2 cm or moderately differentiated

— Permanent section histology; re-excise if margins positive

— Indications: high-risk anatomic sites (H-zone of face: central face, eyelids, nose, lips, ears, periorbital, temple), recurrent tumors, immunosuppressed patients, ill-defined borders, PNI, large/deep tumors

— Advantage: 100% peripheral and deep margin examination via frozen sections; tissue sparing

— Recurrence rates: primary cSCC ~3% at 5 years; recurrent cSCC ~10% (vs 23% with standard excision)

— Acceptable for small, low-risk, non-invasive SCC in situ in non-terminal-hair-bearing skin

— Avoid on lips, ears, scalp, beard, genitalia, and any invasive SCC

— Primary RT: for patients who decline or cannot tolerate surgery; older adults with extensive disease; cosmetically sensitive areas

— Adjuvant RT: post-excision for PNI of named nerves, positive/close margins not amenable to re-excision, T3/T4 tumors, extensive nodal disease (ENE)

— Avoid in genodermatoses (XP, Gorlin) and young patients (long-term carcinogenesis risk)

— Therapeutic neck dissection for clinically positive nodes

— Adjuvant RT for multiple positive nodes or extracapsular extension

— Concurrent cisplatin-based chemoradiation for advanced regional disease

Standard excision (low-risk cSCC):

Mohs micrographic surgery (MMS):

Electrodessication and curettage (ED&C):

Cryosurgery: appropriate for AKs and selected superficial SCC in situ; not for invasive disease

Radiation therapy (RT):

Lymph node management:

Reconstruction: primary closure, flaps, grafts — coordinate with Mohs/plastic surgery; delay reconstruction if margins uncertain.

CCS pearl: In a simulated case of biopsy-proven cSCC on the nasal ala, the correct order is "Refer to Mohs micrographic surgery" rather than "wide local excision in the office" — site-specific risk drives the procedure choice.

Board pearl: Mohs is NCCN category 1 for high-risk cSCC and the single best-answer for facial, recurrent, or transplant-patient SCC on Step 3.

Special Populations — Elderly and Renal/Hepatic Impairment

— Highest absolute incidence of cSCC; competing comorbidities affect treatment choice

— Apply life expectancy assessment — Lee or Schonberg indices, ePrognosis — before aggressive intervention

— For limited life expectancy + low-risk lesion: consider observation, topical therapy, or RT over major surgery

— For high-risk lesions even in elderly: Mohs under local anesthesia is well-tolerated and often the best functional choice

— Assess gait, cognition, polypharmacy before scheduling extensive reconstruction

— Anticoagulation: most dermatologic surgery can proceed without stopping warfarin/DOACs/aspirin — bleeding risk is lower than thromboembolic risk

— 5-FU systemic — dose-reduce in CKD; rarely used in cSCC outside advanced disease

— Cisplatin — significant nephrotoxicity; substitute carboplatin if CrCl <50–60 mL/min, or use cetuximab/cemiplimab

— Topical 5-FU: minimal systemic absorption; generally safe in CKD

— Acitretin: primarily hepatic clearance; routine monitoring of lipids and LFTs; can be used cautiously in CKD

— Cemiplimab: no renal dose adjustment needed

— Acitretin contraindicated in severe hepatic dysfunction; monitor LFTs at baseline, 4 weeks, then every 3 months

— Avoid 5-FU systemically in severe hepatic dysfunction

— Cemiplimab: monitor for immune hepatitis; hold for transaminitis ≥3× ULN

— Voriconazole in lung transplant recipients dramatically increases cSCC risk — switch to alternative azole when possible

— Hydrochlorothiazide — photosensitizing; cumulative dose associated with cSCC; consider alternatives in fair-skinned patients with cumulative use >50,000 mg

— BRAF inhibitors (vemurafenib) — paradoxically induce eruptive SCCs/KAs

Elderly patients (>75 years):

Frailty considerations:

Renal impairment:

Hepatic impairment:

Polypharmacy and SCC:

Board pearl: HCTZ and voriconazole are the two most board-tested medications associated with increased cSCC risk — both deserve substitution counseling in high-risk patients.

Step 3 management: For the frail elderly with a low-risk lesion, shared decision-making with documented goals of care is the right answer over default aggressive excision.

Special Populations — Transplant, Pregnancy, Pediatrics, HIV

— 65–100× risk of cSCC; SCC is the most common malignancy post-transplant

— Lesions are more aggressive, multifocal, and metastasize more often

— Annual full-body skin exam starting at transplant; every 3–6 months if prior NMSC

— Modify immunosuppression in patients with multiple SCCs: switch from calcineurin inhibitors (tacrolimus/CSA) or azathioprine to mTOR inhibitors (sirolimus, everolimus) in coordination with transplant team — reduces new SCC incidence

— Consider nicotinamide 500 mg BID and acitretin for chemoprevention

— Avoid checkpoint inhibitors when possible — high rejection risk

— cSCC is rare in pregnancy; UV-related cancers cluster in older patients

— Avoid: 5-FU (category D), imiquimod (limited data, generally avoided), acitretin (absolutely contraindicated — teratogenic for 3 years post-discontinuation), retinoids generally

— Surgical excision under local anesthesia (lidocaine ± epinephrine) is safe at any trimester

— Delay elective Mohs to second trimester when possible

— RT generally deferred until postpartum unless life-threatening

— Pediatric cSCC is rare; presence suggests genodermatosis — xeroderma pigmentosum (autosomal recessive, NER defect), epidermolysis bullosa, oculocutaneous albinism, Fanconi anemia, dyskeratosis congenita

— Aggressive photoprotection from birth; genetic counseling; multidisciplinary care

— Increased cSCC risk, especially with low CD4; behaves more aggressively

— Anogenital SCC strongly HPV-driven — screen with anal cytology in MSM and immunosuppressed

— Optimize ART; aggressive treatment of biopsy-proven SCC

Solid organ transplant recipients (SOTRs):

Pregnancy:

Pediatrics:

HIV:

CLL/lymphoma patients: baseline immune dysfunction → aggressive cSCC; manage like SOTRs.

Board pearl: A transplant patient with multiple eruptive SCCs → switch from tacrolimus to sirolimus, add nicotinamide ± acitretin, intensify skin surveillance — classic Step 3 answer.

Key distinction: Acitretin is absolutely contraindicated in pregnancy and for 3 years after discontinuation due to prolonged tissue storage — high-yield teratogen.

Complications and Adverse Outcomes

— Recurrence — 5-year rates: low-risk ~5%, high-risk up to 30%; Mohs lowers recurrence vs standard excision

— Cosmetic disfigurement and functional loss — especially nasal ala, eyelid (ectropion), lip (microstomia), ear

— Perineural invasion (PNI) — facial pain, paresthesia, anesthesia, motor deficits (CN V, VII); ~5% of cSCC have PNI; named-nerve PNI carries worst prognosis

— Bone or cartilage invasion — ear, scalp, nasal bridge

— Lymph node metastasis — overall ~4% of cSCC; rises to ~15–30% in high-risk lesions, lip cSCC, transplant patients, Marjolin ulcers

— In-transit metastases between primary and regional basin

— Parotid involvement — common nodal basin for facial/scalp/ear SCC

— Extracapsular extension (ENE) — independent risk factor for recurrence, indicates adjuvant chemoradiation

— Lungs (most common), liver, bone, brain

— Once metastatic, 5-year survival historically <20%, improving with cemiplimab

— Surgery: infection, bleeding, scarring, nerve injury, flap necrosis

— Radiation: acute dermatitis, mucositis, late soft tissue fibrosis, secondary malignancy, osteoradionecrosis

— 5-FU/imiquimod: brisk inflammatory reaction; rarely systemic absorption

— Acitretin: cheilitis, alopecia, hyperlipidemia, hepatotoxicity, teratogenicity, mood changes, hyperostosis

— Cemiplimab/pembrolizumab: irAEs — thyroiditis (most common), pneumonitis, colitis, hepatitis, hypophysitis, type 1 diabetes; rare myocarditis

— Body image, depression, fear of recurrence — particularly with facial lesions

— Address proactively; offer counseling/support resources

Local complications:

Regional complications:

Distant metastasis:

Treatment-related complications:

Psychosocial:

Board pearl: Lip SCC and ear SCC have the highest metastatic potential among cutaneous sites (~10–15%) and warrant aggressive workup and Mohs.

Step 3 management: A patient with biopsy-proven facial cSCC developing new ipsilateral facial paresthesia or weakness → MRI face with contrast to evaluate perineural spread + multidisciplinary referral.

When to Escalate Care — Consults and Multidisciplinary Triage

— Any biopsy-proven invasive cSCC, especially on H-zone face, ears, lips, hands, genitalia

— Recurrent or rapidly enlarging lesions

— Transplant or immunosuppressed patient with new suspicious lesion

— Multiple eruptive SCCs/keratoacanthomas

— High-risk anatomic sites, recurrent disease, ill-defined borders, immunosuppression, large size, deep or perineural invasion

— Palpable lymphadenopathy or imaging-detected nodal disease

— Deep facial/scalp invasion, parotid involvement

— Bone or cartilage involvement requiring complex resection

— Non-surgical candidates; adjuvant indications (PNI of named nerves, positive margins, multiple nodes, ENE)

— Recurrent disease after prior surgery

— Locally advanced unresectable, regional disease beyond surgical clearance, distant metastasis

— Coordinate cemiplimab/pembrolizumab; manage irAEs

— Bleeding from a fungating tumor not controllable in clinic

— Severe local infection/cellulitis requiring IV antibiotics

— Severe irAE from checkpoint inhibitor (e.g., immune colitis, hepatitis, pneumonitis, adrenal crisis)

— Postoperative complications (flap compromise, hematoma, necrotizing infection)

Dermatology referral (urgent):

Mohs surgeon:

Head and neck surgery / surgical oncology:

Radiation oncology:

Medical oncology:

Multidisciplinary tumor board: for advanced, recurrent, or metastatic cSCC; transplant patients with multiple/aggressive lesions

Transplant team: modify immunosuppression (switch to mTOR inhibitor) when SCC burden is high

Inpatient triage — uncommon but consider admission for:

Genetic counseling: young patients, multiple SCCs without UV exposure, family history suggestive of XP or other genodermatosis

CCS pearl: For a CCS case with biopsy-proven cSCC + palpable cervical node, the correct chain is "CT neck with contrast" → "FNA of node" → "ENT/Head & Neck Surgery consult" → "Multidisciplinary tumor board" — staging precedes treatment selection.

Board pearl: Adjuvant radiation is indicated after surgery for named-nerve PNI, positive/close margins not re-excisable, T3/T4 disease, or ≥2 positive nodes or ENE — a high-yield indication set.

Key Differentials — Other Skin Cancers and Neoplasms

— Pearly, translucent papule with telangiectasias, rolled borders; central ulceration ("rodent ulcer")

— Slow-growing, rarely metastasizes; locally destructive

— Subtypes: nodular, superficial, morpheaform/infiltrative (high-risk), pigmented

— Treatment: excision, Mohs for high-risk; topical 5-FU/imiquimod for superficial BCC; vismodegib/sonidegib for advanced

— Asymmetry, Border irregularity, Color variation, Diameter >6 mm, Evolution (ABCDE)

— Pigmented (rarely amelanotic — can mimic SCC); rapid growth in nodular subtype

— Treatment: wide local excision with margins based on Breslow depth; SLNB indicated for ≥0.8 mm

— Rapidly growing, dome-shaped, central keratin crater; may spontaneously involute

— Histologically and clinically considered a well-differentiated SCC variant — treat as SCC (excise; do not wait for involution)

— Rapidly growing, red-violaceous, painless nodule on sun-exposed skin of elderly

— Mnemonic AEIOU: Asymptomatic, Expanding rapidly, Immunosuppressed, Older >50, UV-exposed

— Polyomavirus-associated; high metastatic potential; SLNB indicated; avelumab/pembrolizumab for advanced

— Patches, plaques, tumors in non-sun-exposed sites; chronic course; multiple biopsies often needed

— Violaceous plaques/nodules in HIV/AIDS or elderly Mediterranean men; HHV-8 driven

Basal cell carcinoma (BCC):

Melanoma:

Keratoacanthoma (KA):

Merkel cell carcinoma:

Cutaneous lymphoma (mycosis fungoides):

Adnexal tumors: sebaceous carcinoma (eyelid — Muir-Torre), microcystic adnexal carcinoma; biopsy distinguishes.

Kaposi sarcoma:

Cutaneous metastasis from internal malignancy (breast, lung, GI) — firm dermal nodules; biopsy.

Key distinction: BCC is pearly and indolent; SCC is scaly, indurated, and can metastasize; melanoma is pigmented and asymmetric; Merkel is red, rapid, and elderly. Each has a distinct treatment algorithm — do not lump them as "skin cancer."

Board pearl: A violaceous, rapidly growing, painless nodule in an immunosuppressed elderly patient → think Merkel cell carcinoma, not SCC; biopsy + SLNB.

Key Differentials — Benign and Inflammatory Mimics

— Precursor, not yet invasive; rough scale on erythematous base

— Indistinguishable clinically from early SCC in situ — biopsy if thick, tender, bleeding, or persistent despite field therapy

— "Stuck-on," waxy, well-circumscribed brown papule/plaque with horn cysts

— Benign; no malignant potential; biopsy if changing, inflamed, or atypical

— Sign of Leser-Trélat: eruptive SKs → workup for underlying GI malignancy

— HPV-induced; hyperkeratotic papule with thrombosed capillaries (black dots); pares cleanly

— Periungual warts in immunosuppressed can transform — biopsy if persistent or atypical

— A morphologic description, not a diagnosis — base must be biopsied; ~40% are SCC/AK/SCC in situ at the base

— Friable, rapidly bleeding red papule; common in pregnancy, kids; benign vascular

— Symmetric, pruritic; responds to topical steroids — Bowen disease (SCC in situ) is often initially misdiagnosed as eczema or psoriasis that fails to respond to steroids

— Venous, arterial, pressure, diabetic — biopsy the edge if non-healing >3 months to rule out Marjolin ulcer

— Verrucous plaques; consider in endemic regions or immunosuppressed; tissue culture + histology

Actinic keratosis (AK):

Seborrheic keratosis (SK):

Verruca vulgaris (common wart):

Cutaneous horn:

Pyogenic granuloma:

Eczema/psoriasis:

Chronic non-healing ulcers:

Cutaneous tuberculosis, deep fungal (blastomycosis, sporotrichosis):

Atypical mycobacterial infection in fish-tank/aquarium exposures.

Hypertrophic lichen planus, prurigo nodularis: chronic pruritic hyperkeratotic nodules; biopsy when SCC suspected.

Step 3 management: Any "eczema" or "psoriasis" plaque that fails 4–6 weeks of appropriate topical therapy → biopsy, especially on sun-exposed skin or in older patients. This is a classic Bowen disease miss.

Board pearl: Biopsy the base of every cutaneous horn — clinically it's hyperkeratosis, but the underlying base is malignant in up to 40% of cases.

Secondary Prevention and Long-Term Plan

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

— Mineral (zinc/titanium) sunscreens preferred for sensitive skin and pediatrics

— Sun-protective clothing (UPF 50+), wide-brimmed hat, UV-blocking sunglasses

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

— No safe tanning bed use — counsel cessation; tanning beds increase cSCC risk ~67% with use before age 35

— Nicotinamide 500 mg PO BID — first-line for patients with ≥2 prior NMSCs; ~23% reduction in new lesions (ONTRAC trial); inexpensive, well-tolerated

— Acitretin — for transplant recipients with high tumor burden; specialist-directed

— Field therapy (5-FU, imiquimod) for AK burden — reduces progression to invasive SCC

— Reassess HCTZ, voriconazole, BRAF inhibitors — switch when feasible

— Optimize transplant immunosuppression toward mTOR inhibitors in patients with multiple SCCs

— Monthly head-to-toe; partner-assisted for back/scalp

— "ABCDE" for pigmented lesions; "new, changing, non-healing" for any lesion

— Provide photos and a body diagram

Single most important predictor of future SCC is prior SCC — secondary prevention is core to family medicine follow-up.

Sun protection counseling (USPSTF Grade B recommendation for fair-skinned 6 mo–24 yr; individualized for adults):

Chemoprevention in high-risk patients:

Medication review:

Smoking cessation — particularly relevant for lip SCC and oral SCC

HPV vaccination: routine for ages 9–26 (and shared decision-making 27–45); reduces anogenital and oropharyngeal SCC risk

Vitamin D counseling: address through oral supplementation rather than UV exposure

Patient self-skin exam (SSE):

Board pearl: Nicotinamide 500 mg BID (not regular niacin) is the high-yield chemopreventive answer for patients with recurrent NMSC — niacin causes flushing; nicotinamide does not.

Step 3 management: Document a written "skin cancer prevention plan" in the chart at the post-treatment visit — sunscreen, clothing, SSE, chemoprevention as indicated, and surveillance schedule — to support continuity and quality measures.

Follow-Up, Monitoring, and Surveillance Cadence

— Local (low-risk) cSCC: full-body skin exam every 3–12 months for 2 years, then every 6–12 months for 3 years, then annually for life

— High-risk or regional cSCC: every 2–3 months for year 1, every 2–4 months for year 2, every 4–6 months for years 3–5, then every 6–12 months for life

— Include regional lymph node palpation at every visit for high-risk and regional disease

— Acitretin: fasting lipids, LFTs at baseline, 4 weeks, then every 3 months; pregnancy test monthly in females of childbearing potential (and contraception for 3 years post-discontinuation)

— Cemiplimab/pembrolizumab: TSH, LFTs, CBC, glucose, cortisol/ACTH before each cycle; symptom-directed evaluation for irAEs

— 5-FU/imiquimod: clinical follow-up at 4–8 weeks to assess response; rebiopsy any persistent lesion

— Reinforce SSE and partner-assisted back exam monthly

— Review sun protection adherence and tanning bed avoidance

— Reassess photosensitizing medications

— Address depression, body image, and fear-of-recurrence

— Send a structured note to PCP after Mohs/excision with pathology, margin status, recurrence risk, surveillance plan

— Coordinate with transplant team on immunosuppression adjustments

— Reconcile chemopreventive medications

— Speech therapy and dental rehab after lip/oral resection

— Lymphedema referral after neck dissection

— Scar management (silicone sheets, massage, laser) at 6–12 weeks post-op

NCCN surveillance schedule for cSCC:

Imaging surveillance — not routine for low-risk; for high-risk regional disease, consider cross-sectional imaging (CT/MRI) every 3–6 months for the first 2 years.

Monitoring of medical therapy:

Counseling at follow-up:

Transition of care:

Rehabilitation:

Quality measures: documentation of biopsy before destruction, full-body skin exam in high-risk patients, chemoprevention counseling — track for value-based care.

Board pearl: The first 2 years after treatment carry the highest recurrence and new-primary risk — frequency of follow-up is front-loaded, not evenly spaced.

Step 3 management: Schedule the first follow-up at 1–3 months post-excision to confirm wound healing, review pathology with the patient, set the surveillance schedule, and start chemoprevention — a common CCS sequencing answer.

Ethical, Legal, and Patient Safety Considerations

— Document risks of excision/Mohs: bleeding, infection, scarring, nerve injury, recurrence, need for further surgery, reconstruction options

— Discuss alternatives including radiation and (for elderly/limited prognosis) observation — failure to discuss alternatives is a common malpractice claim

— Confirm capacity; use interpreter services for limited English proficiency — a family member is not an acceptable medical interpreter for consent

— Standard of care is biopsy-proven diagnosis before definitive treatment — cryotherapy or ED&C of a clinically suspected SCC without biopsy is a patient safety and medicolegal pitfall

— Implement a closed-loop result notification system — every biopsy must have documented patient notification; missed SCC diagnoses due to communication failure are a leading source of dermatology malpractice

— Send results in writing via portal/letter + phone for high-risk findings

— When patient moves between PCP, dermatology, Mohs, and oncology, transmit pathology, margin status, surveillance plan in a structured handoff — gaps cause missed recurrences

— Reconcile medications (especially photosensitizers, immunosuppressants, chemopreventives) at every transition

— Cancer registry reporting is required in all US states — typically completed by the treating institution

— Document occupational UV exposure for outdoor workers; some jurisdictions recognize cSCC as a compensable occupational disease (firefighters, agricultural workers)

— For elderly patients with dementia and advanced cSCC, engage surrogate decision-makers; consider palliative RT or observation aligned with goals

— Document the discussion explicitly — POLST/MOLST forms in advanced disease

— cSCC in skin of color is rarer but more often diagnosed late and in non-sun-exposed sites (palms, soles, mucosa) — higher mortality; ensure full-body exams including soles and mucosa

Informed consent for procedures:

Biopsy before destruction:

Pathology and result communication:

Transition of care:

Mandatory reporting and disability:

Decisional capacity and goals of care:

Health equity:

Board pearl: A clinically suspicious lesion treated with cryotherapy without biopsy that later proves to be invasive SCC is a board-favorite safety scenario — the correct answer is always biopsy first.

Step 3 management: Document shared decision-making with surrogate when treating advanced cSCC in patients lacking capacity — a high-yield ethics stem.

High-Yield Associations and Rapid-Fire Clinical Facts

Marjolin ulcer: SCC in chronic burn scars, osteomyelitis sinuses, chronic wounds; aggressive, high metastatic rate

Xeroderma pigmentosum (XP): AR defect in nucleotide excision repair; multiple childhood SCCs, BCCs, melanomas; strict photoprotection from infancy

Epidermolysis bullosa (recessive dystrophic): SCC in chronic blistering sites; often metastatic and fatal

Bazex syndrome: paraneoplastic acrokeratosis with SCC of upper aerodigestive tract — psoriasiform plaques on hands, feet, ears

Bowen disease: SCC in situ; "Bowenoid papulosis" is HPV-related genital variant

Erythroplasia of Queyrat: SCC in situ of glans penis

Leukoplakia/erythroplakia of oral mucosa: premalignant; biopsy

Actinic cheilitis: SCC precursor of lower lip in smokers/outdoor workers

HPV 16/18: anogenital and periungual SCC; HPV vaccination is preventive

Voriconazole: lung transplant patients — strongly associated with multiple aggressive cSCCs; switch to alternative azole

HCTZ: photosensitizer; dose-dependent increased cSCC risk

BRAF inhibitors (vemurafenib, dabrafenib): paradoxical eruptive SCCs/KAs in melanoma patients

PUVA therapy for psoriasis: increased cSCC risk after >250 treatments

Organ transplant: cSCC > BCC (reverse of general population); SCC is the most common post-transplant malignancy

Mohs is NCCN category 1 for high-risk cSCC

Cemiplimab: anti-PD-1; FDA-approved for locally advanced and metastatic cSCC

Nicotinamide 500 mg BID: ONTRAC trial — 23% NMSC reduction; not the same as niacin (no flushing)

Sign of Leser-Trélat: eruptive SKs (not SCC) signaling internal malignancy — distractor in vignettes

AEIOU mnemonic is for Merkel cell, not SCC — high-yield differential trap

Lip and ear SCC carry the highest cutaneous metastatic potential (~10–15%)

BWH staging outperforms AJCC for nodal metastasis prediction

Tumor depth >6 mm or invasion beyond subcutaneous fat is a critical high-risk threshold

Perineural invasion of named nerves mandates MRI and adjuvant radiation

Board pearl: The single most high-yield Step 3 SCC vignette pairs chronic immunosuppression (transplant) + multiple hyperkeratotic lesions on dorsal hands → manage with biopsy, Mohs, nicotinamide, sirolimus switch, intensified surveillance.

Board Question Stem Patterns

— 62 yo kidney transplant on tacrolimus/MMF, voriconazole prophylaxis, with multiple hyperkeratotic papules on dorsal hands

— Best next step: biopsy → if SCC, Mohs + switch tacrolimus to sirolimus + start nicotinamide 500 mg BID + discontinue voriconazole

— 68 yo male smoker, outdoor worker, with a persistent ulcerated nodule on lower lip vermilion × 3 months

— Best next step: wedge/punch biopsy; if SCC, Mohs (high-risk site) + neck node exam ± imaging

— 70 yo with a 6-month erythematous scaly plaque on shin not responding to triamcinolone

— Best next step: biopsy → likely Bowen disease (SCC in situ); treat with 5-FU, imiquimod, or excision

— 75 yo with a temple SCC and new ipsilateral facial paresthesia

— Best next step: MRI face/brain with contrast for perineural spread; multidisciplinary referral; adjuvant RT likely

— 55 yo with a non-healing ulcer in a decades-old burn scar

— Best next step: biopsy edge → Marjolin ulcer → wide excision + nodal evaluation; high metastatic risk

— 80 yo with a 1 cm keratin horn on cheek

— Best next step: excisional biopsy of base (40% chance of malignancy at base)

— 65 yo with a 6-week dome-shaped lesion with central keratin plug on forearm

— Best next step: excision (treat as SCC) — keratoacanthoma variant; do not observe for involution

— 78 yo with biopsy-proven metastatic cSCC to lungs

— Best next step: cemiplimab (anti-PD-1) first-line

— 72 yo on long-term HCTZ with 3 new SCCs in 2 years

— Best next step: switch HCTZ to ACEi/ARB or chlorthalidone alternative; intensify surveillance; start nicotinamide

— Cryotherapy was performed without biopsy on a "wart" that recurs as a 2 cm ulcerated nodule

— Best next step: biopsy now; root cause: failure to biopsy suspicious lesion — patient safety issue

Stem 1 — Transplant patient with eruptive lesions:

Stem 2 — Non-healing lip lesion:

Stem 3 — "Eczema that won't go away":

Stem 4 — Facial numbness with skin lesion:

Stem 5 — Chronic burn scar ulcer:

Stem 6 — Cutaneous horn:

Stem 7 — Rapidly growing dome with crater:

Stem 8 — Advanced metastatic cSCC:

Stem 9 — Medication-induced risk:

Stem 10 — Ethics/safety:

Board pearl: When the stem mentions "non-healing," "indurated," "older fair-skinned," "ear/lip/dorsal hand," or "transplant" — pivot toward biopsy and Mohs, not topical steroids or empirical antifungals.

One-Line Recap

Cutaneous squamous cell carcinoma is a UV- and immunosuppression-driven keratinocyte malignancy that demands biopsy of any non-healing scaly indurated lesion, risk-stratified surgical management (standard excision for low-risk, Mohs for high-risk sites and hosts), lifelong sun protection and surveillance, and chemoprevention with nicotinamide — with cemiplimab reserved for advanced disease.

High-yield recap bullets:

Recognize: non-healing, indurated, hyperkeratotic lesion on sun-exposed skin (ear, lip, dorsal hand, scalp) in fair-skinned older adults or immunosuppressed/transplant patients — always biopsy, never cryo or empiric steroids on a suspicious lesion.

Risk-stratify with NCCN/BWH criteria: size, location (H-zone, ear, lip), depth >6 mm or beyond fat, perineural invasion, poor differentiation, recurrence, immunosuppression. Mohs is first-line for any high-risk feature; standard 4–6 mm excision suffices for low-risk lesions; ED&C only for select small superficial non-hair-bearing in situ disease.

Manage advanced disease with cross-sectional imaging (CT neck/MRI for PNI), FNA of palpable nodes, multidisciplinary referral, adjuvant radiation for named-nerve PNI or ENE, and cemiplimab (anti-PD-1) for locally advanced/metastatic disease — avoid checkpoint inhibitors in solid organ transplant recipients when possible.

Prevent and follow up: rigorous sun protection and tanning bed avoidance, nicotinamide 500 mg BID chemoprevention for recurrent NMSC, mTOR-inhibitor switch (sirolimus) and reduction of voriconazole/HCTZ in transplant patients, full-body skin exams every 3–6 months for high-risk patients for 2 years then annually for life, monthly self-skin exam, and structured transitions of care with closed-loop biopsy result communication to avoid the board-classic safety pitfall of missed diagnosis.

Board pearl: Biopsy first, Mohs for high-risk, nicotinamide for prevention, cemiplimab for advanced — the four-pillar Step 3 framework for cSCC across outpatient, surgical, preventive, and systemic decisions.