Cutaneous squamous cell carcinoma (cSCC) is the second most common keratinocyte carcinoma after basal cell carcinoma. The most important risk factors are cumulative UV exposure, chronic immunosuppression, and a history of precancerous skin lesions (e.g., actinic keratosis). cSCC lesions typically manifest as a friable nonhealing hyperkeratotic papule or plaque with central ulceration on sun-exposed areas of the body. Dermoscopy can be used to support the clinical diagnosis of suspicious lesions, but skin biopsy is required for diagnostic confirmation. Additional diagnostics (e.g., imaging, SLNB) may be required to evaluate for nodal and distant metastasis, especially in individuals with high-risk features of cSCC. Risk stratification of cSCC is used to classify the lesions as low-risk or high-risk for recurrence after excision and thereby guide management. Tumor resection (e.g., Mohs micrographic surgery, surgical excision) is the preferred treatment modality; radiotherapy can be considered if resection is not feasible. Patients with cSCC are at high risk for subsequent skin cancers. All patients should be screened for recurrence and the development of new skin cancers after treatment. Photoprotective measures should be recommended to all individuals for primary prevention and the prevention of recurrent or subsequent skin cancers.
- Incidence 
- Sex: ♂ > ♀ (3:1) 
- Annual disease-specific mortality: 1.5–2% 
Epidemiological data refers to the US, unless otherwise specified.
- Cumulative UV exposure (from the sun or from tanning beds) is the most significant risk factor, especially for individuals with: 
- Male sex 
- Older age; SCC typically affects individuals > 60 years of age. 
- Chronic immunosuppression (e.g., HIV, solid organ transplant recipient) 
- Exposure to chemical carcinogens (e.g., coal tars, arsenic) or 
- Chronic inflammation, e.g.: chronic wounds (see “”) 
- periungual SCC)  infection (for anogenital and
- Genetic predisposition 
Precursor and early lesions
- Precursor lesions (actinic keratosis); and in situ lesions (Bowen disease) typically manifest as a rough, scaly papule or plaque with an erythematous base or as a cutaneous horn. 
Invasive cSCC 
- Characteristic features include:
- Location 
- Typically occurs on sun-exposed areas
- Atypical areas
cSCC is more common South of the upper lip (i.e., it most commonly occurs on the forearms, unlike basal cell carcinoma, which most commonly occurs on the head and neck). 
Subtypes and variants
Risk factors 
- Sun exposure (UV radiation)
- Exposure to carcinogens, e.g., cigarette smoking, chemicals
- Immunosuppressed state
- High-risk human papillomavirus infection
- Genetic predisposition; may be seen in 
Clinical features 
- Rapidly growing, firm, dome-shaped nodule or papule with a central keratotic plug (crateriform tumor)
- Typically located on sun-exposed areas
- Can be solitary (common) or multiple
- Typically 1–2 cm in size; can grow up to 20 cm
Keratoacanthomas may grow by 1–2 cm over the course of weeks or months. 
- Biopsy: or punch biopsy #27967]
- Histopathology: 
Differential diagnoses 
Keratoacanthoma should be treated as cSCC. 
- Early excision is preferred.
- If surgery is not feasible or if multiple lesions are present: Consider systemic retinoids or intralesional injection of chemotherapeutic agents 
- Long-term monitoring after excision is recommended to identify recurrence or new skin tumors; see “Follow-up for cSCC.”
- Spontaneous regression can occur within 12 months in some cases.
- Rarely, metastasis can occur.
- Risk of recurrence after excision: up to 8% 
Marjolin ulcer 
- Nodule with induration
- Nonhealing ulcer with rolled edges and granulation tissue
- Frequently occurs on the lower extremities in areas with, e.g:
- Skin biopsy (e.g., punch biopsy)
- Histology findings: typically well-differentiated squamous cell carcinoma; BCC or melanoma can also occur
General principles 
- A comprehensive clinical examination in patients with suspected cSCC should include:
- A skin biopsy is required for diagnostic confirmation and risk stratification.
- Further evaluation (e.g., SLNB, imaging) for nodal and distant metastasis may be required, especially in patients with high-risk cSCC; see “Staging of cSCC” for details.
Dermoscopy findings of cSCC 
- Characteristic vascular features
- Looped (hairpin) vessels and serpentine vessels
- Glomerular vessels
- Small dotted vessels
Pigmented features of cSCC 
- Gray-brown homogeneous pigmentation
- Small brown globules
- Other features 
Actinic keratosis has a strawberry pattern on dermoscopy: yellow or white dots or haloes on an erythematous background. 
Suspect invasive cSCC if looped and serpentine vessels are seen on dermoscopy. 
Skin biopsy 
Select a biopsy technique based on the clinical features of the lesion and procedural risks ; use shared-decision making.
- Ensure adequate sample size and depth for histopathological examination; if not, a repeat biopsy may be required. 
- To optimize the quality of the pathology report, the following information should be included with the biopsy samples: 
cSCC occurs as a result of malignant transformation of keratinocytes in the stratum spinosum (prickle cell layer) of the epidermis. These atypical keratinocytes appear as enlarged, polygonal cells with nuclear pleomorphism and atypical mitoses. 
Precancerous cSCC (Actinic keratosis)
- ∼ 60% of cSCC lesions arise from AK.
- ∼ 20% progress to invasive cSCC.
- ∼ 50% resolve spontaneously
- Histopathology: atypical keratinocytes confined to the epidermis
- Progression: ∼ 3% progress to invasive cSCC 
- Atypical keratinocytes cross the basement membrane of the epidermis and invade the dermis. 
- Well-differentiated cSCC: characterized by the presence of keratin pearls; (epithelial nests), which are deposits of keratin surrounded by concentric layers of atypical keratinocytes.
- Poorly differentiated cSCC: immature cells; nuclear pleomorphism; no stratification or keratinization
High-risk histological subtypes of cSCC 
Low-risk histological subtypes of cSCC 
Assessment of disease extent 
A thorough clinical examination to assess for lymph node involvement, perineural invasion, local spread (e.g., to the parotid), and distant metastasis should be performed, especially in patients with high-risk features of cSCC. 
There is currently no universally accepted staging system for cSCC. The most commonly used staging systems in the US are:
- AJCC-8 : for head and neck cSCC; unsatisfactory as a prognostic tool
- Brigham and Women's Hospital staging system : superior to AJCC-8 in the prognostication of localized cSCC
Risk stratification of cSCC 
To guide management decisions, stratifying cSCC based on the risk of recurrence, metastasis, and disease-related mortality is recommended. Risk stratification is based on clinical and histopathological features.
- High-risk cSCC
- Low-risk cSCC: lesions with no high-risk features of cSCC
|High-risk features of cSCC |
|Tumor characteristics|| |
General principles 
- Definitive treatment of cSCC is recommended.
- The choice of therapy is based on:
- Treatment options include:
- Consults and referrals
- Ensure appropriate follow-up for cSCC to assess for recurrence or development of subsequent skin cancers.
Overview of treatment options 
|Overview of treatment options for cSCC |
| Mohs micrographic surgery |
| || |
|Surgical excision || |
| Curettage and |
|Radiotherapy (RT) || |
|Cryotherapy || |
|Systemic therapy |
Localized cSCC 
- Preferred: MMS
- Consider adjuvant RT for patients with perineural involvement.
- Standard surgical excision (4–6 mm margins) 
- RT for patients who cannot undergo resection
- Alternatives for small, superficial lesions in patients who cannot undergo resection
- C&E for cSCC in non-hair-bearing areas
Locally advanced or metastatic cSCC 
- Surgical resection ± lymphadenectomy
- Adjuvant RT
- Systemic therapy
- Palliative care
- Enrollment into clinical trials
Follow-up for cSCC 
- Screen for skin cancer every 3–12 months for 2 years.
- Tailor the frequency of further follow-up visits to the individual's risk of new or recurrent skin cancers; for example:
- Follow-up once every 2 years in patients with localized disease if initial follow-up was negative.
- More frequent follow-up is recommended for patients with regional metastasis. 
- Treat actinic keratoses at diagnosis.
- Encourage adherence to .
- Educate patients and/or caregivers on self-examination to detect recurrence, new lesions, and lymph node enlargement.
- 5-year survival rate: ≥ 90% 
- Individuals with a history of cSCC are at an increased risk of developing subsequent cSCC and other skin cancers (BCC, melanoma). 
- cSCC accounts for ∼ 20% of all deaths caused by skin cancers. 
Unresectable locoregional disease is the most common cause of cSCC-related mortality. 
- Screening: Consider recommending regular skin self-examination (e.g., monthly). 
- Encourage all patients regardless of skin type to use photoprotective measures. 
- Prophylactic treatment with systemic retinoids (e.g., isotretinoin, acitretin) can be considered for individuals with certain risk factors for cSCC, e.g.: