Dermatology · PANCE / PANRE

Squamous Cell Carcinoma

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

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).

Try two board-style Squamous Cell Carcinoma questions

Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.

Question 1DermatologyMedium
A 68-year-old fair-skinned man who is a retired farmer presents with a rapidly growing lesion on his right forearm that appeared 5 weeks ago. He says it 'came up out of nowhere' and has been getting bigger almost daily. Exam shows a 1.8-cm dome-shaped, firm, flesh-colored nodule with a central keratin-filled crater on the sun-exposed extensor forearm. There is no surrounding induration, ulceration, or lymphadenopathy. Excisional biopsy shows a well-differentiated squamoproliferative lesion with a central keratin plug and a symmetric, cup-shaped architecture. Which of the following is the most likely diagnosis?
  • AAmelanotic melanoma
  • BNodular basal cell carcinoma
  • CMolluscum contagiosum
  • DKeratoacanthoma
Reveal answer & full explanation
Correct answer: D — Keratoacanthoma
  • AAmelanotic melanoma
  • BNodular basal cell carcinoma
  • CMolluscum contagiosum
  • DKeratoacanthoma✓

Why keratoacanthoma is correct

  • Keratoacanthoma (KA) is a rapidly growing squamoproliferative tumor that classically appears on sun-exposed skin of older, fair-skinned patients.
  • Hallmark: rapid growth over 4–8 weeks to a dome-shaped, flesh-colored nodule with a central keratin-filled crater.
  • If untreated, spontaneous involution over months may occur.
  • Histology shows a symmetric, cup-shaped, well-differentiated squamoproliferative lesion with a central keratin plug.
  • Because KA is histologically and clinically indistinguishable from well-differentiated squamous cell carcinoma in many cases — and the two are now considered to lie on a spectrum — complete surgical excision is the standard of care rather than observation.

Why the others are wrong

  • B) Nodular basal cell carcinoma — typically a slow-growing pearly papule with telangiectasias and rolled borders; lacks the central keratin plug and rapid growth.
  • A) Amelanotic melanoma — can mimic many lesions, but is asymmetric and shows atypical melanocytes on histology, not a symmetric squamoproliferative architecture.
  • C) Molluscum contagiosum — small (2–5 mm) umbilicated papules in children or immunosuppressed adults caused by a poxvirus; far smaller than this nodule and shows characteristic Henderson-Paterson molluscum bodies.
Question 2DermatologyMedium
A 60-year-old man with extensive chronic sun exposure has a 2 cm firm, ulcerated lesion on his lower lip and a palpable ipsilateral submandibular node. Biopsy of the lip lesion shows well-differentiated squamous cell carcinoma. Which of the following is the most appropriate management?
  • AWide excision with neck dissection and radiation
  • BMohs micrographic surgery with clinical surveillance
  • CTopical 5-fluorouracil with imaging surveillance
  • DCryotherapy with serial clinical re-examination
Reveal answer & full explanation
Correct answer: A — Wide excision with neck dissection and radiation
  • AWide excision with neck dissection and radiation✓
  • BMohs micrographic surgery with clinical surveillance
  • CTopical 5-fluorouracil with imaging surveillance
  • DCryotherapy with serial clinical re-examination

Why Wide excision with neck dissection and radiation is correct

  • This is a high-risk cutaneous squamous cell carcinoma: lip location, 2 cm size, ulceration, and a palpable regional node indicating nodal metastasis (N1 disease)
  • Regional metastasis mandates treating both the primary and the nodal basin: wide local excision, therapeutic neck dissection, and adjuvant radiation to the primary site and draining nodes
  • The decisive driver of this multimodality approach here is the palpable regional (N1) node; lip and ear location, depth, and poor differentiation are additional general metastasis risk factors

Why the others are wrong

  • Mohs micrographic surgery with clinical surveillance — Mohs gives excellent margin control for localized high-risk disease but treats only the primary and leaves the established nodal disease untreated (right-diagnosis-wrong-extent trap)
  • Topical 5-fluorouracil with imaging surveillance — topical 5-FU is for actinic keratoses and superficial in-situ disease only and cannot eradicate invasive tumor or nodal metastasis (premature closure on 'skin cancer = topical')
  • Cryotherapy with serial clinical re-examination — reserved for small, low-risk superficial lesions, with no role in invasive carcinoma with regional spread (buzzword-matching on 'skin lesion = freeze it')

Additional high-yield points

  • Cemiplimab (anti-PD-1) is approved for locally advanced or metastatic cutaneous SCC
  • Metastasis risk factors: lip or ear location, size >2 cm, depth >4 mm, perineural invasion, poor differentiation
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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 TierFeaturesPreferred Treatment
SCC in situ (Bowen)Erythematous scaly plaque, intraepidermal5-FU, imiquimod, cryo, PDT, or excision
Low-risk invasive<2 cm, trunk/extremity, well-differentiated, depth <6 mmExcision with 4-6 mm margins
High-risk invasiveFace/H-zone, ear, lip; >2 cm; >6 mm depth; perineural invasion; recurrent; immunosuppressed; poor differentiationMohs micrographic surgery ± adjuvant RT
Locally advanced / metastaticUnresectable; nodal or distant diseaseCemiplimab / 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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Commonly confused with

vs Basal Cell Carcinomavs Actinic Keratosis

Related Dermatology diagnoses

Acne VulgarisRosaceaAtopic Dermatitis (Eczema)Allergic and Irritant Contact DermatitisSeborrheic DermatitisPsoriasisLichen PlanusPityriasis RoseaTinea Infections (corporis, capitis, pedis, cruris, versicolor)Cutaneous CandidiasisScabiesPediculosisImpetigoHerpes Zoster (Shingles)

Differentials & related conditions

Basal Cell CarcinomaActinic Keratosis

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