Squamous Cell Carcinoma

Table of Contents

1. What is Squamous Cell Carcinoma?
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. References and Research
11. Connections
12. Featured Videos

What is Squamous Cell Carcinoma?

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.

SCC causes approximately 15,000 deaths per year in the United States — more than melanoma in absolute numbers, 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 UV-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 UV 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 UV 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 UV-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) — UV-damaged keratinocytes with partial-thickness epidermal dysplasia. Approximately 10–15% of untreated AKs progress to invasive SCC over 10 years. 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 UV 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

UV Radiation (Primary Risk Factor)

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

• Cumulative lifetime UV dose — photodamage is cumulative and largely irreversible; even UVA through glass contributes
• Tanning bed use — increases SCC risk by approximately 83%; 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 UV 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 UV-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.
• HIV/AIDS — advanced immune depletion removes UV-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

HPV Infection

Human papillomavirus plays a dual role. High-risk HPV 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. HPV E6 and E7 oncoproteins inactivate p53 and pRb respectively, mimicking UV-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 UV-induced CPDs. Affected individuals have profound UV hypersensitivity and develop SCCs, BCCs, and melanomas in childhood. XP illustrates the critical role of DNA repair in UV 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 must always be biopsied to exclude 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; mandates 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

The CASTLE Score (Clinical Assessment Score for Treatment of Lesions in Extremities) and similar 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

Tissue biopsy is mandatory for any lesion suspected to be SCC. 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

CT, 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 CT 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. Recommended margins 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; complete circumferential margin evaluation strongly recommended

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 FDA-approved for advanced cutaneous SCC; outcomes with platinum-based chemotherapy were poor. The immunotherapy era has transformed this:

• Cemiplimab (Libtayo) — anti-PD-1 checkpoint inhibitor; 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 (Keytruda) — anti-PD-1; FDA 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 (Erbitux) — 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

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Prevention

Photoprotection

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

• Broad-spectrum SPF 30 or higher sunscreen daily — "broad-spectrum" certification means UVA protection in addition to UVB (SPF measures only UVB). Apply 15–30 minutes before sun exposure; reapply every 2 hours and after swimming or sweating. UVA penetrates glass — year-round use matters.
• Physical blockers — zinc oxide and titanium dioxide provide broad UVA and UVB coverage; no chemical-absorption controversy; recommended for 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
• Avoid midday sun — UV index is highest between 10 am and 4 pm; seek shade or plan outdoor activities around peak hours
• Never use tanning beds — no medically acceptable use; 83% higher SCC risk

Chemoprevention

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

• 23% reduction in new SCCs
• 11% reduction in BCCs
• Significant reduction in actinic keratosis count
• Well-tolerated with minimal side effects
• Effect disappeared 6 months after stopping — requires ongoing use

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

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.

Transplant Patient Surveillance and Management

Organ transplant recipients require aggressive, proactive SCC management:

• 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 mTOR inhibitors (sirolimus, everolimus) may reduce SCC risk — mTOR 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

Patients who have had one SCC face a 35% risk of developing a second primary SCC within 5 years. This reflects the persistent field cancerization in sun-damaged skin. Ongoing dermatologic surveillance is therefore not optional — it is a medical necessity for this population.

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 — CT 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 — teach skin self-examination; instruct patients to report any lesion that grows, bleeds, crusts, or fails to heal within 3 weeks; avoid 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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References and Research

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. PMID: 23652490
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. 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. PMID: 26422523
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. PMID: 22105855
5. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001;344(13):975–983. PMID: 11228279
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. PMID: 30167668
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. PMID: 22406534
8. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis"). J Am Acad Dermatol. 2000;42(1 Pt 2):11–17. PMID: 10607373
9. Nguyen KD, Han J, Nguyen H, et al. Cemiplimab-rwlc for Cutaneous Squamous Cell Carcinoma: An Evidence-Based Review of Pharmacology, Efficacy, and Safety. Onco Targets Ther. 2020;13:3671–3681. PMID: 32210580
10. 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.
11. Wenande E, Haedersdal M. Review of photodynamic therapy for cutaneous malignancy: Mechanisms, evidence and clinical practice. Photodiagnosis Photodyn Ther. 2015;12(4):527–536.
12. 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.

Search PubMed for More Research

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

• Melanoma
• Basal Cell Carcinoma
• Skin Cancer Overview
• Dermatology
• Actinic Keratosis (precursor lesion)
• Psoriasis
• Immunology
• Oncology

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