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; ~1.8 million US cases annually (estimated). 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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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
BKeratoacanthoma
CNodular basal cell carcinoma
DMolluscum contagiosum
EMerkel cell carcinoma
Reveal answer & full explanation
Correct answer: B — Keratoacanthoma
AAmelanotic melanoma
BKeratoacanthoma✓
CNodular basal cell carcinoma
DMolluscum contagiosum
EMerkel cell carcinoma
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
Nodular basal cell carcinoma — typically a slow-growing pearly papule with telangiectasias and rolled borders; lacks the central keratin plug and rapid growth.
Amelanotic melanoma — can mimic many lesions, but is asymmetric and shows atypical melanocytes on histology, not a symmetric squamoproliferative architecture.
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.
Merkel cell carcinoma — shares the rapid growth, older age, fair skin, and sun-exposed site seen here, but this neuroendocrine carcinoma is often red-violaceous, lacks a central keratin-filled crater, and shows sheets of small round blue cells on histology rather than a symmetric, cup-shaped squamoproliferative architecture.
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?
AMohs micrographic surgery with clinical surveillance
BDefinitive radiation to the primary tumor site
CWide excision with neck dissection and radiation
DCurettage and electrodesiccation of the lip lesion
EWide excision with sentinel lymph node biopsy
Reveal answer & full explanation
Correct answer: C — Wide excision with neck dissection and radiation
AMohs micrographic surgery with clinical surveillance
BDefinitive radiation to the primary tumor site
CWide excision with neck dissection and radiation✓
DCurettage and electrodesiccation of the lip lesion
EWide excision with sentinel lymph node biopsy
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 probable nodal metastasis (confirmed by fine-needle aspiration before definitive surgery)
Regional metastasis requires treating both the primary and the nodal basin: wide local excision, therapeutic neck dissection, and adjuvant radiation to the primary site and draining nodes, which is recommended for most node-positive head and neck disease (observation after neck dissection may be considered for a single small node without extranodal extension)
The decisive driver of this multimodality approach here is the palpable regional 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)
Wide excision with sentinel lymph node biopsy — sentinel node biopsy stages a clinically node-negative neck; a palpable node is already clinically positive disease that needs therapeutic neck dissection, not sampling (right-procedure-wrong-nodal-status trap)
Definitive radiation to the primary tumor site — radiation limited to the lip treats only the primary and leaves the nodal disease untreated; primary radiation is reserved for patients who cannot undergo or decline surgery (right-modality-wrong-field trap)
Curettage and electrodesiccation of the lip lesion — an option only for small, low-risk primary tumors, so the well-differentiated histology is tempting, but it provides no margin assessment, is not used for high-risk lesions such as a 2 cm ulcerated lip cancer, and leaves the palpable nodal disease untreated (well-differentiated-means-low-risk trap)
Additional high-yield points
Topical 5-fluorouracil and cryotherapy are limited to actinic keratoses and small, low-risk superficial or in situ lesions
Cemiplimab (anti-PD-1) is approved for locally advanced or metastatic cutaneous SCC
Metastasis risk factors: lip or ear location, size >2 cm, depth >6 mm or invasion beyond subcutaneous fat, perineural invasion, poor differentiation
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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.
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
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
Cryotherapy (small, well-defined lesions) or photodynamic therapy — selected SCC in situ; excision (Mohs at high-risk sites) is preferred when bleeding, ulceration, induration, or irregular borders raise concern for occult invasion
Radiation therapy — primary therapy if non-surgical candidate; adjuvant after high-risk excision (positive margins, perineural invasion, extensive involvement)
Clinically node-positive disease (palpable node, FNA-confirmed): excision of the primary plus therapeutic lymph node dissection (neck dissection ± parotidectomy for head/neck primaries), usually followed by adjuvant RT; SLNB is considered only for clinically node-negative high-risk tumors
Locally advanced / metastatic SCC
Cemiplimab (anti-PD-1) — first-line for advanced cutaneous SCC not candidates for curative surgery/radiation
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 keratinocyte cancers in high-risk immunocompetent patients, but the ONTRANS trial (2023) showed no benefit in organ transplant recipients
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 desmoplastic or poorly differentiated tumors, perineural invasion, immunocompromised)
Regional lymph node metastasis — most common site of spread
Distant metastasis (lung, liver, bone, brain) — uncommon but possible
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.
A cutaneous horn is a descriptive term — its base may be a seborrheic keratosis or wart, an actinic keratosis, SCC in situ, or invasive SCC, so biopsy with a deep shave (saucerization) or excision that includes the base; never clip the keratin alone.
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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