Dermatology · PANCE / PANRE

Squamous Cell Carcinoma

Second most common skin cancer; UV-driven keratinocyte malignancy with real metastatic potential, especially in immunosuppressed.

Also known as: SCC, squamous cell carcinoma, cutaneous SCC, Bowen disease, keratoacanthoma

Overview

Malignant proliferation of keratinocytes invading beyond the basement membrane. Bowen disease (SCC in situ) is confined to the epidermis. Invasive cutaneous SCC ranges from low-risk well-differentiated lesions to aggressive high-risk variants with metastatic potential.

Epidemiology

Second most common skin cancer; ~1 million US cases annually. Lifetime risk ~10% in fair-skinned individuals. Incidence rises sharply with age. Male predominance. Metastasis ~3-5% overall but up to 30% in high-risk subtypes (deep, large, recurrent, immunosuppressed, perineural invasion).

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Risk factors

Cumulative UV exposure (UVB > UVA) — strongest risk factor
Fair skin (Fitzpatrick I-II), light hair/eyes
Age >50
Actinic keratosis (precursor; ~10% lifetime risk of progression per AK)
Immunosuppression — organ transplant recipients have 65-100x increased risk and more aggressive disease; HIV, chronic immunosuppressants, biologics
Chronic inflammation/scarring: burn scars (Marjolin ulcer), chronic ulcers, sinus tracts, lupus vulgaris, hidradenitis suppurativa
HPV (especially high-risk types 16/18) — anogenital, periungual SCC
Arsenic exposure, ionizing radiation, hydrocarbon tar exposure
Photochemotherapy (PUVA), voriconazole long-term use
Genetic syndromes: xeroderma pigmentosum, epidermolysis bullosa, oculocutaneous albinism

Pathophysiology

UV-induced TP53 mutations are early events; NOTCH1/2 and CDKN2A inactivation; RAS pathway activation. Progression from photodamaged skin → actinic keratosis → SCC in situ → invasive SCC over years. Tumor mutational burden among the highest of all human cancers.

Clinical presentation

Symptoms

Often asymptomatic; new growth, non-healing 'sore', or growth in a chronic scar/ulcer
Tenderness, bleeding, crusting
Pain, paresthesia, motor weakness → perineural invasion

Signs / physical exam

Bowen disease (SCC in situ): well-demarcated erythematous scaly slowly enlarging plaque on sun-exposed or sun-protected skin; can mimic psoriasis/eczema
Invasive SCC: indurated, hyperkeratotic, ulcerated nodule or plaque with everted margins; often on sun-exposed sites (face, ears, lip, dorsal hands/forearms, scalp)
Keratoacanthoma: rapidly growing dome-shaped nodule with central keratin-filled crater
Marjolin ulcer: chronic non-healing ulcer in burn scar or chronic wound, often arising decades later
Lip SCC: lower lip (chronic sun damage), often arises in actinic cheilitis
Anogenital SCC: HPV-associated; bowenoid papulosis in younger patients
Perineural invasion signs: dysesthesia, paresthesia, motor weakness, formication

Classic findings

Hyperkeratotic indurated nodule with central ulceration on sun-damaged skin of an older adult, often arising from a pre-existing actinic keratosis.

Differential diagnosis

Basal cell carcinoma — Pearly translucent, rolled border, telangiectasias, slow growth; less hyperkeratotic
Keratoacanthoma — Rapidly growing (weeks) dome-shaped nodule with central keratin plug; may regress spontaneously but treated as well-differentiated SCC
Actinic keratosis — Rough scaly papule/macule on sun-damaged skin; precursor lesion; often felt more than seen
Wart (verruca) — Verrucous, pinpoint black dots, disrupts skin lines; younger patient
Amelanotic melanoma — Pink nodule, biopsy mandatory
Merkel cell carcinoma — Rapidly growing red-purple firm nodule on sun-exposed skin of elderly; aggressive neuroendocrine tumor
Cutaneous metastasis — Firm dermal nodule in patient with known visceral cancer
Chronic non-healing ulcer — Biopsy edge to exclude Marjolin ulcer (SCC in chronic wound)

Diagnostic workup

Diagnostic criteria

Histopathologic confirmation; AJCC 8th edition staging + NCCN/BWH risk stratification

Labs

Skin biopsy (shave, punch, or excisional) — tissue diagnosis required
Histopathology determines depth, differentiation (well/moderate/poor), perineural invasion, and high-risk features

Imaging

Lymph node ultrasound + FNA if palpable lymphadenopathy or high-risk tumor
CT/MRI for large tumors, perineural invasion symptoms, deep tissue/bone involvement
PET/CT for staging in advanced disease
Sentinel lymph node biopsy considered for high-risk SCC (>2 cm, >6 mm depth, poor differentiation, perineural invasion, immunosuppression) — role evolving

Diagnostic algorithm

Risk Tier	Features	Preferred Treatment
SCC in situ (Bowen)	Erythematous scaly plaque, intraepidermal	5-FU, imiquimod, cryo, PDT, or excision
Low-risk invasive	<2 cm, trunk/extremity, well-differentiated, depth <6 mm	Excision with 4-6 mm margins
High-risk invasive	Face/H-zone, ear, lip; >2 cm; >6 mm depth; perineural invasion; recurrent; immunosuppressed; poor differentiation	Mohs micrographic surgery ± adjuvant RT
Locally advanced / metastatic	Unresectable; nodal or distant disease	Cemiplimab / pembrolizumab (anti-PD-1); RT; chemo as second-line

Cutaneous SCC risk-based treatment selection.

Treatment

First-line

Low-risk primary cutaneous SCC: surgical excision with 4-6 mm clinical margins (cure rate >95%)
Mohs micrographic surgery (preferred for high-risk SCC): face/H-zone, ears, lips, genitalia, perineural invasion, recurrent, >2 cm, depth >6 mm, poor differentiation, immunosuppressed host
ED&C for small (<1 cm) low-risk SCC in situ on trunk/extremities (NOT on hair-bearing sites or invasive SCC on face)
Topical 5-fluorouracil 5% cream BID × 2-8 weeks OR imiquimod 5% cream 5x/week × 6-16 weeks — SCC in situ (Bowen disease)
Cryotherapy or photodynamic therapy — selected SCC in situ
Radiation therapy — primary therapy if non-surgical candidate; adjuvant after high-risk excision (positive margins, perineural invasion, extensive involvement)

Locally advanced / metastatic SCC

Cemiplimab (anti-PD-1) — first-line for advanced cutaneous SCC not candidates for curative surgery/radiation
Pembrolizumab (anti-PD-1) — alternative
Cetuximab (anti-EGFR), chemotherapy (carboplatin + paclitaxel, cisplatin + 5-FU) — older options

Organ transplant recipients

Reduce immunosuppression when possible (in consultation with transplant team)
Switch from calcineurin inhibitor to mTOR inhibitor (sirolimus) — reduces SCC incidence
Aggressive sun protection
Acitretin 10-25 mg/day as chemoprevention for high-burden patients
Nicotinamide 500 mg BID — reduces new actinic keratoses and SCC/BCC in immunocompetent (modest evidence in transplant)
Surveillance every 3-6 months

Lip SCC / actinic cheilitis

Excisional therapy (vermilionectomy for diffuse), CO2 laser for actinic cheilitis
Lip protection: SPF 30+ lip balm, hat with brim

Second-line / adjunct

Sentinel lymph node biopsy in selected high-risk patients (role evolving)
Adjuvant radiation for incompletely resected, perineural invasion, or recurrent disease
Skin cancer surveillance every 3-12 months depending on risk; total body skin examination
Genetic counseling if multiple SCCs in young patient or family history (XP)

Complications

Local recurrence (especially morpheaform, perineural invasion, immunocompromised)
Regional lymph node metastasis — most common site of spread
Distant metastasis (lung, liver, bone, brain) — uncommon but possible
Perineural invasion → cranial nerve deficits, intracranial spread
Disfigurement and functional loss
Multiple primary skin cancers (40-50% develop another within 5 years)

PANCE pearls

Any chronic non-healing ulcer, especially in a burn scar (Marjolin ulcer), should be biopsied — SCC develops in chronic wounds decades after injury.
Organ transplant recipients develop SCC at 65-100x baseline rate and have far more aggressive disease — Mohs threshold should be lower.
Keratoacanthoma is now classified as a well-differentiated variant of SCC — treat surgically rather than awaiting spontaneous regression.
Lip SCC has a higher metastatic rate than other cutaneous sites — biopsy any non-healing lip lesion.
Cemiplimab (anti-PD-1) has transformed outcomes for advanced/metastatic SCC — survival was previously dismal.

References

NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology — Squamous Cell Skin Cancer (Version 1.2024)
AAD 2018 — Guidelines of Care for the Management of Cutaneous Squamous Cell Carcinoma (Alam et al., J Am Acad Dermatol 2018)
AJCC 8th Edition — American Joint Committee on Cancer Staging Manual — Cutaneous Squamous Cell Carcinoma (8th edition)

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