Squamous Cell Carcinoma

Table of Contents

1. What Squamous Cell Carcinoma Is
2. Pathophysiology and Molecular Mechanisms
3. Risk Factors
4. Clinical Presentation
5. High-Risk Features and Staging
6. Diagnosis
7. Treatment
8. Prevention
9. Prognosis and Follow-Up
10. Key Research Papers
11. Connections
12. Featured Videos

What Squamous Cell Carcinoma Is

Squamous cell carcinoma (SCC) of the skin is the second most common skin cancer, accounting for approximately 20% of all cutaneous malignancies. An estimated 1.8 million new cases are diagnosed each year in the United States, and incidence is rising by 2–3% annually due to an aging population and cumulative sun exposure.

SCC is a keratinocyte malignancy — it arises from the squamous cells (keratinocytes) of the epidermis. Unlike basal cell carcinoma (BCC), which is locally destructive but almost never spreads distantly, SCC carries genuine metastatic potential. The overall metastasis rate is 2–5%, but the presence of high-risk features can raise this to 30–40% for individual tumors.

A 2013 estimate (Karia et al.) put deaths from SCC among white Americans in 2012 at 3,932 to 8,791, with 186,157 to 419,543 people diagnosed with invasive SCC that year. In the central and southern United States, the authors estimated that SCC deaths may be as common as deaths from melanoma, though melanoma carries a higher case-fatality rate. The primary carcinogen is ultraviolet (UV) radiation, making SCC largely a preventable disease with adequate photoprotection across a lifetime.

SCC exists on a biological continuum: from actinic keratosis (precursor lesion) → SCC in situ (Bowen's disease) → invasive SCC. Understanding this progression is fundamental to early detection and treatment, and to preventing the minority of cases that progress to regional or distant metastasis.

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Pathophysiology and Molecular Mechanisms

SCC originates through ultraviolet-induced DNA damage in epidermal keratinocytes. Ultraviolet B (UVB) radiation causes the formation of cyclobutane pyrimidine dimers (CPDs) — covalent bonds between adjacent pyrimidine bases (C–C or C–T) that distort the DNA helix and impair replication fidelity. When these lesions escape repair, they generate characteristic ultraviolet signature mutations: C→T transitions and CC→TT tandem transitions at dipyrimidine sites. These mutations are found in virtually every SCC and serve as a molecular fingerprint of ultraviolet causation.

The most important molecular event in SCC development is mutation of the TP53 tumor suppressor gene, present in over 90% of SCCs. TP53 normally halts the cell cycle to allow DNA repair or triggers apoptosis in irreparably damaged cells. Loss of p53 function allows ultraviolet-mutated keratinocytes to survive, proliferate, and accumulate additional mutations. Other key molecular alterations include:

• CDKN2A/p16 loss — removes G1 cell cycle checkpoint control, enabling unrestricted proliferation
• NOTCH1/NOTCH2 mutations — NOTCH normally promotes squamous differentiation; loss drives undifferentiated proliferation
• RAS activation — drives downstream proliferative signaling (MAPK, PI3K/AKT pathways)
• EGFR overexpression — present in 80–100% of SCCs; therapeutic target for cetuximab

SCC develops in a stepwise progression:

1. Actinic Keratosis (AK) — ultraviolet-damaged keratinocytes with partial-thickness epidermal dysplasia. In a Veterans Affairs trial that tracked 7,784 AKs on the face and ears of 169 people (Criscione et al., 2009), the risk of an AK turning into SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years; 55% of the AKs were gone by 1 year and 70% by 5 years, and about 65% of all SCCs arose in spots earlier diagnosed as AKs. AKs represent in situ epidermal dysplasia that has not yet breached the basement membrane.
2. Squamous Cell Carcinoma In Situ (SCCIS) / Bowen's Disease — full-thickness epidermal involvement by atypical keratinocytes with preserved basement membrane. Carries a low but present risk of invasion (3–5% of Bowen's disease lesions become invasive over time).
3. Invasive SCC — tumor cells breach the epidermal basement membrane and invade the dermis. Deeper invasion, lymphovascular invasion, and perineural invasion markedly increase the risk of regional metastasis to lymph nodes and, less commonly, distant organs.

An important concept is field cancerization: chronic ultraviolet exposure damages not just isolated keratinocytes but an entire "field" of epidermis — particularly on the face, scalp, and dorsal forearms. This explains why patients with one SCC or AK commonly have multiple lesions in the same anatomic region, and why new SCCs arise in previously treated patients. The concept drives field-directed therapies (5-FU, imiquimod, PDT) that treat the entire photo-damaged field rather than individual lesions.

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Risk Factors

Ultraviolet Radiation (Primary Risk Factor)

Ultraviolet radiation is the dominant etiologic factor, and risk scales with cumulative lifetime exposure. Key ultraviolet risk factors include:

• Cumulative lifetime ultraviolet dose — photodamage is cumulative and largely irreversible; even ultraviolet A (UVA) through glass contributes
• Tanning bed use — a 2012 meta-analysis of 12 studies found a 67% higher SCC risk in people who had ever used indoor tanning (relative risk 1.67), and a relative risk of 2.02 with use before age 25; the risk grows with number of sessions
• Fitzpatrick skin types I–II — fair skin, light eyes, red or blonde hair, tendency to burn rather than tan; highest inherent ultraviolet sensitivity
• Outdoor occupations — farmers, construction workers, sailors, and others with long-term outdoor exposure have 3–4 times the SCC risk of indoor workers

Immunosuppression

Immune surveillance is essential for destroying ultraviolet-mutated pre-malignant cells. When immunity is impaired:

• Organ transplant recipients — face a 65–250-fold increased risk of SCC; it is the most common malignancy after transplant. Risk is proportional to depth and duration of immunosuppression.
• Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) — advanced immune depletion removes ultraviolet-damaged cell surveillance
• Chronic lymphocytic leukemia (CLL) — strongly associated with multiple, aggressive SCCs
• Immunosuppressive drugs — azathioprine, cyclosporine, and mycophenolate impair cytotoxic T-cell surveillance of pre-malignant cells

Human papillomavirus (HPV) Infection

Human papillomavirus plays a dual role. High-risk human papillomavirus types 16, 18, 31, and 33 are causally implicated in genital, perianal, and oropharyngeal SCC. For cutaneous SCC, beta-HPV types are found in lesions of immunosuppressed patients. Human papillomavirus E6 and E7 oncoproteins inactivate p53 and pRb respectively, mimicking ultraviolet-induced TP53 loss and accelerating carcinogenesis.

Chronic Wounds and Scars

Marjolin's ulcer refers to SCC arising within a chronic wound, burn scar, osteomyelitis sinus tract, or venous stasis ulcer. These tumors are characteristically aggressive with higher metastasis rates than de novo SCC. Pathophysiology involves chronic inflammation, impaired immune surveillance, and growth factor signaling within the wound microenvironment.

Radiation Exposure

Prior therapeutic radiation creates a field of chronically damaged skin with impaired DNA repair capacity. SCCs arising in radiation fields have a long latency (often decades) and are treated as high-risk.

Chemical Carcinogens

Chronic arsenic exposure (contaminated drinking water; historical medicinal use) causes arsenical keratoses and Bowen's disease, with high SCC risk. Polycyclic aromatic hydrocarbons (PAHs) in soot, tar, and mineral oils — historically causative in chimney sweeps (Pott's scrotal cancer, the first recognized occupational cancer) — and other chemical exposures are established risk factors.

Genetic Conditions

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of nucleotide excision repair (NER), the pathway that removes ultraviolet-induced CPDs. Affected individuals have profound ultraviolet hypersensitivity and develop SCCs, BCCs, and melanomas in childhood. XP illustrates the critical role of DNA repair in ultraviolet carcinogenesis.

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Clinical Presentation

Actinic Keratosis (Precursor)

AKs are the earliest detectable lesion on the pathway to SCC. They present as rough, sandpaper-textured erythematous papules or patches on chronically sun-exposed areas — the face, bald scalp, ears, dorsal hands, and forearms. They are often better felt than seen: palpation reveals a gritty scale even before the lesion is visually obvious. AKs are frequently painful or tender when touched. Individual lesions may spontaneously regress, persist, or progress; their importance lies in the presence of an extensive photo-damaged field around them, which harbors invisible pre-malignant clones.

Bowen's Disease / SCC In Situ

Bowen's disease presents as a well-demarcated, erythematous, scaly plaque that enlarges slowly over months to years. Unlike AKs, which are typically rough papules, Bowen's disease appears as a flat, psoriasiform patch. It can arise on both sun-exposed and non-sun-exposed skin, including the mucosa. Erythroplasia of Queyrat refers specifically to Bowen's disease on the glans penis — a velvety, moist, well-defined erythematous plaque. Genital and mucosal Bowen's disease carries a higher risk of invasion than cutaneous lesions.

Invasive SCC — Classic Appearance

Invasive SCC typically begins as a keratotic, scaly papule that enlarges into a nodule, often with a central keratinous plug or cutaneous horn. The base is indurated (firm) on palpation — a key clinical sign distinguishing SCC from benign hyperkeratotic lesions, which have soft bases. As tumors grow, they may:

• Ulcerate with raised, rolled, or everted edges — the classic "crater" or "volcano" appearance
• Develop a bleeding, friable surface that fails to heal
• Form a cutaneous horn — a conspicuous keratin protrusion; the base is biopsied to rule out an underlying SCC

High-Risk Anatomic Sites

SCC location dramatically affects prognosis. The lip vermilion, ear, and non-hair-bearing scalp have higher metastasis rates (10–20%) than trunk or extremity tumors. Mucosal SCC — oral mucosa, lip, and genitalia — has the highest metastatic potential (up to 30%) because of rich lymphovascular drainage at these sites. The ear and temple region are associated with parotid gland involvement.

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High-Risk Features and Staging

Not all SCCs are equal. Identifying high-risk features is the most critical clinical task after confirming the diagnosis, because it determines the extent of surgery, the need for adjuvant therapy, and the surveillance schedule.

NCCN High-Risk Features

• Tumor size >2 cm — larger tumors have greater depth and more likely lymphovascular involvement
• High-risk location — lip, ear, non-hair-bearing scalp, genitalia, hands, feet, pre-tibial lower leg
• Tumor depth >2 mm or Clark level IV/V invasion
• Perineural invasion (PNI) — tumor tracking along nerve sheaths; associated with local recurrence, distant spread, and potential for skull base involvement in head/neck tumors; treated as an indication for adjuvant radiation therapy
• Lymphovascular invasion (LVI) — tumor emboli within blood or lymphatic vessels; high metastasis risk
• Poor histologic differentiation — undifferentiated, adenosquamous, or desmoplastic subtypes
• Immunosuppression — especially transplant recipients
• Arising in chronic inflammation, radiation field, or scar
• Recurrent tumor — prior incomplete excision has selected for more aggressive cells

AJCC 8th Edition Staging (Cutaneous Head and Neck SCC)

• T1 — tumor <2 cm, <4 mm thick, no high-risk features
• T2 — tumor ≥2 cm, or any size with one high-risk feature
• T3 — tumor >4 mm Breslow depth, or PNI of a named nerve, or minor bone erosion
• T4a/T4b — cortical bone invasion or skull base/foraminal invasion
• N1–N3 — regional lymph node metastasis; subcategorized by size, number, and extranodal extension
• M1 — distant metastasis

Risk-stratification tools are used in transplant centers to identify patients with SCC at highest risk for an aggressive clinical course, guiding the frequency of surveillance and the threshold for adjuvant therapy.

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Diagnosis

Dermoscopy

Dermoscopy aids in the clinical diagnosis of SCC and AK before biopsy. Key SCC dermoscopic features include:

• Structureless white/yellow keratin areas — surface scale and horn
• Hairpin (coiled) vessels — tortuous looped vessels; hallmark of keratinizing tumors
• Glomerular vessels — coiled capillary tufts resembling renal glomeruli; more characteristic of Bowen's disease
• Rosettes — four-leaf-clover patterns visible under polarized light at follicular openings

Biopsy

SCC is confirmed by a tissue biopsy of the suspicious spot. The biopsy technique matters:

• Shave biopsy — adequate for superficial lesions; risk of transecting deep margin, missing invasion depth
• Punch biopsy — provides full-thickness sample including subcutaneous fat; preferred for assessing invasion depth and perineural involvement
• Excisional biopsy — ideal for small lesions; provides complete pathologic staging data (depth, margins, differentiation)
• Incisional biopsy — for large lesions where complete excision is not feasible diagnostically

Histopathology

The pathologic hallmarks of SCC are atypical squamous cells with pleomorphism, dyskeratosis (individual cell keratinization), keratin pearls (concentric whorls of keratin within nests of tumor cells), and preserved intercellular bridges (desmosomes). In invasive SCC, tumor cell nests penetrate through the basement membrane into the dermis. Histologic grading — well differentiated, moderately differentiated, or poorly differentiated — carries prognostic significance: poorly differentiated SCC has higher recurrence and metastasis rates.

Sentinel Lymph Node Biopsy (SLNB)

SLNB is not yet standard of care for cutaneous SCC outside of clinical trials, but it is increasingly used at academic centers for high-risk primary tumors. Published series report occult nodal metastasis in 5–10% of high-risk cases, identifying a group who benefit from immediate completion lymphadenectomy.

Imaging

Computed tomography (CT), magnetic resonance imaging (MRI), and PET-CT are used for regional and distant staging in high-risk or locally advanced SCC. MRI is particularly important for head and neck SCC with suspected PNI — it best delineates skull base involvement and intracranial extension. Parotid gland involvement is evaluated by computed tomography or ultrasound with FNA.

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Treatment

Surgical Excision (Standard of Care for Most SCC)

Surgical excision with clear histologic margins is the primary treatment for the majority of SCCs. Margins described in guidelines depend on risk stratification:

• Low-risk SCC — 4 mm clinical margins; frozen-section margin confirmation or permanent H&E evaluation
• High-risk SCC — 6 mm or greater margins; guidelines strongly recommend complete circumferential margin evaluation

Mohs Micrographic Surgery (Gold Standard for High-Risk SCC)

Mohs surgery provides 100% margin examination through staged sequential excision with immediate horizontal frozen sections interpreted by the Mohs surgeon. Each stage maps the exact location of residual tumor, allowing targeted re-excision that minimizes removal of uninvolved tissue. Benefits include:

• Lowest recurrence rate for high-risk SCC (<5% for primary tumors)
• Maximum tissue preservation — critical for functional and cosmetic sites (nose, eyelids, lip, ear, fingers)
• Immediate confirmation of clear margins before wound closure

NCCN indications for Mohs surgery include any high-risk feature, cosmetically sensitive anatomic locations, large size, ill-defined clinical borders, recurrent tumors, and PNI.

Radiation Therapy

Radiation therapy (RT) plays several roles in SCC management:

• Adjuvant RT — after surgery for PNI involving named nerves, positive regional lymph nodes, or close/positive surgical margins; typically 60–66 Gy in 2-Gy fractions to the primary site plus regional nodes
• Definitive RT — for patients who are inoperable due to medical comorbidities, tumor extent, or patient refusal; cure rates lower than surgery
• Palliative RT — for painful or bleeding advanced disease

Electrodessication and Curettage (ED&C)

ED&C — scraping (curettage) followed by electrodessication repeated in 2–3 cycles — is acceptable for low-risk, well-defined, superficial SCCs in non-hair-bearing skin. It provides no histologic margin control, making it unsuitable for high-risk tumors. Recurrence rates are higher than for excision even in low-risk SCC.

Field-Directed Therapies for Precancerous Lesions

• Topical 5-fluorouracil (5-FU) cream — 2–4-week courses that ablate dysplastic keratinocytes in the AK field; highly effective for field treatment; not appropriate for invasive SCC
• Imiquimod cream — toll-like receptor 7 agonist; induces innate and adaptive immune responses against dysplastic cells; effective for AK and Bowen's disease
• Photodynamic therapy (PDT) — aminolevulinic acid (ALA) or methyl-ALA (MAL) applied topically; converted to protoporphyrin IX (PPIX) selectively in dysplastic cells; activated by visible light to generate reactive oxygen species; excellent results for Bowen's disease and AK fields; not for invasive SCC
• Cryotherapy — liquid nitrogen for individual AKs; rapid, office-based; less effective for field treatment than topical agents

Systemic Therapy for Advanced SCC

Until 2018, no systemic agent was U.S. Food and Drug Administration-approved for advanced cutaneous SCC; outcomes with platinum-based chemotherapy were poor. The immunotherapy era has transformed this:

• Cemiplimab — anti-PD-1 checkpoint inhibitor; U.S. Food and Drug Administration (FDA) approved September 2018 for locally advanced or metastatic cutaneous SCC in patients who are not candidates for curative surgery or radiation; pivotal trial (Migden et al., NEJM 2018) demonstrated an overall response rate (ORR) of 47% with durable responses exceeding 6 months in most responders. First systemic agent ever approved specifically for cutaneous SCC.
• Pembrolizumab — anti-PD-1; U.S. Food and Drug Administration approved June 2020 for recurrent or metastatic cutaneous SCC not curable by surgery or radiation; ORR approximately 34%; additional option particularly for cemiplimab-refractory patients
• Cetuximab — anti-EGFR monoclonal antibody; second-line option; EGFR is overexpressed in 80–100% of SCCs; partial responses; primarily cytostatic; used when immunotherapy is contraindicated (e.g., severe autoimmune disease)
• Platinum-based chemotherapy — cisplatin ± 5-FU; palliative intent; partial responses in 40–50%; not curative; now reserved for patients ineligible for immunotherapy

Immunotherapy Before and After Surgery

• Cemiplimab after surgery and radiation (adjuvant, C-POST trial, 2025) — 415 people with high-risk SCC (for example spread to lymph nodes with extra-capsular extension, nerve invasion or bone invasion) received cemiplimab or placebo for up to 48 weeks after surgery and radiation. At 24 months, 87.1% on cemiplimab versus 64.1% on placebo were alive without the cancer coming back (hazard ratio 0.32). Local or regional returns numbered 9 versus 40, and distant spread 10 versus 26. Serious (grade 3 or higher) side effects occurred in 23.9% versus 14.2%, and 9.8% versus 1.5% stopped because of side effects (Rischin et al., 2025).
• Cemiplimab before surgery (neoadjuvant, 2022) — in a phase 2 study without a comparison group, 79 people with stage II to IV SCC that could be removed by surgery received up to four doses of cemiplimab before the operation. In 51% no living cancer cells were found in the removed tissue (pathological complete response), and in another 13% 10% or less remained (major response); tumors shrank on scans in 68%. Grade 3 or higher side effects occurred in 18% (Gross et al., 2022).

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Prevention

Photoprotection

Because SCC is causally driven by cumulative ultraviolet exposure, photoprotection is the most powerful prevention strategy. Key measures include:

• Broad-spectrum SPF 30 or higher sunscreen daily — "broad-spectrum" certification means ultraviolet A protection in addition to UVB (SPF measures only ultraviolet B). Sunscreen directions describe applying 15–30 minutes before sun exposure and reapplying every 2 hours and after swimming or sweating. Ultraviolet A penetrates glass — year-round use matters.
• Physical blockers — zinc oxide and titanium dioxide provide broad ultraviolet A and ultraviolet B coverage; no chemical-absorption controversy; described as suited to photosensitive patients
• Protective clothing — UPF-rated garments; wide-brim hats (minimum 3-inch brim covers face, ears, and neck); long sleeves and long pants in high-UV environments
• Midday sun — the ultraviolet index is highest between 10 am and 4 pm; shade and outdoor plans around those hours lower exposure
• Tanning beds — no medically accepted use is described; ever using indoor tanning is linked to a 67% higher SCC risk (2012 meta-analysis)

Chemoprevention

Oral nicotinamide (niacinamide, a form of vitamin B3) 500 mg twice daily is among the few agents tested in a large randomized-controlled trial for SCC chemoprevention. The Chen et al. 2015 NEJM trial enrolled 386 high-risk patients (at least 2 prior keratinocyte carcinomas) and demonstrated:

• 23% fewer new nonmelanoma skin cancers overall at 12 months (the main end point)
• 30% fewer new SCCs
• 20% fewer new BCCs (not statistically significant)
• Fewer actinic keratoses: 11% fewer at 3 months, 14% at 6 months, 20% at 9 months and 13% at 12 months
• No noteworthy difference in side effects compared with placebo
• No benefit was seen after nicotinamide was stopped

Nicotinamide works by replenishing nicotinamide adenine dinucleotide (NAD+) stores depleted by ultraviolet-induced poly(ADP-ribose) polymerase (PARP) activation, enhancing DNA repair and reducing ultraviolet-induced immunosuppression. At approximately $10/month, it is an accessible and affordable intervention for high-risk patients.

Limits of the nicotinamide evidence. In organ transplant recipients, a 2023 trial (158 people, stopped early because too few joined) found no benefit: 207 new keratinocyte cancers on nicotinamide versus 210 on placebo over 12 months (rate ratio 1.0), with no difference in SCC, BCC or actinic keratosis counts (Allen et al., 2023). A 2025 study of United States veterans, which looked back at health records rather than randomizing (12,287 people taking nicotinamide 500 mg twice daily, matched with 21,479 who were not), linked nicotinamide to a 14% lower skin cancer risk overall and a 54% lower risk when it was started after a first skin cancer, with the largest drop for SCC; in transplant recipients it found no overall significant reduction (Breglio et al., 2025).

AK Field Treatment as Cancer Prevention

Treating the entire photo-damaged field — not just visible AKs — reduces subsequent SCC incidence. Annual 5-FU cream courses (2–4 weeks to the face or scalp), photodynamic therapy sessions, or imiquimod cycles reduce the pool of pre-malignant keratinocytes in the field. Dermoscopy-guided field mapping improves targeted treatment.

In the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial (932 veterans with at least 2 keratinocyte carcinomas in the previous 5 years), one standard course of fluorouracil 5% cream to the face and ears, twice daily for 2 to 4 weeks, was followed in the first year by SCC in 1% of the treated group versus 4% on a placebo cream, a 75% lower risk. Over the whole study (up to 4 years) there was no difference in time to a first SCC, and the 11% drop in BCC in year 1 was not statistically significant (Weinstock et al., 2018).

Transplant Patient Surveillance and Management

Transplant dermatology care for organ transplant recipients is described as aggressive and proactive:

• Quarterly skin examinations beginning 1 year post-transplant (or earlier in high-risk individuals)
• Patient education about self-examination and prompt reporting of new or changing lesions
• Switching from calcineurin inhibitors (cyclosporine, tacrolimus) to mechanistic target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) may reduce SCC risk — mechanistic target of rapamycin inhibitors have intrinsic anti-tumor properties and the transition is feasible in stable transplant recipients in collaboration with transplant medicine
• Acitretin (oral retinoid) as chemoprevention in transplant patients with multiple SCCs — reduces new tumor incidence

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Prognosis and Follow-Up

Outcomes by Risk Category

The prognosis of SCC spans a wide range depending on tumor and patient characteristics:

• Low-risk SCC — 5-year disease-specific survival exceeds 95% with adequate excision; recurrence rates below 5%
• High-risk SCC (multiple NCCN high-risk features) — local recurrence rates of 25–70% without Mohs surgery; metastasis in 30–40% with perineural invasion, lymphovascular invasion, or multiple adverse features
• Transplant-associated SCC with metastasis — median survival of 2–3 years; biology is accelerated by persistent immunosuppression; immune reconstitution (dose reduction or discontinuation of immunosuppression) improves outcomes when feasible

Second Primary Risk

A 2000 meta-analysis of 17 studies (Marcil and Stern) found that people who have had one SCC have an 18% risk of another SCC within 3 years, at least 10 times the rate of first SCCs in a comparable general population. This reflects the persistent field cancerization in sun-damaged skin, and it is the reason long-term skin checks are part of follow-up after SCC.

Follow-Up Protocol

Post-treatment surveillance includes:

• High-risk SCC — every 3 months for the first 2 years, then every 6 months for years 3–5, then annually; includes clinical examination of the scar, regional lymph nodes (palpation and/or ultrasound), and full skin examination
• Low-risk SCC — every 6–12 months for the first 2 years, then annually
• Imaging — computed tomography or PET-CT at baseline and annually for 2 years in SCC with confirmed PNI of a named nerve, or at initial staging; not required for most low-risk SCCs
• Patient education — skin self-examination; any lesion that grows, bleeds, crusts, or fails to heal within 3 weeks is a sign that gets checked; no tanning; consistent sunscreen use

The twin goals of SCC surveillance are early detection of recurrence or regional spread — when salvage therapy is still possible — and identification of new primary SCCs in the at-risk photodamaged field. Both goals require a committed long-term partnership between patient and dermatologist.

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Key Research Papers

1. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957–966. — PubMed PMID: 23375456
2. Migden MR, Rischin D, Schmults CD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018;379(4):341–351. — PubMed PMID: 29863979
3. Chen AC, Martin AJ, Choy B, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med. 2015;373(17):1618–1626. — PubMed PMID: 26488693
4. Brougham ND, Dennett ER, Cameron R, Tan ST. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol. 2012;106(7):811–815. — Search PubMed
5. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001;344(13):975–983. — Search PubMed
6. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237–247. — Search PubMed
7. Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest. 2012;122(2):464–472. — Search PubMed
8. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis"). J Am Acad Dermatol. 2000;42(1 Pt 2):11–17. — PubMed PMID: 10607351
9. Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol. 2013;149(5):541–547.
10. Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491–508.
11. Wehner MR, Shive ML, Chren MM, et al. Indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. BMJ. 2012;345:e5909. — PubMed PMID: 23033409
12. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523–2530. — PubMed PMID: 19382202
13. Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol. 2000;136(12):1524–1530. — PubMed PMID: 11115165
14. Rischin D, Porceddu S, Day F, et al. Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2025;393(8):774–785. — PubMed PMID: 40454639
15. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2022;387(17):1557–1568. — PubMed PMID: 36094839
16. Allen NC, Martin AJ, Snaidr VA, et al. Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients. N Engl J Med. 2023;388(9):804–812. — PubMed PMID: 36856616
17. Breglio KF, Knox KM, Hwang J, et al. Nicotinamide for Skin Cancer Chemoprevention. JAMA Dermatol. 2025;161(11):1140–1147. — PubMed PMID: 40960808
18. Weinstock MA, Thwin SS, Siegel JA, et al. Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial. JAMA Dermatol. 2018;154(2):167–174. — PubMed PMID: 29299592

PubMed Topic Searches

1. Cutaneous SCC treatment — PubMed
2. SCC Mohs micrographic surgery — PubMed
3. Cemiplimab cutaneous SCC — PubMed
4. Actinic keratosis to SCC progression — PubMed
5. Transplant immunosuppression and SCC — PubMed

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Connections

• Dermatology
• Ultraviolet Radiation — the cumulative-UV cancer pathway explained
• Sunburn, Tanning & What Ultraviolet Does to Your Skin — interactive animation
• Melanoma
• Basal Cell Carcinoma
• Skin Cancer Overview
• Actinic Keratosis (precursor lesion)
• Psoriasis
• Immunology
• Oncology

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